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Patch testing — Drugs to be used in patch testing are mixed into petrolatum or 0.9 percent saline, applied to a small area of skin under occlusion for 48 hours, and then removed. The site is examined 48 to 96 hours after placement. Concentrations of various drugs for use in patch testing have been established [ 59 ]. Patch testing with drug preparations may be useful in evaluating patients with maculopapular exanthema, acute generalized exanthematous pustulosis, DiHS/DRESS, and flexural exanthema. Patch testing is most useful in evaluating these reactions to certain antibiotics, aromatic anticonvulsants, and abacavir [ 60 ]. It is only occasionally positive if the delayed-appearing skin reaction was mainly macular (no or only moderate cutaneous cell infiltration) or urticarial, or isolated hepatitis or nephritis. Patch testing to the culprit drug is usually negative in patients with past exfoliative reactions, such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and is not recommended [ 61 ].

Intradermal testing with delayed readout — This type of testing should only be performed if a commercially available injectable form of the drug is available. The concentration used should be known to be nonirritating and a prick test should be performed initially to assure there is no immediate response. A positive result consists of erythema and induration at the site, and the site is examined at 24 to 48 hours after placement [ 59 ]. Intradermal testing with delayed readout is slightly more sensitive than patch testing, but somewhat less specific [ 57 ]. It has the same indications as patch testing and may be used in evaluating exanthems, acute generalized exanthematous pustulosis, DRESS/DiHS, fixed drug eruption and symmetrical drug-related intertriginous and flexural exanthema. Intradermal testing with delayed readout has low sensitivity for exfoliative skin reactions, as well as for isolated macular or urticarial skin eruptions. It seems to work best for certain antibiotics in which there is experience with non-irritating drug concentrations [ 39 ]. Only a few preparations of drugs for skin testing are commercially available, so preparations are often made by individual clinicians or centers. This makes it difficult to standardize the procedure or compare results. Overall, patch and intradermal testing with delayed readout appear to have good drug-related specificity, although they can be positive even when recent drug treatment did not cause a reaction. In addition, more work is needed to increase their sensitivity [ 56,62-68 ].

In vitro tests for delayed reactions — In vitro tests for delayed reactions include lymphocyte transformation/activation tests, upregulation of activation markers on T cells (eg, CD69), cytokine production, and drug-induced cytotoxicity assays [ 69 ]. These tests are done in certain centers only, need to be done with a preparation of pure drug, and are still considered research tools. If available, such tests may help in diagnosis, as they can be positive when skin tests are negative. Their specificity for most drug classes seems to be very good (mostly > 95 percent), but the sensitivity needs to be improved [ 66 ]. Where available, in vitro testing may be useful in evaluating patients with maculopapular exanthema, acute generalized exanthematous pustulosis, DiHS/DRESS, and flexural exanthema. The sensitivity of tests based on cell expansion, cell activation, or cytokine release is high in DiHS/DRESS, but low in exfoliative reactions. The role of tests evaluating drug-induced cytotoxic reactions needs to be further evaluated, and may be particularly interesting for bullous skin reactions, as well as for isolated drug-induced hepatitis or nephritis, where skin tests are often negative. GRADED CHALLENGE  — Graded challenge involves administering a medication to a patient in a graduated manner under close observation. This is also called test dosing or drug provocation testing. Indications  — Graded challenge is used to exclude allergy to the medication in question, and is most appropriate for a patient who is UNLIKELY TO BE ALLERGIC to that drug. Graded challenge should NOT be performed in a patient with a positive response in a prior drug allergy test (skin or in vitro). Graded challenge does NOT modify the allergic response to the drug or prevent recurrent reactions. Therefore: Patients who tolerate a drug upon graded challenge prove that they are not allergic to it A challenge procedure in a patient with a suspected IgE-mediated drug allergy could potentially induce anaphylaxis and should be performed by an allergy expert in a setting equipped to manage possible reactions Contraindications  — Graded challenge to the suspect drug is contraindicated in patients with the following types of reactions: Exfoliative dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) Blistering or sloughing of the skin

A challenge procedure in a patient with a suspected IgE-mediated drug allergy could potentially induce anaphylaxis and should be performed by an allergy expert in a setting equipped to manage possible reactions Contraindications  — Graded challenge to the suspect drug is contraindicated in patients with the following types of reactions: Exfoliative dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) Blistering or sloughing of the skin Severe generalized hypersensitivity reactions involving internal organs (DiHS/DRESS) Milder dermatoses with mucous membrane lesions (eg, erythema multiforme) Even minute amounts of the suspect drug can reactivate these reactions, and the response can then escala1ff8te even though no further drug is given [ 70 ]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Future use of related medications' .) Inclusion of placebo doses  — Inclusion of a placebo is strongly recommended to exclude false positive reactions in patients with anxiety or other subjective reactions. Some patients experience unintentional anticipatory reactions (classic conditioning), particularly following a true allergic reaction or a frightening experience in association with drug treatment. These can often be elicited by placebo doses, thus reassuring the clinician and patient alike that the response is not due to the drug in question. Protocols  — The pace of the challenge and degree of caution exercised depends upon the likelihood that the patient may be allergic, the patient's medical stability, and the clinician's experience and level of comfort with the procedure. Other considerations include: Patients should NOT be premedicated with antihistamines or glucocorticoids because these agents may mask early signs of an allergic reaction. Beta blockers taken for control of hypertension should be withheld for 24 hours before challenge, as these agents can interfere with treatment of anaphylaxis with epinephrine , should that be necessary. In contrast, beta blockers that are taken to control arrhythmias should not be withheld without consulting a cardiologist. Patients with asthma, chronic obstructive lung disease, or other pulmonary diseases should have their pulmonary symptoms optimally controlled prior to undergoing challenge.

Beta blockers taken for control of hypertension should be withheld for 24 hours before challenge, as these agents can interfere with treatment of anaphylaxis with epinephrine , should that be necessary. In contrast, beta blockers that are taken to control arrhythmias should not be withheld without consulting a cardiologist. Patients with asthma, chronic obstructive lung disease, or other pulmonary diseases should have their pulmonary symptoms optimally controlled prior to undergoing challenge. For immediate reactions  — If the previous reaction occurred less than one hour after drug administration and there is concern about a possible IgE-dependent reaction, then the challenge should be performed by an allergy expert and in a setting equipped to treat anaphylaxis. The starting challenge dose should be low, typically between 1/10,000 and 1/1000 of the therapeutic dose, depending on the severity of the past reaction. Using this strategy, any symptoms that are elicited should be mild. The oral route is preferred when possible, since oral administration is generally associated with less severe symptoms compared with intravenous administration. Ten-fold increasing doses are administered every 30 to 60 minutes until the full therapeutic dose is reached. If subjective symptoms appear, the clinician can proceed more slowly by using threefold increases for one or two steps. Once the full therapeutic dose has been achieved without incident, continuous therapy should be begun immediately with appropriate monitoring. For delayed reactions  — Challenge schemes for simple delayed exanthema to drugs are usually performed either in the context of research (to document sensitivity) or at a time that the patient actively needs the drug. In the latter situation, the drug may be slowly increased and the patient instructed to contact the clinician immediately if any adverse events are noted. For delayed or nonimmediate types of reactions, challenge procedures are less standardized and are based upon the time course of the patient's reaction and the pharmacology of the drug involved. The optimal approach is not known and experts have differences in practice. In general, the time between doses should be long enough that delayed symptoms have time to develop before the next higher dose is administered. Some protocols may take days or even weeks.

For delayed or nonimmediate types of reactions, challenge procedures are less standardized and are based upon the time course of the patient's reaction and the pharmacology of the drug involved. The optimal approach is not known and experts have differences in practice. In general, the time between doses should be long enough that delayed symptoms have time to develop before the next higher dose is administered. Some protocols may take days or even weeks. An example of a challenge procedure for delayed reactions to cephalosporins involved administering doses at weekly intervals, starting with 1/100 of a usual dose on day 0, 1/10 of a dose on day 7, and a standard dose on day 14 [ 71 ]. However, other studies have documented that some delayed reactions only develop after several days at a full therapeutic dose, or in the presence of a concomitant viral infection [ 72,73 ]. Thus, there may be certain drug reactions that cannot be easily elicited with any challenge protocol [ 74 ]. Other published examples of challenge protocols, when available, are discussed in specific topic reviews. (See "Sulfonamide allergy in non HIV-infected patients", section on 'Desensitization' .) OPTIONS FOR CONTINUING TREATMENT  — There are three options for providing continued treatment in patients with a confirmed drug allergy: Administration of an unrelated medication Administration of a related medication Desensitization to the culprit drug Administration of an unrelated medication  — The most straightforward option is administration of an unrelated medication that is safe and effective for the disorder in question. However, second-line therapies may confer their own risks, such as toxicities and higher costs.

Administration of a related medication Desensitization to the culprit drug Administration of an unrelated medication  — The most straightforward option is administration of an unrelated medication that is safe and effective for the disorder in question. However, second-line therapies may confer their own risks, such as toxicities and higher costs. Penicillin allergy illustrates the issues involved. Patients labeled penicillin allergic often receive non-beta-lactam antibiotics, which can be more expensive, associated with side effects, and in some cases, less efficacious [ 75-78 ]. Specifically, patients carrying the diagnosis of penicillin allergy are more likely to be treated with vancomycin or quinolones [ 75,79-83 ]. The use of these broad-spectrum antibiotics contributes to the development and spread of drug-resistant bacteria [ 84-86 ]. One study assessed various risk factors for the development of vancomycin resistant enterococcus (VRE) in a medical intensive care unit (MICU) [ 87 ]. Among pre-MICU treatment with various classes of antibiotics, quinolones had the strongest association with subsequent development of VRE (odds ratio = 8.6), whereas treatment with penicillins/beta-lactamase inhibitors was not associated with developing VRE [ 87 ]. Some broad-spectrum antibiotics are also associated with Clostridium difficile infection. Thus, use of alternative, unrelated medications is not without risk. Administration of a related medication  Se