FINAL MASTER THESIS
Department of Pediatric Diseases
DRUG HYPERSENSITIVITY IN CHILDREN
A SYSTEMATIC LITERATURE REVIEW
Faculty of Medicine Author: Hazem Karim Supervisor: Vilija Bubnaitiene Lithuania, Kaunas. 2018m
TABLE OF CONTENTS
1. SUMMARY ... 3
2. ACKNOWLEDGMENTS ... 5
3. CONFLICT OF INTEREST ... 5
4. ETHICS COMMITTEE APPROVAL... 5
5. ABBREVIATIONS ... 6
6. INTRODUCTION ... 7
7. AIM AND OBJECTIVES ... 8
8. LITERATURE REVIEW ... 9
9. RESEARCH METHODOLOGY AND METHODS ... 29
10. RESULTS ... 30
11. DISCUSSION ... 34
12. CONCLUSIONS ... 37
1. SUMMARY
Hazem KarimDrug hypersensitivity in children, a systematic literature review
Research aim: The aim of this research is to provide an up-to-date comprehensive literature review
and systematic review on epidemiology, clinical manifestations, diagnostic tools, and current management on drug hypersensitivity in children.
Objectives: To systematically review the literature on the epidemiology, risk factors, and main
elicitors of drug hypersensitivity in children.
Methodology: a systematic search on Medline (PubMed) from January 1997 till December 2017 with
title/abstract keywords: children OR pediatric AND drug allergy OR drug hypersensitivity AND epidemiology OR prevalence OR incidence OR occurrence OR admission OR risk OR factors.
Study participants: for epidemiological data, the review included only results from studies examining
children between the ages of 0-18.
Research results: 15 studies were examined in this review, 5 studies examining epidemiology and 11
studies examining risk factors with one study overlapping. Data on main elicitors was extracted from all results.
Conclusions: Epidemiological data was found to be highly lacking and inconsistent, highlighting the
need for prospective studies to provide more knowledge and insight into the epidemiology of drug hypersensitivity in children. Multiple risk factors were reported in the studies; female gender, HIV infection, older age, dose, presence of other systemic illnesses, hypertension, Chinese and Indian ethnicity. Significance of atopy as a risk factor was disputed between various studies. The most common cause of drug hypersensitivity is beta lactam antibiotics, NBLAs are the second most common and NSAIDs are the third most common. Chemotherapeutics were also identified as a common elicitor of DH.
SANTRAUKA
Hazem KarimPadidėjusio jautrumo reakcijos į vaistus vaikų amžiuje - sisteminė literatūros apžvalga.
Tyrimo tikslas: išanalizuoti literatūros šaltinius ir pateikti mokslinių straipsnių apžvalgą apie
padidėjusio jautrumo reakcijas į vaistus vaikų amžiuje ir jų epidemiologiją, klinikinius simptomus, diagnostikos būdus ir gydymą.
Uždaviniai: išnagrinėti mokslinės literatūros straipsnius apie epidemiologiją, rizikos veiksnius ir
pagrindinius vaistus, dažniausiai sukeliančius padidėjusio jautrumo reakcijas vaikų amžiuje.
Tyrimo metodika: 1997 metų sausio mėnesio - 2017 metų gruodžio mėnesio laikotarpio mokslinės
literatūros sisteminė apžvalga Medline (PubMed) internetinėje svetainėje. Paieškos žodžiai: vaikai AR vaikų IR alergija vaistams AR padidėjusio jautrumo reakcijos į vaistus IR epidemiologija AR paplitimas AR dažnis AR atvejis AR rizika AR veiksniai.
Tyrimo objektas: mokslinės literatūros duomenys apie vaikų nuo 0 iki 18 metų amžiaus padidėjusio
jautrumo reakcijas į vaistus.
Tyrimo rezultatai: išanalizuota 15 straipsnių, iš kurių 5 aprašyta epidemiologija, 11 – rizikos
veiksniai, 1 – abi sritys. Duomenys apie dažniausiai padidėjusio jautrumo reakcijas sukeliančius vaistus buvo surinkti iš visų 15 straipsnių.
Išvados: Išanalizuotoje literatūroje apie padidėjusio jautrumo reakcijas į vaistus vaikų amžiuje buvo
nepakankamai duomenų apie jų epidemiologiją. Literatūroje buvo paminėta daugybė rizikos veiksnių: moteriška lytis, ŽIV infekcija, vyresnis amžius, gretutinės lėtinės ligos, hipertenzija, kinų ir indų tautybės. Apie atopijos kaip rizikos veiksnio svarbą skaitytoje literatūroje vieningos nuomonės nebuvo. Vaistai, dažniausiai sukeliantys padidėjusio jautrumo reakcijas, buvo beta laktaminiai antibiotikai; antroje vietoje - ne beta laktaminiai antibiotikai; trečioje vietoje - nesteroidiniai vaistai nuo uždegimo. Chemoterapiniai vaistai taip pat turėjo didelę įtaką padidėjusio jautrumo reakcijoms išsivystyti.
2. ACKNOWLEDGMENTS
I would like to extend my sincerest gratitude to my supervisor for her continued support and guidance; her patience, motivation and knowledge helped guide me during the writing of this paper and my work would not be complete without her support.
3. CONFLICT OF INTEREST
The author notes no conflicts of interest.4. ETHICS COMMITTEE APPROVAL
Ethics committee approval was not required.5. ABBREVIATIONS
• ADR – Adverse drug reactions• AGEP – Acute generalized exanthematous pustulosis • BAT – Basophil activation test
• BL – Beta lactam antibiotics • BSA – Body surface area • CMV – Cytomegalovirus • DH - Drug Hypersensitivity • DPT – Drug provocation test
• DRESS - Drug reaction with eosinophilia and systemic symptoms • EBV – Epstein Barr virus
• HIV – Human immunodeficiency virus • LTT – Lymphocyte transformation tests • NBLA – Non-Beta lactam antibiotics
• NSAID – Non-steroidal anti-inflammatory drugs • RDD – Rapid Drug Desensitization
• SJS – Stevens Johnson syndrome • SSLR – Serum sickness like reactions • TEN – Toxic epidermal necrolysis
6. INTRODUCTION
An adverse drug reaction is defined by the World Health Organization (WHO) as a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function [1]. The problem of adverse drug reactions is as ancient as the existence of medications. The unwanted effects of drugs are hurdles constantly faced by clinicians during practice because it often leads to delays in treatment, a prolonged hospital stay, innumerable unnecessary investigations, and may even be fatal in some cases. Multiple studies have attempted to innumerate the prevalence of ADRs in the general population; the reported data varied from 10-15% [2]. Nonetheless, studies attempting to confirm these
data have shown much fewer numbers of confirmed cases [3, 4].
Drugs involved in adverse drug reactions and drugs eliciting hypersensitivity reactions vary between adult and pediatric patients and despite the common knowledge about the many subgroups of ADRs, very few studies have attempted to study drug hypersensitivity independently and even fewer studies focused on the paediatric population in particular. This is indicative of a lack of awareness about the epidemiology, clinical symptoms, risk factors and diagnostic options for DH in children. More so, there is an apparent lack of individual guidelines and protocols for management of DH in younger patients.
In this study, a systemic search of available literature attempts to uncover and provide an updated overview of the epidemiology, clinical manifestations, risk factors, elicitors, diagnostic and management options available in order to provide a step forward towards advancing the understanding and management of drug hypersensitivities in children.
7. AIM AND OBJECTIVES
Aim:
The aim of this research is to provide an up-to-date comprehensive literature review and systematic review on epidemiology, clinical manifestations, diagnostic tools, and current management on drug hypersensitivity in children.
Objectives:
To systematically review the literature on the following: 1. Epidemiology of drug hypersensitivity in children. 2. Risk factors of drug hypersensitivity in children. 3. Main elicitors of drug hypersensitivity in children.
8. LITERATURE REVIEW
An adverse drug reaction is defined by the World Health Organization (WHO) as a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function [1]. ADRs are classified into types A and B. Type A reactions are reactions attributed to the pharmacological action of the drug, these reactions are dependent on the dose of the drug, they include known side effects, drug overdose effect, and drug-drug interactions. Type B reactions are not attributed to the pharmacological action but due to an atypical response to the given drug from the host, these include drug intolerances, idiosyncratic drug reactions, and drug hypersensitivities [5].
Drug hypersensitivity reactions can be immune mediated or non-immune mediated reactions. Differentiating the underlying mechanism can be challenging at times as non-immune reaction manifestations can show resemblance to the immune mediated DHs but with a different pathogenesis such as non-specific degranulation of mast cells and subsequent histamine release in response to administration of vancomycin or RCMs [6]. The immune mediated mechanism of DH can be classified
according to the Gell and Coombs classification system summarized in table 1:
Table 1. Gell and Coombs classification of hypersensitivity
Type Description Mechanism Clinical Features
I IgE mediated IgE mediated rapid
degranulation of mast cells and basophils
Urticaria, Bronchospasm, Anaphylaxis
II Cytotoxic Antibody
mediated
IgG or IgM binds to an antigen bound to a cell causing cell death
Neutropenia, Thrombocytopenia
III Immune complex
mediated
IgG or IgM binds to antigen forming a complex that deposits in vessels or tissues
Serum sickness, Vasculitis
IV Cell-mediated Delayed T cell
activation
AGEP, SJS-TEN, DRESS
Class IV of this classification can be further subdivided into classes IV a-d depending on the cytokines released and the cells involved. This is summarised in table 2:
Table 2. Class IV subclasses
Type Cytokines Cells involved Example
IVa IFN-gamma, TNFa Macrophages Tuberculin reaction,
Eczema
IVb IL5, IL4, IL13 Eosinophils Maculopapular
exanthema, DRESS
IVc Perforin, granzyme B T cells Maculopapular
exanthema, SJS/TEN, pustular exanthema
IVd IL8, GM-CSF Neutrophils AGEP
Drug hypersensitivities can be classified according to the time it takes for symptoms to appear. Immediate type drug hypersensitivities usually manifest within the first 6 hours of drug administration. These DHs are mainly IgE mediated type reactions. Non-immediate type reactions (delayed type) can take anywhere from 6 hours to 3 days for symptoms to appear and are commonly associated with type IV hypersensitivity reactions [7].
Risk Factors
Risk factors of Drug allergies can stem from the drug in use, the patient consuming the drug, or a combination of the two [8].
Patient related factors known to be associated with higher incidence of drug hypersensitivities comprise of age, gender, history of certain viral infections and evidence of history of DH reactions to similar or related drug groups.
When comparing age groups, children are an evident minority when compared to adults as shown in multiple studies [9, 10]. This may be attributable to a variety of factors such as lack of
appropriate reporting, lack of research in the subject and lack of long term exposure to multiple drug regimens. Gender plays a role in the incidence of DH in that increased prevalence of drug allergies in girls when compared to boys [11]. Some studies have suggested incidence in females was double that of
of developing drug allergies in particular from NSAIDs and antibiotics [13, 14] but others have denied
the role in atopy as a risk factor for developing DHs but indicate that it may play a role in increased severity of DH reactions [15, 16]. There is an evident close relationship between delayed type (IV) DHs
and some viral infections [17, 18], most identified viruses associated with increased risk of DH are HIV
and herpes virus [19].
Drug-related risk factors depend on the type of drug, Route of administration and exposure levels (dose and length of treatment). Drugs that can act as haptens or prohaptens or bind to immune receptors, these drugs are associated with an increased risk of immune response [20]. High molecular
weight drugs, such as insulin, are also associated with increased IgE mediated immune responses [10].
Intravenous and topical drugs are more likely to illicit an immune response when compared to oral and other routes of administration [21].
When analysing risk factors for hypersensitivities in children, an important consideration is the volume of administered medications in certain diseases. Studies have found that more multiple smaller doses of a drug are more likely to cause DH than one bigger dose [10, 22]. One group in particular that is
at risk are children suffering from cystic fibrosis. This may be due to the chronic use of multiple medications and in particular intravenous antibiotics and other drugs [23, 24].
Table 3 summarises the findings:
Table 3. Risk factors of DH in children
Patient related factors
Age Adults > children
Gender Females > males
Viruses HIV, Herpes viruses
Auto-immune diseases Atopy as a risk for more severe reaction
Drug related factors
Route IV, topical > oral
Type Haptens, prohaptens and high molecular weight compounds
Clinical Manifestations
Dermatological manifestations:
Urticaria
Acute urticaria is expressed as reddish slightly elevated patches and plaques (wheals), they appear transiently lasting 24-36 hours before resolving, although re-occurrence is not uncommon. It is commonly accompanied by pruritus. Urticaria usually lasts up to 6 weeks on its own accord. In minors, the conditions can be quite distinct in that the itchiness may be completely absent but usually is accompanied by angioedema [25]. They may manifest in annular or polycyclic fashion [26].
In the scope of drug allergy, urticaria manifests within 2 weeks of drug administration. it has been most frequently reported in cases of B-lactam antibiotics, sulfonamides, and NSAIDS administrations [27]. Those drugs can cause urticarial reactions due to immunologic and non-immune
mechanisms, the non-immune mechanism is associated with enhanced leukotriene synthesis.
It is problematic to determine the exact cause of acute urticaria in children as the most common cause is infection, and since most of those cases are treated with antibiotics or NSAIDs or a combination of the two, it is difficult to determine the role of the medications [25].
Maculopapular Exanthems
This condition is the most common presentation of Drug allergy. If the patient has not been previously sensitized it usually manifests within 1 or 2 weeks after the intake of the drug. But if sensitization has occurred in the past, exanthems may appear in as little as 6 – 12 hours [25, 28].
There are no peculiarities to maculopapular exanthems in children when compared to adults, it starts with a truncal eruption that spreads upwards to the face and the limps and may take the pattern of a diffuse erythroderma sometimes although often times it is morbilliform. This condition is self-limited and typically resolves on its own within 14 days [25]. This condition is more common in
patients with viral infections, and in particular in cases with acute EBV infections [29].
Acute Generalised Exanthematous Pustulosis
AGEP exhibits as a sudden occurrence of erythema which may be accompanied by itchiness or be asymptomatic. The erythema contains multiple small sterile pustules <5mm in diameter. This is
usually accompanied by fever and weakness. AGEP is a type IVd allergic reaction [30] that is
considered a serious condition because in children it may come with other conditions such as DRESS or SJS/TEN [28].
Fixed Drug Eruption
Fixed drug eruptions are local, well-defined circular reddish-purplish lesions that may appear as patches, vesicles or blisters [31]. They are unique in that they occur in the same place with every time
that a medication is injected or applied [32]. They may be singular or more than one lesion and may
include pain, itchiness or oedema in the affected region. Over time the lesion darkens, leaving only an area of hyperpigmentation after cessation of the causative drug. Repeated administration of the culprit medication results in a faster rate of recurrence of the eruptions [25].
Acneiform eruptions
Acneiform eruptions present as follicular papules and pustules that appear usually in acne-prone areas such as chest back and face but is unique when compared to acne vulgaris in that it may also appear in other places such as the extremities. This condition usually resolves without leaving residual scars.
Corticosteroids are the main drugs known to cause this condition, the severity of the condition depends on the dose and duration of treatment [25].
Stevens-Johnson syndrome/Toxic epidermal necrolysis
Two conditions currently thought to be part of the same condition, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two very dangerous and possibly fatal drug reactions characterised by epidermal and mucosal detachment. Both conditions are considered very rare with about 1 to 7 per million cases per year for SJS and 0.4 to 1.5 cases per million people per year TEN
[33]. Most common causes are NSAIDs, antibiotics, carbamazepine, phenobarbital, and lamotrigine [34].
Initially the conditions can be difficult to diagnose as the first signs may be unclear, patients may present with fever, ophthalmalgia, and/or dysphagia. These symptoms later progress to reddening of the skin and development of purpuric annular macules on the trunk and face. Those symptoms develop into skin erosions and detachment of the epidermis in the form of blisters [25]. The difference
between SJS and TEN lies in the extent of the skin attachment as a percentage of the total body surface area (BSA); if skin detachment is at <10% of BSA it is identified as SJS, if >30% of BSA is involved
then it is considered TEN. Surface areas between 10-30% are known as SJS/TEN overlap [33].
Other Manifestations
Serum sickness like reactions
SSLR is a type III drug hypersensitivity reaction [35] constituting a triad of rash, fever, and
arthralgia in the absence of dermal or generalised vasculitis. The rash is of similar form to urticaria; forming wheals with a clear centre. In contrast to urticaria, SSLR lesions do not disappear after a day or two.
According to one article, it is estimated that SSLR occurs in 0.06% to 0.5% of pediatric patients with 30% of those cases attributed to Drug Hypersensitivity and more-so 60% of those are reported to be due to antibiotics [36].
Drug reaction with eosinophilia and systemic symptoms (DRESS)
DRESS is a systemic condition that involves lymphadenopathy, unusual blood test results such as eosinophilia and/or atypical lymphocytes. DRESS triggers an inflammatory response in a variety of organs manifesting as pneumonitis, heart failure proceeding myocarditis or neurological conditions such as meningitis or encephalitis. Gastroenteritis, pancreatic dysfunction could also occur but the most affected organ in the body is the liver [37].
Initially, DRESS presents with unspecific symptoms such as weakness, itchiness or fever of unknown origin. Later the fever elevates to 38C or beyond that. This fever can develop multiple weeks before the appearance of a generalised maculopapular rash. This rash is present in 95% of all cases appearing initially on the face and chest, spreading and turning darker (purplish) as it spreads [38].
DRESS is a rare condition, the main known drugs to cause it are anticonvulsants occurring in approx. 1/1000 to 1/10000 of patients treated by them. Other known culprits are allopurinol, asprin, lamotrigine and various antibiotics [39]. Diagnosis is based on the criteria set out by The European
Fig. 1. DRESS diagnosis criteria, Kardaun et al. [40]
Bronchospasm
One study that looked at the prevalence of Bronchospasm in ADRs examined 8,191 reports and identified 2% (187) of those cases to be of bronchospasm. In more than half of those cases (55%) the condition was serious. Anti-pain and anti-inflammatory medications were responsible for 24% of the reports. 64.5% of those were serious. Three fatalities were reported to be due to metamizole administration [41].
Anaphylaxis
Anaphylaxis is a life-threatening allergic emergency. Recognition of this serious condition can be quite challenging in infants in the first year of life the patients more often present with vomiting laryngeal edema and urticaria. Cardiovascular manifestations are more common in teenagers [42].
Data on the prevalence of pediatric anaphylaxis varies from one region to another with one study indicating that drugs are responsible for 1/3 of all cases and another Taiwanese study singling out medications as the culprit in more than half of all incidences of anaphylaxis in the region.
Diagnosis
Improper diagnosis techniques lead to over diagnosis of DH in pediatrics, this is evident by studies aiming to confirm previous diagnosis for example in one study, 60 patients with reports of drug allergy were evaluated based on positive skin tests and oral provocation tests and only 3 children were confirmed [43]. Therefore, an algorithm for drug hypersensitivity diagnosis is essential to avoid over
diagnosis.
Any allergy case investigation should start with an accurate and comprehensive history documentation detailing the peculiarities of the reactions in the patient together with the risk factors and the timing and duration of said reactions. Reactions that begin up to one hour after drug administration are considered to be Immediate Reactions and usually are IgE antibody mediated, other reactions that take longer than one hour from drug administration to appearance of symptoms are considered non-immediate reactions and are mediated by T-cells [44, 45]. This separation is of outmost
importance in that it defines the methods and tests used to assess and confirm the diagnosis. Immediate reactions may be initially evaluated using skin prick tests or immediate reading skin tests, whereas non-immediate reactions can be assessed with patch tests and delated reading intradermal tests [46].
Although skin tests are vastly used in allergology, the gold standard in confirmation of diagnosis are drug provocation tests(DPT) [47].
Fig. 2. Summary of diagnosis protocols for DH, Gomes et al. [45]
The diagram im figure 2 was adapted from a very recent report on drug hypersensitivities in children and suggests a plan of action of diagnostic work-up. The report suggests that any comprehensive allergy investigation should be performed 1-3 months after recovery from the main incidence [45]. In
Clinical History
The first step of any allergy investigation must involve taking a complete clinical history from the patient and the guardians as mentioned previously, some of the most crucial points to include in the investigation are as follows [48]:
1. A detailed description of the drug reaction and its features such as time of onset and duration. 2. The names and groups of all drugs taken by the patient prior to initial symptoms.
3. Dose and route of all medications.
4. History of prior administration of the suspected causative drugs.
5. Any medication given to alleviate the symptoms of the reactions and documentation of their effects on the patient.
In order to simplify the process of clinical history documentation the European Network on Drug Allergy has developed a specific questionnaire available in various languages [49].
While it has been recommended to wait until complete recovery before any allergy workup, examining and documenting patients during their reaction can bring a lot of valuable data and could highlight other signs and symptoms that could have been missed otherwise such as lymph node, liver. Or spleen enlargements [50].
Skin Tests
Skin testing is the most commonly used method of diagnosing and confirming DH in children and adults alike. The significance of skin tests in all drugs has not been fully determined to date. Skin testing methods available are: skin prick test, intradermal test and patch test. Selection of the correct skin testing procedure depends on the type of DH suspected [51].
Skin testing can be specially very helpful in drugs that carry protein allergens, for example insulin, heparin, clotting factors and protamine [52]. These drugs cause DH reactions though an IgE
mediated immediate type hypersensitivity for which skin prick tests are of high diagnostic value due to their high specificity, simplicity, cost, availability and speed of testing [53]. In cases where skin prick
tests presented negative results or if there is a need for higher sensitivity, an intradermal skin test is used using an IV for of the suspected drug whenever possible [51]. Studies have shown a tendency to
avoid intradermal testing by paediatricians due to the pain and discomfort associated with the test in children particularly. other drugs that have established skin test protocols are general anaesthetics, biological modifiers and corticosteroids [46]. If protocols are not available, it is helpful to perform a
skin test using the lowest known non-irritating concentration of the medication. If such information is not known, the skin testing can be performed with a maximum intradermal dose of 1-10 mg/ml [50].
limited to type IV delayed DH reactions that present with cutaneous manifestations [52]. The value of
patch tests is high in anticonvulsants and NSAIDs only but undetermined for other drug groups [54].
For all skin tests, the availability of protocols with known concentrations is limited for children, and in most cases, protocols and guidelines established for adults have been inherited in paediatric practice [55].
In order to perform skin testing, comprehensive clinical history must be obtained prior to testing. And if allergy history is unavailable, testing is contraindicated in most cases. Furthermore, patient must be fully recovered from any previous reactions and a period of 4-6 weeks must pass before undertaking any skin testing as performing skin tests during the acute phase of the allergy is not indicated due to a variety of potential factors such as depletion of mediators and/or the possibility of the child taking antihistamines to alleviate the symptoms. This can lead to incorrect results [50].
In vitro tests
The reported data on the use of laboratory testing in the diagnosis of drug allergies is very scarce in adults and even more so in children. Some of the tests known to be in use are IgE quantification, basophil activation test (BAT), lymphocyte transformation tests (LTT), sulfidoleukotriene release test, and ELISPOT assay [45].
IgE quantification is most common test done in children specially in patients with beta-lactam allergy, it measures the amount of specific IgE antibodies to beta-lactams providing high specificity but the test has a low sensitivity hence the low adoption rates in clinical practice [56]. In some papers, it
had been recommended to perform IgE quantification tests in the cases of an anaphylaxis reaction occurring following beta-lactam antibiotics as a way of confirming the specific culprit and determine cross reactivity [57].
Other tests such as BAT and sulfidoleukotriene release tests can be useful when IgE quantification results were negative or not possible. But reported sensitivity of BAT is as low as 60% or even lower and documented use of those tests amongst pediatric populations is scarce [58].
ELISPOT assay is used to provide a measured count of various cytokines and immune cell by-products to prove a clearer diagnosis. The sensitivity of this test increases proportionally to the number of products being measured [59]. A combination of various cytokines could provide a higher diagnostic
Drug provocation testing
Drug provocation tests are the gold standard of drug allergy confirmation [60]. Although it
should only be performed in mild/moderate reaction cases and not in sever allergy suspicions. In general, there is no difference in guidelines for DPTs between adults and children [61].
The principles of DPT involve administering a very low dose of a suspected drug and repeating it at set intervals, gradually increasing the dose until symptoms of an allergy reoccur. The exact dose fraction and intervals vary between different guidelines and papers and between different medications. The intervals for an immediate reaction suspicion can be as low as 30 minutes to a few hours and in the cases of non-immediate reactions the intervals can be a magnitude of days [61]. It is always
important not to exceed the maximum daily dose allowed for any given drug.
One study looked at 211 children with reported drug allergy and performed a DPT, 14.4% turned a positive DPT. The most common culprit was antibiotics followed by NSAIDs [62].
Main Elicitors
Non-steroidal anti-inflammatory medications
It is estimated that NSAIDs are the second most common cause for drug allergies in children worldwide[63]. Approximately 0.6 – 5.7% of the population may be affected. The gold standard of
diagnosis of NSAID hypersensitivity is Drug Provocation Test [64].
Multiple studies have looked at the prevalence of NSAID allergy, one south American study
[65] has observed that NSAIDs are given more than 75% of patients and NSAID allergy accounted for
52.3% of all allergy cases. another study done in Norway [66] has estimated NSAIDs to be responsible
for 32% of cases whilst a study from Turkey reported 21.1% although a more recent Turkish study has reported 25% [43, 67].
Beta lactam antibiotics
Beta lactams are the main causative drugs for allergies in children worldwide. One Spanish study [12] estimate it to be responsible for 47% of all drug allergies with Amoxicillin is responsible for
about 63% of those cases and penicillin for about 30%.
Confirmation of diagnosis by retrospective studies uncovers many cases of incorrect hypersensitivity assumptions in practice. Although skin tests provide a lot of diagnostic value in children and particularly in those with immediate reactions, DPT still remains the gold standard for confirmation of any diagnosis [68], and in particular in cases of non-immediate reactions, with the
exception of children that express severe reactions such as anaphylaxis.
Beta-lactam hypersensitivity is expressed mostly as a cutaneous manifestation in children (92%) and of those children, 71% develop wheals and hives recognised as urticaria and the rest (29%) develop angioedema [12].
Non-beta lactam antibiotics
The analysis of available data on non-beta lactam antibiotics (NBLA) indicated quite a revealing discrepancy in reported data on incidence and prevalence in various populations. Numerous factors play a role in these results; genetic differences between different populations globally may play a significant role, as well as difference guidelines, protocols and financial aspects influencing the practice of antibiotic administration leading to differing prescription rates of different antibiotic groups in various regions.
For example, in Spain, the most implicated NBLA were quinolones, with a significantly rising incidence rate of 5.96% reported in 2009 up from only 0.53% reported in 2005 placing NBLAs in third place to NSAIDs and Beta-lactams [64], in contrast; an American study has indicated that Sulfonamides
were the NBLA group responsible for the highest prevalence, placing them only in second place to NSAIDs, incidence of Sulfonamide hypersensitivity there varied by age group; 0.5% for ages 0-9 and 2.2% in ages 10-19. Macrolides were the third common cause of drug hypersensitivity according to the same study with a prevalence of 0.4% for ages 0-9 and 0.7% for ages 10-19 [69].
The same American study has suggested that reported antibiotic hypersensitivity varies with its popularity and increases with age of patients and during infancy (1st year of life) it also pointed out
that NBLA hypersensitivity is more common amongst males.
Other antibiotics of interest is Minocycline, it is a common cause of Drug reaction with eosinophilia and systemic symptoms (DRESS) [70]. Antibiotics prescribed for tuberculosis show more prevalence in
hypersensitivity in developing countries [71].
Perioperative drugs
induction medications.
Opiate hypersensitivity is rare [72], this includes all opiates such as morphine, fentanyl and
codeine. Opiate allergy manifests as skin rashes, urticarias and oedemas that are not mediated by IgE antibodies but by mast cell activation [73].
Neuromuscular blockers are known to cause anaphylaxis in a similar fashion by mast cell activation or by IgE antibody mediation [72]. Although IgE mediated mechanisms have stronger
manifestation, one group exhibits an enhanced response to histamine release and that is the benzyl isoquinoline derivatives (tubocurarine, atracurium and mivacurium) [74]. In approx. 60-70% of cases
cross reactivity is present between different groups of neuromuscular agents although it is more often observed between drugs of the same group. This is thought to be due to the shared structures between those groups and in particular the quaternary ammonium group [75]. The most common group to cause
hypersensitivity and in particular anaphylactic reactions is suxamethonium ahead of atracurium and rocuronium [76].
In the case intravascular infusions during operations, synthetic colloids are a known causative of anaphylaxis and are the main elicitor of anaphylaxis in approximately 4% of perioperative drug hypersensitivities. Gelatine is the worst offender, solely the cause of 95% of colloid infusion hypersensitivity reactions [77]. Other agents known to cause similar reactions are Albumin, Dextrans,
and hydroxyethyl starch [72].
Lastly, induction agents which are implicated in about 2% of all perioperative anaphylaxis cases [78], are classified in two groups [72]:
• Barbiturates, and in particular Thiopental is known to cause anaphylactic reactions with an incidence of approximately 1 in 30,000 [78].
• Non-barbiturates include all other induction agents such as benzodiazepines, ketamine, propofol and sevoflurane are rarely involved in allergic reactions in children. Although some reactions may be exhibited, it is generally thought to be due to their histamine releasing properties [72].
The diagram in figure 3 below summarises the guidelines proposed by the British society for allergy and clinical immunology (BSACI) for the investigation of plausible allergies to perioperative agents. The society recommends the adoption of serum tryptase levels as a measurement of mediator release and determination of mast cell activation [74]. Testing for cross-reactivity is a point stressed
upon in the guidelines in ordered to find suitable alternatives as opposed to complete avoidance of the offending groups as this might not always be in the patients’ best interest.
Fig. 3. BSACI guidelines for investigating DH in perioperatives, Ewan et al. [74]
Radiocontrast media
Multiple studies have looked at the statistics of pediatric use of radiocontrast media in hospital settings. One such study has looked 11,306 patients spanning a time period of 13 years till 2006 [79].
This study looked in particular at low-osmolality non-ionic radiocontrast media and has found that only 20 (0.18%) cases of acute allergic reactions were reported, including 16 of them were reported to be mild, one moderate and 3 severe with no reports of any fatalities [79].
In a different study, Gadolinium contrasts media hypersensitivity was examined in 2393 patients. Only 40 of those patients have presented with ADRs this is an incidence rate of only 1.7%
Anticonvulsants
Anticonvulsants are particularly known to cause drug allergies. In fact, Anticonvulsant hypersensitivity syndrome was first described in 1950 as a triad of fever rash and internal organ involvement that tends to befall the patient in one to eight weeks after administration [81]. The degree
of severity of those symptoms vary from mild to very severe. Skin involvement occurs in almost all cases with severity ranging from a mild skin rash to a more severe conditions such as SJS/TEN. it is a rare disease with a reported incidence that is in the range of 1 in 1000 to 1 in 10,000 depending on the literature [82].
The three most implicated drugs known to cause this are phenytoin, phenobarbital and carbamazepine [83]. The first 2 month of treatment of a new anticonvulsant agent pose a higher risk of
Anticonvulsant hypersensitivity, incidence in patients during this period increases to 2.3 to 4.5 in 10,000 for phenytoin and 2.3 to 4.5 per 10,000 for carbamazepine [19].
Chemotherapeutics
Pediatric patients with cancer treated with chemotherapy medications commonly express hypersensitivity to the administered agents, the severity of the reactions can be anywhere from mild to very severe. The table below was adapted from a study that has examined allergies to the three most common drugs indicated in pediatric settings; Carboplatin, L-Asparaginase and methotrexate [84].
From the table in figure 4 below, it can be concluded that L-Asparaginase is the most common cause of hypersensitivities between the three, but all medications seem to exhibit similar symptoms through a mainly IgE mediated reaction.
Fig. 4. Most common chemotherapeutics causing DH and their characteristics, Ruggiero et al. [85]
Treatment And Management
Avoidance remains to be the gold standard in management of drug hypersensitivity [45]. Due
to the age of the patients, avoidance becomes a problematic approach when the medications in question are commonly used agents in cases of infections such as antibiotics and anti-inflammatory medications. Whilst alternatives are available for many of the drugs involved, cross-reactivity must be assessed in advance using diagnostic technique such as skin tests and/or drug provocation tests.
Finding alternative medications is not a straightforward task and many of the alternative therapies may not be approved in pediatric settings or contraindicated. Examples of possible alternatives are Acetaminophen as a safe substitute to NSAIDs and in patients that cannot tolerate Acetaminophen Meloxicam is another alternative available [86].
Desensitisation
In some cases, desensitisation is an option that could be approached if deemed necessary [44].
Desensitisation implies exposing the patient to incrementally increased doses of a drug or agent with the goal of achieving a diminished immune response to the drug.
Allergic reactions tend to occur in about 30% of patients during the course and those reactions are usually mild. Even so, the procedure of desensitisation is one that should only be performed by experienced specialists in a specialised centre that has the facilities to deal with emergencies in the case of a severe reaction [87]. Data on this procedure in pediatrics was not found, but reports in adults
estimate success rates to be in the ranges of 58 – 100% according to one study [88].
The dose and rate of administration is an area of continuous debate and review, it is also different for the drug in question and the route of administration. Normally the initial dose is 1/10,000 to 1/100,000 of the therapeutic dose, the initial dose may be even lower in patients with more severe reactions [87]. The dose is then stepped up by a set amount in intervals of minutes if administered
intravenously or hours if administered orally as oral administration yields a more delayed onset of hypersensitivity manifestations. This procedure is mainly used for IgE mediated type 1 hypersensitivities but may also be used in other types of allergies such as non-immediate allergies.
Standardised protocols for a magnitude of medications such as antibiotics, chemotherapeutic agents, monoclonal antibodies, and others have been published by the European Academy of Allergy and Clinical Immunology EAACI. Protocols have also been suggested for non-immediate drug allergies. But in either case, the guidelines are generalised for adults and children and specific pediatric protocols should be thought after in the future.
Desensitisation is of particular interest in patients with chronic high maintenance conditions such cystic fibrosis [89]. The procedure is contraindicated in patients that exhibit severe allergic
conditions such as SJS/TEN or DRESS.
Acute management
Immediate management of drug allergy manifestations primarily involves cessation of the culprit medication to prevent progression of symptoms [90]. Further management is highly dependent of
Mild cutaneous reactions such as urticarias can be self-limited but concomitant symptoms such as pruritus can be managed by anti-histamines. More severe skin manifestations are managed by application of topical corticosteroid creams or gels. More widespread reactions can be managed by the use of systemic corticosteroids in a dose of about 1mg/kg/day until symptoms dissipate followed by incremental phasing down of the dosage [91].
Other more severe hypersensitivity conditions such as DRESS require a more vigorous treatment plan. This usually involves a combination of an oral corticosteroid at 1mg/kg/day and a bolus of intravenous corticosteroids of about 30mg/kg together with other agents; IVIg, cyclophosphamides, cyclosporins and plasmapheresis have been trialled in clinical settings with differing outcomes [38, 92].
SJS/TEN reactions in children have no definite treatment. Close care and attention to blisters on the skin and mucosa must be given. This must include debridement of the wounds and application of moisture retaining topical agents along with biologic dressings, infected wounds must be sterilised and promptly dressed [93]. Fluid management and electrolyte balance must be closely monitored and
adjusted. Intravenous steroids and other immunosuppressive agents along with plasmapheresis and intravenous antibody administration have all been tried and tested in clinical settings [94]. Patients
suspected of exhibiting symptoms of these conditions must be immediately transferred and treated in a pediatric intensive care unit (pICU) or burns centre, specialists in affected areas of the patient must be consulted immediately to provide prompt care.
The success of treatment of SJS/TEN is highly dependent on the early recognition of the symptoms and stopping the responsible agent. One study that has investigated 113 cases over a decade has found out that prognosis is up by approximately 30% for every day between drug cessation and blister formation [95]. Drugs with longer half-lives are more susceptible to cause mortality regardless of
the speed of drug cessation.
Pulmonary reactions such as bronchospasm are effectively managed using bronchodilators such as salbutamol [76]. More severe anaphylactic reactions require a more vigorous treatment plan.
According to the World Allergy Organisation anaphylaxis guidelines, prompt epinephrine administration as a first line treatment in patients experiencing anaphylaxis is of outmost importance
[96]. the guidelines recommend intramuscular administration of epinephrine as opposed to intravascular
route based on a number of studies that observed higher (approx.. 10%) rate of adverse reactions in patients receiving intravenous injections in contrast to a much lower rate (1%) of incidence in cases of patients receiving intramuscular injections using an auto injector [97]. Methylene blue has been
suggested by the aforementioned guidelines as an alternative to epinephrine due to its vasodilatory actions based on some case reports [98].
Perioperative agents and anaesthetics
Pre anaesthetic history documentation and allergy work-up is a standard practice before any kind of surgery. Special precautions should be taken in children with children with known drug allergies; avoidance of neuromuscular blocking agents of the same group if the group is known, avoiding gelatine solutions and substituting them for serum album solutions due to lower hypersensitivity rates, patients allergic to latex should be operated on in a latex free environment and should have priority over other patients to minimise any chances of exposure to latex and operating rooms must show signs warning others not to bring in latex into the theatre. These recommendations were outlined in a review of protocols in perioperative anaphylactic reactions [72].
Emergency surgeries performed on patients with unknown hypersensitivity history are recommended to be operated on under regional anaesthesia if permissible and with minimal latex exposure [72]. Premedication with antihistamines and corticosteroids or a combination of the two has
not been proven to prevent drug allergies [99].
Chemotherapeutics
Discontinuation of chemotherapy may do more harm than good in patients who experience hypersensitivity reactions [84], therefore the prospect of premedication with corticosteroids and
antihistamines has been an area of particular interest in oncology research. Another solution highly thought after management solution is desensitisation. Rapid drug desensitisations (RDD) is performed in order to reach clinical tolerance in a shorter amount of time, it involves giving the full dose of the drug in small but progressively larger doses at set intervals in order to deplete IgE reserves in serum and avoid an acute reaction [100]. RDD was trialled in a 2002 study on 6 pediatric patients with allergy
to carboplatin had a 100% success rate in allowing the patients to complete the course [101]. Currently,
the international society of pediatric oncology recommends seeking substitutes to carboplatin instead of perusing desensitisation procedures [102]. A study in 2009 trialled a combination of premedication
and desensitisation in children with acute lymphocytic leukemia and reported drug allergy to asparaginase by premedicating children exhibiting mild/moderate allergic symptoms and combining premedication and desensitisation in those with severe allergies. Of the 16 children receiving the treatment, 13 completed the course successfully with no further symptoms. 3 developed anaphylaxis
9. RESEARCH METHODOLOGY AND METHODS
: MethodologyThis paper was researched using two separate search criteria. For the literature review; articles with data on drug hypersensitivity (DH) in children were identified by searching the databases of Medline (PubMed) from January 1997 till December 2017. Additional articles were retrieved from archives, UpToDate, and reference lists of the identified articles. Reviews, observational studies, case series, case reports were included. The focus on commonly involved drugs in children, that is, antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, perioperative, and chemotherapeutics drugs. The relevance of the articles was evaluated by the author on the basis of their titles and abstracts. Selected articles were retrieved, analysed, and interpreted.
For the systematic review; a systematic search on Medline (PubMed) from January 1997 till December 2017 with title/abstract keywords: children OR pediatric AND drug allergy OR drug hypersensitivity AND epidemiology OR prevalence OR incidence OR occurrence OR admission OR risk OR factors.
Selection criteria
For epidemiology systematic study, only studies analysing prevalence in pediatric population or studies that made a clear distinction were included. Studies chosen for prevalence analysis must include multiple drug groups, studies analysing one group exclusively were omitted. Studies looking at ADRs as a whole without any clear distinction in the data between ADRs and DHs were also excluded. One study was omitted due to not providing population sample size data. The second study’s full text was in Polish so the data was extrapolated from the available English summary.
For risk factor analysis, wider inclusion criteria were chosen, studies analysing risk factors in single drug groups were included, studies analysing risk factors in the general population (children + adults) and studies focused on a special pediatric group (asthma, CF) were also included. This method was chosen in order to include the most relevant data possible and in order to determine the significance of these conditions as possible risk factors.
In all cases, articles from books, magazines and other review articles were excluded. Figure 5 summarises the search methodology of this review.
Fig. 5. Research methodology
10.
RESULTS
The table below summarises the findings of studies on epidemiology of DH and the main elicitor drugs identified:
Table 4 Results of Epidemiology studies and the main elicitors involved.
Study Population size (n)
Setting Location Prevalence M/F Ratio Main elicitors identified Tan et al. [14] 4752 Self-Reported in Community Singapore 5.4% 45/55 Antibiotics 60.1% of which BL is 54% NSAIDs 19.4% Porebski et al. [104] 4080 Self-Reported in Community Krakow, Poland 3.38% NA BL 48% Sulphonamides 25% NSAIDs 8% Erkocoglu et al. [3] 11,233 Self-Reported in Community Ankara, Turkey 7.87% before confirmation 0.11% after confirmation 49.7/50.3 Antibiotics 71.8% of which BL 65.8% NSAIDs 33.9% Orhan et al. [105] 2855 Self-Reported in Black Sea region, 2.8% Reported as non-BL 59.3% TMP– SMX
Initial keywords search n=219
Epedmiology related results filtered by title
n=14
application of exclusion criteria after analysing
abstracts n=5
Elgibility after assesment of full-text articles n=5, full text unavailable for 1
article
Risk factor related results filtered by title n=31
application of exclusion criteria after analysing
abstracts n=21
Elgibility after assesment of full-text articles n=11
Community Turkey significant 11.1% NSAIDs 9.9% Rebelo et al. [106] 1426 Self- Reported in Clinical setting Porto, Portugal 6% but only 0.05% confirmed 59/41 BL reported to be highest, no data provided
The following table analyses the findings on the risk factors of DH and the main elicitor drugs identified:
Table 5 Results of risk factor studies and the main elicitors involved.
Study Type of study Populati on size (n) Period Main elicitors identified Drug group studied Risk factors identified Indradat et al. [62]
Retrospective 211 6 years Antibiotics Multiple HIV, not atopy
Cousin et al. [107]
Prospective 635 19 years N/A NSAID Atopy, Allergic
rhinoconjunctivit s, chronic urticaria Cavkaytar et al. 2015 [108]
Prospective 121 3 years N/A NSAID Family history
of allergy
Cavkaytar et al 2017
[109]
Prospective 561 4 years Antibiotics-33% NSAIDs-25% Chemothera peutics-19% Multiple Chemotherapeuti cs, systemic illnesses, not atopy Han et al. [110]
Retrospective 88,033 6 years N/A Multiple Older age, Females
Alves et al. [111]
Retrospective 119 6 years Ibuprofen 79%
NSAID First 24h, not
atopy
Mirone et al. [112]
Retrospective 193 4.5 years Neuromuscu lar blocking agents, BL Perioperative drugs Older age, asthma, hypertension Guyer et al. [113]
Retrospective 73 10 years N/A Perioperative drugs
Roehmel et al. [114]
Prospective 100 N/A cefepime and
piperacillin/t azobactam
Antibiotics First 4 days of antibiotics course, cumulative annual exposure Padilla Serrato et al. [115]
Prospective 90 N/A Penicillin Multiple Asthma was not associated
Tan et al.
[14]
Randomized 4752 N/A Antibiotics 60.1% of which BL is 54% NSAIDs 19.4% Multiple Atopy, Increased income, Chinese and Indian ethnicity
11.
DISCUSSION
Epidemiology
The 5 studies showed a variance in the reported prevalence of drug hypersensitivity in the community from 2.8% to 7.87%. Results with data on drug hypersensitivity exclusively were sparse, the possibility to compare those results to other sources was not possible as no other studies exist that examine drug hypersensitivities as a separate entity from adverse drug reactions.
A limitation of the presented data lies in the methodology used in all the studies involved the studies are using questionnaires filled out by the parents, with limited to no clinical followup nor confirmation. This evidently inflates the values reported.
The inaccuracy of the reported values in most epidemiological studies on Drug hypersensitivities is highlighted in the two studies by Erkocohlu et al. and Rebelo et al., both studies reported a significant decrease in prevalence rates from 7.87% to 0.11% and from 6% to 0.05% respectively after confirmation with DPT and skin testing. Though a limitation of Rebelo et al. study is the limited number of children subjected to confirmation tests; only 60 clinic consultations out of 1426 initial responses. Erkocohlu et al. circumvented this hurdle by acquiring a more detailed history through telephone calling and reported that out of 117 subjects identified as plausible history of DH 110 agreed to a clinical evaluation for confirmation.
The analysis of the limited data present stresses the need for a properly planned prospective study on a large scale to identify true DH prevalence and incidence rates in children.
Risk Factors
Various methods for the analysis of identifiable risk factors of DH were employed in the presented studies. the results comprised of five prospective studies, five retrospective studies and one randomized questionnaire. The most significant limitation of this systematic study is the inconsistency of the risk factors reported; although all articles were trying to identify plausible RFs, the focus and approach and depth of their studies varied significantly. For example, Cousin et al., identified patients with atopy, allergic rhinoconjunctyvitis, chronic urticaria as having an increased risk factor for NSAID allergy whilst Alves et al. reported on the timing of the incidence of DHRs and identifying the first 24hrs following administration as being a significant RF.
An interesting discrepancy exists in the reporting of the significance of atopy as a risk factor for development of DH, Cousin et al, Guyer et al., and Tan et al., identified atopy as having a significant value in their studies whilst Indradat et al, Caykaytar et al. 2017, and Alves et al. found
atopy to be non-significant, there is no correlation pattern between reporting on atopy significance and the drugs in question.
The female gender was identified as a RF in only two studies (Guyer et al. and Han et al.) and although more females were reported in three of the five epidemiological studies, all three found this ratio to be insignificant (P>0.05).
Padilla Serrato et al. examined the prevalence of DH in asthmatic children and concluded a lack of association between Asthma and drug allergy incidence. In contrast, Mirone identified asthma as a significant factor for development of DH in surgical patients.
Studies that included a wider age range (Han et al., and Mirone et al.) both identified older age with increased incidence of DHs, this may suggest a lower overall prevalence of DH in children than in adults.
Roehmall et al. identified a unique pattern in incidence of DH in the scope of multiple antibiotic use in cystic fibrosis patients; they identified an increased risk of DH in the first 4 days of antibiotic course and that the incidence of DH is dependent on the cumulative annual exposure to the medication in those patients.
Other risk factors identified in the results of the studies were, HIV, use of chemotherapeutics, presence of other systemic illnesses, hypertension, Chinese and Indian ethnicity. Each of the aforementioned factors was identified only once and in a differing study. This discrepancy in reporting, once again, highlights the need for prospective studies on a wide scale with clear protocols in order to verify the real significance of the previously reported RFs.
Main elicitors
Eleven of the fifteen studies provided data on the most implicated drug groups in their findings. Beta lactam antibiotics were the most commonly identified drug group to illicit DH in children. This was highlighted in five studies that focused on multiple drug groups with the exception of Mirone et al.; which identified neuromuscular blocking agents as the main perioperative drug group responsible in their study. Only two studies (Indradat et al. and Caykar et al. 2017) identified antibiotics as a main culprit without a clear distinction between its subgroups. NBLA were the second most common cause of DH in four studies (Tan et al., Porebski et al., Erkocoglu et a.l, Orhan et al.) but only two studies (Porebski et al. and Orhan et al.) further identified the drugs within the NBLA group, Porebski et al. reported sulphonamides to be responsible for 25% of all incidences in their study and Orhan identified TMP-SMX to be responsible for 11.1% in their respective study. This discrepancy may be accredited to the difference in prescription habits and varying prevalence of certain drugs in different demographics.
NSAIDs were the third most commonly reported drug group in six studies but reported prevalence rates were highly differing in all studies; Porebski et al. reported the lowest prevalence value at only 8% of all cases identified whilst Erkocoglu et al. was the highest at 33.9%. Alves et al. examined NSAID allergy exclusively in their research and identified ibuprofen as the most common NSAID implicated in DHs
Caykaytar indicated a 19% prevalence of chemotherapeutic DH in the 561 DH cases studied in their research. None of the 15 studies examined in this review indicated significant presence of radiocontrast media allergy or anticonvulsant allergy in the populations examined, this may be a pitfall of the dependence on community reporting in DH research as this method tends to overlook severely ill patients in clinical settings depending on more highly specific medication groups not commonly found in the general community and therefore undermine the hypersensitivity risk they may hold.
12.
CONCLUSIONS
This study has looked at the epidemiology, risk factors and main elicitors of drug hypersensitivity in children. The following was observed:
• Epidemiological data was found to be highly lacking and inconsistent highlighting the need for prospective studies to provide more knowledge and insight into the epidemiology of drug hypersensitivity in children.
• Multiple risk factors were reported in the studies; female gender, HIV infection, older age, dose, presence of other systemic illnesses, hypertension, Chinese and Indian ethnicity. Significance of atopy as a risk factor was disputed between various studies.
• The most common cause of drug hypersensitivity is beta lactam antibiotics, NBLAs are the second most common and NSAIDs are the third most common. Chemotherapeutics were also identified as a common elicitor of DH.
13.
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