Antibiotic allergy in Hong Kong

Valerie Chiang 姜穎彤, Maegan HY Yeung 楊瀚欣, Philip H Li 李曦

HK Pract 2022;44:98-105

Summary

摘要

Introduction

Antibiotics are frequently associated with a variety of adverse drug reactions and allergies. ¹ However, many documented antibiotic allergies are based on vague symptom recollection or misinterpretation of non-immunological adverse events as allergies. Such “allergy” labels are rarely clinically verified or rechallenged.² The mislabelling of antibiotics allergies, and that of beta-lactam antibiotics (BL) in particular, pose threats to patient wellbeing and global health, especially in light of the COVID-19 pandemic.

This article provides an overview of antibiotic allergies, the situation in Hong Kong, and initiatives in place to mitigate the issue of misdiagnosed allergies.

What is antibiotic alleregy ?

Not all adverse drug resction (ADR) are drug allergies.

Unfortunately, the terms “adverse drug reaction”, “drug hypersensitivity” and “drug allergies” are often mistakenly used synonymously. ADR refers to any “appreciably harmful or unpleasant reaction” associated with the use of a medical product regardless of aetiology.³ Drug hypersensitivity reactions (DHR) refers to any immune-mediated response to a drug.⁴ Drug allergies have traditionally described IgE-mediated reactions, but have recently expanded to include various non-IgE mediated reactions.⁵

The majority of ADRs (75-80%) are classified as (1) type A: predictable, dose-dependent and non-immunological; (2) type B: unpredictable, dose-independent reactions, or “off-target” reactions, which can be immune-mediated or non-immune mediated.

6-10% of these ADRs are mediated by antibodies or immune cells, and are considered true DHRs.⁶ DHRs can be categorised in four categories under the Gell and Coombs classification⁷ , which correlates onset time and clinical manifestations with causative immune mediators: (i) Type I IgE-mediated reactions, (ii) Type II IgM or IgG-mediated cytotoxic reactions and (iii) Type III immune-complex mediated reactions, are all mediated by antibodies. (iv) Type IV hypersensitivity is cell-mediated, and can be further subdivided into “IVa” – “IVd” reactions, based on T-cells involved and cytokines/chemokine mediators.

Clinically speaking, DHRs can be divided into “immediate” (<1hr) and “delayed” (>1hr) based on time of reaction onset after last drug administration8, which broadly distinguishes type I IgE-mediated hypersensitivity from type IV and other hypersensitivity reactions respectively (Table 1). In addition to type I and IV hypersensitivity, the rarer type II and type III reactions are also considered true DHRs.

(I) Immediate hypersensitivity reactions

Immediate type I hypersensitivity is caused by drug-specific IgE, which are generated from previous exposure to the offending drug and bind to mast cell and basophil FcεRI receptors after formation. Upon re-exposure, the cross-linking of drug-antigen to prebound IgE on the surface receptors activates mast cells, resulting in rapid degranulation and release of vasoactive mediators. Urticarial rash is a hallmark of mast cell degranulation, along with angioedema, pruritus, conjunctivitis, wheezing and gastrointestinal symptoms. In severe cases, anaphylaxis may occur resulting in life-threatening multi-organ damage. Commonly implicated drugs include BL antibiotics, neuromuscular blocking agents, quinolones, and platinum-containing chemotherapy drugs.⁹

There are two clinically-relevant points to note regarding type I hypersensitivity:

1. Allergic reactions may wax and wane over time depending on environmental, microbiological and immunological factors. Initially immunological drug allergy reactions can attenuate over time, and 95% of patients with BL allergy labels lose skin testing sensitivity after 10 years.¹⁰
2. No known prior exposure does not exclude type I IgE responses, since sensitisation can occur through cross-reactive compounds ¹¹ or structurally-similar drugs. ¹² In cases of drug allergies or anaphylaxis, a thorough investigation of drug history apart from most recently administered drug is warranted.

(II) Delayed hypersensitivity reactions

The most common mechanism of delayed DHR is type IV hypersensitivity, which is mediated by antigen-specific effector T cells. Type IV hypersensitivity reactions are orchestrated by cytokines released by Th1 CD4 cells in response to antigen. Macrophages recruited to the site of inflammation by chemokines present antigen to T cells and amplify the response. Interferon (IFN)γ and tumour necrosis factor (TNF) α activate macrophages, increasing the release of inflammatory mediators. The timing of reaction onset varies and depends on various factors, including clonicity of T-cell activation¹³, dose and duration of treatment ¹⁴, presence of viral coinfections¹⁵ and HLA associations.¹⁶

Type IV T-cell reactions primarily present with cutaneous manifestations, as the skin barrier houses a large repository of primed memory-effector T-cells. Most common drug-induced cutaneous reactions are relatively mild. However, severe cutaneous adverse reactions (SCAR - such as SJS, TEN, DRESS and AGEP) can be triggered by superantigen-like stimulation and can be life-threatening due to massive cutaneous necrolysis.

At a glance: antibiotic allergy on Hong Kong -

ADRs exert a major burden on the healthcare system, complicating 10-20% of hospitalised¹⁷ and 23% outpatient cases¹⁸ globally. DHRs comprise up to 20% of all ADRs and account for 38%-58.8% of fatal anaphylaxis.¹⁹ In Hong Kong, drug allergies are reported in 6% of the general population and 14% of hospitalised patients (Figure 1).

Systemic anti-infectives (32%) are the most common drug allergy labels, followed by central nervous system medications such as analgesics and opioids (22%), eye medications (9%) and cardiovascular/hematopoietic medications (9%). (Figure 2)

Within antimicrobial drug allergy labels, the vast majority are attributed to Beta-lactam antibiotics (59%), followed by tetracyclines (9%), macrolides (7%), quinolones (7%) and sulphonamides (6%). Beta-lactam antibiotics (Figure 3) are the most widely used class of antibiotics, and most frequently associated with drug allergy. ^1-3 They include penicillins, along with cephalosporins, carbapenems, and monobactams. Most reactions are benign T-cell mediated delayed exanthemas, with SCARs being uncommon. ²¹ Life-threatening anaphylaxis occurs approximately in 0.001% of cases with parenteral exposure and even less for oral exposure.²²

From 2016-2020, the majority of drug allergy labels created have been due to labels. In 2020, the point prevalence of BL antibiotic allergy labels was 2.0% and cumulative incidence of 107 per 100,000 population.²³ (Figure 4) These findings mirror global trends, with 5-15% patients labelled with penicillin allergy in developed countries.

However, from our experience, many patients carry “false” BL drug allergy labels that are unsubstantiated by proper history or allergy testing. Following formal allergological workup of BL allergies, we discovered that less than 14% of patients labelled with BL “allergy” were genuinely allergic.^23,24 This high rate of inaccurate labelling was similar to reports in western cohorts.²⁵

Consequences of misdiagnosed allergies

The detriment of allergy mislabels affects every branch of clinical medicine, with observable negative consequences on patients, healthcare systems and communities.

(I) Effects on patients

Patients with inappropriate allergy labels may be relegated to use alternative antibiotics with more side effects and lower efficacy, such as fluoroquinolones or vancomycin, even when BL antibiotics are indicated. This inadvertently increases the risk of adverse clinical events, such as increased hospital admission rates and length of stay, treatment costs, and deaths.

While the effects of unnecessary allergy labels are apparent across all age-groups and conditions, they disproportionately affect high-risk patient groups.²⁶ Geriatric patients with BL allergy labels have higher mortality rates and required more frequent transfers to convalescent or rehabilitation care centers.²⁷ Furthermore, surgical patients with penicillin allergy labels are more likely to receive inferior perioperative prophylactic antibiotic choices, increasing the risk of postoperative infections by 50%. ²⁸ Correcting false allergy labels can resume life-saving medications, reduce healthcare costs, and improve quality of life especially for high-risk patient groups.

(II) Effects on healthcare system

1. Antibiotic Resistance: Displacement of first-line antibiotics from inappropriate BL allergy labelling leads to unnecessary usage of second-line broad-spectrum alternatives. The use of these “big-gun” antibiotics inadvertently increases the risk of multidrug-resistant organisms (MDRO), which is particularly relevant in Hong Kong given the significant escalation in cases of methicillin-resistant Staphylococcus aureus, carbapenemase-producing Enterobacteriacese, ESBL- producing Escherichia coli, and multidrug-resistant Acinetobacter baumannii. ²⁹ Correct allergy labelling reinforces proper antibiotic stewardship and mitigates the problem of MRDO.
2. Impact on Coronavirus disease (COVID-19) pandemic: COVID-19 vaccine hesitancy is higher in patients with multiple drug allergy labels. 31% of patients with BL “allergy” labels referred for pre-vaccination assessment at the HKWC (Hong Kong West Cluster) Vaccine Allergy Safety Clinic deferred the first dose of vaccinations due to concerns of vaccine-associated allergies.³⁰ However, given that the vast majority of high-risk patients recommended for vaccination completed their vaccinations safely, inappropriate deferrals likely do more harm than good by increasing the risk of infection without avoidance of adverse effects and impeding herd immunity.

How do we work up an antibiotic allergy?

A comprehensive history is perhaps the most important part of evaluating any drug allergy. In our previous study, we identified that history of anaphylaxis and duration since the index reaction are important predictors of genuine allergy.²⁴ Informative clinical histories can help in patient risk stratification, and in many cases, excludes the need for allergy testing. Some patients deemed at higher risk may undergo further evaluation, including skin testing and in-vitro tests. Drug provocation tests remain as the “gold standard” and are necessary to confidently confirm tolerance of BL.^31,32

The diagnosis of a drug hypersensitivity is usually based on clinical judgement, and the general criteria can be considered under the following general framework:

1. Allergen - The patient was administered a drug that likely caused the symptoms. BL antibiotics are the most common drug allergy, as penicillin (and to a lesser extent cephalosporins) can induce all four types of hypersensitivity reactions.
2. Better explanation - Other causes of symptoms, such as non-immunological mechanisms, need to be effectively excluded. While the constituents of “drug allergies” are discussed above, it is also important to consider what is not considered a drug allergy. ADRs can have non-immunological mechanisms and are often clinically misconstrued as "allergies". The presence of cutaneous manifestations coinciding with drug administration may be due to drug-infection interactions, such as morbilliform rash precipitated by amoxicillin in patients with Epstein–Barr virus-related acute infectious mononucleosis, or a misdiagnosed infection-associated rash.³³
3. Clinical features - The manifestations should be largely consistent with an immune-mediated drug reaction. The commonest manifestation is the classic morbilliform “drug rash” that typically appears 1-3 weeks after drug exposure on the trunk and spreads to the limbs. Urticaria is a hallmark of IgE antibody-mediated type I reactions. It is important to evaluate for severe life-threatening forms of DHR. Red flag signs in type I immediate DHR that signal impending cardiovascular compromise include urticaria with laryngeal edema, hypotension, and bronchospasm. In delayed type IV DHR, symptoms of fever, facial edema, blistering mucous membrane lesions and lymphadenopathy are suggestive of SCARs.
4. Duration - The temporal sequence of symptom onset after drug administration is consistent with a DHR, and broadly correspond with the presentations of immediate and delayed type DHRs. It is also worth differentiating between recent versus childhood history of allergy labels. Many children outgrow penicillin allergies, with 50% of penicillin allergic patients losing sensitivity 5 years after last reaction, and 80% losing sensitivity after 10 years.^10,34

Hong Kong Drug Alleregy Delabelling Initiative: - educate, outsource and empower

Despite extensive and devastating impacts of incorrect BL allergy labels, less than 1% of reported allergies are re-challenged through allergy evaluation per year globally, and 1 in 50 population of HK are waiting to be delabeled annually. Even with the formal establishment of Immunology & Allergy Services in Hong Kong, a lack of specialists and limitation in costs pose an unresolved challenge to comprehensive testing and delabelling. Multidisciplinary efforts across specialties, primary care and hospital settings, allied health professionals, and territory-wide clusters are critically needed. In response to this, the Hospital Authority’s HKWC piloted the territory’s Drug Allergy Delabelling Initiative (DADI) in 2019, following the establishment of the Penicillin Allergy Pathway (Figure 5) and Low-Risk Penicillin Allergy Clinic.

The HKWC Penicillin Allergy Pathway & Low- Risk Penicillin Allergy Clinic

The Penicillin Allergy Pathway is a simple infographic available to all in-patient wards of all hospitals under the HKWC. In addition to antibiotic suggestions during the patient's admission, all unclarified suspected BL allergies are referred to our Immunology Clinic for pro-active allergy delabelling. Patients triaged as low risk for genuine BL allergy are seen at our “fast track” dedicated Low-Risk Penicillin Allergy Clinic. This clinic maximizes the number of patients seen, resulting in 99% of allergy labels removed.

Following the success of the Vaccine Allergy Safety Hub-and-Spoke clinics³⁴, HK-DADI adopted its model for allergy delabelling services. HK-DADI is a protocol-driven, multidisciplinary model designed to tackle penicillin allergy by incorporating nurses and allied health professionals in allergy assessment.³⁴ Patients referred to our Immunology Clinic for workup are first triaged by a nurse-led telephone interview. Those classified as “low-risk” then attend a Low Risk Clinic, where penicillin skin testing and provocation testing are performed by trained nursing professionals, supported by an overseeing physician. Following a negative provocation tests, the patients are counselled and given a detailed and personalised letter with their updated drug allergy record for their future medical reference. Our pilot study removed 90% of penicillin allergy labels from 312 attending patients.

DADI has managed to shorten the waiting time for a routine penicillin allergy consultation from over 7 years to around 1 year. Our pilot analysis also showed a higher rate of future penicillin use following delabelling (compared with the traditional delabelling) and mitigated the need for unnecessary skin testing among low-risk patients. Recognising its success, the Hong Kong Hospital Authority plans to roll-out six additional HK-DADI pathways throughout all regional hospitals of Hong Kong in 2022.

Our Hub-and-Spoke models aim to empower individual spokes and non-allergists to be able to provide service and foster more interest in allergy care. The central hub serves to provide training for other clusters, with multi-disciplinary collaborations with Infectious Disease specialists, pharmacists, and internists. Our success highlights the important role of Allied Health Professionals and the collaborative effort in patient management and care.

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