Post-inhaled corticosteroid pulmonary tuberculosis and pneumonia increases lung cancer in patients with COPD

The prevalence of chronic obstructive pulmonary disease (COPD) in Taiwan is 2.48 % [1]. COPD is a common chronic inflammatory airway disease and is associated with lung cancer [2, 3]. Inhaled (ICS) and oral corticosteroids (OCS) have been used to reduced airway inflammation and acute exacerbations [4‐6]. Lee et al. conducted a nested case-control study with new adult users of ICS. Results showed that ICS use led to a reduced risk of lung cancer [7]. In a separate study, ICS has also reduced lung cancer risk among COPD patients [8] and those who quit smoking [9].

However, there is a close association between ICS use, pulmonary tuberculosis (TB) [10] and pneumonia [11]. TB [12] and pneumonia [13] have been associated with increased risk of lung cancer. Coexistence of COPD and TB correlates with increased incidence and mortality of lung cancer [2, 14]. The association between post-ICS pulmonary infections and lung cancer in patients with COPD remains unclear. In this study, we evaluated the association between post-ICS pulmonary infections and lung cancer using the National Health Insurance Research Database (NHIRD).

We identified 1,196,878 patients with COPD from 2001 to 2005 who were not diagnosed with lung cancer before 2002. We excluded 12,067 patients who received ICS before 2002 and 94,856 patients with incomplete information including sex and registry data. We enrolled 15,714 COPD patients who used ICS for a period of 3 months or more. Further exclusion included the following: participants who died or those that were diagnosed with lung cancer within 2 year after the index date (n = 1970), individuals diagnosed with TB or pneumonia before or 3 months after the index date (n = 4481), people below 20 and above 100 years of age (n = 187), and ICS users without matched controls (n = 263). Therefore, 8813 new users of ICS were matched with 35,252 non-users (Fig. 1).

Information on demographic characteristics, medications, comorbidities, and follow-up durations of the study participants are shown in Table 1. In total, 179 ICS users (i.e. no lung infection, 143 cases; pneumonia, 19; TB, 11, and TB + pneumonia, 6) and 496 non-users had lung cancer (no lung infection, 442 cases; pneumonia, 28; TB, 19, and TB + pneumonia, 7).

Kaplan-Meier plots for TB, pneumonia, and TB + pneumonia stratified by ICS use are presented in Fig. 2. The 5-year cumulative incidence of lung cancers was significantly higher in ICS users without lung infection than their non-user counterparts (2.3 versus 1.6 %; p = 0.0008), and in users with TB than their non-user counterparts (7.5 versus 3.1 %; p = 0.0214).

Table 2 shows the adjusted HRs of lung cancer in COPD patients with TB, pneumonia and TB + pneumonia who were users and non-users of ICS. Post-ICS TB and TB + pneumonia significantly increased the risk of lung cancer. The respective HRs were 2.42 (95 % CI, 1.28–4.58) and 2.37 (95 % CI, 1.01–5.54). There was no significant increase in lung cancer risk among ICS users without lung infection (HR, 0.88; 95 % CI, 0.67–1.14). There was no significant association between lung cancer and pulmonary infections such as TB (HR, 1.42; 95 % CI, 0.89–2.26), pneumonia (HR, 0.95; 95 % CI, 0.62–1.46) and TB + pneumonia (HR, 1.68; 95 % CI, 0.78–3.65) among the non-ICS users. No significant interaction was found between ICS use, TB (p = 0.084), pneumonia (p = 0.259), and TB + pneumonia (p = 0.386) (Table 3).

Corticosteroids are used to control airway inflammation in patients with COPD. They have also increased the risk of pulmonary TB and pneumonia [10, 11]. Many studies have documented a possible link between chronic inflammation, infection and lung cancer [2, 16, 17]. However, little is known about post-ICS pulmonary infections and lung cancer. Results from this study suggest that post-ICS TB with/without pneumonia may serve as risk factors for lung cancer.

COPD, a chronic disease characterized by a chronic inflammation of the lower airways has been associated with lung cancer [18]. The presence of moderate-to-severe obstructive pulmonary function was associated with a higher risk of lung cancer (HR, 2.8; 95 % CI, 1.8–4.4) [19]. Denholm et al. pooled information from seven case–control studies with 12,739 case subjects and 14,945 controls and found that chronic bronchitis and emphysema were positively associated lung cancer in men at odds ratios (ORs) of 1.33 (95 % CI, 1.20–1.48) and 1.50 (95 % CI, 1.21–1.87), respectively [20]. In a study comprising 15,219,024 Taiwanese residents, an increased risk of lung cancer was found in men (HR, 1.56; 95 % CI, 1.51–1.61) and women (HR, 1.33; 95 % CI, 1.26–1.10) with COPD [3].

ICS has been established in the treatment of COPD especially in symptomatic patients who experience useful gains in the quality of life, reduction in acute exacerbations, and an attenuation of the yearly rate of deterioration in lung function [21]. Acute severe exacerbations require the addition of systemic corticosteroids to control respiratory symptoms and improve lung function [22]. In an analysis including new adult ICS users (9177 cases and 37,048 controls), ICS use had a significant linear association with a decreased lung cancer incidence (OR, 0.79; 95 % CI, 0.69–0.90) [7]. In an epidemiologic study involving 10,474 veterans with COPD, a dose-response relationship was observed between ICS exposure and lung cancer [8]. Participants (n = 219) who received high-dose ICS (triamcinolone ≧1200 ug/day) had a decrease risk of lung cancer (HR, 0.39; 95 % CI, 0.16–0.96). After excluding subjects who had a lung cancer diagnosis within 1 year after enrollment, there was no significant dose-response reduction in lung cancer risk even at the higher doses of ICS. A retrospective cohort study of patients with a first-time diagnosis of COPD who had quit smoking and were regular users of ICS found a risk reduction when assessing a dose-response relationship of lung cancer [9]. The HRs were 0.88 (95 % CI, 0.51–1.52) and 0.51 (95 % CI, 0.30–0.84) in ICS users with 1–2 and 3 or more prescriptions/year, respectively. In our study, there was no decreased risk of lung cancer in ICS users with no pulmonary infections.

Immunosuppressive effects of glucocorticoids include inhibition of macrophage differentiation, production of cytokines, tumoricidal and microbicidal activities of activated macrophages, and T-cell activation [23]. The joint statement of the American Thoracic Society and the Centers for Disease Control and Prevention acknowledges that an administration of prednisone ≧ 15 mg/day (or its equivalent of another steroids) for a period of 1 month or more serves as a risk factor for TB [24]. A retrospective cohort study reported that ICS use was an independent risk factor for the development of pulmonary TB in patients who had normal chest radiographs (HR, 9.08; 95 % CI, 1.01–81.43) and in those who had radiologic findings of previous pulmonary TB (HR, 24.95; 95 % CI, 3.09–201.37) [25]. In a nested case-control study with 4139 TB cases and 20,583 controls, ICS use had a significant linear association with increased risk of TB: The OR was 1.20 (95 % CI, 1.08–1.34) [10]. In Taiwan, Chung et al. reported that there was a multiplicatively increased risk of TB in patients who used ICS and OCS compared to their non-user counterparts (OR, 4.31; 95 % CI, 3.39–5.49) [26]. Moreover, ICS has been associated with pneumonia in patients with COPD. In a nested case-control study of patients≧65 years, current users of ICS were 1.38 (OR, 1.38; 95 % CI, 1.31–1.45) times more likely to have a hospitalization of pneumonia [11]. A study has reported a gradual decrease in acute exacerbation rate of COPD and an increased incidence of pneumonia after ICS use (i.e. from 0.10 to 0.21 event/person-year) [27].

Patients with newly diagnosed TB were at increased risk of lung cancer with an adjusted HR of 3.32 (95 % CI, 2.70–4.09) [28]. Nonsmokers with TB had a significant association with lung squamous cell carcinoma and adenocarcinoma for both genders, whereas male smokers with TB were associated with squamous cell carcinoma, small cell carcinoma, and adenocarcinoma, and female smokers with TB were associated with adenocarcinoma [29]. In a separate study that recruited patients with pneumonia (22,034 patients and 88,136 matched controls), pneumonia was associated with an increased risk of lung cancer (HR, 4.24; 95 % CI, 3.96–4.55) [13]. In a meta-analysis, the relative risks of lung cancer in patients with a previous history of pneumonia and TB were 1.43 (95 % CI, 1.22–1.68) and 1.76 (95 % CI, 1.49–2.08), respectively [30]. When the analysis was restricted to nonsmokers, effects remained significant for pneumonia 1.36 (95 % CI, 1.10–1.69) and TB 1.90 (95 % CI, 1.45–2.50). In this study, increased risks of lung cancer were observed mainly in patients with post-ICS TB and TB + pneumonia.

Jian et al. reported a stronger association between coexisting COPD and TB and lung cancer [2]. The HRs were 2.42 (95 % CI, 2.18–2.69) in men and 2.41 (95 % CI,1.90–3.07) in women. Biologically, the additive effects of ICS, COPD, pneumonia, and TB on lung cancer may be explained by corticosteroids-induced compromised immune clearance of Mycobacterium tuberculosis, bacteria and malignant cells, and COPD and TB-related chronic inflammatory processes of the lung. More studies ought to be conducted to investigate the association between post-ICS pulmonary infections and lung cancer.

This study had several strengths. First, the sample size was large and the period of follow-up was long, hence reducing the likelihood of selection biases. Second, lung cancer was confirmed histologically, hence allowing the little possibility of misclassification. Third, with at least 2 years from the initiation of ICS and diagnosis of lung cancer, the chances of misclassifications were less.

Nevertheless, there were certain limitations. First, information on medication were assessed solely by refills, not by whether the subjects actually used the medication that were prescribed. Second, information regarding laboratory and image findings including airflow obstruction by spirometry and chest X-ray findings for TB were not available in the NHIRD. Third, frequent hospital visits might have led to a higher detection rate of TB and early-stage lung cancer. Fourth, the databases do not contain detailed information regarding smoking history, radon exposure, occupational exposures, diet preference, and family history, all of which may be risk factors for lung cancer. When looking at COPD and lung cancer risk, pack-years of cigarette smoking is critical.

We found that post-ICS TB with/without pneumonia conferred a higher risk of lung cancer in COPD patients. Because of the high mortality of lung cancer, cancer screening is recommended for COPD patients with post-ICS TB with/without pneumonia.