INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a smoking-related inflammatory disease with a high prevalence rate worldwide.21 Data from meta-analysis and population-based sampling show the prevalence rate ranging from 8.2% (China), 8.3% (western Pacific), 10.7% (Austria), 10.9% (Japan), 14.3% (Latin America), 19.6% (United States), 23.8% (South Africa), to 26.1% (Australia),3,9,12,16,22 indicating a large burden in both developed and developing countries. No pharmacologic therapy has been documented to reduce mortality in patients with COPD, and current medications are used to improve symptoms and pulmonary function. Inhaled corticosteroids (ICS), along with long-acting β-agonists, have been shown by several randomized controlled trials to decrease exacerbations in patients with severe COPD whose forced expiratory volume in the first second (FEV1) was <50% predicted.19,27 International guidelines thus recommend combination therapy with ICS and long-acting β-agonists for patients with severe COPD and repeated exacerbations.21
ICS therapy, however, increased the likelihood of pneumonia in several large randomized clinical trials.5,34 Causative microorganisms of pneumonia were not described. Although systemic administration of corticosteroids is a known risk factor for tuberculosis (TB),11 whether ICS therapy is associated with increased risk of TB has not been investigated. Therefore, we conducted this study to evaluate the influence of ICS on the risk of pulmonary TB in patients with COPD.
PATIENTS AND METHODS
Patients
We conducted the study in a 2150-bed tertiary-care referral center in northern Taiwan; it was approved by the Institutional Review Boards of the hospital. We identified all patients aged more than 40 years who had irreversible airflow limitation between August 2000 and July 2008. The irreversible airflow limitation was defined as 1) ratio of FEV1 to forced vital capacity (FVC) ≤0.70,21 and 2) a reversibility of <12% and <200 mL from prebronchodilator FEV1 to FEV1 after 200 μg albuterol inhalation.2,21 Among these patients, only those who had been followed in our hospital for >3 months were included for further analysis. Patients who had chronic lung disease other than COPD were excluded.
Data Collection
We recorded clinical data, pulmonary function data, acute exacerbations during follow-up, and survival status at the end of follow-up. COPD was classified into 4 severity groups based on FEV1.21 Pulmonary function testing was performed using spirometers-MasterScreen (Jaeger, Germany) or Vmax 6200 (Sensormedics Corp., United States)-according to the current guidelines.17,18 Patient data, including age, sex, weight, height, drug history, and smoking status, were collected via standard questionnaire before pulmonary function testing.
For each patient we divided the total quantity of ICS and of oral corticosteroids he or she received during follow-up by the duration of treatment to obtain the average daily doses, which were then converted to the equivalent dose of fluticasone in μg per day2 and of prednisolone in mg per day,11 respectively. We then stratified patients into 4 groups based on daily equivalent fluticasone dose: high dose (HD)(>500 μg/d), medium dose (MD)(250∼500 μg/d), low dose (LD)(<250 μg/d), and no ICS.2,8 We recorded average daily dose of oral corticosteroids as ≥10 mg, <10 mg, or no use of prednisolone.25
Acute exacerbation events21 and development of culture-confirmed pulmonary TB were recorded. Mycobacteriologic studies were performed as previously described.20,31 Patients were considered to have prior pulmonary TB based on medical records and compatible pulmonary lesions on chest films, including fibrotic, fibrocalcified pulmonary shadows and thickened pleura with obvious calcifications. Chest radiographs were reviewed as described previously.30
Follow-up pulmonary function data were collected. Changes in FEV1 and FVC in the initial 6 months of follow-up (acute change) were expressed as mL. After 6 months of follow-up, the changes (long-term change) were calculated as the rate of decline (mL/mo).
Statistics
Inter-group differences were compared using the 1-way ANOVA test for numerical variables and the chi-square test or the Fisher exact test for categorical variables, as appropriate. Multiple comparisons were performed using the Bonferroni method. Curves of time to acute exacerbations, time to active pulmonary TB, and survival for each variable were generated using the Kaplan-Meier method and were compared using the log-rank test. Variables that showed a significant difference (p < 0.05) in univariate analysis were entered in multivariate analysis by Cox proportional hazard regression method.
RESULTS
During the study period, 36,684 patients underwent pulmonary function testing. Among them, 554 patients were included for analysis: 50 who had received HD ICS, 72 MD ICS, 194 LD ICS, and 238 no ICS (Figure 1). The 4 groups with different daily doses of ICS had similar age and prevalence of underlying comorbid conditions and prior pulmonary TB (Table 1). Male sex was more predominant in the MD ICS and no ICS groups. More patients in the HD ICS group ever smoked, used oral prednisolone, and had severe or very severe COPD. Baseline lung function including FEV1 and FVC was worst in those received HD ICS, and best in those who received no ICS at all. The duration of ICS treatment and cumulative ICS dosage in each group are shown in Table 1.
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FIGURE 1: Disposition of the study subjects.
TABLE 1: Clinical Characteristics of 544 Patients
A total of 134 patients had a follow-up pulmonary function test within 6 months (Table 2). Compared with baseline data, the changes of FEV1 and FVC in the 4 groups with different ICS dose were not significantly different. A total of 355 patients had repeated pulmonary function testing after 6 months. After 3-4 years, the FEV1 of all groups showed mild improvement except for the no ICS group, and FVC was slightly decreased in all. The inter-group difference was not significant.
TABLE 2: Changes of Pulmonary Function After ICS Therapy
During follow-up of 25,544 patient-months (Table 3), 22 patients died; there was no inter-group difference in mortality. Sixteen patients developed active pulmonary TB in a median interval of 20.4 months (range, 3.2-58.2 mo) (Table 4). Patients in the HD ICS group had the highest risk (10%). Of the 16 patients, sputum mycobacterial cultures were performed at the initial visit in 3 patients (19%) and between the initial visit and the index mycobacterial culture in 8 (50%), and all were negative. Among the 538 patients who did not develop TB during follow-up, 88 (16%) underwent sputum smears for acid-fast bacilli and mycobacterial cultures at the initial visit. In the initial 6 months of follow-up, 2 patients in the HD ICS group developed TB. Neither of them had sputum acid-fast smear or mycobacterial culture performed at initial visit. One patient showed pleural thickening and calcification in the initial chest radiograph. Two isolates (40%) in the HD ICS group and 3 isolates (27%) in the other groups showed resistance to at least 1 of the tested first-line drugs (see Table 3). One (20%) isolate in the HD ICS group was a multidrug-resistant strain (defined as simultaneously resistant to isoniazid and rifampicin).
TABLE 3: Outcome
TABLE 4: Details of the 16 Patients Who Developed Pulmonary Tuberculosis
The use of different doses (HD vs. MD vs. LD vs. none) of ICS was associated with significantly different risks of developing active pulmonary TB (p = 0.014, Figure 2A). Compared with the patients who did not receive ICS, those in the HD ICS group had a significantly higher risk of developing active pulmonary TB in univariate analysis (p = 0.001, Figure 2B). Multivariate analysis revealed that the use of HD ICS, receiving oral prednisolone ≥10 mg/d, and having prior pulmonary TB were 3 independent risk factors for the development of active pulmonary TB (Table 5). Among the 176 patients having 1 risk factor during a follow-up of 3733.4 person-months, 12 (6.8%) developed active TB (0.018 TB cases per 1000 person-months). In the 4 patients with all 3 of the risk factors, TB occurred in 2 (50%) within 157.2 person-months follow-up (3.2 TB cases per 1000 person-months). To investigate the possible influence of the severity of COPD on the ICS dose and the risk of developing active pulmonary TB, we performed a multivariate Cox regression analysis containing the 3 significant variables (ICS dose, oral corticosteroids dose, and prior pulmonary TB), as well as the severity of COPD. The effects of the 3 variables remained unchanged, and the severity of COPD was not a significant factor for developing active pulmonary TB (p = 0.236).
FIGURE 2: Probability curves of patients remaining with no active pulmonary TB during follow-up (A) in all 554 patients; (B) in the HD ICS and no ICS groups; (C) in 553 patients, excluding the 1 patient whose chest film showed an old TB lesion and who developed active pulmonary TB within first 6 months; and (D) in the HD ICS and no ICS groups among the 553 patients. Patients were classified according to the daily equivalent dose of inhaled fluticasone as described in the Methods section. We calculated the p values using the Kaplan-Meier method with log-rank test. Black dots represent patients still free of TB at the end of follow-up.
TABLE 5: Multivariate Analysis of Factors Possibly Associated With Development of Active TB
If we exclude the 1 patient whose chest film showed an old TB lesion and who developed active pulmonary TB within 6 months after HD ICS therapy (Table 4, Patient 2), the association between HD ICS and active pulmonary TB is statistically insignificant, although the trend still shows that patients in the HD ICS group have the highest risk of developing active pulmonary TB (p = 0.080, Figure 2C). If we compare only the HD ICS group and the no ICS group, the inter-group difference in the risk of developing active pulmonary TB in the HD ICS group was still significant (p = 0.008, Figure 2D).
During follow-up, 228 episodes of acute exacerbations of COPD that required hospitalization in 70 patients were recorded. The mean intervals from initial visit to the first episode of acute exacerbations in different groups were significantly different (p = 0.024, see Table 3). Multivariate analysis revealed that age older than 65 years, severe COPD, use of HD ICS, and receiving oral prednisolone were independent risk factors predicting acute exacerbations (Table 6).
TABLE 6: Multivariate Analysis of Factors Possibly Associated With Acute Exacerbation Requiring Hospitalization
DISCUSSION
In the current retrospective study focusing on COPD patients whose diagnosis was confirmed by pulmonary function testing, we found that the use of HD ICS, receiving 10 mg or more of prednisolone per day on average, and prior pulmonary TB were 3 independent risk factors for the development of active pulmonary TB. Patients who had received HD ICS did not show statistically better survival compared with those who had not received HD ICS. Factors associated with acute exacerbations of COPD that required hospitalization included age older than 65 years, severe or very severe COPD, receiving oral prednisolone, and the use of HD ICS.
COPD is characterized by persistent and prominent airway inflammation presumably due to inhalation of toxic particles or gases.6,10 Severity of airway inflammation parallels that of airflow limitation.7 Therefore, several randomized trials have evaluated the effect of ICS in patients with moderate or severe COPD, with or without the concomitant use of long-acting β-agonists. Researchers found that such treatment did not improve the mortality, but did improve pulmonary function and reduce exacerbations in patients with severe COPD,4,5 and led to a 1.6- to 3-fold increase in pneumonia.5,34 Details about the pathogens of pneumonia were not described.5,34 Opportunistic infections, such as fungal pulmonary infection, Legionella pneumonia, and Pneumocystis jiroveci pneumonia, have been reported in patients receiving ICS.1,14 The finding is compatible with a previous study showing that long-term use of ICS could attenuate the adaptive immunity of the airways.23 This is an important clinical concern because pulmonary infection is the most common precipitating factor for acute exacerbations of COPD and increases mortality.24 The complication can be more serious in TB-endemic areas, since suppression of the essential defense mechanism against Mycobacterium tuberculosis in the airways may increase the risk of active pulmonary TB.
The association between HD ICS and active TB is not well studied. Laryngeal TB has been reported in a patient with asthma who received a medium dose of inhaled budesonide.33 Whether the use of ICS precipitated or just accelerated the development of TB in that patient is not discussed. In the current study, 16 TB cases were found during the follow-up of 25,544 person-months, corresponding to 752 cases per 100,000 person-years. The incidence is 4.8-fold higher than that (157 cases per 100,000 person-years) of the similar age-group (patients aged 65-70 yr) in the general population of Taiwan in 2006.13 The incidence is also 4.7-fold higher when compared with COPD patients who had not received ICS.
The higher incidence of pulmonary TB in our COPD patients may have several causes. Pulmonary TB may have been the original etiology of COPD in some of them, as 22% of the entire study population had prior pulmonary TB, and at least 36% of patients in the HD ICS group and 45% of patients in other groups were never smokers. The observation that several mycobacterial isolates from our patients showed resistance to at least 1 first-line anti-TB drug, and 1 was a multidrug-resistant strain, suggests that the patients' pulmonary TB could have reactivated from previous TB lesions. The second possible cause was that COPD patients were often treated with systemic corticosteroids during acute exacerbations, sometimes of high dose and for an extended period of time, which predisposed them to TB. Previous studies also indicate that the incidence of recurrent disease in patients with prior pulmonary TB is 4-fold higher than the TB incidence in the general population.28,32
The reasons that this significant association between the use of HD ICS and pulmonary TB was not found in previous large prospective studies are also probably multiple. First and possibly the most important, the current study was conducted in an endemic area of TB. The association might not exist in regions with low TB prevalence. Second, the mean follow-up duration was 46.1 months, longer than the follow-up time in previous clinical trials of COPD (no more than 3 years).4,5,26,34 Finally, instead of comparing the percentage of TB patients at certain time points, we analyzed the probability of developing TB during the study period, which could possibly provide a more detailed evaluation of the effects of HD ICS.
In addition to pulmonary infection, several ICS-related systemic side effects have been reported, such as cataract, adrenal suppression, and skin thinning and bruising.15,29 The systemic effect of inhaled fluticasone has been reported to be equal to one-tenth of that of oral prednisolone in the same dose.35 Therefore, the equivalent oral prednisolone dosages of total ICS used in our HD, MD, and LD groups were 101.06 mg, 48.37 mg, and 12.95 mg, respectively. Although the systemic equivalent dosage of prednisolone is not very large, the long-term effect of ICS use deserves further studies.
Our analysis showed that the changes in pulmonary function were not significantly different among the 4 groups with different doses of ICS. Similar to old age, advanced stage of COPD, and receiving systemic corticosteroids, the use of HD ICS was an independent risk factor for acute exacerbations requiring hospitalization. Previous randomized clinical trials comparing the effect of ICS plus long-acting β-agonists with those of either 1 component or placebo showed that combination therapy could improve pulmonary function and reduce exacerbations.4,5 Doses of ICS used in those trials were all high (1000 μg fluticasone daily). Whether ICS of lower doses would have achieved similar effects is not known. As for acute exacerbations, old age and advanced stage of COPD have been known risk factors, due to the presence of coexisting diseases and poor functional status of respiratory, cardiovascular, mental, neurologic, and musculoskeletal systems in the 2 subpopulations.24
Given that HD ICS is associated with the development of pulmonary TB and acute exacerbations, and is not associated with decreased mortality, the optimum dosage of ICS for patients with severe COPD should be carefully studied. Of equal importance is that every patient with COPD should undergo chest radiography, sputum acid-fast smear, and mycobacterial culture before receiving, as well as regularly during, HD ICS therapy.
The current study has some limitations. First, in the retrospective study, sputum acid-fast smear and mycobacterial culture were not routinely performed before initiating ICS therapy and regularly thereafter for every patient, which means we could have either missed the diagnosis of active TB that was already present before the initiation of ICS, or underestimated the incidence of active TB during follow-up. Second, because the study was conducted in a medical center in an endemic area of TB, our patients may represent a selected population, and may not represent the general COPD population, especially in areas with low TB prevalence or where testing for latent TB before corticosteroid treatment is recommended. Third, the daily doses of ICS and oral corticosteroids were calculated by dividing the total amount of prescribed drugs by the follow-up duration. These estimations could be wrong since patients' drug adherence was not assessed. Last, the conclusion was not solid due to the small number of patients who finally developed active pulmonary TB. Further large-scale prospective studies are needed to address these issues.
In conclusion, the use of high-dose ICS (> equivalent dose of 500 μg fluticasone daily), the use of ≥10 mg of prednisolone daily, and prior pulmonary TB were associated with an increased risk of pulmonary TB in patients with COPD. Chest radiography and sputum smear/culture for M tuberculosis should be performed before initiating HD ICS and regularly thereafter.
ACKNOWLEDGMENT
We thank the Pharmacy Department of National Taiwan University Hospital for providing the records of patients' medication.
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