Practical Guidance for the Evaluation and Management of Drug Hypersensitivity: Specific Drugs

Speciﬁc Drugs

Practical Guidance for the Evaluation and

Management of Drug Hypersensitivity: Specific

Drugs

Ana Dioun Broyles, MD

, Aleena Banerji, MD

, Sara Barmettler, MD

, Catherine M. Biggs, MD

Kimberly Blumenthal, MD

, Patrick J. Brennan, MD, PhD

, Rebecca G. Breslow, MD

, Knut Brockow, MD

Kathleen M. Buchheit, MD

, Katherine N. Cahill, MD

, Josefina Cernadas, MD, iPhD

, Anca Mirela Chiriac, MD

Elena Crestani, MD, MS

, Pascal Demoly, MD, PhD

, Pascale Dewachter, MD, PhD

, Meredith Dilley, MD

Jocelyn R. Farmer, MD, PhD

, Dinah Foer, MD

, Ari J. Fried, MD

, Sarah L. Garon, MD

, Matthew P. Giannetti, MD

David L. Hepner, MD, MPH

, David I. Hong, MD

, Joyce T. Hsu, MD

, Parul H. Kothari, MD

, Timothy Kyin, MD

Timothy Lax, MD

, Min Jung Lee, MD

, Kathleen Lee-Sarwar, MD, MS

, Anne Liu, MD

, Stephanie Logsdon, MD

Margee Louisias, MD, MPH

, Andrew MacGinnitie, MD, PhD

, Michelle Maciag, MD

, Samantha Minnicozzi, MD

Allison E. Norton, MD

, Iris M. Otani, MD

, Miguel Park, MD

, Sarita Patil, MD

, Elizabeth J. Phillips, MD

Matthieu Picard, MD

, Craig D. Platt, MD, PhD

, Rima Rachid, MD

, Tito Rodriguez, MD

, Antonino Romano, MD

Cosby A. Stone, Jr., MD, MPH

, Maria Jose Torres, MD, PhD

, Miriam Verdú,MD

, Alberta L. Wang, MD

Paige Wickner, MD

, Anna R. Wolfson, MD

, Johnson T. Wong, MD

, Christina Yee, MD, PhD

aaa

Joseph Zhou, MD, PhD

bbb

, and Mariana Castells, MD, PhD

ccc

Boston, Mass; Vancouver and Montreal, Canada; Munich,

Germany; Nashville, Tenn; Porto, Portugal; Montpellier and Paris, France; Chicago, Ill; Charlottesville, Va; Newport Beach, Palo Alto,

and San Francisco, Calif; Cincinnati, Ohio; Al-Kuwait, Kuwait; Catania, Italy; Málaga and Ceuta, Spain

INTRODUCTION

Allergists and clinical immunologists around the world are

increasingly faced with the task of addressing drug allergy and

hypersensitivity due to the increase in drug reactions. Furthermore,

this is often required to maintain patients on ﬁrst-line therapies,

including antibiotics for those with cystic ﬁbrosis, chemothera-

peutic agents for those with cancer, and mAbs for patients with

chronic inﬂammatory diseases. The endeavor assumes minor risks

Division of Allergy/Immunology, Boston Children’s Hospital, Boston, Mass

Division of Rheumatology, Allergy and Immunology, Massachusetts General

Hospital, Boston, Mass

Division of Rheumatology, Allergy and Immunology, Massachusetts General

Hospital, Boston, Mass

Department of Pediatrics, British Columbia Children’s Hospital, University of

British Columbia, Vancouver, Canada

Division of Rheumatology, Allergy and Immunology, Massachusetts General

Hospital, Boston, Mass

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Sports Medicine, Brigham and Women’s Hospital, Boston, Mass

Department of Dermatology and Allergy Biederstein, School of Medicine, Tech-

nical University of Munich, Munich, Germany

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medi-

cine, Vanderbilt University Medical Center, Nashville, Tenn

Allergology and Immunology Service, Centro Hospitalar Universitário de S.João

Hospital, Porto, Portugal

Division of Allergy, Department of Pulmonology, Hôpital Arnau d de Villeneuve,

University Hospital of Montpellier, Montpellier, France

Division of Allergy/Immunology, Boston Children’s Hospital, Boston, Mass

Division of Allergy, Department of Pulmonology, Hôpital Arnaud de Villeneuve,

University Hospital of Montpellier, Montpellier, France

Department of Anesthesiology and Intensive Care Medici ne, Groupe Hospitalier

Paris-Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris, Paris, France

Division of Allergy/Immunology, Boston Children’s Hospital, Boston, Mass

Division of Rheumatology, Allergy and Immunology, Massachusetts General

Hospital, Boston, Mass

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Allergy/Immunology, Boston Children’s Hospital, Boston, Mass

Associated Allergists and Asthma Specialists, Chicago, Ill

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and

Women’s Hospital, Boston, Mass

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Asthma, Allergy & Immunology, University of Virginia, Charlottes-

ville, Va

Division of Allergy and Inﬂammation, Beth Israel Deaconess Medical Center,

Boston, Mass

Allergy and Immunology at Hoag Medical Group, Newport Beach, Calif

Channing Division of Network Medicine, Brigham and Women’s Hospital, Bos-

ton, Mass

Division of Allergy / Immunology, Stanford University School of Medicine, Palo

Alto, Calif

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Chil-

dren’s Hospital Medical Center, Cincinnati, Ohio

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Allergy/Immunology, Boston Children’s Hospital, Boston, Mass

Chief Editors: Ana Dioun Broyles, MD, Aleena Banerji, MD, and Mariana Castells, MD, PhD

S16

such as urticaria and major risks that include anaphylaxis and

Stevens-Johnson syndrome. Most of the time these must be

addressed without navigation tools or clear algorithms for the

mechanisms of reactions. There are few standardized skin tests/in

vitro tests for diagnosis and rare validated desensitization protocols.

Drug testing and desensitization should be considered on the basis

of consensus reports (International Consensus [ICON], Interna-

tional Collaboration in Asthma, Allergy and Immunology

[ICALL], Practical Allergy [PRACTALL]) as well as practice pa-

rameters. However, new and targeted drugs that better address

diseases in a precise and personalized fashion are emerging rapidly,

and they induce new, unpredictable, and poorly understood re-

actions. This publication was born out of a grassroots need to

provide the seeds of a new discipline: the understanding, diagnosis,

management, and treatment of drug allergy and hypersensitivity as

a practical clinical endeavor.

Dr Thomas Fleisher embraced this as his presidential theme, as

mentioned in the Introduction section of this supplement. In the

General Concepts article in this supplement, Drs Ana Dioun

Broyles, Aleena Banerji, and Mariana Castells provided the foun-

dational steps in describing the phenotypes, endotypes, and bio-

markers of drug reactions, amplifying the Gell and Coombs

classiﬁcation and providing practical algorithms for the diagnosis

and management.

The lead authors next consulted drug hyper-

sensitivity experts from around the world to precisely deﬁne speciﬁc

drugs and/or drug classes regarding the phenotypic presentations of

reactions, diagnostic tools such as skin testing, in vitro testing, and

challenges, and the best management and treatment approaches

including desensitization. The numerous authors who contributed

to this section of the supplement have provided the most current

information on and the standards for in vitro and in vivo testing and

desensitization procedures when these exist. Their efforts have

resulted in an accurate compilation of drug hypersensitivity pro-

cedures data that can be applied in a personalized fashion to each

drug-allergic patient.

The hope is that this supplement will provide a user-friendly in-

strument that will be used in clinics, hospitals, wards, and the

emergency department on a daily basis, and that its principles will

guide and increase allergist immunologists’ skills and level of comfort

with a practical approach to drug hypersensitivity. The application of

thestandardsdescribedhereshouldhelpstreamlinetheclinical

practice of drug hypersensitivity and provide the most updated and

safe care to all patients with drug hypersensitivity. It is also hoped that

his resource will be updated every 2 to 3 years with new developments

that arise in the diagnosis and management of drug hypersensitivity

so as to continue to improve the quality and safety of care.

ANTIMICROBIAL AGENTS

Penicillins (by Timothy Lax, MD, and Antonino

Romano, MD)

General.

Penicillins are commonly used to treat infections caused

by both gram-negative and gram-positive organisms. Penicillin al-

lergy is one of the most commonly reported drug allergies, with a

prevalence of 5% to 10%.

2,3

The reported prevalence is higher

among hospitalized patients, at 11% to 15%.

4,5

Individuals with a

history of penicillin hypersensitivity are more likely to receive

alternative antibiotic therapy, which can lead to added expense,

Division of Allergy and Clinical Immunology, Respiratory Medicine, Department

of Pediatrics, University of Virginia, Charlottesville, Va

Division of Allergy, Immunology and Pulmonology, Monroe Carell Jr. Children’s

Hospital at Vanderbilt, Nashville, Tenn

Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine,

University of California, San Francisco Medical Center, San Francisco, Calif

Division of Allergic Diseases, Mayo Clinic, Rochester, Minn

Division of Rheumatology, Allergy and Immunology, Massachusetts General

Hospital, Boston, Mass

Department of Medicine & Pathology, Microbiology and Immunology, Vanderbilt

University Medical Center, Nashville, Tenn

Division of Allergy and Clinical Immunology, Department of Medicine, Hôpital

Maisonneuve-Rosemont, Université de Montréal , Montréal, Québec, Canada

Division of Immunology, Boston Children’s Hospital, Boston, Mass

Drug Allergy Department, Al-Rashed Allergy Center, Sulaibikhat, Al-Kuwait,

Kuwait

IRCCS Oasi Maria S.S., Troina, Italy & Fondazione Mediterranea G.B. Morgagni,

Catania, Italy

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University

Medical Center, Nashville, Tenn

Allergy Unit and Research Group, Hospital Regional Universitario de Málaga,

UMA-IBIMA-BIONAND, ARADyAL, Málaga, Spain

Allergy Unit, Hospital Universitario de Ceuta, Ceuta, Spain

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital,

Boston, Mass

Division of Rheumatology, Allergy and Immunology, Massachusetts General

Hospital, Boston, Mass

Division of Rheumatology, Allergy and Immunology, Massachusetts General

Hospital, Boston, Mass

aaa

Division of Immunology, Boston Children’s Hospital, Boston, Mass

bbb

Division of Allergy/Immunology, Boston Children’s Hospital, Boston, Mass

ccc

Drug hypersensitivity and Desensitization Center, Brigham and Women’s Hos-

pital, Boston, Mass

Conﬂicts of interest: K. Blumenthal reports grants from the National Institutes of

Health (NIH), CRICO, American Academy of Allergy, Asthma, and Immunology

(AAAAI) Foundation, and Massachusetts General Hospital; and a beta-lactam

allergy clinical decision support tool licensed to Persistent Systems. K. Buchheit

receives royalties from UpToDate and grant support from NIAID. K. N. Cahill

receives grant support from NIAID. A. M. Chi riac was part of the HYCOR

Scientiﬁc Advisory Board for biology of drug hypersensitivity. P. Dewachter is on

the advisory board dedicated to “Neuromuscular blocking agents and fast-tracking

anesthesia” for MSD France and receives lecture and travel fees from MSD

France, outside of the submitted work. M. P. Giannetti receives research funding

and salary support from Blueprint Pharmaceuticals, not relevant to this article. J.

T. Hsu reports consulting fees from EBSCO, grants from Vedanta Biosciences,

outside the submitted work. T. Kyin is on an advisory board for Sanoﬁ Regeneron.

M. Louisias reports grants fro m Brigham and Women’s Hospital, Agency for

Healthcare Research and Quality (AHRQ ), and NIH. S. Patil receives royalties

from UpToDate for writing on a different topic and research funding from the NIH

National Institute of Allergy and Infectious Diseases (NIAID) and the Charles H.

Hood Foundation Child Health Grant on a different topic. E. J. Philips reports

grants from NIH (P50GM115305, R01HG010863, R01AI152183, R21AI139021,

U01AI154659) and from the National Health and Medical Research Council of

Australia; receives royalties from UpToDate and consulting fees from Biocryst; is

co-director of IIID Pty Ltd that holds a patent for HLA-B*57:01 testing for

abacavir hypersensitivity; and holds a patent for Detection of Human Leukocyte

Antigen-A*32:01 in connection with Diagnosing Drug Reaction with Eosinophilia

and Systemic Symptoms without any ﬁnancial remuneration and not directly

related to the submitted work. A. Romano is a consultan t for Diater SA (Leganés,

Spain). C. A. Stone Jr receives funding support from AHRQ (K12HS026395) for

research in risk-stratiﬁed management of penicillin allergy. P. Wickner receives

support from a CRICO grant that is not relevant to the content of this article. The

rest of the authors declare that they have no relevant conﬂicts of interest.

Received for publication August 10, 2020; accepted for publication August 10, 2020.

This article is published as part of a supplement supported by the American Acad-

emy of Allergy, Asthma & Immunology.

2213-2198

Ó 2020 American Academy of Allergy, Asthma & Immunology

https://doi.org/10.1016/j.jaip.2020.08.006

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S17

Abbreviations used

ACD- Allergic contact dermatitis

ADR- Adverse drug reaction

AERD- Aspirin-exacerbated respiratory disease

AGEP- Acute generalized exanthematous pustulosis

ART- Antiretroviral

BAT- Basophil activation test

COPD- Chronic obstructive pulmonary disease

COX- Cyclooxygenase

CYC- Cyclophosphamide

CYP450- Cytochrome p450

DHR- Delayed hypersensitivity reaction

DMCD- Direct mast cell degranulation

DRESS- Drug rash (or reaction) with eosinophilia and systemic

symptoms

EAACI- European Academy of Allergy and Clinical

Immunology

EGFR- Epidermal growth factor receptor

EMB- Ethambutol

ENDA- European Network of Drug Allergy

FDA- Food and Drug Administration

HCV- Hepatitis C virus

HIT- Heparin-induced thrombocytopenia

HMW- High molecular weight

IDT- Intradermal test

IM-ADR- Immunologically mediated adverse drug reaction

INH- Isoniazid

LA- Local anesthetic

LMWH- Low-molecular-weight heparin

MM- Multiple myeloma

MTX- Methotrexate

NMBA- Neuromuscular-blocking agent

NSAID- Nonsteroidal anti-inﬂammatory drug

PH- Progestogen hypersensitivity

PI- Protease inhibitor

PPI- Proton pump inhibitor

PPL- Penicilloyl-polylysine

PT- Prick test

PZA- Pyrazinamide

RCM- Radiocontrast media

RMS- Red men syndrome

SCAR- Severe cutaneous adverse reaction

SJS- Stevens-Johnson syndrome

SMZ-TMP- Sulfamethoxazole-trimethoprim

SPT- Skin prick test

TB- Tuberculosis

TEN- Toxic epidermal necrolysis

TKI- Tyrosine kinase inhibitor

UFH- Unfractionated heparin

vWD- von Willebrand disease

lengthened hospital stays, and increased risk for resistant or-

ganisms such as vancomycin-resistant Enterococcus, Clostridium

difﬁcile, and methicillin-resistant Staphylococcus aureus.

6,7

Despite

the frequency of reported allergy, avoidance of penicillin is not

necessary in the vast majority of individuals. Approximately 90%

to 95% of patients with a reported penicillin allergy can tolerate a

rechallenge after an appropriate allergy evaluation has been per-

formed.

8,9

The discrepancy between reported and actual peni-

cillin allergy may be explained by the waning of penicillin IgE

antibodies over time or by the misclassiﬁcation of an adverse

reaction or infectious manifestation as a drug reaction.

10-12

Sensitization to penicillin has been reported to decrease every 10

years, and after 20 years fewer than 1% of patients with initial

clinical symptoms compatible with an allergic reaction continue to

maintain their sensitivity. Therefore, a formal allergy evaluation is

recommended by both North American and European guidelines

to optimize patient management.

13-15

Major symptoms of hypersensitivity. Hypersensitivity

reactions to penicillin are classiﬁable as immediate or nonimmediate

according to their clinical manifestation, time since the last drug

administration, and the onset of symptoms.

16,17

Immediate re-

actions are predominantly IgE-mediated. They can occur within 6

hours after the last drug administration but typically occur within 1

hourof the ﬁrstdose of a new treatmentcourse.

17,18

Symptomsofan

acute hypersensitivity reaction include urticaria, angioedema,

conjunctivitis, respiratory symptoms (rhinitis, bronchospasm,

cough, dyspnea), gastrointestinal symptoms (nausea, vomiting,

diarrhea, abdominal pain), and/or anaphylaxis.

Nonimmediate reactions occur more than 1 hour after the initial

drug exposure, and they often develop days to weeks after medication

initiation. Manifestations of nonimmediate reactions include mac-

ulopapular or morbilliform exanthems, particularly during treatment

with amoxicillin or ampicillin. In addition, penicillins can elicit

delayed urticaria/angioedema, exfoliative dermatitis, acute general-

ized exanthematous pustulosis (AGEP), and more severe bullous

exanthems such as Stevens-Johnson syndrome (SJS) and toxic

epidermal necrolysis (TEN). Furthermore, hematologic alterations

may occur with certain penicillins, such as methicillin and ampicillin,

and can cause interstitial nephritis, pneumonitis, hepatitis, and/or

vasculitis with or without signs of serum sickness including joint

involvement. The combination of skin eruptions, visceral involve-

ment, hematologic alteration, fever, and lymphadenopathy is termed

drug-induced hypersensitivity syndrome or drug rash (or reaction)

with eosinophilia and systemic symptoms (DRESS). The pathogenic

mechanisms involved in nonimmediate reactions are heterogeneous.

Allergic maculopapular exanthems are T-cellemediated diseases, in

which drug-speciﬁc cytotoxic CD4 T cells migrate into the skin.

These T cells then produce IL-5 and kill keratinocytes that present

MHC class II molecules in a perforin-dependent manner.

19,20

Diagnosis. Based on the clinical history and presenting

symptoms, there are distinct diagnostic approaches for an im-

mediate reaction and for a nonimmediate reaction to penicillin.

For patients with a history of TEN, SJS, DRESS, interstitial

nephritis, or hemolytic anemia, reexposure through either drug

challenge or desensitization is contraindicated, unless there are

special circumstances.

Immediate reactions. Penicillins contain a core bicyclic

structure that is composed of a 4-member

-lactam ring and a 5-

member thiazolidine ring along with 1 side chain (R1) (Figure 1).

Although too small to be antigenic in its native state, penicillin gains

immunogenicity by spontaneously degrading and covalently binding

to tissue or serum proteins to form haptens.

Approximately 95% of

penicillin degrades to form a penicilloyl complex, which is called the

major determinant.

21,22

The remaining penicillin remains in its

native form (benzylpenicillin) or degrades further to form minor

determinants, which include benzylpenicilloate and benzylpenilloate.

For an immediate reaction to penicillin or another

-lactam

antibiotic, an IgE antibody to the common

-lactam ring as well

as to a possible side chain must be assessed. A drug challenge test

is the criterion standard for evaluating an IgE-mediated allergy

both to penicillin and to other

-lactams. Skin testing and in

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S18 BROYLES ET AL

vitro testing have been developed to identify a sensitization to a

major/minor determinant and/or side chain and decrease the risk

for a positive drug challenge test result.

Penicillin skin testing. For patients with a history concern-

ing for an IgE-mediated reaction to penicillin, or whose past

history is unclear, American and European guidelines recommend

skin testing with both major penicillin antigenic determinants

(penicilloyl-polylysine [PPL]) and minor antigenic determinants

(benzylpenicillin [penicillin G], benzylpenicilloate, and benzylpe-

nilloate).

13,15,23

In the United States, penicillin G is the only

commercially available minor determinant, and it is used in

combination with PPL (PRE-PEN; AllerQuest LLC, West

Hartford, Conn), whereas in Europe, benzylpenicilloyl-octa-

L-

lysine and sodium benzylpenilloate (DAP; Diater, Madrid, Spain)

are available as major and minor determinant, respectively.

It has been estimated that skin testing with PPL and penicillin

G, without the use of penilloate and penicilloate, may miss 10% to

20% of penicillin-sensitized subjects.

8,9,24-30

The clinical utility of

penilloate and penicilloate is controversial because studies from

North America have found a comparable negative predictive value

(>95%) between skin testing to PPL and penicillin G only versus

PPL and minor determinant mixture reagent in patients challenged

to penicillin. Skin testing with penicillin G alone without the use of

PPL is not recommended, because up to 70% of patients who have

a positive skin test result react only to PPL, and these patients can

still have a severe reaction.

Furthermore, the patient populations who have undergone

skin testing with PPL and penicillin G alone are not comparable

to the ones who had all the reagents used for testing. Hence, it is

not possible to compare the negative predictive value. In addi-

tion, recent or severe historical reactors are not typically included

when only PPL and penicillin G are used for skin testing.

Epicutaneous and intradermal skin testing to PPL is performed

using the commercially available undiluted concentration of 6 

5

mol/L. A ﬁnal epicutaneous and intradermal concentration

used for penicillin G ranges between 5,940 and 10,000 U/mL and

between 0.01 and 0.02 M for the other minor determinants (pen-

icilloate and penilloate).

8,13

It is recommended that dilutions use

saline, rather than sterile wate r, to lessen the possibility of

false-positive reactions. A 1:10 or 1:100 dilution of PPL and minor

determinants may be used selectively in patients who have experi-

enced extremely severe reactions. In most guidelines, a positive result

is a wheal having its greatest diameteratleast3mmlargerthanthat

seen with negative control, though some authors suggest a 5-mm

wheal for increased sensitivity, especially for PPL, for which a 5-mm

wheal for prick puncture testing is recommended in the package

insert.

8,13-15,31

Concentrations for penicillin skin testing are pre-

sented in Table I.

Pediatric patients and pregnant women who have experienced

immediate reactions should be evaluated using the diagnostic pro-

tocol discussed earlier. Several studies have conﬁrmed the safety of

skin tests in children, with a rate of 1% to 3% of patients experiencing

systemic reactions to skin testing.

32-34

The negative predictive value

of an allergy evaluation that includes skin tests and drug challenge

tests has been shown to be higher than 97% in children.

34,35

Skin testing was also found to be safe in 56 pregnant women

with group B Streptococcus colonization, with only 2 (4%) women

experiencing a mild reaction during skin testing.

An oral chal-

lenge was not performed at the time of the skin testing, but of the

skin testenegative women, 47 (89%) went on to receive a full

therapeutic dose of a penicillin-class antibiotic during the peri-

partum period with no systemic reactions observed.

In vitro tests. Serum-speciﬁc IgE assays offer the most common

in vitro method for evaluating immediate reactions to penicillins in

both Europe and the United States. The most widely used

commercial method is the ﬂuoroimmunoassay (ImmunoCAP;

TABLE I. Concentrations for penicillin skin testing

Reagent Epicutaneous Intradermal

Penicilloyl-polylysine (PRE-PEN) 6  10

5

M6 10

5

Penicillin G 10,000 units/mL 100 units/mL*

1,000 units/mL*

10,000 units/mL

Penicilloate 0.01-0.02 M 0.01-0.02 M

Penilloate 0.01-0.02 M 0.01-0.02 M

M, mole.

*Optional, based on physician discretion.

FIGURE 1. Basic chemical structures of

-lactams. R represents side chains that distinguish a

-lactam from other members of the same

class of antibiotics.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S19

Thermo-Fisher, Uppsala, Sweden), which is available for a limited

number of penicillins: penicillin G, penicillin V, amoxicillin, and

ampicillin. The low sensitivity (0%-50%) has limited its use in the

United States and seems to correlate with the severity of the reac-

tion.

37-40

Basophil activation test (BAT) has also been evaluated as a

diagnostic tool for immediate hypersensitivity reactions to

penicillin and other

-lactams. Its sensitivity is approximately

50%, with a speciﬁcity of more than 90%.

39,41

This test has not

been validated, is not commercially available, and is not rec-

ommended for clinical use at this time.

Drug challenge tests. The negative predictive value for

penicillin skin testing has been shown to be greater than 95% in

North American studies. A small subpopulation of patients re-

mains at risk for a potentially severe hypersensitivity reaction

when rechallenged to penicillin.

8,28

Drug challenge is the diagnostic criterion standard for the

exclusion of an immediate reaction and is recommended after

allergy evaluation when the patient is deemed unlikely to be

allergic to the given drug.

After negative penicillin skin test result, amoxicillin is typically

administered as a drug challenge often as a single full dose and oc-

casionally as 1/10th of the ﬁnal dose and then the ﬁnal dose.

Amoxicillin is the penicillin most commonlyused for drug challenges

because it has both immunologically signiﬁcant core penicillin

structures and potentially signiﬁcant R-group side chains.

Chal-

lenge with the drug that caused the reaction, such as amoxicillin-

clavulanate, may also be considered.

Retesting. Resensitizationisanuncommonoccurrencethatde-

velops in upto 2% of patients after re-treatment with a penicillin.

43-45

The use of parenteral antibiotics may increase the risk.

Both North

American and European guidelines suggest that repeat skin testing

may be considered for patients with severe immediate reactions,

especially after parenteral administration, even when a therapeutic

course ofpenicillin has previously been tolerated.

13-15

However, most

patients with a history of penicillin allergy who have undergone

negative skin testing and challenge may receive future courses of

penicilllins without a signiﬁc antly increased risk of reactions,

compared with the general population. A recent retrospective study of

32 patients indicated that in patients who report penicillin allergy and

have negative penicillin skin testing result, repeated administration of

intravenous penicillin antibiotics appears safe.

Nonimmediate reactions. Both delayed reading of intra-

dermal tests (IDTs) and patch tests have been described as

diagnostic tools for nonimmediate reactions. These tests have not

yet been standardized or validated. In the United States, patch

testing and delayed reading of IDTs are not yet routinely per-

formed, but they are included in European guidelines.

Delayed-reading IDTs. IDT is performed using penicillin

G as well as any other suspect penicillins or

-lactams. Delayed

skin testing with PPL and other minor determinants has been

found to have limited diagnostic value.

Penicillin G is administered at a concentration of 10,000 U/mL,

whereas a concentration of 1 to 20 mg/mL can be used for other

suspect penicillins (eg, ampicillin and amoxicillin).

The clinician

should start with epicutaneous prick testing. If results are negative

after 15 to 20 minutes have elapsed, one should proceed next to

IDT.Again, results are read after 20 minutes to assessany immediate

responses. Additional readings of delayed reaction to skin tests are

performed after 48 and 72 hours. Any inﬁltrated erythema with a

diameter larger than 5 mm is considered to be a positive reaction.

Patch test. A patch test for penicillin and other suspect

penicillins/

-lactams is performed using a concentration of 5%

to 10% penicillin in petrolatum. The patch should be worn for

48 hours, with readings 15 minutes after removal of the strips

and again 24 hours later.

The speciﬁcity for both delayed reading of IDTs and patch

testing is high (90%-100%), but the sensitivity is less than 50% to

60%.

20,49

Delayed-reading IDTs appear to be more sensitive than

patch testing but may also be less speciﬁc.

50,51

Repeat exposure to

the drug is often avoided, but there is limited data on the utility of

using these 2 procedures to assist in the evaluation of noneIgE-

mediated drug reactions.

49,52,53

A recent consensus document

indicated that patch testing and delayed intradermal readings could

be of use for the diagnosis of maculopapular rashes, AGEP, and

DRESS. Although patch testing may be considered in SJS and

TEN, delayed reading of IDT is contraindicated in these 2 con-

ditions.

A multicenter study evaluated 134 patients with severe

cutaneous reactions to drugs: 72 with DRESS, 45 with AGEP, and

17 with SJS⁄TEN.

Patch tests were ﬁrst performed with drugs

diluted to 1%, and if the results were negative, they were repeated

with the drug diluted to 30% in petrolatum. Seventy-six partici-

pants (56.7%) had positive patch-test results: 46 (64%) of the 72

with DRESS (of the antibiotics, 8 were positive to amoxicillin, 1 to

dicloxacillin, 2 to ceftriaxone, and 1 to imipenem), 26 (58%) of the

45 with AGEP (7 were positive to amoxicillin and 1 to ceftriaxone),

and 4 (24%) of the 17 with SJS⁄TEN (1 was sensitive to amoxi-

cillin). In patients with negative patch-test results, 4 of 11 patients

with AGEP and 3 of 4 patients with DRESS associated with

lactams were positive on delayed-reading IDTs.

Drug challenge test. A drug challenge test may be consid-

ered for some nonimmediate reactions. Multiple protocols have

been published for such drug challenge tests.

14,15

A full thera-

peutic dose can be administered on the ﬁrst day or can be given

incrementally over days to weeks. Some studies suggest that an

additional treatment course for 7 to 10 days after the full ther-

apeutic dose is needed to sufﬁciently exclude a nonimmediate

reaction.

55,56

A potential caveat of this approach lies in exposing

patients with a history of benign reactions to an unnecessary

therapeutic course of penicillin.

Other penicillins

Aminopenicillins.

Amoxicillin and ampicillin are 2 of the most

commonly prescribed aminopenicillins. Immediate reactions are

IgE-mediated to either the common

-lactam structure or the R-

group side chain.

Patients who are suspected or found to have a

sensitization to amoxicillin or ampicillin should avoid drugs with

similar or identical R-group side chains (until a formal allergy

evaluation can be performed). These drugs include cefadroxil, cef-

prozil, and cefatrizine (identical side chain shared with amoxicillin

and similar for ampicillin) as well as cephalexin, cefaclor, cephradine,

cephaloglycin, and loracarbef (similar for amoxicillin and identical

for ampicillin).

13,14

The avoidance of cephalosporins with identical/

similar side chains does not hold true if the patient has already

tolerated 1 of them, even if he or she is still avoiding penicillins.

Studies have suggested that amoxicillin sensitivity is more

prevalent among European patients, with up to 50% of patients

with a history of penicillin allergy determined to be sensitized to

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S20 BROYLES ET AL

amoxicillin only, compared with 0% to 6% in North Amer-

ica.

8,26,58

As a result, European guidelines recommend that

amoxicillin skin testing be performed concurrently with peni-

cillin for all patients, whereas testing for amoxicillin is not

consistently performed in North America.

14,15

Unlike skin testing for penicillin, skin testing for amoxicillin and

ampicillin is not validated, and the predictive value is unknown. A

drug challenge test is required to assess for an immediate reaction.

Skin testing can be performed using nonirritatingconcentrations that

can potentially help identify sensitized individuals. Nonirritating

concentrations of amoxicillin range from 3 to 25 mg/mL. Similar to

penicillin-speciﬁc IgE, amoxicillin-speciﬁc IgE diminishes over time.

One study found that all 24 patients who were found to be skin test

positive after exposure to the drug were skin test negative after 5

years.

Because the parenteral form of amoxicillin is not available in

the United States, equivalent concentrations for skin testing cannot

be reliably achieved. For ampicillin, skin testing is performed using a

concentration of 2.5 to 25 mg/mL. Recently, the Food and Drug

Administration (FDA) is evaluating a Penicillin Kit that will contain

amoxicillin.

If skin testing result is negative, a drug challenge test is rec-

ommended. If either skin testing result or the oral challenge is

positive, then avoidance or desensitization is recommended.

Carbapenems. Carbapenems (imipenem/cilastatin, mer-

openem, ertapenem) share a common

-lactam ring, giving rise to

concern for possible cross-reactivity (Figure 1). Studies over the last

decade, performed either on adults or on children, have demon-

strated an absence or very low (1%) rate of cross-reactivity between

penicillins and carbapenems.

59-65

Nonirritating concentrations for

skin testing to common carbapenems are listed in Table II.

For patients with a history of an immediate reaction and negative

skin testing result to penicillin, carbapenem should prove safe. If

penicillin skin testing is not available or cannot be performed, then a

carbapenem drug challenge test is recommended. For a positive

penicillin skin test result, carbapenem can be administered as a 2-

step graded challenge.

If skin testing result is negative, it is

reasonable to administer a single full-dose challenge.

Monobactams. Monobactams consist of a monocyclic

-lactam ring structure with no adjoining rings (Figure 1).

Currently, the only commercially available monobactam is

aztreonam. Studies have demonstrated a lack of cross-reactivity

between penicillin and aztreonam.

61,66,67

A lack of cross-reac-

tivity has also been demonstrated between cephalosporins and

aztreonam, with the exception of ceftazidime, which shares an

identical side chain.

Skin testing is performed with a nonirri-

tating concentration of 2 mg/mL. Aztreonam may be given to

patients with a history of penicillin allergy.

Clavulanate. Clavulanate is a

-lactam inhibitor and is

frequently combined with a penicillin such as amoxicillin.

Although uncommon, clavulanate has been reported as a caus-

ative agent for immediate hypersensitivity reactions. Skin testing

with an epicutaneous concentration of clavulanate at 10 mg/mL

and intradermal concentrations of 0.1 and 1 mg/mL was found

to be nonirritating in 1 small case series.

Skin testing with

intravenous solutions of amoxicillin-clavulate has also been re-

ported.

Given the limited availability of isolated clavulanate/

clavulanic acid and intravenous amoxicillin/clavulanic acid in the

United States, a drug challenge to amoxicillin/clavulanic is rec-

ommended if clavulanate is suspected and the initial drug chal-

lenge to amoxicillin is negative.

Management

High-risk patients.

Individuals with a demonstrated sensi-

tivity to penicillin, either on positive skin testing or on failed

drug challenge tests, should avoid the responsible drug as well as

those that are potentially cross-reactive. It is reasonable to repeat

skin testing if many years have passed since previous skin testing.

If there are no reasonable alternatives, both oral and intravenous

desensitization protocols have been well established in American

and European guidelines.

13,15

Examples of these are provided in

Tables III and IV, respectively.

70,71

Low-risk patients. For patients who are at low risk of an

immediate hypersensitivity reaction, including those with a his-

tory of itching without urticaria, mild maculopapular rash (ie,

less than 1-week duration), or other benign rash, a drug challenge

test may be considered without the use of skin testing.

Tools,

such as a recently published clinical pathway for patients with

penicillin allergy, can help guide physicians in deciding whether

TABLE II. Nonirritating concentrations for penicillin and

-lactams

Penicillin Nonirritating concentration

Penicillin G

14,79

10,000 units/mL

Aminopenicillins

Amoxicillin

14,21,79

3-25 mg/mL

Ampicillin

14,21,79

2.5-25 mg/mL

-Lactamaseeresistant

Nafcillin

g/mL

Carboxypenicillins

Ticarcillin

20 mg/mL

Ureidopenicillins

Piperacillin

928

20 mg/mL

Carbapenems

Meropenem

1 mg/mL

Imipenm

61,63

0.5-1 mg/mL

Ertapenem

1 mg/mL

Monobactam

Aztreonam

2 mg/mL

TABLE III. Oral penicillin desensitization protocol*

Step Penicillin V (units/mL) mL Units Cumulative dose (units)

1 1,000 0.1 100 100

2 1,000 0.2 200 300

3 1,000 0.4 400 700

4 1,000 0.8 800 1,500

5 1,000 1.6 1,600 3,100

6 1,000 3.2 3,200 6,300

7 1,000 6.4 6,400 12,700

8 10,000 1.2 12,000 24,700

9 10,000 2.4 24,000 48,700

10 10,000 4.8 48,000 96,700

11 80,000 1.0 80,000 176,700

12 80,000 2.0 160,000 336,700

13 80,000 4.0 320,000 656,700

14 80,000 8.0 640,000 1,296,700

*Fifteen-minute intervals between each step. Cumulative dose is 1.3 million units

given over a total of 3h 45 min.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S21

drug challenge, drug sensitization, drug avoidance, or further

allergy evaluation presents the best course of action.

Cephalosporins (by Kimberly Blumenthal, MD)

General.

Cephalosporin adverse drug reactions (ADRs) affect

about 0.5% to 2.5% of patients. ADRs include nephropathy and

acquisition of C difﬁcile colitis.

Although cephalosporin allergy

is approximately 10-fold less common than penicillin allergy, it

remains one of the most commonly reported drug allergies in the

United States.

Major symptoms. Cephalosporins can elicit various hyper-

sensitivity reactions, including IgE-mediated reactions charac-

terized by urticaria, angioedema, rhinitis, bronchospasm, and

anaphylaxis. Notably, cephalosporins, especially cefaclor and

cefprozil, may cause serum sicknesselike reactions.

They may

also less frequently lead to severe cutaneous adverse reactions

(SCARs) and isolated eosinophilia.

74,76

Diagnosis

Immediate hypersensitivity skin testing.

Most hyper-

sensitivity reactions to cephalosporins are directed at the R-group

side chain (Figure 2) rather than the core

-lactam ring mole-

cule.

77,78

However, it may be useful to also perform penicillin

skin testing when patients present with possible sensitivity to

cephalosporins, particularly those in the earlier generations,

which include the aminocephalosporins (cefaclor, cephalexin,

and cefadroxil; Table V). Although skin testing to native ceph-

alosporins is not standardized, a positive skin test result with a

nonirritating concentration suggests the presence of drug-speciﬁc

IgE antibodies.

79,80

A negative skin test result does not rule out

an allergy, and must be followed by an observed graded challenge

(Table VI). Similar to data suggestive of loss of IgE-mediated

hypersensitivity to penicillins, patients with IgE-mediated allergy

to cephalosporins may lose sensitivity over time.

Delayed hypersensitivity skin testing. For SCARs, us-

ing the RegiSCAR scoring method for diagnosis is recommended,

and skin biopsy is usually indicated.

Patch testing may be useful,

especially for DRESS syndrome and AGEP.

Patch tests to

cephalosporins may be performed using a 30% dilution of the drug

in petrolatum (not commercially available in the United States),

with readings at 48 and 72 hours.

Management

General/clinical pathways.

For patients with true or re-

ported cephalosporin allergy, management can be challenging,

especially for nonallergist providers. A clinical pathway that in-

corporates both cephalosporin generation (because of

-lactam

ring relevance by generation) and cephalosporin side chain

(because of cross-reactivity by side chain/R group) can help direct

safe use of

-lactam in the setting of previously reported hy-

persensitivity, though outcome data are limited (Figure 3, A).

Similar pathways have been implemented for demonstration of

cephalosporin tolerance in patients with historical penicillin al-

lergies (Figure 3, B).

To date, data on these clinical pathways

conﬁrm that they increase

-lactam use in acute therapeutic

situations and increase ﬁrst-line antibiotic treatment in an

appropriately risk-adverse manner (reactions were observed in

0.5%-4.0% of patients).

73,83

Oral challenge. An oral challenge to cephalosporin would be

appropriate if the reaction appeared to be (1) unlikely to have been

caused by the cephalosporin, (2) not immune-mediated/serious/

life-threatening, or (3) in response to a different cephalosporin with

low to medium risk of cross-reactivity (eg, cephalosporins with

dissimilar side chain, history of IgE-mediated penicillin allergy). As

with any other drug challenge, the potential risks, beneﬁts, and

alternatives should be discussed with the patient and/or the pa-

tient’s parents/guardians and informed consent should be ob-

tained. The procedure should be performed in a monitored clinical

setting where emergency support is readily available. Generally,

drug challenges to dissimilar cephalosporins are safe to perform.

TABLE IV. Example of intravenous desensitization protocol for

-lactam dose of 1 g*

Solution Volume of diluent (mL) Drug concentration (mg/mL) Total drug to be injected into each bottle (mg)

Solution 1 250 0.04 10

Solution 2 250 0.4 100

Solution 3 250 4 1000

Step Solution Rate (mL/h) Time (min) Administered dose (mg) Cumulative dose (mg)

1 1 2 15 0.02 0.02

2 1 5 15 0.05 0.07

3 1 10 15 0.1 0.17

4 1 20 15 0.2 0.37

5 2 5 15 0.5 0.87

6 2 10 15 1 1.87

7 2 20 15 2 3.87

8 2 40 15 4 7.87

9 3 10 15 10 17.87

10 3 20 15 20 37.87

11 3 40 15 40 77.87

12 3 80 172.9 922.13 1000

Total infusion time 337.9 min

*Modiﬁed with permission from Castells.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S22 BROYLES ET AL

Increased caution, warranting skin testingeguided treatment,

choosing alternative agents, or performing a desensitization, may

be indicated for cephalosporin administration with similar side

chains, or for patients with severe reaction histories, or clinically

unstable patients. In cases of serum sicknesselike reaction to

cefaclor or cefprozil, it is appropriate to use another

cephalosporin, preferably one with dissimilar R1 side chains. A

standard 2-step test dose protocol is as safe as longer protocols,

but less likely to induce tolerance (Table IV).

83,84

Desensitization. The most common desensitization protocol

for cephalosporins comprises 12 steps and it is intended for IgE-

mediated reactions (Table IV ).

Contraindications to desensi-

tization include severe T-cellemediated reactions such as

DRESS, TEN, or SJS. Although initiating treatment with stan-

dard desensitization protocol is recommended, its duration may

be modiﬁed in such a manner that it takes into account a pa-

tient’s relevant history and considers both comorbidities and

acuity of the present illness.

FIGURE 2. Cephalosporin cross-reactivity.

-Lact am antibiotics can hav e similar or identical R1 or R2 side chains , which may make cross-

reactivity more lik ely. This matrix indicates either a similar (gray) or an identical (red) side chain. Empty box es indicate a lack of side-chain simi larity.

TABLE V. Immediate hypersensitivity cephalosporin skin testing

80,929-931

Test type Cephalexin Cefazolin Cefuroxime Cefotaxime Ceftazidime Ceftriaxone Cefepime* Cefixime

Step 1: Epicutaneous 25 mg/mL 330 mg/mL 100 mg/mL 100 mg/mL 100 mg/mL 100 mg/mL 200 mg/mL 2 mg/mL

Step 2: Intradermal† NAz 3.3 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 2 mg/mL NAz

Step 3: Intradermal NAz 33 mg/mL 10 mg/mL 10 mg/mL 10 mg/mL 10 mg/mL 20 mg/mL NAz

NA, Non-applicable/not available.

Penicillin skin testing may also be appropriate for patients presenting with cephalosporin allergy.

*Nonirritating in clinical practice, MGH Allergy Associates (unpublished data, 2020).

†Optional for patients with history of severe and/or recurrent reactions.

zCephalexin and ceﬁxime are not available as an intravenous preparation.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S23

Sulfamethoxazole-trimethoprim (by Miguel Park, MD)

Epidemiology.

Sulfamethoxazole-trimethoprim (SMZ-TMP)

is a common cause of hypersensitivity and ADRs. Before 1982,

SMZ-TMP was the second most common medication behind

amoxicillin to result in cutaneous ADRs in the hospital.

These

reactions are primarily due to hypersensitivity to the sulfonamide

component, and speciﬁc hypersensitivity to trimethoprim is rare

and has been reported anecdotally.

Patients with HIV have been

reported to have a rate of sensitivity to SMZ-TMP that ranges from

34% to 50%

87,88

; however, the frequency of cutaneous ADRs

exceeds that of those that occur in response to aminopenicillins.

Most ADRs to SMZ-TMP are morbilliform, maculopapular

eruptions. IgE-mediated reactions including urticaria/angioe-

dema and anaphylaxis, severe delayed hypersensitivity reactions

(DHRs) such as SJS, TEN, and DRESS, and hepatic, renal, and

hematologic reactions have also been described.

Diagnosis. Validated diagnostic testing is not currently avail-

able for SMZ-TMP hypersensitivity.

However, if an IgE-medi-

ated ADR to SMZ-TMP is suspected, skin testing using a

nonirritating concentration of 1:100 dilution of 80 mg/mL, or 0.8

mg/mL, may be considered.

A positive result could suggest IgE-

mediated sensitization, and a negative result would not rule out an

IgE-mediated reaction to SMZ-TMP. Oral challenge, either as a

single full dose or as 1/10th of the dose followed by the full dose,

may be considered on the basis of clinical history and skin test

results.

Dapsone may be tolerated in patients with histories of

sulfonamide reactions; however, there is conﬂicting information

on cross-reactivity, and avoidance of dapsone is recommended in

patients with histories of severe reactions to sulfonamides.

Management. Desensitization is an important component in

the management of SMZ-TMP hypersensitivity. The term

desensitization has traditionally been used for IgE-mediated sensi-

tivity. It has also been applied to treatments for reactions to SMZ-

TMP, even when the mechanisms underlying the reaction are

unclear. The Joint Task Force on Practice Parameters has recom-

mended that the term “temporary induction of tolerance”

more appropriate than desensitization in these circumstances.

In the event of severe DHRs (SJS, TEN, DRESS, and others)

to SMZ-TMP, the drug should be avoided. If no alternatives

exist and the beneﬁts of treatment with SMZ-TMP outweigh the

risk of death from a severe hypersensitivity reaction,

a previ-

ously reported temporary induction of tolerance protocol that

was successfully used for 2 patients may be considered.

Most literature on the temporary induction of tolerance to

SMZ-TMP focuses on the HIV patient population. The various

protocols for temporary induction of tolerance to SMZ-TMP

have shown similar success rates (initial success: 80%-90%; long-

term: 60%-80%) (Table VII).

89,94-104

There is no current

consensus on the best protocol for SMZ-TMP temporary in-

duction of tolerance. Interestingly, when patients with a history

of mild to moderate SMZ-TMP hypersensitivity were random-

ized to temporary induction of tolerance or full-dose challenge,

they showed similar success rates in tolerating the drug

(Table VIII). Some studies found full-dose challenge success rates

to range from 58% to 72% and those of temporary induction of

tolerance to range from 60% to 80%.

94,97,102

Leoung et al

reported a 75% success rate in the temporary induction of

tolerance group compared with 58% in the full-dose challenge

group (58%) (P ¼ .014). Therefore, a full-dose challenge could

be considered for patients with mild reactions to SMZ-TMP as

an alternative to an induction of tolerance procedure.

Very few studies have examined the temporary induction of

tolerance to SMZ-TMP in non-HIV patient populations.

99,105

Mann et al

described 4 patients with a history of SMZ-TMP

hypersensitivity (leukopenia, hives, macular rash, morbilliform

rash) who underwent a successful temporary induction of toler-

ance using either an 8-day protocol or a 22-day protocol.

106,107

Pyle et al

108

reported that 90% of 72 patients with a history of

SMZ-TMP hypersensitivity who required the drug and under-

went temporary induction of tolerance had successful outcomes

with the 6-step, 14-step, or more than 1-day protocols. The data

suggest that SMZ-TMP temporary induction of tolerance may

be considered in non-HIV patients with a history of related

hypersensitivity. The procedure appears to result in success rates

comparable to those seen in patients with HIV.

In summary, temporary induction of tolerance to SMZ-TMP

can be used safely and effectively in patients with and without

HIV who have SMZ-TMP hypersensitivity. For HIV-positive

patients with a history of a mild SMZ-TMP hypersensitivity, a

full-dose challenge can be considered; however, this option may

result in higher rates of ADRs than those associated with the

temporary induction of tolerance. A standardized temporary in-

duction of tolerance protocol for SMZ-TMP is not currently

available, and a range of temporary induction of tolerance pro-

tocols may be appropriate for use with HIV-positive patients

(Table VII). Tables IX, X, and XI present protocols described by

Pyle et al,

108

which offer options for temporary induction of

tolerance to SMZ-TMP for non-HIV patients.

Quinolones (by Maria Jose Torres, MD)

Introduction.

The frequency of hypersensitivity reactions to

quinolones, especially anaphylactic reactions, is increasing, likely

related to the increase in their use. They can induce IgE- and

T–celledependent reactions, with the IgE type being the most

common, and moxiﬂoxacin as an increasing inductor of re-

actions.

109-112

Factors inﬂuencing the increase in moxiﬂoxacin IgE

hypersensitivity in countries whereitisprescribed are notknown.

109-

111

A mast cellespeciﬁc receptor has been identiﬁed (MRGPRX2),

which is a target for direct activation by quinolones and some other

drugs with tetrahydroisoquinoline (THIQ) motifs.

113

A previous

diagnosis of immediate hypersensitivity to

-lactams can be a risk

factor for developing IgE reactions to quinolones.

110

Ciproﬂoxacin is

the main quinolone involved in delayed reactions.

112

Clinical symptoms. The most frequent clinical symptoms

are immediate urticaria and anaphylaxis, with some reports

indicating that they can be severe.

109-112

Delayed reactions

usually reported are maculopapular exanthem, delayed urticaria,

and ﬁxed drug eruptions. Although less frequent, other reactions

such as AGEP, SJS, and TEN have also been described.

Diagnosis. Various factors can complicate the diagnosis of

immediate hypersensitivity reactions to quinolones. First, the

clinical history is often unreliable, because nearly 70% of patients

with a clinical history of quinolone hypersensitivity ultimately

TABLE VI. Cephalosporin drug challenge

73,84

Step 1

of an oral dose/pill/1/10th of parenteral or oral liquid dose,

observe for 30-60 min

Step 2 1 full dose, observe for 60 min

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S24 BROYLES ET AL

can tolerate the drug and are therefore not allergic.

110,112

Second,

skin testing has resulted in a high number of false-positive results,

likely due to the capacity of some quinolones to induce direct

histamine release.

109,110,112,114

Table XII summarizes quinolone

concentrations most frequently recommended in the current

literature.

112,114,115

Therefore, drug challenge is the most useful

diagnostic assay, and procedure-related anaphylaxis is rare in

properly selected patients. Table XIII presents the recommended

procedures for drug challenge tests. Recently, in vitro approaches,

such as radioimmunoassay and BAT, have proved useful tools for

diagnosis, though their sensitivity is not optimal and they are not

commercially available.

109,110,114

The diagnosis of delayed reaction is also difﬁcult, and

particularly relevant is the lack of reliability of the clinical history,

where fewer than 5% of cases evaluated are ﬁnally conﬁrmed as

allergic.

110,112

Patch testing has shown high speciﬁcity but low

sensitivity. In cases with maculopapular exanthems or delayed

urticaria, the most frequent clinical symptoms, the diagnosis is

usually conﬁrmed with a drug challenge test.

Management. Although there are no general rules for pre-

dicting cross-reactivity, this seems to exist between ﬁrst- and

second-generation quinolones, with lower levels seen with the

third- and fourth-generation quinolones. Therefore, patients

with immediate hypersensitivity to quinolones are recommended

to avoid the administration of the whole group, and speciﬁc

recommendations of tolerance need to be made on a patient-by-

patient basis using a drug challenge test. For higher-risk patients,

desensitization to quinolones may be considered (Table XIV).

However, cross-reactivity in delayed reactions seems to be low.

Macrolides (by Miriam Verdu Benhamu, MD, Anca

Mirela Chiriac, MD, and Pascal Demoly, MD, PhD)

General.

Macrolide antibiotics are considered to be some of

the safest antibiotic treatments available. Their chemical struc-

ture is characterized by a large lactone ring, which can vary from

12 to 16 atoms, with 1 or more sugar chains attached.

116

There

are more than 20 macrolide antibiotics available; erythromycin

Type I (IgE-mediated) HSR

Anaphylaxis

Angioedema

Wheezing or shortness of breath

Laryngeal edema

Hypotension

Hives/urticaria

Unknown reaction with no further details available from

patient/proxy

Mild reaction

Minor rash

(not hives)

Maculopapular rash

(mild Type IV HSR)

Record lists allergy, but patient

denies

Unknown reaction, but patient

denies mucosal involvement,

skin desquamation, organ

involvement, or need for

medical evaluation

OK to:

Use a different generation

cephalosporin and cephalosporin

with dissimilar side chains

†

Use penicillin by

Test Dose Procedure

Use carbapenem

Use alternative agents by microbial

coverage

Type II-IV HSR

Serum sickness

Stevens-Johnson Syndrome

Toxic Epidermal Necrolysis

Acute interstitial nephritis (AIN)

Drug Rash Eosinophilia

Systemic Symptoms (DRESS)

syndrome

Hemolytic anemia

Drug Fever

Avoid using PCNs,

cephalosporins, and

carbapenems

(not amenable to

desensitization)

Use alternative agents by

microbial coverage

If clinical indication for a

beta-lactam, please involve

the Infectious Disease

service and Allergy, if

available

OK to:

Administer 3

generation cephalosporin if

dissimilar side chains

†

Test Dose Procedure

Use carbapenem

Use alternative agents by

microbial coverage

If a PCN or a 1

generation cephalosporin

is the preferred therapy,

or one of the alternative

agents is substandard,

PCN skin testing is

indicated, call/consult

Allergy, if available

OK to:

Administer PCN or

cephalosporin if dissimilar

side chains

†

Test Dose Procedure

Use carbapenem

Use alternative agents by

microbial coverage

Reaction to:

Generation

FIGURE 3. Cephalosporin hypersensitivity pathway

in patients with a history of reported hypersensitivity to (A) cephalosporins and (B)

penicillin. PCN, Penicillin class antibiotic.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S25

OK to:

Use 3

/4th/5th generation cephalosporins by Test

Dose Procedure

Use alternative agent by microbial coverage

Aztreonam or carbapenem

If a PCN or a 1st/2nd generation cephalosporin is

preferred PCN skin testing is indicated, call/

consult Allergy, if available.

Type I (IgE-mediated) HSR

Anaphylaxis

Angioedema

Wheezing or shortness of breath

Laryngeal edema

Hypotension

Hives/urticaria

Unknown reaction with no further details available

from patient/proxy

Mild reaction

Minor rash

(not hives)

Maculopapular rash

(mild Type IV HSR)

Record lists allergy, but patient

denies

Unknown reaction, but patient

denies mucosal involvement,

skin desquamation, organ

involvement, or need for

medical evaluation

OK to:

Use full dose

cephalosporin

Use penicillin by

Test Dose Procedure

Use carbapenem

Type II-IV HSR

Serum sickness

Stevens-Johnson Syndrome

Toxic Epidermal Necrolysis

Acute interstitial nephritis (AIN)

Drug Rash Eosinophilia Systemic

Symptoms (DRESS) syndrome

Hemolytic anemia

Drug Fever

Avoid using PCNs,

cephalosporins, and

carbapenems

(not amenable to

desensitization)

Use alternative agents by

microbial coverage

If clinical indication for a beta-

lactam, please involve the

Infectious Disease service and

Allergy, if available

FIGURE 3. (CONTINUED).

TABLE VII. SMZ-TMP temporary induction of tolerance in patients with HIV

Study author/year No. of subjects

Protocol Success rate (%)

Starting dose No. of steps/duration Initial Long- term*

Absar et al,

1994 28 2 mg 10/10 d 82% 61%

Gluckstein and Ruskin,

1995 22 0.02 mg 6/5 h 86% 71%

Nguyen et al,

100

1995 45 10 ng 40/36 h 82% 60%

Kalanadhabhatta et al,

1996 13 2 ng 37/27 h 100% 100%

Caumes et al,

1997 48 4 mg 8/3 d 83% 77%

Rich et al,

101

1997 22 20 ng 8/8 d 86% 86%

Ryan et al,

102

1998 13 2 mg 33/33 d 69% 62%

Yoshizawa et al,

104

2000 17 2 mg 10/5 d 88%† 88%

Bonfanti et al,

932

2000 34 10 ng 40/36 h 79% 79%

Leoung et al,

2001 97 50 mg 12/6 d 93.8% 75%

Straatmann et al,

103

2002 9 75 mg 11/22 d 60% 60%

*Those who died unrelated to SMZ-TMP and lost to follow-up were counted as part of the successful group.

†Some patients required multiple tries before successful completion.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S26 BROYLES ET AL

was the ﬁrst macrolide used, and this molecule has 14 atoms in

the lactone ring (14-C), such as clarithromycin and roxi-

thromycin; azithromycin is the only macrolide with 15-C, and

josamycin and spiramycin have 16-C. Macrolide antibiotics

usually have a bacteriostatic effect by inhibiting the mRNA-

direct protein synthesis after binding to the 50S ribosomal

subunit; they are broad-spectrum antibiotics effective against

gram-positive, gram-negative, and atypical pathogens. Their

clinical uses include upper and lower respiratory tract infections,

skin infections, sexually transmitted diseases, and the eradication

regimen of Helicobacter pylori. Their pharmacokinetic properties

include low to moderate oral bioavailability and extensive

diffusion into tissues and ﬂuids due to their lipophilic nature.

The 14-membered ring macrolides have an afﬁnity for cyto-

chrome p450 (CYP450); therefore, potential drug interactions

must be taken into account when other drugs metabolized by

CYP450 enzymes (such as phenytoin, cyclosporine, theophyl-

line, and carbamazepine) are coprescribed.

Major symptoms. Published hypersensitivity reactions to

macrolides include both immediate (<1 hour after drug intake)

and nonimmediate (delayed) reactions.

116-120

Urticaria and/or

angioedema are the most commonly described symptoms, but

maculopapular exanthems (some severe, evocative of DRESS),

ﬁxed drug eruptions, and bullous skin reactions are also seen.

Anaphylaxis caused by macrolides has also rarely been described.

In addition to hypersensitivity reactions, macrolides can induce

gastrointestinal side effects, such as nausea, vomiting, diarrhea, and

abdominal cramps, because they stimulate gut contractility.

116

Macrolides can also cause sensorineural ototoxicity, which is

usually transient, as well as prolongation of the QT interval.

116

Diagnosis. When hypersensitivity to macrolides is suspected,

the most common approach adopted by physicians is avoidance

especially because these agents are rarely indicated as ﬁrst-line

treatment.

116,121

However, clinical history alone is insufﬁcient to

ascertain the diagnosis, and published series reveal that, after

performing a drug challenge test, hypersensitivity to macrolides is

conﬁrmed in only 2.7% to 17% of cases.

118,120

Therefore, in

some situations, including the prevention/treatment of Toxo-

plasma gondii, eradication of H pylori, and treatment of some

atypical Mycobacteria , testing should be performed.

A detailed clinical history including the macrolide involved, the

chronology, and type of reaction, as well as the treatment used, is

always needed.

Skin tests (prick and sequenced IDT for immediate reactions with

the few available injectable forms and delayed-reading IDTs and

patch tests for nonimmediate reactions) can be helpful in the diag-

nostic evaluation. They are not fully validated, because it is necessary

to perform them in a large number of patients with proper controls,

and therefore, real predictive values are unknown. In a study by

Empedrad et al,

concentrations for intradermal testing with

erythromycin and azithromycin were tested in 25 healthy subjects

TABLE IX. SMZ-TMP temporary induction of tolerance short

protocol*

Steps Dose of SMZ-TMP

1 0.02 mg/0.004 mg

2 0.2 mg/0.04 mg

3 2 mg/0.4 mg

4 20 mg/4 mg

5 200 mg/40 mg

6 Final dose

Single (SS): 400 mg/80 mg PO or Double (DS):

800 mg/160 mg PO

PO, per os (by mouth).

*Dosing intervals are scheduled 15, 30, or 60 min apart. Depending on the dosing

interval, the test will take 2 h at 15-min intervals, 3

h at 30-min intervals, and 6

at 60-min intervals. Modiﬁed from the temporary induction of tolerance protocol by

Gluckstein and Ruskin.

TABLE X. SMZ-TMP temporary induction of tolerance long

protocol*

Steps Dose of SMZ-TMP

1 0.08 mg/0.016 mg

2 0.16 mg/0.032 mg

3 0.32 mg/0.064 mg

4 0.64 mg/0.128 mg

5 1.28 mg/0.256 mg

6 2.5 mg/0.512 mg

7 5 mg/1 mg

8 10 mg/2 mg

920mg/4mg

10 40 mg/8 mg

11 80 mg/16 mg

12 160 mg/32 mg

13 320 mg/64 mg

14 440 mg/88 mg

*Dosing interval is 15 min apart. The test will take 4 to 5 h. Modiﬁed from the

temporary induction of tolerance protocol by Kalanadhabhatta et al.

TABLE XI. SMZ-TMP temporary induction of tolerance 10-

d protocol*

Steps Dose of SMZ-TMP

1 2 mg /0.4 mg

2 4 mg/0.8 mg

3 8 mg/1.6 mg

4 16 mg/3.2 mg

5 40 mg/8 mg

6 80 mg/16 mg

7 160 mg/32 mg

8 320 mg/64 mg

9 400 mg/80 mg

10 800 mg/160 mg

*Dosing interval is daily. The test will take 2 h on the ﬁrst day and 90 min on

subsequent days. Modiﬁed from the temporary induction of tolerance protocol by

Absar et al.

TABLE VIII. SMZ-TMP temporary induction of tolerance vs full-

dose challenge

Study author/year

Success rate %

(total no. of subjects in the group)

Temporary induction

of tolerance

Full-dose

challenge

Bonfanti et al,

931

2000 79.5% (34) 72% (25)

Leoung et al,

2001 75% (97) 58% (94)

Straatmann et al,

103

2002 60% (9) 60% (9)

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S27

and nonirritating dilutions were set at 0.05 mg/mL and 0.01 mg/

mL, respectively. Mori et al

122

performed an allergy workup in

children with histories of suspected clarithromycin and azi-

thromycin hypersensitivity. Skin tests were performedto these drugs

on both subjects and negative controls. The highest nonirritating

concentrations used for the prick and intradermal tests were 50 mg/

mL and 0.5 mg/mL, respectively, for clarithromycin and 100 mg/

mL and 0.01 mg/mL, respectively, for azithromycin. There are

concerns about false-positive and false-negative reactions associated

with macrolide skin testing; therefore, graded challenge remains the

criterion standard. Furthermore, clarithromycin is not available in

intravenous form in the United States.

In vitro tests, such as BATs and lymphocyte transformation

tests, and detection of macrolide-speciﬁ c IgE antibodies have

been used in several case reports, but they are yet to be stan-

dardized and are not commercially available.

Drug challenge tests remain the criterion standard to establish

or exclude macrolide hypersensitivity.

16,118,123

Drug challenge can

be performed for the suspected drug, a structurally related one, or

an alternative substance; however, the challenge must always be

carried out under strict medical surveillance and after a conscious

assessment of a risk-beneﬁt analysis on a per-patient basis. It is best

performed as single-blinded, with increasing doses given every 30

minutes to achieve the maximum daily dose. Mori et al

122

used a

3-dose protocol, that is, 10%-20%-70% of the daily therapeutic

dose on day 1, followed by a full-dose administration on day 2. In

patients with a history of nonimmediate reactions, the challenge

was continued for 5 days at a therapeutic dose.

Other macrolides. Nonantibiotic macrolides have also been

involved in drug hypersensitivity reactions, ranging from allergic

contact dermatitis (ACD) due to topical application of tacroli-

mus in patients with atopic dermatitis, to generalized reactions

elicited by systemic administration. Saito et al

124

performed a

literature review on oral tacrolimuserelated drug hypersensitivity

reactions. Considering its immunosuppressive effects, it is not

surprising that most patch-test results (but not all) were negative

and most of these cases were diagnosed with a lymphocyte

stimulation test.

124,125

Severe reactions, namely, hypersensitivity

pneumonitis or DRESS, have been attributed (without drug

hypersensitivity workup) to drug-eluting stents involving zotar-

olimus and everolimus, respectively.

126,127

Management. Cross-reactivity among different macrolides has

not been extensively studied, but when it was tested, most patients

with a demonstrated hypersensitivity to a certain macrolide could

tolerate another with a different number of atoms in the lactone

ring.

80,116

Mori et al

122

reported double positivity in 2 patients

with clinical histories of anaphylaxis to clarithromycin (14-C) and

azithromycin (15-C). One of them had experienced anaphylaxis to

both drugs, whereas the other one had never taken clarithromycin.

Macrolide antibiotics are unlikely to cross-react with macro-

lide immunosuppressants, such as 23-C tacrolimus and 29-C

sirolimus. In a published case, cross-reactivity was suspected

between clarithromycin and tacrolimus, but for both drugs, the

assumption of drug hypersensitivity was based on clinical history

alone and no speciﬁc workup was performed.

128

Very few case reports of desensitization protocols to macro-

lides have been published (eg, to spiramycin in a pregnant

woman suffering from toxoplasmosis or to clarithromycin in 2

patients infected by Mycobacterium chelonae and Mycobacterium

avium, respectively) (Tables XV-XVII).

129-131

To our knowl-

edge, there are no reports to date for other commonly prescribed

macrolides, such as azithromycin and/or erythromycin.

Tetracyclines (by Stephanie Logsdon, MD)

General.

Tetracyclines are a broad-spectrum antibiotic class of

which 4 are available for systemic use in the United States:

tetracycline, demeclocycline, doxycycline, and minocycline. In

TABLE XII. Recommended concentrations of quinolones for skin

testing*

80,11 2 ,11 5

Quinolone

Concentration

prick (mg/mL)

Concentration

IDT (mg/mL) References

Moxiﬂoxacin 1.6 Not performed Seitz et al,

112

2009

Tablet, 400 mg

suspended

in saline

Not performed Venturini et al,

115

2007

Ciproﬂoxacin 2 Not performed Seitz et al,

112

2009

0.02 0.02 Venturini et al,

115

2007

Levoﬂoxacin 5 Not performed Seitz et al,

112

2009

5 0.05 Venturini et al,

115

2007

0.025 0.025 Empedrad et al,

2003

*Although these concentrations are currently recommended for skin testing, there is

controversy about nonirritating concentrations.

TABLE XIII. Recommended doses for drug provocation tests with

quinolones*

109,11 2

Quinolone

Doses administered

at intervals of 30 min

109

Doses administered

at intervals of 60 min

112

Moxiﬂoxacin 5-50-100-100-150 25-50-100-200

Ciproﬂoxacin 5-50-100-150-200 50-125-250-500

Levoﬂoxacin 5-50-100-150-200 50-125-250-500

*Increasing doses of the suspected ﬂuoroquinolone were administered orally at in-

tervals of 30 min or 60 min until reaching the full dose or until symptoms of a drug

reaction occurred. Drug challenge protocols with less steps may also be considered

such as 1/10th of the dose followed by the full dose.

TABLE XIV. Recommended ciprofloxacin desensitization

procedure*

933

Time

(h) Route

Ciprofloxacin

concentration

(mg/mL)

Volume

given (mL)

Absolute

amount (mg)

Cumulative

total dose (mg)

0:00 IV 0.01 5.0 0.05 0.05

0:15 IV 0.1 1.0 0.1 0.15

0:30 IV 0.1 2.0 0.2 0.35

0:45 IV 0.1 4.0 0.4 0.75

1:00 IV 0.1 8.0 0.8 1.55

1:15 IV 1.0 1.6 1.6 3.15

1:30 IV 1.0 3.2 3.2 6.35

1:45 IV 1.0 6.4 6.4 12.75

2:00 IV 1.0 12.8 12.8 25.55

2:15 IV 10.0 2.5 25.0 50.55

2:30 IV 10.0 5.0 50.0 100.55

2:45 IV 10.0 10.0 100.0 200.55

3:00 Oral NA 250-mg tablet 450.55

IV, Intravenous; NA, not available.

*The patient should take the next oral dose of 500 mg that evening.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S28 BROYLES ET AL

addition, tigecycline is a glycylcycline, which is a new class of

antimicrobials with similar antimicrobial activity as the tetracy-

clines. Adverse reactions involving IgE-mediated hypersensitivity

are rare, and studies suggest that adverse reactions to minocycline

are more common than to doxycycline. Differences in side-chain

structures are hypothesized to be responsible.

132

Major symptoms. For all tetracyclines, most hypersensitivity

reactions are noneIgE-mediated, and include DRESS, papulosis,

lupus-like reactions, serum sicknesselike reactions, and photo-

sensitivity.

133-136

Nonetheless, IgE-mediated reactions do occur,

and anaphylaxis has been reported.

137-139

One report of drug fever

secondary to tigecycline use has also been published.

140

Rates of

cross-reactivity between tetracycline antibiotics are not established;

however, 1 report includes a patient with doxycycline hypersen-

sitivity who did exhibit cross-sensitization with minocycline.

141

Diagnosis. For patients with suspected IgE-mediated reactions,

skin testing is not standardized for any of the tetracycline antimi-

crobials, and positive and negative predictive values have not been

established. One case report has noted positive skin prick testing

result to full-strength tetracycline.

138

In addition, the minimum

nonirritating concentration for intradermal testing in control sub-

jects was 0.0002 mg/mL for minocycline and 0.001 mg/mL for

doxycycline. The following step-wise skin testing protocols have

been recommended: for minocycline, skin prick testing 0.2 mg/mL,

intradermal testing 0.00002 mg/mL, intradermal testing 0.0002

mg/mL. For doxycycline, skin prick testing 10 mg/mL, intradermal

testing 0.0001 mg/mL, intradermal testing 0.001 mg/mL.

142

Management. In patients with low clinical suspicion for

anaphylactic reactions and negative skin testing result, a graded drug

challenge may be considered.

In cases of high suspicion for

anaphylaxis or positive skin testing result where a tetracycline anti-

biotic is required, desensitization can be performed. There are no

published reports of effective rapid desensitization protocols for

these drugs, but some success has been seen with oral desensitization

to minocycline and doxycycline. A 14-step protocol was used for

minocycline, starting at 0.01 mg, followed by dose doubling at 30-

minute intervals until the cumulative goal was reached. Further-

more, an oral desensitization protocol for doxycycline (Table XVIII)

was successful, starting at 0.00001 mg and increasing in 10-fold

steps every 30 minutes until 1 mg was reached, and then increasing

by 2-fold increments until the goal dose was reached.

142

Successful desensitization to tigecycline using a 12-step pro-

tocol has also been recently reported.

142

Vancomycin (by Johnson Wong, MD)

General.

Vancomycin is a tricyclic glycopeptide antibiotic that

is used intravenously to treat various gram-positive cocci bacterial

infections including those caused by methicillin-resistant Staph-

ylococcus aureus and enterococcus, gram-positive cocci infections

among patients with

-lactam hypersensitivity, and gram-posi-

tive cocci infections in patients with renal failure. Oral vanco-

mycin is used to treat C difﬁcile infections.

Major symptoms

“Red men syndrome”.

Red men syndrome (RMS) refers to

ﬂushing and pruritus, which are commonly induced by the rate-

dependent direct mast cell degranulation (DMCD) effect of

vancomycin. In severe cases, hypotension, bronchospasm, and

urticaria may also accompany RMS. At a rate of 1 g/h or more,

10% to 80% of subjects developed RMS, whereas a much lower

incidence occurred when the rate was reduced to 1 g over 2

hours.

143

Histamine is often elevated early on, whereas tryptase

was not found elevated at 10 minutes. Treatment of choice of

TABLE XV. Desensitization protocol to spiramycin

130

Day Daily dose (IU)

1 300

600

900

1,200

3,000

9,000

12,000

Total: 33,000

2 30,000

60,000

90,000

120,000

150,000

180,000

Total: 630,000

3 300,000

600,000

900,000

1,200,000

3,000,000

Total: 6,000,000

4 3,000,000 thrice a day

Total: 9,000,000

5 3,000,000 four times a day

Total: 12,000,000

IU, International units.

TABLE XVI. Oral clarithromycin desensitization protocol

129

Step (15-min

intervals)

Clarithromycin

suspension

(mg/mL)

Volume

(mL)

Dose

(mg)

Cumulative

dose (mg)

1 0.05 0.1 0.005 0.0

2 0.05 0.2 0.01 0.0

3 0.05 0.4 0.02 0.0

4 0.05 1 0.05 0.1

5 0.05 2 0.1 0.2

6 0.05 4 0.2 0.4

7 0.5 0.8 0.4 0.8

8 0.5 1.6 0.8 1.6

9 0.5 3.2 1.6 3.2

10 0.5 6.4 3.2 6.4

11 5 1.2 6 12.4

12 5 2.4 12 24.4

13 5 4.8 24 48.4

14 50 1 50 98.4

15 50 2 100 198.4

16 50 4 200 398.4

17 50 8 400 798.4

18 50 10 500 1298.4

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S29

mild to moderate RMS is to slow the infusion rate to half the

previous infusion rate or 1 g per 2 hours or less, with antihis-

tamine pretreatment.

Anaphylactoid reactions/anaphylaxis/severe refractory

RMS.

This may occur in a small subgroup of patients. Although an

IgE-mediated mechanism is possible, most of these cases appeared to be

asevereformofDMCD.Vancomycin-speciﬁc IgE measurement has

not been reported in the literature. Skin testing has been proposed as a

surrogate for both DMCD sensitivity and possible IgE-mediated

sensitivity (see Skin Testing section below).

144-146

This highly sensitive

group can generally receive a rapid continuous intravenous protocol as a

method to induce temporary drug tolerance as described for vanco-

mycinaswellasotherdrugs.

147-150

Its advantage lies in the provision of

continuous small increments that avoid periodic substantial increases in

the rate of drug delivery. In several cases, one can reach a threshold level

only the ﬁrst day and the dose need to be gradually increased over

several days. When possible, stopping concurrent narcotics or other

agents that also have DMCD property may often allow a difﬁcult

desensitization to be successful.

Morbilliform rash/hematologic changes/DRESS.

Morbilliform rash is relatively common and often occurs in

isolation. It may also be accompanied by various combinations of

fever, hematologic changes, and/or end-organ dysfunction. The

hematologic changes commonly include eosinophilia and neu-

tropenia, and rarely, leukemoid reaction, lymphocytosis, throm-

bocytopenia, lymphadenopathy, and vasculitis. The end organs

that may be affected include kidney and liver. The combination of

drug reaction, eosinophilia, and systemic symptoms constitutes the

DRESS reaction, and a recent report indicated that HLA:A*32:01

is strongly associated with vancomycin-induced DRESS.

147

Another study suggested that circulating IFN-

vancomycin-

speciﬁc T cells may be isolated in such patients.

151

For patients

who are receiving multiple drugs and develop these reactions,

vancomycin should join

-lactam antibiotics high in the differ-

ential.

152

For patients with renal failure, vancomycin should be

considered as a culprit agent, because of its long half-life, even if the

reaction occurs weeks after the last dose. Management consists of

drug withdrawal and supportive treatment.

Linear IgA bullous diseases/TEN. Vancomycin is the

most commonly reported cause of the rare linear IgA bullous

diseases that may present as TEN-like reactions.

153

In addition,

TEN without identifying the mechanism has been reported.

Management is drug withdrawal and supportive treatment.

These reactions serve as absolute contraindication for re-

administration or desensitization.

Teicoplanin as alte rnative treatment. Teicoplanin is a

similar glycopeptide antibiotic that is available only outside the

United States. A major retrospective study and a prospective

study from the same institution over different time frames

showed that 12 of 117 (10%) and 14 of 24 (58%) patients,

respectively, who had a hypersensitivity reaction to vancomycin

also developed one to teicoplanin.

154,155

There was a high

recurrence rate and new occurrence rate for neutropenia,

leukopenia, and thrombocytopenia (10 of 14). Therefore, tei-

coplanin may not be an ideal alternative treatment option for

patients with vancomycin hypersensitivity.

Skin testing and implications. Skin testing has been

proposed as a surrogate for both DMCD sensitivity and possible

IgE-mediated sensitivity. Polk et al

146

performed titration of

vancomycin skin test reactivity as a function of vancomycin

concentration in a group of 12 healthy male volunteers. At

concentrations of more than or equal to 10

g/mL (0.02 mL

intradermally), all volunteers showed detectable wheal and ﬂare.

The area of the ﬂare, but not the wheal size, increased with

higher concentration, up to 40 to 100

g/mL (0.02 mL intra-

dermally) before reaching a plateau. Because these were healthy

volunteers without previous vancomycin exposure, the wheal-

and-ﬂare responses were assumed to be due to DMCD at doses

of more than or equal to 10

g/mL (0.02 mL intradermally) and

not an IgE-mediated mechanism. The size of the ﬂare at 25

mL (0.02 mL intradermally) correlated poorly with the area of

ﬂushing when the subjects were challenged with vancomycin

infusion. Case reports of patients with “anaphylactoid/anaphy-

laxis/pruritus” who developed wheal and ﬂare at vancomycin

concentrations of 0.1 to 5

g/mL (0.02 mL intradermally) on

TABLE XVII. Oral clarithromycin desensitization protocol*

131

Dose no.

(15-min intervals)

Concentration

(mg/mL) Dose (mL) Dose (mg)

1 0.025 1.25 0.03

2 0.025 2.5 0.06

3 0.025 5 0.125

4 0.25 1 0.25

5 0.25 2 0.5

6 0.25 4 1

7 2.5 0.8 2

8 2.5 1.6 4

9 2.5 3.2 8

10 2.5 6.4 16

11 25 1.3 32

12 25 2.5 64

13 25 5 125

14 25 10 250

Cumulative dose 503

*Serial 10-fold dilutions of a clarithromycin suspension of 125 mg/5 mL (25 mg/mL)

were performed to make clarithromycin solutions at 2.5, 0.25, and 0.025 mg/mL.

TABLE XVIII. Doxycycline oral desensitization protocol*

Step Doxycycline (mg) Cumulative dose (mg)

1 0.00001 0.00001

2 0.0001 0.00011

3 0.001 0.00111

4 0.01 0.01111

5 0.1 0.11111

6 1 3.11111

7 2 3.11111

8 4 7.11111

9 8 15.11111

10 12 27.11111

11 25 52.11111

12 50 102.11111

Total time 360 min

*Steps with 30-min interva ls. Lowest dilution was based on 1:100 dilution of the

concentration that lead to positive skin testing result. Serial dilutions of doxycycline

suspension were prepared with puriﬁed water.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S30 BROYLES ET AL

skin testing were interpreted as representing IgE-mediated

sensitivity.

144,145

However, the cutaneous reactivity, even at 0.1

g/mL, may represent increased propensity for DMCD or

increased sensitivity to the mast cell release products (induced by

concurrent narcotic or due to intrinsic sensitivity of the pa-

tient).

150

Overall, the general consensus is that 50 mg/mL for

skin prick testing and 0.005 mg/mL for intradermal skin testing

are nonirritating concentrations (Table XIX).

Aminoglycosides (by Catherine Biggs, MD)

General.

Aminoglycosides are a broad-spectrum class of anti-

biotics that are structurally composed of hydrophilic sugars

possessing amine and hydroxyl functional groups.

156

Type IV

hypersensitivity reactions in the form of ACD are commonly

associated with aminoglycosides. The prevalence of ACD to

neomycin sulfate reported by the North American Contact

Dermatitis Group from 1985 to 2004 ranged from 7.2% to

13.1%.

157

Systemic contact dermatitis to aminoglycosides, as

well as severe type IV hypersensitivity reactions such as TEN and

DRESS syndrome, have also been described.

158-160

IgE-mediated

reactions to aminoglycosides are uncommon but may occur after

exposure to topical, inhaled, and systemic preparations.

161-163

Major symptoms of hypersensitivity. IgE-mediated re-

actions described in the literature include urticarial reactions in

response to both intravenous and inhaled tobramycin, as well as

anaphylaxis to topical and systemic aminoglycosides.

161-163

ACD

may present as erythematous/pruritic/edematous papules, pla-

ques, and/or vesicles at the site of contact.

157

TEN caused by

streptomycin has been associated with high fever, vomiting, and

diffuse erythema, followed by extensive bullae formation and

skin denudation.

159

Features of DRESS syndrome include a

maculopapular and edematous skin rash, facial edema, and fever;

laboratory studies may demonstrate eosinophilia, atypical

lymphocytosis, abnormal liver enzymes, and coagulopathy.

158

Diagnosis. IgE-mediated reactions are diagnosed on the basis

of clinical features in keeping with an immediate hypersensitivity

reaction, and have been conﬁrmed in the literature using skin

testing. Systemic reactions to epicutaneous and intradermal

testing have been described in patients with a history of

anaphylaxis to topical and systemic aminoglycosides, respec-

tively.

161,164,165

Skin testing should therefore be approached

with caution, and one may consider beginning with a 10-fold

dilution for the ﬁrst intradermal dose in patients with a history of

anaphylaxis to an aminoglycoside (Table XX).

The diagnosis of type IV hypersensitivity reactions may be

supported diagnostically by patch testing to the aminoglycoside

in question. Signiﬁcant cross-reactivity among aminoglycosides

has been reported in ACD.

157

Management. Avoidance of the offending agent is recom-

mended for patients with a history of type IV hypersensitivity

reactions. In the setting of negative skin testing result and low

clinical suspicion for an IgE-mediated allergy, a graded challenge

can be performed. Rapid desensitization is recommended for

patients with an IgE-mediated allergy to an aminoglycoside who

require the medication when no suitable alternative antibiotic

exists.

167

Table XXI presents an example of a desensitization

protocol for tobramycin.

Clindamycin (by Jocelyn R. Farmer, MD)

General.

Clindamycin, a semisynthetic derivative of linco-

mycin, is a bacteriostatic agent that inhibits protein synthesis. It

has been on the market since 1968 and is generally well tolerated.

Common adverse reactions include a metallic taste in the mouth,

transient elevation of transaminases, and a propensity for C

difﬁcile infection, with an increased risk for diarrhea (10%-23%)

and pseudomembranous colitis (2%).

168

Major symptoms of hypersensitivity. Immediate hy-

persensitivity to clindamycin is rare, though clindamycin-

induced anaphylaxis has been reported.

169-171

Delayed hyper-

sensitivity to clindamycin is much more common, initially esti-

mated at 10% in small clinical studies from the 1970s, but

revised to be less than 1% in a large retrospective chart review of

clindamycin administration at a single US center from 1995 to

1997.

172-174

Delayed maculopapular exanthems are predomi-

nantly seen; however, SJS, DRESS, TEN, sweet syndrome, and

AGEP have all been reported in the literature.

175-183

TABLE XIX. Vancomycin rapid intravenous desensitization

protocol*†

Time

(h:min)

Vancomycin

concentration

(mg/mL)

Fluid infusion

rate (mL/h)

Vancomycin

infusion rate

(mg/h)

Cumulative

dose (mg)

0:00 0.0001z 60.0 0.0060 0

0:15 0.001 20.0 0.020 0.0015

0:30 0.001x 60.0 0.060 0.0065

0:45 0.01 20.0 0.20 0.022

1:00 0.01 60.0 0.60 0.072

1:15 0.1 20.0 2.0 0.22

1:30 0.1 60.0 6.0 0.77

1:45 1.0 20.0 20 2.2

2:00 1.0 60.0 60 7.7

2:15 10 12.5 125 22

2:30k{# 10 25.0 250 54

*Adapted from the original protocol of Wong et al.

150

†H

antihistamine pretreatment.

zTypical starting concentration for patients with severe systemic reactions to pre-

vious vancomycin infusions.

xTypical starting concentration for patients with moderate systemic reactions to

previous vancomycin infusions.

kContinue at this infusion rate for the remainder of the dosage.

{Minimize concurrent narcotic and other direct mast degranulators if possible.

#May need to stay just below a threshold vancomycin infusion rate the ﬁrst day and

advance as tolerated.

TABLE XX. Immediate hypersensitivity testing recommended for

aminoglycosides

80,162,166

Aminoglycoside SPT dilutions (mg/mL) IDT dilutions (mg/mL)

Gentamycin

(preservative free)

40 0.04*

0.4

Tobramycin 40 0.04*

0.4

*Optional step that is recommended for patients with a history of anaphylaxis to an

aminoglycoside.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S31

Clindamycin-induced cytopenias have also been described,

including anemia, neutropenia, and thrombocytopenia. The

underlying mechanism is unclear, though direct myelosup-

pression at the level of the hematopoietic stem cell has been

shown.

184

Diagnosis. Immediate hypersensitivity skin testing to clinda-

mycin has been studied. Skin prick at 150 mg/mL and intra-

dermal injection at 15 mg/mL have been identiﬁed as

nonirritating concentrations.

80,185

However, skin testing for

immediate hypersensitivity to clindamycin was shown to be

inferior to direct drug challenge in a study of 31 patients with a

history of adverse clindamycin reaction, where 0 of 31 patients

demonstrated a positive skin test result but 10 of 31 patients

(32%) reacted during an oral challenge with 150 mg clindamy-

cin.

185

The utility of immediate hypersensitivity skin testing to

clindamycin in routine clinical practice has been questioned. In

contrast, delayed hypersensitivity patch testing to clindamycin

has been more promising. In patients with a predominant history

of delayed maculopapular exanthems, patch testing via clinda-

mycin 150-mg tablet pulverized and diluted in 1 mL saline or via

pure clindamycin diluted to 10% in petrolatum resulted in

positive reactions in 15% to 30% of patients, respectively.

186,187

Therefore, clindamycin patch testing may be useful in the

context of a convincing history of delayed hypersensitivity.

Management. Most adverse reactions to clindamycin are

mild and the drug can be continued safely. In cases of severe

DHRs to clindamycin (eg, SJS, DRESS, TEN, and AGEP), the

drug should be empirically avoided and there are no suitable

alternatives. For nonsevere DHRs to clindamycin (eg, isolated

maculopapular exanthem), a single case of oral desensitization

has been described.

188

The DHR to clindamycin was conﬁrmed

on repeat oral challenge. The starting dose for the desensitization

was clindamycin 20 mg every 8 hours, with dose escalation over

7 days as given in Table XXII. The patient was without adverse

reaction at the 13-month follow-up, demonstrating proof of

principle for clindamycin desensitization in the treatment of

delayed drug hypersensitivity. More recently, clindamycin

desensitization in the treatment of immediate drug hypersensi-

tivity was reported in the literature in a single pediatric case using

a rapid 9-step oral clindamycin desensitization protocol over 4

hours to a cumulative dose of 11 mg/kg per dose (300 mg/dose),

which was then continued every 8 hours for the duration of the

antimicrobial course.

189

Linezolid (by Jocelyn R. Farmer, MD)

General.

Linezolid is an oxazolidinone that works by inhibit-

ing the initiation of bacterial protein synthesis. It was ﬁrst

introduced for clinical use in the United States in 2000 and is

generally well tolerated. Among the known adverse reactions,

linezolid-induced cytopenias are best described and occur more

frequently with long-term therapy (>14 days), increased daily

dose (22 mg/kg), high serum concentration, and comorbidities

including renal insufﬁciency.

190-193

Prevalence rates vary widely

by study design but have been estimated at 15% to 50% for

thrombocytopenia, 4.2% to 16% for anemia, and 2.2% to 4.5%

for leukopenia.

194-196

The underlying mechanism is felt to be

myelosuppression secondary to off-target inhibition of host

protein synthesis in the bone marrow, which aligns with the

dose-dependent and reversible nature of linezolid-induced cyto-

penias and the fact that linezolid-dependent antiplatelet anti-

bodies have not been described.

197

Less frequent adverse

reactions to linezolid include lactic acidosis, which typically oc-

curs with long-term therapy (>6 weeks) and has been attributed

to the underlying mitochondrial inhibitory mechanism of the

drug.

198

In addition, there has been a case report of peripheral

and optic neuropathy.

199-201

Major symptoms of hypersensitivity. Immediate hy-

persensitivity to linezolid is rare. In a review of 828 linezolid

treatment courses from 1997 to 2000, treatment-limiting

dermatologic events including rash and pruritus occurred in

1.7% of cases, and only 2 patients had anaphylactic-type re-

actions.

194

Subsequently, a case of immediate urticaria and

angioedema to linezolid and 2 more detailed descriptions of

suspected linezolid anaphylaxis were reported in the litera-

ture.

202-204

Delayed hypersensitivity to linezolid is also infre-

quent and can include acute interstitial nephritis and/or

TABLE XXI. Example of a desensitization protocol for intravenous

tobramycin*

167

Tobramycin Full therapeutic dose [ 100 mg IV q8h

Tobramycin

solutions†

1. 1 mg/200 mL NS

(ﬁnal concentration ¼ 0.005 mg/mL)

2. 10 mg/200 mL NS

(ﬁnal concentration ¼ 0.050 mg/mL)

3. 99 mg/200 mL NS

(ﬁnal concentration ¼ 0.495 mg/mL)

Step Solution

Rate

(mL/h)

Time

(min)

Administered

dose (mg)

Cumulative

dose (mg)

1 1 2.5 15 0.0031 0.0031

2 1 5 15 0.0063 0.0094

3 1 10 15 0.0125 0.0219

4 1 20 15 0.0250 0.0469

5 2 5 15 0.0625 0.1094

6 2 10 15 0.1250 0.2344

7 2 20 15 0.2500 0.4844

8 2 40 15 0.5000 0.9844

9 3 10 15 1.2377 2.2221

10 3 20 15 2.4754 4.6975

11 3 40 15 4.9508 9.6482

12 3 80 136.875 90.3518 100.0000

IV, Intravenous; NS, normal saline; q8h, every 8 h.

*Dosage will vary on the basis of indication and patient weight.

†The total volume and dose dispensed of the tobramycin solutions are more than the

ﬁnal dose given to patient because the initial solutions are not completely infused.

TABLE XXII. Protocol for clindamycin desensitization for the

management of delayed hypersensitivity

188

Day Oral clindamycin dose (mg q8h)

120

240

380

4 150

5 300

6 600

7 600 (q6h)

q6h, Every 6 h; q8h, every 8 h.

J ALLERGY CLIN IMMUNOL PRACT

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S32 BROYLES ET AL

DRESS.

205-208

In a recent systematic chart review of 824 out-

patients receiving monitored antibiotic therapy, linezolid was

signiﬁcantly associated with increased risk for peripheral eosin-

ophilia but not end-organ damage including nephritis and

DRESS.75 Together, these data suggest a known but small risk

for severe DHRs after linezolid therapy.

Diagnosis. To date, no standardized immediate or delayed

hypersensitivity skin testing protocols for linezolid have been

published. Diagnosis is therefore limited to direct oral or intra-

venous challenge in cases in which it is clinically safe to do so.

Management. Treatment-limiting adverse reactions to line-

zolid include gastrointestinal complaints (with oral preparations),

cytopenias, rash, and angioedema.

194,195

In cases of severe DHRs

to linezolid (eg, acute interstitial nephritis or DRESS), the drug

should be empirically avoided. Alternatively, for immediate hy-

persensitivity reactions, linezolid desensitization has been

described.

202,203

Given that the drug has an oral bioavailability of

approximately 100% in healthy volunteers, the ﬁrst protocol

used oral desensitization to linezolid. The patient tolerated 14

sequential dilutions in the absence of breakthrough symp-

toms.

203

More recently, intravenous linezolid desensitization for

immediate hypersensitivity was accomplished as presented in

Table XXIII. The patient had no breakthrough symptoms and

subsequently made a transition to oral linezolid 600 mg every 12

hours to complete a 2-week course.

Nitrofurantoin (by Jocelyn R. Farmer, MD)

General.

Nitrofurantoin is a broad-spectrum antibiotic that

was ﬁrst approved as clinical treatment for urinary tract infections

in 1953. Intracellular nitroreductase produces the active drug

metabolite, which functions to inhibit bacterial DNA and RNA

synthesis.

209

Adverse reactions to nitrofurantoin are infrequent

(5%-16%) and generally mild, reversible, and predominantly

gastrointestinal (nausea and abdominal discomfort).

210

Major symptoms of hypersensitivity. Immediate hy-

persensitivity reactions to nitrofurantoin are rare. Nitrofurantoin-

induced anaphylaxis has been reported, and acute pulmonary

reactions with symptoms consisting of shortness of breath,

cough, fever, and peripheral eosinophilia within days to weeks of

drug initiation have been reported at a rate of 1 in 5000 ﬁrst

administrations.

211-214

Lung pathology can demonstrate vascu-

litis, mild interstitial inﬂammation, eosinophils, and reactive type

II pneumocytes.

215

In general, with drug discontinuation, pa-

tients have prompt recovery, and nitrofurantoin-induced acute

pulmonary reactions have an overall mortality rate of only

0.5%.

216

Delayed hypersensitivity to nitrofurantoin can include

pulmonary ﬁbrosis, hepatotoxicity, erythema multiforme, ery-

thema nodosum, agranulocytosis, megaloblastic anemia, and

optic neuritis.

210

However, these adverse reactions are rare, with

incidence rates per nitrofurantoin course previously calculated at

0.001% for all pulmonary reactions combined, 0.0003% for

hepatotoxicity, 0.0004% for hematologic events, and 0.0007%

for neurologic complications.

217

Nitrofurantoin-induced pul-

monary ﬁ brosis and hepatotoxicity have been associated with

systemic autoantibody production and lymphocytic inﬁltrates to

the end organ with subsequent risk for ﬁbrosis.

215,218

An un-

derlying mechanism of direct drug injury (via reactive oxygen

species) and indirect drug injury (via induced cellular hyper-

sensitivity) has been described.

219,220

In general, patients have

pronounced recovery with drug cessation, though occasionally

steroid therapy is also required.

215,218

Diagnosis. To date, no standardized immediate or delayed

hypersensitivity skin testing protocols for nitrofurantoin have

been published despite a few case reports.

214,221

Diagnosis is

therefore limited to direct oral challenge in cases in which it is

clinically safe to do so.

Management. Most adverse reactions (eg, nausea and

abdominal discomfort) are mild and the drug can be continued

safely. However, in rare cases of severe nitrofurantoin-induced

immediate hypersensitivity reactions (eg, anaphylaxis and acute

pulmonary reactions), or DHRs (eg, pulmonary ﬁbrosis and

hepatitis), nitrofurantoin should be discontinued immediately

and empirically avoided. Case reports of drug desensitization

have not been described.

Antituberculous drugs (by Stephan ie Logsdon, MD,

and Josefina Cernadas, MD)

Introduction.

Tuberculosis (TB), an infection caused by

Mycobacterium tuberculosis, is a curable infectious disease, prev-

alent worldwide, and potentially fatal if proper treatment is not

instituted. It remains a major cause of global mortality and

morbidity. Most of the 2 billion people estimated to be infected

with M tuberculosis have asymptomatic infection, termed latent

TB infection.

222-224

Similar to other Mycobacterial infections, treatment of TB

requires simultaneous administration of multiple drugs. In the

absence of bacterial resistance, treatment usually consists of

isoniazid (INH), rifampicin, pyrazinamide (PZA), ethambutol

(EMB), and streptomycin for 6 months.

Although most treatment courses progress with minor side

effects, ADRs can occur. No consensus has been reached con-

cerning the overall incidence of ADRs to these drugs. Different

studies report an incidence of 5.5% to 57.8% according to

different populations and ADR deﬁnitions.

225-230

Adverse effects

or drug interactions can make it necessary to modify or discon-

tinue treatment.

A major ADR to any of the anti-TB drugs, which implicates

the discontinuation of that drug, can have severe implications.

Alternative agents may lead to greater toxicity and are often less

effective, frequently requiring longer treatment courses. As a

result, the risk of treatment failure and relapse is higher in these

cases. In these patients, management is further complicated by

the difﬁcult task of identifying the culprit agent for the reaction

when they are on a typical multidrug regimen. In patients with

SCARs, there are reports of further challenge with selected drugs

because of the limited availability of treatment; however, as with

any other SCAR, avoidance is typically recommended.

231

Rifampin (Rifampicin). Rifampin remains a common ther-

apy for latent and active TB, and is also used for infections with

aerobic gram-negative organisms including the asymptomatic

Neisseria meningitidis carrier state. It is rarely implicated in hy-

persensitivity reactions, ranging from pruritic skin eruptions to

anaphylaxis, despite its frequent use, but is associated with

multiple side effects.

Side effects of rifampin include an inﬂuenza-like syndrome,

hepatotoxicity, skin exanthems, and induction of SMZ-TMP,

which may cause signiﬁcant drug-drug interactions.

232

The most

commonly reported ADR is the inﬂuenza-like syndrome, which

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S33

consists of fever, chills, headaches, myalgia, and rash. Published

reports have also described rifampin hypersensitivity reactions in

both adult and pediatric populations, ranging from pruritic skin

eruptions to anaphylaxis.

233

Diagnosis of rifampin hypersensitivity can be difﬁcult, because

many reactions are likely not IgE-mediated. Skin testing can be

helpful in determining the likelihood of reaction, though nega-

tive skin test reactions do not indicate lack of sensitivity. Skin

testing should be performed on the basis of published protocols

in which the highest intradermal nonirritating drug concentra-

tion in nonallergic control subjects was 0.002 mg/mL.

234

Similar

nonirritating intradermal concentrations have been reported in

the literature for evaluation of rifampin hypersensitivity

235

Rifampin is a critical component of anti-TB therapy and often

alternative drugs are not available. Therefore, in cases of hyper-

sensitivity to rifampin, desensitization to the medication is often

required. Recommended dosing of rifampin for TB is 600 mg

daily, but maintaining a desensitized state with this dose can be

problematic secondary to the drug’s short half-life of 3

hours.

235,236

Despite this, various techniques for desensitization

have been published, from rapid protocols to those of 7 or more

days’ duration.

235,237

Three pediatric case reports have been

published.

238-240

Although uncommon, adverse reaction during

rapid desensitization to rifampin may occur. In 1 previously

published report, a pediatric patient developed a reaction during

the protocol despite premedication, whereas the other 2 patients

tolerated rapid desensitization without premedication. Another

report described an adult patient who developed anaphylaxis

during an oral desensitization procedure after positive skin

testing result.

241

A new, alternating-dose rapid oral desensitization protocol for

rifampin was completed in a pediatric patient to achieve appro-

priate serum concentrations while safely maintaining the desen-

sitized state.

240

The protocol used a regimen of 600 mg in the

morning followed by 300 mg rifampin in the evening. This

dosing was chosen because of the short half-life of rifampin, to

maintain desensitization. For oral rifampin, the 13-step rapid

oral desensitization protocol outlined in Table XXIV is effective

and safe. Strict adherence to an every-12-hour dosing schedule is

required to safely maintain the desensitized state.

Pyrazinamide. PZA, a synthetic pyrazine analogue of nico-

tinamide, is one of the most effective anti-TB drugs and is

generally well tolerated. Like any other drug it may cause adverse

reactions. These reactions are mainly toxic and may affect several

organs: liver (cytolysis), joints (arthralgia), and the gastrointes-

tinal system with nausea, vomiting, diarrhea, and abdominal

pain. This drug may also induce more severe reactions such as

nephrotoxicity, but the most severe one is hepatotoxicity ranging

to fulminant hepatitis. Also, the drug most likely responsible for

the occurrence of hepatitis during therapy for active TB is PZA.

Cutaneous manifestations are the most common reactions to

PZA, though true allergic reactions are rare

242-244

It can also be

associated with early onset of maculopapular rash with pruritus,

sometimes in association with dyspnea (possibly due to bron-

chospasm) and abdominal pain, suggesting anaphylactic/

anaphylactoid reaction. The mechanisms underlying these re-

actions are undetermined.

225,245

Among anti-TB medications, the incidence of serious side

effects, deﬁned as those requiring a documented change in

therapy or hospitalization, is highest with PZA. These serious

side effects are associated with female sex, older age, Asian origin,

and HIV infection.

225

Hypersensitivity reactions should be suspected if an immedi-

ate skin rash develops at the initiation of PZA treatment. If the

degree of skin involvement is not severe, sequential reintro-

duction of the drugs ﬁrst at low, then at full dosage may be

attempted.

Bavbek et al

246

described an allergic reaction in a patient who

had positive skin prick test (SPT) result to PZA, with negative

results in 10 controls, and a positive oral challenge test result.

246

The SPTs were performed with PZA tablets at a concentration of

500 mg/mL along with a positive histamine control and a

negative saline control 1 week after the initial reaction. The PZA

tablets were smashed in a mortar and diluted with 1 mL of 0.9%

NaCI. A positive reaction was seen only with PZA, producing a

TABLE XXIII. Protocol for linezolid desensitization for the management of immediate hypersensitivity

202

Step Bag (no.)

Bag

(mg/mL in D5W) Time

Rate

(mL/h)

Infusion

duration (min)

Monitoring

duration (min)

Volume

infused (mL) Dose (mg)

Cumulative

dose (mg)

1 1 0.02 0:00 18.0 5 10 1.50 0.03 0.03

2 1 0.02 0:15 42.0 5 10 3.50 0.07 0.10

3 2 0.20 0:30 9.0 5 10 0.75 0.15 0.25

4 2 0.20 0:45 18.0 5 10 1.50 0.30 0.55

5 2 0.20 1:00 36.0 5 10 3.00 0.60 1.15

6 2 0.20 1:15 72.0 5 10 6.00 1.20 2.35

7 3 2.00 1:30 13.8 5 10 1.20 2.30 4.65

8 3 2.00 1:45 28.2 5 10 2.30 4.70 9.35

9 3 2.00 2:00 56.4 5 10 4.70 9.40 18.75

10 3 2.00 2:15 112.5 5 10 9.40 18.75 37.50

11 3 2.00 2:30 225.0 5 10 18.80 37.50 75.00

12 3 2.00 2:45 450.0 5 10 37.50 75.00 150.00

13 3 2.00 3:00 300.0 15 10 75.00 150.00 300.00

14 3 2.00 3:25 600.0 15 30 150.00 300.00 600.00

Total time 4:10

DSW, Dextrose 5% in water.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S34 BROYLES ET AL

wheal of 3 mm surrounded by erythema of 5 mm after 15 mi-

nutes.

246

The positive SPT result suggested an IgE-mediated

mechanism, although in vitro measurement of PZA-speciﬁc IgE

in the circulation was not conducted.

In cases of vital indication of this drug, when no alternative

treatment is available, drug desensitization is an option

(Table XXV).

225

Isoniazid. INH is a bactericidal antibiotic against M tubercu-

losis. It acts by inhibiting mycolic acid biosynthesis. INH also

disrupts DNA, lipid, carbohydrate, and nicotinamide adenine

dinucleotide synthesis, and/or metabolism. The incidence of

adverse reactions to INH in more than 2000 patients has been

estimated to be 5.4%.

225,247

Although the incidence of adverse reactions to INH is low, the

best described are hepatic, neurologic, skin reactions, and fe-

ver.

248-253

Skin eruptions are rare, mild, and often transient, and

usually consist of morbilliform and maculopapular rashes, urti-

caria, and pruritus.

254-256

Cutaneous reactions in patients

receiving therapy are often difﬁcult to diagnose because several

drugs are frequently taken simultaneously. The liver is the most

commonly affected organ and up to 20% of patients experience

mild liver injury, which is usually subclinical and self-limited.

257

A less common form of reaction to INH is hepatitis, a more

serious form of liver injury that can be fatal. The mechanism of

liver damage is not completely understood, though it seems

related to the direct toxicity of the drug.

The diagnosis is based on the regression of symptoms with

discontinuation of the drug and the reproducibility with rein-

troduction. The reintroduction of antibiotics separately is

necessary to identify the culprit(s). This approach to diagnosis

cannot be done in the presence of severe reactions such as

exfoliative dermatitis and hepatotoxicity. These are absolute

contraindications for challenge.

The rare cases of type I IgE-mediated allergic reaction require

study with skin testing, with injectable forms for prick and in-

tradermal tests.

258

Rodrigues Carvalho et al

259

performed skin testing in a case of

a generalized maculopapular rash, fever, and diarrhea after

treatment with several anti-TB drugs. Prick test (PT) with INH

was performed with an undiluted solution of 100 mg/mL and

IDT with a 10 mg/mL concentration.

Several protocols have been published regarding the desensi-

tization to INH based on adapted protocols from desensitization

to penicillin (Table XXVI).

239,259-261

Ethambutol. EMB is a bacteriostatic antimycobacterial drug

most commonly used in combination with other drugs in the

treatment of TB. The mechanism of action is not completely

known. There is evidence that the drug exerts its bacteriostatic

activity by inhibiting arabinosyltransferase, an enzyme that po-

lymerizes arabinose into arabinan and then arabinogalactan, a

mycobacterial cell wall constituent.

The dose of EMB is dependent on body weight, frequency of

administration, and indication. It is generally well tolerated. Side

effects are usually dose-related and more common when doses

exceed 15 mg/kg.

The main side effect of EMB is ocular toxicity due to optic

neuritis. Intermittent dosing may decrease the risk of ocular

toxicity, as conﬁrmed by Grifﬁth et al

262

in a study of 229 pa-

tients treated with EMB for pulmonary M avium complex

disease.

The combination of EMB with PZA for the treatment of

latent TB in patients exposed to multidrug-resistant strains has

been associated with a high incidence of hepatotoxicity or

gastrointestinal intolerance, leading to discontinuation of therapy

(w60% of treated subjects in 1 report).

263

Hypersensitivity reactions to EMB such as rash and drug fever

have been reported in 0.5% and 0.3% of patients, respec-

tively.

264

Other reactions, such as dermatosis-like pigmentation,

lichenoid eruptions, pulmonary inﬁltrates, and TEN, have also

been described.

265-268

In cases of severe reactions such as exfoliative dermatitis, oral

challenge tests are not recommended. Skin and serological tests

are usually unreliable, with single reports of positive patch-test

TABLE XXIV. Rifampin oral desensitization protocol*

240

Solution Volume Concentration

Solution A 10 mL 0.001 mg/mL

Solution B 10 mL 0.01 mg/mL

Solution C 30 mL 0.1 mg/mL

Solution D 10 mL 6 mg/mL

Solution E 15 mL 60 mg/mL

Step no.

Dose

(mg)

Solution

no.

Volume

(mL)

Time

(min)

Cumulative

dose (mg)

1 0.0002 A 0.2 30 0.0002

2 0.002 B 0.2 30 0.002

3 0.02 B 2 30 0.02

4 0.2 C 2 30 0.2

5 2 D 0.3 30 2.2

6 4 D 0.7 30 6.2

7 8 D 1.3 30 14.2

8 16 D 2.7 30 30.2

9 30 E 0.5 30 60.2

10 50 E 0.8 30 110.2

11 100 E 1.7 30 210.2

12 150 E 2.5 30 360.2

13 250 E 4.2 30 610.2

*Full therapeutic dose administered 12 h after initiation of step 13.

TABLE XXV. Oral desensitization protocol with PZA

259

Time (min) Dose (mg) Cumulative dose (mg) Reactions

Day 1

0 6.25 6.25

30 12.5 18.75

60 25 43.75

90 50 93.75

150 75 168.75

210 125 239.75

270 250 543.75

Day 2

0 500 500

30 1000 1500

Day 3

0 750

60 750 Total

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BROYLES ET AL S35

results and positive lymphocyte stimulation test result to

EMB.

254

Skin prick and intradermal tests can be performed according

to European Academy of Allergy and Clinical Immunology

(EAACI) guidelines.

269

Immediate and late readings of IDT

performed with sterile solutions of 1 mg/mL and 10 mg/mL are

necessary because hypersensitivity reactions are mostly nonIgE-

mediated. Immediate reading can be negative with late positive

intradermal readings.

270

The decision to desensitize should be

made in conjunction with the infectious disease specialist to

determine the beneﬁtofﬁrst-line therapy over alternatives, the

duration of treatment, and the goals of therapy.

Drug desensitization should not be attempted in cases of se-

vere skin reactions or those involving the mouth or mucous

membranes (eg, exfoliative dermatitis and SJS). Tables XXVII,

XXVIII, and XXIX summarize one institution’s protocols that

were used for several patients from the infectious disease

department who had cutaneous hypersensitivity reactions to

EMB.

Rodrigues Carvalho et al

259

described successful use of a

modiﬁed 1-day temporary induction of tolerance protocol in a

patient with reactions to several anti-TB drugs. The protocol

consisted of a 2-fold increase in drug dose every 45 minutes until

the desired total daily dose was reached.

Another protocol was used in a clinically non-IgE hypersen-

sitivity reaction to EMB in which the previously described pro-

tocol was ineffective.

The patient had facial erythema,

angioedema of the neck and upper limbs followed by a pruritic

scaling maculopapular exanthem involving the neck, trunk, and

upper and lower limbs, associated with mild dyspnea with no

hemodynamic change 2 months before ﬁnishing treatment with

EMB. Symptoms resolved after stopping the drug and reap-

peared after reintroduction. Skin tests were performed using

solutions of 1 mg/mL and 10 mg/mL prepared from diluting a

crushed 400-mg EMB tablet.

271

Immediate reading result was

negative, but a positive intradermal reaction was present at 6

hours, with resolution at 72 hours. Because of the clinical pre-

sentation, positive delayed skin testing result, and reproducibility

of the reaction on reexposure, a hypersensitivity reaction to EMB

was diagnosed. The applied protocol was designed on the basis of

the 12-step protocol by Castells et al (Table XXX), using slower

dose increments and premedication with 25 mg of hydroxyzine

and 40 mg of oral prednisone.

271,272

Streptomycin. Streptomycin is in the aminoglycoside class of

medications and can be used to treat TB in combination with

other medications. It works by blocking the ability of 30S ri-

bosomal subunits to make proteins that result in bacterial death.

Common side effects include dizziness, vomiting, numbness of

the face, fever, and rash.

159

Most ADRs due to intramuscular injection of streptomycin

are gastrointestinal problems (38.09%), followed by skin re-

actions (30.48%) and hepatotoxicity (14.28%).

158

Streptomycin is vestibulotoxic, ototoxic, and nephrotoxic.

Nephrotoxicity can potentially interfere with the diagnosis of

kidney malfunction. The most concerning side effects, as with

other aminoglycosides, are nephrotoxicity and ototoxicity.

Ototoxicity and nephrotoxicity are more likely to be found when

therapy is continued for more than 5 days and at higher doses. In

very high doses, streptomycin can also produce a curare-like ef-

fect with neuromuscular blockade that results in respiratory

TABLE XXVI. Rapid oral tolerance induction protocol to

isoniazid*

259

Time (min) Dose (mg) Cumulative dose (mg)

0 0.050 0.050

20 0.10 0.15

40 0.25 0.40

60 0.50 0.90

80 1.00 1.90

100 2.00 2.90

120 4.10 8.00

140 8.20 16.20

160 16.30 32.50

180 30.60 63.10

200 50.30 113.40

340 100 213.40

480 (8 h) 150.00 363.40 (total daily dose)

*Serial dilutions of the 50 mg/5 mL suspension were prepared using puriﬁed water.

TABLE XXVII. General protocol for oral desensitization to EMB in

adults*

Time from start (h:min) EMB 1 mg/mL

0:00 0.1

00:45 0.5

01:30 1

02:15 2

03:00 4

03:45 8

04:30 16

05:15 32

06:00 50

06:45 100

07:30 200

11:00 400

Next day, 06:30 400 thrice a day

*Serial dilutions of the 50 mg/5 mL suspension were prepared using puriﬁed water.

TABLE XXVIII. Rapid oral tolerance induction to EMB*

259

Time (min) Dose (mg) Cumulative dose (mg)

0 0.10 0.10

45 0.50 0.60

90 1.00 1.60

135 2.00 3.60

180 4.00 7.60

225 8.00 15.60

270 16.00 31.60

315 32.00 63.60

360 50.00 113.60

405 100.00 213.60

450 200.00 413.60

495 400.00 813.60

660 (11 h) 400.00 1213.60 (total daily dose)

*Serial dilutions of the 50 mg/5 mL suspension were prepared using puriﬁed water.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S36 BROYLES ET AL

paralysis. It is not recommended in patients with myasthenia

gravis.

273

In general, streptomycin has little allergenic potential, and

hypersensitivity reactions are rare. However, skin rashes, eosin-

ophilia, fever, blood dyscrasias, angioedema, exfoliative derma-

titis, stomatitis, and anaphylactic shock have been reported.

274

Sanchez-Borges et al

275

report that positive skin test results

have been observed with streptomycin. However, a cautious

approach must be taken when evaluating anaphylactic reactions

to streptomycin, because systemic reactions have been observed

after skin prick testing. The starting concentrations suggested for

SPTs range from 0.1 to 1 mg/mL, gradually reaching the con-

centration of 20 mg/mL if tolerated. If SPT results are negative,

intradermal testing can be performed and nonirritating concen-

trations of 4 mg/mL for intradermal testing have been established

for gentamicin and tobramycin. There is no evidence of positive

serum IgE to aminoglycosides. Patch tests with reading at 72 and

96 hours are recommended for the diagnosis of nonimmediate

reactions. The concentration is 1% in petrolatum for

streptomycin.

275

In patients with streptomycin hypersensitivity, avoidance of

the antibiotic is recommended. There are 2 reports of desensi-

tization to streptomycin, one describing a 3-hour protocol with

streptomycin beginning with 1 mg administered intravenously

and the other consisting of streptomycin given intramuscularly,

10 mg, on the ﬁrst day and doubled every day until it reached

800 mg, then 1.0 g, twice weekly.

276,277

Patients reached 1.0 g of

streptomycin on the ninth day.

Metronidazole (by Sara Barmettler, MD)

General.

Metronidazole is a 5-nitroimidazol compound that is

active against a wide array of anaerobes, protozoa, and micro-

aerophilic bacteria. Metronidazole is the treatment of choice for

most anaerobic infections, including mild to moderate C difﬁcile

infections.

278

The 5-nitroimidazole drugs (including metroni-

dazole or tinidazole) are the only class of drugs that provide

curative therapy for trichomoniasis and thus, given the low ef-

ﬁcacy of any drug other than the 5-nitroimidazole drugs, the

Centers for Disease Control and Prevention guidelines recom-

mend that patients with trichomoniasis who have experienced an

IgE-mediated allergy to metronidazole and/or tinidazole be

referred for desensitization rather than using an alternative class

of drugs.

279

Major symptoms. A number of nonallergic adverse effects of

metronidazole have been described, including gastrointestinal

symptoms, nervous system effects, genitourinary effects, and

disulﬁram-like reactions.

278

Hypersensitivity reactions caused by

metronidazole appear to be rare, and case reports have been

infrequently described in the literature. Several types of reactions

have been reported, including immediate reactions and

anaphylaxis, delayed reactions, ﬁxed drug eruption, serum

sicknesselike reaction, and SJS/TEN.

280-285

Diagnosis. Skin testing for metronidazole hypersensitivity has

been described.

280,286

Skin prick testing was performed at a

concentration of 125 mg/mL. Using this concentration, a patient

tested in 1 study had previously suspected anaphylaxis to

metronidazole and was positive on skin prick testing on 2

different occasions.

280

This case report also found skin prick

testing result with metronidazole to be negative in 10 control

patients.

280

In another case series, 4 patients with a history of

cutaneous pruritic exanthemas were skin tested with prick testing

at a concentration of 125 mg/mL of metronidazole followed by

IDT with metronidazole at 0.5%, 5%, and 10%, with readings

including delayed readings at 48 and 96 hours.

286

One patient

had a positive result on the metronidazole SPT and did not

undergo oral challenge. Oral challenge with doses of 250 to 500

mg provoked symptoms within 45 minutes to 1 hour in 2 pa-

tients and after 7 hours in the third. These patients were treated

with intravenous corticosteroids and antihistamines with reso-

lution. Ten control subjects who tested negative on skin prick

testing passed an oral challenge to metronidazole in that

study.

286

These results call into question the utility of skin

testing to metronidazole.

Management. In patients who require metronidazole, but for

whom there is documented positive skin testing result or a high

clinical suspicion for immediate hypersensitivity reaction, and

there are no alternative agents available or the alternative agents

are not preferred (such as for trichomoniasis, as described before),

desensitization can be performed. There are published

TABLE XXX. Protocol for intravenous metronidazole

desensitization*

289

Step Dose Metronidazole concentration (mg/mL) Volume (mL)

g 0.005 1

215

g 0.005 3

350

g 0.05 1

4 150

g 0.05 3

5 500

g 0.5 1

6 1.5 mg 0.5 3

7 5 mg 5.0 1

8 15 mg 5.0 3

9 30 mg 5.0 6

10 60 mg 5.0 12

11 125 mg 5.0 25

12 250 mg 250 mg orally Tablet

13 500 mg 500 mg orally Tablets

14 2000 mg 2000 mg orally Tablets

*Intravenous increments administered at 15- to 20-min intervals. Oral doses

given 1 h apart.

TABLE XXIX. Desensitization protocol for EMB*

271

Solution

(mg/mL) Time (min) Dose (mL) Dose (mg)

Cumulative

dose (mg)

0.01 0 1 0.01 0.01

30 2 0.02 0.03

60 4 0.04 0.07

90 8 0.08 0.15

0.1 120 1 0.1 0.25

150 2 0.2 0.45

180 4 0.4 0.85

210 8 0.8 1.65

1 240 1 1 2.65

270 10 10 12.65

10 300 10 100 112.65

330 30 300 412.65

*Serial dilutions of the 50 mg/5 mL suspension were prepared using puriﬁed water.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S37

desensitization protocols for metronidazole via oral desensitiza-

tion and intravenous desensitization.

287-289

Tables XXX and

XXXI list the protocols for intravenous and oral desensitization,

respectively. Desensitization protocols have proven to be very

effective in a case series that found that oral and intravenous

metronidazole desensitization regimens were 100% effective (15

of 15) in the management of trichomonas infection in women

with nitroimidazole hypersensitivity.

290

Patch-test data suggest some cross-reactivity between metro-

nidazole and other imidazoles such as clotrimazole, ketoconazole,

miconazole, and albendazole.

291-293

Therefore, in patients with a

proven hypersensitivity reaction to metronidazole, avoiding

theses agents is recommended if possible.

Antimalarials (by Sara Barmettler, MD)

General.

Antimalarial drugs are used for the treatment and

prophylaxis of malarial infection. Most antimalarial drugs target

the erythrocytic stage of malaria infection, which is the phase of

infection that causes symptomatic illness. There are several

classes of antimalarial drugs including quinoline derivatives,

antifolates, antimicrobials, and artemisinin derivatives. The an-

timicrobials used in malaria treatment and prophylaxis will not

be described in this section.

Major symptoms. Quinoline derivatives include chloro-

quine, quinine, meﬂoquine, and primaquine. Chloroquine was

one of the ﬁrst antimalarials produced on a large scale; however,

there is increasing resistance to chloroquine in many malaria-

endemic countries. Commonly described side effects of chloro-

quine include headaches, dizziness, abdominal discomfort,

vomiting, and diarrhea.

294

Chloroquine-induced pruritus has

been described, most frequently in African populations, is tran-

sient (lasting 48-72 hours), and is not responsive to antihista-

mines.

295

Chloroquine has also been described to cause TEN,

and other reactions including ﬁxed drug eruption, bullous

pemphigoid, exfoliative dermatitis, and exacerbation of

psoriasis.

296,297

Oral quinine is associated with cinchonism, which includes a

number of unpleasant adverse effects including nausea, headache,

tinnitus, dysphoria, and blurred vision.

297

Pruritus, skin ﬂush-

ing, and urticaria are associated with quinine hypersensitivity.

Other cutaneous manifestations such as photosensitivity, cuta-

neous vasculitis, and lichenoid photosensitivity after quinine

have been described in case reports.

297

Meﬂoquine has been associated with a number of adverse

effects including skin reactions such as pruritus (frequency of

4%-10%) and maculopapular rash (frequency of 30%).

298

As-

sociations have also been drawn between meﬂoquine and urti-

caria, facial lesions, cutaneous vasculitis, SJS, and TEN.

298

Meﬂoquine is known to cause serious neuropsychiatric toxicity,

including seizures, encephalopathy, and psychosis, which occur

in 0.1% to 5% of patients treated for malaria.

299

Other adverse

effects include vomiting and dizziness.

297

Primaquine is the only 8-aminoquinoline in clinical use and is

generally well tolerated. It can cause hemolytic anemia in patients

with glucose-6-phosphate dehydrogenase deﬁciency, leukocytosis

and leukopenia, and gastrointestinal upset.

297

Antifolates include sulfonamides (including dapsone), pyri-

methamine, and proguanil. Atovaquone/proguanil is an anti-

malarial combination with good efﬁcacy and tolerability when

used for prophylaxis and treatment. The most common side

effects included headache, gastrointestinal symptoms of abdom-

inal pain, anorexia, nausea, vomiting, diarrhea, and cough.

300,301

Atovaquone has been associated with SJS as well as acute

eosinophilic pneumonia and maculopapular rash.

302,303

One

case of anaphylaxis was described during clinical trials.

304

The

combination of chloroquine and proguanil has also been

described to cause AGEP and cutaneous vasculitis.

305,306

A rare

but serious adverse effect is drug-induced hypersensitivity syn-

drome or DRESS. Up to 3.6% of dapsone recipients develop this

syndrome, and as many as 13% of these die as a result.

307

The artemisinin derivatives have excellent efﬁcacy and safety,

with very few attributable adverse effects.

308

One study reported

an incidence of type I hypersensitivity reactions including urti-

caria and anaphylaxis at 0.03%.

309

Diagnosis. There are rare case reports in which skin testing

was used to evaluate for a type I hypersensitivity reaction to

antimalarial agents. Unfortunately, there is no standardized

nonirritating concentration of these drugs that both uses negative

controls to establish nonirritating concentrations and identiﬁes a

positive case-control with a suggestive history. Speciﬁcally, skin

prick testing has been described for atovaquone-proguanil, but

the concentration used was not published and there was no

mention of negative controls tested.

310

Similarly, in another case

report, result of epicutaneous testing performed with chloro-

quine, proguanil, and me ﬂ oquine was negative, but again, there

was no mention of the concentration used or whether there were

negative controls. Patch testing for several antimalarial drugs

(including malarone, proguanil, atovaquone, quinine, chloro-

quine, and meﬂoquine) has been described, with the drugs

diluted at 30% in a petrolatum base.

303

Management. In most literature describing hypersensitivity

reactions, management includes cessation of the suspected culprit

drug and selection of an alternate therapy. Given the large

number of different classes of medications available for the

treatment and prophylaxis of malaria, the selection of an alter-

native agent with equal efﬁcacy generally has not provided an

unsurmountable challenge, and thus there is a lack of speciﬁc oral

challenge protocols or desensitization protocols available for

antimalarial agents.

Antiparasitics (by Sara Barmettler, MD)

General.

Antiparasitics are a class of medications used to treat

diseases caused by nematodes, cestodes, trematodes, amoeba, and

protozoa. The main type of antiparasitic drug is the anti-

helminthic group, which includes the antinematodes and

TABLE XXXI. Protocol for oral metronidazole desensitization*

288

Step Dose (mg)

Metronidazole

concentration (mg/mL) Volume (mL)

Cumulative

dose (mg)

1 0.0025 0.025 0.1 0.0025

2 0.025 0.025 1 0.0275

3 0.25 0.25 1 0.2775

4 2.5 2.5 1 2.7775

5 25 2.5 10 27.78

6 250 250 mg Tablet 277.8

7 750 750 mg Tablets 1027.8

8 1000 1000 mg Tablets 2027.8

*Doses given over the course of 1 d.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S38 BROYLES ET AL

anticestodes. Within the antiparasitics, a number of adverse ef-

fects are associated with each drug, but case reports of hyper-

sensitivity reactions are infrequent.

Major symptoms. Ivermectin is a semisynthetic derivative of

avermectin and is useful in the treatment of a number of parasitic

infections, including onchocerciasis, strongyloidiasis, ascariasis,

trichuriasis, enterobiasis, scabies, head lice, and ﬁlarial

worms.

311,312

Adverse effects include gastrointestinal upset,

abdominal pain, fatigue, urticarial or maculopapular rashes,

pruritus, and rarely, hepatotoxicity or neurologic side effects, and

it has been implicated in a mucosal drug eruption with hemor-

rhagic scabs/erosions.

311,313-315

Ivermectin has also been

described to cause a Mazzotti-type reaction (pruritus and aden-

opathy due to dying microﬁlaria) after the treatment of

onchocerciasis.

311

The benzimidazole class of antiparasitics includes albendazole,

mebendazole, thiabendazole, and triclabendazole. Side effects of

albendazole include abdominal pain, nausea, vomiting, and

diarrhea, as well as rare side effects of transient transaminitis,

agranulocytosis, and urticarial or other dermatologic manifesta-

tions.

316,317

Contact urticaria and contact dermatitis have been

described in association with albendazole.

318

Albendazole has

also been reported to cause ﬁxed drug reaction.

319

The side-effect

proﬁle of mebendazole is similar to that of albendazole and in-

cludes gastrointestinal symptoms such as mild abdominal pain

and diarrhea, as well as urticaria, pruritus, and edema.

320

serious cutaneous manifestations have been reported with the

combination of mebendazole and metronidazole, which was

associated with an outbreak of SJS/TEN.

321

A number of adverse

reactions have been described with the use of thiabendazole,

including dizziness, nausea, vomiting, drowsiness, pruritus,

headache, neuropsychiatric disturbances, hepatitis, and hyper-

sensitivity reactions such as SJS.

320,322

Praziquantel has activity against cestodes and trematodes

including parasites such as schistosomiasis, intestinal tapeworms,

cysticercosis, and other ﬂukes. Side effects include headache,

dizziness, drowsiness, nausea, and abdominal discomfort, and less

commonly, itching/rash.

323

Although rare, hypersensitivity re-

actions to praziquantel have been described.

324-327

Interestingly,

mouse model data have suggested that anaphylactic reactions

may be induced by parasite antigen release rather than true hy-

persensitivity reactions to the praziquantel.

328

Diethylcarbamazine is a piperazine derivative with activity

against lymphatic ﬁlariasis, loiasis, and visceral larva migrans.

Side effects include fever, headache, dizziness, gastrointestinal

symptoms of abdominal pain and nausea, and urticaria/pruri-

tus.

320

Administration of diethylcarbamazine in the setting of

onchocerciasis is associated with a risk of precipitating the

Mazzotti reaction (which includes symptoms of fever, urticaria,

tender lymphadenopathy, tachycardia, arthralgias, edema,

abdominal pain, and hypotension, and correlates with infection

intensity).

329

Antiprotozoals include eﬂornithine, melarsoprol, tinidazole,

and metronidazole. Eﬂornithine is effective in the early and late

central nervous system stage of infections with Trypanosoma

brucei gambiense but not Trypanosoma brucei rhodesiense.

Frequent side effects include diarrhea, anemia, leukopenia, and

hair loss.

330

Melarsoprol is used to treat late-stage African

trypanosomiasis. Use of melarsoprol is limited by its toxicity,

which occurs commonly and includes severe adverse effects such

as encephalopathy, polyneuropathy, exfoliative dermatitis,

myocarditis, and hypersensitivity reactions such as bullous re-

actions.

330,331

Please see separate section on metronidazole for a

detailed description of hypersensitivity reactions associated with

the use of this drug. Antimalarials are also discussed in detail in a

separate section.

Diagnosis. A few case reports describe the use of skin testing

in the evaluation for a type I hypersensitivity reaction to anti-

parasitic agents. Skin prick testing and intradermal testing have

been described for mebendazole and albendazole.

332

However,

despite negative skin prick testing and intradermal testing results

for mebendazole and albendazole, the patient in that case

developed hives on oral challenge with both medications, thus

suggesting a poor predictive value of this skin test.

332

Skin prick

testing and intradermal testing have been described for prazi-

quantel, and results for both were positive in the patient tested;

however, that report did not mention the concentrations used or

whether negative controls were used to establish nonirritating

concentrations of the drug.

325

Patch testing for albendazole has

been described, with 4 of 9 patients tested having positive results,

though notably the patient with a clinical history of contact

dermatitis did not test positive.

318

Management. Management of hypersensitivity reactions in

most cases reported involved cessation of the suspected culprit

drug and selection of alternate therapy. Rarely, case reports have

described desensitization to the antiparasitic agent. Desensitiza-

tion has been described for praziquantel.

324,325

In 1 case, oral

desensitization to praziquantel was attempted using a modiﬁed

desensitization protocol with increasing doses of 30, 60, 100,

150, 300, 600, and 1200 mg administered 90 minutes apart.

The patient described in this case did develop symptoms

requiring hydrocortisone, antihistamine, and an H

-blocker

treatment during the desensitization, but was able to tolerate

therapeutic doses of praziquantel given for 3 days subse-

quently.

325

In another case, desensitization was attempted using

13 doses of praziquantel at 15-minute intervals (ﬁrst 6 doses were

18 mg each, the next 3 were 180 mg each, and the ﬁnal 3 were

360 mg each). In this case, the patient developed generalized

urticaria, difﬁculty swallowing, and chest tightness within 1 hour

of his last dose. He was able to receive praziquantel on subse-

quent days without symptoms but was also given concomitant

corticosteroids, so it was unclear whether true desensitization was

achieved.

324

Oral challenge has been reported in the case of ﬁxed

drug eruption secondary to albendazole, with cross-reactivity

reported with metronidazole.

319

Antifungals (by Stephanie Logsdon, MD)

General.

Antifungal medications including the azoles have

been used in treatment and prophylaxis for various fungal in-

fections for decades, while newer antifungal medications,

including the echinocandin class, have gained increasingly

widespread use in the treatment of pediatric and adult fungal

infections. The azole drug class is composed of triazoles

(including ﬂuconazole, itraconazole, voriconazole, posaconazole,

and isavuconazole) and imidazoles (including clotrimazole, ke-

toconazole, and miconazole). These drugs disrupt the fungal cell

membrane through impairment of ergosterol synthesis.

333

Each

drug in the azole class has distinctive indications for use, ranging

from mucosal candidiasis to invasive mycoses. These drugs are

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S39

critical for managing the increasing frequency of fungal infections

in all age groups, while offering a cost-effective option for pro-

phylaxis in immunosuppressed patients.

334

Azoles are available in

oral, intravenous, and topical formulations. Ketoconazole and

miconazole are associated with increased rates of toxicity with

administration, while newer triazoles have improved safety pro-

ﬁles and reduced drug-drug interactions, and are generally well

tolerated in adult and pediatric patients. All azoles exhibit inhi-

bition of the CYP450 enzymes.

333

The echinocandin drug class includes micafungin and caspo-

fungin, both of which inhibit

-(1,3)-D-glucan synthase. The

frequency of invasive fungal infections is increasing in all age

groups, thus escalating the need for effective therapies such as the

echinocandins.

335

These medications have fewer adverse events

and drug-drug interactions, and improved safety proﬁles over

other antifungal agents. This is important because many patients

who receive micafungin or caspofungin have other serious un-

derlying medical illnesses. Both medications are administered

intravenously, because their large molecular weight precludes

acceptable gastrointestinal absorption. Importantly, neither agent

appreciably affects the SMZ-TMP system, thus reducing the

amount of drug-drug interactions.

Major symptoms of hypersensitivity. Hypersensitivity

reactions have been reported for both azoles and echinocandins.

The most common ADRs to the azole drug class include hepa-

totoxicity, skin exanthems, and gastrointestinal symptoms. In

addition, each individual azole carries a distinctive side-effect

proﬁle.

333,334

Multiple case reports describe TEN, ﬁxed drug

eruptions, and other hypersensitivity reactions including

anaphylaxis to ﬂuconazole, voriconazole, and itraconazole.

336-339

Hypersensitivity to imidazoles, posaconazole, and isavuconazole

is not well described. Common ADRs to the echinocandin drug

class include transaminitis, electrolyte imbalances, fever, and skin

exanthems.

340,341

There are single case reports describing the

development of secondary TEN and hypersensitivity to caspo-

fungin use in adult patients.

342,343

Beyond case reports, hyper-

sensitivity to micafungin and caspofungin is not well described in

the literature.

Diagnosis. Although skin prick testing for azoles is not vali-

dated, case reports have described protocols. Skin testing was

performed in an adult patient with a history of anaphylaxis to

voriconazole and 2 control patients. In this case report, testing

comprised prick testing with 0.5 mg/mL and 0.05 mg/mL vor-

iconazole with negative saline control. The patient had a positive

result with the 0.5-mg/mL dilution, whereas both control pa-

tients had negative results to this dilution.

339

Skin testing to

ﬂuconazole has also been described in case reports. An adult

patient who developed cutaneous and respiratory symptoms

during treatment with ﬂuconazole underwent intradermal skin

testing with 0.2 mg/mL of the drug. Her skin test result was

positive, whereas the skin test result was negative in a nonallergic

control patient.

344

No further skin testing protocols are obtain-

able. Therefore, skin testing may be helpful for the diagnosis of

hypersensitivity to azoles, but further investigation into ideal

concentrations is needed.

Skin prick testing for the echinocandins is not well validated as

well. Only 1 published description of skin testing to caspofungin

was found during a literature review. Skin testing was completed

on an adult patient with history of anaphylaxis to micafungin.

This test included 1 intradermal injection of 0.05 mg caspo-

fungin with a normal saline negative control.

343

No further skin

testing protocols are available. Therefore, obtaining a complete

clinical history remains critical in the diagnosis of echinocandin

hypersensitivity because appropriate skin testing concentrations

remain unclear.

Management. Drug desensitization protocols have been

published for oral ﬂuconazole, oral itraconazole, and intravenous

voriconazole.

336,339

There is extensive variability in the protocols

used for ﬂuconazole desensitization, with protocol durations

ranging from hours to days (Table XXXII).

337,338,344

For IgE-

mediated allergy, preference should be given to desensitizations

that occur over hours, rather than a prolonged protocol. No

intravenous desensitization protocols for ﬂuconazole are pub-

lished. Each protocol was completed without signiﬁcant systemic

reactions, indicating that desensitization to azoles may be safely

completed. Continued inquiry into the management of hyper-

sensitivity to azole antifungals is necessary, because these medi-

cations continue to be critically required.

Micafungin and caspofungin are becoming critical therapeutic

agents for patients with disseminated or virulent fungal in-

fections, and thus these medications will likely be required in the

future for use in patients who have hypersensitivity reactions to

these medications. Drug desensitization may be an important

tool for these patients. A recently published desensitization

regimen used a standard 12-step protocol that has been suc-

cessfully used with antibiotics such as penicillin

(Table XXXIII).

345

The entire protocol was completed without

reaction, and the patient completed the remainder of her ther-

apeutic course uneventfully. This indicates that rapid de-

sensitizations can be successfully completed in a safe and effective

manner. Strict adherence to the dosing schedule is required to

safely maintain the desensitized state. Further investigation into

these medications will help physicians evaluate and manage

echinocandin hypersensitivities.

Antivirals (by Tito Rodriguez, MD, and Elizabeth

Phillips, MD)

Antiretrovirals

General.

More than 30 antiretroviral (ART) drugs are

currently available in the United States for the treatment of HIV-

1, and these include 6 FDA-approved single-tablet regimens of 3

or more drugs as of March 2016. Six different categories of ART

drugs (nucleoside reverse transcriptase inhibitors, nonnucleoside/

tide reverse transcriptase inhibitors, protease inhibitors [PIs],

entry inhibitors [including fusion inhibitors and CCR5 in-

hibitors], and integrase inhibitors) can be used in combinations

of 3 or more drugs. Current treatment recommendations are to

initiate combination ART drugs in all patients with HIV.

346-348

Nearly all ART drugs have been implicated in hypersensitivity

reactions, usually presenting as delayed onset and ranging from

the usual mild exanthem to less common life-threatening SJS/

TEN or DRESS (Table XXXIV) reactions, with type I hyper-

sensitivity reactions rarely seen.

349

These reactions can be

confused by the presence of underlying opportunistic infections,

immune restoration disease, or the fact that HIV-infected pa-

tients may take other drugs for prophylaxis of opportunistic in-

fections that can also cause the full spectrum of clinically

indistinguishable hypersensitivity reactions (eg, sulfamethoxa-

zole/trimethoprim).

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S40 BROYLES ET AL

Based on current evidence-based me dicine, there should be

no restrictions on who gets ART drugs and this should be

considered in all patients after individual discussion and con-

siderations pre senting with HIV-1 regardless of CD4

T-cell

count, viral load, or AIDS-deﬁni ng i llness history. From ol der

data, hypersensitivity reactions have been described as occurring

100timesmorecommonlyinHIV-infectedpatientsthaninthe

general population, but data from contemporary HIV pop-

ulations are lacking.

349

In general, diagnosis of hypersensitivity

reactions related to HIV therapy is made on the basis of clin ical

presentation, temporal relationship with drug exposure (typi-

cally 1-6 weeks), and e xclusio n of other etiologies.

346

Patients

presenting with mild rash alone without fever or organ

involvement can develop tolerance with continued dosing and

uninterrupted treatment is recomm ended (e g, efavirenz and

PIs).

349,350

Major symptoms and management. Abacavir, a nucle-

oside reverse transcriptase inhibitor, is a common cause of severe

hypersensitivity reactions, occurring in 2.3% to 9% of patients

exposed to the drug.

349

The clinical syndrome of abacavir hy-

persensitivity includes fever, constitutional symptoms, and

gastrointestinal disturbance. Rash is later in onset, and may be

absent in up to 30% of patients.

349

These reactions have been

associated with the presence of the MHC class I allele HLA-

B*5701.

349,351-353

In clinical trials, HLA testing has shown

100% sensitivity of HLA-B*5701 for skin patch-testeconﬁrmed

abacavir hypersensitivity reactions as well as 100% negative

predictive value; genetic screening for HLA-B*5701 has been

part of guideline-based therapy before abacavir prescription since

2008.

349,351-353

A history of abacavir hypersensitivity reactions is

an absolute contraindication to rechallenge, because subsequent

reactions are often more rapid and severe than the initial reac-

tion.

349,351-353

Particularly with the advent of HLA-B*5701 screening,

contemporary single-tablet regimens used as ﬁrst-line ART

therapy in clinical practice in the United States are associated

with a very low risk of hypersensitivity reactions.

Abacavir hypersensitivity is unique compared with other drug

hypersensitivity syndromes in that fever and malaise can develop

within the ﬁrst few days of initial dosing and with relatively late

and inconsistent (70%) appearance of rash. The clinical symp-

toms, signs, and pharmacogenomics of other drug hypersensi-

tivity syndromes are outlined in Table XXXIV.

349

Currently,

abacavir is the only ART drug with an associated hypersensitivity

for which a guideline-approved pharmacogenomic pretreatment

and preventive screening strategy exists.

349

HLA-B*5701 testing

before prescription of abacavir has become consistent practice in

the developed world but is still not widely used in regions where

either abacavir is not widely used (eg, Africa) or where the allele

frequency of HLA-B*5701 is less than 1% (South and Southeast

Asia, excluding Northern Thailand) and India where HLA-

B*5701 carriage rate is as high as 10%.

353

Immediate reactions have been rarely reported, and there are

no standardized protocols for skin prick and intradermal

testing.

354

Antiehepatitis C drugs. Hepatitis C virus (HCV) affects

more than 170 million people globally. Traditional HCV

treatment, which i ncluded pegylated IFN and ribavi rin, had a

low efﬁcacy (45%) and has now been largely replaced by the

direct-acting agents. In all HCV treatment regimens, the rates

of rash were high, noted in up to 20% to 30% of cases.

349

Early direct-acting agents, such as the HCV NS3.4A serine PI

telaprevir developed for genotype 1 HCV infection, in com-

bination with ribavirin and IFN, have now largely been

replaced with newer direct-acting agents. Telaprevir-associated

rash was described in 50% or more of those initiating therapy,

with more than 90% of these being mild to moderate

eczematous rashes that were controlled symptomatically with

antihistamines or topical corticosteroids and resulted in

TABLE XXXII. Fluconazole oral desensitization protocol*

344

Fluconazole 200 mg PO q24h

Full dose 197.76 mg

Step Concentration

Volume

administered (mL)

Dose

administered (mg)

Cumulative

dose (mg)

1 0.02 1.00 0.02 0.02

2 0.02 2.00 0.04 0.06

3 0.02 4.00 0.08 0.14

4 0.2 0.80 0.16 0.30

5 0.2 1.60 0.32 0.62

6 0.2 3.20 0.64 1.26

7 2 0.75 1.50 2.76

8 2 1.50 3.00 5.76

9 2 3.00 6.00 11.76

10 20 0.60 12.00 23.76

11 20 1.20 24.00 47.76

12 20 2.50 50.00 97.76

13 20 5.00 100.00 197.76

PO, Per os (by mouth); q24h, every 24 h.

*Fifteen-minute intervals are given between doses. The ﬁrst full dose is administered

24 h after completion of step 13.

TABLE XXXIII. Micafungin intravenous desensitization

protocol*

345

Micafungin 150 mg IV q24h

Total to be injected

in each bottle (mg)

Full dose 150 mg

Solution 1 250 mL of 0.006 mg/mL 1.5

Solution 2 250 mL of 0.06 mg/mL 15

Solution 3 250 mL of 0.595 mg/mL 148.82

Step Solution

Rate

(mL/h)

Time

(min)

Administered

dose (mg)

Cumulative

dose (mg)

1 1 2 15 0.003 0.003

2 1 5 15 0.0075 0.0105

3 1 10 15 0.015 0.0255

4 1 20 15 0.03 0.0555

5 2 5 15 0.075 0.1305

6 2 10 15 0.15 0.2805

7 2 20 15 0.3 0.5805

8 2 40 15 0.6 1.1805

9 3 10 15 1.4882 2.6687

10 3 20 15 2.9764 5.6451

11 3 40 15 5.9528 11.5979

12 3 75 186 138.4021 150

Total time 351 min

*The ﬁrst full dose is administered 24 h after initiation of step 12.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S41

discontinuation in less than 10%. One study showed that in

patients presenting with more than 50% body surface

without DRESS/SJS/TEN, continuation with close mo ni-

toring was a safe alternative.

355

Less common reactions

includedDRESSin5%andSJS/TENinlessthan1%.

Newer direct-acting agents have infrequently been associated

with skin rash. Simeprevir is a second-generation NS3/4A

HCV PI that has been primarily associated with photosen-

sitivity in up to 5% of patients,whichmaybedose-related.

Simeprevir is codosed with sofosbuvir, which was not

associated with phototoxicity in earlier trials when dosed

without simeprevir. There have been no reports of photo-

patch testing that would accurately and reliably differentiate

between phototoxicity and photosensitivity. Reports in the

literature have been mixed, wit h early reports suggesting an

allergic and a lichenoid pattern on histology favoring

phototoxicity.

356,357

Diagnosis of anti-HCV drug hyperse n-

sitivity is based on clinical assessment of the syndrome.

TABLE XXXIV. Clinical manifestations, incidence, and pharmacogenomics of antiviral hypersensitivity syndromes

349

Class Agent Reaction Incidence Treatment limiting HLA association (population)

ART treatments

349

PIs Atazanavir Rash 6% <1% None known

Darunavir Rash 10% <1% None known

SJS/TEN/DRESS <1% 100% None known

Fosamprenavir Rash—moderate to

severe

19% <1% None known

Lopinavir/

ritonavir

Rash 2% <1% None known

Tipranavir Rash 10% <1% None known

NNRTIs Efavirenz Rash 4.6%-20% <2% HLA-DRB1*01 (French)

SJS/TEN/DRESS 0.1% 100% Not known

Etravirine Rash 10% <2% Not known

DRESS/SJS/TEN <0.1% 100% Not known

Nevirapine Rash 4%-38% 6% HLA-B*35:05 (Thai)

HLA-C*04 (African, Asian,

European, Thai)

HLA-DRB1*01 (French)

B*35:05, rs1576*G CCHR1 (Thai)

DRESS Up to 5%;

0.3%-1%

100% HLA-B*14/C*08 (Sardinian/Japanese)

HLA-B*35/C*04 (SE Asian)

HLA-C*04 þ CYP2B6 516 G-/ T

(European/Asian/African)

CYP2B6 (rs2054675, rs3786547,

rs3745274)

HLA-B*35:05/01 (Thai/European)

SJS/TEN 100% CYP2B6 G-/T

HLA-C*04:01 (African/Malawian)

CYP2B6 983 T/C(Mozambique)

Hepatitis <5% HLA-DRB1*01:01 (European)

HLA-DRB1*02:01 (South African)

HLA-B*58:01 (South African)

Rilpivirine Rash 2% <1% None known

Fusion

inhibitors

Enfuvirtide Hypersensitivity

reaction

<1% Mostly for

subcutaneous

reactions not

HSR

None known

NRTIs Tenofovir Rash 5%-7% <1%

None known

Abacavir HSR (fever, GI

symptoms, rash

in 70%)

5%-8% 100%, hypotension,

severe morbidity

on rechallenge

HLA-B*57:01 (European/black)

(100% negative predictive value,

55% positive predictive value)

Rash only 3% <1% Not known

Emtricitabine Pruritus, rash 17%-30% <1% Not known

Integrase

inhibitors

Raltegravir Pruritus, diaphoresis,

rash

2%-7% <1% Not known

DRESS/SJS/TEN <1% 100% HLA-B*53:01 (African ancestry)

933

CCR5

inhibitors

Maraviroc Pruritus 3.8% <1% Not known

GI, Gastrointestinal; HSR, hypersensitivity reaction; NRTI, nucleoside reverse transcriptase inhibitor.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S42 BROYLES ET AL

Other antiviral drugs. Commercially available antivirals for

herpes virus—acyclovir, valacyclovir, famciclovir, and penciclo-

vir—have close chemical structures, and the alternative antiviral

drugs available—foscarnet and cidofovir—present with relevant

side effects. Hypersensitivity reactions to herpes virus antivirals

are infrequent, usually consisting of contact allergy or delayed

systemic reactions most frequently described for acyclovir.

Immediate reactions have been described, but skin testing is

not well standardized and it has been described only in case re-

ports with none or low number of controls.

358

Patch testing has

been shown to be useful in case reports at 10% or higher con-

centration, but there are no data on its sensitivity and predictive

values.

359

Other than abacavir there are no data on the diagnostic

utility of patch testing for other antivirals. Cross-reactivity among

structurally related acyclovir, valaciclovir, and famciclovir is

partial, with approximately 50% of patients tolerating famci-

clovir after reaction to valacyclovir or acyclovir; therefore, chal-

lenge with a suitable alternative after a negative patch-test result

must be considered before desensitization.

360

Hypersensitivity reactions to inﬂuenza antivirals are limited to

individual case reports that do not include details on cross-re-

activities or skin testing standardization. Anaphylaxis and delayed

reactions have been reported to oseltamivir.

361

Desensitization. Desensitization protocols to ART drugs

have been described for patients with severe delayed reactions

limited to the skin where the speciﬁc antiviral agent was the only

possible treatment for that patient (Table XXXV).

362,363

Although failures have been reported in several case reports with

rapid desensitization protocols to enfuvirtide, it remains the

preferred method due to the unknown risk of resistance with

slow desensitization protocols.

362

If the rapid protocol fails, a

published 2- to 3-day slow desensitization protocol can be

used.

364

Because the mechanism underlying delayed antiviral

hypersensitivity to most antivirals remains unclear, such slow

protocols should be used with caution and only when no alter-

native therapeutic option is possible. Desensitization is contra-

indicated in patients who have experienced severe, life-

threatening immunocytotoxic reactions, vasculitis, or bullous

skin diseases such as SJS/TEN and DHS/DRESS and for aba-

cavir in HLA-B*5701epositive patients.

270

The role of skin testing or desensitization for HCV antivirals

has not been determined, but 2 case reports have described slow

desensitization protocols for ribavirin.

365

Desensitization has

been described in immediate reactions conﬁrmed by challenge

and in some unclear delayed reactions for herpes simplex virus

antivirals. No desensitization protocol to inﬂuenza antiviral

treatment has been described.

CHEMOTHERAPEUTIC AGENTS

Carboplatin (by Sarita Patil, MD)

General.

In oncology patients, repeated administration of

platinum-based chemotherapeutic agents can result in the

development of hypersensitivity.

366,367

In particular, the inci-

dence of hypersensitivity reactions increases from 1% after the

ﬁrst dose of carboplatin to 27% after 7 doses.

366

The peak rate of

hypersensitivity reactions occurs with the eighth or ninth dose,

which often corresponds with the second or third cycle after

restarting treatment for malignancy recurrence.

368

Drug

desensitization has been found to effectively deliver carboplatin

to patients with hypersensitivity.

272

Major symptoms of hypersensitivity. Hypersensitivity

reactions to carboplatin can range from mild cutaneous symp-

toms (ﬂushing, pruritus, urticaria) to systemic anaphylaxis,

deﬁned as involving more than 2 organ systems, often with

cutaneous, gastrointestinal, respiratory, and cardiac symptoms.

Up to 50% of reactions include moderately severe reactions.

272

These reported hypersensitivity reactions do not include SJS,

TEN, erythema multiforme, or serum sickness.

Diagnosis. In addition to a clinical history of reactions

consistent with hypersensitivity, skin testing can aid in the

diagnosis of carboplatin hypersensitivity. Standard carboplatin

skin testing protocols use step-wise skin prick testing (10 mg/

mL) and 3-step intradermal testing (0.1, 1, and either 3 or 5 mg/

mL) with 0.02 mL, in addition to a positive control (0.1 mg/mL

histamine base) and a negative control (saline). Higher intra-

dermal skin testing concentrations (10 mg/mL) cause irritation

and carry a risk of skin necrosis.

368

A positive skin test result can

be deﬁned as a wheal-and-ﬂare reaction, with the wheal’s greatest

diameter being at least 3 mm larger than that seen with saline.

369

Because of potential for false-negative skin testing results in

certain patients, particularly in those with a recent history of

anaphylaxis (within 4-6 weeks of skin testing), repeat skin testing

is recommended for patients whose clinical history is consistent

with a hypersensitivity reaction and who have a negative initial

skin test result on evaluation. These patients’ condition can be

managed with desensitization while they are awaiting repeat skin

testing.

369,370

Management. In patients with carboplatin hypersensitivity,

desensitization with a 12-step protocol (Table XXXVI)ina

monitored setting (in an inpatient setting supervised by an al-

lergy specialist) has been effective in delivering adequate

chemotherapeutic doses to patients requiring therapy. A 13-step

protocol similar to the 12-step protocol, with an additional 60

mL/h step between steps 11 and 12, can also be used.

TABLE XXXV. Rapid subcutaneous (A) enfuvirtide desensitiza-

tion protocol and (B) oral darunavir desensitization protocol

A* B†

Dose Enfuvirtide Dose Darunavir

1 6.25

g125

2 62.5

g 2 250

3 0.125 mg 3 500

4 0.25 mg 4 1 mg

5 0.5 mg 5 2 mg

6 1 mg 6 5 mg

7 2 mg 7 10 mg

8 5.65 mg 8 25 mg

9 11.25 mg 9 50 mg

10 22.5 mg 10 100 mg

11 45 mg 11 200 mg

12 90 mg 12 300 mg

1-h interval between doses 30-min interval between doses

*Adapted from DeSimone et al.

362

†Adapted from Marcos Bravo et al.

363

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S43

Patients undergoing evaluation with repeat skin testing,

because of a history of hypersensitivity reactions but with a

negative initial skin test result, have also been able to safely

receive their chemotherapeutic dose using a modiﬁed 8-step

desensitization protocol (Table XXXVII). Antihistamine pre-

medication is recommended before the use of these desensitiza-

tion protocols.

368,369

Low-risk patients who have a history of nonpruritic, non-

blistering delayed rash or those who have a negative skin test

result between 6 weeks and 6 months after their initial hyper-

sensitivity reactions and who are therefore at a lower risk of

having a falsely negative skin test result may be candidates to

receive carboplatin by infusion at 50% of the standard infusion

rate in an outpatient infusion center setting.

370

For premedication, patients are advised to use 20 mg of oral

cetirizine on the evening before desensitization, the morning of

desensitization, and immediately before initiation of desensi-

tization, but no data are available on optimal premedication

regimens. In addition, before the start of the desensitization

protocol, patients with initial skin symptoms such as pruritus

or urticaria can be given o ral or intravenous diphenhydramine

25 mg and oral ranitidine 150 mg (intravenous ra nitidin e 50

mg or famotidine can be substituted). Patients with mild

cutane ous symptoms (ﬂushing, erythe ma) as part of their hy-

persensitivity reactions may also beneﬁtfrompremedication

with oral aspirin 325 mg on the night before t hei r desensiti-

zation and again 1 hour before their desensitization protocol

begins.

During desensitization, hypersensitivity reactions are treated

with cessation of the protocol and administration of intravenous

diphenhydramine 50 mg for mild reactions. More severe or

recurrent reactions are treated with intravenous methylprednis-

olone 60 mg, and systemic anaphylaxis should be treated with

intramuscular epinephrine 0.3 mg. Once hypersensitivity reac-

tion symptoms resolve, the desensitization can be resumed at a

previous step and completed.

Oxaliplatin (by David Hong, MD)

General.

Oxaliplatin is a third-generation platinum-based

chemotherapeutic agent most commonly used to treat metastatic

colon cancer in combination with leucovorin and ﬂuorouracil

(FOLFOX regimen). As with cisplatin and carboplatin, the risk

of developing type I hypersensitivity reactions increases with

successive exposures. Most patients develop reactions after the

sixth treatment cycle, with the incidence being as high as 20%,

comparable to that of carboplatin (incidence 27% after the sixth

dose).

272

Major symptoms of hypersensitivity. Symptoms of

oxaliplatin hypersensitivity are typical of a mast cellemediated

process; common symptoms include ﬂushing, pruritus, urti-

caria, and back pain. Cardiovascular and respiratory anaphylaxis

is less common but has greater life-threatening potential. Less

commonly, reactions featuring fever and chills/rigors with or

without hypotension, nausea, and diarrhea have been described

in case reports. IL-6 and TNF-

levels are often elevated acutely,

and these reactions have been described as “idiosyncratic” or

“cytokine stormelike.”

Diagnosis. Oxaliplatin hypersensitivity appears to be pre-

dominantly IgE-mediated because skin testing using skin prick

and intradermal testing appears to have a high negative predictive

value, ranging from 80% to 100%, and a positive predictive

value of 66% to 80% when skin prick and intradermal testing is

performed. Typically, testing involves skin prick testing with

oxaliplatin at 1 to 5 mg/mL, to be followed, if the result is

negative, by intradermal testing using 10-fold serial dilutions

starting at 10

2

and 10

1

dilutions and undiluted.

371-373

Symptoms of skin irritation, including injection-site pain and

erythema, are more common with higher strengths of intrader-

mal testing. In cases with a clinical history suggestive of type I

hypersensitivity to oxaliplatin but negative skin test result, it may

be appropriate to repeat testing after subsequent infusions of

oxaliplatin, especially if there have been 8 or more previous

lifetime exposures to oxaliplatin.

374

Conversion to a positive skin

test result in such patients would deem them candidates for

desensitization if continuing oxaliplatin therapy is desired.

Management. Type I hypersensitivity to oxaliplatin can be

managed by desensitization in most cases. Various protocols have

been used, with the total duration of infusion ranging from 90

minutes to 16 hours. Castells et al have described the greatest

number of patients desensitized to platin-based chemothera-

peutics using a 12-step protocol with three 10-fold dilutions of

the drug given over approximately 6 hours. An example 12-step

desensitization protocol is included in Table XXXVIII.

Most protocols premedicate patients with antihistamines to

minimize the risk and/or severity of breakthrough reactions with

desensitization. Additional premedication with a combination of

aspirin and montelukast appears to be helpful for those patients

whose reactions have prominently included ﬂushing, thought to

be mediated by the release of prostaglandins, and other inﬂam-

matory lipid mediators generated as a consequence of mast cell

activation.

The literature describing idiosyncratic/cytokine stormelike

reaction is quite limited, but management seems to revolve

around intense premedication regimens of steroids with or

without antihistamines.

375

Coadministration of intravenous

ﬂuids and infusion rate reduction have also been found to be

useful interventions. The role for desensitization in this clinical

scenario is not yet deﬁned.

Taxanes (by Matthieu Picard, MD)

General.

Immediate hypersensitivity reactions to paclitaxel and

docetaxel occur in around 10% of patients, most commonly on

ﬁrst exposure, despite premedication with antihistamines and

corticosteroids.

376-378

Nab-paclitaxel and cabazitaxel are less

frequently associated with such reactions.

377

Cremophor-EL

(contained in the paclitaxel formulation) and polysorbate 80

(contained in the docetaxel and cabazitaxel formulation) are

thought to be responsible for immediate hypersensitivity re-

actions because they can cause complement activation and

generate anaphylatoxins.

377

An IgE-mediated mechanism could

also be responsible for some of these reactions.

378,379

Major symptoms of hypersensitivity. Most immediate

reactions are moderate in severity, with the most frequently re-

ported symptoms being skin ﬂushing, dyspnea, chest pain, and

back pain.

376,378

In patients with hypotension, a serum tryptase

level can be measured; an elevated level supports a mast

cellemediated reaction.

378

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S44 BROYLES ET AL

Paclitaxel and docetaxel can cause nonimmediate skin re-

actions with onset from 12 hours to 15 days after the infusion.

378

These reactions are most frequently characterized by ﬂushing or

by a maculopapular skin eruption.

378

Although much less common, severe hypersensitivity reactions

(SJS, TEN, acute interstitial pneumonitis, and subacute cuta-

neous lupus erythematosus) have been described in case reports

in association with paclitaxel, docetaxel, and nab-paclitaxel.

377

Diagnosis. Skin testing can be used to guide the method of

reexposure: desensitization versus challenge in patients with an

immediate taxane-induced hypersensitivity reaction.

378

Con-

centrations used for paclitaxel skin testing range from 1 to 6 mg/

mL (SPT) and from 0.001 to 6 mg/mL (IDT).

378,380

False-

positive results can occur at 6 mg/mL (IDT).

380

Concentrations

used for docetaxel skin testing range from 4 to 10 mg/mL (SPT)

and from 0.04 to 10 mg/mL (IDT).

378,380

Skin testing with

cabazitaxel and nab-paclitaxel has not been reported.

Management. Following an immediate taxane-induced hy-

persensitivity reaction, reexposure through a regular or slowed

infusion with or without additional premedication appears to be

tolerated by many patients.

376,380,381

However, severe reactions

were reported with this approach and desensitization can be used

as an alternative, especially in patients with a positive skin test

response and/or a moderate to severe initial hypersensitivity re-

action (Figure 4).

376,378,380,381

The risk of recurrent reaction

appears to decrease with repeated exposures, and desensitization

protocols can be progressively shortened in patients with good

tolerance to eventually perform a challenge and, if tolerated,

resume regular infusions (Table XXXIX).

378,381

Patients with a delayed skin reaction and a positive skin test

response may be at risk of an immediate hypersensitivity reaction

on reexposure and may require desensitization.

378

The risk of a

recurrent delayed reaction also decreases with repeated exposures

and many can eventually tolerate regular infusions.

378

contrast, patients with severe nonimmediate hypersensitivity re-

actions (eg, SJS) should not be reexposed to taxanes.

Methotrexate (by Andrew MacGinnitie, MD, PhD,

and Min Jung Lee, MD)

General.

Methotrexate (MTX) is an antifolate chemotherapy

and immunosuppressant agent that is used for the management

of osteosarcoma, acute lymphocytic leukemia, and rheumatoid

arthritis, along with other autoimmune diseases in adults and

children. It inhibits the activity of dihydrofolate reductase, which

is needed for de novo purine synthesis. Adverse effects, more

commonly seen with high doses used in cancer therapy, include

abdominal cramping, malaise, mucositis, myelosuppression, and

renal and hepatic toxicity.

382

MTX pneumonitis that can prog-

ress to interstitial ﬁbrosis has also been reported.

383

Although the

incidence of hypersensitivity reaction is unknown, it is likely rare,

and case reports of anaphylactic or anaphylactoid reactions have

been described.

384,385

Major symptoms of hypersensitivity. The signs and

symptoms of hypersensitivity reactions have been seen with

standard-dose, high-dose, oral, intramuscular, intrathecal, and/or

TABLE XXXVI. Twelve-step carboplatin desensitization protocol*

Step Solution Concentration (mg/mL) Rate (mL/h) Time (min) Administered dose (mg) Cumulative dose (mg)

1 1 0.02456 2.5 15 0.0154 0.0154

2 1 0.02456 5 15 0.0307 0.0461

3 1 0.02456 10 15 0.0614 0.1075

4 1 0.02456 20 15 0.1228 0.2303

5 2 0.2456 5 15 0.307 0.5373

6 2 0.2456 10 15 0.614 1.1513

7 2 0.2456 20 15 1.228 2.3793

8 2 0.2456 40 15 2.456 4.8353

9 3 2.45666 10 15 6.0916 10.9269

10 3 2.45666 20 15 12.1833 23.1102

11 3 2.45666 40 15 24.3666 47.4768

12 3 2.45666 80 174.375 566.5232 614

*For a total dose of 614 mg carboplatin.

TABLE XXXVII. Eight-step carboplatin desensitization protocol*

Step Solution Concentration (mg/mL) Rate (mL/h) Time (min) Administered dose (mg) Cumulative dose (mg)

1 1 0.1656 5 15 0.207 0.207

2 1 0.1656 10 15 0.414 0.621

3 1 0.1656 20 15 0.828 1.449

4 1 0.1656 40 15 1.656 3.105

5 2 1.64358 10 15 4.109 7.214

6 2 1.64358 20 15 8.2179 15.4319

7 2 1.64358 40 15 16.4358 31.8677

8 2 1.64358 80 174.375 382.1324 414

*For a total dose of 414 mg carboplatin.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S45

intravenous forms of MTX. The reactions can include pruritus,

urticaria, angioedema, wheezing, dyspnea, hypotension, and/or

loss of consciousness.

386,387

Although most reactions occur

subsequently after the ﬁrst exposure, hypersensitivity reactions

occurring on ﬁrst exposure have also been described.

388

Diagnosis. The sensitivity and speciﬁcity of MTX skin

testing as well as nonir ritating skin testing concentrations have

not been established. However, the following concentrations

have been used for prick testing (10 mg/mL) and intradermal

testing (0.1 mg/mL and 1 mg/mL).

386

Other skin testing

concentrations with IDT (2.5 mg/mL), which w ere nonirri-

tating in 2 healthy controls, have also been used in an adult

patient.

389

Additional case reports in adults have demonstrated

positive prick skin testing result.

390,391

In the pediatric pop-

ulation, a recent retrospective review of a single-center expe-

rience with MTX showed that only 1 of 4 patients tested

positive on skin testing.

386

This may suggest immediate type I

hypersensitivity as part of the pathogenesis in some patients.

Management. For patients with MTX reactions, the man-

agement should be individualized in the context of overall clin-

ical picture after considering risks and beneﬁts of reintroduction.

If the patient has a negative skin testing result and/or history of

minor reaction, challenge may be considered. The challenge can

be performed starting with 1/100th of the total dose. Patients

with severe reactions (especially involving vital sign changes,

pharyngeal edema, respiratory and cardiovascular involvement,

etc) should receive desensitization regardless of the skin test

result. Case reports have described prolonged infusion ranging

from 6 to 27 hours.

392-394

However, at some institutions, the

current practice for both adults and children involves a desen-

sitization protocol with 3 bags of different concentrations that are

administered via 12 steps, with the ﬁrst bag consisting of 1/100th

of the total dose, the second bag 1/10th of the total dose, and the

third bag containing the remainder of the dose. A 16-step pro-

tocol involving 4 bags has also been performed in cases with

severe reactions. Each step involves doubling of the concentra-

tions every 15 minutes until the last step (step 12) is reached.

The premedications can include H

and H

antagonists in

addition to leukotriene receptor antagonists and/or corticoste-

roids (Table XL).

Cyclophosphamide (by Rebecca Breslow, MD)

General.

Adverse reactions to cyclophosphamide (CYC) are

most commonly due to drug toxicity. The major determinant is

the cumulative dose received; toxicities are related to both dose

and duration of exposure to this agent. Major toxicities associated

with CYC are bone marrow suppression, increased susceptibility

to infection, gonadal toxicity leading to infertility, increased risk

of hematologic and skin malignancies, cystitis, and bladder

cancer.

395

Less common adverse reactions are described in several

case reports, and are dermatologic. One patient with systemic

lupus erythematosus treated with CYC developed a neutrophilic

eccrine hidradenitis.

396

Another with multiple myeloma (MM)

developed a neutrophilic folliculitis.

397

Type I hypersensitivity reactions to CYC are relatively

rare, but case reports can be found in the literature. Vis-

itsunthorn et al

398

described a pediatric patient treated with

CYC for systemic lupus erythematosus who developed urti-

caria on the ﬁfth exposure to the agent. Skin testing result

was negative, and the pati ent then underwent successful

graded challenge. Rosas et al

399

described another pediatric

patient with acute lymphoblastic leukemia, being treated with

CYC/2-mercaptoethane sulfonate sodium who developed a

maculopapular rash, diaphoresis, respiratory distress, and

TABLE XXXVIII. Twelve-step desensitization protocol for oxaliplatin*

Target dose (mg)

Standard volume

per bag (mL)

Final rate of

infusion (mL/h)

Calculated final

concentration (mg/mL)

Standard time of

infusion (min)

500.0 250 80 2 187.5

Total mg per bag

Solution 1 250 mL of 0.020 mg/mL 5.000

Solution 2 250 mL of 0.200 mg/mL 50.000

Solution 3 250 mL of 1.984 mg/mL 496.065

Step Solution Rate (mL/h) Time (min) Volume infused per step (mL) Dose administered with this step (mg) Cumulative dose (mg)

1 1 2.0 15 0.50 0.0100 0.0100

2 1 5.0 15 1.25 0.0250 0.0350

3 1 10.0 15 2.50 0.0500 0.0850

4 1 20.0 15 5.00 0.1000 0.1850

5 2 5.0 15 1.25 0.2500 0.4350

6 2 10.0 15 2.50 0.5000 0.9350

7 2 20.0 15 5.00 1.0000 1.9350

8 2 40.0 15 10.00 2.0000 3.9350

9 3 10.0 15 2.50 4.9607 8.8957

10 3 20.0 15 5.00 9.9213 18.8170

11 3 40.0 15 10.00 19.8426 38.6596

12 3 80.0 174.375 232.50 461.3405 500.0000

Total time (min) ¼ 339.375 ¼ 5.66 h

*The total volume and dose dispensed are more than the ﬁnal dose given to patient because many of the solutions are not completely infused.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S46 BROYLES ET AL

anxiety during his fourth cycle of CYC/2-mercaptoethane

sulfonate sodium.

399

The symptoms resolved with steroid

and anti histamine treatment. Skin testing result was also

negative, but on rechallenge, the patient again presented with

a similar rash. He underwent rapid desensitization, which he

tolerated wit hout a reaction, and was able to receive a sub-

seq uent t rea tment 2 days after his desensitization via standard

administration.

Diagnosis. Type I hypersensitivity reaction to CYC is

diagnosed on the basis of clinical history with or without

skin testing. Signs and symptoms consistent with IgE-medi-

ated hypersensitivity, such as hives, ﬂushing, angioedema,

pru ritus, wheezing, an d h ypotension occurring during or

shortly after receiving a dose of CYC, are highly suggestive of

a type I hypersensitivity reaction. Skin testing can be used to

conﬁrm the clinical history; providers perform percutaneous

prick testing with 10 mg/mL and intradermal testing with 1

mg/mL (1:10) and 10 mg/mL (1:1). In the case report by

Visitsunthorn et al,

398

prick and intradermal testing was

performed with 0.02 mL of the following dilutions of CYC:

1:100, 1:10, and 1:1. Rosas et al

399

also performed prick

testing with 10 mg/mL and intradermal testing with 1 mg/

mL. In all cases, prick and intradermal tests with CYC were

compared with a histamine-positive c ontrol and a diluent-

negative control, and results were determined on the basis of

this comparison. Neither of these published studies included

controls to determine o ptimal nonirritating skin testing

concentrations for CYC.

Management. Patients with an equivocal history and negative

skin testing result may be subjected to graded challenge. Vis-

itsunthorn et al

398

described a successful graded challenge to

CYC, in which the patient received antihistamine pretreatment

and was challenged, with doubling of doses every 15 minutes;

however, they did not include the number of doses received and

quantity given with each dose.

Patients with a convincing clinical history with or without a

positive skin test result may undergo rapid desensitization. Pa-

tients may be successfully desensitized using a standard 3-bag 12-

step protocol, with premedication with H

and H

blockers

(Table XLI).

272

Brieﬂy, bag 1 contains a solution diluted 1:100,

bag 2 a solution diluted 1:10, and bag 3 an undiluted solution.

The rate of infusion is then doubled every 15 minutes until a

threshold dose is reached; the patients may then receive the

remainder of the undiluted bag 3 at a ﬁnal rate of infusion of 80

mL/h. The protocol reported by Rosas et al

399

used an initial

dose of 0.12 mg CYC diluted 1:4000, doubled every 15 to 30

FIGURE 4. Approach to taxane reintroduction in patients with hypersensitivity reaction. Mild immediate hypersensitivity reactions

present with symptoms that are limited to the skin (eg, flushing) or that involve a single organ/system and that are mild (eg, mild back

pain). Moderate hypersensitivity reactions present with symptoms that involve at least 2 organs/systems (eg, flushing and dyspnea) but

without a significant drop in blood pressure or in oxygen saturation. Severe hypersensitivity reactions present with symptoms that

typically involve at least 2 organs/systems and with a significant drop in blood pressure (systolic 90 mm Hg and/or syncope) and/or in

oxygen saturation (92%). In patients with a hypersensitivity reaction with desensitization or challenge, premedication can be adjusted

for the next procedure, which can be administered using either the same or a longer protocol. Patients in whom the hypersensitivity

reaction does not recur can then be treated with a shorter desensitization protocol, challenge, or regular infusion according to the al-

gorithm. To ensure the patient’s tolerance, each procedure can be repeated several times before proceeding with a shorter desensitization

protocol, challenge, or regular infusion.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S47

minutes until a 1500-mg dose was delivered, for a cumulative

dose of 2500 mg.

Doxorubicin (by Kathleen Lee-Sarwar, MD)

General.

Doxorubicin is an inhibitor of DNA and RNA syn-

thesis that intercalates between DNA base pairs, inhibits topo-

isomerase II, and leads to production of free radicals.

Doxorubicin is available without liposomal encapsulation (trade

name Adriamycin), in liposomal form (trade name Myocet), and

in pegylated liposomal form (trade name Doxil). Liposomal

encapsulation allows for preferential concentration in tumor

tissue.

The nonliposomal form of doxorubicin is very rarely associ-

ated with hypersensitivity reactions. In contrast, the incidence of

hypersensitivity reactions to pegylated liposomal doxorubicin is

approximately 8%, with some series reporting up to a 25%

incidence.

400

Reactions usually occur during the ﬁrst cycle. The

mechanism of hypersensitivity on ﬁrst exposure may be

explained at least in part by complement activation, which has

been demonstrated in vivo during infusion of pegylated lipo-

somal doxorubicin and may lead to mast cell activation.

400

Interestingly, in the setting of carboplatin hypersensitivity,

combining carboplatin with pegylated liposomal doxorubicin

appears to have a protective effect and is associated with reduced

incidence of hypersensitivity reactions compared with carbopla-

tin as a single agent or in combination with paclitaxel.

401

Major symptoms of hypersensitivity. Typical clinical

features include those of mast cellemediated reactions such as

ﬂushing, pruritus, urticaria, dyspnea, sense of doom, and hypo-

tension. Macular eruption and chest pain or back pain may also

occur.

272

Hypersensitivity reaction severity ranges from mild to

life-threatening.

Doxorubicin may also cause adverse effects that mimic, but

are not, hypersensitivity reactions. Liposomal doxorubicin is

associated with palmar-plantar erythrodysesthesia, also called

hand-foot syndrome, which is a relatively common dermatologic

toxic reaction associated with cytotoxic chemotherapy that can

limit the use of such drugs. Deﬁnitive prevention and treatment

strategies for palmar-plantar erythrodysesthesia have not yet been

established. This typically occurs in the ﬁrst 3 cycles of treat-

ment.

402

Other cutaneous adverse effects include diffuse follic-

ular rash, intertrigo-like eruption, and radiation recall

dermatitis.

403

Acute cardiotoxicity is rare and may present with

arrhythmias such as atrial ﬁbrillation, acute heart failure,

myocarditis, or acute myocardial infarction. Chronic cardiomy-

opathy is a more common and dose-limiting adverse effect.

Diagnosis. The ability to perform skin testing in the evalua-

tion of doxorubicin hypersensitivity is limited by cutaneous

toxicity.

404

Doxorubicin hypersensitivity is therefore generally

diagnosed clinically, and there are no published skin testing

protocols at this time.

Management. Desensitization has been successfully per-

formed in patients with hypersensitivity reactions to doxorubicin

and is an option for management when there is no effective

alternative treatment.

271

In a report of 413 cases of rapid

desensitization, desensitization to doxorubicin was successfully

completed in a total of 29 patients. A 12-step rapid desensiti-

zation protocol may be used in cases with mild or moderate

symptoms (Table XLII).

272

In the case of severe reactions

including hypoxemia or hypotension, a 16-step rapid desensiti-

zation protocol should be used for the patient’s ﬁrst lifetime

desensitization. If this is tolerated, a 12-step rapid desensitization

protocol may be considered for subsequent infusions. Standard

pretreatment includes a histamine H

-receptor antagonist and a

long-acting histamine H

-receptor antagonist, with optional

additional premedications tailored to the patient’s initial

reaction.

Pemetrexed (by Paige Wickner, MD)

General.

Pemetrexed is an antifolate agent approved for use in

patients with lung cancer and malignant pleural mesothelioma.

The exact incidence of hypersensitivity reactions to pemetrexed is

unknown. In phase III trials, 17% to 22% of patients receiving

this agent developed a rash.

405

The literature includes case re-

ports of pemetrexed-induced pneumonitis, pemetrexed-induced

urticarial vasculitis, angioedema, AGEP, and anaphylactic

reactions.

Diagnosis. The clinical symptoms should be closely evaluated

and if IgE is suspected, skin testing and desensitization can be

considered. If a more serious reaction occurred that is not felt to

be IgE-mediated, alternative treatment options should be

considered. Intradermal skin testing results with pemetrexed at

dilutions of 1:10,000, 1:1,000, 1:100, and 1:10 have been re-

ported. However, more data are needed to determine optimal

nonirritating skin test concentrations.

Management. For patients with suspected IgE-mediated re-

actions with no reasonable alternatives, desensitization has been

successfully reported (Table XLIII).

Lenalidomide (by Paige Wickner, MD)

General.

Lenalidomide is an antiangiogenic agent that is pri-

marily used for the treatment of MM, myelodysplastic syndrome,

and mantle cell lymphoma. The exact incidence of hypersensi-

tivity reactions to lenalidomide is unknown. The literature re-

ports rashes occurring in 29% to 43% of patients, depending on

underlying disease indication. A spectrum of rashes has been

reported, including facial swelling, SJS, erythema multiforme,

neutrophlic predominant rashes, and urticaria. Timing of re-

actions has been reported as both acute and delayed in onset.

Diagnosis. Clinical symptoms should be reviewed, evaluated,

and continued, or alternative treatment options discussed. At

present, there are no published nonirritating skin test concen-

trations for lenalidomide.

Management. There are case reports of desensitization to

lenalidomide. An outpatient desensitization protocol used a

starting dose of 2.5 mg and desensitized 5 patients to lenalido-

mide without adverse events. A shortened version of the outpa-

tient desensitization can be repeated if the ﬁrst desensitization

has no adverse events (Tables XLIV and XLV). There are pub-

lished rapid desensitization protocols for typical IgE-mediated

symptoms as well as noneIgE-mediated symptoms.

406

Patients

with evidence or suggestion of SJS/TEN or medication-induced

laboratory abnormalities are not good candidates for

desensitization.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S48 BROYLES ET AL

TABLE XXXIX. Examples of desensitization and challenge protocols for paclitaxel (135-175 mg/m

) infused every 3 wk over 3 h

(example ¼ 294 mg)

Four-bag/16-step protocol

Bag Volume per bag (mL) Concentration per bag (mg/mL) Amount of bag infused (mL) Dose infus ed per bag (mg)

Solution 1 250 0.00118 9.38 0.011

Solution 2 250 0.0118 9.38 0.111

Solution 3 250 0.118 18.75 2.213

Solution 4 250 1.167 250 291.665

Step Solution Rate (mL/h) Time (min) Volume infused (mL) Dose infused per step (mg) Cumulative dose (mg)

1 1 2.5 15 0.625 0.001 0.001

2 1 5 15 1.25 0.001 0.002

3 1 10 15 2.5 0.003 0.005

4 1 20 15 5 0.006 0.011

5 2 2.5 15 0.625 0.007 0.018

6 2 5 15 1.25 0.015 0.033

7 2 10 15 2.5 0.030 0.063

8 2 20 15 5 0.059 0.122

9 3 5 15 1.25 0.148 0.270

10 3 10 15 2.5 0.295 0.565

11 3 20 15 5 0.590 1.155

12 3 40 15 10 1.18 2.335

13 4 10 15 2.5 2.917 5.252

14 4 20 15 5 5.834 11.086

15 4 40 15 10 11.667 22.753

16 4 80 174.4 232.5 271.262 294.0

Total time (h) ¼ 6.67

Three-bag/12-step protocol

Bag Volume (mL) per bag Concentration (mg/mL) per bag Amount of bag infused (mL) Dose infused per bag (mg)

Solution 1 250 0.0118 9.38 0.111

Solution 2 250 0.118 18.75 2.213

Solution 3 250 1.167 250 291.676

Step Solution Rate (mL/h) Time (min) Volume infused (mL) Dose infused per step (mg) Cumulative dose (mg)

1 1 2.5 15 0.625 0.007 0.007

2 1 5 15 1.25 0.015 0.022

3 1 10 15 2.5 0.030 0.052

4 1 20 15 5 0.059 0.111

5 2 5 15 1.25 0.148 0.259

6 2 10 15 2.5 0.295 0.554

7 2 20 15 5 0.590 1.144

8 2 40 15 10 1.18 2.324

9 3 10 15 2.5 2.917 5.241

10 3 20 15 5 5.834 11.075

11 3 40 15 10 11.667 22.742

12 3 80 174.4 232.5 271.328 294.0

Total time (h) ¼ 5.67

Two-bag/8-step protocol

Bag Volume (mL) per bag Concentration (mg/mL) per bag Amount of bag infused (mL) Dose infused per bag (mg)

Solution 1 250 0.118 18.75 2.213

Solution 2 250 1.167 250 291.787

Step Solution Rate (mL/h) Time (min) Volume infused (mL) Dose infused per step (mg) Cumulative dose (mg)

1 1 5 15 1.25 0.148 0.148

2 1 10 15 2.5 0.295 0.443

3 1 20 15 5 0.590 1.033

4 1 40 15 10 1.18 2.213

(continued)

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S49

Thalidomide (by Margee Louisias, MD, MPH)

General.

Thalidomide is an immunomodulatory drug with

antiangiogenic properties.

407

It is approved for use in erythema

nodosum leprosum and MM, with off-label use in many con-

ditions such as HIV apthous ulcers and graft-versus-host dis-

ease.

408

It is administered alone for erythema nodosum or in

conjunction with dexamethasone for MM. Because of its known

severe teratogenic effects it can be prescribed and dispensed only

by prescribers and pharmacies enrolled in the THALOMID

REMS program in the United States.

409

It is available as capsules

in the United States. It is soluble at 25



C in dimethyl sulfoxide

and sparingly soluble in water and ethanol. The incidence of

thalidomide hypersensitivity reactions ranges from 6.3% to

47.7% among several thalidomide clinical trials.

407

Major symptoms. Thalidomide hypersensitivity presents

with delayed (usually within ﬁrst month of treatment) skin re-

actions of varying severity.

407

However, in a retrospective review,

skin reactions were seen more than 12 weeks after initiation with

thalidomide or thalidomide analogs (lenalidomide, pomalido-

mide), in the setting of dose escalation or steroid tapering.

410

Dry skin, pruritic maculopapular rash, morbilliform rash, diffuse

erythematous eruptions, scaling erythroderma, eosinophilia, and

TEN/SJS have been described in the literature.

407,411

Body

distribution is variable but is reported to mostly affect the trunk

and proximal limbs.

407

Diagnosis. There is no standardized skin testing or patch

testing protocol available. Nucera et al

412

performed prick-by-

prick testing with a solution made from a tablet dissolved in

saline. However, because thalidomide (capsule) is soluble only in

dimethyl sulfoxide, which is a skin irritant, skin prick testing can

be done only with thalidomide dissolved in saline in accordance

with European Network of Drug Allergy/EAACI (ENDA/

EAACI) guidelines.

Nucera et al

412

also performed intradermal

testing with thalidomide at a concentration of 0.04 mg/dL. Patch

testing was also done according to ENDA/EAACI and American

Academy of Dermatology guidelines. Patches were applied to the

interscapular area with commercially available adhesive anallergic

gauze strips and assessed at 48 and 72 hours.

269,413

Saline and

histamine were used as negative and positive controls for all

testing, respectively; however, whether these concentrations are

nonirritating was not established.

Management. The challenge protocol given in Table XLVI is

adapted from Nucera et al

412

who performed it in an ambulatory

setting. The patient experienced a pruritic, erythematous rash

after completion of day 2. Symptoms improved with an anti-

histamine. The desensitization protocol is also adapted from

Nucera et al,

412

who performed it over 5 days in a hospital

setting (Table XLVII). The same patient underwent desensiti-

zation without adverse reaction and completed treatment

without any issues. Oral antihistamine was used as

premedication.

Tyrosine kinase inhibitors (by Joyce Hsu, MD)

Since the introduction of imatinib in 2001, the tyrosine kinase

inhibitor (TKI) family of therapeutics has continued to expand

rapidly. Currently, there are 31 FDA-approved medications in

this family, including (with targets) the following

414,415

 ALK: crizotinib, ceritinib, alectinib, and brigatinib

 BCR-Abl: bosutinib, dasatinib, imatinib, nilotinib, and

ponatinib

 BTK: ibrutinib

 c-Met: crizotinib and cabozantinib

 Epidermal growth factor receptor (EGFR) family: geﬁtinib,

erlotinib, lapatinib, vandetanib, afatinib, and osimertinib

 JAK family: ruxolitinib and tofacitinib

 PDGFR alpha/beta: axitinib, geﬁtinib, imatinib, lenvatinib,

nintedanib, pazopanib, regorafenib, sorafenib, and sunitinib

 RET: vandetanib

 Src family: bosutinib, dasatinib, ponatinib, and vandetanib

 Vascular EGFR family: axitinib, lenvatinib, nintedanib,

regorafenib, pazopanib, sorafenib, and sunitinib

TKIs are used in the treatment of numerous malignancies

and myeloproliferative disorders, as well as hypereosinophilic

syndrome and aggressive systemic mastocytosis in the case of

imatinib. As a family, they are associated with signiﬁcant

cutaneous and systemic side effects that are important to

differentiate from true hypersensitivity.

TABLE XXXIX. (Continued)

Step Solution Rate (mL/h) Time (min) Volume infused (mL) Dose infused per step (mg) Cumulative dose (mg)

5 2 10 15 2.5 2.917 5.130

6 2 20 15 5 5.834 10.964

7 2 40 15 10 11.667 22.631

8 2 80 174.4 232.5 271.369 294.0

Total time (h) ¼ 4.67

Challenge protocol

Bag Volume per bag (mL) Concentration per bag (mg/mL) Amount of bag infused (mL) Dose infus ed per bag (mg)

Solution 1 250 1.176 250 294

Step Solution Rate (mL/h) Time (min) Volume infused (mL) Dose infused (mg) per step Cumulative dose (mg)

1 1 2 15 0.5 0.588 0.588

2 1 8 15 2 2.352 2.940

3 1 80 185.625 247.5 291.06 294.0

Total time ¼ 3.59 h

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S50 BROYLES ET AL

Skin rash—often erythematous and papular or pustular—is

commonly associated with TKIs, particularly EGFR inhibitors

(up to 100% of patients).

416

Because of the association between

EGFR- and vascular endothelial growth factor and its

receptoreassociated rash development and improved survival

outcomes, supportive care with steroids, antihistamines, and

antibiotics is preferable in many cases.

417

Hand-foot skin reac-

tion, characterized by pain and blistering on the palms and soles,

is associated with sorafenib, sunitinib, and other vascular EGFR

inhibitors. It occurs generally in the ﬁrst 2 to 4 weeks of treat-

ment. Oral dysesthesia and mucositis occurs with TKIs, partic-

ularly sorafenib and sunitinib, and may occur simultaneously

with skin rash and hand-foot syndrome.

418

Mucosal involvement

may also include conjunctivitis with EGFR inhibitors and peri-

orbital edema with imatinib. These symptoms can be difﬁcult to

differentiate from systemic drug reactions, and skin biopsy can be

helpful.

419

Diarrhea is also observed commonly with TKIs as a class.

Several of the TKIs, such as lapatinib, sunitinib, and pazopanib,

carry a black box warning for liver toxicity, but it occurs

commonly with other TKIs including geﬁtinib.

420

Dose reduc-

tion or drug discontinuation should be considered with hepa-

totoxicity as well as severe and chronic diarrhea.

419

Desensitization protocols have been described for several TKIs.

Imatinib. Ten patients with imatinib hypersensitivity who

underwent subsequent desensitization were described by Nelson

et al

421

in 2006. These patients had predominantly cutaneous

initial reactions, though several had additional fever, blistering,

edema, or diarrhea. One patient was skin tested by skin prick

testing at 0.01 and 0.1 mg/mL and intradermal testing at 0.001

mg/mL, 0.01 mg/mL, and 0.1 mg/mL. Erythema was reported

on intradermal testing. Of these 10 patients who completed a 4-

hour rapid oral desensitization (Table XLVIII), 8 were subse-

quently able to tolerate daily imatinib without hypersensitivity

symptoms. The other 2 patients developed rash hours to days

after desensitization.

Subsequently, Paolo

422

published a case report describing

slow oral desensitization to imatinib over 23 days for a patient

who developed eosinophilic dermatitis after 6 weeks

(Table XLIX). Skin testing result was negative, using skin prick

0.1 mg/mL, and intradermal testing with 0.0001 mg/mL,

0.001mg/mL,0.01mg/mL,and0.1mg/mLimatinib.Patch

testing was also performed, and the result was negative using

0.1 mg/mL imatinib in 5% petrolatum. For the rapid oral

desensitization, sam e-day dose increases were administered

every 20 minutes. The patient initially failed rapid desensiti-

zation twice, but was able to tolerate imatinib after slow oral

desensitizati on (Table XLIX).

Crizotinib. Rash w ith crizotin ib occurs in about 10% of pa-

tients, and is generally mild to moderate in severity. Hyper-

sensitivity reactions are rare, but reported. Sanchez-Lopez

et al

423

described a patient presenting with urticaria and facial

edema f or more than 40 days after initiation of treatment. Skin

testing w as performed with crizotinib capsules suspended in

water (skin prick 25 mg/mL, intradermal testing 0.025 mg/mL

and 0.25 mg/mL) and the result was negative. Five normal

controls also had negative results to skin testing with t his

regimen. The patient was premedicated with intramuscular

dexchlorpheniramine 5 mg and methylprednisolone 40 mg, and

the 5-step oral desensitization was performed with 30-minute

intervals and 120 minutes of observation on completion

(Table L). The patient subsequently tolerated crizotinib

without hypersensitivity symptoms.

In 2014, Awad et al

424

also described 2 patients with more

rapid-onset crizotinib hypersensitivity, one with immediate ur-

ticaria and edema and the other with a delayed maculopapular

rash. Patients were premedicated 1 hour and 12 hours before

desensitization with 10 mg of loratadine and 10 mg of cetirizine.

Both patients were successfully desensitized to crizotinib using a

12-step rapid desensitization protocol, with 15-minute intervals

between steps (Table LI).

Sorafenib. Sorafenib is more commonly associated with hand-

foot skin reaction and other symptoms related to toxicity, but it

can rarely (<1%) trigger allergic symptoms, including urticaria.

In 2008, Bauer et al

425

described a patient who developed a

pruritic generalized maculopapular rash after 2 weeks of sorafenib

therapy. The rash resolved with discontinuation of sorafenib and

treatment with oral antihistamines and topical steroids. They

TABLE XL. Samples of 2 desensitization protocols for MTX*

Step

MTX

(mg/mL)

Volume

infused per

step (mL)

Dose

administered

with this step (mg)

Cumulative

dose (mg)

Twelve-step protocol

1 0.002 0.5 0.001 0.001

2 0.002 1.25 0.0025 0.0035

3 0.002 2.5 0.005 0.0085

4 0.002 5 0.01 0.0185

5 0.02 1.25 0.025 0.0435

6 0.02 2.5 0.05 0.0935

7 0.02 5 0.1 0.1935

8 0.02 10 0.2 0.3935

9 0.2 2.5 0.4961 0.8896

10 0.2 5 0.9921 1.8817

11 0.2 10 1.9843 3.866

12 0.2 232.5 46.134 50

Sixteen-step protocol

1 0.0002 0.5 0.0001 <0.001

2 0.0002 1.25 0.00025 <0.001

3 0.0002 2.5 0.0005 0.001

4 0.0002 5 0.001 0.002

5 0.002 0.5 0.001 0.003

6 0.002 1.25 0.0025 0.005

7 0.002 2.5 0.005 0.010

8 0.002 5 0.01 0.020

9 0.02 1.25 0.025 0.045

10 0.02 2.5 0.05 0.095

11 0.02 5 0.1 0.195

12 0.02 10 0.2 0.395

13 0.2 2.5 0.4961 0.891

14 0.2 5 0.9921 1.883

15 0.2 10 1.9843 3.867

16 0.2 232.5 46.134 50.000

*Goal dose of MTX was 50 mg via intravenous administration. Premedications

include H

and H

antagonists with or without a leukotriene receptoreblocking agent

with or without cortico steroids. Interval of 15 min between steps and the rate of

infusion at the last step is continued until the end of infusion.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S51

were able to restart sorafenib using premedication and a 6-day

oral tolerance protocol, with day 1 doses given every 15 minutes

(Table LII, A). The patient developed erythema after the 11-step

protocol, which was treated with 4 mg dimethindene maleate,

with resolution. The patient was premedicated with methyl-

prednisolone 24 mg on day 1, and premedicated with methyl-

prednisolone 24 mg and fexofenadine 180 mg on days 2 to 12.

Thereafter, fexofenadine was used only as needed.

More recently, Linauskiene et al

426

described a patient with

sorafenib treatment complicated by fever and generalized urti-

caria 10 days into treatment. The urticaria resolved 5 days after

discontinuation of sorafenib, systemic glucocorticoids, and oral

antihistamines. The 8-day oral tolerance protocol (Table LII, B)

was based on the Bauer et al

425

study, and was complicated by

antihistamine-responsive pruritus during the ﬁrst several days of

the protocol.

426

This patient also developed facial urticaria after

TABLE XLI. Twelve-step desensitization protocol for CYC*

Target dose (mg)

Standard volume

per bag (mL) Final rate of infusion (mL/h)

Calculated target

concentration (mg/mL)

Standard time of

infusion (min)

1000 250 80 4 187.5

Total mg per bag

Solution 1 250 mL of 0.040 mg/mL 10.000

Solution 2 250 mL of 0.400 mg/mL 100.000

Solution 3 250 mL of 3.969 mg/mL 992.130

Step Solution Rate (mL/h) Time (min) Volume infused per step (mL) Dose administered with this step (mg) Cumulative dose (mg)

1 1 2.0 15 0.50 0.0200 0.0200

2 1 5.0 15 1.25 0.0500 0.0700

3 1 10.0 15 2.50 0.1000 0.1700

4 1 20.0 15 5.00 0.2000 0.3700

5 2 5.0 15 1.25 0.5000 0.8700

6 2 10.0 15 2.50 1.0000 1.8700

7 2 20.0 15 5.00 2.0000 3.8700

8 2 40.0 15 10.00 4.0000 7.8700

9 3 10.0 15 2.50 9.9213 17.7913

10 3 20.0 15 5.00 19.8426 37.6339

11 3 40.0 15 10.00 39.6852 77.3191

12 3 80.0 174.375 232.50 922.6809 1000.0000

Total time (min) ¼ 339.375 ¼ 5.66 h

*The total volume and dose dispensed are more than the ﬁnal dose given to patient because many of the solutions are not completely infused.

TABLE XLII. Example 12-step/3-bag desensitization doxorubicin protocol

Target dose 58 mg

Standard volume per bag 250 mL

Solution Volume per bag (mL) Concentration (mg/mL) Total dose per bag (mg)

Solution 1 250 0.00232 0.58

Solution 2 250 0.0232 5.8

Solution 3 250 0.23017 57.543

Step Solution Rate (mL/h) Time per step (min) Dose administered per step (mg) Cumulative dose (mg) Fold increase per step

1 1 2.5 15 0.0015 0.0015 NA

2 1 5 15 0.0029 0.0044 2

3 1 10 15 0.0058 0.0102 2

4 1 20 15 0.0116 0.0218 2

5 2 5 15 0.029 0.0508 2.5

6 2 10 15 0.058 0.1088 2

7 2 20 15 0.116 0.2248 2

8 2 40 15 0.232 0.4568 2

9 3 10 15 0.5754 1.0322 2.48

10 3 20 15 1.1509 2.183 2

11 3 40 15 2.3017 4.4848 2

12 3 80 175 53.5152 58 2

Total time ¼ 5.66 h

NA, Not applicable/available.

J ALLERGY CLIN IMMUNOL PRACT

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S52 BROYLES ET AL

reaching the maintenance dose of 400 mg twice daily, which was

managed with dose reduction to 400 mg in the morning and 200

mg in the evening. Premedication with prednisolone 30 mg and

bilastine 20 mg was used on days 1 to 4, and premedication with

bilastine 20 mg on days 5 to 7.

Sunitinib. Generalized hypersensitivity reactions are rare with

sunitinib. Bar-Sela et al

427

described a patient presenting with

onset of generalized acute urticaria and facial edema 4 days after

starting sunitinib. The patient was desensitized 1 week after

resolution of his symptoms, with oral premedications including

prednisone 20 mg and promethazine 25 mg given 1 hour before

initiation. Each of the 10 steps was carried out in 1-hour in-

tervals, and he was observed overnight before discharge

(Table LIII). The patient required desensitization with this

protocol twice, because of a treatment pause. A mild pruritic rash

developed after the ﬁrst desensitization, but resolved with oral

steroid and antihistamine, and he was able to continue the

medication. The second desensitization was well tolerated, and

he subsequently was continued on sunitinib treatment without

hypersensitivity reactions.

Alectinib. In one report, a patient developed a skin rash

affecting the arms and trunk starting 10 days after initiation of

alectinib.

428

Skin biopsy was notable for perivascular inﬁltration

of histiocytes, neutrophils, and lymphocytes in the upper dermis.

The rash resolved completely after discontinuation of alectinib,

and the patient underwent successful oral desensitization using a

protocol that was administered over 9 days (Table LIV).

BIOLOGICALS

Rituximab (by Patrick Brennan, MD, and Meredith

Dilley, MD)

General.

Rituximab is a chimeric mouse-human mAb directed

against CD20, an abundant surface receptor found on B lym-

phocytes. The incidence of clinically signiﬁcant reactions to rit-

uximab is very high, and varies widely with the indication for

treatment. Most studies have reported reaction rates during the

initial infusion ranging from 25% to more than 75%.

429-433

The

incidence of reactions during subsequent infusions is much

lower.

430,432

It should be noted, however, that severe infusion

reactions can also occur only after several exposures, or on

reexposure after a long hiatus. Most infusion reactions respond to

symptomatic treatment and/or lowering of the infusion rate, and

most reactions can be managed by the supervising oncologist or

rheumatologist. Only a fraction of infusion reactions to ritux-

imab warrant evaluation and treatment by an allergy specialist.

Because of the high incidence of reactions, however, identifying

cases that are appropriate for referral can be challenging. An al-

lergist’s evaluation is recommended for patients who have

experienced reactions that are consistent with immediate-type

hypersensitivity, severe reactions, repeated reactions, or progres-

sive reactions with multiple medication administrations.

Major symptoms of hypersensitivity. Common infu-

sion reactions can involve symptoms that are consistent with

immediate-type hypersensitivity, including hypotension, bron-

chospasm, angioedema, urticaria, ﬂushing, rhinitis, and pruritus.

The use of rituximab for lymphoid malignancy also often pre-

cipitates malaise, fever, and chills, possibly secondary to tumor

lysis. In autoimmune diseases, headache, nausea, and diarrhea

have been commonly reported. The allergy specialist should also

be aware of the possibility for serious, nonimmediate adverse

reactions including serum sickness, SJS, TEN, myocardial

infarction, arrhythmia, shock, and pulmonary toxicity.

434

Diagnosis. Reactions to rituximab can be IgE-mediated. In

patients with suspected rituximab hypersensitivity referred to an

academic allergy practice, skin testing result for rituximab was

reported as positive in 6 of 9 patients tested, suggesting that at

least some reactions to rituximab may be IgE-mediated.

435

A case

report has more thoroughly demonstrated the presence of anti-

rituximab IgE in a patient who had experienced progressive

hypersensitivity symptoms after rituximab exposure.

436

The use

of a BAT has also been reported for reactions to rituximab, but

further study is required before this modality can be used in

clinical practice.

437

As a practical approach, skin testing to rit-

uximab using 10 mg/mL epicutaneously, followed by 0.01 mg/

mL, 0.1 mg/mL, and 1 mg/mL intradermally, is recommended.

It should be noted that systematic testing of nonirritating con-

centrations for most mAbs has not been reported. A positive skin

test result after a reaction consistent with immediate hypersen-

sitivity should be interpreted as conﬁrmation of allergy.

TABLE XLIV. Rapid lenalidomide desensitization protocol

Time (min) Dilution (mg/mL) Volume (mL)

0 0.025 mg/mL 0.01

30 0.05

60 0.1

90 0.5

120 1

150 5

180 3.34

210 0.25 mg/mL 1

240 2

270 3

300 4

330 1.50 mg/mL 1

360 2

390 6

TABLE XLIII. Desensitization protocol for pemetrexed

Step Solution* Infusion rate (mL/h) Infusion time (min)

1C 5 15

2 C 10 15

3 C 20 15

4 C 50 15

5 C 100 17.25

6 B 20 15

7 B 50 15

8 B 100 19.5

9 A 20 15

10 A 50 15

11 A 100 15

12 A 200 15.6

*Solution A: pemetrexed 815 mg þ normal saline 100 mL; solution B: pemetrexed

40.75 mg þ normal saline 50 mL; solution C: pemetrexed 4.075 mg þ normal saline

50 mL.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S53

However, a negative skin testing result should not dismiss the

possibility of immediate hypersensitivity, because the sensitivity

of this testing is not known. In addition, there may be non eIgE-

mediated reactions to rituximab infusion that involve mast cell

degranulation and mediators of allergic disease, and these re-

actions would also be amenable to the management approaches

described herein. Therefore, a careful history of the reaction(s)

experienced remains a valuable diagnostic tool.

Management. Although not standardized, both antihista-

mines and systemic glucocorticoids are routinely used as ritux-

imab premedications for both oncologic and autoimmune

indications. If a reaction occurs, the infusion should be stopped,

and symptoms treated. For nonanaphylactic reactions, after

symptoms have resolved, the infusion can generally be restarted

at a slower rate. Because most infusion reactions occur during the

ﬁrst exposure and are not seen with subsequent exposures,

standard reinfusion after a ﬁrst-exposure infusion reaction is

reasonable in the absence of a life-threatening reaction.

In a retrospective review of 67 patients who reacted to rit-

uximab, 63% of reactions occurred during the ﬁrst exposure; of

these, 88% were grade 1 or 2.

438

Of these patients, 88% were

rechallenged with rituximab on the same day, and those with a

grade 1 reaction were able to complete the infusion. However, all

4 patients with a grade 3 reaction had a reaction during rechal-

lenge. After a grade 2 reaction, 84% tolerated same-day chal-

lenge, but 5 patients had a subsequent mild reaction.

For patients referred for evaluation by an allergist, skin testing

can be useful in guiding management.

439,440

If skin testing result

is negative after a mild to moderate reaction that was consistent

with immediate hypersensitivity, a graded dose challenge can be

considered; 1/100 and 1/10 dose challenges before the full dose,

with a 1-hour interval, are recommended. For patients with

positive skin testing result, or for those with negative skin test

results who experienced severe reactions consistent with imme-

diate hypersensitivity, rapid desensitization to rituximab is rec-

ommended. Reinstituting treatment with mAbs is often urgent

and time-sensitive, making the process of evaluation with skin

testing difﬁcult because of time limitations. When treatment

options are limited, desensitization should be considered to allow

for the continued use of these drugs in patients who have a re-

action consistent with immediate hypersensitivity. Rapid desen-

sitization has been a highly successful strategy for preventing

immediate-type hypersensitivity reactions to rituximab and other

mAbs.

440

In 2 case series of 14 and 7 adult patients with clinical

histories consistent with rituximab hypersensitivity, all were

successfully desensitized.

435,441

Successful desensitization has

subsequently been reported with multiple protocols.

442

A 12-

step protocol for desensitization of adults is recommended for the

initial desensitization (Table LV).

Successful rapid desensitization to rituximab and other mAbs

has also been reported in pediatric populations.

443-445

In a pe-

diatric case series, rituximab desensitization was successfully used

in 3 patients and a total of 17 infusions.

444

For an adolescent

TABLE XLVI. Thalidomide challenge protocol

Day Time (h) Dose (mg)

10 1

0.5 2

1.5 4

Observation for 6 h

20 25

0.5 25

150

Observation for 6 h

TABLE XLV. Slow desensitization to lenalidomide and schematic illustration of desensitization schedule*

Week† Monday Tuesday Wednesday Thursday Friday Saturday Sunday

1 2.5 mg

2 2.5 mg 2.5 mg 2.5 mg

3 2.5 mg 2.5 mg 2.5 mg 2.5 mg

4 2.5 mg 2.5 mg 2.5 mg 5 mg 2.5 mg 5 mg 2.5 mg

5 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg

6 10 mg 5 mg 10 mg 5 mg 10 mg 10 mg/d

Step Lenalidomide dose

1 2.5 mg PO during outpatient clinic visit and observation for 1 h. No further doses  1wk

2 2.5 mg PO every 3 d  3 doses

3 2.5 mg PO every other day  3 doses

4 2.5 mg PO qd  3 doses

5 2.5 mg PO alternating with 5 mg PO  6 doses

6 5 mg PO qd  6 doses

7 5 mg PO alternating with 10 mg PO  6 doses

8 10 mg/d*

PO, Per os (by mouth); qd, every day.

*This is an example using a target dose of 10 mg. Weekly complete blood cell counts with differential and liver function tests were obtained during desensitization.

†This regimen can be altered depending on the ﬁnal target dose. For example, a target dose of 25 mg could be achieved by alternating the 10-mg dose with the 20-mg dose for a

few doses, then introducing 25 mg/d. Once the patient has tolerated slow desensitization, repeat desensitization can be done over a 1-wk period, starting at 2.5 mg  2d,5mg

2 d, 7.5 mg  2 d, and then 10 mg/d.

J ALLERGY CLIN IMMUNOL PRACT

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S54 BROYLES ET AL

patient in this series, a similar 12-step protocol was used suc-

cessfully (Table LVI). Two younger patients, however, experi-

enced signiﬁcant reactions when a 12-step protocol was used. For

these patients, the desensitization protocol was successfully

adapted to adjust for the patients’ weight, with rate increases of

not more than approximately 0.5 mg/kg/h, and with the ﬁnal

infusion rate not exceeding 2 mg/kg/h.

Cetuximab (by Timothy Kyin, MD)

Cetuximab is a chimeric mouse-human IgG

mAb against

EGFR approved in 2005 for use in the United States for the

treatment of metastatic colorectal cancer and squamous cell

carcinoma of the head and neck. According to the product in-

formation, 3% of patients will experience a severe allergic reac-

tion, with 90% of these reactions occurring on ﬁrst exposure.

Symptoms can include difﬁculty breathing, low blood pressure,

shock, loss of consciousness, and/or heart attack.

Since its release, it has become evident that the rate of ﬁrst-

exposure hypersensitivity reaction is higher than previously

described, with a regional preference for the southeastern United

States. A 2007 review of patients receiving treatment with

cetuximab at major centers in North Carolina and Tennessee

showed that a grade 3 to 4 hypersensitivity reaction occurred in

19 (22%) of 88 patients.

446

Another multicenter study

demonstrated that most patients who experienced a hypersensi-

tivity reaction had preformed IgE to cetuximab without any

previous exposure. The antibody was speci ﬁ c for galactose-

-1,3-

galactose, which is present in the Fab portion of the cetuximab

heavy chain.

447

Unlike most mAbs, cetuximab is generated in a

mouse cell line (SP2/0), which expresses the gene for

-1,3-

galactosyltransferase. Investigation of this regional variation in

reaction rates led to the discovery that tick bites are the cause of

IgE production to galactose-

-1,3-galactose.

448

This antibody

has also been linked to delayed red meat anaphylaxis.

449

Some

have suggested that evaluation of preexisting anticetuximab IgE

could be used as a screening tool for pretreatment risk

stratiﬁcation.

450

Current manufacturer guidelines recommend discontinuation

of cetuximab after a severe allergic reaction, but there have been

reports of successful desensitizations to this medication. The ﬁrst

such report was in 2009 in a 60-year-old woman with metastatic

breast cancer who had hypotension, tachycardia, and oxygen

desaturation after receiving only 28 mg of a planned 843-mg

dose during her ﬁrst exposure.

451

She was later found to have

preexisting IgE to cetuximab. She was subsequently able to un-

dergo a complete desensitization with a 5-bag, 20-step protocol.

At Brigham and Women’s Hospital, in conjunction with the

Dana Farber Cancer Institute, a modiﬁed rapid desensitization

has been used (unpublished data). This was in a 49-year-old

woman with ﬁrst-exposure hypersensitivity, involving urticaria,

nausea, vomiting, and throat-closing sensation, and who had a

positive intradermal skin test result at 1:10 dilution. A modiﬁed

1-bag, 5-step protocol with manipulation of the infusion rate was

used for desensitization in this patient (Table LVII). Because of

the proprietary nature of the cetuximab solution, there was

concern about compound stability if the cetuximab was diluted

with standard buffers. She has thus far completed 8 de-

sensitizations of cetuximab with this protocol without

complications.

Therefore, based on these experiences, it seems reasonable that

desensitization is a viable option for this medication in the

appropriate clinical setting.

Other mAbs (by Matthieu Picard, MD)

TNF-

inhibitors

General.

TNF-

inhibitors are used for the treatment of in-

ﬂammatory bowel disease, rheumatoid arthritis, ankylosing

spondylitis, and psoriasis.

452-456

This class of biologics includes

inﬂiximab, certolizumab, adalimumab, golimumab, and

etanercept.

Major symptoms of hypersensitivity. Immediate hy-

persensitivity reactions to inﬂiximab: Immediate hypersensitivity

reactions to inﬂiximab occur in about 10% of patients and

present with features that can suggest mast cell/basophil activa-

tion (ﬂushing, pruritus, dyspnea, dizziness/hypotension) as well

as with nonspeciﬁc symptoms (headache, increased blood pres-

sure, chest and back pain, fever, and chills).

435,445,457-459

Im-

mediate hypersensitivity reactions may occur with the ﬁrst

exposure but their incidence peaks around the seventh

infusion.

435,457

Injection-site reactions and systemic reactions to certolizumab,

adalimumab, golimumab, and etanercept: Injection-site reactions

occur in about 20% of patients treated with adalimumab or

etanercept and in 2% to 6% of patients treated with certolizu-

mab or golimumab.

460,461

Reactions to etanercept occur in

median on the fourth injection, have their onset 1 to 2 days after

injection, last 2 to 3 days, and may be accompanied by recall

TABLE XLVII. Thalidomide desensitization protocol

Day Time (h) Dose

1 0 0.1

0.5 0.2

1 0.3

1.5 0.4

Observation for 1 h

201

0.5 2

1.5 4

Observation for 1 h

3 0 0.1 mg

0.5 0.2 mg

1 0.3 mg

1.5 0.4 mg

Observation for 1 h

401mg

0.5 2 mg

13mg

1.5 4 mg

210mg

2.5 20 mg

330mg

3.5 40 mg

Observation for 1 h

5 0 100 mg

Observation for 1 h

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S55

reactions (local reactions at the site of previous injections).

461

These reactions usually wane over time.

461

Systemic reactions

have rarely been reported with TNF-

inhibitors that are

administered subcutaneously.

462

Nonimmediate hypersensitivity reactions: Serum

sicknesselike reactions have been described with inﬂiximab and

adalimumab although they are much less frequent than imme-

diate hypersensitivity reactions.

460

Onset is typically from 5 to 7

days after infusion, and the hypersensitivity reaction may involve

fever, malaise, arthralgia/arthritis, and an erythematous

(sometimes) urticarial skin eruption.

463

Psoriasiform and

eczematous skin eruptions may develop during treatment with

TNF-

inhibitors.

464

Other rare reactions that may occur

include symmetrical drug-related intertriginous and ﬂexural ex-

anthem, erythema multiforme, SJS, and various autoimmune

diseases such as drug-induced lupus.

465-468

Diagnosis. IgE-mediated reactions account for a subset of

immediate hypersensitivity reactions to inﬂiximab and may be

the cause of some injection-site reactions and also of rare sys-

temic reactions to adalimumab and etanercept.

445,462

A positive

immediate skin test response to inﬂiximab and anti-inﬂiximab

IgEs were seen on average in 28% (range, 4%-67%) and 21%

(range, 13%-27%) of reactive patients, respectively.

435,445,469-471

Suggested skin testing concentrations for the various TNF-

inhibitors are presented in Table LVIII. In patients with a

negative skin test result, an IgG-mediated mechanism may be

responsible for the hypersensitivity reaction. Patients with anti-

inﬂiximab IgGs are at increased risk (relative risk varies from 2.4

to 4.0) of immediate hypersensitivity reactions compared with

patients without such antibodies.

472,473

TABLE XLVIII. Imatinib rapid oral desensitization*

421

Step Concentration Volume (mL) Dose (mg)

1 10 ng/mL 1, 2, 4 0.00007

2 100 ng/mL 1, 2, 4 0.00075

g/mL 1, 2, 4 0.0075

410

g/mL 1, 2, 4 0.075

5 100

g/mL 1, 2, 4 0.75

6 1 mg/mL 1, 2, 4 7.5

7 10 mg/mL 1, 2, 4 75

8 100-mg tablet 1 100

9 100-mg tablet  2 2 200

*Each step was administered sequentially in 15-min intervals to the 200-mg dose. An additional 100 mg was given at home the evening after desensitization, and the

maintenance dose of 400 mg daily was started the next morning.

TABLE XLIX. Imatinib slow oral desensitization*

422

Day Concentration Volume (mL) Daily dose (mg)

1 1 mg/mL 1, 2, 4 7

2-4 10 mg/mL 1, 2, 4 70

5-7 100-mg tablet 1 tablet 100

8 100-mg tablet 1 tablet 107

1 mg/mL 1, 2, 4

9-11 100-mg tablet 1 tablet 170

10 mg/mL 1, 2, 4

12-14 100-mg tablet 2 tablets 200

15 100-mg tablet 2 tablets 270

10 mg/mL 1, 2, 4

16-21 100-mg tablet 3 tablets 300

22 100-mg tablet 3 tablets 370

10 mg/mL 1, 2, 4

23 100-mg tablet 4 tablets 400

*Daily doses were administered once daily. When multiple doses were administered on the same day, each step was administered in 20-mi n intervals.

TABLE L. Crizotinib rapid oral desensitization*

423

Step Dose (mg)

110

215

325

450

5 100

*Each step was administered sequentially in 30-min intervals.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S56 BROYLES ET AL

Management. When treatment is indicated, patients with an

immediate hypersensitivity reaction to inﬂiximab should prefer-

ably be reexposed through desensitization (Table LIX) if skin

testing result is positive or the initial hypersensitivity reaction was

severe or they experienced recurrent hypersensitivity reactions

despite added premedication and/or a slowed infusion

rate.

435,459,469,470,474

In others, re-treatment using the protocols

developed by Cheifetz et al can be used and appear to be

safe.

459,469,475

These protocols vary depending on the severity of

the initial reaction and consist of slowly increasing the infusion

rate after administering premedication (H

antihistamine, acet-

aminophen, and corticosteroids for severe reactions) (Figure 5).

The risk of a recurrent reaction with subsequent exposures is

around 33% on the ﬁrst reexposure and progressively decreases

thereafter.

475

Therefore, in patients who tolerate desensitization

well, it may be reasonable to progressively shorten desensitization

protocols and eventually proceed to a challenge procedure except

in those with an IgE-mediated allergy (Figure 6).

476

Anti-inﬂiximab antibodies do not cross-react with adalimu-

mab.

477

However, patients who develop anti-inﬂiximab anti-

bodies are more prone to develop antiadalimumab antibodies

and have a higher treatment failure rate with adalimumab.

461

Also, rare cases of patients with immediate hypersensitivity re-

action to inﬂiximab have been described who also reacted to

adalimumab (injection-site reaction or serum sicknesselike re-

actions).

469,478

Despite these caveats, switching to adalimumab

after a hypersensitivity reaction to inﬂiximab can be

attempted.

459,469

Injections-site reactions to etanercept, adalimumab, golimu-

mab, or certolizumab are usually treated with ice, an oral anti-

histamine, topical corticosteroids, and analgesics.

460

Desensitization could be considered for those with important

injection-site reactions or with systemic reactions (Table LX).

462

Desensitization is not a safe method of preventing non-

immediate hypersensitivity reactions to TNF-

inhibitors, but

the optimal approach remains unclear. Switching to another

TNF-

inhibitor has not been adequately studied, though some

authors have reported that reexposure to the suspected culprit

drug may not necessarily lead to a recurrent reaction.

465,479

Ofatumumab and obinutuzumab. Ofatumumab and

obinutuzumab target CD20 and are used in the treatment of B-

cell malignancies.

480-482

Immediate hypersensitivity reactions,

thought to be caused by a cytokine release syndrome, occur in

more than 50% of patients treated with 1 of these mAbs on ﬁrst

exposure.

481,483,484

Although the incidence of hypersensitivity

reactions rapidly decreases with subsequent infusions, severe

reactions that led to drug discontinuation and even fatal hy-

persensitivity reactions, in the case of ofatumumab, have been

reported.

481,483,485

Skin testing to these mAbs has not been

studied. The approach used for hypersensitivity reactions to

rituximab can be applied to these agents because at least 2 pa-

tients were successfully desensitized to obinutuzumab

(Figure 6).

474,476

Brentuximab vedotin. Brentuximab vedotin is a chimeric

mAb coupled with a microtubule-disrupting agent used in the

treatment of CD30

lymphomas.

486

Several cases of anaphylaxis

have been reported, which usually occurred after at least 1 un-

eventful exposure.

487-489

Skin testing to brentuximab vedotin

could help identify patients with an IgE-mediated allergy.

474

Desensitization appears to be the method of choice for reexposure

in patients with anaphylaxis (Table LIX)(Figure 6).

474,487-489

Trastuzumab. Trastuzumab is a humanized mAb against the

human EGFR 2 used in the treatment of breast cancer.

490

Sixteen percent to 40% of patients experience an immediate

hypersensitivity reaction during their ﬁrst exposure to trastuzu-

mab, with clinical features suggestive of a cytokine release syn-

drome.

491,492

Most of these patients tolerate future infusions

after premedication with an antihistamine and a corticoste-

roid.

490-492

Patients who experience an immediate hypersensi-

tivity reaction after tolerating several infusions of trastuzumab are

likely to have developed an IgE-mediated reaction to the mAb.

Skin testing (Table LVIII) can be useful to identify those pa-

tients.

435,470

Although most patients with a mild to moderate

hypersensitivity reaction due to cytokine release will tolerate

reexposure through a standard reinfusion, desensitization

(Table LIX) should be considered for those with a severe cyto-

kine release reaction or with an IgE-mediated reaction

(Figure 6).

435,470,474,491,492

Papulopustular acneiform skin

eruptions have been reported in some patients treated with

trastuzumab. All were able to continue treatment with trastu-

zumab and responded well to acne treatment.

493

Pertuzumab. Pertuzumab is a humanized mAb that,

compared with trastuzumab, recognizes a different epitope of

human EGFR 2.

494

These 2 mAbs are used in combination in

the treatment of breast cancer.

494-496

Very few patients experi-

ence immediate hypersensitivity reactions to pertuzumab.

495

However, in a recent case report, a patient with anaphylaxis on

second exposure to pertuzumab was successfully reexposed

through desensitization.

497

Skin testing result to pertuzumab was

negative (Table LVIII), but a BAT result was positive, suggesting

an IgE-mediated mechanism.

497

Therefore, desensitization

(Table LIX) could be considered for patients with suspected IgE-

mediated reactions to this mAb even in the absence of a positive

skin test result (Figure 6).

474,476

Bevacizumab. Bevacizumab is a humanized mAb used in the

treatment of many types of cancer that targets vascular endo-

thelial growth factor.

498

Immediate hypersensitivity reactions to

bevacizumab occur in less than 3% of patients and are usually

mild.

499

Of the rare patients with an immediate hypersensitivity

reaction, most tolerate subsequent exposures with premedication

TABLE LI. Crizotinib rapid oral desensitization*

424

Step Concentration (mg/mL) Volume (mL) Dose (mg)

1 0.05 1.25 0.0625

2 0.05 2.5 0.125

3 0.5 0.5 0.25

4 0.5 1 0.5

5 0.5 2 1

6 5 0.4 2

7 5 0.8 4

8 5 1.6 8

9 5 3.2 16

10 5 6.25 31.25

11 5 12.5 62.5

12 5 25 125

*Each step was administered sequentially in 15-min intervals.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S57

with an antihistamine and a reduction in the infusion rate.

500

However, in 2 recent studies, two-thirds of patients with an

immediate hypersensitivity reaction to bevacizumab had a

positive skin test result (Table LVIII) and all underwent suc-

cessful desensitization (Table LIX).

470,474

Therefore, an IgE-

mediated mechanism should be suspected in those with recurrent

hypersensitivity reactions or with a severe immediate hypersen-

sitivity reaction (Figure 6).

474,476

Tocilizumab. Tocilizumab is a humanized mAb that binds

to IL-6 receptors to block IL-6 signaling.

501

It is used to treat

rheumatoid arthritis and systemic or polyarticular juvenile

arthritis.

501

Immedi ate hype rsensitivity reactions to tocilizu-

mab are rare, but several cases of anaphylaxis have been re-

ported occurring from the second exposure onward.

502,503

Skin

testing (Table LVIII) is usually useful in identifyin g patients

with an IgE-mediated hypersensitivity reaction, and desensiti-

zation (Table LIX) should be considered the method of choic e

to reexpo se those patients to tocilizumab

(Figure 6).

470,474,502, 503

Omalizumab. Omalizumab is a humanized mAb that binds

free IgE antibodies.

504

It is administered subcutaneously and is

used in the treatment of moderate to severe allergic asthma and

chronic idiopathic urticaria.

504

Anaphylaxis to omalizumab is

rare and is estimated to occur in 0.1% to 0.2% of patients.

505

history of anaphylaxis, regardless of the cause, was recently

shown to increase the risk of developing anaphylaxis to omali-

zumab to 0.6%.

506

More than half the cases of anaphylaxis to

omalizumab occur less than 1 hour after medication adminis-

tration. However, delayed reactions ( >24 hours after the injec-

tion) and a protracted course, with symptoms progressively

developing over the course of several hours, have been re-

ported.

506,507

Two patients with symptom onset more than 24

hours after the injection were rechallenged and both had recur-

rent reactions, strengthening the causality of omalizumab in these

reactions.

507

The mechanism of immediate hypersensitivity re-

actions to omalizumab remains elusive. Skin prick testing pro-

tocols with full-strength concentration followed by intradermal

testing with 1:10,000 dilution have been reported.

508

Serum

tryptase was normal in all patients with anaphylaxis to omalizumab

in whom it was measured.

509,510

Speciﬁc IgE or IgG against

omalizumab were not detected in 21 cases of anaphylaxis.

507

Skin

testing result to nonirritating concentrations of omalizumab was

negative in all patients tested (Table LVIII).

506

For patients with

hypersensitivity reactions to omalizumab, the approach remains

uncertain, but rechallenge is not recommended especially in pa-

tients with severe reactions.

476

Desensitization (Tables LXI and

LXII) may be attempted, followed by weekly or biweekly admin-

istration to preserve the desensitized state and may allow for

continued administration in some patients.

474,511

Insulin (by Christina Yee, MD, PhD)

General.

Adverse reactions to insulin have decreased in fre-

quency since the introduction of synthetic recombinant DNA

human insulin analogues, but recombinant humanized insulin

can still be associated with hypersensitivity reactions. Prevalence

of suspected insulin allergy has been reported in as few than 3%

of patients annually.

512

Pediatric and adult patients with either

type 1 or type 2 diabetes may be affected.

Recombinant human insulin analogues such as lispro, aspart,

and glulisine (short-acting) or detemir and glargine (long-acting)

have decreased immunogenicity compared with bovine or porcine

TABLE LII. Sorafenib oral tolerance induction

Day Step Dose (mg) Intervals

425

1 1 0.4 Every 15 min

2 0.8

3 1.6

4 3.2

612

724

850

9 100

10 200

11 400

2 1 100 mg Every 2 h

2 100 mg

3 200 mg

4 200 mg

3-5 1 200 mg Every 2 h

2 200 mg

3 200 mg

4 200 mg

6 and onwards 1 400 mg Every 12 h

2 400 mg

426

1 1 0.4 Every 15 min

2 0.8

3 1.6

4 3.2

612

724

850

9 100

10 200

11 400

2 1 100 mg

2 100 mg 3 h later

3 200 mg 2 h later

3 1 100 mg Every 2 h

2 200 mg

3 200 mg

4 1 200 mg Every 2 h

2 200 mg

3 200 mg

5-7 1 200 mg Every 2 h

2 200 mg

3 200 mg

4 200 mg

8 and onwards 1 400 mg Every 12 h

2 400 mg

J ALLERGY CLIN IMMUNOL PRACT

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S58 BROYLES ET AL

insulin preparations. Short-acting insulin preparations are believed

to be the least frequently associated with sensitivity because the

rapidity of absorption is thought to decrease immune

exposure. Allergic sensitization may also occur because of insulin

additives or materials used to administer insulin injections or

infusions.

Insulin reactions can pose signiﬁcant challenges for diabetic

patients, who may have no alternatives to lifelong insulin therapy.

Major symptoms of hyperse nsitivity. Adverse reactions

to insulin may present as immediate-type (IgE-mediated) hy-

persensitivity, delayed-type hypersensitivity, serum sickness, or

other reactions.

Immediate-type hypersensitivity reactions (type I, or IgE-

mediated) are the most commonly reported insulin reactions.

The causative antigen may be the insulin itself or other com-

ponents of the preparation. Symptoms may encompass the full

TABLE LIII. Sunitinib rapid oral desensitization*

427

Step Concentration (mg/mL) Volume (mL) Dose (mg)

1 0.2 0.25 0.05

2 0.2 0.5 0.1

3 0.2 1 0.2

4 0.2 2.5 0.5

51 11

61 22

71 44

81 88

9 16-mg capsule 1 capsule 16

10 25-mg capsule 1 capsule 25

*Each step was administered sequentially in 60-min intervals.

TABLE LIV. Alectinib slow oral desensitization*

428

Day Dose (mg)

1, 2 40

3, 4 80

5, 6 160

7, 8 300

9 Twice-daily 300

*Each step was administered daily, with the exception of day 9 and on.

TABLE LV. Rituximab desensitization protocol (1000 mg)*

Solution 1 250 mL of 0.040 mg/mL

Solution 2 250 mL of 0.400 mg/mL

Solution 3 250 mL of 3.969 mg/mL

Step Solution Rate (ml/h) Time (min) Volume infused per step (mL) Dose administered with this step (mg) Cumulative dose (mg)

1 1 2.0 15 0.50 0.02 0.02

2 1 5.0 15 1.25 0.05 0.07

3 1 10.0 15 2.50 0.10 0.17

4 1 20.0 15 5.00 0.20 0.37

5 2 5.0 15 1.25 0.50 0.87

6 2 10.0 15 2.50 1.00 1.87

7 2 20.0 15 5.00 2.00 3.87

8 2 40.0 15 10.00 4.00 7.87

9 3 10.0 15 2.50 9.92 17.79

10 3 20.0 15 5.00 19.84 37.63

11 3 40.0 15 10.00 39.69 77.32

12 3 80.0 175 232.50 922.68 1000.00

*Total time 5 h 40 min.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S59

spectrum of immediate-type reactions, from mild pruritus or rash

to generalized urticaria or to dyspnea, hypotension, or other

symptoms of anaphylaxis. Localized symptoms may be most

prominent near the site of the insulin injection or infusion.

Systemic reactions are rare, but anaphylaxis to insulin has been

reported even with recombinant insulin preparations.

513-515

Immediate-type insulin allergy frequently occurs within several

weeks after initiation of insulin therapy or after restarting ther-

apy, but it can also develop after years of treatment.

Symptoms of insulin reactions may also be delayed in pre-

sentation. In the case of immune complexemediated (type III)

reactions, subcutaneous nodules may develop at the injection site

after 2 to 6 hours, with later symptoms of serum sickness

including pruritic rash, joint pains, fatigue, and elevated in-

ﬂammatory markers.

516

Delayed-type hypersensitivity (type IV)

reactions to insulin detemir have also been reported, with

symptoms of prolonged induration, pain, warmth, and swelling

at the injection site, or, in 1 case report, leukoclastic vascu-

litis.

517,518

Delayed-type hypersensitivity reactions may also

occur in response to components of insulin preparations, such as

protamine or metacresol or from components of equipment used

for insulin administration, such as adhesives or tubing.

519,520

Insulin resistance and lipoatrophy at injection sites were re-

ported in patients receiving bovine or porcine insulin, and were

linked to circulating antibodies to insulin.

521

Transition to re-

combinant human insulins has eliminated many impurities

associated with animal insulin preparations, and such associated

side effects are now rare.

Diagnosis. A careful history is vital in the evaluation for a

potential insulin reaction. Other causes of symptoms must be

excluded. In a retrospective study, 59% of suspected cases of

insulin “allergy” did not have an allergic cause.

522

Patients with

diabetes mellitus have increased incidence of other autoimmune

diseases, which should also be considered on the differential

diagnosis. Chronic urticaria, atopic dermatitis, psoriasis, vascu-

litis, and other systemic autoimmune diseases may present with

rash or other skin manifestations.

Timing and characteristics of associated symptoms should be

considered to determine the likely type of reaction. Allergic re-

actions to insulin can occur to the insulin itself; to preservatives

and solvents such as metacresol, phenol, or sodium phosphate; or

to insulin additives such as protamine or zinc, which help slow

insulin absorption.

523-526

In addition, hypersensitivity reactions

have been reported to injection or infusion pump equipment,

latex, nickel, epoxy resin, and local disinfectants.

527,528

There-

fore, consideration must also be given to components of the

insulin preparation being used, as well as to components of

equipment used for infusion (syringes, needles, infusion pump

tubing, adhesives, etc), latex in this equipment or in the stopper

of insulin vials, and possible reactions to alcohol or disinfectant

wipes.

TABLE LVI. Rituximab desensitization protocol for pediatric patients*

444

Solution Total volume (mL) Drug per bag (mg) Concentration (mg/mL)

1 250 2.06 0.008

2 250 20.6 0.082

3 250 205.189 0.821

Step Solution Rate(mL/h) Rate (mg/kg/h) Time (min) Dose per step (mg) Cumulative dose (mg)

1 1 1 0.0006 15 0.0021 0.0021

2 1 2.5 0.002 15 0.0052 0.0072

3 1 5 0.003 15 0.0103 0.0175

4 1 10 0.006 15 0.0206 0.0381

5 2 2.5 0.02 15 0.0515 0.0896

6 2 5 0.03 15 0.103 0.1926

7 2 10 0.07 15 0.206 0.3986

8 2 20 0.1 15 0.412 0.8106

9 3 5 0.3 15 1.0259 1.8366

10 3 10 0.7 15 2.0519 3.8885

11 3 20 1.3 15 4.1038 7.9922

12 3 30 2 482.5 198.0078 206

*Total infusion time: 648 min; ﬁnal infusion rate: 2.0 mg/kg/h.

TABLE LVII. Cetuximab desensitization protocol: 1-solution, 5-step protocol*

Step Solution Rate (mL/h) Time (min) Volume infused per step (mL) Dose administered with this step (mg) Cumulative dose (mg)

11† 5.0 30 2.50 5.0658 5.0658

2 10.0 30 5.00 10.1316 15.1974

3 20.0 30 10.00 20.2632 35.4606

4 40.0 30 20.00 40.5264 75.9870

5 80.0 256.87 342.49 694.0011 769.9881

*Target dose: 770.0 mg; volume per bag: 380 mL; ﬁnal rate of infusion: 80 mL/h; calculated ﬁnal concentration: 2.026 mg/mL; total time: 376.87 min (6.28 h).

†Solution 1: 380 mL of 2.026 mg/mL (total per bag: 770.002 mg).

J ALLERGY CLIN IMMUNOL PRACT

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S60 BROYLES ET AL

Although diagnostic testing for anti-insulin IgE and IgG

antibodies has been studied, the presence of insulin-speciﬁc an-

tibodies cannot be used to establish a diagnosis of insulin allergy,

because anti-insulin IgE antibodies can be present in patients

with no apparent allergy.

529

BATs have also been used to mea-

sure in vitro responses to insulin, but their clinical utility has not

been established, and the tests are not commercially available.

Skin testing for the insulin preparations used, alternative in-

sulin preparations, and additives may help distinguish the speciﬁc

allergenic component or components (Table LXIII). Skin testing

for short-acting insulins (Table LXIV), which may be less aller-

genic, may be considered for patients with possible allergic

symptoms to continuous subcutaneous insulin infusion, or pa-

tients with allergy to other forms of insulin for whom this

therapy may be considered.

Positive insulin skin testing results have been reported in

patients receiving insulin without allergic symptoms, so skin test

results must be correlated with clinical symptoms.

522

It may be

helpful to include alternative insulin preparations in skin testing,

to identify preparations to which a patient may not be sensitized.

Testing should also include additives present in each formulation

of interest. Sterile diluent vials (eg, Lily Sterile Diluent 1-ND

800) are commonly used for injection teaching and diluting

insulin. These contain additives such as metacresol and glycerin

at concentrations equivalent to insulin preparations, so they may

be helpful in skin testing.

In the case of a suspected reaction to a long-acting insulin

preparation containing protamine, sensitization to protamine

should also be excluded. Testing result should be interpreted

with care, because a signiﬁcant percentage of diabetic patients

who have received neutral protamine Hagedorn insulin without

history of adverse reaction may have positive skin testing result

and/or serum-speciﬁc IgE to protamine.

530,531

Skin prick testing

for protamine may be performed at a dilution matching the

approximate concentrations contained in neutral protamine

Hagedorn insulin (350

g/mL, a 30-fold dilution of stock

protamine, 10 mg/mL).

532

If the insulin preparation has a stopper containing latex, skin and/

or blood testing for latex allergy may also be included in the evalu-

ation. However, many preparations of insulin are now latex-free.

Serum sicknessetype reactions to insulin are relatively rare,

and have been diagnosed primarily on the basis of clinical

symptoms. Skin biopsy has shown perivascular lymphocytic

inﬁltrate in some cases.

518

For evaluation of delayed-type hy-

persensitivity to insulin, intradermal skin testing result to insulin

has been reported to be positive in some patients after 24 or 48

hours.

522,532

Patch testing can also been performed for potential

contact dermatitis reactions to nickel in subcutaneous infusion

needles, acrylates in infusion catheters, adhesives in butterﬂy

catheters, or other additives such as parabens, phenol, and

isophane.

If timing and location of symptoms are insufﬁcient to establish

the diagnosis, skin biopsy may be helpful to rule out systemic

dermatologic conditions such as vasculitis, psoriasis, or eczema.

Management. Initial management of suspected allergic re-

actions to insulin may include antihistamines and/corticoste-

roids, particularly for local reactions.

Changing therapy may be considered. Patients with type 2

diabetes and insulin allergy can have a trial of conventional oral

hypoglycemic medications. Liraglutide, a glucagon-like peptide-1

receptor agonist that promotes endogenous insulin secretion, has

also been used in insulin allergy.

533

TABLE LVIII. Suggested skin testing concentrations for mAbs*

Agent SPT IDT

Adalimumab†

462

40 mg/mL (full strength) 0.4 mg/mL (1/100 dilution)

Bevacizumab†

380,470

25 mg/mL (full strength) 2.5 mg/mL (1/10 dilution)z

Brentuximab vedotin

474

1.8 mg/mL 0.18 mg/mL

Certolizumab NA NA

Cetuximab†

380,470

2 mg/mL (full strength) 0.2 mg/mL (1/10 dilution)x

Etanercept†

462

50 mg/mL (full strength) 0.5 mg/mL (1/100 dilution)

Golimumab NA NA

Inﬂiximab†

380,445

10 mg/mL (full strength) 1 mg/mL (1/10 dilution)

Obinutuzumab NA NA

Ofatumumab NA NA

Omalizumab†

508

125 mg/mL (full strength)k 0.00125 mg/mL (1/100,000 dilution)

Pertuzumab

497

1.6 mg/mL (z1/20){ 0.16 mg/mL (z1/200 dilution)x

Rituximab†

380,435

10 mg/mL (full strength) 1 mg/mL (1/10 dilution)#

Tocilizumab†

502

20 mg/mL (full strength) 20 mg/mL (full strength)

Trastuzumab

435

21 mg/mL (full strength) 2.1 mg/mL (1/10 dilution)

NA, Not available.

*All dilutions should be made in normal saline (from Picard et al).

476

†Concentrations shown to be nonirritating by testing on healthy control subjects.

zA concentration of 25 mg/mL was also shown to be nonirritating.

380

xA concentration of 0.5 mg/mL was shown to be nonirritating in 8 controls, and another group reported a concentration of 5 mg/mL to be nonirritating.

380,450

kOmalizumab should be reconstituted with normal saline to avoid false-positive results.

508

{Full-strength concentration is 30 mg/mL. Pertuzumab was tested on only 1 reactive subject, with negative results at 1.6 mg/mL (SPT) and up to 0.16 mg/mL (IDT). Higher

concentrations could be nonirritating.

#Although 1 mg/mL (IDT) is more commonly used, a maximal concentration of 10 mg/mL (full strength) for rituximab IDT is recommended by the European Network on Drug

Allergies and does not seem irritating.

380

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S61

If ongoing insulin therapy is required, changing to an alter-

native insulin preparation may be sufﬁcient to avoid further

symptoms. In the case of immediate-type reactions, if switching

insulin preparations is not feasible or alternative therapies do not

adequately control blood sugar levels, immunotherapy in the

form of desensitization may be considered. Established desensi-

tization protocols may administer insulin as increasing in-

crements of subcutaneous doses, continuous subcutaneous

infusions delivered by insulin pumps, or (rarely) by intravenous

infusion, with either regular insulin forms or recombinant in-

sulin.

534-537

Insulin desensitization has been performed starting

with subcutaneous infusion at 1  10

3

units and doubling

every 15 to 20 minutes, up to a dose of 1 unit, then switching to

continuous infusion through the insulin pump to maintain

desensitization. Transition from regular insulin to longer-acting

forms of insulin can also be attempted in desensitization

(Table LXV). Depending on patient size and total dose of in-

sulin, blood glucose levels may be monitored before, after, and

Immediate HSR to inﬂiximab

Pretreat with diphenhydramine (25-50 mg PO) and

acetaminophen (650 mg PO) 30 minutes before the next infusion

and depending on the severity of the reacon:

Mild

Moderate

Severe

- Start infusion at 10 mL/h

for 15 minutes

- If tolerated, increase

infusion rate to infuse

over 3 hours

- Start infusion at 10 mL/h

for 15 minutes

- If tolerated, increase

infusion rate to 20 mL/h

for 15 minutes

- 40 mL/h for 15 minutes

- 80 mL/h for 15 minutes

- 100 mL/h for 15 minutes

- 125 mL/h through

compleon

- Add prednisone (50 mg

PO) x 3 over 12 hours

before infusion or

hydrocorsone (100 mg

IV) or methylprednisonole

(2-40 mg IV) 20 minutes

before infusion

- Start infusion at 10 mL/h

for 15 minutes

- If tolerated, increase

infusion rate to 20 mL/h

for 15 minutes

- 40 mL/h for 15 minutes

- 80 mL/h for 15 minutes

- 100 mL/h for 15 minutes

- 125 mL/h through

compleon

FIGURE 5. Protocol for desensitization to infliximab.

475

IV, Intravenous; PO, per os (by mouth).

TABLE LIX. Example of a 3-bag/12-step desensitization protocol that is applicable for most mAbs administered intravenously

Rituximab desensitization protocol (1000 mg)

Solution 1 250 mL of 0.040 mg/mL

Solution 2 250 mL of 0.400 mg/mL

Solution 3 250 mL of 3.969 mg/mL

Step Solution Rate (mL/h) Time (min) Volume infused per step (mL) Dose administered with this step (mg) Cumulative dose (mg)

1 1 2.0 15 0.50 0.02 0.02

2 1 5.0 15 1.25 0.05 0.07

3 1 10.0 15 2.50 0.10 0.17

4 1 20.0 15 5.00 0.20 0.37

5 2 5.0 15 1.25 0.50 0.87

6 2 10.0 15 2.50 1.00 1.87

7 2 20.0 15 5.00 2.00 3.87

8 2 40.0 15 10.00 4.00 7.87

9 3 10.0 15 2.50 9.92 17.79

10 3 20.0 15 5.00 19.84 37.63

11 3 40.0 15 10.00 39.69 77.32

12 3 80.0 175 232.50 922.68 1000.00

Total time 5 h 40 min

J ALLERGY CLIN IMMUNOL PRACT

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S62 BROYLES ET AL

during the desensitization. For severe or refractory cases, desen-

sitization has been combined with systemic cortisosteroids or

other immune modulators such as prednisolone, rituximab,

omalizumab, or mycophenolate.

538

Delayed reactions at the injection site may be of either type III

or type IV, and skin patch testing result may be negative. Large

local reactions may respond to antihistamines or, if needed, local

injections of steroids (100 mg dexamethasone diluted in 100

units insulin and used for subcutaneous injections or continuous

infusion with insulin pump). Topical cromolyn sodium may also

be compounded as a lotion or cream for local application. If local

injections are not sufﬁcient to control symptoms, desensitization

can also be attempted. For treatment of delayed reactions, change

in insulin preparations may also be beneﬁcial. For type III re-

actions, successful treatment with MTX,

518

colchicine, and

6-mercaptopurine (6-MP),

539

as well as plasmapheresis,

540

have

been reported.

Conclusions. Insulin allergy is a rare, but serious condition.

Patients may be sensitized to insulin itself, to additives in insulin

preparations, or to equipment used to administer subcutaneous

doses. Evaluation begins with a history and close examination of

additives contained in the form of insulin administered

(Table LXIII). Skin testing with insulin and additives may be

helpful to evaluate immediate-type reactions, and patch testing

may be useful for delayed reactions. The ﬁrst steps in manage-

ment are to identify potential alternative insulin forms and treat

symptoms with antihistamine and steroids if indicated. Large

local reactions may beneﬁt from local steroid injection and

topical cromolyn preparation, and may improve over time. If

initial strategies are not successful in preventing reactions, sub-

cutaneous desensitization may be attempted.

Progestogens including progesterone (by Dinah

Foer, MD, Andrew MacGinnitie, MD, PhD, and

Kathleen M. Buchheit, MD)

General.

Progesterone is an endogenous steroid hormone

involved in the menstrual cycle and pregnancy. Synthetic pro-

gesterone preparations known as progestins are also used as

contraception and hormone replacement, particularly in the

setting of in vitro fertilization. Adverse reactions to both

endogenous progesterone and exogenous progestins have been

documented and were initially termed autoimmune progesterone

FIGURE 6. Suggested algorithm for the management of immediate hypersensitivity reactions to mAbs. Reactions due to cytokine release

syndrome typically occur on the first administration and wane rapidly with subsequent exposures. Symptoms usually include fever, chills,

rigors, and dyspnea but flushing, dizziness/hypotension, and gastrointestinal symptoms can also be seen. IgE-mediated and IgG-mediated

reactions generally occur after at least 1 uneventful administration although IgE-mediated reactions have been described on first exposure

to cetuximab due to preformed IgEs. IgG-mediated reactions have not been clearly demonstrated in humans, but they could account for

reactions similar to IgE-mediated hypersensitivity reactions but in which IgE antibodies cannot be demonstrated (eg, skin testing result is

negative). Grade 1 immediate hypersensitivity reactions present with symptoms that are limited to the skin (eg, flushing) or that involve a

single organ/system and that are mild (eg, mild back pain). Grade 2 hypersensitivity reactions present with symptoms that involve at least

2 organs/systems (eg, flushing and dyspnea) but without a significant drop in blood pressure or in oxygen saturation. Grade 3 hyper-

sensitivity reactions present with symptoms that typically involve at least 2 organs/systems and with a significant drop in blood pressure

(systolic  90 mm Hg and/or syncope) and/or in oxygen saturation (92%). Modified with permission from Picard et al.

476

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S63

dermatitis, but more recently, the terminology has been changed

to progestogen hypersensitivity (PH) to more accurately reﬂect

the pathobiology.

541,542

Hypersensitivity reactions to progester-

one are rare, with just over 100 cases reported, but with the

increased use of exogenous progestogens, PH has become more

frequently described.

543

Clinical presentation. Onset of symptoms can occur in

women any time between menarche and menopause. Endoge-

nously triggered presentations are often cyclical, because pro-

gesterone levels peak approximately 1 week before the onset of

menses.

544

In cases of PH associated with exogenous progester-

one, the timing of symptoms should correlate with progestin

TABLE LX. Desensitization protocol for etanercept and adalimumab*

Time (min) Dose (mg) Diluti on Volume administered (mL)

Etanercept

Day 1

0 0.25 1/100 1

30 0.5 1/10 0.2

60 1 1/10 0.4

90 2 1/10 0.8

120 4 Undiluted 0.16

150 4.5 Undiluted 0.18

Day 2

0 0.25 1/100 1

30 0.5 1/10 0.2

60 1 1/10 0.4

90 2 1/10 0.8

120 4 Undiluted 0.16

150 4.5 Undiluted 0.18

Day 3

0 0.5 1/100 1

30 1 1/10 0.2

60 2 1/10 0.4

90 4 1/10 0.8

120 8 Undiluted 0.16

150 16 Undiluted 0.32

180 18.5 Undiluted 0.37

Adalimumab

0 0.5 1/100 1

30 0.75 1/10 0.15

60 1.25 1/10 0.25

90 2.5 1/10 0.5

120 5 Undiluted 0.1

150 10 Undiluted 0.2

180 20 Undiluted 0.4

*Once desensitization was achieved, patients were administe red the mAb weekly to maintain desensitization (adapted from Bavbek et al

462

TABLE LXI. Desensitization protocol for omalizumab*

Time (min) Dose (mg) Diluti on Volume administered (mL)

0 0.0625 1/100 0.05

30 0.625 1/100 0.5

60 1.25 1/10 0.1

90 2.5 1/10 0.2

120 5 1/10 0.4

150 10 1/10 0.8

180 20 Undiluted 0.16

210 37-40† Undiluted 0.30-0.32

240 37-55† Undiluted 0.30-0.44

270 37-55† Undiluted 0.30-0.44

*The dose of omalizumab to which patients were desensitized was lower than their target dose and subsequent injections were administered weekly or biweekly.

†Depending on the total dose to be administered.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S64 BROYLES ET AL

TABLE LXII. Desensitization protocol for omalizumab (target dose ¼ 150 mg)*

Time (min) Dose (mg) Dilution Volume administered (mL)

0 1.5 12.5 mg/mL 0.12

30 3 12.5 mg/mL 0.24

60 6 12.5 mg/mL 0.48

90 12 12.5 mg/mL 0.96

120 23.75 125 mg/mL 0.19

150 48.75 125 mg/mL 0.39

180 55 125 mg/mL 0.44

*Adapted from Isabwe et al.

474

TABLE LXIII. Insulin formulations, additives, and concentrations for skin testing

522,532,933

Insulin formulation;

manufacturer Duration of action Protamine Other additives

Stock

concentration

SPT

concentration

IDT dilutions

(0.02 mL)

Insulin aspart (NovoLog);

Novo Nordisk

Rapid None Metacresol 1.72 mg/mL,

glycerin 16 mg/mL, phenol

1.5 mg/mL, zinc oxide 19.6

g/mL

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Insulin glulisine (Apidra);

Sanoﬁ

Rapid None Metacresol 3.15 mg/mL,

tromethamine 6 mg/mL,

polysorbate-20 0.01 mg/

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Insulin lispro (Humalog U-

100); Eli Lily

Rapid None Metacresol 3.15 mg/mL,

glycerin 16 mg/mL, zinc

oxide 19.7

g/mL (46

mL for U-200)

100 IU/mL

(200 IU/mL

for U-200)

100 IU/mL 1 IU/mL

10 IU/mL

Regular insulin (Humulin R

U-100); Eli Lily

Short None Metacresol 2.5 mg/ml,

glycerin 16 mg/mL, zinc

oxide 17

g/100 IU

100 IU/mL

(500 IU/mL

for U-500)

100 IU/mL 1 IU/mL

10 IU/mL

Regular insulin (Novolin R);

Novo Nordisk

Regular None Metacresol 3 mg/mL, glycerol

16 mg/mL, zinc oxide 7

g/mL

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Lily Sterile Diluent (1-ND

800); Eli Lily

NA None Metacresol 1.6 mg/mL,

glycerin 16 mg/mL

NA Undiluted 1:100

1:10 (dilutions)

Insulin NPH (Novolin N);

Novo Nordisk

Intermediate Protamine sulfate

w0.35 mg/mL

Metacresol 1.5 mg/mL,

glycerol 16 mg/mL, phenol

0.65 mg/mL, zinc w33.5

µg/mL (vial) and

32.2 µg/mL (FlexPen)

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Insulin NPH (Humalin N);

Eli Lilly

Intermediate Protamine sulfate

0.35 mg/mL

Metacresol 1.6 mg/mL,

glycerin 16 mg/mL, phenol

0.65 mg/mL, zinc oxide 25

g/mL, glycerin 16 mg/mL

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Humalog 75/25; Eli Lilly Intermediate Protamine sulfate

0.28 mg/mL

Metacresol 1.76 mg/mL,

glycerin 16 mg/mL, phenol

0.715 mg/mL, zinc oxide

g/mL

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Novolog 70/30; Novo

Nordisk

Intermediate Protamine sulfate

0.32 mg/mL

Metacresol 1.72 mg/mL,

glycerin 16 mg/mL

(Flexpen only), phenol 1.5

mg/mL, zinc 19.6

g/mL,

mannitol 36.4 mg/mL

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Insulin detemir (Levemir);

Novo Nordisk

Intermediate/

long

None Metacresol 2.06 mg/mL,

glycerin 16 mg/mL, phenol

1.8 mg/mL, zinc 65.4

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Insulin glargine (Lantus,

Optisulin); Sanoﬁ-Aventis

Long None Metacresol 3

g/mL, glycerin

1.7 mg/mL, zinc 3

g/mL,

polysorbate-20 2

g/mL*

100 IU/mL 100 IU/mL 1 IU/mL

10 IU/mL

Protamine sulfate; Fresenius

Kabi

NA 10 mg/mL Parabens 10 mg/mL 1 mg/mL

532

10 mg/mL

522,532

0.0001 mg/mL

522

IU, International unit; NPH, neutral protamine Hagedorn.

*For 10-mL vial, 3-mL cartridge has no polysorbate-20 and 3.3 higher concentrations for all other additives.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S65

exposure. Use of high-dose progestogens in women undergoing

in vitro fertilization may predispose them to the development of

PH and make it difﬁcult for patients to undergo fertility treat-

ment.

543

Therefore, a careful history of both symptom timing

and exposures is critical to making the diagnosis of PH.

Major symptoms. PH is a multisystem disorder. It is char-

acterized by skin lesions, which include urticaria, eczema, ery-

thema multiforme, papulopustular lesions, vesiculobullous and

vesiculopustular lesions, as well as angioedema.

545-547

Non-

dermatologic hypersensitivity symptoms have also been

described, including asthma and anaphylaxis.

546,548

Both non-

dermatologic and dermatologic manifestations have been

described in the same patient.

546

Diagnosis. Diagnosis is primarily based on clinical symptoms

correlating with progestogen exposure. Skin testing for PH may

be used in the appropriate clinical context to conﬁrm possible

cases of PH. The results must be interpreted with caution

because the sensitivity and speciﬁcity are unknown and false-

positive reactions frequently occur.

542

This may be due to the

progesterone vehicle because it is not water soluble and must be

dissolved in an oil- or ethanol-based diluent. Therefore, the skin

testing diluent should be included as a control in addition to

appropriate saline (negative) and histamine (positive) controls.

Table LXVI lists a published skin testing protocol. An uncon-

vincing history, regardless of skin test result, should prompt the

clinician to consider a broader differential diagnosis. Because

approximately half of patients with PH have positive skin test

results and there are concerns about false-positive testing results,

response of symptoms to administration of a gonadotrophin-

releasing hormone agonist has been proposed as an alternative

diagnostic strategy, at least for those with symptoms from

endogenous exposure.

542,549

Management. Management of PH varies widely on the basis

of patient’s symptoms and long-term goals. First-line treatment

includes symptom management with antihistamines and/or oral

or topical steroids as appropriate. In patients who do not expe-

rience relief with symptomatic therapies, additional therapies

such as oral contraceptive pills, tamoxifen, attenuated androgens,

gonadotropin-releasing hormone agonists, and omalizumab can

be considered.

550-553

However, these therapies may have long-

term adverse side effects limiting patient tolerance. In extreme

cases of endogenously triggered PH, oophorectomy remains a

curative option.

554

Progesterone desensitization has been demonstrated as a safe

and efﬁcacious option for PH management. Consideration must

be given to premedication, trained staff, and clinical settings

before initiating desensitization.

543

Indications for desensitiza-

tion include need for high-dose progesterone therapy for fertility

TABLE LXIV. Short-acting insulin testing

Insulin SPT concentration (IU/mL) IDT dilutions (IU/mL)

Novolog (insulin aspart) 100 IU/mL 1 IU/mL

10 IU/mL

Humalog (lispro) 100 IU/mL 1 IU/mL

10 IU/mL

Apidra (glulisine) 100 IU/mL 1 IU/mL

10 IU/mL

Lily Sterile Diluent Undiluted 1:100 dilution

IU, International unit.

TABLE LXV. Desensitization protocol for regular/NPH insulin by subcutaneous injection*

Step Time (min) Dose administered (units) Type of insulin Cumulative dose (units)

1 0 0.01 Regular 0.01

2 30 0.02 Regular 0.03

3 60 0.05 Regular 0.08

4 90 0.1 Regular 0.18

5 120 0.2 Regular 0.38

6 150 0.5 Regular 0.88

7 180 1 Regular 1.88

8 210 2 Regular 3.88

9 240 5 Regular 8.88

10 60 min after previous dose 10 NPH 18.88

11 12 h after previous dose 10 NPH 28.88

NPH, Neutral protamine Hagedorn.

*Blood glucose by ﬁngerstick should also be checked every 60 min during steps 1 to 10, and per routine thereafter. After the completion of this protocol, the patient should

remain on NPH 10 units twice a day. His endocrinologist can then gradually increase the insu lin dose in the outpatient setting, because this dose is likely not adequate.

TABLE LXVI. Progesterone skin testing protocol

541,542

Diagnostic modality Progesterone concentration (mg/mL)*

Skin test 50

Intradermal 0.05

0.5

*Diluent benzyl alcohol or olive oil.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S66 BROYLES ET AL

treatment and persistent hypersensitivity symptoms. For women

undergoing in vitro fertilization, intravaginal and intramuscular

desensitization has been used (Table LXVII, A and B).

542,543

These cases are often managed in conjunction with a repro-

ductive endocrinologist to optimize desensitization timing. Slow

oral desensitization has been proposed for patients with derma-

titis refractory to standard therapies (Table LXVII, C).

542

Sub-

sequently, patients must continuously cycle on an oral

contraceptive to maintain a steady state of progesterone to avoid

resensitization.

Glatiramer acetate (Copaxone) (by Elena Crestani, MD)

General.

Glatiramer acetate (Copaxone) is a mixture of small

polypeptides approved by the FDA as a ﬁrst-line disease-modi-

fying agent in the treatment of patients with relapsing-remitting

multiple sclerosis, given its ability to decrease the frequency of

relapse and the progression of disability in affected in-

dividuals.

555

It is administered as a 1-mL subcutaneous injection,

either daily (20 mg/mL) or 3 times per week (40 mg/mL).

Major symptoms of hypersensitivity. Immediate in-

jection-site reactions are very common, occurring in up to

60% of the patients, and present with erythema, edema,

and pruritus.

556

These reactions are thought to be due to

direct mast cell activation at the site of injection causing the

release of histamine and other mediators. Other local re-

actions have also been described in the literature, thought to

be caused by either direct drug toxicity (skin necrosis,

lobular panniculitis) or immunomodulation (erythema

nodosum, urticarial vasculitis).

557-563

About 10% of patients

experience an immediate postinjection systemic reaction

characterized by various combinations of ﬂushing, hives,

chest pain, anxiety, subjective sensation of dyspnea, and

throat constriction. These reactions can develop at any time

during treatment with glatiramer acetate, even after pro-

longed use, and their severity usually prompts discontinua-

tion of treatment, which otherwise offers a relatively benign

side-effect proﬁle. This can be detrimental, especially for

those patients who may not be candidates for other treat-

ments. Although some of these reactions may represent

true IgE-mediated anaphylaxis, other immediate—and occa-

sionally delayed—cases are associated with negative allergy

testing and are likely due to alternative immunologic

mechanisms.

561,564-567

TABLE LXVII. Progesterone desensitization protocols

A. Intravaginal progesterone desensitization

541

Time (h) Dose (mg)*

00:00 (ﬁrst day) 0.1

00:45 1

01:30 5

02:15 10

03:00 25

00:00 (next day) 50

00:45 100

01:30 100

B. Intramuscular progesterone desensitization

542

0 min 1

30 min 2

60 min 4

90 min 8

120 min 16

150 min 18.5

Total dose 50

Target daily dose Intravaginal progesterone 50-90 mg† depending on IVF protocol

C. Slow oral progestin desensitizationz

542

Day Dose (based on norethindrone component) No. of capsules 3 capsule dose per day Total daily dose

1 1.25

g in AM, 2.5

ginPM 1 1.25

g; 2  1.25

g 3.75

2 2.5

g in AM, 12.5

ginPM 2 1.25

g; 1  12.5

g15

3 12.5

g in AM, 25

ginPM 1 12.5

g; 2  12.5

g 37.5

4 37.5

g in AM, 37.5

ginPM 3 12.5

g; 3  12.5

g75

550

g in AM, 75

ginPM 1 50

g; 1  50

g þ 2  12.5

g 125

6 250

g2 125

g 250

7 500

g4 125

g 500

8 500

g4 125

g 500

9 1 mg 1  1mg 1mg

IVF, In vitro fertilization.

*Dosing based on target progestogen concentration.

†8% gel once daily.

zTarget dose: norethindrone 1 mg/ethinyl estradiol 0.02 mg.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S67

Diagnosis. Skin prick testing is performed using the full

concentration of 20 mg/mL of glatiramer acetate (which is

negative in nonexposed controls). If prick testing result is

negative, intradermal testing is performed using 0.00002 mg/mL

(1:1,000,000 dilution), and if still negative, 0.0002 mg/mL

(1:100,000 dilution), which is the highest nonirritating con-

centration reported in a study.

568

Previous reports indicated a

high rate of false-positive reactions in control subjects when

higher concentrations were used. Also, each 20-mg vial of gla-

tiramer acetate contains 40 mg of mannitol, which is an irritant

that could at least in part be responsible for the high frequency of

nonspeciﬁc reactions reported.

569,570

Speciﬁc IgE to glatiramer

acetate have been measured via ELISA in a few patients and levels

were found to be elevated in most, though not all, patients with

positive skin testing result.

567,569

These determinations were

performed on a research basis, because speciﬁc IgE testing is not

available commercially. Finally, BAT was reported in a series of 3

patients with systemic reactions and positive skin testing result,

and the result was positive in 2 of them. Overall, though gla-

tiramer acetate skin testing has not been validated, it appears to

be the most useful diagnostic tool to assist in the evaluation and

management of patients with a history of reactions to glatiramer

acetate to determine whether an IgE-mediated mechanism may

be involved; this could help in making a decision about future

desensitization if indicated.

Management. Successful desensitization to glatiramer acetate

in the context of immediate IgE-mediated hypersensitivity has

TABLE LXVIII. Glatiramer acetate desensitization protocol*

567

Solution Volume (mL) Concentration (mg/mL) Timing Dose (mg) Cumulative dose (mg)

1 0.5 0.000002 0:00 0.000001 0.000001

2 0.5 0.00002 0:30 0.00001 0.000011

3 0.5 0.0002 1:00 0.0001 0.000111

4 0.5 0.002 1:30 0.001 0.001111

5 0.5 0.02 2:00 0.01 0.011111

6† 0.5 0.2 2:30 0.1 0.1

7 0.5 2 3:00 1 1

8 0.2 10 3:30 2 3

8 0.3 10 4:00 3 6

9 0.2 20 4:30 4 10

*After successful desensitization, start treatment with 10 mg twice daily for 2 doses and then switch to 20 mg daily if no reactions.

†Numbers rounded at step 6.

TABLE LXIX. Rapid desensitization protocol for intravenous administration of imiglucerase (1500 IU)

578

Solution Step Rate (mL/h) Time (min) Dose administered with each step (units) Cumulative dose (units)

1 1 2.0 15 0.0300 0.0300

1 2 5.0 15 0.0750 0.1050

1 3 10.0 15 0.1500 0.2550

1 4 20.0 15 0.3000 0.5550

2 5 5.0 15 0.7500 1.3050

2 6 10.0 15 1.5000 2.8050

2 7 20.0 15 3.000 5.8050

2 8 30.0 15 4.5000 10.3050

3 9 7.0 15 10.4279 20.7329

3 10 15.0 15 22.3454 43.0783

3 11 30.0 15 44.6909 87.7691

3 12 80.01 177.75 1412.2309 1500.0000

IU, International unit.

Description: Solution 1, 0.060 U/mL; Solution 2, 0.600 U/mL; Solution 3, 5.959 U/mL.

Total administration time: 5.71 h.

Premedication: dimetindene, 4 mg administered intravenously 20 min before rapid desensitization.

TABLE LXX. Protocol for vaccine graded dose administration/desensitization*

Step Volume (mL) Dilution

1 0.05 1:10

2 0.05 Full strength

3 0.1 Full strength

4 0.15 Full strength

5 0.2 Full strength

*Adapted with permission from Kelso et al.

586

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S68 BROYLES ET AL

been described both in adult and in pediatric patients. A report

in 2010 described a desensitization protocol that was successfully

applied to 6 adult patients with a history of both immediate or

delayed systemic reactions and positive skin testing result.

571

Also, a modiﬁed, more gradual version of the protocol, which

included premedication with steroids and antihistamines, was

successfully carried out to desensitize another adult patient.

572

similar protocol was applied to a 51-year-old woman with

generalized urticarial and positive skin testing result to glatiramer

acetate.

569

The youngest patient ever documented to undergo

successful desensitization was a 14-year-old girl who experienced

a severe systemic reaction and was found to have positive skin

testing result; she was successfully desensitized to the full dose of

20 mg of glatiramer acetate (10 mg every 12 hours) and was

eventually transitioned to daily injections (20 mg daily) with no

further adverse reactions

568

(Table LXVIII). The same protocol

has been successfully used to desensitize another pediatric pa-

tient, and doctors were able to switch the patient to daily dosing

within 24 hours of desensitization. H

and H

blockers, anti-

leukotriene, or leukotriene receptor antagonists may be used for

pretreatment and/or treatment of breakthrough reactions.

Imiglucerase (Cerezyme) (by Joseph Zhou, MD, PhD)

General.

Imiglucerase (Cerezyme) is a highly puriﬁed human

enzyme used for long-term enzyme replacement therapy for type

1 Gaucher disease. Up to 15% of patients may experience

adverse reactions.

573

Reported adverse events include gastroin-

testinal irritation (nausea, vomiting, abdominal pain, diarrhea),

nonspeciﬁc constitutional symptoms (fatigue, fever, headache,

chills, rash, and backache), and tachycardia. Approximately 15%

of patients have developed IgG antibodies, and although more

than 90% of these patients tolerated the infusion for at least 24

to 36 months, almost half of these antibody-positive patients

later experienced symptoms suggestive of hypersensitivity.

574,575

In general, hypersensitivity reactions to imiglucerase intravenous

infusion have been reported in approximately 13.8% of patients.

IgE-mediated hypersensitivity reactions caused by imiglucerase

are not common, and anaphylaxis to imiglucerase infusion is rare

(reported in <1% of patients).

576,577

Given the detrimental consequence of anaphylaxis, patients

with symptoms suggesting hypersensitivity reaction to imiglu-

cerase need to be evaluated carefully and managed accordingly.

Skin testing and graded challenge can be used to evaluate imi-

glucerase hypersensitivity. Desensitization for continued admin-

istration of imiglucerase can be considered in patients who have

an established diagnosis of imiglucerase hypersensitivity without

appropriate alternative therapy.

Evaluation. The positive and negative predictive value of

imiglucerase skin test is unknown due to limited data; therefore,

skin testing is not recommended as a routine procedure. How-

ever, if the clinical symptoms associated with imiglucerase in-

fusions suggest possible IgE-mediated hypersensitivity, skin

testing and/or graded challenge with imiglucerase solution can be

considered. Skin testing is recommended only for those patients

who experience moderate or severe recurrent imiglucerase

infusioneassociated reactions and the reactions are suggestive of

IgE-mediated hypersensitivity such as persistent symptoms of

bronchospasm, hypotension, and/or urticaria.

Imiglucerase is reconstituted at the concentration of 200 units

in 5 mL of sterile water to make a 40 units/mL solution. This

concentration can be used for skin prick testing. For intradermal

testing, 10-fold serial dilutions can be made with 0.9% sterile

saline, and the highest nonirritating concentration for intrader-

mal testing is 4 units/mL.

573

Provider discretion can be used

regarding the least concentrated dilution at which to start testing.

For patients who experience mild adverse reactions to imi-

glucerase infusion that are not consistent with a hypersensitivity

reaction, imiglucerase may be delivered with 2- or 3-step graded

challenge protocols depending on the severity of the adverse

reaction. If a 3-step protocol is used, 1% of the total therapeutic

dose can be infused over 1 hour as the ﬁrst step. If there are no

adverse reactions at the end of the infusion, the infusion rate can

be increased so that 10% of the total dose is delivered over

1 hour. The rest of the therapeutic dose (90%) can be given at

the regular rate if the patient successfully tolerates the ﬁrst 2

steps. If no adverse events are noted at the end of the third-step

infusion, the patient is not likely to have imiglucerase allergy, and

the challenge is not needed in the future unless the patient de-

velops new reactions that may suggest hypersensitivity.

Management. Desensitization is recommended for patients

who h ave hypersensi tivity reactions to imiglucerase and have

no alternative treatment. An example protocol could include 5

bags (from 1 unit/mL to 0.0001 unit/mL) with 10 steps each

to deliver roughly 140 units of imiglucerase in 5 hours. Then

another 4-step infusion protocol can be used to achieve the

regular infusion rate of 100 mL/h at the ﬁnal step.

573

The total

desensitization time varies depending on the dose but typically

takes 6 to 9 hours.

TABLE LXXI. Clinical presentation of immediate hypersensitivity according to the modified Ring and Messmer Scale

603,608-611

Grades Clinical signs

I Mucocutaneous signs: generalized erythema and/or extensive urticaria with or without angioedema

II Moderate multivisceral signs: mucocutaneous signs  hypotension  tachycardia  moderate bronchospasm  gastrointestinal disturbances

III Life-threatening mono or multivisceral signs: Cardiovascular collapse, tachycardia or bradycardia  cardiac dysrhythmia  mucocutaneous

signs  severe bronchospasm  gastrointestinal disturbances

IV Circulatory arrest

TABLE LXXII. Classification of LAs mostly used in the perioper-

ative setting

Amides Esters

Bupivacaine Chloroprocaine

Levobupivacaine Procaine

Lidocaine Tetracaine

Mepivacaine

Prilocaine

Ropivacaine

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S69

A few more case reports regarding successful imiglucerase

desensitization have been reported by Peroni et al

574

(a 7-step

rush protocol, total infusion time of 4 hours, ﬁnal infusion rate

of 400 units/h), Erdogdu et al,

578

and Tsilochristou et al.

579

The 12-step protocol for administration of 1500 units of imi-

glucerase over 5.7 hours is presented in Table LXIX.

578

Vaccines (by Matthew Giannetti, MD)

General.

The reported incidence of any adverse effect after

vaccine administration is 11.4 per 100,000, of which fever and

injection-site reactions are most common.

580

The incidence of

IgE-mediated hypersensitivity is much lower. One retrospective

US study analyzed data from 2009 to 2011 and reported 33 of

25,173,965 cases of anaphylaxis with no deaths (1.31 cases/

million doses).

581

Another study reported an incidence of im-

mediate hypersensitivity to be 1 of 450,000 vaccines adminis-

tered. Thirty-one percent of reactions occurred after the ﬁrst

administration of the vaccine, thus suggesting preexisting

sensitization.

582

Clinical manifestations. Clinical symptoms can be divided

into immediate and delayed reactions. Immediate reactions occur

minutes to hours after vaccination and may include urticaria/

angioedema, ﬂushing, pruritus, wheezing, dyspnea, and hypo-

tension.

583

Delayed reactions occur more than 60 minutes after

vaccination and include rash, fever, and joint pain.

584

Symptoms

such as fever and injection-site edema are not considered mani-

festations of hypersensitivity and should not preclude future

doses of the vaccine.

585

Diagnosis. IgE-mediated reactions are more likely to be

directed at vaccine components than the active ingredient.

584

Causative components include gelatin, egg protein, latex, and

yeast. Therefore, skin testing should encompass the vaccine and

TABLE LXXIV. Maximum nonirritating concentrations for skin testing of opiods

Drug Skin prick (mg/mL) Intradermal (mg/mL)

Morphine 1 0.01

Fentanyl 0.05 0.005

Alfentanil 0.5 0.05

Sufentanil 0.005 0.0005

Remifentanil 0.05 0.005

TABLE LXXIII. Concentrations of anesthetic agents normally nonreactive during skin tests

61 1

Drugs PTs IDTs

International nonproprietary name Concentration (mg/mL) Dilution Maximal concentration (mg/mL) Dilution Maximal concentration (

g/mL)

Atracurium 10 1/10 1 1/1000 10

cis-Atracurium 2 Undiluted 2 1/100 20

Mivacurium 2 1/10 0.2 1/1000 2

Pancuronium 2 Undiluted 2 1/10 200

Rocuronium 10 Undiluted 10 1/200 50

Suxamethonium 50 1/5 10 1/500 100

Vecuronium 4 Undiluted 4 1/10 400

Etomidate 2 Undiluted 2 1/10 200

Midazolam 5 Undiluted 5 1/10 500

Propofol 10 Undiluted 10 1/10 1000

Ketamine 100 1/10 10 1/100 1000

Alfentanil 0.5 Undiluted 0.5 1/10 50

Fentanyl 0.05 Undiluted 0.05 1/10 5

Morphine 10 1/10 1 1/1000 10

Remifentanil 0.05 Undiluted 0.05 1/10 5

Sufentanil 0.005 Undiluted 0.005 1/10 0.5

Bupivacaine 2.5 Undiluted 2.5 1/10 250

Lidocaine 10 Undiluted 10 1/10 1000

Mepivacaine 10 Undiluted 10 1/10 1000

Ropivacaine 2 Undiluted 2 1/10 200

TABLE LXXV. Desensitization protocol for sublingual

buprenorphine*

663

Step (30 min apart) Dose (sublingual)

1 0.002

2 0.02

3 0.2

4 0.002 mg

5 0.02 mg

6 0.2 mg

7 0.6 mg

8 1.2 mg

*For target dose of 2 mg sublingual buprenorphine twice daily with cetirizine 10 mg

premedication followed by daily administration.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S70 BROYLES ET AL

all potential culprit components contained in the vaccine. When

skin testing to the vaccine itself, testing should use an identical

vaccine (same dose and manufacturer) as that which caused the

reaction.

Skin prick testing should begin with full-strength vaccine. If

the PT result is negative (with appropriate controls), proceed to

intradermal testing using 0.02 mL of a 1:100 dilution.

586

Skin

testing to gelatin, egg, latex, and yeast should be conducted in

the usual manner. If skin testing is not possible (standardized

latex and gelatin are not routinely available in the United States),

substitution with in vitro speciﬁc IgE-antibody assays is appro-

priate, though sensitivity is typically lower with speciﬁc IgE

testing.

587

If testing result is positive, the patient must be

considered allergic. Negative skin testing result virtually excludes

the possibility of an IgE antibody to the vaccine or vaccine

component.

586

Management. Patients who present with mild symptoms

that are not compatible with IgE-mediated hypersensitivity

maybeadministeredthevaccine in the usual manner. Ex-

ceptions include absolute contraindications such as Guillain-

Barré, SJS, encephalopathy, and other severe delayed

reactions.

All patients who report symptoms consistent with IgE-

mediated hypersensitivity should undergo skin testing. Since

negative skin testing virtually excludes the presence of an IgE-

mediated reaction, these patients may be given the vaccine in

the usual manner, followed by a 30-minute observation

period.

586

Alternatively, one-tenth of the vaccine may be

administered, followed by a 30-minute observation period,

then the remaining dose. Patients with positive skin testing

result are more likely allergic to the vaccine; however, patients

with positive skin testing result have also received the vaccine

uneventfully. If additional doses are required, these should be

administered usin g a graded dose protocol (Table LXX). In all

cases, appropriate medication should be available for imme-

diate treatment as necessary.

Patients with a preexisting allergy to a vaccine component

(without previous exposure to the vaccine itself) may warrant

further evaluation. Patients with gelatin allergy should undergo

skin testing to gelatin before receiving the varicella zoster, mea-

sles-mumps-rubella, or rabies vaccines.

588

Gelatin skin testing is

typically not available in the United States; testing for both

bovine and porcine gelatin speciﬁc IgE is an appropriate alter-

native. However, Kelso et al

586

describe a gelatin preparation

made by dissolving 1 teaspoon (5 g) of any sugared gelatin

powder (eg, Jell-O) in 5 mL of normal saline to create an SPT

solution, recognizing that this is not a standardized, validated,

FDA-approved method. Patients allergic to egg require evalua-

tion before receiving the yellow fever vaccine (all other vaccines

are safe in patients with egg allergy).

589,590

Patients akkergic to

yeast should be evaluated before receiving the hepatitis B and

human papillomavirus vaccines. Evaluation should include

serum-speciﬁc IgE to Saccharomyces cerevisiae (baker’s yeast) and/

or skin prick testing to S cerevisiae. Finally, a history of imme-

diate hypersensitivity to latex, neomycin, streptomycin, or

polymyxin B warrants evaluation before the administration of a

vaccine containing these compounds. Positive skin testing result

should prompt desensitization to the necessary vaccine.

Table LXX assumes a vaccine with a standard volume of 0.5

mL. Each dose should be followed by a 15-minute observation

before proceeding to the next step. After completion, the patient

should be observed for 30 minutes.

LOCAL AND GENERAL ANESTHETICS AND

OPIATES

Perioperative immediate hypersensitivity (by Pascale

Dewachter, MD, PhD, and David L. Hepner, MD, MPH)

Epidemiology.

In the early 1980s, the overall incidence of

perioperative immediate hypersensitivity was estimated to be 1 in

5,000 to 13,000 anesthetics administered in Australia, 1 in 4,600

in France, 1 in 1,250 to 5,000 in New Zealand, and 1 in 3,500

in the United Kingdom.

591-594

By the end of the 1990s, the

overall incidence of perioperative IgE-mediated anaphylaxis was

1 in 1,000 to 20,000 anesthetics administered in Australia and 1

in 13,000 in France.

595,596

Recently, over the last decade, the

combined allergic and nonallergic anaphylaxis rate with an

anesthetic was estimated to be 1 in 11,000 in Western Australia

and 1 in 10,000 in the United Kingdom.

597,598

More precisely,

an IgE-mediated mechanism has been involved in half and up to

two-thirds of the cases of perioperative immediate hypersensi-

tivity in the United States, Spain, Norway, and France.

599-602

Perioperative IgE-mediated allergy mainly occurs after anesthetic

induction and is primarily linked to neuromuscular-blocking

agents (NMBAs) and antibiotics such as

-lactam drugs; it may

also arise during the maintenance phase of anesthesia and agents

unrelated to anesthetics are then usually involved.

603

A female

predominance has been regularly reported for both IgE-mediated

and noneIgE-mediated hypersensitivity reactions, irrespective of

the causal agent, whereas immediate IgE-mediated drug allergy is

uncommon in children.

599-602

The incidence of perioperative

latex allergy continues to decrease.

The morbidity rate of perioperative IgE-mediated anaphylaxis

remains unknown. The latest National Audit Project (NAP6)

reported a mortality rate of 3.8% among 266 reports of

anaphylaxis from all UK National Health Service hospitals over 1

year (November 2015 to November 2016).

598

In contrast, a

previous Western Australian retrospective study (January 2000 to

December 2009) suggested that perioperative anaphylaxis mor-

tality rate is within the range of 0% to 1.4% and that the higher

rates, that is, 3% and up to 10%, reported during the last 2

decades may be an overestimate.

597,604-607

In summary, the incidence of perioperative anaphylaxis likely

remains underestimated because not all cases are investigated,

reported to the Drug Safety Monitoring Authorities, or included in

a national register. Conversely, the related mortality seems to be

lower than previously reported.

Clinical presentation. Perioperative immediate hypersensi-

tivity mainly occurs within minutes after anesthetic induction

and is primarily linked to agents administered intravenously.

603

The initial diagnosis of perioperative immediate hypersensitivity

is based on the ongoing features and their severity, as well as the

timing between the introduction of the suspected drug and the

onset of clinical symptoms. The clinical presentation of periop-

erative nonallergic hypersensitivity is usually mild or moderate

and less severe than that of IgE-mediated allergic hypersensitiv-

ity, this latter condition being mostly life-threatening.

603,608

The

care management of perioperative immediate hypersensitivity is

guided by the clinical expression of the reaction.

600,609-612

J ALLERGY CLIN IMMUNOL PRACT

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TABLE LXXVI. Desensitization protocols for AERD and non-AERD NSAID hypersensitivity reactions

Aspirin desensitization for patients with AERD*

Oral protocols

Time Aspirin dose (mg)

Two-day protocol

Dose escalation 180 min

Day 1 8:00 am 20-40†

11:00 am 40-60

2:00 pm 60-100

5:00 pm Discharge

Day 2 8:00 am 150

11:00 am 325

2:00 pm Discharge

One-day protocol

Dose escalation 90 min

8:00 am 40.5†

9:30 am 81

11:00 am 162

12:30 pm 325

2:00 pm Discharge

Intranasal ketorolac and oral aspirin protocol

Day 1 8:00 am 1.26 mg ketorolac† (1 spray in 1 nostril)

8:30 am 2.52 mg ketorolac (1 spray in each nostril)

9:00 am 5.04 mg ketorolac (2 sprays in each nostril)

9:30 am 7.56 mg ketorolac (3 sprays in each nostril)

10:30 am 60

12:00 pm 60

3:00 pm Discharge

Day 2 8:00 am 150

11:00 am 325

2:00 pm Discharge

Aspirin desensitization for patients without AERDz

Option 1: Dose escalation: Every 15-30 min until target daily dose has been tolerated

682

Day 1 0 1

15 2

30 5

45 10

60 20

75 40

90 81x

Option 2: Dose repeated every 90 min until no further reaction symptoms

682

Day 1

0 40.5

90 40.5x

180 Repeat 40.5 only if patient reactsx

Recommendations for treatment of NSAID-induced reactions

Respiratory Bronchodilators and zileuton if severe

Nasal/ocular H

antagonists, topical decongestants

Cutaneous H

antagonists and zileuton if severe

Gastrointestinal H

antagonists and zileuton if severe

Hypotension Intramuscular epinephrine

Laryngeal Racemic epinephrine

*Pretreatment with leukotriene receptor antagonists is strongly recommended for all AERD protocols.

†Lung function and vital signs are monitored before each dose and at the onset of a reaction. Reaction symptoms are treated for patient safety and comfort. Once symptoms

subside, typically within 3 h, the threshold dose is repeated and the dose- escalation interval resumes.

zNo medication pretreatment recommended for rapid oral protocols.

xOn subsequent days, start aspirin 81 mg daily.

J ALLERGY CLIN IMMUNOL PRACT

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S72 BROYLES ET AL

How to stratify immediate hypersensitivity. Although

the Ring and Messmer 4-step grading scale does not take into

account the pathophysiologic mechanisms involved (allergic vs

nonallergic), it is appropriate for grading the clinical severity of

drug-induced immediate hypersensitivity into 4 categories

(grades I-IV) and guiding its clinical care. This 4-step grading

scale, widely used in Europe, has been adapted as follows for the

perioperative setting (Table LXXI).

603,608-611

Grade I reactions

involve mucocutaneous signs only, whereas grade II reactions

correspond to mucocutaneous features that may be associated

with mild cardiovascular (hypotension, tachycardia) and/or res-

piratory signs. The cardinal sign of grade III reactions is car-

diovascular collapse, which may be associated with

mucocutaneous signs and bronchospasm. Grade IV reactions

present with circulatory arrest. Thus, grade I and II reactions are

not life-threatening conditions and usually of nonallergic origin

but sometimes may be IgE-mediated. However, grade III and IV

reactions are typically being referred to as anaphylaxis, that is, a

life-threatening immediate hypersensitivity more likely to be IgE-

mediated. All these grades thus require subsequent allergologic

investigation.

Major symptoms. Cardiovascular homeostasis disturbances

are the hallmark of drug-induced perioperative immediate hy-

persensitivity. These cardiovascular features are usually associated

with mucocutaneous signs and may be associated with respira-

tory symptoms. NoneIgE-mediated immediate hypersensitivity

may include mucocutaneous signs alone or hypotension associ-

ated with tachycardia and mucocutaneous signs. The most

common pattern of perioperative drug-induced IgE-mediated

allergy is consistent with cardiovascular collapse usually associ-

ated with tachycardia, or in some cases with bradycardia and

cutaneous features (generalized erythema and/or extensive urti-

caria). These cutaneous features are sometimes associated with

mucous signs (eyelid and/or lip angioedema). Particularly during

the maintenance phase of anesthesia, cutaneous signs may be

initially missed because of surgical drapes. In grade III reactions,

the cardiovascular collapse may rapidly evolve into cardiac

arrhythmia and/or circulatory arrest if not recognized and/or

treated appropriately. Cardiovascular collapse as the sole feature

or circulatory arrest may also be the inaugural event of periop-

erative drug-induced allergic anaphylaxis.

608-612

In this setting,

circulatory arrest usually presents as pulseless electrical

activity.

598,603,613,614

Mucocutaneous signs (eg, generalized erythema) are usually

present since the early stage of anaphylaxis but may be absent

before the restoration of hemodynamic parameters. Broncho-

spasm may also be present, especially in patients with poorly

controlled underlying airway hyperreactivity (eg, asthma and

chronic obstructive pulmonary disease [COPD]). In contrast,

isolated bronchospasm is never of allergic origin.

615

Gastroin-

testinal signs are usually not reported during the perioperative

setting.

603,608

Tako-Tsubo syndrome following perioperative

anaphylaxis.

Tako-Tsubo syndrome is characterized by an

acute but reversible left ventricular systolic dysfunction and

shares common features with acute coronary syndrome.

616

This

condition has been previously described under different names

including broken heart syndrome or stress cardiomyopathy or apical

ballooning syndrome. Recently, an international expert consensus

provided diagnostic criteria for the diagnosis of Tako-Tsubo

syndrome to improve its identiﬁcation and stratiﬁcation.

617,618

The main diagnostic criteria include the following: (1) transient

left ventricular dysfunction; (2) electrocardiographic abnormal-

ities (rare cases may exist without any electrocardiographic

changes); (3) levels of cardiac biomarkers (troponin and creatine

kinase) moderately elevated in most cases; signiﬁcant elevation in

level of brain natriuretic peptide is common; (4) neurologic

disorders (eg, subarachnoid hemorrhage and stroke) and pheo-

chromocytoma may serve as triggers; and (5) emotional and/or

physical triggers may precede the syndrome.

Four major variants of Tako-Tsubo syndrome have been

described, based on the anatomic distribution of regional wall

motion abnormalities. The left ventricular apical ballooning, also

known as the typical form of Tako-Tsubo syndrome, is the most

common phenotype. Atypical phenotypes include wall motion

patterns in the basal, midventricular, and focal anatomic areas.

Tako-Tsubo syndrome following perioperative anaphylaxis has

been published. In this setting, inappropriate high doses of

exogenous epinephrine appear to be the common trigger.

619,620

The basal phenotype has been reported to be associated with

epinephrine-induced Tako-Tsubo syndrome, which is charac-

terized by a rapid onset of symptoms after epinephrine admin-

istration.

617,620

However, the contributive role of endogenous

catecholamines in response to anaphylaxis cannot be ruled

out.

621

Agents involved. Perioperative IgE-mediated anaphylaxis

usually occurs within minutes of anesthetic induction.

608

In this

clinical setting, NMBAs and antibiotics (mainly

-lactam agents)

are the main drugs involved.

599,601,602

Anaphylaxis may also arise

during the maintenance phase of anesthesia and is usually due to

agents unrelated to the anesthetic. These agents given during a

surgery include dyes (methylene blue, patent blue V and its

derivative isosulfan blue), colloid (modiﬁed ﬂuid gelatin), anti-

septics (chlorhexidine, povidone iodine), iodinated contrast

agents, aprotinin (some ﬁbrin glue products contain aprotinin),

and other biological sealants.

603,608

Ethylene oxideeinduced

anaphylaxis has also been suggested as a cause of perioperative

anaphylaxis. However, it appears that most of the reactions

attributed to ethylene oxide were due to latex.

622

Systemic

cooling has also been reported as a trigger for perioperative

anaphylaxis.

623

Finally, anaphylaxis may also occur toward the

end of the anesthetic induction or during the recovery period

after the injection of sugammadex or neostigmine used for

NMBA reversal.

624,625

Neuromuscular-blocking agents. NMBAs are quater-

nary ammonium compounds with positively charged radicals

(CH

)

] mimicking the quaternary nitrogen radical of

acetylcholine. This similarity in structure attracts NMBAs to

nicotinic receptors. NMBAs can be classiﬁed according to their

mechanism of action, as depolarizing and nondepolarizing

agents. Succinylcholine, a depolarizing agent, is an agonist at

acetylcholine receptors. Nondepolarizing agents are competitive

antagonists at the acetylcholine receptor and grouped according

to their chemical structure into steroidal (pancuronium,

rocuronium, vecuronium) and benzylisoquinolin (atracurium,

cis-atracurium, and mivacurium) compounds.

All NMBAs may elicit IgE-mediated allergic immediate hy-

persensitivity, which is usually a life-threatening condition, that

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S73

is, grade III reaction, and in some rare cases, consistent with an

inaugural grade IV reaction.

603,626

The substituted (tertiary as

well as quaternary) ammonium ions have been suggested to be

the allergenic determinants of NMBAs since the 1980s.

627,628

Although cross-reactivity between NMBAs is common, it is

unusual that an individual is allergic to all NMBAs.

629

Cross-

reactivity refers to the drug allergenicity and to the allergenic

proﬁle of the patient.

A higher prevalence of serum IgE antibodies to tertiary and/or

quaternary ammonium ions among blood donors and atopic

patients was reported in Norway but not in Sweden. The only

difference in environmental chemical exposure was the use of

cough syrups containing pholcodine available only in Norway.

630

Other work demonstrated a higher prevalence of serum IgE

antibodies to tertiary and/or quaternary ammonium ions and/or

to pholcodine, morphine, and suxamethonium after pholcodine

exposure in atopic patients and in a few patients with a history of

NMBA-induced anaphylaxis.

630-632

The use of drugs containing

pholcodine was therefore questioned, because of the potential

risk for NMBA hypersensitivity.

631,632

However, no relationship

has been clinically established between these increased IgE levels

and the occurrence of NMBA allergy during a subsequent

anesthetic. The European Medicines Agency therefore stated that

the existing evidence does not support the use of pholcodine-

containing medicines as a risk for developing NMBA allergy.

633

Currently, the only known risk factor for NMBA-allergic

hypersensitivity is a previous noninvestigated immediate hyper-

sensitivity reaction that occurred during a previous anesthetic

induction conducted with an NMBA.

609-611,626

Nevertheless,

uneventful previous exposure to an NMBA does not exclude the

risk for IgE-mediated allergy during a subsequent anesthetic

induction.

608,609

In addition, NMBA allergy may occur without

previous NMBA exposure.

609,611,626,628

Finally, benzylisoquinoline NMBAs, such as atracurium and

mivacurium (both are not available in the United States), may

directly stimulate histamine release (ie, nonallergic immediate

hypersensitivity), whereas cis-atracurium does not.

Sugammadex. Sugammadex is a modiﬁed

-cyclodextrin

with a lipophilic core and hydrophilic periphery. It is used to

reverse neuromuscular blockade by encapsulating steroidal

NMBAs (rocuronium, vecuronium) and displacing them from

their receptors. Cyclodextrins are made up of dextrose units (

-, and

-cyclodextrins). Sugammadex-induced immediate

allergic hypersensitivity has been reported.

625

The

-cyclodextrin

unit that contains 8 thiopropionate side chains may be respon-

sible for hypersensitivity reactions.

Neostigmine. Neostigmine is structurally similar to acetyl-

choline but contains a carbamate group instead of the acetyl

group. Neostigmine is an inhibitor of the enzyme acetylcholin-

esterase, which hydrolyzes the neurotransmitter acetylcholine at

synapses. Accumulation of acetylcholine at the neuromuscular

junction competitively antagonizes nondepolarizing NMBAs. A

few IgE-mediated cases of allergy to neostigmine have been

reported.

624,634

Hypnotic agents. Propofol: Propofol is an alkylphenol

derivative (2,6-di-isopropylphenol) marketed as an oil-water

emulsion using 10% soybean oil, 2.25% glycerol, and 1.2% egg

lecithin as the emulsifying agent. This intravenous induction

agent is widely used. Propofol may directly stimulate histamine

release, especially in young and/or stressed patients experiencing

TABLE LXXVII. Oral challenge protocols for acetaminophen*

Step

Acetaminophen dose (mg)

Rojas-Perez-Ezquerra et al

697

Yilmaz et al

693

1 250 10

2 500 50

3 1000-Final 250

4 500-Final

*Doses separated by 1-h intervals.

TABLE LXXVIII. Details of diagnostic testing to thienopyridines

706

Immediate hypersensitivity testing* Delayed hypersensitivity testing†

Clopidogrel 75 mg/mL Clopidogrel (20% in petroleum alba and 30% in water)

Step 1: Epicutaneous: 1/100 dilution

Step 2: Intradermal: 1/1000 dilution

Step 3: Intradermal : 1/100 dilution

Ticlopidine 6.25 mg/mL Ticlopidine (75% in water)

Step 1: Epicutaneous: 1/100 dilution

Step 2: Intradermal: 1/1000 dilution

Step 3: Intradermal: 1/100 dilution

Prasugrel 5 mg/mL Prasugrel (5% in water)

Step 1: Epicutaneous: 1/10 dilution

Step 2: Intradermal: 1/100 dilution

Step 3: Intradermal: 1/10 dilution

*Epicutanous PTs and IDTs were performed with same concentration in this series, but a further 1:10 dilution is suggested for intradermal testing.

†Patch tests read at 48 and 72 h.

J ALLERGY CLIN IMMUNOL PRACT

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S74 BROYLES ET AL

cutaneous signs (eg, localized or extensive erythema).

635

Conversely, IgE-mediated allergic hypersensitivity to propofol re-

mains extremely rare relative to its widespread use.

609-611

The few

documented propofol-induced IgE-mediated reactions have been

shown to be elicited by the isopropyl or phenol groups rather than

the lipid vehicle. A retrospective investigation of 171 anesthetic

charts from 99 patients with elevated speciﬁc IgE to egg, soy, or

peanut showed no documented IgE-mediated allergy to propo-

fol.

636

According to this study and previous reports, there is no

reason to avoid propofol in patients with allergy to egg, soy, and

peanut.

626,636

Other intravenous induction drugs: IgE-mediated allergic hy-

persensitivity to midazolam (hydrosoluble benzodiazepine) is

extremely rare relative to its widespread use.

79,610,611

Ketamine is

a hydrosoluble aryl-cyclo-alkylamine. There is no documented

report of IgE-mediated allergic hypersensitivity to this drug.

Inhaled anesthetics. Halogenated general anesthetic agents

are volatile liquids administered by inhalation of the vapor. The

chemical structures of these agents include ﬂuorinated methyl-

ethyl-ethers (desﬂurane, isoﬂurane) and a poly-ﬂuorinated-

isopropyl-methyl-ether (sevoﬂurane). There is no report of

IgE-mediated allergic hypersensitivity to these volatile

anesthetics.

Opioids. Morphine is a tertiary amine that, when insufﬁciently

diluted, causes nonspeciﬁc direct histamine release leading to false-

positive skin test results.

610,611

Alfentanil, fentanyl, remifentanil,

and sufentanil belong to the phenylpiperidine derivatives and have

no local effect on mast cells. No IgE-mediated allergy has been re-

ported with alfentanil, remifentanil, and sufentanil. A few cases of

immediate allergy to fentanyl have been reported, but the diagnosis

has not been proven because of methodologic issues.

637,638

Local anesthetics. Local anesthetics (LAs) belong to the

ester or amide groups (Table LXXII). Ester LAs (procaine,

chloroprocaine, and tetracaine) have a lipophilic or aromatic

group, an intermediate ester linkage, and a hydrophilic residue

with a tertiary amine. The metabolism of ester LAs is via plasma

cholinesterases. Para-aminobenzoic acid is the common metab-

olite of ester LAs inducing immediate and delayed hypersensi-

tivity reactions. Cross-reactivity is the rule among esters due to

para-aminobenzoic acid.

Amide LAs, such as lidocaine, mepivacaine, prilocaine, bupi-

vacaine, levobupivacaine, and ropivacaine, differ from esters in

that they have an intermediate amide linkage. The metabolism of

amide LAs is primarily in the liver. IgE-mediated allergy to amide

LAs is extremely rare relative to their widespread use.

609-611

Most

reported reactions are vasovagal episodes or toxic reactions from

inadvertent intravascular injection of an LA or epinephrine.

Delayed hypersensitivity to amide LAs has also been reported.

Cross-reactivity in the amide group has been established for

immediate and delayed hypersensitivity reactions.

639-641

There is

no cross-reactivity between amide and ester LAs.

Chlorhexidine. Perioperative IgE-mediated allergy to chlor-

hexidine is being increasingly recognized in Denmark and the

United Kingdom but not in France.

598,642,643

In a retrospective

(July 2004 to July 2012) single-center study, speciﬁc IgE and

skin tests (including PTs and IDT) to chlorhexidine were

completed in 228 patients investigated for suspected periopera-

tive allergic reactions.

642,643

About 10% of examined cases met

criteria for chlorhexidine allergy deﬁned as a relevant clinical

reaction combined with 2 or more positive test results. The

highest combined estimated sensitivity and speciﬁcity was found

for speciﬁc IgE and SPT to chlorhexidine.

Latex. The incidence of perioperative latex allergy is drastically

decreasing.

600,602

This is because most hospitals now use pow-

der-free latex gloves with negligible residual protein concentra-

tions and/or nonlatex gloves.

635

In addition, the use of natural

rubber latex in medical products and/or equipment has been

reduced. Latex-induced immediate allergy is now infrequently

reported in the perioperative setting.

Diagnosis. The etiologic diagnosis of perioperative immediate

hypersensitivity is linked to a triad including clinical evidence

along with biological and allergologic results.

609-612

The inter-

pretation of the biological and allergologic assessment should

always be correlated to the careful and complete review of the

clinical history including the management care. The joint anal-

ysis of these elements helps to determine the pathomechanism

involved (allergic vs nonallergic), identify the culprit agent, and

provide subsequent and appropriate advice for further

anesthetics.

In vivo biochemical tests. Plasma histamine: Plasma his-

tamine is a preformed inﬂammatory mediator stored in mast cells

and basophils. An elevated concentration of plasma histamine

indicates in vivo release and is observed during both allergic and

nonallergic immediate hypersensitivity. The peak of plasma

histamine is immediate (normal <10 nmol/L), and its plasma

elimination half-life is short (w15-20 minutes). Diamine-oxi-

dase enzyme inactivates histamine in humans and shows the

highest expression in the intestine, kidney, and placenta. Because

the enzymatic activity of diamine-oxidase increases several hun-

dred-fold during gestation compared with nonpregnant in-

dividuals and plasma histamine rapidly decreases in a

concentration-dependent manner to levels below 1 ng/mL,

plasma histamine should not be measured after the ﬁrst trimester

of pregnancy.

609-611,644

Plasma histamine should ideally be measured within 15 mi-

nutes after the onset of clinical features in cases of grade I re-

action, within 30 minutes after a grade II reaction, and within 2

hours in grade III and IV reactions.

609-611

Tryptase: Tryptases are neutral serine proteases stored pre-

dominantly in mast cells. In vivo, 2 major forms can be

measured. Pro-

tryptase reﬂects mast cell burden and is elevated

in mastocytosis. Mature

-tryptase is preferentially stored in mast

cells granules and is released during episodes of mast cell acti-

vation, such as IgE-mediated allergy. The total tryptase level

(normal <11 or 13

g/L) measures both forms. Tryptase can be

measured in serum or plasma. Total tryptase concentrations reach

a peak at 1 hour after the onset of the reaction and decline under

ﬁrst-order kinetics (elimination half-life of w90 minutes).

609-612

Although an increase in tryptase can be measured 30 to 60

minutes after the onset of symptoms in cases of mild reactions

(eg, nonallergic immediate hypersensitivity due to histamine

release), it may not be elevated. Sampling is recommended

within 30 minutes and 2 hours in cases of grade III and IV re-

actions.

611,612

An increase in tryptase is highly suggestive of mast

cell activation, but its absence does not preclude the diagnosis of

IgE-mediated anaphylaxis. Baseline tryptase level should be ob-

tained more than 24 hours after the clinical event or when the

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S75

patient is referred for investigation and compared with acute

tryptase levels.

645,646

Histamine and tryptase concentrations correlate with the

severity of the clinical reaction.

13,611

Combined histamine

and tryptase measurements are recommended for the diag-

nosis of perioperative immediate hypersensitivity in the

United States and France.

13,611,635

The British and Scandi-

navian guidelines only recommend tryptase measure-

ment.

609,610

The collection of 24-hour histamine metabolites

(urinary methyl-histamine) is also recommended in the

United States, because it is elevated for a longer duration of

time than plasma histamine.

13,635

Its measurement has been

discontinued in Europe.

609-611

In vitro biochemical tests. Speci ﬁc serum IgE measurement:

In vitro tests detect the presence of IgE antibodies by binding the

allergen onto a solid phase and using radioactive system detection

(radioallergosorbent test) or by binding the allergen onto a sponge

matrix using ﬂuorescent detection (ﬂuoroimmunoassay or CAP

system).

13,609-611

Radioallergosorbent test is now rarely used.

In vitro tests have been developed for the detection of speciﬁc

IgEs directed to the tertiary or quaternary ammonium groups of

NMBAs using a quaternary ammonium (choline chloride). They

work by coupling an analogue of choline onto a polysaccharide

support on sepharose or p-aminophenylphosphoryl-choline on

agarose, the latter being marketed only in France.

647,648

Subse-

quently, a morphine-based solid-phase IgE was proposed,

because the tertiary methyl-amino group of morphine cross-re-

acts in vitro with NMBAs.

649

In Europe, the suxamethonium-speciﬁ c assay is currently

available among the different commercialized NMBAs. Its

sensitivity is relatively low, around 30% to 60%.

629

Speciﬁc

serum IgE measurement is also available for other drugs

including

-lactams (eg, ampicillin and amoxicillin and peni-

cil lins G and V), morphine, chlorhexidine, and p rotamine in

Europe and only to penicillin G and V in the United States.

Howeve r, these in vitro speciﬁcIgEassaystodrugsare

less sensitive and speciﬁcwhencomparedwithskin

testing.

13,609-611

Thus, identiﬁcation of serum IgE to certa in

drugs provides possible e vidence of IgE sensitization but does

notprovebyitselfthatthedruginducedtheimmediatehy-

persensitivity reaction.

609

In addition, IgE-antibody assay is commercially available for

latex. Although skin testing has a higher sensitivity (95%-99%)

compared with IgE testing (35%-76%), a skin test reagent to latex

is not commercially available in the United States.

650

IgE-antibody

testing may be performed at the time of the reaction or later.

609-611

Basophil activation test. BAT is a sophisticated technique

using ﬂow cytometry, which allows quantifying the ex vivo ca-

pacity of sensitized blood basophil activation. The upregulation

of certain markers (CD63 and CD203c) present on the granule

membrane is expressed on the basophil membrane on activation

with the suspected allergen. BAT might add to the etiologic

diagnosis of immediate drug hypersensitivity (eg, NMBA) and

help to identify both cross-reactive and safe alternative com-

pounds.

609-611

However, this technique is not commercially

available. The latest recommendations provided by the ENDA

and the Drug Allergy Interest Group of the EAACI stated that

BAT is recommended for diagnosing NMBA immediate hy-

persensitivity and, when available, BAT should be performed

before skin testing, especially in life-threatening reactions.

651

However, a recent study showed that combined CD63 and

CD203c markers did not increase BAT sensitivity compared

with CD203c alone in the investigation of NMBA immediate

hypersensitivity. BAT allowed identiﬁcation of the culprit drug

in 80% of patients with allergy to NMBA and yielded concor-

dant cross-reactivity results in only 60% of the cases compared

with skin tests results. The authors thus conclude that BAT

combining CD63 and CD203c markers does not replace skin

testing in the assessment of NMBA allergy.

645

However, BAT is

not commercially available and the role of BAT needs to be

better deﬁned in the diagnostic approach of NMBA-induced

immediate hypersensitivity, because skin testing is more sensitive

than in vitro tests.

609-611

Skin testing. Skin testing remains the criterion standard for

the detection of IgE-mediated allergy versus nonallergic imme-

diate hypersensitivity. All drugs to which the patient was exposed

within minutes before the clinical reaction must be skin

tested.

609-612

Investigation of anesthetics is performed by PTs

followed by IDTs using commercialized solutions undiluted or

diluted without exceeding the maximum recommended con-

centrations (ie, corresponding to the maximum nonirritant drug

concentration).

79,609-611,629

PTs may produce false-negative re-

sults, whereas IDTs are more sensitive but less speciﬁc than

PTs.

609,610

However, IDTs are more likely to trigger a systemic

allergic reaction and, thus, should be performed only if PT re-

sults are negative.

609,610

Diagnostic criteria for a positive skin test

result (including PT and IDT) and maximum recommended

concentrations have been deﬁned in France.

611

They have been

recommended and/or adapted by others, and endorsed by

EAACI/ENDA (Table LXXIII).

79,609,610,629

Skin testing should be performed according to the patho-

mechanism of the immediate hypersensitivity reaction and

thus interpreted by readin g it within 15 to 20 minutes of the

skin test. If the PT results are negative, IDT is performed by

injecting 0.03 to 0.05 mL o f the correspondi ng drug (eg,

beginning at 1:10,000 or 1:1,000 dilution). If the IDT result is

negative, a 10-fold increased concentration is used with in-

cremental 15- to 20-minute intervals between each IDT until

the test result is posit ive or the highest nonirritant concen-

tration is achieved.

It is usua lly recommende d that skin testing be done at least

4 to 6 weeks after the c linical reaction to avoid false-negative

test results.

652

Dialysis and heavy tobacco s moking may lead

to a decr eased response due to cutane ous vasoconstriction,

whereas cutaneous reactivity may be increased in ca ses of

dermographism. Finally, skin testing can be performed at any

point during the pregnancy, especially for LAs and

NMBAs.

611

In conclusion, a suggestive clinical history with a mild reaction

without an increase in tryptase and a negative skin test result is

indicative of a nonallergic reaction, such as histamine release.

The use of preoperative H

-receptor antagonists reduces the

clinical effects of histamine release. Conversely, immediate hy-

persensitivity reactions requiring emergency treatment, and

associated with an increased tryptase and positive skin test results

to the suspected drug/agent, constitute evidence of an IgE-

mediated mechanism.

609-612

In this latter condition, the identi-

ﬁed drug/agent should be avoided in the future, whereas negative

skin-tested drugs can be used for further procedures.

608,611

J ALLERGY CLIN IMMUNOL PRACT

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S76 BROYLES ET AL

 NMBAs: The sensitivity of skin tests to NMBAs in patients

having experienced NMBA anaphylaxis is greater than 95%,

and their reproducibility is excellent.

611

Testing should be

done by PTs, followed by IDTs. When skin testing result with

an NMBA is positive, investigation for cross-reactivity with

other available NMBAs should be performed to identify a safe

alternative (ie, negative skin-tested NMBAs) for further

procedures.

608,611,645,653

 Sugammadex: Sugammadex may be skin tested undiluted by

PTs followed by IDTs if PT is negative (up to 1/100 dilution,

which appeared nonirritant).

625

 Neostigmine: Neostigmine may be skin tested undiluted by

PTs followed by IDTs if PT is negative (up to 1/100 dilution,

which appeared nonirritant).

628

 Hypnotic agents: These drugs may be skin tested undiluted by

PTs, followed by IDTs (up to 1/10 dilution) if PT results are

negative.

79,611

 Opioids: Phenylpiperidines may be skin tested undiluted by

PTs followed by IDTs if PT results are negative (1/10 dilution

should not be exceeded). However, 1/10 and 1/1000

morphine dilutions are recommended for PT and IDT,

respectively.

79,611

 LAs: LAs (without epinephrine) may be skin tested undiluted

by PTs followed by IDTs if PT is negative (1/10 dilution

should not be exceeded).

79,611

A protocol for subcutaneous

incremental challenge (graded challenge) involves injections of

increasing volumes of LA to which the patient has been proven

to be skin-tested negative. A single-blind saline step is done 15

to 20 minutes after the skin PT to rule out nonallergic causes.

Following this (typically 15-20 minutes), 0.1 mL, 0.5 mL, and

1 mL of undiluted subcutaneous injections of LA are used as

challenge steps. It is ideal to wait 15 to 20 minutes between

steps.

654

 Chlorhexidine: Chlorhexidine (without alcohol) may be skin

tested up to 5 mg/mL by PTs followed by IDTs (up to 0.002

mg/mL) if PT is negative.

 Latex: In contrast to the United States, in Europe, latex allergy

investigation is performed by PTs using commercial extracts.

The sensitivity of skin tests with latex is excellent.

Opioids and buprenorphine (by Parul Kothari, MD)

General

Opioids are generally used to treat both acute and

chronic pain.

The Drug Enforcement Agency classiﬁes opi-

oids in 5 different scheduling classes on the basis of their po-

tential for abuse and addiction, which are the main concerns with

their long-term use. Structurally, opioids can be placed into the

following 4 chemical classes

655

 Phenanthrenes, whose members include morphine, codeine,

hydromorphone, oxycodone, hydrocodone, oxymorphone,

and buprenorphine.

 Benzomorphans, which include only pentazocine as a

member.

 Phenylpiperidines, which include fentanyl, alfentanil, sufen-

tanil, and meperidine.

 Diphenylheptanes, which include propoxyphene and

methadone.

In addition, based on their interaction with the

, and

receptors, opioids can be classiﬁed as agonists (eg, morphine),

partial agonists (eg, buprenorphine), or antagonists (eg,

naloxone), with the latter used to treat opioid overdose.

Major symptoms of hyperse nsitivity. True type I im-

mediate hypersensitivity reactions to opioids are rare and are

limited to case reports in the literature.

656-658

Most adverse re-

actions to opioids are side effects, often due to nonspeciﬁc, direct

release of mast cell mediators through interactions with the mast

cell opioid receptor. However, it is often difﬁcult to distinguish

between these 2 possibilities because their clinical manifestations

can overlap. Both can cause pruritus, ﬂushing, urticaria, nausea,

vomiting, bronchospasm, and hypotension. DHRs to opioids

have also been reported.

659,660

Diagnosis. Although some case reports have demonstrated the

presence of speciﬁc IgE via skin or serum testing, currently there

is no validated test for diagnosing an immediate hypersensitivity

reaction.

656-658

Skin testing with narcotics can lead to nonspe-

ciﬁc release of mast cell mediators, thereby eliciting a wheal-and-

ﬂare response even in the absence of speciﬁc IgE.

661

As such,

distinguishing between immune- and nonimmune-mediated re-

actions is based on a careful history as well as physical exami-

nation ﬁndings at the time of the reaction. Nonirritating

concentrations for skin testing that have been reported are pre-

sented in Table LXXIV.

Although ACD has been reported for several different opioids,

it appears to be most commonly associated with transdermal

buprenorphine.

659,660

In these small case series, the diagnosis was

conﬁrmed with patch testing, and the ability to tolerate other

opioids (oral and/or transdermal) was demonstrated. In 1 case,

oral buprenorphine was given without any adverse reaction.

Management. Prevention of future reactions will depend on

the underlying mechanism. Nonspeciﬁc adverse reactions, a class

effect, can be inhibited by pretreating with antihistamines and/or

steroids, using lower doses, or using opioids with less histamine-

releasing properties, such as fentanyl.

662

However, for immune-

mediated hypersensitivity reactions, strict avoidance of the

culprit and metabolites is recommended. As such, because co-

deine is metabolized to morphine, patients who are able to

tolerate codeine but react to morphine are unlikely to have a true

allergy but those with evidence of an IgE-mediated allergic re-

action to morphine should also avoid codeine.

For patients with evidence of an immediate or delayed hy-

persensitivity to an opioid, currently data to determine the risk of

cross-reactivity within and across different structural classes are

limited. Case reports and series have shown that most patients

with an allergic reaction are able to tolerate at least 1 other opioid

but too few patients have been studied to make accurate pre-

dictions. Thus, if a patient requires treatment with a narcotic, it

is recommended to use one that has been tolerated previously. If

that information is not known, one should determine which

alternative agent(s) could be safely administered by performing

an oral challenge in a monitored setting. There are currently no

standardized desensitization protocols for narcotic analgesics, but

a desensitization protocol to sublingual buprenorphine has been

reported for a noneIgE-mediated reaction (Table LXXV).

663

The serial dilutions for desensitization were made by grounding

and suspending buprenorphine sublingual tablets (2 mg). Given

the lack of data on the stability of buprenorphine in solution,

dilutions were prepared close to the time of administration to

minimize any possible loss of potency.

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S77

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Aspirin (by Katherine N. Cah ill, MD, and Ari J. Fried,

MD)

General.

Aspirin and other nonsteroidal anti-inﬂammatory drugs

(NSAIDs) are uniﬁed by their ability to inhibit cyclooxygenase

(COX)-1. Any inhibitor of COX-1 can cause acute or delayed

hypersensitivity reactions. Aspirin-induced reactions are generally

the result of altered eicosanoid pathways following COX-1 inhibi-

tion. The ease of access to NSAIDs and their clinical utility make

them one of the leading causes of hypersensitivity reactions. The

reported prevalence of hypersensitivity reaction to aspirin and other

COX-1 inhibitors in children is 0.3% and in adults is 1.9%; the

prevalence among patients with asthma is an estimated 5% in

children and 7.2% in adults.

664-667

True NSAID hypersensitivity

needs to be distinguished from an adverse reaction or intolerance to

an NSAID such as tinnitus or gastrointestinal bleeding.

Major symptoms of hypersensitivity. Cross-reacting

COX-1 inhibitor reactions include (1) aspirin-exacerbated res-

piratory disease (AERD), (2) NSAID-exacerbated cutaneous

disease, and (3) NSAID-induced urticaria and/or angioedema.

Acute NSAID hypersensitivity reactions that do not cross-react

are known as selective NSAID-induced urticaria, angioedema,

and/or anaphylaxis. Selective NSAID-induced delayed reactions

such as mild maculopapular exanthems, SJS, TEN, ﬁxed drug

eruptions, DRESS, pneumonitis, aseptic meningitis, and

nephritis are much less common than acute reactions

(Table LXXVI).

668

Both acute and delayed reactions have been

reported in children and adults.

669

AERD is unique among the NSAID-exacerbated reactions

with the associated comorbidities of asthma and nasal polyposis.

NSAID-exacerbated reactions in AERD include nasal conges-

tion, rhinorrhea, postnasal drip, ocular injection, ocular and

oropharyngeal pruritus, and bronchospasm within 15 to 180

minutes of NSAID exposure. Less frequently, angioedema, ur-

ticaria, macular eruptions, abdominal pain, nausea, vomiting,

diarrhea, and hypotension have been reported. AERD is gener-

ally considered an adult-onset disease, but AERD has been re-

ported to develop as early as at age 8 years.

670

Diagnosis. The diagnostic workup for identiﬁcation of

NSAID hypersensitivity is the same for children and adults.

Distinguishing selective COX inhibitor hypersensitivity from

cross-reactive hypersensitivity is crucial to determine the best

strategy for further management. The evaluation has to start with

a careful analysis of the history including symptom pattern and

time course of the reaction.

Oral aspirin challenge is the criterion standard for the diagnosis

of AERD.

671

NSAID-exacerbated cutaneous disease (NECD)

patients have chronic urticaria and a history of an acute ﬂare of

urticaria and/or angioedema from NSAID, while patients with

NSAID–induced urticaria and/or angioedema (NIUA) have had

acute urticaria and/or angioedema from NSAID, and do not have

an associated chronic respiratory or cutaneous condition. Patients

with either NECD or NIUA exhibit cross-reaction to structurally

unrelated COX-1 inhibitors—which should be avoided. Chal-

lenge procedures are commonly performed to aspirin in these

patients when aspirin 81 mg daily is required for cardioprotection.

Desensitization is not recommended in the setting of NECD but

can be accomplished in patients with NIUA. For patients with a

history suggesting selective NSAID-induced urticaria, angioedema,

and/or anaphylaxis, a challenge to another COX-1 inhibitor can

be performed to rule out a cross-reacting NSAID hypersensitiv-

ity.

17,672

The role of skin testing or basophil activation testing to

NSAIDs has not been validated and is not recommended. Serum-

speciﬁc IgE has been reported in a case series of pyrazolone-

induced anaphylaxis, a class of NSAIDs no longer available in the

United States.

673

The detection of serum-speciﬁc IgEs for other

NSAIDs has not been reported. In the setting of severe delayed

reactions, reexposure to the culprit agent is not recommended and

exposure to another member of the NSAID class can be consid-

ered if medically necessary. With rare exception, selective COX-2

inhibitors are tolerated by patients with a history of COX-1 hy-

persensitivity reactions, but reactions to selective COX-2 in-

hibitors in patients with a history of COX-1 inhibitor

hypersensitivity have been reported; as a precaution it may be

appropriate to administer the initial dose under observation based

on clinical circumstances.

674

Management. Although challenge protocols conﬁrm the diag-

nosis and subtype of NSAID hypersensitivity, desensitization pro-

tocols provide a means to allow the patient to safely tolerate daily

aspirin (Table LXXVI).

675

Aspirin challenge or desensitization

followed by daily aspirin therapy is indicated for adult and pediatric

patients with AERD who require revision polypectomies or

frequent or daily corticosteroid therapy. Any patient with a history

of an acute NSAID hypersensitivity reaction with a medical indi-

cation (cardiovascular or rheumatologic disease) for aspirin or other

COX-1 inhibitor should be offered desensitization.

676

Before

initiating a challenge or desensitization protocol, it is recommended

that FEV

be greater than 60% predicted and at least 1.5 L. Use of

a leukotriene receptor antagonist in advance of the desensitization

in patients with AERD decreases the severity of bronchospasm.

677

In a small subset of patients with AERD, the use of leukotriene

receptor antagonists will completely mask the symptoms of a re-

action. However, it is generally accepted that the added safety

beneﬁt from their use outweighs this risk. Inhaled or oral cortico-

steroids and long-acting bronchodilators should be continued and

asthma should be optimized at the time of desensitization, with oral

steroids added if necessary. Oral antihistamines and decongestants

arediscontinued48hoursbeforeandshort-acting

-agonists the

morning of desensitization to avoid masking a clinical reaction.

Challenge/desensitization protocols for AERD can take place in the

outpatient setting, including for pediatric cases, with the exception

of patients with recent myocardial infarction, continuous

-blocker

therapy, or uncontrolled asthma.

678

A standard oral aspirin desensitization protocol for AERD

begins with a dose of 40 mg of aspirin, with dose escalation every

90 to 180 minutes, as outlined in Table LXXVI. At the onset of

reaction symptoms, the patient is monitored and symptomatic

treatment with

-agonists, antihistamines, nasal decongestants,

and 5-lipooxygenase inhibitors can be used to ensure patient

safety and comfort. Shorter oral protocols have been reported in

the literature.

679

Alternatively, a modiﬁed protocol using intra-

nasal ketolorac is available that reduces extrapulmonary reactions

during desensitization.

680

Once a patient has tolerated 325 mg of

aspirin without evidence of symptoms, they can increase their

dose of aspirin to the recommended treatment dose of 650 mg

twice daily at home. If aspirin is discontinued for more than 48

hours, the desensitized state can be lost and repeat desensitization

is recommended. In the event of a planned surgical procedure

during which aspirin should be avoided, the daily aspirin dose

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S78 BROYLES ET AL

can be decreased to 81 mg leading up to the procedure, held the

day before and the morning of the procedure, and immediately

resumed after the procedure is completed.

For other non-AERD reactions to NSAIDs, challenge pro-

tocols are published.

675

In clinical practice, there is less consensus

about the dose and timing intervals for challenge/desensitization

due to the wide range of clinical history, reaction severity, and

subtype of NSAID hypersensitivity encountered. Aspirin is the

preferred agent in a desensitization protocol for non-AERD

NSAID hypersensitivity because there are no veriﬁed reports of

anaphylaxis from aspirin.

681

For those with non-AERD NSAID

hypersensitivity and a clinical indication for daily aspirin use such

as after cardiac stent placement, aspirin challenge or desensiti-

zation using 1 of 2 rapid protocols has demonstrated success.

682

Both protocols reach the established antiplatelet threshold of 81

mg within 2 to 3 hours (Table LXXVI).

Acetaminophen (by Samantha Minnicozzi, MD)

Acetaminophen is one of the most commonly used drugs in the

world. It is a medication that is generally well tolerated, and it is

frequently used as an alternative agent for patients with aspirin

hypersensitivity.

683

Hypersensitivity reactions are exceedingly rare,

with limited data and reports of suspected IgE-mediated reactions.

There are numerous case reports and some case series describing

anaphylaxis or anaphylactoid reactions to acetaminophen.

683-696

Acetaminophen is classiﬁed as an NSAID, but it is a weak

cyclooxygenase inhibitor and does not provide any anti-inﬂam-

matory effects.

683

However, a number of patients who are aspirin

intolerant can also be intolerant of acetaminophen, and some

acetaminophen-speciﬁc reactions can also be either dependent on

or independent of dose.

684,689,691,692

Major symptoms of hypersensitivity. In a review of

acetaminophen hypersensitivity reactions reported over a 4-year

period to a private allergy clinic in France, 84 patients were

identiﬁed.

683

Of these 84 patients, 13 were considered identiﬁed

to have an allergy based on history and oral challenge testing.

Their symptoms consisted of maculopapular eruptions, urticaria,

bronchospasm, rhinitis, and laryngeal edema.

683

Other case re-

ports highlight patients who experience similar symptoms but

also have hypotension, vomiting, and/or diarrhea.

686,690,694,697

In addition to immediate hypersensitivity reactions, case re-

ports in the literature have described acetaminophen’s association

with SJS reactions.

698

Diagnosis. The validity of skin testing to acetaminophen is

unknown. However, in case reports citing skin prick and intra-

dermal testing at various concentrations, all control subjects have

been negative.

685,687,688,692,696,697

Of the skin testing protocols

proposed, many are not feasible because the sterile forms

required for intradermal testing do not exist in many countries.

Currently, the only intravenous formulation of acetaminophen is

a single concentration of 10 mg/mL. This only allows for in-

tradermal testing to occur with dilutions of this formulation. The

protocol described by Rojas-Perez-Ezquerra et al

697

uses the

intravenous formulation of acetaminophen with a concentration

of 10 mg/mL for skin prick testing, and a dilution of 1 mg/mL as

well as the undiluted 10 mg/mL for intradermal testing. How-

ever, patients and control subjects in that study tested negative

on skin prick and intradermal testing.

Other reviews published on acetaminophen allergy use solely

SPTs up to concentrations of 200 mg/mL despite evidence

elsewhere demonstrating that concentrations more than 10 mg/

mL can be known irritants leading to false positives for

drugs.

688,692,696

Management. Of the studies identifying patients with a

history concerning for acetaminophen hypersensitivity, the cur-

rent recommendations for deﬁnitive evidence of a reaction are

oral-based challenge tests.

696

This is because of the relatively

infrequent occurrence of hypersensitivity reactions associated

with acetaminophen use.

683,688,689,695

Table LXXVII highlights

the common methods of graded challenges performed for both

suspicion of anaphylaxis and NSAID-related reactions.

693,696

recent meta-analysis including 259 patients who underwent oral

challenges to acetaminophen for diagnostic conﬁrmation or

exclusion estimates the prevalence of true acetaminophen hy-

persensitivity to be 10.1% in adults and 10.2% in pediatric

patients.

699

ANTICOAGULANTS AND COA GULATION

FACTORS

Clopidogrel and antiplatelet agents (by Kimberly

Blumenthal, MD)

General.

Clopidogrel (Plavix) is a selective, irreversible inhib-

itor of ADP-induced platelet aggregation for oral use. It belongs

to the class of second-generation thienopyridine antiplatelet

agents. Within ADP2Y12 platelet receptor inhibitors, there are

thienopyridines (clopidogrel, prasugrel, and ticlopidine) or

cyclopentyl-triazolo-pyrimidines (ticagrelor and cangrelor). Clo-

pidogrel is the standard of care for patients who have undergone

coronary stenting, especially in drug-eluting stents. Additional

indications include acute management of myocardial infarctions,

peripheral artery disease, or cerebral vascular accident. The

incidence of hypersensitivity reactions to clopidogrel have been

reported to range from 1% to 6% of exposures, with most es-

timates ranging from 1% to 3%.

700-702

Major symptom s. The most common hypersensitivity re-

action to clopidogrel is rash, commonly macular, morbilli-

form, or diffuse and erythematous, beginning about 5 days

into treatment.

703,704

In addition to these likely T-

cellemediated drug eruptions, IgE-mediated reactions

comprise about 5% to 7% of clopidogrel hypersensitivity re-

actions.

705,706

In 1 case series, patients with urticaria repre-

sented 17% of reactions to clopidogrel.

707

Worldwide

postmarketing pharmaceutical experience reports that

anaphylactic reactions occur in fewer tha n 1% of cases.

701

Other reactions including systemic hypersensitivity s yndromes

have been described, including a serum sickness elike reaction,

ﬁxeddrugeruption,andSJS.

708

Current literature review does

not describe DRESS syndrome, TEN, or acute interstitial

nephritis attributed to clopidogrel use.

Diagnosis. There is no validated skin testing or patch testing

to clopidogrel. However, diagnostic testing could follow the

procedures of the largest case series (42 patients) evaluated with

both immediate hypersensitivity testing and patch testing after a

history suggestive of hypersensitivity to clopidogrel

(Table LXXVIII).

706

Of the 42 patients tested, most had a his-

tory consistent with a delayed rash. Although none were positive

by epicutaneous prick, 3 patients—all with previous symptoms

suggestive of an IgE-mediated reaction—were positive on

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S79

intradermal testing. Most patients, 34 of 42 or 81%, had positive

patch testing result to clopidogrel.

706

Caveats include that there

were no documented controls and there are no data to inform a

nonirritating skin testing concentration for immediate hyper-

sensitivity skin testing. In addition, the utility of testing for

cutaneous eruptions that are not IgE-mediated is unknown, but

can be helpful for some cutaneous eruptions, including mac-

ulopapular eruptions, AGEP, and ﬁxed drug eruptions.

13,51,709-

711

Management

Alternative agents.

Alternative agents could include

another thienopyridine (ticlopidine or prasugrel), ticagrelor,

warfarin, or cilostazol.

Ticlopidine is as effective as clopidogrel. It is not ﬁrst-line

therapy because of an unfavorable side-effect proﬁle, including

serious adverse reactions of neutropenia and thrombotic

thrombocytopenic purpura (in 2%). There is concern about

cross-reactivity between clopidogrel and ticlopidine because the

structure differs only by an addition of a caboxymethyl group

and they have shared metabolites in vitro ( Figure 7). Cross-

reactivity determined by patch-test result was found in 24% of

patients.

706

Given available data to date, if ticlopidine were to be

used in a patient with a history of allergy to clopidogrel, an oral

challenge would be advised (Table LXXIX).

Prasugrel is the most potent of the thienopryridines, but it is

contraindicated in patients with previous cerebrovascular acci-

dent, age more than 75 years, or weight less than 60 kg. There is

concern regarding cross-reactivity to clopidogrel, because they are

structurally similar (Figure 7 ). No data currently exist on cross-

reactivity between clopidogrel and prasugrel, because the clinical

trials for prasugrel excluded patients with a history of allergy to

ticlopidine or clopidogrel. One study demonstrated a 17% cross-

reactivity with prasugrel using patch testing, and there are reports

of patients with a history of allergy to clopidogrel who subse-

quently tolerated prasugrel.

706,712-714

Given available allergy

data, if prasugrel were to be used in a patient with a history of

allergy to clopidogrel, or vice versa, an oral challenge would be

recommended (Table LXXIX).

Ticagrelor, which is a reversible P2Y12 inhibitor and a strong

antiplatelet, is completely structurally dissimilar from clopidog-

rel. Although a previous report hypothesized cross-reactivity,

review of the case and symptoms reported more likely reﬂected a

reaction to the clopidogrel and stronger evidence supports that

ticagrelor can be safely administered to patients with clopidogrel

hypersensitivity.

715-717

Oral challenge. An oral graded challenge to clopidogrel

would be appropriate if the reaction (1) was unlikely to have

been caused by clopidogrel, (2) was not IgE-mediated/serious/

life-threatening and the beneﬁts of clopidogrel use outweighed

the risk of reaction, and (3) led to initiation of a potentially cross-

reactive drug (eg, ticlopidine).

Desensitization. Desensitization protocols for clopidogrel

hypersensitivity are safe and successful, and have been used both

for IgE-mediated reactions and for delayed cutaneous reactions.

Contraindications to desensitization include severe T-

cellemediated reactions such as DRESS, TEN, or SJS. In a study

of 24 patients who underwent a desensitization procedure, 100%

of the patients had successful desensitization and all patients were

taking clopidogrel at the 6-month follow-up. Most patients

(83%) did not have reactions during the desensitization pro-

cedure.

707

Published desensitization procedures range from 2 to

8 hours (Table LXXX).

718

The 2-hour or 7-hour desensitization

procedures are recommended on the basis of severity of the al-

lergy history, considering both the type and severity of the re-

action, as well as considering comorbidities and acuity of the

patient’s illness. Recently, outpatient multiday protocols have

been used for patients with clopidogrel hypersensitivity (largely

rash, but 1 patient had angioedema) with success.

719

One

disadvantage of using a desensitization protocol for clopidogrel

hypersensitivity, particularly after stent placement, is that it re-

quires initial cessation of clopidogrel to allow for a washout

period and symptom resolution. However, patients may be

treated with an alternative agent (eg, ticlopidine) during this

period.

Drug continuation with treatment with steroids and

antihistamines.

Because cardiology data show a signiﬁcant

risk (25%-30%) of thrombosis with interruption of antiplatelet

therapy, some groups have used a “treating though” strategy for

cutaneous clopidogrel hypersensitivity reactions

(Table LXXXI).

720

Sixty-two patients with cutaneous reactions

(both urticarial and nonurticarial rashes) to clopidogrel were

treated with a 30-mg twice-daily tapering prednisone course and

benadryl 25 to 50 mg Q6-8PRN without drug stoppage. This

approach was successful in 98% of patients, with the rashes

resolving in about 5 days and all patients had uninterrupted dual

platelet therapy. Among their 62 patients, this approach failed in

1 patient who developed angioedema and required hospitaliza-

tion.

706

Among 25 patients with delayed rashes who were treated

with steroids (methylprednisolone) and antihistamines (fex-

ofenadine 180 mg every day with 25-50 mg diphenhydramine

QHS) for a mean of 10  8 days without interruption of clo-

pidogrel, 22 of 25 (88%) patients had no adverse effects/events

in long-term follow-up, and all completed clopidogrel therapy

according to the America Heart Association guidelines.

705

The

mean duration of steroid treatment was 10 days. Two patients

had recurrent symptoms, treated with more corticosteroids (18

days starting with prednisone 60 mg), an antileukotriene

(montelukast 10 mg), and antihistamines. In sum, 3 patients

failed this therapy, with 1 patient each having angioedema, a

desquamating rash, and intolerable pruritus. Another group used

prednisone 30 mg twice a day with cetirizine 10 mg daily with

success.

721

Given these encouraging data, this strategy is

reasonable for benign, maculopapular, or erythematous eruptions

that are likely to be T-cellemediated and without organ

involvement. However, this strategy is not recommended in IgE-

mediated reactions, especially those involving organ systems

beyond the skin, where desensitization is indicated, or rashes

suggestive of a severe T-cellemediated reaction. Caution is also

warranted when using this approach for cutaneous reactions

suggestive of IgE (eg, urticaria) given that these studies demon-

strating this approach to urticarial rashes are not robust enough

to determine the safety of this approach.

Heparin and protamine (by Cosby Stone Jr, MD,

MPH, and Allison Norton, MD)

General.

Heparin is a widely used anticoagulating agent for the

active treatment and prophylaxis of thrombosis in at-risk pa-

tients. Side effects of heparin are overall quite rare considering

the frequency of its use in hospitalized patients for the prevention

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S80 BROYLES ET AL

of deep venous thrombosis. Most reports of hypersensitivity to

heparin are DHRs, which can affect up to 7.5% of patients

treated, and heparin-induced thrombocytopenia (HIT).

722-724

There are, however, rare reports of immediate hypersensitivity

reactions.

725,726

In the past, when heparin products were

contaminated with overly sulfated chondroitin sulfates, non-

eIgE-mediated anaphylaxis was reported via the kinin-kalikrein

pathway through the production of bradykinin, as well as C3a

and C5a anaphylatoxins.

727

In addition, immediate hypersensi-

tivity to protamine, the main reversal agent for heparin-mediated

anticoagulation, has occurred, and can easily be mistaken for an

allergy to heparin or insulin.

728,729

Heparins are sulfated carbohydrates of the glycosamino-

glycan family ﬁrst puriﬁed from pig intestines with the

property of being naturally occurring activators of anti-

thrombin III, and they achieve their anticoagulation effects

by antithrombin IIIemediated inactivation of thrombin.

730

Unfractionated heparin (UFH) can include heparins of

various molecular weights and lengths, typically averaging 14

to 18 kDa.

722,730

Low-molecular-weight heparins (LMWHs)

have been modiﬁed by fractionation or depolymerizaton to

provide a puriﬁed product, in which at least 60% of chains

are less than 8 kDa in length, to reduce the biological

unpredictability of UFH. Heparinoids are synthetic mole-

cules designed to mimic the binding site of heparin to

antithrombin III (Table LXXXII).

722

Because of their strong negative charge, UFH and LMWHs

can be inactivated by the highly cationic peptide protamine, a

compound originally derived from salmon spermatozoa. Prot-

amine has itself been shown to cause IgE-mediated hypersensi-

tivity reactions, especially in patients previously exposed to

protamine-containing insulins.

13,531,728,731

Fish allergy and va-

sectomy have previously been alleged as risk factors for protamine

reaction, but there is no substantiated evidence to support this

claim.

732,733

Cross-reactivity. Wide ranges of cross-reactivity have been

reported to occur in LMWHs in DHR, but fondaparinux and

danaparoid are generally well tolerated.

722

Hypersensitivity to

UFH is reported to be frequently cross-reactive with LMWHs

and heparinoids.

723,726

Hypersensitivity to heparin is not cross-reactive with struc-

turally distinct anticoagulants such as hirudins or factor Xa in-

hibitors, and these are often used as alternative agents.

725,734

Major symptoms of hypersens itivity. Heparins have

been demonstrated most commonly to cause DHR, of which the

most typical feature is an itching, eczematous plaque, or mac-

ulopapular eruption that ﬁrst appears around sites of injection

after 7 to 10 days of continuous initial treatment, and can appear

more rapidly on subsequent exposures.

723,726,730,735,736

Immediate-type hypersensitivity to heparins can present with

palmoplantar pruritus, urticaria, conjunctivitis, bronchospasm,

and anaphylaxis, and are only rarely reported.

722,726,730,737

Hy-

potension, angioedema, and swelling of the larynx have devel-

oped in patients after receiving heparin products contaminated

with oversulfated chondroitin sulfates.

727

Mild thrombocytopenia is noted in the setting of UFH use in

about 30% to 50% of critically ill patients, but severe HIT via

IgG speciﬁc for large complexes of heparin bound to platelet

factor 4 occurs in around 1%.

722,738

HIT usually occurs after 5

days of treatment with either UFH or LMWHs, and, in severe

cases, can present with profound thrombocytopenia, thrombosis,

or cutaneous necrosis.

13,730,739,740

Immediate reactions can

occur on the ﬁrst dose for previously sensitized patients with

HIT, with symptoms including fever, ﬂushing, dyspnea, mental

status change, and hypertension.

722

Immediate hypersensitivity to protamine has been reported

with urticaria, hypotension, and anaphylaxis, via IgE- and none

IgE-mediated mechanisms.

13,530,531,728,731,741

Dose-dependent

hypotension after rapid infusion of protamine is most likely

triggered by nonspeciﬁc histamine release.

Protamine is a rare

cause of intraoperative anaphylaxis and is most often reported

during cardiac surgeries when quick reversal of heparin anti-

coagulation is required.

531

Cases of delayed hypersensitivity to protamine with

erythematous plaques at injection sites can occur to protamine-

containing insulin, with 1 report including eosinophilia and renal

dysfunction.

742,743

Diagnosis. Nonirritating concentrations for the evaluation of

immediate hypersensitivity to heparins and heparinoids have

been reported and shown to be useful in clinical decision

FIGURE 7. Biochemical structures of the thienopyridines.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S81

making.

79,726

Skin testing is generally performed via PT with

commercially available undiluted product. IDTs with 1:10 and

1:100 dilution may be useful, though lower concentrations are

associated with lower sensitivity.

The European concentration

for heparin is 25,000 units/mL for prick and 2,500 units/mL for

IDT, but the highest US concentration is 10,000 units/mL, so

PT with 10,000 units/mL and IDT with 1,000 units/mL is

recommended. In clinical experience, because cross-reactivity

between UFH, LMWHs, and heparinoids can occur, it is rec-

ommended that a panel of all these products be used during

testing.

Diagnosis of delayed hypersensitivity to heparins has been

reported to be more sensitive when using delayed intradermal

testing at 1:10 dilution compared with patch testing. These are

typically read 2 to 7 days after placement.

79,723,744

Testing for IgG antibodies to platelet factor 4 is the mainstay

of early diagnosis for HIT when it is suspected clinically, with a

sensitivity greater than 90% and quick turnaround times.

738

Serotonin release assays remain the criterion standard for HIT

diagnosis in terms of speciﬁcity, but they are limited by avail-

ability, specialized equipment, and longer time to obtain

results.

738

Immediate hypersensitivity s kin testing and serum-speciﬁc

IgE testing to protamine have been reported in the literature,

but have not been well studied and recommended testing di-

lutions vary widely.

530,728,745

Ebo et al

629

suggest using a

maximum undiluted protamine concentration of 50 mg/mL

for skin prick testing and 50

g/mL maximum concentration

for intradermal testing. However, a case series using 53 con-

trols suggested that intradermal testing at 30

g/mL may cause

nonspeciﬁc histamine release. They suggest skin prick testing

at concentrations of 300 to 330

g/mLand0.03to30

g/mL

for intradermal testing.

532

Management. Management of heparin sensitivity should

focus on choosing an alternative nonecross-reactive agent or

desensitization if there is no alternative. Patients with hyper-

sensitivity to UFH are often cross-sensitized to LMWHs, and

additionally may be sensitized to heparinoids.

722

Given that the

negative predictive value of heparin and protamine skin testing

remains unknown, a high suspicion of clinical reactivity with

negative testing still warrants desensitization or if feasible, se-

lection of an alternative agent. Generally, patients with both

immediate and delayed hypersensitivity can tolerate the non-

structurally related hirudins, factor Xa inhibitors, but rare pa-

tients with sensitization to structurally dissimilar anticoagulants

have been reported.

722

TABLE LXXIX. Ticlopodine test dose protocol (graded oral challenge)

Step 1

of a pill/dose, observe for 60 min

Step 2 1 pill/full dose, observe for 60 min

TABLE LXXX. Desensitization protocols for clopidogrel

718

Time (h) Dose Concentration mL

Seven-hour protocol

0:00 0.005 0.5 mg/mL 0.01

0:30 0.01 0.02

1:00 0.02 0.04

1:30 0.04 0.08

2:00 0.08 0.16

2:30 0.16 0.32

3:00 0.3 0.6

3:30 0.6 1.2

4:00 1.2 5 mg/mL 0.24

4:30 2.5 0.5

5:00 5 1

5:30 10 2

6:00 20 4

6:30 40 8

7:00 75 75-mg tablet 1 tablet

Two-hour protocol

0:00 0.02 0.5 mg/mL 0.04

0:15 0.05 0.1

0:30 0.15 0.3

0:45 0.5 1

1:00 1.5 5 mg/mL 0.3

1:15 5 1

1:30 15 3

1:45 45 9

2:00 75 75 mg 1 tablet

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S82 BROYLES ET AL

Several case reports have described successful heparin desen-

sitization for immediate hypersensitivity reactions, typically over

4 to 5 days.

746-750

Dave and Park

747

describe a protocol in which

heparin doses are continuously infused intravenously over 12-

hour periods in half-log 10 increments to a goal infusion of 1000

unit/h of heparin (Table LXXXIII). The patient successfully

tolerated a 50,000 unit bolus of heparin after completing this

desensitization and a subsequent smaller dose of heparin.

Management of HIT similarly involves immediate cessation of

the offending agent, use of alternative anticoagulants, and future

avoidance of both UFH and LMWHs.

739

Because of the nature of its use as a reversal agent, there is little

role for desensitization for intraoperative protamine. Manage-

ment for these reactions typically focuses on modiﬁcation of

operative protocols where it is to be used, because there are no

clinically available alternatives to protamine. In the future, there

may be alternatives approved by the FDA; there are already

several products in advanced clinical phases.

751

Desensitization to protamine-containing insulin may be

necessary for diabetic patients who have no alternatives; this has

been described in the literature using the product neutral prot-

amine Hagedorn. One protocol successfully describes a starting

dose of 0.001 units intradermally, doubling every 20 to 30 mi-

nutes until a dose of 0.1 unit is reached. The protocol then

continues with subcutaneous injections until they reach the goal

dose of 4 units.

752

Coagulation factors (by Craig D. Platt, MD, PhD)

General.

The use of coagulation factors is the cornerstone of

treatment for hemophilia A (deﬁciency of factor VIII), hemo-

philia B (deﬁciency of factor IX), and type III von Willebrand

disease (vWD) (the most severe form of vWD).

753,754

TABLE LXXXI. Protocol for treating through cutaneous clopidogrel hypersensitivities

720

Initial therapy Continue clopidogrel 75 mg/d

Methylprednisolone taper (6-d Medrol Dosepak)

Antihistamines until symptom resolution (fexofenadine 180 mg/d and diphenhydramine 25-50 mg

at bedtime)

Secondary therapy for hypersensitivity reoccurrence Continue clopidogrel 75 mg/d

Longer course of corticosteroids (up to 18 d, eg, prednisone 60 mg, taper by 10 mg every 3 d)

Montelukast 10 mg/d

Antihistamines as needed

TABLE LXXXII. Anticoagulants by structural and functional category

Heparins Direct thrombin inhibitors Factor Xa inhibitors

UFH Hirudins Apixaban

LMWHs Bivalirudin Rivaroxaban

Ardeparin Desirudin

Certoparin Lepirudin

Dalteparin Argatroban

Enoxaparin Dabigatran etexilate

Nadroparin

Reviparin

Tinzaparin

Heparinoids

Danaparoid

Synthetic heparins

Fondaparinux

TABLE LXXXIII. Heparin desensitization protocol*

Step Solution (U/mL) Rate (U/h IV) Time (h) Volume infused per step (mL) Dose infused per step (units) Cumulative dose (units)

1 1 0.5 0-12 6 6 6

2 1 1.5 12-24 18 18 24

3 10 4.5 24-36 5.4 54 78

4 10 13.6 36-48 16.32 163.2 241.2

5 10 40.8 48-60 48.96 489.6 730.8

6 100 122.5 60-72 14.7 1,470 2,200.8

7 100 367.4 72-84 44.09 4,408.8 6,609.6

8 100 1008.0 84-96 120.96 12,096 18,705.6

The patient was preoperative for cardiac bypass and maintained at a dose of 1000 units/h until surgery. Additional desensitization protocols are reviewed in the same reference.

Available solution concentrations may vary depending on institution.

*Modiﬁed from Dave and Park.

747

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S83

Unfortunately, 2 major complications can prevent optimal

therapy in a subset of patients. First, inhibitory alloantibodies

(predominantly of the isotype IgG) to the exogenously supplied

coagulation factors can develop.

755,756

Such inhibitors substan-

tially increase the risk of morbidity and mortality due to

incomplete hemostasis. Second, acute hypersensitivity reactions,

often with features of anaphylaxis, can occur with in-

fusions.

755,756

In some cases, patients simultaneously develop

inhibitors and hypersensitivity reactions, a challenging clinical

scenario that signiﬁcantly limits treatment options.

755,756

Major symptoms of hypersensitivity. Symptoms of

anaphylaxis associated with factor infusion have been most

commonly described in patients with hemophilia B. Although

only 3% to 5% of patients develop inhibitory antibodies, the

development of such antibodies is a major risk factor for

anaphylaxis.

755-757

Warrier et al

757

reviewed 18 such cases. The

clinical manifestations of hypersensitivity reactions were (listed

from most to least frequent) rash, bronchospasm, angioedema,

emesis, restlessness, cough, hypotension, and syncope.

757

Pa-

tients with complete factor IX gene deletion have been shown to

TABLE LXXXIV. Recommended immediate hypersensitivity testing for vWF-containing products and FVIII

762

Product SPT IDT 1 IDT 2

Wilate vWF 100 IU/mL, FVIII 100 IU/mL vWF 10 IU/mL, FVIII 10 IU/mL vWF 100 IU/mL, FVIII 100 IU/mL

Humate P vWF 120 IU/mL, FVIII 50 IU/mL vWF 12 IU/mL, FVIII 5 IU/mL vWF 120 IU/mL, FVIII 50 IU/mL

Helixate 300 IU/mL 30 IU/mL 300 IU/mL

Advate 300 IU/mL 30 IU/mL 300 IU/mL

Xytha 300 IU/mL 30 IU/mL 300 IU/mL

Monoclate 300 IU/mL 30 IU/mL 300 IU/mL

FVIII, Factor VIII; vWF, von Willebrand factor.

TABLE LXXXV. Recommended immediate hypersensitivity testing for factor IX

764

Product SPT IDT 1 IDT 2

Mononine 100 IU/mL 1 IU/mL 10 IU/mL

Monoclate 100 IU/mL 1 IU/mL 10 IU/mL

IU, International unit.

TABLE LXXXVI. Desensitization protocol to factor IX*

Day Dose (units/kg) Cumulative dose (units/kg) Method Interval from infusion of previous dose

Day 1 0.01 0.1 Slow IV push 0 min

0.02 0.3 Slow IV push 10 min

0.04 0.7 Slow IV push 10 min

0.08 0.15 Slow IV push 10 min

0.1 0.25 Slow IV push 10 min

0.2 0.45 Slow IV push 20 min

0.4 0.85 Slow IV push 20 min

0.8 1.65 Slow IV push 20 min

1.5 3.15 Slow IV push 20 min

3.0 6.15 Continuous infusion over 30 min —

6.0 12.15 Continuous infusion over 30 min —

8.0 20.15 Continuous infusion over 30 min —

9.0 29.15 Continuous infusion over 60 min —

11.0 40.15 Continuous infusion over 60 min —

12.0 52.15 Continuous infusion over 60 min —

14.0 66.15 Continuous infusion over 60 min —

16.0 82.15 Continuous infusion over 60 min —

18.0 100.15 Continuous infusion over 60 min —

Day 2 100 100 Continuous infusion over 10 h —

Day 3 100 100 Continuous infusion over 8 h —

Day 4 100 100 Continuous infusion over 6 h —

Day 5 100 100 Continuous infusion over 4 h —

Day 6 100 100 Continuous infusion over 2 h —

Day 7 100 100 Continuous infusion over 1 h —

Day 8 100 100 Continuous infusion over 30 min —

*This protocol was devised and used successfully, given severe persistent urticaria with a standard 12-step approach.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S84 BROYLES ET AL

be at the greatest risk of developing inhibitors and anaphy-

laxis.

757

There does not seem to be a single common mechanism

for anaphylaxis, because the development of IgG

, IgG

, and IgE

to factor IX has been described.

756

Although up to 30% of patients with hemophilia A receiving

factor VIII replacement develop inhibitors, anaphylaxis is a very

rare complication.

756

Unlike in hemophilia B, there does not

appear to be a correlation with anaphylaxis and the development

of inhibitory antibodies.

756

Published reports of such reactions

have included respiratory distress, hypotension, and diffuse ur-

ticaria or erythroderma.

758,759

In several cases, allergic reactions

to factor VIII infusions have been presumed to be triggered by

concentrate components other than the factor VIII itself.

759,760

Inhibitory antibodies develop in approximately 10% of pa-

tients with type III vWD.

761,762

Anaphylaxis has been reported

in a number of these patients, though good estimates of the

incidence of anaphylaxis in patients with inhibitors is lack-

ing.

719,756,761-763

Two siblings with type III vWD have been

recently described, one of whom developed shortness of breath,

urticaria, tachycardia, and mild hypotension. His sibling’s

symptoms were limited to respiratory distress and back pain.

762

Diagnosis. Skin testing protocols have been described for

factor XIII (Table LXXXIV), factor IX (Table LXXXV), and von

Willebrand factor (Table LXXXIV).

762,764,765

However, in most

cases, IgG alloantibodies are responsible for the reactions and

these antibodies are not detected on such testing.

755,756

Patients

with hemophilia B and vWD with documented inhibitory an-

tibodies should be considered at risk for anaphylaxis with factor

infusions.

755,756

Patients with hemophilia A, even those with

high levels of inhibitors, are not considered at elevated risk of an

acute hypersensitivity reaction.

755,756

Management. The use of bypassing agents recombinant factor

VII activated and activated prothrombin complex concentrates

including factor VIII inhibitor bypassing activity has been

described for acute bleeding episodes in patients with hemophilia

A, hemophilia B, and vWD.

766,767

Desensitization protocols have

been published for all 3 disorders as well (Tables LXXXVI and

LXXXVII).

762-765

For patients with inhibitors to these factors,

such protocols can be the ﬁrst step of an immune tolerance in-

duction protocol.

762,768

It is important to note that nephrotic

syndrome is a relatively common complication of immune toler-

ance induction in patients with hemophilia B and therefore

episodic control with recombinant factor VII activated rather than

immune tolerance induction should be strongly considered.

768

OTHER DRUGS

Radiographic contrast media (by Knut Brockow,

MD)

General.

Adverse reactions to iodinated radiocontrast media

(RCM) may be either chemotoxic (eg, cardiotoxicity, neurotoxicity,

and nephrotoxicity) or due to hypersensitivity.

769

Hypersensitiv ity

reactions manifest either immediately (<1 hour of administration)

or are nonimmediate responses (>1 hour). Immediate hypersensi-

tivity reactions present with anaphylaxis, and nonimmediate re-

actions predominantly are exanthems.

769

The pathogenesis is

normally related to the molecular RCM structure and not to iodine

or to seafood allergy.

770

Thereisincreasingevidencethatsomeof

these reactions may be immunologic and that allergy tests may help

to identify agents that may be tolerated.

769,771

Mild immediate

TABLE LXXXVII. Twelve-step desensitization protocol to wilate*

Full therapeutic dose: 435 IU daily

Premedication Diphenhydramine†

A. Prepared solutions

Solution mL/bag IU/bag IU/mL

1 250 4.35 0.017

2 250 43.5 0.174

3 250 431.6 1.726

B. Desensitization

Step Solution Rate (mL/h) Time (min) Dose (IU) Cumulative dose (IU)

1 1 2 15 0.009 0.009

2 1 5 15 0.022 0.031

3 1 10 15 0.044 0.074

4 1 20 15 0.087 0.161

5 2 5 15 0.218 0.379

6 2 10 15 0.435 0.814

7 2 20 15 0.870 1.684

8 2 40 15 1.740 3.424

9 3 10 15 4.316 7.739

10 3 20 15 8.632 16.371

11 3 40 15 17.263 33.634

12 3 75 186 401.37 435.000

Total time 351 min

IU, International unit.

*The total IU dose injected is more than the ﬁnal dose because solutions 1 and 2 are not completely infused.

†Oral dose of 1 mg/kg, 1 h before start of desensitization and 1 h before each subsequent dose.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S85

hypersensitivity reactions, such as urticaria and pruritus, have been

reported to occur in 0.7% to 3.1% of patients receiving modern

nonionic RCM, whereas severe life-threatening reactions occur in

0.02% to 0.04% of patients, and fatal hypersensitivity in 1 to 3 per

100,000 RCM administrations.

769

The fre quency of reported

nonimmediate exanthems varies greatly and has been reported to

affect about 1% to 3% of RCM-exposed patients.

769

Major symptoms. Immediate RCM hypersensitivity re-

actions manifest with symptoms of anaphylaxis.

771

Pruritus and

urticaria with or without angioedema are most common.

Gastrointestinal symptoms such as nausea, vomiting, abdominal

pain, and diarrhea may occur. Reactions may involve the respi-

ratory and cardiovascular systems and present with dyspnea,

bronchospasm, and/or a sudden drop in blood pressure. Hypo-

tension may be associated with loss of consciousness (anaphy-

lactic shock). The onset of immediate hypersensitivity reactions

is within 5 minutes after injection in about 70% of reactions

771

;

96% of severe or fatal reactions manifest within 20 minutes.

Nonimmediate RCM hypersensitivity reactions are usually

mild to moderate in severity and are self-limiting. The typical

clinical manifestation is a maculopapular exanthem occurring

within a few hours to several days after the RCM administra-

tion.

771

Uncommon skin reactions including erythema, urticaria,

angioedema, ﬁxed drug eruption, erythema multiforme, SJS,

TEN, and papulopustular eruptions have been described.

771

Diagnosis. For immediate hypersensitivity reactions, anaphy-

laxis may be conﬁrmed by obtaining blood samples for histamine

analysis drawn immediately, or for tryptase ideally drawn 1 to 2

hours after the onset of symptoms. The further allergy workup

should be performed within 6 months after the reaction for best

test results (Figure 8).

771

It consists of a SPT with undiluted RCM

followed by IDT with RCM (300-320 mg/mL) diluted 10-fold in

sterile saline and reading after 20 minutes (Table LXXXVIII).

771

In case of a positive reaction, a panel of several different RCM

should be tested. There is no commercial assay for RCM-speciﬁc

IgE antibodies. Increased basophil activation to RCM has been

described, but the reliability of this or other in vitro tests has not

yet been sufﬁciently established. Several studies from Europe and

Asia have shown that skin testing may be helpful in patients with

past hypersensitivity reactions to RCM. Skin tests with RCM will

give positive results only in a minority (w10%-25%) of imme-

diate and 30% to 70% of nonimmediate reactions with clinical

pictures typical for drug hypersensitivity reactions.

771,772

For nonimmediate exanthems, it is recommended to use SPT

and patch tests with undiluted RCM and IDTs with 10-fold

diluted products in physiologic saline with delayed readings after

48 and 72 hours (in case of local pruritus or erythematous pla-

ques also at additional time points; Table LXXXVIII).

771

RCM-

related T-cell activity may additionally be assessed in vitro by

lymphocyte transformation test and by lymphocyte activation

test, although their sensitivity and speciﬁcity remain unknown,

and these tests are not commercially available.

Drug challenge has not been generally recommended because

intravenous applications of as low as 1 mL RCM have anec-

dotally led to severe anaphylaxis. However, evidence is increasing

that, in experienced centers, challenge tests can be performed to

conﬁrm results of skin tests.

773

Graded drug challenge tests have been recommended to conﬁrm

negative skin test results, for example, 1/10 of the full dose on day 1,

of the full dose on day 2, and the full dose on day 3 at the

radiology department, becau se a neg ative skin test result does

indicate, but does not necessarily guarantee, tolerance.

769

At this

time there is inadequate published experience in the pediatric

population; therefore, the approach to hypersensitivity to RCM in

children has been modeled from the one used for adults.

Management. Patients with previous hypersensitivity reactions

to RCM are at risk for developing new reactions on reexposure.

769

If such patients need another contrasted examination, the culprit

preparation should be avoided, particularly if there is a history of

severe reactions. In those with positive skin test reaction to the

culprit, cross-reactivity to other RCMs is common.

772

The risk of

RCM cross-reactivity to different RCMs appears to be related to

the structure of the culprit. Three different groups of RCM have

been proposed, with frequent reactions within groups and scarce

skin test positivity among RCMs of different groups.

772

In case of

a positive reaction, a skin testenegative product should be iden-

tiﬁed. The preventive value for the selection of an alternative

RCM by skin test still has to be further conﬁrmed. The beneﬁtis

limited to those patients with positive skin tests to RCM. In the

United States, skin testing after immediate reactions to RCM is

not considered standard of care; however, the role of skin tests in

the evaluation is evolving. In 1 study, however, the negative pre-

dictive value of reapplication of RCM in combination with skin

tests was reported to be high.

773

A fractionated challenge test may

be considered in nonimmediate exanthems. In patients with

negative skin test result or in whom skin tests are not performed,

the use of premedication with antihistamines and/or glucocorti-

coids is no longer recommended. The anaphylaxis 2020 practice

–

negative negative

–

positive

Adverse reaction to RCM

Chemotoxic,

unspecific or

unrelated event

No test

Typical symptoms of

allergic reactions

Urticaria, symptoms of

anaphylaxis (immediate)

Exanthema

(nonimmediate)

SPT followed by IDT,

reading after 20 minutes

(optional: BAT)

SPT, IDT, PT, reading after

20 minutes, 48-72 hours

(optional: LTT, LAT)

Skin test

alternative agents

Skin test

alternative agents

Consider doing

provocation test

Consider doing

provocation test

Check necessity, use test-negative

alternative, after severe reactions

consider additional premedication

1. Use other nonrelated RCM

2. Consider premedication (eg, 50 mg prednisone 13, 7,

and 1 hour and 50 mg diphenhydramine 1 hour

before the procedure for immediate reactions and

50 mg prednisone 13, 7, and 1 hour before the

procedure

for nonimmediate exanthemas)

3. Emergency preparedness

FIGURE 8. Test procedure in RCM hypersensitivity.

769

LAT,

lymphocyte activation test; LTT, lymphocyte transformation test.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S86 BROYLES ET AL

parameter update performed a systematic review and Grading of

Recommendations, Assessment, Development, and Evaluation

(GRADE) analysis and suggested against premedication to prevent

anaphylaxis in patients with prior radiocontrast HSRs when

readministration of a low- or iso-osmolar, nonionic RCM agent is

required.

774

This was a conditional recommendation with the

certainty rating of evidence as being very low. Therefore pre-

medication may be considered in clinical circumstances associated

with a high level of perceived risk of anaphylaxis or comorbidities

associated with greater anaphylaxis fatality risk (such as underlying

cardiovascular disease, use of beta-blockers, or prior severe

anaphylaxis), although evidence is lacking to clearly support this

practice and breakthrough reactions may still occur. Corticoste-

roids (eg, 50 mg prednisone 13, 7, and 1 hour before the pro-

cedure) and H

(eg, 50 mg diphenhydramine 1 hour before the

procedure)  H

antihistamines are the most frequently recom-

mended premedication agents. Physicians dealing with these pa-

tients should not rely on the efﬁcacy of premedication.

Corticosteroids (by Iris Otani, MD, and Rima Rachid,

MD)

Background.

Corticosteroids are used in the treatment of

several con ditions, i ncluding al lergi c conditi ons, malignancy,

autoimmunity, and transplantation. Immediate

TABLE LXXXVIII. Skin test concentrations for radiocontrast media*

Test Concentration*

Readings

Immediate reaction Nonimmediate reaction

Skin prick test Undiluted 20 min 20 min, 48 h, 72 h†

Intradermal test 1/10 diluted 20 min 20 min, 48 h, 72 h†

Patch test Undiluted 20 min, 48 h, 72 h†

*Radiocontrast media with an iodine concentration of 300-320 mg/mL.

†If the patient notices a positive reaction (pruritus, erythema) at the skin test site at other time points, additional readings may be performed (eg, after 24 h or 96 h).

TABLE LXXXIX. Recommended immediate hypersensitivity testing for corticosteroids and excipients*

777-781,792,802,804

Corticosteroid SPT dilutions (mg/mL) IDT dilutions (mg/mL) References

Betamethasone sodium phosphate 4-6 0.006 SPT: Asakawa, Figueredo, Venturini, Rachid

0.06 IDT: Figueredo, Rachid

0.6

4-6

Betamethasone acetate 6 6 SPT: Mace

IDT: Montoro

Budesonide 0.25 0.0025 SPT: Venturini

0.025 IDT: Venturini

Dexamethasone sodium phosphate 4 0.004 SPT: Mace, Venturini, Rachid

0.04 IDT: Rachid, Baker, Venturini

0.4

Hydrocortisone sodium succinate 10-100 0.01-1 SPT: Figueredo, Venturini, Rachid

0.1-10 IDT: Rachid, Venturini, Montoro

10-25

Methylprednisolone acetate 40 0.4 ST: Mace, Venturini

4 IDT: Baker, Venturini

Methylprednisolone sodium succinate 10-40 0.01 ST: Mace, Rachid

0.1-0.4 IDT: Baker, Rachid

4-10

Prednisone 3-30 No IDT Venturini, Rachid

Prednisolone 3-10 No IDT Venturini, Rachid

Triamcinolone acetonide 10-40 0.01 SPT: Venturini, Rachid

0.1-0.4 IDT: Baker, Venturini, Montoro, Rachid

1-4

10-40

Polyethylene glycol† 10 (1:100) 0.1 (1:10,000) SPT: Sohy

100 (1:10) 1 (1:1,000)

10 (1:100)

Carboxymethylcellulose† 5 0.005 Venturini

0.05

*Dilutions adapted from cited publications.

†Dilutions based on literature and not personal experience.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S87

hypersensitivity reactions to corticosteroids are overall rare.

The exact incidence is unknown, but hypersensitivity reactions

to corticosteroids have been reported with an estimated pre v-

alence of 0.1% to 0.3%.

Clinical presentation. Most immediate h ypersensitivity

reactions to corticosteroids occur within an hour of adminis-

tration. Symptoms may include 1 or more of the following:

urticaria, angioede ma, wheezing, bronchospasm, nausea,

vomiting, hypotension, or even cardiovascular collapse.

775,776

Recognition of corticosteroids as the culprit for these reactions

is sometimes challenging, because they are often used to treat

conditions that may lead to similar symptoms, such as allergic

reactions, status asthmaticus, anaphylaxis, or shock. Hence,

hypersensitivity reactions to corticosteroids may go unrecog-

nized and patients may develop more than 1 reaction before

thisdiagnosisissuspected.Itisnotclearwhethersometypesof

corticosteroids are more prone to causing hypersensitivity re-

actions than others, or whether the likelihood of reactions is

related to the frequency of administration of speciﬁccortico-

steroids. In a recent review of the literature from 2004 to 2014,

120 hypersensitivity reactions to corticosteroids were reported

in 106 patients. Methylprednisolone was impl icat ed in 41% of

all types of reactions, followed by prednisolone (20%),

triamcinolone (14%), and hydrocortisone (10%).

775,776

Re-

actions occur most commonly after intravenous (44% of cases)

and oral (26%) administration, though reports of reactions

after intra-articular, ophthalmic, and topical administration

have also been published.

775-777

Diagnosis and management of imm ediate hyper-

sensitivity reactions.

Identiﬁcation of an alternative cortico-

steroid for future use is possible in most cases with skin prick and

intradermal testing at nonirritating concentrations (Table LXXXIX)

andgradedchallenge.

775,776 ,778-781

Whenever possible, testing

should be performed with a preservative-free corticosteroid, in

addition to preservative testing if needed. Negative skin test results

should be conﬁrmed with drug challenge.

782-800

Cross-reactivity

patterns based on structural characteristics have not been clearly

established for immediate hypersensitivity reactions as they have

been for delayed reactions as described by Coopman et al.

801-804

Some reports suggested that hydrocortisone is more cross-reactive

with methylprednisolone than with halogenated corticosteroids such

as dexamethasone and betamethasone, whereas others did not ﬁnd a

deﬁn ite pattern of cross-reactivity based on the history and skin and

intradermal testing.

802,805,806

Hydrophobic corticosteroids are sometimes chemically

bonded to an ester such as sodium succinate or sodium phos-

phate to transform them into soluble injectable products. Im-

mediate hypersensitivity reactions have been reported to the

succinate ester component of the corticosteroids.

784,786,804,807-

811

Hence, when evaluating a reaction that is thought to be

secondary to esteriﬁed corticosteroids, it is recommended to

include the suspected corticosteroids in the skin and intradermal

testing, and, in addition, the same corticosteroids without the

ester component or with a different ester.

Immediate hypersensitivity reactions can also occur because of

excipients or preservatives in a corticosteroid preparation. Sen-

sitivities to lactose, carboxymethylcellulose, polyethylene glycol,

and hexylene glycol have been reported.

782,783,785,787,789-

793,803,812-816

When preservatives or excipients are present in the

corticosteroid preparation, skin testing with these agents can be

considered. Skin testing with milk proteins can be considered in

patients with milk allergy reacting to lactose-containing corti-

costeroid preparations.

Desensitization to methylprednisolone has been successfully

performed and is an option when an alternative therapeutic agent

cannot be identiﬁed (Table XC).

807

Contact dermatitis (delayed hypersensitivity) to

topical corticosteroids

Background.

Contact dermatitis to topical corticosteroids has

been reported with a frequency of 0.5% to 5%.

788

Contact

dermatitis to corticosteroids occurs more frequently in women

(3:1 women to men), and among the following occupations:

housewife (18%), ofﬁce work (17%), retired (7%), housekeeping

(6%), education (5%), student (5%), and health care (4%).

795

Diagnosis and management. Patch testing is the stan-

dard fo r diagnosing con tact dermatitis.

797

A combination of

TABLE XC. Previously published desensitization protocol for methylprednisolone

807

Bag Volume per bag (mL) Concentration (mg/mL)

1 250 0.040

2 250 0.400

3 250 3.969

Step Bag Rate (mL/h) Time (min) Administered volume (mL) Administered dose (mg) Cumulative dose (mg)

1 1 2 15 0.5 0.02 0.02

2 1 5 15 1.25 0.05 0.07

3 1 10 15 2.5 0.1 0.17

4 1 20 15 5 0.2 0.37

5 2 5 15 1.25 0.5 0.87

6 2 10 15 2.5 1 1.87

7 2 20 15 5 2 3.87

8 2 40 15 10 4 7.87

9 3 10 15 2.5 9.921 17.791

10 3 20 15 5 19.843 37.634

11 3 40 15 10 39.685 77.319

12 3 80 174.375 232.5 922.681 1000

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S88 BROYLES ET AL

tixocortol-21-pivalate and budesonide included in the thin-

layer r apid use epic utaneous test can id entif y 9 1.3% of

corticosteroid-sensitivity patients.

796

Supplemental patch

testing is needed to identify the culprit corticosteroid in the

remaining patients. Baeck et al

795

provide comprehensive

vehicle and c oncen tration recommendati ons fo r corti coster oid

patch testing in their review. Cross-reactivity patterns within

modiﬁed Coopman classiﬁcation groups have been observed

for delayed reactions (Table XCI).Forpatientswithpositive

reactions to tixocortol-21-pivalate or budesonide on thin-layer

rapid use epicutaneous test, consideration of cross-reactivity

patterns and supplemental patch testing can help identify

corticosteroids that can be tolerated for future therapeutic

use.

Vehicles used for topical corticosteroid preparations can also

cause irritation or contact dermatitis. Parabens, formaldehyde-

releasing preservatives (quaternium-15), isothiazolinones, lanolin,

ethylenediamine, sorbitan sesquioleate, fragrance, and propylene

glycol are all known contact allergens commonly used in topical

corticosteroid preparations.

794,798-800,817-819

The thin-layer rapid

use epicutaneous test includes all these additives except for pro-

pylene glycol, for which testing can be performed with 30%

aqueous solutions, and sorbitan sesquioleate, for which testing can

be performed with 20% petrolatum preparations.

820,821

Proton pump inhibitors (by Anna Wolfson, MD)

General.

Proton pump inhibitors (PPIs) are widely used in-

hibitors of gastric acid secretion. PPIs are generally well tolerated,

with a 1% to 2% risk of minor adverse reactions with rare reports

of serious adverse events.

822

Hypersensitivity is also rarely

described.

823-825

PPIs are modiﬁed benzimidazoles that contain a pyridine ring

and unique side-chain substitutions. Omeprazole and pan-

toprazole have a methoxy and a diﬂuoromethoxy chain in their

benzimidazole rings, respectively, whereas lansoprazole and

rabeprazole have a triﬂuoroethoxy and methoxypropoxy chain in

their pyridine rings, respectively. Multiple case reports have

described possible cross-reactivity among PPIs, based on the

underlying structural similarity and conﬁrmed by skin

testing.

823,826-828

Three patterns of cross-reactivity are described

on the basis of combining the data from the most recent

literature.

829

1. Hypersensitivity to omeprazole showed cross-reactivity with

all other PPIs.

825,828

2. Hypersensitivity to omeprazole showed cross-reactivity with

pantoprazole, or with pantoprazole and esomeprazole or

rabeprazole, but not with lansoprazole.

824-826,828

3. Hypersensitivity to lansoprazole showed cross-reactivity with

1 (omeprazole, pantoprazole, rabeprazole, esomeprazole) but

not with any of the other PPIs.

824,828,830,831

Major symptoms of hypersensitivity. Among the PPIs,

lansoprazole, followed by omeprazole, is most frequently impli-

cated as the cause of immediate hypersensitivity.

823,824

IgE-

mediated reactions are most commonly reported, accounting for

86% of all hypersensitivity reactions in a recent review of 118

cases.

823

In this same review, the clinical manifestations of hy-

persensitivity reactions were (listed from most to least frequent)

urticaria, generalized itching or pruritus, angioedema, hypoten-

sion, skin rash other than urticaria, erythema, and dyspnea or

shortness of breath.

823

The clinician should keep in mind that,

TABLE XCI. Observed cross-reactivity patterns within corticosteroid groupings based on the classification by Coopman et al

801

and

modified by Matura and Goossens

788

Group Structure Cross-reactivity

A—Hydrocortisone type

 Hydrocortisone

 Methylprednisolone

 Prednisolone

Short-chain ester or thioester on C

Within group

With budesonide-(S)-isomer and group D2

corticosteroids

B—Triamcinolone acetonide type

 Desonide

 Fluocinolone

 Tramcinolone

-cis-ketal or -diol Within group

Budesonide-(S)-isomer cross-reacts with

group A and D2 corticosteroids

C—Betamethasone type C

-methyl substitution

 Betamethasone

 Dexamethasone

 Desoximetasone

Nonesteriﬁed Betamethasone and/or dexamethasone and

group B

 Diﬂucortolone

 Fluocortolone

 Clocortolone

Stable esters (-valerate, -propionate, -diﬂucortolone

valerate, -ﬂumethasone pivalate)

No signiﬁcant cross-reactivity pattern

observed

D—Hydrocortisone-17-butyrate type Long-chain ester at C

or C

and C

with or without

-methyl substitution

 Clobetasol-17-propionate

 Betamethasone dipropionate

 Mometasone furoate

 Aclometasone dipropionate

methyl substitution on B ring Rare cross-reactivity between aclomethasone

dipropionate and group A, budesonide,

group D2

 Hydrocortisone-17-butyrate

 Hydrocortisone valerate

Lacks long-chain ester and methyl substitution

Lipophilic prodrugs that penetrate skin easily

Within group

With group A corticosteroids

With budesonide-(S)-isomer

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S89

because many of the drugs are delayed release preparations, pa-

tients may present with hypersensitivity symptoms 2 to 3 hours

after ingestion as opposed to the classic teaching of 1 hour.

823

The remaining 14% of cases were noneIgE-mediated and

included 1 case of DRESS to esomeprazole (a subsequent case

reported DRESS to omeprazole

832

), 1 case of TEN to lanso-

prazole, 1 case of hypersensitivity vasculitis, and 5 cases of

contact dermatitis (3 of which were occupational exposures, 1 to

lansoprazole and 2 to omeprazole).

823

A subsequent large case

series of 96 cases of occupational sensitization to omeprazole

identiﬁed 36 patients with evidence of sensitization to omepra-

zole based on patch testing and lymphocyte transformation

test.

833

Acute interstitial nephritis has been well described with

PPI use.

834

Subacute cutaneous lupus erythematosus has also

been described.

835

Diagnosis. The validity of skin testing for the evaluation of

immediate hypersensitivity to PPIs has been studied in a pro-

spective analysis by Kepil Ozdemir et al,

824

who reported a

sensitivity of 58.8%, speciﬁcity of 100%, negative predictive

value of 70.8%, and positive predictive value of 100%. Their

skin testing protocol is outlined in Table XCII as well as the

protocol proposed by Bose et al,

823

which is based on a broader

literature review. In clinical experience, cross-reactivity among all

the PPIs can be seen.

836

Unfortunately, the low negative pre-

dictive value of skin testing means that this is often observed

during the oral challenge. The BAT, when used in conjunction

with skin testing, has been described as being a useful guide for

whether oral challenge should be performed.

837

Patch testing has been used in cases of suspected delayed

hypersensitivity. Ghatan et al

833

used an omeprazole sodium salt

TABLE XCII. Recommended immediate hypersensitivity testing for PPIs

823,824

PPI

Bose et al

823

Kepil Ozdemir et al

824

SPT dilutions (mg/mL) IDT dilutions (mg/mL)* SPT dilutions (mg/mL) IDT dilutions (mg/mL)*

Omeprazole 40 0.04 0.4 0.004

0.4 4 0.04

4 20 0.4

Esomeprazole 40 0.04 0.8 0.008

0.4 8 0.08

4 20 0.8

Lansoprazole 30 0.03 30 None

0.3

Pantoprazole 40 0.04 0.4 0.004

0.4 4 0.04

4 40 0.4

Rabeprazole 20 0.02 20 None

0.2

*Intradermal testing should only be performed using injectable intravenous preparations of PPIs.

TABLE XCIII. Oral desensitization protocol for omeprazole*

839

Time (h) Concentration (mg/mL) Dose (mL) Dose (mg) Cumulative dose (mg)

0:20 0.002 0.5 0.001 0.001

0:40 0.002 1 0.002 0.003

1:00 0.002 2 0.004 0.007

1:20 0.002 4 0.008 0.015

1:40 0.02 0.5 0.01 0.025

2:00 0.02 1 0.02 0.045

2:20 0.02 2 0.04 0.085

2:40 0.02 4 0.08 0.165

3:00 0.2 0.5 0.1 0.265

3:20 0.2 1 0.2 0.465

3:40 0.2 2 0.4 0.865

4:00 0.2 4 0.8 1.665

4:20 2 0.5 1 2.665

4:40 2 1 2 4.665

5:00 2 2 4 8.665

5:20 2 4 8 16.665

5:40 2 8 16 32.665

*Omeprazole granules were dissolved into bicarbonate solution to create serial dilutions.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S90 BROYLES ET AL

in saline solution at 0.1%, 0.5%, and 1% for patch testing. In

the case of severe, life-threatening delayed reactions to PPIs, such

as DRESS and TEN, reexposure to a suspected culprit for testing

purposes must be performed with extreme caution and empiric

avoidance is recommended.

Management. Many patients with hypersensitivity to a PPI

can tolerate an alternative PPI, and skin testing (usually to the

culprit PPI, and to at least 1 other PPI) followed by oral chal-

lenge can identify candidate alternates.

838

Finally, a successful

desensitization protocol to omeprazole in the context of imme-

diate IgE-mediated hypersensitivity has been published

(Table XCIII).

839

Allopurinol (by Alberta L. Wang, MD)

General.

Allopurinol is the primary therapeutic agent used for

the treatment of gout and hyperuricemia. Most allopurinol hy-

persensitivity reactions are delayed, with a median time of onset

of 3 weeks, but reactions have been reported to occur years after

initiation of therapy.

840

Rash is the most common manifestation

of allopurinol hypersensitivity, with an overall incidence of

approximately 2%.

841

SCARs to allopurinol, including DRESS,

SJS, and TEN, are rare but have a high associated mortality of up

to 27%.

842

Allopurinol is rapidly metabolized by xanthine oxidase to

oxypurinol, which has a half-life of 23 hours, and is excreted by

the kidney. Allopurinol hypersensitivity is primarily mediated by

CD4

and CD8

T-cell responses to oxypurinol.

843

The risk of

hypersensitivity reaction is increased by factors that decrease

oxypurinol excretion, including impaired kidney function and

concurrent diuretic use. The HLA-B*58:01 allele is also associ-

ated with an increased risk for allopurinol hypersensitivity.

844

There is an increased prevalence of allopurinol hypersensitivity in

Asian subpopulations, which has been correlated with higher

HLA-B*58:01 allele frequencies. HLA-B*58:01 screening is

recommended for patients of Korean ethnicity with chronic

kidney disease stage 3 or worse and patients of Han Chinese or

Thai ethnicity irrespective of renal function before initiation of

allopurinol.

845

Major symptoms of hypersensitivity. The most com-

mon hypersensitivity reaction to allopurinol is a maculopapular

exanthem. The incidence of SCARs, including DRESS, SJS, and

TEN, is rare (w0.1%). However, allopurinol users have a 10

times higher relative risk of a SCAR compared with nonusers,

and allopurinol is a common cause of SJS and TEN.

846,847

addition, systemic hypersensitivity with acute interstitial

nephritis has been described in case reports.

848,849

TABLE XCIV. Rapid 2-d oral desensitization protocol for immediate hypersensitivity to allopurinol

Interval (min) Solution* Volume (mL) Dose (mg)

Day 1 B 0.25 0.05

30 B 0.5 0.1

30 B 1 0.2

30 B 2.5 0.5

30 B 5 1

30 A 2.5 5

30 A 5 10

30 A 12.5 25

30 Half 100-mg tablet — 50

30 100-mg tablet — 100

Day 2 100-mg tablet — 100

60 Two 100-mg tablets — 200

*Solution A: Crush 2 tablets of 100 mg allopurinol into a volume of 100 mL diluent (Ora-Plus/Ora-Sweet 1:1) to a ﬁ nal concentration of 2 mg/mL; Solution B: 1:10 dilution of

solution A to a ﬁnal concentration 0.2 mg/mL.

TABLE XCV. Twenty-eight-day allopurinol desensitization protocol for delayed hypersensitivity*

Days Daily dose Allopurinol administration instructions (by mouth)

1-3 50

g 0.25 mL of suspension A

4-6 100

g 0.5 mL of suspension A

7-9 200

g 1 mL of suspension A

10-12 500

g 2.5 mL (

tsp) of suspension A

Then change to suspension B

13-15 1 mg 1 mL of suspension B

16-18 5 mg 5 mL (1 tsp) of suspension B

19-21 10 mg 10 mL (2 tsp) of suspension B

22-24 25 mg

of a 100-mg tablet or 25 mL (5 tsp) of suspension B

25-27 50 mg

of a 100-mg tablet

28 and on 100 mg 1 full 100-mg tablet

tsp, Teaspoon.

*Suspension A: Allopurinol 0.2 mg/1 mL (100 mL); Suspension B: allopurinol 1 mg/1 mL (200 mL).

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S91

Diagnosis. Diagnosis is based on clinical history and symptom

recognition, in particular, the temporal relationship between

allopurinol initiation and symptom onset. Allopurinol skin

testing concentrations for IgE-mediated reactions are not stan-

dardized or validated. Intradermal skin testing with 0.1

gof

allopurinol has been reported with negative result in a patient

who presented with IgE-mediated symptoms.

850

Patch testing

with allopurinol has also been reported with low sensitivity.

842

Drug patch testing for systemic hypersensitivity reactions is not

standardized and the predictive value is unknown.

Management. The mainstay of treatment is cessation of

allopurinol and supportive care. For patients with a continued

indication for urate-lowering therapy, an alternative agent should

be considered. If allopurinol treatment is necessary and the initial

hypersensitivity reaction was not severe, desensitization can be

performed on an individual basis weighing the risks and beneﬁts

of treatment. The type and severity of the initial reaction, patient

comorbidity, and urgency of treatment should be considered

when choosing a desensitization protocol.

In patients with a history of IgE-mediated reaction to allo-

purinol, case reports have described success with rapid intrave-

nous desensitization.

851

In addition, a rapid 2-day oral

desensitization protocol with a target dose of 200 mg has been

published (Table XCIV).

852

Published desensitization protocols for DHRs range from 16

to 78 days.

13,853,854

The standard 28-day oral desensitization

protocol (Table XCV) is generally well tolerated.

853

The 28-day

protocol balances the reduction of breakthrough reactions during

desensitization, such as fever and rash, and the length of

desensitization. The 28-day protocol reaches a target dose of 100

mg/d. For a target dose higher than this, one can continue to

increase the dose up to 2-fold every 3 days as tolerated. The

protocol can be modiﬁed with dosage adjustments and by

lengthening the time between steps if breakthrough reactions

occur. In patients who need allopurinol more urgently, a shorter

16-day oral desensitization protocol that reaches a target dose of

300 mg can be used (Table XCVI).

853

A longer 78-day oral

desensitization protocol is recommended for high-risk patients

who are frail or elderly with multiple medical comorbidities,

TABLE XCVI. Sixteen-day allopurinol desensitization protocol for delayed hypersensitivity*

Day Solution Amount Dose (mg)

1 A 1 mL 0.3

2 A 2 mL 0.6

3 A 4 mL 1.2

4 A 8 mL 2.4

5 A 10 mL 3

6B 3mL 18

7B 6mL 36

8 B 10 mL 60

9 100-mg tablet

tablet 75

10 100-mg tablet 1 tablet 100

11 100-mg tablet 1

tablet 125

12 100-mg tablet 1

tablet 150

13 100-mg tablet 1

tablet 175

14 100-mg tablet 2

tablet 225

15 100-mg tablet 2

tablet 250

16 300-mg tablet 1 tablet 300

*Source solution: 150-mg allopurinol tablet in 50 mL 5% dextrose (ﬁnal concentration 3 mg/mL); Solution A: 1:10 source solution (0.3 mg/mL); Solution B: 300-mg allopurinol

tablet in 50 mL 5% dextrose (ﬁnal concentration 6 mg/mL).

TABLE XCVII. Seventy-eight-day allopurinol desensitization protocol for delayed hypersensitivity

Daily dose Concentration/tablet Amount Days

g 1 mg/5 mL 0.05 mL 1-7

g 1 mg/5 mL 0.12 mL 8-14

g 1 mg/5 mL 0.25 mL 5-21

100

g 1 mg/5 mL 0.5 mL 22-28

200

g 1 mg/5 mL 1 mL 29-35

500

g 1 mg/5 mL 2.5 mL 36-42

1 mg 1 mg/5 mL 5 mL 43-49

5 mg 10 mg/5 mL 2.5 mL 50-56

10 mg 10 mg/5 mL 5 mL 57-63

25 mg 10 mg/5 mL 12.5 mL 64-70

50 mg 100-mg tablet

tablet 71-77

100 mg 100-mg tablet 1 tablet 78

J ALLERGY CLIN IMMUNOL PRACT

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S92 BROYLES ET AL

renal impairment, or history of widespread cutaneous eruptions

with fever (Table XCVII).

Although allopurinol desensitization

is largely successful, there have been reports of unmanageable

recurrent rash and signiﬁcant adverse reactions necessitating

discontinuation of treatment.

13,854

Therefore, continued vigi-

lance and monitoring are essential.

Antiepileptics (by Sarah L. Garon, MD, and Elizabe th

Phillips, MD)

General.

Aromatic antiepileptic drugs such as carbamazepine,

oxcarbazepine, phenytoin, phenobarbital, lamotrigine, felbamate,

and zonisamide have been associated with a number of

hypersensitivity drug reactions, and a clinical presentation of

benign, delayed rash is the most common manifestation (rates

ranging from 5% to 17%). On the spectrum of potentially severe

immunologically mediated adverse drug reactions (IM-ADRs),

isolated benign exanthem is most common and mild; however,

more SCARs exist, which include DRESS, AGEP, ﬁxed drug

eruption, and SJS/TEN.

855

These SCAR syndromes differ ac-

cording to their clinical presentation, morbidity and mortality,

time between initiation of the drug and onset of symptoms,

immunopathogenesis, HLA and pharmacogenomic associations,

and utility of in vivo (patch and delayed prick/intradermal)

testing (Table XCVIII).

353,856,857

SCARs are not rare in

TABLE XCVIII. Pharmacogenomics of severe immunologically mediated adverse reactions associated with antiepileptic drugs

353,868

Drug Clinical phenotype Genetic association Population

Carbamazepine SJS/TEN HLA-B*15:02

HLA-B*15:21*

Han Chinese, Thai, Malaysian, Hindu Indian

HLA-B*15:11 Korean, Japanese

HLA-B*15:18 Japanese

HLA-B*59:01 Japanese

HLA-A*31:01 Northern European

HLA-A*31:01 Japanese, Korean

DRESS HLA-A*31:01 European, Japanese, Chinese

Oxcarbazepine SJS/TEN HLA-B*15:02, HLA-B*15:18 Han Chinese

Phenytoin SJS/TEN HLA-B*15:02 Han Chinese, Thai

HLA-B*13:01 Han Chinese

HLA-C*08:01/DRB1*16:02 Han Chinese

SJS/TEN/DRESS CYP2C9*3 Taiwan, Japan, Malaysia

Phenobarbital SJS/TEN ?HLA-B*51:01 Japan

Lamotrigine SJS/TEN HLA-B*15:02

HLA-B38

HLA-A*68:01

Han Chinese

Zonisamide SJS/TEN ?HLA-A*02:07 Japan

*HLA-B*15:21 is an important association with carbamazepine SJS/TEN.

TABLE XCIX. Valproic acid oral desensitization protocol*

Interval (d) Solution† Volume (mL) Daily dose (mg)

1-2 A 0.5 0.05

3-4 A 1 0.1

5-6 A 2.5 0.25

7-8 A 5 0.5

9-10 A 7.5 0.75

11-12 B 0.2 1

13-14 B 0.5 2.5

15-16 B 1 5

17-18 B 2 10

19-20 B 5 25

21-22 C 0.25 50

23-24 C 0.5 100

25-26 1 tablet — 200

27-28 1 tablet twice a day — 400

29-30 2 tablets twice a day — 800

*As adapted by Toker et al.

881

†Solution A: The solution was made by 1:50 dilution of solution B to a ﬁnal concentration of 0.1 mg/mL. Solution B: The solution was prepared by diluting 2 mL of valproic

acid solution (Depalept Oral Solution-CTS; 200 mg/mL) into a volume of 78 mL diluent (water) to a ﬁnal concentration of 5 mg/mL. Solution C: Valproic acid oral solution

(Depalept Oral Solution-CTS; 200 mg/mL). Valproic acid tablet (Depalept-CTS; 200 mg).

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S93

anticonvulsant drug users. Immediate IgE-mediated reactions

such as urticaria or angioedema are rarely described as compared

with the DHR.

Major symptoms of hypersensitivity. The term “anti-

convulsant hypersensitivity syndrome” has been used to encap-

sulate the triad of fever, rash, and internal organ involvement,

but other features such as lymphadenopathy and eosinophilia are

commonly present.

855

This is likely a form of DRESS when

anticonvulsant therapy is implicated. In early literature, the

clinical cross-reactivity between aromatic amines such as

phenytoin, carbamazepine, and phenobarbital was as high as

75% as ascertained by positive rechallenge reactions.

855

In Eu-

ropean populations, an estimate of the higher end of risk of this

syndrome is 4.5/10,000. Later studies have shown that many

severe IM-ADRs associated with aromatic antiepileptic drugs are

associated with speciﬁc HLA alleles; however, even before these,

case reports suggested a familial predisposition and 10- to 1000-

fold overrepresentation of some of the IM-ADRs in speciﬁc

ethnicities in which the risk HLA alleles are prevalent.

353,856-858

Immediate-type, IgE-mediated symptoms have been described

in the literature. Case reports have described urticaria and/or

angioedema to oxcarbazapine in 9 pediatric patients, to pheno-

barbital in 1 pediatric patient, to carbamazepine in an adult, and

tongue angioedema to phenytoin in a child.

859,860

Anaphylaxis is

rarely reported. It is important to be aware that immediate-type

symptoms may occur, but these are not as frequent as delayed-

type drug hypersensitivity reactions. Many of these case reports

cannot be validated as truly mediated by IgE. Also, angioedema

or other benign exanthem may be misdiagnosed as IgE-mediated

when in fact it may be the presenting cutaneous manifestation of

anticonvulsant syndrome.

One study examining different appearances of rashes associ-

ated with anticonvulsants reported that aromatic anticonvulsants

are signiﬁcantly associated with IgE-mediated (immediate) type I

and cell-mediated (nonimmediate or delayed) type IV drug

TABLE C. Desensitization protocol for pentobarbital

877,880

Desensitization strategy

 Pentobarbital 0.25

g/kg  ____ kg ¼ ____

g in 5 mL normal saline (NS) intravenously (IV)  1 over 30 min, followed immediately by

 Pentobarbital 2.5

g/kg  ____kg ¼ ____

g in 5 mL NS IV  1 over 30 min, followed immediately by

 Pentobarbital 25

g/kg  ____kg ¼ ____

g in 5 mL NS IV  1 over 30 min, followed immediately by

 Pentobarbital 250

g/kg  ____kg ¼ ____

g in 5 mL NS IV  1 over 30 min, followed immediately by

 Pentobarbital 500

g/kg  ____kg ¼ ____

g in 5 mL NS IV  1 over 30 min, followed immediately by

 Pentobarbital 10 mg/kg  ____kg ¼ ____

g in 5 mL NS IV  1 over 120 min, followed immediately by the full therapeutic starting dose

Full therapeutic starting dose: Must be continued on schedule without interruption

 Pentobarbital 1 mg/kg/h  ____kg ¼ ____ mg/h IV continuous solution

TABLE CI. Intravenous iron preparations*

Drug Trade name Available in the United States Test dose TDI* FDA boxed warning

HMW-ID DexFerrum; Imferon N (discontinued) Y Y Y

LMW-ID InFeD Y Y Y Y

Ferric gluconate Ferrlecit Y N N N

Iron sucrose Venofer Y N N N

Ferumoxytol Feraheme Y N Y Y

Iron isomaltoside Monofer Y N Y N

Ferric carboxymaltose Injectafer Y N N N

ID, Iron dextran; LMW, low molecular weight; N, no; TDI, total dose infusion; Y, yes.

*Allowing single dose administration of a patient’s entire iron requirement, rather than needing multiple smaller doses.

TABLE CII. Treatment of parenteral iron reactions

Mild Arthralgias, myalgias, ﬂushing, mild chest tightness,

mild hypotension, nausea, itching

Pause infusion until symptoms resolve, then resume at 25%-50% rate.

Consider pausing and giving a steroid if recurs. Observe 60 min after

completion of infusion

Mild with urticaria As above, with urticaria Pause infusion, give antihistamine or steroid. Observe until symptoms

subside, then resume infusion

Moderate Severe chest pain, cough, nausea, tachycardia,

hypotension

Stop infusion. Give IV ﬂuids, steroids, and antihistamines. Consider

alternative agent

Severe Bronchospasm, stridor, hypoxemia, signiﬁcant

hypotension, tachycardia, angioedema

Stop infusion. Give epinephrine, oxygen, inhaled

-agonists, IV ﬂuids,

steroids, antihistamines, other resuscitation

Delayed Arthralgias, myalgias, ﬂushing Corticosteroid premedication

NSAIDs for symptomatic treatment

IV, Intravenous.

J ALLERGY CLIN IMMUNOL PRACT

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S94 BROYLES ET AL

hypersensitivity reaction, with a reported odds ratio of 2.15 and

6.06, respectively. The caveat, however, was that clinical phe-

notypes were not validated by additional formal causality

assessment or additional diagnostic (eg, skin) testing. The aro-

matic amine anticonvulsants have been more signi ﬁcantly asso-

ciated with delayed cutaneous reactions.

861

Pharmacogenetic studies. The aromatic amine anticon-

vulsants share an aromatic benzene ring and are metabolized by

SMZ-TMP enzymes to hydroxylated aromatic amine com-

pounds (arene oxides). It was initially hypothesized that reactive

metabolites of these drugs haptenated cellular proteins leading to

an antigen-speciﬁc response. More recently, cellular models have

supported HLA-restricted, dose-dependent, and noncovalent

interactions between these aromatic amine anticonvulsant drugs

and HLA molecules/T-cell receptor. The genetic associations

have been strongest for HLA serotype B75 alleles, such as HLA-

B*15:02 and carbamazepine SJS/TEN, which are more prevalent

in Southeast Asian populations. Since 2007, the FDA has rec-

ommended HLA-B*15:02 screening for all patients of known or

suspected Southeast Asian ancestry before initiating carbamaze-

pine treatment. A prospective 1-arm study from Taiwan has

supported a reduction in the incidence of carbamazepine SJS/

TEN in association with HLA-B*15:02 screening.

862,863

Another study from Hong Kong showed that mandated HLA-

B*15:02 screening did not result in a reduction in the incidence

of SJS/TEN overall. This is because HLA-B*15:02 testing

appeared to lead to displacement of carbamazepine prescribing

with the prescription of phenytoin and a subsequent increase in

phenytoin SJS/TEN, thus underscoring the fact that provider

engagement and education is often necessary for clinical trans-

lation.

864

HLA risk alleles have had a low (<5%) positive pre-

dictive value for the development of IM-ADRs associated with

antiepileptic drugs, suggesting that other factors are important in

the immunopathogenesis. More recently, a dominant T-cell re-

ceptor clonotype has been found from blister ﬂuid and PBMCs

in patients with acute- and recovery-phase carbamazepine SJS/

TEN.

353

Testing and diagnosis. The utility and cost-effectiveness of

HLA screening is currently largely based on the population

prevalence of disease carriage rate of the speciﬁc HLA allele in the

population in question and the positive predictive value of the

HLA risk allele for the development of the IM-ADR. The

number needed to treat to prevent 1 case of IM-ADR can vary

from a few hundred to more than 10,000.

353,857

Cost-effec-

tiveness decisions, however, are also driven by the fact that SJS/

TEN, the most severe of IM-ADRs associated with these aro-

matic anticonvulsants, has signiﬁcant long-term morbidity and

mortality of up to 50% or higher, particularly in aging pop-

ulations.

865-867

The prevalence of HLA-B*15:02 is 7% to 15%

or higher in Southeast Asia and India but less than 1% in

populations of European and African ancestry.

353

HLA-A*31:01

has been associated with carbamazepine exanthem (mac-

ulopapular eruption) and DRESS in multiple ethnicities

including European. However, the generalizability of an associ-

ation between HLA-A*31:01 and carbamazepine SJS/TEN needs

to be further clariﬁed.

353,858,865,867,868

Lamotrigine has also been

associated with a risk of severe immunologically mediated drug

reactions, though it is primarily glucuronidated rather than

oxidized like the other aromatic anticonvulsants.

855

Graded dose

introduction has been an effective way to reduce the incidence of

isolated drug eruptions associated with lamotrigine. Valproic acid

and newer structurally disparate anticonvulsants have been safe

to administer in patients with reactions to the aromatic antiep-

ileptic drugs. However, the risk of a cutaneous reaction is

increased with concurrent use of valproic acid and lamotrigine

because of metabolic interactions that lead to an increased

elimination half-life of lamotrigine and accumulation of the

parent drug.

869

In vivo testing such as patch testing has been used successfully

in such studies, showing sensitivity of more than 80%, particu-

larly in carbamazepine-associated DRESS in some studies, but

signiﬁcantly less than 50% in others. Overall sensitivity for patch

testing with antiepileptic drugs varies from less than 20% to

more than 80%.

52,870,871

Patch tests should be left in situ for 48

hours and ideally read at 48 hours, 72 hours, 96 hours, and 1

week. The vehicle and concentration appear to be important, and

TABLE CIII. Sample 12-step rapid desensitization protocol for ferric gluconate

Solution (100 mL each) Concentration (mg/mL) mg/bag Volume infused (mL)

1 0.0125 1.25 9.25

2 0.125 12.5 18.75

3 1.2254 122.5 100

Step Solution Rate (mL/h) Time (min) Volume (mL) Dose (mg) Cumulative dose (mg)

1 1 2 15 0.5 0.0063 0.0063

2 1 5 15 1.25 0.0156 0.0219

3 1 10 15 2.5 0.0313 0.0531

4 1 20 15 5 0.0625 0.1156

5 2 5 15 1.25 0.1563 0.2719

6 2 10 15 2.5 0.3125 0.5844

7 2 20 15 5 0.6250 1.2094

8 2 40 15 10 1.2500 2.4594

9 3 10 15 2.5 3.0635 5.5229

10 3 20 15 5 6.1270 11.6499

11 3 40 15 10 12.2541 23.9040

12 3 80 61.875 82.5 101.0960 125.0000

J ALLERGY CLIN IMMUNOL PRACT

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BROYLES ET AL S95

sensitivity is highest in DRESS>AGEP>SJS/TEN.

For patch

testing, it is recommended to use between 1% and 10% (wt/wt)

of pure drug or 30% (wt/wt) concentration of the powdered

commercial tablet when the pure drug form cannot be patch

tested. Variability in positive results of patch testing with varying

concentrations across different anticonvulsants signiﬁes the need

for patch testing with several concentrations for accurate results,

most commonly 1%, 10%, and 30% of the various antiepileptics

in petrolatum.

52,871,872

Carbamazepine patch testing appears to

be associated with the highest sensitivity, and some studies have

been able to show a signiﬁcant cross-reactivity on patch testing

between drugs such as carbamazepine and phenytoin.

52,871,872

The genetic signiﬁcance of this is still not known because there is

a much weaker association between phenytoin SJS/TEN and

HLA-B*15:02. From a recent genome-wide association study

that included populations from Taiwan, Malaysia, and Japan

with phenytoin SJS/TEN/DRESS, a strong association was

identiﬁed with a poor metabolizing genotype of the primary

oxidizing enzyme of phenytoin, CYP2C9 (CYP2C9*3), and not

signiﬁcantly with genes in the HLA region.

873-875

One study

showed greater sensitivity of delayed prick and intradermal

testing compared with patch testing, but this has not been uni-

versally applied.

The lack of commercial availability of sterile

intravenous solutions for the aromatic anticonvulsants has

limited the use of intradermal testing for anticonvulsant hyper-

sensitivity.

In addition, prick and intradermal testing have been

avoided in very severe reactions such as SJS/TEN because of the

rare instances of systemic reactions. Ex vivo and in vitro tests such

as ELISpot, lymphocyte toxicity assay, and lymphocyte trans-

formation tests for the aromatic anticonvulsant drugs have been

used in the research setting. They currently lack sufﬁcient posi-

tive and negative predictive value and have not been quality

assured for clinical use.

353,855,857,876

True immediate reactions (IgE-mediated) to antiepileptic

drugs including the aromatic amine anticonvulsants are very

uncommon, and validated skin testing protocols for immediate

hypersensitivity reactions to antiepileptics are hence not avail-

able. One case study has described successful skin testing to

phenobarbital and pentobarbital. For skin testing, 0.1 mg/mL

and 1 mg/mL concentrations were nonirritating in both the

patient and control and may be considered.

877

Caution is also

advised, because on second exposure to the implicated anticon-

vulsant drug or a structurally related aromatic amine anticon-

vulsant, a reaction that is actually T-cellemediated can appear

immediate or accelerated in nature because it is a second-expo-

sure memory T-cell response. These reactions are mechanistically

distinct from IgE-mediated reactions and noneIgE-mediated

mast cell activation. Many are potentially severe reactions that

can be life-threatening with continued dosing of the drugs.

Management. Many patients with hypersensitivity to one

aromatic anticonvulsant may experience similar symptoms with

other cross-reactive aromatic anticonvulsants, but there are

alternative agents without this structural similarity. Desensitiza-

tion and slow reintroduction protocols exist and are aimed to-

ward patients with histories of delayed reactions including mild

rashes without accompanying fever, internal organ, mucosal, or

severe skin involvement.

878,879

SCAR hypersensitivity reactions

should result in discontinuation of the offending drug, and

desensitization protocols should not be performed on these pa-

tients. There are a few published desensitization protocols in the

literature to both oxcarbazepine and valproic acid following mild-

delayed rashes (Table XCIX).

877,878,880,881

Both an oral desen-

sitization to phenobarbital and an intravenous desensitization to

pentobarbital have been reported to be successful in cases of

immediate hypersensitivity (Table C).

877,880

Benzodiazepines (by Parul Kothari, MD)

General.

Benzodiazepines are prescribed for a wide variety of

disorders, including anxiety, seizures, insomnia, muscle spasms,

and alcohol withdrawal. They act in the central nervous system

to enhance the inhibitory effect of

-aminobutyric acid. Because

they have the potential to be abused, they are controlled sub-

stances regulated by the US Drug Enforcement Agency. They are

commonly classiﬁed as short-, intermediate-, or long-acting, on

the basis of their half-life.

Structurally, benzodiazepines are composed of benzene and

diazepine rings that are fused together. Benzodiazepines differ by

their side chains, which can alter their speciﬁc pharmacologic

properties. Among the structural differences, alprazolam has a

unique triazole ring and tetrazepam a cyclohexene ring.

Major symptoms of hypersensitivity. Allergic reactions

to benzodiazepines are rare, and most of the literature is limited

to case reports and small case series.

882-887

Both immediate and

delayed reactions have been reported to range in severity from

mild to severe, including SJS and TEN. A recent cohort study

estimated the cumulative incidence of SJS/TEN to benzodiaze-

pines to be 3.76 per million new users.

886

The most common

benzodiazepine implicated in the literature to date has been

tetrazepam, which is not available in the United States.

Diagnosis. Although diagnostic testing for hypersensitivity

reactions to benzodiazepines is not validated, there are reports in

the literature of skin and patch testing to support the diagnosis.

Currently, the determination of a benzodiazepine allergy relies

on a careful history with attention to objective ﬁndings at the

time of the reaction. For midazolam, the maximum nonirritating

concentration for skin testing has been reported as 1 to 5 mg/mL

and 0.25 to 0.5 mg/mL for PTs and IDTs, respectively.

79,888

Management. Given the rarity of allergic reactions to ben-

zodiazepines, there are no studies that have evaluated cross-

reactivity among members of this class of medication. In a case

report of an IgE-mediated hypersensitivity reaction to tetraze-

pam, the patient had a negative skin test result and tolerated a

challenge to diazepam.

885

In a case series of delayed cutaneous

reactions to tetrazepam, all 9 subjects were tolerant to other

benzodiazepines, as demonstrated by negative testing result and/

or challenge

.883

This was attributed to differences between the

structure of tetrazepam and other benzodiazepines. However,

others have reported cross-reactivity between tetrazepam and

diazepam as well as contact dermatitis to multiple benzodiaze-

pines.

884,889

If an alternative benzodiazepine is required, one that

has been previously tolerated should be used and/or a supervised

oral challenge performed. Currently, there are no desensitization

protocols for benzodiazepines in the literature.

Muscarinic antagonists (by Samantha Minnicozzi,

MD)

General.

Muscarinic antagonists are drugs that bind to

muscarinic receptors and inhibit acetylcholine from binding and

its subsequent downstream effects. For example, atropine is used

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S96 BROYLES ET AL

for the treatment of childhood myopia and for pupillary dilation

and bradycardia, and as an antidote for cholinergic toxicity.

Scopolamine is used to prevent nausea during chemotherapy

regimens and postoperatively. Glycopyrrolate decreases secre-

tions, and is commonly used preoperatively and perioperatively

for airway management. Oxybutynin is used to treat patients

with bladder difﬁculties including urge and incontinence.

All antimuscarinic agents have wide side-effect proﬁles

depending on which muscarinic receptor is targeted. Common

side effects of antimuscarinic agents include mydriasis, dry

mouth, tachycardia, agitation, delirium, and hyperthermia. In-

fants and children are particularly susceptible to these hyper-

thermic effects.

A review of topical atropine use found a 1% to 4% risk of

minor reactions, with more severe effects observed with intra-

venous administration including cardiac arrhythmias.

890,891

Hypersensitivity reactions have rarely been reported, with very

few case reports describing atropine and cyclopentolate causing

suspected IgE-mediated reactions.

892-894

Major symptom s of hypersensitivity. Among the anti-

muscarinic drugs, atropine has the largest accumulation of case

reports describing anaphylaxis to parenteral and topical formu-

lations. In a review of atropine applied topically in pediatric

patients for the treatment of myopia, 3.2% developed allergic

conjunctivitis, with 0.8% experiencing an allergic dermatitis.

890

In case reports of suspected atropine and cyclopentolate,

anaphylaxis symptoms included generalized urticaria, facial and

eyelid edema, pruritus, vomiting, and hypotension.

892-895

Delayed hypersensitivities and contact allergies to anti-

muscarinic agents are another drug-related allergy. In a large

study evaluating the safety of topical atropine for the treatment of

myopia in children, up to 0.8% developed a contact allergy.

890

Oral oxybutynin has been implicated in a case of ﬁxed drug

eruption that continued intermittently over months, coinciding

with the use of oxybutynin, and resolved only once therapy was

discontinued.

896

Inhaled antimuscarinic agents are a mainstay in the treatment

of COPD. A review of the literature on either asthma or COPD

found no case reports of history of inhaled agents such as ipra-

tropium or tiotropium causing immediate hypersensitivity re-

actions. There was a single case report of a patient with COPD

who developed an intermittent whole-body pruritic rash for

several years.

897

A biopsy of the rash was consistent with a drug

eruption. The patient was initially given a tiotropium inhaler,

which was discontinued. Following discontinuation, the patient

was started on an ipratropium metered-dose inhaler, after which

the rash recurred 3 days later and disappeared 5 days after dis-

continuing therapy. The patient continued to develop a similar

rash waxing and waning with the use of umeclidinium and

aclidinium until all inhaled antimuscarinic therapy was

discontinued.

897

Diagnosis. Skin testing for the evaluation of immediate hy-

persensitivity to antimuscarinic agents has not been commonly

performed and has not been validated on review of the literature.

Cavanah and Casale

898

describe antimuscarinic intradermal skin

testing to atropine and scopolamine in 7 healthy volunteers using

volumes of 20 nmol and 2 nmol. The solutions used for testing

in this protocol were created by diluting either atropine or

scopolamine in 0.9% saline, 0.03% human albumin, and 0.4%

phenol in water and then buffering the solution to a pH of 6.5 to

7.5. All subjects developed a wheal-and-ﬂare reaction to atropine

at both doses.

898

In comparison, all subjects reacted with a

wheal-and-ﬂare response to 20 nmol of scopolamine and none

had a response to 2 nmol.

898

Fisher and Bowey

899

performed atropine skin testing as part of

their perioperative anaphylaxis evaluation in 10 individuals. They

performed skin prick testing using undiluted atropine at a con-

centration of 0.6 mg/mL and intradermal testing at a dilution of

1:1000.

899

Similarly, Cabrera-Freitag et al

892

performed skin

prick and intradermal drug testing to atropine to evaluate a case

of anaphylaxis. Atropine was used at a concentration of 1 mg/mL

for skin prick testing and a dilution of 0.1 mg/mL for intra-

dermal testing. The patient had a positive result on intradermal

testing, with negative intradermal testing result in 10 control

subjects.

892

Management. There is little evidence in the literature

regarding cross-reactivity in patients with reported allergy to one

antimuscarinic agent and their ability to tolerate other anti-

muscarinic agents. The case reports discussing allergic reactions

recommend avoidance of similar antimuscarinic drugs in the

future and do not discuss class alternatives. Desensitization

protocols to antimuscarinic agents are yet to be described.

Iron (by Anne Liu, MD)

General.

Intravenous iron is an essential aspect of iron-

deﬁciency anemia when side effects or absorption limit the use of

oral formulations. Intravenous iron preparations are colloids of

iron-carbohydrate nanoparticles that vary by iron core size and

type of surrounding carbohydrate, processed and released as free

labile iron.

Formulations available in the United States include low-mo-

lecular-weight iron dextran, ferric gluconate, iron sucrose, fer-

umoxytol, iron isomaltoside, and ferric carboxymaltose

(Table CI). High-molecular-weight (HMW) iron dextrans were

discontinued in the United States.

Hypersensitivity reactions. Labile plasma iron may pro-

duce nonspeciﬁc oxidative stress and complement activa-

tion.

900,901

Excluding HMW iron dextrans, evidence for

immune complex formation and IgE-mediated mechanisms is

paltry, and tryptase elevation is exceedingly rare.

902,903

Adverse reactions may be infusion rateedependent and typi-

cally manifest as dyspnea, chest and/or back pain, acute ar-

thralgias and myalgias, hypotension, tachycardia, nausea/

vomiting, and pruritus.

904-906

Minor reactions usually abate

without treatment or with rate reduction and may not recur on

rechallenge.

905

Angioedema and urticaria may signal a distinct

reaction type. Severe reactions including anaphylaxis can be fatal.

Rarely, delayed reactions may exhibit hypotension, arthralgias/

myalgias, malaise, and vomiting. Iron sucrose can uniquely cause

peripheral edema and renal injury in a rate- and concentration-

related manner.

906,907

Excluding HMW iron dextrans, incidence of serious adverse

reactions is less than 1 in 200,000, accounting for approximately

0 to 5 deaths per year in the United States.

906,908

The high re-

action rate and mortality associated with iron dextrans has been

attributed to the HMW iron dextran formulation.

908-910

Limited

data suggest iron isomaltoside carries a higher reaction risk than

ferric carboxymaltose.

911

Signiﬁcant differences in reaction risk

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S97

have not been shown among low-molecular-weight iron dextran,

iron sucrose, ferric gluconate, and ferric carboxymaltose.

908,912-917

Adverse event reporting initially suggested an increased risk of

fatal reactions from ferumoxytol, but randomized comparisons of

ferumoxytol with iron sucrose and ferric carboxymaltose reported

similar rates of adverse reactions.

918-921

Risk factors for severe hypersensitivity reactions include atopy

and multiple drug allergies including previous iron hypersensi-

tivity reactions.

900,905,922

Diagnosis. Evaluation of an iron reaction should document

the speciﬁc product and dose, route, and rate of administration,

and include a detailed description of the reaction, treatment, and

response.

Graded challenge is required only for low-molecular-weight

iron dextrans and may not predict serious hypersensitivity re-

actions.

922

Skin testing has limited utility because most reactions

are not IgE-mediated, but it may detect a subset of patients who

are sensitized via typical allergic pathways. A protocol for ferric

gluconate skin testing has been used: skin prick at 12.5 mg/mL,

and IDT at 0.0125, 0.125, and 1.25 mg/mL at the Brigham and

Women’s Hospital. Skin testing to iron sucrose should not be

performed, because a permanent tattoo can form from deposition

of iron pigment.

Management. Table CII outlines suggested reaction treat-

ments based on expert panel consensus.

916,922

Premedication

with antihistamines is not advised because of ineffectiveness and

side effects.

916,922

Switching agents can be considered in patients

with mild to moderate reactions, but expert panels advise

avoiding all parenteral iron after a severe reaction.

916

Ferric

gluconate and iron sucrose, but not ferumoxytol, are considered

alternatives for patients sensitive to iron dextran.

902,923,924

Desensitization to HMW iron dextrans has been re-

ported.

925,926

Desensitization protocols to ferric carboxymaltose

and iron sucrose have been reported in patients with a history of

anaphylaxis to other iron products.

927,928

In the Brigham and

Women’s Hospital experience, allergists have successfully per-

formed ferric gluconate desensitizations (Table CIII). Desensi-

tization to iron dextrans has been difﬁcult to complete because of

treatment-refractory reactions. Iron sucrose desensitization is not

done because of poor stability at lower concentrations. Further

data are needed to elucidate a role for rapid desensitization after

parenteral iron anaphylaxis.

Acknowledgments

We thank Dawn Angel, Becky Drager, Margaret Lemay,

Beena Rao, and Erin Scott for their invaluable medical editorial

assistance with this manuscript and Michael Schatz for his

steadfast encouragement and support of this project

REFERENCES

1. Broyles AD, Banerji A, Castells M. Practical guidelines for the evaluation and

management of drug hypersensitivity: general concepts. J Allergy Clin

Immunol Pract 2020;8:S3-15.

2. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr

Opin Allergy Clin Immunol 2005;5:309-16.

3. Solensky R. Allergy to

-lactam antibiotics. J Allergy Clin Immunol 2012;130:

1442.e5.

4. Macy E. Routine penicillin skin testing in hospitalized patients with a history

of penicillin allergy. Perm J 2004;8:20-4.

5. Lee CE, Zembo wer TR, Fotis MA, Postelnick MJ, Greenberger PA,

Peterson LR, et al. The incidence of antimicrobial allergies in hospitalized

patients. Arch Intern Med 2000;160:2819.

6. Sade K, Holtzer I, Levo Y, Kivity S. The economic burden of antibiotic

treatment of penicillin-allergic patients in internal medicine wards of a general

tertiary care hospital. Clin Exp Allergy 2003;33:501-6.

7. Macy E, Contreras R. Health care use and serious infection prevalence asso-

ciated with penicillin “allergy” in hospitalized patients: a cohort study.

J Allergy Clin Immunol 2014;133:790-6.

8. Macy EM, Ngor E. Safely diagnosing clinically signiﬁcant penicillin allergy

with only penicilloyl-poly-lysine, penicillin, and oral amoxicillin. J Allergy

Clin Immunol 2013;131:AB234.

9. del Real GA, Rose ME, Ramirez-Atamoros MT, Hammel J, Gordon SM,

Arroliga AC, et al. Penicillin skin testing in patients with a history of

-lactam

allergy. Ann Allergy Asthma Immunol 2007;98:355-9.

10. Blanca M, Torres MJ, García JJ, Romano A, Mayorga C, de Ramon E, et al.

Natural evolution of skin test sensitivity in patients allergic to

-lactam anti-

biotics. J Allergy Clin Immunol 1999;103:918-24.

11. Sullivan TJ, Wedner HJ, Shatz GS, Yecies LD, Parker CW. Skin testing to

detect penicillin allergy. J Allergy Clin Immunol 1981;68:171-80.

12. Kerns D, Shira JE, Go S, Summers RJ, Schwab JA, Plunket DC. Ampicillin

rash in children: relationship to penicillin allergy and infectious mono-

nucleosis. Am J Dis Child 1973;125:187-90.

13. Joint Task For ce on Practice Para meters; Amer ican Academ y of Allergy,

Asthma and Imm unology; American College o f Allergy, Asthma and

Immunology; Joint Council of Allergy Asthma and Imm unology. Drug

allergy: an updated practice parameter. Ann Allergy Asthma Immunol

2010;105:259-273.e7 8.

14. Mirakian R, Leech SC, Krishna MT, Richter AG, Huber PAJ, Farooque S,

et al. Managemen t of allergy to penicillins and other beta-lactams. Clin Exp

Allergy 2015;45:300-27.

15. Blanca M, Romano A, Torres MJ, Férnandez J, Mayorga C, Rodriguez J, et al.

Update on the evaluation of hypersensitivity reactions to betalactams. Allergy

2009;64:183-93.

16. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA,

et al. International Consensus on drug allergy. Allergy 2014;69:420-37.

17. Romano A, Torres MJ, Castells M, Sanz ML, Blanca M. Diagnosis and

management of drug hypersensitivity reactions. J Allergy Clin Immunol 2011;

127:S67-73.

18. Bircher AJ, Scherer Hofmeier K. Drug hypersensitivity reactions: inconsis-

tency in the use of the classiﬁcation of immediate and nonimmediate reactions.

J Allergy Clin Immunol 2012;129:263-4.

19. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;

139:683.

20. Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, et al.

Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004;

59:1153-60.

21. Solensky R. Hypersensitivity reactions to beta-lactam antibiotics. Clin Rev

Allergy Immunol 2003;24:201-20.

22. Feingold DS, Parris EE, Levine BB. Immunologic mechanisms of penicillin

allergy. N Engl J Med 1966;275:1115-25.

23. Torres MJ, Blanca M, Fernandez J, Romano A, Weck A, Aberer W, et al.

Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy

2003;58:961-72.

24. Gadde J, Spence M, Wheeler B, Adkinson NF Jr. Clinical experience with

penicillin skin testing in a large inner-city STD clinic. JAMA 1993;270:

2456-63.

25. Geng B, Eastman JJ, Mori K, Braskett M, Riedl MA. Utility of minor de-

terminants for skin testing in inpatient penic illin allergy evaluation. Ann Al-

lergy Asthma Immunol 2017;119:258-61.

26. Lin E, Saxon A, Riedl M. Penicillin allergy: value of including amoxicillin as a

determinant in penicillin skin testing. Int Arch Allergy Immunol 2010;152:

313-8.

27. Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin skin

testing: multi-year follow-up. Allergy 2002;57:1151-8.

28. Rosenﬁeld L, Kalicinsky C, Warrington R. A retrospective comparison of false

negative skin test rates in penicillin allergy, using pencilloyl-poly-lysine and

minor determinants or Penicillin G, followed by open challenge. Allergy

Asthma Clin Immunol 2015;11:34.

29. Sogn DD, Evans R III, Shepherd GM, Casale TB, Condemi J, Greenberger PA,

et al. Results of the National Institute of Allergy and Infectious Diseases

Collaborative Clinical Trial to test the predictive value of skin testing with

major and minor penicillin derivatives in hospitalized adults. Arch Intern Med

1992;152:1025-32.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S98 BROYLES ET AL

30. Solensky R, Jacobs J, Lester M, Lieberman P, McCafferty F, Nilsson T, et al.

Penicillin allergy evaluation: a prospective, multicenter, open-label evaluatio n

of a comprehensive penicillin skin test kit. J Allergy Clin Immunol Pract 2019;

7:1876-1885.e3.

31. Conﬁno-Cohen R, Rosman Y, Lachover I, Meir Shafrir K, Goldberg A. The

importance of amoxicillin and amoxicillin-clavulanate determinants in the

diagnosis of immediate allergic reactions to beta-lactams. Int Arch Allergy

Immunol 2016;170:62-6.

32. Atanaskovic-Markovic M, Velickovic TC, Gavrovic-Jankulovic M,

Vuckovic O, Nestorovic B. Immediate allergic reactions to cephalosporins and

penicillins and their cross-reactivity in children. Pediatr Allergy Immunol

2005;16:341-7.

33. Pichichero ME, Pichichero DM. Diagnosis of penicillin, amoxicillin, and

cephalosporin allergy: reliability of examination assessed by skin testing and

oral challenge. J Pediatr 1998;132:137-43.

34. Ponvert C, Weilenmann C, Wassenberg J, Walecki P, Bourgeois ML, de

Blic J, et al. Allergy to betalactam antibiotics in children: a prospective follow-

up study in re-treated children after negative responses in skin and challenge

tests. Allergy 2007;62:42-6.

35. Iglesias-Souto J, Gonzalez R, Poza P, Sanchez-Machin I, Matheu V. Evalu-

ating the usefulness of retesting for beta-lactam allergy in children. Pediatr

Infect Dis J 2012;31:1091-3.

36. Macy E. Penicillin skin testing in pregnant women with a history of penicillin

allergy and group B streptococcus colonization. Ann Allergy Asthma Immunol

2006;97:164-8.

37. Blanca M , Mayorga C, Torre s MJ, Reche M, Moy a MC, Rodriguez JL,

et al. Clinical evaluation of Pharmacia CAP System RAST FEIA amox-

icilloyl and benzylpenicillo yl in patients with p enicillin allergy. Allergy

2001;56:862-70.

38. Fontaine C, Mayorga C, Bousquet PJ, Arnoux B, Torres MJ, Blanca M, et al.

Relevance of the determination of serum-speciﬁc IgE antibodies in the diag-

nosis of immediate beta-lactam allergy. Allergy 2007;62:47-52.

39. Sanz ML, Gamboa PM, Antepara I, Uasuf C, Vila L, Garcia-Aviles C, et al.

Flow cytometric basophil activation test by detection of CD63 expression in

patients with immediate-type reactions to betalactam antibiotics. Clin Exp

Allergy 2002;32:277-86.

40. Torres MJ, Romano A, Mayorga C, Moya MC, Guzman AE, Reche M, et al.

Diagnostic evaluation of a large group of patients with immediate allergy to

penicillins: the role of skin testing. Allergy 2001;56:850-6.

41. Torres MJ, Padial A, Mayorga C, Fernandez T, Sanchez-Sabate E, Cornejo-

Garcia JA, et al. The diagnostic interpreta tion of basophil activation test in

immediate allergic reactions to betalactams. Clin Exp Allergy 2004;34:

1768-75.

42. Macy E. Penicillin allergy: optimizing diagnostic protocols, public health

implications, and future research needs. Curr Opin Allergy Clin Immunol

2015;15:308-13.

43. Hershkovich J, Broides A, Kirjner L, Smith H, Gorodischer R. Beta lactam

allergy and resensitization in children with suspected beta lactam allergy. Clin

Exp Allergy 2009;39:726-30.

44. Macy E, Mangat R, Burchette RJ. Penicillin skin testing in advance of need:

multiyear follow-up in 568 test result-negative subjects exposed to oral peni-

cillins. J Allergy Clin Immunol 2003;111:1111-5.

45. Solensky R, Earl HS, Gruchalla RS. Lack of penicillin resensitization in pa-

tients with a history of penicillin allergy after receiving repeated penicillin

courses. Arch Intern Med 2002;162:822-6.

46. Parker PJ, Parrinello JT, Condemi JJ, Rosenfeld SI. Penicillin resensitization

among hospitalized patients. J Allergy Clin Immunol 1991;88:213-7.

47. Dorman SM, Seth S, Khan DA. Risk of allergic reactions to recurrent intra-

venous penicillin administration in penicillin skin test negative patients.

J Allergy Clin Immunol Pract 2018;6:196-200.

48. Romano A, Gaeta F, Valluzzi RL, Caruso C, Rumi G, Bousquet PJ. The very

limited usefulness of skin testing with penicilloyl-polylysine and the minor

determinant mixture in evaluating nonimmediate reactions to penicillins. Al-

lergy 2010;65:1104-7.

49. Padial A, Antunez C, Blanca-Lopez N, Fernandez TD, Cornejo-Garcia JA,

Mayorga C, et al. Non-immediate reactions to beta-lactams: diagnostic

value of skin testing and drug provocation test. Clin Exp Allergy 2008;38:

822-8.

50. Patriarca G, D’Ambrosio C, Schiavino D, Larocca LM, Nucera E, Milani A.

Clinical usefulness of patch and challenge tests in the diagnosis of

cell-mediated allergy to betalactams. Ann Allergy Asthma Immunol 1999;83:

257-66.

51. Romano A, Viola M, Mondino C, Pettinato R, Di Fonso M, Papa G, et al.

Diagnosing nonimmediate reactions to penicillins by in vivo tests. Int Arch

Allergy Immunol 2002;129:169-74.

52. Barbaud A, Collet E, Milpied B, Assier H, Staumont D, Avenel-Audran M,

et al. A multicentre study to determine the value and safety of drug patch tests

for the three main classes of severe cutaneous adverse drug reactions. Br J

Dermatol 2013;168:555-62.

53. Pinho A, Coutinho I, Gameiro A, Gouveia M, Goncalo M. Patch testing—a

valuable tool for investigating non-immediate cutaneous adverse drug re-

actions to antibiotics. J Eur Acad Dermatol Venereol 2017;31:280-7.

54. Phillips EJ, Bigliardi P, Bircher AJ, Broyles A, Chang YS, Chung WH, et al.

Controversies in drug allergy: testing for delayed reactions. J Allergy Clin

Immunol 2019;143:66-73.

55. Borch JE, Bindslev-Jensen C. Full-course drug challenge test in the diagnosis

of delayed allergic reactions to penicillin. Int Arch Allergy Immunol 2011;155:

271-4.

56. Hjortlund

J, Mortz CG, Skov PS, Bindslev-Jensen C. Diagnosis of penicillin

allergy revisited: the value of case history, skin testing, speciﬁc IgE and pro-

longed challenge. Allergy 2013;68:1057-64.

57. Baldo BA. Penicillins and cephalosporins as allergens–structural aspects of

recognition and cross-reactions. Clin Exp Allergy 1999;29:744-9.

58. Blanca M, Vega JM, Garcia J, Carmona MJ, Terados S, Avila MJ, et al. Al-

lergy to penicillin with good tolerance to other penicillins: study of the inci-

dence in subjects allergic to beta-lactams. Clin Exp Allergy 1990;20:475-81.

59. Atanaskovic-Markovic M, Gaeta F, Gavrovic-Jankulovic M, Velickovic TC,

Valluzzi RL, Romano A. Tolerability of imipenem in children with IgE-

mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2009;124:

167-9.

60. Atanaskovic-Markovic M, Gaeta F, Medjo B, Viola M, Nestorovic B,

Romano A. Tolerability of meropenem in children with IgE-mediated hyper-

sensitivity to penicillins. Allergy 2008;63:237-40.

61. Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A.

Tolerability of aztreonam and carbapenems in patients with IgE-mediated

hypersensitivity to penicillins. J Allergy Clin Immunol 2015;135:972-6 .

62. Romano A, Gaeta F, Valluzzi RL, Caruso C, Rumi G, Bousquet PJ. IgE-

mediated hypersensitivity to cephalosporins: cross-reactivity and tolerability of

penicillins, monobactams, and carbapenems. J Allergy Clin Immunol 2010;

126:994-9.

63. Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Pettinato R, Gueant JL.

Imipenem in patients with immediate hypersensitivity to penicillins. N Engl J

Med 2006;354:2835-7.

64. Romano A, Viola M, Gueant-Rodriguez RM, Gaeta F, Valluzzi R, Gueant JL.

Brief communication: tolerability of meropenem in patients with IgE-mediated

hypersensitivity to penicillins. Ann Intern Med 2007;146:266-9.

65. Sodhi M, Axtell SS, Callahan J, Shekar R. Is it safe to use carbapenems in

patients with a history of allergy to penicillin? J Antimicrob Chemother 2004;

54:1155-7.

66. Saxon A, Swabb EA, Adkinson NF Jr. Investigation into the immunologic

cross-reactivity of aztreonam with other beta-lactam antibiotics. Am J Med

1985;78:19-26.

67. Vega JM, Blanca M, Garcia JJ, Miranda A, Carmona MJ, Garcia A, et al.

Tolerance to aztreonam in patients allergic to beta-lactam anti biotics. Allergy

1991;46:196-202.

68. Sanchez-Morillas L, Perez-Ezquerra PR, Reano-Martos M, Laguna-

Martinez JJ, Sanz ML, Martinez LM. Selective allergic reactions to clavulanic

acid: a report of 9 cases. J Allergy Clin Immunol 2010;126:177-9.

69. Torres MJ, Ariza A, Mayorga C, Dona I, Blanca- Lopez N, Rondon C, et al.

Clavulanic acid can be the component in amoxicillin-clavulanic acid respon-

sible for immediate hypersensitivity reactions. J Allergy Clin Immunol 2010;

125:502-505.e2.

70. Wendel GD Jr, Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin

allergy and desensitization in serious infections during pregnancy. N Engl J

Med 1985;312:1229-32.

71. Castells M. Rapid desensitization for hypersensitivity reactions to medications.

Immunol Allergy Clin North Am 2009;29:585-606.

72. Caubet JC, Kaiser L, Lemaitre B, Fellay B, Gervaix A, Eigenmann PA. The

role of penicillin in benign skin rashes in childhood: a prospective study based

on drug rechallenge. J Allergy Clin Immunol 2011;127:218-22.

73. Blumenthal KG, Shenoy ES, Varughese CA, Hurwitz S, Hooper DC,

Banerji A. Impact of a clinical guideline for prescribing antibiotics to inpatients

reporting penicillin or cephalosporin allergy. Ann Allergy Asthma Immunol

2015;115:294-300.e2.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S99

74. Macy E, Contreras R. Adverse reactions associated with oral and parenteral use

of cephalosporins: a retrospective population-based analysis. J Allergy Clin

Immunol 2015;135:745-752.e5.

75. Macy E, Poon KYT. Self-reported antibiotic allergy incidence and prevalence:

age and sex effects. Am J Med 2009;122:778.e1-e7.

76. Blumenthal KG, Youngster I, Rabideau DJ, Parker RA, Manning KS,

Walensky RP, et al. Peripheral blood eosinophilia and hypersensitivity re-

actions among patients receiving outpatient parenteral antibiotics. J Allergy

Clin Immunol 2015;136:1288-1294.e1.

77. Blumenthal KG, Shenoy ES, Wolfson AR, Berkowitz DN, Carballo VA,

Balekian DS, et al. Addressing inpatient beta-lactam allergies: a multihospital

implementation. J Allergy Clin Immunol Pract 2017;5:616-625.e7.

78. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Zafﬁro A, Caruso C, et al.

IgE-mediated hypersensitivity to cephalosporins: cross-reactivity and tolera-

bility of alternative cephalosporins. J Allergy Clin Immuno l 2015;136:

685-691.e3.

79. Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A,

Bilo MB, et al. Skin test concentrations for systemically administered drugs –

an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013;

68:702-12.

80. Empedrad R, Darter AL, Earl HS, Gruchalla RS. Nonirritating intradermal skin

test concentrations for commonly prescribed antibiotics. J Allergy Clin

Immunol 2003;112:629-30.

81. Romano A, Gaeta F, Valluzzi RL, Zafﬁro A, Caruso C, Quaratino D. Natural

evolution of skin-test sensitivity in patients with IgE-mediated hypersensitivity

to cephalosporins. Allergy 2014;69:806-9.

82. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schroder W,

Roujeau JC, et al. Correlations between clinical patterns and causes of ery-

thema mult iforme majus, Stevens-Johnson syndrome, and toxic epidermal

necrolysis: results of an international prospective study. Arch Dermatol 2002;

138:1019-24.

83. Blumenthal KG, Wickner PG, Hurwitz S, Pricco N, Nee AE, Laskowski K,

et al. Tackling inpatient penicillin allergies: assessing tools for antimicrobial

stewardship. J Allergy Clin Immunol 2017;140:154-61.e6.

84. Iammatteo M, Blumenthal KG, Saff R, Long AA, Banerji A. Safety and

outcomes of test doses for the evaluation of adverse drug reactions: a 5-year

retrospective review. J Allergy Clin Immunol Pract 2014;2:768-74.

85. Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions: a report

from the Boston Collaborative Drug Surveillance Program on 15,438

consecutive inpatients, 1975 to 1982. JAMA 1986;256:3358-63.

86. Cabanas R, Caballero MT, Vega A, Martin-Esteban M, Pascual C. Anaphy-

laxis to trimethoprim. J Allergy Clin Immunol 1996;97:137-8.

87. Jaffe HS, Abrams DI, Ammann AJ, Lewis BJ, Golden JA. Complications of

co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneu-

monia in homosexual men. Lancet 1983;2:1109-11.

88. Kennedy CA, Pimentel JA, Lewis DE, Anderson MD, Weiss PJ,

Oldﬁeld EC III. Crossover of human immunodeﬁciency virus-infected patients

from aerosolized pentamidine to trimethoprim-sulfamethoxazole: lack of he-

matologic toxicity and relationship of side effects to CD4þ lymphocyte count.

J Infect Dis 1993;168:314-7.

89. Coopman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and drug

reactions in HIV infection. N Engl J Med 1993;328:1670-4.

90. Dibbern DA Jr, Montanaro A. Allergies to sulfonamide antibiotics and

sulfur-containing drugs. Ann Allergy Asthma Immunol 2008;100:

91-100.

91. Krantz MS, Stone CA Jr, Abreo A, Phillips EJ. Oral challenge with trimeth-

oprim-sulfamethoxazole in patients with “sulfa” antibiotic allergy. J Allergy

Clin Immunol Pract 2020;8:757-760.e4.

92. Khan DA, Knowles SR, Shear NH. Sulfonamide hypersensitivity: fact and

ﬁction. J Allergy Clin Immunol Pract 2019;7:2116-23.

93. Douglas R, Spelman D, Czarny D, O’Hehir RE. Successfu l desensitization

of two patients w ho previously developed Stevens-Johnson syndrome

while re ceiving trimethoprim-sulfame thoxazole. Clin I nfect Dis 1997;25 :

1480.

94. Absar N, Daneshvar H, Beall G. Desensitization to trimethoprim/sulfameth-

oxazole in HIV-infected patients. J Allergy Clin Immunol 1994;93:1001-5.

95. Caumes E, Guermonprez G, Lecomte C, Katlama C, Bricaire F. Efﬁcacy and

safety of desensitization with sulfamethoxazole and trimethoprim in 48 pre-

viously hypersensitive patients infected with human immunodeﬁ

ciency virus.

Arc

h Dermatol 1997;133:465-9.

96. Gluckstein D, Ruskin J. Rapid oral desensitization to trimethoprim-sulfa-

methoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii pneu-

monia in patients with AIDS who were previously intolerant to TMP-SMZ.

Clin Infect Dis 1995;20:849-53.

97. Kalanadhabhatta V, Muppidi D, Sahni H, Robles A, Kramer M. Successful

oral desensitization to trimethoprim-sulfamethoxazole in acquired immune

deﬁciency syndrome. Ann Allergy Asthma Immunol 1996;77:394-400.

98. Leoung GS, Stanford JF, Giordano MF, Stein A, Torres RA, Giffen CA, et al.

Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct

rechallenge for Pneumocystis carinii pneumonia prophylaxis in human im-

munodeﬁciency virus-infected patients with previous adverse reaction to TMP-

SMZ. J Infect Dis 2001;184:992-7.

99. Mann R, Badesch D, Zamora M, Dreskin SC. Desensitization to trimethoprim-

sulfamethoxazole following lung transplantation. Chest 1997;111:1147.

100. Nguyen MT, Weiss PJ, Wallace MR. Two-day oral desensitization to

trimethoprim-sulfamethoxazole in HIV-infect ed patients. AIDS 1995;9:573-5.

101. Rich JD, Sullivan T, Greineder D, Kazanjian PH. Trimethoprim/sulfameth-

oxazole incremental dose regimen in human immunodeﬁciency virus-infected

persons. Ann Allergy Asthma Immunol 1997;79:409-14.

102. Ryan C, Madalon M, Wortham DW, Graziano FM. Sulfa hypersensitivity in

patients with HIV infection: onset, treatment, critical review of the literature.

WMJ 1998;97:23-7.

103. Straatmann A, Bahia F, Pedral-Sampaio D, Brites C. A randomized, pilot trial

comparing full versus escala ting dose regimens for the desensitization of AIDS

patients allergic to sulfonamides. Braz J Infect Dis 2002;6:276-80.

104. Yoshizawa S, Yasuoka A, Kikuchi Y, Honda M, Gatanaga H, Tachikawa N, et al.

A 5-day course of oral desensitization to trimethoprim/sulfamethoxazole (T/S) in

patients with human immunodeﬁciency virus type-1 infection who were previ-

ously intolerant to T/S. Ann Allergy Asthma Immunol 2000;85:241-4.

105. Soffritti S, Ricci G, Prete A, Rondelli R, Menna G, Pession A. Successful

desensitization to trimethoprim-sulfamethoxazole after allogeneic haemato-

poietic stem cell transplantation: preliminary observations. Med Pediatr Oncol

2003;40:271-2.

106. Moreno JN, Poblete RB, Maggio C, Gagnon S, Fischl MA. Rapid oral

desensitization for sulfonamides in patients with the acquired immunodeﬁ-

ciency syndrome. Ann Allergy Asthma Immunol 1995;74:140-6.

107. White MV, Haddad ZH, Brunner E, Sainz C. Desensitization to trimethoprim

sulfamethoxazole in patients with acquired immune deﬁciency syndrome and

Pneumocystis carinii pneumonia. Ann Allergy 1989;62:177-9.

108. Pyle RC, Butterﬁeld JH, Volcheck GW, Podjasek JC, Rank MA, Li JT, et al.

Successful outpatient graded administration of trimethoprim-sulfamethoxazole

in patients without HIV and with a history of sulfonamide adverse drug re-

action. J Allergy Clin Immunol Pract 2014;2:52-8.

109. Aranda A, Mayorga C, Ariza A, Dona I, Rosado A, Blanca-Lopez N, et al. In

vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones.

Allergy 2011;66:247-54.

110. Blanca-Lopez N, Ariza A, Dona I, Mayorga C, Montanez MI, Garcia-

Campos J, et al. Hypersensitivity reactions to ﬂuoroquinolones: analysis of the

factors involved. Clin Exp Allergy 2013;43:560-7.

111. Sachs B, Riegel S, Seebeck J, Beier R, Schichler D, Barger A, et al. Fluo-

roquinolone-associated anaphylaxis in spontaneous adverse drug reaction re-

ports in Germany: differences in reporting rates between individual

ﬂuoroquinolones and occurrence after ﬁrst-ever use. Drug Saf 2006;29:

1087-100.

112. Seitz CS, Brocker EB, Trautmann A. Diagnostic testing in suspected ﬂuo-

roquinolone hypersensitivity. Clin Exp Allergy 2009;39:1738-4 5.

113. McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, et al. Identi-

ﬁcation of a mast-cell-speciﬁc receptor crucial for pseudo-allergic drug re-

actions. Nature 2015;519:237-41.

114. Manfredi

M, Severino M, Testi S, Macchia D, Ermini G, Pichler WJ, et al.

Detection of speciﬁc IgE to quinolones. J Allergy Clin Immuno l 2004;113:

155-60.

115. Venturini Diaz M, Lobera Labairu T, del Pozo Gil MD, Blasco Sarramian A,

Gonzalez Mahave I. In vivo diagnostic tests in adverse reactions to quinolones.

J Investig Allergol Clin Immunol 2007;17:393-8.

116. Araujo L, Demoly P. Macrolides allergy. Curr Pharm Des 2008;14:2840-62.

117. Barni S, Butti D, Mori F, Pucci N, Rossi ME, Cianferoni A, et al. Azi-

thromycin is more allergenic than clarithromycin in children with suspected

hypersensitivity reaction to macrolides. J Investig Allergol Clin Immunol

2015;25:128-32.

118. Benahmed S, Scaramuzza C, Messaad D, Sahla H, Demoly P. The accuracy of

the diagnosis of suspected macrolide antibiotic hypersensitivity: results of a

single-blinded trial. Allergy 2004;59:1130-3.

119. Chia FL, Thong BY. Macrolide allergy: which tests are really useful? Allergol

Immunopathol (Madr) 2011;39:191-2.

120. Lammintausta K, Kortekangas-Savolainen O. Oral challenge in patients with

suspected cutaneous adverse drug reactions: ﬁndings in 784 patients during a

25-year-period. Acta Derm Venereol 2005;85:491-6.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S100 BROYLES ET AL

121. Kuyucu S, Mori F, Atanaskovic-Markovic M, Caubet JC, Terreehorst I,

Gomes E, et al. Hypersensitivity reactions to non-betalactam antibiotics in

children: an extensive review. Pediatr Allergy Immunol 2014;25:534-43.

122. Mori F, Pecorari L, Pantano S, Rossi ME, Pucci N, De Martino M, et al.

Azithromycin anaphylaxis in children. Int J Immunopathol Pharmacol 2014;

27:121-6.

123. Cavkaytar O, Karaatmaca B, Yilmaz EA, Sekerel BE, Soyer O. Testing for

clarithromycin hypersensitivity: a diagnostic challenge in childhood. J Allergy

Clin Immunol Pract 2016;4:330-2.e1.

124. Saito R, Sawada Y, Nakamura M. Two cases of eczematous drug eruption caused

by oral tacrolimus administration. Contact Dermatitis 2017;77:128-30.

125. Poveda-Montoyo I, Alvarez-Chinchilla PJ, Garcia Del Pozo MC, Encabo B,

Silvestre JF. Spiramycin-related cutaneous eruption conﬁrmed by patch

testing. Contact Dermatitis 2018;78:233-4.

126. Bianchi L, Carafﬁni S, Lisi P. Drug reaction with eosinophilia and systemic

symptoms syndrome caused by an everolimus-eluting stent. Int J Dermatol

2014;53:e286-e288.

127. Shin HW, Nam CW, Kim H, Hur SH, Kim YN , Kim KB, et al. Zotarolimus-

eluting stent-induced hypersensitivity pneumonitis. Korean J Intern Med 2013;

28:108-11.

128. Riley L, Mudd L, Baize T, Herzig R. Cross-sensitivity reaction between

tacrolimus and macrolide antibiotics. Bone Marrow Transplant 2000;25:

907-8.

129. Holmes NE, Hodgkinson M, Dendle C, Korman TM. Report of oral clari-

thromycin desensitization. Br J Clin Pharmacol 2008;66:323-4.

130. Nucera E, Roncallo C, Masini L, Buonomo A, De Pasquale T, Pollastrini E,

et al. Successful tolerance induction to spiramycin in pregnancy. Scand J Infect

Dis 2002;34:550-1.

131. Swamy N, Laurie SA, Ruiz-Huidobro E, Khan DA. Successful clarithromycin

desensitization in a multiple macrolide-allergic patient. Ann Allergy Asthma

Immunol 2010;105:489-90.

132. Webster GF, Graber EM. Antibiotic treatment for acne vulgaris. Semin Cutan

Med Surg 2008;27:183-7.

133. Kalai C, Brand R, Yu L. Minocycline-induced Sweet syndrome (acute febrile

neutrophilic dermatosis). J Am Acad Dermatol 2012;67:e289-91.

134. Lebrun-Vignes B, Kreft-Jais C, Castot A, Chosidow O, French Network of

Regional Centers of Pharmacovigilance. Comparative analysis of adverse drug

reactions to tetracyclines: results of a French national survey and review of the

literature. Br J Dermatol 2012;166:1333-41.

135. Maubec E, Wolkenstein P, Loriot MA, Wechsler J, Mulot C, Beaune P, et al.

Minocycline-induced DRESS: evidence for accumulation of the culprit drug.

Dermatology 2008;216:200-4.

136. Talsania N, O’Toole EA. Severe hypersensitivity reaction to minocycline in

association with lymphomatoid papulosis. Clin Exp Dermatol 2009;34:e397-8.

137. Jang JW, Bae YJ, Kim YG, Jin YJ, Park KS, Cho YS, et al. A case of

anaphylaxis to oral minocycline. J Korean Med Sci 2010;25:1231-3.

138. Ogita A, Takada K, Kawana S. Case of anaphylaxis due to tetracycline hy-

drochloride. J Dermatol 2011;38:597-9.

139. Raeder JC. Anaphylactoid reacti on caused by intravenous doxycycline during

general anesthesia and beta-blockade treatment. Drug Intell Clin Pharm 1984;

18:481-2.

140. Shao QQ, Qin L, Ruan GR, Chen RX, Luan ZJ, Ma XJ. Tigecycline-induced

drug fever and leukemoid reaction: a case report. Medicine (Baltimore) 2015;

94:e1869.

141. Correia O, Delgado L, Polonia J. Genital ﬁxed drug eruption: cross-reactivity

between doxycycline and minocycline. Clin Exp Dermatol 1999;24:137.

142. Maciag MC, Ward SL, O’Connell AE, Broyles AD. Hypersensitivity to tet-

racyclines: skin testing, graded challenge, and desensitization regimens. Ann

Allergy Asthma Immunol 2020;124:589-93.

143. Polk RE, Healy DP, Schwartz LB, Rock DT, Garson ML, Roller K. Vanco-

mycin and the red-man syndrome: pharmacodynamics of histamine release.

J Infect Dis 1988;157:502-7.

144. Anne S, Middleton E Jr, Reisman RE. Vancomycin anaphylaxis and successful

desensitization. Ann Allergy 1994;73:402-4.

145. Hwang MJ, Do JY, Choi EW, Seo JH, Nam YJ, Yoon KW, et al. Immuno-

globulin E-mediated hypersensitivity reaction after intraperitoneal adminis-

tration of vancomycin. Kidney Res Clin Pract 2015;34:57-9.

146. Polk RE, Israel D, Wang J, Venitz J, Miller J, Stotka J. Vancomycin skin tests

and prediction of “red man syndrome” in healthy volunteers. Antimicrob

Agents Chemother 1993;37:2139-43.

147. Rwandamuriye FX, Chopra A, Konvinse KC, Choo L, Trubiano JA,

Shaffer

CM, et al. A rapid allele-speciﬁc assay for HLA-A*32:01 to identify

patients at risk for vancomycin-induced drug reaction with eosinophilia and

systemic symptoms. J Mol Diagn 2019;21:782-9.

148. Wong JT, Ling M, Patil S, Banerji A, Long A. Oxaliplatin hypersensitivity:

evaluation, implications of skin testing, and desensitization. J Allergy Clin

Immunol Pract 2014;2:40-5.

149. Wong JT, Nagy CS, Krinzman SJ, Maclean JA, Bloch KJ. Rapid oral chal-

lenge-desensitization for patients with aspirin-related urticaria-angioedema.

J Allergy Clin Immunol 2000;105:997-1001.

150. Wong JT, Ripple RE, MacLean JA, Marks DR, Bloch KJ. Vancomycin hy-

persensitivity: synergism with narcotics and “desensitization” by a rapid

continuous intravenous protocol. J Allergy Clin Immunol 1994;94:189-94.

151. Haw W. Vancomycin-speciﬁc T cell responses and teicoplanin cross-reac-

tivity. Clin Transl Allergy 2016;164.

152. Blumenthal KG, Patil SU, Long AA. The importance of vancomycin in drug

rash with eosinophilia and systemic symptoms (DRESS) syndrome. Allergy

Asthma Proc 2012;33:165-71.

153. Waldman MA, Black DR, Callen JP. Vancomycin-induced linear IgA bullous

disease presenting as toxic epidermal necrolysis. Clin Exp Dermatol 2004;29:

633-6.

154. Hsiao SH, Chou CH, Lin WL, Lee EJ, Liao LH, Chang HJ, et al. High risk of

cross-reactivity between vancomycin and sequential teicoplanin therapy. J Clin

Pharm Ther 2012;37:296-300.

155. Hung YP, Lee NY, Chang CM, Lee HC, Wu CJ, Chen PL, et al. Tolerability of

teicoplanin in 117 hospitalized adults with previous vancomycin-induced fe-

ver, rash, or neutropenia: a retrospective chart review. Clin Ther 2009;31:

1977-86.

156. Kotra LP, Haddad J, Mobashery S. Aminoglycosides: perspectives on mech-

anisms of action and resistance and strategies to counter resistance. Antimicrob

Agents Chemother 2000;44:3249-56.

157. Gehrig KA, Warshaw EM. Allergic contact dermatitis to topical antibiotics:

epidemiology, responsible allergens, and management. J Am Acad Dermatol

2008;58:1-21.

158. Bensaid B, Rozieres A, Nosbaum A, Nicolas JF, Berard F. Amikacin-induced

drug reaction with eosinophilia and systemic symptoms syndrome: delayed

skin test and ELISPOT assay results allow the identiﬁcation of the culprit drug.

J Allergy Clin Immunol 2012;130:1413-4.

159. Hmouda H, Laouani-Kechrid C, Nejib Karoui M, Denguezli M, Nouira R,

Ghannouchi G. A rare case of streptomycin-induced toxic epidermal necrolysis

in a patient with tuber culosis: a therapeutic dilemma. Ann Pharmacother 2005;

39:165-8.

160. Paniagua MJ, Garcia-Ortega P, Tella R, Gaig P, Richart C. Systemic contact

dermatitis to gentamicin. Allergy 2002;57:1086-7.

161. Proebstle TM, Jugert FK, Merk HF, Gall H. Severe anaphylactic reaction to

topical admin istration of framycetin. J Allergy Clin Immunol 1995;96:429-30.

162. Connolly M, McAdoo J, Bourke JF. Gentamicin-induced anaphylaxis. Ir J

Med Sci 2007;176:317-8.

163. Earl HS, Sullivan TJ. Acute desensitization of a patient with cystic ﬁbrosis

allergic to both beta-lactam and aminoglycoside antibiotics. J Allergy Clin

Immunol 1987;79:477-83.

164. Jung DM, Kim JH, Choi NY, Choi JH, Hwang YI, Jang SH, et al. Anaphylaxis

associated with streptomycin skin testing. Ann Allergy Asthma Immunol 2014;

112:81-2.

165. Schulze S, Wollina U. Gentamicin-induced anaphylaxis. Allergy 2003;58:

88-9.

166. Spigarelli MG, Hurwitz ME, Nasr SZ. Hypersensitivity to inhaled TOBI

following reaction to gentamicin. Pediatr Pulmonol 2002;33:311-4.

167. Legere HJ III, Palis RI, Rodriguez Bouza T, Uluer AZ, Castells MC. A safe

protocol for rapid desensitization in patients with cystic ﬁbrosis and antibiotic

hypersensitivity. J Cyst Fibros 2009;8:418-24.

168. Gurwith MJ, Rabin HR, Love K. Diarrhea associated with clindamycin and

ampicillin therapy: preliminary results of a cooperative study. J Infect Dis

1977;135:S104-10.

169. Bulloch MN, Baccas JT, Arnold S. Clindamycin-induced hypersensitivity re-

action. Infection 2016;44:357-9.

170. Chiou CS, Lin SM, Lin SP, Chang WG, Chan KH, Ting CK. Clindamycin-

induced anaphylactic shock during general anesthesia. J Chin Med Assoc

2006;69:549-51.

171. Lochmann O, Kohout P, Vymola F. Anaphylactic shock following the

administration of clindamycin. J Hyg Epidemiol Microbiol Immunol 1977;21:

441-7.

172. Fass RJ, Scholand JF, Hodges GR, Saslaw S. Clindamycin in the treatment of

serious anaerobic infections. Ann Intern Med 1973;78:853-9.

173. Geddes AM, Bridgwater FA, Williams DN, Oon J, Grimshaw GJ. Clinical and

bacteriological studies with clindamycin. Br Med J 1970;2:703-4.

174. Mazur N, Greenberger PA, Regalado J. Clindamycin hypersensitivity appears

to be rare. Ann Allergy Asthma Immunol 1999;82:443-5.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S101

175. Fulghum DD. Stevens-Johnson syndrome from clindamycin. JAMA 1973;223:

318.

176. Kandula S, Burke WS, Goldfarb JN. Clindamycin-induced Sweet syndrome.

J Am Acad Dermatol 2010;62:898-900.

177. Kapoor R, Flynn C, Heald PW, Kapoor JR. Acute generalized exanthematous

pustulosis induced by clindamycin. Arch Dermatol 2006;142:1080-1.

178. Paquet P, Schaaf-Lafontaine N, Pierard GE. Toxic epidermal necrolysis

following clindamycin treatment. Br J Dermatol 1995;132:665-6.

179. Sahagun Flores JE, Soto Ortiz JA, Tovar Mendez CE, Cardenas Ochoa EC,

Hernandez Flores G. Stevens-Johnson syndrome plus intrahepatic cholestasis

caused by clindamycin or chlorpheniramine. Dermatol Online J 2009;15:12.

180. Schwab RA, Vogel PS, Warschaw KE. Clindamycin-induced acute general-

ized exanthematous pustulosis. Cutis 2000;65:391-3.

181. Sulewski RJ Jr, Blyumin M, Kerdel FA. Acute generalized exanthematous

pustulosis due to clindamycin. Dermatol Online J 2008;14:14.

182. Tian D, Mohan RJ, Stallings G. Drug rash with eosinophilia and

systemic symptoms syndrome associated with clindamycin. Am J Med 2010;

123:e7-8.

183. Valois M, Phillips EJ, Shear NH, Knowles SR. Clindamycin-associated acute

generalized exanthematous pustulosis. Contact Dermat itis 2003;48:169.

184. Morales MP, Carvallo AP, Espinosa KA, Murillo EE. A young man with

myelosuppression caused by clindamycin: a case report. J Med Case Rep 2014;

8:7.

185. Notman MJ, Phillips EJ, Knowles SR, Weber EA, Shear NH. Clindamycin

skin testing has limited diagnostic potential. Contact Dermatitis 2005;53:

335-8.

186. Pereira N, Canelas MM, Santiago F, Brites MM, Goncalo M. Value of patch

tests in clindamycin-related drug eruptions. Contact Dermatitis 2011;65:202-7.

187. Seitz CS, Brocker EB, Trautmann A. Allergy diagnostic testing in clindamy-

cin-induced skin reactions. Int Arch Allergy Immunol 2009;149:246-50.

188. Marcos C, Sopena B, Luna I, Gonzalez R, de la Fuente J, Martinez-Vazquez C.

Clindamycin desensitization in an AIDS patient. AIDS 1995;9:1201-2.

189. Esty B, Minnicozzi S, Chu EC, Broyles AD, Yee CSK. Successful rapid oral

clindamycin desensitization in a pediatric patient. J Allergy Clin Immunol

Pract 2018;6:2141-2.

190. Chen C, Guo DH, Cao X, Cai Y, Xu Y, Zhu M, et al. Risk factors for

thrombocytopenia in adult Chinese patients receiving linezolid therapy. Curr

Ther Res Clin Exp 2012;73:195-206.

191. Hiraki Y, Tsuji Y, Hiraike M, Misumi N, Matsumoto K, Morita K, et al.

Correlation between serum linezolid concentration and the development of

thrombocytopenia. Scand J Infect Dis 2012;44:60-4.

192. Niwa T, Suzuki A, Sakakibara S, Kasahara S, Yasuda M, Fukao A, et al.

Retrospective cohort chart review study of factors associated with the devel-

opment of thrombocytopenia in adult Japanese patients who received intra-

venous linezolid therapy. Clin Ther 2009;31:2126-33.

193. Wu VC, Wang YT, Wang CY, Tsai IJ, Wu KD, Hwang JJ, et al. High fre-

quency of linezolid-associated thrombocytopenia and anemia among patients

with end-stage renal disease. Clin Infect Dis 2006;42:66-72.

194. Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH,

Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive

infections: experience from a compassionate-use program. Clin Infect Dis

2003;36:159-68.

195. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical

outcomes but high rates of adverse reactions during linezolid therapy for

serious infections: a proposed protocol for monitoring therapy in complex

patients. Antimicrob Agents Chemother 2006;50:1599-602.

196. Natsumoto B, Yokota K, Omata F, Furukawa K. Risk factors for linezolid-

associated thrombocytopenia in adult patients. Infection 2014;42:1007-12.

197. Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, et al. He-

matologic effects of linezolid: summary of clinical experience. Antimicrob

Agents Chemother 2002;46:2723-6.

198. Im JH, Baek JH, Kwon HY, Lee JS. Incidence and risk factors of linezolid-

induced lactic acidosis. Int J Infect Dis 2015;31:47-52.

199. Lee E, Burger S, Shah J, Melton C, Mullen M, Warren F, et al. Linezolid-

associated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis 2003;37:

1389-91.

200. Rho JP, Sia IG, Crum BA, Dekutoski MB, Trousdale RT. Linezolid-associated

peripheral neuropathy. Mayo Clin Proc 2004;79:927-30.

201. Zivkovic SA, Lacomis D. Severe sensory neuropathy associated with long-

term linezolid use. Neurology 2005;64:926-7.

202. Bagwell AD, Stollings JL, White KD, Fadugba OO, Choi JJ. Linezolid

desensitization for a patient with multiple medication hypersensitivity re-

actions. Ann Pharmacother 2013;47:e30.

203. Cawley MJ, Lipka O. Intravenous linezolid administered orally: a novel

desensitization strategy. Pharmacotherapy 2006;26:563-8.

204. Yang M, Xu M. Linezolid-induced angioedema and urticaria in a patient with

renal failure. Braz J Infect Dis 2012;16:606-7.

205. Esposito L, Kamar N, Guilbeau-Frugier C, Mehrenberger M, Modesto A,

Rostaing L. Linezolid-induced interstitial nephritis in a kidney-transplant pa-

tient. Clin Nephrol 2007;68:327-9.

206. Hammer MC, Tomada JRT, Rich M, Bonilla H. Linezolid-induced acute

interstitial nephritis. Infect Dis Clin Pract 2009;17:61-2.

207. Savard

S, Desmeules S, Riopel J, Agharazii M. Linezolid-associated acute

interstitial nephritis and drug rash with eosinophilia and systemic symptoms

(DRESS) syndrome. Am J Kidney Dis 2009;54:e17-e20.

208. Nayak S, Nandwani A, Rastogi A, Gupta V. Acute interstitial nephritis and

drug rash with secondary to linezolid. Indian J Nephrol 2012;22:367-9.

209. McOsker CC, Fitzpatrick PM. Nitrofurantoin: mechanism of action and im-

plications for resistance development in common uropathogens. J Antimicrob

Chemother 1994;33:23-30.

210. Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U,

Mouton JW. Nitrofurantoin revisited: a systematic review and meta-analysis of

controlled trials. J Antimicrob Chemother 2015;70:2456-6 4.

211. Fisk AA. Brief recording: anaphylactoid reaction to nitrofurantoin. N Engl J

Med 1957;256:1054.

212. Jick SS, Jick H, Walker AM, Hunter JR. Hospitalizations for pulmonary re-

actions following nitrofurantoin use. Chest 1989;96:512-5.

213. Khorsandian R, Bremer EM, Nodine JH. Anaphylactic reaction caused by

treatment with nitrofurantoin. JAMA 1963;184:500-2.

214. Tykal P, Wilms H. Anaphylactic shock following oral administration of

nitrofurantoin and demonstration of reagins using the heterologous intracuta-

neous test (Prausnitz-Kustner) [in German]. Deutsch Med Wochenschr 1972;

97:256-7.

215. Sovijarvi AR, Lemola M, Stenius B, Idanpaan-Heikkila J. Nitrofurantoin-

induced acute, subacute and chronic pulmonary reactions. Scand J Respir Dis

1977;58:41-50.

216. Liesching T, O’Brien A. Dyspnea, chest pain, and cough: the lurking

culprit. Nitrofurantoin-induced pulmonary toxicity. Postgrad Med 2002;

112:19-20.

217. D’Arcy PF. Nitrofurantoin. Drug Intell Clin Pharm 1985;19:540-7.

218. Sherigar JM, Fazio R, Zuang M, Arsura E. Autoimmune hepatitis induced by

nitrofurantoin: the importance of the autoantibodies for an early diagnosis of

immune disease. Clin Pract 2012;2:e83.

219. Kelly BD, Heneghan MA, Bennani F, Connolly CE, O’Gorman TA. Nitro-

furantoin-induced hepatotoxicity mediated by CD8þ T cells. Am J Gastro-

enterol 1998;93:819-21.

220. Suntres ZE, Shek PN. Nitrofurantoin-induced pulmonary toxicity: in vivo

evidence for oxidative stress-mediated mechanisms. Biochem Pharmacol 1992;

43:1127-35.

221. Lammintausta K, Kortekangas-Savolainen O. The usefulness of skin tests to

prove drug hypersensitivity. Br J Dermatol 2005;152:968-74.

222. Connell DW, Berry M, Cooke G, Kon OM. Update on tuberculosis: TB in the

early 21st century. Eur Respir Rev 2011;20:71-84.

223. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement.

Global burden of tuberculosis: estimated incidence, prevalence, and mortality

by country. WHO Global Surveillance and Monitoring Project. JAMA 1999;

282:677-86.

224. Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, et al. LTBI:

latent tuberculosis infection or lasting immune responses to M. tuberculosis?A

TBNET consensus statement. Eur Respir J 2009;33:956-73.

225. Aouam K , Chaabane A, Lous saief C, Ben Romdh ane F, Boughattas NA,

Chakroun M. Adverse effec ts of antitubercula r drugs: epidemiolog y,

mechanisms, and patient ma nagement [i n French]. Med Mal I nfect 2007;

37:253-61.

226. Combs DL, O’Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course

Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of

ﬁnal results. Ann Intern Med 1990;112:397-406.

227. Nikolaeva OD. Side effects of chemotherapy in patients with pulmonary

tuberculosis and concomitant diseases [in Russian]. Lik Sprava 2003;(3-4):

74-8.

228. Kishore PV, Palaian S, Ojha P, Shankar PR. Pattern of adverse drug reactions

experienced by tuberculosis patients in a tertiary care teaching hospital in

Western Nepal. Pak J Pharm Sci 2008;21:51-6.

229. Snider DE Jr, Long MW, Cross FS, Farer LS. Six-months isoniazid-rifampin

therapy for pulmonary tuberculosis: report of a United States Public Health

Service Cooperative Trial. Am Rev Respir Dis 1984;129:573-9.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S102 BROYLES ET AL

230. Vieira DE, Gomes M. Adverse effects of tuberculosis treatment: experience at

an outpatient clinic of a teaching hospital in the city of Sao Paulo, Brazil.

J Bras Pneumol 2008;34:1049-55.

231. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S,

Haahtela T, et al. A revised nomenclature for allergy. An EAACI position

statement from the EAACI Nomenclature Task Force. Allergy 2001;56:

813-24.

232. Aristoff PA, Garcia GA, Kirchhoff PD, Showalter HD. Rifamycins–obstacles

and opportunities. Tuberculosis (Edinb) 2010;90:94-118.

233. Martinez E, Collazos J, Mayo J. Hypersensitivity reactions to rifampin:

pathogenetic mechanisms, clinical manifestations, management strategies, and

review of the anaphylactic-like reactions. Medicine (Baltimore) 1999;78:

361-9.

234. Broz P, Harr T, Hecking C, Grize L, Scherer K, Jaeger KA, et al. Nonirritant

intradermal skin test concentrations of ciproﬂoxacin, clarithromycin, and

rifampicin. Allergy 2012;67:647-52.

235. Buergin S, Scherer K, Hausermann P, Bircher AJ. Immediate hypersensitivity

to rifampicin in 3 patients: diagnostic procedures and induction of clinical

tolerance. Int Arch Allergy Immunol 2006;140:20-6.

236. Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and

pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet 2001;

40:327-41.

237. Matz J, Borish LC, Routes JM, Rosenwasser LJ. Oral desensitization to

rifampin and ethambutol in mycobacterial disease. Am J Respir Crit Care Med

1994;149:815-7.

238. Hildebrand KJ, Atkinson A, Kitai I. Rifampin hypersensitivity in a 2-year-old

child with successful rapid oral desensitization. Pediatr Infect Dis J 2014;33:

787.

239. Kim JH, Kim HB, Kim BS, Hong SJ. Rapid oral desensitization to isoniazid,

rifampin, and ethambutol. Allergy 2003;58:540-1.

240. Logsdon S, Ramirez-Avila L, Castells M, Dioun A. Successful rifampin

desensitization in a pediatric patient with latent tuberculosis. Pediatr Allergy

Immunol 2014;25:404-5.

241. Syrigou E, Grapsa D, Nanou E, Zande M, Vassias A, Gkiozos I, et al.

Anaphylaxis during rapid oral desensitization to rifampicin. J Allergy Clin

Immunol Pract 2016;4:173-4.

242. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC,

Friedman LN, et al. American Thoracic Society/Centers for Disease Control

and Prevention/Infectious Diseases Society of America: treatment of tuber-

culosis. Am J Respir Crit Care Med 2003;167:603-62.

243. Olivier C, Radal M, Mazaud S, Jonville-Bera AP, Martel C, Autret E. Éruption

après une première prise d’une quadrithérapie antituberculeuse: penser au

pyrazinamide [in French]. Arch Pediatr 1998;5:289-90.

244. Radal M, Jonville-Bera AP, Van-Egroo C, Carre P, Lemarie E, Autret E.

Eruption after the 1st dose of standard antitubercular chemotherapy: thoughts

on pyrazinamide. Rev Mal Respir 1998;15:305-6.

245. Vervloet D, Pradal M, Castela M. Drug Allergy. Uppsala, Sweden: Pharmacia

& UpJohn; 1999.

246. Bavbek S, Yilmaz I, Aydin O, Ozdemir SK. Pyrazinamide-induced anaphy-

laxis: diagnosed by skin test and successful desensitization. Int Arch Allergy

Immunol 2012;157:209-12.

247. Holdiness MR. Adver se cutaneous reactions to antituberculosis drugs. Int J

Dermatol 1985;24:280-5.

248. Durand F, Pessayre D, Fournier M, Belghiti J, Erlinger S, Bernuau J. Anti-

tuberculous therapy and acute liver failure. Lancet 1995;345:1170.

249. Holdiness MR. Contact dermatitis to antituberculosis drugs. Contact Derma-

titis 1986;15:282-8.

250. Nariman S. Adverse reactions to drugs used in the treatment of tuberculosis.

Adverse Drug React Acute Poisoning Rev 1988;7:207-27.

251. Rubira N, Baltasar MA, Marti E. Hypersensitivity syndrom e from isoniazid.

Allergy 1999;54:1011-2.

252. Herrejon Silvestre A, Furest Carrasco I, Marin Gonzalez M. Fiebre por iso-

niacida. Arch Bronconeumol 2000;36:112-3.

253. Lee CH, Hsiue TR, Chen CW, Chang HY, Chen CR. Isoniazid-induced fever.

J Formos Med Assoc 1996;95:632-4.

254. Bakkum RS, Waard-Van Der Spek FB, Thio HB. Delayed-type hypersensi-

tivity reaction to ethambutol and isoniazid. Contact Dermatitis 2002;46:359.

255. Girling DJ. Adverse effects of antituber culosis drugs. Drugs 1982;23:56-74.

256. Honeycutt WM. Reactions to isoniazid. Arch Dermatol 1963;88:190.

257. Mitchell JR, Zimmerman HJ, Ishak KG, Thorgeirsson UP, Timbrell JA,

Snodgrass WR, et al. Isoniazid liver injury: clinical spectrum, pathology, and

probable pathogenesis. Ann Intern Med 1976;84:181-92.

258. Lafourcade MP, Martinl M, Revolte X, Ba L, Hamoudi M, Bara R. Reaction

allergique aux antituberculeux majeurs. Revue Francaise d’Allergologie 2009;

49:496-9.

259. Rodrigues Carvalho S, Silva I, Leiria-Pinto P, Rosado-Pinto J. Rapid oral

tolerance induction to isoniazid and pyrazinamide and controlled administra-

tion

of ethambutol: clinical case. Allergol Immunopathol (Madr) 2009;37:

336-8.

260. Abadoglu O, Epozturk K, Atayik E. Rapid oral desensitisation to prophylactic

isoniazid. Allergol Immunopathol (Madr) 2011;39:311-2.

261. Rodrigues J, Moreira A, Fonseca J, Vaz M. Oral desensitization to izoniazid.

R Port Alergologia 2007;9:263-4.

262. Grifﬁth DE, Brown-Elliott BA, Shepherd S, McLarty J, Grifﬁth L, Wallace RJ Jr.

Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium

complex lung disease. Am J Respir Crit Care Med 2005;172:250-3 .

263. Younossian AB, Rochat T, Ketterer JP, Wacker J, Janssens JP. High hepato-

toxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis.

Eur Respir J 2005;26:462-4.

264. Brunton LL, Lazo JS, Parker KL. Goodman & Gilman’s the Pharmacological

Basis of Therapeutics. 11th ed. New York: McGraw-Hill Professional; 2006.

265. Grossman ME, Warren K, Mady A, Satra KH. Lichenoid eruption associated

with ethambutol. J Am Acad Dermatol 1995;33:675-6.

266. HiraokaK,NagataN,SuzukiK,Kawajiri T, Kurokawa S, Kawamura T,

et al. A case of pulmon ary reaction with skin eruption showing a positive

peripheral lymp hocyte stim ulation tes t result for etham butol. J UOEH

1998;20:145-51.

267. Pegram PS Jr, Mountz JD, O’Bar PR. Ethambutol-induced toxic epidermal

necrolysis. Arch Intern Med 1981;141:1677-8.

268. Srivastava N, Solanki LS, Chand S, Garbyal RS, Singh S. Ashy dermatosis-

like pigmentation due to ethambutol. Indian J Dermatol Venereol Leprol 2008;

74:281-2.

269. Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. General

considerations for skin test procedures in the diagnosis of drug hypersensi-

tivity. Allergy 2002;57:45-51.

270. Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, et al.

General considerations on rapid desensitization for drug hypersensitivity—a

consensus statement. Allergy 2010;65:1357-66.

271. Cernadas JR, Santos N, Pinto C, Mota PC, Castells M. Hypersensitivity re-

action and tolerance induction to ethambutol. Allergy 2011;66:381.

272. Castells MC, Tennant NM, Sloane DE, Ida Hsu F, Barrett NA , Hong DI, et al.

Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid

desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574-80.

273. Athira B, Manju CS, Jyothi E. A study on adverse drug reactions to ﬁrst line

antitubercular drugs in DOTS therapy. Int J Pharmacol Clin Sci 2015;4:7-11.

274. Macpherson P. Sensitization to P.A.S., streptomycin, and isoniazid. Br Med J

1957;2:505-6.

275. Sanchez-Borges M, Thong B, Blanca M, Ensina LF, Gonzalez-Diaz S,

Greenberger PA, et al. Hypersensitivity reactions to non beta-lactam antimi-

crobial agents, a statement of the WAO special committee on drug allergy.

World Allergy Organ J 2013;6:18.

276. Chakravarty S. A method of desensitization of allergy due to streptomycin with

prednisone. Dis Chest 1957;32:310-4.

277. Russell B. Desensitization to streptomycin and P.A.S. Br Med J 1953;2:1322.

278. Lofmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for

treatment of anaerobic infections. Clin Infect Dis 2010;50:S16-23.

279. Workowski KA, Bolan GA, Centers for Disease Control and Prevention.

Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm

Rep 2015;64:1-137.

280. Asensio Sanchez T, Davila I, Moreno E, Laffond E, Macias E, Ruiz A, et al.

Anaphylaxis due to metronidazole with positive skin prick test. J Investig

Allergol Clin Immunol 2008;18:138-9.

281. Gastaminza G, Anda M, Audicana MT, Fernandez E, Munoz D. Fixed-drug

eruption due to metronidazole with positive topical provocation. Contact

Dermatitis 2001;44:36.

282. Kumar N, Sundriyal D, Walia M, Trisal D. Metronidazole-induced ﬁxed drug

eruption. BMJ Case Rep 2013;2013:bcr2013200470.

283. Mazumdar G, Shome K. Stevens-Johnson syndrome following use of metro-

nidazole in a dental patient. Indian J Pharmacol 2014;46:121-2.

284. Short KA, Fuller LC, Salisbury JR. Fixed drug eruption following metroni-

dazole therapy and the use of topical provocation testing in diagnosis. Clin Exp

Dermatol 2002;27:464-6.

285. Weart CW, Hyman LC. Serum sickness associated with metronidazole.

Southern Med J 1983;76:410-1.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S103

286. Garcia-Rubio I, Martinez-Cocera C, Santos Magadan S, Rodriguez-Jimenez B,

Vazquez-Cortes S. Hypersensitivity reactions to metronidazole. Allergol

Immunopathol (Madr) 2006;34:70-2.

287. Gendelman SR, Pien LC, Gutta RC, Abouhassan SR. Modiﬁed oral metroni-

dazole desensitization protocol. Allergy Rhinol (Providence) 2014;5:66-9.

288. Kurohara ML, Kwong FK, Lebherz TB, Klaustermeyer WB. Metronidazole

hypersensitivity and oral desensitization. J Allergy Clin Immunol 1991;88:

279-80.

289. Pearlman MD, Yashar C, Ernst S, Solomon W. An incremental dosing pro-

tocol for women with severe vaginal trichomoniasis and adverse reaction to

metronidazole. Am J Obstet Gynecol 1996;174:934-6.

290. Helms DJ, Mosure DJ, Secor WE, Workowski KA. Management of tricho-

monas vaginalis in women with suspected metronidazole hypersensitivity. Am

J Obstet Gynecol 2008;198:370.e1-7.

291. Kanwar AJ, Sharma R, Rajagopalan M, Kaur S. Fixed drug eruption due to

tinidazole with cross-reactivity with metronidazole. Dermatologica 1990;180:

277.

292. Mishra D, Mobashir M, Zaheer MS. Fixed drug eruption and cross-reactivity

between tinidazole and metronidazole. Int J Dermatol 1990;29:740.

293. Thami GP, Kanwar AJ. Fixed drug eruption due to metronidazole and tini-

dazole without cross-sensitivity to secnidazole. Dermatology 1998;196:368.

294. Petersen E, Ronne T, Ronn A, Bygbjerg I, Larsen SO. Reported side effects to

chloroquine, chloroquine plus proguanil, and meﬂoquine as chemoprophylaxis

against malaria in Danish travelers. J Travel Med 2000;7:79-84.

295. Ekpechi OL, Okoro AN. A pattern of pruritus due to chloroquine. Arch

Dermatol 1964;89:631-2.

296. Boffa MJ, Chalmers RJ. Toxic epidermal necrolysis due to chloroquine

phosphate. Br J Dermatol 1994;131:444-5.

297. Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf 2004;27:

25-61.

298. Smith HR, Croft AM, Black MM. Dermatological adverse effects with the

antimalarial drug meﬂoquine: a review of 74 published case reports. Clin Exp

Dermatol 1999;24:249-54.

299. Deen JL, von Seidlein L, Dondorp A. Therapy of uncomplicated malaria in

children: a review of treatment principles, essential drugs and current recom-

mendations. Trop Med Int Health 2008;13:1111-30.

300. Looareesuwan S, Chulay JD, Canﬁeld CJ, Hutchinson DB. Malarone (atova-

quone and proguanil hydrochloride): a review of its clinical development for

treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med

Hyg 1999;60:533-41.

301. McKeage K, Scott L. Atovaquone/proguanil: a review of its use for the pro-

phylaxis of Plasmodium falciparum malaria. Drugs 2003;63:597-623.

302. Emberger M, Lechner AM, Zelger B. Stevens-Johnson syndrome associated

with Malarone antimalarial prophylaxis. Clin Infect Dis 2003;37:e5-7.

303. Just N, Carpentier O, Brzezinki C, Steenhouwer F, Staumont-Salle D. Severe

hypersensitivity reaction as acute eosinophil ic pneumonia and skin eruption

induced by proguanil. Eur Respir J 2011;37:1526-8 .

304. Kremsner PG, Looareesuwan S, Chulay JD. Atovaquone and proguanil hy-

drochloride for treatment of malaria. J Travel Med 1999;6:S18-20.

305. Janier M, Froidevaux D, Lons-Danic D, Daniel F. Acute generalized exan-

thematous pustulosis due to the combination of chloroquine and proguanil.

Dermatology 1998;196:271.

306. Luong MS, Bessis D, Raison-Peyron N, Pinzani V, Guilhou JJ, Guillot B.

Severe mucocutaneous necrotizing vasculitis associated with the combination

of chlor oquine and proguanil. Acta Derm Venereol 2003;83:141.

307. Zhang FR, Liu H, Irwanto A, Fu XA, Li Y, Yu GQ, et al. HLA-B*13:01 and

the dapsone hypersensitivity syndrome. N Engl J Med 2013;369:1620-8.

308. Price R, van Vugt M, Phaipun L, Luxemburger C, Simpson J, McGready R,

et al. Adverse effects in patients with acute falciparum malaria treated with

artemisinin derivatives. Am J Trop Med Hyg 1999;60:547-55.

309. Leonardi E, Gilvary G, White NJ, Nosten F. Severe allergic reactions to oral

artesunate: a report of two cases. Trans R Soc Trop Med Hyg 2001;95:182-3.

310. AlKadi HO. Antimalarial drug toxicity: a review. Chemotherapy 2007;53:

385-91.

311. Fox LM. Ivermectin: uses and impact 20 years on. Curr Opin Infect Dis 2006;

19:588-93.

312. Ottesen EA, Campbell WC. Ivermectin in human medicine. J Antimicrob

Chemother 1994;34:195-203.

313. Fujimoto K, Kawasaki Y, Morimoto K, Kikuchi I, Kawana S. Treatment for

crusted scabies: limitations and side effects of treatment with ivermectin.

J Nippon Med Sch 2014;81:157-63.

314. Gann PH, Neva FA, Gam AA. A randomized trial of single- and two-do se

ivermectin

versus thiabendazole for treatment of strongyloidiasis. J Infect Dis

1994;169:1076-9.

315. Orion E, Matz H, Wolf R. The life-threatening complications of dermatologic

therapies. Clin Dermatol 2005;23:182-92.

316. Horton J. Albendazole: a review of anthelmintic efﬁcacy and safety in humans.

Parasitology 2000;121:S113-S132.

317. Solaymani-Mohammadi S, Genkinger JM, Loffredo CA, Singer SM . A meta-

analysis of the effectiveness of albendazole compared with metronidazole as

treatments for infections with Giardia duodena lis . PLoS Negl Trop Dis 2010;

4:e682.

318. Macedo NA, Pineyro MI, Carmona C. Contact urticaria and contact dermatitis

from albendazole. Contact Dermatitis 1991;25:73-5.

319. Mahboob A, Haroon TS. Fixed drug eruption with albendazole and its cross-

sensitivity with metronidazole–a case report. J Pak Med Assoc 1998;4 8:316-7.

320. Bagheri H, Simiand E, Montastruc JL, Magnaval JF. Adverse drug reactions to

anthelmintics. Ann Pharmacother 2004;38:383-8.

321. Chen KT, Twu SJ, Chang HJ, Lin RS. Outbreak of Stevens-Johnson syn-

drome/toxic epidermal necrolysis associated with mebendazole and metroni-

dazole use among Filipino laborers in Taiwan. Am J Public Health 2003;93:

489-92.

322. Grove DI. Treatment of strongyloidiasis with thiabendazole: an analysis of

toxicity and effectiveness. Trans R Soc Trop Med Hyg 1982;76:114-8.

323. Zwang J, Olliaro PL. Clinical efﬁcacy and tolerability of praziquantel for in-

testinal and urinary schistosomiasis—a met a-analysis of comparative and non-

comparative clinical trials. PLoS Negl Trop Dis 2014;8:e3286.

324. Huang SW. A clinical approach to a patient with praziquantel hypersensitivity.

J Allergy Clin Immunol 1992;90:867.

325. Kyung SY, Cho YK, Kim YJ, Park JW, Jeong SH, Lee JI, et al.

A paragonimiasis patient with allergic reaction to praziquantel and resistance to

triclabendazole: successful treatment after desensitization to praziquantel.

Korean J Parasitol 2011;49:73-7.

326. Lee JM, Lim HS, Hong ST. Hypersensitive reaction to praziquantel in a clo-

norchiasis patient. Korean J Parasitol 2011;49:273-5.

327. Shen C, Choi MH, Bae YM, Yu G, Wang S, Hong ST. A case of anaphylactic

reaction to praziquantel treatment. Am J Trop Med Hyg 2007;76:603-5.

328. Matsumoto J. Adverse effects of praziquantel treatment of Schistosoma

japonicum infection: involvement of host anaphylactic reactions induced by

parasite antigen release. Int J Parasitol 2002;32:461-71.

329. Francis H, Awadzi K, Ottesen EA. The Mazzotti reaction following treatment

of onchocerciasis with diethylcarbamazine: clinical severity as a function of

infection intensity. Am J Trop Med Hyg 1985;34:529-36.

330. Docampo R, Moreno SN. Current chem otherapy of human African trypano-

somiasis. Parasitol Res 2003;90:S10-3.

331. Blum J, Nkunku S, Burri C. Clinical description of encephalopathic syn-

dromes and risk factors for their occurrence and outcome during melarso-

prol treatment of human African trypanosomiasis. Trop Med Int Health

2001;6:390-400.

332. Gonzalez-Mendiola R, Martinez Borque N, Palomeque Rodriguez T, Torre-

cillas Toro M, Martinez Bohigas D. Type I allergic reaction to benzimidazole

antihelmintics. Allergy 2007;62:713-4.

333. Nett JE, Andes DR. Antifungal agents: spectrum of activity, pharmacology,

and clinical indications. Infect Dis Clin North Am 2016;30:51-83.

334. Zonios DI, Bennett JE. Update on azole antifungals. Semin Respir Crit Care

Med 2008;29:198-210.

335. Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of anti-

fungals. Ann Pharmacother 2009;43:1647-57.

336. Bittleman DB, Stapleton J, Casale TB. Report of successful desensitization to

itraconazole. J Allergy Clin Immunol 1994;94:270-1.

337. Craig TJ, Peralta F, Boggavarapu J. Desensitization for ﬂuconazole hyper-

sensitivity. J Allergy Clin Immunol 1996;98:845-6.

338. Jariwala S, Vernon N, de Vos G. A novel method of desensitization for ﬂu-

conazole hypersensitivity in a patient with AIDS. Ann Allergy Asthma

Immunol 2011;106:542-3.

339. Jean T, Kwong K. Successful desensitization of voriconazole in an immuno-

suppressed pediatric patient. J Allergy Clin Immunol Pract 2015;3:637-8.

340. Arrieta

AC, Maddison P, Groll AH. Safety of micafungin in pediatric clinical

trials. Pediatr Infect Dis J 2011;30:e97-e102.

341. Zaoutis TE, Jafri HS, Huang LM, Locatelli F, Barzilai A, Ebell W, et al.

A prospective, multicenter study of caspofungin for the treatment of docu-

mented Candida or Aspergillus infections in pediatric patients. Pediatrics 2009;

123:877-84.

342. Lee MC, Ni YW, Wang CH, Lee CH, Wu TW. Caspofungin-induced severe

toxic epidermal necrolysis. Ann Pharmacother 2010;44:1116-8.

343. Patel S, Alangaden GJ, Lum LG, Cronin SM, Abidi MH, Dieterle N, et al.

Immediate cross-hypersensitivity between micafungin and caspofungin: a case

report. J Oncol Pharm Pract 2009;15:187-9.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S104 BROYLES ET AL

344. Randolph C, Kaplan C, Fraser B. Rapid desensitization to ﬂuconazole

(Diﬂucan). Ann Allergy Asthma Immunol 2008;100:616-7.

345. Ward SL, Maciag MC, Jones S, Lee J, Lee J, Broyles A. Successful rapid

desensitization to micafungin in a pediatric patient [published online ahead of

print July 21, 2020]. Ped Allergy Immunol Pulmonmol. https://doi.org/10.

1089/ped.2020.1204.

346. Group ISS, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al.

Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl

J Med 2015;373:795-807.

347. EMPRANO ANRS 12136 Study GroupDanel C, Moh R, Gabillard D,

Badje A, Le Carrou J, et al. A trial of early antiretrovirals and isoniazid pre-

ventive therapy in Africa. N Engl J Med 2015;373:808-22.

348. Gunthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, et al.

Antiretroviral drugs for treatment and prevention of HIV infection in Adults:

2016 Recommendations of the International Antiviral Society-USA Panel.

JAMA 2016;316:191-210.

349. Milpied-Homsi B, Moran EM, Phillips EJ. Antiviral drug allergy. Immunol

Allergy Clin North Am 2014;34:645-62.

350. Putterman C, Rahav G, Shalit M, Rubinow A. “Treating through” hypersen-

sitivity to co-trimoxazole in AIDS patients. Lancet 1990;336:52.

351. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al.

HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;

358:568-79.

352. Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, et al. High

sensitivity of human leukocyte antigen-b*5701 as a marker for immunologi-

cally conﬁrmed abacavir hypersensitivity in white and black patients. Clin

Infect Dis 2008;46:1111-8.

353. White KD, Chung WH, Hung SI, Mallal S, Phillips EJ. Evolving models of the

immunopathogenesis of T cell-mediated drug allergy: the role of host, path-

ogens, and drug response. J Allergy Clin Immunol 2015;136:219-34.

354. Walensky RP, Goldberg JH, Daily JP. Anaphylaxis after rechallenge with

abacavir. AIDS 1999;13:999-1000.

355. Strazzula L, Pratt DS, Zardas J, Chung RT, Thiim M, Kroshinsky D. Wide-

spread morbilliform eruption associated with telaprevir: use of dermatologic

consultation to increase tolerability. JAMA Dermatol 2014;150:756-9.

356. Eyre ZW, Secrest AM, Woodcock JL. Photo-induced drug eruption in a patient

on combination simeprevir/sofosbuvir for hepatitis C. JAAD Case Rep 2016;2:

224-6.

357. Simpson CL, McCausland D, Chu EY. Photo-distributed lichenoid eruption

secondary to direct anti-viral therapy for hepatitis C. J Cutan Pathol 2015;42:

769-73.

358. Ebo DG, Bridts CH, De Clerck LS, Stevens WJ. Immediate allergy from

valacyclovir. Allergy 2008;63:941-2.

359. Lammintausta K, Makela L, Kalimo K. Rapid systemic valaciclovir reaction

subsequent to aciclovir contact allergy. Contact Dermatitis 2001;45:181.

360. Shah SA, Gulbis A, Wilhelm K. A case series using famciclovir in stem cell

transplant recipients with valacyclovir hypersensitivity reactions. J Oncol

Pharm Pract 2015;21:305-9.

361. Hirschfeld G, Weber L, Renkl A, Scharffetter-Kochanek K, Weiss JM.

Anaphylaxis after Oseltamivir (Tamiﬂu) therapy in a patient with sensitization to

star anise and celery-carrot-mugwort-spice syndrome. Allergy 2008;63:243-4.

362. DeSimone JA, Ojha A, Pathak R, Cohn J. Successful desensitization to

enfuvirtide after a hypersensitivity reaction in an HIV-1-infected man. Clin

Infect Dis 2004;39:e110-2.

363. Marcos Bravo MC, Ocampo Hermida A, Martinez Vilela J, Perez

Rodriguez MT, Gavilan Montenegro MJ, Arenas Villarroel LJ, et al. Hyper-

sensitivity reaction to darunavir and desensitization protocol. J Investig

Allergol Clin Immunol 2009;19:250-1.

364. Quiros-Roldan E, Tirelli V, Torti C, Sosta E, Tosoni C, Damiolini E, et al.

Successful long-course after failure of short-course desensitization in a patient

with severe hypersensitivity reaction to enfuvirtide. AIDS 2007;21:1388-9.

365. Toker O, Tal Y, Daher S, Shalit M. Ribavirin desensitization in chronic

hepatitis C. Isr Med Assoc J 2015;17:583-4.

366. Markman M, Kennedy A, Webster K, Elson P, Peterson G, Kulp B, et al.

Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol

1999;17:1141.

367. Polyzos A, Tsavaris N, Kosmas C, Arnaouti T, Kalahanis N, Tsigris C, et al.

Hypersensitivity reactions to carboplatin administration are common but not

always severe: a 10-year experience. Oncology 2001;61:129-33.

368. Hesterberg PE, Banerji A, Oren E, Penson RT, Krasner CN, Seiden MV, et al.

Risk strati ﬁ cation for desensitization of patients with carboplatin hypersensi-

tivity: clinical presentation and management. J Allergy Clin Immunol 2009;

123:1262-7.e1.

369. Patil

SU, Long AA, Ling M, Wilson MT, Hesterberg P, Wong JT, et al.

A protocol for risk stratiﬁcation of patients with carboplatin-induced hyper-

sensitivity reactions. J Allergy Clin Immunol 2012;129:443-7.

370. Lax T, Long A, Banerji A. Skin testing in the evaluation and management of

carboplatin-related hypersensitivity reactions. J Allergy Clin Immunol Pract

2015;3:856-62.

371. Caiado J, Castells M. Presentation and diagnosis of hypersensitivity to plat-

inum drugs. Curr Allergy Asthma Rep 2015;15:15.

372. Leguy-Seguin V, Jolimoy G, Coudert B, Pernot C, Dalac S, Vabres P, et al.

Diagnostic and predictive value of skin testing in platinum salt hypersensi-

tivity. J Allergy Clin Immunol 2007;1 19:726-30.

373. Pagani M, Bonadonna P, Senna GE, Antico A. Standardization of skin tests for

diagnosis and prevention of hypersensitivity reactions to oxaliplatin. Int Arch

Allergy Immunol 2008;145:54-7.

374. Wang AL, Patil SU, Long AA, Banerji A. Risk-stratiﬁcation protocol for

carboplatin and oxaliplatin hypersensitivity: repeat skin testing to identify drug

allergy. Ann Allergy Asthma Immunol 2015;115:422-8.

375. Tonini G, Santini D, Vincenzi B, Borzomati D, Dicuonzo G, La Cesa A, et al.

Oxaliplatin may induce cytokine-release syndrome in colorectal cancer pa-

tients. J Biol Regul Homeost Agents 2002;16:105-9.

376. Banerji A, Lax T, Guyer A, Hurwitz S, Camargo CA Jr, Long AA. Man-

agement of hypersensitivity reactions to carboplatin and paclitaxel in an

outpatient oncology infusion center: a 5-year review. J Allergy Clin Immunol

Pract 2014;2:428-33.

377. Picard M, Castells MC. Re-visiting hypersensitivity reactions to taxanes: a

comprehensive review. Clin Rev Allergy Immunol 2015;49:177-91.

378. Picard M, Pur L, Caiado J, Giavina-Bianchi P, Galvao VR, Berlin ST, et al.

Risk stratiﬁcation and skin testing to guide re-exposure in taxane-induced

hypersensitivity reactions. J Allergy Clin Immunol 2016;137:1154-64.e12.

379. Prieto García A, Pineda de la Losa F. Immunoglobulin E-mediated severe

anaphylaxis to paclitaxel. J Investig Allergol Clin Immunol 2010;20:170-1.

380. Alvarez-Cuesta E, Madrigal-Burgaleta R, Angel-Pereira D, Urena-Tavera A,

Zamora-Verduga M, Lopez-Gonzalez P, et al. Delving into cornerstones of

hypersensitivity to antineoplastic and biological agents: value of diagnostic

tools prior to desensitization. Allergy 2015;70:784-94.

381. Otani IM, Lax T, Long AA, Slawski BR, Camargo CA Jr, Banerji A. Utility of

risk stratiﬁcation for paclita xel hypersensitivity reactions. J Allergy Clin

Immunol Pract 2018;6:1266-1273.e2.

382. Pﬁzer Laboratories (Pty) Ltd. Methotrexate prescribing information. Available

from: http://labeling.pﬁzer.c om/ShowLabeling.aspx?id¼1093. Accessed July

28, 2020.

383. Alarcon GS, Kremer JM, Macaluso M, Weinblatt ME, Cannon GW,

Palmer WR, et al. Risk factors for methotrexate-induced lung injury in patients

with rheumatoid arthritis: a multicenter, case-control study. Methotrexate-Lung

Study Group. Ann Intern Med 1997;127:356-64.

384. Caldeira T, Costa V, Silva I, Oliva T, Norton L. Anaphylactoid reaction to

high-dose methotrexate and re-administration after a successful desensitization.

Pediatr Hematol Oncol 2008;25:131-4.

385. Pichler WJ. Drug Hypersensitivity. Bern, Switzerland: Karger AG; 2007.

386. Dilley MA, Lee JP, Broyles AD. Methotrexate hypersensitivity reactions in

pediatrics: evaluation and management. Pediatr Blood Cancer 2017;64.

387. Ruggiero A, Triarico S, Trombatore G, Battista A, Dell’acqua F, Rizzari C,

et al. Incidence, clinical features and management of hypersensitivity reactions

to chemotherapeutic drugs in children with cancer. Eur J Clin Pharmacol 2013;

69:1739-46.

388. Pugi A, Benemei S, Vietri M, Tondo A, Calvani AM, Mugelli A, et al.

Anaphylaxis during the ﬁrst course of high-dose methotrexate: a case report

and literature review. J Clin Pharm Ther 2012;37:245-8.

389. Davis KA, Williams P, Walker JC. Successful desensitization to high-dose

methotrexate after systemic anaphylaxis. Ann Allergy Asthma Immunol 2003;

90:87-9.

390. Lluch-Bernal M, Cuesta-Herranz J, De las Heras M, Figueredo E,

Umpierrez A, Fernandez M, et al. Anaphylactic reaction to methotrexate.

Allergy 1997;52:1150-1.

391. Vega A, Cabanas R, Contreras J, Lopez Cazana J, Lopez Serrano C, Pascual C,

et al. Anaphylaxis to met hotrexate: a possible IgE-mediated mechanism.

J Allergy Clin Immunol 1994;94:268-70.

392. Bouchireb

K, Dodille A, Ponvert C, Gouraud F, Dubrel M, Brugieres L.

Management and successful desensitization in methotrexate-induced anaphy-

laxis. Pediatr Blood Cancer 2009;52:295-7.

393. Oulego-Erroz I, Maneiro-Freire M, Bouzon-Alejandro M, Vazquez-

Donsion M, Couselo JM. Anaphylactoid reaction to high-dose methotrexate

and successful desensitization. Pediatr Blood Cancer 2010;55:557-9.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S105

394. Scott JR, Ward DA, Crews KR, Panett a JC, Navid F. Hypersensitivity reaction

to high-dose methotrexate and successful rechallenge in a pediatric patient with

osteosarcoma. Pediatr Blood Cancer 2014;61:373-5.

395. Clowse MB, McCune WJ. General toxicity of cyclophosphamide in rheumatic

diseases. UpToDate. 2020. Available from: https://www.uptodate.com/

contents/general-toxicity-of-cyclophosphamide-in-rheumatic-diseases. Accessed

July 28, 2020.

396. Lienesch DW, Mutasim DF, Singh RR. Neutrophilic eccrine hidradenitis

mimicking cutaneous vasculitis in a lupus patient: a complication of cyclo-

phosphamide. Lupus 2003;12:707-9.

397. Kovalyshyn I, Bijal AD, Lacouture ME, Brownell I. Cyclophosphamide-

associated acneiform drug eruption in a patient with multiple myeloma. J Am

Acad Dermatol 2011;65:657-9.

398. Visitsunthorn N, Utsawapreechawong W, Pacharn P, Jirapongsananuruk O,

Vichyanond P. Immediate type hypersensitivity to chemotherapeutic agents in

pediatric patients. Asian Paciﬁc J Allergy Immunol 2009;27:191-7.

399. Rosas-Vargas MA, Casas-Becerra B, Velazquez-Armenta Y, Sienra-Monge JJ,

Del Rio-Navarro BE. Cyclophosphamide hypersensitivity in a leukemic child.

Ther Drug Monit 2005;27:263-4.

400. Chanan-Khan A, Szebeni J, Savay S, Lieb es L, Raﬁque NM, Alving CR, et al.

Complement activation following ﬁrst exposure to pegylated liposomal

doxorubicin (Doxil ): possible role in hypersensitivity reactions. Ann Oncol

2003;14:1430-7.

401. Joly F, Ray-Coquard I, Fabbro M, Donoghoe M, Boman K, Sugimoto A, et al.

Decreased hypersensitivity reactions with carboplatin-pegylated liposomal doxo-

rubicin compared to carboplatin-paclitaxel combination: analysis from the GCIG

CALYPSO relapsing ovarian cancer trial. Gynecol Oncol 2011;122:226-32.

402. Farr KP, Safwat A. Palmar-plantar erythrodysesthesia associated with

chemotherapy and its treatment. Case Rep Oncol 2011;4:229-35.

403. Reyes-Habito CM, Roh EK. Cutaneous reactions to chemotherapeutic drugs

and targeted therapies for cancer, part I: conventional chemotherapeutic drugs.

J Am Acad Dermatol 2014;71:203.e1-2.

404. Balsari A, Lombardo N, Ghione M. Skin and perivascular toxicity induced

experimentally by doxorubicin. J Chemother 1989;1:324-9.

405. Lopes G, Vincek V, Raez LE. Pemetrexed-associated urticarial vasculitis.

Lung Cancer 2006;51:247-9.

406. Phillips J, Kujawa J, Davis-Lorton M, Hindenburg A. Successful desensiti-

zation in a patient with lenalidomide hypersensitivity. Am J Hematol 2007;82:

1030.

407. Hall VC, El-Azhary RA, Bouwhuis S, Rajkumar SV. Dermatologic side effects

of thalidomide in patients with multiple myeloma. J Am Acad Dermatol 2003;

48:548-52.

408. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering

thalidomide: a review of its mechanism of action, side effects, and potential

uses. J Am Acad Dermatol 1996;35:969-79.

409. Celgene Corporation. THALOMID REMSÒ. 2017. Available from: https://

www.thalomidrems.com/. Accessed July 28, 2020.

410. Barley K, He W, Agarwal S, Jagannath S, Chari A. Outcomes and manage-

ment of lenalidomide-associated rash in patients with multiple myeloma. Leuk

Lymphoma 2016;57:2510-5.

411. Rajkumar SV, Gertz MA, Witzig TE. Life-threatening toxic epidermal nec-

rolysis with thalidomide therapy for myeloma. N Engl J Med 2000;343:972-3.

412. Nucera E, Schiavino D, Hohaus S, Leone G, Buonomo A, Lombardo C, et al.

Desensitization to thalidomide in a patient with multiple myeloma. Clin

Lymphoma Myeloma 2008;8:176-8.

413. Marks JG Jr, Belsito DV, DeLeo VA, Fowler JF Jr, Fransway AF, Maibach HI,

et al. North American Contact Dermatitis Group patch-test results, 1996-1998.

Arch Dermatol 2000;136:272-3.

414. Bhullar KS, Lagaron NO, McGowan EM, Parmar I, Jha A, Hubbard BP, et al.

Kinase-targeted cancer therapies: progress, challenges and future directions.

Mol Cancer 2018;17:48.

415. Widmer N, Bardin C, Chatelut E, Paci A, Beijnen J, Leveque D, et al. Review

of therapeutic drug monitoring of anticancer drugs, part two–targeted thera-

pies. Eur J Cancer 2014;50:2020-36.

416. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor

receptor inhibitors. Target Oncol 2009;4:107-9.

417. Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S. Relationship between

skin rash and outcome in non-small-cell lung cancer patients treated with anti-

EGFR tyrosine kinase inhibitors: a literature-b ased meta-analysis of 24 trials.

Lung Cancer 2012;78:8-15.

418. Elting LS, Chang YC, Parelkar P, Boers-Doets CB, Michelet M, Hita G, et al. Risk

of oral and gastrointestinal mucosal injury among patients receiving selected tar-

geted agents: a meta-analysis. Support Care Cancer 2013;21:3243-54.

419. Liu S, Kurzrock R. Understanding toxicities of targeted agents: implications

for anti-tumor activity and management. Semin Oncol 2015;42:863-75.

420. Sugiyama

E, Umemura S, Nomura S, Kirita K, Matsumoto S, Yoh K, et al.

Impact of single nucleotide polymorphisms on severe hepatotoxicity induced

by EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer

harboring EGFR mutations. Lung Cancer 2015;90:307-13.

421. Nelson RP Jr, Cornetta K, Ward KE, Ramanuja S, Fausel C, Cripe LD.

Desensitization to imatinib in patients with leukemia. Ann Allergy Asthma

Immunol 2006;97:216-22.

422. Paolo CD. Cutaneous adverse reactions to imatinib: a case report of a suc-

cessful slow protocol for induction of drug tolerance. J Allergy Ther 2015;6:

1000203.

423. Sanchez-Lopez J, Vinolas N, Munoz-Cano R, Pascal M, Reguart N, Bartra J,

et al. Successfu l oral desensitization in a patient with hypersensitivity reaction

to crizotinib. J Investig Allergol Clin Immunol 2015;25:307-8.

424. Awad MM, Lax TP, Slawski BR, Shaw AT. Successful desensitization of two

patients with ALK-positive lung cancer and hypersensitivity to crizotinib.

J Thorac Oncol 2014;9:1726-8.

425. Bauer C, Przybilla B, Rueff F. Severe cutaneous reaction to sorafenib: in-

duction of tolerance. Acta Derm Venereol 2008;88:627-8.

426. Linauskiene K, Malinauskiene L, Vitkauskaite E, Chomiciene A, Blaziene A.

Severe adverse skin reaction and desensitization to sorafenib. Ann Allergy

Asthma Immunol 2016;117:209-10.

427. Bar-Sela G, Kedem E, Hadad S, Pollack S, Haim N, Atrash F, et al. Successful

desensitization protocol for hypersensitivity reaction caused by sunitinib in a

patient with a gastrointestinal stromal tumor. Jpn J Clin Oncol 2010;40:163-5.

428. Shirasawa M, Kubotaa M, Harada S, Niwa H, Kusuhara S, Kasajima M, et al.

Successful oral desensitization against skin rash induced by alectinib in a

patient with anaplastic lymphoma kinase-positive lung adenocarcinoma: a case

report. Lung Cancer 2016;99:66-8.

429. Brown BA, Torabi M. Incidence of infusion-associated reactions with ritux-

imab for treating multiple sclerosis: a retrospective analysis of patients treated

at a US centre. Drug Saf 2011;34:117-23.

430. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell

depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J

Med 2008;358:676-88.

431. Hawker K, O’Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, et al.

Rituximab in patients with primary progressive multiple sclerosis: results of a

randomized double-blind placebo-controlled multicenter trial. Ann Neurol

2009;66:460-71.

432. McLaughlin P, Hagemeister FB, Grillo-Lopez AJ. Rituximab in indolent

lymphoma: the single-agent pivotal trial. Semin Oncol 1999;26:79-87.

433. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC,

et al. Efﬁcacy and safety of rituximab in moderately-to-severely active sys-

temic lupus erythematosus: the randomized, double-blind, phase II/III systemic

lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:

222-33.

434. RituxanÒ. In: Schwab M, editor. Encyclopedi a of Cancer. Heidelberg, Ger-

many: Springer-Verlag; 2017.

435. Brennan PJ, Rodriguez Bouza T, Hsu FI, Sloane DE, Castells MC. Hyper-

sensitivity reactions to mAbs: 105 desensitizations in 23 patients, from eval-

uation to treatment. J Allergy Clin Immunol 2009;124:1259-66.

436. Vultaggio A, Matucci A, Nencini F, Pratesi S, Petroni G, Cammelli D, et al.

Drug-speciﬁc Th2 cells and IgE antibodies in a patient with anaphylaxis to

rituximab. Int Arch Allergy Immunol 2012;159:321-6.

437. Piva E, Chieco-Bianchi F, Krajcar V, Aversa S, Plebani M. Adverse reactions

in patients with B-cell lymphomas during combined treatment with rituximab:

in vitro evaluation of rituximab hypersensitivity by basophil activation test.

Am J Hematol 2012;87:E130-1.

438. Levin AS, Otani IM, Lax T, Hochberg E, Banerji A. Reactions to rituximab in

an outpatient infusion center: a 5-year review. J Allergy Clin Immunol Pract

2017;5:107-113.e1.

439. Hong DI, Bankova L, Cahill KN, Kyin T, Castells MC. Allergy to monoclonal

antibodies: cutting-edge desensitization methods for cutting-edge therapies.

Expert Rev Clin Immunol 2012;8:43-52.

440. Hong DI, Dioun AF. Indications, protocols, and outcomes of drug de-

sensitizations for chemotherapy and monoclonal antibodies in adults and

children. J Allergy Clin Immunol Pract 2014;2:13-9.

441. Lebel E, Ben-Yehuda D, Bohbot E, Dranitzki Z, Shalit M, Tal Y. Hypersen-

sitivity reactions to rituximab: 53 successful desensitizations in 7 patients with

severe, near-fatal reactions. J Allergy Clin Immunol Pract 2016;4:1000-2.

442. Wong JT, Long A. Rituximab hypersensitivi ty: evaluation, desensitization, and

potential mechanisms. J Allergy Clin Immunol Pract 2017;5:1564-71.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S106 BROYLES ET AL

443. Caimmi SM, Caimmi D, Riscassi S, Marseglia GL. A new pediatric protocol

for rapid desensitization to monoclonal antibodies. Int Arch Allergy Immunol

2014;165:214-8.

444. Dilley MA, Lee JP, Platt CD, Broyles AD. Rituximab desensitization in pe-

diatric patients: results of a case series. Pediatr Allergy Immunol Pulmonol

2016;29:91-4.

445. Matucci A, Pratesi S, Petroni G, Nencini F, Virgili G, Milla M, et al. Aller-

gological in vitro and in vivo evaluation of patients with hypersensitivity re-

actions to in ﬂ iximab. Clin Exp Allergy 2013;43:659-64.

446. O’Neil BH, Allen R, S pigel DR, Stinchcombe TE, Moore DT, Berlin JD,

et al. High incidence of ce tuximab-relate d infusion reactions in Tennes see

and North Carolina and the association with atopic history. J Clin Oncol

2007;25:3644-8.

447. Arnold DF, Misbah SA. Cetuximab-induced anaphylaxis and IgE speciﬁc for

galactose-alpha-1,3-galactose. N Engl J Med 2008;358:2735, author reply

2735-6.

448. Slavin R. Faculty of 1000 Evaluation for the Relevance of Tick Bites to the

Production of IgE Antibodies to the Mammalian Oligosaccharide Galactose-

alpha-1,3-galactose. London, UK: Faculty of 1000, Ltd; 2011.

449. Sicherer S, Wang J. Faculty of 1000 evaluation for delayed anaphylaxis,

angioedema, or articaria after c onsumption o f red meat in patien ts with

IgE antibodies speciﬁc for galactose-alpha-1,3-galactose. London, UK:

Faculty of 1000, Ltd; 2009.

450. Jacquenet S, Moneret-Vautrin DA, Bihain BE. Mammalian meat-induced

anaphylaxis: clinical relevance of anti-galactose-alpha-1,3-galactose IgE

conﬁrmed by means of skin tests to cetuximab. J Allergy Clin Immunol 2009;

124:603-5.

451. Jerath MR, Kwan M, Kannarkat M, Mirakhur B, Carey L, Valgus J, et al.

A desensitization protocol for the mAb cetuximab. J Allergy Clin Immunol

2009;123:260-2.

452. Gernez Y, Freeman AF, Ho lland SM, Garabedian E, Patel NC, Puck JM, et al.

Autosomal dominant hyper-IgE syndrome in the USIDNET Registry. J Allergy

Clin Immunol Pract 2018;6:996-1001.

453. Modena BD, White AA. Can diet modiﬁcation be an effective treatment in

aspirin-exacerbated respiratory disease? J Allergy Clin Immunol Pract 2018;6:

832-3.

454. Gergen PJ. Rethinking access to care. J Allergy Clin Immunol Pract 2018;6:

853-4.

455. Rejnö G, Lundholm C, Larsson K, Larsson H, Lichtenstein P,

D’Onofrio BM, e t al. Adverse pregnancy outcomes in asthmatic women: a

population-based family design study. J Allergy Clin Immunol Pract 2018;6:

916-922.e6.

456. Zeiger RS, Tran TN, Butler RK, Schatz M, Li Q, Khatry DB, et al. Rela-

tionship of blood eosinophil count to exacerbations in chronic obstructive

pulmonary disease. J Allergy Clin Immunol Pract 2018;6:944-954.e5.

457. Choquette D, Faraawi R, Chow A, Rodrigues J, Bensen WJ, Nantel F. Inci-

dence and management of infusion reactions to inﬂiximab in a prospective

real-world community registry. J Rheumatol 2015;42:1105-11.

458. Ducharme J, Pelletier C, Zacharias R. The safety of inﬂiximab infusions in the

community setting. Can J Gastroenterol 2010;24:307-11.

459. Mourad AA, Boktor MN, Yilmaz-Demirdag Y, Bahna SL. Adverse reactions

to inﬂiximab and the outcome of desensitization. Ann Allergy Asthma

Immunol 2015;115:143-6.

460. Feuerstein JD, Cheifetz AS. Miscellaneous adverse events with biologic agents

(excludes infection and malignancy). Gastroenterol Clin North Am 2014;43:

543-63.

461. Zeltser R, Valle L, Tanck C, Holyst MM, Ritchlin C, Gaspari AA. Clinical,

histological, and immunophenotypic characteristics of injection site reactions

associated with etanercept: a recombinant tumor necrosis factor alpha receptor:

Fc fusion protein. Arch Dermatol 2001;137:893-9.

462. Bavbek S, Ataman S, Akinci A, Castells M. Rapid subcutaneous desensiti-

zation for the management of local and systemic hypersensitivity reactions to

etanercept and adalimumab in 12 patients. J Allergy Clin Immunol Pract 2015;

3:629-32.

463. Gamarra RM, McGraw SD, Drelichman VS, Maas LC. Serum sickness-like

reactions in patients receiving intravenous inﬂiximab. J Emerg Med 2006;30:

41-4.

464. Cleynen I, Van Moerkercke W, Billiet T, Vandecandelaere P, Vande

Casteele N, Breynaert C, et al. Characteristics of skin lesions associated with

anti-tumor necrosis factor therapy in patients with inﬂammatory

bowel disease:

a cohort study. Ann Intern Med 2016;164:10-22.

465. Bulur I, Keseroglu HO, Saracoglu ZN, Gonul M. Symmetrical drug-related

intertriginous and ﬂexural exanthema (Baboon syndrome) associated with

inﬂiximab. J Dermatol Case Rep 2015;9:12-4.

466. Mounach A, Rezqi A, Nouijai A, Ghozlani I, Achemlal L, Maghraoui AE,

et al. Stevens-Johnson syndrome complicating adalimumab therapy in rheu-

matoid arthritis disease. Rheumatol Int 2013;33:1351-3.

467. Ramos-Casals M, Brito-Zeron P, Munoz S, Soria N, Galiana D, Bertolaccini L,

et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233

cases. Medicine (Baltimore) 2007;86:242-51.

468. Vergara G, Silvestre JF, Betlloch I, Vela P, Albares MP, Pascual JC. Cuta-

neous drug eruption to inﬂiximab: report of 4 cases with an interface dermatitis

pattern. Arch Dermatol 2002;138:1258-9.

469. Freling E, Peyrin-Biroulet L, Poreaux C, Morali A, Waton J, Schmutz JL, et al.

IgE antibodies and skin tests in immediate hypersensitivity reactions to

inﬂiximab in inﬂammatory bowel disease: impact on inﬂiximab retreatment.

Eur J Gastroenterol Hepatol 2015;27:1200-8.

470. Sloane D, Govindarajulu U, Harrow-Mortelliti J, Barry W, Hsu FI, Hong D,

et al. Safety, costs, and efﬁcacy of rapid drug desensitizations to chemotherapy

and monoclonal antibodies. J Allergy Clin Immunol Pract 2016;4:497-504.

471. Vultaggio A, Matucci A, Nencini F, Pratesi S, Parronchi P, Rossi O, et al.

Anti-inﬂiximab IgE and non-IgE antibodies and induction of infusion-related

severe anaphylactic reactions. Allergy 2010;65:657-61.

472. Maneiro JR, Salgado E, Gomez-Reino JJ. Immunogenicity of monoclonal

antibodies again st tumor necrosis factor used in chronic immune-mediated

Inﬂammatory conditions: systematic review and meta-analysis. JAMA Intern

Med 2013;173:1416-28.

473. O’Meara S, Nanda KS, Moss AC. Antibodies to inﬂiximab and risk of infusion

reactions in patients with inﬂammatory bowel disease: a systematic review and

meta-analysis. Inﬂamm Bowel Dis 2014;20:1-6.

474. Isabwe GAC, Garcia Neuer M, de Las Vecillas Sanchez L, Lynch DM,

Marquis K, Castells M. Hypersensitivity reactions to therapeutic monoclonal

antibodies: phenotypes and endotypes. J Allergy Clin Immuno l 2018;142:

159-170.e2.

475. Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, et al. The

incidence and management of infusion reactions to inﬂiximab: a large center

experience. Am J Gastroenterol 2003;98:1315-24.

476. Picard M, Galvao VR. Current knowledge and management of hypersensitivity

reactions to monoclonal antibodies. J Allergy Clin Immunol Pract 2017;5:

600-9.

477. Ben-Horin S, Yavzori M, Katz L, Kopylov U, Picard O, Fudim E, et al. The

immunogenic part of inﬂiximab is the F(ab’)2, but measuring antibodies to the

intact inﬂiximab molecule is more clinically useful. Gut 2011;60:41-8.

478. Steenholdt C, Svenson M, Bendtzen K, Thomsen OO, Brynskov J,

Ainsworth MA. Acute and delayed hypersensitivity reactions to inﬂ iximab and

adalimumab in a patient with Crohn’s disease. J Crohns Colitis 2012;6:108-11.

479. Miheller P, Muzes G, Lakatos G, Mihaly E, Tulassay Z. Repeated in ﬂ iximab

therapy after serum sickness-like reaction in Crohn’s

disease. J Emerg Med

2007;32:209-10, author reply 210.

480. Kattan M, Bacharier LB, O’Connor GT, Cohen R, Sorkness RL, Morgan W,

et al. Spirometry and impulse oscillometry in preschool children: acceptability

and relationship to maternal smoking in pregnancy. J Allergy Clin Immunol

Pract 2018;6:1596-1603.e6.

481. Korycka-Wolowiec A, Wolowiec D, Robak T. Ofatumumab for treating

chronic lymphocytic leukemia: a safety proﬁle. Expert Opin Drug Saf 2015;14:

1945-59.

482. Skirvin JA, Kowalczyk R. Obinutuzumab (GazyvaÒ). Oncology Times 2017;

39:21.

483. Dunlop JH, Keet CA, Mudd K, Wood RA. Long-term follow-up after baked

milk introduction. J Allergy Clin Immunol Pract 2018;6:1699-704.

484. Taylor PC, Quattrocchi E, Mallett S, Kurrasch R, Pete rsen J, Chang DJ.

Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-

naive, rheumatoid arthritis patients with an inadequate response to metho-

trexate: a randomised, double-blind, placebo-controlled clinical trial. Ann

Rheum Dis 2011;70:2119-25.

485. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al.

Obinutuzumab plus chlorambucil in patients with CLL and coexisting condi-

tions. N Engl J Med 2014;370:1101-10.

486. Morgan BW, Siddharthan T, Grigsby MR, Pollard SL, Kalyesubula R,

Wise RA, et al. Asthma and allergic disorders in Uganda: a population-based

study across urban and rural settings. J Allergy Clin Immunol Pract 2018;6:

1580-7.e2.

487. Arora A, Bhatt VR, Liewer S, Armitage JO, Bociek RG. Brentuximab vedotin

desensitization in a patient with refractory Hodgkin’s lymphoma. Eur J Hae-

matol 2015;95:361-4.

488. DeVita MD, Evens AM, Rosen ST, Greenberger PA, Petrich AM. Multiple

successful desensitizations to brentuximab vedotin: a case report and literature

review. J Natl Compr Canc Netw 2014;12:465-71.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S107

489. O’Connell AE, Lee JP, Yee C, Kesselheim J, Dioun A. Successful desensiti-

zation to brentuximab vedotin after anaphylaxis. Clin Lymphoma Myeloma

Leuk 2014;14:e73-5.

490. NICE rules that PCTs must make Herceptin available. Nurse Prescribing 2006;

4:310-1.

491. Cook-Bruns N. Retrospective analysis of the safety of Herceptin immuno-

therapy in metastatic breast cancer. Oncology 2001;61:58-66.

492. Thompson LM, Eckmann K, Boster BL, Hess KR, Michaud LB, Esteva FJ,

et al. Incidence, risk factors, and management of infusion-related reactions in

breast cancer patients receiving trastuzumab. Oncologist 2014;19:228-34.

493. Sheu J, Hawryluk EB, Litsas G, Thakuria M, LeBoeuf NR. Papulopustular

acneiform eruptions resulting from trastuzumab, a HER2 inhibitor. Clin Breast

Cancer 2015;15:e77-e81.

494. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus

trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;

366:109-19.

495. Product update: Perjeta extended indication in breast cancer. The Pharma-

ceutical Journal. August 21, 2015. Available from: https://www.

pharmaceutical-journal.com/news-and-analysis/notice-board/perjeta-extended-

indication-in-breast-cancer/20069160 .article. Accessed July 30, 2020.

496. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al.

Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast

cancer. N Engl J Med 2015;372:724-34.

497. Gonzalez-de-Olano D, Morgado JM, Juarez-Guerrero R, Sanchez-Munoz L,

Letellez-Fernandez J, Malon-Gimenez D, et al. Positive basophil activation test

following anaphylaxis to pertuzumab and successful treatment with rapid

desensitization. J Allergy Clin Immunol Pract 2016;4:338-40.

498. Wang J-Y, Yao T-C, Tsai Y-T, Wu AC, Tsai H-J. Increased dose and duration

of statin use is associated with decreased asthma-related emergency department

visits and hospitalizations. J Allergy Clin Immunol Pract 2018;6:1588-15895.

e1.

499. Song X, Long SR, Barber B, Kassed CA, Healey M, Jones C, et al. Systematic

review on infusion reactions associated with chemotherapies and

monoclonal antibodies for metastatic colorectal cancer. Curr Clin Pharmacol

2012;7:56-65.

500. Reidy DL, Chung KY, Timoney JP, Park VJ, Hollywood E, Sklarin NT, et al.

Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol

2007;25:2691-5.

501. Sun A, Alshuaibi W, Petroni D, Skoda-Smith S, Goldberg MJ, Hale S. Im-

mune modulation in a patient with Morquio syndrome treated with enzyme

replacement therapy. J Allergy Clin Immunol Pract 2018;6:1749-51.

502. Justet A, Neukirch C, Poubeau P, Arrault X, Borie R, Dombret MC, et al.

Successful rapid tocilizumab desensitization in a patient with Still disease.

J Allergy Clin Immunol Pract 2014;2:631-2.

503. Rocchi V, Puxeddu I, Cataldo G, Del Corso I, Tavoni A, Bazzichi L, et al.

Hypersensitivity reactions to tocilizumab: role of skin tests in diagnosis.

Rheumatology (Oxford) 2014;53:1527-9.

504. Ben-Yakov G, Kapuria D, Marko J, Cho MH, Pittaluga S, Kleiner DE, et al.

Liver disturbances in activated phosphoinositide 3-kinase

syndrome. J Al-

lergy Clin Immunol Pract 2018;6:1763-5.

505. Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV.

American Academy of Allergy, Asthma & Immunology/American College of

Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-

associated anaphylaxis. J Allergy Clin Immunol 2007;120:1373-7.

506. Lieberman PL, Umetsu DT, Ca rrigan GJ, Rahmaoui A. Anaphylactic reactions

associated with omalizumab administration: analysis of a case-control study.

J Allergy Clin Immunol 2016;138:913-915.e2.

507. Limb SL, Starke PR, Lee CE, Chowdhury BA. Delayed onset and protracted

progression of anaphylaxis after omalizumab administration in patients with

asthma. J Allergy Clin Immunol 2007;120:1378-81.

508. Lieberman P, Rahmaoui A, Wong DA. The safety and interpretability of skin

tests with omalizumab. Ann Allergy Asthma Immunol 2010;105:493-5.

509. Cox L, Lieberman P, Wallace D, Simons FE, Finegold I, Platts-Mills T, et al.

American Academy of Allergy, Asthma & Immunology/American College of

Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint

Task Force follow-up report. J Allergy Clin Immunol 2011;128:210-2.

510. Price KS, Hamilton RG. Anaphylactoid reactions in two patients after omali-

zumab administration after successful long-term therapy. Allergy Asthma Proc

2007;28:313-9.

511. Owens G, Petrov A. Successful desensitization of three patients with hyper-

sensitivity reactions to omalizumab. Curr Drug Saf 2011;6:339-42.

512. Fineberg SE, Huang J, Brunelle R, Gulliya KS, Anderson JH Jr. Effect of long-

term exposure to insulin lispro on the induction of antibody response in pa-

tients with type 1 or type 2 diabetes. Diabetes Care 2003;26:89-96.

513. Blanco C, Castillo R, Quiralte J, Delgado J, Garcia I, de Pablos P, et al.

Anaphylaxis to subcutaneous neutral protamine Hagedorn insulin with

simultaneous sensitization to protamine and insulin. Allergy 1996;51:421-4.

514. Fernandez L, Duque S, Montalban C, Bartolome B. Allergy to human insulin.

Allergy 2003;58:1317.

515. Perez E, Gonzalez R, Martinez J, Iglesias J, Matheu V. Detemir insulin-

induced anaphylaxis. Ann Allergy Asthma Immunol 2009;102:174-5.

516. Silva ME, Mendes MJ, Ursich MJ, Rocha DM, Brito AH, Fukui RT, et al.

Human insulin allergy—immediate and late type III reactions in a long-

standing IDDM patient. Diabetes Res Clin Pract 1997;36:67-70.

517. Blumer IR. Severe injection site reaction to insulin detemir. Diabetes Care

2006;29:946.

518. Mandrup-Poulsen T, Molvig J, Pildal J, Rasmussen AA, Andersen L,

Skov BG, et al. Leukocytoclastic vasculi tis induced by subcutaneous injection

of human insulin in a patient with type 1 diabetes and essential thrombocy-

temia. Diabetes Care 2002;25:242-3.

519. Kim D, Baraniuk J. Delayed-type hypersensitivity reaction to the meta-cresol

component of insulin. Ann Allergy Asthma Immunol 2007;99:194-5.

520. Kollner A, Senff H, Engelmann L, Kalveram KJ, Velcovsky HG, Haneke E.

Delayed hypersensitivity to protamine and immediate hypersensitivity to in-

sulin [in German]. Deutsch Med Wochenschr 1991;116:1234-8.

521. Berson SA, Yalow RS, Bauman A, Rothschild MA, Newerly K. Insulin-I131

metabolism in hum an subjects: demonstration of insulin binding globulin in

the circulation of insulin treated subjects. J Clin Invest 1956;35:170-90.

522. Bodtger U, Wittrup M. A rational clinical approach to suspected insulin al-

lergy: status after ﬁve years and 22 cases. Diabetic Med 2005;22:102-6.

523. Clerx V, Van Den Keybus C, Kochuyt A, Goossens A. Drug intolerance re-

action to insulin therapy caused by metacresol. Contact Dermatitis 2003;48:

162-3.

524. Dykewicz MS, Kim HW, Orfan N, Yoo TJ, Lieberman P. Immunologic

analysis of anaphylaxis to protamine component in neutral protamine Hage-

dorn human insulin. J Allergy Clin Immunol 1994;93:117-25.

525. Feinglos MN, Jegasothy BV. “Insulin” allergy due to zinc. Lancet 1979;1:

122-4.

526. Stewart WJ, McSweeney SM, Kellett MA, Faxon DP, Ryan TJ. Increased risk

of severe protamine reactions in NPH insulin-dependent diabetics undergoing

cardiac catheterization. Circulation 1984;70:788-92.

527. Chen YM, Huang H. Allergy to soft cannula of insulin pump in diabetic pa-

tient. Pakistan J Med Sci 2017;33:245-7.

528. Roest MA, Shaw S, Orton DI. Insulin-injection-site reactions associated with

type I latex allergy. N Engl J Med 2003;348:265-6.

529. Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL,

Krasner AS. Immunological responses to exogenous insulin. Endocrine Rev

2007;28:625-52.

530. Horrow JC, Pharo GH, Levit LS, Freeland C. Neither skin tests nor serum

enzyme-linked immunosorbent assay tests provide speciﬁcity for protamine

allergy. Anesth Analg 1996;82:386-9.

531. Weiss ME, Nyhan D, Peng ZK, Horrow JC, Lowenstein E, Hirshman C, et al.

Associatio

n of protamine IgE and IgG antibodies with life-threatening re-

actions to intravenous protamine. N Engl J Med 1989;320:886-92.

532. Lee AY, Chey WY, Choi J, Jeon JS. Insulin-induced drug eruptions and

reliability of skin tests. Acta Derm Venereol 2002;82:114-7.

533. Kawanami D, Ito T, Watanabe Y, Kinoshita J, Sakamoto M, Isaka T, et al.

Successful control of a case of severe insulin allergy with liraglutide.

J Diabetes Investig 2013;4:94-6.

534. Castera V, Dutour-Meyer A, Koeppel M, Petitjean C, Darmon P. Systemic

allergy to human insulin and its rapid and long acting analogs: successful

treatment by continuous subcutaneous insulin lispro infusion. Diabetes Metab

2005;31:391-400.

535. Eapen SS, Connor EL, Gern JE. Insulin desensitization with insulin lispro and

an insulin pump in a 5-year-old child. Ann Allergy Asthma Immunol 2000;85:

395-7.

536. Matheu V, Perez E, Hernandez M, Diaz E, Darias R, Gonzalez A, et al. Insulin

allergy and resistance successfully treated by desensitisation with Aspart in-

sulin. Clin Mol Allergy CMA 2005;3:16.

537. Wheeler BJ, Taylor BJ. Successful management of allergy to the insulin

excipient metacresol in a child with type 1 diabetes: a case report. J Med Case

Rep 2012;6:263.

538. Yong PF, Malik R, Arif S, Peakman M, Amiel S, Ibrahim MA, et al. Ritux-

imab and omalizumab in severe, refractory insulin allergy. N Engl J Med 2009;

360:1045-7.

539. Murray BR, Jewell JR, Jackson KJ, Agboola O, Alexander BR, Sharma P.

Type III hypersensitivity reaction to subcutaneous insulin preparations in a

type 1 diabetic. J Gen Intern Med 2017;32:841-5.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S108 BROYLES ET AL

540. Bayraktar F, Akinci B, Demirkan F, Yener S, Yesil S, Kirmaz C, et al. Serum

sickness-like reactions associated with type III insulin allergy responding to

plasmapheresis. Diabetic Med 2009;26:659-60.

541. Buchheit KM, Bernstein JA. Progestogen hypersensitivity: heterogeneous

manifestations with a common trigger. J Allergy Clin Immunol Pract 2017;5:

566-74.

542. Foer D, Buchheit KM, Gargiulo AR, Lynch DM, Castells M, Wickner PG.

Progestogen hypersensitivity in 24 cases: diagnosis, management, and pro-

posed renaming and classiﬁcation. J Allergy Clin Immunol Pract 2016;4:

723-9.

543. Prieto-Garcia A, Sloane DE, Gargiulo AR, Feldweg AM, Castells M. Auto-

immune progesterone dermatitis: clinical presentation and management with

progesterone desensitization for successful in vitro fertilization. Fertil Steril

2011;95:1121.e9-e13.

544. Cocuroccia B, Gisondi P, Gubinelli E, Girolomoni G. Autoimmune proges-

terone dermatitis. Gynecol Endocrinol 2006;22:54-6.

545. Asai J, Katoh N, Nakano M, Wada M, Kishimoto S. Case of autoimmune

progesterone dermatitis presenting as ﬁxed drug eruption. J Dermatol 2009;36:

643-5.

546. Bernstein IL, Bernstein DI, Lummus ZL, Bernstein JA. A case of progester-

one-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune

dermatitis. J Womens Health (Larchmt) 2011;20:643-8.

547. Wintzen M, Goor-van Egmond MB, Noz KC. Autoimmune progesterone

dermatitis presenting with purpura and petechiae. Clin Exp Dermatol 2004;29:

316.

548. Snyder JL, Krishnaswamy G. Autoimmune progesterone dermatitis and its

manifestation as anaphylaxis: a case report and literature review. Ann Allergy

Asthma Immunol 2003;90:469-77.

549. Li RC, Buchheit KM, Bernstein JA. Progestogen hypersensitivity. Curr Al-

lergy Asthma Rep 2018;18:1.

550. Baptist AP, Baldwin JL. Autoimmune progesterone dermatitis in a patient with

endometriosis: case report and review of the literature. Clin Mol Allergy CMA

2004;2:10.

551. Hefﬂer E, Fichera S, Nicolosi G, Crimi N. Anaphylaxis due to progesterone

hypersensitivity successfully treated with omalizumab. J Allergy Clin Immunol

Pract 2017;5:852-4.

552. Shahar E, Bergman R, Pollack S. Autoimmune progesterone dermatitis:

effective prophylactic treatment with danazol. Int J Dermatol 1997;36:708-11.

553. Wojnarowska F, Greaves MW, Peachey RD, Drury PL, Besser GM. Proges-

terone-induced erythema multiforme. J R Soc Med 1985;78:407-8.

554. Medeiros S, Rodrigues-Alves R, Costa M, Afonso A, Rodrigues A, Cardoso J.

Autoimmune progesterone dermatitis: treatment with oophorectomy. Clin Exp

Dermatol 2010;35:e12-e13.

555. Johnson KP. Glat iramer acetate for treatment of relapsing-remitting multiple

sclerosis. Expert Rev Neurother 2012;12:371-84.

556. Ziemssen T, Neuhaus O, Hohlfeld R. Risk-beneﬁt assessment of glatiramer

acetate in multiple sclerosis. Drug Saf 2001;24:979-90.

557. Bosca I, Bosca M, Belenguer A, Evole M, Hernandez M, Casanova B, et al.

Necrotising cutaneous lesions as a side effect of glatiramer acetate. J Neurol

2006;253:1370-1.

558. Cicek D, Kandi B, Oguz S, Cobanoglu B, Bulut S, Saral Y. An urticarial

vasculitis case induced by glatiramer acetate. J Dermatolog Treat 2008;19:

305-7.

559. Feldmann R, Schierl M, Rauschka H, Sator PG, Breier F, Steiner A. Necro-

tizing skin lesions with involvement of muscle tissue after subcutaneous in-

jection of glatiramer acetate. Eur J Dermatol 2009;19:385.

560. Harde V, Schwarz T. Embolia cutis medicamentosa following subcutaneous

injection of glatiramer acetate. J Dtsch Dermatol Ges 2007;5:1122-3.

561. Kluger N, Thouvenot E, Camu W, Guillot B. Cutaneous adverse events related

to glatiramer acetate injection (copolymer-1, Copaxone). J Eur Acad Dermatol

Venereol 2009;23:1332-3.

562. Koller S, Kranke B. Nicolau syndrome following subcutaneous glatiramer-

acetate injection. J Am Acad Dermatol 2011;64:e16-7.

563. Thouvenot E, Hillaire-Buys D, Bos-Thompson MA, Rigau V, Durand L,

Guillot B, et al. Erythema nodosum and glatiramer acetate treatment in re-

lapsing-remitting multiple sclerosis. Mult Scler 2007;13:941-4.

564. Baumgartner A, Stich O, Rauer S. Anaphylactic reaction after injection of

glatiramer acetate (Copaxone(R)) in patients with relapsing-remitting multiple

sclerosis. Eur Neurol 2011;66:368-70.

565. Mayorga C, Blazquez AB, Dona I, Gomez F, Chaves P, Sanchez-

Quintero MJ, et al. Immunological mechanisms underlying delayed-type

hypersensitivity reactions to glatiramer acetate. Ann Allergy Asthma

Immunol 2012;109:47-51.

566. Rauschka H, Farina C, Sator P, Gudek S, Breier F, Schmidbauer M. Severe

anaphylactic reaction to glatiramer acetate with speciﬁc IgE. Neurology 2005;

64:1481-2.

567. Soriano Gomis V, Perez Sempere A, Gonzalez Delgado P, Sempere JM,

Niveiro

Hernandez E, Marco FM. Glatiramer acetate anaphylaxis: detection of

antibodies and basophil activation test. J Investig Allergol Clin Immunol 2012;

22:65-6.

568. Crestani E, Lee J, Gorman M, Castells M, Dioun Broyles AF. IgE-mediated

hypersensitivity reaction and desensitization to glatiramer acetate in a pediatric

patient. Pediatr Allergy Immunol 2014;25:821-3.

569. Sanchez-Lopez J. Allergy workup in immediate-type local reactions to gla-

tiramer acetate. J Investig Allergol Clin Immunol 2010;20:521-3.

570. Syrigou E, Psarros P, Grapsa D, Syrigos K. Successful rapid desensitization to

glatiramer acetate in a patient with multiple sclerosis. J Investig Allergol Clin

Immunol 2015;25:214-5.

571. Bains SN, Hsieh FH, Rensel MR, Radojicic C, Katz HT, Inamdar SR, et al.

Glatiramer acetate: successful desensitization for treatment of multiple scle-

rosis. Ann Allergy Asthma Immunol 2010;104:321-5.

572. Sheth SS, Posner MA. Modiﬁ ed protocol for desensitization to glatiramer

acetate. Ann Allergy Asthma Immunol 2010;105:190.

573. Genezyme Corporation. Guideline to re-challenge administration of Cerezyme

(imiglucerase for injection). Cerezyme Monogr 2010:1-10.

574. Peroni DG, Pescollderungg L, Piacentini GL, Cassar W, Boner AL. Effective

desensitization to imiglucerase in a patient with type I Gaucher disease.

J Pediatr 2009;155:940-1.

575. Zhao H, Bailey LA, Grabowski GA. Enzyme therapy of gaucher disease:

clinical and biochemical changes during production of and tolerization for

neutralizing antibodies. Blood Cells Mol Dis 2003;30:90-6.

576. Brooks DA, Kakavanos R, Hopwood JJ. Signiﬁcance of immune response to

enzyme-replacement therapy for patients with a lysosomal storage disorder.

Trends Mol Med 2003;9:450-3.

577. Starzyk K, Richards S, Yee J, Smith SE, Kingma W. The long-term interna-

tional safety experience of imiglucerase therapy for Gaucher disease. Mol

Genet Metab 2007;90:157-63.

578. Erdogdu D, Gelincik A, Canbaz B, Colakoglu B, Buyukozturk S, Tanakol R.

Successful desensitization to imiglucerase of an adult patient diagnosed with

type I Gaucher disease. Int Arch Allergy Immunol 2013;160:215-7.

579. Tsilochristou O, Gkavogiannakis NA, Ioannidou EN, Makris M. Successful

rapid desensitization to imiglucerase in an adult patient with Gaucher disease

and documented IgE-mediated hypersensitivity. J Allergy Clin Immunol Pract

2015;3:624-6.

580. Zhou W, Pool V, Iskander JK, English-Bullard R, Ball R, Wise RP, et al.

Surveillance for safety after immunization: Vaccine Adverse Event Reporting

System (VAERS)–United States, 1991-2001. MMWR Surveill Summ 2003;

52:1-24.

581. McNeil MM, Weintraub ES, Duffy J, Sukumaran L, Jacobsen SJ, Klein NP,

et al. Risk of anaphylaxis after vaccination in children and adults. J Allergy

Clin Immunol 2016;137:868-78.

582. Zent O, Arras-Reiter C, Broeker M, Hennig R. Immediate allergic reactions after

vaccinations–a post-marketing surveillance review. Eur J Pediatr 2002;161:21-5.

583. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Bock SA,

Branum A, et al. Second symposium on the deﬁnition and management of

anaphylaxis: summary report–Second National Institute of Allergy and In-

fectious Disease/Food Allergy and Anaphylaxis Network symposium.

J Allergy Clin Immunol 2006;117:391-7.

584. Wood RA, Berger M, Dreskin SC, Setse R, Engler RJ, Dekker CL, et al. An

algorithm for treatment of patients with hypersensitivity reactions after vac-

cines. Pediatrics 2008;122:e771-e777.

585. General recommendations on immunization—recommendations of the Advi-

sory Committee on Immunization Practices (ACIP). MMWR Recomm Rep

2011;60:1-64.

586. Kelso JM, Greenhawt MJ, Li JT, Nicklas RA, Bernstein DI, Blessing-Moore J,

et al. Adverse reactions to vaccines practice parameter 2012 update. J Allergy

Clin Immunol 2012;130:25-43.

587. Blanco C, Carrillo T, Ortega N, Alvarez M, Dominguez C, Castillo R. Com-

parison of skin-prick test and speciﬁc serum IgE determination for the diag-

nosis of latex allergy. Clin Exp Allergy 1998;28:971-6.

588. Sakaguchi M, Nakayama T, Inouye S. Food allergy to gelatin in children with

systemic immediate-type reactions, including anaphylaxis, to vaccines.

J Allergy Clin Immunol 1996;98:1058-61.

589. Greenhawt MJ, Spergel JM, Rank MA, Green TD, Mansoor D, Sharma H,

et al. Safe administration of the seasonal trivalent inﬂuenza vaccine to children

with severe egg allergy. Ann Allergy Asthma Immunol 2012;109:426-30.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S109

590. Turner PJ, Southern J, Andrews NJ, Miller E, Erlewyn-Lajeunesse M, SNIF-

FLE Study Investigators. Safety of live attenuated inﬂuenza vaccine in atopic

children with egg aller gy. J Alle rgy Clin Immunol 2015;136:376-81.

591. Fisher MM, More DG. The epidemiology and clinical features of anaphylactic

reactions in anaesthesia. Anaesth Intensive Care 1981;9:226-34.

592. Galletly DC, Treuren BC. Anaphylactoid reactions during anaesthesia: seven

years’ experience of intradermal testing. Anaesthesia 1985;40:329-33.

593. Hatton F, Tiret L, Maujol L, N’Doye P, Vourc’h G, Desmonts JM, et al.

INSERM. Epidemiological survey of anesthesia. Initial results [in French].

Ann Fr Anesth Reanim 1983;2:331-86.

594. Watkins J. Adverse anaesthetic reactions: an update from a proposed national

reporting and advisory service. Anaesthesia 1985;40:797-800.

595. Laxenaire MC. Epidemiology of anesthetic anaphylactoid reactions: fourth

multicenter survey (July 1994-December 1996) [in French]. Ann Fr Anesth

Reanim 1999;18:796-809.

596. Whittington T, Fisher MM. Anaphylactic and anaphylactoid reactions. Bail-

liere’s Clin Anaesthesiol 1998;12:301-23.

597. Gibbs NM, Sadleir PH, Clarke RC, Platt PR. Survival from perioperative

anaphylaxis in Western Australia 2000-2009. Br J Anaesth 2013;111:589-93.

598. Harper NJN, Cook TM, Garcez T, Farmer L, Floss K, Marinho S, et al.

Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and

clinical features of perioperative anaphylaxis in the 6th National Audit Project

(NAP6). Br J Anaesth 2018;121:159-71.

599. Dong SW, Mertes PM, Petitpain N, Hasdenteufel F, Malinovsky JM. GERAP.

Hypersensitivity reactions during anesthesia: results from the ninth French

survey (2005-2007). Minerva Anestesiol 2012;78:868-78.

600. Gurrieri C, Weingarten TN, Martin DP, Babovic N, Narr BJ, Sprung J, et al.

Allergic reactions during anesthesia at a large United States referral center.

Anesth Analg 2011;113:1202-12.

601. Harboe T, Guttormsen AB, Irgens A, Dybendal T, Florvaag E. Anaphylaxis

during anesthesia in Norway: a 6-year single-center follow-up study. Anes-

thesiology 2005;102:897-903.

602. Lobera T, Audicana MT, Pozo MD, Blasco A, Fernandez E, Canada P, et al.

Study of hypersensitivity reactions and anaphylaxis during anesthesia in Spain.

J Investig Allergol Clin Immunol 2008;18:350-6.

603. Dewachter P, Mouton-Faivre C, Hepner DL. Perioperative anaphylaxis: what

should be know n? Curr Allergy Asthma Rep 2015;15:21.

604. The Association of Anaesthetists. Suspected anaphylactic reactions associated

with anaesthesia. London, UK: The Association of Anaesthetists of Great Britain

and Ireland and British Society for Allergy and Clinical Immunology; 2003.

Available from: https://anaesthetists.org/H ome/Resources-publications/

Guidelines/Archived-guidelines. Accessed July 30, 2020.

605. Currie M, Webb RK, Williamson JA, Russell WJ, Mackay P. The Australian

Incident Monitoring Study. Clinical anaphylaxis: an analysis of 2000 incident

reports. Anaesth Intensive Care 1993;21:621-5.

606. Lienhart A, Auroy Y, Pequignot F, Benhamou D, Warszawski J, Bovet M,

et al. Survey of anesthesia-related mortality in France. Anesthesiology 2006;

105:1087-97.

607. Mitsuhata H, Hasegawa J, Matsumoto S, Ogawa R. The epidemiology and

clinical features of anaphylactic and anaphylactoid reactions in the perioper-

ative period in Japan: a survey with a questionnaire of 529 hospitals approved

by Japan Society of Anesthesiology [in Japanese]. Masui 1992;41:1825-31.

608. Dewachter P, Mouton-Faivre C, Emala CW. Anaphylaxis and anesthesia:

controversies and new insights. Anesthesiology 2009;111:1141-50.

609. Harper NJ, Dixon T, Dugue P, Edgar DM, Fay A, Gooi HC, et al. Suspected

anaphylactic reactions associated with anaesthesia. Anaesthesia 2009;64:

199-211.

610. Kroigaard M, Garvey LH, Gillberg L, Johansson SG, Mosbech H, Florvaag E,

et al. Scandinavian Clinical Practice Guidelines on the diagnosis, management

and follow-up of anaphylaxis during anaesthesia. Acta Anaesthesiol Scand

2007;51:655-70.

611. Societe Francaise d’anesthesie et Reanimation, Societe Francaise d’allergolo-

gie. Reducing the risk of anaphylaxis during anaesthesia [in French]. Ann Fr

Anesth Reanim 2011;30:212-22.

612. ANZAAG anaphylaxis management guidelines. Australian & New Zealand

Anaesthetic Allergy Group. 2016. Available from: http://www.anzaag.com/

Mgmt%20Resources.aspx. Accessed July 30, 2020.

613. Kolawole H, Marshall SD, Crilly H, Kerridge R, Roessler P. Australian and

New Zealand Anaesthetic Allergy Group/Australian and New Zealand College

of Anaesthetists Perioperative Anaphylaxis Management Gu idelines. Anaesth

Intensive Care 2017;45:151-8.

614. Schumacher J. Fatal anaphylaxis to atracurium: a case report. A A Pract 2019;

12:145-6.

615. Dewachte

r P, Mouton-Faivre C, Emala CW, Beloucif S. Case scenario:

bronchospasm during anesthetic induction. Anesthesiology 2011;114:1200- 10.

616. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP,

Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to

sudden emotional stress. N Engl J Med 2005;352:539-48.

617. Ghadri JR, Wittstein IS, Prasad A, Sharkey S, Dote K, Akashi YJ, et al. In-

ternational Expert Consensus Document on Takotsubo syndrome (Part I):

clinical charact eristics, diagnostic criteria, and pathophysiology. Eur Heart J

2018;39:2032-46.

618. Litvinov IV, Kotowycz MA, Wassmann S. Iatrogenic epinephrine-induced

reverse Takotsubo cardiomyopathy: direct evidence supporting the role of

catecholamines in the pathophysiology of the “broken heart syndrome”. Clin

Res Cardiol 2009;98:457-62.

619. Dewachter P, Tanase C, Levesque E, Nicaise-Roland P, Chollet-Martin S,

Mouton-Faivre C, et al. Apical ballooning syndrome following perioperative

anaphylaxis is likely related to high doses of epinephrine. J Anesth 2011;25:

282-5.

620. Y-Hassan S. Clinical features and outcome of epinephrine-induced takotsubo

syndrome: analysis of 33 publishedcases. Cardiovasc RevascMed2016;17:450-5.

621. Suk EH, Kim DH, Kweon TD, Na SW, Shin JA. Stress-induced cardiomy-

opathy following cephalosporin-induced anaphylactic shock during general

anesthesia. Can J Anaesth 2009;56:432-6.

622. Dewachter P, Tchotourian S, Nicaise-Roland P, Fargeot C, Escalup R. Peri-

operative anaphylaxis to ethylene oxide: twenty years after, a diagnosis

revisted. J Allergy Ther 2010;1:1000102.

623. Maciag MC, Nargozian C, Broyles AD. Intraoperative anaphylaxis secondary

to systemic cooling in a pediatric patient with cold-induced urticaria. J Allergy

Clin Immunol Pract 2018;6:1394-5.

624. Hermite L, Louvier N, Hilaire P, Orry D, Seltzer S, Collet E. Neostigmine

induced anaphylaxis in the wake of surgery. Anaesth Crit Care Pain Med 2015;

34:109-11.

625. Ue KL, Kasternow B, Wagner A, Rutkowski R, Rutkowski K. Sugammadex:

an emerging trigger of intraoperative anaphylaxis. Ann Allergy Asthma

Immunol 2016;117:714-6.

626. Dewachter P, Mouton-Faivre C, Castells MC, Hepner DL. Anesthesia in the

patient with multiple drug allergies: are all allergies the same? Curr Opin

Anaesthesiol 2011;24:320-5.

627. Baldo BA. Relevance and value of a morphine immunoassay as a diagnostic

aid for neuromuscular blocking drug-induced anaphylaxis. Anesthesiology

2011;115:657-9, author reply 659-60.

628. Baldo BA, Fisher MM, Pham NH. On the origin and speciﬁcity of antibodies

to neuromuscular blocking (muscle relaxant) drugs: an immunochemical

perspective. Clin Exp Allergy 2009;39:325-44.

629. Ebo DG, Fisher MM, Hagendorens MM, Bridts CH, Stevens WJ. Anaphylaxis

during anaesthesia: diagnostic approach. Allergy 2007;62:471- 87.

630. Florvaag E, Johansson SG, Oman H, Venemalm L, Degerbeck F, Dybendal T,

et al. Prevalence of IgE antibodies to morphine: relation to the high and low

incidences of NMBA anaphylaxis in Norway and Sweden, respectively. Acta

Anaesthesiol Scand 2005;49:437-44.

631. Florvaag E, Johansson SG, Oman H, Harboe T, Nopp A. Pholcodine stimu-

lates a dramatic increase of IgE in IgE-sensitized individuals: a pilot study.

Allergy 2006;61:49-55.

632. Harboe T, Johansson SG, Florvaag E, Oman H. Pholcodine exposure raises

serum IgE in patients with previous anaphylaxis to neuromuscular blocking

agents. Allergy 2007;62:1445-50.

633. Questions and answers on the review of the marketing authorisations for

medicines containing pholcodine. London, UK: European Medicines Agency.

2012. Available from: https://www.ema.europa.eu/en/documents/referral/

questions-answ ers-rev iew-mar keting-au thoris ations-medic ines-con taining-

pholcodine_en.pdf. Accessed July 28, 2020.

634. Seed MJ, Ewan PW. Anaphylaxis caused by neostigmine. Anaesthesia 2000;

55:574-5.

635. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI,

et al. The diagnosis and management of anaphylaxis practice parameter: 2010

update. J Allergy Clin Immunol 2010;126:477-480.e1-e42.

636. Asserhoj LL, Mosbech H, Kroigaard M, Garvey LH. No evidence for con-

traindications to the use of propofol in adults allergic to egg, soy or peanut†.Br

J Anaesth 2016;116:77-82.

637. Belso N, Kui R, Szegesdi I, Kakuja M, Kapitany K, Kemeny L, et al.

Propofol and fentanyl induced perioperative anaphylaxis. Br J Anaesth

2011;106:283-4.

638. Cummings KC III, Arnaut K. Case report: fentanyl-associated intraoperative

anaphylaxis with pulmonary edema. Can J Anaesth 2007;54:301-6.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S110 BROYLES ET AL

639. De Pasquale TMA, Buonomo A, Pucci S. Delayed-type allergy to articaine

with cross-reactivity to other local anesthetics from the amide group. J Allergy

Clin Immunol Pract 2018;6:305-6.

640. Gonzalez-Delgado P, Anton R, Soriano V, Zapater P, Niveiro E. Cross-reac-

tivity among amide-type local anesthetics in a case of allergy to mepivacaine.

J Investig Allergol Clin Immunol 2006;16:311-3.

641. Venemalm L, Degerbeck F, Smith W. IgE-mediated reaction to mepivacaine.

J Allergy Clin Immunol 2008;121:1058-9.

642. Opstrup MS, Malling HJ, Kroigaard M, Mosbech H, Skov PS, Poulsen LK,

et al. Standardized testing with chlorhexidine in perioperative allergy–a large

single-centre evaluation. Allergy 2014;69:1390-6.

643. Tacquard C, Collange O, Gomis P, Malinovsky JM, Petitpain N, Demoly P, et al.

Anaesthetic hypersensitivity reactions in France between 2011 and 2012: the

10th GERAP epidemiologic survey. Acta Anaesthesiol Scand 2017;61:290-9.

644. Velicky P, Windsperger K, Petroczi K, Pils S, Reiter B , Weiss T, et al.

Pregnancy-associated diamine oxidase originates from extravillous tro-

phoblasts and is decreased in ea rly-onset pre eclampsia . Sci Rep 2018;8:

6342.

645. Dewachter P, Chollet-Martin S, Mouton-Faivre C, de Chaisemartin L, Nicaise-

Roland P. Comparison of basophil activation test and skin testing perfor-

mances in NMBA allergy. J Allergy Clin Immunol Pract 2018;6:1681-9.

646. Sadleir PH, Clarke RC, Platt PR. Cefalotin as antimicrobial prophylaxis in

patients with known intraoperative anaphylaxis to cefazolin. Br J Anaesth

2016;117:464-9.

647. Gueant JL, Mata E, Monin B, Moneret-Vautrin DA, Kamel L, Nicolas JP, et al.

Evaluation of a new reactive solid phase for radioimmunoassay of serum

speciﬁc IgE against muscle relaxa nt drugs. Allergy 1991;46:452-8.

648. Guilloux L, Ricard-Blum S, Ville G, Motin J. A new radioimmunoassay using

a commercially available solid support for the detection of IgE antibodies

against muscle relaxants. J Allergy Clin Immunol 1992;90:153-9.

649. Fisher MM, Baldo BA. Immunoassays in the diagnosis of anaphylaxis to

neuromuscular blocking drugs: the value of morphine for the detection of IgE

antibodies in allergic subjects. Anaesth Intensive Care 2000;28:167-70.

650. Kelly KJ, Sussman G. Latex allergy: where are we now and how did we get

there? J Allergy Clin Immunol Pract 2017;5:1212-6.

651. Mayorga C, Celik G, Rouzaire P, Whitaker P, Bonadonna P, Rodrigues-

Cernadas J, et al. In vitro tests for drug hypersensitivity reactions: an ENDA/

EAACI Drug Allergy Interest Group position paper. Allergy 2016;71:1103-34.

652. Lafuente A, Javaloyes G, Berroa F, Goikoetxea MJ, Moncada R, Nunez-

Cordoba JM, et al. Early skin testing is effective for diagnosis of hypersen-

sitivity reactions occurring during anesthesia. Allergy 2013;68:820-2.

653. Miller J, Clough SB, Pollard RC, Misbah SA. Outcome of repeat anaesthesia

after investigation for perioperative anaphylaxis. Br J Anaesth 2018;120:

1195-201.

654. Schatz M. Skin testing and incremental challenge in the evaluation of adverse

reactions to local anesthetics. J Allergy Clin Immunol 1984;74:606-16.

655. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician

2008;11:S133-53.

656. Levy JH, Rockoff MA. Anaphylaxis to meperidine. Anesth Analg 1982;61:

301-3.

657. Yoo HS, Yang EM, Kim MA, Hwang SH, Shin YS, Ye YM, et al. A case of

codeine induced anaphylaxis via oral route. Allergy Asthma Immunol Res

2014;6:95-7.

658. Zucker-Pinchoff B, Ramanathan S. Anaphylactic reaction to epidural fentanyl.

Anesthesiology 1989;71:599-601.

659. Kyrklund C, Hyry H, Alanko K. Allergic contact dermatitis caused by trans-

dermal buprenorphine. Contact Dermatitis 2013;69:60-1 .

660. Vander Hulst K, Parera Amer E, Jacobs C, Dewulf V, Baeck M, Pujol

Vallverdu RM, et al. Allergic contact dermatitis from transdermal buprenor-

phine. Contact Dermatitis 2008;59:366-9.

661. Nasser SM, Ewan PW. Opiate-sensitivity: clinical characteristics and the role

of skin prick testing. Clin Exp Allergy 2001;31:1014-20.

662. Flacke JW, Flacke WE, Bloor BC, Van Etten AP, Kripke BJ. Histamine

release by four narcotics: a double-blind study in humans. Anesth Analg 1987;

66:723-30.

663. Stutius LM, Pessach I, Lee J, Lo MS, Levy S, Schram P, et al. Sublingual

desensitization for buprenorphine hypersensitivity. J Allergy Clin Immunol

2010;125:938-9.

664. Gomes E, Cardoso MF, Praca F, Gomes L, Marino E, Demoly P. Self-reported

drug allergy in a general adult Portuguese population. Clin Exp Allergy 2004;

34:1597-601.

665. Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin

induced asthma and its implications for clinical practice. BMJ 2004;328:434.

666. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of aspirin-

exacerbated respiratory disease among asthmatic patients: a meta-analysis of

the literature. J Allergy Clin Immunol 2015;135:676-81.e1.

667. Settipane GA. Aspirin and allergic diseases: a review. Am J Med 1983;74:

102-9.

668. Stevenson DD, Sanchez-Borges M, Szczeklik A. Classiﬁcat

ion of allergic and

pseudoallergic reactions to drugs that inhibit cyclooxygenase enzymes. Ann

Allergy Asthma Immunol 2001;87:177-80.

669. Kidon M, Blanca-Lopez N, Gomes E, Terreehorst I, Tanno L, Ponvert C, et al.

EAACI/ENDA Position Paper: diagnosis and management of hypersensitivity

reactions to non-steroidal anti-inﬂammatory drugs (NSAIDs) in children and

adolescents. Pediatr Allergy Immunol 2018;29:469-80.

670. Tuttle KL, Schneider TR, Henrickson SE, Morris D, Abonia JP, Spergel JM,

et al. Aspirin-exacerbated respiratory disease: not always “adult-onset”.

J Allergy Clin Immunol Pract 2016;4:756-8.

671. Dursun AB, Woessner KA, Simon RA, Karasoy D, Stevenson DD. Predicting

outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and

chronic sinusitis. Ann Allergy Asthma Immunol 2008;100:420-5.

672. Zisa G, Riccobono F, Bommarito L, D’Antonio C, Calamari AM, Poppa M,

et al. Provocation tests with the offending nonsteroidal anti-inﬂammatory

drugs in patients with urticaria/angioedema reactions. Allergy Asthma Proc

2012;33:421-6.

673. Himly M, Jahn-Schmid B, Pittertschatscher K, Bohle B, Grubmayr K,

Ferreira F, et al. IgE-mediated immediate-type hypersensitivity to the pyr-

azolone drug propyphenazone. J Allergy Clin Immunol 2003;111:882-8.

674. Weberschock TB, Muller SM, Boehncke S, Boehncke WH. Tolerance to

coxibs in patients with intolerance to non-steroidal anti-inﬂammatory drugs

(NSAIDs): a systematic structured review of the literature. Arch Dermatol Res

2007;299:169-75.

675. Quiralte J, Blanco C, Castillo R, Delgado J, Carrillo T. Intolerance to

nonsteroidal antiinﬂammatory drugs: results of controlled drug challenges in

98 patients. J Allergy Clin Immunol 1996;98:678-85.

676. Buchheit KM, Laidlaw TM. Update on the management of aspirin-exacerbated

respiratory disease. Allergy Asthma Immunol Res 2016;8:298-304.

677. White AA, Steve nson DD, Simon RA. The blockin g effect of essential

controller medications during aspirin challenges in patients with aspirin-

exacerbated resp iratory d isease. Ann A llergy Asth ma Immun ol 2005;95:

330-5.

678. Lee RU, Stevenson DD. Aspirin-exacerbated respiratory disease: evaluation

and management. Allergy Asthma Immunol Res 2011;3:3-10.

679. Chen JR, Buchmiller BL, Khan DA. An hourly dose-escalation desensitization

protocol for aspirin-exacerbated respiratory disease. J Allergy Clin Immunol

Pract 2015;3:926-31.e1.

680. Lee RU, White AA, Ding D, Dursun AB, Woessner KM, Simon RA, et al. Use

of intranasal ketorolac and modiﬁed oral aspir in challenge for desensitization

of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol

2010;105:130-5.

681. Walters KM, Woessner KM. An overview of nonsteroidal antiinﬂammatory

drug reactions. Immunol Allergy Clin North Am 2016;36:625-41.

682. Cook KA, White AA. Rapid aspirin challenge in patients with aspirin allergy

and acute coronary syndromes. Curr Allergy Asthma Rep 2016;16:11.

683. Kvedariene V, Bencherioua AM, Messaad D, Godard P, Bousquet J,

Demoly P. The accuracy of the diagnosis of suspected paracetamol (acet-

aminophen) hypersensitivity: results of a single-blinded trial. Clin Exp Allergy

2002;32:1366-9.

684. Boussetta K, Ponvert C, Karila C, Bourgeois ML, Blic J, Scheinmann P.

Hypersensitivity reactions to paracetamol in children: a study of 25 cases.

Allergy 2005;60:1174-7.

685. Galindo PA, Borja J, Mur P, Feo F, Gomez E, Garcia R. Anaphylaxis to

paracetamol. Allergol Immunopathol (Madr) 1998;26:199-200.

686. Ho MH, Tung JY, Lee TL, Tsoi NS, Lau YL. Anaphylaxis to paracetamol.

J Paediatr Child Health 2008;44:746-7.

687. Martin JA, Lazaro M, Cuevas M, Alvarez-Cuesta E. Paracetamol anaphylaxis.

Clin Exp Allergy 1993;23:534.

688. Numata T, Fukushi R, Ito T, Tsuboi R, Harada K. Acetaminophen anaphylaxis

diagnosed by skin prick test. Allergol Int 2016;65:490-1.

689. Settipane RA, Schrank PJ, Simon RA, Mathison DA, Christiansen SC,

Stevenson DD. Prev alence of cross-sensitivity with acetaminophen in aspirin-

sensitive asthmatic subjects. J Allergy Clin Immunol 1995;96:480-5.

690. Stricker BH, Meyboom RH, Lindquist M. Acute hypersensitivity reactions to

paracetamol. Br Med J (Clin Res Ed) 1985;291:938-9.

691. Szczekl

ik A. Analgesics, allergy and asthma. Br J Clin Pharmacol 1980;10:

401S-5.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S111

692. Tsujino Y, Okamoto N, Morita E. Acetaminophen-induced urticaria without

aspirin intolerance. J Dermatol 2007;34:224-6.

693. Yilmaz O, Ertoy Karagol IH, Bakirtas A, Topal E, Celik GE, Demirsoy MS,

et al. Challenge-proven nonsteroidal anti-inﬂammatory drug hypersensitivity in

children. Allergy 2013;68:1555-61.

694. Van Diem L, Grilliat JP. Anaphylactic shock induced by paracetamol. Eur J

Clin Pharmacol 1990;38:389-90.

695. Leung R, Plomley R, Czarny D. Paracetamol anaphylaxis. Clin Exp Allergy

1992;22:831-3.

696. de Paramo BJ, Gancedo SQ, Cuevas M, Camo IP, Martin JA, Cosmes EL.

Paracetamol (acetaminophen) hypersensitivity. Ann Allergy Asthma Immunol

2000;85:508-11.

697. Rojas-Perez-Ezquerra P, Sanchez-Morillas L, Gomez-Traseira C, Gonzalez-

Mendiola R, Alcorta Valle AR, Laguna-Martinez J. Selective hypersensitivity

reactions to acetaminophen: a 13-case series. J Allergy Clin Immunol Pract

2014;2:343-5.

698. Ban GY, Ahn SJ, Yoo HS, Park HS, Ye YM. Stevens-Johnson syndrome and

toxic epidermal necrolysis associated with acetaminophen use during viral

infections. Immune Netw 2016;16:256-60.

699. Gabrielli S, Langlois A, Ben-Shoshan M. Prevalence of hypersensitivity re-

actions in children associated with acetaminophen: a systematic review and

meta-analysis. Int Arch Allergy Immunol 2018;176:106-14.

700. Caprie Steering Committee. A randomised, blinded, trial of clopidogrel versus

aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering

Committee. Lancet 1996;348:1329-39.

701. Plavix (clopidogrel bisulfate) prescribing information. Bridgewater, NJ: Bristol-

Myers Squibb Co and Sanoﬁ Pharmaceuticals; 2019. Available from: https://

packageinserts.bms.com/pi/pi_plavix.pdf. Accessed July 29, 2020.

702. Henke PK. Commentary. Prasugrel versus clopidogrel in patients with acute

coronary symptoms. Perspect Vasc Surg Endovasc Ther 2008;20:223-4.

703. Lokhandwala J, Best PJ, Henry Y, Berger PB. Alle rgic reactions to clopidogrel

and cross-reactivity to other agents. Curr Allergy Asthma Rep 2011;11:52-7.

704. Lokhandwala JO, Best PJ, Butterﬁeld JH, Skelding KA, Scott T,

Blankenship JC, et al. Frequency of allergic or hematologic adverse reactions

to ticlopidine among patients with allergic or hematologic adverse reactions to

clopidogrel. Circ Cardiovasc Interv 2009;2:348-51.

705. Campbell KL, Cohn JR, Fischman DL, Walinsky P, Mallya R, Jaffrani W,

et al. Management of clopidogrel hypersensitivity without drug interruption.

Am J Cardiol 2011;107:812-6.

706. Cheema AN, Mohammad A, Hong T, Jakubovic HR, Parmar GS, Sharieff W,

et al. Characterization of clopidogrel hypersensitivity reactions and manage-

ment with oral steroids without clopidogrel discontinuation. J Am Coll Cardiol

2011;58:1445-54.

707. von Tiehl KF, Price MJ, Valencia R, Ludington KJ, Teirstein PS, Simon RA.

Clopidogrel desensitization after drug-eluting stent placement. J Am Coll

Cardiol 2007;50:2039-43.

708. Peppard SR, Held-Godgluck BM, Beddingﬁeld R. Use of prasugrel in a patient

with clopidogrel hypersensitivity. Ann Pharmacother 2011;45:e54.

709. Barbaud A, Reichert-Penetrat S, Trechot P, Jacquin-Petit MA, Ehlinger A,

Noirez V, et al. The use of skin testing in the investigation of cutaneou s

adverse drug reactions. Br J Dermatol 1998;139:49-58.

710. Britschgi M, Steiner UC, Schmid S, Depta JP, Senti G, Bircher A, et al. T-cell

involvement in drug- induced acute generalized exanthematous pustulosis.

J Clin Invest 2001;107:1433-41.

711. Cuerda Galindo E, Goday Bujan JJ, Garcia Silva JM, Martinez W, Verea

Hernando M, Fonseca E. Fixed drug eruption from piroxicam. J Eur Acad

Dermatol Venereol 2004;18:586-7.

712. Chopra P, Verma P, Klaustermeyer WB. Successful use of prasugrel, an

alternative antiplatelet agent, in a patient with clopidogrel allergy. Ann Allergy

Asthma Immunol 2011;107:541-2.

713. Kim SH, Park SD, Baek YS, Lee SY, Shin SH, Woo SI, et al. Prasugrel-

induced hypersensitivity skin reaction. Korean Circ J 2014;44:355-7.

714. van Werkum JW, Braber TL, Verheggen PW, Van Der Have-Roeffel SM.

Prasugrel as alternative treatment strategy in a case with a hypersensitivity

reaction to clopidogrel. Platelets 2011;22:77-8.

715. Chin N, Rangamuwa K, Mariasoosai R, Carnes J, Thien F. Oral antiplatelet

agent hypersensitivity and cross-reactivity managed by successful desensiti-

sation. Asia Pac Allergy 2015;5:51-4.

716. Harris JR, Coons JC. Ticagrelor use in a patient with a documented clopidogrel

hypersensitivity. Ann Pharmacother 2014;48:1230-3.

717. Manchette AM, Drucker AG, Januzzi JL Jr. Acute coronary syndrome

antiplatelet alternatives in clopidogrel allergy. Pharmacotherapy 2014;34:

e152-e156.

718. Owen P, Garner J, Hergott L, Page RL II. Clopidogrel desensitization: case

report and review of published protocols. Pharmacotherapy 2008;28:259-70.

719. Fajt

M, Petrov A. Clopidogrel hypersensitivity: a novel multi-day outpatient

oral desensitization regimen. Ann Pharmacother 2010;44:11-8.

720. Vishnevsky A, Savage MP, Fischman DL. Treatment of clopidogrel hyper-

sensitivity: the Jefferson approach. Curr Vasc Pharmacol 2019;17:123-6.

721. Ramotowski B, Budaj A. Clopidogrel allergy successfully treated with corti-

costeroids without clopidogrel withdrawal. Kardiol Pol 2016;74:489.

722. Gonzalez-Delgado P, Fernandez J. Hypersensitivity reactions to heparins. Curr

Opin Allergy Clin Immunol 2016;16:315-22.

723. Koch P, Münssinger T, Rupp-John C, Uhl K. Delayed-type hypersensitivity

skin reactions caused by subcutaneous unfractionated and low-molecular-

weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol

2000;42:612-9.

724. Pföhler C, Müller CS, Pindur G, Eichler H, Schäfers HJ, Grundmann U, et al.

Delayed-type heparin allergy: diagnostic procedures and treatment alterna-

tives—a case series including 15 patients. World Allergy Organ J 2008;1:

194-9.

725. Anders D, Trautmann A. Allergic anaphylaxis due to subcutaneously injected

heparin. Allergy Asthma Clin Immunol 2013;9:1.

726. Phan C, Vial-Dupuy A, Autegarden JE, Amsler E, Gaouar H, Abuaf N, et al.

A study of 19 cases of allergy to heparins with positive skin testing. Ann

Dermatol Venereol 2014;141:23-9.

727. Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S,

Pelzer K, et al. Contaminated heparin associated with adverse clinical events

and activation of the contact system. N Engl J Med 2008;358:2457-67.

728. Gottschlich GM, Georgitis JW. Protamine-speciﬁc IgE, IgG, AND IgG sub-

class antibodies in protamine anaphylaxis. J Allergy Clin Immunol 1988;8 1:

238.

729. Porsche R, Brenner ZR. Allergy to protamine sulfate. Heart Lung 1999;28:

418-28.

730. Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersensitivity reactions to

anticoagulant drugs: diagnosis and management options. Allergy 2006;61:

1432-40.

731. Vincent GM, Janowski M, Menlove R. Protamine allergy reactions during

cardiac catheterization and cardiac surgery: risk in patients taking protamine-

insulin preparations. Cathet Cardiovasc Diagn 1991;23:164-8.

732. Comunale ME, Maslow A, Robertson LK, Haering JM, Mashikian JS,

Lowenstein E. Effect of site of venous protamine administration, previously

alleged risk factors, and preoperative use of aspirin on acute protamine-induced

pulmonary vasoconstriction. J Cardiothor Vasc Anesth 2003;17:309-13.

733. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weintraub WS. Evaluation of

patients at risk for protamine reacti ons. J Thoracic Cardiovasc Surg 1989;98:

200-4.

734. Ellis ER. Successful use of bivalirudin in place of heparin infusion for pul-

monary vein isolation using a cryoballoon catheter in a patient with heparin

allergy. HeartRhythm Case Rep 2017;3:10-2.

735. Jappe U, Gollnick H. Allergy to heparin, heparinoids, and recombinant hir-

udin: diagnostic and therapeutic alternatives. Hautarzt 1999;50:406-11.

736. Wütschert R, Piletta P, Bounameaux H. Adverse skin reactions to low mo-

lecular weight heparins: frequency, management and prevention. Drug Saf

1999;20:515-25.

737. Bottio T, Pittarello G, Bonato R, Fagiolo U, Gerosa G. Life-threatening

anaphylactic shock caused by porcine heparin intravenous infusion during

mitral valve repair. J Thorac Cardiovasc Surg 2003;126:1194-5.

738. Favaloro EJ, McCaughan G, Pasalic L. Clinical and laboratory diagnosis of

heparin induced thrombocytopenia: an update. Pathology 2017;49:346-55.

739. Keeling D, Davidson S, Watson H. Haemostasis and Thrombosis Task Force

of the British Committee for Standards in Haematology. The management of

heparin-induced thrombocytopenia. Br J Haematol 2006;133:259-69.

740. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition,

treatment, and prevention: the Seventh ACCP Conference on Antithrombotic

and Thrombolytic Therapy. Chest 2004;126:311S-7S.

741. Morel DR, Costabella PM, Pittet JF. Adverse cardiopulmonary effects and

increased plasma thromboxane concentrations following the neutralization of

heparin with protamine in awake sheep are infusion rate-dependent. Anes-

thesiology 1990;73:415-24.

742. Raap U, Liekenbröcker T, Kapp A, Wedi B. Delayed-type hypersensitivity to

protamine as a complication of insulin therapy. Contact Dermatitis 2005;53:57-8.

743. Wu W, Cheng H, Bu R. Protamine-containing insulin allergy and renal

dysfunction in a patient with type 2 diabetes. J Diabetes Investig 2015;6:591-3.

744. Sullivan T. Drug allergy. In: Middleton Jr E, editor. Allergy: Principles and

Practice. St Louis: Mosby; 1993.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S112 BROYLES ET AL

745. Kim R. Anaphylaxis to protamine masquerading as an insulin allergy. Del Med

J 1993;65:17-23.

746. al-Eryani AY, al-Momen AK, Fayed DF, Allam AK. Successful heparin

desensitization after heparin-induced anaphylactic shock. Thrombosis Res

1995;79:523-6.

747. Dave S, Park MA. Successful heparin desensitization: a case report and review

of the literature. J Cardiac Surg 2008;23:394-7.

748. Kavut AB, Koca E. Successful desensitization with un-fractionated heparin in

a patient with heparin allergy and tolerance to fondaparinux. Asian Pac J

Allergy Immunol 2012;30:162-6.

749. Parekh K, Burkhart HM, Hatab A, Ross A, Muller BA. Heparin allergy:

successful desensitization for cardiopulmonary bypass. J Thorac Cardiovasc

Surg 2005;130:1455-6.

750. Patriarca G, Rossi M, Schiavino D, Schinco G, Fais G, Varano C, et al. Rush

desensitization in heparin hypersensitivity: a case report. Allergy 1994;49:

292-4.

751. Sokolowska E, Kalaska B, Miklosz J, Mogielnicki A. The toxicology of

heparin reversal with protamine: past, present and future. Expert Opin Drug

Metab Toxicol 2016;12:897-909.

752. Bollinger ME, Hamilton RG, Wood RA. Protamin e allergy as a complication

of insulin hypersensitivity: a case report. J Allergy Clin Immunol 1999;104:

462-5.

753. Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative

review. Orphanet J Rare Dis 2012;7:24.

754. Lillicrap D. von Willebrand disease: advances in pathogenetic understanding,

diagnosis, and therapy. Blood 2013;122:3735-40.

755. Cugno M, Gualtierotti R, Tedeschi A, Meroni PL. Au toantibodies to coagu-

lation factors: from pathophysiology to diagnosis and therapy. Autoimmun

Rev 2014;13:40-8.

756. Franchini M, Lippi G, Montagnana M, Targher G, Zaffanello M, Salvagno GL,

et al. Anaphylaxis in patients with congenital bleeding disorders and inhibitors.

Blood Coagul Fibrinolysis 2009;20:225-9.

757. Warrier I, Ewenstein BM, Ko erper MA, Shapiro A, Key N, DiMichele D, et al.

Factor IX inhibitors and anaphylaxis in hemophilia B. Haemophilia 1997;3:

231-2.

758. Kadar JG, Schuster J, Hunzelmann N. IgE-mediated anaphylactic reaction to

puriﬁed and recombinant factor VIII in a patient with severe haemophilia A.

Haemophilia 2007;13:104-5.

759. Shopnick RI, Kazemi M, Brettler DB, Buckwalter C, Yang L, Bray G, et al.

Anaphylaxis after treatment with recombinant factor VIII. Transfusion 1996;

36:358-61.

760. Helmer RE III, Alperin JB, Yunginger JW, Grant JA. Anaphylactic reactions

following infusion of factor VIII in a patient with classic hemophilia. Am J

Med 1980;69:953-7.

761. James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand dis-

ease. Blood 2013;122:636-40.

762. Platt CD, D’Angelo L, Neufeld EJ, Broyles AD. Skin testing, graded chal-

lenge, and desensitization to von Willebrand factor (VWF) products in type III

von Willebrand disease (VWD). J Allergy Clin Immunol Pract 2016;4:1006-8.

763. Lak M, Peyvandi F, Mannucci PM. Clinical manifestations and complications

of childbirth and replacement therapy in 385 Iranian patients with type 3 von

Willebrand disease. Br J Haematol 2000;111:1236-9.

764. Dioun AF, Ewenstein BM, Geha RS, Schneider LC. IgE-mediated allergy and

desensitization to factor IX in hemophilia B. J Allergy Clin Immunol 1998;

102:113-7.

765. Jamieson DM, Stafford CT, Maloney MJ, Lutcher CL. Desensitization to

factor VIII in a patient with classic hemophilia and C2 deﬁciency. Ann Allergy

1987;58:215-20.

766. Franchini M, Veneri D, Lippi G. The use of recombinant activated factor VII in

congenital and acquired von Willebrand disease. Blood Coagul Fibrinolysis

2006;17:615-9.

767. Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia.

Blood 2014;124:3365-72.

768. Benson G, Auerswald G, Elezovic I, Lambert T, Ljung R, Morﬁni M, et al.

Immune tolerance induction in patients with severe hemophilia with inhibitors:

expert panel views and recommendations for clinical practice. Eur J Haematol

2012;88:371-9.

769. Brockow K. Immediate and delayed cutaneous reactions to radiocontrast me-

dia. Chem Immunol Allergy 2012;97:180-90.

770. Scherer K, Harr T, Bach S, Bircher AJ. The role of iodine in hypersensitivity

reactions to radio contrast media. Clin Exp Allergy 2010;40:468-75.

771. Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P,

et al. Skin testing in patients with hypersensitivity reactions to iodinated

contrast media—a

European multicenter study. Allergy 2009;64:234-41.

772. Lerondeau B, Trechot P, Waton J, Poreaux C, Luc A, Schmutz JL, et al.

Analysis of cross-reactivity among radiocontr ast media in 97 hypersensitivity

reactions. J Allergy Clin Immunol 2016;137:633-5.e4.

773. Caimmi S, Benyahia B, Suau D, Bousquet-Rouanet L, Caimmi D,

Bousquet PJ, et al. Clinical value of negative skin tests to iodinated contrast

media. Clin Exp Allergy 2010;40:805-10.

774. Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA,

Campbell RL, et al. Anaphylaxis-a 2020 practice parameter update, systematic

review, and Grading of Recommendations, Assessment, Development and

Evaluation (GRADE) analysis. J Allergy Clin Immunol 2020;145:1082-123.

775. Kamm GL, Hagmeyer KO. Allergic-type reactions to corticosteroids. Ann

Pharmacother 1999;33:451-60.

776. Patel A, Bahna SL. Immediate hypersensitivity reactions to corticosteroids.

Ann Allergy Asthma Immunol 2015;115:178-82.e3.

777. Baker A, Empson M, The R, Fitzharris P. Skin testing for immediate hyper-

sensitivity to corticosteroids: a case series and literature review. Clin Exp

Allergy 2015;45:669-76.

778. Asakawa H, Araki T, Imai I, Tsutsumi Y, Kawakami F. Skin tests of steroid

allergy. Allergy 1999;54:645-6.

779. Figueredo E, Cuesta-Herranz JI, De Las Heras M, Lluch-Bernal M,

Umpierrez A, Sastre J. Anaphylaxis to dexamethasone. Allergy 1997;52:877.

780. Mace S, Vadas P, Pruzanski W. Anaphylactic shock induced by intraarticular

injection of methylprednisolone acetate. J Rheumatol 1997;24:1191-4.

781. Montoro J, Valero A, Serra-Baldrich E, Amat P, Lluch M, Malet A.

Anaphylaxis to paramethasone with tolerance to other corticosteroids. Allergy

2000;55:197-8.

782. Al Hadithy A, van Maaren M, Vermes A. Anaphylactic reactions following

Kenacort-A(R) injection: carboxymethylcellulose is involved once again.

Contact Dermatitis 2011;64:179-80.

783. Bordere A, Stockman A, Boone B, Franki AS, Coppens MJ, Lapeere H, et al.

A case of anaphylaxis caused by macrogol 3350 after injection of a cortico-

steroid. Contact Dermatitis 2012;67:376-8.

784. Caimmi S, Caimmi D, Bousquet PJ, Demoly P. Succinate as opposed to

glucocorticoid itself allergy. Allergy 2008;63:1641-3 .

785. Dewachter P, Mouton-Faivre C. Anaphylaxis to macrogol 4000 after a

parenteral corticoid injection. Allergy 2005;60:705-6.

786. Koutsostathis N, Vovolis V. Severe immunoglobulin E-mediated anaphylaxis

to intravenous methylprednisolone su ccinate in a patient who tolerated oral

methylprednisolone. J Investig Allergol Clin Immunol 2009;19:330-2.

787. Levy Y, Segal N, Nahum A, Marcus N, Garty BZ. Hypersensitivity to

methylprednisolone sodium succinate in children with milk allergy. J Allergy

Clin Immunol Pract 2014;2:471-4.

788. Matura M, Goossens A. Contact allergy to corticosteroids . Allergy 2000;55:

698-704.

789. Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA.

Contamination of dry powder inhalers for asthma with milk proteins con-

taining lactose. J Allergy Clin Immunol 2004;113:558-60.

790. Patterson DL, Yunginger JW, Dunn WF, Jones RT, Hunt LW. Anaphylaxis

induced by the carboxymethylcellulose component of injectable triamcinolone

acetonide suspension (Kenalog). Ann Allergy Asthma Immunol 1995;74:163-6.

791. Savvatianos S, Giavi S, Stefanaki E, Siragakis G, Manousakis E,

Papadopoulos NG. Cow’s milk allergy as a cause of anaphylaxis to systemic

corticosteroids. Allergy 2011;66:983-5.

792. Sohy C, Vandenplas O, Sibille Y. Usefulness of oral macrogol challenge in

anaphylaxis after intra-articular injection of corticosteroid preparation. Allergy

2008;63:478-9.

793. Spoerl D, Scherer K, Bircher AJ. Contact urticaria with systemic symptoms

due to hexylene glycol in a topical corticosteroid: case report and review of

hypersensitivity to glycols. Dermatology 2010;220:238-42.

794. Asarch A, Scheinman PL. Sorbitan sesquioleate, a common emulsiﬁer in topical

corticosteroids, is an important contact allergen. Dermatitis 2008;19:323-7.

795. Baeck M, Chemelle JA, Terreux R, Drieghe J, Goossens A. Delayed hyper-

sensitivity to corticosteroids in a series of 315 patients: clinical data and patch

test results. Contact Dermatitis 2009;61:163-75.

796. Boffa MJ, Wilkinson SM, Beck MH. Screening for corticosteroid contact

hypersensitivity. Contact Dermatitis 1995;33:149-51.

797. Fonacier LS, Sher JM. Allergic contact dermatitis. Ann Allergy Asthma

Immunol 2014;113:9-12.

798. Hogan D, Ledet JJ. Impact of regulation on contact dermatitis. Dermatol Clin

2009;27:385-94. viii.

799. Wolf R, Orion E, Ruocco E, Baroni A, Ruocco V. Contact dermatitis: facts and

controversies. Clin Dermatol 2013;31:467-78.

800. Yim E, Baquerizo Nole KL, Tosti A. Contact dermatitis caused by pre-

servatives. Dermatitis 2014;25:215-31.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S113

801. Coopman S, Degreef H, Dooms-Goossens A. Identiﬁcation of cross-reaction

patterns in allergic contact dermatitis fro m topical corticosteroids. Br J Der-

matol 1989;121:27-34.

802. Rachid R, Leslie D, Schneider L, Twarog F. Hypersensitivity to systemic

corticosteroids: an infrequent but potentially life-threatening condition.

J Allergy Clin Immunol 2011;127:524-8.

803. Rodrigues-Alves R, Spinola-Santos A, Pedro E, Branco-Ferreira M, Pereira-

Barbosa M. Immediate hypersensitivity to corticosteroids: ﬁnding an alterna-

tive. J Investig Allergol Clin Immunol 2007;17:284-5.

804. Venturini M, Lobera T, del Pozo MD, Gonzalez I, Blasco A. Immediate hy-

persensitivity to corticosteroids. J Investig Allergol Clin Immunol 2006;16:51-6.

805. Calogiuri GF, Muratore L, Nettis E, Ventura MT, Ferrannini A, Tursi A.

Anaphylaxis to hydrocortisone hemisuccinate with cross-sensitivity to related

compounds in a paediatric patient. Br J Dermatol 2004;151:707-8.

806. Ventura MT, Calogiuri GF, Matino MG, Dagnello M, Buquicchio R, Foti C,

et al. Alternative glucocorticoids for use in cases of adverse reaction to sys-

temic glucocorticoids: a study on 10 patients. Br J Dermatol 2003;148:139-41.

807. Angel-Pereira D, Berges-Gimeno MP, Madrigal-Burgaleta R, Urena-

Tavera MA, Zamora-Verduga M, Alvarez-Cuesta E. Successful rapid desen-

sitization to methylprednisolone sodium hemisuccinate: a case report. J Allergy

Clin Immunol Pract 2014;2:346-8.

808. Currie GP, Paterson E, Keenan F, Nath S, Watt SJ. An unexpected response to

intravenous hydrocortisone succinate in an asthmatic patient. Br J Clin Phar-

macol 2005;60:342.

809. Gelincik A, Yazici H, Emre T, Yakar F, Buyukozturk S. An alternative

approach to a renal transplant patient who experienced an immediate type

systemic reaction due to methylprednisolone sodium succinate. J Investig

Allergol Clin Immunol 2009;19:162-3.

810. Nucera E, Lombardo C, Aruanno A, Colagiovanni A, Buonomo A, de

Pasquale T, et al. ‘Empty sella syndrome’: a case of a patient with sodium

succinate hydrocortisone allergy. Eur J Endocrinol 2011;164:139-40.

811. Walker AI, Rawer HC, Sieber W, Przybilla B. Immediate-type hypersensitivity

to succinylated corticosteroids. Int Arch Allergy Immunol 2011;155:86-92.

812. Eda A, Sugai K, Shioya H, Fujitsuka A, Ito S, Iwata T, et al. Acute allergic

reaction due to milk proteins contaminating lactose added to corticosteroid for

injection. Allergol Int 2009;58:137-9.

813. Field S, Falvey E, Barry J, Bourke J. Type 1 hypersensitivity reaction to

carboxymethylcellulose following intra-articular triamcinolone injection.

Contact Dermatitis 2009;61:302-3.

814. Laing ME, Fallis B, Murphy GM. Anaphylactic reaction to intralesional

corticosteroid injection. Contact Dermatitis 2007;57:132-3.

815. Moran DE, Moynagh MR, Alzanki M, Chan VO, Eustace SJ. Anaphylaxis at

image-guided epidural pain block secondary to corticosteroid compound.

Skeletal Radiol 2012;41:1317-8.

816. Steiner UC, Gentinetta T, Hausmann O, Pichler WJ. IgE-mediated anaphylaxis

to intraarticular glucocorticoid preparations. AJR Am J Roentgenol 2009;193:

W156-W157.

817. Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. Dermatitis 2008;19:

38-42.

818. Funk JO, Maibach HI. Propylene glycol dermatitis: re-evaluation of an old

problem. Contact Dermatitis 1994;31:236-41.

819. Warshaw EM, Botto NC, Maibach HI, Fowler JF Jr, Rietschel RL, Zug KA,

et al. Positive patch-test reactions to propylene glycol: a retrospective cross-

sectional analysis from the North American Contact Dermatitis Group, 1996 to

2006. Dermatitis 2009;20:14-20.

820. Nelson JL, Mowad CM. Allergic contact dermatitis: patch testing beyond the

TRUE test. J Clin Aesthet Dermatol 2010;3:36-41.

821. Pereira F, Cunha H, Dias M. Contact dermatitis due to emulsiﬁers. Contact

Dermatitis 1997;36:114.

822. Thomson AB, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term

use of proton pump inhibitors. World J Gastroenterol 2010;16:2323-30.

823. Bose S, Guyer A, Long A, Banerji A. Evaluation and management of hypersen-

sitivity to protonpumpinhibitors.Ann AllergyAsthma Immunol2013;111:452-7.

824. Kepil Ozdemir S, Yilmaz I, Aydin O, Buyukozturk S, Gelincik A,

Demirturk M, et al. Immediate-type hypersensitivity reactions to proton pump

inhibitors: usefulness of skin tests in the diagnosis and assessment of cross-

reactivity. Allergy 2013;68:1008-14.

825. Sanchez-Morillas L, Rojas Perez-Ezquerra P, Gonzalez Mendiola R, Gomez-

Tembleque Ubeda P, Santos Alvarez A, Laguna-Martinez JJ. Eleven cases of

omeprazole hypersensitivity: diagnosis and study of cross-reactivity. J Investig

Allergol Clin Immunol 2014;24:130-2.

826. Lobera T, Navarro B, Del Pozo MD, Gonzalez I, Blasco A, Escudero R, et al.

Nine cases of omeprazole allergy: cross-reactivity between proton pump in-

hibitors. J Investig Allergol Clin Immunol 2009;19:57-60.

827. Mota I, Gaspar A, Chambel M, Morais-Almeida M. Anaphylaxis induced by

proton pump inhibitors. J Allergy Clin Immunol Pract 2016;4:535-6.

828. Sobrev

ia Elfau MT, Garces Sotillos M, Ferrer Claveria L, Segura Arazuri N,

Monzon Ballarin S, Colas Sanz C. Study of cross-reactivity between proton

pump inhibitors. J Investig Allergol Clin Immunol 2010;20:157-61.

829. Otani IM, Banerji A. Immediate and delayed hypersen sitivity reactions to

proton pump inhibitors: evaluation and management. Curr Allergy Asthma

Rep 2016;16:17.

830. Perez Pimiento AJ, Prieto Lastra L, Rodriguez Cabreros MI, Gonzalez

Sanchez LA, Mosquera MR, Cubero AG. Hypersensitivity to lansoprazole and

rabeprazole with tolerance to other proton pump inhibitors. J Allergy Clin

Immunol 2006;117:707-8.

831. Porcel S, Rodriguez A, Jimenez S, Alvarado M, Hernandez J. Allergy to

lansoprazole: study of cross-reactivity among proton-pump inhibitors. Allergy

2005;60:1087-8.

832. Bourneau-Martin D, Leclech C, Jamet A, Drablier G, Trenque T, Juengel K,

et al. Omeprazole-induced drug reaction with eosinophilia and systemic

symptoms (DRESS). Eur J Dermatol 2014;24:413-5.

833. Ghatan PH, Marcusson-Stahl M, Matura M, Bjorkheden C, Lundborg P,

Cederbrant K. Sensitization to omeprazole in the occupational setting. Contact

Dermatitis 2014;71:371-5.

834. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control

study indicates an increased risk of acute interstitial nephritis with proton pump

inhibitor use. Kidney Int 2014;86:837-44.

835. Sandholdt LH, Laurinaviciene R, Bygum A. Proton pump inhibitor-induced

subacute cutaneous lupus erythematosus. Br J Dermatol 2014;170:342-51.

836. Turedi O, Sozener ZC, Kendirlinan R, Bavbek S. A case of pantoprazole

anaphylaxis with cross reactivity to all proton pump inhibitors: ﬁnding a safe

alternative. Curr Drug Saf 2017;12:198-200.

837. Laguna JJ, Bogas G, Salas M, Mayorga C, Dionicio J, Gonzalez-Mendiola R,

et al. The basophil activation test can be of value for diagnosing immediate

allergic reactions to omeprazole. J Allergy Clin Immunol Pract 2018;6:

1628-1636.e2.

838. Benito-Garcia F, Chambel M, Morais-Almeida M. Anaphylaxis due to proton

pump inhibitors: current understanding and important clinical considerations.

Expert Rev Clin Immunol 2018;14:653-6.

839. Conﬁno-Cohen R, Goldberg A. Anaphylaxis to omeprazole: diagnosis and

desensitization protocol. Ann Allergy Asthma Immunol 2006;96:33-6.

840. Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad

Dermatol 1979;1:365-74.

841. Excess of ampicillin rashes associated with allopurinol or hyperuricemia: a

report from the Boston Collaborative Drug Surveillance Program, Boston

University Medical Center. N Engl J Med 1972;286:505-7.

842. Ramasamy SN, Korb-Wells CS, Kannanga ra DR, Smith MW, Wang N,

Roberts DM, et al. Allopurinol hypersensitivity: a systematic review of all

published cases, 1950-2012. Drug Saf 2013;36:953-80.

843. Yun J, Mattsson J, Schnyder K, Fontana S, Largiader CR, Pichler WJ,

et al. Allopurinol hypersensitivity is primarily mediated by dose-depen-

dent oxypurinol-speciﬁc T cell response. Clin Exp Allergy 2013;43:

1246-55.

844. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. HLA-

B*5801 allele as a genetic marker for severe cutaneous adverse reactions

caused by allopurinol. Proc Natl Acad Sci U S A 2005;102:4134-9.

845. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012

American College of Rheumat ology guidelines for management of gout, part

1: systematic nonpharmacologic and pharmacologic therapeutic approaches to

hyperuricemia. Arthritis Care Res (Hoboken) 2012;64:1431-46.

846. Kim SC, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous

reactions requiring hospitalization in allopurinol initiators: a population-based

cohort study. Arthritis Care Res (Hoboken) 2013;65:578-84.

847. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes

Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis:

assessment of medication risks with emphasis on recently marketed drugs. The

EuroSCAR-study. J Invest Dermatol 2008;128:35-44.

848. Gelbart DR, Weinstein AB, Fajardo LF. Allopurinol-induced interstitial

nephritis. Ann Intern Med 1977;86:196-8.

849. Magner P, Sweet J, Bear RA. Granulomatous interstitial nephritis associated

with allopurinol therapy. CMAJ 1986;135:496-7.

850. Walz-LeBlanc BA, Reynolds WJ, MacFadden DK. Allopurinol sensitivity in a

patient with chronic tophaceous gout: success of intravenous desensitization

after failure of oral desensitization. Arthritis Rheum 1991;34:1329-31.

851. Schumacher MJ, Copeland JG. Intravenous desensitization to allopurinol in a

heart transplant patient with gout. Ann Allergy Asthma Immunol 2004;92:

374-6.

J ALLERGY CLIN IMMUNOL PRACT

OCTOBER 2020

S114 BROYLES ET AL

852. Toker O, Tvito A, Rowe JM, Ashkenazi J, Ganzel C, Tal Y, et al. Rapid oral

allopurinol desensitization in a patient with chronic myeloid leukemia. Isr Med

Assoc J 2014;16:461-2.

853. Dursun AB, Sahin OZ. Allopurinol desensitization with a 2 weeks modiﬁed

protocol in an elderly patients with multiple comorbidities: a case report. Al-

lergy Asthma Clin Immunol 2014;10:52.

854. Fam AG, Dunne SM, Iazzetta J, Paton TW. Efﬁcacy and safety of desensiti-

zation to allopurinol following cutaneous reactions. Arthritis Rheum 2001;44:

231-8.

855. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syn-

drome: incidence, prevention and management. Drug Saf 1999;21:489-501.

856. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical

genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486.

857. Pavlos R, Mallal S, Ostrov D, Pompeu Y, Phillips E. Fever, rash, and systemic

symptoms: understanding the role of virus and HLA in severe cutaneous drug

allergy. J Allergy Clin Immunol Pract 2014;2 :21-33.

858. McCormack M, Alﬁrevic A, Bourgeois S, Farrell JJ, Kasperaviciute D,

Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensi-

tivity reactions in Europeans. N Engl J Med 2011;364:1134-43.

859. Knudsen JF, Flowers CM, Kortepeter C, Awaad Y. Clinical pro ﬁ le of oxcar-

bazepine-related angioneurotic edema: case report and review. Pediatr Neurol

2007;37:134-7.

860. Mondal R, Sarkar S, Sabui T, Pan PP. Phenytoin induced life threatening

macroglossia in a child. J Neurosci Rural Pract 2013;4:75-7.

861. Wang XQ, Shi XB, Au R, Chen FS, Wang F, Lang SY. Inﬂuence of chemical

structure on skin reactions induced by antiepileptic drugs–the role of the ar-

omatic ring. Epilepsy Res 2011;94:213-7.

862. Phillips EJ, Mallal SA. HLA-B*1502 screening and toxic effects of carba-

mazepine. N Engl J Med 2011;365:672, author reply 673.

863. Chen P, Lin JJ, Lu CS, Ong CT, Hsieh PF, Yang CC, et al. Carbamazepine-

induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med

2011;364:1126-33.

864. Chen Z, Liew D, Kwan P. Effects of a HLA-B*15:02 screening policy on

antiepileptic drug use and severe skin reactions. Neurology 2014;83:2077-84.

865. Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, et al.

Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to

reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia

2014;55:496-506.

866. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL Jr, Tran E, Berger R,

et al. Clinical Pharmacogenetics Implementation Consortium guidel ines for

HLA-B genotype and carbamazepine dosing. Clin Pharmacol Therapeut 2013;

94:324-8.

867. Yip VL, Marson AG, Jorgensen AL, Pirmohamed M, Alﬁrevic A. HLA ge-

notype and carbamazepine-induced cutaneous adverse drug reactions: a sys-

tematic review. Clin Pharmacol Therapeut 2012;92:757-65.

868. Phillips EJ, Sukasem C, Whirl-Carrillo M, Muller DJ, Dunnenb erger HM,

Chantratita W, et al. Clinical Pharmacogenetics Implementation Consortium

(CPIC) guideline for HLA genotype and use of carbamazepine and oxcarba-

zepine: 2017 update. Clin Pharmacol Therapeut 2018;103:574-81.

869. Patsalos PN, Froscher W, Pisani F, van Rijn CM. The importance of drug

interactions in epilepsy therapy. Epilepsia 2002;43:365-85.

870. Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH, Koren G. Patch

testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a sys-

tematic review. Drug Saf 2009;32:391-408.

871. Lin YT, Chang YC, Hui RC, Yang CH, Ho HC, Hung SI, et al. A patch testing

and cross-sensitivity study of carbamazepine-induced severe cutaneous

adverse drug reactions. J Eur Acad Dermatol Venereol 2013;27:356-64.

872. Shiny TN, Mahajan VK, Mehta KS, Chauhan PS, Rawat R, Sharma R. Patch

testing and cross sensitivity study of adverse cutaneous drug reactions due to

anticonvulsants: a preliminary report. World J Methodol 2017;7:25-32.

873. Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, et al.

Clinical pharmacogenetics implementation consortium guidelines for CYP2C9

and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Therapeut 2014;

96:542-8.

874. Chung WH, Hung SI. Genetic factors associated with severe cutaneous adverse

reactions–reply. JAMA 2014;312:2166.

875. Wang W, Hu FY, Wu XT, An DM, Yan B, Zhou D. Genetic susceptibility to

the cross-reactivity of aromatic antiepileptic drugs-induced cutaneous adverse

reactions. Epilepsy Res 2014;108:1041-5.

876. Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH, Koren G. In

vitro testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a

systematic review. Mol Diagnosis Ther 2009;13:313-30.

877. Butte

MJ, Dodson B, Dioun A. Pentobarbital desensitization in a 3-month-old

child. Allergy Asthma Proc 2004;25:225-7.

878. Lee B, Yu HJ, Kang ES, Lee M, Lee J. Human leukocyte antigen genotypes

and trial of desensitization in patients with oxcarbazepine-induced skin rash: a

pilot study. Pediatr Neurol 2014;51:207-14.

879. Lee J, Park EG, Lee M, Lee J. Desensitization to oxcarbazepine: long-term

efﬁcacy and tolerability. J Clin Neurol 2017;13:47-54.

880. Froscher W, Kleinhans D. Succe ssful induction of tolerance in an epilepsy

patient with phenobarbital allergy. Nervenarzt 1998;69:158-61.

881. Toker O, Tal Y, Horev L, Shmoeli D, Gilboa T. Valproic acid hypersensitivity

and desensitization. Dev Med Child Neurol 2015;57:1076-8.

882. Asero R. Hypersensitivity to diazepam. Allergy 2002;57:1209.

883. Barbaud A, Girault PY, Schmutz JL, Weber-Muller F, Trechot P. No cross-

reactions between tetrazepam and other benzodiazepines: a possible chemical

explanation. Contact Dermatitis 2009;61:53-6.

884. Kampgen E, Burger T, Brocker EB, Klein CE. Cross-reactive type IV hy-

persensitivity reactions to benzodiazepines revealed by patch testing. Contact

Dermatitis 1995;33:356-7.

885. Martinez-Tadeo JA, Perez- Rodriguez E, Hernandez-Santana G, Garcia-

Robaina JC, de la Torre-Morin F. Anaphylaxis caused by tetrazepam without

cross-reactivity with other benzodiazepines. Ann Allergy Asthma Immunol

2012;108:284-5.

886. Martin-Merino E, de Abajo FJ, Gil M. Risk of toxic epidermal necrolysis and

Stevens-Johnson syndrome associated with benzodiazepines: a population-

based cohort study. Eur J Clin Pharmacol 2015;71:759-66.

887. Shrivastava S. An experience with midazolam anaphylactoid reaction. J Anesth

2012;26:642-3.

888. Hagau N, Bologa RO, Indrei CL, Longrois D, Dirzu DS, Gherman-Ionica N.

Maximum non-reactive concentration of midazolam and ketamine for skin testing

study in non-allergic healthy volunteers. Anaesth Intensive Care 2010;38:513-8.

889. Swinnen I, Ghys K, Kerre S, Constandt L, Goossens A. Occupational airborne

contact dermatitis from benzodiazepines and other drugs. Contact Dermatitis

2014;70:227-32.

890. Chia A, Chua WH, Cheung YB, Wong WL, Lingham A, Fong A, et al.

Atropine for the treatment of childhood myopia: safety and efﬁcacy of 0.5%, 0.

1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). Ophthal-

mology 2012;119:347-54.

891. Lonnerholm G, Widerlov E. Effect of intravenous atropine and methylatropine

on heart rate and secretion of saliva in man. Eur J Clin Pharmacol 1975;8:

233-40.

892. Cabrera-Freitag P, Gastaminza G, Goikoetxea MJ, Lafuente A, de la

Borbolla JM, Sanz ML. Immediate allergic reaction to atropine in ophthalmic

solution conﬁrmed by basophil activation test. Allergy 2009;64:1388-9.

893. Coelho D, Fernandes T, Branga P, Malheiro D, Rodrigues J. Intraoperative

anaphylaxis after intravenous atropine. Eur J Anaesthesiol 2007;24:289-90.

894. Tayman C, Mete E, Catal F, Akca H. Anaphylactic reaction due to cyclo -

pentolate in a 4-year-old child. J Investig Allergol Clin Immunol 2010;20:

347-8.

895. Aguilera L, Martinez-Bourio R, Cid C, Arin o JJ, Saez de Eguilaz JL,

Arizaga A. Anaphylactic reaction after atropine. Anaesthesia 1988;43:955-7.

896. Pemberton MN, Yar R, Sloan P. Fixed drug eruption to oxybutynin. Oral Surg

Oral Med Oral Pathol Oral Radiol Endod 2008;106:e19-e21.

897. Issak A, Nystrom P. Cutaneous drug eruption associated with all FDA

approved inhaled muscarinic antagonists. Am J Respir Crit Care Med 2015;

191:A5646.

898. Cavanah DK, Casale TB. Cutaneous responses to anticholinergics: evidence

for muscarinic receptor subtype participation. J Allergy Clin Immunol 1991;

87:971-6.

899. Fisher MM, Bowey CJ. Intradermal compared with prick testing in the diag-

nosis of anaesthetic allergy. Br J Anaesth 1997;79:59-63.

900. Szebeni J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, Patni S, et al.

Hypersensitivity to intravenous iron: classiﬁcation, terminology, mechanisms

and management. Br J Pharmacol 2015;172:5025-36.

901. Tovbin D, Mazor D, Vorobiov M, Chaimovitz C, Meyerstein N. Induction of

protein oxidation by intravenous iron in hemodialysis patients: role of

inﬂammation. Am J Kidney Dis 2002;40:1005-12.

902. Coyne DW, Adkinson NF, Nissenson AR, Fishbane S, Agarwal R,

Eschbach JW, et al. Sodium ferric gluconate complex in hemodialysis patients,

II: adverse reactions in iron dextran-sensitive and dextran-tolerant patients.

Kidney Int 2003;63:217-24.

903. Santosh S, Podaralla P, Miller B. Anaphylaxis with elevated serum tryptase

after administration of intravenous ferumoxytol. NDT Plus 2010;3:341-2.

J ALLERGY CLIN IMMUNOL PRACT

VOLUME 8, NUMBER 9S

BROYLES ET AL S115

904. Barton JC, Barton EH, Bertoli LF, Gothard CH, Sherrer JS. Intravenous iron

dextran therapy in patients with iron deﬁciency and normal renal function who

failed to respond to or did not tolerate oral iron supplementation. Am J Med

2000;109:27-32.

905. Fishbane S, Ungureanu VD, Maesaka JK, Kaupke CJ, Lim V, Wish J. The

safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis

1996;28:529-34.

906. Wysowski DK, Swartz L, Borders-Hemphill BV, Goulding MR, Dormitzer C.

Use of parenteral iron products and serious anaphylactic-type reactions. Am J

Hematol 2010;85:650-4.

907. Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: estab-

lishing a safe dose. Am J Kidney Dis 2001;38:988-91.

908. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug

events associated with parenteral iron. Nephrol Dialysis Transplant 2006;21:

378-82.

909. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related

adverse drug events in hemodialysis patients. Am J Kidney Dis 2001;37:

743-9.

910. McCarthy JT, Regnier CE, Loebertmann CL, Bergstral h EJ. Adverse events in

chronic hemodialysis patients receiving intravenous iron dextran–a comparison

of two products. Am J Nephrol 2000;20:455-62.

911. Mulder MB, van den Hoek HL, Birnie E, van Tilburg AJP,

Westerman EM. Westerman EM. Comparison of hypersensitivity reactions

of intravenous iron: iron isomaltoside-1000 (Monofer

) versus ferric car-

boxy-maltose (Ferinject

). A single center, cohort study. Br J Clin Phar-

macol 2019;85:385-92.

912. Christoph P, Schuller C, Studer H, Irion O, De Tejada BM, Surbek D. Intra-

venous iron treatment in pregnancy: comparison of high-dose ferric carbox-

ymaltose vs. iron sucrose. J Perin Med 2012;40:469-74.

913. Mahey R, Kriplani A, Mogili KD, Bhatla N, Kachhawa G, Saxena R. Ran-

domized controlled trial comparing ferric carboxymaltose and iron sucrose for

treatment of iron deﬁciency anemia due to abnormal uterine bleeding. Int J

Gynaecol Obstetr 2016;133:43-8.

914. Okam MM, Mandell E, Hevelone N, Wentz R, Ross A, Abel GA. Comparative

rates of adverse events with different formulations of intravenous iron. Am J

Hematol 2012;87:E123-E124.

915. Pfenniger A, Schuller C, Christoph P, Surbek D. Safety and efﬁcacy of high-

dose intravenous iron carboxymaltose vs. iron sucrose for treatment of post-

partum anemia. J Perinat Med 2012;40:397-402.

916. Rampton D, Folkersen J, Fishbane S, Hedenus M, Howaldt S, Locatelli F,

et al. Hypersensitivity reactions to intravenous iron: guidance for risk mini-

mization and management. Haematologica 2014;99:1671-6.

917. Sav T, Tokgoz B, Sipahioglu MH, Deveci M, Sari I, Oymak O, et al. Is there a

difference between the allergic potencies of the iron sucrose and low molecular

weight iron dextran? Renal Failure 2007;29:423-6.

918. Adkinson NF, Strauss WE, Macdougall IC, Bernard KE, Auerbach M, Kaper RF,

et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose

in iron deﬁciency anemia: a randomized trial. Am J Hematol 2018;93:683-90.

919. Bailie GR. Comparison of rates of reported adverse events associated with i.v.

iron products in the United States. Am J Health-Syst Pharm 2012;69:310-20.

920. Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: ferumoxytol for intra-

venous iron therapy in adult patients with chronic kidney disease. Am J

Hematol 2010;85:315-9.

921. Macdougall IC, Strauss WE, McLaughlin J, Li Z, Dellanna F, Hertel J.

A randomized comparison of ferumoxytol and iron sucrose for treating iron

deﬁciency anemia in patients with CKD. Clin J Am Soc Nephrol 2014;9:705-12.

922. Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA,

Stenvinkel P, et al. Iron management in chronic kidn ey disease: conclusions

from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Contro-

versies Conference. Kidney Int 2016;89:28-39.

923. Bastani B, Rahman S, Gellens M. Lack of reaction to ferric gluconate in he-

modialysis patients with a history of severe reaction to iron dextran. ASAIO J

2002;48:404-6.

924. Van Wyck DB, Cavallo G, Spinowitz BS, Adhikarla R, Gagnon S,

Charytan C, et al. Safety and efﬁcacy of iron sucrose in patients sensitive to

iron dextran: North American clinical trial. Am J Kidney Dis 2000;36:88-97.

925. Altman LC, Petersen PE. Successful prevention of an anaphylactoid reaction to

iron dextran. Ann Intern Med 1988;109:346-7.

926. Monaghan MS, Glasco G, St John G, Bradsher RW, Olsen KM. Safe

administration of iron dextran to a patient who reacted to the test dose.

Southern Med J 1994;87:1010-2.

927. Jimenez B, Dominguez-Ortega J, Nunez-Acevedo B, Cava-Sumner B, Kin-

delan-Recarte C, Montojo-Guillen C. Rapid iron desensitization after gener-

alized urticaria and facial angioedema. Investig Allergol Clin Immunol 2014;

24:69-71.

928. Rodriguez-Jimenez B, Dominguez-Ortega J, Nunez-Acevedo B, Cava-

Sumner B, Kindelan-Recarte C, Mon tojo-Guillen C. Rapid iron desensitization

after generalized urticaria and facial angioedema. J Investig Allergol Clin

Immunol 2014;24:69-71.

929. Romano A, Di Fonso M, Viola M, Adesi FB, Venuti A. Selective hypersen-

sitivity to piperacillin. Allergy 2000;55:787.

930. Romano A, Gueant-Rodriguez RM, Viola M, Amoghly F, Gaeta F, Nicolas JP,

et al. Diagnosing immediate reactions to cephalosporins. Clin Exp Allergy

2005;35:1234-42.

931. Gaig P. Selective type-1 hypersensitivity to ceﬁxime. Allergy 1999;54:901-2.

932. Bonfanti P, Pusterla L, Parazzini F, Libanore M, Cagni AE, Franzetti M, et al.

The effectiveness of desensitization versus rechallenge treatment in HIV-

positive patients with previous hypersensitivity to TMP-SMX: a randomized

multicentric study. C.I.S.A.I. Group. Biomed Pharmacother 2000;54:45-9.

933. Lantner RR. Ciproﬂoxacin desensitization in a patient with cystic ﬁbrosis.

J Allergy Clin Immunol 1995;96:1001-2.

934. Thomas M, Hopkins C, Duffy E, Lee D, Loulergue P, Ripamonti D, et al.

Association of the HLA-B*53:01 allele with drug reaction with eosinophilia

and

systemic symptoms (DRESS) syndrome during treatment of HIV infection

with raltegravir. Clin Infect Dis 2017;64:1198-203.

935. Heinzerling L, Raile K, Rochlitz H, Zuberbier T, Worm M. Insulin allergy: clinical

manifestations and management strategies. Allergy 2008;63:148-55.

936. Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA Jr, Phillips EJ.

Pharmacogenomics of off-target adverse drug reactions. Br J Clin Pharmacol

2017;83:1896-911.

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