Patch,prick or intradermal tests to detect delayed hypersensitivity to corticosteroids?

Background. Contact allergy to topical corticosteroids is usually detected by patch testing. Objectives. This study compares the test results obtained with patch, prick and intradermal testing, to assess the most sensitive method for diagnosing corticosteroid hypersensitivity. Patients/Methods. Nineteen corticosteroid‐allergic subjects and three control subjects were included. Patch, prick and intradermal tests were performed with five commercial corticosteroid preparations, as well as with the respective active principles diluted in ethanol. The test readings were performed at different time points, i.e. at 8, 24, 48 and 96 hr, and at 7 days. Results. Patch tests with ethanolic preparations produced more positive reactions than the commercial ones. The intradermal tests became positive earlier than the patch tests, a concordance between patch and intradermal tests being found in 11/15 (two positive intradermal test results with negative patch test results and vice versa). However, several subjects developed skin atrophy (14/22) at intradermal injection sites. Conclusion. Patch testing with the active principles diluted in ethanol remains the diagnostic method of choice for the detection of delayed hypersensitivity to corticosteroids. Intradermal tests with late readings, despite detecting additional contact allergy cases, should not be routinely performed, because of an important risk of atrophy, particularly with corticosteroid suspensions.     

Allergy to systemic and intralesional corticosteroids

In this study, allergic reactions to systemic or intralesional corticosteroids were characterized, and skin tests utilized in the diagnosis of corticosteroid allergy. Five patients who had developed a rash when treated with systemic or intralesional hydrocortisone, methylprednisolone, prednisolone or betamethasone, were challenged with oral or intra-articular corticosteroid preparations, and skin tested. Upon provocation the patients reacted with diffuse erythema principally on the trunk or on the face. The erythema appeared within a period ranging from a few hours to 24 h and faded in 1–3 days. On patch testing, one patient reacted to prednisolone and methylprednisolone, which induced a positive response upon provocation, and two patients were positive to Pivalone®. Patients who were sensitive to hydrocortisone or methylprednisolone, as judged by anamnestic data and provocations, reacted to these corticosteroids in the intradermal tests. Allergy to betamethasone could not be verified by intradermal or patch tests. A combination of intradermal and patch tests is recommended when allergy to systemic or intralesional corticosteroids is suspected. If these skin tests remain negative, provocation is the method of choice.     

Delayed hypersensitivity to topical corticosteroids

Topical hypersensitivity to corticosteroids was studied by epicutaneous testing using the Finn Chamber technic. The steroids were tested in both ethanol and white petrolatum and, in certain cases, in dimethyl sulfoxide. Additionally, commercial preparations were tested. Three groups of patients were studied: (1) patients with a history of hypersensitivity to at least two topical preparations (five of ten patients studied showed a positive patch test reaction for corticosteroids), (2) patients in whom topical corticosteroid hypersensitivity was suspected because of treatment-resistant eczema (seven of twenty-five patients showed a positive patch test reaction), and (3) dermatologic inpatients and outpatients undergoing epicutaneous testing for suspected topical hypersensitivity. Hydrocortisone-17-butyrate (H-17-B) was included in the standard patch test series; of 450 patients tested, two showed a positive patch test reaction. All the patients with corticosteroid hypersensitivity had a positive reaction to H-17-B. In six patients, additional hypersensitivities to one or several other steroid preparations were seen. Use testing was performed as an open test, with 0.1% or 1% H-17-B in ethanol on normal skin of the flexor side of the upper extremities. A positive test reaction was seen in only one of nine patients. Results of use testing with the commercial 0.1% H-17-B (Locoid) ointment were always negative. Our study suggests that the sensitivity of patch tests for corticosteroid hypersensitivity can be increased by using ethanol as vehicle.     

A prospective study into the value of patch and intradermal tests in identifying topical corticosteroid allergy

We have prospectively performed patch and intradermal tests on 105 consecutive patients, attending for patch testing, to determine the optimum method of screening for corticosteroid hypersensitivity. Patch tests with Pivalone and a corticosteroid series (all 1% in ethanol) detected all the patients with steroid sensitivity. However, intradermal tests were essential to exclude false positive reactions and detect all relevant steroid allergies in any individual patient.     

Delayed-type hypersensitivity to lidocaine

BACKGROUND: Lidocaine hydrochloride is the preferred anesthetic agent used in outpatient surgical procedures. While type I hypersensitivity reactions to lidocaine are uncommon, type IV hypersensitivity is reported even less frequently. OBSERVATIONS: Between January 1, 2001, and December 31, 2001, 183 patients were patch tested at the Penn State Milton S. Hershey Medical Center (Hershey, Pa) to the North American Contact Dermatitis Group tray. All patients who had a positive patch test reaction to lidocaine were challenged with 0.1 mL of preservative-free 1% lidocaine intradermally. Of the 183 patients patch tested, 4 had positive reactions to lidocaine, 2 of whom had histories of sensitivity to local injections of lidocaine manifested by dermatitis. CONCLUSIONS: Delayed-type hypersensitivity to lidocaine may occur more frequently than previously thought. In cases of suspected lidocaine contact type IV sensitivity, patients should be patch tested to lidocaine. Positive patch test reactions should be confirmed by intradermal challenge with lidocaine. To provide the patient with alternative local anesthetics, patch testing should be performed with other injectable anesthetics. If positive patch test results occur, intradermal testing should follow.     

Allergy to local anesthetics: Comparison of patch test with prick and intradermal test results

The interrelation between immediate and delayed hypersensitivity reactions to local anesthetics is poorly understood. Especially, the relevance of positive patch test reactions to local anesthetics with regard to the compatibility of injected local anesthetics is unclear. We therefore subjected 104 patch test-positive probands to prick and intradermal tests with seven local anesthetic agents. All prick tests were negative. Only 14 patients showed positive reactions in intradermal tests: 11 with the ester local anesthetic procaine, one with the amide local anesthetic butanilicaine, and two with both. Procaine yielded both immediate and delayed reactions; butanilicaine, only immediate reactions. All other local anesthetics showed negative reactions. It is concluded that in patients with positive patch test reactions to local anesthetics and negative history of anaphylactoid reactions, positive skin test reactions to intradermal application are rare and that, therefore, the risk of anaphylactic reactions to injection anesthesia with amide local anesthetics, except butanilicaine, appears low in these patients.     

Contact hypersensitivity to hydrocortisone-free-alcohol in patients with allergic patch test reactions to tixocortol pivalate

It has been suggested that contact allergy to hydrocortisone alcohol is a frequent phenomenon, A recent study showed that all patients with allergic patch reactions to tixocortol pivalate reacted to intradermal hydrocortisone sodium phosphate. We studied patients with positive patch test reactions to tixocortol pivalate but negative to hydrocortisone alcohol, with penetration enhancers in hydrocortisone alcohol patch tests and oral challenges with hydrocortisone alcohol. Additionally, prick and intradermal tests with hydrocortisone sodium succinate were used. Using penetration enhancers and oral challenges enabled detection of more contact allergies to hydrocortisone alcohol compared to conventional patch testing alone. 9/12 patients with allergic reactions to tixocortol pivalate reacted to intradermal hydrocortisone sodium succinate. No immediate reactions were seen in prick or intradermal tests, suggesting that hydrocortisone contact hypersensitivity is probably not associated with immediate allergy to hydrocortisone. The present study suggests that allergic patch test reactions to tixocortol pivalate are caused by hypersensitivity to hydrocortisone alcohol itself or to one of its metabolites in the skin.     

Intradermal testing in the diagnosis of allergic contact dermatitis

Contact hypersensitivity may be diagnosed with patch testing or intradermal testing. Although these methods have been used earlier in parallel, patch testing has gradually become the only method in routine diagnosis of contact allergy. Recent findings in corticosteroid contact hypersensitivity have shown that patch testing is not always an optimal method, especially when poor penetrants are used. Therefore, a reappraisal of intradermal testing is presented, based on the literature. Studies employing both patch and intradermal testing are reviewed and the advantages and disadvantages of intradermal tests as compared to patch tests in contact allergy diagnostics are discussed. We find that it might be worthwile to evaluate whether contact allergy to compounds other than corticosteroids may be easier to detect with intradermal than patch test.     

Detection of contact hypersensitivity to topical corticosteroids with hydrocortisone-17-butyrate

We showed earlier that most patients with contact dermatitis due to corticosteroids show cross-reactions when patch tested with hydrocortisone-17-butyrate (H-17-B). To test whether H-17-B could be used for detecting topical corticosteroid allergy, we screened patients undergoing routine patch testing with H-17-B. Patients with clearly allergic or doubtful/mildly irritant patch test reactions to H-17-B, and with a history suggesting topical corticosteroid allergy, were further tested with a large panel of steroid preparations. 20 out of 4039 patients (0.5%) showed definite allergic test reactions to corticosteroids. A further 165 patients with clinically suspected corticosteroid allergy were directly tested with a panel of steroid preparations; 14 patients showed positive patch test reactions. Altogether, 33 out of 34 patients with corticosteroid allergy had positive test reactions to H-17-B. Inclusion of 1.0% H-17-B in ethanol in the standard patch test series improves the diagnosis of topical corticosteroid hypersensitivity.     

Reactivity of tixocortol pivalate-positive patients in intradermal and oral provocation tests

Pivalone®/tixocortol pivalate commonly yields positive reactions in the patch test series. The clinical relevance of these positive reactions was investigated in more detail. In the standard patch test series 5.6% (73 of 1306) ofthe patients were positive to corticosteroids. 5.2% to 0.1% tixocortol pivalate in ethanol (Pivalone® nasal spray diluted 1:10) and 2.3% to 1% hydrocortisone butyrate in ethanol. Some ofthe patients were tested in parallel with Pivalone® and 1% tixocortol pivalate in petrolatum. The former test reagent yielded some false-positive reactions, whereas with the latter, some allergic responses were missed. Intradermal tests with the succinate esters of hydrocortisone, methylprednisolone and prednisolone were performed with 52 patients positive to Pivalone®. Of these 76.9% (40 of 52) were positive in the intradermal tests; 38 to hydrocortisone. 35 to methylprednisolone and 30 to prednisolone. Twelve patients who had been positive in the intradermal tests were challenged orally with corticosteroids and they all showed positive reactions to hydrocortisone, methylprednisolone or prednisolone. The patients developed localized reactions at the sites of previous eczema or positive skin tests or diffuse erythema or exanthema. The oral doses of hydrocortisone eliciting positive delayed skin reactions ranged from 20 to 200 mg. Reactivity to tixocortol pivalate is closely related to sensitivity to hydrocortisone, methylprednisolone and prednisolone, but high oral doses of these corticosteroids may be required to produce allergic symptoms.     

Delayed systemic allergic reactions to corticosteroids

From the limited number of reports in the literature, it would appear that various types of delayed reactions from systemically, intralesionally, and intra-articularly administered corticosteroids are rare, particularly given their widespread use. The purpose of this literature review is to summarize in table form the reported cases of generalized delayed systemic corticosteroid reactions with respect to patient presentation, methods of evaluation, and conclusions reached. In total, 24 cases of generalized delayed systemic corticosteroid reactions have been reported in the literature. Clinical presentation (timing and cutaneous manifestations) as well as evaluation of these patients has been variable; reactions reported include eczematous or exanthematous eruptions, with or without bullae or purpura. In 16 cases, the diagnoses have been supported by positive patch or intradermal testing. Overall, it appears that generalized delayed systemic reactions to corticosteroids show considerable variability and are infrequently reported. Patch and intradermal tests with standardized allergens appear to be the most useful tests currently available to support this clinical diagnosis.     

Contact allergy to corticosteroids in patients using inhaled or intranasal corticosteroids for allergic rhinitis or asthma.

BACKGROUND: Patients using topically applied corticosteroids are at risk of developing allergic contact hypersensitivity. OBJECTIVE: To assess prevalence of allergic contact hypersensitivity reactions to inhaled or intranasal corticosteroids. METHODS: A prospective study of 30 adult patients using inhaled or intranasal corticosteroids for conditions such as allergic rhinitis was performed. We used epicutaneous patch testing to determine the prevalence of allergic contact hypersensitivity to corticosteroids and common additives (propylene glycol and benzalkonium chloride) in inhaled and nasal corticosteroid preparations in this population. RESULTS: Of 30 patients, 4 (13%) had positive patch test results. 3 (10%) were allergic reactions and 1 (3%) was an irritant reaction. Half of the reactions were to a corticosteroid (budesonide) and half were to a common preservative in nasal preparations (benzalkonium chloride). CONCLUSION: This study supports other clinical evidence that contact dermatitis/mucositis from inhaled or intranasal corticosteroid products can occur. The corticosteroids or added agents such as preservatives can be causative and may result in allergic or irritant reactions, which can be relevant to clinical symptoms.     

Evaluation of skin test reactions in patients with non-immediate type drug eruptions

Skin test reactions were evaluated in 242 patients who appeared to develop delayed type drug eruptions from the clinical course. The patch testing was positive in 62 (31.5%) of 197 patients tested and the intradermal testing in 105 (89.7%) of 117 patients. The positive ratios of intradermal testing were higher in maculopapular (MP), erythema multiforme (EM), and erythrodermic (ED) types than in eczematous (Ecz) type drug eruptions, while those of patch testing were comparatively high in ED, Ecz type, and anticonvulsant-induced drug eruptions. It is considered that the combination of patch testing and intradermal testing is useful for determination of causative drugs in delayed type drug eruptions.     

Allergic paraben and benzyl alcohol hypersensitivity relationship of the "delayed" and "immediate" varieties

From a review of the literature, and the results of scratch, intracutaneous and subcutaneous injections of patients with parbens and benzyl alcohol sensitivity of the delayed type characterized by allergic contact dermatitis and strongly positive patch patch tests, it would appear that such sensitivity is not usually accompanied by the immediate urticarial type of allergic sensitivity. This communication concerns itself with results of testing patients with clinical sensitivity and positive patch test reactions to the parabens or benzyl alcohol with scratch, intracutaneous and subcutaneous injections of these preservatives in order to determine the relationship of the "delayed" type of allergic hypersensitivity to the parabens and benzyl alcohol with the "immediate" variety of hypersensitivity. The parabens and benzyl alcohol are widely employed as preservatives for many allergenic extracts used in scratch and intracutaneous testing. In addition, these preservatives are used in injectable corticosteroid medicaments and in local anesthetic solutions. In order to determine whether the presence of these preservatives in allergenic extracts would produce false positive scratch or intracutaneous tests or might produce an immediate, urticarial or anaphylactic reaction in patients with allergic contact dermatitis and positive patch test reactions to these preservatives, two patients with positive patch test reactions and allergic contact dermatitis to the parabens and two with similar benzyl alcohol sensitivity were tested in the manner detailed in the following case reports.     

The use of skin testing in the investigation of cutaneous adverse drug reactions

Skin testing with the suspected compound has been reported to be helpful in determining the cause of cutaneous adverse drug reactions (ADRs), but the value and specificity of these tests need to be determined. In this study, 72 patients with presumed drug eruptions (27 maculopapular, 18 urticarial, seven erythrodermic, nine eczematous, four photosensitivity, three fixed drug eruptions, three with pruritus and one with acute generalized exanthematous pustulosis) were assessed. All had drug patch tests; 46 also had prick tests and 30 had intradermal tests (performed on hospitalized patients using a sterile solution of the suspected drug, diluted sequentially) with immediate and delayed readings. Among these patients, 52 (72%) had a positive skin test reaction, 43%, 24% and 67% in patch, prick and intradermal skin tests, respectively. The results of skin tests varied with the drug tested and with the clinical type of cutaneous ADR, as a significantly higher number of positive patch tests was observed in maculopapular rashes than in urticarial reactions ( P =  0.001). This study supports the value of careful sequential drug skin testing in establishing the cause of cutaneous ADR. Guidelines are proposed for performing these tests, and these include the use of appropriate negative control patients to avoid false-positive results.     

Intradermal testing in doubtful cases of contact allergy to metals

Among 1670 consecutively patch tested patients an intradermal test with chromium, cobalt and nickel was added in 66 cases. There were three indications for intradermal testing: 1) the patch test reaction at 72 h was difficult to interpret; among 49 patients with one or more doubtful reactions a metal allergy was confirmed in 24 and rejected in 54. 2) ten patients with a negative patch test in spite of a positive history of metal allergy; among these, one was positive to cobalt, two to nickel and the other seven negative. 3) seven patients checked for a previously diagnosed allergy; a metal allergy was confirmed in four. Intradermal testing is recommended for confirmation of doubtful patch test reactions, particularly to disclose false positive reactions to metals.     

Contact allergies to topical corticosteroids: 10 cases of contact dermatitis

Patients who noticed worsening of their skin disease after using topical corticosteroid preparations were patch tested both with the commercial preparation and the corticosteroid itself. Between 1987 and 1989, 10 cases of contact dermatitis due to topical corticosteroids were detected in this way. The corticosteroids wee amcinonide (2 patients), hydrocortisone butyrate, clobetasol propionate (2), betamethasone valerate (2), prednicarbate and fluocortolone (2). Patch tests with the commercial preparations and the corticosteroids themselves elicited reactions almost identical in time course and severity. Individual sensitivity seems to be more important for test results than test conditions. 9 of the 10 patients underwent further patch testing with a corticosteroid series. In 2 patients, a true cross-reaction between budesonide and hydrocortisone butyrate was found. All 9 patients showed further sensitivities to other corticosteroids. Most of the cross or concomitant reactions could be categorized into recently defined corticosteroid classes. To improve our understanding of corticosteroid sensitization, and to help the patient avoid reactions to other topical corticosteroids, a corticosteroid series should be patch tested in every case of corticosteroid sensitivity.     

Allergic contact dermatitis from natural latex.

BACKGROUND: Reports on natural latex allergy have increased steadily during the last 10 years. Latex allergy generally refers to a type 1 reaction to natural rubber latex (NRL) proteins with clinical manifestations ranging from contact urticaria to asthma and anaphylaxis. Previous United States studies on NRL allergy largely have been reported by allergists with little detailed information on hand eczema, contact allergy, or on outcome. The present study was performed from March 1998 to November 1999 with the aim of finding out the prevalence of type IV hypersensitivity to latex in patients with suspected rubber allergy. MATERIALS AND METHODS: A total of 167 patients with hand eczema and contact with rubber products underwent patch testing with the standard screening and rubber components (test series Deutsche Kontaktallergiegruppe), and NRL pure provided by Regent (liquid high ammonia 0.7% NRL, accelerator, and preservative-free latex) between March 1998 and November 1999. The charts of all NRL positive patients are reported with the results of history, prick, patch tests, total IgE, specific IgE to latex (FEIA) test and follow-up data (after 6 months). RESULTS: Four patients (3 men) showed positive patch test results to NRL. One of these patients also reacted to the rubber chemical tetraethylthiuram monosulfide, and another one of these patients revealed a type 1 reaction to NRL, diagnosed by positive reaction to prick test. The other 3 patients with patch test reactions to NRL had negative reactions to prick tests to NRL extracts after 20 minutes. All 4 patients had a positive delayed prick test reaction to NRL. Latex FEIA test result was negative in all 4 patients. The contact eczema healed after elimination of the latex gloves and medical latex devices in all patients. Furthermore, 10 of the 167 patch testing patients (6%) were positive for tetramethylthiuram monosulfide 1%. CONCLUSION: In the present study with 167 patients, the prevalence of type IV hypersensitivity to latex was 2.4%. We recommend that the patch test with NRL as well as with rubber additives should be performed in patients of suspected contact dermatitis caused by rubber products.     

Use of patch testing for the diagnosis of abacavir-related hypersensitivity reaction in HIV patients

Background: The use of antiretroviral drug abacavir (ABC) has been often associated with cutaneous hypersensitivity reactions, the majority being severe. Objective: The present study discusses the issues of patch testing associated with pharmacogenetic screening in light of the development of abacavir hypersensitivity reactions (HSRs). Methods: The present authors classified 100 patients into three groups: 20 patients (group A) had experienced a hypersensitivity reaction when treated with highly active antiretroviral therapy (HAART) including ABC; 60 HIV‐positive patients (group B) were receiving HAART scheme including ABC; 20 HIV‐negative patients acted as control group (group C). Patients of group A and B were patch tested with ABC as such, then with an ABC extract diluted to 1 and 10% in petrolatum. Group C patients underwent patches with petrolatum only. A biopsy of the lesion was performed in those patients who showed a positive skin reaction. All patients had been tested for HLA‐B5701. Results: A correlation between positive ABC‐patch testing and HLA‐B5701 was found in 50% of patients enrolled in group A, while in group B and C, all patients tested negative for both genetic marker and ABC‐patch testing. Histopathology findings confirmed a vigorous CD4+ and CD8+ cellular response that is compatible with HSR. Conclusions: Patch testing is a safe and sensitive method that can be used for to confirm or exclude any correlation between abacavir and hypersensitivity skin reactions in patients who have been previously treated with abacavir during HAART. Correlation between patch test, immunohistochimical, and genetic tests results shows that genetic testing increases the possibility to identify patients with a true reaction.     

Clindamycin skin testing has limited diagnostic potential

We examined the role of clindamycin prick and intradermal skin testing in a tertiary care clinic population. Experience with diagnostic modalities such as prick and intradermal testing has been limited with clindamycin. A retrospective chart review was conducted for patients with immunologic reactions temporally associated with clindamycin who were referred to the Drug Safety Clinic (Toronto, Ontario). A total of 31 patients were identified who had undergone prick and intradermal skin testing. All 31 negative immediate prick and intradermal tests were followed by a 150 mg oral dose of clindamycin. 10/31 (32%) subjects had significant reactions to the oral clindamycin provocation. 2 patients reported delayed reactions at the clindamycin intradermal test sites. Our experience suggests that prick and intradermal skin testing is not adequate in identifying patients with previous allergic reactions associated with clindamycin. Oral provocation tests can be used in patients with histories of clindamycin adverse reactions; however, it should be offered on a risk-benefit basis.