Key Points
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While true drug hypersensitivity is relatively uncommon, many children are labeled as being ‘allergic’ to various medications, particularly antibiotics. They end up carrying this label into adulthood and are likely to be treated with alternative antibiotics, which may be less effective, more toxic, more expensive and lead to the development and spread of certain types of drug-resistant bacteria.
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In children, the drugs most frequently involved in suspected drug hypersensitivity reactions are similar to those in the adult population: β-lactam antibiotics, nonsteroidal antiinflammatory drugs, other antibiotics, acetaminophen/paracetamol and others.
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The entire spectrum of drug hypersensitivity reactions can be seen in children, even the most severe cutaneous and organ-specific types.
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Most of the lessons learnt from drug hypersensitivity reactions in adults can be and have been extrapolated and applied to the pediatric population. However, some peculiarities arise in children in terms of prevalence and involved classes as well as practical aspects of the drug allergy work-up.
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Certain approaches such as simplifying and reducing the protocol steps in highly selected pediatric populations seem increasingly attractive to groups working in pediatric settings. It remains to be seen whether they will stand the test of time and be accepted as a general rule in drug allergy work-up in children.
Introduction
Drug hypersensitivity reactions (DHRs) are adverse effects of pharmaceutical formulations (including active drugs and excipients) that clinically resemble allergy. Iatrogenic by nature, drug allergy goes against the ultimate purpose of prescribing a drug, which is to alleviate, and not to induce a disease. DHRs represent a public health problem whose burden arises from:
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misdiagnosis: both underdiagnosis (due to under-reporting ) and overdiagnosis (due to an over-use of the term ‘allergy’, e.g. in the presence of symptoms due to co-existing factors such as infections );
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prevalence: affecting more than 7% of the general population;
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misbeliefs: not only is the suspicion of DHRs long lasting, with patients carrying the ‘allergy’ label into adulthood, but the field of DHRs must be one of the very few in medicine where the suspicion of a condition may persist even after the diagnosis has been discarded with the best available means.
The work of numerous groups dealing with DHR management has provided a growing body of evidence leading to guidelines and/or consensus documents to support medical decision making on several aspects of DHR. These documents vary in scope and methodology in that they: (1) are national, regional, or international; (2) concern one specific drug class; (3) focus specifically on evaluation tools/management; or (4) are more general. Recently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL) contributed to the issue of an International Consensus (ICON) on drug allergy, a comprehensive reference aimed at highlighting the key messages that are common to the existing guidelines, while critically reviewing and commenting on any differences. As for the ICON on pediatric asthma, unmet needs, research and guideline update recommendations were generated.
Most of the lessons learnt from DHR in adults have been extrapolated and applied to the pediatric population. However, some peculiarities arise in terms of prevalence and involved classes as well as practical aspects of drug allergy work-up. For instance, a shorter algorithm of testing has been recently proposed by some groups in highly selected pediatric patients with a suspicion of β-lactam (BL) allergy. Nevertheless, there are hardly any specific recommendations for the pediatric population. Currently, a Task Force on Paediatric Drug Allergy is ongoing within the European Academy of Allergy and Clinical Immunology (EAACI) drug allergy interest group (DAIG) and its core group, the European Network of Drug Allergy (ENDA).
Clinicians and researchers working in the field of DHR are aware that there is a risk of iatrogenesis in subjects with histories that suggest, but do not always confirm, DHR. Proper identification of a DHR, and all the steps leading to it, upholds the principle of ‘ primum non nocere ’.
Due to space limitation, the entire spectrum of DHRs cannot be addressed and, for this, the reader is referred to the previously mentioned guidelines. This chapter will focus on the most clinically relevant reactions: to antibiotics, aspirin (acetylsalicylic acid; ASA) and other nonsteroidal antiinflammatory drugs (NSAIDs) and vaccines. There is an emphasis on novel approaches in drug allergy work-up in children.
Epidemiology
Patients and physicians commonly refer to all adverse drug reactions (ADRs) as being ‘allergic’. This causes confusion and misconception with regards to drug hypersensitivity. Drugs can indeed induce several different types of immunologic reactions that, together with nonallergic DHRs, comprise 15% of all ADRs. Nonallergic DHRs resemble allergy, but have no proven immunologic mechanism.
While true DHR is relatively uncommon, many children are labeled as being ‘allergic’ to various medications, particularly antibiotics such as penicillins (or more widely, BL). They end up carrying this label into adulthood. These patients are more likely to be treated with alternative antibiotics, which may be less effective, more toxic, more expensive and lead to the development and spread of certain types of drug-resistant bacteria.
Estimates of the prevalence of DHR in the pediatric population vary widely between studies. Recent cross-sectional surveys revealed that the incidence of self-reported DH ranged between 2.5% and 10.2% of children.
A systematic review and meta-analysis concluded that the overall incidence of ADRs in hospitalized children was 9.5%, and that for outpatient children it was 1.5%. A large study from the USA found that the overall incidence of self-reported antibiotic allergy was 15.3%, and that increasing age had a significant correlation with antibiotic allergy prevalence. Nonetheless, these data are based on studies that, in most cases, have addressed ADRs in general, ignoring the underlying mechanism. Indeed, a study on children in Portugal highlighted the fact that although ADRs were frequently reported in an outpatient pediatric survey (10.2%), after a complete evaluation very few (4.5%) of these reactions could be attributed to DHRs.
It is assumed that in children most skin reactions are attributable to infectious diseases or interactions between drugs and infectious agents rather than to the drugs themselves.
Whether or not children carry a drug hypersensitivity into adulthood is not known; there are no follow-up studies addressing this aspect of the natural history of DHRs. While there is little or no evidence regarding nonallergic DHRs, we do have some insight with respect to allergic DHRs: the IgE response (to BL) is known to decrease with time (in adults), while T cell mediated response is long lasting. Proven DHR seems to be less common in children compared with adults. However, the validity of a negative drug allergy work-up performed in adults who have had a reaction suggesting drug hypersensitivity in childhood can be questioned because of the time that has elapsed since the occurrence of the reaction. In a study involving 3,275 patients, Rubio and colleagues reported that when the first reaction occurred during childhood, the prevalence rate of positive tests was similar whether the test was carried out during childhood (10.6%) or adulthood (10.6%). It could be therefore extrapolated that drug hypersensitivity in childhood does not resolve with time, although prescription habits have dramatically changed over the last 20 years, with increasing use of antibiotics in particular.
In children, the drugs most frequently involved in suspected DHRs are similar to those in the adult population: BL antibiotics, NSAIDs, other antibiotics, acetaminophen/paracetamol and local anesthetics.
Clinical Manifestations
Drug hypersensitivity reactions are classified artificially into two types, according to the delay in onset of the reaction after the last administration of the drug: (1) immediate reaction, occurring less than 1 hour after the last drug intake, and (2) non-immediate reaction, with variable cutaneous symptoms occurring after more than 1 hour and up to several days after the last drug intake.
The entire spectrum of DHRs ( Table 55-1 ) can be seen in children, even the most severe cutaneous and organ-specific types.
| Type | Type of Immune Response | Pathophysiology | Clinical Symptoms | Typical Chronology of the Reaction |
|---|---|---|---|---|
| I | IgE | Mast cell and basophil degranulation | Anaphylactic shock Angioedema Urticaria Bronchospasm | Within 1–6 hours after the last intake of the drug |
| II | IgG and complement | IgG and complement-dependent cytotoxicity | Cytopenia | 5–15 days after the start of the eliciting drug |
| III | IgM or IgG and complement or FcR | Deposition of immune complexes | Serum sickness Urticaria Vasculitis | 7–8 days for serum sickness/urticaria 7–21 days after the start of the eliciting drug for vasculitis |
| IVa | Th1 (IFNγ) | Monocytic inflammation | Eczema | 1–21 days after the start of the eliciting drug |
| IVb | Th2 (IL-4 and IL-5) | Eosinophilic inflammation | Maculopapular exanthem (MPE), DRESS | 1 to several days after the start of the eliciting drug for MPE 2–6 weeks after the start of the eliciting drug for DRESS |
| IVc | Cytotoxic T cells (perforin, granzyme B, FasL) | Keratinocyte death mediated by CD4 or CD8 | Maculopapular exanthem, SJS/TEN, pustular exanthem | 1–2 days after the start of the eliciting drug for fixed drug eruption 4–28 days after the start of the eliciting drug for SJS/TEN |
| IVd | T cells (IL-8/CXCL8) | Neutrophilic inflammation | Acute generalized exanthematous pustulosis | Typically 1–2 days after the start of the eliciting drug (but could be longer) |
Drug Allergy Work-Up
Evaluation of the Clinical History
The suspicion of DHR arises from several factors elicited from the clinical history. The following details should be addressed: (1) the timing of the reaction (with respect to drug administration), (2) the nature of the drugs involved, (3) the history of a previous exposure to the same drug or to cross-reactive drugs, (4) the medical/genetic background, (5) the circumstances of the occurrence of the reaction and (6) differential diagnosis. If possible, these details should be compiled in a standardized manner. Documentation of the presence of severity signs ( Table 55-2 ) is mandatory since they will tailor the drug allergy work-up and establish contraindications to re-exposure.
| Visible Severity Signs | Invisible Severity Parameters | |
|---|---|---|
| Immediate reactions | Sudden onset of multisystem symptoms (respiratory, skin and mucosal) | High levels of serum tryptase * |
| Reduced blood pressure | ||
| Dyspnea | ||
| Dysphonia | ||
| Sialorrhea | ||
| Non-immediate reactions | General | Changes in blood count † |
| Lymphadenopathy | Cytopenia | |
| Fever > 38.5°C | Eosinophilia | |
| Organ specific | Alteration of liver function tests † | |
| Painful skin | ||
| Skin extension > 50% | Alteration of kidney function † | |
| Atypical target lesions | ||
| Erosions of mucosa | ||
| Skin blisters, bullae | ||
| Centrofacial edema | ||
| Purpuric infiltrated papules, cutaneous necrosis |
* No clinical utility in the acute setting.
† If a severe delayed DHR is suspected, all patients should have complete blood count and liver and kidney function tests.
Skin Tests
General Aspects of Skin Tests
Skin tests are the first step in in vivo re-exposure to the drug, and are therefore of utmost importance. If positive at validated, nonirritant concentrations, they confirm the diagnosis of sensitization to the culprit and/or cross-reactive drugs and avoid the need for a drug provocation test (DPT). The tests should follow standard operating procedures and should be performed by personnel trained in their practice and interpretation. They have to be applied according to the suspected pathogenetic mechanism of the DHR, with immediate and/or late-reading prick tests and intradermal tests according to the initial clinical presentation (patch tests can also be used to explore delayed DHRs, but late-reading intradermal tests are preferred whenever possible, because of their demonstrated higher sensitivity for BL in adults). The diagnostic value of skin tests is limited by several factors:
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They only address true allergic reactions, providing evidence for type I and type IV drug allergies.
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For most drug allergens, standardized and validated test concentrations and vehicles have not been elucidated. The European Network of Drug Allergy/Drug Allergy Interest Group (ENDA/DAIG) network took on the task of reviewing the literature for evidence to support the recommendation of specific appropriate drug concentrations for systemically administered drugs. Their conclusions and recommendations have recently been published.
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Sometimes the drug is not available in an adequately reactive form (generally because it is a metabolic derivative that is immunogenic and not the parent drug).
Peculiar Aspects of Skin Tests in Children
The pain of intradermal tests may limit their use in young children and, in the absence of therapeutic necessity, a ‘waiting approach’ is generally adopted until the patient is older. On the other hand, viral infections are thought to be the most common cause of maculopapular or urticarial eruptions in children and this hypothesis is strongly favored after a negative drug allergy work-up. With these two considerations in mind, a shorter algorithm of testing, i.e. bypassing skin tests, in highly selected pediatric patients has been proposed by some groups. In the first prospective study of its kind, Caubet et al performed DPT in 88 children with benign delayed eruptions (maculopapular exanthema or urticaria) to BL antibiotics, irrespective of skin test results. The lack of any criteria of severity had been confirmed by a trained allergist in the acute phase of the reaction. Six out of 88 children (6.8%) had a positive DPT (4 of them also had immediate positive intradermal tests but, interestingly, none had positive patch tests or delayed-reading intradermal tests). The authors found that the group with positive intradermal tests did have a significantly higher rate of positive DPT ( P < .05), but that none of the 6 patients with a positive DPT developed a more severe reaction than the index event. They thus concluded that skin tests had a limited value in the diagnosis of these benign cutaneous eruptions in children and suggested performing DPT without previous skin testing in these selected patients.
Drug Provocation Tests
General Aspects of Drug Provocation Tests
The DPT is performed at the end of a stepwise approach in the drug allergy work-up. There is general agreement that this procedure has better sensitivity than all the other available diagnostic tools, and that it may considerably improve patient management. However, its use as the ‘gold standard’ to establish (or exclude) the diagnosis of DHR is not unanimously accepted or widespread in the medical community, due to its inherent risks. Interestingly, however, a study carried out in three European centers dealing with the patient’s perspective and satisfaction with regard to DPT revealed that most patients accepted DPT for diagnostic purposes, irrespective of the final test results. Furthermore, 95% of them believed that it was useful and stated that they would recommend it to others. Similar findings were observed across other centers, in adults as well as in children.
Although not well established, the negative predictive value (NPV) of DPTs is important for both the patient and the physician. One of the main limitations of DPT is that a negative test does not prove beyond any doubt tolerance for the drug in the future, but rather that there is no DHR at the time of the test. Studies regarding the NPV of DPTs are, however, encouraging and display virtually the same results in both adult and pediatric populations. A high NPV of BL DPT of 94% to 98% was found in a large study involving 256 children, and most of the reactions reported by the patients were mild and non-immediate. This information should reassure the patients and their doctors about prescription of drugs after negative DPT.
General considerations on DPTs, with regard to indications, contraindications, methods, limitations and interpretation, have been thoroughly addressed and protocols published. Nevertheless, the precise DPT procedure may vary considerably from one team to the next. Moreover, in pediatric settings, novel approaches arise, awaiting either validation or refutation by larger studies in the future.
Particular Aspects of Drug Provocation Testing in Children
(1)
Methodology of DPT.
Technical aspects vary between published studies in terms of initial dose, number of and interval between protocol steps, and duration of DPT. In a child with negative testing and in the absence of contraindications, drug hypersensitivity should be ruled out or confirmed by administering an age- and weight-appropriate cumulative dose of the drug to which the patient initially reacted. An observation period should then follow, before discharging the child, in order to ensure that no life-threatening reaction occurs. Informed consent should be obtained (ideally from both parents).
A maximum single dose of the specific drug must be achieved and the administration of the defined daily dose is desirable.
(2)
Duration of the DPT.
Depending on the type of the drug itself, the severity of the DHR under investigation and the expected time latency between application and reaction, the DPT may take hours, days or, occasionally, weeks before it is complete.
There is controversy among different groups as to whether one full therapeutic dose (of the tested drug) is sufficient to elicit reactions in non-immediate responders, particularly in children. Hence, prolonged courses have been suggested to increase the sensitivity of DPTs. However, this suggestion is still subject to debate and must be considered with caution in terms of diagnostic improvement, cost and medical implications.
Another matter for discussion concerning non-immediate reactions is the duration of the DPT, and also, for some authors, the location. Theoretically, DPT should be performed in the hospital, under medical supervision. In the study of Ponvert et al, DPTs were carried out either in a hospital setting (for immediate reactors) or at home (for a group of children with a clinical history of mild to moderately severe non-immediate reactions). The latter group was prescribed the daily therapeutic dose for up to 10 days, according to the chronology of the index reaction. Eighty-eight reactions were reported for DPT performed at home, accounting for 6.1% of the 1,431 tested patients. One urticaria with asthma exacerbation and two severe serum sickness-like reactions (SSLR) were elicited by DPT performed at home.
(3)
Step Dosing.
Based on their initial results in the prospective study of 88 children with benign delayed cutaneous reactions during BL treatment (challenged irrespective of skin test outcome), Caubet et al concluded that, in these patients, performing a single-dose DPT can be considered safe. The group is currently generating data with this practice (single-dose protocol, followed by 30-minute observation). The authors emphasize that this procedure requires careful primary evaluation by an experienced allergist and cannot be performed in patients suspected of having a more severe reaction. Such a level of certainty about the initial reaction history is only possible if the clinician has observed the reaction first hand, or if there is clear documentation of the reaction in the medical record. Otherwise, in case of doubt, the group recommends performing a complete drug allergy work-up, including skin testing, prior to a more progressive DPT.
Other authors have also performed DPT with or without skin testing. Chambel et al implemented this practice and reported a 6-year experience of drug allergy work-up in children with clinical histories of either immediate or delayed reactions to BL antibiotics. However, in this study, patients with positive skin tests were not challenged, and in about one third of the patients (32 out of 114, 28%) who underwent DPT directly, an alternative cross-reactive drug was used. Of the 68 patients not skin tested to BL and submitted to a DPT with the culprit antibiotic, almost two thirds (62.5%) could not specify the chronology of the initial reaction. In this study, there were more DPT reactors in the subgroup with immediate index reactions than in the delayed-type reaction group (36.4% vs 16.9%). Conversely, there were more DPT negative patients in the delayed group (19.7% vs 9% who had presented immediate reactions in their clinical history), although this difference did not reach statistical significance in simple univariate analysis.
Regarding these practices (bypassing skin testing, single-dose DPT), no recommendation has been issued by the national or international allergology societies. A growing body of evidence regarding (1) standardization of the various protocols, (2) precise identification of the selected pediatric patients that could benefit from it, and (3) safety profile must be provided before its possible acceptance and adoption as a standard practice in the diagnosis of BL allergy in children.
(4)
DPT Contraindications.
Drug provocation testing should never be performed on patients who have experienced severe, life-threatening immunocytotoxic reactions, vasculitic syndromes, exfoliative dermatitis, erythema multiforme major/Stevens-Johnson syndrome, drug-induced hypersensitivity reactions (with eosinophilia)/DRESS, toxic epidermal necrolysis or organ involvement. In a large retrospective study regarding BL allergy in children, Ponvert et al suggested that SSLR, erythema multiforme and Stevens-Johnson syndrome in children are mainly due to viral infections and that in such patients, with a negative allergologic work-up based on late-reading intradermal and patch tests, DPT might be considered for essential (future necessity) BL. However, this course of action must be regarded with the utmost caution, given that supporting evidence is lacking and due to the high risk of recurrence of such reactions.
Desensitization
In order to confirm or rule out DHR, elective testing, i.e. performing a drug allergy work-up in children labeled ‘allergic’ to important drugs (BL, NSAIDs, local anesthetics), is always preferred to testing during situations of acute need. However, in cases where testing could not be performed before the situation that required therapeutic administration, and in the absence of contraindication, desensitization is an option. Referral to successfully applied existing protocols is recommended because there are no generally accepted protocols for drug desensitization in immediate DHRs,. For non-immediate DHRs the literature is more controversial and desensitization should be restricted to uncomplicated exanthems or fixed drug eruption, due to the unpredictability and limited therapeutic options in severe DHRs.
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