Clinical and genetic risk factors of self-reported penicillin allergy

doi:10.1016/j.jaci.2008.03.037

Journal of Allergy and Clinical Immunology

Volume 122, Issue 1, July 2008, Pages 152-158

https://doi.org/10.1016/j.jaci.2008.03.037 Get rights and content

Background

Patients with self-reported penicillin allergy are frequently denied β-lactam antibiotics.

Objective

To identify and correlate clinical and genetic risk factors of self-reported penicillin allergy.

Methods

We conducted a case-control study of adults recruited from allergists' offices. Cases had a history of urticaria, angioedema, wheeze, hypotension, vomiting, or anaphylaxis after a dose of penicillin. DNA from buccal swabs was genotyped for variants associated with candidate genes linked to immediate hypersensitivity (IL4, IL4R, and IL10) and penicillin metabolism (LACTB). Logistic regression was used to calculate the association between penicillin allergy and clinical and genetic factors.

Results

Seventeen allergists identified 76 adults. Complete data were available for 23 cases and 39 controls. Penicillin allergy was associated with a history of penicillin allergy in first-degree relatives (P = .002), a history of other adverse drug reactions (P = .008), and atopy (P = .039). However, in the multivariable analysis, only family history of penicillin allergy remained significant. IL4 single nucleotide polymorphisms (SNPs) rs11740584 (P = .012), rs10062446 (P = .021), and rs2070874 (P = .035) were associated and LACTB SNP rs2729835 (P = .058) was marginally associated with penicillin allergy. Adding rs11740584 or rs10062446 individually improved the clinical multivariable model (R² increased from 0.23 to 0.33). Haplotype analysis did not provide additional information to the SNP analysis.

Conclusion

Self-reported penicillin allergy may be influenced by clinical and genetic factors such as IL4.

Section snippets

Study design and protocol summary

We undertook a case-control study of adults with and without a history of clinical penicillin allergy. Allergist-immunologists identified patients with penicillin allergy (cases) and comparison patients without penicillin allergy with similar demographic characteristics (controls). All participants completed a brief questionnaire assessing the history of the allergic reaction in cases and the presence of risk factors of penicillin allergy hypothesized in the literature: a history of atopy,

Participants

Seventeen allergists identified 76 adults; 65 patients returned all required study information. Three patients were excluded because the buccal swabs contained no detectable DNA. The 62 remaining patients, 23 (37%) with and 39 (63%) without penicillin allergy, were predominantly female and white (Table I).

Of the 23 adults with penicillin allergy, 21 (91%) reported urticaria, 9 (39%) angioedema or swelling, and 7 (30%) shortness of breath or chest tightness or wheeze after receiving penicillin.

Discussion

There is very little current research addressing the diagnosis of drug allergy. We explored clinical and genetic risk factors of self-reported penicillin allergy to understand the underlying complex, multifactorial etiology of this trait, including the clinical, immunologic, and genetic contributions. This is a unique approach for dissecting a clinical diagnosis. We used self-reported allergy not only because penicillin skin testing reagents are unavailable but also because currently it is by

References (38)

G.R. Green et al.
Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G: a cooperative prospective study of the penicillin study group of the American Academy of Allergy
J Allergy Clin Immunol
(1977)
B.B. Levine et al.
Prediction of penicillin allergy by immunological tests
J Allergy
(1969)
A.J. Apter et al.
Re-prescription of penicillin following allergic-like events
J Allergy Clin Immunol
(2004)
F.D. Finkelman et al.
Molecular mechanisms of anaphylaxis: lessons from studies with murine models
J Allergy Clin Immunol
(2005)
S. Kerdine et al.
Interleukin-4 plays a dominant role in Th1- or Th2-like responses during the primary immune response to the hapten penicillin
Mol Immunol
(1996)
D.B. Goldstein et al.
Potential genetic causes of heterogeneity of treatment effects
Am J Med
(2007)
F.E. Simons et al.
Risk assessment in anaphylaxis: current and future approaches
J Allergy Clin Immunol
(2007)
P.A. Greenberger
Drug allergy
J Allergy Clin Immunol
(2006)
M.A. Park et al.
Female sex as a risk factor for penicillin allergy
Ann Allergy Asthma Immunol
(2007)
N.F. Adkinson
Drug allergy

P.A. Greenberger

Drug allergy, part B: allergic reactions to individual drugs: low molecular weight

A. Saxon et al.

Immediate hypersensitivity reactions to beta-lactam antibiotics

Ann Intern Med

(1987)

M.A. Riedl et al.

Adverse drug reactions: types and treatment options

Am Fam Physician

(2003)

D.D. Sogn 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)

C. Fontaine et al.

Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy

Allergy

(2007)

A.R. Salkind et al.

The rational clinical examination: is this patient allergic to penicillin? an evidence-based analysis of the likelihood of penicillin allergy

JAMA

(2001)

J. Gadde et al.

Clinical experience with penicillin skin testing in a large inner-city STD clinic

JAMA

(1993)

B.B. Levine

Immunologic mechanisms of penicillin allergy: a haptenic model system for the study of allergic diseases of man

N Engl J Med

(1966)

B.B. Levine et al.

Penicillin allergy and the heterogenous immune responses of man to benzylpenicillin

J Clin Invest

(1966)

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Genetic association of beta-lactams-induced hypersensitivity reactions: A systematic review of genome-wide evidence and meta-analysis of candidate genes
2023, World Allergy Organization Journal
Beta-lactams (BLs) are the most prescribed antibiotics, being the most frequent cause of drug allergy. However, the association between BL allergy and genetic variations is still unclear.
This systematic review and meta-analysis aimed to summarize the genetic effects of BL-induced hypersensitivity using existing evidence.
We searched PubMed, Medline, Scopus, EMBASE, CINAHL, and Cochrane Library from inception to September 15, 2022 with no language restriction. Genetic association studies investigating genetic variant/polymorphism and risk of drug-induced hypersensitivity reactions among individuals receiving BL-antibiotics were included. We excluded studies of acute interstitial nephritis, drug-induced liver injury, serum sickness, and isolated drug fever. Data were comprehensively synthesized and quality of study were assessed using STrengthening the Reporting of Genetic Association Studies (STREGA). The record screening, extraction and quality assessment were performed by two reviewers and discussions were made to resolve discrepancies. The effects of each variant were pooled and evaluated by modified Venice criteria.
A total of 9276 records were identified, and 31 studies were eligible for inclusion. Twenty-seven were candidate-gene association studies (5416 cases and 5939 controls), while the others were next-generation sequencing (NGS) or genome-wide association studies (GWASs) (119 838 cases and 1 487 111 controls). Forty-nine polymorphisms were identified and most of them located in allergic reaction pathways. Meta-analyses of 15 candidate variants in a mixture of both immediate and non-immediate reactions revealed weak genetic effects of rs1801275 (8 studies; n = 1,560; odd ratio 0.73; 95%CI: 0.57–0.93) and rs20541 (4 studies; n = 1,482; odd ratio 1.34; 95%CI: 1.07–1.68) in IL4R and IL13, respectively. Results from GWASs and NGS identified, and confirmed associations in HLA regions including HLA-DRA, HLA-B, HLA-DQA, HLA-DRB1, and HLA-DRB3.
Our study summarized genetic evidence influencing BL-induced hypersensitivity and estimated effects of potential variants. We postulated that the genomic studies provide better insights to the mechanism of reactions and suggest potential effects of HLA Class II variants. However, results were inconsistent and unable to generalize in different settings. Further high-throughput studies with a well-defined function, epigenetic interaction, incorporated with clinical factors, would be beneficial for risk identification in BL-induced hypersensitivity.
Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort
2021, Journal of Allergy and Clinical Immunology
β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.
We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.
Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.
Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10⁻¹⁴); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10⁻⁷) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10⁻⁷). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10⁻⁹). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.
HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.
The Low Risks and High Rewards of Penicillin Allergy Delabeling: An Algorithm to Expedite the Evaluation
2019, Journal of Pediatrics
Citation Excerpt :
A study of Italian and Spanish patients with penicillin allergies found single nucleotide polymorphisms within HLA-DRA and HLA-DRB5 predicted skin test positivity to amoxicillin and penicillins, but not cephalosporins.57 A candidate gene approach identified variants in genes associated with atopy and T helper type 2 skewing have suggested variants in IL-4, IL-13, and IL-10 among others.58-64 Taken together, these studies are limited by inconsistent definitions of what constitutes a penicillin allergy.
Beta-lactam allergy in Chinese patients and factors predicting genuine allergy
2019, World Allergy Organization Journal
Beta-lactams (BL) are the most frequently reported drug allergy, but the vast majority of patients are found not to be genuinely allergic after evaluation. Few studies have investigated the clinical predictors of genuine BL allergy, and the prevalence in hospitalized Chinese patients is unknown.
Patients admitted to a tertiary hospital in Hong Kong (HK) were analyzed to identify the prevalence and factors associated with the presence of BL allergy labels among hospitalized Chinese patients. A combined cohort of patients having completed allergy investigation for suspected BL allergies in the United Kingdom (UK) and HK were analyzed to identify predictors of genuine allergy.
The prevalence of BL allergy labels in hospitalized HK Chinese was 5%, which was associated with female gender and concomitant non-BL antibiotic allergy labels. The rate of genuine BL allergy patients referred for suspected allergies in the UK and HK cohort was only 14%. History of anaphylaxis and interval of less than a year since the index reaction were independent clinical predictors of genuine BL allergy. The negative predictive value of penicillin skin testing was 90%, confirming the need for drug provocation testing after negative skin testing. There was a high rate of confirmed piperacillin-tazobactam allergy.
The estimated true prevalence of genuine BL allergy in hospitalized HK Chinese is around 0.5%. This high rate of BL mislabeling highlights the need for comprehensive allergy evaluation and screening. History of anaphylaxis and duration since the index reaction are important predictors of genuine allergy. Piperacillin-tazobactam allergy may pose a unique challenge in this population with a high prevalence of suspected allergies, surging antibiotic resistance, and lack of testing available.
Markers of anaphylaxis – a systematic review
2018, Advances in Medical Sciences
Anaphylaxis is defined as severe, life-threatening, systemic or general, immediate reaction of hypersensitivity, with repeatable symptoms caused by the dose of stimulus which is well tolerated by healthy persons. The proper diagnosis, immediate treatment and differential diagnosis are crucial for saving patient's life. However, anaphylaxis is relatively frequently misdiagnosed or confused with other clinical entities. Thus, there is a continuous need for identifying detectable markers improving the proper diagnosis of anaphylaxis. Here we presented currently known markers of anaphylaxis and discussed in more detail the most clinically valuable ones: tryptase, platelet activacting factor (PAF), PAF-acethylhydrolase, histamine and its metabolites.
Evaluation and Management of Penicillin Allergy
2018, Mayo Clinic Proceedings
Penicillin allergy is the most commonly reported drug allergy in the United States. Although penicillin allergy is widely reported, 80% to 90% of individuals with self-reported penicillin allergy are actually able to tolerate penicillins after undergoing evaluation for penicillin allergy. Because most patients with self-reported penicillin allergy will have subsequent negative allergy testing results and tolerate penicillins, they may be unnecessarily exposed to broader-spectrum antibiotics. Use of such antibiotics leads to increased risks of developing antibiotic-resistant microorganisms and incur higher health care utilization costs. In this article, we provide an overview of penicillin allergy and its clinical manifestations as well as an approach for the evaluation and management of penicillin allergy.

View all citing articles on Scopus

: Supported by the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics Cooperative Agreement (HS10399) and the National Heart, Lung, and Blood Institute (HL K23 04337-01 to A.J.A.), and National Institutes of Health grant P20RR02074.

: Disclosure of potential conflict of interest: H. Schelleman has attended scientific conferences paid for by pharmacoepidemiology training funds contributed by pharmaceutical manufacturers. The rest of the authors have declared that they have no conflict of interest.

View full text

Food, drug, insect sting allergy, and anaphylaxisClinical and genetic risk factors of self-reported penicillin allergy

Background

Objective

Methods

Results

Conclusion

Section snippets

Study design and protocol summary

Participants

Discussion

J Allergy Clin Immunol

J Allergy

J Allergy Clin Immunol

J Allergy Clin Immunol

Mol Immunol

Am J Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

Drug allergy

Drug allergy, part B: allergic reactions to individual drugs: low molecular weight

Immediate hypersensitivity reactions to beta-lactam antibiotics

Ann Intern Med

Adverse drug reactions: types and treatment options

Am Fam Physician

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

Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy

Allergy

The rational clinical examination: is this patient allergic to penicillin? an evidence-based analysis of the likelihood of penicillin allergy

JAMA

Clinical experience with penicillin skin testing in a large inner-city STD clinic

JAMA

Immunologic mechanisms of penicillin allergy: a haptenic model system for the study of allergic diseases of man

N Engl J Med

Penicillin allergy and the heterogenous immune responses of man to benzylpenicillin

J Clin Invest

Food, drug, insect sting allergy, and anaphylaxis
Clinical and genetic risk factors of self-reported penicillin allergy