Introduction
Systemic drug-induced hypersensitivity reactions (HSRs) have been reported for a variety of drugs, and are thought to have a combined immunological, genetic and metabolic basis. These diverse idiosyncratic reactions are both drug and host dependent, and subsequent rechallenge with the drugs responsible can result in a potentially life-threatening clinical reaction.
Hypersensitivity has been observed in regard to several drugs used to manage HIV and associated infections, with the antiretrovirals nevirapine and abacavir being the best characterized of the syndromes. These events represent a high cost both to the patient and the healthcare system, and those labelled as being hypersensitive to one or both drugs may find their treatment options significantly reduced.
The identification of HSRs can be challenging due to the heterogeneity of their clinical manifestations. Furthermore, with multidrug regimens - common in HIV management - it may be difficult to identify the drug responsible. Epicutaneous patch testing, a procedure well established in contact dermatitis, has also been used as a supplementary diagnostic test for several drug-related HSRs; its usefulness, however, depends on both the drug and syndrome involved. This study discusses HSRs and the application of patch testing to their investigation, with particular emphasis on HIV and abacavir - the antiretroviral with which patch testing has been most studied [1,2].
Drug hypersensitivity reactions
Drug HSRs are unpredictable (type B) drug-related adverse events affecting a minority of patients receiving a wide variety of pharmaceuticals. Unlike type A events, which are predictable and related to a drug's expected pharmacological activity, HSRs are host-dependent and have no simple dose-response relationship. The precise immunopathogenesis of most of drug HSRs is not yet understood. Based on the underlying immune mechanisms, these reactions are primarily classified as delayed T-cell-mediated (type IV) allergic responses, though a combination of antibody-mediated and cell-mediated reactivity can exist [3-6]. There is evidence that major histocompatibility complex (MHC)-restricted presentation of the drug (or conjugated metabolite) as an antigen - prompting peptide-specific T-cell recognition and activation in predisposed individuals - is a likely mechanism underlying at least some HSRs, and genetic associations between drug reactions and human leukocyte antigen (HLA) alleles appear to support this [3-5,7,8]. Nevertheless, it is not clear whether the differences in clinical patterns associated with drug HSRs result from immune responses of different intensity, or quality, or both [3]. It is also not understood why patients experience different types of reactions to the same drug. The influence of genetic factors, however, has become increasingly recognized.
Despite extensive variation in the clinical manifestations of HSRs the skin is frequently affected, often with mild exanthematous rashes [9,10]. In addition to skin involvement, drug hypersensitivity syndrome [DHS; sometimes referred to as drug rash with eosinophilia and systemic symptoms (DRESS)] typically manifests with systemic symptoms, such as fever and malaise, and internal organ involvement of varying severity.
Several drugs in common use have well characterized HSRs, as typified by β-lactam antibiotics - the most frequent cause of cutaneous drug reactions [11-13]. Reactions mostly affect the skin [typically exanthema, nonimmediate urticaria, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis or acute generalized exanthematous pustulosis (AGEP)], but can manifest as DHS, most commonly involving the liver, lungs and/or kidneys [13-15]. Serious systemic HSRs are also associated with anticonvulsants [16-20], sulfonamide antimicrobials [21,22], dapsone [23] and allopurinol [24,25]. Rechallenge after an initial reaction can cause a more intense and immediate reaction. Controlled rechallenge (drug provocation testing), either with the culprit drug or a pharmacologically related agent, is therefore contraindicated following most DHS, with the risk of a more severe reaction weighing heavily against any therapeutic benefit [26].
Drug hypersensitivity in HIV
Drug HSRs are a significant concern to HIV physicians. HIV-infected patients have a substantially higher frequency of drug allergies than the noninfected population - potential explanations for which have been discussed elsewhere [3,9,10,27-29] - and are typically exposed to many different drugs over the course of the disease. Permanent discontinuation of drugs suspected of causing a severe reaction can limit optimal treatment [10,30].
HSRs are associated with several medications used to manage HIV-related opportunistic infections, including sulfonamide antimicrobials and antimycobacterial drugs, which are associated with higher rates of drug reactions in HIV-infected individuals than in HIV-negative individuals [9,10,21,22,27,31-35]. Several antiretroviral agents, including amprenavir, efavirenz and enfuvirtide, have also been linked with HSRs; however, the best characterized reactions occur with nevirapine and abacavir [36-43].
Nevirapine hypersensitivity can include any combination of fever, rash and internal organ involvement, but most commonly manifests as isolated rash within 6 weeks of initiating drug (mean delay 14 days [44,45]). Nevirapine-attributable rash occurs at a rate of about 16% in clinical trials, and approximately 7% of patients discontinue treatment because of cutaneous events [37]. Although rashes are mostly mild to moderate, a relatively high incidence of more severe cutaneous reactions, such as SJS (0.3%), has been reported with nevirapine [37,46-48]. Severe cutaneous events and rash-associated hepatitis have been associated with nevirapine more frequently in women, HIV-infected subjects with higher CD4+ cell counts and in HIV-negative individuals initiating nevirapine for postexposure prophylaxis [37,49]. The abacavir hypersensitivity syndrome is a well characterized systemic inflammatory reaction that usually occurs within 6 weeks of initiating abacavir-containing therapy (mean delay 11 days), with an incidence of approximately 5% in clinical trials [38,50,51]. It is associated with a more nonspecific range of clinical signs and symptoms than nevirapine HSR, including fever, malaise, gastrointestinal symptoms and respiratory symptoms [38,50-54], which can mimic other infectious and inflammatory causes. Rash is absent in about 30% of cases of abacavir HSR and is often a late feature. Rechallenge is associated with severe, rapid and potentially life-threatening reactions, and is therefore contraindicated [38,51,55].
Immunogenetic basis of drug hypersensitivity reactions
Genetic factors involving class I MHC alleles have recently been implicated in severe drug HSRs. A strong association between the HLA-B*1502 allele and carbamazepine-induced SJS has been demonstrated in Han Chinese, but no such association was found in whites, with varying severities of carbamazepine-associated DHS [56-59]. A genetic predisposition to severe cutaneous adverse reactions to allopurinol, associated with the HLA-B*5801 allele, has also been identified in Han Chinese [60].
In HIV, both nevirapine and abacavir HSRs have known immunogenetic susceptibility factors. Nevirapine HSRs, which may be CD4-dependent or CD4-independent, have been associated with class I HLA-Cw8 alleles in Sardinian and Japanese HIV-infected patients [61,62], whereas carriage of the class II MHC allele HLA-DRB1*0101 combined with a higher CD4+ T-cell percentage was a predictor of systemic reactions to nevirapine in the Western Australian HIV Cohort [63]. CD4-independent carriage of HLA-DRB1*01 has also been linked recently to nevirapine-associated and efavirenz-associated rash without hepatic involvement in a group of French patients [64]. Several studies have established a link between HLA-B*5701 and abacavir hypersensitivity in whites, suggesting that prospective screening for this allele could reduce the frequency of abacavir HSRs in the clinic [65-70], a hypothesis that has been tested in a powered, prospective evaluation: the Prospective Randomized Evaluation of DNA screening in a Clinical Trial (PREDICT-1) study [71].
Diagnosing drug hypersensitivity
Diagnosing drug HSRs can be difficult as clinical manifestations may mimic other inflammatory and infectious causes, leading to significant potential for misdiagnosis (patients labelled with other inflammatory disorders, such as infection or connective tissue disease) and overdiagnosis (patients falsely labelled as allergic to a drug) [5,72]. Results from randomized, placebo-controlled trials of abacavir, in which hypersensitivity has been diagnosed at rates of 2-7% in participants not receiving abacavir, illustrate this overdiagnosis [73-76].
The diagnostic work-up of suspected drug hypersensitivity includes a detailed clinical history, physical examination, rechallenge and dechallenge information (symptom resolution on withdrawal of drug), supplementary laboratory tests and investigations to document disorder and internal organ involvement. Drug-specific in-vitro and cutaneous testing can be helpful adjuncts, but are not standardized or broadly available [11,77]. Patch testing is the most studied cutaneous testing approach in delayed drug reactions, and is considered the most specific and clinically useful of such tests in determining causality [12,77]. The true diagnostic sensitivity of patch testing is not known for most drugs.
Background to patch testing
Patch testing was first used for identifying allergens in allergic contact dermatitis (ACDs) over a century ago, and is now considered the 'gold standard' for confirming an ACD diagnosis and distinguishing the causal allergen [78-82]. In contrast, patch testing to assess drug culpability in a suspected HSR is a relatively undeveloped discipline, though the use of the skin as a model to re-create drug reactions is based on a sound and informed rationale [4,5]. The test relies on penetration of drug from the patch into the epidermis where the hapten - either the parent drug or a reactive metabolite formed by drug-metabolizing enzymes in the skin - conjugates with host proteins to form an antigen. These immunogenic conjugates are recognized by MHC-expressing, antigen-presenting cells (including epidermal Langerhans cells), which process and present them to the effector cells of the immune system. This triggers peptide-specific CD8+ (class-I-mediated responses)/CD4+ (class-II-mediated responses) T cells to migrate into the skin and proliferate, and the release of proinflammatory cytokines and chemokines, causing a localized response (Fig. 1).
Patch testing provides a controlled method of nonsystemic drug rechallenge in cases of a suspected drug HSR in which systemic rechallenge could have severe consequences. The test performance depends on the clinical features of the drug reaction (it is particularly useful in cases of exanthematous rash, fixed drug eruption (FDE), AGEP and DHS [77,83-90]) and the drug responsible (examples of drugs for which patch testing seems useful for determining HSRs are documented elsewhere [84,89]).
The patch test process
A number of guidelines for drug patch testing, based on well established procedures in ACD, have been published [12,77,87,91,92].
Test agents
In addition to the commercialized form of the suspect drug, both the purified active agent(s) and any excipients should be included separately in the patch test to avoid false-positive results arising from contact allergy to an additive (although reactions to excipients are rare in practice). The type of vehicle used to carry the test agents - commonly petrolatum or water - and the concentration of test drug can affect penetration of drug into the skin and hence the results. Optimal test concentrations have not been determined for all drugs; however, the highest nonirritating concentration is preferred to minimize false-negative results. Guidelines have recommended concentrations of 1-10% of the pure drug and 30% of the commercialized form. Lower concentrations can, however, be used in patients with severe reactions. Testing of chemically or pharmacologically related agents may provide information on cross-reactivity.
Application of patch test
The optimal time interval between a suspected HSR and patch test application is not clear, but a minimum of 4-6 weeks after resolution is generally accepted. At this stage the appearance of the skin should have normalized, although it can still be in a state of hyperreactivity. Phototherapy and systemic corticosteroid or immunosuppressive therapy should be discontinued 1 month prior to testing, and topical corticosteroids should not be applied to the patch test area in the week before the test.
A typical patch test comprises a series of small, aluminium wells containing test agents mounted on hypoallergenic tape. Overfilling and underfilling can lead to false-positive, false-negative or uninterpretable results and must be avoided. Generally, patches are best applied to normal skin (shaved or clipped if excessively hairy) between the shoulder blades but avoiding the paraspinal skin (Fig. 2a). If the patient has any skin condition in this area that could complicate the test results or be irritated, application to the outer side of the upper arm can be considered, although there is a greater risk of dislodging the patch (Fig. 2b). Patch tests for FDE must be applied to the affected site. Patients should be advised to keep the patch dry and avoid vigorous activities that could displace it.
Reading and interpretation of patch test
The standard occlusion time for patch tests after application (day 0) is 48 h, with the first reading on day 2 generally 15-30 min after patch removal. This reduces the risk of positive patch test erythema being blanched by a patch pressure reaction and to allow nonrelevant erythema (dermographism or irritant reactions) to subside. A second reading is taken at day 3 or 4, and in some cases (e.g. with corticosteroid testing [93]) a late reading at day 7 may be informative. For FDE, the occlusion time is usually 24 h, with readings performed at day 1 and day 2 or 3.
Results are recorded using a standardized scoring system (Table 1). Doubtful and weak-positive reactions can be the most difficult to interpret, but are generally considered negative unless the intensity of the reaction increases at a subsequent reading. In the case of a doubtful reaction, a second patch test can be considered, but this risks inducing sensitization in a patient not previously sensitized. If a positive reaction is observed (Fig. 3), a judgement must be made on whether it could be an irritant reaction and therefore a false-positive result. Irritant reactions are generally not durable and often subside between the first and second reading [94].
A patch test can give a false-negative result if it insufficiently reproduces the conditions of the original reaction (e.g. transient drug intolerance due to concomitant factors, such as acute viral infection). Other causes of false-negative results include inadequate penetration of reagents into the epidermis (suboptimal vehicle used/test concentration too low), testing of drugs for which the hapten is a reactive metabolite not formed in the skin, or when there is no immune mechanism involved in the drug reaction. A negative test result does not, therefore, allow a definitive conclusion regarding the drug's lack of culpability.
Adverse effects of patch testing
Patch testing is considered a generally safe procedure; any adverse effects are usually mild and localized. Some patients can show signs of angry back or a flare of dermatitis elsewhere if the patch test is applied too soon after the initial reaction, and others can experience an alteration of pigmentation. Testing with some allergens (e.g., gold salts) has been associated with persistent positive reactions. Active sensitization is possible but is uncommon, its likelihood partly depending on the concentration of the test substance. Such reactions tend to occur more than 10 days after patch testing and are generally associated with strong allergens, such as paraphenylenediamine (a black dye) or primin (some primrose plants). There is also a remote risk of evoking a serious immediate reaction [95].
Patch testing in HIV disease
To date, success with patch testing in cases of suspected antiretroviral hypersensitivity has been limited to abacavir. Patch testing has the potential to improve case ascertainment for suspected immunologically mediated HSRs without the risks associated with a systemic rechallenge, and can therefore be useful by eliminating 'noise' from studies that include a hypersensitivity endpoint. The utility of patch testing as an adjunctive test for defining immunologically mediated abacavir hypersensitivity has been investigated in a number of studies [1,86,96] and was successfully employed as a research tool in recent pharmacogenetic studies of abacavir hypersensitivity [71,97-99]. In the PREDICT-1 study consensus was reached among an expert panel that reviewed digital images of abacavir patch tests and were blinded to patient and reagent wells [97]. Review of digital photographs by an expert panel was also used as an adjunct in the Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation (SHAPE) [99]. Three recent studies, including the PREDICT-1, SHAPE and a multinational study, have shown 100% sensitivity for HLA-B*5701 in patch-test confirmed abacavir HSR [97-99]. A multinational study looked at patients clinically labelled with abacavir HSR from five sites across Canada, Switzerland and Australia who underwent abacavir patch testing. The study showed that 100% (25/25) of those who were patch test positive carried HLA-B*5701 versus 7% (2/30; P < 0.001) of those with negative tests [98]. The PREDICT-1 study, a large randomized controlled study to examine the effectiveness of HLA-B*5701 screening to reduce abacavir HSR, showed that patch test-confirmed HSR occurred in 0% (0/802) of the screened arm versus 2.7% (23/842) of the control, unscreened arm (P < 0.0001) [97], indicating the benefit of screening and highlighting the problem of false-positive clinical diagnosis of abacavir HSR. Finally, the SHAPE study, a retrospective case-control study that used patch testing to evaluate the sensitivity and specificity of HLA-B*5701 in white and black patients, found HLA-B*5701 in 100% of white (42/42) and black (5/5) patch test positive patients [99], supporting the use of generalized screening across ethnic backgrounds. In the PREDICT-1 study, 100 patients who tolerated abacavir for at least 6 weeks were patch test negative, giving abacavir patch testing a diagnostic specificity of 100% [97]. Clinical characteristics of patch test positive patients diagnosed with abacavir HSR differed significantly from patch test negative patients with abacavir HSR from the PREDICT-1, SHAPE and multinational studies. Abacavir patch test positive patients were significantly more likely to have experienced fever and have onset of symptoms of abacavir HSR within 3 weeks of initiating the drug. This supports a potential role for the use of clinical characteristics of abacavir patch test positive patients to revise the clinical case definition of abacavir HSR [97-100]. Previous research has also supported a strong immunopathogenetic case to support the use of patch testing as a research tool to identify true immunologically mediated abacavir HSR [69,101]. Skin biopsies from positive abacavir patch test reactions are concordant with biopsies obtained during acute abacavir HSRs (Fig. 4) [1], and alcohol dehydrogenase - one of the two primary enzymes involved in abacavir metabolism [38] - is ubiquitous in the skin. The immunogenetic basis of abacavir HSR - a durable, class-I-mediated, CD8-dependent immune response - could also be an important factor in the high success rate seen with the abacavir patch test [101,102].
Although abacavir patch testing has clear value as a research tool for refining a statistical endpoint, it is however important that the clinical limitations are recognized. It is not understood what test performance, host and acquired factors contribute to a false-negative result, nor is the patch test clinically validated. All positive abacavir patch tests to date associated with a clinical diagnosis of abacavir in the PREDICT-1, SHAPE and multinational studies (n = 95) have been in individuals who carry HLA-B*5701, suggesting a good correlation between patch, immunological and pharmacogenetic testing [97-99]. Although false-positive abacavir patch tests have not been reported to occur, a case of an HLA-B*5701 negative patient who subsequently developed potential symptoms of abacavir HSR 8 weeks following its initiation was reported to have a positive patch test as part of a London, UK clinic's screening experience [103]. This case illustrates that given the strong association between HLA-B*5701 and patch test positivity now confirmed in several studies, any positive patch test that occurs in patients who have developed abacavir HSR despite negative HLA-B*5701 screening should be carefully documented and ideally include a digital photograph, skin biopsy showing extensive CD8+ infiltration and evidence of ex-vivo cellular responses to abacavir. From the PREDICT-1 study the diagnostic sensitivity of patch testing for abacavir hypersensitivity is estimated to be 87%, and, therefore, a negative result does not exclude a diagnosis of abacavir HSR [97]. Patch testing for abacavir or any other drug hypersensitivity has no value as a screening test because a response requires prior immunological priming or sensitization; and as current data suggest that testing must be performed several weeks after drug discontinuation and not during the acute HSR, patch testing cannot be considered an aid to clinical diagnosis (Fig. 1). The duration of patch test positivity is also unknown, although ongoing studies have identified patients with positive patch tests at least 6 years after experiencing an abacavir HSR [1,98,99]. Abacavir patch test reagents as standardized for the PREDICT-1 and SHAPE studies have been shown to be stable at room temperature for at least 1 year (data on file, GSK, Brentford, Middlesex, UK).
No dermatological allergy test is a tool for routine patient management by primary care physicians - prick tests, intradermal tests and patch tests for allergies are all procedures that should be performed only in experienced specialist dermatology or allergology clinics. 'Home-brew' patch test reagents are neither standardized nor quality assured, and variable performance between batches will likely exacerbate any operator errors.
Abacavir patch testing should not be seen as a tool for de-labelling patients with a suspected abacavir HSR. Across pharmacotherapy as a whole, de-labelling systemic hypersensitivities via controlled rechallenge can be considered only for some types of drug reaction in some patients, and only under controlled conditions by experienced clinicians [26]. A negative patch test does not definitively preclude an HSR, and, in accordance with product labelling and established clinical practice, if HSR cannot be clinically ruled out, abacavir should be permanently discontinued [38].
Conclusion
Patch testing has demonstrated value in assessing the individual drug culpability in a range of type IV cutaneous and systemic HSRs. Its simplicity is, however, deceptive; the test has a number of important limitations, and its interpretation can be complex.
Although patch testing to improve abacavir HSR diagnostic precision for a study endpoint has been successfully used in recent clinical trials, abacavir patch testing remains a research tool and not a validated diagnostic test to identify which patients can take abacavir. As with any other type of drug HSR, patch testing and de-labelling is the province of dermatologists and allergologists, and it requires specialist facilities and careful assessment of risk-benefit ratio. Neither should be undertaken by primary treating physicians. Clinical vigilance and judgement remains the cornerstone of identifying and managing the abacavir hypersensitivity syndrome.
Acknowledgements
The authors would like to acknowledge Sandra Knowles for her contributions to the development of abacavir patch testing and Caroline Minshull and Nick Fitch for editorial assistance in the preparation of this article. Financial assistance to support this service was provided by GlaxoSmithKline.
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