Abstract
Rationale: Treatment with substantial doses of oral corticosteroids (OCS) for prolonged periods increases the risk of tuberculosis (TB). However, little is known about the effect of inhaled corticosteroids (ICS) in this respect.
Objectives: We quantified the independent contribution of ICS to the risk of TB in a population of patients with airway diseases.
Methods: A population-based cohort design with a nested case-control analysis was used. A cohort of patients with airways disease was formed using the Quebec databases. TB cases were identified and age-matched control subjects were selected from all subjects who entered the cohort in the same month as the cases. TB incidence among the cohort was compared with the general population of Quebec using the standardized incidence ratio.
Measurements and Main Results: The cohort consisted of 427,648 subjects. There were 564 cases of TB identified between 1990 and 2005. The standardized incidence ratio was 3.9 (95% confidence interval [CI], 2.6–5.4). Any and current users of ICS are at an increased risk of TB (rate ratio [RR], 1.27; 95% CI, 1.05–1.53; and RR, 1.33; 95% CI, 1.04–1.71, respectively). Among users of OCS, no significant relationship could be demonstrated. Among subjects without OCS exposure, adjusted RRs were significant for any ICS use (RR, 1.26; 95% CI, 1.02–1.56) and current use (RR, 1.48; 95% CI, 1.11–1.97) and at the current high dose exposure level (RR, 1.97; 95% CI, 1.18–3.3).
Conclusions: Exposure to ICS is not associated with risk of TB in the presence of OCS but is associated with increased TB risk in nonusers of OCS.
Treatment with oral corticosteroids (OCS) for prolonged periods increases the risk of tuberculosis (TB). However, little is known about the effect of inhaled corticosteroids (ICS) in this respect.
We found that exposure to ICS does not add to the risk of TB in the presence of OCS but increases the risk of TB among nonusers of OCS, especially at the high exposure levels of steroids equivalent to fluticasone 1,000 μg/d or more. Results of this study are supportive of published guidelines that recommend TB screening before initiation of any immunosuppressive therapy. ICS, particularly at higher doses, appears to increase the risk of TB.
Observations from case reports regarding the potential association of inhaled corticosteroid use and subsequent TB have been inconsistent (6–9). We aimed to quantify the independent contribution of ICS to the risk of TB among a population of patients with airway diseases.
We used the health databases of the Régie de l'Assurance Maladie du Québec, the agency responsible for administering the universal health insurance program of the province of Quebec, Canada, for all its 7 million residents. These databases capture all physician visits, procedures, and hospitalizations, as well as patient demographics. The International Classification of Diseases, Ninth Revision (ICD-9) (10) was used to assign billing and hospitalization diagnosis codes (1 per physician and up to 15 per hospitalization) until 31 March 2006 and ICD-10 afterward. Study subjects were limited to those registered in the provincial pharmacy claims database, which covers all residents aged 65 years and older, those who receive social assistance, and those who do not have private drug insurance through their employer. This covers approximately 50% of Quebec residents. Values in key fields, such as drugs, quantity, date dispensed, and duration, are missing or out of range in less than 0.5% of records (11). These databases have been used previously to study the risk of fractures, cataracts, glaucoma, and pneumonia associated with ICS (12–15).
A population-based cohort design with a nested case-control analysis was used. We chose subjects with airway diseases because they were more likely to receive ICS medication. Thus, the source population consisted of all subjects who, between January 1, 1990 and December 31, 2005, were dispensed at least one of the following respiratory medications: any form of β-agonist, theophylline, ipratropium bromide, tiotropium, sodium cromoglycate, nedocromil, ketotifen, the leukotriene antagonists montelukast and zafirlukast, or ICS. A cohort of patients with airways disease (mostly asthma and chronic obstructive pulmonary disease [COPD]) was formed from this source population by identifying all subjects with three or more prescriptions for these respiratory medications in any 1-year period and on at least two different dates.
Among eligible subjects, cohort entry was taken as the date of the third prescription. These subjects were observed until the earliest of the date of termination of enrollment in the health plan, the date of death, the end of the study period (31 December 2007), or the date of the outcome of interest. TB cases were identified during follow-up if they had TB as a primary hospitalization diagnosis (ICD-9 codes: 010–018, ICD-10 codes: A15–A19) or if TB was part of a medical claim and they had at least two of the usual first-line anti-TB medications prescribed (isoniazid, rifampin, pyrazinamide, or ethambutol), and if treatment lasted at least 6 months. TB cases that occurred before the date of cohort entry were excluded from the cohort.
For each case subject, 10 control subjects matched for age (within 1 yr), were selected at random from all subjects who entered the cohort in the same month as the case subject and ensuring that control subjects were at risk on the day that the case occurred. This date was designated as the index date.
All forms of prescribed ICS were examined during the 12-month period preceding the index date. ICS included oral inhaled beclomethasone, budesonide, triamcinolone, fluticasone, and flunisolide, whether dispensed alone or in a combination inhaler with an inhaled β-agonist. The estimation of equivalencies was chosen on the basis of relative topical potency based on comparative dosages proposed in the National Asthma Education and Prevention expert panel report II (16) and the Canadian asthma consensus statement (17). Accordingly, the equivalent doses for ICS are beclomethasone 100 μg, beclomethasone HFA 50 μg, budesonide 80 μg, triamcinolone 200 μg, fluticasone 50 μg, and flunisolide 200 μg. All doses were converted to fluticasone equivalents and categorized according to defined daily dose (18) as high (fluticasone 1,000 μg/d or more), moderate (fluticasone 500–999 μg/d), and low (fluticasone less than 500 μg). Current exposure categories were defined on the most recent prescription within 30 days of the index date.
Age and sex were used as covariates to define the study sample. We included comorbid clinical conditions known to increase the risk of TB (3), such as diabetes, chronic renal failure and/or hemodialysis, solid organ transplantation (such as renal or heart transplantation), carcinoma of the head or neck, and silicosis. These were based on diagnoses made at any time before the index date.
OCS users were defined by any use in the 1 year before the index date. The cumulative dose and the number of prescriptions for oral corticosteroids in the year before the index date were calculated. The prescriptions of oral corticosteroids were converted to prednisone using the following equivalent doses: hydrocortisone (cortisol) 20 mg, cortisone 25 mg, prednisone 5 mg, prednisolone 5 mg, methylprednisolone 4 mg, triamcinolone 4 mg, betamethasone 0.75 mg, dexamethasone 0.75 mg (19). Disease-modifying antirheumatic drugs (DMARDs) known to increase the risk of TB included gold salts, methotrexate, azathioprine, hydroxychloroquine, chloroquine, sulfasalazine, leflunomide, cyclophosphamide, cyclosporine, minocycline, or penicillamine in the year before the index date. Use of the newer anti–tumor necrosis factor medication (biological DMARDs) was absent in this cohort.
We quantified the severity of respiratory disease, independently of corticosteroid use, by the number of dispensed prescriptions of respiratory medications (β-agonists, ipratropium bromide, tiotropium, theophylline, antileukotrienes, and cromolyns), and the presence of a hospitalization with a primary diagnosis of asthma or COPD, all measured in the year before the index date.
The total person-years of follow-up in the entire cohort were used to estimate TB incidence in those patients with respiratory diseases, which were compared with the Quebec general population TB incidence for the same time period. To adjust for the potential confounding effect of sex and age, rates were standardized using the direct method and the midyear 1996 Quebec population as the reference to estimate the standardized incidence ratio (SIR). Population data were made available through Statistics Quebec (20).
To assess the rate ratio (RR) of TB associated with ICS use, odds ratios and 95% confidence intervals (CIs) were estimated from the nested case-control analysis within the cohort. The RR is approximated accurately by the odds ratio from a nested case-control design wherein controls are selected from person-time at risk, as done in this study (21).
Conditional logistic regression was used to adjust the estimates for the concurrent use of DMARDs, other respiratory medications, and cumulative dose of oral corticosteroids, as well as for age, sex, and all comorbid clinical conditions. Subjects were considered as current ICS users if the last prescription was dispensed within 30 days of the index date, and nonuse during the prior year was used as the reference category. Subjects whose last prescription was dispensed between 31 and 365 days before the index date were classified as past ICS users. Age and calendar time were inherently accounted for by the matching. The RR for ICS use was estimated among users and nonusers of oral corticosteroids in the year before the index date. All analyses were conducted with SAS version 9.1 (SAS Institute, Cary, NC).
The cohort consisted of 427,648 subjects, of which 55.8% were females. The mean ± SD subject age at time of cohort entry was 52.2 ± 27.0 years. There were 564 cases of TB identified during the follow-up period (23.3 per 100,000 per yr). The mean age ± SD of TB cases was 69.4 ± 17.0 years. The age and sex standardized rate to the Quebec population was 16.7 per 100,000 person-years compared with 4.24 per 100.000 population in Quebec for the same time period (SIR, 3.9; 95% CI, 2.6–5.4). Table 1 shows the baseline characteristics of the case patients with TB compared with the control subjects. The mean duration of follow-up was 3.2 years. TB cases were more likely males, were more frequently hospitalized for COPD or asthma, and were more frequently dispensed oral corticosteroids and traditional DMARDs than control subjects. They were less likely than controls to have diabetes but had more other comorbid conditions. The cumulative dose of oral corticosteroid received in the previous year was, respectively, 271.4 mg and 98.7 mg for cases and for controls. Overall, any and current users of ICS are at an increased risk of TB (RR, 1.27; 95% CI, 1.05–1.53; and RR, 1.33; 95% CI, 1.04–1.71, respectively) and no dose response could be demonstrated among current users (Table 2). We also performed a sensitivity analysis using a 60-day time window to define current ICS users; results were similar with small variation in the point estimates. Results were also similar if we adjusted for number of prescriptions instead of the cumulative dose of OCS. Among users of OCS, no significant relationship could be demonstrated with any, past, or current use (Table 3). Among those subjects without OCS exposure in the previous year, adjusted RRs were significant for any ICS use (RR, 1.26; 95% CI, 1.02–1.56) and current use (RR, 1.48; 95% CI, 1.11–1.97) and at the current high dose exposure level (RR, 1.97; 95% CI, 1.18–3.3) (Table 3).
Cases | Control Subjects | |||
|---|---|---|---|---|
| No. | 564 | 5,640 | ||
| Age, yr, mean ± SD | 69.4 ± 17.0 | 69.3 ± 16.9 | ||
| Follow-up, yr, mean ± SD | 3.2 ± 3.3 | 3.2 ± 3.3 | ||
| Male, % | 54.1 | 42.7 | ||
| In the year before index date: | ||||
| Hospitalization for COPD and/or asthma, % | 7.3 | 2.9 | ||
| Respiratory drugs, mean number of Rx ± SD | 5.0 ± 7.4 | 3.4 ± 6.2 | ||
| Oral corticosteroids, mean number of Rx ± SD | 0.8 ± 2.3 | 0.4 ± 2.4 | ||
| Oral corticosteroids, cumulative dose, mg, mean ± SD | 271.4 ± 846.7 | 98.7 ± 458.3 | ||
| Traditional DMARDS, % | 2.7 | 1.5 | ||
| Diabetes, % | 9.0 | 9.9 | ||
| Other comorbid conditions, % | 5.1 | 3.5 | ||
Adjusted* | ||||||
|---|---|---|---|---|---|---|
| Cases | Controls | Crude RR | RR | 95% CI | ||
| No. of subjects | 564 | 5,640 | ||||
| No use, % | 54.4 | 62.7 | 1.00 | 1.00 | Reference | |
| Any use, % | 45.6 | 37.3 | 1.43 | 1.27 | 1.05–1.53 | |
| Current use, 30 d, % | 20.4 | 15.4 | 1.58 | 1.33 | 1.04–1.71 | |
| High dose, % | 5.0 | 3.2 | 1.94 | 1.55 | 0.99–2.44 | |
| Medium dose, % | 12.1 | 9.6 | 1.50 | 1.25 | 0.93–1.68 | |
| Low dose, % | 3.4 | 2.7 | 1.49 | 1.40 | 0.84–2.33 | |
| Past use, 31–365 d, % | 25.2 | 21.9 | 1.33 | 1.23 | 0.98–1.53 | |
Adjusted* | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cases | Controls | Crude RR | RR | 95% CI | ||||||
| Among OCS users | ||||||||||
| No. of subjects | 97 | 174 | ||||||||
| No use, % | 40.2 | 35.6 | 1.00 | 1.00 | Reference | |||||
| Any use, % | 59.8 | 64.4 | 0.79 | 0.77 | 0.41–1.44 | |||||
| Current use, 30 d, % | 25.8 | 26.9 | 0.82 | 0.76 | 0.37–1.59 | |||||
| High dose, % | 4.1 | 6.2 | 0.54 | 0.38 | 0.10–1.50 | |||||
| Medium dose, % | 20.6 | 18.6 | 0.92 | 0.95 | 0.43–2.09 | |||||
| Low dose, % | 1.0 | 2.1 | 0.70 | 0.61 | 0.04–9.56 | |||||
| Past use, 31–365 d, % | 34.0 | 37.5 | 0.75 | 0.78 | 0.37–1.63 | |||||
| Among non-OCS users | ||||||||||
| No. of subjects | 431 | 3,791 | ||||||||
| No use, % | 59.4 | 65.0 | 1.00 | 1.00 | Reference | |||||
| Any use, % | 40.6 | 35.0 | 1.28 | 1.26 | 1.02–1.56 | |||||
| Current use, 30 d, % | 19.7 | 14.8 | 1.53 | 1.48 | 1.11–1.97 | |||||
| High dose, % | 5.1 | 2.9 | 2.10 | 1.97 | 1.18–3.30 | |||||
| Medium dose, % | 10.4 | 9.0 | 1.34 | 1.29 | 0.91–1.85 | |||||
| Low dose, % | 4.2 | 2.9 | 1.64 | 1.63 | 0.96–2.77 | |||||
| Past use, 31–365 d, % | 20.9 | 20.2 | 1.11 | 1.12 | 0.86–1.46 | |||||
This is, as far as we know, the first attempt to quantify the risk of TB among ICS users. We found that exposure to ICS does not add to the risk of TB in the presence of OCS but increases the risk of TB among nonusers of OCS, especially at the high exposure levels of steroids equivalent to fluticasone 1,000 μg/d or more. The risk of TB among OCS users has been well documented and the additional contribution of ICS to this risk seems negligible even at high doses.
High doses of ICS are known to be associated with systemic effects and 1,000 μg of inhaled fluticasone, the most commonly used inhaled corticosteroid in Canada, is estimated to be equivalent to approximately 10 mg of prednisone per day when the systemic effect is evaluated by suppression of serum cortisol (22). Thus, our findings in patients receiving high doses of ICS are compatible with the increased risk of TB seen with equivalent doses of OCS. Indeed, the joint statement of the American Thoracic society and the Centers for Diseases Control and Prevention acknowledges that 15 mg/d or more of oral prednisone (or its equivalent) administered for 1 month or longer is a risk factor for TB (3). Recently, this threshold was further refined and the risk of TB was found to be significantly increased at doses as low as prednisone 7.5 mg daily among current users, although there were no clear effects of duration or cumulative dose of OCS on this risk (1).
To what extent this excess risk of TB might be due to the underlying respiratory disease rather than exposure to oral or inhaled corticosteroids needs to be considered (1, 23), as disease activity is intimately linked to medication exposure. To address such confounding by disease severity, we adjusted for the number of other respiratory medications prescribed and for exacerbations as reflected by prescriptions for OCS as well as the number of hospitalizations for respiratory disease, all in the year before the diagnosis of TB. Furthermore, a recent study showed an association between the prior diagnosis of obstructive pulmonary disorders (emphysema, bronchitis, and asthma) and the risk of TB independent of glucocorticoid use (1). Our observed SIR supports this observation in showing that patients with respiratory diseases are close to four times more likely to develop TB than the general population. Obstructive pulmonary disease may well be an important and independent risk factor for TB and its addition to guidelines regarding the risk assessment of TB may be considered. Based on the magnitude of the estimated RR from the nested case-control analysis and the baseline rate of TB among the cohort of 23.3 per 100,000 per year, we can quantify the expected excess number of TB cases from 6.3 to 7.7 cases per 100,000 person-years among a cohort of subjects with respiratory diseases with, respectively, any or current exposure to ICS.
Unfortunately, we could not capture other factors associated with the risk of TB, such as country of birth, Aboriginal race/ethnicity, socioeconomic status, a history of recent contact with an individual with active TB disease, and the presence of TB-associated abnormal findings on a chest radiograph (3). Information on HIV status or smoking behavior was also lacking (24, 25). If at-risk groups were overrepresented in our cohort, it may explain the high observed risk of TB compared with the general population. Our findings probably reflect in part the life experience of this older cohort, which was more likely than the relatively younger age group to have been exposed to TB in their youth when TB was highly prevalent in Canada (26).
This study was based entirely on computerized claims databases, which are extremely useful to conduct analysis with large samples of rare diseases and outcomes but make it impossible to validate the diagnosis of respiratory disease or TB. However, for both diseases definitions we required an exposure to a specific drug therapy, thus optimizing accuracy. A great strength of our study is that the provincial coverage for TB medications is universally free and recorded in the pharmacy claims database, thus improving the accuracy of our TB case definition.
Although results of this study are supportive of published guidelines that recommend TB screening before initiation of any immunosuppressive therapy (27–29), the excess risk previously described among patients with COPD (1) and the additional risk with high doses of inhaled corticosteroids suggest that their use be limited to patients with asthma for whom the benefit is clear, as well as patients with COPD who have a significant component of reactive airway disease, and that the lowest possible dose be used.
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