(Chest. 2003;123:1014-1017.)
© 2003
American College of Chest Physicians
High-Dose Inhaled Fluticasone and Delayed Hypersensitivity Skin Testing*
Ronald W. England, MD, Capt, USAF, MC;
Jeffrey S. Nugent, MD, Capt, USAF, MC;
Kurt W. Grathwohl, MD, Maj, USAF, MC;
Larry Hagan, MD, Col, USAF, MC and
James M. Quinn, MD, Lt Col, USAF, MC
* From Wilford Hall Medical Center, Lackland AFB, San Antonio, TX.
Correspondence to: Ronald W. England, MD, Capt, USAF, MC, 759MDOS/MMIA, 2200 Bergquist Dr., Ste 1, Wilford Hall, TX 78236-5300; e-mail: Ronald.England{at}lackland.af.mil
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Abstract
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Introduction: Systemic steroids have been associated with anergy. Treatment with high-dose inhaled steroids has many documented systemic side effects, including adrenal suppression, reduction in growth velocity, and increased bone metabolism; however, little is known about their effect on delayed-type hypersensitivity (DTH).
Study objectives: The purpose of this study was to determine if a 28-day course of high-dose inhaled fluticasone suppresses DTH to a standard panel of antigens.
Methods: Forty-five healthy, steroid-naïve subjects volunteered for this randomized, double-blinded, placebo-controlled trial. All subjects had baseline DTH assessed by intradermal skin testing to a standard panel of antigens (tetanus, candida, mumps, and tuberculin) read 72 h after placement. Subjects were then randomized to receive placebo or high-dose inhaled fluticasone (880 µg/d) for 28 days, after which a second DTH panel was performed. A third DTH panel was performed after a 30-day washout period.
Measurements and results: Of the 45 enrolled subjects, 38 subjects completed the study, including 20 subjects in the placebo group and 18 subjects in the drug group. There was no significant difference in the amount of induration between drug and placebo groups for any of the three periods tested.
Conclusion: Twenty-eight days of treatment with high-dose inhaled fluticasone did not suppress DTH in healthy volunteers.
Key Words: anergy • delayed-type hypersensitivity • inhaled corticosteroids • purified protein derivative testing
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Introduction
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Systemic steroids have been associated with anergy since the 1950s. In 1958, the effect of systemic steroids on tuberculin skin testing was studied in Thailand in 70 patients with positive delayed-type hypersensitivity (DTH) to purified protein derivative (PPD).1
PPD testing was repeated every 72 h. All subjects were treated with prednisone, 10 mg po qid. Prednisone completely suppressed the PPD skin test in 68 of the 70 patients, with an average rate of reversion to negative PPD of 13 ± 10 days (mean ± SD) after starting the prednisone. The average rate of reconversion to positive PPD after stopping prednisone was 6 ± 3 days. Articles addressing this topic have been sparse since these initial studies were done.
Treatments with high-dose inhaled steroids has been shown to have systemic effects, including adrenal suppression,2
3
reduction in growth velocity,4
5
and increased bone metabolism.6
7
A study by Sharma et al8
suggested that DTH reactions may also be suppressed by high-dose inhaled steroids. In that study,8
10 healthy volunteers were recruited for a small, nonplacebo-controlled, prospective study. All subjects received fluticasone, 880 µg/d, for 30 days. The Multitest CMI (Connaught Laboratories; Swiftwater, PA) was performed before and after inhaled steroid treatment as well as after a 6-week washout period to assess DTH. Eight of nine subjects were reported to have a reduction in cumulative skin score on the DTH panel, and two of nine subjects also acquired anergy (ie, reduction in reactivity of < 3 mm for all tested antigens) after inhaled steroid treatment. One of four subjects with a history of a positive PPD had no reaction to tuberculin after fluticasone therapy. The purpose of this study was to prospectively assess whether 28 days of high-dose inhaled fluticasone was able to suppress DTH in a steroid-naïve population, compared to placebo.
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Materials and Methods
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Study Design
This was a randomized, double-blinded, placebo-controlled trial. Healthy volunteers (age range, 18 to 50 years) recruited largely from employees at a military hospital gave informed consent and were enrolled in the study as approved by the local institutional review board. Exclusion criteria included systemic or inhaled steroids within the past 6 months, nasal steroids within the past month, pregnancy, or chronic illnesses associated with anergy, such as malignancy, chronic infection, or autoimmune disease. Baseline DTH responses were measured on all subjects on entry into the study. Subjects were then randomly assigned to receive placebo or inhaled fluticasone, 880 µg/d (Flovent; GlaxoWellcome; Research Triangle Park, NC) for 28 days, after which a second DTH panel was measured. A third DTH panel was performed after a 4-week washout period.
DTH Skin Testing and Interpretation
Using the standard Mantoux technique, intradermal injections of 0.1 mL of candida (Candin; Allermed Laboratories; San Diego, CA), mumps (Mumps Skin Test Antigen USP; Aventis Pasteur; Swiftwater, PA), tetanus (Tetanus Toxoid USP; Aventis Pasteur), and PPD (Tuberculin Purified Protein Derivative [Mantoux] Tubersol; Aventis Pasteur) were placed on the volar aspect of the forearm. Panels were placed on alternating arms to prevent local effects from the previous test.9
10
The induration at each site was measured, using the ballpoint pen technique,11
12
72 h after placement by two independent observers who were blinded to the treatment group. Orthogonal diameters of the induration were measured for each reaction, and the sum of these diameters was recorded. The pen mark was washed off using alcohol between the readings of each observer. If there was a difference > 5 mm between the sum of the diameters between the readings of the two observers, a third independent reading was obtained. The average of the sum of orthogonal diameters of the two closest readings was reported as the outcome variable.
Medication Blinding and Dosing
A pharmacy representative blinded the drug (fluticasone, 220 µg/puff) and placebo inhalers by peeling off the labels, applying study labels to all canisters, and inserting all blinded canisters into fluticasone (Flovent) actuators. Instructions were provided on proper use of a metered-dose inhaler with a spacer (Ellipse; GlaxoWellcome), including rinsing the mouth following administration of the study drug. All subjects were instructed to take two puffs bid from the blinded inhaler.
Statistical Analysis
A Pearson 
2 test was employed to ensure baseline comparability between the demographics of the two groups. A student t test was used to compare mean ages of the two groups. A repeated-measures analysis of variance was calculated to compare the mean diameters of the two groups for the three DTH panels (ie, presteroids, poststeroids, and after washout period). A Pearson 2 test was performed to determine difference between groups with regard to compliance.
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Results
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Subjects
Forty-five subjects were enrolled from April to November 2002. Thirty-eight subjects completed the study, including 20 subjects who received placebo and 18 subjects who received active drug. Seven subjects withdrew: four subjects were unable to comply with the study schedule, one subject desired to discontinue the study after testing positive to PPD on the first test, one subject in the fluticasone group acquired hoarseness, and a one subject in the placebo group acquired an upper respiratory tract infection.
The subjects were predominately white and male (mean age, 33 years; Table 1
). There was no significant significance found between treatment groups with regard to previous use of systemic steroids, inhaled steroids, and nasal steroids ever or within the past 6 months.
DTH Testing
No patient who completed the study had a positive PPD test result. Depicted in light gray, Figure 1
shows individual measurements of the sum of orthogonal diameters for each of the three candida, mumps, and tetanus DTH skin tests comparing drug and placebo groups. Each graph depicts the mean with corresponding SD error bars as solid black lines for each of these subgroups. No statistical significance was found between drug and placebo groups comparing the baseline skin test with the postdrug skin test for candida, mumps, and tetanus. A subanalysis comparing those who received nasal steroids 2 to 6 months prior to initiation of the study to those who had not received nasal steroids showed no statistical difference between groups.
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Figure 1. Means of the sum of orthogonal diameters in millimeters are shown on vertical axis for graphs A through F: Top left, A: drug group, Candida; top right, B: placebo group, Candida; center left, C: drug group, mumps; center right, D: placebo group, mumps; bottom left, E: drug group, tetanus; bottom right, F: placebo group, tetanus. The test number is portrayed on the horizontal axis. Test 1 is the presteroid DTH test, test 2 is the poststeroid test, and test 3 was performed after the washout period. The individual measurements of tests 1 to 3 are depicted by the light gray lines. Only 16 subjects in the drug group were included for analysis of third skin test, as 2 subjects did not complete this skin test. The mean for each graph are represented by the solid black lines. SD error bars are shown for each skin test. Analysis of variance found no statistically significant difference between the drug and placebo groups for Candida, mumps, or tetanus for the three DTH skin tests.
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Anergy (defined as induration < 3 mm to a selected panel of DTH antigens) was not seen in any of the subjects before or immediately following use of the study drug (ie, tests 1 and 2). However, three subjects were anergic following the washout period (ie, test 3). Two of the subjects with anergic responses were in the placebo group, and one subject was in the drug group. None of these subjects had received nasal steroids or any form of steroids previously, including nasal steroids.
Compliance and Side Effect Surveys
Compliance surveys were completed by 37 of 38 subjects, demonstrating no statistically significant difference between active and placebo groups (placebo, 2.16 doses missed per week; fluticasone, 1.93 doses missed per week). Few side effects were reported in either group with regard to inhaler use, including sore throat, hoarseness, cotton-mouth, and dysgeusia. Local side effects from DTH skin testing, including pruritus, pain, erythema, edema, and discoloration of skin, were not statistically significant between the groups.
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Discussion
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Studies in the 1950s directly linked systemic steroids to anergy.1
13
Since these initial studies, several retrospective chart reviews of hospitalized patients have verified that patients receiving systemic steroids are at increased risk for anergy.14
15
16
It has been suggested that inhaled steroids may also cause anergy.8
However, in our study, use of high-dose inhaled fluticasone for 28 days did not suppress DTH reactions when compared to placebo. Equally important, no subjects in the drug or placebo groups had anergic responses after the first two DTH panels.
There is only one previous study addressing the effect of inhaled steroids on DTH, reporting suppression of DTH in healthy subjects receiving high-dose inhaled steroids.8
This study only examined nine healthy adults without a placebo control and employed the Multitest CMI to assess DTH. The Multitest CMI uses a multipuncture device that is dipped into wells of a battery of seven recall antigens: tuberculin, tetanus, diphtheria, streptococcus, candida, trichophyton, and proteus. The most recent guidelines for PPD placement by the American Thoracic Society do not recommend multipuncture devices for PPD screening due to concern about delivery of consistent amounts of antigen.17
Due to these concerns, we believed it was important to use the standard Mantoux technique in our study.
The strength of this study includes use of a placebo-controlled design as well as the blinding of skin test readers, investigators, and subjects. Limitations include interobserver variability, as the same person could not read all tests in our clinic. Attempts were made to minimize this variability by taking an average of the two closest readings. Prestudy power analysis revealed that a sample size of 20 per group provided an 89% chance of detecting large differences (ie, 0.8 to 1.0 SD) between groups. The large variability of individual DTH responses was an unforeseen finding. This variability may have limited the ability to detect differences between the study groups. Another limitation was that our subjects were predominately men recruited from employees of a military hospital. In addition, previous use of various forms of steroids may have been higher than expected in our subjects compared to the general population. This may be explained by recruitment of military health-care workers who have free access to medical care. However, despite these limitations, no subjects in the drug group acquired anergy after 28 days of high-dose inhaled steroid treatment.
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Conclusion
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Use of high-dose inhaled fluticasone for 28 days compared to placebo did not suppress DTH reaction to candida, mumps, and tetanus in healthy, steroid-naïve volunteers. Further study may be warranted in subjects who have a history of a positive PPD in addition to conditions such as asthma or COPD requiring the use of inhaled steroids.
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Footnotes
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Abbreviations: DTH = delayed-type hypersensitivity; PPD = purified protein derivative
The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Air Force or the Department of Defense.
There was no outside financial support for the project, but some complimentary samples of fluticasone (Flovent), placebo inhalers, and Ellipse spacers were provided by GlaxoWellcome, who was not involved in the design of the protocol or any other phase of the project.
Received for publication May 21, 2002.
Accepted for publication September 16, 2002.
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References
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- Wilson, AM, McFarlane, LC, Lipworth, BJ Dose-response effect for adrenal suppression with repeated twice daily inhaled fluticasone propionate and triamcinolone acetonide in adult asthmatics. Am J Respir Crit Care Med 1997;156,1274-1277[Abstract/Free Full Text]
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Abstract
Introduction
