Inhaled Corticosteroids and Mycobacterial Infection in Patients with Chronic Airway Diseases

Search Strategy

We searched [#1(inhaled corticosteroid); #2(ICS); #3(tuberculosis); #4(TB); #5(non-tuberculous mycobacteria); #6(NTM); #7(lung); #8(pulmonary)] in PubMed (MEDLINE), Cochrane, Web of Science, and EMBASE databases for articles that were published during and before 2021 with the search type: (#1 OR #2) AND (#7 OR #8) AND [(#3 OR #4) OR (#5 OR #6)]. Literature search was conducted by three authors (Y.Y., Y.N., and G.S.).

Inclusion and Exclusion Criteria

This meta-analysis included studies that met the following selection criteria. (1) All patients in the study were diagnosed with a chronic airway disease, such as asthma, COPD, and bronchiectasis according to the International Classification of Diseases (ICD), 9th (ICD-9) or 10th (ICD-10). (2) Chronic airway disease patients with NTM or TB infection were defined using microbiological criteria: two or more sputa culture positive or one bronchoscopy or lung biopsy or pleural specimen culture positive. (3) All studies evaluated ICS use and mycobacterium risk. (4) Using a case-control or cohort design or retrospective cohort study. (5) ICS use; dose of ICS use; type of ICS use; oral corticosteroids’ (OCS) use; patients with prior pulmonary TB, bronchiectasis, asthma, and COPD were included. Preclinical studies, editorials, review articles, commentaries, conference abstracts, and book chapters were excluded.

Data Extraction

All articles identified in the initial database search were filtered by title, abstract, and full-text to confirm eligibility and avoid data overlap. Titles and abstracts were screened by 3 authors (Y.Y., Y.N., and G.S.), and studies unrelated to the topic were excluded. Relevant data were extracted from eligible publications: first author name, year of publication, number of patients analyzed, baseline characteristics, etc. Disagreement about the study judgment was discussed by three authors (Y.Y., Y.N., and G.S.).

Statistical Analysis

We evaluated the risk of NTM infection in patients who used ICS because of asthma, COPD, bronchiectasis. Subgroup analysis evaluated the risk of NTM infection according to ICS dose and type of ICS. We also evaluated the risk of TB infection in patients who use ICS and OCS because of asthma, COPD, and bronchiectasis. Continuous variables were presented as standardized mean differences with 95% confidence intervals (CIs). Pooled standardized mean difference with 95% CI was calculated, and p < 0.05 was accepted with statistical significance. Heterogeneity of the study was determined by I² statistics using Cochrane Review Manager 5.3. I² ≥ 25%, 50%, and 75% were considered mild, moderate, and high heterogeneity, respectively. For I² > 50%, a random-effects model was used to evaluate the overall effect of a given comparison. The classified data were presented as odds ratios (ORs) with 95% CI. Random-effects model was used for meta-analysis.

Quality Score and the Risk of Bias Assessment

To assess the risk of bias assessments for the included studies, we made a funnel diagram through Rev-man5 software, and to assess the quality, three reviewers independently scored the studies according to the Newcastle Ottawa Scale (NOS), which evaluates cohort and case-control studies in terms of selection of participants (source and selection of case and control) and comparability of case and control to exposure (determination of exposure and no-response rates). The 9-point NOS contains 3 items: selection (0–4), comparability (0–2), and exposure (0–3). Research with an NOS score of more than 7 was considered high quality. Disagreement among the three judges was discussed.

ICS Use with NTM Infection in Chronic Respiratory Diseases Patients

ICSs were commonly used to treat chronic airway diseases, particularly asthma and COPD. Several studies in chronic airway diseases patients with NTM infection have reported the ICS use increased odds of NTM infection [28]; Liu et al. [27] showed that corticosteroid was an important factor for NTM infection, their crude OR was 3.88 (2.87–5.26); Andréjak et al. [16] showed that chronic respiratory disease, treated with ICS, is a strong risk factor for NTM pulmonary disease, and their adjusted OR was 15.6 (8.9–27.5). Our results demonstrate once again the ICS use increases the odds of NTM infection in chronic airway disease patients.

Hojo et al. [25] performed a single-institution nested case-control study of asthma patients, in which NTM-infected patients received a higher daily dose of ICS than controls (p < 0.01), and Andréjak et al. [16] showed that when ICS was further subdivided by ICS dose and type, the NTM infection risk in COPD patients increased from 28.1 for doses lower than 800 μg/day (low dose) to 47.5 for doses higher than 800 μg/day (high dose); our pooled result (2.28; 2.08–2.48) also proved that high doses of ICS increased odds of NTM infection. In addition, our result showed that NTM infection risk in fluticasone was higher than in budesonide. The OR 2.42 (2.23–2.63) was consistent with the study by Brode et al. [3]; their crude OR for fluticasone was 2.09 (1.80–2.43), and for this result, the study by Brode et al. [3] ran two post hoc-adjusted analyses to explore whether there was a differential risk between fluticasone and budesonide. (1) They changed the reference group to current budesonide users and found that current fluticasone use was associated with a significantly increased risk of NTM-PD compared with current budesonide use (aOR 1.76, 95% CI 1.50–2.07; p < 0.001). (2) They divided current users of fluticasone and budesonide into those exposed to low, moderate, or high mean daily dose (based on beclomethasone equivalents), in order to account for the higher potency of fluticasone. Finally, with high-dose budesonide users as the reference group, they found that current use of low-, moderate-, or high-dose fluticasone was associated with increased risk of NTM-PD. However, in our study, the dose-response relationship was not found.

ICS Use with TB Infection in Chronic Respiratory Disease Patients

TB was the leading cause of death worldwide by an identifiable infectious agent [29], systemic corticosteroid therapy would increase risk of reactivation of LTBI, and numerous studies have reported that ICS use increased odds of TB infection [30]. The study by Lee et al. [31] showed that ICS use increased the odds of TB infection in patients with COPD and asthma, their adjusted OR was 1.20 (1.08–1.34). Chung et al. [24] found that there was a significant association between ICS use and the risk of TB infection in patients with chronic airway disease. In the study by Brode et al. [3], their crude OR for ICS use with TB infection was 1.47 (1.10–1.96), which was consistent with our pooled analysis, and this proved that ICS use increased odds of TB infection. In addition, there were studies concerned about the relationship between ICS use and TB infection in COPD patients [31^-33]; the study by Lee et al. [18] reported that their unadjusted OR was 1.47 (1.3–1.66), our pooled result OR was 1.41 (1.26–1.59), which means that ICS use would increase odds of TB infection in COPD patients, and our results were also consistent with a meta-analysis by Ni et al. [10]. As the dose of ICS use, studies have reported that high-dose ICS use increased the odds of TB infection; Brassard et al. [29] reported their adjusted RR result was 1.55 (0.99–2.44), and our result was 1.58 (1.05–2.28) which proves that high doses of the ICS would increase TB infection.

Overall, ICS use was common in chronic airway diseases but the mechanism of the association between ICS use and increased odds of mycobacteria infection remains unclear, animal data showed that ICS alter cellular immune functions that were essential for host response and resistance to pathogens [34]. For example, ICS reduced mucosal-associated invariant T cells in bronchial tissue of patients with COPD, and mucosal-associated invariant T cells cells help prevent mycobacterial infection. However, airway remodeling and mucus gland impaction were not weakened by ICS [35].

We should thus strengthen the standardized management of chronic airway disease, clarify the indication of treatment containing ICS, reduce the exposure of ICS, and reduce the risk of mycobacterial infection. Previous studies [10^, 36] have revealed the relationship between ICS use and TB infection, but few studies revealed the relationship between ICS use and NTM infection. Our current study was the first meta-analysis to investigate the association between ICS use and risk of NTM and TB infection in patients with chronic respiratory diseases. Our meta-analysis revealed that in routine clinical assessment, when using ICS, clinicians should pay attention not only to TB infection but also to NTM infection, and pay attention to the types and dose of ICS use.

However, this systematic overview has some limitations based on the predefined data abstraction form. First, a few minor changes were made to facilitate data pooling. Second, the lack of data on some of the outcomes reduced the number of eligible studies. Third, the low and high dose of ICS results included only two articles, and because the number of people included in the study by Andréjak et al. [16] was too small compared to Brode et al. [3], it may require careful interpretation and further study. In addition, our study involving 517,556 patients was assessed to be of moderate to high quality, and among our study’s limitations, the most important was the high heterogeneity between included studies about ICS use and mycobacterial infection risk in chronic respiratory diseases. In order to explain this, we performed sensitivity analysis. We omitted one study per round, but the fluctuation range of heterogeneity results was small, then we have done subgroup analysis of age, sex, population region, comorbidities, but there were no meaningful results to explain the heterogeneity. When we reread all included studies, we knew that the actual relationship was complicated, such as HIV, malnutrition, alcohol misuse, smoking, or diabetes, which were consistently considered risk factors for mycobacterial infection, and another reason maybe was that in some studies, ICS use increased higher risk, and in other studies, ICS use has no risk of mycobacterial infection, but the whole effect showed that ICS use increases odds of mycobacterial infection. So, for a better explanation of heterogeneity, more studies need to be analyzed in the future. Although our results indicated that ICS use increased odds of mycobacterial infection, but the impact of this risk factor on the epidemiology of NTM or TB was limited; our work here has not been able to fully explain the heterogeneity, so we should pay more attention to this question in future studies. In addition, a burden of chronic respiratory diseases was reported high in the Asian region, we thus believed that our results may provide useful data on the epidemiology of ICS use with NTM or TB infection in Asia. However, no study performed in countries other than Canada and Denmark was found, so any inference could be highly biased.