Discussion
We found a strong and dose-dependent association between ICS use and risk of lower respiratory tract sample with M. catarrhalis in patients with COPD. High doses of ICS were associated to an almost threefold increased risk, but even low doses of ICS showed increased risk (HR 1.65). Results remained stable in sensitivity analyses.
To our knowledge, the relationship between ICS and risk of lower respiratory tract infection with M. catarrhalis has not previously been investigated. It is well described that ICS use, especially in high doses, is associated with increased risk of pneumonia in patients with COPD.7 8 24 25 However, different risk/incidence rates have been reported due to differences in selected population (age, BMI, FEV1, etc) and exposures including ICS type and dose.
Long-term use of ICS in patients with COPD has been shown to affect the lung microbiome, and although much is yet to be learnt, current data suggest that ICS use may increase bacterial load and may promote the persistence of certain bacterial pathogens including H. influenzae.10 26 M. catarrhalis has previously been described to often participate as a copathogen in respiratory tract infections with other bacteria including H. influenzae and P. aeruginosa.13 This pattern was also present in the data presented here, in which we found copathogens to be present in 34% of cases. Previous work from our group has demonstrated dose-dependent increased is risk of both P. aeruginosa (HR 3.58 (95% CI 2.75 to 4.65) for >800 µg budesonide equivalents compared with ICS non-users)27 and H. influenzae (HR 1.90 (95% CI 1.52 to 2.38) for >300 µg budesonide equivalents compared with non-users)28 related to ICS use.
Although it is difficult to extrapolate and compare exact risks due to differences in design, as well as dose and type of ICS, the overall picture is that ICS is associated to an increased risk of infection with a variety of different pathogens, and that the risk is dose-dependent. Our results are well in line with this.
The Danish COPD registry in combination with the national registries, based on personal identification numbers, allow for uniquely detailed epidemiological data on a patient level. Strengths of the current study include observations based on a large and well-characterised population of patients with a respiratory specialist verified and spirometry confirmed diagnosis of COPD. In addition, our registry includes many important confounders such as smoking status, oral and ICS use, lung function by FEV1, MRC and BMI.
Limitations of this study include limited knowledge of the clinical situation in which the samples were obtained. This especially since the pathogenic potential of M. catarrhalis has been cause for discussion both historically and in more recent years.12 13 For example, Murphy et al found that a significant part of positive M. catarrhalis sputum samples were associated to asymptomatic colonisation.16 Contradictory to this we found that the vast majority (87%) of patients with a sample positive for M. catarrhalis were either admitted to hospital or redeemed a prescription for an antibiotic, that is, had a clinically significant infection. This discrepancy likely arises from the difference in testing routines in the two studies. In the study by Murphy et al, sputum samples were collected when patients had signs of exacerbation but also routinely monthly. The data represented in this study, on the other hand, stem from the Danish clinical setting where samples are collected primarily on suspicion of infection and most often in the hospital setting.
Another limitation of the study is that we only know from the available data that the ICS prescriptions were redeemed, and not whether the patients adhered to treatment. This, however, could be considered an advantage as it makes the data more ‘real life’ where compliance is not given. Finally, we have defined ICS exposure in the year prior to study entry, and thus, there may be cases where ICS was discontinued in the study period.
The results presented here are in line with previous findings in other studies regarding ICS use and respiratory infections, but due to the observational design of the study, we cannot determine a causal relationship. Prospective studies examining ICS exposure in different doses, clinically confirming pneumonia, identifying microbiological agents and studying the imposed effect on mortality and quality of life are needed to confirm the correlation and clarify clinical significance.
In conclusion, our findings support that ICS, especially high doses must be prescribed with care in patients with COPD. We note that potency of the different ICS products should be kept in mind.