Long-term oral corticosteroid therapy does not alter the results of immediate-type allergy skin prick tests

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1 Long-term oral corticosteroid therapy does not alter the results of immediate-type allergy skin prick tests Anne Des Roches, IVID, Louis Paradis, MD, Yves-Henri Bougeard, MD, Philippe Godard, MD, Jean Bousquet, MD, and Pascal Chanez, MD Montpellier, France Background: Medications can modulate the results of skin prick tests (SPTs). Short-term corticosteroid therapy does not alter IgE-mediated skin tests, but the impact of long-term oral corticosteroid therapy on SPT results is unclear. A prospective study was carried out in patients with steroid-dependent asthma who rece&ed oral corticosteroids for a long period to detelrnine whether this treatment reduced skin test reactivity. Methods: Thirty-three patients with steroid-dependent asthma (median age, 59 years) were compared with 66 patients with asthma who served as a control group, matched for age, sex, and atopic status. SPTs with codeine phosphate and a screening battery of standardized allergen extracts were performed before commencement and after at least I year of daily oral prednisone treatment (median duration, 2 years; median daily dose, 20 rag). Results: Fifteen patients with corticosteroid-dependent asthma were allergic before treatment, and their sensitization was not changed by long-term treatment with oral corticosteroids. The median wheal diameters induced by codeine phosphate were similar in both groups. The median wheal diameters induced by allergens, and more specifically, by Dermatophagoides pteronyssinus and D. farinae were similar in both groups and did not change in the steroid group after treatment. Conclusions: Systemic corticosteroid therapy (prednisone, 10 to 60 rag/day) for 2 or more years does not seem to alter SPT reactivity. (J Allergy Clin Immunol 1996;98:522-7.) Key words: Skin prick test, corticosteroids, asthma Skin prick tests (SPTs) are widely used to provide confirmatory evidence for an IgE-mediated allergic reaction that has been implicated on clinical grounds. The concomitant administration of various medications can modulate results of SPTs. 1 Although many drugs, including Hi-blockers, are known to decrease skin test reactivity to allergens and histamine, the effects of corticosteroids are less well characterized. Systemic corticosteroids used for a short period and in low to moderate doses do not diminish immediate skin test reactivity to histamine, compound 48/80, or allergens. 2, 3 Topical corticosteroids applied to the skin induce From Service des Maladies Respiratoires, H6pital Arnaud de Villeneuve, Montpellier, France. Received for publication Sept. 6, 1995; revised Jan. 17, 1996; accepted for publication Feb. 7, Reprint requests: Pascal Chanez, MD, H6pital Arnaud de Villeneuve, Montpellier-Cedex 5, France. Copyright 1996 by Mosby-Year Book, Inc /96 $ /1/ Abbreviations used CST: Corticosteroid therapy SPT: Skin prick test local side effects, including skin thinning, 4 and decrease the immediate allergic skin reaction. 5 The effects of corticosteroids on the inflammatory component of the immediate-phase allergic reaction are difficult to characterize because a single dose of inhaled steroids does not block the immediate bronchial or nasal reaction, 6 whereas the administration of the same drugs for a longer period blocks both the immediate- and late-phase reactions. 7 Corticosteroids do not appear to reduce mediator release 8-1 but are highly effective in blocking the influx of inflammatory cells, u The impact of long-term oral corticosteroid therapy (CST) on skin test reactivity is poorly understood

2 J ALLERGY CLIN IMMUNOL Des Roches et al. 523 VOLUME 98, NUMBER 3 because only a few studies have been performed. A prolonged course of corticosteroids was found to decrease the intradermal skin responses to codeine phosphate. 2 On a clinical basis, the evolution of steroiddependent asthma is often variable, and the importance of allergic components is always open to question. It is possible that long-term systemic CST could alter skin test results and would render the interpretation of a negative skin test result ambiguous in this group of patients. The aim of this study was to evaluate the effect of long-term systemic CST on SPT reactivity in a population with steroid-dependent asthma requiring systemic corticosteroids for at least 1 year. Skin test reactivity to codeine phosphate and different allergens was assessed before CST was started and at least 1 year after a continuous daily oral treatment. An age-matched control group of patients with asthma who had not received oral corticosteroids was used to compare responses. METHODS Patients Thirty-three patients with steroid-dependent asthma (age range, 20 to 71 years; median age, 59 years; 19 male) were studied. Fifteen of them were sensitive to at!east one aeroallergen as assessed by SPTs (Table I). The patients were included in the study on the basis of a clinical history of asthma as previously described in detail, 12 and all had a reversibility of airway obstruction of 12% of FEV 1 from baseline and an absolute value of 200 ml. 13 Steroid-dependent asthma was defined as the need for daily oral corticosteroid treatment for optimal control of asthma symptoms. The duration of continuous oral corticosteroid treatment was at least 2 years. Atopic status was defined as the presence of a positive SPT response and/or the presence of serum allergen-specific IgE correlating with symptoms. A control group was selected from individuals attending an outpatient clinic who were matched for age, sex, and atopic status and tested over the same time period. The control group consisted of 66 patients (age range, 21 to 73 years; median age, 58 years; 38 male). Thirty patients had mild asthma with or without seasonal and/or perennial allergic rhinitis, and 36 were nonatopic asthmatic control subjects. None of the patients in the control group had received systemic, inhaled, or topical corticosteroids for at least 1 year preceding the SPTs. None of the subjects in both groups had received immunotherapy. The study was approved by the ethical committee of the clinic. Patients gave informed consent for the study. TABLE I. Demographic characteristics of the subjects Steroid Control group No. of patients Age (yr) 59 (20-71) 58 (21-73) Sex 19M: 14F 38M: 28F Asthma (%) Rhinitis (%) IgE-mediated allergy (%) Oral prednisone Duration of treatment (yr) 2 (2-14) 0 Mean dose (mg) 20 (5-60) 0 Results are expressed as medians and 25th to 75th percentiles. Skin test reactivity Extracts. Standardized extracts were used for most allergens (Stallerg6nes Laboratories, Fresnes, France). A screening battery of aeroallergens found in the Montpellier area was tested including house dust mites (Dermatophagoides pteronyssinus and D. farinae), animal danders (cat and dog), several grass and tree pollens, molds (including Alternaria and Cladosporium species). 14 Extracts were labeled in index of reactivity (IR), and each standardized extract was used at a strength of 100 IR. SPTs. SPTs were performed by using the modified prick test technique according to the method of Pepys, as previously described in detail. ~5 To avoid possible circadian differences in skin reactivity, skin tests were performed between 9:00 AM and 11:00 AM. All SPTs were done in duplicate. Three of the investigators conducted the study. However, the same tester did the SPTs before and after the treatment for the same patient. Moreover, the reproducibility of the skin testers was evaluated in a double-blind, randomized skin test carried out on five volunteers with histamine concentrations of 1, 10, and 100 mg/ml. The histamine solutions were prepared by a blinded nurse who dispensed them into 30 blinded containers according to a randomized scheme. A record sheet stating the anatomic location at which to place each test was also supplied. The resulting wheals were traced, and the outlines were transferred to a record sheet by using transparent adhesive tape. The mean diameter and the mean area of the wheal were subsequently determined by using an AMS Optomax V image analyzer (Numonics Corp., Montgomeryville, Pa.). Each tester had a low coefficient of variability. Moreover, there was a correlation of over 90% among the three testers. The wheals induced by the allergen extracts were recorded 15 minutes after the tests, and wheals elicited by 9% codeine phosphate positive control or by a negative control solution (consisting of a 50% glycerol solution) were recorded 10 minutes after the tests by using the Scotch tape technique. The mean wheal diameter was measured. SPT results were considered positive if the wheal size induced by the allergen extract was at least 70% of the one elicited by the positive control.

3 524 Des Roches et an. J ALLERGY CLiN IMMUNOL SEPTEMBER A Codeine Phosphate B Allergens 12 g g q~. O0 ~3. _ o OOOO 00 OOOOOOOO go OOOOOO O0 OOO OO 0 O O0 CS Controls CS Controls FIG. 1. SPT responses to 9% codeine phosphate (A) and to D. pteronyssinus allergen (B) in 33 steroid-treated patients and 66 control subjects. Only patients allergic to D. pteronyssinus are represented in B. CS, Corticosteroid-treated patients. Serum-specific IgE Serum-specific IgE was evaluated by Phadebas CAP System (Pharmacia Diagnostics AB, Uppsala, Sweden). Treatment course All subjects had been receiving daily oral prednisone (10 to 60 rag/day) for at least 1 year. They were also regularly receiving inhaled steroids (beclomethasone dipropionate, 1500 to 2 i~g/day or budesonide, 1600 ~g/day) and regular or as-needed inhaled 132-agonists. None of the subjects had received any theophylline for 12 hours, any antihistamines for at least 72 hours, any terfenadine for at least 1 week, any astemizole for 6 weeks, or any ketotifen or imipramine for at least 2 weeks. None of them were using topical skin corticosteroids. Patients receiving salmeterol were asked to discontinue the drug for a period of 48 hours before testing because this drug might alter the results of SPTs. Design of the study This was a prospective study. SPTs were performed before and at the end of at least 1 year of daily oral CST. Because most allergic patients were sensitized to house dust mites, variation in skin test size was only determined by using a lyophilized standardized D. pteronyssinus extract, reconstituted every month in glycerol. 16 Statistical analyses were performed with nonparametric tests. Results are expressed as medians and 25th to 75th percentiles. RESULTS Characteristics of the patients Demographic data are described in Table I. The steroid-dependent population received a median daily dose of 20 mg of prednisone throughout the study period. They had received prednisone for a median period of 2 years (range, 2 to 6 years). There was no significant difference in terms of age and sex between patients with steroid-dependent asthma and the control group. Skin test response to 9% codeine phosphate All the patients with steroid-dependent asthma had a positive SPT response to codeine phosphate. There was no significant difference in the median response before and after CST (6 mm; range, 4 to 8 mm vs 5 mm; range, 3 to 8 mm). The median response in the control group (5 mm; range, 4 to 6 mm) was comparable to that in the steroid-treated group after 2 years of treatment (Fig. 1).

4 J ALLERGY CLIN IMMUNOL Des Roches et at, 525 VOLUME 98, NUMBER 3 TABLE II. Sensitization of the subjects tested Steroid-dependent asthma Before CST After CST Control group No. of allergic patients No. of sensitivities per patient 3 (2-7) 4 (2-7) 5 (2-9) Percent polysensitization* Sensitivity House dust mites 14 (93%) 16 (94%) 15 (50%) Animal danders 7 (47%) 9 (53%) 13 (43%) Molds 6 (40%) 9 (53%) 9 (30%) Grass pollen 9 (60%) 11 (65%) 21 (70%) Tree pollen 9 (60%) 9 (53%) 20 (66%) Results are expressed as medians and 25th to 75th percentiles. *Polysensitization: more than one positive SPT response. Skin test response to allergens At the beginning of the study, 15 patients with steroid-dependent asthma had positive skin test reactivity to at least one aeroallergen (Table II). Fourteen of them were sensitized to D. pteronyssinus (positive skin test response and specific IgE antibodies). Patients without any positive SPT responses at the beginning of the study did not develop new sensitivity during the trial. Also, none of the patients with a positive SPT response to an allergen lost sensitivity after 2 years of oral corticosteroid treatment. Fifty-three percent of the patients had no change in skin test reactivity during the study, and an increase in the number of positive skin test results was observed in 47% of them. However, very few new sensitivities were observed. In three patients, sensitization toambrosia pollen was noticed. Two patients had a new sensitization to D. pteronyssinus, and two others had a new sensitization to dog and/or cat danders. Finally, three patients had new sensitivities to Altemaria species. The median size of skin test responses to D. pteronyssinus was 4 mm (range, 3 to 6 ram) before CST (Figs. 1 and 2). After CST, the median response to the allergen was similar (Wilcoxon W test) with a size of 4 mm (range, 3 to 7 mm). There was no significant difference (Mann-Whitney U test) in skin test size for D. pteronyssinus between patients with steroid-dependent asthma tested during the steroid treatment period and the control group (median, 4 ram; range, 2.5 to 12 mm). DISCUSSION The results of this study indicate that 2 years of oral CST in patients with steroid-dependent asthma does not alter SPT reactivity to codeine phosphate or allergens when compared before and after 2 years of treatment. Moreover, the results of SPTs in patients treated with steroids, when compared with a control group of patients not treated with steroids, were not significantly different. To our knowledge, this is the first time that a prospective study has evaluated the effects of long-term oral CST on skin test reactivity to allergens and codeine phosphate. In this study we evaluated the wheal response only, because the flare of patients with corticosteroid-dependent asthma is usually difficult to read. The wheal sizes are small but interpretable both for the diagnosis of IgE-mediated allergy and comparative studies. The standardization of our skin test extracts is based on a wheal size of around 5 to 6 ram. It is possible that in other countries, in which different extracts are used, the wheal size is greater; but this is not usually the case in many European countries. It is clear, however, that a greater size would have increased the precision of the comparison. We chose to use mean orthogonal diameters because we have previously compared the mean sizes and areas of SPT responses and found that there was a highly significant correlation between both methods. All patients were receiving 1500 to 2 txg of inhaled steroids, which are known to have a small but unavoidable systemic effect. However, such a small systemic dose does not appear to induce an effect on skin tests, no study has examined the effects of inhaled steroids on skin tests, and the comparison between the control group without inhaled steroid treatment and the group treated with inhaled steroids before the introduction of systemic corticosteroids did not shown a W significant difference in SPT reactivity.

5 526 Des Roches et al. J ALLERGY CLIN IMMUNOL SEPTEMBER 1996 & ~3 (u q) (b J Before NS After FIG. 2. Evolution of the size of SPT wheals in response to D. pteronyssinus allergen before and after 2 years of oral CST (n = 14). None of the patients had lost their allergic sensitization. On the other hand, about half of the patients had new sensitizations. For Ambrosia pollen, this was due to a new exposure to this allergen, which is now spreading in France. For cat and dog dander, the patients had recently acquired a pet, and the new sensitization may have been related to a new allergen exposure. For Alternaria species, new sensitizations may be related to the improvement of the standardized allergen. Finally, we have no clear explanation for the new sensitizations to house dust mites, which may be related to the quality of the extract, although the standardization of D. pteronyssinus extract was done over 10 years ago. The study proves, however, that patients receiving long-term oral corticosteroids may develop allergic sensitivities. The effects of steroids on skin test results have been investigated by using intradermal skin tests in many studies evaluating skin reactivity and skin histamine content 1 week or 1 year after administration of a single dose, after I week and 1 year of continuous systemic CST. 2'3' 17, 18 Such investigations showed that systemic steroids did not change the intensity of the skin reactions to allergen. However, the tests were only performed after treatment, and none of these studies were carried out with the SPT. Our results are compatible with these studies and show that skin reactivity to allergens is not altered by treatment with systemic corticosteroids. Moreover, this study was performed by using skin prick testing, which is the recommended technique for the diagnosis of immediate-type allergy, l, 19 We were unable to find a difference between patients tested before and during steroid treatment, nor between a control group and patients with steroid-dependent asthma. Therefore this study shows that SPTs can be used accurately in patients with steroid-dependent asthma to diagnose immediate-type allergic reactions. The results of this study are somewhat surprising because long-term oral steroid treatment induces dermal changes, and long-term local CST reduces the IgE-mediated allergic reaction. Thinning of the skin, increased risk of bruising, and impaired wound healing are the most frequent skin abnormalities caused by CST. 2 In this study treatment did not cause alterations in wheal size. Although some patients had clinical evidence of corticosteroid-induced abnormalities, the results of the SPTs were not influenced. However, in these patients the flare was difficult to read. Long-term local CST reduces the early and late allergic reactions in the nose ~j and in the bronchi, 22 whereas a short treatment course usually only affects the late-phase reaction. 6, 23 The release of mediators by inflammatory cells in patients receiving long-term corticosteroid treatment appears to differ depending on the in vitro model, and there may be some target organ differences. At the cellular level, it is known that corticosteroids inhibit many mediators including arachidonic acid metabolites, platelet activating factor. IL-1, IL-2. IL-3. tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, leukotrienes, or prostanoid. 11 On the other hand. it has been demonstrated that incubation of lung mast cells for 24 hours with dexamethasone had no effect on the release of mast cell mediators, including histamine. ~ The results of this study show that skin reactivity to codeine phosphate, a mast cell-degranulating agent, or allergen is not altered and confirms the data of Zweiman et at. 17" At the same time, the results of this study show that the nonspecific reactivity of the skin mast cell induced by codeine phosphate is not changed by administration of systemic corticosteroid when evaluated before and during the treatment. Zweiman et al? have shown a different result in their study, which was done in 11 patients treated with systemic corticosteroid for 1 year. The result of the skin test with codeine phosphate, when

6 J ALLERGY CLiN IMMUNOL Des Roches et al. 527 VOLUME 98, NUMBER 3 compared with histamine, was demonstrated to be significantly reduced after 1 year of treatment. However, the skin tests with codeine phosphate and histamine were not done prospectively before and during treatment. This is a major difference in the study by Zweiman et al. 2 compared with our study. This difference can be explained by a different level of reactivity of codeine phosphate to histamine. In addition, the action of codeine phosphate is different from that of histamine. Essentially, codeine phosphate acts on the mast cell, so the wheal induced by codeine phosphate is dependent on the number of mast cells in the skin. For histamine, the effect is directly on the receptor and is not dependent on mast cells and evaluates only the effectiveness of the skin reactivity. These differences in action make difficult the comparison of both tests in the evaluation of the effect of cordcosteroid on the SPTs. In patients with corticosteroid-dependent asthma, long-term treatment with oral corticosteroid does not alter nonspecific and allergen-mediated skin reactivity. It may therefore be concluded that SPT evaluation in a patient receiving long-term CST is accurate. REFERENCES 1. Bousquet J, Michel F. In vivo methods for study of allergy. Skin tests, techniques and interpretation. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW, editors. Allergy: principles and practice, 4th ed. St Louis: Mosby, 1993: Olson R, Karpink MH, Shelanski S, Atkins PC, Zweiman B. Skin reactivity to codeine and histamine during prolonged corticosteroid therapy. J Allergy Clin Immunol 1990;86: Slott R, Zweiman B. A controlled study of the effect of corticosteroids on immediate skin test reactivity. J Allergy Clin Immunol 1974;54: Goette DK, Odom RB. Adverse effects of corticosteroids. Cutis 1979;23: Andersson M, Popcorn U. 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