Correspondence to Dr Jens-Ulrik Stæhr Jensen; [email protected]
WHAT IS ALREADY KNOWN ON THIS TOPIC
The use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) is associated to an increased risk of pneumonia, seemingly in a dose-dependent manner. Moreover, ICS use has been linked to an increased risk of several specific bacterial pathogens.
WHAT THIS STUDY ADDS
To our knowledge, the association between ICS and Moraxella catarrhalis, one of the most common causes of infectious exacerbation in patients with COPD, has not previously been examined. We found a strong and dose-dependent association between ICS and risk of lower respiratory tract infection with M. catarrhalis.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
More knowledge is needed regarding the increased risk of infections associated with ICS. This is necessary to best balance beneficial effect against risk of adverse events, and hence provide the best possible treatment for patients with COPD in the future.
Introduction
Chronic obstructive pulmonary disease (COPD) comprises a combination of bronchitis and emphysema and involves chronic inflammation of the lung. Inhaled corticosteroids (ICS) are anti-inflammatory drugs that are recommended in patients with COPD with frequent or severe exacerbations (≥2 or ≥1 leading to hospital admission within the last year) and increased blood eosinophil count.1 2 In this group of patients, ICS in combination with bronchodilators have been shown to reduce the risk of recurrent exacerbations and may improve lung function.3 However, studies have not been unequivocal in regard to effect on all-cause mortality,4–6 and the use of ICS in patients with COPD has been associated with an increased risk of pneumonia.7 8
The immunosuppressive effects of ICS have been shown to affect the interplay between microbiome and host and may augment the bacterial burden and alter the lower airway microbial composition.9 10 Both bacterial colonisation and infection with pathogenic bacteria play an important role in COPD pathogenesis, contributing to inflammatory response, lung damage and exacerbations.11
Moraxella catarrhalis, a Gram-negative aerobic diplococcus, is an important cause of upper and lower respiratory tract infections. It is known to affect patients with COPD and is a common cause of bacterial exacerbation.12 13 M. catarrhalis may also colonise the lower airways in stable COPD, which is associated to worsened COPD symptoms and increased risk of subsequent exacerbation.14–16
M. catarrhalis is often found as a copathogen with other bacterial species or viruses13 and thus, risk of lower respiratory tract infection with M. catarrhalis could be especially susceptible to changes in lung microbiome and immunosuppression.
The aim of the study was to find out whether there is an association between ICS use and the rate of lower respiratory tract sample positive for M. catarrhalis in patients with COPD.
Methods
Data sources
Data from regional and nationwide administrative registries was accessed. Linkage between registries was done by using unique personal identifications numbers, ensuring exact linkage on patient level allowing complete follow-up.
The following registries were used:
The Danish Register of COPD (DrCOPD) was used to identify patients with COPD. It is a nationwide register that holds individual patient data on demographics and all outpatient visits at all hospital-based pulmonary clinics and hospital admissions due to exacerbation of COPD since 2010.17
The Danish National Patient Registry holds data on all hospital admissions and all hospital outpatient visits including primary and secondary diagnoses, and was used to characterise comorbidities in the study population.18
The Danish National Database of Reimbursed Prescriptions (DNDRP) includes data on all reimbursed prescriptions redeemed at Danish community-based and hospital-based outpatient pharmacies.19 DNDRP was used to identify prescribed and redeemed medication.
Information on deaths was obtained from The Danish register of Causes of Death.
Microbiological data from the Clinical Microbiology Departments in Eastern Denmark (Region Zealand and Capital Region) was used to identify samples positive for M. catarrhalis and copathogens.
Study population
The study considered all patients registered in DrCOPD with an outpatient clinic visit between 1 January 2010 and 31 October 2017. Table 1 presents an overview of the study population. Study entry was defined as the first outpatient clinic visit. Patients with only in-hospital registrations were not included as these contacts do not hold information on patient characteristics for example, severity of airflow obstruction, degree of dyspnoea and smoking status. Likewise, patients with outpatient contacts but no registration of body mass index (BMI), forced expired volume in the 1 s (FEV1) or smoking status, in neither the first nor following contacts, were excluded allowing for complete case analysis. Patients from western Denmark were excluded as we could not gain access to microbiological data from western Denmark. M. catarrhalis was identified in a lower respiratory tract culture (ie, sputum, tracheal secretion, bronchial secretion or bronchial alveolar lavage) obtained after study entry. Patients with a lower respiratory tract culture positive for M. catarrhalis 30 days prior to study entry were excluded.
Table 1Baseline characteristics of the study population
| Total | No ICS | Low ICS | Medium ICS | High ICS | |
| No of subjects | 18 867 (100.0) | 5687 (30.1) | 4361 (23.1) | 4457 (23.6) | 4362 (23.1) |
| Demographics | |||||
| Age | 69.6 (62.0–77.0) | 68.5 (60.3–76.0) | 69.3 (61–76.8) | 70.3 (63.4–77.5) | 70.6 (63.7–77.6) |
| Female | 10 188 (54.0) | 2691 (47.3) | 2278 (52.2) | 2486 (55.8) | 2732 (62.6) |
| BMI, median (IQR) | 25 (21–29) | 25 (22–29) | 25 (22–29) | 25 (21–29) | 24 (21–28) |
| Pulmonary parameters | |||||
| FEV1 (%) median (IQR) | 49 (36–63) | 57 (44–70) | 53 (40–66) | 45 (34–58) | 40 (29–53) |
| FEV1 (%) | |||||
| ≥80 | 1262 (6.7) | 620 (10.9) | 337 (7.7) | 183 (4.1) | 122 (2.8) |
| 50–79 | 8101 (42.9) | 3048 (53.6) | 2177 (49.9) | 1664 (37.3) | 1212 (27.8) |
| 30–49 | 6578 (34.9) | 1609 (28.3) | 1399 (32.1) | 1760 (39.5) | 1810 (41.5) |
| <30 | 2926 (15.5) | 410 (7.2) | 448 (10.3) | 850 (19.1) | 1218 (27.9) |
| Smoking status | |||||
| Current | 7206 (38.2) | 2610 (45.9) | 1732 (39.7) | 1435 (32.2) | 1429 (32.8) |
| Former | 10 990 (58.2) | 2879 (50.6) | 2442 (56.0) | 2871 (64.4) | 2798 (64.1) |
| Never | 671 (3.6) | 198 (3.5) | 187 (4.3) | 151 (3.4) | 135 (3.1) |
| Severe COPD exacerbations* | |||||
| 0 | 12 944 (68.6) | 4626 (81.3) | 2974 (68.2) | 2863 (64.2) | 2481 (56.9) |
| 1 | 3822 (20.3) | 826 (14.5) | 952 (21.8) | 984 (22.1) | 1060 (24.3) |
| ≥2 | 2101 (11.1) | 235 (4.1) | 435 (10.0) | 610 (13.7) | 821 (18.8) |
| Comorbidity | |||||
| All-cause hospitalisation* | 11 938 (63.3) | 3414 (60.0) | 2852 (65.4) | 2793 (62.7) | 2879 (66.0) |
| Hypertension | 5010 (26.6) | 1583 (27.8) | 1167 (26.8) | 1189 (26.7) | 1071 (24.6) |
| Atrial fibrillation | 2459 (13.0) | 773 (13.6) | 595 (13.6) | 589 (13.2) | 502 (11.5) |
| Myocardial infarction | 949 (5.0) | 290 (5.1) | 219 (5.0) | 206 (4.6) | 234 (5.4) |
| Heart failure | 2774 (14.7) | 865 (15.2) | 681 (15.6) | 617 (13.8) | 611 (14.0) |
| Peripheral vascular disease | 1533 (8.1) | 525 (9.2) | 350 (8.0) | 345 (7.7) | 313 (7.2) |
| Cerebrovascular disease | 1184 (6.3) | 384 (6.8) | 299 (6.9) | 251 (5.6) | 250 (5.7) |
| Diabetes mellitus | 2023 (10.7) | 662 (11.7) | 489 (11.2) | 418 (9.4) | 454 (10.4) |
| Renal disease | 756 (4.0) | 277 (4.9) | 185 (4.2) | 147 (3.3) | 147 (3.4) |
| Asthma | 2158 (11.4) | 296 (5.2) | 501 (11.5) | 676 (15.2) | 685 (15.7) |
| Bronchiectasi | 243 (1.3) | 76 (1.3) | 54 (1.2) | 53 (1.2) | 60 (1.4) |
| Use of medication* | |||||
| LABA or LAMA | 13 341 (70.7) | 2941 (51.7) | 2990 (68.6) | 3619 (81.2) | 3791 (86.9) |
| Theofylline | 645 (3.4) | 43 (0.8) | 80 (1.8) | 177 (4.0) | 345 (7.9) |
| Oral corticosteroids | 7233 (38.3) | 1074 (18.9) | 1578 (36.2) | 2070 (46.4) | 2511 (57.5) |
Data are presented as n (%) unless otherwise specified. Further baseline characteristics are available in online supplemental file 2.
*12 months prior to study entry.
BMI, body mass index; FEV1, forced expiratory volume in 1 s; ICS, inhaled corticosteroids; LABA, long-acting β2-agonis; LAMA, long-acting muscarinic antagonist; MRC, Medical Research Council.
Patients with malignant neoplasm (International Classification of Disease (ICD-10 codes: C00–43 and C45–C97) or immunodeficiency (ICD-10 codes: D80–84, D85, D89) 5 years prior to study entry or prescription of disease-modifying antirheumatics drugs (Anatomical Therapeutic Chemical (ATC)-codes: L04A×03, L01AA01, A07EC01, L04AD01, L04AA13, L04A×01, L04AA06, P01BA02) 12 months prior to study entry were excluded, since these conditions and drugs are suspected to be associated with the study outcome. For the same reasons patients prescribed with azithromycin prophylaxis, defined as reimbursed prescriptions for accumulated ≥30 tablets (500 mg) of azithromycin 12 months prior to study entry, were excluded. Online supplemental table 1 lists the ICD-10 codes used to define exclusion criteria and comorbidities. Patients were followed for 365 days from study entry until first positive sample with M. catarrhalis, death or end of study 31 October 2017.
Exposure to ICS
All prescriptions for ICS, alone or in a combination inhaler, redeemed within 365 days prior to study entry were identified. Doses of ICS were converted to budesonide-equivalent doses: Beclomethasone and mometasone were considered equivalent to budesonide. Fluticasone propionate and furoate were considered 2 and 10 times as potent as budenoside, respectively. Ciclesonide was considered 2.5 times as potent as budenoside.20 21
Dose response was assessed by categorising ICS exposure by tertiles based on the accumulated dose of ICS in the year prior to study entry (low, moderate or high dose). Non-use was used as a reference category.
Clinical M. catarrhalis infection
Clinical M. catarrhalis infection was defined as admission to hospital within 7 days before or 14 days after a positive culture with M. catarrhalis and/or redemption of antibiotics from a Danish pharmacy for airway infection 7 days before or 14 days after a positive culture with M. catarrhalis.
Following antibiotics were considered as given for airway infection: phenoxymethylpenicillin, amoxicillin, amoxicillin with clavulanic acid, azithromycin, roxithromycin, clarithromycin, moxifloxacin, ciprofloxacin and doxycycline (ATC codes: J01CE02, J01CA04, J01CR02, J01FA01, J01FA06, J01FA09, J01FA10, J01MA02, J01MA14, J01AA02). Not all of these are active towards M. catarrhalis. However, in the definition of the outcome, prescription of antibiotics was used as a proxy for clinical infection (not as ‘adequate treatment’), and further, many prescriptions could be done before the culture sample was reported to the physician.
Copathogens
A copathogen was defined as a lower respiratory tract culture, obtained on the same date as a positive M. catarrhalis sample, positive for a different pathogen. We did not include samples for fungal or viral pathogens.
Statistical analysis
The risk of lower respiratory tract sample with M. catarrhalis associated with use of ICS was estimated using a Cox proportional hazard regression model. Death was handled as a competing risk in the model since it impedes the occurrence of M. catarrhalis. The model was adjusted for the following suspected confounders and markers of disease severity: age, sex, severity of airway obstruction (percentage of predicted FEV1), BMI, smoking status (never, former or current smoker), calendar year of entry in DrCOPD and accumulated dose of oral corticosteroids 365 days prior to study entry.
Two models were applied as sensitivity analysis—a propensity score matched model using the greedy-match method and a propensity score weighted model using multinominal propensity scores.
For the propensity matched model, patients exposed to high or moderate ICS doses were matched 1:1 with patients exposed to low or no ICS dose in a propensity matched population, based on the same variables used in the main analysis. An unadjusted Cox proportional hazard regression model was then used to estimate the risk of a positive sample with M. catarrhalis associated with ICS use.
The propensity score weighted model was applied using multinominal propensity score weighting22 based on the same variables used in the adjusted main analysis. Covariate balance between treatment groups was assessed using absolute standardised mean differences (ASMD) with ASMD≤0.1 indicating sufficient balance. A weighted Cox proportional hazard regression model was then used to estimate the risk of a lower respiratory tract sample with M. catarrhalis associated with the use of ICS.
The regression models were tested for proportion of hazards and linearity of continuous variables and were found to be valid. A p<0.05 was considered statistically significant. All statistical analyses were performed by using SAS statistical software (V.3.71 Enterprise Edition, SAS Institute), except for the propensity weighted model, for which the Twang package23 for R statistical software (V.2022.07.2, RStudio) was used.
Results
We included 18 867 patients (figure 1). Table 1 shows details on the study population, including comorbidities and prescriptions. A total of 521 (2.8%) patients were found to have a lower respiratory tract sample positive for M. catarrhalis. Mean follow-up time was 332 days (SD±84 days).
Enlarge this image.Figure 1. Flow chart illustrating the selection of the study population. DrCOPD, Danish Register of Chronic Obstructive Pulmonary Disease; DMARDS, disease-modifying antirheumatics drugs.
The group of patients with low ICS exposure received <328 µg budesonide equivalents daily, moderate dose received 328–821 µg, and high dose received >821 µg. Details regarding ICS use are shown in table 2.
Table 2Overview of ICS use in the study population
| Total | Low ICS | Moderate ICS | High ICS | |
| No of subjects, n (%) | 13 180 (69.9) | 4361 (23.1) | 4457 (23.6) | 4362 (23.1) |
| Accumulated daily budesonide equivalent dose (µg), median (IQR) | ||||
| Total ICS | 579 (263–1041) | 164 (105–263) | 579 (473–658) | 1397 (1052–1894) |
| Budesonide | 421 (164–658) | 158 (105–263) | 526 (421–631) | 947 (631–1262) |
| Fluticasone proprionate | 904 (329–1644) | 164 (164–329) | 493 (329–658) | 1479 (986–1973) |
| Fluticasone furoate | 454 (227–832) | 189 (76–302) | 454 (227–548) | 907 (454–1097) |
| Beclometasone | 219 (110–460) | 110 (110–197) | 329 (197–526) | 395 (197–778) |
| Mometasone | 658 (247–1085) | 132 (66–263) | 461 (157–707) | 888 (625–1430) |
| Ciclesonide | 263 (132–395) | 132 (132–263) | 263 (197–395) | 461 (263–756) |
| No of individual users, n (%) | ||||
| Budesonide | 9410 (49.9) | 3550 (81.4) | 3682 (82.6) | 2178 (49.9) |
| Fluticasone proprionate | 4901 (26.0) | 862 (19.8) | 1121 (25.2) | 2918 (66.9) |
| Fluticasone furoate | 118 (0.6) | 18 (0.4) | 48 (1.1) | 52 (1.2) |
| Beclometasone | 190 (1.0) | 58 (1.3) | 77 (1.7) | 55 (1.3) |
| Mometasone | 51 (0.3) | 9 (0.2) | 10 (0.2) | 32 (0.7) |
| Ciclesonide | 42 (0.2) | 15 (0.3) | 13 (0.3) | 14 (0.3) |
Please note that individuals may have received more than one type of ICS.
ICS, inhaled corticosteroids.
Crude incidence rate of a M. catarrhalis a positive sample the control group with no ICS use was 1.1% per person-year. Incidence rates were found to be higher with increasing ICS dose, reaching 6.1% in the high ICS group (table 3 and figure 2) corresponding to a crude number needed to harm of 20.0.
Table 3Results of main analysis and sensitivity analyses with sample positive for Moraxella catarrhalis as outcome
| No of patients | No of events | Crude incidence rate | Cox multivariate regression model (n=18 867) | Propensity matched analysis (n=13 536) | Propensity weighted analysis (n=18 867) | |||||
| n | n | Events per person-year | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | ||
| Total | 18 867 | 521 | 0.0303 | |||||||
| No ICS | 5687 | 59 | 0.0113 | Ref. | Ref. | Ref. | ||||
| Low ICS | 4361 | 92 | 0.0229 | 1.65 (1.19 to 2.30) | 0.003 | 1.90 (1.31 to 2.75) | 0.0008 | 1.57 (1.35 to 1.83) | <0.0001 | |
| Moderate ICS | 4457 | 134 | 0.0329 | 1.82 (1.32 to 2.51) | 0.0002 | 2.15 (1.50 to 3.07) | <0.0001 | 1.76 (1.52 to 2.05) | <0.0001 | |
| High ICS | 4362 | 236 | 0.0612 | 2.80 (2.06 to 3.82) | <0.0001 | 3.61 (2.57 to 5.07) | <0.0001 | 2.65 (2.30 to 3.05) | <0.0001 | |
Patients with no ICS use 12 months prior to study entry are not included in the table. Low <328 µg, moderate 328–821 µg, high >821 µg daily budesonide equivalents. Non-use of ICS was used as reference in all analyses.
ICS, inhaled corticosteroids.
Enlarge this image.Figure 2. Cumulative incidence of lower respiratory tract sample positive for Moraxella catarrhalis according to ICS exposure in 18 867 patients with COPD. COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids.
Main analysis
Adjusted Cox regression showed significantly higher risk of lower respiratory tract sample with M. catarrhalis among patients with ICS use compared with non-users (table 3). For low and moderate doses of ICS HR was 1.65 (95% CI 1.19 to 2.30, p=0.003) and 1.82 (95% CI 1.32 to 2.51, p=0.0002), respectively. In the group of patients with highest ICS exposure, the HR of M. catarrhalis was 2.80 (95% CI 2.06 to 3.82, p<0.0001).
Sensitivity analyses
The propensity score matched population comprised 13 536 patients, consisting of 6769 patients receiving no or low-dose ICS matched 1:1 to patients with moderate or high-dose ICS. Results remained stable compared with the main analysis, although with somewhat more marked increase in risk of lower respiratory tract sample with M. catarrhalis in the high ICS group (HR 3.61 (95% CI 2.57 to 5.07, p<0.0001)) relatively to the low and moderate ICS group (HR 1.90 (95% CI 1.31 to 2.75, p=0,0008) and 2.15 (95% CI 1.50 to 3.05, p<0.0001), respectively).
The multinominal propensity score weighted analysis yielded results similar to those of the main analysis, with HR 2.65 (95% CI 2.30 to 3.05, p<0.0001) for risk of positive sample with M. catarrhalis among users of high-dose ICS compared with non-users (table 3).
A post hoc stratification for asthma was performed using the same Cox multivariate regression model as in the main analysis. Results remained stable when analysing the strata containing only patients with no registration of an asthma diagnosis 5 years prior to study entry (online supplemental table 3). In the strata containing only patients who did have an asthma diagnosis, results did not reach statistical significance.
Clinical M. catarrhalis infection
Of the 521 patients with a positive culture for M. catarrhalis 455 (87%) patients were found to have clinical M. catarrhalis infection (defined in methods). A total of 309 patients were admitted to hospital within 7 days before or 14 days after the positive sample was obtained. A total of 258 patients redeemed a prescription for a relevant antibiotic within 7 days before or 14 days after a positive culture for M. catarrhalis.
In the Cox multivariate regression model using clinical M. catarrhalis infection as outcome, results remained similar compared with the main analysis with HR 1.57 (95% CI 1.09 to 2.224, p=0.014), HR 1.85 (95% CI 1.31 to 2.60, p=0.0004) and HR 2.88 (95% CI 2.07 to 4.02, p<0.0001) for low, medium and high ICS respectively compared with non-users (table 4).
Table 4Sensitivity analysis using clinical Moraxella catarrhalis infection as outcome
| No of patients | No of events | Cox multivariate regression model (n=18 867) | ||
| n | n | HR (95% CI) | P value | |
| Total | 18 867 | 455 | ||
| No ICS | 5687 | 59 | Ref. | |
| Low ICS | 4361 | 92 | 1.57 (1.09 to 2.24) | 0.014 |
| Moderate ICS | 4457 | 134 | 1.85 (1.31 to 2.60) | 0.0004 |
| High ICS | 4362 | 236 | 2.88 (2.07 to 4.02) | <0.0001 |
Clinical M. catarrhalis infection was defined as a lower respiratory tract culture positive for M. catarrhalis combined with admission to hospital and/or redeemed prescription for an antibiotic related to airway infections, within 7 days before or 14 days after the positive sample was obtained.
ICS, inhaled corticosteroids.
Copathogens
In 176 (34%) individual patients with a positive culture for M. catarrhalis, one or more different pathogens were present in samples obtained on the same day. In 29 patients, 2 or more copathogens were found. In total, there were 206 positive samples for copathogens. The most common bacteria were Streptococcus pneumoniae (34.5%), Hemophilus influenzae (25.8%), Pseudomonas aeruginosa (9.7%) and Staphylococcus aureus (5.8%). We found similar prevalence of copathogens regardless of ICS dose (online supplemental table 4).
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.
Data availability statement
Data stems from national registries that are not publicly available as they contain identifiable personal and medical information.
Ethics statements
Patient consent for publication
Not applicable.
Ethics approval
This study involves human participants and was approved by Data Protection Agency: 2012-58-0004; The Danish National Committee on Health Research Ethics: H-15010949. Informed consent is not required for registry-based studies according to Danish legislation.
Contributors RHJ designed and planned the study, contributed to collection of data and was the primary investigator in analysis of data, data interpretation and reporting. PS, JE and J-USJ designed and planned the study, contributed to data collection, were involved in the data interpretation and in the drafting, critical revision, and approval of the manuscript. J-USJ was also responsible for data analysis. CKH, JBB, RBD and CO contributed to collection of data, data interpretation and in the drafting, critical revision, and approval of the manuscript. CKH also contributed to data analysis. The corresponding author, J-USJ, attested that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted. The corresponding author is the guarantor and affirms that the manuscript is an honest, accurate and transparent account of the study being reported and that no important aspects of the study have been omitted.
Funding The study was financed by grants from the Novo Nordisk Foundation (No. NNF20OC0060657).
Disclaimer The funding sources had no influence on study design, data collection, analysis, or reporting of data.
Competing interests RBD reports having received payment for expert testimony. Remaining authors have no conflicts of interest.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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; Christian Kjer Heerfordt 1
; Boel, Jonas Bredtoft 2 ; Dessau, Ram Benny 3
; Ostergaard, Christian 4 ; Sivapalan, Pradeesh 1 ; Eklöf, Josefin 1 ; Jensen, Jens-Ulrik Stæhr 1 1 Section of Respiratory Medicine, Department of Medicine, Herlev-Gentofte Hospital, University of Copenhagen, Gentofte, Denmark
2 Department of Clinical Microbiology, Herlev-Gentofte Hospital, Herlev, Denmark
3 Department of Clinical Microbiology, Zealand University Hospital, University of Copenhagen, Slagelse, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
4 Department of Clinical Microbiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark