Drug Allergy Diagnosis Anca M. Chiriac,
MD
a
, Pascal Demoly,
MD, PhD
a,b,
*
KEYWORDS Drug hypersensitivity reaction Natural history Severity signs Drug allergy work-up Imputability KEY POINTS There is no substitute for a proper assessment of the clinical history when a drug hypersensitivity reaction is suspected. When assessing a patient with a presumed drug hypersensitivity reaction in the symptomatic phase, it is mandatory to look for severity signs, because they portend a poor prognosis. Confirmation of a drug hypersensitivity relies mostly on in vivo tests, and their contraindications must be rigorously observed. The available literature does not answer the numerous questions regarding the natural history of drug hypersensitivity. When the diagnosis is confirmed, lifelong avoidance of the drug causing the reaction is recommended.
INTRODUCTION
Drug allergy that is poorly documented and often self-reported is a frequent problem in daily clinical practice and has a considerable impact on prescription choices. When drug reactions resembling allergy occur, they are called drug hypersensitivity (DH) reactions (DHRs) before showing evidence of either drug-specific antibodies or T cells. The term drug allergies should be reserved for immunologically mediated DHRs. The diagnostic work-up of DHRs allows a better classification of the reactions and provides patients with more reliable information and recommendations for future treatments. Several guidelines and consensus documents on general or specific drug class–induced DHRs are available to support the diagnosis. This article is based on the recent International Consensus (iCON) on Drug Allergy,1 a consensus that was reached by leading allergy organizations worldwide (the European Academy of Allergy
Disclosure Statement: The authors declare no conflict of interest for this work. a Allergy Unit, Respiratoty and Addictology Department, Hoˆpital Arnaud de Villeneuve, 371, Avenue du Doyen Gaston Giraud, University Hospital of Montpellier Cedex 5, Montpellier 34295, France; b Sorbonne Universite´s, UPMC Paris 06, UMR-S 1136, IPLESP, Equipe EPAR, Paris 75013, France * Corresponding author. Allergy Unit, De´partement de Pneumologie et Addictologie, Hoˆpital Arnaud de Villeneuve, 371, Avenue du Doyen Gaston Giraud, University Hospital of Montpellier Cedex 5, Montpellier 34295, France. E-mail address: [email protected] Immunol Allergy Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.iac.2014.03.002 immunology.theclinics.com 0889-8561/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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and Clinical Immunology [EAACI], the American Academy of Allergy Asthma and Immunology [AAAAI], the American College of Allergy Asthma and Immunology [ACAAI] and the World Allergy Organization [WAO]) to synthesize multiple guidelines into 1 generally approved and accepted consensus document. CLINICAL MANIFESTATIONS
DHRs are classified artificially into 2 types, according to the delay of onset of the reaction after the last administration of the drug: (1) immediate reaction, occurring less than 1 hour after the last drug intake, usually in the form of isolated urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, gastrointestinal symptoms (nausea, vomiting, diarrhea), or anaphylaxis with or without cardiovascular collapse (anaphylactic shock); and (2) nonimmediate reaction, with variable cutaneous symptoms occurring after more than 1 hour and up to several days after the last drug intake, such as late-occurring urticaria, maculopapular eruptions, fixed drug eruptions, vasculitis, blistering diseases (such as toxic epidermal necrolysis [TEN], StevensJohnson syndrome [SJS], and generalized bullous fixed drug eruptions), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and symmetric drug-related intertriginous and flexural exanthemas. Internal organs can be affected either alone or with cutaneous symptoms including hepatitis, renal failure, pneumonitis, anemia, neutropenia, and thrombocytopenia. The first category is mostly mediated through specific immunoglobulin E (IgE), whereas the second is specific T cell mediated. For specific descriptions, the readers are referred to previous issues of The Clinics of North America.2,3 SEVERITY SIGNS OF DHRS
When assessing a patient with a presumed DHR in the symptomatic phase, it is mandatory to look for severity signs and, after doing so, to update the risk/benefit balance of exploring the suspected drug(s) on a case-by-case basis. Severity (danger) signs may include both clinical symptoms and biological/laboratory parameters, according to the type of reaction.1 Some are well-established criteria and have been assigned individual weights in scoring systems for classifying the severity of delayed reactions.4 Severity signs are either obvious to the naked eye (clinical), or invisible (mainly biological) (Table 1). The latter must be looked for thoroughly, to reveal internal organ damage. In immediate reactions, the clinical picture is self-explanatory. Symptoms develop rapidly and cutaneous and mucosal involvement may quickly escalate toward lifethreatening airway, breathing, or circulatory problems. Measurements of histamine or tryptase have no value for the therapeutic management in the acute setting, but may a posteriori support the diagnosis of allergic anaphylaxis, especially in cases of drug allergy in perioperative settings.5 Nonimmediate reactions are more heterogeneous and there may be overlap between different patterns. When confronted with a suspicion of a delayed DHR, both general and organ-specific severity/danger signs must be systematically looked for (see Table 1). Daily reevaluation is mandatory to identify progression or signs of recovery. Regardless of the type of reaction, the presence of severity signs warrants the immediate withdrawal of the suspected drug(s), appropriate supportive treatment of the patient, and special care later during the exploration phase. However, in the absence of these signs and if the drug is mandatory, treating through might be an option.
Drug Allergy Diagnosis
Table 1 Severity/danger signs in DHR Visible Severity Signs
Invisible Severity Parameters
Immediate reactions
Sudden onset of multisystem symptoms (respiratory, skin, and mucosal) Reduced blood pressure Dyspnea Dysphonia Sialorrhea
High levels of serum tryptasea
Nonimmediate reactions
General Lymphadenopathy Fever >38.5 C Organ specific Painful skin Skin extension >50% Atypical target lesions Erosions of mucosa Skin blisters, bullae Centrofacial edema Purpuric infiltrated papules, cutaneous necrosis
Changes in blood countb Cytopenia Eosinophilia Alteration of liver function testsb Alteration of kidney functionb
a
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. Adapted from Bircher AJ. Symptoms and danger signs in acute drug hypersensitivity. Toxicology 2005;209(2):204; with permission. b
NATURAL HISTORY OF DHRS
The natural history of DHR is difficult to assess, for several reasons, and can only be analyzed by a firm initial diagnosis and later reexposures. The current knowledge in this area is scant but needs to be understood when diagnosing a DHR. First, unlike respiratory or food allergy, for which the ubiquitous nature of certain allergens makes it difficult to adhere to strict avoidance of the culprit allergen (which can easily be encountered at eliciting doses in everyday life), in DHR, once the diagnosis has been established, lifelong avoidance of the causative drug is recommended and generally observed, both by the patient and by health care professionals in therapeutic settings. Medicolegal consequences are involved. However, an unpredictable subliminal contact is thought to occur because certain drugs, namely antibiotics, are present in small and hidden amounts in foods. It is not known to what extent this ongoing contact may influence the natural history of DH to antibiotics in the absence of therapeutic exposure. Second, DH is a heterogeneous clinical entity (in terms of clinical manifestations and eliciting drugs) and although the frame is virtually the same (clinical history, drug allergy work-up, avoidance), it is difficult, if not impossible, to put all drugs in the same category and extrapolate the existent data on some antibiotics or nonsteroidal antiinflammatory drugs (NSAIDs) to, for instance, drugs like biological agents. In addition, instances in which the drug is given despite a previous DH provide some insight into how patients may evolve and sometimes outgrow their DH. Data regarding the natural history of DHRs arises from articles addressing this question in a direct or indirect way.
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Follow-up of Patients with a Confirmed DH: Skin Test Conversion
When nonirritant concentrations are used for skin testing (eg, b-lactams), the positive predictive value of skin tests in the presence of a history compatible with a DH has been reported to be 100% for immediate reactions and more than 92% for delayed reactions.6 However, little is known about the clinical consequences of the negativization of a previous positive immunologic response, either assessed by means of skin or biological tests. The IgE antibody response is not permanent over time, and prospective studies of skin test and/or specific IgE reactivity showed that decreased antibody levels may occur months to years after the occurrence of a DH. This finding was mainly reported for penicillin allergy,7 with patients having a selective response to the aminopenicillin side chain switching from positive to negative skin responses sooner than in patients with reactivity to several penicillin determinants. After 5 years, none of the selective responders had positive skin tests. Submitting these patients to reexposure would not be acceptable in the absence of highly specific therapeutic indications because it is suspected that the lack of skin reactivity does not warrant the systemic tolerance of the drug. Vultaggio and colleagues8 reported the case of a patient in whom retreatment after negativization of serum-specific IgE to rituximab led to the development of a new and more severe reaction associated with higher levels of serum IgE antibodies and positive skin tests. The same team9 observed a rapid decrease of specific IgE antibodies to infliximab with none of the patients showing skin test positivity or specific serum IgE within 1 year after the first analysis. However, IgE sensitization may also persist for years, as shown for neuromuscular blocking agents.10 T-cell memory seems to be even stronger for delayed DHRs.11 Follow-up of Patients After Drug Desensitization
Once it is achieved, tolerance through desensitization is maintained by continuous administration of the drug. The process is reversible and, when the drug is discontinued, tolerance is lost over hours or days.12 When the drug is mandatory, as is often the case for chemotherapeutic or biological agents, and in the absence of contraindications, it is common practice that patients undergo desensitization at each cure. Although experts recommend it, it is not clear whether repeat desensitization is required for each drug infusion in all patients. It is known that a subset of patients continues to have reactions during successive desensitizations, suggesting persistent DH. However, some investigators13 reported patients in whom skin test results convert from positive to negative after repeated desensitization and the drug is subsequently tolerated through standard infusion with no reaction. It is unclear whether this tolerance is compatible with a natural loss of sensitivity and instead the investigators put forward the hypothesis of the maintenance of the desensitized state caused by the long half-life of monoclonal therapeutics. Influence of the Underlying Disease
Aspirin-exacerbated cutaneous disease is an entity per se within the large spectrum of ASA/NSAID hypersensitivity. Up to one-third of the patients with chronic spontaneous urticaria (CSU) experience exacerbation of their skin symptoms on ingestion of ASA/ NSAIDs. In contrast, up to 37% of NSAID-hypersensitive patients may develop CSU in the future.14 The degree of sensitivity to NSAIDs may show temporary fluctuations related to the activity of their underlying CSU and sensitivity may even disappear in some patients.15,16
Drug Allergy Diagnosis
Influence of Age
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 DH in childhood can be questioned because of the time elapsed since the occurrence of the reaction. In a study involving 3275 patients, Rubio and colleagues17 reported that, when the first reaction occurred during childhood, the prevalence rate of positive tests was similar whether the test was during childhood (10.6%) or adulthood (10.6%); thus, it could be argued that DH in childhood does not resolve with time. The Multiple Drug Hypersensitivity Syndrome
The immune response in drug allergy is highly specific and often restricted to a drug or drug class. However, under certain circumstances, sensitizations for different drugs occur simultaneously, accounting for the multiple DH (MDH) syndrome.18 Recent studies place severe cutaneous adverse reactions (SCARs), and particularly DRESS, at high risk of inducing multiple drug sensitizations. Antimicrobials or antiepileptics are often involved and are considered the primary eliciting drugs, but neosensitizations also involve drugs given as concomitant therapy for several weeks before the onset of the SCAR.11 Thus, MDH with simultaneous sensitizations could be regarded as a model of how an acquired DH facilitates a new DH. In these patients, drug sensitization (as proved by either positive skin tests or lymphocyte transformation test) is persistent and detectable for many years after the allergic reaction.11,19,20 EVALUATION OF THE CLINICAL HISTORY
The suspicion of DHR arises on a constellation of data that make up the clinical history. Two main situations occur in everyday practice: the patient is seen during the symptomatic phase, or the patient is referred to the allergy consultation after recovery. When patients are seen during the symptomatic phase, physical examination is mandatory to provide invaluable information (ie, the presence/absence of danger signs) and to help ensure that a severe reaction is not overlooked. Otherwise, diagnosis is more difficult and, in this case, photographs taken at the time of the reaction are helpful. In addition, there are inpatients and outpatients. For hospitalized patients, data can more easily be tracked from medical records. For outpatients, it is especially important to enquire about over-the counter medications and health supplements, because patients often do not report these as medications. The approach to assessing a suspicion of DHR could be conceived as a pyramid. The first step (ie, the basis) is as exhaustive as possible. It encompasses symptoms, physical examination, and a complete drug administration history, including starting and stopping points of each medication. Then, several things help narrow down the list of potential causes of a DHR. Among them, the timing is of paramount importance, with its multifaceted distribution: the temporal relationship between the administration of each drug and the onset of symptoms, the effect of stopping the treatment, and the time to recovery. Several chronologies have been described,1 and they refer typically to naive patients (ie, those experiencing the DHR for the first time). However, if the causative drug is readministered by mistake, the delay can be considerably shorter. Although any drug can cause a DHR, the nature of the drugs involved and the knowledge of the classes most likely to be associated with the type of reaction may help in establishing extrinsic imputability. Special attention should be paid to dose changes, because for certain drugs and clinical presentations, dose changes are known to accelerate the onset of symptoms. Procedures involving administration of contrast
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media or dyes should be tracked, because these agents are potential elicitors. Moreover, iodinated radiocontrast media (RCM) have been reported to elicit very delayed DHRs (ie, several days after a single administration) and this kind of peculiarity should be kept in mind when considering imputability related to timing.21 A history of previous uneventful exposure and/or prior DHR is equally important. For instance, patterns of reaction have been established for certain drugs, such as the occurrence of DHRs to platinum salts or biological agents.13,22 Besides the differential diagnosis (eg, food allergy, infection), the circumstances surrounding the onset of the reaction should be recorded. Cofactors like physical effort or exposure to light should not be overlooked. In addition, interpreting the data in the medical/genetic background of the patient produces additional information. Specific questioning for a medical condition, such as chronic urticaria/chronic rhinosinusitis (which can be aggravated by the intake of certain drugs; eg aspirin and non–cyclooxygenase-2–selective NSAIDs), or autoimmune or infectious disease (eg, patients infected with human immunodeficiency virus) facilitates the interpretation. Moreover, recent findings have shown a strong genetic association between human leukocyte antigen alleles and susceptibility to specific immune-mediated DHRs.23,24 Data should ideally be recorded in a uniform format and, in order to harmonize the DHR diagnostic procedures, members of EAACI-DAIG/ENDA have developed a questionnaire25 that is available in many different languages. In complex situations, a flow diagram including clinical manifestations and biological parameters should be drawn, for a more comprehensive overall view of the available data. There is no substitute for a proper assessment of the clinical history. However, in most cases clinical history alone is not reliable, for various reasons (concomitant medication, imprecise information, heterogeneity of the clinical manifestations).26 PHARMACOVIGILANCE ALGORITHMS
Causality assessment methods performed by pharmacovigilance authorities are based principally on the clinical history (which may be insufficient or inaccurate) and are not designed to make definite decisions but rather to classify adverse drug reactions from the likelihood of a causal relationship between the drug and the reaction, as well as to detect new alerts. Moreover, they do not specifically address DHR. Therefore their sensitivity to ascertain DHRs is low, and allergy testing is often necessary.26 An algorithm tailored to SJS/TEN, with parameters chosen from clinicians’ knowledge of experts and available scoring systems, has been proposed by the RegiSCAR Study Group.27 SKIN TESTS
Skin tests (STs) are of utmost importance for the diagnosis of DHRs. Their use and interpretation is sometimes hampered by lack of data regarding nonirritant concentrations and vehicles. To address this pitfall, the EAACI-DAIG/ENDA experts recently reviewed the available literature in order to recommend appropriate concentrations for systemically administered drugs.28 The conclusions are summarized in Table 2. The sensitivity of STs seems to be moderate to high for immediate DHRs to b-lactam antibiotics, perioperative drugs, heparins, and platinum salts but low for many other drugs. For most drugs, the sensitivity of STs is higher in immediate DH compared with nonimmediate DH.28 A recent multicenter study to determine the
Drug Allergy Diagnosis
Table 2 Nonirritating skin test concentrations for some systemically administered drugs Drug or Drug Class
SPT
IDT
Patch
Heparinsa
Undiluted
1/10 diluted
Undiluted
Heparinoidsb
Undiluted
1/10 diluted
Undiluted
Carboplatin
10 mg/mL
1 mg/mL
NA
Oxaliplatin
1 mg/mL
0.1 mg/mL
NA
Cisplatin
1 mg/mL
0.1 mg/mL
NA
Pyrazolonesc
Powder
0.1 mg/mL
10%
Coxibsd
Powder
—
10%
Other NSAIDse
Powder
0.1 mg/mL
10%
Anticoagulants
Platinum Salts
NSAIDs
Biologics Adalimumab
50 mg/mL
50 mg/mL
Undiluted
Etanercept
25 mg/mL
5 mg/mL
NA
Infliximab
10 mg/mL
10 mg/mL
NA
Omalizumab
1.25 mg/mL
1.25 mg/mL
NA
Others Local anesthetics
Undiluted
1/10 diluted
Undiluted
Iodinated RCM
Undiluted
1/10 diluted
Undiluted
Gadolinium chelates
Undiluted
1/10 diluted
NA
Patent blue
Undiluted
1/10 diluted
NA
Methylene blue
—
1/100 diluted
—
Fluorescein
Undiluted
1/10 diluted
Undiluted
PPIf
Undiluted
40 mg/mL
10%
Anticonvulsantsg
NA
NA
10%
Chlorhexidine digluconate
5 mg/mL
0.002 mg/mL
1%
Abbreviations: IDT, intradermal test; NA, not applicable or no test concentration recommended; PPI, proton pomp inhibitors; SPT, skin prick test. a Heparins: heparin sodium, nadroparin, dalteparin, and enoxaparin; testing contraindicated in heparin-induced thrombopenia. b Heparinoids: danaparoid and fondaparinux. c Pyrazolones: metamizol, paracetamol, propyphenazone, aminopyrine, phenazone, and phenylbutazone. d Coxibs: celecoxib, etoricoxib, and valdecoxib. e Other NSAIDs: for example, aspirin, ibuprofen, naproxen, indomethacin, diclofenac, fenoprofen, meloxicam, mefenamic acid, and nimesulide. f For lansoprazole and rabeprazole, no intravenous solution is available: SPT with powder; IDT not possible. g In case of history of severe reaction, test first with 1%. From Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs - an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013; 68(6):705; with permission.
value and safety of drug patch tests for the 3 main classes of SCARs found a sensitivity of 64% among cases with DRESS, 58% for AGEP, and 24% for SJS/TEN. For nonimmediate reactions, delayed-reading intradermal tests have a higher sensitivity than patch tests.29
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Preliminary results regarding the satisfactory negative predictive value (NPV) of STs in immediate DHR to iodinated RCM, gadolinium contrast agents, or myorelaxants30–32 await confirmation in larger series. Although there is general agreement among Allergology Societies and Academies on the importance of ST in drug allergy work-up, it is still a matter of debate for some drugs. The US Practice Parameters33 suggest that immediate DHRs to iodinated RCM are all nonallergic (described as anaphylactoid) and therefore STs are not included in the management of patients who have experienced a previous DHR to iodinated RCM. The European experience34 challenges this position. Testing patients without a prior history of DHR is not supported by available studies and therefore is not recommended, in particular in preoperative settings.5 BIOLOGICAL TESTS
There is no universal biological test either to diagnose or to predict DHRs. With some exceptions, the currently available biological methods to diagnose drug allergy lack sensitivity, although they are normally considered to be specific.1 A negative test does not exclude the imputability of the drug, whereas a positive result shows a sensitivity to the drug but does not reliably confirm its causality. For specific descriptions, readers are referred to previously published guidelines and reviews.1,35 PROVOCATION TESTS
The drug provocation test (DPT) comes at the end of a stepwise approach in the drug allergy work-up. It is the procedure with the highest sensitivity among all the other available diagnostic tools, but its use as the gold standard to establish (rather than just to exclude) the diagnosis of DHR is not unanimously accepted, mostly because of the reactions it may trigger, ranging from mild to severe. Although protocols are not standardized among centers, and the precise challenge procedure varies from one team to another, there is general consensus with regard to 2 prerequisites: contraindications must be strictly observed before deciding whether or not to perform a DPT, and immediate treatment must be available, allowing complete and rapid recovery. Several recent studies discussed the concerns that had already been raised about DPT protocols and methodology. There is some controversy among different groups about whether 1 full therapeutic dose of a tested drug is sufficient to elicit reactions in nonimmediate responders. Hence, full therapeutic courses have been suggested to increase the sensitivity of DPTs.36 However, such an indication must be regarded cautiously, in terms of diagnostic improvement, cost, and medical implications, and is yet to be debated. In contrast, groups37,38 performing DPTs in the pediatric population suggest that a 1-dose DPT in children with a history of delayed-onset benign reaction to b-lactams (assessed by a careful primary evaluation in the acute phase by an experienced allergist) can be considered sufficient and safe, even in the absence of an ST.37 Although tempting, this approach needs validation in larger studies. Patients do not like to be reexposed to drugs that they consider harmful. However, recent data collected from 3 centers in Europe revealed that most patients accepted DPTs for diagnostic purpose irrespective of the test results, and 95% of them thought that DPT was useful and that they would recommend it to others.39 A negative DPT does not prove tolerance to the drug in the future, but rather that there is no DH at the time of the challenge and to the doses challenged. Nevertheless, a high NPV of b-lactam DPT of 94% to 98% was found in large studies involving both children and adults,40,41 and most of the reactions reported by patients were both mild
Drug Allergy Diagnosis
and nonimmediate. The NPV of DPT with NSAIDs similarly seems to be high (more than 96%) whatever the NSAID (the one negatively tested or an alternative), and none of the false-negative patients described a life-threatening reaction.42 SUMMARY
The diagnosis of DHR remains largely clinical. Reasoning is almost identical for all drugs and all clinical presentations. With the help of some allergy tests that are available for some of the drug classes and a careful approach, a firm diagnosis is often possible no matter which drug is involved. However, a lot still needs to be done for severe cutaneous reactions for which DPTs are contraindicated and in biological diagnosis.43 Clinicians and researchers working in DH are aware that there is a risk of iatrogenesis in subjects with histories that suggest but are not always confirmed as DH. Proper identification of a DH upholds the principle of primum non nocere, and this principle is a challenge that weighs heavily in all their considerations. The attitude of not evaluating a suspicion of DH carries the risk of using unnecessary avoidance measures (with the obvious medical consequences) or overlooking alternative diagnoses. All this renders the field of DH diagnosis a very vivid one, because universal acceptance of classifications, diagnostic tests, or protocols is difficult to achieve. REFERENCES
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11. Barbaud A, Collet E, Milpied B, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol 2013;168(3):555–62. 12. Cernadas JR, Brockow K, Romano A, et al. General considerations on rapid desensitization for drug hypersensitivity - a consensus statement. Allergy 2010; 65(11):1357–66. 13. Brennan PJ, Rodriguez Bouza T, Hsu FI, et al. Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol 2009;124(6):1259–66. 14. Asero R. Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria. J Allergy Clin Immunol 2003;111(5):1095–8. 15. Kowalski ML, Makowska JS, Blanca M, et al. Hypersensitivity to nonsteroidal antiinflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy 2011;66(7):818–29. 16. Setkowicz M, Mastalerz L, Podolec-Rubis M, et al. Clinical course and urinary eicosanoids in patients with aspirin-induced urticaria followed up for 4 years. J Allergy Clin Immunol 2009;123(1):174–8. 17. Rubio M, Bousquet PJ, Gomes E, et al. Results of drug hypersensitivity evaluations in a large group of children and adults. Clin Exp Allergy 2012;42(1):123–30. 18. Chiriac AM, Demoly P. Multiple drug hypersensitivity syndrome. Curr Opin Allergy Clin Immunol 2013;13(4):323–9. 19. Gex-Collet C, Helbling A, Pichler WJ. Multiple drug hypersensitivity–proof of multiple drug hypersensitivity by patch and lymphocyte transformation tests. J Investig Allergol Clin Immunol 2005;15(4):293–6. 20. Gaig P, Garcia-Ortega P, Baltasar M, et al. Drug neosensitization during anticonvulsant hypersensitivity syndrome. J Investig Allergol Clin Immunol 2006;16(5): 321–6. 21. Kanny G, Pichler W, Morisset M, et al. T cell-mediated reactions to iodinated contrast media: evaluation by skin and lymphocyte activation tests. J Allergy Clin Immunol 2005;115(1):179–85. 22. Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122(3):574–80. 23. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358(6):568–79. 24. Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLAB*1502 screening in Taiwan. N Engl J Med 2011;364(12):1126–33. 25. Demoly P, Kropf R, Bircher A, et al. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. Allergy 1999;54(9):999–1003. 26. Benahmed S, Picot MC, Dumas F, et al. Accuracy of a pharmacovigilance algorithm in diagnosing drug hypersensitivity reactions. Arch Intern Med 2005; 165(13):1500–5. 27. Sassolas B, Haddad C, Mockenhaupt M, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther 2010;88(1):60–8. 28. Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs - an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013;68(6):702–12. 29. Torres MJ, Gomez F, Dona I, et al. Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media. Allergy 2012;67(7):929–35.
Drug Allergy Diagnosis
30. Caimmi S, Benyahia B, Suau D, et al. Clinical value of negative skin tests to iodinated contrast media. Clin Exp Allergy 2010;40(5):805–10. 31. Chiriac AM, Audurier Y, Bousquet PJ, et al. Clinical value of negative skin tests to gadolinium contrast agents. Allergy 2011;66(11):1504–6. 32. Ramirez LF, Pereira A, Chiriac AM, et al. Negative predictive value of skin tests to neuromuscular blocking agents. Allergy 2012;67(3):439–41. 33. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, et al. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2010;105:259–73. 34. Brockow K, Romano A, Aberer W, et al. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European multicenter study. Allergy 2009;64(2):234–41. 35. Ebo DG, Leysen J, Mayorga C, et al. The in vitro diagnosis of drug allergy: status and perspectives. Allergy 2011;66(10):1275–86. 36. Hjortlund J, Mortz CG, Skov PS, et al. One-week oral challenge with penicillin in diagnosis of penicillin allergy. Acta Derm Venereol 2012;92(3):307–12. 37. Caubet JC, Kaiser L, Lemaitre B, et al. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol 2011;127(1):218–22. 38. Ponvert C, Perrin Y, Bados-Albiero A, et al. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol 2011;22(4):411–8. 39. Gomes ER, Kvedariene V, Demoly P, et al. Patients’ satisfaction with diagnostic drug provocation tests and perception of its usefulness. Int Arch Allergy Immunol 2011;156(3):333–8. 40. Ponvert C. Diagnosis of allergic and non-allergic hypersensitivity reactions to commonly used drugs and biological substances in children: diagnostic algorithm. Arch Pediatr 2011;18(4):486–92 [in French]. 41. Demoly P, Romano A, Botelho C, et al. Determining the negative predictive value of provocation tests with beta-lactams. Allergy 2010;65(3):327–32. 42. Defrance C, Bousquet PJ, Demoly P. Evaluating the negative predictive value of provocation tests with nonsteroidal anti-inflammatory drugs. Allergy 2011;66(11): 1410–4. 43. Papadopoulos NG, Agache I, Bavbek S, et al. Research needs in allergy: an EAACI position paper, in collaboration with EFA. Clin Transl Allergy 2012;2(1):21.
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MD
a
, Pascal Demoly,
MD, PhD
a,b,
*
KEYWORDS Drug hypersensitivity reaction Natural history Severity signs Drug allergy work-up Imputability KEY POINTS There is no substitute for a proper assessment of the clinical history when a drug hypersensitivity reaction is suspected. When assessing a patient with a presumed drug hypersensitivity reaction in the symptomatic phase, it is mandatory to look for severity signs, because they portend a poor prognosis. Confirmation of a drug hypersensitivity relies mostly on in vivo tests, and their contraindications must be rigorously observed. The available literature does not answer the numerous questions regarding the natural history of drug hypersensitivity. When the diagnosis is confirmed, lifelong avoidance of the drug causing the reaction is recommended.
INTRODUCTION
Drug allergy that is poorly documented and often self-reported is a frequent problem in daily clinical practice and has a considerable impact on prescription choices. When drug reactions resembling allergy occur, they are called drug hypersensitivity (DH) reactions (DHRs) before showing evidence of either drug-specific antibodies or T cells. The term drug allergies should be reserved for immunologically mediated DHRs. The diagnostic work-up of DHRs allows a better classification of the reactions and provides patients with more reliable information and recommendations for future treatments. Several guidelines and consensus documents on general or specific drug class–induced DHRs are available to support the diagnosis. This article is based on the recent International Consensus (iCON) on Drug Allergy,1 a consensus that was reached by leading allergy organizations worldwide (the European Academy of Allergy
Disclosure Statement: The authors declare no conflict of interest for this work. a Allergy Unit, Respiratoty and Addictology Department, Hoˆpital Arnaud de Villeneuve, 371, Avenue du Doyen Gaston Giraud, University Hospital of Montpellier Cedex 5, Montpellier 34295, France; b Sorbonne Universite´s, UPMC Paris 06, UMR-S 1136, IPLESP, Equipe EPAR, Paris 75013, France * Corresponding author. Allergy Unit, De´partement de Pneumologie et Addictologie, Hoˆpital Arnaud de Villeneuve, 371, Avenue du Doyen Gaston Giraud, University Hospital of Montpellier Cedex 5, Montpellier 34295, France. E-mail address: [email protected] Immunol Allergy Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.iac.2014.03.002 immunology.theclinics.com 0889-8561/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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and Clinical Immunology [EAACI], the American Academy of Allergy Asthma and Immunology [AAAAI], the American College of Allergy Asthma and Immunology [ACAAI] and the World Allergy Organization [WAO]) to synthesize multiple guidelines into 1 generally approved and accepted consensus document. CLINICAL MANIFESTATIONS
DHRs are classified artificially into 2 types, according to the delay of onset of the reaction after the last administration of the drug: (1) immediate reaction, occurring less than 1 hour after the last drug intake, usually in the form of isolated urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, gastrointestinal symptoms (nausea, vomiting, diarrhea), or anaphylaxis with or without cardiovascular collapse (anaphylactic shock); and (2) nonimmediate reaction, with variable cutaneous symptoms occurring after more than 1 hour and up to several days after the last drug intake, such as late-occurring urticaria, maculopapular eruptions, fixed drug eruptions, vasculitis, blistering diseases (such as toxic epidermal necrolysis [TEN], StevensJohnson syndrome [SJS], and generalized bullous fixed drug eruptions), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and symmetric drug-related intertriginous and flexural exanthemas. Internal organs can be affected either alone or with cutaneous symptoms including hepatitis, renal failure, pneumonitis, anemia, neutropenia, and thrombocytopenia. The first category is mostly mediated through specific immunoglobulin E (IgE), whereas the second is specific T cell mediated. For specific descriptions, the readers are referred to previous issues of The Clinics of North America.2,3 SEVERITY SIGNS OF DHRS
When assessing a patient with a presumed DHR in the symptomatic phase, it is mandatory to look for severity signs and, after doing so, to update the risk/benefit balance of exploring the suspected drug(s) on a case-by-case basis. Severity (danger) signs may include both clinical symptoms and biological/laboratory parameters, according to the type of reaction.1 Some are well-established criteria and have been assigned individual weights in scoring systems for classifying the severity of delayed reactions.4 Severity signs are either obvious to the naked eye (clinical), or invisible (mainly biological) (Table 1). The latter must be looked for thoroughly, to reveal internal organ damage. In immediate reactions, the clinical picture is self-explanatory. Symptoms develop rapidly and cutaneous and mucosal involvement may quickly escalate toward lifethreatening airway, breathing, or circulatory problems. Measurements of histamine or tryptase have no value for the therapeutic management in the acute setting, but may a posteriori support the diagnosis of allergic anaphylaxis, especially in cases of drug allergy in perioperative settings.5 Nonimmediate reactions are more heterogeneous and there may be overlap between different patterns. When confronted with a suspicion of a delayed DHR, both general and organ-specific severity/danger signs must be systematically looked for (see Table 1). Daily reevaluation is mandatory to identify progression or signs of recovery. Regardless of the type of reaction, the presence of severity signs warrants the immediate withdrawal of the suspected drug(s), appropriate supportive treatment of the patient, and special care later during the exploration phase. However, in the absence of these signs and if the drug is mandatory, treating through might be an option.
Drug Allergy Diagnosis
Table 1 Severity/danger signs in DHR Visible Severity Signs
Invisible Severity Parameters
Immediate reactions
Sudden onset of multisystem symptoms (respiratory, skin, and mucosal) Reduced blood pressure Dyspnea Dysphonia Sialorrhea
High levels of serum tryptasea
Nonimmediate reactions
General Lymphadenopathy Fever >38.5 C Organ specific Painful skin Skin extension >50% Atypical target lesions Erosions of mucosa Skin blisters, bullae Centrofacial edema Purpuric infiltrated papules, cutaneous necrosis
Changes in blood countb Cytopenia Eosinophilia Alteration of liver function testsb Alteration of kidney functionb
a
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. Adapted from Bircher AJ. Symptoms and danger signs in acute drug hypersensitivity. Toxicology 2005;209(2):204; with permission. b
NATURAL HISTORY OF DHRS
The natural history of DHR is difficult to assess, for several reasons, and can only be analyzed by a firm initial diagnosis and later reexposures. The current knowledge in this area is scant but needs to be understood when diagnosing a DHR. First, unlike respiratory or food allergy, for which the ubiquitous nature of certain allergens makes it difficult to adhere to strict avoidance of the culprit allergen (which can easily be encountered at eliciting doses in everyday life), in DHR, once the diagnosis has been established, lifelong avoidance of the causative drug is recommended and generally observed, both by the patient and by health care professionals in therapeutic settings. Medicolegal consequences are involved. However, an unpredictable subliminal contact is thought to occur because certain drugs, namely antibiotics, are present in small and hidden amounts in foods. It is not known to what extent this ongoing contact may influence the natural history of DH to antibiotics in the absence of therapeutic exposure. Second, DH is a heterogeneous clinical entity (in terms of clinical manifestations and eliciting drugs) and although the frame is virtually the same (clinical history, drug allergy work-up, avoidance), it is difficult, if not impossible, to put all drugs in the same category and extrapolate the existent data on some antibiotics or nonsteroidal antiinflammatory drugs (NSAIDs) to, for instance, drugs like biological agents. In addition, instances in which the drug is given despite a previous DH provide some insight into how patients may evolve and sometimes outgrow their DH. Data regarding the natural history of DHRs arises from articles addressing this question in a direct or indirect way.
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Follow-up of Patients with a Confirmed DH: Skin Test Conversion
When nonirritant concentrations are used for skin testing (eg, b-lactams), the positive predictive value of skin tests in the presence of a history compatible with a DH has been reported to be 100% for immediate reactions and more than 92% for delayed reactions.6 However, little is known about the clinical consequences of the negativization of a previous positive immunologic response, either assessed by means of skin or biological tests. The IgE antibody response is not permanent over time, and prospective studies of skin test and/or specific IgE reactivity showed that decreased antibody levels may occur months to years after the occurrence of a DH. This finding was mainly reported for penicillin allergy,7 with patients having a selective response to the aminopenicillin side chain switching from positive to negative skin responses sooner than in patients with reactivity to several penicillin determinants. After 5 years, none of the selective responders had positive skin tests. Submitting these patients to reexposure would not be acceptable in the absence of highly specific therapeutic indications because it is suspected that the lack of skin reactivity does not warrant the systemic tolerance of the drug. Vultaggio and colleagues8 reported the case of a patient in whom retreatment after negativization of serum-specific IgE to rituximab led to the development of a new and more severe reaction associated with higher levels of serum IgE antibodies and positive skin tests. The same team9 observed a rapid decrease of specific IgE antibodies to infliximab with none of the patients showing skin test positivity or specific serum IgE within 1 year after the first analysis. However, IgE sensitization may also persist for years, as shown for neuromuscular blocking agents.10 T-cell memory seems to be even stronger for delayed DHRs.11 Follow-up of Patients After Drug Desensitization
Once it is achieved, tolerance through desensitization is maintained by continuous administration of the drug. The process is reversible and, when the drug is discontinued, tolerance is lost over hours or days.12 When the drug is mandatory, as is often the case for chemotherapeutic or biological agents, and in the absence of contraindications, it is common practice that patients undergo desensitization at each cure. Although experts recommend it, it is not clear whether repeat desensitization is required for each drug infusion in all patients. It is known that a subset of patients continues to have reactions during successive desensitizations, suggesting persistent DH. However, some investigators13 reported patients in whom skin test results convert from positive to negative after repeated desensitization and the drug is subsequently tolerated through standard infusion with no reaction. It is unclear whether this tolerance is compatible with a natural loss of sensitivity and instead the investigators put forward the hypothesis of the maintenance of the desensitized state caused by the long half-life of monoclonal therapeutics. Influence of the Underlying Disease
Aspirin-exacerbated cutaneous disease is an entity per se within the large spectrum of ASA/NSAID hypersensitivity. Up to one-third of the patients with chronic spontaneous urticaria (CSU) experience exacerbation of their skin symptoms on ingestion of ASA/ NSAIDs. In contrast, up to 37% of NSAID-hypersensitive patients may develop CSU in the future.14 The degree of sensitivity to NSAIDs may show temporary fluctuations related to the activity of their underlying CSU and sensitivity may even disappear in some patients.15,16
Drug Allergy Diagnosis
Influence of Age
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 DH in childhood can be questioned because of the time elapsed since the occurrence of the reaction. In a study involving 3275 patients, Rubio and colleagues17 reported that, when the first reaction occurred during childhood, the prevalence rate of positive tests was similar whether the test was during childhood (10.6%) or adulthood (10.6%); thus, it could be argued that DH in childhood does not resolve with time. The Multiple Drug Hypersensitivity Syndrome
The immune response in drug allergy is highly specific and often restricted to a drug or drug class. However, under certain circumstances, sensitizations for different drugs occur simultaneously, accounting for the multiple DH (MDH) syndrome.18 Recent studies place severe cutaneous adverse reactions (SCARs), and particularly DRESS, at high risk of inducing multiple drug sensitizations. Antimicrobials or antiepileptics are often involved and are considered the primary eliciting drugs, but neosensitizations also involve drugs given as concomitant therapy for several weeks before the onset of the SCAR.11 Thus, MDH with simultaneous sensitizations could be regarded as a model of how an acquired DH facilitates a new DH. In these patients, drug sensitization (as proved by either positive skin tests or lymphocyte transformation test) is persistent and detectable for many years after the allergic reaction.11,19,20 EVALUATION OF THE CLINICAL HISTORY
The suspicion of DHR arises on a constellation of data that make up the clinical history. Two main situations occur in everyday practice: the patient is seen during the symptomatic phase, or the patient is referred to the allergy consultation after recovery. When patients are seen during the symptomatic phase, physical examination is mandatory to provide invaluable information (ie, the presence/absence of danger signs) and to help ensure that a severe reaction is not overlooked. Otherwise, diagnosis is more difficult and, in this case, photographs taken at the time of the reaction are helpful. In addition, there are inpatients and outpatients. For hospitalized patients, data can more easily be tracked from medical records. For outpatients, it is especially important to enquire about over-the counter medications and health supplements, because patients often do not report these as medications. The approach to assessing a suspicion of DHR could be conceived as a pyramid. The first step (ie, the basis) is as exhaustive as possible. It encompasses symptoms, physical examination, and a complete drug administration history, including starting and stopping points of each medication. Then, several things help narrow down the list of potential causes of a DHR. Among them, the timing is of paramount importance, with its multifaceted distribution: the temporal relationship between the administration of each drug and the onset of symptoms, the effect of stopping the treatment, and the time to recovery. Several chronologies have been described,1 and they refer typically to naive patients (ie, those experiencing the DHR for the first time). However, if the causative drug is readministered by mistake, the delay can be considerably shorter. Although any drug can cause a DHR, the nature of the drugs involved and the knowledge of the classes most likely to be associated with the type of reaction may help in establishing extrinsic imputability. Special attention should be paid to dose changes, because for certain drugs and clinical presentations, dose changes are known to accelerate the onset of symptoms. Procedures involving administration of contrast
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media or dyes should be tracked, because these agents are potential elicitors. Moreover, iodinated radiocontrast media (RCM) have been reported to elicit very delayed DHRs (ie, several days after a single administration) and this kind of peculiarity should be kept in mind when considering imputability related to timing.21 A history of previous uneventful exposure and/or prior DHR is equally important. For instance, patterns of reaction have been established for certain drugs, such as the occurrence of DHRs to platinum salts or biological agents.13,22 Besides the differential diagnosis (eg, food allergy, infection), the circumstances surrounding the onset of the reaction should be recorded. Cofactors like physical effort or exposure to light should not be overlooked. In addition, interpreting the data in the medical/genetic background of the patient produces additional information. Specific questioning for a medical condition, such as chronic urticaria/chronic rhinosinusitis (which can be aggravated by the intake of certain drugs; eg aspirin and non–cyclooxygenase-2–selective NSAIDs), or autoimmune or infectious disease (eg, patients infected with human immunodeficiency virus) facilitates the interpretation. Moreover, recent findings have shown a strong genetic association between human leukocyte antigen alleles and susceptibility to specific immune-mediated DHRs.23,24 Data should ideally be recorded in a uniform format and, in order to harmonize the DHR diagnostic procedures, members of EAACI-DAIG/ENDA have developed a questionnaire25 that is available in many different languages. In complex situations, a flow diagram including clinical manifestations and biological parameters should be drawn, for a more comprehensive overall view of the available data. There is no substitute for a proper assessment of the clinical history. However, in most cases clinical history alone is not reliable, for various reasons (concomitant medication, imprecise information, heterogeneity of the clinical manifestations).26 PHARMACOVIGILANCE ALGORITHMS
Causality assessment methods performed by pharmacovigilance authorities are based principally on the clinical history (which may be insufficient or inaccurate) and are not designed to make definite decisions but rather to classify adverse drug reactions from the likelihood of a causal relationship between the drug and the reaction, as well as to detect new alerts. Moreover, they do not specifically address DHR. Therefore their sensitivity to ascertain DHRs is low, and allergy testing is often necessary.26 An algorithm tailored to SJS/TEN, with parameters chosen from clinicians’ knowledge of experts and available scoring systems, has been proposed by the RegiSCAR Study Group.27 SKIN TESTS
Skin tests (STs) are of utmost importance for the diagnosis of DHRs. Their use and interpretation is sometimes hampered by lack of data regarding nonirritant concentrations and vehicles. To address this pitfall, the EAACI-DAIG/ENDA experts recently reviewed the available literature in order to recommend appropriate concentrations for systemically administered drugs.28 The conclusions are summarized in Table 2. The sensitivity of STs seems to be moderate to high for immediate DHRs to b-lactam antibiotics, perioperative drugs, heparins, and platinum salts but low for many other drugs. For most drugs, the sensitivity of STs is higher in immediate DH compared with nonimmediate DH.28 A recent multicenter study to determine the
Drug Allergy Diagnosis
Table 2 Nonirritating skin test concentrations for some systemically administered drugs Drug or Drug Class
SPT
IDT
Patch
Heparinsa
Undiluted
1/10 diluted
Undiluted
Heparinoidsb
Undiluted
1/10 diluted
Undiluted
Carboplatin
10 mg/mL
1 mg/mL
NA
Oxaliplatin
1 mg/mL
0.1 mg/mL
NA
Cisplatin
1 mg/mL
0.1 mg/mL
NA
Pyrazolonesc
Powder
0.1 mg/mL
10%
Coxibsd
Powder
—
10%
Other NSAIDse
Powder
0.1 mg/mL
10%
Anticoagulants
Platinum Salts
NSAIDs
Biologics Adalimumab
50 mg/mL
50 mg/mL
Undiluted
Etanercept
25 mg/mL
5 mg/mL
NA
Infliximab
10 mg/mL
10 mg/mL
NA
Omalizumab
1.25 mg/mL
1.25 mg/mL
NA
Others Local anesthetics
Undiluted
1/10 diluted
Undiluted
Iodinated RCM
Undiluted
1/10 diluted
Undiluted
Gadolinium chelates
Undiluted
1/10 diluted
NA
Patent blue
Undiluted
1/10 diluted
NA
Methylene blue
—
1/100 diluted
—
Fluorescein
Undiluted
1/10 diluted
Undiluted
PPIf
Undiluted
40 mg/mL
10%
Anticonvulsantsg
NA
NA
10%
Chlorhexidine digluconate
5 mg/mL
0.002 mg/mL
1%
Abbreviations: IDT, intradermal test; NA, not applicable or no test concentration recommended; PPI, proton pomp inhibitors; SPT, skin prick test. a Heparins: heparin sodium, nadroparin, dalteparin, and enoxaparin; testing contraindicated in heparin-induced thrombopenia. b Heparinoids: danaparoid and fondaparinux. c Pyrazolones: metamizol, paracetamol, propyphenazone, aminopyrine, phenazone, and phenylbutazone. d Coxibs: celecoxib, etoricoxib, and valdecoxib. e Other NSAIDs: for example, aspirin, ibuprofen, naproxen, indomethacin, diclofenac, fenoprofen, meloxicam, mefenamic acid, and nimesulide. f For lansoprazole and rabeprazole, no intravenous solution is available: SPT with powder; IDT not possible. g In case of history of severe reaction, test first with 1%. From Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs - an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013; 68(6):705; with permission.
value and safety of drug patch tests for the 3 main classes of SCARs found a sensitivity of 64% among cases with DRESS, 58% for AGEP, and 24% for SJS/TEN. For nonimmediate reactions, delayed-reading intradermal tests have a higher sensitivity than patch tests.29
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Preliminary results regarding the satisfactory negative predictive value (NPV) of STs in immediate DHR to iodinated RCM, gadolinium contrast agents, or myorelaxants30–32 await confirmation in larger series. Although there is general agreement among Allergology Societies and Academies on the importance of ST in drug allergy work-up, it is still a matter of debate for some drugs. The US Practice Parameters33 suggest that immediate DHRs to iodinated RCM are all nonallergic (described as anaphylactoid) and therefore STs are not included in the management of patients who have experienced a previous DHR to iodinated RCM. The European experience34 challenges this position. Testing patients without a prior history of DHR is not supported by available studies and therefore is not recommended, in particular in preoperative settings.5 BIOLOGICAL TESTS
There is no universal biological test either to diagnose or to predict DHRs. With some exceptions, the currently available biological methods to diagnose drug allergy lack sensitivity, although they are normally considered to be specific.1 A negative test does not exclude the imputability of the drug, whereas a positive result shows a sensitivity to the drug but does not reliably confirm its causality. For specific descriptions, readers are referred to previously published guidelines and reviews.1,35 PROVOCATION TESTS
The drug provocation test (DPT) comes at the end of a stepwise approach in the drug allergy work-up. It is the procedure with the highest sensitivity among all the other available diagnostic tools, but its use as the gold standard to establish (rather than just to exclude) the diagnosis of DHR is not unanimously accepted, mostly because of the reactions it may trigger, ranging from mild to severe. Although protocols are not standardized among centers, and the precise challenge procedure varies from one team to another, there is general consensus with regard to 2 prerequisites: contraindications must be strictly observed before deciding whether or not to perform a DPT, and immediate treatment must be available, allowing complete and rapid recovery. Several recent studies discussed the concerns that had already been raised about DPT protocols and methodology. There is some controversy among different groups about whether 1 full therapeutic dose of a tested drug is sufficient to elicit reactions in nonimmediate responders. Hence, full therapeutic courses have been suggested to increase the sensitivity of DPTs.36 However, such an indication must be regarded cautiously, in terms of diagnostic improvement, cost, and medical implications, and is yet to be debated. In contrast, groups37,38 performing DPTs in the pediatric population suggest that a 1-dose DPT in children with a history of delayed-onset benign reaction to b-lactams (assessed by a careful primary evaluation in the acute phase by an experienced allergist) can be considered sufficient and safe, even in the absence of an ST.37 Although tempting, this approach needs validation in larger studies. Patients do not like to be reexposed to drugs that they consider harmful. However, recent data collected from 3 centers in Europe revealed that most patients accepted DPTs for diagnostic purpose irrespective of the test results, and 95% of them thought that DPT was useful and that they would recommend it to others.39 A negative DPT does not prove tolerance to the drug in the future, but rather that there is no DH at the time of the challenge and to the doses challenged. Nevertheless, a high NPV of b-lactam DPT of 94% to 98% was found in large studies involving both children and adults,40,41 and most of the reactions reported by patients were both mild
Drug Allergy Diagnosis
and nonimmediate. The NPV of DPT with NSAIDs similarly seems to be high (more than 96%) whatever the NSAID (the one negatively tested or an alternative), and none of the false-negative patients described a life-threatening reaction.42 SUMMARY
The diagnosis of DHR remains largely clinical. Reasoning is almost identical for all drugs and all clinical presentations. With the help of some allergy tests that are available for some of the drug classes and a careful approach, a firm diagnosis is often possible no matter which drug is involved. However, a lot still needs to be done for severe cutaneous reactions for which DPTs are contraindicated and in biological diagnosis.43 Clinicians and researchers working in DH are aware that there is a risk of iatrogenesis in subjects with histories that suggest but are not always confirmed as DH. Proper identification of a DH upholds the principle of primum non nocere, and this principle is a challenge that weighs heavily in all their considerations. The attitude of not evaluating a suspicion of DH carries the risk of using unnecessary avoidance measures (with the obvious medical consequences) or overlooking alternative diagnoses. All this renders the field of DH diagnosis a very vivid one, because universal acceptance of classifications, diagnostic tests, or protocols is difficult to achieve. REFERENCES
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