The Prevalence of Tuberculosis and Positive Tuberculin Skin Tests in a Steroid-Treated Asthmatic Population MICHAEL SCHATZ, M.D., ROY PATTERSON, M.D., ROBERT KLONER, M.D., Ph.D., and JERROLD FALK, M.D., Chicago, Illinois
The prevalence of active tuberculosis and positive tuberculin skin tests was assessed in 132 corticosteroid-treated asthmatics for an evaluation period that represented 620 corticosteroid-years of therapy. There was no evidence of active tuberculosis in any of these patients. Positive intermediate-strength tuberculin tests were present in 2 8 % of patients and correlated with increased age. In patients treated with daily corticosteroids, tuberculin negativity was associated with a higher dose of corticosteroids. Positive second-strength tuberculin tests were found in 4 2 . 3 % of the patients with negative intermediate-strength tests and also correlated with increased age. Based on these data as well as the prevalence of significant liver disease in older patients receiving isoniazid (INH), routine INH chemoprophylaxis for corticosteroid-treated asthmatic patients, regardless of their tuberculin cutaneous reactivity, is not indicated.
THE CURRENT RECOMMENDATIONS of the Center for Dis-
ease Control (CDC) regarding the chemoprophylaxis of tuberculosis include the administration of isoniazid (INH) to patients with positive tuberculin reactivity who are treated with corticosteroids for a prolonged period of time (1). Some authors have interpreted a prolonged period of time to be more than 2 weeks (2). There is a population of asthmatic patients who require prolonged treatment with corticosteroids to prevent life-threatening status asthmaticus, multiple hospitalizations, frequent emergency room visits, or otherwise disabling asthma. As stated above, the prophlactic INH recommendations would apply to this population. There are, however, several facts suggesting that these recommendations should not be applied routinely to the steroid-treated asthmatic population. First, in reviews of large numbers of asthmatic patients treated with corticosteroids, the incidence of tuberculosis has been small (3, 4). Second, although the recommendations for INH prophylaxis are based on the presence of cutaneous tuberculin reactivity prior to the initiation of corticosteroid therapy, in practice this knowledge is often not available because the patient is frequently on corticosteroid therapy when first evaluated. Thus, because corticosteroids are known • From the Section of Allergy, Department of Medicine, Northwestern University Medical School, Chicago, Illinois. Annals of Internal Medicine 84:261-265, 1976
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to suppress cutaneous tuberculin reactivity (5, 6 ) , the reliability of the tuberculin test in this population is uncertain. Finally, the occurrence of liver disease due to INH is established (7-10), and the risk of INH prophylaxis is a factor of concern in patients who might not require such chemoprophylaxis. The patient population to be described began as a small group of patients gradually referred to this center for management. Most of these patients were on corticosteroid therapy without INH prophylaxis. As these patients were assessed and no cases of tuberculosis had developed, they were continued without prophylactic therapy under close observation. As additional numbers of corticosteroid-dependent patients were managed and no cases of tuberculosis occurred, a policy was developed to observe closely without INH prophylaxis. The current study is a retrospective analysis of this approach. We have ascertained the prevalence of active tuberculosis and cutaneous tuberculin reactivity in a large group of asthmatic patients treated with corticosteroids to determine the applicability of the CDC's recommendations on chemoprophylaxis to this population. Patients
Patients with asthma attending the Northwestern University Allergy Service, who had been taking corticosteroids continuously for more than 2 months, were included in this study. These patients were evaluated at a time when their corticosteroid doses were stable and as close as possible to their minimal required doses. One patient who had been begun elsewhere on INH prophylaxis was excluded from the study. An attempt was made to study all steroid-treated asthmatic patients attending this service not on INH, but consistently unstable corticosteroid doses prevented 10 patients from being included in the study. A stable corticosteroid dose was felt to be necessary to appropriately evaluate tuberculin reactivity in relation to corticosteroid dose. There was no evidence of active tuberculosis in any of these patients not included in the study. Materials and Methods
Connaught Tuberculin Purified Protein Derivative (Mantoux test) Stabilized Solution (Ormont Drug & Chemical Company, Englewood, New Jersey) was used. Testing was done with first-strength: 1-tuberculin-unit (1-TU); intermediatestrength: 5-tuberculin-unit (5-TU); and second-strength: 250tuberculin-unit (250-TU) doses. Before administration of the skin tests, patients were interviewed regarding a history of tuberculosis and their medical records were examined to ascertain their present and usual corticosteroid regimen. Doses of corticosteroid preparations 261
other than prednisone were converted to the prednisone-equivalent dosage (11). Skin tests were done by injecting 0.1 ml of test dose intradermally. Patients were instructed orally and in writing to circle the cutaneous induration (not erythema) after 48 hours with ink that was then transferred to transparent adhesive tape, attached to a postcard, and mailed to the Allergy Service. If there was no swelling, the patient was instructed to check a box on the postcard labelled "no swelling" and to mail the card. The diameters of induration represented on the postcards were measured and recorded. A positive test was defined as greater than 10-mm induration, as previously suggested (12). Initial testing was done with the 5-TU dose except for patients who gave a possible past history of tuberculosis. The latter were tested with an initial dose of 1 TU. In patients with a negative 5-TU test, a 250-TU test was applied while the patient was on a dose of prednisone similar to his usual dose and similar to the dose at which the 5-TU test was negative. If, by the time of the 250-TU test, the corticosteroid dose had changed significantly, a repeat 5-TU test was done before administration of a 250-TU test. Some patients with a negative 5-TU test were either unavailable or not on a stable corticosteroid dose so that a 250-TU test could not be done. Medical records were reviewed to ascertain the patient's age, duration of corticosteroid treatment, and evidence of active tuberculosis. A chest X ray was obtained on all patients during the study and interpreted by members of the Radiology Department without knowledge of the ongoing study. Statistical analysis comparing means was done using the Student / test. The remaining statistics were done by Chi-square analysis. Results PATIENTS
One hundred thirty-two patients were studied, of whom
Table 1. Characteristics of 132 Patients \with Asthma cm Corticosteroid Therapy, Who had Possitive and Neg ative 5-Tuberc ulin-Unit Cutaneous Test Results Positive
Number of patients Mean age, yrs Men Women Chest X ray showing old granulomatous disease Number on alternate-day regimen Mean daily dose—daily regimen, mg Mean daily dose— alternate-day regimen, mg Mean duration steroid treatment, yrs
no. 37 53.2 17 20
Negative
no. 28.0 95 44.7 45.9 35 54.1 60
%*
2
5.4
8
20
54.1
58
11.6
Statistical Analysis of Difference
%* 72.0 P < 0.0025 36.8 P > 0.05 63.2 P > 0.05 8.4 P > 0.05 61.1
18
P > 0.05 P < 0.0005
8.0
8.9
P > 0.05
5.1
4.7
P > 0.05
* Per cent of total patient group.
80 were female (60.6%) and 52 were male (39.4%). These patients were from a wide range of socioeconomic classes. The ages ranged from 9 to 76 with a mean of 47 years. All but 4 patients had been receiving steroids for more than 3 months prior to being studied. The mean duration of treatment was 4.7 years and the cumulative corticosteroid-treatment period for the 132 patients represented 620 corticosteroid-years of therapy. Sixty percent of the patients were on an alternate-day corticosteroid regimen, with a range of 2.5 to 75.0 mg and a mean dose of 17.2 mg on alternate days. The remaining patients were on daily corticosteroids ranging from 2.5 to 40.0 mg per day with a mean dose of 16 mg. HISTORY AND PREVALENCE OF TUBERCULOSIS
Only one patient presented a well-documented history of tuberculosis. This 19-year-old man was hospitalized at age 5 months for 2Vi years with a diagnosis of miliary tuberculosis. He had been on alternate-day corticosteroids for 5.5 years, usually 50 to 60 mg on alternate days. He was treated with 1 year of INH prophylaxis during his first year of corticosteroid therapy. Ten patients (7.6%) had evidence of calcified granulomatous disease on chest X ray. There was no clinical or radiographic evidence of active tuberculosis in any of the patients in this study. RESULTS OF 5-TU TESTS
Figure 1 . Results of 5-tuberculin-unit skin tests in patients receiving corticosteroids daily. 262
Thirty-seven patients (28%) had positive intermediatestrength orfirst-strength(1 patient) skin tests. Characteristics of the patients with 5-TU positive and negative results are compared in Table 1. The 5-TU positive patients were significantly older than 5-TU negative patients. Chest X-ray evidence of old granulomatous disease was found in more 5-TU negative than 5-TU-positive patients. The prevalence of alternate-day corticosteroid regimens in the two groups did not differ significantly, nor did the corticosteroid dosage in those members of each group or an alternate-day regi-
March 1976 • Annals of Internal Medicine • Volume 84 • Number 3
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men. In the patients on daily prednisone, the mean daily dose was significantly higher in the 5-TU negative regimen patients than in the 5-TU positive patients. There was no significant difference in duration of corticosteroid therapy between the two groups. In patients receiving daily corticosteroids, there was statistical correlation between age and dose. The distribution of steroid doses in the 5-TU positive and negative patients is shown in Figure 1 for the patients on daily regimens and Figure 2 for the patients on alternate-day regimens. In the patients given daily corticosteroids, the distribution is different in the 5-TU positive and negative groups in that significantly more patients on greater than 19 mg of prednisone per day have negative tests than do those on less than 19 mg per day P < 0.25). Figure 1 also shows that a positive 5-TU skin test is uncommon in patients on daily corticosteroid doses greater than 15 mg per day and uniformly absent in patients receiving greater than 20 mg per day. There is no significant difference in the dose distributions of those patients on alternate-day regimens (Figure 2). RESULTS OF 250-TU TESTS
Seventy-one patients who had negative 5-TU tests received 250-TU tests, 30 of which (42.3%) were positive. Characteristics of the patients with 250-TU positive and negative results are compared in Table 2. The 250-TU positive patients were significantly older than 250-TU negative patients. There was no difference in the prevalence of old granulomatous disease on chest X ray in the two groups. Although a higher percentage of the patients with 250-TU positive results were on an alternate-day corticosteroid regimen, this difference was not statistically significant. Also not statistically significant was the somewhat higher daily and alternate-day corticosteroid dosage and duration of therapy in the 250-TU negative group. The distribution of steroid doses in the patients with 250-TU positive and negative results are shown in Figure 3 for the patients on daily regimens and Figure 4 for the patients on alternate-day regimens. There was no statistically significant difference in these distributions between the patients 250-TU positive and negative results.
Figure 2. Results of 5-tuberculin-unit skin tests in patients receiving corticosteroids on alternate days.
must be quite low. No cases have occurred in 132 patients representing 620-corticosteroid-years of treatment and of whom 28% had positive intermediate-strength tuberculin skin tests. Our skin-test data were derived using a method of patient reading of the tests. Although this approach may not be as accurate as physician reading of the skin tests, Table 2. Characteristics of 71 Patients \vith Asthma on Corticosteroid Therapy, Who had P 0.05 P > 0.05
4
9.8
P > 0.05
20
48.8
P > 0.05
18
P > 0.05
7.7
9.2
P > 0.05
4.4
5.1
P > 0.05
* Per cent of total patient group. Seriate et a/. • Tuberculosis and Steroid Treatment
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263
tuberculin skin tests in our population, and this is true in the general population as well (17). In patients on daily corticosteroids, higher steroid dosage was correlated with negative skin tests, but in patients on alternate-day regimens, no relation between dose and skin reactivity was found. This would be expected based on previous data showing that alternate-day corticosteroids do not suppress cutaneous delayed hypersensitivity, even at high doses (16). We interpret these data, along with our relatively high prevalence of 5-TU positive patients, as showing that in asthmatic patients on alternate-day corticosteroids or less than 15 mg of daily prednisone equivalent, intermediatestrength tuberculin skin tests can be considered reliable— that is, to accurately represent the state of prior tuberculin antigen exposure and immunologic responsiveness. In contrast, it appears that in some patients on higher doses of daily corticosteroids, tuberculin reactivity was suppressed. It has been reported that the increased frequency of infections associated with treatment with corticosteroids is eliminated or decreased in association with corticosteroid regimens that preserve delayed cutaneous hypersensitivity (16, 19). If this information can be extrapolated to resistance to tuberculosis, the patients treated with corticosteroids retaining 5-TU reactivity may be less likely to develop active tuberculosis than patients whose delayed hypersensitivity to tuberculin is suppressed. Unfortunately,
Figure 3. Results of 250-tuberculin-unit skin tests in patients receiving corticosteroids daily.
this method has proved to be reliable (15). It has been well documented that significant daily doses of corticosteroids suppress cutaneous delayed hypersensitivity, including tuberculin reactivity (5, 6 ) , and that alternate-day corticosteroid regimens in general do not (16). In 70 patients with positive 5-TU skin tests, 40 mg of predisone per day led to inhibition of 5-TU reactivity in all patients (6). The mean time between starting corticosteroids and skin-test inhibition was 13.6 ± 10.1 days, suggesting that almost all patients on 40 mg of prednisone per day have their tuberculin reactivity suppressed by 1 month. The relation between inhibition of tuberculin skin reactivity and smaller doses of daily corticosteroids is less clear. Our data suggest that patients receiving daily corticosteroids at a dose greater than 15 mg per day will be unlikely to retain intermediate-strength tuberculin reactivity. Of our patients, 28% had positive 5-TU skin tests. Although a control population was not simultaneously assessed in this study, the prevalence of positive 5-TU skin tests in the general population is reported as 17% to 19% for the age group 45 to 50 years old (17). The higher results in our study may have been due to the urban nature of our population (17), the use of stablized tuberculin test materials (18), socioeconomic characteristics of our population (17), or unidentified factors. This higher prevalence is notable because our population was being treated with corticosteroids at the time of testing. Increased age was statistically correlated with positive 264
Figure 4. Results of 250-tuberculin-unit skin tests in patients receiving corticosteroids on alternate days.
March 1976 • Annals of Internal Medicine • Volume 84 • Number 3
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in a population treated with corticosteroids at the time the skin tests are done, it is not possible to ascertain with certainty which patient is truly 5-TU nonreactive due to inadequate exposure to tuberculin antigens and which patients' reactivity is suppressed. Our data do suggest that suppression would be more likely to occur in patients on higher daily doses of corticosteroids. The significance of the positive 250-TU skin tests in our study is uncertain. One of the first studies to suggest that 250-TU reactivity in the face of 5-TU nonreactivity represented immunologic responsiveness to cross-reacting antigens reported a prevalence of 33.6% 250-TU positive tests in student nurses with negative 5-TU tests (20). Because the prevalence of positive 250-TU tests increased with age in our series, it would appear that a prevalence of 42% 250TU positive is, if anything, less than would be expected in a general population of similar age. Thus, although it is possible that some of these 250-TU reactors represent suppressed 5-TU reactors, and thus patients with exposure to Mycobacterium tuberculosis, not cross-reacting antigens, this cannot be ascertained from the present data. Moreover, it is quite possible that 250-TU reactivity has been suppressed in some of our patients, especially those on higher corticosteroid doses. Of concern in the chemoprophylaxis of tuberculosis in corticosteroid-treated asthmatic patients is the prevalence of of INH-induced liver disease. Mild hepatic dysfunction occurs in 10% to 20% of individuals taking INH (7-10). The prevalence of more severe hepatic-function abnormalities, including symptomatic and fatal hepatitis, increases with age and may occur in as many as 2.3% of patients on INH, older than the age of 50 (1, 10). Finally, there arefinancialconsiderations regarding INH prophylaxis. The cost of INH and of frequent liverfunction tests must be balanced against the result achieved. Based on the data presented in this study, we conclude that routine chemoprophylaxis with INH is not indicated for asthmatic patients on prolonged corticosteroid therapy, whether they are tuberculin skin-test positive or negative. We do recommend that patients with asthma treated with corticosteroids have close follow-up to insure that the lowest dose of corticosteroids necessary is used, that alternate-day regimens are instituted when possible and adhered to by the patient, and that appropriate chest Xray evaluation is done. In addition, surveillance should be individualized and the intensity of this surveillance should be varied depending on the dose of corticosteroids and whether daily or alternate-day corticosteroids are given. Patients with positive 5-TU skin tests may warrant special surveillance. Finally, corticosteroid-treated asthmatic pa-
tients with a well-documented history of tuberculosis should probably receive INH prophylaxis. ACKNOWLEDGMENTS: The authors thank the physicians and staff of the Northwestern University Allergy Service and Laboratory for their cooperation in the completion of this study. Grant support: United States Public Health Service grant AI 11403 and the Ernest S. Bazley Grant. Received 12 November 1975; accepted 10 December 1975. • Requests for reprints should be addressed to Roy Patterson, M.D., Chairman, Department of Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. References 1. Current trends: preventive therapy of tuberculosis infection. Morbid Mortal Week Rep 24:71-78, 1975 2. DALE DC, PETERSDORF RG: Corticosteroids and infectious diseases. Med Clin North Am 57:1277-1287, 1973 3. LIEBERMAN P, PATTERSON R, KUNSKE R:
Complications of
long-term steroid treatment for asthma. / Allergy Clin Immunol 49: 329, 1972 4. SMYLLIE HC, CONNOLLY CK: Incidence of serious complications of corticosteroid therapy in respiratory disease. Thorax 23: 571-581, 1968 5. GABRIELSON AE, GOOD RA: Chemical suppression of adoptive immunity. Adv Immunol 6:91-229, 1967 6. BOVORNKITTI S, KANGSADAL P, SATHIRAPAT P, et al: Reversion
and reconversion rate of tuberculin skin reactions in correlation with the use of prednisone. Dis Chest 38:51-55, 1960 7. SCHAREC L, SMITH JP: Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 71:1113-1120, 1969 8. BYRD RB, NELSON R, ELLIOTT TC: Isoniazid toxicity.
9. BAILEY WC, TAYLOR SL, DESCOMB HE, et al: Disturbed hepatic
function during isoniazid chemoprophylaxis for tuberculosis. Am Rev Respir Dis 107:523-529, 1973 * 10. BAILEY WC, WEILL H, DEROWEN TA, et al: The effect of iso-
niazid on transaminase levels. Ann Intern Med 81:200-202, 1974 11. SAYERS G, TRAVIS RH: Adrenocortinal hormones; adrenocortical steroids and their synthetic analogues, in The Pharmacological Basis of Therapeutics, 4th ed., edited by GOODMAN LS, GILMAN A. London, The Macmillan Company, 1970, p. 1629 12. Diagnostic Standards and Classification of Tuberculosis, 12th ed. New York, National Tuberculosis and Respiratory Disease Association, 1969 13. DES PREZ R: Tuberculosis, in Textbook of Medicine, edited by BEESON PB, MCDERMOTT W. Philadelphia, W. B. Saunders,
1975, p. 395 14. D E S PREZ RM, MUSCHENHEIM C: The chemoprophylaxis of
tuberculosis. J Chronic Dis 15:599-610, 1962 15. MAGBOOL S, ASNES RS, GREBIN B: Tine test compliance in a
clinic setting. Pediatrics 55:388-391, 1975 16. MACGREGOR RR, SHEAGREN JN, LIPSETT MB, et al: Alternate-
day prednisone therapy: evaluation of delayed hypersensitivity responses, control of disease and steroid side effects. N Engl J Med 280:1427-1431, 1969 17. Tuberculosis Programs 1973. (DHEW Publications No. (CDC) 75-8189), Atlanta, United States Department of Health, Education and Welfare, 1974 18. ZACK MB, FULKERSON LL: Clinical reliability of stabilized and non-stabilized tuberculin purified protein derivative. Am Rev Respir Dis 102:91-93, 1970 19. PORTNER MM, THAYER KH, HARTER JG, et al: Successful initia-
tion of alternate-day prednisone in chronic steroid dependent asthmatic patients. / Allergy Clin Immunol 49:16-26, 1972 20. PALMER CE: Tuberculin sensitivity and contact with tuberculosis. Am Rev Tuber 68:678-694, 1953
Schatz et al. • Tuberculosis and Steroid Treatment
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JAMA
220:1471-1473, 1972
265
The prevalence of active tuberculosis and positive tuberculin skin tests was assessed in 132 corticosteroid-treated asthmatics for an evaluation period that represented 620 corticosteroid-years of therapy. There was no evidence of active tuberculosis in any of these patients. Positive intermediate-strength tuberculin tests were present in 2 8 % of patients and correlated with increased age. In patients treated with daily corticosteroids, tuberculin negativity was associated with a higher dose of corticosteroids. Positive second-strength tuberculin tests were found in 4 2 . 3 % of the patients with negative intermediate-strength tests and also correlated with increased age. Based on these data as well as the prevalence of significant liver disease in older patients receiving isoniazid (INH), routine INH chemoprophylaxis for corticosteroid-treated asthmatic patients, regardless of their tuberculin cutaneous reactivity, is not indicated.
THE CURRENT RECOMMENDATIONS of the Center for Dis-
ease Control (CDC) regarding the chemoprophylaxis of tuberculosis include the administration of isoniazid (INH) to patients with positive tuberculin reactivity who are treated with corticosteroids for a prolonged period of time (1). Some authors have interpreted a prolonged period of time to be more than 2 weeks (2). There is a population of asthmatic patients who require prolonged treatment with corticosteroids to prevent life-threatening status asthmaticus, multiple hospitalizations, frequent emergency room visits, or otherwise disabling asthma. As stated above, the prophlactic INH recommendations would apply to this population. There are, however, several facts suggesting that these recommendations should not be applied routinely to the steroid-treated asthmatic population. First, in reviews of large numbers of asthmatic patients treated with corticosteroids, the incidence of tuberculosis has been small (3, 4). Second, although the recommendations for INH prophylaxis are based on the presence of cutaneous tuberculin reactivity prior to the initiation of corticosteroid therapy, in practice this knowledge is often not available because the patient is frequently on corticosteroid therapy when first evaluated. Thus, because corticosteroids are known • From the Section of Allergy, Department of Medicine, Northwestern University Medical School, Chicago, Illinois. Annals of Internal Medicine 84:261-265, 1976
Downloaded From: http://annals.org/ by a University of Otago User on 12/13/2016
to suppress cutaneous tuberculin reactivity (5, 6 ) , the reliability of the tuberculin test in this population is uncertain. Finally, the occurrence of liver disease due to INH is established (7-10), and the risk of INH prophylaxis is a factor of concern in patients who might not require such chemoprophylaxis. The patient population to be described began as a small group of patients gradually referred to this center for management. Most of these patients were on corticosteroid therapy without INH prophylaxis. As these patients were assessed and no cases of tuberculosis had developed, they were continued without prophylactic therapy under close observation. As additional numbers of corticosteroid-dependent patients were managed and no cases of tuberculosis occurred, a policy was developed to observe closely without INH prophylaxis. The current study is a retrospective analysis of this approach. We have ascertained the prevalence of active tuberculosis and cutaneous tuberculin reactivity in a large group of asthmatic patients treated with corticosteroids to determine the applicability of the CDC's recommendations on chemoprophylaxis to this population. Patients
Patients with asthma attending the Northwestern University Allergy Service, who had been taking corticosteroids continuously for more than 2 months, were included in this study. These patients were evaluated at a time when their corticosteroid doses were stable and as close as possible to their minimal required doses. One patient who had been begun elsewhere on INH prophylaxis was excluded from the study. An attempt was made to study all steroid-treated asthmatic patients attending this service not on INH, but consistently unstable corticosteroid doses prevented 10 patients from being included in the study. A stable corticosteroid dose was felt to be necessary to appropriately evaluate tuberculin reactivity in relation to corticosteroid dose. There was no evidence of active tuberculosis in any of these patients not included in the study. Materials and Methods
Connaught Tuberculin Purified Protein Derivative (Mantoux test) Stabilized Solution (Ormont Drug & Chemical Company, Englewood, New Jersey) was used. Testing was done with first-strength: 1-tuberculin-unit (1-TU); intermediatestrength: 5-tuberculin-unit (5-TU); and second-strength: 250tuberculin-unit (250-TU) doses. Before administration of the skin tests, patients were interviewed regarding a history of tuberculosis and their medical records were examined to ascertain their present and usual corticosteroid regimen. Doses of corticosteroid preparations 261
other than prednisone were converted to the prednisone-equivalent dosage (11). Skin tests were done by injecting 0.1 ml of test dose intradermally. Patients were instructed orally and in writing to circle the cutaneous induration (not erythema) after 48 hours with ink that was then transferred to transparent adhesive tape, attached to a postcard, and mailed to the Allergy Service. If there was no swelling, the patient was instructed to check a box on the postcard labelled "no swelling" and to mail the card. The diameters of induration represented on the postcards were measured and recorded. A positive test was defined as greater than 10-mm induration, as previously suggested (12). Initial testing was done with the 5-TU dose except for patients who gave a possible past history of tuberculosis. The latter were tested with an initial dose of 1 TU. In patients with a negative 5-TU test, a 250-TU test was applied while the patient was on a dose of prednisone similar to his usual dose and similar to the dose at which the 5-TU test was negative. If, by the time of the 250-TU test, the corticosteroid dose had changed significantly, a repeat 5-TU test was done before administration of a 250-TU test. Some patients with a negative 5-TU test were either unavailable or not on a stable corticosteroid dose so that a 250-TU test could not be done. Medical records were reviewed to ascertain the patient's age, duration of corticosteroid treatment, and evidence of active tuberculosis. A chest X ray was obtained on all patients during the study and interpreted by members of the Radiology Department without knowledge of the ongoing study. Statistical analysis comparing means was done using the Student / test. The remaining statistics were done by Chi-square analysis. Results PATIENTS
One hundred thirty-two patients were studied, of whom
Table 1. Characteristics of 132 Patients \with Asthma cm Corticosteroid Therapy, Who had Possitive and Neg ative 5-Tuberc ulin-Unit Cutaneous Test Results Positive
Number of patients Mean age, yrs Men Women Chest X ray showing old granulomatous disease Number on alternate-day regimen Mean daily dose—daily regimen, mg Mean daily dose— alternate-day regimen, mg Mean duration steroid treatment, yrs
no. 37 53.2 17 20
Negative
no. 28.0 95 44.7 45.9 35 54.1 60
%*
2
5.4
8
20
54.1
58
11.6
Statistical Analysis of Difference
%* 72.0 P < 0.0025 36.8 P > 0.05 63.2 P > 0.05 8.4 P > 0.05 61.1
18
P > 0.05 P < 0.0005
8.0
8.9
P > 0.05
5.1
4.7
P > 0.05
* Per cent of total patient group.
80 were female (60.6%) and 52 were male (39.4%). These patients were from a wide range of socioeconomic classes. The ages ranged from 9 to 76 with a mean of 47 years. All but 4 patients had been receiving steroids for more than 3 months prior to being studied. The mean duration of treatment was 4.7 years and the cumulative corticosteroid-treatment period for the 132 patients represented 620 corticosteroid-years of therapy. Sixty percent of the patients were on an alternate-day corticosteroid regimen, with a range of 2.5 to 75.0 mg and a mean dose of 17.2 mg on alternate days. The remaining patients were on daily corticosteroids ranging from 2.5 to 40.0 mg per day with a mean dose of 16 mg. HISTORY AND PREVALENCE OF TUBERCULOSIS
Only one patient presented a well-documented history of tuberculosis. This 19-year-old man was hospitalized at age 5 months for 2Vi years with a diagnosis of miliary tuberculosis. He had been on alternate-day corticosteroids for 5.5 years, usually 50 to 60 mg on alternate days. He was treated with 1 year of INH prophylaxis during his first year of corticosteroid therapy. Ten patients (7.6%) had evidence of calcified granulomatous disease on chest X ray. There was no clinical or radiographic evidence of active tuberculosis in any of the patients in this study. RESULTS OF 5-TU TESTS
Figure 1 . Results of 5-tuberculin-unit skin tests in patients receiving corticosteroids daily. 262
Thirty-seven patients (28%) had positive intermediatestrength orfirst-strength(1 patient) skin tests. Characteristics of the patients with 5-TU positive and negative results are compared in Table 1. The 5-TU positive patients were significantly older than 5-TU negative patients. Chest X-ray evidence of old granulomatous disease was found in more 5-TU negative than 5-TU-positive patients. The prevalence of alternate-day corticosteroid regimens in the two groups did not differ significantly, nor did the corticosteroid dosage in those members of each group or an alternate-day regi-
March 1976 • Annals of Internal Medicine • Volume 84 • Number 3
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men. In the patients on daily prednisone, the mean daily dose was significantly higher in the 5-TU negative regimen patients than in the 5-TU positive patients. There was no significant difference in duration of corticosteroid therapy between the two groups. In patients receiving daily corticosteroids, there was statistical correlation between age and dose. The distribution of steroid doses in the 5-TU positive and negative patients is shown in Figure 1 for the patients on daily regimens and Figure 2 for the patients on alternate-day regimens. In the patients given daily corticosteroids, the distribution is different in the 5-TU positive and negative groups in that significantly more patients on greater than 19 mg of prednisone per day have negative tests than do those on less than 19 mg per day P < 0.25). Figure 1 also shows that a positive 5-TU skin test is uncommon in patients on daily corticosteroid doses greater than 15 mg per day and uniformly absent in patients receiving greater than 20 mg per day. There is no significant difference in the dose distributions of those patients on alternate-day regimens (Figure 2). RESULTS OF 250-TU TESTS
Seventy-one patients who had negative 5-TU tests received 250-TU tests, 30 of which (42.3%) were positive. Characteristics of the patients with 250-TU positive and negative results are compared in Table 2. The 250-TU positive patients were significantly older than 250-TU negative patients. There was no difference in the prevalence of old granulomatous disease on chest X ray in the two groups. Although a higher percentage of the patients with 250-TU positive results were on an alternate-day corticosteroid regimen, this difference was not statistically significant. Also not statistically significant was the somewhat higher daily and alternate-day corticosteroid dosage and duration of therapy in the 250-TU negative group. The distribution of steroid doses in the patients with 250-TU positive and negative results are shown in Figure 3 for the patients on daily regimens and Figure 4 for the patients on alternate-day regimens. There was no statistically significant difference in these distributions between the patients 250-TU positive and negative results.
Figure 2. Results of 5-tuberculin-unit skin tests in patients receiving corticosteroids on alternate days.
must be quite low. No cases have occurred in 132 patients representing 620-corticosteroid-years of treatment and of whom 28% had positive intermediate-strength tuberculin skin tests. Our skin-test data were derived using a method of patient reading of the tests. Although this approach may not be as accurate as physician reading of the skin tests, Table 2. Characteristics of 71 Patients \vith Asthma on Corticosteroid Therapy, Who had P 0.05 P > 0.05
4
9.8
P > 0.05
20
48.8
P > 0.05
18
P > 0.05
7.7
9.2
P > 0.05
4.4
5.1
P > 0.05
* Per cent of total patient group. Seriate et a/. • Tuberculosis and Steroid Treatment
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tuberculin skin tests in our population, and this is true in the general population as well (17). In patients on daily corticosteroids, higher steroid dosage was correlated with negative skin tests, but in patients on alternate-day regimens, no relation between dose and skin reactivity was found. This would be expected based on previous data showing that alternate-day corticosteroids do not suppress cutaneous delayed hypersensitivity, even at high doses (16). We interpret these data, along with our relatively high prevalence of 5-TU positive patients, as showing that in asthmatic patients on alternate-day corticosteroids or less than 15 mg of daily prednisone equivalent, intermediatestrength tuberculin skin tests can be considered reliable— that is, to accurately represent the state of prior tuberculin antigen exposure and immunologic responsiveness. In contrast, it appears that in some patients on higher doses of daily corticosteroids, tuberculin reactivity was suppressed. It has been reported that the increased frequency of infections associated with treatment with corticosteroids is eliminated or decreased in association with corticosteroid regimens that preserve delayed cutaneous hypersensitivity (16, 19). If this information can be extrapolated to resistance to tuberculosis, the patients treated with corticosteroids retaining 5-TU reactivity may be less likely to develop active tuberculosis than patients whose delayed hypersensitivity to tuberculin is suppressed. Unfortunately,
Figure 3. Results of 250-tuberculin-unit skin tests in patients receiving corticosteroids daily.
this method has proved to be reliable (15). It has been well documented that significant daily doses of corticosteroids suppress cutaneous delayed hypersensitivity, including tuberculin reactivity (5, 6 ) , and that alternate-day corticosteroid regimens in general do not (16). In 70 patients with positive 5-TU skin tests, 40 mg of predisone per day led to inhibition of 5-TU reactivity in all patients (6). The mean time between starting corticosteroids and skin-test inhibition was 13.6 ± 10.1 days, suggesting that almost all patients on 40 mg of prednisone per day have their tuberculin reactivity suppressed by 1 month. The relation between inhibition of tuberculin skin reactivity and smaller doses of daily corticosteroids is less clear. Our data suggest that patients receiving daily corticosteroids at a dose greater than 15 mg per day will be unlikely to retain intermediate-strength tuberculin reactivity. Of our patients, 28% had positive 5-TU skin tests. Although a control population was not simultaneously assessed in this study, the prevalence of positive 5-TU skin tests in the general population is reported as 17% to 19% for the age group 45 to 50 years old (17). The higher results in our study may have been due to the urban nature of our population (17), the use of stablized tuberculin test materials (18), socioeconomic characteristics of our population (17), or unidentified factors. This higher prevalence is notable because our population was being treated with corticosteroids at the time of testing. Increased age was statistically correlated with positive 264
Figure 4. Results of 250-tuberculin-unit skin tests in patients receiving corticosteroids on alternate days.
March 1976 • Annals of Internal Medicine • Volume 84 • Number 3
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in a population treated with corticosteroids at the time the skin tests are done, it is not possible to ascertain with certainty which patient is truly 5-TU nonreactive due to inadequate exposure to tuberculin antigens and which patients' reactivity is suppressed. Our data do suggest that suppression would be more likely to occur in patients on higher daily doses of corticosteroids. The significance of the positive 250-TU skin tests in our study is uncertain. One of the first studies to suggest that 250-TU reactivity in the face of 5-TU nonreactivity represented immunologic responsiveness to cross-reacting antigens reported a prevalence of 33.6% 250-TU positive tests in student nurses with negative 5-TU tests (20). Because the prevalence of positive 250-TU tests increased with age in our series, it would appear that a prevalence of 42% 250TU positive is, if anything, less than would be expected in a general population of similar age. Thus, although it is possible that some of these 250-TU reactors represent suppressed 5-TU reactors, and thus patients with exposure to Mycobacterium tuberculosis, not cross-reacting antigens, this cannot be ascertained from the present data. Moreover, it is quite possible that 250-TU reactivity has been suppressed in some of our patients, especially those on higher corticosteroid doses. Of concern in the chemoprophylaxis of tuberculosis in corticosteroid-treated asthmatic patients is the prevalence of of INH-induced liver disease. Mild hepatic dysfunction occurs in 10% to 20% of individuals taking INH (7-10). The prevalence of more severe hepatic-function abnormalities, including symptomatic and fatal hepatitis, increases with age and may occur in as many as 2.3% of patients on INH, older than the age of 50 (1, 10). Finally, there arefinancialconsiderations regarding INH prophylaxis. The cost of INH and of frequent liverfunction tests must be balanced against the result achieved. Based on the data presented in this study, we conclude that routine chemoprophylaxis with INH is not indicated for asthmatic patients on prolonged corticosteroid therapy, whether they are tuberculin skin-test positive or negative. We do recommend that patients with asthma treated with corticosteroids have close follow-up to insure that the lowest dose of corticosteroids necessary is used, that alternate-day regimens are instituted when possible and adhered to by the patient, and that appropriate chest Xray evaluation is done. In addition, surveillance should be individualized and the intensity of this surveillance should be varied depending on the dose of corticosteroids and whether daily or alternate-day corticosteroids are given. Patients with positive 5-TU skin tests may warrant special surveillance. Finally, corticosteroid-treated asthmatic pa-
tients with a well-documented history of tuberculosis should probably receive INH prophylaxis. ACKNOWLEDGMENTS: The authors thank the physicians and staff of the Northwestern University Allergy Service and Laboratory for their cooperation in the completion of this study. Grant support: United States Public Health Service grant AI 11403 and the Ernest S. Bazley Grant. Received 12 November 1975; accepted 10 December 1975. • Requests for reprints should be addressed to Roy Patterson, M.D., Chairman, Department of Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. References 1. Current trends: preventive therapy of tuberculosis infection. Morbid Mortal Week Rep 24:71-78, 1975 2. DALE DC, PETERSDORF RG: Corticosteroids and infectious diseases. Med Clin North Am 57:1277-1287, 1973 3. LIEBERMAN P, PATTERSON R, KUNSKE R:
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long-term steroid treatment for asthma. / Allergy Clin Immunol 49: 329, 1972 4. SMYLLIE HC, CONNOLLY CK: Incidence of serious complications of corticosteroid therapy in respiratory disease. Thorax 23: 571-581, 1968 5. GABRIELSON AE, GOOD RA: Chemical suppression of adoptive immunity. Adv Immunol 6:91-229, 1967 6. BOVORNKITTI S, KANGSADAL P, SATHIRAPAT P, et al: Reversion
and reconversion rate of tuberculin skin reactions in correlation with the use of prednisone. Dis Chest 38:51-55, 1960 7. SCHAREC L, SMITH JP: Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 71:1113-1120, 1969 8. BYRD RB, NELSON R, ELLIOTT TC: Isoniazid toxicity.
9. BAILEY WC, TAYLOR SL, DESCOMB HE, et al: Disturbed hepatic
function during isoniazid chemoprophylaxis for tuberculosis. Am Rev Respir Dis 107:523-529, 1973 * 10. BAILEY WC, WEILL H, DEROWEN TA, et al: The effect of iso-
niazid on transaminase levels. Ann Intern Med 81:200-202, 1974 11. SAYERS G, TRAVIS RH: Adrenocortinal hormones; adrenocortical steroids and their synthetic analogues, in The Pharmacological Basis of Therapeutics, 4th ed., edited by GOODMAN LS, GILMAN A. London, The Macmillan Company, 1970, p. 1629 12. Diagnostic Standards and Classification of Tuberculosis, 12th ed. New York, National Tuberculosis and Respiratory Disease Association, 1969 13. DES PREZ R: Tuberculosis, in Textbook of Medicine, edited by BEESON PB, MCDERMOTT W. Philadelphia, W. B. Saunders,
1975, p. 395 14. D E S PREZ RM, MUSCHENHEIM C: The chemoprophylaxis of
tuberculosis. J Chronic Dis 15:599-610, 1962 15. MAGBOOL S, ASNES RS, GREBIN B: Tine test compliance in a
clinic setting. Pediatrics 55:388-391, 1975 16. MACGREGOR RR, SHEAGREN JN, LIPSETT MB, et al: Alternate-
day prednisone therapy: evaluation of delayed hypersensitivity responses, control of disease and steroid side effects. N Engl J Med 280:1427-1431, 1969 17. Tuberculosis Programs 1973. (DHEW Publications No. (CDC) 75-8189), Atlanta, United States Department of Health, Education and Welfare, 1974 18. ZACK MB, FULKERSON LL: Clinical reliability of stabilized and non-stabilized tuberculin purified protein derivative. Am Rev Respir Dis 102:91-93, 1970 19. PORTNER MM, THAYER KH, HARTER JG, et al: Successful initia-
tion of alternate-day prednisone in chronic steroid dependent asthmatic patients. / Allergy Clin Immunol 49:16-26, 1972 20. PALMER CE: Tuberculin sensitivity and contact with tuberculosis. Am Rev Tuber 68:678-694, 1953
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