The Effect of Inhaled Corticosteroids on Pneumonia Risk in Patients With COPD-Bronchiectasis Overlap

Abstract

BackgroundInhaled corticosteroids (ICS) increase the risk of pneumonia in COPD and commonly are used in patients with COPD-bronchiectasis overlap.Research QuestionIs the risk of pneumonia associated with ICS further heightened in COPD-bronchiectasis?Study Design and MethodsElectronic health care records (from 2004-2019) were used to obtain a cohort of patients with COPD and a nested case-control group (age and sex matched 1:4). Analyses were conducted to determine the risk of hospitalization for pneumonia in COPD associated with ICS use in those with bronchiectasis. Findings were confirmed by several sensitivity analyses. Additionally, a smaller nested case-control group containing only patients with COPD-bronchiectasis overlap and those with recent blood eosinophil counts (BECs) was used to determine any association with BEC.ResultsThree hundred sixteen thousand six hundred sixty-three patients were eligible for the COPD cohort; bronchiectasis significantly increased the risk of pneumonia (adjusted hazard ratio, 1.24; 95% CI, 1.15-1.33). In the first nested case-control group of 84,316 patients with COPD, ICS was found to increase the odds of pneumonia (adjusted OR [AOR], 1.26; 95% CI, 1.19-1.32) only if used in the previous 180 days. However, bronchiectasis was a significant modifier such that ICS use did not augment further the already elevated bronchiectasis-associated pneumonia risk (COPD-bronchiectasis: AOR, 1.01; 95% CI, 0.8-1.28; no bronchiectasis: AOR, 1.27; 95% CI, 1.20-1.34). Several sensitivity analyses and a second smaller nested case-control group confirmed these findings. Finally, we found that BEC modified the ICS-associated pneumonia risk in COPD-bronchiectasis overlap, where lower BEC was associated significantly with pneumonia (BEC ≤ 3 × 109/L: AOR, 1.56; 95% CI, 1.05-2.31; BEC > 3 × 109/L: AOR, 0.89; 95% CI, 0.53-1.24).InterpretationICS use does not augment further the already increased risk of hospitalization for pneumonia associated with concomitant bronchiectasis in patients with COPD. Inhaled corticosteroids (ICS) increase the risk of pneumonia in COPD and commonly are used in patients with COPD-bronchiectasis overlap. Is the risk of pneumonia associated with ICS further heightened in COPD-bronchiectasis? Electronic health care records (from 2004-2019) were used to obtain a cohort of patients with COPD and a nested case-control group (age and sex matched 1:4). Analyses were conducted to determine the risk of hospitalization for pneumonia in COPD associated with ICS use in those with bronchiectasis. Findings were confirmed by several sensitivity analyses. Additionally, a smaller nested case-control group containing only patients with COPD-bronchiectasis overlap and those with recent blood eosinophil counts (BECs) was used to determine any association with BEC. Three hundred sixteen thousand six hundred sixty-three patients were eligible for the COPD cohort; bronchiectasis significantly increased the risk of pneumonia (adjusted hazard ratio, 1.24; 95% CI, 1.15-1.33). In the first nested case-control group of 84,316 patients with COPD, ICS was found to increase the odds of pneumonia (adjusted OR [AOR], 1.26; 95% CI, 1.19-1.32) only if used in the previous 180 days. However, bronchiectasis was a significant modifier such that ICS use did not augment further the already elevated bronchiectasis-associated pneumonia risk (COPD-bronchiectasis: AOR, 1.01; 95% CI, 0.8-1.28; no bronchiectasis: AOR, 1.27; 95% CI, 1.20-1.34). Several sensitivity analyses and a second smaller nested case-control group confirmed these findings. Finally, we found that BEC modified the ICS-associated pneumonia risk in COPD-bronchiectasis overlap, where lower BEC was associated significantly with pneumonia (BEC ≤ 3 × 109/L: AOR, 1.56; 95% CI, 1.05-2.31; BEC > 3 × 109/L: AOR, 0.89; 95% CI, 0.53-1.24). ICS use does not augment further the already increased risk of hospitalization for pneumonia associated with concomitant bronchiectasis in patients with COPD. FOR EDITORIAL COMMENT, SEE PAGE 809Take-home PointsStudy Question: Is the use of inhaled corticosteroids (ICS) associated with an enhanced risk of pneumonia in people with COPD-bronchiectasis overlap as compared with those with COPD alone?Results: ICS did not augment the already elevated pneumonia risk in those with COPD-bronchiectasis overlap, but this seemed to be found only in those with an elevated eosinophil count.Interpretation: An elevated blood eosinophil count seems to protect patients with COPD from any additional ICS-associated increased pneumonia risk that might be expected with concomitant bronchiectasis. FOR EDITORIAL COMMENT, SEE PAGE 809 Study Question: Is the use of inhaled corticosteroids (ICS) associated with an enhanced risk of pneumonia in people with COPD-bronchiectasis overlap as compared with those with COPD alone? Results: ICS did not augment the already elevated pneumonia risk in those with COPD-bronchiectasis overlap, but this seemed to be found only in those with an elevated eosinophil count. Interpretation: An elevated blood eosinophil count seems to protect patients with COPD from any additional ICS-associated increased pneumonia risk that might be expected with concomitant bronchiectasis. Inhaled corticosteroids (ICS) are prescribed commonly for COPD and currently are recommended to reduce the risk of exacerbations in those with severe COPD.1Hurst J.R. Vestbo J. Anzueto A. et al.Susceptibility to exacerbation in chronic obstructive pulmonary disease.N Engl J Med. 2010; 363: 1128-1138Crossref PubMed Scopus (2212) Google Scholar, 2Halpin D. Celli B. Criner G. et al.The GOLD Summit on chronic obstructive pulmonary disease in low-and middle-income countries.Int J Tuberc Lung Dis. 2019; 23: 1131-1141Crossref PubMed Scopus (79) Google Scholar, 3Bloom C.I. Elkin S.L. Quint J.K. Changes in COPD inhaler prescriptions in the United Kingdom, 2000 to 2016.Int J Chron Obstruct Pulmon Dis. 2019; 14: 279-287Crossref PubMed Scopus (27) Google Scholar Their usefulness is debated because they have little impact on lung function; are not effective in all patients4Bafadhel M. Peterson S. De Blas M.A. et al.Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials.Lancet Respir Med. 2018; 6: 117-126Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar,5Magnussen H. Disse B. Rodriguez-Roisin R. et al.Withdrawal of inhaled glucocorticoids and exacerbations of COPD.N Engl J Med. 2014; 371: 1285-1294Crossref PubMed Scopus (517) Google Scholar; and increase the risk of pneumonia, Pseudomonas outgrowth, and mycobacterial infections.6Kew K.M. Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2014; 2014: CD010115PubMed Google Scholar, 7Brassard P. Suissa S. Kezouh A. et al.Inhaled corticosteroids and risk of tuberculosis in patients with respiratory diseases.Am J Respir Crit Care Med. 2011; 183: 675-678Crossref PubMed Scopus (101) Google Scholar, 8Andréjak C. Nielsen R. Thomsen V.Ø. et al.Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.Thorax. 2013; 68: 256-262Crossref PubMed Scopus (260) Google Scholar, 9Eklöf J. Ingebrigtsen T.S. Sørensen R. et al.Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease.Thorax. 2022; 77: 573-580Crossref PubMed Scopus (20) Google Scholar ICS prescribing also is cautioned in those with COPD-bronchiectasis overlap.10Dente F.L. Roggi M.A. Del Cesta R. et al.COPD and asthma overlap with bronchiectasis.Eur Respir Monograph. 2018; 81: 167-185Google Scholar Underdiagnosis of bronchiectasis is common, but reports estimate that the burden of bronchiectasis varies from 4% of the 2,164 patients with COPD in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort11Agusti A. Calverley P.M. Celli B. et al.Characterisation of COPD heterogeneity in the ECLIPSE cohort.Respir Res. 2010; 11: 122Crossref PubMed Scopus (909) Google Scholar to 58% in a smaller cohort of 92 patients with COPD.12Martínez-García M. Soler-Cataluña J.J. Donat Sanz Y. et al.Factors associated with bronchiectasis in patients with COPD.Chest. 2011; 140: 1130-1137Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar COPD-bronchiectasis overlap is associated with more severe COPD,10Dente F.L. Roggi M.A. Del Cesta R. et al.COPD and asthma overlap with bronchiectasis.Eur Respir Monograph. 2018; 81: 167-185Google Scholar a higher risk of community-acquired pneumonia (CAP),13Lin S.H. Ji B.C. Shih Y.M. et al.Comorbid pulmonary disease and risk of community-acquired pneumonia in COPD patients.Int J Tuberc Lung Dis. 2013; 17: 1638-1644Crossref PubMed Scopus (22) Google Scholar prolonged hospitalization for COPD exacerbations,14Patel I.S. Vlahos I. Wilkinson T.M. et al.Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2004; 170: 400-407Crossref PubMed Scopus (358) Google Scholar and higher mortality.15Goeminne P.C. Nawrot T.S. Ruttens D. et al.Mortality in non-cystic fibrosis bronchiectasis: a prospective cohort analysis.Respir Med. 2014; 108: 287-296Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar The characteristic dysregulated immunity and impaired airway clearance results in mucus accumulation and increased susceptibility to acute and persistent lung infections. Therefore, it may be anticipated that ICS further dampens host-defense mechanisms, leading to an even greater risk of pneumonia. No studies of a COPD-bronchiectasis overlap cohort have compared ICS use directly with no ICS use, nor have they addressed this question using real-world data, which typically have the advantages of larger sample size and a wealth of prescribing data. Interestingly, a US study of patients with primary bronchiectasis used Medicare data to compare the effect of macrolide therapy with that of ICS. The study investigated respiratory infection in general and found that patients using ICS—as compared with those using macrolide antibiotics—were at an increased risk of all respiratory infections requiring hospitalization, including respiratory viral infections, bacterial infections, and bronchiectasis exacerbations.16Henkle E. Curtis J.R. Chen L. et al.Comparative risks of chronic inhaled corticosteroids and macrolides for bronchiectasis.Eur Respir J. 2019; 54: 1801896Crossref PubMed Scopus (30) Google Scholar However, because the effect of ICS was in comparison with the effect of only the antibiotic, it is difficult to extrapolate conclusions regarding ICS-associated risks directly from that study. Furthermore, the study population was patients with primary bronchiectasis, but patients with COPD-bronchiectasis overlap may demonstrate a different ICS-associated infection risk profile. Martinez-Garcia et al,17Martinez-Garcia M.A. Faner R. Oscullo G. et al.Inhaled steroids, circulating eosinophils, chronic airway infection, and pneumonia risk in chronic obstructive pulmonary disease. A network analysis.Am J Respir Crit Care Med. 2020; 201: 1078-1085Crossref PubMed Scopus (0) Google Scholar in a study of 201 selected patients with COPD, of whom just more than one-half had bronchiectasis, found ICS use and bronchiectasis both to be independent risk factors for pneumonia; however, they did not assess the interaction of the two risk factors. The latest European Respiratory Society adult bronchiectasis guidelines acknowledged this paucity of evidence in COPD-bronchiectasis overlap and conclude that “in the absence of definitive data, the presence of bronchiectasis should not lead to a decision to withdraw ICS from patients with established COPD.”18Polverino E. Goeminne P.C. McDonnell M.J. et al.European Respiratory Society guidelines for the management of adult bronchiectasis.Eur Respir J. 2017; 501700629Crossref Scopus (704) Google Scholar Herein, we conducted a study that leveraged a nationwide data source enriched with prescription data to investigate if ICS use—compared with no ICS use—further augments the risk of hospitalization for pneumonia in those with an already elevated pneumonia risk because of the presence of COPD-bronchiectasis overlap. The Clinical Practice Research Datalink Aurum is a database of pseudoanonymized UK primary care electronic health care records that includes approximately 20% of the UK population and has been shown to be nationally representative.19Herrett E. Gallagher A.M. Bhaskaran K. et al.Data resource profile: Clinical Practice Research Datalink (CPRD).Int J Epidemiol. 2015; 44: 827-836Crossref PubMed Scopus (1702) Google Scholar This represents one of the largest, extensively validated longitudinal health care databases worldwide.20Wolf A. Dedman D. Campbell J. et al.Data resource profile: Clinical Practice Research Datalink (CPRD) Aurum.Int J Epidemiol. 2019; 48 (1740-1740g)Crossref Scopus (254) Google Scholar Clinical Practice Research Datalink data were linked individually to Hospital Episode Statistics data (hospital admissions for England), socioeconomic data (Index of Multiple Deprivation; see Covariates section) and Office of National Statistics mortality data. We identified patients with COPD using validated Read codes.21Quint J.K. H. et of chronic obstructive pulmonary disease in the Clinical Practice Research Datalink 2014; Scopus Google Scholar cohort on the latest of the COPD 2004; the general were on the of of general with fibrosis were an ICS patients were prescribed ICS cohort were A because it of of and nested case-control were from the case-control group all patients with COPD and matched a sensitivity a smaller nested case-control group was including only patients and had COPD-bronchiectasis overlap and a recent blood eosinophil count of the of case-control patients from the cohort and those by the reduce the of patients as compared with the cohort from which the case-control group was with identified using of and were We the of the for pneumonia as the was matched on the using matched on of and sex from the of were matched to were not patients were matched to three We all ICS prescription records in the the ICS use was as a no the recent prescription ≤ and > 180 of ICS and of ICS in the cohort were at in the nested case-control group were on the was using A of bronchiectasis cohort but have been COPD as as lower respiratory infections, disease, disease, chronic disease, lung and lung disease was using Read by two I. R. and C. I. at the of the cohort the cohort and were at the the nested case-control The of Multiple is the of in the United and is on and records were used to and the of COPD were Research COPD exacerbation requiring hospitalization, and the of of corticosteroids to acute COPD exacerbations in the cohort using the the were using the of × as D. A. et and chronic obstructive pulmonary disease: a GOLD J Respir Crit Care Med. 2022; PubMed Scopus Google Scholar use was as any prescription used for lower respiratory infections and and The analysis was the association ICS use and pneumonia requiring hospitalization and any by bronchiectasis case-control However, we first the risk of pneumonia requiring hospitalization associated with bronchiectasis for the this cohort we for to first pneumonia requiring hospitalization using as the the of were by the and for the analyses of nested case-control and was used to determine effect were for use and of Multiple COPD for Lung Research and of exacerbations requiring and and disease, and using analyses were conducted in nested case-control group for bronchiectasis and in nested case-control group for were used to for and were Several sensitivity analyses were conducted in nested case-control group patients with use in the were if the association ICS and requiring hospitalization no was was this the association was by a interaction analysis was conducted using a different chronic respiratory M. E. a for and in 2010; PubMed Scopus Google Scholar This was a because is not anticipated to the association ICS use and requiring if also modified the this in the interaction patients with prescribed requiring hospitalization were because it be use may any by bronchiectasis. analyses were conducted using The for this was by the for Database Research management was by the and at the of The COPD cohort and are shown in The was and were of the patients were using ICS at the of cohort and had bronchiectasis The COPD cohort a increased risk of requiring hospitalization associated with concomitant bronchiectasis (adjusted hazard ratio, 1.24; 95% CI, the COPD patients were eligible for the ICS cohort from which the two nested case-control were The first nested case-control group patients and matched The second group was from only those with COPD-bronchiectasis overlap and a recent this group patients and matched in nested case-control group a of and were in nested case-control group a of and were and and but patients a higher with greater socioeconomic more severe COPD and previous however, patients in nested group also in of and higher eosinophil Clinical and of use ICS ICS ICS of COPD exacerbations requiring Lung lung are as community-acquired pneumonia; ICS inhaled of Multiple Deprivation; lower respiratory Research in a are as community-acquired pneumonia; ICS inhaled of Multiple Deprivation; lower respiratory Research A increased odds of requiring hospitalization was associated with using ICS (adjusted OR [AOR], 1.26; 95% CI, 1.19-1.32) ICS use the but the association was no significant by 180 ICS use AOR, 1.27; 95% CI, AOR, 95% CI, AOR, 95% CI, AOR, 95% CI, The of ICS prescriptions in the the did not the of the association the effect of different ICS we found an increased odds with 95% CI, and 95% CI, but not with budesonide 95% CI, and ICS of ICS and of ICS in use in of ICS in of ICS used in for socioeconomic (Index of Multiple Research use of pneumonia, of lower respiratory infections, exacerbations in the of corticosteroids in the bronchiectasis, lung lung disease, pneumonia and ICS inhaled in a for socioeconomic (Index of Multiple Research use of pneumonia, of lower respiratory infections, exacerbations in the of corticosteroids in the bronchiectasis, lung lung disease, pneumonia and ICS inhaled In nested case-control group concomitant bronchiectasis was found to be a significant modifier of the association ICS and requiring hospitalization In patients with COPD-bronchiectasis overlap, ICS was not associated significantly with pneumonia 1.01; 95% CI, in COPD bronchiectasis 1.27; 95% CI, 1.20-1.34). In the was not found to be an effect that significant in the was > sensitivity analyses were patients with use in the previous had a impact on the effect the of recent use, use was in all those with bronchiectasis: of bronchiectasis patients had been prescribed in the the use of macrolides in only of patients patients with prescription in the the had a impact on the effect a further sensitivity nested case-control group only patients with COPD-bronchiectasis was ICS use was not associated with requiring hospitalization in those with COPD-bronchiectasis overlap 95% CI, case-control group also was used to investigate any effect from BEC. An interaction analysis found were a significant modifier of the association ICS use and requiring hospitalization BEC × was not associated with requiring hospitalization 0.89; 95% CI, but a eosinophil count × was associated with requiring hospitalization 1.56; 95% CI, In this we identified a cohort of > patients with COPD and investigated the association of ICS use and pneumonia requiring hospitalization in those with concomitant bronchiectasis. a cohort we that concomitant bronchiectasis was associated with a increased risk of requiring hospitalization, from one study in US data and P. P. et al.Inhaled use in chronic obstructive pulmonary disease and the risk of hospitalization for J Respir Crit Care Med. PubMed Scopus (358) Google Scholar, C. Calverley P. J. et risk in COPD patients inhaled corticosteroids in study Respir J. PubMed Scopus Google Scholar, C. K. et and pneumonia mortality in patients with COPD with of inhaled and matched cohort study 2013; PubMed Scopus Google Scholar we used a nested case-control to determine that ICS use was associated with increased odds of requiring hospitalization and that this in a Finally, by using an interaction we were to determine that in people with COPD-bronchiectasis overlap, ICS use did not augment further the already elevated bronchiectasis-associated pneumonia were for including COPD and Furthermore, to if additional was we conducted a The was chronic respiratory that not be expected to the association ICS use and pneumonia. Therefore, if was found also to the this that the case-control was however, did not the sensitivity analysis was to a second nested case-control but this containing only those with COPD-bronchiectasis overlap, in a smaller sample we found the that ICS use did not further increase the already elevated pneumonia sensitivity analyses including patients with prescriptions use, also did not the effect data an ICS association with that is on the ICS use, but no association with the of ICS that pneumonia risk to the of ICS use, than the effect of ICS of the and A. L. et al.Inhaled of and bacterial infection in chronic obstructive pulmonary Med. 2019; PubMed Scopus Google P. on Respir J. PubMed Scopus Google Scholar which may increase bacterial and the in the M. A. et of inhaled corticosteroids on bacterial and viral in Respir J. 2017; PubMed Scopus Google Scholar The odds of pneumonia were increased with and with but were not increased with which the with a lower and more pulmonary leading to a effect because of a more the M. G. H. and of inhaled Full Text Full Text PDF PubMed Scopus Google Scholar in the study by Suissa et S. et al.Inhaled corticosteroids in COPD and the risk of 2013; 68: PubMed Scopus Google Scholar with bronchiectasis may for respiratory infections than those bronchiectasis. Additionally, they may E. Goeminne P.C. McDonnell M.J. et al.European Respiratory Society guidelines for the management of adult bronchiectasis.Eur Respir J. 2017; 501700629Crossref Scopus (704) Google Scholar use of have the risk of ICS-associated pneumonia in those with bronchiectasis. in those with bronchiectasis were more to but the use of macrolides was in this primary care Furthermore, patients prescribed had on the effect are the airway in bronchiectasis, but the of was the inflammation 2022; PubMed Scopus Google Scholar In a analysis of bronchiectasis data from inhaled bronchiectasis exacerbations in those with BEC of S. G. et inhaled response in bronchiectasis.Eur Respir J. 2020; PubMed Scopus Google Scholar A European cohort of patients with bronchiectasis that approximately of patients eosinophil counts of > A. M. et of bronchiectasis: a European J Respir Crit Care Med. 2022; PubMed Google Scholar that elevated were an effective of eosinophils, and these were associated with that in bronchiectasis, inflammation and are In in COPD, a of inflammation is associated with chronic bacterial Martinez-Garcia et M.A. Faner R. Oscullo G. et al.Inhaled steroids, circulating eosinophils, chronic airway infection, and pneumonia risk in chronic obstructive pulmonary disease. A network analysis.Am J Respir Crit Care Med. 2020; 201: 1078-1085Crossref PubMed Scopus (0) Google Scholar in a study of 201 patients with COPD also had that those with had an increased of bacterial and pneumonia and that ICS use further increased the A analysis of of in patients with COPD found that the risk of pneumonia was higher in patients with a BEC of S. Anzueto A. et eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a Respir Med. Full Text Full Text PDF PubMed Scopus Google Scholar Additionally, using real-world data, patients with COPD using with a BEC of a higher risk of M. E. et to inhaled therapy in a primary care COPD Res. 2022; PubMed Scopus Google Scholar the of the for Lung a that that are associated with an increased risk of bacterial infections and pneumonia in COPD and that these risks are increased by ICS D. A. et and chronic obstructive pulmonary disease: a GOLD J Respir Crit Care Med. 2022; PubMed Scopus Google Scholar Therefore, study these studies that BEC is associated with higher pneumonia using a different and is the first study to study this directly in a population with COPD-bronchiectasis overlap. Furthermore, a recent from a bronchiectasis found that ICS use the risk of a bronchiectasis exacerbation only in those with elevated BEC of > M.A. R. et al.The eosinophil count and bronchiectasis the effect of inhaled Full Text Full Text PDF PubMed Scopus Google Scholar these that ICS may be with risk of pneumonia in patients with elevated BEC and COPD-bronchiectasis overlap, in with the recent in the European Respiratory Society adult bronchiectasis However, from ICS use should be This study has several as with all database we did not have on to the ICS This may have effect the of bronchiectasis a resource that to in this a in bronchiectasis A. Calverley P.M. Celli B. et al.Characterisation of COPD heterogeneity in the ECLIPSE cohort.Respir Res. 2010; 11: 122Crossref PubMed Scopus (909) Google M. Soler-Cataluña J.J. Donat Sanz Y. et al.Factors associated with bronchiectasis in patients with COPD.Chest. 2011; 140: 1130-1137Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar In the increase of did not use in the case-control may that several of these patients in had primary bronchiectasis with but were as COPD, which impact on the effect of ICS. we did not have to data data on of bronchiectasis for we did not have on pneumonia risk use is not and at risk of in care that may we only for increase in pneumonia requiring hospitalization and did not assess requiring hospitalization, which of the in COPD as K.M. Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2014; 2014: CD010115PubMed Google Scholar Finally, and we have to and we have not because of the of the study. is that ICS use and concomitant bronchiectasis increase the risk of pneumonia requiring hospitalization, no further from ICS use in patients with COPD-bronchiectasis overlap. Additionally, in smaller cohort of only those with COPD-bronchiectasis overlap, we found that an elevated BEC seems to protect patients from the ICS-associated increased pneumonia found in previous with COPD. by the National for Research Research

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