Chronic obstructive pulmonary disease (COPD) is the most prevalent chronic respiratory disease that leads to a significant burden on health.1 In 2017, COPD was the seventh leading cause of global disability.2 In 2019, COPD caused 3.23 million deaths globally, making it the third leading cause of death.3 In Australia, COPD was one of the top 5 leading causes of death; there were 7113 deaths due to COPD in 2018, and COPD was the third leading cause of overall disease burden in Australia in 2015.4,5 Moreover, COPD is associated with multimorbidity including osteoporosis, diabetes, hypertension, cardiovascular disease, depression, and lung cancer.1,6–8

Because of the significant worldwide burden of COPD, the Global initiative for chronic Obstructive Lung Disease (GOLD) has created evidence-based guidelines that are updated annually.1 According to the self-reported data from the 2017–18 Australian Bureau of Statistics (ABS) National Health Survey (NHS), approximately 4.8% of Australians aged 45 years and over have COPD.9 The weighted prevalence of COPD in Australians, based on the ratio of post-bronchodilator forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.7, was estimated to be 8.3% in adults aged 40+ years, and 19.8% in adults aged 75+ years.10 Although COPD is relevant in Australia and associated with a significant health burden, previous Australian studies have not reported indirect burdens such as lost time off work or social activities and healthcare utilization in community-living patients with a diagnosis of COPD based on GOLD spirometric criteria. Indeed, core Australian data on COPD from the Australian Institute of Health and Welfare (AIHW) come from surveys in which people with COPD are identified only by self-reporting a diagnosis of COPD, emphysema or chronic bronchitis, without lung function testing.4

COPD is a highly symptomatic disease that requires symptom-based treatments.1 The physical and emotional symptoms of COPD are known to have a negative impact on the quality of life in patients.11 Because COPD is irreversible and progressive, quality of life is a useful tool for assessing COPD severity and treatment outcomes.

The Burden of Obstructive Lung Disease (BOLD) Australia study collected measures of lung function by spirometry and self-reported outcomes by questionnaires including indirect burdens (defined as lost time off work or social activities and healthcare utilization), respiratory symptoms, comorbidities, and quality of life.12 Although the GOLD 2023 report1 has proposed an assessment tool based on symptoms and exacerbation history, the BOLD Australia database did not have complete information on the ABE assessment tool, especially the exacerbation history and the Australian and New Zealand guidelines for the management of COPD (COPD-X)13 has not yet adopted the ABE classification. BOLD Australia could still provide an opportunity to more thoroughly understand the impacts of different GOLD grades of airflow limitation in Australians aged ≥40 years.

Our study aimed to investigate the relationship between health burden and different GOLD grades of severity of airflow limitation in Australian adults aged ≥40 years.



We used data from the BOLD Australia study, which is the largest geographically diverse population-based study of spirometrically confirmed COPD in Australia. It was a cross-sectional study conducted between 2006 and 2012 of individuals aged ≥40 years from six study sites across Australia, including Sydney, rural New South Wales, Melbourne, Tasmania (Hobart and Launceston) and Busselton and Broome in Western Australia.12 In Western Australia, participants were recruited from a household census data in Broome and local aboriginal communities within the Kimberley region or were randomly recruited from the Busselton Health Study. The study design and detailed information for the sample selection were published previously.12,14 Participants who were not contactable, institutionalized, or aged younger than 40 years were excluded. Participants in the BOLD Australia study who were missing spirometry test results were excluded from these analyses. Data for all six Australian sites are included in this analysis; some results from the Sydney site have been published previously in an analysis of data from 17 BOLD countries.15

Description of Variables

All participants completed the BOLD core questionnaire that included details of demographics, smoking status, occupational exposures, respiratory medication use, and respiratory symptoms (Supplementary Information S1).12,16 Socioeconomic status was reported by using quintiles of Socio-Economic Indexes for Areas (SEIFA), with SEIFA 1 being the “most disadvantaged” and SEIFA 5 being the “least disadvantaged” area.17 Occupational exposures were reported as having worked in a dusty job for at least 1 year.

Respiratory symptoms included cough, phlegm, wheeze, and breathlessness. Activity limitation due to breathlessness was measured by the modified Medical Research Council (mMRC) dyspnoea scale.18 We defined “linically important breathlessness” as mMRC dyspnoea grade ≥2. Specific comorbidities reported were asthma, heart disease, hypertension, diabetes, lung cancer, and stroke. The disease-related indirect burdens reported were lost time off work or social activities, and healthcare utilization. Healthcare utilization included visits to a general practitioner (GP) and hospitalizations in the last 12 months, due to breathing problems.

Quality of life was reported as domain scores of the Short-Form (SF)-12 questionnaire.19 The BOLD Australia survey did not collect the answer to all SF-12 questions for Indigenous participants, those participants only answered the first question in the SF-12 questionnaire (“In general, would you say your health is ….”). Thus, we use the result of the first question (SF-1) in the SF-12 to define self-reported general health status. We defined participants who reported excellent, very good, and good as good or above general health. Since there were no Australian norms available, the physical and mental component summary scores (PCS, MCS) of SF-12 were computed using US norms.19

Spirometry was measured according to the American Thoracic Society/European Respiratory Society standards, using the EasyOne spirometer (ndd Medizintechnik, Zürich, Switzerland).12,16 All spirograms were reviewed and quality graded by a senior respiratory scientist.12 The highest recorded post-bronchodilator forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from acceptable trials20 were collected. Spirometry predicted values were calculated using the Global Lung Function Initiative (GLI) reference equations.21 Caucasian predicted values were used. The severity of airflow limitation was graded using the GOLD criterion for COPD (post-bronchodilator FEV1/FVC ratio <0.70): mild, GOLD 1, FEV1 ≥ 80% predicted; moderate, GOLD 2, 50% ≤ FEV1 < 80% predicted; severe or very severe, GOLD 3 or 4, FEV1 < 50% predicted.1

Statistical Analysis

All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). The study population was grouped according to GOLD spirometry grades (No airflow limitation, GOLD 1, GOLD 2, and GOLD 3–4). Data are presented as numbers with proportions for categorical variables and means ± standard deviations (SD) or median with interquartile range [IQR] for continuous variables. The differences between groups were assessed using χ2 tests for categorical variables, analysis of variance for continuous variables that followed normal distributions, and Wilcoxon rank-sum tests for continuous variables that did not follow normal distributions. A p-value <0.05 was considered statistically significant.

A multivariate logistic regression model was used to analyze general health by the severity of airflow limitation, and multiple linear regression was used in the multiple variable analyses with PCS and MCS. In this analysis, the selection of potential confounders for adjustment was based on a causal inference approach, using Directed Acyclic Graphs (DAGs). As shown in Figures S1S3, these identified age, sex, body mass index (BMI) status, smoking status, socioeconomic status, heart disease, hypertension, and diabetes as potential confounders, because they may open a back-door pathway association between exposure and outcome, therefore, should be adjusted for in the analyses.22


From among 10760 eligible participants in the BOLD Australia study,12 3518 (32.7%) participants with acceptable pre- and post-bronchodilator spirometry results were included in the present analysis. Using minimal information data collected from those who chose not to participate, we found that the sample included in this analysis was younger and more likely to have self-reported diagnosed respiratory disease. Among all participants, 2969 (84.4%) did not have airflow limitation, 294 (8.4%) were classified as GOLD stage 1, 212 (6.0%) GOLD 2 and 43 (1.2%) GOLD 3 or 4.

Table 1 describes the demographic characteristics of all participants. The characteristics of age, gender, ethnicity, smoking status, BMI status, highest education, and experience of working in a dusty job were significantly different among the four groups. However, there were no significant differences in socioeconomic status among the four groups.

Table 1 Demographic Characteristics of the BOLD Australia Sample, by GOLD Spirometric Grades

From the no airflow limitation group to the GOLD 3 or 4 group, the proportions having any of the self-reported respiratory symptoms were increased, and there were significant differences across the four groups (Table 2). Almost three quarters (72.1%) of the GOLD 3 or 4 group reported using respiratory medications, compared with 41.5% of those with GOLD 2 and 20.4% of GOLD 1. The proportions of having current asthma, hypertension, diabetes, lung cancer, stroke, and having 2 or more comorbidities were reported most frequently in the GOLD 3 or 4 group, followed by GOLD 2, GOLD 1, and no airflow limitation groups (Table 2). Only the GOLD 2 group reported a higher proportion of having heart disease compared to the GOLD 3 or 4 group.

Table 2 Respiratory Symptoms Respiratory Medication Use and Comorbidities of the BOLD Australia Sample, by GOLD Spirometric Grades

Participants with GOLD 3 or 4 reported the highest proportions of lost time off work or lost time for social activities (25.6%), and healthcare utilization (25.8% for GP visits and 5.9% for hospitalizations), followed by GOLD 2, GOLD 1, and no airflow limitation groups (Table 3). However, although the proportion of healthcare utilization varied across groups, among those who had reported any healthcare utilization, there were no significant differences in the median number of GP visits or median number of hospitalizations across the four groups.

Table 3 Lost Time from Work/Social Activities and Hospital/GP Visits of the BOLD Australia Sample, by GOLD Spirometric Grades

Quality of life among the four groups is compared in Table 4. Regarding general health, the no airflow limitation group reported the highest proportion of excellent general health and the lowest proportion of poor general health, while the GOLD 3 or 4 group reported the lowest proportion of excellent and highest proportion of poor health. The proportion of self-reported good or above general health decreased as airflow limitation became worse across the groups. The PCS and MCS also decreased from the no airflow limitation group to the GOLD 3 or 4 group.

Table 4 Quality of Life (SF-12) of the BOLD Australia Sample, by GOLD Spirometric Grades


To our knowledge, this is the first Australian study to evaluate the relationship between respiratory symptoms, comorbidities, indirect health burdens, quality of life, and GOLD spirometry grades in a general population sample including healthy subjects and subjects with COPD. We found, in adults aged ≥40 years, that presence of respiratory symptoms and respiratory medication use was associated with worse airflow limitation. The likelihood of multimorbidity and disease-related indirect burden (lost time off work or social activities and healthcare utilization) also increased with worsening/increasing airflow limitation. Additionally, the quality of life evaluated by SF-12, including general health SF-1, MCS, and PCS, deteriorated as the GOLD spirometry grade severity worsened. However, the mental component scale (MCS) did not deteriorate as much as the GOLD spirometry grade severity worsened.

We found that the proportions of people having any respiratory symptoms and using respiratory medications were progressively higher from the no airflow limitation group to the GOLD 3 or 4 group. However, we found that large proportions of participants in the GOLD 2 and GOLD 3 or 4 group (post-bronchodilator FEV1 < 80% predicted) did not receive any respiratory medication treatment in the past 12 months. The reason for these COPD patients not receiving respiratory medication may be misdiagnosis or underdiagnosis, as reported in the BOLD Australia study,23 and as also observed internationally.24,25 These findings help confirm the importance of spirometry in the diagnosis of COPD in real-life clinical practice, especially in primary care.

A previous global BOLD paper reported that participants with airflow limitation (GOLD 1 to 4) were more likely to suffer from heart disease, hypertension, and stroke than those without COPD, and only having diabetes had a weak association between participants with and without COPD, consistent with our findings.15 Previous studies found that patients with both asthma and COPD had worse lung function,26 we also found that the proportion having current asthma was increased from participants without airflow limitation to GOLD 3 or 4.

Previous studies found that adults with COPD had more work absences than the general population.27 We also showed a trend toward increased time lost from work or daily activities with higher GOLD spirometry grades. We observed that the proportion of healthcare utilization increased across grades of airflow limitation, as observed previously.28 However, for participants who visited GPs or hospitalizations in 12 months, the number of GP visits and hospitalizations was not significantly different across the four groups. These results may be attributed to the small number of participants in the GOLD 2 and GOLD 3 or 4 group.

We found that general health was independently associated with the severity of GOLD spirometry grades. The proportion of participants reporting good or above general health status significantly decreased from participants without airflow limitation to participants with GOLD 3 or 4. Previous studies also reported that COPD is related to poorer health status.15 We also observed that the negative impact on quality of life increased with increasing severity of GOLD spirometry grades, which has also been reported previously.15,28 The impact of COPD was greater on the physical than the mental aspects of quality of life, which was similar to previous studies.15,29

The main strengths of this study included the data from a large nationwide population sample, the use of standardized methods of data collection, together with a high level of quality control, increasing the internal validity of the analyses.12,16 The study protocol and core questionnaire were harmonized with the BOLD international protocol, allowing for comparisons between countries.30

However, our study also had several limitations. The cross-sectional design did not allow for the assessment of causality or long-term outcomes. The low overall response rate may introduce the possibility of selection bias, with participants included in this analysis being slightly younger and more likely to self-report a diagnosis of respiratory disease compared with those who provided only minimal data.12 The GOLD 2023 report introduced an ABE assessment tool to assess the severity of COPD, but the BOLD Australia dataset did not include complete information about exacerbations required by the GOLD ABE assessment tool. Thus, we used the GOLD spirometry grades to assess the severity of COPD in our analysis. BOLD Australia also did not collect data on depression, which has been confirmed to be associated with worse health status in patients with COPD.31

Another limitation was that the information on comorbidities in BOLD Australia was collected from the self-reported questionnaire, which could introduce recall bias. The BOLD Australia data did not include the answer to all SF-12 questions for Indigenous participants, so we could not calculate the MCS and PCS of those participants. Participants were not a completely random sample of the Australian population as the six study sites themselves were not randomly selected. Another limitation is that the BOLD Australia study was conducted between 2006 and 2012, the study data is old and could not provide recent information. However, post-hoc weights were used in previous work to adjust prevalence estimates to reflect the Australian population better; in this analysis sample prevalence estimates were used.12 Finally, the single spirometry measurement was also a limitation as spirometry results can vary between days, resulting in differences in diagnostic criteria.32

Nonetheless, our findings have significant implications for the development of COPD management strategies. These findings confirm the value of the GOLD grades of airflow limitation for providing insight into the impact and burden of COPD. Therefore, the GOLD grades of airflow limitation remain important to health professionals in clinical practice. Further research should include information on the exacerbation history, which may provide a more comprehensive indication of the impact of different severities of COPD. Further research is also needed to improve prevention and treatment strategies for airflow limitation, which may help to reduce future long-term risks. Patients with COPD may benefit from improved interventions in the future.


This study comprehensively characterized respiratory symptoms, disease-related indirect burdens, and quality of life in Australian adults aged 40 years and over, according to GOLD spirometry grade. Adults with greater severity of airflow limitation, as indicated by higher GOLD grades, had more frequent respiratory symptoms and comorbidities compared with those with lower grades or without airflow limitation. The severity of airflow limitation was also associated with indirect burdens in terms of lost time off work or social activities, and healthcare utilization. Additionally, higher severity of airflow limitation was related to a lower quality of life. The effects of different airflow limitation grades on the physical aspects of quality of life were stronger than on the mental aspects. These findings confirm the utility of the GOLD spirometry grades for providing insight into the impact and burden of COPD. Most importantly, there was significant variation across the GOLD grades, especially with regard to the use of respiratory medicines.

Data Sharing Statement

The data that support the findings of this study are available at reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Human/Animal Ethics Approval Declaration

The BOLD Australia Study was approved by the Human Research Ethics Committee of the University of Sydney (ref. no. 12-2006/9724) and complies with the Declaration of Helsinki. Each study site also obtained local HREC approval, including approval from the Western Australian Aboriginal Health Information and Ethics Committee. Informed participant consent was obtained as per site-specific ethics approvals.


The BOLD study in Australia was funded by the National Health & Medical Research Council, Project Grant 457385. The BOLD study in Sydney was funded by grants from Air Liquide P/L, AstraZeneca P/L, Boehringer Ingelheim P/L, GlaxoSmithKline Australia P/L and Pfizer Australia P/L.

Operations Centre: Mrs Tessa E. Bird and Dr Wei Xuan (Woolcock Institute of Medical Research). Sydney: Professor Christine R. Jenkins, Mrs Tessa E. Bird, Dr Kate Hardaker and Dr Paola Espinel (Woolcock Institute of Medical Research).

Busselton: the late Professor A. W. (Bill) Musk, Dr Michael L. Hunter, Ms Elspeth Inglis and Ms Peta Grayson (University of Western Australia). Kimberley: Professor David N. Atkinson, Mr Dave Reeve, Dr Nathania Cooksley, Dr Matthew Yap, Ms Mary Lane, Dr Wendy Cavilla and Ms Sally Young (University of Western Australia). Melbourne: Ms Angela Lewis, Ms Joan Raven, Ms Joan Green and Ms Marsha Ivey (Monash University). Tasmania: Professor E. Haydn Walters, Mrs Carol Phillips and Ms Loren Taylor (University of Tasmania). NSW Rural: Dr Phillipa J. Southwell, Dr Bruce J. Graham, Dr Brian Spurrell, Mrs Robyn Paton, Ms Melanie Heine, Ms Cassandra Eccleston and Dr Julie Cooke (Charles Sturt University).


MJA holds investigator initiated grants from Pfizer, Boehringer-Ingelheim, Sanofi and GSK. He has conducted an unrelated consultancy for Sanofi. He has also received a speaker’s fee from GSK. MJA and RWB report cohort grants from the National Health & Medical Research Council. GBM has received funding for advisory boards with AstraZeneca. HKR holds investigator initiated grants from AstraZeneca, GlaxoSmithKline, Novartis, Perpetual Philanthropy. She has received consulting fees from AstraZeneca and GlaxoSmithKline and honoraria from AstraZeneca, GlaxoSmithKline, TEVA, Boehringer-Ingelheim, Sanofi, Getz, Chiesi and Alkem. HKR holds leadership roles in the Global Initiative for Asthma (GINA) and National Asthma Council (NAC). All other authors declare no competing interests in this work.


1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for prevention, diagnosis and management of COPD: 2023 report. global initiative for chronic obstructive lung disease; [updated December 05, 2022]. Available from: Accessed December 01, 2022.

2. Roth GA, Abate D, Abate KH, et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2018;392(10159):1736–1788.

3. World Health Organization (WHO). Chronic obstructive pulmonary disease (COPD). WHO; 2023 [updated March 16 2023]. Available form: Accessed May 12, 2023.

4. Australian Institute of Health Welfare. Chronic obstructive pulmonary disease (COPD), associated comorbidities and risk factors. AIHW. Available form: Accessed April 21, 2023.

5. Australian Institute of Health Welfare. Australian burden of disease study 2015: interactive data on disease burden. AIHW. [updated 2020]. Available from: Accessed April 15, 2023.

6. Sarkar M, Bhardwaj R, Madabhavi I, Khatana J. Osteoporosis in chronic obstructive pulmonary disease. Clin Med Insights Circ Respir Pulm Med. 2015;9:S22803.

7. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32(4):962–969. doi:10.1183/09031936.00012408

8. Yohannes AM, Alexopoulos GS. Depression and anxiety in patients with COPD. Eur Respir Review. 2014;23(133):345–349. doi:10.1183/09059180.00007813

9. Australian Bureau of Statistics (ABS). National health survey: first results. ABS. [Updated 2017-2018]. Available from: Accessed July 25, 2022.

10. Toelle BG, Ampon RD, Abramson MJ, et al. Prevalence of chronic obstructive pulmonary disease with breathlessness in Australia: weighted using the 2016 Australian census. Intern Med J. 2021;51(5):784–787. doi:10.1111/imj.15325

11. Viegi G, Pistelli F, Sherrill D, Maio S, Baldacci S, Carrozzi L. Definition, epidemiology and natural history of COPD. Eur Respir J. 2007;30(5):993–1013. doi:10.1183/09031936.00082507

12. Toelle BG, Xuan W, Bird TE, et al. Respiratory symptoms and illness in older Australians: the Burden of Obstructive Lung Disease (BOLD) study. Med J AU. 2013;198(3):144–148. doi:10.5694/mja11.11640

13. Dabscheck E, George J, Hermann K, et al. COPD‐X Australian guidelines for the diagnosis and management of chronic obstructive pulmonary disease: 2022 update. Med J AU. 2022;217(8):415–423. doi:10.5694/mja2.51708

14. Cooksley NA, Atkinson D, Marks GB, et al. Prevalence of airflow obstruction and reduced forced vital capacity in an Aboriginal Australian population: the cross‐sectional BOLD study. Respirology. 2015;20(5):766–774. doi:10.1111/resp.12482

15. Janson C, Marks G, Buist S, et al. The impact of COPD on health status: findings from the BOLD study. Eur Respir J. 2013;42(6):1472–1483. doi:10.1183/09031936.00153712

16. Buist AS, Vollmer WM, Sullivan SD, et al. The Burden of Obstructive Lung Disease initiative (BOLD): rationale and design. J Chronic Obstr Pulm Dis. 2005;2(2):277–283. doi:10.1081/COPD-57610

17. Australian Bureau Of Statistics. Socio-economic indexes for areas (SEIFA). Australian Bureau of Statistics; 2011.

18. Bestall J, Paul E, Garrod R, Garnham R, Jones P, Wedzicha J. Usefulness of the medical research council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7):581–586. doi:10.1136/thx.54.7.581

19. Kosinski M, Ware JE, Turner-Bowker DM, Gandek B. User’s Manual for the SF-12v2 Health Survey: With a Supplement Documenting the SF-12® Health Survey. QualityMetric Incorporated; 2007.

20. Miller M. ATS/ERS task force: standardisation of spirometry. Eur Respir J. 2005;26:319–338. doi:10.1183/09031936.05.00034805

21. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respiratory Soc. 2012;40:1324–1343.

22. Lederer DJ, Bell SC, Branson RD, et al. Control of confounding and reporting of results in causal inference studies. Guidance for authors from editors of respiratory, sleep, and critical care journals. Ann Am Thorac Soc. 2019;16(1):22–28. doi:10.1513/AnnalsATS.201808-564PS

23. Petrie K, Toelle BG, Wood-Baker R, et al. Undiagnosed and misdiagnosed chronic obstructive pulmonary disease: data from the BOLD Australia Study. Int J Chron Obstruct Pulmon Dis. 2021;16:467. doi:10.2147/COPD.S287172

24. Diab N, Gershon AS, Sin DD, et al. Underdiagnosis and overdiagnosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198(9):1130–1139. doi:10.1164/rccm.201804-0621CI

25. Reddel HK, Vestbo J, Agustí A, et al. Heterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort. Eur Respir J. 2021;58(3):2003927. doi:10.1183/13993003.03927-2020

26. Menezes AMB, de Oca MM, Pérez-Padilla R, et al. Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma. Chest. 2014;145(2):297–304. doi:10.1378/chest.13-0622

27. Dierick BJ, Flokstra-de Blok BM, van der Molen T, et al. Work absence in patients with asthma and/or COPD: a population-based study. NPJ Prim Care Respir Med. 2021;31(1):9. doi:10.1038/s41533-021-00217-z

28. Choi HS, Yang D-W, Rhee CK, et al. The health-related quality-of-life of chronic obstructive pulmonary disease patients and disease-related indirect burdens. Korean J Intern Med. 2020;35(5):1136. doi:10.3904/kjim.2018.398

29. Varela ML, De Oca MM, Halbert R, et al. Sex-related differences in COPD in five Latin American cities: the PLATINO study. Eur Respir J. 2010;36(5):1034–1041. doi:10.1183/09031936.00165409

30. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet. 2007;370(9589):741–750. doi:10.1016/S0140-6736(07)61377-4

31. Gudmundsson G, Gislason T, Lindberg E, et al. Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity. Respir Res. 2006;7(1):1–8. doi:10.1186/1465-9921-7-109

32. Schermer TR, Robberts B, Crockett AJ, et al. Should the diagnosis of COPD be based on a single spirometry test? NPJ Prim Care Respir Med. 2016;26(1):1–8. doi:10.1038/npjpcrm.2016.59

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Nontuberculous mycobacterial lung disease (NTMLD) in patients with chronic obstructive pulmonary disease (COPD) is associated with a substantial incremental mortality burden, according to study findings published in BMC Infectious Diseases.

Due to shared common nonspecific symptoms (cough, phlegm, fatigue, dyspnea) in NTMLD, COPD, and other respiratory diseases, NTMLD may escape the notice of health care providers, resulting in delayed diagnosis and potentially leading to disease progression and poor clinical outcomes. Investigators therefore assessed older adults with COPD to evaluate the risk of incremental mortality associated with NTMLD.

This retrospective cohort study used ICD-9 and -10 codes in the US Medicare claims database from 2010 to 2017 to identify 4926 patients with preexisting COPD and NTMLD, who were subsequently matched 1:3 by sex (54.4% women) and age (at least 65 years; mean [SD] age, 76.7 [6.7] years) with patients with COPD without NTMLD (control cohort; n=14,778). The majority of patients in both groups were White (NTMLD/COPD cohort, 91.4%; control cohort, 89.0%). Follow-up was from index (first medical claim with diagnosis of NTMLD) through December 2017 or until death. In all participants, COPD was diagnosed prior to the first NTMLD diagnosis, and the first NTMLD diagnosis was between 2011 and 2016.

A higher proportion of patients with NTMLD/COPD vs patients with COPD only had nonpulmonary comorbid conditions including underweight or abnormal weight loss (21.9% vs 6.0%), reflux (41.1% vs 29.0%), and rheumatoid arthritis (6.9% vs 4.3%). A lower proportion of patients with NTMLD/COPD vs patients with COPD only had nonpulmonary comorbid conditions including diabetes, and overweight and obesity.

The substantial incremental mortality burden associated with NTMLD in patients with COPD highlights the importance of developing interventions targeting this high-risk group and may indicate an unmet need for timely and appropriate management of NTMLD.

Patients with NTMLD/COPD vs patients with COPD only had a higher proportion of pulmonary symptoms (cough, 63.0% vs 24.4%; emphysema, 39.0% vs 10.3%; pneumonia, 58.5% vs 12.2%; dyspnea, 72.7% vs 37.6%; all P <.0001).

A higher proportion of deaths occurred in the NTMLD/COPD cohort vs the control cohort (41.5% vs 26.7%); patients with NTMLD/COPD had a shorter time to death as well as higher unadjusted annual mortality rates (158.5 vs 86.0 deaths/1000 person-years) (all P <.0001), in univariate analyses.

Multivariate analyses (controlling for sex, age, selected comorbidities, COPD severity) showed a similar increased mortality risk. Patients with COPD and NTMLD had higher mortality rates (rate ratio, 1.36; 95% CI, 1.28-1.45), higher hazard of death (hazard ratio, 1.37; 95% CI, 1.28-1.46), and were more likely to die (odds ratio, 1.39; 95% CI, 1.27-1.51) (all P <.0001).

Study limitations include the retrospective design, coding errors, and the lack of pharmacotherapy data to confirm validity of the COPD population.

“The substantial incremental mortality burden associated with NTMLD in patients with COPD highlights the importance of developing interventions targeting this high-risk group and may indicate an unmet need for timely and appropriate management of NTMLD,” the study authors concluded.

Disclosure: This research was supported by Insmed Incorporated (Bridgewater, NJ). Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

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Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung disease characterised by chronic respiratory symptoms such as dyspnoea, cough, and sputum production due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that causes persistent, often progressive, airflow obstruction.1 Patients with COPD often experience symptoms despite maximal medical management including ongoing dyspnoea, cough, dry mouth, fatigue, pain, trouble sleeping, depression, and anxiety.2–6 The impact of multiple symptoms within an individual can be conceptualised by the term “symptom burden” which may be defined as “the sum of the severity and impact of symptoms reported by a significant proportion of patients with a given disease or treatment”7 and is best quantified by validated symptom instruments. Symptom burden is a significant problem in patients with severe COPD as it has been comparable to those with cancer.8–10 Given that symptoms are specific to the individual, aspects of life including living situation, disease severity, comorbidities, quality of life, and sex/gender may have an impact on symptom burden. Therefore, understanding the epidemiology of symptoms in specific populations serves to enable development of strategies to ameliorate distress and reduce suffering.11

The Westmead Breathlessness Service (WBS) undertakes a comprehensive assessment of patients with moderate to very severe COPD which includes symptom burden, and provides multidisciplinary, non-pharmacological management of breathlessness in patients who remain troubled by breathlessness despite receiving appropriate therapy from their usual care providers. A protocol outlining the model of care has been recently published.12 To be able to address the problem of symptom burden in this population, it is necessary to quantify the extent of the burden and identify factors that are predictive of symptom burden. Therefore, we aimed to, firstly, describe the physical and psychological symptom burden for patients attending the WBS and, secondly, identify factors that are independently associated with symptom burden.


Study Design and Setting

We performed a cross-sectional study of all patients with a diagnosis of COPD who were enrolled in a randomised controlled trial (RCT) of a non-pharmacological integrated care intervention to reduce the impact of breathlessness through the WBS12 who underwent an initial assessment between March 2017 and May 2022 [The Australian New Zealand Clinical Trial Registry ACTRN12617000499381]. The RCT study was conducted at a single site (Westmead Hospital) after approval from Western Sydney Local Health District Human Research Ethics Committee (WSLHD HREC), informed written consent was obtained for each participant, and the RCT was conducted in accordance with the Declaration of Helsinki. For this study, analysis of baseline data prior to intervention was also approved by WSLHD HREC (2023–01 QA). Individual deidentified participant baseline data in this study will be made available for five years after manuscript publication in Excel spreadsheet form upon request via email.

Inclusion criteria for referral to the WBS required all three of the following criteria:

  1. a diagnosis of moderate to very severe COPD (ie, FEV1/FVC ratio ≤0.7 and FEV1% predicted ≤60%),
  2. severe breathlessness (modified Medical Research Council [mMRC] breathlessness scale ≥2), and
  3. being willing and able to actively participate in own care.

Participants who were assessed as being unable to participate in interventions to address breathlessness were excluded from the WBS (see12 for the full list of exclusion criteria).

Participants were referred by respiratory specialists, general practitioners, nurses, and allied health staff in Western Sydney and were assessed for suitability for WBS intervention by staff prior to enrolment.


Demographic Data

We obtained demographic data at the initial multidisciplinary assessment clinic which included age, sex, body-mass index (BMI), smoking status, comorbidities, pulmonary rehabilitation completion in the last 12 months, and social situation (eg, living arrangements, country of birth).

Lung Function

We obtained standardised measurements of lung function via spirometry (MicroLab 36-ML3500 MK80STK, CareFusion) and recorded forced expiratory volume in the first second (FEV1), FEV1 as percent predicted (FEV1%), forced vital capacity (FVC), and FVC as percent predicted (FVC%). Where possible, participants performed two standardised six-minute walk tests (6MWT) at the initial assessment, and the best distance was recorded.

Symptom Burden Assessment

Symptom burden was assessed using the Condensed Memorial Symptom Assessment Scale (CMSAS) which is a brief, well-validated scale that assesses the ‘bothersomeness’ of eleven common physical symptoms on a 5-point Likert scale and the frequency of three psychological symptoms on a 4-point Likert scale.13 Three scores are calculated: CMSAS PHYS assesses overall physical symptom bothersomeness, CMSAS PSYCH assesses psychological symptom frequency, and CMSAS total contains all 14 symptoms. Symptoms which are scored in the upper half of the scale are regarded as more severe.14 We used a modification of the CMSAS which has been used in other studies related to COPD,15,16 adding in two additional physical symptoms (cough and sputum) and one additional psychological symptom (feeling anxious) as previously described,16 given that these symptoms are common in patients with COPD. To preserve the integrity of the CMSAS scores, these additional symptoms were not included in the calculation of any scores.

Other Questionnaires

Overall COPD-specific quality of life was assessed using the COPD Assessment Test (CAT) which is a patient-completed questionnaire assessing the impact of eight COPD symptoms (each scoring 0–5; total score 40) on health status with higher scores representing more severe impact of COPD.17 We used the Hospital Anxiety and Depression Scale (HADS), a 14-item scale, to assess anxiety and depression.18

Statistical Analysis

We described demographic and baseline assessment data as either mean (standard deviation), median (interquartile range), or number (% of total). We compared variables between men and women using unpaired t tests or Mann–Whitney tests for continuous variables, and Fisher’s exact tests for categorical variables. To look for significant predictors of CMSAS total in our population, we performed univariable linear regressions using CMSAS total and CMSAS PHYS as the dependent variable and the following independent variables: age, gender, country of birth, indigenous status, level of education, living arrangements, previous pulmonary rehabilitation, smoking status, FEV1 (% predicted), FVC (% predicted), 6-minute walk distance (6MWD), CAT, HADS-Anxiety (HADS-A), HADS-Depression (HADS-D), and mMRC (2 or 3 versus 4). All independent variables with univariable p<0.20 were included in a backward elimination multiple regression model. Variables with p<0.05 were included in the final regression model. We assessed for: (1) potential confounders by testing for interactions; (2) collinearity by examining variance inflation factors; and (3) the assumptions of multiple regression by examining residual plots. Data were analysed using Stata/IC 15.1 (StataCorp, TX, USA).


Data were available on 89 patients with COPD, mean age 72.6 (7.7) years, 55% male with an average smoking history of 61.9 pack-years. As a requirement for entry to the breathlessness clinic was a MMRC score ≥2, 52% of patients had MMRC 2 or 3 while 48% had MMRC of 4. Most lived with a carer (70%) and 30% of patients had completed pulmonary rehabilitation in the previous 12 months. Mean FEV1 was 32% predicted consistent with severe COPD. The average CAT score was elevated at 23.2 and median HADS-A was 8 while HADS-D was 6. Other details of subjects are presented in Table 1. In our population, women were younger on average than men (mean age 70.6 versus 74.3 years, respectively), but there was no significant difference in lung function measured as % predicted, BMI, or six-minute walk distance (Table 1). More men had a history of ischaemic heart disease (51% of men compared with 25% of women; p=0.017), but more women had a history of depression (42.5% of women compared with 14.3% of men; p=0.004). There was no difference in the prevalence of chronic asthma, hypertension, cardiac failure, diabetes mellitus, or vascular disease (Table 1).

Table 1 Summary of Demographics and Clinical Characteristics of Patients

The overall symptom burden was high in our population. Patients reported an average of 8.9 symptoms (SD 2.8) including 6.9 (SD 2.5) CMSAS physical symptoms and 1.6 (SD 1.1) CMSAS psychological symptoms (Table 1). Highly prevalent physical symptoms (Figure 1) included shortness of breath (100%), lack of energy (80%), dry mouth (70%), sputum (70%), and cough and drowsiness (both 67%). Over 50% of patients reported more severe shortness of breath and lack of energy that caused “quite a bit” or “very much” distress. Prevalent reported psychological symptoms (Figure 2) included worrying (65%), feeling anxious (61%), and feeling sad (51%), and nearly 40% of patients reported feeling anxious “frequently” or “almost constantly”. The median CMSAS total score was 1.14, the CMSAS PHYS score was 1.16, and the CMSAS PSYCH score was 1.33 (Table 1).

Figure 1 Prevalence of reported physical symptoms and more severe symptoms (% of total patients).

Note: “More severe symptoms” defined as symptoms which bothered or distressed patients quite a bit or very much in the past 7 days.

Figure 2 Prevalence of reported psychological symptoms and more severe symptoms (% of total patients).

Note: “More severe symptoms” defined as symptoms which occurred frequently or almost constantly in the past 7 days.

Of the physical symptoms, women reported being more bothered by pain (p=0.02) and nausea (p=0.04) than men but there was no significant sex difference in the CMSAS PHYS score (p=0.15; Table 1). Women had a higher CMSAS PSYCH total than men (p=0.014) with worrying (p=0.008) and feeling nervous (p=0.011) occurring more frequently than in men, but there was no difference in the frequency of feeling sad (p=0.63). The median CMSAS total score was higher in women compared with men (1.34 versus 1.04, respectively; p=0.03; Table 1). There was no sex difference in the CMSAS modified symptoms of the bothersomeness of cough or sputum (both p>0.53), but women experienced feeling nervous (p=0.011) and anxious (p=0.005) more frequently than men.

Univariable regression showed significant positive relationships between CMSAS total and female sex, being born in Australia, CAT score, HADS-A, HADS-D, and mMRC (all univariable p<0.05; Table 2). Weaker associations were found for lower level of education (high school completion or less; p=0.096) and 6MWD (p=0.053). Using the backward elimination method, the final multiple linear regression model established that female sex (p=0.003), HADS-A (p=0.0001), and HADS-D (p=0.0001) were very strongly positively associated with the CMSAS total score and explained 63% of the variability of the CMSAS total score (F3,85=48.12, p=0.0001; R2=0.63). Females had on average a higher CMSAS total score than males by 0.24 units after adjusting for HADS-A and HADS-D (95% CI 0.082 to 0.399 units). For a unit increase in HADS-A, CMSAS total increased by 0.062 units after adjusting for sex and HADS-D (95% CI 0.039 to 0.085 units), and for each unit increase in HADS-D, CMSAS total increased by 0.056 units after adjustment for HADS-A and sex (95% CI 0.025 to 0.083 units). CMSAS total can be summarised as follows: CMSAS total (units)=0.057+(0.24×sex)+(0.062×HADS-A)+(0.056×HADS-D), where sex is coded 0 for males and 1 for females. There was no evidence of collinearity and examination of residuals confirmed the assumptions of linearity in the final model.

Table 2 Regression Diagnostic Data with CMSAS Total as the Dependent Variable

Multiple linear regression using CMSAS PHYS as the dependent variable demonstrated that CAT (p=0.023) and HADS-A and HADS-D (both p=0.001) were significantly positively related in a multivariable model (Table 3); however, the effect of sex was no longer significant.

Table 3 Regression Diagnostic Data with CMSAS Physical as the Dependent Variable


Although other studies have looked at symptom burden in patients with COPD using a multi-dimensional symptom burden assessment tool,2–4,19–21 to our knowledge our study is the first to look at independent predictors of overall symptom burden including the influence of anxiety, depression, and sex. We have demonstrated the high prevalence of multiple physical and psychological symptoms that contribute to overall symptom burden in a group of stable breathless outpatients with COPD. Some of these symptoms may be directly attributable to the pathophysiology of COPD including shortness of breath, cough, and sputum; however, we highlight other symptoms that may be troubling for these patients which may not necessarily be assessed in the setting of an outpatient consultation such as lack of energy, pain, feeling drowsy, difficulty sleeping, dry mouth, worrying, and feeling sad, nervous, and anxious. Overall symptom burden is high with an average of 8.9 symptoms, and more than 50% of patients experiencing more severe shortness of breath and lack of energy.

Our results show that women experience a greater overall symptom burden than men with a CMSAS total score which was almost 30% higher despite similar FEV1 (as % predicted), breathlessness (as per mMRC values), and anxiety or depression at the time of assessment (as per HADS results). The increase in symptom burden in women was mainly driven by being more bothered by pain or nausea, and being more frequently worried or nervous. Of concern, the psychological symptom burden that women experienced was approximately triple that experienced by men as shown by the CMSAS Psych scores (men=0.67; women=2.0; Table 1). The symptoms that are more troublesome for women than men are consistent with the “emotional symptom burden cluster” which includes worrying, feeling nervous, and pain, more than the “gastrointestinal symptom burden cluster” (ie weight loss, constipation, nausea) or the “unwellness symptom burden cluster” (ie feeling drowsy, lack of appetite, difficulty swallowing, or shortness of breath).22

Understanding the Complex Interplay Between Symptoms, Influencing Factors, and Outcomes

The theory of unpleasant symptoms highlights the relationship between a symptom that an individual may be experiencing, influencing factors that cause or modify the symptom, and the effect that the symptom may have on the individual,23 and the complex interactions between influencing factors, multiple symptoms, and the subsequent influence of their impacts on performance on the original influencing factors and the symptoms themselves.24 Symptoms may be described in terms of duration, quality, and intensity but how much distress they cause (ie bothersomeness) is the aspect that has been shown to contribute most to quality of life.24 Influencing factors on COPD symptoms include: (1) physiologic factors such as degree of airflow obstruction, the presence of chronic bronchitis, malnutrition and weight loss, and gender; (2) psychologic state such as mental state and the reaction to illness state; and (3) situational factors such as the presence or absence of social supports, employment, and social isolation. In turn, the impact of the symptom burden on patients with COPD may determine their functional status, cognitive functioning, and physical performance;24 therefore a comprehensive assessment of contributors to symptom burden apart from physiologic factors may help identify areas to improve not only quality of life but also overall performance status.

Use of CMSAS Over MSAS in COPD Assessment

The Memorial Symptom Assessment Scale (MSAS) has only been validated in advanced cancer populations14 and consists of 32 items, but has been used to describe symptom burden in patients with COPD2–4,19–21 although one study made a minor adjustment by replacing the symptom “hair loss” with “weight gain” to be more relevant to COPD.2 However, we utilised the shorter 14-item CMSAS as it has been shown to demonstrate approximately equivalent quality of life information in cancer patients and only takes 2–4 minutes to complete,13 making it a more practical assessment tool in patients with COPD who are acutely unwell15 and also in the clinical consultation setting.25 The MSAS and CMSAS directly ask about the distress or bothersomeness of 11 physical symptoms and frequency of psychological symptoms in the last 7 days; these aspects differs from the COPD assessment test and St George’s Respiratory Questionnaire which mostly assess the impact of physical symptoms on patients’ lives. Therefore, the CMSAS may be a useful tool to quickly identify symptoms that may be most distressing to the patient with COPD and therefore impacting the most on their quality of life.

Sex/Gender Influences on Symptom Burden

Patients with advanced COPD have been shown to have distress greater than the severity of their symptoms,26 which implies that the associated emotional burden is greater for the patient than the actual physiological impact of the symptom.10 For female patients with COPD, whether the increased frequency of feeling worried or nervous compared to males related specifically to their COPD disease, or other influences such as the increased underlying prevalence of depression or social pressures of the female responsibility in the household and their interactions with COPD is not able to be determined from our data and further qualitative research is required.

Several recent review articles have highlighted the increasing awareness and importance of sex and gender differences in lung diseases27–29 including COPD.30 Previous studies have demonstrated that women with COPD have greater levels of anxiety, depression, dyspnoea, and symptom-related quality of life than men for the same or lesser degree of lung impairment.31,32 Therefore, as anxiety and depression are more prevalent among women with COPD, one may conclude that sex/gender is a confounder of the increased symptom burden that patients with COPD bear. However, our data show that female sex is independently associated with increased symptom burden even after adjusting for anxiety and depression, which may therefore relate to sex differences (ie biological differences between males and females including physiological, hormonal, or functional differences) or gender differences (ie social factors that include cultural, behavioural, or individual self-identity that are defined by a society or culture).29

Anxiety and Depression Influences on Symptom Burden

Anxiety and depression are important comorbidities in COPD33 and are strongly associated with poorer quality of life and health status, more than spirometric values.34 Patients with chronic medical illnesses including COPD report more symptoms if they have comorbid depression or anxiety than those without when disease severity is controlled.35 We have demonstrated independent linear relationships for both anxiety and depression and total symptom burden as measured by the CMSAS, demonstrating that a reduction in either or both may result in improvement in overall symptoms. Although pharmacological interventions may be considered for anxiety and depression in patients with COPD to alleviate symptom burden, there is inconclusive evidence of their benefit at this stage and further trials are needed.36,37 On the other hand, meta-analysis data from pulmonary rehabilitation trials have shown a moderate improvement in anxiety symptoms and a large improvement in depression symptoms,38 highlighting the importance of this intervention in patients with COPD. Recent data from a moderate to severe COPD cohort referred to a pulmonary rehabilitation programme demonstrated that one in three patients had both anxiety and depression and that the pulmonary rehabilitation programme resulted in a larger improvement in quality of life, and reduction in dyspnoea and stress than those with only anxiety or depression alone, or with neither.39 The significant benefits on symptom burden from pulmonary rehabilitation may be due to its effect on multiple areas of the unpleasant symptom theory24 including improvement in physiology (eg exercise capacity, muscle function), psychological factors (eg social support through the programme, interactions with healthcare professionals), and situational factors (eg less isolation, increased independence) but which components of the rehabilitation programme provide these benefits remain unclear.40

Finally, a systematic review and meta-analysis of holistic services for patients with breathlessness due to a diverse variety of advanced disease has shown a reduction in distress due to breathlessness and a significant reduction in depression but not anxiety.41 Whether a novel non-pharmacological breathlessness service like the WBS specifically for patients with COPD may reduce anxiety, depression, and overall symptom burden in addition to breathlessness is not yet known and further RCT data are required.


Patients attending the Westmead Breathlessness Service with moderate to severe COPD reported a wide range of non-respiratory symptoms beyond the classic COPD symptoms of breathlessness, cough, and sputum and there is a high symptom burden within this population. Although having similar baseline demographics, female patients with COPD reported the bothersomeness of pain and nausea, and frequency of psychological symptoms more often than males. There is a need to further identify and understand sex differences for COPD symptoms and to study interventions that reduce anxiety and depression to see if they can significantly reduce overall symptom burden in this population.


The authors thank Ms Jan Gesling for assistance in data collection.


The authors report no conflicts of interest in this work.


1. Venkatesan P. GOLD COPD report: 2023 update. Lancet Respir Med. 2023;11(1):18. doi:10.1016/S2213-2600(22)00494-5

2. Christensen VL, Holm AM, Cooper B, et al. Differences in Symptom Burden Among Patients With Moderate, Severe, or Very Severe Chronic Obstructive Pulmonary Disease. J Pain Symptom Manage. 2016;51(5):849–859. doi:10.1016/j.jpainsymman.2015.12.324

3. Melhem O, Savage E, Al Hmaimat N, et al. Symptom burden and functional performance in patients with chronic obstructive pulmonary disease. Appl Nurs Res. 2021;62:151510. doi:10.1016/j.apnr.2021.151510

4. Melhem O, Savage E, Lehane E. Symptom burden in patients with chronic obstructive pulmonary disease. Appl Nurs Res. 2021;57:151389. doi:10.1016/j.apnr.2020.151389

5. Mihaltan F, Adir Y, Antczak A, et al. Importance of the relationship between symptoms and self-reported physical activity level in stable COPD based on the results from the SPACE study. Respir Res. 2019;20(1):89. doi:10.1186/s12931-019-1053-7

6. Miravitlles M, Ribera A. Understanding the impact of symptoms on the burden of COPD. Respir Res. 2017;18(1):67. doi:10.1186/s12931-017-0548-3

7. Cleeland CS. Symptom Burden: multiple Symptoms and Their Impact as Patient-Reported Outcomes. JNCI Monographs. 2007;2007(37):16–21. doi:10.1093/jncimonographs/lgm005

8. Habraken JM, ter Riet G, Gore JM, et al. Health-related quality of life in end-stage COPD and lung cancer patients. J Pain Symptom Manage. 2009;37(6):973–981. doi:10.1016/j.jpainsymman.2008.07.010

9. Walke LM, Gallo WT, Tinetti ME, et al. The burden of symptoms among community-dwelling older persons with advanced chronic disease. Arch Intern Med. 2004;164(21):2321–2324. doi:10.1001/archinte.164.21.2321

10. Joshi M, Joshi A, Bartter T. Symptom burden in chronic obstructive pulmonary disease and cancer. Curr Opin Pulm Med. 2012;18(2):97–103. doi:10.1097/MCP.0b013e32834fa84c

11. Emanuel L. Relief of suffering is the business of every discipline. Arch Intern Med. 2006;166(2):149–150. doi:10.1001/archinte.166.2.149

12. Smith TA, Roberts MM, Cho JG, et al. Protocol for a Single-Blind, Randomized, Parallel-Group Study of a Nonpharmacological Integrated Care Intervention to Reduce the Impact of Breathlessness in Patients with Chronic Obstructive Pulmonary Disease. Palliat Med Rep. 2020;1(1):296–306. doi:10.1089/pmr.2020.0081

13. Chang VT, Hwang SS, Kasimis B, et al. Shorter symptom assessment instruments: the Condensed Memorial Symptom Assessment Scale (CMSAS). Cancer Invest. 2004;22(4):526–536. doi:10.1081/CNV-200026487

14. Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assessment Scale: an instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer. 1994;30A(9):1326–1336. doi:10.1016/0959-8049(94)90182-1

15. Smith TA, Ingham JM, Jenkins CR. Respiratory Failure, Noninvasive Ventilation, and Symptom Burden: an Observational Study. J Pain Symptom Manage. 2019;57(2):282–289 e1. doi:10.1016/j.jpainsymman.2018.10.505

16. Srinivasan M, Swami V, Roberts M, Cho J, Wheatley J, Smith T. Symptom Burden for Inpatients with Acute Exacerbations of COPD. Respirology. 2019;24(1):127. doi:10.1111/resp.13437

17. Jones PW, Harding G, Berry P, et al. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648–654. doi:10.1183/09031936.00102509

18. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983;67(6):361–370. doi:10.1111/j.1600-0447.1983.tb09716.x

19. Eckerblad J, Tödt K, Jakobsson P, et al. Symptom burden in stable COPD patients with moderate or severe airflow limitation. Heart Lung. 2014;43(4):351–357. doi:10.1016/j.hrtlng.2014.04.004

20. Jablonski A, Gift A, Cook KE. Symptom assessment of patients with chronic obstructive pulmonary disease. West J Nurs Res. 2007;29(7):845–863. doi:10.1177/0193945906296547

21. Park SK, Stotts NA, Douglas MK, et al. Symptoms and functional performance in Korean immigrants with asthma or chronic obstructive pulmonary disease. Heart Lung. 2012;41(3):226–237. doi:10.1016/j.hrtlng.2011.09.014

22. Kenne Sarenmalm E, Browall M, Gaston-Johansson F. Symptom Burden Clusters: a Challenge for Targeted Symptom Management. A Longitudinal Study Examining Symptom Burden Clusters in Breast Cancer. J Pain Symptom Manage. 2014;47(4):731–741. doi:10.1016/j.jpainsymman.2013.05.012

23. Lenz ER, Suppe F, Gift AG, et al. Collaborative development of middle-range nursing theories: toward a theory of unpleasant symptoms. ANS Adv Nurs Sci. 1995;17(3):1–13. doi:10.1097/00012272-199503000-00003

24. Lenz ER, Pugh LC, Milligan RA, et al. The middle-range theory of unpleasant symptoms: an update. ANS Adv Nurs Sci. 1997;19(3):14–27. doi:10.1097/00012272-199703000-00003

25. Fasolino T, O’Hara S. Assessing SPACES in Patients with Chronic Obstructive Pulmonary Disease Helps Identify Unmet Needs. J Palliat Med. 2023;26(1):149–152. doi:10.1089/jpm.2022.0178

26. Blinderman CD, Homel P, Billings JA, et al. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease. J Pain Symptom Manage. 2009;38(1):115–123. doi:10.1016/j.jpainsymman.2008.07.006

27. Sodhi A, Pisani M, Glassberg MK, et al. Sex and Gender in Lung Disease and Sleep Disorders: a State-of-The-Art Review. Chest. 2022;162(3):647–658. doi:10.1016/j.chest.2022.03.006

28. Somayaji R, Chalmers JD. Just breathe: a review of sex and gender in chronic lung disease. Eur Respir Rev. 2022;31(163):210111. doi:10.1183/16000617.0111-2021

29. Silveyra P, Fuentes N, Rodriguez Bauza DE. Sex and Gender Differences in Lung Disease. Adv Exp Med Biol. 2021;1304:227–258. doi:10.1007/978-3-030-68748-9_14

30. Gut-Gobert C, Cavaillès A, Dixmier A, et al. Women and COPD: do we need more evidence? Eur Respir Rev. 2019;28(151):180055. doi:10.1183/16000617.0055-2018

31. Di Marco F, Verga M, Reggente M, et al. Anxiety and depression in COPD patients: the roles of gender and disease severity. Respir Med. 2006;100(10):1767–1774. doi:10.1016/j.rmed.2006.01.026

32. Raherison C, Tillie-Leblond I, Prudhomme A, et al. Clinical characteristics and quality of life in women with COPD: an observational study. BMC Womens Health. 2014;14(1):31. doi:10.1186/1472-6874-14-31

33. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of COPD. 2023 Report. Available from: Accessed March 24, 2023.

34. Tsiligianni I, Kocks J, Tzanakis N, et al. Factors that influence disease-specific quality of life or health status in patients with COPD: a review and meta-analysis of Pearson correlations. Prim Care Respir J. 2011;20(3):257–268. doi:10.4104/pcrj.2011.00029

35. Katon W, Lin EH, Kroenke K. The association of depression and anxiety with medical symptom burden in patients with chronic medical illness. Gen Hosp Psychiatry. 2007;29(2):147–155. doi:10.1016/j.genhosppsych.2006.11.005

36. Usmani ZA, Carson KV, Cheng JN, et al. Pharmacological interventions for the treatment of anxiety disorders in chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;11:Cd008483.

37. Pumar MI, Gray CR, Walsh JR, et al. Anxiety and depression-Important psychological comorbidities of COPD. J Thorac Dis. 2014;6(11):1615–1631. doi:10.3978/j.issn.2072-1439.2014.09.28

38. Gordon CS, Waller JW, Cook RM, et al. Effect of Pulmonary Rehabilitation on Symptoms of Anxiety and Depression in COPD: a Systematic Review and Meta-Analysis. Chest. 2019;156(1):80–91. doi:10.1016/j.chest.2019.04.009

39. Yohannes AM, Casaburi R, Dryden S, et al. The effectiveness of pulmonary rehabilitation on chronic obstructive pulmonary disease patients with concurrent presence of comorbid depression and anxiety. Respir Med. 2022;197:106850. doi:10.1016/j.rmed.2022.106850

40. Coventry PA. Does pulmonary rehabilitation reduce anxiety and depression in chronic obstructive pulmonary disease? Curr Opin Pulm Med. 2009;15(2):143–149. doi:10.1097/MCP.0b013e3283218318

41. Brighton LJ, Miller S, Farquhar M, et al. Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis. Thorax. 2019;74(3):270–281. doi:10.1136/thoraxjnl-2018-211589

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Lung inflammation can be caused by exposure to airborne toxins or irritants, respiratory infections, and lung diseases like asthma or chronic bronchitis. Symptoms may include wheezing, shortness of breath, chest pain, and coughing.

Lung inflammation can be acute (rapidly occurring and severe) or chronic (persistent or recurrent). The diagnosis may involve a physical exam, blood tests, imaging tests, and other procedures. Treatment is typically focused on treating the underlying cause, but anti-inflammatory or immunosuppressant drugs may be prescribed to directly treat the inflammation. Sometimes surgery is needed.

This article explains some common symptoms and causes of different types of lung inflammation. It also discusses how inflammation in the lungs is diagnosed and treated.

Verywell / Nez Riaz

Lung Inflammation Symptoms

Symptoms of lung inflammation can develop very suddenly or gradually over time. The symptoms vary based on the underlying cause, the extent of the inflammation, and your general health.

Symptoms of lung inflammation may include:

  • Fatigue
  • Wheezing
  • Shortness of breath
  • Productive (wet) or non-productive (wet) cough
  • Easy exhaustion with physical exertion
  • Chest discomfort, pain, or tightness

With chronic lung inflammation, a loss of appetite and unintended weight loss are common.


When severe, lung inflammation can limit airflow or lower your ability to absorb oxygen. This can cause hypoxemia (low blood oxygen) or hypoxia (low oxygen in tissues), leading to symptoms like:

  • Extreme restlessness
  • Slow heart rate (bradycardia)
  • Blueish skin (cyanosis)
  • Dizziness or fainting

Over time, chronic lung inflammation can change the thickness, composition, or volume of the airways, leading to a condition known as bronchiectasis. Bronchiectasis is a long-term, progressive condition in which the airways become permanently widened, leading to a build-up of mucus in the lungs and an increased risk of infection.

These changes can also result in hypercapnia in which it is harder to get carbon dioxide out of the lungs. In cases like this, a mechanical ventilator may be needed to help you breathe.

What Causes Lung Inflammation?

Inflammation is the body's natural response to injury or infection. There are many different reasons why this might occur in the lungs. While inflammation is a means for the body to heal itself, persistent inflammation can cause damage to airways and lung tissues.

Common causes of lung inflammation include:

Respiratory Irritants

When airborne toxins or irritants enter the lungs, the body responds with inflammation. This causes the airways to swell and produce a gooey substance called mucus that surrounds the particles and protects the wall of the airways. Mucus can then be dislodged with coughing.

Some common irritants include:

  • Cigarette smoke
  • Air pollution
  • Industrial aerosols
  • Household ammonia or chlorine
  • Solvents
  • Smoke

You can also have hypersensitivity pneumonitis in which your immune system overreacts to an inhaled irritant and triggers an extreme allergic response with lung inflammation. Dust mites, pollen, and pet dander are common triggers.

Lung Infections

There are many different pathogens (disease-causing agents) that cause lung infections. These include viruses that tend to cause acute infection, bacteria that can cause acute and chronic lung infections, and fungi that tend to cause severe infections in people with compromised immune systems.

Examples include:

Severe lung infections may cause acute respiratory distress syndrome (ARDS), a potentially life-threatening condition in which you cannot get enough oxygen in your blood.


Asthma is a condition in which your airways narrow and swell in response to different airborne triggers or health conditions. It causes episodes of bronchospasm in which the airways spasm violently, causing wheezing and coughing. Mucus might also be produced.

People with poorly managed asthma have a higher risk of pneumonia as a result of persistent lung inflammation.

Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is associated with chronic lung inflammation and an increased risk of bronchiectasis and pneumonia. Cigarette smoking is strongly linked to COPD. The disease progresses from chronic bronchitis (inflammation of the major airways) to emphysema (in which the lungs are heavily pitted).

People with advanced COPD often require inhaled corticosteroids (steroids) to reduce and control lung inflammation.


A chest injury or infection can lead to a condition called costochondritis in which the cartilage that joins your rib bone to your breastbone becomes inflamed. Costochondritis causes sharp or stinging pain and pressure on the chest wall.

Autoimmune Diseases

Lupus, rheumatoid arthritis, sarcoidosis, and scleroderma are all autoimmune diseases in which the body's own immune systems attacks healthy cells and tissues. Each of these diseases can directly or indirectly affect the lung and trigger lung inflammation. All autoimmune diseases are inflammatory.

Autoimmune diseases affecting the lungs can lead to interstitial lung disease (ILD). ILD affects tissues around the airways, causing progressive scarring (pulmonary fibrosis). The scarring causes the lungs to stiffen and makes it harder to breathe. Lung damage from ILD is often irreversible and gets worse over time.


Any type of trauma to the lungs or chest wall can cause acute lung inflammation. These include injuries like a rib fracture, a puncture wound, or a collapsed lung (pneumothorax) following a car accident.

People who suffer severe chest or lung trauma are vulnerable to pneumonia due to the build-up of fluid in or around the lungs. Penetrating wounds also allow bacteria to enter the chest wall, leading to a potentially severe infection.

Cystic Fibrosis

Cystic fibrosis (CF) is a progressive genetic disease that affects the lungs, pancreas, and other organs. CF causes the excess build-up of mucus in the lungs, making it harder to breathe.

While CF isn't primarily an inflammatory disease, the blockage of the airways can trigger severe inflammation, particularly as the disease worsens.


Pericarditis is an inflammation of the sac (pericardium) that surrounds the heart. Pericarditis can be caused by an infection, heart attack, certain diseases, and even some medical treatments.

While pericarditis directly affects the lining of the heart, the inflammation can spread to the lungs, particularly if the underlying cause is severe or chronic.

Pulmonary Embolism

Pulmonary embolism (PE) occurs when a blood clot (embolus) gets stuck in the artery of the lung. The clot often develops in the lower extremities due to a condition called deep vein thrombosis (DVT). When a clot in the artery of the leg is dislodged, it can travel to the lungs and cause PE.

Large clots can cause severe chest pain and other overt symptoms. Smaller clots may be less noticeable at first but still cause significant damage due to the loss of oxygen in the surrounding tissues. The damage can be worsened by high levels of inflammation at the site of the obstruction.

Lung Cancer

Lung cancer is characterized by chronic lung inflammation as the immune system launches an assault again the cancerous tumor.

Lung inflammation is also a common side effect of cancer treatments, including radiation, chemotherapy, and newer targeted drugs and immunotherapies. All of these treatments trigger an inflammatory response as they target cancer cells for destruction.

How Is Lung Inflammation Diagnosed?

The causes of lung inflammation are many and require no less than a physical exam (including a check of breath sounds) and a review of your medical and family. Based on the findings, other tests and procedures may be ordered.

These include lab tests like:

Procedures your healthcare provider may order include:

  • Pulse oximeter: A device placed on the finger that can tell how saturated oxygen is in your blood
  • Pulmonary function tests (PFTs): A battery of tests involving devices you breathe into that measure the volume and strength of your lungs
  • Electrocardiogram (ECG): A non-invasive test that measures the electrical activity of the heart
  • Bronchoscopy: A procedure in which a narrow scope is passed through your nose or mouth and into your lungs to view the airways
  • Lung biopsy: A procedure in which a sample of lung tissue is removed with a needle or scalpel to view the airways

Imaging tests may include:

  • Chest X-ray: An imaging test that creates black-and-white images with low-dose ionizing radiation
  • Computed tomography (CT): An imaging test that composites multiple X-ray images to create three-dimensional "slices" of the lungs
  • Magnetic resonance imaging (MRI): An imaging test that used powerful magnetic and radio waves to create highly detailed images of soft tissues
  • Echocardiogram: An imaging test that evaluates how well the heart's chambers and valves are working using reflected sound waves
  • Ventilation-perfusion scan: An imaging test traces the flow of air and blood through your lungs

How Is Lung Inflammation Treated?

Treating lung inflammation depends on the cause. For lung inflammation due to viral infections, such as the cold or flu, time and supportive care are all that is really involved. Lung inflammation due to other types of infection, such as Tb, will usually resolve once the underlying infection is treated.

Other causes may need treatments specific to lung inflammation to bring the inflammation under control.

Urgent Care

If you're having a breathing emergency, you may need oxygen therapy to bring your arterial blood gasses back to normal. In severe care, respiratory support may be needed to help you breathe. This support could include mechanical ventilation with intubation. This is when a tube is fed into the mouth and down the throat to deliver oxygen under controlled pressure.


Different medications may be used to alleviate lung inflammation either directly or indirectly. These include:

  • Antibiotics: Used to treat bacterial lung infections
  • Antivirals: Sometimes used to treat viral infections (like Paxlovid for COVID-19)
  • Antifungals: Given by mouth or intravenously (into a vein) to treat fungal lung infections
  • Antihistamines: Used to relieve inflammation due to allergy or atopic diseases
  • Inhaled corticosteroids (steroids): Often used to control lung inflammation in people with asthma or COPD
  • Oral corticosteroids: Including drugs like prednisone intended for short-term use of acute inflammation
  • Biologic drugs: Including drugs like Humira (adalimumab) that suppress parts of the immune system to treat different types of autoimmune diseases

Procedures and Surgery

Home oxygen therapy may be indicated for chronic lung conditions that severely restrict oxygen blood saturation. It involves a portable oxygen tank and thin tubing (called a cannula) that delivers oxygen into your nostrils.

Surgery may sometimes be needed to remove an area of the lung that has been damaged by disease. Generally, lung cancer surgery involves removing a lobe of a lung or sometimes an entire lung to ensure the tumor and any cancer cells are extracted. Surgery for COPD entails removing damaged areas of the lung to improve airflow.


Lung inflammation may be due to infection, disease, injury, or exposure to environmental toxins or irritants. Lung inflammation can make it harder to breathe. Over time, if the inflammation doesn't improve, it can damage your lungs.

Diagnosing lung inflammation may involve a review of your medical history, a physical exam, blood test, imaging tests, and procedures to measure how well your lungs and heart are working. Treatment is typically focused on treating the underlying cause. If needed, oral or inhaled steroids can help temper the inflammation, while oxygen therapy can help if you have trouble breathing. Surgery is needed in some cases.

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Respules Market

Respules Market

The Business Research Company's global market reports are now updated with the latest market sizing information for the year 2023 and forecasted to 2032

The Business Research Company's Respules Global Market Report 2023 identifies rise in the incidence of respiratory disorders as the major driver for the Respules market's growth in the forecast period. Respiratory disorders refer to lung diseases and illnesses, including tuberculosis, lung cancer, pulmonary hypertension, mesothelioma, cystic fibrosis, emphysema, and asthma. Respules treat various respiratory disorders, including bronchial asthma.

The global respules market is expected to grow from $1.57 billion in 2022 to $1.69 billion in 2023 at a compound annual growth rate (CAGR) of 8%. The Russia-Ukraine war disrupted the chances of global economic recovery from the COVID-19 pandemic. The war between these two countries has led to economic sanctions on multiple countries, a surge in commodity prices, and supply chain disruptions, causing inflation across goods and services and affecting many markets across the globe. The respules market is expected to reach $2.27 billion in 2027 at a CAGR of 7.6%.

Download Free Sample Of Respules Market Report -

Major competitors in the Respules market are AstraZeneca PLC, GlaxoSmithKline PLC, Teva Pharmaceutical Industries Ltd., Mylan N.V., Sandoz International GmbH, Macleods Pharmaceuticals Ltd.

A key trend in the Respules market includes product innovations. Major companies operating in the respules market are focused on developing innovative products to strengthen their position in the market. For instance, in March 2020, Cipla Limited, an India-based pharmaceutical company, launched Glycohale Respules, an anticholinergic drug employed in managing chronic obstructive pulmonary disease (COPD) COPD. Emphysema, chronic bronchitis, or both are long-term (chronic) lung diseases that comprise COPD.

Read More On The Global Respules Market Report Here:

The Respules market is segmented -
• By Drug Type: Budesonide, Albuterol, Bromide, Salbutamol Sulphate And Bromide
• By Dosage And Strength: 0.25 mg/2 mL, 0.5 mg/2 mL, 1mg/2 mL, Other Dosage And Strength Types
• By Distribution Channel: Hospital Pharmacy, Retail Pharmacy, Online Pharmacy, Other Distribution Channels
• By Geography: Asia-Pacific, Western Europe, Eastern Europe, North America, South America, Middle East, Africa. North America was the largest region in the Respules market.

The Business Research Company's "Global Respules Market Report 2023" provides a thorough understanding of the market across 60 geographies. The report covers market size, growth rate, segments, drivers and trends in every region and country. In addition, the report offers insights on historical and forecast growth, helping players analyze and strategize better.

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The Table Of Content For The Respules Market Include:

1. Executive Summary
2. Respules Market Characteristics
3. Respules Market Trends And Strategies
4. Respules Market - Macro Economic Scenario
5. Global Respules Market Size and Growth
32. Global Respules Market Competitive Benchmarking
33. Global Respules Market Competitive Dashboard
34. Key Mergers And Acquisitions In The Respules Market
35. Respules Market Future Outlook and Potential Analysis
36. Appendix

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Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory condition that represents the third leading cause of death worldwide.1,2 According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 definition, COPD is a

Heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, expectoration, and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.2

People with HIV (PWH) are particularly vulnerable to the development and progression of COPD, with both higher rates of COPD and an earlier and more rapid decline in lung function than in the general population, even after accounting for cigarette smoking and other known risk factors, such as intravenous drug use.3–7 The exact mechanisms that underlie HIV-associated COPD are incompletely known, but environmental exposures, heightened immune activation and systemic inflammation, accelerated aging, a predilection for the development of pneumonia, and alterations in the lung microbiome likely play important roles (Figure 1).8–11 The purpose of this review is to describe what is currently understood about the epidemiology and pathobiology of COPD among PWH, to indicate selected areas of active investigation, and to outline screening, diagnostic, prevention, and treatment strategies.

Figure 1 Drivers of COPD in PWH.



As survival among PWH has improved with the use of antiretroviral therapy (ART), COPD has become an increasingly important comorbidity. PWH develop an earlier and more rapid decline in lung function, even after adjustment for traditional risk factors.3,5–7,12–15 A recent retrospective study evaluating comorbidities in PWH based on hospital discharge data found that COPD was the most common comorbidity across the 10-year study period and that COPD prevalence was higher among PWH than among those without HIV (23.5% versus 14.0%).16 Prevalence estimates of COPD among PWH have ranged from 3.4% to over 40% in prior studies; notably, most of these have been conducted in Europe and North America.17,18 Part of this heterogeneity is due to differences in COPD classification methods, such as self-report, International Classification of Diseases (ICD) diagnostic codes, use of CT scans, and spirometry.17,19 For example, a systematic review and meta-analysis by Bigna et al evaluating the global prevalence of COPD among PWH found that the prevalence varied from 5.6% to 10.6% depending on the diagnostic criteria used, with a higher prevalence when using spirometric criteria instead of self-report or ICD diagnostic codes.4


COPD in PWH occurs anywhere PWH reside. However, the risk factors for the development of COPD in PWH vary regionally due to differences in age, rates and duration of tobacco smoking, exposure to biomass fuels, and prevalence of tuberculosis, all of which have been implicated in COPD development.2,20–22 While the majority of studies on COPD in PWH have been conducted in the US and Europe, most PWH live in sub-Saharan Africa, where there is a high prevalence of both tuberculosis (TB) and exposure to biomass fuels, and where patients are typically younger and less likely to smoke tobacco. While earlier studies suggested that ART itself may be a risk factor for worsening lung function,23,24 Kunisaki et al conducted a multinational randomized controlled trial (RCT) in the modern ART era and did not find a difference in lung function based on timing of ART initiation.25

Biologic Sex

Biologic sex may also contribute to differences in COPD trajectories among PWH. In one study of longitudinal lung function changes in PWH, female sex was associated with distinct lung function trajectories, including baseline low diffusing capacity for carbon monoxide (DLco).26 In a study by McNeil et al of virally suppressed adults with HIV and their seronegative counterparts in Uganda, women with HIV demonstrated an accelerated FEV1 decline as compared to women without HIV, a finding that was not seen among men with and without HIV.27 Interestingly, in a large US-based cross-sectional analysis comparing women with and without HIV, women with HIV had a lower DLco than women without HIV, but there were no differences in spirometric outcomes by HIV status.28,29 In another study including the same cohort of women, baseline COPD prevalence was similar among men with and without HIV and women with and without HIV, but COPD incidence was higher among men with HIV when compared to men without HIV.30 In contrast, Abelman et al found in a post-pneumonia Ugandan cohort that women with HIV had over three-fold higher odds of COPD on spirometry compared to men with HIV, a sex-based difference not found in women and men without HIV.31 Further work is currently underway to investigate whether these reported HIV-associated sex-specific differences in COPD rates are driven by immunologic, hormonal, or environmental factors.

Risk Factors for COPD in PWH

There are many risk factors for the development of COPD in PWH including HIV itself,5,32 cigarette smoking and other inhalational exposures, air pollution, opportunistic infections and pneumonia, microbiome alterations,33,34 accelerated aging,35–38 and socioeconomic factors.39 This section focuses on the major drivers, such as smoking, as well as potential risk factors under investigation, such as chronic cytomegalovirus (CMV) coinfection.


Smoking is the key risk factor for COPD in PWH. Smoking is more prevalent among PWH compared to their seronegative counterparts.40–42 However, studies of co-exposure to HIV and tobacco smoke suggest that PWH who smoke may also be more susceptible to smoking-induced lung damage than HIV-uninfected people who smoke. For example, Diaz et al found emphysema to be more prevalent among smokers with HIV as compared to smokers without HIV.43 Further, in a longitudinal multi-center cohort of 13,687 veterans with and without HIV, Crothers et al found that the prevalence and incidence of both COPD and lung cancer were higher among those with HIV compared to those without HIV despite similar levels of smoking.5 Importantly, among PWH on ART, smoking may reduce life expectancy more than HIV itself.44–46 While the pathophysiologic mechanism driving this HIV-associated difference is incompletely known, recent work suggests that, among PWH, tobacco smoke suppresses alveolar macrophage production of T-cell recruiting chemokines. This impairs the migration of cytotoxic T cells from the airway mucosa into the alveolar space, leading to localized airway mucosa inflammation and tissue destruction.47

Air Pollution

Air pollution – the leading environmental cause of death globally48 – is now the greatest threat to human health,49 and COPD is a leading cause of the nearly 7 million annual deaths attributed to air pollution.48,50 Air pollution results from a variety of human-related activities and natural events that include emissions from vehicles, factories, and power plants; traffic-related products; biomass fuel burning (ie, charcoal, firewood, animal dung, crop residues) for cooking and heating; dust storms; forest fires; and volcanic eruptions. The dominant pollution sources vary by region. Traffic- and industry-related sources drive exposure in high-income countries and urban settings, while biomass-related sources drive exposure in low- and middle-income countries and rural settings.51 Air pollution causes acute and chronic lung dysfunction, structural lung abnormalities, submaximal lung growth in childhood and adolescence, and augments lung disease risk in vulnerable populations.52–63 Even small acute increases in fine particulate matter (PM2.5) exposure worsen mortality,64 and there is no “safe” level of exposure.65 Biomass-associated COPD, compared to tobacco-associated COPD, is characterized by more small airways disease and fibrosis, less emphysema, higher DLco, and less airflow obstruction – in effect, a more fibrotic and less emphysematous phenotype.66–69 Exposure to biomass fuel smoke has also been associated with defective bacterial phagocytosis.70 In addition, PM2.5 exposure may also potentiate TB risk,21,71,72 which by itself is a risk factor for COPD and an important consideration in TB-endemic regions.

Similar to the influence of tobacco smoke, PWH may be more susceptible to air pollution-associated lung damage. For example, among PWH living in San Francisco, exposure to higher levels of outdoor air pollution was associated with increased susceptibility to Pneumocystis infection.73–75 Using ambulatory carbon monoxide (CO) sensors to measure personal air pollution exposure among 260 adults with and without HIV in rural Uganda, North et al found that exposure to short-term CO levels that exceed WHO air quality guidelines was associated with self-reported respiratory symptoms among PWH but not among HIV-uninfected comparators.76 Characterizing air pollution exposure among PWH and exploring the potentially outsized influence of air pollution exposure on lung health in this population is an area of ongoing investigation. As global smoking prevalence continues to decline and rapid industrialization and urbanization progresses, air pollution is poised to replace tobacco as the leading cause of chronic lung disease,77–79 and a multifaceted approach that also focuses on this often overlooked risk factor for lung disease among PWH is critical.

Opportunistic Infections and Pneumonia

PWH have historically had higher rates of pneumonia, and while incidence of bacterial pneumonia has decreased with the advent of ART,80,81 it remains common in this population.82–84 In the current era, PWH have similar rates of acute respiratory infections as people without HIV, but PWH experience more severe disease.85 Pneumonia has been associated with higher rates of COPD and lung function abnormalities in PWH.86–89 For example, Drummond et al conducted a US-based multi-center study evaluating spirometry in adults with and without HIV and found that participants with airflow obstruction were more likely to have a history of bacterial pneumonia and Pneumocystis jirovecii (PJP) infection.90 Specifically, PJP, an opportunistic infection that occurs in PWH with CD4 counts <200 cells/mm,3 elevated HIV RNA, and colonization by Pneumocystis have each been associated with higher risk of COPD among PWH.88,91,92 There are numerous contributors to the increased risk of pneumonia in PWH, including alterations in immunity, which lead to persistently elevated markers of immune activation and inflammation, as well as environmental and behavioral risk factors, and a higher prevalence of COPD, which is both a consequence of and a risk factor for pneumonia.9,93–96

Globally, tuberculosis is the leading infectious cause of death among PWH;97 PWH are 19 times more likely to develop TB disease than their seronegative counterparts.98,99 Pulmonary TB has been found to cause permanent scarring, bronchiectasis, pleural fibrosis, damage to small and large airways, as well as lung parenchymal damage, all of which may contribute to permanent lung function impairment.20,100 Whereas during the treatment phase of TB this impairment is typically restrictive, there is increasing evidence of a relationship between prior pulmonary TB infection and the subsequent development of obstruction and COPD.20,87 Rates differ significantly by the population under study, but pulmonary TB has been found to lead to airway obstruction in 18.4–86% of people in the general population.100 HIV is now recognized as a risk factor for post-TB lung disease, although the extent of this relationship is currently under study.87,100–104 There is some evidence to suggest that HIV may be associated with reduced severity of post-TB lung disease, but this is an area that merits further evaluation.100,105,106

Chronic CMV Infection

CMV is an important and omnipresent coinfection in HIV that has been associated with cardiovascular and cerebrovascular disease, other non-AIDS events, and increased mortality.107–112 Given the high rates of CMV antibody seropositivity among PWH, CMV IgG titers are commonly used as markers of CMV activity and have been shown to correlate with adverse outcomes.112,113 However, studies of CMV’s effect on lung function and COPD in PWH are limited. While chronic CMV infection in children with perinatally acquired HIV on ART has been associated with an abnormal FEV1,114 CMV’s association with COPD and other chronic lung diseases in adults with HIV has not been evaluated. Emerging data from the general population, however, suggest that chronic CMV infection is associated with COPD,115 and that higher CMV IgG titers are associated with COPD-related mortality.113 CMV is also associated with abnormal DLco in solid organ transplant recipients, although this has not been studied in PWH.116–118

There are several proposed mechanisms for CMV-mediated systemic immune effects, including persistent immune activation, endothelial dysfunction, and alterations in the gut microbiome.17,119–121 Similar biomarker activation patterns are noted in PWH with CMV and those with COPD. For example, sCD163, sCD14, and IL-6 are increased in both CMV IgG-positive PWH122–124 and PWH with lung function abnormalities, including both abnormal spirometry and abnormal DLco.10,121 These data suggest that there may be a shared mechanistic pathway between chronic CMV infection and chronic lung disease in PWH, but further work is needed to understand and characterize this relationship.

HIV-Specific Influences on COPD Pathogenesis

Several HIV-specific mechanisms may contribute to the increased incidence and accelerated development of COPD in PWH. Chronic HIV infection and the direct effects of HIV-related proteins on lung cells, altered lung and systemic immune responses (both immunosuppressive and pro-inflammatory), altered airway and gut microbial communities, impaired response to pathogens, and toxicity from antiretroviral therapies may all contribute to COPD pathogenesis in this population.23,24,125–132

HIV Infection

As the lung acts as a reservoir for HIV even after viral suppression, chronic HIV infection may directly contribute to COPD pathogenesis in various ways.132–134 Newly replicated viral particles released slowly over time bind to and interact with many cell types within the lung, which can lead to direct injury, oxidative stress, low-level chronic inflammation, and impaired response to pathogens.128,135 Although other cell types in the lung may be infected, alveolar macrophages are the best studied reservoir of HIV in the lung.132 HIV infection impairs macrophage phagocytic activity, thus hindering response to pathogens.127,132 HIV also skews the macrophage phenotype towards a pro-inflammatory and protease-producing phenotype through the release of a host of cytokines, chemokines, oxidants, and proteases, all of which contribute to COPD pathology. Cytokine and chemokine signaling in HIV-infected macrophages trigger a pro-inflammatory response including neutrophil and lymphocyte infiltration. Kaner et al found that alveolar macrophage expression of proteases such as matrix metalloproteinases 9 and 12 (MMP-9, MMP-12) is higher in PWH who smoke with emphysema than their seronegative counterparts.131 In murine models, MMPs degrade the extracellular matrix, directly contributing to emphysematous tissue destruction.136

Altered Adaptive Immune Responses

COPD development is not only mediated by HIV direct effects, but also by the altered cell-mediated adaptive immune responses in PWH, in particular, altered CD4+ T-cell responses. Numerous studies have shown a relationship between low CD4+ T cell counts and COPD or accelerated lung function decline, although conflicting data also exists.23,125,126,137 T cell exhaustion is typically seen in response to chronic antigen stimulation, such as chronic viral infection, and results in decreased functionality. In PWH, CD4+ T cells show signs of exhaustion even in the presence of ART, with an increased expression of programmed cell death protein-1 (PD-1), as well as impaired proliferative capacity.130,138,139 Furthermore, in PWH with COPD, airway mucosal CD4+ T cell numbers are depleted and poorly responsive to pathogens.130 These findings suggest that dysfunctional CD4+ T cell responses may uniquely contribute to COPD pathogenesis in PWH.

Activated and dysfunctional CD8+ T cells also appear to contribute to the disordered adaptive immune response in chronic HIV infection, and thus could contribute to COPD pathogenesis.138,139 PWH show persistent expansion of CD8+ T cells in blood and alveolar compartments, and the decreased CD4+/CD8+ ratio is associated with lung abnormalities even in PWH on ART.140,141 These expanded CD8+ T cell populations also show dysfunction, which is typically indicative of an accelerated aging or “immunosenescent” response. Like CD4+ T cells, CD8+ T cells display exhaustion markers, including PD-1, and a low proliferative capacity.138,139 The expanded population skews towards memory T cell and terminally differentiated CD8+ T cell populations unable to respond to new insults. Despite their impaired function, these exhausted T-cells produce a low-grade inflammatory response at mucosal surfaces, which is considered central to COPD pathology.

Changes to the Airway Epithelium

Alterations to the airway epithelium, the main barrier protecting the lungs from outside insults, such as cigarette smoke, air pollution, and inhaled toxins, can also play a major role in COPD pathogenesis. HIV has both direct and indirect effects on the airway epithelium, contributing to disordered barrier function, decreased mucociliary clearance, and generation of pro-inflammatory mediators. For example, HIV enters epithelial cells and disrupts cell–cell adhesion.129 HIV-associated proteins released from other infected cells disrupt epithelial tight junctions and induce oxidative stress.142 HIV and cigarette smoke synergistically disrupt mucociliary clearance, additively suppressing CFTR expression to decrease mucus hydration in cell culture models and inducing goblet cell metaplasia/hyperplasia to increase mucus production in simian models.143,144 Finally, when HIV binds specifically to basal cells, epithelial progenitor cells release proteases such as MMP-9 and pro-inflammatory mediators that induce migration and proliferation of macrophages and neutrophils.145

Changes in the Lung and Gut Microbiome

Lastly, shifts in both the lung and the gut microbiome can also contribute to chronic inflammatory responses in the lung and, hence, COPD pathogenesis. Data are conflicting on whether lung microbial communities differ in PWH based on 16S sequencing.146–148 However, subtle differences in the microbiome at the species or strain level or at a functional level cannot be discerned via these sequencing methods. It is plausible that at least a subset of PWH experience pathologic microbial alterations in the airways because of a more hospitable environment for pathogen growth. If present in PWH, microbiome perturbations could contribute to chronic airway inflammation. Furthermore, microbial translocation from a compromised gut mucosa, stimulating a chronic systemic inflammatory response, may contribute to lung disease in PWH as has been seen in asthma and pulmonary infections.149

Diagnosis and Clinical Findings of COPD in PWH

Screening and Diagnosis

COPD remains both underdiagnosed and misdiagnosed in people with HIV.150,151 While currently the US Preventative Services Task Force does not recommend screening for COPD in the general population,152 higher COPD prevalence among PWH raises the question whether screening should be done in this subpopulation. Currently, there are no screening and diagnostic criteria specific to PWH. While several studies have evaluated different screening approaches, no conclusive recommendations can be made regarding COPD screening and diagnosis in PWH at this time.150,153–156 For example, a group in Canada offered screening spirometry to all patients in an HIV clinic;156 notably, less than a third of the invited participants agreed to participate, and only 11% had airflow obstruction.

Recruitment and retention throughout the screening-to-diagnosis cascade have been major challenges in all studies. For example, a group in Italy implemented a three-step case-finding program, involving a 5-question screening questionnaire (which included questions about age, smoking history, cough and sputum production, shortness of breath, and exercise limitation), portable spirometry, and diagnostic spirometry.150 They found that 282 participants (19.6%) had a positive screening questionnaire, defined as having a positive answer to at least three questions, but only 33 participants ultimately completed diagnostic spirometry, of whom 22 met criteria for COPD. High participant dropout at each step of the screening process has been similarly reported elsewhere,153–155 even when the authors bypassed the screening spirometry and had a shorter questionnaire.155 Even within these limitations, COPD prevalence based on the screening outcomes has been consistently higher than the known COPD prevalence in each respective clinic,154 further underscoring the underappreciated burden of chronic lung disease in this population. Additional challenges with screening this high-risk population include lack of a high-performing, validated screening questionnaire in PWH and poor correlation between respiratory symptoms and obstruction on pulmonary function tests (PFTs).155 To our knowledge, qualitative studies focused on identifying patient, provider, or systems-level issues contributing to high dropout rates in screening studies among PWH have not been conducted. Having diagnostic spirometry available at the time of a positive screening questionnaire may help reduce high dropout rates.

Any PWH suspected of having COPD should undergo diagnostic testing with, at a minimum, portable spirometry and, in our opinion, full PFTs with pre- and post-bronchodilator spirometry, total lung capacity and lung volumes if spirometry is abnormal, and DLco measurement. Chest radiography demonstrates classic findings (Figure 2) mostly in individuals with advanced disease but is useful in ruling out alternative etiologies that also present with respiratory symptoms similar to those of COPD. Occasionally, additional testing such as chest computed tomography (CT) scans may be warranted to characterize the observed PFT abnormalities, and certain CT findings such as the presence of large bulla (Figure 3) may lead to consideration of additional therapies (eg, bullectomy).

Figure 2 Chest radiograph from person with HIV and COPD demonstrating hyperinflation, flattened diaphragms, and bilateral bullous lung disease (Courtesy of Laurence Huang, MD).

Figure 3 Chest computed tomography from the same person with HIV and COPD demonstrating large, bilateral bullae. This individual eventually underwent bullectomy with dramatic improvement in his respiratory status (Courtesy of Laurence Huang, MD).

Longitudinal Lung Function Trajectories of COPD in PWH

While there is a paucity of data on the natural history of COPD in PWH, lung function declines faster in PWH compared to HIV-negative controls, even when HIV is well-controlled and smoking rates are comparable.6,7,157 Notably, findings from the Pittsburgh HIV Lung Cohort suggested that there may be distinct lung function trajectories among PWH, in which differences in the rate of decline are associated with specific symptoms and distinct profiles of elevated immune activation biomarkers.26 Importantly, this study did not exclusively enroll individuals with COPD. In the general population, COPD studies have shown that lung function decline accelerates as COPD severity increases,158 but whether similar trajectories are seen in PWH is an area currently under study. In a study evaluating factors associated with lung function decline among PWH by Li et al, the authors found that lung function decline occurred more rapidly in older individuals and those with GOLD stage 1 than those with GOLD stage 0 COPD.126 Taken together, these studies suggest that PWH with COPD may demonstrate distinct lung function trajectories when compared to their seronegative counterparts, although additional study is needed in this area.

Lung Function Trajectories in People with Perinatally Acquired HIV

While this review is focused on COPD in adults with HIV, the growing number of individuals with perinatally acquired HIV and their lung function trajectory should also be considered. Children and adolescents with HIV have a higher risk of pulmonary infections, including TB, and even with early ART initiation they remain more vulnerable to small airways dysfunction and risk of obstructive lung disease and other pulmonary abnormalities on spirometry and imaging.159–166 Even children who were exposed to but not infected with HIV remain at risk for abnormal lung function.167 Further, lung function in children seems to be affected by the timing of maternal ART initiation (pre-pregnancy versus during pregnancy).167 In addition, lung development and the ability to reach maximal lung function is impaired by HIV, repeat infections, smoking, pollution, and poverty, which in turn increases the risk for the development of chronic lung disease in adulthood.168,169 As this vulnerable population ages, we are likely to see an increased burden of chronic obstructive disease earlier in life. As most of our understanding of lung function trajectories in PWH with COPD comes from adult PWH from higher income settings, focused efforts for early screening, diagnosis, and management of this condition are needed in areas with high prevalence of adolescents and adults with perinatally acquired HIV.

Diffusing Capacity for Carbon Monoxide

Abnormal diffusing capacity for carbon monoxide is the most prevalent finding on PFTs in PWH, even when spirometry is normal.29,170 DLco impairment is non-specific and can be attributed to emphysema, fibrosis, pulmonary hypertension, or anemia. In PWH, it is also often associated with prior respiratory infections such as PJP, TB, or bacterial pneumonia, and the DLco abnormality may persist long after clinical and radiographic resolution of infection.89,126 Other risk factors for abnormal DLco include HIV infection, CD4 < 200 cells/mm,3 intravenous drug use, and hepatitis C infection.29,101,170–172

DLco abnormalities can predict the development, symptoms, and outcomes of COPD. Among people who smoke, DLco can become abnormal before spirometric criteria for COPD are met; DLco may also be a marker of early emphysema prior to the development of spirometric obstruction, small airways disease, or early vascular abnormalities.173–175 While there are additional and unique risk factors for abnormal DLco in PWH compared to the general population, perhaps suggestive of an HIV-specific lung function abnormality,10,176 it is also plausible that isolated DLco abnormalities may serve as a marker for early COPD in some patients. Among PWH, abnormal DLco, like abnormal FEV1, is an independent predictor of worse respiratory symptoms (such as dyspnea, cough, and mucus production),170 as well as a worse 6-minute walk test.177,178 Finally, abnormal DLco is an independent predictor of mortality in PWH with COPD.179,180

Imaging Findings in PWH with COPD

New techniques for quantitative imaging assessment have allowed in-depth characterization of imaging abnormalities in people with COPD. As current GOLD criteria define COPD based on chronic respiratory symptoms,2 chest imaging findings such as emphysema describe the structural abnormalities that drive this clinical entity. In the general population of people who smoke, studies have found that evidence of small airways disease and air trapping on imaging could predict COPD development and faster spirometry decline.181,182 Importantly, multiple imaging findings such as early interstitial lung abnormalities,183 pulmonary artery to aorta ratio >1,184 pulmonary arterial vascular pruning,185 progression186 and homogeneity of emphysema,187 airway wall thickness,188,189 and air trapping have all been associated with disease severity and adverse outcomes in COPD.181

Studies in PWH have shown a high prevalence of emphysema even in individuals without overt respiratory disease.190 In addition, Leung et al found that people with low DLco and a combination of centrilobular and paraseptal emphysema were more likely to have progression of emphysema,191 and significant emphysema burden was associated with increased mortality.192 Elevated TNFα and IL-1β, soluble CD14, nadir CD4, and low CD4/CD8 ratio are also independently associated with emphysema in PWH,140,193,194 although reports of a direct association of HIV with emphysema are contradictory.194,195 While the exact mechanisms are an area of active investigation, HIV-mediated chronic inflammation and immune dysregulation likely play an important role in emphysema formation.

Symptoms, Exacerbations, and Mortality

Compared to HIV-negative individuals, PWH with COPD have a higher respiratory symptom burden, worse quality of life, and an increased risk for COPD exacerbations.24,196–202 For example, PWH with emphysema have a worse chronic cough, increased mucus production, and decreased 6-minute walk distance compared to HIV-negative controls.198 In PWH who inject drugs, obstructive lung disease has been associated with more severe dyspnea than in their seronegative counterparts.203 In addition, PWH perform worse on six-minute walk testing.178 While COPD is associated with increased frailty in individuals with and without HIV, physical limitation scores are worse among PWH.204,205 Finally, COPD in PWH is not only often comorbid with cardiovascular disease, but also a risk factor for myocardial infarction206 and has been associated with increased mortality.180,192

Management of COPD in PWH

PWH have historically been excluded from large randomized controlled trials of COPD treatments. Therefore, there are very few HIV-specific data on COPD management, and instead general COPD guidelines for both chronic disease management and COPD exacerbations are applied to PWH.207 These management strategies include guideline-driven inhaler therapy, pulmonary rehabilitation, routine vaccinations, surgical or bronchoscopic lung volume reduction in qualifying patients, and management of other medical comorbidities.2 Here, we will focus on a few HIV-specific considerations.

Smoking Cessation

Given the high smoking prevalence among PWH and the excess morbidity and mortality associated with smoking in this population, smoking cessation remains a fundamental aspect of COPD care in PWH. Unfortunately, prescribing rates for smoking cessation therapies have been low for PWH with tobacco use disorder for many reasons, including competing clinical priorities, lack of time, low rates of provider training in smoking cessation interventions, and limited knowledge of nicotine replacement therapies and varenicline.208,209 In addition, PWH face additional challenges on the path to sustained smoking cessation that are due to HIV-related stigma, high rates of comorbid substance use, anxiety and depression, financial instability, lack of insurance, low level of education, and racial biases.210–213 Tailoring smoking cessation therapies to this population is an active area of research.209,214–226 Increased awareness among HIV care providers of the importance of smoking cessation, financial support for smoking cessation initiatives, and intervention studies inclusive of PWH are needed to identify the best ways to support smokers with HIV on their path to quitting.

Choice of Inhalers

Special attention should be paid in the treatment of COPD to PWH who are taking ritonavir or other boosted ART regimens. Ritonavir and cobicistat block the CYP3A4 isozyme and can increase the concentration of most corticosteroids. As a result, use of inhaled corticosteroids (ICS) in patients on these medications has been reported to cause Cushing’s syndrome.227–230 Beclomethasone is the ICS drug with the best side effect profile and can be used in PWH treated with ritonavir or cobicistat.230 In PWH who are receiving ritonavir or cobicistat, an added consequence is the inability to use any combination medication for COPD that includes an ICS as fluticasone- and budesonide-containing combination inhaler therapies are contraindicated and beclomethasone is only available as a single, standalone inhaler. Given the already elevated risk of pulmonary tuberculosis and other pneumonias in this population, additional caution should be applied when using ICS, as they can increase the risk of lung infections in this already vulnerable population.231,232

Modulation of Chronic Inflammation

While no HIV-specific COPD therapies exist, there is an interest in the role of modulating chronic inflammation to improve lung function and clinical outcomes. For example, in a small double-blind pilot clinical RCT of rosuvastatin taken daily for the management of COPD in PWH, Morris et al showed that after 24 weeks of daily rosuvastatin therapy, FEV1 stabilized and DLco improved significantly.233 Another trial studied the role of weekly azithromycin in HIV-related chronic lung disease, defined as an irreversible obstructive defect with minimal radiographic abnormalities, in children and adolescents.234 While the authors found no improvement in lung function parameters after 72 weeks of treatment, they noted an increased time to and fewer total exacerbations. Furthermore, data in the general population have shown benefit of using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) in slowing down the progression of emphysema on chest CT in COPD, albeit with no effect on longitudinal lung function on spirometry.235 A randomized controlled trial by MacDonald et al measured pneumoprotein levels as a proxy for lung function decline in PWH with COPD randomized to placebo or losartan treatment, but did not see any significant changes in the pneumoprotein plasma concentrations after 12 months of follow-up.236 Finally, an NHLBI-funded multi-site randomized controlled trial evaluating the influence of twice daily doxycycline on change in DLco among PWH who smoke is currently underway.237 In sum, findings from prior studies suggest that targeting chronic inflammation has the potential to improve lung function of PWH with COPD, but currently there are no definitive data to support any single drug’s use.

Prevention of COPD in PWH

Smoking Cessation

Smoking is perhaps the single most important modifiable risk factor for COPD among PWH. Evidence suggests that PWH may metabolize nicotine more rapidly than HIV-uninfected smokers,238 which could have important implications for the effectiveness of smoking cessation interventions among this population. A growing body of literature is focused on identifying effective smoking cessation interventions among PWH; Table 1 summarizes the randomized controlled trials that have been conducted or have recently completed enrollment on smoking cessation in PWH.218,220,225,226,239–262 For example, O’Cleirigh et al found that among 41 PWH who smoke and reported motivation to quit, those who were randomized to receive cognitive behavioral therapy for smoking cessation and anxiety/depression treatment in addition to nicotine replacement therapy were more likely to quit smoking compared to those who received nicotine replacement therapy alone,225 highlighting the importance of focusing concomitantly on smoking cessation and mental health in this population. A Cochrane review summarizing 14 randomized controlled trials of smoking cessation interventions among PWH in the United States found that pairing behavioral interventions with medications may facilitate short-term abstinence in comparison to medications alone but did not appear to facilitate long-term abstinence.263 Further, a systematic review of smoking cessation interventions among PWH found that successful smoking cessation was most likely when the intervention included cellphone-based technology.264 Although long-term smoking cessation is the goal, any reduction in exposure to tobacco products is likely to have significant health impacts. Using a Monte Carlo microsimulation model, Reddy et al demonstrated that sustained smoking cessation among PWH could result in over 260,000 expected years of life gained.44 This per-person survival gain is more than the life expectancy gained with early ART initiation or improved ART adherence, and among the general population is more than the life expectancy gained by initiating statins for primary cardiovascular disease prevention or clopidogrel for secondary cardiovascular disease prevention. Therefore, encouraging and supporting smoking cessation must remain a priority in the care for PWH.

Table 1 Summary of Randomized Controlled Trials of Smoking Cessation in People with HIV

Air Pollution Mitigation

Interventions aimed at reducing personal air pollution exposure can be categorized into policy-level approaches (regional, national, international) and personal-level approaches. Overall, there is no level of air pollution exposure below which there are no negative health impacts. In fact, evidence suggests that the greatest gains in health per unit reduction in air pollution exposure may occur at the lowest end of the exposure spectrum.265 While attention is being paid to regional and national air quality guidelines, individuals with HIV can adopt behavioral changes that may reduce their personal exposure. Evidence to guide these decisions is still an area of active research. In 2019, Carlsten et al published a summary of 10 key approaches to reduce personal exposure to outdoor and indoor pollution sources, including: using close-fitting face masks when exposure is unavoidable; preferential use of active transport (walking or cycling) rather than motorized transport; choosing travel routes that minimize near-road air pollution exposure; optimizing driving style and vehicle settings when in polluted conditions; moderating outdoor physical activity when and where air pollution levels are high; monitoring air pollution levels to inform when individuals should act to minimize exposure; minimizing exposure to household air pollution by using clean fuels, optimizing household ventilation, and adopting efficient cookstoves where possible; and using portable indoor air cleaners.266 Unfortunately, the data supporting these strategies are not of high quality, which highlights the importance of future work focused on carefully designed studies leveraging implementation science methodology to characterize the feasibility, acceptability, and effectiveness of behavioral interventions focused on improving air pollution-associated lung disease.

Infection Prevention

As pulmonary infections, many of which are preventable, have been implicated in the development of COPD among PWH, infection prevention is important for mitigating COPD risk. First, early ART initiation is imperative, as many pulmonary infections such as PJP are opportunistic infections and develop in the setting of high HIV viral loads and low CD4 counts. Primary prophylaxis for PJP prevention is recommended in PWH with CD4 counts <200 cells/mm3 and considered in those with CD4% <14%.267 Given the high morbidity and mortality associated with pneumococcal infection in PWH, pneumococcal immunization has been recommended in all adults with HIV.268 Consistent with general population recommendations, PWH should also receive annual flu vaccination, as well as the full COVID-19 vaccination series. Given the increased risk of TB disease and its associated mortality among PWH, screening for TB is recommended for all PWH at the time of HIV diagnosis and once a CD4 count ≥200 cells/mm3.269 PWH should be tested annually only if they have a history of a negative test for latent TB infection and are at high-risk for repeated or ongoing exposure to people with active TB disease.269 Among PWH diagnosed with latent TB, TB preventive treatment reduces both mortality and progression to active TB and thus should be offered to all PWH with a positive TB screening test without evidence of active TB disease.269,270

Future Directions

Although progress has been made in understanding the underlying mechanisms of COPD among PWH, significant knowledge gaps remain. For example, there are many cross-sectional studies evaluating the prevalence of COPD among PWH but only limited data on the natural disease course of COPD in PWH and whether it differs from the general population. Additionally, while studies suggest that PWH demonstrate a higher risk of COPD and a higher symptom burden, there are no HIV-specific screening guidelines for COPD in PWH. Further research is also needed on the interplay between risk factors such as mode of HIV transmission, biologic sex, aging, CMV infection, air pollution, and TB, as well as a deeper understanding of the epidemiology, development, and progression of chronic lung disease in PWH. Management strategies designed specifically for PWH with COPD are also warranted. Lastly, while much progress has been made in understanding the mechanistic pathways that render PWH particularly vulnerable to developing COPD, we remain limited in our ability to counteract these pathways and prevent COPD development. These are only a few examples highlighting the multiple avenues for future research, all of which have the potential to substantially improve both our scientific understanding of COPD among PWH and our ability to effectively prevent and treat this deadly, irreversible condition.


COPD is highly prevalent among PWH. With an aging global population of PWH, high rates of cigarette smoking, and air pollution, COPD is a growing health challenge, and improved diagnosis and treatment of COPD in PWH will become increasingly important. Further research is needed to understand the underlying mechanisms driving COPD in PWH, as well as HIV-specific screening and treatment modalities.


Katerina L Byanova and Rebecca Abelman are co-first authors for this study. Dr. Byanova was supported by NIH F32 HL166065. Dr. Abelman was supported by NIH T32 AI060530 and K12 HL143961. Dr. North was supported by NIH K23 HL154863. Dr. Christenson was supported by NIH R01 HL143998, she also reports personal fees from AstraZeneca, Sanofi, Regeneron, GlaxoSmithKline, Amgen, MJH Holdings LLC: Physicians’ Education Resource, Glenmark Pharmaceuticals, and Axon Advisors, outside the submitted work. Dr. Huang was supported by NIH R01 HL128156, R01 HL128156-07S2, and R01 HL143998.


1. World Health Organization. The Top 10 Causes of Death; 2020. Available from: Accessed March 31, 2023.

2. GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Global Initiative for Chronic Obstructive Lung Disease; 2023.

3. Crothers K, Butt AA, Gibert CL, et al. Increased COPD among HIV-positive compared to HIV-negative veterans. Chest. 2006;130(5):1326–1333. doi:10.1378/chest.130.5.1326

4. Bigna JJ, Kenne AM, Asangbeh SL, Sibetcheu AT. Prevalence of chronic obstructive pulmonary disease in the global population with HIV: a systematic review and meta-analysis. Lancet Glob Health. 2018;6(2):e193–e202. doi:10.1016/S2214-109X(17)30451-5

5. Crothers K, Huang L, Goulet JL, et al. HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era. Am J Respir Crit Care Med. 2011;183(3):388–395. doi:10.1164/rccm.201006-0836OC

6. Drummond MB, Merlo CA, Astemborski J, et al. The effect of HIV infection on longitudinal lung function decline among IDUs: a prospective cohort. AIDS. 2013;27(8):1303–1311. doi:10.1097/QAD.0b013e32835e395d

7. Thudium RF, Ronit A, Afzal S, et al. Faster lung function decline in people living with HIV despite adequate treatment: a longitudinal matched cohort study. Thorax. 2023;78:535–542.

8. Shenoy MK, Iwai S, Lin DL, et al. Immune response and mortality risk relate to distinct lung microbiomes in patients with HIV and pneumonia. Am J Respir Crit Care Med. 2017;195(1):104–114. doi:10.1164/rccm.201603-0523OC

9. Cribbs SK, Crothers K, Morris A. Pathogenesis of HIV-related lung disease: immunity, infection, and inflammation. Physiol Rev. 2020;100(2):603–632. doi:10.1152/physrev.00039.2018

10. Jan AK, Moore JV, Wang RJ, et al. Markers of inflammation and immune activation are associated with lung function in a multi-center cohort of persons with HIV. AIDS. 2021;35(7):1031–1040. doi:10.1097/QAD.0000000000002846

11. Jeon D, Chang EG, McGing M, et al. Pneumoproteins are associated with pulmonary function in HIV-infected persons. PLoS One. 2019;14(10):e0223263. doi:10.1371/journal.pone.0223263

12. Morris A, George MP, Crothers K, et al. HIV and chronic obstructive pulmonary disease: is it worse and why? Proc Am Thorac Soc. 2011;8(3):320–325. doi:10.1513/pats.201006-045WR

13. Madeddu G, Fois AG, Calia GM, et al. Chronic obstructive pulmonary disease: an emerging comorbidity in HIV-infected patients in the HAART era? Infection. 2013;41(2):347–353. doi:10.1007/s15010-012-0330-x

14. Schouten J, Wit FW, Stolte IG, et al. Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin Infect Dis. 2014;59(12):1787–1797. doi:10.1093/cid/ciu701

15. Petrache I, Diab K, Knox KS, et al. HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism. Thorax. 2008;63(5):463–469. doi:10.1136/thx.2007.079111

16. Rowell-Cunsolo TL, Hu G, Bellerose M, Liu J. Trends in comorbidities among human immunodeficiency virus-infected hospital admissions in New York City from 2006–2016. Clin Infect Dis. 2021;73(7):e1957–e1963. doi:10.1093/cid/ciaa1760

17. Byanova K, Kunisaki KM, Vasquez J, Huang L. Chronic obstructive pulmonary disease in HIV. Expert Rev Respir Med. 2021;15(1):71–87. doi:10.1080/17476348.2021.1848556

18. Kunisaki KM. Recent advances in HIV-associated chronic lung disease clinical research. Curr Opin HIV AIDS. 2021;16(3):156–162. doi:10.1097/COH.0000000000000679

19. Leung JM. HIV and chronic lung disease. Curr Opin HIV AIDS. 2023;18(2):93–101. doi:10.1097/COH.0000000000000777

20. Allwood BW, Myer L, Bateman ED. A systematic review of the association between pulmonary tuberculosis and the development of chronic airflow obstruction in adults. Respiration. 2013;86(1):76–85. doi:10.1159/000350917

21. Kurmi OP, Sadhra CS, Ayres JG, Sadhra SS. Tuberculosis risk from exposure to solid fuel smoke: a systematic review and meta-analysis. J Epidemiol Community Health. 2014;68(12):1112–1118. doi:10.1136/jech-2014-204120

22. Lee KK, Bing R, Kiang J, et al. Adverse health effects associated with household air pollution: a systematic review, meta-analysis, and burden estimation study. Lancet Glob Health. 2020;8(11):e1427–e1434. doi:10.1016/S2214-109X(20)30343-0

23. Gingo MR, George MP, Kessinger CJ, et al. Pulmonary function abnormalities in HIV-infected patients during the current antiretroviral therapy era. Am J Respir Crit Care Med. 2010;182(6):790–796. doi:10.1164/rccm.200912-1858OC

24. George MP, Kannass M, Huang L, Sciurba FC, Morris A, Pai NP. Respiratory symptoms and airway obstruction in HIV-infected subjects in the HAART era. PLoS One. 2009;4(7):e6328. doi:10.1371/journal.pone.0006328

25. Kunisaki KM, Niewoehner DE, Collins G, et al. Pulmonary effects of immediate versus deferred antiretroviral therapy in HIV-positive individuals: a nested substudy within the multicentre, international, randomised, controlled strategic timing of antiretroviral treatment (START) trial. Lancet Respir Med. 2016;4(12):980–989. doi:10.1016/S2213-2600(16)30319-8

26. Konstantinidis I, Qin S, Fitzpatrick M, et al. Pulmonary function trajectories in people with HIV: analysis of the Pittsburgh HIV Lung Cohort. Ann Am Thorac Soc. 2022;9(12):2013–2020. doi:10.1513/AnnalsATS.202204-332OC

27. McNeill J, Okello S, Sentongo R, et al. Chronic HIV infection is associated with accelerated FEV1 decline among women but not among men: a longitudinal cohort study in Uganda. Ann Am Thorac Soc. 2022;19(10):1779–1783. doi:10.1513/AnnalsATS.202111-1275RL

28. Wang RJ, Nouraie M, Kunisaki KM, et al. Lung function in women with and without human immunodeficiency virus. Clin Infect Dis. 2023;76(3):e727–e735. doi:10.1093/cid/ciac391

29. Fitzpatrick ME, Gingo MR, Kessinger C, et al. HIV infection is associated with diffusing capacity impairment in women. J Acquir Immune Defic Syndr. 2013;64(3):284–288. doi:10.1097/QAI.0b013e3182a9213a

30. Gingo MR, Balasubramani GK, Rice TB, et al. Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts. BMC Pulm Med. 2014;14(1):75. doi:10.1186/1471-2466-14-75

31. Abelman RA, Fitzpatrick J, Zawedde J, et al. Sex modifies the risk of HIV-associated obstructive lung disease in Ugandans post-pneumonia. AIDS. 2023;37(11):1683–1692. doi:10.1097/QAD.0000000000003626

32. Ronit A, Lundgren J, Afzal S, et al. Airflow limitation in people living with HIV and matched uninfected controls. Thorax. 2018;73(5):431–438. doi:10.1136/thoraxjnl-2017-211079

33. Yang L, Dunlap DG, Qin S, et al. Alterations in oral microbiota in HIV are related to decreased pulmonary function. Am J Respir Crit Care Med. 2020;201(4):445–457. doi:10.1164/rccm.201905-1016OC

34. Shipley TW, Kling HM, Morris A, et al. Persistent pneumocystis colonization leads to the development of chronic obstructive pulmonary disease in a nonhuman primate model of AIDS. J Infect Dis. 2010;202(2):302–312. doi:10.1086/653485

35. Hernandez Cordero AI, Yang CX, Obeidat M, et al. DNA methylation is associated with airflow obstruction in patients living with HIV. Thorax. 2021;76(5):448–455. doi:10.1136/thoraxjnl-2020-215866

36. Hernandez Cordero AI, Yang CX, Yang J, et al. Airway aging and methylation disruptions in HIV-associated chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2022;206(2):150–160. doi:10.1164/rccm.202106-1440OC

37. Liu JC, Leung JM, Ngan DA, et al. Absolute leukocyte telomere length in HIV-infected and uninfected individuals: evidence of accelerated cell senescence in HIV-associated chronic obstructive pulmonary disease. PLoS One. 2015;10(4):e0124426. doi:10.1371/journal.pone.0124426

38. Xu S, Vucic EA, Shaipanich T, et al. Decreased telomere length in the small airway epithelium suggests accelerated aging in the lungs of persons living with human immunodeficiency virus (HIV). Respir Res. 2018;19(1):117. doi:10.1186/s12931-018-0821-0

39. Crothers K. Chronic obstructive pulmonary disease in patients who have HIV infection. Clin Chest Med. 2007;28(3):575–587, vi. doi:10.1016/j.ccm.2007.06.004

40. Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys. Ann Intern Med. 2015;162(5):335–344. doi:10.7326/M14-0954

41. Mdege ND, Shah S, Ayo-Yusuf OA, Hakim J, Siddiqi K. Tobacco use among people living with HIV: analysis of data from demographic and health surveys from 28 low-income and middle-income countries. Lancet Glob Health. 2017;5(6):e578–e592. doi:10.1016/S2214-109X(17)30170-5

42. Johnston PI, Wright SW, Orr M, et al. Worldwide relative smoking prevalence among people living with and without HIV. AIDS. 2021;35(6):957–970. doi:10.1097/QAD.0000000000002815

43. Diaz PT, King MA, Pacht ER, et al. Increased susceptibility to pulmonary emphysema among HIV-seropositive smokers. Ann Intern Med. 2000;132:369–372.

44. Reddy KP, Parker RA, Losina E, et al. Impact of cigarette smoking and smoking cessation on life expectancy among people with HIV: a US-based modeling study. J Infect Dis. 2016;214(11):1672–1681. doi:10.1093/infdis/jiw430

45. Helleberg M, May MT, Ingle SM, et al. Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America. AIDS. 2015;29(2):221–229. doi:10.1097/QAD.0000000000000540

46. Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis. 2013;56(5):727–734. doi:10.1093/cid/cis933

47. Corleis B, Cho JL, Gates SJ, et al. Smoking and human immunodeficiency virus 1 infection promote retention of CD8(+) T cells in the airway mucosa. Am J Respir Cell Mol Biol. 2021;65(5):513–520. doi:10.1165/rcmb.2021-0168OC

48. Cohen AJ, Brauer M, Burnett R, et al. Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the global burden of diseases study 2015. Lancet. 2017;389(10082):1907–1918. doi:10.1016/S0140-6736(17)30505-6

49. Campbell-Lendrum D, Prüss-Ustün A. Climate change, air pollution and noncommunicable diseases. Bull World Health Organ. 2019;97(2):160–161. doi:10.2471/BLT.18.224295

50. Health Effects Institute. State of Global Air 2020: A Special Report on Global Exposure to Air Pollution and Its Health Impacts. Boston, MA: Health Effects Institute; 2020.

51. Karagulian F, Belis CA, Dora CFC, et al. Contributions to cities’ ambient particulate matter (PM): a systematic review of local source contributions at global level. Atmos Environ. 2015;120:475–483. doi:10.1016/j.atmosenv.2015.08.087

52. Gauderman WJ, Avol E, Gilliland F, et al. The effect of air pollution on lung development from 10 to 18 years of age. N Engl J Med. 2004;351(11):1057–1067. doi:10.1056/NEJMoa040610

53. Rice MB, Ljungman PL, Wilker EH, et al. Long-term exposure to traffic emissions and fine particulate matter and lung function decline in the Framingham heart study. Am J Respir Crit Care Med. 2015;191(6):656–664. doi:10.1164/rccm.201410-1875OC

54. Rice MB, Li W, Schwartz J, et al. Ambient air pollution exposure and risk and progression of interstitial lung abnormalities: the Framingham Heart Study. Thorax. 2019;74(11):1063–1069. doi:10.1136/thoraxjnl-2018-212877

55. Rice MB, Ljungman PL, Wilker EH, et al. Short-term exposure to air pollution and lung function in the Framingham Heart Study. Am J Respir Crit Care Med. 2013;188(11):1351–1357. doi:10.1164/rccm.201308-1414OC

56. Sack C, Vedal S, Sheppard L, et al. Air pollution and subclinical interstitial lung disease: the multi-ethnic study of atherosclerosis (Mesa) air-lung study. Eur Respir J. 2017;50(6):1700559. doi:10.1183/13993003.00559-2017

57. Guarnieri M, Balmes JR. Outdoor air pollution and asthma. Lancet. 2014;383(9928):1581–1592. doi:10.1016/S0140-6736(14)60617-6

58. Li J, Sun S, Tang R, et al. Major air pollutants and risk of COPD exacerbations: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2016;11:3079–3091. doi:10.2147/COPD.S122282

59. Goss CH, Newsom SA, Schildcrout JS, Sheppard L, Kaufman JD. Effect of ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis. Am J Respir Crit Care Med. 2004;169(7):816–821. doi:10.1164/rccm.200306-779OC

60. Rhee J, Dominici F, Zanobetti A, et al. Impact of Long-Term Exposures to Ambient PM(2.5) and Ozone on ARDS Risk for Older Adults in the United States. Chest. 2019;156(1):71–79. doi:10.1016/j.chest.2019.03.017

61. Pope D, Diaz E, Smith-Sivertsen T, et al. Exposure to household air pollution from wood combustion and association with respiratory symptoms and lung function in nonsmoking women: results from the RESPIRE trial, Guatemala. Environ Health Perspect. 2015;123(4):285–292. doi:10.1289/ehp.1408200

62. Siddharthan T, Grigsby MR, Goodman D, et al. Association between household air pollution exposure and chronic obstructive pulmonary disease outcomes in 13 low- and middle-income country settings. Am J Respir Crit Care Med. 2018;197(5):611–620. doi:10.1164/rccm.201709-1861OC

63. Wang M, Aaron CP, Madrigano J, et al. Association between long-term exposure to ambient air pollution and change in quantitatively assessed emphysema and lung function. JAMA. 2019;322(6):546–556. doi:10.1001/jama.2019.10255

64. Liu C, Chen R, Sera F, et al. Ambient particulate air pollution and daily mortality in 652 cities. N Engl J Med. 2019;381(8):705–715. doi:10.1056/NEJMoa1817364

65. Cromar KR, Gladson LA, Ewart G. Trends in excess morbidity and mortality associated with air pollution above American thoracic society-recommended standards, 2008–2017. Ann Am Thorac Soc. 2019;16(7):836–845. doi:10.1513/AnnalsATS.201812-914OC

66. Ramirez-Venegas A, Sansores RH, Quintana-Carrillo RH, et al. FEV1 decline in patients with chronic obstructive pulmonary disease associated with biomass exposure. Am J Respir Crit Care Med. 2014;190(9):996–1002. doi:10.1164/rccm.201404-0720OC

67. González-García M, Maldonado Gomez D, Torres-Duque CA, et al. Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease. J Bras Pneumol. 2013;39(2):147–154. doi:10.1590/S1806-37132013000200005

68. Camp PG, Ramirez-Venegas A, Sansores RH, et al. COPD phenotypes in biomass smoke- versus tobacco smoke-exposed Mexican women. Eur Respir J. 2014;43(3):725–734. doi:10.1183/09031936.00206112

69. Rivera RM, Cosio MG, Ghezzo H, Salazar M, Perez-Padilla R. Comparison of lung morphology in COPD secondary to cigarette and biomass smoke. Int J Tuberc Lung Dis. 2008;12(8):972–977.

70. Ghosh B, Gaike AH, Pyasi K, et al. Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass smoke-related COPD. Eur Respir J. 2019;53(2):1702273. doi:10.1183/13993003.02273-2017

71. Sumpter C, Chandramohan D. Systematic review and meta-analysis of the associations between indoor air pollution and tuberculosis. Trop Med Int Health. 2013;18(1):101–108. doi:10.1111/tmi.12013

72. Rivas-Santiago CE, Sarkar S, Cantarella P, et al. Air pollution particulate matter alters antimycobacterial respiratory epithelium innate immunity. Infect Immun. 2015;83(6):2507–2517. doi:10.1128/IAI.03018-14

73. Blount RJ, Djawe K, Daly KR, et al. Ambient air pollution associated with suppressed serologic responses to Pneumocystis jirovecii in a prospective cohort of HIV-infected patients with Pneumocystis pneumonia. PLoS One. 2013;8(11):e80795. doi:10.1371/journal.pone.0080795

74. Djawe K, Levin L, Swartzman A, et al. Environmental risk factors for Pneumocystis pneumonia hospitalizations in HIV patients. Clin Infect Dis. 2013;56(1):74–81. doi:10.1093/cid/cis841

75. Blount RJ, Daly KR, Fong S, et al. Effects of clinical and environmental factors on bronchoalveolar antibody responses to Pneumocystis jirovecii: a prospective cohort study of HIV+ patients. PLoS One. 2017;12(7):e0180212. doi:10.1371/journal.pone.0180212

76. North CM, MacNaughton P, Lai PS, et al. Personal carbon monoxide exposure, respiratory symptoms, and the potentially modifying roles of sex and HIV infection in rural Uganda: a cohort study. Environ Health. 2019;18(1):73. doi:10.1186/s12940-019-0517-z

77. World Health Organization. WHO Global Report on Trends in Prevalence of Tobacco Use 2000–2025. Geneva: World Health Organization; 2019.

78. Collaborators GBDT, Fullman N, Ng M. Smoking prevalence and attributable disease burden in 195 countries and territories, 1990–2015: a systematic analysis from the global burden of disease study 2015. Lancet. 2017;389(10082):1885–1906. doi:10.1016/S0140-6736(17)30819-X

79. Han L, Zhou W, Li W, Li L. Impact of urbanization level on urban air quality: a case of fine particles (PM(2.5)) in Chinese cities. Environ Pollut. 2014;194:163–170. doi:10.1016/j.envpol.2014.07.022

80. O’Connor J, Vjecha MJ, Phillips AN, et al. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per muL: secondary outcome results from a randomised controlled trial. Lancet HIV. 2017;4(3):e105–e112. doi:10.1016/S2352-3018(16)30216-8

81. Balakrishna S, Wolfensberger A, Kachalov V, et al. Decreasing Incidence and Determinants of Bacterial Pneumonia in People With HIV: the Swiss HIV Cohort Study. J Infect Dis. 2022;225(9):1592–1600. doi:10.1093/infdis/jiab573

82. Hull MW, Phillips P, Montaner JSG. Changing global epidemiology of pulmonary manifestations of HIV/AIDS. Chest. 2008;134(6):1287–1298. doi:10.1378/chest.08-0364

83. Sogaard OS, Lohse N, Gerstoft J, et al. Hospitalization for pneumonia among individuals with and without HIV infection, 1995–2007: a Danish population-based, nationwide cohort study. Clin Infect Dis. 2008;47(10):1345–1353. doi:10.1086/592692

84. Aston SJ, Ho A, Jary H, et al. Etiology and risk factors for mortality in an adult community-acquired pneumonia cohort in Malawi. Am J Respir Crit Care Med. 2019;200(3):359–369. doi:10.1164/rccm.201807-1333OC

85. Brown J, Pickett E, Smith C, et al. The effect of HIV status on the frequency and severity of acute respiratory illness. PLoS One. 2020;15(5):e0232977. doi:10.1371/journal.pone.0232977

86. Varkila MRJ, Vos AG, Barth RE, et al. The association between HIV infection and pulmonary function in a rural African population. PLoS One. 2019;14(1):e0210573. doi:10.1371/journal.pone.0210573

87. North CM, Allen JG, Okello S, et al. HIV infection, pulmonary tuberculosis and COPD in rural Uganda: a cross-sectional Study. Lung. 2018;196(1):49–57. doi:10.1007/s00408-017-0080-8

88. Morris A, Sciurba FC, Norris KA. Pneumocystis: a novel pathogen in chronic obstructive pulmonary disease? COPD. 2008;5(1):43–51. doi:10.1080/15412550701817656

89. Morris A, Huang L, Bacchetti P, et al. Permanent declines in pulmonary function following pneumonia in human immunodeficiency virus-infected persons. Am J Respir Crit Care Med. 2000;162(2):612–616. doi:10.1164/ajrccm.162.2.9912058

90. Drummond MB, Huang L, Diaz PT, et al. Factors associated with abnormal spirometry among HIV-infected individuals. AIDS. 2015;29(13):1691–1700. doi:10.1097/QAD.0000000000000750

91. Fitzpatrick ME, Tedrow JR, Hillenbrand ME, et al. Pneumocystis jirovecii colonization is associated with enhanced Th1 inflammatory gene expression in lungs of humans with chronic obstructive pulmonary disease. Microbiol Immunol. 2014;58(3):202–211. doi:10.1111/1348-0421.12135

92. Norris KA, Morris A, Patil S, Fernandes E. Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome. Immunol Res. 2006;36(1–3):175–187. doi:10.1385/IR:36:1:175

93. Attia E, McGinnis K, Feemster LC, et al. Association of COPD with risk for pulmonary infections requiring hospitalization in HIV-infected veterans. J Acquir Immune Defic Syndr. 2015;70(3):280–288. doi:10.1097/QAI.0000000000000751

94. Alexandrova Y, Costiniuk CT, Jenabian MA. Pulmonary Immune Dysregulation and Viral Persistence During HIV Infection. Front Immunol. 2021;12:808722. doi:10.3389/fimmu.2021.808722

95. Hunt PW, Lee SA, Siedner MJ. Immunologic biomarkers, morbidity, and mortality in treated HIV infection. J Infect Dis. 2016;214(suppl 2):S44–S50. doi:10.1093/infdis/jiw275

96. De P, Farley A, Lindson N, Aveyard P. Systematic review and meta-analysis: influence of smoking cessation on incidence of pneumonia in HIV. BMC Med. 2013;15(11):1–12.

97. UNAIDS. UNAIDS Tuberculosis and HIV; 2022. Available from: Accessed March 13, 2023.

98. World Health Organization. Global Tuberculosis Report 2022. Geneva: World Health Organization; 2022.

99. Vasiliu A, Abelman R, Kherabi Y, Iswari Saktiawati AM, Kay A. Landscape of TB infection and prevention among people living with HIV. Pathogens. 2022;11(1552):1–14. doi:10.3390/pathogens11010001

100. Allwood BW, Byrne A, Meghji J, Rachow A, van der Zalm MM, Schoch OD. Post-tuberculosis lung disease: clinical review of an under-recognised global challenge. Respiration. 2021;100(8):751–763. doi:10.1159/000512531

101. Samperiz G, Guerrero D, Lopez M, et al. Prevalence of and risk factors for pulmonary abnormalities in HIV-infected patients treated with antiretroviral therapy. HIV Med. 2014;15(6):321–329. doi:10.1111/hiv.12117

102. Ralph AP, Kenangalem E, Waramori G, et al. High morbidity during treatment and residual pulmonary disability in pulmonary tuberculosis: under-recognised phenomena. PLoS One. 2013;8(11):e80302. doi:10.1371/journal.pone.0080302

103. Fiogbe AA, Agodokpessi G, Tessier JF, et al. Prevalence of lung function impairment in cured pulmonary tuberculosis patients in Cotonou, Benin. Int J Tuberc Lung Dis. 2019;23(2):195–202. doi:10.5588/ijtld.18.0234

104. Hnizdo E, Singh T, Churchyard G. Chronic pulmonary function impairment caused by initial and recurrent pulmonary tuberculosis following treatment. Thorax. 2000;55:32–38. doi:10.1136/thorax.55.1.32

105. Manji M, Shayo G, Mamuya S, Mpembeni R, Jusabani A, Mugusi F. Lung functions among patients with pulmonary tuberculosis in Dar es Salaam - a cross-sectional study. BMC Pulm Med. 2016;16(1):58. doi:10.1186/s12890-016-0213-5

106. Meghji J, Lesosky M, Joekes E, et al. Patient outcomes associated with post-tuberculosis lung damage in Malawi: a prospective cohort study. Thorax. 2020;75(3):269–278. doi:10.1136/thoraxjnl-2019-213808

107. Hsue PY, Hunt PW, Sinclair E, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS. 2006;20:2275–2283. doi:10.1097/QAD.0b013e3280108704

108. Cheng J, Ke Q, Jin Z, et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog. 2009;5(5):e1000427. doi:10.1371/journal.ppat.1000427

109. Levi LI, Sharma S, Schleiss MR, et al. Cytomegalovirus viremia and risk of disease progression and death in HIV-positive patients starting antiretroviral therapy. AIDS. 2022;36(9):1265–1272. doi:10.1097/QAD.0000000000003238

110. Lichtner M, Cicconi P, Vita S, et al. Cytomegalovirus coinfection is associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients. J Infect Dis. 2015;211(2):178–186. doi:10.1093/infdis/jiu417

111. Wang H, Peng G, Bai J, et al. Cytomegalovirus infection and relative risk of cardiovascular disease (ischemic heart disease, stroke, and cardiovascular death): a meta-analysis of prospective studies up to 2016. J Am Heart Assoc. 2017;6(7). doi:10.1161/JAHA.116.005025

112. Hodowanec AC, Lurain NS, Krishnan S, Bosch RJ, Landay AL. Increased CMV IgG antibody titer is associated with Non-AIDS events among virologically suppressed HIV-positive persons. Pathog Immun. 2019;4(1):66–78. doi:10.20411/pai.v4i1.255

113. Nenna R, Zhai J, Packard SE, et al. High cytomegalovirus serology and subsequent COPD-related mortality: a longitudinal study. ERJ Open Res. 2020;6(2):00062–2020. doi:10.1183/23120541.00062-2020

114. Hameiri Bowen D, Sovershaeva E, Charlton B, et al. Cytomegalovirus-specific immunoglobulin G is associated with chronic lung disease in children and adolescents from sub-saharan Africa living with perinatal human immunodeficiency virus. Clin Infect Dis. 2021;73(1):e264–e266. doi:10.1093/cid/ciaa1757

115. Burkes R, Osterburg A, Hwalek T, Lach L, Panos RJ, Borchers MT. Cytomegalovirus seropositivity is associated with airflow limitation in a cohort of veterans with a high prevalence of smoking. Chronic Obstr Pulm Dis. 2021;8(4):441–449. doi:10.15326/jcopdf.2021.0221

116. van Son WJ, Tegzess AM, Hauw T, et al. Pulmonary dysfunction is common during a cytomegalovirus infection after renal transplantation even in asymptomatic patients. Possible relationship with complement activation. Am Rev Respir Dis. 1987;136(3):580–585. doi:10.1164/ajrccm/136.3.580

117. Wasilewska E, Kuziemski K, Niedoszytko M, et al. Impairment of lung diffusion capacity-a new consequence in the long-term childhood leukaemia survivors. Ann Hematol. 2019;98(9):2103–2110. doi:10.1007/s00277-019-03745-4

118. de Maar EF, Verschuuren EAM, Harmsen MC, The TH, van Son WJ. Pulmonary involvement during cytomegalovirus infection in immunosuppressed patients. Transpl Infect Dis. 2003;5(3):112–120. doi:10.1034/j.1399-3062.2003.00023.x

119. Ramendra R, Isnard S, Lin J, et al. CMV seropositivity is associated with increased microbial translocation in people living with HIV and uninfected controls. Clin Infect Dis. 2020;71(6):1438–1446. doi:10.1093/cid/ciz1001

120. Christensen-Quick A, Vanpouille C, Lisco A, Gianella S. Cytomegalovirus and HIV Persistence: pouring Gas on the Fire. AIDS Res Hum Retroviruses. 2017;33(S1):S23–S30. doi:10.1089/aid.2017.0145

121. Fitzpatrick ME, Nouraie M, Gingo MR, et al. Novel relationships of markers of monocyte activation and endothelial dysfunction with pulmonary dysfunction in HIV-infected persons. AIDS. 2016;30(9):1327–1339. doi:10.1097/QAD.0000000000001092

122. Lurain NS, Hanson BA, Hotton AL, Weber KM, Cohen MH, Landay AL. The association of human cytomegalovirus with biomarkers of inflammation and immune activation in HIV-1-infected women. AIDS Res Hum Retroviruses. 2016;32(2):134–143. doi:10.1089/aid.2015.0169

123. Hodowanec A, Williams B, Hanson B, et al. Soluble CD163 but not soluble CD14 is associated with cytomegalovirus immunoglobulin G antibody levels in virologically suppressed HIV+ individuals. J Acquir Immune Defic Syndr. 2015;70(5):e171–174. doi:10.1097/QAI.0000000000000841

124. Vita S, Lichtner M, Marchetti G, et al. Soluble CD163 in CMV-infected and CMV-uninfected subjects in virologically suppressive antiretroviral therapy in the ICONA cohort. J Acquir Immune Defic Syndr. 2017;74(3):347–352. doi:10.1097/QAI.0000000000001232

125. Risso K, Guillouet-de-Salvador F, Valerio L, et al. COPD in HIV-infected patients: CD4 cell count highly correlated. PLoS One. 2017;12(1):e0169359. doi:10.1371/journal.pone.0169359

126. Li Y, Nouraie SM, Kessinger C, et al. Factors associated with progression of lung function abnormalities in HIV-infected individuals. J Acquir Immune Defic Syndr. 2018;79(4):501–509. doi:10.1097/QAI.0000000000001840

127. Collini PJ, Bewley MA, Mohasin M, et al. HIV gp120 in the lungs of antiretroviral therapy-treated individuals impairs alveolar macrophage responses to pneumococci. Am J Respir Crit Care Med. 2018;197(12):1604–1615. doi:10.1164/rccm.201708-1755OC

128. Cota-Gomez A, Flores AC, Ling XF, Varella-Garcia M, Flores SC. HIV-1 Tat increases oxidant burden in the lungs of transgenic mice. Free Radic Biol Med. 2011;51(9):1697–1707. doi:10.1016/j.freeradbiomed.2011.07.023

129. Brune KA, Ferreira F, Mandke P, et al. HIV impairs lung epithelial integrity and enters the epithelium to promote chronic lung inflammation. PLoS One. 2016;11(3):e0149679. doi:10.1371/journal.pone.0149679

130. Popescu I, Drummond MB, Gama L, et al. Activation-induced cell death drives profound lung CD4(+) T-cell depletion in HIV-associated chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;190(7):744–755. doi:10.1164/rccm.201407-1226OC

131. Kaner RJ, Santiago F, Crystal RG. Up-regulation of alveolar macrophage matrix metalloproteinases in HIV1(+) smokers with early emphysema. J Leukoc Biol. 2009;86(4):913–922. doi:10.1189/jlb.0408240

132. Cribbs SK, Lennox J, Caliendo AM, Brown LA, Guidot DM. Healthy HIV-1-infected individuals on highly active antiretroviral therapy harbor HIV-1 in their alveolar macrophages. AIDS Res Hum Retroviruses. 2015;31(1):64–70. doi:10.1089/aid.2014.0133

133. Lamers SL, Rose R, Maidji E, et al. HIV DNA is frequently present within pathologic tissues evaluated at autopsy from combined antiretroviral therapy-treated patients with undetectable viral loads. J Virol. 2016;90(20):8968–8983. doi:10.1128/JVI.00674-16

134. Costiniuk CT, Salahuddin S, Farnos O, et al. HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy. AIDS. 2018;32(16):2279–2289. doi:10.1097/QAD.0000000000001962

135. Gundavarapu S, Mishra NC, Singh SP, et al. HIV gp120 induces mucus formation in human bronchial epithelial cells through CXCR4/alpha7-nicotinic acetylcholine receptors. PLoS One. 2013;8(10):e77160. doi:10.1371/journal.pone.0077160

136. Atkinson JJ, Lutey BA, Suzuki Y, et al. The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema. Am J Respir Crit Care Med. 2011;183(7):876–884. doi:10.1164/rccm.201005-0718OC

137. Drummond MB, Kirk GD, Astemborski J, et al. Association between obstructive lung disease and markers of HIV infection in a high-risk cohort. Thorax. 2012;67(4):309–314. doi:10.1136/thoraxjnl-2011-200702

138. Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12(10):1198–1202. doi:10.1038/nm1482

139. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350–354. doi:10.1038/nature05115

140. Triplette M, Attia EF, Akgun KM, et al. A low peripheral blood CD4/CD8 ratio is associated with pulmonary emphysema in HIV. PLoS One. 2017;12(1):e0170857. doi:10.1371/journal.pone.0170857

141. Serrano-Villar S, Sainz T, Lee SA, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014;10(5):e1004078. doi:10.1371/journal.ppat.1004078

142. Lassiter C, Fan X, Joshi PC, et al. HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction. AIDS Res Ther. 2009;6(1):1. doi:10.1186/1742-6405-6-1

143. Chinnapaiyan S, Dutta R, Bala J, et al. Cigarette smoke promotes HIV infection of primary bronchial epithelium and additively suppresses CFTR function. Sci Rep. 2018;8(1):7984. doi:10.1038/s41598-018-26095-z

144. Chand HS, Vazquez-Guillamet R, Royer C, et al. Cigarette smoke and HIV synergistically affect lung pathology in cynomolgus macaques. J Clin Invest. 2018;128(12):5428–5433. doi:10.1172/JCI121935

145. Chung NPY, Khan KMF, Kaner RJ, O’Beirne SL, Crystal RG. HIV induces airway basal progenitor cells to adopt an inflammatory phenotype. Sci Rep. 2021;11(1):3988. doi:10.1038/s41598-021-82143-1

146. Beck JM, Schloss PD, Venkataraman A, et al. Multicenter comparison of lung and oral microbiomes of HIV-infected and HIV-uninfected individuals. Am J Respir Crit Care Med. 2015;192(11):1335–1344. doi:10.1164/rccm.201501-0128OC

147. Segal LN, Alekseyenko AV, Clemente JC, et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome. 2013;1(1):19. doi:10.1186/2049-2618-1-19

148. Twigg HL, Knox KS, Zhou J, et al. Effect of advanced HIV Infection on the respiratory microbiome. Am J Respir Crit Care Med. 2016;194(2):226–235. doi:10.1164/rccm.201509-1875OC

149. Li SX, Armstrong A, Neff CP, Shaffer M, Lozupone CA, Palmer BE. Complexities of gut microbiome dysbiosis in the context of HIV infection and antiretroviral therapy. Clin Pharmacol Ther. 2016;99(6):600–611. doi:10.1002/cpt.363

150. Quiros-Roldan E, Pezzoli MC, Berlendis M, et al. A COPD case-finding program in a large cohort of HIV-infected persons. Respir Care. 2019;64(2):169–175. doi:10.4187/respcare.06247

151. Zifodya JS, Triplette M, Shahrir S, et al. A cross-sectional analysis of diagnosis and management of chronic obstructive pulmonary disease in people living with HIV: opportunities for improvement. Medicine (Baltimore). 2021;100(37):e27124. doi:10.1097/MD.0000000000027124

152. USPSTF. Final recommendation statement: chronic obstructive pulmonary disease: screening. US Preventive Services Task Force; 2022.

153. Shirley DK, Kaner RJ, Glesby MJ. Screening for Chronic Obstructive Pulmonary Disease (COPD) in an Urban HIV Clinic: a Pilot Study. AIDS Patient Care STDS. 2015;29(5):232–239. doi:10.1089/apc.2014.0265

154. Ghadaki B, Kronfli N, Vanniyasingam T, Haider S. Chronic obstructive pulmonary disease and HIV: are we appropriately screening? AIDS Care. 2016;28(10):1338–1343. doi:10.1080/09540121.2016.1189499

155. Lambert AA, Drummond MB, Kisalu A, et al. Implementation of a COPD screening questionnaire in an outpatient HIV clinic. COPD. 2016;13(6):767–772. doi:10.3109/15412555.2016.1161016

156. Costiniuk CT, Nitulescu R, Saneei Z, et al. Prevalence and predictors of airflow obstruction in an HIV tertiary care clinic in Montreal, Canada: a cross-sectional study. HIV Med. 2019;20(3):192–201. doi:10.1111/hiv.12699

157. Verboeket SO, Boyd A, Wit FW, et al. Changes in lung function among treated HIV-positive and HIV-negative individuals- analysis of the prospective AGEhIV cohort study. Lancet Healthy Longev. 2021;2(4):e202–211. doi:10.1016/S2666-7568(21)00033-7

158. Tantucci C, Modina D. Lung function decline in COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:95–99. doi:10.2147/COPD.S27480

159. Githinji LN, Gray DM, Hlengwa S, Myer L, Zar HJ. Lung function in South African adolescents infected perinatally with HIV and treated long-term with antiretroviral therapy. Ann Am Thorac Soc. 2017;14(5):722–729. doi:10.1513/AnnalsATS.201612-1018OC

160. Desai SR, Nair A, Rylance J, et al. Human immunodeficiency virus-associated chronic lung disease in children and adolescents in Zimbabwe: chest radiographic and high-resolution computed tomographic findings. Clin Infect Dis. 2018;66(2):274–281. doi:10.1093/cid/cix778

161. Barrera CA, du Plessis A-M, Otero HJ, et al. Quantitative CT analysis for bronchiolitis obliterans in perinatally HIV-infected adolescents—comparison with controls and lung function data. Eur Radiol. 2020;30(8):4358–4368. doi:10.1007/s00330-020-06789-7

162. du Plessis AM, Andronikou S, Machemedze T, et al. High-resolution computed tomography features of lung disease in perinatally HIV-infected adolescents on combined antiretroviral therapy. Pediatr Pulmonol. 2019;54(11):1765–1773. doi:10.1002/ppul.24450

163. Githinji LN, Gray DM, Zar HJ. Lung function in HIV-infected children and adolescents. Pneumonia. 2018;10(6):1–10. doi:10.1186/s41479-017-0045-y

164. Attia EF, Bhatraju PK, Triplette M, et al. Endothelial activation, innate immune activation, and inflammation are associated with postbronchodilator airflow limitation and obstruction among adolescents living with HIV. J Acquir Immune Defic Syndr. 2020;83(3):267–277. doi:10.1097/QAI.0000000000002255

165. Attia EF, Jacobson D, Yu W, et al. Immune imbalance and activation are associated with lower lung function in youth with perinatally acquired HIV. J Allergy Clin Immunol. 2020;145(5):1473–1476. doi:10.1016/j.jaci.2019.12.890

166. Attia EF, Maleche-Obimbo E, West TE, et al. Adolescent age is an independent risk factor for abnormal spirometry among people living with HIV in Kenya. AIDS. 2018;32(10):1353–1359. doi:10.1097/QAD.0000000000001815

167. Gray DM, Wedderburn CJ, MacGinty RP, et al. Impact of HIV and antiretroviral drug exposure on lung growth and function over 2 years in an African Birth Cohort. AIDS. 2020;34(4):549–558. doi:10.1097/QAD.0000000000002444

168. Voraphani N, Stern DA, Zhai J, et al. The role of growth and nutrition in the early origins of spirometric restriction in adult life: a longitudinal, multicohort, population-based study. Lancet Respir Med. 2022;10(1):59–71. doi:10.1016/S2213-2600(21)00355-6

169. Rylance S, Masekela R, Banda NPK, Mortimer K. Determinants of lung health across the life course in sub-Saharan Africa. Int J Tuberc Lung Dis. 2020;24(9):892–901. doi:10.5588/ijtld.20.0083

170. Crothers K, McGinnis K, Kleerup E, et al. HIV infection is associated with reduced pulmonary diffusing capacity. J Acquir Immune Defic Syndr. 2013;64(3):271–278. doi:10.1097/QAI.0b013e3182a9215a

171. Raju S, Astemborski J, Drummond MB, et al. HIV is associated with impaired pulmonary diffusing capacity independent of emphysema. J Acquir Immune Defic Syndr. 2022;89(1):64–68. doi:10.1097/QAI.0000000000002818

172. Simonetti JA, Gingo MR, Kingsley L, et al. Pulmonary function in HIV-Infected recreational drug users in the era of anti-retroviral therapy. J AIDS Clin Res. 2014;5(11):365. doi:10.4172/2155-6113.1000365

173. Kirby M, Owrangi A, Svenningsen S, et al. On the role of abnormal DL(CO) in ex-smokers without airflow limitation: symptoms, exercise capacity and hyperpolarised helium-3 MRI. Thorax. 2013;68(8):752–759. doi:10.1136/thoraxjnl-2012-203108

174. Garcia-Rio F, Miravitlles M, Soriano JB, et al. Prevalence of reduced lung diffusing capacity and CT scan findings in smokers without airflow limitation: a population-based study. BMJ Open Respir Res. 2023;10(1):e001468. doi:10.1136/bmjresp-2022-001468

175. Criner RN, Hatt CR, Galban CJ, et al. Relationship between diffusion capacity and small airway abnormality in COPDGene. Respir Res. 2019;20(1):269. doi:10.1186/s12931-019-1237-1

176. Byanova KL, Fitzpatrick J, Jan AK, et al. Isolated abnormal diffusing capacity for carbon monoxide (iso↓DLco) is associated with increased respiratory symptom burden in people with HIV infection. PLoS One. 2023;18(7):e0288803. doi:10.1371/journal.pone.0288803

177. Diaz AA, Pinto-Plata V, Hernandez C, et al. Emphysema and DLCO predict a clinically important difference for 6MWD decline in COPD. Respir Med. 2015;109(7):882–889. doi:10.1016/j.rmed.2015.04.009

178. Robertson TE, Nouraie M, Qin S, et al. HIV infection is an independent risk factor for decreased 6-minute walk test distance. PLoS One. 2019;14(4):e0212975. doi:10.1371/journal.pone.0212975

179. Chandra D, Gupta A, Fitzpatrick M, et al. Lung function, coronary artery disease, and mortality in HIV. Ann Am Thorac Soc. 2019;16(6):687–697. doi:10.1513/AnnalsATS.201807-460OC

180. Gingo MR, Nouraie M, Kessinger CJ, et al. Decreased lung function and all-cause mortality in HIV-infected individuals. Ann Am Thorac Soc. 2018;15(2):192–199. doi:10.1513/AnnalsATS.201606-492OC

181. Bhatt SP, Washko GR, Hoffman EA, et al. Imaging Advances in Chronic Obstructive Pulmonary Disease. Insights from the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) Study. Am J Respir Crit Care Med. 2019;199(3):286–301. doi:10.1164/rccm.201807-1351SO

182. Arjomandi M, Zeng S, Barjaktarevic I, et al. Radiographic lung volumes predict progression to COPD in smokers with preserved spirometry in SPIROMICS. Eur Respir J. 2019;54(4):1802214. doi:10.1183/13993003.02214-2018

183. Ash SY, Harmouche R, Ross JC, et al. Interstitial features at chest CT enhance the deleterious effects of emphysema in the COPDGene cohort. Radiology. 2018;288(2):600–609. doi:10.1148/radiol.2018172688

184. LaFon DC, Bhatt SP, Labaki WW, et al. Pulmonary artery enlargement and mortality risk in moderate to severe COPD: results from COPDGene. Eur Respir J. 2020;55(2):1901812. doi:10.1183/13993003.01812-2019

185. Washko GR, Nardelli P, Ash SY, et al. Arterial vascular pruning, right ventricular size, and clinical outcomes in chronic obstructive pulmonary disease. A longitudinal observational study. Am J Respir Crit Care Med. 2019;200(4):454–461. doi:10.1164/rccm.201811-2063OC

186. Ash SY, San Jose Estepar R, Fain SB, et al. Relationship between emphysema progression at CT and mortality in ever-smokers: results from the COPDGene and ECLIPSE cohorts. Radiology. 2021;299(1):222–231. doi:10.1148/radiol.2021203531

187. Ju J, Li R, Gu S, et al. Impact of emphysema heterogeneity on pulmonary function. PLoS One. 2014;9(11):e113320. doi:10.1371/journal.pone.0113320

188. Grydeland TB, Dirksen A, Coxson HO, et al. Quantitative computed tomography measures of emphysema and airway wall thickness are related to respiratory symptoms. Am J Respir Crit Care Med. 2010;181(4):353–359. doi:10.1164/rccm.200907-1008OC

189. Grydeland TB, Thorsen E, Dirksen A, et al. Quantitative CT measures of emphysema and airway wall thickness are related to D(L)CO. Respir Med. 2011;105(3):343–351. doi:10.1016/j.rmed.2010.10.018

190. Leader JK, Crothers K, Huang L, et al. Risk factors associated with quantitative evidence of lung emphysema and fibrosis in an HIV-infected cohort. J Acquir Immune Defic Syndr. 2016;71(4):420–427. doi:10.1097/QAI.0000000000000894

191. Leung JM, Malagoli A, Santoro A, et al. Emphysema distribution and diffusion capacity predict emphysema progression in human immunodeficiency virus infection. PLoS One. 2016;11(11):e0167247. doi:10.1371/journal.pone.0167247

192. Triplette M, Justice A, Attia EF, et al. Markers of chronic obstructive pulmonary disease are associated with mortality in people living with HIV. AIDS. 2018;32(4):487–493. doi:10.1097/QAD.0000000000001701

193. Thudium RF, Ringheim H, Ronit A, et al. Independent associations of tumor necrosis factor-alpha and interleukin-1 beta with radiographic emphysema in people living with HIV. Front Immunol. 2021;12:668113. doi:10.3389/fimmu.2021.668113

194. Attia EF, Akgun KM, Wongtrakool C, et al. Increased risk of radiographic emphysema in HIV is associated with elevated soluble CD14 and nadir CD4. Chest. 2014;146(6):1543–1553. doi:10.1378/chest.14-0543

195. Ronit A, Kristensen T, Hoseth VS, et al. Computed tomography quantification of emphysema in people living with HIV and uninfected controls. Eur Respir J. 2018;52(1):1800296. doi:10.1183/13993003.00296-2018

196. Lambert AA, Kirk GD, Astemborski J, Mehta SH, Wise RA, Drummond MB. HIV infection is associated with increased risk for acute exacerbation of COPD. J Acquir Immune Defic Syndr. 2015;69(1):68–74. doi:10.1097/QAI.0000000000000552

197. Sims Sanyahumbi AE, Hosseinipour MC, Guffey D, et al. HIV-infected Children in Malawi have decreased performance on the 6-minute walk test with preserved cardiac mechanics regardless of antiretroviral treatment status. Pediatr Infect Dis J. 2017;36(7):659–664. doi:10.1097/INF.0000000000001540

198. Triplette M, Attia E, Akgun K, et al. The differential impact of emphysema on respiratory symptoms and 6-minute walk distance in HIV infection. J Acquir Immune Defic Syndr. 2017;74(1):e23–e29. doi:10.1097/QAI.0000000000001133

199. Brown J, Roy A, Harris R, et al. Respiratory symptoms in people living with HIV and the effect of antiretroviral therapy: a systematic review and meta-analysis. Thorax. 2017;72(4):355–366. doi:10.1136/thoraxjnl-2016-208657

200. Campo M, Oursler KK, Huang L, et al. Association of chronic cough and pulmonary function with 6-minute walk test performance in HIV infection. J Acquir Immune Defic Syndr. 2014;65(5):557–563. doi:10.1097/QAI.0000000000000086

201. Drummond MB, Kirk GD, Ricketts EP, et al. Cross sectional analysis of respiratory symptoms in an injection drug user cohort: the impact of obstructive lung disease and HIV. BMC Pulm Med. 2010;10(27):1–9. doi:10.1186/1471-2466-10-27

202. Depp TB, McGinnis KA, Kraemer K, et al. Risk factors associated with acute exacerbation of chronic obstructive pulmonary disease in HIV-infected and uninfected patients. AIDS. 2016;30(3):455–463.

203. Drummond MB, Kirk GD, McCormack MC, et al. HIV and COPD: impact of risk behaviors and diseases on quality of life. Qual Life Res. 2010;19(9):1295–1302. doi:10.1007/s11136-010-9701-x

204. Akgun KM, Tate JP, Oursler KK, et al. Association of chronic obstructive pulmonary disease with frailty measurements in HIV-infected and uninfected Veterans. AIDS. 2016;30(14):2185–2193. doi:10.1097/QAD.0000000000001162

205. Lorenz DR, Mukerji SS, Misra V, et al. Predictors of transition to frailty in middle-aged and older people with HIV: a prospective cohort study. J Acquir Immune Defic Syndr. 2021;88(5):518–527. doi:10.1097/QAI.0000000000002810

206. Crothers K, Nance RM, Whitney BM, et al. COPD and the risk for myocardial infarction by type in people with HIV. AIDS. 2023;37(5):745–752. doi:10.1097/QAD.0000000000003465

207. Agusti A, Celli BR, Criner GJ, et al. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Am J Respir Crit Care Med. 2023;207(7):819–837. doi:10.1164/rccm.202301-0106PP

208. Bold KW, Deng Y, Dziura J, et al. Practices, attitudes, and confidence related to tobacco treatment interventions in HIV clinics: a multisite cross-sectional survey. Transl Behav Med. 2022;12(6):726–733. doi:10.1093/tbm/ibac022

209. Foster MG, Toll BA, Ware E, Eckard AR, Sterba KR, Rojewski AM. Optimizing the implementation of tobacco treatment for people with HIV: a pilot study. Int J Environ Res Public Health. 2022;19(19):12896. doi:10.3390/ijerph191912896

210. Agterberg S, Weinberger AH, Stanton CA, Shuter J. Perceived racial/ethnic discrimination and cigarette smoking behaviors among a sample of people with HIV. J Behav Med. 2023;46(5):801–811. doi:10.1007/s10865-023-00401-1

211. Calvo-Sanchez M, Martinez E. How to address smoking cessation in HIV patients. HIV Med. 2015;16(4):201–210. doi:10.1111/hiv.12193

212. Cartujano-Barrera F, Lee D’Abundo M, Arana-Chicas E, et al. Barriers and facilitators of smoking cessation among latinos living with HIV: perspectives from key leaders of community-based organizations and clinics. Int J Environ Res Public Health. 2021;18(7):3437. doi:10.3390/ijerph18073437

213. Shirley DK, Kesari RK, Glesby MJ. Factors associated with smoking in HIV-infected patients and potential barriers to cessation. AIDS Patient Care STDS. 2013;27(11):604–612. doi:10.1089/apc.2013.0128

214. Cui Q, Robinson L, Elston D, et al. Safety and tolerability of varenicline tartrate (Champix((R))/Chantix((R))) for smoking cessation in HIV-infected subjects: a pilot open-label study. AIDS Patient Care STDS. 2012;26(1):12–19. doi:10.1089/apc.2011.0199

215. Elzi L, Spoerl D, Voggensperger J, et al. A smoking cessation programme in HIV-infected individuals: a pilot study. Antivir Ther. 2005;11:787–795.

216. Huber M, Ledergerber B, Sauter R, et al. Outcome of smoking cessation counselling of HIV-positive persons by HIV care physicians. HIV Med. 2012;13(7):387–397. doi:10.1111/j.1468-1293.2011.00984.x

217. Kierstead EC, Harvey E, Sanchez D, et al. A pilot randomized controlled trial of a tailored smoking cessation program for people living with HIV in the Washington, D.C. metropolitan area. BMC Res Notes. 2021;14(2):1–7. doi:10.1186/s13104-020-05417-3

218. Kim SS, Darwish S, Lee SA, Sprague C, DeMarco RF. A randomized controlled pilot trial of a smoking cessation intervention for US women living with HIV: telephone-based video call vs voice call. Int J Womens Health. 2018;10:545–555. doi:10.2147/IJWH.S172669

219. Kim SS, DeMarco RF. The Intersectionality of HIV-related stigma and tobacco smoking stigma with depressive and anxiety symptoms among women living with HIV in the United States: a cross-sectional study. J Assoc Nurses AIDS Care. 2022;33(5):523–533. doi:10.1097/JNC.0000000000000323

220. Kim SS, Lee SA, Mejia J, Cooley ME, Demarco RF. Pilot randomized controlled trial of a digital storytelling intervention for smoking cessation in women living with HIV. Ann Behav Med. 2020;54(6):447–454. doi:10.1093/abm/kaz062

221. Labbe AK, Wilner JG, Coleman JN, et al. A qualitative study of the feasibility and acceptability of a smoking cessation program for people living with HIV and emotional dysregulation. AIDS Care. 2019;31(5):609–615. doi:10.1080/09540121.2018.1533225

222. Lam JO, Levine-Hall T, Hood N, et al. Smoking and cessation treatment among persons with and without HIV in a U.S. integrated health system. Drug Alcohol Depend. 2020;213:108128. doi:10.1016/j.drugalcdep.2020.108128

223. Ledgerwood DM, Yskes R. Smoking cessation for people living with HIV/AIDS: a literature review and synthesis. Nicotine Tob Res. 2016;18(12):2177–2184. doi:10.1093/ntr/ntw126

224. Mann-Jackson L, Choi D, Sutfin EL, et al. A qualitative systematic review of cigarette smoking cessation interventions for persons living with HIV. J Cancer Educ. 2019;34(6):1045–1058. doi:10.1007/s13187-019-01525-2

225. O’Cleirigh C, Zvolensky MJ, Smits JAJ, et al. Integrated treatment for smoking cessation, anxiety, and depressed mood in people living with HIV: a randomized controlled trial. J Acquir Immune Defic Syndr. 2018;79(2):261–268. doi:10.1097/QAI.0000000000001787

226. Shuter J, Morales DA, Considine-Dunn SE, An LC, Stanton CA. Feasibility and preliminary efficacy of a web-based smoking cessation intervention for HIV-infected smokers: a randomized controlled trial. J Acquir Immune Defic Syndr. 2014;67(1):59–66. doi:10.1097/QAI.0000000000000226

227. Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J. Exogenous glucocorticoid excess as a result of ritonavir-fluticasone interaction. Intern Med J. 2005;35(1):67–68. doi:10.1111/j.1445-5994.2004.00723.x

228. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med. 2008;9(6):389–396. doi:10.1111/j.1468-1293.2008.00579.x

229. Kedem E, Shahar E, Hassoun G, Pollack S. Iatrogenic Cushing’s syndrome due to coadministration of ritonavir and inhaled budesonide in an asthmatic human immunodeficiency virus infected patient. J Asthma. 2010;47(7):830–831. doi:10.3109/02770903.2010.485666

230. Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management. HIV Med. 2013;14(9):519–529. doi:10.1111/hiv.12039

231. Brassard P, Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and risk of tuberculosis in patients with respiratory diseases. Am J Respir Crit Care Med. 2011;183(5):675–678. doi:10.1164/rccm.201007-1099OC

232. Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34(3):641–647. doi:10.1183/09031936.00193908

233. Morris A, Fitzpatrick M, Bertolet M, et al. Use of rosuvastatin in HIV-associated chronic obstructive pulmonary disease. AIDS. 2017;31(4):539–544. doi:10.1097/QAD.0000000000001365

234. Ferrand RA, McHugh G, Rehman AM, et al. Effect of once-weekly azithromycin vs placebo in children with HIV-associated chronic lung disease: the BREATHE randomized clinical trial. JAMA Netw Open. 2020;3(12):e2028484. doi:10.1001/jamanetworkopen.2020.28484

235. Parikh MA, Aaron CP, Hoffman EA, et al. Angiotensin-converting inhibitors and angiotensin II receptor blockers and longitudinal change in percent emphysema on computed tomography. the multi-ethnic study of atherosclerosis lung study. Ann Am Thorac Soc. 2017;14(5):649–658. doi:10.1513/AnnalsATS.201604-317OC

236. MacDonald DM, Collins G, Wendt CH, et al. Short communication: a pilot study of the effects of losartan versus placebo on pneumoproteins in HIV: a secondary analysis of a randomized double blind study. AIDS Res Hum Retroviruses. 2022;38(2):127–130. doi:10.1089/aid.2020.0285

237. Doxycycline for emphysema in people living with HIV (The DEPTH Trial). Weill Medical College of Cornell University; 2023. Available from: Accessed March 1, 2023.

238. Ashare RL, Thompson M, Leone F, et al. Differences in the rate of nicotine metabolism among smokers with and without HIV. AIDS. 2019;33(6):1083–1088. doi:10.1097/QAD.0000000000002127

239. Stanton CA, Papandonatos GD, Shuter J, et al. Outcomes of a tailored intervention for cigarette smoking cessation among latinos living with HIV/AIDS. Nicotine Tob Res. 2015;17(8):975–982. doi:10.1093/ntr/ntv014

240. Tseng TY, Krebs P, Schoenthaler A, et al. Combining text messaging and telephone counseling to increase varenicline adherence and smoking abstinence among cigarette smokers living with HIV: a randomized controlled study. AIDS Behav. 2017;21(7):1964–1974. doi:10.1007/s10461-016-1538-z

241. Gritz ER, Danysh HE, Fletcher FE, et al. Long-term outcomes of a cell phone-delivered intervention for smokers living with HIV/AIDS. Clin Infect Dis. 2013;57(4):608–615. doi:10.1093/cid/cit349

242. Vidrine DJ, Arduino RC, Gritz ER. Impact of a cell phone intervention on mediating mechanisms of smoking cessation in individuals living with HIV/AIDS. Nicotine Tob Res. 2006;8 Suppl 1(1):S103–108. doi:10.1080/14622200601039451

243. Vidrine DJ, Arduino RC, Lazev AB, Gritz ER. A randomized trial of a proactive cellular telephone intervention for smokers living with HIV/AIDS. AIDS. 2006;20(2):253–260. doi:10.1097/01.aids.0000198094.23691.58

244. Vidrine DJ, Marks RM, Arduino RC, Gritz ER. Efficacy of cell phone-delivered smoking cessation counseling for persons living with HIV/AIDS: 3-month outcomes. Nicotine Tob Res. 2012;14(1):106–110. doi:10.1093/ntr/ntr121

245. Ingersoll KS, Cropsey KL, Heckman CJ. A test of motivational plus nicotine replacement interventions for HIV positive smokers. AIDS Behav. 2009;13(3):545–554. doi:10.1007/s10461-007-9334-4

246. Lloyd-Richardson EE, Stanton CA, Papandonatos GD, et al. Motivation and patch treatment for HIV+ smokers: a randomized controlled trial. Addiction. 2009;104(11):1891–1900. doi:10.1111/j.1360-0443.2009.02623.x

247. Moadel AB, Bernstein SL, Mermelstein RJ, Arnsten JH, Dolce EH, Shuter J. A randomized controlled trial of a tailored group smoking cessation intervention for HIV-infected smokers. J Acquir Immune Defic Syndr. 2012;61(2):208–215. doi:10.1097/QAI.0b013e3182645679

248. Cropsey KL, Hendricks PS, Jardin B, et al. A pilot study of screening, brief intervention, and referral for treatment (SBIRT) in non-treatment seeking smokers with HIV. Addict Behav. 2013;38(10):2541–2546. doi:10.1016/j.addbeh.2013.05.003

249. Cropsey KL, Jardin BF, Burkholder GA, Clark CB, Raper JL, Saag MS. An algorithm approach to determining smoking cessation treatment for persons living with HIV/AIDS: results of a pilot trial. J Acquir Immune Defic Syndr. 2015;69(3):291–298. doi:10.1097/QAI.0000000000000579

250. Humfleet GL, Hall SM, Delucchi KL, Dilley JW. A randomized clinical trial of smoking cessation treatments provided in HIV clinical care settings. Nicotine Tob Res. 2013;15(8):1436–1445. doi:10.1093/ntr/ntt005

251. Manuel JK, Lum PJ, Hengl NS, Sorensen JL. Smoking cessation interventions with female smokers living with HIV/AIDS: a randomized pilot study of motivational interviewing. AIDS Care. 2013;25(7):820–827. doi:10.1080/09540121.2012.733331

252. Pengpid S, Peltzer K, Puckpinyo A, et al. Screening and concurrent brief intervention of conjoint hazardous or harmful alcohol and tobacco use in hospital out-patients in Thailand: a randomized controlled trial. Subst Abuse Treat Prev Policy. 2015;10(1):22. doi:10.1186/s13011-015-0018-1

253. Mercie P, Arsandaux J, Katlama C, et al. Efficacy and safety of varenicline for smoking cessation in people living with HIV in France (ANRS 144 Inter-ACTIV): a randomised controlled phase 3 clinical trial. Lancet HIV. 2018;5(3):e126–e135. doi:10.1016/S2352-3018(18)30002-X

254. Mussulman LM, Faseru B, Fitzgerald S, Nazir N, Patel V, Richter KP. A randomized, controlled pilot study of warm handoff versus fax referral for hospital-initiated smoking cessation among people living with HIV/AIDS. Addict Behav. 2018;78:205–208. doi:10.1016/j.addbeh.2017.11.035

255. Ashare RL, Thompson M, Serrano K, et al. Placebo-controlled randomized clinical trial testing the efficacy and safety of varenicline for smokers with HIV. Drug Alcohol Depend. 2019;200:26–33. doi:10.1016/j.drugalcdep.2019.03.011

256. Ditre JW, LaRowe LR, Vanable PA, De Vita MJ, Zvolensky MJ. Computer-based personalized feedback intervention for cigarette smoking and prescription analgesic misuse among persons living with HIV (PLWH). Behav Res Ther. 2019;115:83–89. doi:10.1016/j.brat.2018.10.013

257. Gryaznov D, Chammartin F, Stoeckle M, et al. Smartphone app and carbon monoxide self-monitoring support for smoking cessation: a randomized controlled trial nested into the Swiss HIV cohort study. J Acquir Immune Defic Syndr. 2020;85(1):e8–e11. doi:10.1097/QAI.0000000000002396

258. Shuter J, Chander G, Graham AL, Kim RS, Stanton CA. Randomized trial of a web-based tobacco treatment and online community support for people with HIV attempting to quit smoking cigarettes. J Acquir Immune Defic Syndr. 2022;90(2):223–231. doi:10.1097/QAI.0000000000002936

259. Shuter J, Kim RS, An LC, Abroms LC. Feasibility of a smartphone-based tobacco treatment for HIV-infected smokers. Nicotine Tob Res. 2020;22(3):398–407. doi:10.1093/ntr/nty208

260. Stanton CA, Kumar PN, Moadel AB, et al. A multicenter randomized controlled trial of intensive group therapy for tobacco treatment in HIV-infected cigarette smokers. J Acquir Immune Defic Syndr. 2020;83(4):405–414. doi:10.1097/QAI.0000000000002271

261. Schnall R, Liu J, Alvarez G, et al. A smoking cessation mobile app for persons living with HIV: preliminary efficacy and feasibility study. JMIR Form Res. 2022;6(8):e28626. doi:10.2196/28626

262. Tindle HA, Freiberg MS, Cheng DM, et al. Effectiveness of varenicline and cytisine for alcohol use reduction among people with HIV and substance use: a randomized clinical trial. JAMA Netw Open. 2022;5(8):e2225129. doi:10.1001/jamanetworkopen.2022.25129

263. Pool ER, Dogar O, Lindsay RP, Weatherburn P, Siddiqi K. Interventions for tobacco use cessation in people living with HIV and AIDS. Cochrane Database Syst Rev. 2016;6:CD011120.

264. Moscou-Jackson G, Commodore-Mensah Y, Farley J, DiGiacomo M. Smoking-cessation interventions in people living with HIV infection: a systematic review. J Assoc Nurses AIDS Care. 2014;25(1):32–45. doi:10.1016/j.jana.2013.04.005

265. Pope CA, Cropper M, Coggins J, Cohen A. Health benefits of air pollution abatement policy: role of the shape of the concentration-response function. J Air Waste Manag Assoc. 2015;65(5):516–522. doi:10.1080/10962247.2014.993004

266. Carlsten C, Salvi S, Wong GWK, Chung KF. Personal strategies to minimise effects of air pollution on respiratory health: advice for providers, patients and the public. Eur Respir J. 2020;55(6):1902056. doi:10.1183/13993003.02056-2019

267. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV; 2019. Available from: Accessed March 13, 2023.

268. Kobayashi M, Farrar JL, Gierke R, et al. Use of 15-valent pneumococcal conjugate vaccine and 20-valent pneumococcal conjugate vaccine among U.S. adults: updated recommendations of the advisory committee on immunization practices - United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(4):109–117. doi:10.15585/mmwr.mm7104a1

269. World Health Organization. Evidence and research gaps identified during development of policy guidelines for tuberculosis; 2021;

270. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010;2010(1):Cd000171. doi:10.1002/14651858.CD000171.pub3

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Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory condition that affects nearly 50 million people in India, causing persistent breathing difficulties and reducing the overall quality of life. COPD is an umbrella term which encompasses chronic bronchitis and emphysema and is characterized by persistent airflow limitation and difficulty in breathing. 

COPD often results from long-term exposure to irritating gases or particulate matter, most commonly from cigarette smoke. Additional risk factors of COPD include untreated asthma, exposure to air pollution, exposure to biomass fuel and second-hand smoke.

How Heated Steam Therapy Works

Unsplash/Representational image

While existing COPD treatments aim to alleviate symptoms and improve lung function, they may fall short in repairing the underlying damage to the lung tissue. Moderate to severe cases often require more targeted approaches to address the structural changes and promote healing within the lungs.

Heated steam therapy (Bronchoscopic thermal vapour ablation) via bronchoscope represents a cutting-edge treatment designed to directly target damaged lung tissue. This minimally invasive procedure involves the introduction of heated steam into the airways through a bronchoscope, a thin, flexible tube equipped with a light and camera. While heated steam therapy holds great promise, it is essential to carefully select patients based on the type and severity of their COPD and overall health. The procedure may be most beneficial for individuals with emphysema localized to upper parts of the lung who have not responded optimally to traditional treatments.

The procedure begins with the insertion of a bronchoscope into the patient's airways, allowing the medical professional to visualize the affected areas. Once the bronchoscope is in position, heated steam is carefully delivered to the targeted regions within the lungs. The controlled application of heat aims to promote tissue repair and reduce inflammation.

Benefits of Heated Steam Therapy:


- Precision Targeting: Unlike systemic treatments, heated steam therapy precisely targets the affected areas within the lungs, maximizing its therapeutic impact.

- Minimally Invasive: The procedure is minimally invasive, reducing the risks associated with more invasive surgical interventions. Patients typically experience shorter recovery times and fewer complications.

- Improved Lung Function: By promoting tissue repair and regeneration, heated steam therapy aims to enhance lung function, potentially leading to improved breathing and overall quality of life.

Heated steam therapy (Bronchoscopic thermal vapour ablation) via bronchoscope represents a groundbreaking advancement in the field of COPD treatment. By directly addressing damaged lung tissue this innovative approach offers hope to individuals with moderate to severe COPD who seek not only symptom relief despite optimal medical therapy. 

As research and clinical trials continue to unfold, heated steam therapy (Bronchoscopic thermal vapour ablation) may become a transformative option, heralding a new era in the management of chronic respiratory conditions. Always consult with healthcare professionals to determine the most suitable treatment approach based on individual health circumstances.

About the author: Dr. Vivek Singh is the Director, Respiratory and Sleep Medicine, Medanta, Gurugram. All views/opinions expressed in the article are of the author. 

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JONESBORO, Ark. (Edited News Release/KAIT) - November is COPD Awareness Month—a time to raise awareness, take action, and help make a difference in the lives of people living with chronic obstructive pulmonary disease (COPD).

The disease, which includes chronic bronchitis and emphysema, is long-term, and progressive and makes it hard to breathe.

There is currently no cure for COPD, but the disease is treatable.

As the month comes to a close, the American Lung Association is driving attention to its recently released COPD State Briefs, which include data about prevention, diagnosis, health outcomes, and treatment of the disease for all 50 states and Washington, D.C.

The State Briefs found that Arkansas has one of the highest COPD prevalence rates in the country.

Nationally, approximately 5 percent of adults, or 12.5 million people, are living with COPD in Arkansas:

  • 223,174 adults have been diagnosed with COPD
  • The COPD prevalence rate is 9.6 percent
  • 2,338 people die each year from COPD
  • The annual cost of COPD treatment is $295 million
  • 202,540 days of work are lost each year due to COPD

“Unfortunately, here in Arkansas, we face a higher burden of COPD, but together, we can work to help prevent COPD and support our community members living with the disease to live longer and more active lives,” said Laura Turner, senior manager of advocacy for Arkansas at the American Lung Association.

“The new COPD State Briefs also examine key indicators for COPD in Arkansas, such as air quality, tobacco use, education, income level, and vaccination rate, which can help us determine where to focus our prevention efforts and help those most impacted by the disease.”

The Lung Association recommends the following actions to reduce the burden of COPD in Arkansas:

  • Use a validated COPD screening tool for people who may be at risk of COPD or reporting symptoms
  • Confirm a COPD diagnosis using spirometry, especially in primary care
  • Use evidence-based tobacco prevention and cessation services;
  • Promote recommended vaccinations
  • Recommend pulmonary rehabilitation, COPD education, and a COPD Action Plan

Arkansas is one of 11 states with the highest COPD rates and highest burden in the country.

The other states are Alabama, Indiana, Kentucky, Louisiana, Missouri, Maine, Mississippi, Ohio, Tennessee and West Virginia.

COPD prevalence rates range from 3.7 percent in Hawaii to 13.6 percent in West Virginia.

The goal of the COPD State Briefs is to raise awareness for COPD and empower public health and healthcare professionals to take actionable steps to prevent the onset of illness, reduce health inequities, set goals for earlier diagnosis, and ensure clinical guidelines are used to manage and treat COPD.

The COPD State Briefs were created with support from the Centers for Disease Control and Prevention. Learn more and view the COPD State Briefs at

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CHICAGO -- Chest CT images reveal that cigarette and marijuana smokers are at higher risk of developing emphysema, according to research presented November 28 at the RSNA annual meeting.

In her presentation, Jessie Kang, MD, from Dalhousie University in Halifax, Nova Scotia, Canada, showed findings suggesting that people who combine marijuana and cigarettes are 12 times more likely to develop centrilobular emphysema than non-smokers.

“With our study, we show that there are physical effects of marijuana smoking on the lungs and that cigarette smoking and marijuana smoking may have a combined damaging effect on the lungs,” Kang said in a statement.

While there is clear evidence that cigarette smoking causes harm to the lungs, little is known about smoking marijuana’s effects, as well as the combined effects of smoking both.

Kang also noted that marijuana is the most widely used illicit psychoactive substance in the world. Canada legalized nonmedical marijuana in 2018.

Kang and colleagues investigated the effects of marijuana smoking on the lungs and chest wall by evaluating CT chest images in regular marijuana smokers.

The team included people who have at least a two-year history of marijuana use, including use four times a month, and who have had a chest CT. The group excluded people who use marijuana as edibles or oral drops.

CT images show airway changes in a 66-year-old male marijuana and tobacco smoker with cylindrical bronchiectasis and bronchial wall thickening (arrowheads) in multiple lung lobes in a background of paraseptal and centrilobular emphysema. Image and caption courtesy of the RSNA.CT images show airway changes in a 66-year-old male marijuana and tobacco smoker with cylindrical bronchiectasis and bronchial wall thickening (arrowheads) in multiple lung lobes in a background of paraseptal and centrilobular emphysema. Image and caption courtesy of the RSNA.

The researchers found that the proportion of patients with paraseptal emphysema is higher in the cigarette smoker and combined smoker groups. They also found that marijuana smoking was tied to a five- to seven-times higher risk of developing paraseptal emphysema than nonsmokers.

Additionally, the researchers found that the combined smoking group was 12 times more likely to have centrilobular emphysema than nonsmokers. This is a type of pulmonary emphysema where the air sacs within the lungs are damaged, leading to breathing difficulties and other serious respiratory symptoms.

Finally, the team reported that the combined smoker group had a four times higher risk of developing bronchial wall thickening than nonsmokers. However, it also found no significant association between marijuana smokers and gynecomastia.

Kang said this study addressed misconceptions about smoking marijuana’s health effects on the lungs. However, she also called for more research to study the long-term effects, so that the public can make an informed decision on recreational usage of marijuana.

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A State brief from the American Lung Association has released data showing Arkansas has the highest rates of COPD in the country and has recommendations on how to reduce the burden.

The disease known as chronic obstructive pulmonary disease is long-term, includes chronic bronchitis and emphysema, is progressive, and makes it hard to breathe, the brief said.

The ALA stated that the goal of the COPD State Briefs is to raise awareness for COPD and empower public health and healthcare professionals to take actionable steps to prevent the onset of illness, reduce health inequities, set goals for earlier diagnosis, and ensure clinical guidelines are used to manage and treat COPD.

A news release stated that Arkansas is one of 11 states with the highest COPD rates and highest burden in the country. The other states are Alabama, Indiana, Kentucky, Louisiana, Missouri, Maine, Mississippi, Ohio, Tennessee and West Virginia.

“Unfortunately, here in Arkansas, we face a higher burden of COPD, but together we can work to help prevent COPD and support our community members living with the disease to live longer and more active lives,” said Laura Turner, senior manager of advocacy for Arkansas at the American Lung Association. “The new COPD State Briefs also examine key indicators for COPD in Arkansas, such as air quality, tobacco use, education, income level, and vaccination rate, which can help us determine where to focus our prevention efforts and help those most impacted by the disease.”

Nationally, approximately 5 percent of adults, or 12.5 million, people are living with COPD In Arkansas:

  • 223,174 of adults have been diagnosed with COPD;
  • The COPD prevalence rate is 9.6 percent;
  • 2,338 people die each year from COPD;
  • Annual cost of COPD treatment is $295 million; and
  • 202,540 days of work are lost each year due to COPD.

There is currently no cure for COPD, but the disease is treatable.

As November comes to a close, the American Lung Association is driving attention to its recently released COPD State Briefs, which include data about prevention, diagnosis, health outcomes, and treatment of the disease for all 50 states and Washington, D.C.

The Lung Association recommends the following actions to reduce the burden of COPD in Arkansas:

  • Use a validated COPD screening tool for people who may be at risk of COPD or reporting symptoms;
  • Confirm a COPD diagnosis using spirometry, especially in primary care;
  • Use evidence-based tobacco prevention and cessation services;
  • Promote recommended vaccinations; and
  • Recommend pulmonary rehabilitation, COPD education, and a COPD Action Plan.

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CHICAGO , Nov. 28, 2023 /PRNewswire/ -- Smoking marijuana in combination with cigarettes may lead to increased damage of the lung's air sacs, according to research being presented today at the annual meeting of the Radiological Society of North America (RSNA).

It is commonly believed that smoking marijuana is not harmful to the lungs. There is an abundance of established research that identifies the harms of cigarette smoking. In contrast, very little is known about the effects of marijuana smoking, and even less research has been done on the combined effects of smoking marijuana and cigarettes.

"Marijuana is the most widely used illicit psychoactive substance in the world, and its use has increased in Canada since the legalization of non-medical marijuana in 2018," said study co-author Jessie Kang, M.D., cardiothoracic radiologist and assistant professor in the Department of Diagnostic Radiology at Dalhousie University in Halifax, Nova Scotia, Canada. "Currently, not much research exists on the effects of marijuana smoking on the lungs."

To determine the effects of marijuana and cigarette smoking, researchers for the multicenter prospective study examined the chest CT images of four patient groups: non-smokers, cigarette smokers, marijuana smokers, and combined marijuana and cigarette smokers. Marijuana smokers included in the study had smoked marijuana at least four times a month for two years. Patients who ingested marijuana via edibles or oral drops were excluded from the study.

The researchers found that people who combined marijuana and cigarettes were 12 times more likely to have centrilobular emphysema than non-smokers. Centrilobular emphysema is a type of pulmonary emphysema where the air sacs within the lungs are damaged. This can lead to breathing difficulties and other serious respiratory symptoms.

"The mean number of marijuana smoking years was less than compared to cigarette smokers and combined marijuana and cigarette smokers," Dr. Kang said. "However, marijuana that is smoked is often unfiltered, which can potentially lead to more damaging particles entering the airways and lungs."

Combined marijuana and cigarette smokers were three to four times more likely to have airway wall thickening, which can lead to infections, scarring and further airway damage. Association with marijuana only and smoking only with bronchial wall thickening was not as significant. Similar results were seen with centrilobular and paraseptal emphysema, suggesting that the combination of cigarette and marijuana smoking may have a synergistic role on the lungs and airways.

"With our study, we show that there are physical effects of marijuana smoking on the lungs and that cigarette smoking and marijuana smoking may have a combined damaging effect on the lungs," Dr. Kang said.

According to Dr. Kang, further research is needed to identify the long-term effects of smoking marijuana.

"There is a common public misconception that marijuana smoking is not harmful," Dr. Kang said. "More research needs to be done in this area, so the public can make an informed decision on their recreational usage of marijuana."

Co-authors are Sebastian Karpinski, B.Sc., Paul Sathiadoss, M.B.B.S., Eric Lam, M.Sc., Eric Hutfluss, M.D., O. Osorio, M.D., D. A. Hashem, M.D., Matthew D. F. McInnes, M.D., and Giselle Y. Revah, M.D.

Note: Copies of RSNA 2023 news releases and electronic images will be available online at

RSNA is an association of radiologists, radiation oncologists, medical physicists and related scientists promoting excellence in patient care and health care delivery through education, research and technologic innovation. The Society is based in Oak Brook, Illinois. (

Editor's note: The data in these releases may differ from those in the published abstract and those actually presented at the meeting, as researchers continue to update their data right up until the meeting. To ensure you are using the most up-to-date information, please call the RSNA Newsroom at 1-312-791-6610.

For patient-friendly information on chest CT, visit

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Alpha-1 antitrypsin (AAT) is a glycoprotein serine protease inhibitor (coded by the SERPINA1 gene). AAT is mainly synthesized in the liver and released into serum. The main physiological function of AAT is to protect the lung from damage by inhibiting neutrophil elastase but also has anti-inflammatory, immunomodulatory, and anti-infective properties on a wide range of cell types.1,2 The allele coding for the normal AAT protein is designated as M and the homozygous Pi*MM genotype is present in 85–90% of individuals, which leads to the production of serum levels of functional AAT between 90 and 200 mg/dL.3

Alpha-1 antitrypsin deficiency (AATD) is a chronic, autosomal co-dominant hereditary condition characterized by decreased serum AAT levels, which may potentially lead to a loss of pulmonary function, emphysema, and development of liver disease, panniculitis, and vasculitis.4,5 So far, more than 150 mutations of the SERPINA1 gene have been identified, in which 40% of them are responsible for causing AATD.6 The risk for lung disease due to AATD depends on the AAT genotype, the AAT serum levels, and environmental exposures to hazardous agents.4,7 The two most common deficiency mutations are the S and Z alleles, which result in five deficiency genotypes: MS, SS, MZ, SZ, and ZZ.3 The homozygous Pi*ZZ genotype is characterized by a reduction in AAT levels below the protective threshold of 11 µM,8 and predisposes the carriers to develop lung disease (emphysema and premature onset of chronic obstructive pulmonary disease [COPD]) and liver disease (cirrhosis in children and adults, cholestasis, and hepatocarcinoma).9 The remaining deficient AAT genotypes are grouped as rare variants, such as Pi*I and Pi*M malton, and null variants, in which no serum AAT levels are detected.10

Clinical practice guidelines recommend that all symptomatic patients with COPD, emphysema, or asthma with airflow obstruction and relatives of someone with AATD or COPD should undergo specific testing for AATD.4,5,11,12 However, AATD is still a highly underdiagnosed disorder, with less than 10% of patients diagnosed.3 This is often due to the fact that a confirmatory testing needs to be conducted in specialized centers.13,14 Early identification of patients with AATD is recommended because delayed diagnosis worsens clinical status, including COPD-related symptoms.15

Overall, it is estimated that 3.4 million individuals worldwide have one of the deficient allele combinations. When reviewing the epidemiology of the disease, AATD frequency varies markedly among countries worldwide. Specifically, the mean prevalence of Pi*ZZ genotype in Europe is 1 in 35,702, being higher in north-western countries and decreasing gradually from west to east, and in America, the Pi*ZZ prevalence is 1 in 26,002 patients.3 Therefore, there are approximately 74,000 individuals in the European countries and 44,000 in North America with severe AATD of the Pi*ZZ genotype.3 In addition, differences in the risk for developing AATD have been reported depending on the ethnic of the individuals.2 Of note is that mutations rarely described in European patients may be predominantly detected in other countries.16 In some regions of the Mediterranean area, such as southern Italy and central Tunisia, the frequency of rare variant PI*M malton has been described over Pi*Z.16,17

In Turkey, there are limited data on the frequency of AATD and the presence of rare variants.18,19 Considering that prevalence data may differ greatly among countries, regions, and ethnicities, targeted screening programs are needed in countries such as Turkey to identify carriers of AATD variants. Therefore, the aims of the study were to identify AATD as a genetic underlying cause of lung disease in patients with COPD, bronchiectasis, or asthma and to report the frequency of AATD alleles in Turkey.

Materials and Methods

This was a non-interventional, multicenter, prospective study conducted at eight sites in Turkey between October 2021 and June 2022. The study was based on analysis of clinical data obtained under standard clinical practice conditions and enrolled patients with documented COPD or other reasons for AATD testing, such as a relative in whom AATD has been diagnosed.


Patients were selected on the basis of the following inclusion criteria: male or female adult (≥18) of any ethnic origin with documented respiratory symptoms, ie, COPD, bronchiectasis, or asthma, or another reason for wanting to exclude or confirm AATD (for example, liver symptoms or AATD in family members), and willingness to participate in the study. Patients were excluded if they had been previously tested for AATD. Screening of COPD patients in search of AATD was carried out following the ATS-ERS AATD Guidelines.4,5

The protocol was reviewed and approved by the independent ethics committee from the Aydin Adnan Menderes University Medical Faculty and submitted to the national regulatory health authorities (approval number E-66175679-514.05.04–443436) prior to patient enrollment. All patients signed a written informed consent form before the study was initiated, and all study procedures were compliant with the ICH standards for Good Clinical Practice (GCP). The study was conducted in full conformance with applicable local and national laws and regulations and the Declaration of Helsinki.


At screening, demographic and clinical characteristics of patients were recorded (age, sex, ethnicity, and family members with known AATD or COPD), liver disease history (neonatal hepatitis, or a diagnosis with any liver disease), diagnosis of pulmonary disease (COPD, emphysema, bronchiectasis, or asthma), pulmonary function tests (forced expiratory volume in 1 sec % [FEV1], forced vital capacity [FVC], FEV1/FVC), smoking history, respiratory symptoms (chronic cough, sputum production, or shortness of breath), number of COPD exacerbations during the last year, and the number hospitalizations due to exacerbations during the last 2 years. Data from patients were collected on a case report form (CRF).

AAT levels were measured by nephelometry.20 AAT levels should not be measured when patients have an infection since AAT levels would be increased as an acute-phase reaction. Adverse events (AEs) were recorded during the study visit including up to at least 30 minutes after the collection of blood samples. This study was conducted with an in vitro device with no direct contact with the patient except for the blood draw.

Genotyping Test

Whole blood samples were collected as dried blood spots (DBS) by finger stick capillary blood on filter paper for AATD genotyping testing. The diagnostic test also allowed sampling from oral mucosa with a buccal swab. However, that procedure was not approved by health authorities when the study was conducted. Genomic DNA was extracted from whole-blood sample and the allele-specific genotyping was carried out with the validated A1AT Genotyping Test (Progenika, a Grifols company, Derio, Spain). This was a qualitative, PCR, and hybridization-based in vitro diagnostic test (FDA cleared, and CE marked). It relies on allele-specific probes attached to color-coded microspheres, which hybridize specifically to the labelled PCR products. A subsequent fluorescent labelling step allows detection and quantification of the hybridization signal with the Luminex 200TM (Diasorin, Saluggia, Italy) instrument for the simultaneous detection and identification of 14 allelic variants and their associated alleles found in the AAT codifying gene SERPINA1: PI*F, PI*I, PI*S, PI*Z, PI*M procida, PI*M malton, PI*S iiyama, PI*Q0 granite falls, PI*Q0 west, PI*Q0 bellingham, PI*P lowell, PI*Q0 mattawa, PI*Q0 clayton, and PI*M heerlen. The absence of any of the 14 alleles included in the analysis was interpreted, with over 99% of probability, as an M/M genotype.

The AAT allelic variant genotypes and associated allele results, when used in conjunction with clinical findings and other laboratory tests, are intended as an aid in the diagnosis of individuals with AATD.

Statistical Analysis

A sample size of approximately 1000 patients was planned anticipating 10% AATD gene carriers and between three and five cases of severe AATD in that population.3,21 Continuous variables were summarized using the following standard descriptive statistics: number of observations, mean, standard deviation, or median and minimum and maximum ranges, as applicable. Categorical data are described using absolute and relative frequencies. All patients with genotyping analysis results were analyzed. Statistical analysis was descriptive by calculating the different percentages to obtain the frequencies of each AATD genotype. No inferential statistical analysis was conducted.


Study Patients’ Characteristics and Disease Activity

A total of 1090 patients were enrolled during the study period. Two of them (0.18%) did not meet eligibility criteria and were excluded from the analysis. Baseline patient characteristics were available for a total of 1087 patients. The majority were male (85.6%), with a mean age of 61.7 years, and current smokers (32.2%). Patients were diagnosed with COPD (92.7%), bronchiectasis (20.7%) or asthma (19.2%). Some patients had overlapping diagnoses with two or more conditions. The most frequent respiratory symptoms were shortness of breath in 855 (78.7%), sputum production in 683 (68.2%) and chronic cough in 628 (57.8%) patients (Table 1).

Table 1 Demographic and Clinical Data of Assessable Patients Included in the Study. Data Were Available for n=1087 Patients

When patients were stratified by the presence or absence of AATD mutation, no relevant differences between groups were observed in respirometry, smoking habits, or workplace exposure to dust, fumes, or gases. Likewise, no differences were observed in the percentage of patients diagnosed with COPD or emphysema. Liver disease was slightly more common in the group containing AATD mutation than in the non-AATD group (5.9% vs 2.1%). In the AATD group, 35% of the patients had exacerbations in the last year, compared with the 47% in the non-AATD group, although the mean number of exacerbations was the same (Table 1).

AAT serum levels were available for 168 (15%) of patients, with a mean (range) of 1.78 (0.2–20.1) g/L. As expected, AAT serum levels in AATD patients were lower (1 [0.2–1.94] g/L) than in patients without AATD (1.8 [1.3–20.1] g/L).

No adverse events (AEs) or any other safety signal were reported. This was an in vitro device with no direct contact of the device with the patient and no patient contact except for the blood draw.

AATD Genotyping results

The distribution of mutations is shown in Figure 1. Overall, there were 1037 patients (95%) carrying no mutations and 51 (5%) patients with a AATD mutation of any type. Of the patients with mutations, 15 (29.4%) showed the well-known mutations S or Z, whereas 36 patients (70.6%) carried rare alleles (Pi*M malton, Pi*I, Pi*P lowell, Pi*M heerlen, and Pi*S iiyama). The most frequent combinations reported were Pi*M/Z (n=12, 24%), followed by Pi*M/M malton (n=11, 22%). The percentage of patients carrying two deficiency alleles, was 19.6% (n=10 patients): two of them with Pi*Z/Z genotype, seven had a severe deficiency associated with the M malton allele (Pi*M malton/M malton and Pi*Z/M malton), and one had the genotype Pi*Z/M Heerlen (Figure 1).

Figure 1 Distribution of AATD mutations in the study cohort. Data are expressed as absolute values with percentages in parenthesis: the first percentage is referred to the total number of patients with mutations (n=51 patients); the second percentage is referred to the total number of patients in the study cohort (n=1088 patients).

Eighteen (35.3%) patients presented with the Pi*Z mutation. Most of them were former or current smokers (n=17) and had COPD (n=16). Moreover, evidence of advanced COPD (post-bronchodilator FEV1 of 60% or lower) was reported in 10 patients, with the following genotypes: Pi*Z/Z (n=2), Pi*Z/M malton (n=2), Pi*Z/M heerlen (n=1), and Pi*M/Z (n=5).

Rare Genotypes

In this study, AATD mutation Pi*M malton was observed in 18 patients (35.3% of the total mutations), achieving the same frequency as the Z allele. Of those patients with one or two M malton alleles, 11 (61%) had the diagnosis COPD, and all of them were former or current smokers. Three patients with genotypes Pi*M malton/M malton (n=2) and Pi*Z/M malton (n=1) had a post-bronchodilator FEV1 below 30%, indicating severe COPD and emphysema. Six patients were diagnosed with the M malton mutation without having major respiratory symptoms, and one patient was diagnosed with the severe genotype Pi*M malton/M malton who suffered from COPD and was a relative of an individual with AATD.

The heterozygous genotypes P*M/I and P*M/P lowell were identified in eight (16%) and seven (14%) patients, respectively. All of them were current or former smokers who suffered from COPD. The Pi*M heerlen mutation was detected in two (4%) patients. One had the combination with the Z allele (Pi*Z/M heerlen) and had severe AATD. The other was heterozygous with one normal allele (Pi*M/M heerlen). Both patients were former smokers and suffered from severe COPD (FEV1 of 36% and 22%, respectively) with AAT serum levels of 0.44 g/L and 1.03 g/L, respectively. The heterozygous genotypes Pi*M/S and Pi*M/S iiyama corresponded to former smokers with advanced COPD (post-bronchodilator FEV1% of 44%) and emphysema.

The geographic distribution of AATD alleles in Turkey is shown in Figure 2. Geographic data were available for 46 out of 51 patients (90.2%). Most of the AATD mutations (n=24, 52%) were documented in the Eastern Black Sea region of Turkey, whereas in the south (Mediterranean region), no AATD mutations were reported. Of note is that many of the patients diagnosed with an M malton allele came from the Black Sea region (Rize, n=8) and Eastern Anatolia (Erzurum, n=2).

Figure 2 Geographic distribution of AATD mutations among the seven geographical regions of Turkey: Black Sea, Marmara, Aegean, Central Anatolia, Eastern Anatolia, Southeastern Anatolia and Mediterranean. Out of n=51 patients with AATD mutations, data about their geographic origin was available for n=46 patients. Map obtained from

AAT Levels in Patients with AATD Mutation

AAT serum levels were available in 11 (21.1%) patients with AATD mutation and varied according to the mutation. The highest AAT level (1.94 g/L) corresponded to a patient with the Pi*M/I genotype and a FEV1 of 82%, whereas the lowest AAT level (0.21 g/L) was associated with a patient with two deficiency alleles, Pi*Z/M malton and a FEV1 of 60% (Table 2).

Table 2 Alpha-1 Antitrypsin (AAT) Serum Levels (g/L) and Clinical Phenotype Based on Each Genotype in Patients with AATD. AAT Levels Were Available for n=11 (21.6%) Patients with AATD Mutations


This prospective study conducted under standard clinical practice conditions described the frequency of each AATD genotype in a selected sample population of Turkish individuals with pulmonary disease. Specifically, this study was designed to identify patients who were previously diagnosed with COPD, bronchiectasis, or asthma that have a mutation in the SERPINA1 gene, a potential underlying genetic cause of lung disease.

Despite knowing that early diagnosis could help manage patients with AATD, this condition remains widely underdiagnosed.4,11 The present study evidenced that AATD was detected in 5% of patients with COPD, bronchiectasis, and asthma. Interestingly, this percentage was similar to two recent studies, which reported genetic AAT mutations in 7.1% and 3.5% of Turkish patients with COPD.18,19 Similarly, these results were aligned with previous studies that evaluated AATD distribution in patients with other pulmonary diseases,22,23 and reinforced the utility of routine screening for AATD in these patients. The percentage of male patients in our study (85.6%) was unusually high when compared with the COPD and AATD series from other countries, but it was similar to values reported in other Turkish studies (80.6%, 90.5%).18,19 It is possible that cultural reasons in Turkey keep women more hesitant to consult a doctor regarding pulmonary and other diseases.24

Family members of patients with AATD are expected to have more AATD mutations, and a targeted approach for this subgroup usually yields a higher AATD detection rate.25 We identified seven AATD patients with a family history of AATD, six of whom had no respiratory symptoms. This result emphasizes the importance of early testing for AATD in adults with first-degree relatives with severe AATD, regardless of respiratory symptoms, as an important test targeting strategy. Altogether, more extensive screening for AATD could prevent certain clinical consequences by allowing patients to receive early therapeutic intervention or at least smoking prevention or cessation counseling.

The prevalence of AATD mutations in European countries has been extensively evaluated, but there is limited evidence in Turkey. In Finland, the allele frequencies were 19.7 per 1000 habitants for Pi*Z and 10.2 cases per 1000 habitants for Pi*S.26 Similarly, Poland reported a frequency of 17.5 per 1000 for the Pi*S allele and 10.5 per 1000 habitants for the Pi*Z allele.27 The highest frequency of the S allele was observed in the Iberian Peninsula (100–200 cases per 1000 habitants).28

In the present study, we observed a considerably lower frequency for the Pi*S genotype (0.09%) compared with these studies. These differences between geographic areas are to be expected since the distribution of Pi*Z and Pi*S alleles is different among countries and even within different regions of the same country.28 Interestingly, the proportions of the Pi*Z and Pi*S mutations in our Turkish population (35.3% and 2%, respectively) were consistent with the percentages obtained in a feasibility study of the A1AT genotyping test that evaluated the percentage of these mutations in Turkey (36.4% and 5%, respectively).29

The use of AATD genotyping testing is also useful to analyze the most prevalent rare variants in each region. In Turkey, we identified a total of 36 patients who carried rare alleles (Pi*M malton, Pi*I, Pi*P lowell, Pi*M heerlen, and Pi*S iiyama). This high frequency of rare alleles has been previously detected in other countries, evidencing that the so-called rare AATD alleles may not be as rare as expected.10 In Italian patients with AATD, the prevalence of rare AAT genotypes was 11%.17 Similarly, in Switzerland, rare AAT alleles represented 7%,30 and in Japan, the most common deficient variant is the PI*S iiyama, a rare variant present in most patients with AATD.31

Regarding the worldwide geographic distribution of AATD, the highest frequency of Pi*ZZ is located in the Atlantic region of Europe. Then, it decreases gradually from west to east, and in the most remote regions of the south of the continent, until it almost disappears in Asia.28,32 Here, we observed a similar geographic distribution in the frequency of AATD variants since a higher percentage of mutations was observed in the north and decreasing gradually to the south of Turkey.

This study revealed the high frequency of rare AAT variants in Turkey, especially the Pi*M malton, being the most frequent mutation detected. Thirty-five percent of all AATD mutations were associated with the Pi*M malton rare allele, which has the same frequency as the most prevalent mutation (Z allele) in other regions. This finding is in agreement with previous research in which the rare variant Pi*M malton prevails over Z and S alleles in particular regions of the Mediterranean area, such as southern Italy,17 central Tunisia, and North Africa.16,33 Human migrations, commercial purposes, and ethnic relationships between these countries have been proposed to be responsible for spreading rare AATD variants in these regions.16,19,33 The Pi*M malton mutations and other rare AATD variants seem to be widespread in regions in which the frequency of Pi*ZZ is lower.16,17 In the current study, the geographic distribution of patients carrying the rare AATD variant Pi*M malton were mainly located in the Black Sea region in northern Turkey. More importantly, individuals with the Pi*M malton may develop pulmonary emphysema and polymeric intrahepatic inclusions like in AATD patients with Pi*ZZ genotype.10 Indeed, it has been shown that rare AATD mutations could be identified in up to 17% of clinical cases.34 In the present study, most of the reported Pi*M malton cases presented with pulmonary emphysema. Since rare AATD variants remain unexplored in many regions worldwide, targeted screening programs could be recommended even in countries in which a high prevalence of the disease has been reported.

One of the potential benefits of conducting extensive AATD genetic testing is to consider providing early lifestyle interventions, such as smoking prevention, and to prevent delayed introduction of augmentation therapy to preserve lung parenchyma in patients with emphysema. The S iiyama allele is another extremely rare variant mainly identified among Japanese patients that has very rarely been found outside of Japan.31 It was found in the study cohort in a heterozygous Pi*M/S iiyama variant patient who was a former smoker with advanced COPD. Altogether, more than 150 mutations of the SERPINA-1 gene have been described in the literature,34 and new mutations are currently being identified.35 Evidence is emerging that rare AATD mutations may play an important role in Turkey. For example, Pi*M malton was found to have the same frequency as Pi*Z and lead to comparable clinical symptoms.

AATD is characterized by a diverse clinical expression and prognosis. Augmentation therapy with AAT is indicated for patients with severe AATD, in which serum AAT levels are below the protective threshold of 11 µM (or 0.5 g/L),4 and who have evidence of advanced lung disease. Early identification of those patients with extremely low AAT levels is paramount since they are more prone to developing COPD and emphysema.8,36 In our analysis, only three patients were documented to have AAT serum levels below the protective threshold: 0.33 g/L (Pi*ZZ genotype), 0.21 g/L (Pi*Z/M malton) and 0.44 g/L (Pi*Z/M heerlen). AAT serum levels were not routinely available in the study centers. It would be important to better establish AAT serum-level testing in Turkey for the future.

One of the limitations of this study is that the real AATD prevalence was overestimated since this was a highly selected population in which patients with family members known to have AATD disease were included. This could have increased the probability of identifying a patient with AATD. AATD prevalence in a whole-population-based study is usually lower compared to a study conducted in a targeted population.37 Additional limitations are that AAT serum levels were only available for a small number of patients because it was not routinely collected and that female patients were underrepresented. The inclusion of these patients would have strengthened the generalizability of the study results.


In conclusion, our results confirm AATD as a genetic underlying cause of lung disease and determine the frequencies of different AATD alleles in a selected population of Turkish individuals.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.


Eugenio Rosado, PhD, and Jordi Bozzo, PhD CMPP (Grifols), are acknowledged for medical writing and editorial support in the preparation of this manuscript. The authors wish to thank all the patients who contributed to this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas and took part in drafting, revising, or critically reviewing the article. MP: conceptualization, study design, methodology, resources, data acquisition, data curation, investigation, writing – review and editing. STO, SA, NS, MÇ, DK, AŞ, BPY, NK, SAB, and SKC: study design, methodology, resources, data acquisition, data curation, validation, investigation, writing – review and editing. AN and BD: conceptualization, formal analysis, project administration, supervision, validation, visualization, writing – review and editing. All authors critically revised, edited, agreed, and approved the final version of the article before submission, and during the revision, of the manuscript. Authors agreed in the journal to which the article is submitted, take responsibility, and are accountable for the contents of the article.


This study was funded by Grifols, manufacturer of A1AT Genotyping Test and plasma-derived alpha-1 antitrypsin medicinal products.


AN and BD are full-time employees of Grifols. DK reports honoraria paid to her institution, as speaker, from AstraZeneca, Abdi İbrahim, Novartis and Grifols, outside the submitted work. The remaining authors have no conflicts of interest to declare for this work.


1. de Serres F, Blanco I. Role of alpha-1 antitrypsin in human health and disease. J Intern Med. 2014;276(4):311–335. doi:10.1111/joim.12239

2. de Serres FJ, Blanco I, Fernández-Bustillo E. Ethnic differences in alpha-1 antitrypsin deficiency in the United States of America. Ther Adv Respir Dis. 2010;4(2):63–70. doi:10.1177/1753465810365158

3. Blanco I, Bueno P, Diego I, et al. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update. Int J Chron Obstruct Pulmon Dis. 2017;12:561–569. doi:10.2147/copd.S125389

4. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α(1)-antitrypsin deficiency. Eur Respir J. 2017;50(5). doi:10.1183/13993003.00610-2017

5. Stoller JK, American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818–900. doi:10.1164/rccm.168.7.818

6. Silva D, Oliveira MJ, Guimarães M, Lima R, Gomes S, Seixas S. Alpha-1-antitrypsin (SERPINA1) mutation spectrum: three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal. Respir Med. 2016;116:8–18. doi:10.1016/j.rmed.2016.05.002

7. Mayer AS, Stoller JK, Bucher Bartelson B, James Ruttenber A, Sandhaus RA, Newman LS. Occupational exposure risks in individuals with PI*Z alpha(1)-antitrypsin deficiency. Am J Respir Crit Care Med. 2000;162(2 Pt 1):553–558. doi:10.1164/ajrccm.162.2.9907117

8. Ferrarotti I, Thun GA, Zorzetto M, et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax. 2012;67(8):669–674. doi:10.1136/thoraxjnl-2011-201321

9. Patel D, Teckman JH. Alpha-1-Antitrypsin Deficiency Liver Disease. Clin Liver Dis. 2018;22(4):643–655. doi:10.1016/j.cld.2018.06.010

10. Rodriguez-Frias F, Miravitlles M, Vidal R, Camos S, Jardi R. Rare alpha-1-antitrypsin variants: are they really so rare? Ther Adv Respir Dis. 2012;6(2):79–85. doi:10.1177/1753465811434320

11. Sandhaus RA, Turino G, Brantly ML, et al. The Diagnosis and Management of Alpha-1 Antitrypsin Deficiency in the Adult. Chronic Obstr Pulm Dis. 2016;3(3):668–682. doi:10.15326/jcopdf.3.3.2015.0182

12. Casas F, Blanco I, Martínez MT, et al. Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update. Arch Bronconeumol. 2015;51(4):185–192. doi:10.1016/j.arbres.2014.05.008

13. Miravitlles M, Nuñez A, Torres-Durán M, et al. The Importance of Reference Centers and Registries for Rare Diseases: the Example of Alpha-1 Antitrypsin Deficiency. Copd. 2020;17(4):346–354. doi:10.1080/15412555.2020.1795824

14. Gurevich S, Daya A, Da Silva C, Girard C, Rahaghi F. Improving Screening for Alpha-1 Antitrypsin Deficiency with Direct Testing in the Pulmonary Function Testing Laboratory. Chronic Obstr Pulm Dis. 2021;8(2):190–197. doi:10.15326/jcopdf.2020.0179

15. Tejwani V, Nowacki AS, Fye E, Sanders C, Stoller JK. The Impact of Delayed Diagnosis of Alpha-1 Antitrypsin Deficiency: the Association Between Diagnostic Delay and Worsened Clinical Status. Respir Care. 2019;64(8):915–922. doi:10.4187/respcare.06555

16. Denden S, Zorzetto M, Amri F, et al. Screening for Alpha 1 antitrypsin deficiency in Tunisian subjects with obstructive lung disease: a feasibility report. Orphanet J Rare Dis. 2009;4:12. doi:10.1186/1750-1172-4-12

17. Ferrarotti I, Baccheschi J, Zorzetto M, et al. Prevalence and phenotype of subjects carrying rare variants in the Italian registry for alpha1-antitrypsin deficiency. J Med Genet. 2005;42(3):282. doi:10.1136/jmg.2004.023903

18. Çörtük M, Demirkol B, Arslan MA, et al. Frequency of alpha-1 antitrypsin deficiency and unexpected results in COPD patients in Turkey; rare variants are common. Turk J Med Sci. 2022;52(5):1478–1485. doi:10.55730/1300-0144.5486

19. Önür ST. Initial alpha-1 antitrypsin screening in Turkish patients with chronic obstructive pulmonary disease. Turk J Med Sci. 2023;53(4):1012–1018.

20. Ferrarotti I, Scabini R, Campo I, et al. Laboratory diagnosis of alpha-1-antitrypsin deficiency. Transl Res. 2007;150(5):267–274. doi:10.1016/j.trsl.2007.08.001

21. Greulich T, Rodríguez-Frias F, Belmonte I, Klemmer A, Vogelmeier CF, Miravitlles M. Real world evaluation of a novel lateral flow assay (AlphaKit® QuickScreen) for the detection of alpha-1-antitrypsin deficiency. Respir Res. 2018;19(1):151. doi:10.1186/s12931-018-0826-8

22. Carreto L, Morrison M, Donovan J, et al. Utility of routine screening for alpha-1 antitrypsin deficiency in patients with bronchiectasis. Thorax. 2020;75(7):592–593. doi:10.1136/thoraxjnl-2019-214195

23. Veith M, Tüffers J, Peychev E, et al. The Distribution of Alpha-1 Antitrypsin Genotypes Between Patients with COPD/Emphysema, Asthma and Bronchiectasis. Int J Chron Obstruct Pulmon Dis. 2020;15:2827–2836. doi:10.2147/copd.S271810

24. Tackett S, Young JH, Putman S, Wiener C, Deruggiero K, Bayram JD. Barriers to healthcare among Muslim women: a narrative review of the literature. Women’s Studies International Forum. 2018;69:190–194.

25. Brantly M, Campos M, Davis AM, et al. Detection of alpha-1 antitrypsin deficiency: the past, present and future. Orphanet J Rare Dis. 2020;15(1):96. doi:10.1186/s13023-020-01352-5

26. Häggblom J, Kettunen K, Karjalainen J, Heliövaara M, Jousilahti P, Saarelainen S. Prevalence of PI*Z and PI*S alleles of alpha-1-antitrypsin deficiency in Finland. Eur Clin Respir J. 2015;2:28829. doi:10.3402/ecrj.v2.28829

27. Kaczor MP, Sanak M, Libura-Twardowska M, Szczeklik A. The prevalence of alpha(1)-antitrypsin deficiency in a representative population sample from Poland. Respir Med. 2007;101(12):2520–2525. doi:10.1016/j.rmed.2007.06.032

28. Blanco I, de Serres FJ, Fernandez-Bustillo E, Lara B, Miravitlles M. Estimated numbers and prevalence of PI*S and PI*Z alleles of α1-antitrypsin deficiency in European countries. Eur Respir J. 2006;27(1):77–84. doi:10.1183/09031936.06.00062305

29. Lopez-Campos JL, Osaba L, Czischke K, et al. Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis. Respir Res. 2022;23(1):152. doi:10.1186/s12931-022-02074-x

30. Zorzetto M, Russi E, Senn O, et al. SERPINA1 gene variants in individuals from the general population with reduced α1-antitrypsin concentrations. Clin Chem. 2008;54(8):1331–1338. doi:10.1373/clinchem.2007.102798

31. Seyama K, Nukiwa T, Souma S, Shimizu K, Kira S. Alpha 1-antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of alpha 1-antitrypsin deficiency in Japan. Am J Respir Crit Care Med. 1995;152(6 Pt 1):2119–2126. doi:10.1164/ajrccm.152.6.8520784

32. de Serres FJ, Blanco I, Fernández-Bustillo E. Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of α1-antitrypsin deficiency in Asia. Eur Respir J. 2006;28(6):1091–1099. doi:10.1183/09031936.00029806

33. Denden S, Lakhdar R, Keskes NB, Hamdaoui MH, Chibani JB, Khelil AH. PCR-based screening for the most prevalent alpha 1 antitrypsin deficiency mutations (PI S, Z, and Mmalton) in COPD patients from Eastern Tunisia. Biochem Genet. 2013;51(9–10):677–685. doi:10.1007/s10528-013-9597-6

34. Seixas S, Marques PI. Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum. Appl Clin Genet. 2021;14:173–194. doi:10.2147/tacg.S257511

35. Presotto MA, Veith M, Trinkmann F, et al. Clinical characterization of a novel alpha1-antitrypsin null variant: piQ0(Heidelberg). Respir Med Case Rep. 2022;35:101570. doi:10.1016/j.rmcr.2021.101570

36. Gadek JE, Klein HG, Holland PV, Crystal RG. Replacement therapy of alpha 1-antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects. J Clin Invest. 1981;68(5):1158–1165. doi:10.1172/jci110360

37. Acquavella J, Vágó E, Sorensen HT, Horváth-Puhó E, Hess GP. Registry-based cohort study of alpha-1 antitrypsin deficiency prevalence, incidence and mortality in Denmark 2000-2018. BMJ Open Respir Res. 2022;9(1). doi:10.1136/bmjresp-2022-001281

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COPD Includes Chronic Lung Diseases Like Emphysema, Some Types of Asthma, and Chronic Bronchitis

Smoking is Main Cause of COPD; Support for Those Who Want to Quit is Available & Affordable in NYS

ALBANY, N.Y. (November 27, 2023) – The New York State Department of Health recognizes November as Chronic Obstructive Pulmonary Disease (COPD) Awareness Month. COPD describes chronic lung diseases that include emphysema, chronic bronchitis, and some types of refractory (severe) asthma. Chronic lower respiratory diseases, including COPD and asthma, were the fifth leading cause of death in New York State in 2020, according to the most recent 2022 Behavioral Risk Factor Surveillance System (BRFSS) report.

"Chronic Obstructive Pulmonary Disease, COPD, is a serious lung disease that can permanently damage the lungs, making early diagnosis and treatment even more important," State Health Commissioner Dr. James McDonald said. "The most important thing people can do to prevent COPD is to quit smoking, even better, never start smoking. For those who need help quitting, I encourage you to reach out to a doctor and learn about smoking cessation options available in New York State."

About 15.7 million adults in the U.S. have been diagnosed with COPD, with more than 900,000 of those living in New York State. COPD is commonly misdiagnosed and many people who have COPD may not be diagnosed until the disease is advanced. Smoking – both current smoking and smoking in the past – is the main cause of COPD.

Data from the most recent 2022 Behavioral Risk Factor Surveillance System (BRFSS) and the Centers for Disease Control and Prevention (CDC) estimates that 5.3 percent of adult New Yorkers have COPD, while the median national prevalence was 6.7 percent. Data from that BRFSS report also found COPD prevalence varies by smoking status, with 13.1 percent among people who currently smoke, 9.5 percent among people who used to smoke, and 2 percent among those who never smoked.

While smoking is the main cause of COPD, it's not the only cause. As many as one in four people with COPD never smoked. Other risk factors for COPD include long-term exposure to air pollution including secondhand smoke, and occupational exposure to chemical fumes dust. Certain respiratory infections may also contribute to diagnosed cases, as well as a rare, inherited disorder called alpha-1-antitrypsin deficiency (AATD). People with COPD are at increased risk of developing heart disease, lung cancer, and a variety of other conditions.

Symptoms of COPD can develop slowly over time. As symptoms worsen, they can limit the ability to do everyday activities.

COPD symptoms include the following:

  • Chronic or frequent coughing and wheezing
  • Excess phlegm, mucous, or sputum production
  • Shortness of breath or chest tightness, especially with physical activity
  • Extreme fatigue
  • Difficulty taking a deep breath
  • Frequent respiratory infections

Lifestyle choices and treatment may slow down the progression of COPD, however, the damage to the lungs is permanent and cannot be reversed. For those who smoke, the most important thing they can do is quit.

For information and assistance with quitting smoking, vaping, and other tobacco products, contact the New York State Smokers' Quitline at 1-866-NYQUITS (1-866-697-8487), or text 'Quit Now' to 333888.

It's also important for people with COPD to avoid lung infections and stay up to date on recommended respiratory vaccines to prevent the flu, COVID, and pneumonia. There is a vaccine available for adults 60 years and older to protect against Respiratory Syncytial Virus (RSV), which can be administered in New York pharmacies without a prescription.

More information on COPD can be found here.

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Long-term treatment with Olympus’ Spiration Valve System (SVS) safely led to sustained improvements in lung function — and in life quality — among people with severe emphysema, a form of chronic obstructive pulmonary disease (COPD).

That’s according to two-year follow-up data from the EMPOWER trial, which had tested the approved treatment with an eye toward any potential adverse effects due to its use.

These findings point “to the significant and positive long-term impact SVS treatment can have on the day-to-day functions of emphysema patients,” John de Csepel, MD, chief medical officer at Olympus, said in a company press release.

“Meaningful improvement in breathing can mean fuller lives for patients for activities as simple as the ability to go on daily walks or enjoying time with grandchildren,” deCsepel added.

The long-term data were detailed in a study, “Sustained Clinical Benefits of Spiration Valve System in Severe Emphysema Patients: 24-Month Follow-Up of EMPROVE,” published in the journal Annals of the American Thoracic Society.

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An illustration shows a close-up view of damaged and inflamed lungs.

SVS found to improve life quality in severe emphysema patients

Emphysema is a progressive form of COPD characterized by damage to the small air sacs, or alveoli, of the lungs. Such damage reduces the lungs’ elasticity and causes chronic shortness of breath, or dyspnea.

As a result, patients’ ability to perform physical tasks and their quality of life typically are impaired.

The Spiration Valve System, known as SVS for short, was approved in the U.S. in late 2018 as a minimally invasive treatment to improve breathing and quality of life in people with severe emphysema.

It is a small, umbrella-shaped device that works by rerouting air circulating inside the airways into healthier parts of the lungs. In so doing, it diverts air away from damaged regions that risk becoming overinflated due to the stiffening of damaged lung tissue.

The SVS is placed in damaged lung areas using a bronchoscope — a small, flexible tube that is inserted into the patient’s throat — in a procedure that is considered minimally invasive.

Its regulatory approval was based on positive data from the EMPROVE trial (NCT01812447), which enrolled 172 people, ages 40 and older, with severe emphysema and severe dyspnea. The trial was conducted at sites across the U.S. and Canada.

Participants were randomly assigned to receive the SVS device — 113 patients — or standard medical management alone, as part of a control group. A total of 59 patients served as controls.

SVS-treated patients showed significant and sustained improvements in lung function after six and 12 months relative to controls. Lung function was assessed with a validated measure called the mean forced expiratory volume in 1 second, or FEV1.

The SVS group also showed significantly greater reductions in lung overinflation and dyspnea, as well as life quality improvements, as compared with those on standard management.

The benefits [of SVS] compared to the control group at 24 months are long lasting, statistically significant and clinically meaningful. … SVS treatment offers an important opportunity to improve a patient’s lung function and quality of life.

Still, this approach may be associated with potential adverse events, which may include COPD exacerbations, or periods of sudden symptom worsening, and pneumothorax, or a collapsed lung due to air leaking into the space between the lung and chest wall.

To that end, researchers tracked patients over a 24-month period.

The newly published follow-up data showed that the SVS group continued to show significantly greater FEV1 improvements compared with the control group after two years.

Significant dyspnea reductions with SVS also were sustained with longer follow-up, as were significant improvements in several health-related quality of life measures, including the St. George’s Respiratory Questionnaire and the COPD Assessment Test.

Importantly, the rate of adverse events was similar between the SVS and control groups. Acute COPD exacerbations occurred in 13.7% of SVS-treated patients versus 15.6% of those in the control group. One patient in the SVS group and none in the control group developed a pneumothorax.

These results highlight that “SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and [qualify of life], as well as a statistically significant reduction in dyspnea, for at least 24 months, while maintaining an acceptable safety profile,” the researchers wrote.

Gerard Criner, MD, the director of Temple University’s Temple Lung Center and lead investigator of the trial, said that “the results from the EMPROVE trial demonstrate the positive impact the Spiration Valve can have on emphysema patients.”

“The benefits compared to the control group at 24 months are long lasting, statistically significant and clinically meaningful,” and the “SVS treatment offers an important opportunity to improve a patient’s lung function and quality of life,” Criner added.

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Rick Scroggins has worked hard and played hard throughout his 75 years. So, it didn't sit well with him when severe emphysema and chronic obstructive pulmonary disease (COPD) forced him to slow down and rely on oxygen treatment to handle even minor daily tasks. In fact, it was so bad, that it took him minutes to climb the 12 steps to his home office, while having to stop and rest at each landing after four steps. "I've gone 110 miles per hour my whole life," he says. "It's very difficult for me to have to slow down."

Thanks to the experts at The Christ Hospital Physicians – Pulmonary Medicine, and a breakthrough minimally-invasive treatment called The Zephyr Valve, Rick is back to enjoying long periods of physical activity, usually without the need for external oxygen.

Zephyr Valve - A groundbreaking and “breath-giving” procedure

The lungs of patients with COPD are often damaged and can get clogged with or blocked by phlegm, which restricts airflow and can cause air to be trapped in the damaged lobes. This restricts the ability for other lobes to inflate properly, causing shortness of breath and restricting the intake of air/oxygen, which can lead to many other health concerns such as heart problems, weakened muscles and brittle bones, and depression and anxiety.

The Zephyr Valve is a minimally invasive treatment qualifying patients with COPD and emphysema that involves the insertion of valves through the airway and into a lung with no incision required. They make it easier for patients to breathe by deflating and restricting airflow to the more damaged lobe(s), which lessens the restriction on the healthier adjacent lobes.

Eligible patients are typically those with moderate to severe emphysema, and stage three or four COPD, according to Vishal Jivan, MD, the pulmonologist with The Christ Hospital Physicians-Pulmonary Medicine who implanted the five valves in Rick’s lungs. Patients undergo a series of testing and scans to determine if the valves will work for them, and to identify the best location to implant them.

“We’re looking to deflate the part of the lung that has the most emphysema, and the lowest amount of blood supply,” Dr. Jivan says. “This diverts the airflow to the healthier lobes which were impeded by the lobe with more emphysema and allows them to supply more oxygen to the blood, which gives the patient more energy.”

Some patients, including Rick, see a significant reduction in the need for the use of external oxygen, but Dr. Jivan reminds his patients that isn’t the case for everyone. Still, he says, even if they still need oxygen, the differences in their breathing, energy, and stamina are noticeable.

“We’re looking for a difference in tolerance for exercise and physical activity,” he says. “Even for those who still require oxygen, they’re going to notice a big difference in that tolerance. I recently spoke with a patient who was excited to be able to walk around a county fair for four hours, where before, he couldn’t walk for more than an hour.”

What to expect after a Zephyr Valve procedure

The procedure to implant the valves is minimally invasive with little physical stress on the patient, and according to Dr. Jivan, patients can notice an immediate difference, and continue to feel better in the weeks after receiving the implants. However, he points out that the valve does require a minimum three night stay for observation.

“There is a minor risk for a collapsed lung during the first three days, and it’s important for us to monitor for that during that period,” he says.

There is also a risk for the valves to come loose after they are implanted, often from the patient coughing. This isn’t a major concern, however, and Dr. Jivan points out that the procedure to remove and replace the loose valve is the same simple procedure as the original.

“It’s not a medical emergency and there’s very little risk to the patient when the valve comes loose,” Dr. Jivan says. “But they do experience a return of their original symptoms, so we like to move quickly to get them feeling better as soon as possible.”

Rick has experienced a valve coming loose from coughing. “It’s no big deal,” he says. “It’s the same easy procedure and well worth it.”

A lifesaving scan

Zephyr Valve implants require ongoing follow-up scans. When Rick went for a follow-up after having a loose valve replaced, the results indicated that a small nodule that had been previously detected during scans had grown. Rick had lung cancer.

Rick wasn’t going to lose his new-found momentum, however, and began the journey to beat the cancer.

“I had some help,” he says. “My wife and my daughter, who happens to be a nurse, were with me for every visit. I always tell me people, ‘I have my nurse and my bodyguard with me, I’ll be OK.”

Julian Guitron-Roig, MD, a thoracic and cardiac surgeon with The Christ Hospital Physicians – Heart & Vascular, successfully removed the top lobe Rick’s right lung that contained the cancer. Then began the road to recovery, that was admittedly longer and more challenging than recovery from the valve implants, but after about a month of inpatient care, Rick’s back to enjoying his active life, but he wants people to know that he had help.

“The people at The Christ Hospital are great,” he says. “There are none better. And that’s not just Dr. Jivan, Dr. Guitron and the other doctors. That’s everybody from the nurses in the endoscopy department to the nurses in the stepdown unit after cancer surgery. In fact, I’ve told Katie, a nurse in the endoscopy department, ‘Your bubbly personality and positive attitude make this easier. You can take somebody having a terrible day and having to go through with this and make them feel like they are having the best day ever.”

Back to 110 miles per hour

Rick’s procedure did reduce the need for oxygen and he’s back to enjoying some his favorite activities with his family. “I’m not out here running any races,” he says, “but I’m comfortable to cover a lot of ground.”

He and his wife of more than 50 years have two adult daughters and four grown grandchildren, and they’ve always enjoyed travelling with their family. Rick is happy to be back to travel activities such as walking for miles on the beach in Florida or hiking in the mountains of Tennessee with his wife. He also enjoys helping out for hours at a time at the farm owned by his oldest daughter and her husband.

“It’s amazing what I can do that I couldn’t do before,” Rick says. “There’s no way I could have done any of this before those valves.”

Current patients can ask their primary pulmonologist if they believe they may be a candidate for a Zephyr Valve, or call our office at 513-241-5489 for more information. Ask your primary care provider about a referral if you believe you may be a candidate but if you are not an existing patient of The Christ Hospital Physicians - Pulmonary Medicine.

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If you have been coughing and wheezing a lot lately, you may be wondering whether you have chronic obstructive pulmonary disease (COPD). Symptoms of COPD may be similar to other conditions affecting your lungs and breathing, such as asthma and bronchitis. But there are differences between these conditions. Knowing what to look for and when to seek medical attention can help you better manage this condition.

COPD Symptoms

The most common symptom of COPD is a cough that doesn’t go away. The cough may be accompanied by wheezing, chest tightness and mucus production and may cause you to feel short of breath. Below is a list of COPD symptoms, but keep in mind that symptoms may not appear to be very bothersome until COPD has progressed to the point where significant lung damage has occurred.

  1. A chronic cough
  2. Shortness of breath
  3. Mucus/phlegm/sputum production
  4. Wheezing
  5. Chest tightness
  6. Frequent respiratory infections
  7. Fatigue/lack of energy
  8. Weight loss with no known cause
  9. Swelling in feet, ankles or legs

Symptoms may occasionally become worse for periods of time (called exacerbations) before they are under control again. The most common cause of exacerbation is due to infection in the lungs or airways.

Who is most at risk for COPD?

Anyone can develop COPD, but your risk increases if:

  • You are a current or former smoker
  • You are exposed to secondhand smoke, air pollution, dust, fumes or chemicals on a regular basis, such as at work

The most common cause of COPD is long-term exposure to smoke, irritating gases or particulate matter. People who experience chronic bronchitis or emphysema are more likely to develop COPD. People over age 40 are also more likely to develop the condition. But if you experience symptoms of COPD, don’t assume it’s just due to age. See a doctor for further evaluation. A doctor can perform a simple breathing test, called spirometry. This measures the amount of air you blow out and how fast you blow it out. It can determine whether you have COPD.

Does COPD get worse over time?

COPD is a progressive disease, meaning it usually gets worse over time. Although there is no cure for the disease, the condition is treatable and treatment is aimed at managing symptoms. This can improve your quality of life and makes it less likely you will experience complications from related health issues.

The sooner COPD is diagnosed, the sooner treatment can begin. This can prevent further damage to the lungs or loss of lung function.

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Despite nearly a decade of experiencing smog during the winter in the provincial capital, it seems that the government has accepted its failure to combat air pollution by dedicating a season to it, now known as smog-season, instead of enacting measures to make Lahore’s air breathable again.

The city’s first rodeo with smog was reported back in November of 2015 and ever since then Lahore’s air quality has only gone downhill as it has become a regular in the 10 most polluted cities of the world list. And this year is no different. Air Quality Index (AQI) readings since the start of November show that the highest pollution levels in the city have been recorded at Gulberg, Polo Ground, Pakistan Engineering Services Headquarters, and Mall Road.

And just like previous years, the solutions proposed to combat the community-wide polluted air by the provincial government are also not any different. For instance, a mask mandate is being enforced, businesses are being told to shut down earlier than usual, schools and workplaces are being asked to remain closed on Fridays and Saturdays.

Anila Kausar, a resident of the Cantt area in Lahore, feels that the tried and tested stopgap measures are disproportionate and will not bear any fruit. “The city’s smog crisis gave me respiratory issues and the government’s inefficiency in combating it will lead to many others developing the same illnesses,” predicted the 44-year-old.

“I do not know how any of us will survive in this air,” she added.

Kausar’s fears are not misplaced. As per a report of the United States Environmental Protection Agency, breathing smoggy air can be hazardous because smog contains ozone, a pollutant that can harm our health when there are elevated levels in the air we breathe. The report further states that ozone can irritate the respiratory system, reduce lung function, aggravate asthma, inflame and damage the lining of the lung, and aggravate chronic lung diseases, such as emphysema and bronchitis.

Read Lockdown expanded as smog tightens chokehold on city

Khalida Tariq, a 60-year-old, who resides in the Garhi Shahu area of the city, which has clocked AQI readings of 200 and above since the start of November, is presently feeling the effects of smog that the report highlights. “I have some underlying conditions but as soon as smog-season starts I find it hard to breathe, start getting lethargic, and just pray for this menace to end,” an irate Tariq informed.

And presently it seems that only divine intervention can end the city’s smog crisis because provincial governments past and present have found it hard to decrease the dependence on the city’s foremost contributor to air pollution - transport. According to a report of the autonomous and technical arm of the Punjab government, the Urban Unit, 83.15 per cent of Lahore’s air pollution is due to transport. 9.07 per cent is due to industries, 3.9 per cent due to agriculture, 3.6 per cent due to trash burning, 0.14 per cent due to commercial activities, and 0.11 per cent due to domestic activities.

Nevertheless, Dawar Butt, an expert on environmental public policy, feels that mere mortals could also effectively curb the air pollution crisis if they were willing to do so. “In nearly a decade of experiencing smog we now know that transport, industries, and power plants are the main culprits. As far as transport is concerned, the provincial government needs to end people’s reliance on their own vehicles by connecting the entirety of the city with public transport,” suggested Butt.

When pointed out that the government had tried to end this dependence in the past but had failed to do so, Butt was of the view that the planning and execution had been poor. “Public transport fares should be reduced during peak hours, special discount cards should be issued for students and senior citizens, and public transport should offer free or affordable services on weekends for entertainment purposes,” the public policy expert explained, adding that practical initiatives revolving around increasing the reliance on public transport were long-term solutions which would help improve air quality instead of the stopgap solutions the Punjab government implemented every year.

“Moreover, the three sectors [transport, industries, and power plants] also exacerbate the air quality crisis by relying on substandard fuel. Our neighbour India, has moved to Euro-5 and Euro-6 quality fuel, whereas we are still stuck using Euro-2. We have to make the usage of high quality fuel mandatory,” he added.

Aleem Butt, the Director of an organisation working on Lahore’s environment, agrees. “Smart lockdowns, fines for factories and kiln owners, vehicle seizures, and extra school holidays are short-term solutions. While beneficial, these measures lack permanence,” he asserted.

“Addressing substandard fuel use in vehicles and industries and creating separate industrial zones away from urban populations is imperative to avoid recurring problems.”

Read more Smart lockdown proves fruitless

However, in the absence of such measures residents of Lahore might have to accept smog as just another season and make do with the stopgap solutions. In doing so, Lahoris will also have to put up with experiencing respiratory issues during the entirety of the smog-season every year, as per Dr Sajid Rashid, Principal Professor of the College of Earth and Environmental Sciences at Punjab University. “There are numerous health risks associated with Lahore’s hazardous air, which has a particulate matter (PM) 2.5 concentration more than 40 times the recommended World Health Organisation (WHO) annual air quality guideline value,” explained Dr Rashid, “if residents of this city start treating this as normal then they are agreeing to having a shorter life span.”

Nonetheless, Arsalan Ahmed, who works for a software company in Lahore, is not okay with having a shorter life span just due to the government’s inefficiency and negligence. “The government instead of enforcing successful measures like work from home is relying on absurd measures which it knows no one will follow,” critiqued Ahmed, further stating that working from home had proven to be effective during the coronavirus and would also prove effective in reducing smog.

Data obtained by the Express Tribune from the Meteorological Department Lahore backs Ahmed’s assertions, as air quality in Lahore improved significantly during the lockdown imposed in 2020 due to the coronavirus. The AQI readings from the lockdown period, from 26th of February to 31st of August 2020, recorded a minimum of 45 AQI and a maximum of 76 AQI.

Given the high levels of air quality in 2020, Noreen Fatima, a student of a private university in Lahore, believes that schools should also switch to online classes instead of just being closed on Fridays and Saturdays. “There is no reason to subject students to toxic air when the online method of instructing has worked before,” remarked Fatima, further adding that teaching online would mean that a significant chunk of students who travel in vehicles to schools and universities would not be using the vehicles. “Hence, resulting in a decline in transport related pollution.”

Muhammad Ejaz, who drops and picks his children daily from schools, finds wisdom in Fatima’s suggestion. “Instead of the government asking students to show up to school in masks, making them study at home is a better solution,” he said.

Even if the provincial government were to pay no heed to shutting schools in favour of online education and insisted on its mask mandate, Dr Salman Kazmi, the General Secretary of the Young Doctors Association, believes that masks do precious little to curb the harmful effects of smog. “Only the N-95 masks will offer respite against smog but no one is going to buy those because of the high cost. Therefore, the government’s vision is incredibly limited if it feels that normal surgical masks will help in combating air pollution induced respiratory illnesses,” said Dr Kazmi matter-of-factly.

Read further Artificial rain planned for next week

In light of Dr Kazmi’s revelations, when quizzed about the mask mandate, the caretaker provincial minister for health, Dr Javed Akram, conceded that only N-95 masks could significantly control the effects of smog, whereas surgical masks could not completely prevent smog exposure.

Since stopgap solutions are not going to help rid Lahore of its smog crisis, the provincial capital is in dire need of research-backed policies to make the city’s air breathable again, as per Butt, the environmental policy expert. In this regard, the Express Tribune spoke to the Pakistan Muslim League Nawaz’s (PML-N) General Secretary, Ahsan Iqbal, regarding the party’s glaring inattention towards the city’s polluted air, despite considering it as its political fort. “Our recently constituted manifesto committee is working on proposals for the smog issue and how it can be eliminated. We are aware of how important a clean atmosphere is for our voters and Lahore’s residents,” claimed Iqbal.

The Express Tribune also spoke to Dr Firdous Ashiq Awan, Spokesperson of the Istehkam-e-Pakistan Party (IPP), which is also vying for Punjab’s Chief Ministerial slot, regarding the party’s lack of attention towards the air pollution crisis. “We realise the importance of having a clean environment and we will work towards making Punjab’s air breathable again,” assured Dr Awan.

However, Butt feels that politicians only make hollow promises. “A Smog Commission was constituted on the directions of the Lahore High Court, which after examining the causes of air pollution and smog, formulated long-term and short-term proposals, but most of the recommendations of the commission have never been considered or implemented,” he informed.

Butt’s opinion holds weight as some of the Smog Commission’s recommendations regarding transport included making public transport mandatory for 75 per cent of students in educational institutions and regulating vehicle usage on specific days according to their number plates but none saw light of day.

Published in The Express Tribune, December 27th, 2023.

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this chronic obstructive pulmonary disease, as. .and be known chronic obstructive pulmonary disease It is a potentially fatal disease in humans.

Most of the time this is due to Smoking habitSecond, exposure to biomass (smoke) at some point in life due to air pollution, this is especially true for people who grew up in rural areas where firewood is used for heating and cooking, which is also the case in Chile An important cause of the sequelae of tuberculosis is that it often produces symptoms of bronchial obstruction that are indistinguishable from other causes of COPD.

At RedSalud we have Bronchopulmonologist COPD specialist and Psychiatrist Used to treat addictive behaviors such as smoking. Appointment.

What is COPD?

this chronic obstructive pulmonary disease COPD is a common lung disease in which Reduce air flow and cause respiratory problems.

In COPD, mucus clogs and damages the lungs, causing symptoms such as coughing, wheezing, fatigue and difficulty breathing.

COPD comes in two forms: chronic bronchitis, which is accompanied by a prolonged cough and mucus, and emphysema, which involves damage to the lungs.

Most people with COPD suffer from both conditions.

he Smoking and pollution Air is the main cause, and people with COPD are at greater risk for other health problems.

Although there is no cure for COPD, its symptoms can be improved by quitting smoking, avoiding pollution, adhering to vaccinations, and engaging in effective pulmonary rehabilitation.

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Causes of chronic obstructive pulmonary disease

COPD may be caused by narrowing of the airways, destruction of parts of the lungs, or airway obstruction caused by secretions or inflammation.

Causes of these forms of COPD include:

  • Exposure to tobacco through smoking or passive smoking.
  • Exposure to dust, chemicals or fumes.
  • Indoor pollution caused by the use of biofuels for cooking or heating.
  • Disorders of fetal development and the first years of life, such as delayed birth or respiratory illnesses common in childhood.
  • Asthma in children.
  • Congenital alpha-1 antitrypsin deficiency.

It’s important to note that smoking is the leading cause of COPD, meaning the more a person smokes, the more likely they are to develop the disease.

risk factors

Risk factors for chronic obstructive pulmonary disease (COPD) include:

  • Exposure to tobacco smoke, cigarettes or pipes.
  • People with asthma.
  • Prolonged exposure to dust or chemicals.
  • Exposure to fuel combustion.
  • Genetic factors, such as alpha-1-antitrypsin deficiency.


Since the main cause of COPD is smoking, the best way to prevent the disease is not to smoke.

For smokers, quitting smoking is crucial. If you can’t quit smoking on your own, there are help programs, medical treatments, and medications to help you achieve this goal.

When COPD is caused by exposure to chemical gases or dust at work, it’s important to talk to your supervisor to improve working conditions.

It may involve the use of respiratory protective equipment and other methods to protect lung health.

Another preventive measure is annual influenza vaccination and pneumococcal pneumonia vaccination to reduce the risk of respiratory infections.

What are your symptoms?

The main symptoms of chronic obstructive pulmonary disease (COPD) include:

  • Difficulty breathing.
  • Chronic cough.
  • Feeling tired.

  • Cough with phlegm.
  • Frequent respiratory infections.
  • respite.
  • Difficulty breathing.
  • fatigue.

Difficulty performing daily activities due to shortness of breath, and other symptoms such as depression and anxiety may also occur.

Likewise, pathology can cause financial problems due to limitations in work productivity and medical costs.

When COPD symptoms worsen rapidly, the exacerbations may last for several days and require additional medication.

People with COPD are also at greater risk for other health problems, such as:

  • lung infection.
  • Lung cancer.
  • Heart disease (such as right heart failure).
  • Muscle weakness.
  • Osteoporosis.
  • Arrhythmias.
  • Malnutrition.
  • Collapse of lung.

When should you consult a doctor?

If respiratory distress worsens significantly, an emergency physician should be consulted.

If you are experiencing symptoms of chronic obstructive pulmonary disease (COPD), visit our emergency services at one of our RedSalud clinics nationwide.

We provide high-quality emergency services and exceptional care to patients with varying life-threatening conditions 24 hours a day. Check availability here.

Control and treatment of patients with COPD

To diagnose COPD, your doctor may order a lung function test called spirometry.

It assesses lung capacity by blowing forcefully into a machine, and the results are immediate.

Professionals may also listen with a stethoscope, order an X-ray or tomography scan, or use an arterial blood gas test to measure oxygen levels in the blood.

In addition to stopping smoking or breathing polluted air, COPD can be controlled and treated by:

  • Inhaled bronchodilator drugs, which may be combined with corticosteroids.
  • Pulmonary rehabilitation, breathing techniques and exercise capacity.

  • Inhaled anti-inflammatory drugs to reduce respiratory inflammation
  • Take antibiotics for a long time.
  • Oxygen therapy, which gives low levels of oxygen to the blood.
  • Mechanical breathing assistance.

How to live with chronic obstructive pulmonary disease (COPD)?

Lifestyle changes can help improve symptoms of COPD, so it’s important to:

  • Quit smoking.
  • Avoid smoking areas.
  • Get physically active.
  • Protect yourself from lung infections.
  • Get vaccinated against influenza, pneumonia and COVID-19.
  • Avoid extreme cold or heat.
  • Avoid smoking, cleaning the kitchen or chimney at home.
  • Control stress and emotions.
  • Eat healthy.

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Respiratory Trainer Market

BURLINGAME, CALIFORNIA, UNITED STATES, November 24, 2023 / -- The Respiratory Trainer Market is estimated for 2023 for the forecast period 2023-2030, as highlighted in a new report published by Coherent Market Insights.

Respiratory trainers aid in the treatment of various respiratory diseases and conditions by strengthening the respiratory muscles and lungs. They are devices used for breathing exercises and to improve respiratory strength, capacity, and endurance.

Market Dynamics:

The respiratory trainer market is expected to witness significant growth over the forecast period owing to the increasing prevalence of respiratory diseases worldwide. According to the WHO, chronic respiratory diseases like asthma, emphysema and COPD account for 6% of all deaths globally. Moreover, lifestyle habits like smoking and rising air pollution levels have contributed to the rising incidence of these diseases. Respiratory trainers aid in managing the symptoms and help patients to perform breathing exercises correctly. Technological advancements with integration of apps and sensors have made respiratory training more efficient.

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Some of the Top Players in Respiratory Trainer Market:

Medline Industries, Inc., Koninklijke Philips N.V., Smiths Medical, Inc., Vyaire Medical, Inc., IngMar Medical, POWERbreathe International Limited, PN Medical, Aleas Europe LLC, Aspire Products, LLC, Airofit, Project Electronics Limited, Biegler GmbH, Nidek Medical India, Besmed Health Business Corp, Forumed S.L., and Angiplast Private Limited.

Note: Major Players are sorted in no particular order.

Detailed Segmentation:

Global Respiratory Trainer Market, By Product Type:

Resistance Training Devices

Endurance Training Devices

Global Respiratory Trainer Market, By Technique:

Inspiratory Muscle Training

Inspiratory Flow Resistive Loading

Inspiratory Pressure Threshold Loading

Expiratory Muscle Training

Combination of Both

Global Respiratory Trainer Market, By Disease Indication:


Chronic Obstructive Pulmonary Disease


Global Respiratory Trainer Market, By End User:



Increasing Prevalence of Respiratory Diseases Drives Demand for Respiratory Trainers

One of the key drivers propelling the growth of the respiratory trainer market is the rising prevalence of chronic respiratory diseases across the globe. Chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis are becoming highly common due to factors such as rising air pollution levels, growing tobacco consumption, and aging population. According to the World Health Organization (WHO), chronic respiratory diseases accounted for over 4 million deaths globally in 2019. Respiratory trainers help in improving breathing functions and lung capacity in patients suffering from chronic respiratory conditions. With the surging patient pool of respiratory disorders, the demand for effective therapeutic and rehabilitation solutions including respiratory trainers is increasing significantly among healthcare facilities and individuals.

Growing Geriatric Population Fuels the Need for Respiratory Trainers

Another major factor driving the respiratory trainer market is the global demographic shift towards an aging population. Older adults above the age of 65 years have higher susceptibility to respiratory problems due to age-related physiological changes and declining immune functions. Respiratory diseases such as COPD and pneumonia are highly prevalent in the geriatric population. According to the UN data, the population aged 65 years or above is projected to reach nearly 1.5 billion by 2050 from present 703 million. With the expansion of the aging demographic, the prevalence of respiratory disorders requiring rehabilitation is expected to grow exponentially in the coming years. Respiratory trainers help senior citizens in improving lung capacity and respiratory muscle strength, thereby meeting the rising rehabilitation needs of the growing elderly patient pool.

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High Cost of Respiratory Trainers Hinders Adoption Rates

One of the key challenges restraining the growth of the respiratory trainer market is the high cost associated with these therapeutic devices. Respiratory trainers feature sophisticated technology and require periodic maintenance for safety and efficacy. This makes them quite expensive for use in homecare settings as well as budget-constrained healthcare facilities in developing nations. The cost of a basic respiratory trainer device ranges from several hundred to a few thousand dollars based on features. Moreover, additional maintenance costs further add to the overall expense. The high prices pose significant affordability issues, especially in price-sensitive developing markets. This acts as a major adoption barrier, particularly for the general mass unable to bear steep device costs. Product affordability remains a key area of concern needed to be addressed by manufacturers to expand consumer base.

Telehealth and Remote Monitoring Create Avenues for Market Growth

The rapid digitalization of the healthcare industry presents lucrative opportunities for players in the respiratory trainer market. With telehealth and remote patient monitoring gaining widespread acceptance, there is scope for incorporating smart connectivity into respiratory training devices. Integration of sensors, software, and wireless technologies allows remote monitoring of patients' rehabilitation progress and therapeutic adherence. This can help clinicians track treatment response, identify issues if any, and adjust plans accordingly without physical visits. The capability of digital tools and telehealth models to overcome distances creates opportunities to expand services to remote areas as well. The ongoing healthcare IT revolution provides incentives to innovators for developing next-gen "smart" respiratory trainers with intelligent connectivity and analytics. This can help open up new channels for market reach, especially in the current pandemic scenario favoring virtual care.

Transition Towards Portable Devices Marks Key Market Trend

One of the major trends witnessed in the respiratory trainer market includes growing preference for portable devices with compact designs. Traditionally, respiratory trainers were bulky stationary devices used mainly in clinical settings. However, technology advancements have enabled manufacturers to shrink device footprints and make them more convenient for home use. Portable respiratory trainers with rechargeable batteries, lightweight designs, and easy-to-use interfaces are emerging popular. Their compactness allows discreet usage during travel or outdoor activities. It also appeals to a wider consumer base seeking discretion and mobility. In fact, technological miniaturization has enabled development of wearable respiratory trainers integrated into clothing. The ongoing transition towards more portable form factors reflects consumers' increasing priorities of discretion, ease-of-use and an active lifestyle even while undergoing respiratory rehabilitation therapy.

Regional Analysis -

‣ North America (USA and Canada)

‣ Europe (UK, Germany, France and the rest of Europe)

‣ Asia Pacific (China, Japan, India, and the rest of the Asia Pacific region)

‣ Latin America (Brazil, Mexico, and the rest of Latin America)

‣ Middle East and Africa (GCC and rest of the Middle East and Africa)

Reasons to Purchase this Report:

‣ Regional report analysis highlighting the consumption of products/services in a region also shows the factors that influence the market in each region.

‣ Reports provide opportunities and threats faced by suppliers in the Respiratory Trainer industry around the world.

‣ The report shows regions and sectors with the fastest growth potential.

‣ A competitive environment that includes market rankings of major companies, along with new product launches, partnerships, business expansions, and acquisitions.

‣ The report provides an extensive corporate profile consisting of company overviews, company insights, product benchmarks, and SWOT analysis for key market participants.

‣ This report provides the industry’s current and future market outlook on the recent development, growth opportunities, drivers, challenges, and two regional constraints emerging in advanced regions.

Questions Answered by the Report:

(1) Which are the dominant players of the Respiratory Trainer Market?

(2) What will be the size of the Respiratory Trainer Market in the coming years?

(3) Which segment will lead the Respiratory Trainer Market?

(4) How will the market development trends change in the next five years?

(5) What is the nature of the competitive landscape of the Respiratory Trainer Market?

(6) What are the go-to strategies adopted in the Respiratory Trainer Market?

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Table of Contents

Chapter 1 Market Overview

1.1 Definition

1.2 Assumptions

1.3 Research Scope

1.4 Market Analysis by Regions

1.5 Market Size Analysis from 2023 to 2030

Chapter 2 Competition by Types, Applications, and Top Regions and Countries

2.1 Market (Volume and Value) by Type

2.3 Market (Volume and Value) by Regions

Chapter 3 Production Market Analysis

3.1 Worldwide Production Market Analysis

3.2 Regional Production Market Analysis

Chapter 4 Respiratory Trainer Sales, Consumption, Export, Import by Regions (2023-2023)

Chapter 5 North America Market Analysis

Chapter 6 Europe Market Analysis

Chapter 7 Middle East and Africa Market Analysis

Chapter 8 Asia Pacific Market Analysis

Chapter 9 Latin America Market Analysis

Chapter 10 Company Profiles and Key Figures in Respiratory Trainer Business

Chapter 11 Market Forecast (2023-2030)

Chapter 12 Conclusions

Mr. Shah
Coherent Market Insights Pvt. Ltd.
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Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease characterized by high prevalence, disability, and mortality. Acute exacerbation (AE) of chronic obstructive pulmonary disease (AECOPD) is defined as the worsening of a series of respiratory symptoms, such as dyspnea, increased cough, and sputum, in the presence of stable COPD within 14 days of medication adjustments.1 COPD is one of the four most common diseases globally, with an annual incidence of approximately 12% and a global prevalence of 9%-10% in people ≥40 years of age.2,3 It became the top three causes of global death in 2016 and was ranked as the fifth leading cause of death in China in the same year. A large epidemiologic survey in 2017 showed that COPD numbered about 300 million people globally, with a prevalence rate of 3.9% in the whole population and became the fourth leading cause of death in America, accounting for 6% of all-cause deaths globally.4,5 Further, the disease burden is expected to increase in the coming decades.6,7 Additionally, COPD showed a prevalence of 8.6% and 13.7% in adults over 20 and 40 years old, respectively, based on a 2018 study by the China Pulmonary Health (CPH). The number of individuals with COPD in China is estimated at approximately 100 million.7 As the population ages and exposure to related risk factors gradually increases, the prevalence of COPD will continue to increase and the age of onset will gradually decrease, causing a major health burden and economic pressure on society and families, rendering COPD one of the major public health problems globally.

The literature suggests that approximately 25% of patients with COPD exhibit declined lung function, attributable to AE.8 Patients with COPD experience AEs 0.5–3.5 times per year.9 As a dangerous stage and key event in the course of COPD, AE can worsen disease progression and comorbidities, seriously affecting the patients’ quality of life and shortening their survival. Patients with frequent AEs (≥2 times/year) experience a more rapid decline in lung function and have a worse prognosis, and an increased risk of death than those with infrequent AEs (<2 times/year).10 It has been shown that patients with COPD hospitalized for AEs have a mortality rate of 25% and 65% at one year and five years, respectively.11 Approximately 2%-19% of hospitalized AECOPD patients are ultimately transferred to the Intensive Care Unit (ICU),12–15 and the ultimate in-hospital mortality rate for such patients is 12–24%,16–18 with 35% of surviving patients expected to be readmitted to the hospital 3 months after discharge.19,20 Owing to various factors, such as the large population of people with COPD in China and their widespread distribution, limited awareness of the disease among most patients, and unstandardized diagnosis and treatment of COPD primary medical care, most patients are unable to recognize AE at an early stage and cannot receive timely and effective standardized treatment and management. To this end, China has gradually implemented a hierarchical system for COPD diagnosis and treatment by formulating relevant work plans and promoting health programs to improve the early diagnosis and management of COPD at the primary level.

The 2023 edition of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) for the treatment of COPD states that the goal of AE treatment is to minimize its negative effects and prevent its recurrence. Early prevention, timely detection, and aggressive interventional treatment can significantly reduce the readmission and death disability rates of patients with COPD, significantly shorten their lost life years, and substantially increase their quality of life after hospital discharge. Therefore, understanding the risk factors that may cause AE and strengthening the prevention of AE can improve the outcomes of COPD treatment and reduce the occurrence of adverse events during the course of the patients’ illnesses.

Risk Factors


Bacterial infection

Bacterial infections are generally considered to be an important factor in the exacerbation of COPD, and bacteria can be isolated from sputum specimens of 40−60% of patients with AECOPD.21,22 The occurrence of AE involves a variety of bacterial pathogens, with common bacterial pathogens including Haemophilus influenza, Moraxella catarrhalis, streptococcus pneumonia, pseudomonas aeruginosa, etc.21 However, there are differences in the prevalence of bacteria among different countries, with Pseudomonas aeruginosa, Klebsiella pneumoniae, and Haemophilus influenzae being more common in China,23 and Haemophilus influenza, Pseudomonas aeruginosa, and moraxella catarrhalis being more common in Australia and other countries.24 The bacterial infection leads to neutrophil and interleukin-8 (IL-8) production and increased production of matrix metalloproteinases (MMPs) by neutrophils and macrophages, which promote disease progression by participating in the pulmonary inflammatory response, airway remodeling, and development of emphysema.25–28

The strains colonizing the airways in the stable phase of COPD highly overlap with those isolated in the acute phase. However, strain population changes in the acute phase are more strongly associated with the degree of respiratory infection and systemic inflammatory response than those in the stable phase.29 Although bacterial infections are associated with poor clinical outcomes in cases of COPD, there is a quantitative relationship between levels of airway inflammatory markers.30 A microbiota homeostasis generated by the balance of bacterial migration and elimination already exists in the lungs; however, during AE, there is ciliary dysfunction in the lungs, increased mucus secretion, and enhanced bacterial migration, and the original airway flora balance is disrupted, leading to bacterial proliferation beyond the clearance capacity of the respiratory tract.31 Based on this, it may be hypothesized that AE triggers a homeostatic imbalance in which the microflora attacks the host’s respiratory and systemic immune systems. This therefore suggests that bacterial infections are unidirectionally associated with AE. However, regardless of the direction of the association, most clinical studies still find traces of bacterial infection in samples from respiratory secretions or tissues of patients in acute exacerbation.24,32,33

Viral Infection

Advances in detection technology have shown that viral infections are more closely associated with AE than bacterial infections.34–37 Additionally, 40−80% of AE cases with high-frequency hospitalization are attributed to viral infections.38 Common viruses isolated from the secretion specimens of patients with AE include rhinovirus, coronavirus, influenza virus, parainfluenza virus, adenovirus, and respiratory syncytial virus,21 with rhinovirus, influenza virus, and respiratory syncytial virus being the most common.39 In addition, there are geographical differences in the prevalence of respiratory viruses; for example, small RNA viruses are most common in the West, while the influenza viruses are most common in the East (Asia).40

Among these respiratory viruses, rhinoviruses are thought to play an important role in the occurrence of AE.41,42 When the body is infected with rhinovirus, the production of interferons and neutrophils is reduced, leading to the occurrence of viral AE, which eventually aggravates the physical changes and symptoms in the patient’s body.43 In addition, the impact of the 2019 novel coronavirus (2019-nCoV) pandemic on patients with COPD cannot be ignored. The 2019-nCoV promotes viral binding to the angiotensin-converting enzyme 2 (ACE-2) receptors and cell entry by carrying envelope burst proteins. As mRNA expression of ACE-2 receptors is increased in patients with COPD, the 2019-nCoV and other coronaviruses have a deleterious effect on respiratory health and pose a significant threat to patients with COPD.44

In addition to common respiratory viral infections, human immunodeficiency virus (HIV) infections increase the risk of AE by accelerating lung aging and promoting chronic lung inflammation, oxidative stress, immune activation, and alteration of lung microbiota.45,46 HIV attacks the human immune system by targeting CD4+T lymphocytes, resulting in decreased immune function and a significant increase in the risk of respiratory tract infections. One study found that HIV carriers and patients with COPD and low CD4+ T lymphocyte counts had >4-fold higher risk of AE compared to patients not infected with HIV.47

Respiratory symptoms, length of hospital stay, and systemic symptoms were also significantly worse in patients with AE and viral infections, compared to those without viral infection.36,48 Some viruses are still detectable in patients with stable COPD, owing to the presence of lung microbiota. However, the detection rates of viruses and bacteria in patients with AECOPD was significantly higher than those in the stable phase.49 This finding demonstrates the important role of viral infections in the development of AE. Acute viral infections increase airway reactivity and airway epithelial damage, causing the development of airway inflammatory edema, thus worsening airflow obstruction, which, in turn, leads to systemic inflammation.50–52

In most cases of AECOPD, mixed viral and bacterial infections occur more frequently than single viral or bacterial infections. Approximately 73% of patients with viral infections develop secondary bacterial infections within 14 days of the onset of worsening symptoms, suggesting that bacterial infections may be more important in the later stages of viral-induced deterioration.53 The percentage of bacterial and viral detection was positively correlated with the levels of hypersensitive C-reactive proteins (CRP), leukocytes, and other biological markers.35,54 Therefore, clinical practitioners’ can determine the AE status of patients with COPD by testing the levels of the corresponding biomarkers.

Tobacco Smoke Inhalation

Tobacco smoke inhalation is widely recognized as an essential factor in the development and progression of AECOPD. GOLD 2023 shows that smoking is a major risk factor for COPD, accounting for more than 70% of the total factors in high-income countries, whereas in lower-middle-income countries, smoking accounts for 30−40% of the total factors. A CPH Study states that the incidence of COPD is 13.7% in smokers, 10.9% in former smokers, and 6.2% in never-smokers,7 and significantly higher in smokers compared to non-smokers. Tobacco smoke is the main risk factor for frequent exacerbations in patients with COPD and can enhance the risk of hospital visits or readmissions due to AE.55,56 Research at the Nantong University demonstrated that active smokers with AE had more severe clinical symptoms, impaired lung function, and worse follow-up treatment outcomes, compared to non-smokers.57 Most AE patients with a smoking history of >30 pack-years use non-invasive ventilation (NIV), which increased during hospitalization.58 Notably, smoking cessation significantly reduced COPD readmission rates.59

Tobacco smoke causes immune deficiency, impairs immune homeostasis and defense mechanisms, and has a reverse effect on the antimicrobial signaling cascade, which influences inflammatory response to microorganisms.60 Another study showed that tobacco smoke affects intrapulmonary mechanical barriers (such as intraepithelial cells and cilia) by decreasing the frequency of ciliary oscillations and inducing squamous metaplasia, leading to a decrease in the number of ciliated cells and an increase in the number of cup cells and submucosal glands, causing excessive mucus production and favoring the growth of microbial pathogens,61,62 which indirectly proves the correlation between tobacco smoke inhalation and AE.

Air Pollution

Outdoor Air Pollution

Air pollution is also a crucial risk factor in the course of COPD.7,63–65 The prevalence of COPD in an PM2.5 exposed group was significantly increased by two-fold compared to that in the general and never-smoking populations.7 Additionally, there was a positive correlation between airborne fine particulate matter concentrations and COPD incidence, hospitalizations, and mortality.66–68 A study that selected air samples from seven randomized areas in the Guangdong Province of China found that particulate matter concentrations were negatively associated with some lung function indicators (FEV1, FVC, and FEV1/FVC).69 In addition, increased PM2.5 exposure was associated with increased COPD hospitalizations and mortality;67 for every 10 µg/m3 increase in PM2.5, patients with COPD had a 2.5% increased risk of emergency department visits and hospitalizations for AE.66 Several regional studies in China reported that airborne pollutants may increase the occurrence of AE.70–74 Part of this theory suggests that air pollutants can trigger AE by damaging the airway epithelium and macrophages, thereby affecting ciliary clearance, or by inducing alveolar inflammation and disturbing respiratory homeostasis.71,74,75 It is evident that the influence of outdoor air pollution in the development and deterioration of COPD should not be underestimated.67,76–78

Indoor Air Pollution

Household biomass exposure was correlated with an increased risk of COPD, with an additive effect and no significant sex differences.79 In recent years, the prevalence of COPD in females has gradually become equal to that of males, with 80% of non-smoking COPD patients being female.80,81 Exposure to household biomass in real life is common in the female population. Particulate matter, CO, SO2, NO2, and other components of biomass fumes have irritating effects on the respiratory tract and are strongly oxidizing. This can cause destructive changes in the airway and alveolar structure, inducing cupped cell hyperplasia of the airway mucosa and excessive secretion of airway mucus, resulting in persistent airway hyperreactivity and respiratory inflammation.82,83 The clinical signs of AE from biomass smoke were slightly different from those of tobacco smoke. Patients with COPD under former exposure have a less emphysematous phenotype and more often present with a small airway disease phenotype and more clinical symptoms such as cough, sputum, and shortness of breath, often with comorbidities such as bronchial asthma or allergic rhinitis, which aggravates clinical symptoms in patients with AE.83–85


More than 80% of patients are estimated to have at least one chronic comorbidity, which can affect patient quality of life and disease prognosis, increase the risk of AE, and reduce patient survival.86–89 The Charlson Comorbidity Index (CCI) was first proposed in 1987, and current research suggests that CCI can be an independent risk factor for AE or death.90 Patients with COPD had lower survival rates and higher CCI scores, and patients with CCI scores ≥5 (patients with ≥4 comorbidities) had five or more times the mortality rate than did patients without comorbidities.91 A randomized controlled trial of elderly patients with COPD after hospital discharge also found that the risk of death, length of stay, and readmission increased in COPD populations with a higher CCI.92 In addition, the number of comorbidities was significantly associated with the risk of readmission in patients with COPD; that is, each additional comorbidity was associated with a 47% higher risk of readmission.93

COPD comorbidities mainly involve the cardiovascular system, respiratory system, mental status, or endocrine metabolism, and include ischemic heart disease, coronary artery disease, heart failure, pulmonary hypertension, dyslipidemia, lung cancer, pulmonary fibrosis, anxiety and depression disorders, osteoporosis, malnutrition, and diabetes.89,94 Among them, cardiovascular disease is more common and at a higher risk than other systemic diseases.87

Severe pulmonary hypertension is a complication of advanced COPD. Long-term pulmonary hypertension can stimulate proliferation of the vascular smooth muscle layer, leading to thickening of the pulmonary artery, which is currently being evaluated as a marker of pulmonary vascular disease.95 The mechanism of AE caused by pulmonary artery thickening may be related to cardiac systolic and diastolic dysfunction, a pulmonary parenchymal disease with the absence of a capillary bed, etc.96 The ratio of pulmonary artery diameter to aortic diameter (PA: A) correlates with right ventricular hypertrophy, right ventricular enlargement, and reduced right ventricular function; thus, cardiac-pulmonary interactions are critical during acute exacerbations.97 Most studies have shown a significant increase in AE risk when the PA: A ratio exceeds a threshold of 1.98 Pulmonary artery thickening (PA: A>1) is closely associated with AE and predicts the development of AECOPD.96,97

Chronic Bronchitis (CB) is also a more common comorbidity. A previous study showed a significant increase in annual AE rates and hospital admissions in COPD patients with combined CB and a higher probability of combined CB in patients with GOLD grade 2–4.99 CB is strongly associated with annual AE rates, adverse events, and accelerated disease progression in patients with COPD.

In addition, patients with chronic diseases are prone to electrolyte disorders, and hyponatremia is a common electrolyte disorder in patients with AECOPD.100,101 Hyponatremia causes a decrease in the body’s serum osmolality, which leads to the development of pulmonary edema and pleural effusion by modulation of the transient receptor potential ion channel 4, further exacerbating COPD.102,103 Most studies have concluded that the severity of hyponatremia severity is associated with longer hospital stays, higher mortality rates, higher readmission rates, and increased need for post-discharge care in patients with AECOPD, and can be used as a predictor of the occurrence of an adverse clinical outcome in AECOPD.104–106

Airflow Limitation

The primary pathophysiological alteration observed in individuals with COPD is the restriction of airflow. This is primarily caused by inflammation in the small airways, the accumulation of mucus, and the development of fibrous tissue, all of which contribute to an increase in resistance within the small airways. In cases of emphysema, the normal ability of alveoli to exert a pulling force on the small airways is diminished, along with a significant reduction in the elastic retraction force of the alveoli. Consequently, this leads to obstructive ventilation dysfunction, resulting in persistent limitations in expiratory flow, the retention of carbon dioxide within the lungs, and an adverse impact on the body’s metabolic processes and gas exchange function, particularly during AE.107 The FEV1%Pred, which serves as a lung function indicator, is frequently employed to assess the extent of airflow limitation in individuals diagnosed with COPD. Based on the decline in FEV1%Pred, the GOLD Grades categorize patients into four distinct grades. Research conducted in Japan revealed that COPD patients experiencing AE exhibited more severe FEV1 impairment, higher GOLD Grades, and elevated modified Medical Research Council (mMRC) scores compared to those without AE.108 The presence of high airflow limitation and low FEV1 has been found to potentially elevate the likelihood of recurrent AE. FEV1 can serve as an independent prognostic factor for AE, as well as being associated with predicting adverse clinical outcomes such as mortality and the need for mechanical ventilation in individuals with COPD. Furthermore, additional research has indicated a positive correlation between the frequency of AE and the decline in FEV1, suggesting a mutually causal relationship between airflow limitation and AE.109,110 Hence, in the diagnosis and management of COPD, consistent utilization of bronchodilators and regular monitoring of pulmonary function indicators assume paramount significance.


Abnormal Levels of Eosinophils

It is well known that an important part of the inflammatory response in COPD is the activation and aggregation of neutrophils, however, in recent years several studies have shown that eosinophilic inflammation also plays an essential role. A total of 10%-40% of COPD patients with have eosinophilic airflow limitation.111 Since induced sputum is highly correlated with the proportion of eosinophils in the peripheral blood, increased blood eosinophils may be somewhat predictive of sputum eosinophils.111,112 Studies have shown that lung function is worsens and the risk of AEs is increased when sputum and peripheral blood eosinophils levels are elevated.112–114 The risk of AE is increased 1.85-fold when the percentage of peripheral blood eosinophils is more than 2%, the risk of AE is higher in patients with moderate to severe COPD with blood eosinophil counts ≥150 cells/μL, and the risk of AE is increased 3.21-fold with blood eosinophil counts ≥340 cells/μL.111,113,115,116 There is a degree of eosinophilic airflow limitation in any period of COPD.117,118 High level of eosinophils in the stable phase may predict an increased risk of progression,113 however, the proportion of eosinophils in AE is more than 30 times higher than that in the stable phase.119 Eosinophils regulate type 2 immune response, and when eosinophils are recruited, they can mediate a stronger inflammatory response, activating the secretion of various cytokines and cytotoxic granules that can cause airway damage.120 Eosinophilis has also been associated with a variety of disorders such as metaplastic, infectious, and rheumatologic disorders, which may also contribute to the development of AEs and increased readmission rate.

Moreover, a low eosinophil status predicts a decline in lung function and an increased risk of mortality due to critical illness. It was positively correlated with the length of hospitalization and mortality within 12 months in patients with AECOPD.121 In contrast to eosinophilia, low levels of eosinophilia indicate that the body is susceptible to infection and should be treated with antibiotics to prevent infection.122

Vitamin D (VitD) Deficiency

Several studies have confirmed the prevalence of low serum VitD levels in patients; that is, the higher the severity of COPD, the lower the serum VitD levels.123,124 The risk of disease deterioration is three times higher in COPD patients with VitD deficiency than in those without.123 Although Vit D supplementation does not increase the risk of upper respiratory tract infections, it has a protective effect against severe exacerbations in patients.125 Low vitamin D levels increase the risk of frequent respiratory infections, and reduced levels of VitD, an immunomodulatory effector in the body, can affect the body’s immune capacity, increase airway smooth muscle hyperplasia, and aggravate airflow limitation.123,126,127

High Fibrinogen Levels

Fibrinogen (FIB) is the primary plasma protein produced by hepatocytes and serves as an acute-phase reactant in the human body, with its expression being upregulated in response to inflammatory mediators. In patients with COPD, the occurrence of airflow limitation, thromboembolism, emphysema, and atherosclerosis are more prevalent when FIB levels exceed 4g/L.128,129 Several studies have demonstrated a negative correlation between FIB level and FEV1, as well as a positive correlation with AE rate, readmission rate, exercise tolerance, and COPD mortality. This suggests that FIB level can serve as a biomarker for predicting the failure of NIV in COPD patients.129–132 Furthermore, a meta-analysis consisting of 45 studies further supports the notion that higher FIB concentration is associated with greater severity of COPD.133 Mannino et al conducted a study on the relationship between FIB level and mortality, revealing that COPD mortality significantly increased when FIB levels reached or exceeded 4.03g/L.134 Another consistent study also indicated that elevated level of FIB (≥3.5g/L) was linked to increased rates of readmission within one year and higher mortality rates within three years.131 Currently, FIB is recognized as one of the most diverse inflammatory biomarkers in the progression of COPD.129,135–137 It possesses the potential to predict individuals at a heightened risk of COPD exacerbation and mortality, while also offering a less invasive means of measurement. Consequently, the Food and Drug Administration (FDA) has acknowledged FIB as a valuable tool in the management of COPD.137


Uric acid (UA) is a byproduct of purine metabolism that can generate reactive oxygen free radicals in the human body. Consequently, UA serves as a potential indicator of oxidative stress.138 Hyperuricemia has been linked to systemic inflammation and cardiovascular incidents. Hypoxia caused by exacerbation of COPD can stimulate increased UA synthesis.139 Moreover, increased blood UA level can impair renal function, disrupt the prognosis of hypercapnic AECOPD patients, and increase the risk of cardiovascular events, and exacerbate the burden of comorbidities in AECOPD patients.140 According to the study’s findings, individuals with stage GOLD 3–4 and hypoxemia had greater levels of serum UA than patients with stage GOLD 1–2 and non-hypoxemia.141,142 Furthermore, it was observed that there existed a positive correlation between the elevation of serum UA level and the deterioration of lung function, an increased susceptibility to adverse clinical events (AE), and the serum UA level upon admission could be utilized as a standalone prognostic indicator for mortality within a 30-day timeframe.143,144 Consequently, given its accessibility and affordability, serum UA can be regarded as a valuable biomarker for assessing the severity of COPD in the clinic.

Previous Deterioration History

A history of disease progression is one of the most influential risk factors for future exacerbation, readmission, and death.145 The higher the risk of AE, the more frequent the deterioration and increased mortality of patients. Therefore, a history of previous deterioration can be an important independent predictor of frequent COPD deterioration.146–150 In a follow-up trial study of 73,106 patients selected for the first hospitalization for COPD, the risk of re-AE was found to increase approximately three times after experiencing a second exacerbation compared to the first exacerbation population; when patients experienced a tenth severe exacerbation, the risk of re-AE increased to 24 times. Mortality after the second exacerbation was 1.9 times higher compared to after the first exacerbation, and up to 5 times higher after the tenth exacerbation.151 Notably, 85.5% of patients with a history of AE in the previous year will experience one AE in the following year.148 As each AE occurs, the median survival time between exacerbations decreases, and the patients’ quality of survival and health status gradually decline after each AE, with the risk of re-AE peaking three months after discharge.151

Natural Killer (NK) Cell Abnormalities

As an essential component of the body’s innate immune system, NK cells are involved in the mechanisms of airway remodeling and emphysema, regulating antiviral, antitumor, and immune processes in the body. Therefore, abnormal NK cell status in patients with COPD substantially increases the risk of AE. Abnormal NK cell status can lead to an inflammatory response and tissue damage in the body, affecting a patient’s stability and susceptibility status.152,153 A majority view is that patients have insufficient expression of inhibitory CD94 receptors on the surface of NK cells, which are the main sources of pro-inflammatory cytokines and granzymes. Notably, the expression and release of granzyme B and perforin are increased in patients with COPD, with a consequent increase in NK cell-killing activity.154 A study has found that the NK cell-killing activity was significantly enhanced in alveolar lavage fluid specimens from patients with COPD,155 which supports the above view. Additionally, other study has reported that the proportion of NK cells is higher in patients with severe airway obstruction, frequent AE episodes, and poor nutritional status.156

Smoking, the number of AE episodes, and certain viral infections affect NK cell stability,152,156,157 and FPR3 expression levels in NKT cells are low in former smokers. Insufficient FPR3 expression is directly related to severe airflow limitation in COPD.158 Therefore, abnormalities in the NK cell status not only directly affect the stability of the respiratory system itself but also indirectly affect the course of COPD by altering other risk factors. Recent studies have indicated that NK cells may serve as specific biomarkers of AECOPD.155–157 As NK cell research continues to advance, it is expected that NK cells or NKT-like cells will be used as therapeutic entry targets to interfere with cytotoxicity and related inflammatory mediator production.

Immunoglobulin G (IgG) Deficiency

The relationship between nonspecific and acquired immunities and the onset and progression of chronic obstructive pulmonary disease (COPD) is evident.159 B-lymphocytes play a crucial role in the mediation of humoral immunity, which serves as a prominent immune defense mechanism against infections. Immunoglobulins, as integral constituents of the humoral immune response, hold significant importance.160 Immunoglobulins, as integral constituents of the humoral immune response, hold significant importance. IgG is the predominant serum immunoglobulin that actively engages in the process of phagocytosis, thereby facilitating the eradication of a diverse array of viruses, bacteria, and toxins within the human body.161 The most common cause of AE is infection. The compromised immune system of the patients heightens the susceptibility to infection, consequently leading to detrimental consequences on the patients’ development and prognosis through recurrent infections.162 Moreover, 25% of patients with COPD have humoral immunodeficiency and reduced IgG levels and are prone to hypogammaglobulinemia (<7.0 g/L).159,161 This presentation increases the risk of COPD hospitalization by 30%, the risk of future hospitalization by 60%, and the risk of AE by 50%-100%.159,161,163 Additionally, it positively correlates with the risk of death in hospitalized patients with COPD.164,165 As the number of AE increased, the proportion and frequency of hypogammaglobulinemia also increased. In COPD patients are more than two AE, hypogammaglobulinemia increased to 35.9%.161,163 Furthermore, the presence of IgG deficiency is associated with an elevated susceptibility to non-respiratory ailments, including allergic and autoimmune diseases, as well as cardiovascular system disorders. This deficiency also heightens the likelihood of complications and indirectly exacerbates the risk of AE. Consequently, the implementation of immunoglobulin replacement therapy among individuals with IgG deficiency may effectively mitigate the occurrence of AECOPD within clinical settings.


To date, over 20 genes have been identified as significantly linked to the status of COPD.166 Mannose-Binding Lectin (MBL), a protein that activates the complement system in the body to eliminate pathogens, holds a crucial position in the immune system.167 The presence of MBL2 polymorphism is associated with inadequate levels of serum MBL, and defects in the MBL gene resulting from MBL2 polymorphism impact the frequency of recurrent respiratory tract infections and the duration of hospitalization for individuals with COPD.168,169 A comprehensive study comprising a sample size of 1796 individuals was conducted to explore the association between MBL and the susceptibility to COPD exacerbations. The results indicated that individuals with COPD who possessed the MBL2 gene demonstrated a diminished likelihood of experiencing AE, a heightened variety of lung microorganisms, and decreased levels of airway obstruction.170 Furthermore, three smaller studies have demonstrated that polymorphisms in the human MBL2 gene, leading to MBL deficiency, are associated with a heightened susceptibility to AE and a less favorable prognosis for the ailment. Conversely, studies have indicated that increased level of serum MBL are associated with improved survival rates among patients with COPD and a reduced risk of exacerbations.171–173

Furthermore, several studies have demonstrated the involvement of human hedgehog interacting protein (HHIP) in the process of lung development, whereby diminished level of HHIP result in lung hypoplasia.174 Additionally, the presence of single nucleotide polymorphisms within HHIP has been linked to an increased susceptibility to COPD, airflow limitation, and alterations in lung function.175 Moreover, a prospective study conducted across 46 clinical centers in 12 countries (n=1719) observed a significant correlation between genetic variants of HHIP and the occurrence of moderate to severe AE within the past year.176 However, the current investigation into genetic factors linked to AECOPD is still relatively limited in its scope of examining the entire genome. Our comprehension of the genetic factors that contribute to AECOPD remains restricted, thus requiring further exploration of a wider array of genetic variations.

Muscle and Nutritional Status Abnormalities

The most common extrapulmonary manifestations in COPD patients are muscle disorders and wasting, which can become more severe as the patient’s condition worsens.177 Malnutrition leads to abnormalities in muscle mass and function, with a significant positive correlation between COPD progression and adverse events, which can have a significant impact on the respiratory system and the whole body.177–180 BMI is a common clinical measure of a patient’s nutritional status, and studies have shown that a BMI <20 kg/m2 can be an independent risk factor for mortality in partial respiratory disease.181 Patients with COPD who are malnourished or potentially malnourished have increased readmission rates, length of stay, other comorbidities, and four times increased risk of death after 2 years.182–185

Patients with COPD are prone to nutritional events.186 The clinical outcome of Malnutrition leads to dysfunction of the respiratory muscles and diaphragm, resulting in decreased lung function, increased dyspnea, limitation of daily activities, and muscle atrophy or weakness. Damage to the respiratory muscles and surrounding muscle groups is significantly correlated with the severity of the disease at the time and frequency of admission, and in severe cases, respiratory failure or more complex cachexia.177,179

Other Factors

Negative Mentalities

Patients with depression or anxiety are at an increased risk of COPD progression and death.187–189 In a clinical study of 376 patients with AECOPD, the prevalence of depression at admission was found to be 44.4%. Furthermore, patients with COPD and depression had lower survival rates, longer hospital stays, and a higher disease burden at one-year follow-up.190 COPD patients with high depression and anxiety (anxiety > 50, depression > 53) were at higher risk of AE.191 Depression is significantly associated with poorer social functioning and economic status, low family or marital happiness, and low educational attainment.93,190 Some studies have suggested that the pathological mechanisms of negative psychological states effects on AE, among others, may be related to systemic inflammatory responses or neuronal necrosis in the hippocampus.

Seasonal Temperature Variations

A global-scale study of COPD exacerbation and seasonal correlation indicated a nearly two-fold increase in AE risk in winter compared to summer. AE was common between December and February in 9% of patients in the northern region, compared to 5% in summer, and 12% of patients in the southern region had higher AE rates between December and February, compared to 7% in summer.192 Excluding the tropic regions, COPD has a higher AE rate in winter, and the seasonality of AE is more pronounced. Another Spanish regional study showed that COPD was particularly prevalent in winter, followed by autumn, spring, and summer; additionally, the number of hospitalizations also increased with lower temperatures, with a 4.7% increase for every 1 °C drop in temperature,193 supporting the effect of seasonal temperature changes on AE.


AE is the outcome of multiple risk factors, including individual and environmental factors, which act together in the body to trigger AE (Figure 1, Table 1). The majority of these AE are initiated by respiratory pathogens, including viruses and bacteria. Currently, global research predominantly concentrates on the microscopic level, delving extensively into the mechanisms underlying AECOPD. The objective is to identify novel regulatory pathways and pharmaceutical treatments utilizing genomic and biomarker technologies.

Figure 1 Diagram of risk factors associated with chronic obstructive pulmonary disease.

Table 1 Risk Factors Associated with Acute Exacerbation of COPD

Due to the large size of the COPD population, and with the world population gradually aging and multiple risk factors continuing to attack, the mortality and disability rates of COPD patients will continue to increase in the future. For these reasons, preventive diagnosis and treatment of COPD, early identification, timely diagnosis and treatment, and whole process intervention are particularly important. Long-term standardized management and intervention in COPD patients will likely improve the negative impact of AE in the course of COPD to a greater extent, and improve patients’ disease prognosis and quality of life. Currently, there remains a dearth of research literature pertaining to the long-term standardized management intervention for patients with COPD in the context of investigating risk factors and predicting AE. Furthermore, completed studies on standardized management factors may exhibit limitations, including inadequate sample sizes, incomplete incorporation and analysis of indicators, and suboptimal patient adherence.

With the increasing emphasis on chronic diseases in the international health community, most countries are gradually implementing standardized training for respiratory physicians, public health education, early screening of high-risk groups for COPD, and actively build standardized supervision and management system for primary care. These efforts aim to investigate novel medical intervention strategies that can effectively mitigate the occurrence of AE. With the popularization and improvement of network information, the combination of the Internet and medical treatment will become the mainstream trend for precise treatment, full management, and prevention of AE for patients with COPD in both urban and rural communities in the future.


AECOPD, Acute exacerbations of chronic obstructive pulmonary disease; VitD, Vitamin D; CB, Chronic Bronchitis; CCI, Charlson Comorbidity Index; NIV, non-invasive ventilation; CRP, C-reactive proteins; ACE-2, angiotensin-converting enzyme 2; MMPs, matrix metalloproteinases; NK, Natural killer; HIV, human immunodeficiency virus; mMRC, modified Medical Research Council; FIB, fibrinogen; UA, uric acid; IgG, Immunoglobulin G; MBL, Mannose-Binding Lectin; HHIP, human hedgehog interacting protein.


This work was supported by Ningbo Science And Technology Bureau (Project Number: 202003N4023).


The authors report no conflicts of interest in this work.


1. Venkatesan P. GOLD COPD report: 2023 update. Lancet Respir Med. 2023;11(1):18. doi:10.1016/S2213-2600(22)00494-5

2. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: systematic review and meta-analysis. J Glob Health. 2015;5(2):020415. doi:10.7189/jogh.05.020415

3. Vos T, Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204–1222. doi:10.1016/S0140-6736(20)30925-9

4. Heron M. Deaths: leading Causes for 2017. Natl Vital Stat Rep. 2019;68(6):1–77.

5. Global. regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789–1858. doi:10.1016/S0140-6736(18)32279-7

6. Christenson SA, Smith BM, Bafadhel M, Putcha N. Chronic obstructive pulmonary disease. Lancet. 2022;399(10342):2227–2242. doi:10.1016/S0140-6736(22)00470-6

7. Wang C, Xu J, Yang L, et al. Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study. Lancet. 2018;391(10131):1706–1717. doi:10.1016/S0140-6736(18)30841-9

8. Ko FW, Chan KP, Hui DS, et al. Acute exacerbation of COPD. Respirology. 2016;21(7):1152–1165. doi:10.1111/resp.12780

9. Han MK, Quibrera PM, Carretta EE, et al. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017;5(8):619–626. doi:10.1016/S2213-2600(17)30207-2

10. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11(1):181. doi:10.1186/1741-7015-11-181

11. Celli BR, Fabbri LM, Aaron SD, et al. Differential Diagnosis of Suspected Chronic Obstructive Pulmonary Disease Exacerbations in the Acute Care Setting: best Practice. Am J Respir Crit Care Med. 2023;207(9):1134–1144. doi:10.1164/rccm.202209-1795CI

12. Marcos PJ, Sanjuán P, Huerta A, et al. Relationship Between Severity Classification of Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Clinical Outcomes in Hospitalized Patients. Cureus. 2017;9(1):e988. doi:10.7759/cureus.988

13. Pozo-Rodríguez F, López-Campos JL, Alvarez-Martínez CJ, et al. Clinical audit of COPD patients requiring hospital admissions in Spain: AUDIPOC study. PLoS One. 2012;7(7):e42156. doi:10.1371/journal.pone.0042156

14. Escarrabill J, Torrente E, Esquinas C, et al. Clinical audit of patients hospitalized due to COPD exacerbation. MAG-1 Study. Arch Bronconeumol. 2015;51(10):483–489. doi:10.1016/j.arbres.2014.06.023

15. Iheanacho I, Zhang S, King D, Rizzo M, Ismaila AS. Economic Burden of Chronic Obstructive Pulmonary Disease (COPD): a Systematic Literature Review. Int J Chron Obstruct Pulmon Dis. 2020;15:439–460. doi:10.2147/COPD.S234942

16. Afessa B, Morales IJ, Scanlon PD, Peters SG. Prognostic factors, clinical course, and hospital outcome of patients with chronic obstructive pulmonary disease admitted to an intensive care unit for acute respiratory failure. Crit Care Med. 2002;30(7):1610–1615. doi:10.1097/00003246-200207000-00035

17. Berenyi F, Steinfort DP, Abdelhamid YA, et al. Characteristics and Outcomes of Critically Ill Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Australia and New Zealand. Ann Am Thorac Soc. 2020;17(6):736–745. doi:10.1513/AnnalsATS.201911-821OC

18. Prediletto I, Giancotti G, Nava S. COPD Exacerbation: why It Is Important to Avoid ICU Admission. J Clin Med. 2023;12(10):3369. doi:10.3390/jcm12103369

19. Hartl S, Lopez-Campos JL, Pozo-Rodriguez F, et al. Risk of death and readmission of hospital-admitted COPD exacerbations: european COPD Audit. Eur Respir J. 2016;47(1):113–121. doi:10.1183/13993003.01391-2014

20. Hoogendoorn M, Hoogenveen RT, Rutten-van Mölken MP, Vestbo J, Feenstra TL. Case fatality of COPD exacerbations: a meta-analysis and statistical modelling approach. Eur Respir J. 2011;37(3):508–515. doi:10.1183/09031936.00043710

21. Wedzicha JA, Seemungal TAR. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370(9589):786–796. doi:10.1016/S0140-6736(07)61382-8

22. Ritchie AI, Wedzicha JA. Definition, Causes, Pathogenesis, and Consequences of Chronic Obstructive Pulmonary Disease Exacerbations. Clin Chest Med. 2020;41(3):421–438. doi:10.1016/j.ccm.2020.06.007

23. Ye F, He LX, Cai BQ, et al. Spectrum and antimicrobial resistance of common pathogenic bacteria isolated from patients with acute exacerbation of chronic obstructive pulmonary disease in mainland of China. Chin Med J. 2013;126(12):2207–2214.

24. Wark PA, Tooze M, Powell H, Parsons K. Viral and bacterial infection in acute asthma and chronic obstructive pulmonary disease increases the risk of readmission. Respirology. 2013;18(6):996–1002. doi:10.1111/resp.12099

25. Hou HH, Wang HC, Cheng SL, Chen YF, Lu KZ, Yu CJ. MMP-12 activates protease-activated receptor-1, upregulates placenta growth factor, and leads to pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol. 2018;315(3):L432–L442. doi:10.1152/ajplung.00216.2017

26. Churg A, Zhou S, Wright JL. Series “matrix metalloproteinases in lung health and disease”: matrix metalloproteinases in COPD. Eur Respir J. 2012;39(1):197–209. doi:10.1183/09031936.00121611

27. Liu J, Ran Z, Wang F, Xin C, Xiong B, Song Z. Role of pulmonary microorganisms in the development of chronic obstructive pulmonary disease. Crit Rev Microbiol. 2021;47(1):1–12. doi:10.1080/1040841X.2020.1830748

28. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359(22):2355–2365. doi:10.1056/NEJMra0800353

29. Hurst JR, Perera WR, Wilkinson TMA, Donaldson GC, Wedzicha JA. Systemic and Upper and Lower Airway Inflammation at Exacerbation of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2006;173(1):71–78. doi:10.1164/rccm.200505-704OC

30. Sapey E. COPD exacerbations.2: aetiology. Thorax. 2006;61(3):250–258. doi:10.1136/thx.2005.041822

31. Wypych TP, Wickramasinghe LC, Marsland BJ. The influence of the microbiome on respiratory health. Nat Immunol. 2019;20(10):1279–1290. doi:10.1038/s41590-019-0451-9

32. Rohde G. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study. Thorax. 2003;58(1):37–42. doi:10.1136/thorax.58.1.37

33. Choi KJ, Cha SI, Shin KM, et al. Prevalence and predictors of pulmonary embolism in Korean patients with exacerbation of chronic obstructive pulmonary disease. Respiration. 2013;85(3):203–209. doi:10.1159/000335904

34. Aaron SD, Angel JB, Lunau M, et al. Granulocyte Inflammatory Markers and Airway Infection during Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2001;163(2):349–355. doi:10.1164/ajrccm.163.2.2003122

35. Clark TW, Medina MJ, Batham S, Curran MD, Parmar S, Nicholson KG. C-reactive protein level and microbial aetiology in patients hospitalised with acute exacerbation of COPD. Eur Respir J. 2015;45(1):76–86. doi:10.1183/09031936.00092214

36. Hosseini SS, Ghasemian E, Jamaati H, Tabaraie B, Amini Z, Cox K. Association between respiratory viruses and exacerbation of COPD: a case-control study. Infect Dis. 2015;47(8):523–529. doi:10.3109/23744235.2015.1022873

37. Hewitt R, Farne H, Ritchie A, Luke E, Johnston SL, Mallia P. The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma. Ther Adv Respir Dis. 2016;10(2):158–174. doi:10.1177/1753465815618113

38. Stolz D, Papakonstantinou E, Grize L, et al. Time-course of upper respiratory tract viral infection and COPD exacerbation. Eur Respir J. 2019;54(4):1900407. doi:10.1183/13993003.00407-2019

39. Zwaans WA, Mallia P, van Winden ME, Rohde GG. The relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease-a systematic review. J Clin Virol. 2014;61(2):181–188. doi:10.1016/j.jcv.2014.06.025

40. Mohan A, Chandra S, Agarwal D, et al. Prevalence of viral infection detected by PCR and RT-PCR in patients with acute exacerbation of COPD: a systematic review. Respirology. 2010;15(3):536–542. doi:10.1111/j.1440-1843.2010.01722.x

41. Biancardi E, Fennell M, Rawlinson W, Thomas PS. Viruses are frequently present as the infecting agent in acute exacerbations of chronic obstructive pulmonary disease in patients presenting to hospital. Intern Med J. 2016;46(10):1160–1165. doi:10.1111/imj.13213

42. Kwak HJ, Park DW, Kim JE, et al. Prevalence and Risk Factors of Respiratory Viral Infections in Exacerbations of Chronic Obstructive Pulmonary Disease. Tohoku J Exp Med. 2016;240(2):131–139. doi:10.1620/tjem.240.131

43. Mallia P, Message SD, Kebadze T, Parker HL, Kon OM, Johnston SL. An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study. Respir Res. 2006;7(1). doi:10.1186/1465-9921-7-116

44. Leung JM, Niikura M, Yang CWT, Sin DD. COVID-19 and COPD. Eur Respir J. 2020;56(2):2002108. doi:10.1183/13993003.02108-2020

45. Cribbs SK, Crothers K, Morris A. Pathogenesis of HIV-Related Lung Disease: immunity, Infection, and Inflammation. Physiol Rev. 2020;100(2):603–632. doi:10.1152/physrev.00039.2018

46. Liu JC, Leung JM, Ngan DA, et al. Absolute leukocyte telomere length in HIV-infected and uninfected individuals: evidence of accelerated cell senescence in HIV-associated chronic obstructive pulmonary disease. PLoS One. 2015;10(4):e0124426. doi:10.1371/journal.pone.0124426

47. Lambert AA, Kirk GD, Astemborski J, Mehta SH, Wise RA, Drummond MB. HIV Infection Is Associated With Increased Risk for Acute Exacerbation of COPD. J Acquir Immune Defic Syndr. 2015;69(1):68–74. doi:10.1097/QAI.0000000000000552

48. Dimopoulos G, Lerikou M, Tsiodras S, et al. Viral epidemiology of acute exacerbations of chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2012;25(1):12–18. doi:10.1016/j.pupt.2011.08.004

49. Choi J, Oh JY, Lee YS, et al. Bacterial and Viral Identification Rate in Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Korea. Yonsei Med J. 2019;60(2):216–222. doi:10.3349/ymj.2019.60.2.216

50. Almansa R, Socias L, Andaluz-Ojeda D, et al. Viral infection is associated with an increased proinflammatory response in chronic obstructive pulmonary disease. Viral Immunol. 2012;25(4):249–253. doi:10.1089/vim.2011.0095

51. Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J. 2007;29(3):527–534. doi:10.1183/09031936.00092506

52. Hegele RG, Hayashi S, Hogg JC, Paré PD. Mechanisms of airway narrowing and hyperresponsiveness in viral respiratory tract infections. Am J Respir Crit Care Med. 1995;151(5):1659–1664. doi:10.1164/ajrccm/151.5_Pt_1.1659

53. George SN, Garcha DS, Mackay AJ, et al. Human rhinovirus infection during naturally occurring COPD exacerbations. Eur Respir J. 2014;44(1):87–96. doi:10.1183/09031936.00223113

54. Mackay AJ, Kostikas K, Murray L, et al. Patient-reported Outcomes for the Detection, Quantification, and Evaluation of Chronic Obstructive Pulmonary Disease Exacerbations. Am J Respir Crit Care Med. 2018;198(6):730–738. doi:10.1164/rccm.201712-2482CI

55. Montserrat-Capdevila J, Godoy P, Marsal JR, Barbe F, Galvan L. Risk factors for exacerbation in chronic obstructive pulmonary disease: a prospective study. Int J Tuberc Lung Dis. 2016;20(3):389–395. doi:10.5588/ijtld.15.0441

56. Eisner M. The impact of SHS exposure on health status and exacerbations among patients with COPD. Int J Chron Obstruct Pulmon Dis. 2009;169. doi:10.2147/COPD.S4681

57. Li X, Wu Z, Xue M, Du W. Smoking status affects clinical characteristics and disease course of acute exacerbation of chronic obstructive pulmonary disease: a prospectively observational study. Chron Respir Dis. 2020;17:1479973120916184. doi:10.1177/1479973120916184

58. Saad AB, Adhieb A, Migaou A, et al. Effect of intensity of smoking intoxication on severity parameters of acute exacerbations of chronic obstructive pulmonary disease treated in a hospital milieu. Pan Afr Med J. 2021;38:91. doi:10.11604/pamj.2021.38.91.21512

59. Godtfredsen NS. Risk of hospital admission for COPD following smoking cessation and reduction: a Danish population study. Thorax. 2002;57(11):967–972. doi:10.1136/thorax.57.11.967

60. Bauer CMT, Morissette MC, Stampfli MR. The influence of cigarette smoking on viral infections: translating bench science to impact COPD pathogenesis and acute exacerbations of COPD clinically. Chest. 2013;143(1):196–206. doi:10.1378/chest.12-0930

61. Mehta H, Nazzal K, Sadikot RT. Cigarette smoking and innate immunity. Inflammation Res. 2008;57(11):497–503. doi:10.1007/s00011-008-8078-6

62. Johnston S, Molyneaux P, Singanayagam A, Joshi B, Mallia P. Lung microbiology and exacerbations in COPD. Int J Chron Obstruct Pulmon Dis. 2012;555. doi:10.2147/COPD.S28286

63. Jin Y, Cheng Y, Wang H, Zhao C. Effects of air pollution from burning coal on respiratory diseases in adults. Wei Sheng Yan Jiu. 2001;30(4):241–243, 246.

64. Schikowski T, Mills IC, Anderson HR, et al. Ambient air pollution: a cause of COPD? Eur Respir J. 2014;43(1):250–263. doi:10.1183/09031936.00100112

65. Gershon AS, Warner L, Cascagnette P, Victor JC, To T. Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study. Lancet. 2011;378(9795):991–996. doi:10.1016/S0140-6736(11)60990-2

66. DeVries R, Kriebel D, Sama S. Outdoor Air Pollution and COPD-Related Emergency Department Visits, Hospital Admissions, and Mortality: a Meta-Analysis. COPD. 2017;14(1):113–121. doi:10.1080/15412555.2016.1216956

67. Li MH, Fan LC, Mao B, et al. Short-term Exposure to Ambient Fine Particulate Matter Increases Hospitalizations and Mortality in COPD: a Systematic Review and Meta-analysis. Chest. 2016;149(2):447–458. doi:10.1378/chest.15-0513

68. Wordley J, Walters S, Ayres JG. Short term variations in hospital admissions and mortality and particulate air pollution. Occup Environ Med. 1997;54(2):108–116. doi:10.1136/oem.54.2.108

69. Liu S, Zhou Y, Liu S, et al. Association between exposure to ambient particulate matter and chronic obstructive pulmonary disease: results from a cross-sectional study in China. Thorax. 2017;72(9):788–795. doi:10.1136/thoraxjnl-2016-208910

70. Sun XW, Chen PL, Ren L, et al. The cumulative effect of air pollutants on the acute exacerbation of COPD in Shanghai, China. Sci Total Environ. 2018;622-623:875–881. doi:10.1016/j.scitotenv.2017.12.042

71. Xie J, Teng J, Fan Y, Xie R, Shen A. The short-term effects of air pollutants on hospitalizations for respiratory disease in Hefei, China. Int J Biometeorol. 2019;63(3):315–326. doi:10.1007/s00484-018-01665-y

72. Hwang SL, Lin YC, Guo SE, Chou CT, Lin CM, Chi MC. Fine particulate matter on hospital admissions for acute exacerbation of chronic obstructive pulmonary disease in southwestern Taiwan during 2006-2012. Int J Environ Health Res. 2017;27(2):95–105. doi:10.1080/09603123.2017.1278748

73. Wang W, Ying Y, Wu Q, Zhang H, Ma D, Xiao W. A GIS-based spatial correlation analysis for ambient air pollution and AECOPD hospitalizations in Jinan, China. Respir Med. 2015;109(3):372–378. doi:10.1016/j.rmed.2015.01.006

74. Liang L, Cai Y, Barratt B, et al. Associations between daily air quality and hospitalisations for acute exacerbation of chronic obstructive pulmonary disease in Beijing, 2013–17: an ecological analysis. Lancet Planetary Health. 2019;3(6):e270–e279. doi:10.1016/S2542-5196(19)30085-3

75. Kelly FJ, Fussell JC. Air pollution and airway disease. Clin Exp Allergy. 2011;41(8):1059–1071. doi:10.1111/j.1365-2222.2011.03776.x

76. Morantes-Caballero JA, Fajardo Rodriguez HA. Effects of air pollution on acute exacerbation of chronic obstructive pulmonary disease: a descriptive retrospective study (pol-AECOPD). Int J Chron Obstruct Pulmon Dis. 2019;14:1549–1557.

77. Peacock JL, Anderson HR, Bremner SA, et al. Outdoor air pollution and respiratory health in patients with COPD. Thorax. 2011;66(7):591–596. doi:10.1136/thx.2010.155358

78. Lin MT, Kor CT, Chang CC, et al. Association of meteorological factors and air NO2 and O3 concentrations with acute exacerbation of elderly chronic obstructive pulmonary disease. Sci Rep. 2018;8(1):10192. doi:10.1038/s41598-018-28532-5

79. Hu G, Zhou Y, Tian J, et al. Risk of COPD from exposure to biomass smoke: a metaanalysis. Chest. 2010;138(1):20–31. doi:10.1378/chest.08-2114

80. Gut-Gobert C, Cavailles A, Dixmier A, et al. Women and COPD: do we need more evidence? Eur Respir Rev. 2019;28(151):180055. doi:10.1183/16000617.0055-2018

81. Celli BR, Halbert RJ, Nordyke RJ, Schau B. Airway obstruction in never smokers: results from the Third National Health and Nutrition Examination Survey. Am J Med. 2005;118(12):1364–1372. doi:10.1016/j.amjmed.2005.06.041

82. Salvi S, Barnes PJ. Is exposure to biomass smoke the biggest risk factor for COPD globally? Chest. 2010;138(1):3–6. doi:10.1378/chest.10-0645

83. Cheng LL, Liu YY, Su ZQ, Liu J, Chen RC, Ran PX. Clinical characteristics of tobacco smoke-induced versus biomass fuel-induced chronic obstructive pulmonary disease. J Transl Int Med. 2015;3(3):126–129. doi:10.1515/jtim-2015-0012

84. Golpe R, Mengual-Macenlle N, Sanjuán-López P, Cano-Jiménez E, Castro-Añón O, Pérez-de-Llano LA. Prognostic Indices and Mortality Prediction in COPD Caused by Biomass Smoke Exposure. Lung. 2015;193(4):497–503.

85. Cho J, Lee C-H, Hwang SS, et al. Risk of acute exacerbations in chronic obstructive pulmonary disease associated with biomass smoke compared with tobacco smoke. BMC Pulm Med. 2019;19(1). doi:10.1186/s12890-019-0833-7

86. Putcha N, Drummond MB, Wise RA, Hansel NN. Comorbidities and Chronic Obstructive Pulmonary Disease: prevalence, Influence on Outcomes, and Management. Semin Respir Crit Care Med. 2015;36(4):575–591. doi:10.1055/s-0035-1556063

87. Sievi NA, Senn O, Brack T, et al. Impact of comorbidities on physical activity in COPD. Respirology. 2015;20(3):413–418. doi:10.1111/resp.12456

88. McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007;62(5):411–415. doi:10.1136/thx.2006.072348

89. Cavaillès A, Brinchault-Rabin G, Dixmier A, et al. Comorbidities of COPD. Eur Respir Rev. 2013;22(130):454–475. doi:10.1183/09059180.00008612

90. Lin Z, Chunmei P, Xiuhong N. Predictive Value of Charlson Comorbidity Index in Prognosis of Aged Chronic Obstructive Pulmonary Disease Patients. Chine J Respir Critical Care Med. 2016;15(4):333–336.

91. Almagro P, Calbo E, Ochoa de Echagüen A, et al. Mortality after hospitalization for COPD. Chest. 2002;121(5):1441–1448. doi:10.1378/chest.121.5.1441

92. Almagro P, Cabrera FJ, Diez J, et al. Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study. Chest. 2012;142(5):1126–1133. doi:10.1378/chest.11-2413

93. Wong AW, Gan WQ, Burns J, Sin DD, van Eeden SF. Acute exacerbation of chronic obstructive pulmonary disease: influence of social factors in determining length of hospital stay and readmission rates. Can Respir J. 2008;15(7):361–364. doi:10.1155/2008/569496

94. Negewo NA, Gibson PG, McDonald VM. COPD and its comorbidities: impact, measurement and mechanisms. Respirology. 2015;20(8):1160–1171. doi:10.1111/resp.12642

95. Wells JM, Dransfield MT. Pathophysiology and clinical implications of pulmonary arterial enlargement in COPD. Int J Chron Obstruct Pulmon Dis. 2013;8:509–521. doi:10.2147/COPD.S52204

96. Cuttica MJ, Bhatt SP, Rosenberg SR, et al. Pulmonary artery to aorta ratio is associated with cardiac structure and functional changes in mild-to-moderate COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:1439–1446. doi:10.2147/COPD.S131413

97. Wells JM, Morrison JB, Bhatt SP, Nath H, Dransfield MT. Pulmonary Artery Enlargement Is Associated With Cardiac Injury During Severe Exacerbations of COPD. Chest. 2016;149(5):1197–1204. doi:10.1378/chest.15-1504

98. Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367(10):913–921. doi:10.1056/NEJMoa1203830

99. Corhay JL, Vincken W, Schlesser M, Bossuyt P, Imschoot J. Chronic bronchitis in COPD patients is associated with increased risk of exacerbations: a cross-sectional multicentre study. Int J Clin Pract. 2013;67(12):1294–1301. doi:10.1111/ijcp.12248

100. Ramírez E, Rodríguez A, Queiruga J, et al. Severe Hyponatremia Is Often Drug Induced: 10-Year Results of a Prospective Pharmacovigilance Program. Clin Pharmacol Ther. 2019;106(6):1362–1379. doi:10.1002/cpt.1562

101. Cuesta M, Slattery D, Goulden EL, et al. Hyponatraemia in patients with community-acquired pneumonia; prevalence and aetiology, and natural history of SIAD. Clin Endocrinol (Oxf). 2019;90(5):744–752. doi:10.1111/cen.13937

102. García-Sanz MT, Martínez-Gestoso S, Calvo-álvarez U, et al. Impact of Hyponatremia on COPD Exacerbation Prognosis. J Clin Med. 2020;9(2):503. doi:10.3390/jcm9020503

103. Urso C, Brucculeri S, Caimi G. Physiopathological, Epidemiological, Clinical and Therapeutic Aspects of Exercise-Associated Hyponatremia. J Clin Med. 2014;3(4):1258–1275. doi:10.3390/jcm3041258

104. Chalela R, González-García JG, Chillarón JJ, et al. Impact of hyponatremia on mortality and morbidity in patients with COPD exacerbations. Respir Med. 2016;117:237–242. doi:10.1016/j.rmed.2016.05.003

105. Al Mawed S, Pankratz VS, Chong K, Sandoval M, Roumelioti ME, Unruh M. Low serum sodium levels at hospital admission: outcomes among 2.3 million hospitalized patients. PLoS One. 2018;13(3):e0194379. doi:10.1371/journal.pone.0194379

106. De Vecchis R, Di Maio M, Di Biase G, Ariano C. Effects of Hyponatremia Normalization on the Short-Term Mortality and Rehospitalizations in Patients with Recent Acute Decompensated Heart Failure: a Retrospective Study. J Clin Med. 2016;5(10):92. doi:10.3390/jcm5100092

107. Anzueto A, Miravitlles M. Pathophysiology of dyspnea in COPD. Postgrad Med. 2017;129(3):366–374. doi:10.1080/00325481.2017.1301190

108. Yamaya M, Usami O, Nakayama S, et al. Malnutrition, Airflow Limitation and Severe Emphysema are Risks for Exacerbation of Chronic Obstructive Pulmonary Disease in Japanese Subjects: a Retrospective Single-Center Study. Int J Chron Obstruct Pulmon Dis. 2020;15:857–868. doi:10.2147/COPD.S238457

109. Gulati S, Wells JM. Bringing Stability to the Chronic Obstructive Pulmonary Disease Patient: clinical and Pharmacological Considerations for Frequent Exacerbators. Drugs. 2017;77(6):651–670. doi:10.1007/s40265-017-0713-5

110. Miravitlles M, Guerrero T, Mayordomo C, Sánchez-Agudo L, Nicolau F, Segú JL. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group. Respiration. 2000;67(5):495–501. doi:10.1159/000067462

111. Gao J, Chen B, Wu S, Wu F. Blood cell for the differentiation of airway inflammatory phenotypes in COPD exacerbations. BMC Pulm Med. 2020;20(1):50. doi:10.1186/s12890-020-1086-1

112. Hastie AT, Martinez FJ, Curtis JL, et al. Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017;5(12):956–967. doi:10.1016/S2213-2600(17)30432-0

113. Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood Eosinophils and Exacerbations in Chronic Obstructive Pulmonary Disease. The Copenhagen General Population Study. Am J Respir Crit Care Med. 2016;193(9):965–974. doi:10.1164/rccm.201509-1869OC

114. Brusselle G, Pavord ID, Landis S, et al. Blood eosinophil levels as a biomarker in COPD. Respir Med. 2018;138:21–31. doi:10.1016/j.rmed.2018.03.016

115. Bafadhel M, Pavord ID, Russell REK. Eosinophils in COPD: just another biomarker? Lancet Respir Med. 2017;5(9):747–759. doi:10.1016/S2213-2600(17)30217-5

116. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015;3(6):435–442. doi:10.1016/S2213-2600(15)00106-X

117. Papi A, Romagnoli M, Baraldo S, et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162(5):1773–1777. doi:10.1164/ajrccm.162.5.9910112

118. Gao P, Zhang J, He X, Hao Y, Wang K, Gibson PG. Sputum inflammatory cell-based classification of patients with acute exacerbation of chronic obstructive pulmonary disease. PLoS One. 2013;8(5):e57678. doi:10.1371/journal.pone.0057678

119. Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994;150(6 Pt 1):1646–1652. doi:10.1164/ajrccm.150.6.7952628

120. Eltboli O, Bafadhel M, Hollins F, et al. COPD exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils. BMC Pulm Med. 2014;14:112. doi:10.1186/1471-2466-14-112

121. Abidi K, Khoudri I, Belayachi J, et al. Eosinopenia is a reliable marker of sepsis on admission to medical intensive care units. Crit Care. 2008;12(2):R59. doi:10.1186/cc6883

122. Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med. 2016;4(9):731–741. doi:10.1016/S2213-2600(16)30148-5

123. Lokesh KS, Chaya SK, Jayaraj BS, et al. Vitamin D deficiency is associated with chronic obstructive pulmonary disease and exacerbation of COPD. Clin Respir J. 2021;15(4):389–399. doi:10.1111/crj.13310

124. Burkes RM, Ceppe AS, Doerschuk CM, et al. Associations Among 25-Hydroxyvitamin D Levels, Lung Function, and Exacerbation Outcomes in COPD: an Analysis of the SPIROMICS Cohort. Chest. 2020;157(4):856–865. doi:10.1016/j.chest.2019.11.047

125. Martineau AR, James WY, Hooper RL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med. 2015;3(2):120–130. doi:10.1016/S2213-2600(14)70255-3

126. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013;5(7):2502–2521. doi:10.3390/nu5072502

127. Jung JY, Kim YS, Kim SK, et al. Relationship of vitamin D status with lung function and exercise capacity in COPD. Respirology. 2015;20(5):782–789. doi:10.1111/resp.12538

128. Sun W, Cao Z, Ma Y, Wang J, Zhang L, Luo Z. Fibrinogen, a Promising Marker to Evaluate Severity and Prognosis of Acute Exacerbation of Chronic Obstructive Pulmonary Disease: a Retrospective Observational Study. Int J Chron Obstruct Pulmon Dis. 2022;17:1299–1310. doi:10.2147/COPD.S361929

129. Miller BE, Tal-Singer R, Rennard SI, et al. Plasma Fibrinogen Qualification as a Drug Development Tool in Chronic Obstructive Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease Biomarker Qualification Consortium. Am J Respir Crit Care Med. 2016;193(6):607–613. doi:10.1164/rccm.201509-1722PP

130. Valvi D, Mannino DM, Müllerova H, Tal-Singer R. Fibrinogen, chronic obstructive pulmonary disease (COPD) and outcomes in two United States cohorts. Int J Chron Obstruct Pulmon Dis. 2012;7:173–182. doi:10.2147/COPD.S29892

131. Mannino DM, Tal-Singer R, Lomas DA, et al. Plasma Fibrinogen as a Biomarker for Mortality and Hospitalized Exacerbations in People with COPD. Chronic Obstr Pulm Dis. 2015;2(1):23–34. doi:10.15326/jcopdf.2.1.2014.0138

132. Celli BR, Locantore N, Yates J, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065–1072. doi:10.1164/rccm.201110-1792OC

133. Zhou B, Liu S, He D, et al. Fibrinogen is a promising biomarker for chronic obstructive pulmonary disease: evidence from a meta-analysis. Biosci Rep. 2020;40(7). doi:10.1042/BSR20193542

134. Mannino DM, Valvi D, Mullerova H, Tal-Singer R. Fibrinogen, COPD and mortality in a nationally representative U.S. cohort. Copd. 2012;9(4):359–366. doi:10.3109/15412555.2012.668249

135. Wang J, Pathak R, Garg S, Hauer-Jensen M. Fibrinogen deficiency suppresses the development of early and delayed radiation enteropathy. World J Gastroenterol. 2017;23(26):4701–4711. doi:10.3748/wjg.v23.i26.4701

136. Bellou V, Belbasis L, Konstantinidis AK, Evangelou E. Elucidating the risk factors for chronic obstructive pulmonary disease: an umbrella review of meta-analyses. Int J Tuberc Lung Dis. 2019;23(1):58–66. doi:10.5588/ijtld.18.0228

137. Duvoix A, Dickens J, Haq I, et al. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax. 2013;68(7):670–676. doi:10.1136/thoraxjnl-2012-201871

138. Zhang Y, Yamamoto T, Hisatome I, et al. Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells. Mol Cell Endocrinol. 2013;375(1–2):89–96. doi:10.1016/j.mce.2013.04.027

139. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179–191. doi:10.7326/0003-4819-155-3-201108020-00008

140. Kahnert K, Alter P, Welte T, et al. Uric acid, lung function, physical capacity and exacerbation frequency in patients with COPD: a multi-dimensional approach. Respir Res. 2018;19(1):110. doi:10.1186/s12931-018-0815-y

141. Li H, Chen Y. Serum uric acid level as a biomarker for chronic obstructive pulmonary disease: a meta-analysis. J Int Med Res. 2021;49(1):300060520983705. doi:10.1177/0300060520983705

142. Kir E, Güven Atici A, Güllü YT, Köksal N, Tunçez H. The relationship between serum uric acid level and uric acid/creatinine ratio with chronic obstructive pulmonary disease severity (stable or acute exacerbation) and the development of cor pulmonale. Int J Clin Pract. 2021;75(8):e14303. doi:10.1111/ijcp.14303

143. Bartziokas K, Papaioannou AI, Loukides S, et al. Serum uric acid as a predictor of mortality and future exacerbations of COPD. Eur Respir J. 2014;43(1):43–53. doi:10.1183/09031936.00209212

144. Horsfall LJ, Nazareth I, Petersen I. Serum uric acid and the risk of respiratory disease: a population-based cohort study. Thorax. 2014;69(11):1021–1026. doi:10.1136/thoraxjnl-2014-205271

145. Hogea SP, Tudorache E, Fildan AP, Fira-Mladinescu O, Marc M, Oancea C. Risk factors of chronic obstructive pulmonary disease exacerbations. Clin Respir J. 2020;14(3):183–197. doi:10.1111/crj.13129

146. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128–1138. doi:10.1056/NEJMoa0909883

147. Cardoso J, Coelho R, Rocha C, Coelho C, Semedo L, Bugalho Almeida A. Prediction of severe exacerbations and mortality in COPD: the role of exacerbation history and inspiratory capacity/total lung capacity ratio. Int J Chron Obstruct Pulmon Dis. 2018;13:1105–1113. doi:10.2147/COPD.S155848

148. Margüello MS, Garrastazu R, Ruiz-Nuñez M, et al. Independent effect of prior exacerbation frequency and disease severity on the risk of future exacerbations of COPD: a retrospective cohort study. NPJ Prim Care Respir Med. 2016;26:16046. doi:10.1038/npjpcrm.2016.46

149. Dixit D, Bridgeman MB, Andrews LB, et al. Acute exacerbations of chronic obstructive pulmonary disease: diagnosis, management, and prevention in critically ill patients. Pharmacotherapy. 2015;35(6):631–648. doi:10.1002/phar.1599

150. Montserrat-Capdevila J, Godoy P, Marsal JR, Barbé F, Galván L. Risk of exacerbation in chronic obstructive pulmonary disease: a primary care retrospective cohort study. BMC Fam Pract. 2015;16(1):173. doi:10.1186/s12875-015-0387-6

151. Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012;67(11):957–963. doi:10.1136/thoraxjnl-2011-201518

152. Osterburg AR, Lach L, Panos RJ, Borchers MT. Unique natural killer cell subpopulations are associated with exacerbation risk in chronic obstructive pulmonary disease. Sci Rep. 2020;10(1):1238. doi:10.1038/s41598-020-58326-7

153. Rao Y, Le Y, Xiong J, Pei Y, Sun Y. NK Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Front Immunol. 2021;12:666045. doi:10.3389/fimmu.2021.666045

154. Suzuki M, Sze MA, Campbell JD, et al. The cellular and molecular determinants of emphysematous destruction in COPD. Sci Rep. 2017;7(1):9562. doi:10.1038/s41598-017-10126-2

155. Hodge G, Mukaro V, Holmes M, Reynolds PN, Hodge S. Enhanced cytotoxic function of natural killer and natural killer T-like cells associated with decreased CD94 (Kp43) in the chronic obstructive pulmonary disease airway. Respirology. 2013;18(2):369–376. doi:10.1111/j.1440-1843.2012.02287.x

156. Pascual-Guardia S, Ataya M, Ramírez-Martínez I, et al. Adaptive NKG2C+ natural killer cells are related to exacerbations and nutritional abnormalities in COPD patients. Respir Res. 2020;21(1):63. doi:10.1186/s12931-020-1323-4

157. Cong J, Wei H. Natural Killer Cells in the Lungs. Front Immunol. 2019;10:1416. doi:10.3389/fimmu.2019.01416

158. Chen YC, Lin MC, Lee CH, et al. Defective formyl peptide receptor 2/3 and annexin A1 expressions associated with M2a polarization of blood immune cells in patients with chronic obstructive pulmonary disease. J Transl Med. 2018;16(1):69. doi:10.1186/s12967-018-1435-5

159. Leitao Filho FS, Won Ra S, Mattman A, et al. Serum IgG and risk of exacerbations and hospitalizations in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2017;140(4):1164–1167.e1166. doi:10.1016/j.jaci.2017.01.046

160. Palikhe NS, Niven M, Fuhr D, et al. Low immunoglobulin levels affect the course of COPD in hospitalized patients. Allergy Asthma Clin Immunol. 2023;19(1):10. doi:10.1186/s13223-023-00762-x

161. Leitao Filho FS, Mattman A, Schellenberg R, et al. Serum IgG Levels and Risk of COPD Hospitalization: a Pooled Meta-analysis. Chest. 2020;158(4):1420–1430. doi:10.1016/j.chest.2020.04.058

162. Jang JH, Kim JH, Park HS. Current Issues in the Management of IgG Subclass Deficiencies in Adults With Chronic Respiratory Diseases. Allergy Asthma Immunol Res. 2023;15(5):562–579. doi:10.4168/aair.2023.15.5.562

163. Leitao Filho FS, Ra SW, Mattman A, et al. Serum IgG subclass levels and risk of exacerbations and hospitalizations in patients with COPD. Respir Res. 2018;19(1):30. doi:10.1186/s12931-018-0733-z

164. Alotaibi NM, Filho FSL, Mattman A, et al. IgG Levels and Mortality in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2021;204(3):362–365. doi:10.1164/rccm.202102-0382LE

165. Lee H, Kovacs C, Mattman A, et al. The impact of IgG subclass deficiency on the risk of mortality in hospitalized patients with COPD. Respir Res. 2022;23(1):141. doi:10.1186/s12931-022-02052-3

166. Ragland MF, Benway CJ, Lutz SM, et al. Genetic Advances in Chronic Obstructive Pulmonary Disease. Insights from COPDGene. Am J Respir Crit Care Med. 2019;200(6):677–690. doi:10.1164/rccm.201808-1455SO

167. Ingebrigtsen TS, Marott JL, Vestbo J, et al. Characteristics of undertreatment in COPD in the general population. Chest. 2013;144(6):1811–1818. doi:10.1378/chest.13-0453

168. Ingebrigtsen TS, Marott JL, Nordestgaard BG, Lange P, Hallas J, Vestbo J. Statin use and exacerbations in individuals with chronic obstructive pulmonary disease. Thorax. 2015;70(1):33–40. doi:10.1136/thoraxjnl-2014-205795

169. Lipson DA, Crim C, Criner GJ, et al. Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2020;201(12):1508–1516. doi:10.1164/rccm.201911-2207OC

170. Dicker AJ, Crichton ML, Cassidy AJ, et al. Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD. Thorax. 2018;73(6):510–518. doi:10.1136/thoraxjnl-2016-209931

171. Lin CL, Siu LK, Lin JC, et al. Mannose-binding lectin gene polymorphism contributes to recurrence of infective exacerbation in patients with COPD. Chest. 2011;139(1):43–51. doi:10.1378/chest.10-0375

172. Mandal J, Malla B, Steffensen R, et al. Mannose-binding lectin protein and its association to clinical outcomes in COPD: a longitudinal study. Respir Res. 2015;16(1):150. doi:10.1186/s12931-015-0306-3

173. Vogt S, Leuppi JD, Schuetz P, et al. Association of mannose-binding lectin, ficolin-2 and immunoglobulin concentrations with future exacerbations in patients with chronic obstructive pulmonary disease: secondary analysis of the randomized controlled REDUCE trial. Respir Res. 2021;22(1):227. doi:10.1186/s12931-021-01822-9

174. Shi W, Chen F, Cardoso WV. Mechanisms of lung development: contribution to adult lung disease and relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6(7):558–563. doi:10.1513/pats.200905-031RM

175. Van Durme YM, Eijgelsheim M, Joos GF, et al. Hedgehog-interacting protein is a COPD susceptibility gene: the Rotterdam Study. Eur Respir J. 2010;36(1):89–95. doi:10.1183/09031936.00129509

176. Pillai SG, Kong X, Edwards LD, et al. Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182(12):1498–1505. doi:10.1164/rccm.201002-0151OC

177. Vilaró J, Ramirez-Sarmiento A, Martínez-Llorens JM, et al. Global muscle dysfunction as a risk factor of readmission to hospital due to COPD exacerbations. Respir Med. 2010;104(12):1896–1902. doi:10.1016/j.rmed.2010.05.001

178. Gea J, Agusti A, Roca J. Pathophysiology of muscle dysfunction in COPD. J Appl Physiol. 2013;114(9):1222–1234. doi:10.1152/japplphysiol.00981.2012

179. Keogh E, Mark Williams E. Managing malnutrition in COPD: a review. Respir Med. 2021;176:106248. doi:10.1016/j.rmed.2020.106248

180. Martinez CH, Diaz AA, Meldrum CA, et al. Handgrip Strength in Chronic Obstructive Pulmonary Disease. Associations with Acute Exacerbations and Body Composition. Ann Am Thorac Soc. 2017;14(11):1638–1645. doi:10.1513/AnnalsATS.201610-821OC

181. Liang Y, Sun YC. Nutrition management of patients with acute exacerbation of chronic obstructive pulmonary disease hospitalized in Respiratory Intensive Care Unit. Zhonghua Jie He He Hu Xi Za Zhi. 2022;45(9):920–925. doi:10.3760/cma.j.cn112147-20220422-00342

182. Marco E, Sánchez-Rodríguez D, Dávalos-Yerovi VN, et al. Malnutrition according to ESPEN consensus predicts hospitalizations and long-term mortality in rehabilitation patients with stable chronic obstructive pulmonary disease. Clin Nutr. 2019;38(5):2180–2186. doi:10.1016/j.clnu.2018.09.014

183. Limpawattana P, Putraveephong S, Inthasuwan P, Boonsawat W, Theerakulpisut D, Chindaprasirt J. Frailty syndrome in ambulatory patients with COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:1193–1198. doi:10.2147/COPD.S134233

184. Ter Beek L, van der Vaart H, Wempe JB, et al. Coexistence of malnutrition, frailty, physical frailty and disability in patients with COPD starting a pulmonary rehabilitation program. Clin Nutr. 2020;39(8):2557–2563. doi:10.1016/j.clnu.2019.11.016

185. Jingrong LI. Analysis of the prevalence and influencing factors of chronic obstructive pulmonary disease in elderly hospitalized patients: a study based on a Comprehensive Geriatric Assessment System in Yunnan Province. Chinese General Practice. 2022;25(11):1320–1326.

186. Tramontano A, Palange P. Nutritional State and COPD: effects on Dyspnoea and Exercise Tolerance. Nutrients. 2023;15(7):1786. doi:10.3390/nu15071786

187. Yohannes AM, Mülerová H, Lavoie K, et al. The Association of Depressive Symptoms With Rates of Acute Exacerbations in Patients With COPD: results From a 3-year Longitudinal Follow-up of the ECLIPSE Cohort. J Am Med Dir Assoc. 2017;18(11):955–959.e956. doi:10.1016/j.jamda.2017.05.024

188. Atlantis E, Fahey P, Cochrane B, Smith S. Bidirectional associations between clinically relevant depression or anxiety and COPD: a systematic review and meta-analysis. Chest. 2013;144(3):766–777. doi:10.1378/chest.12-1911

189. Holas P, Michalowski J, Gaweda L, Domagala-Kulawik J. Agoraphobic avoidance predicts emotional distress and increased physical concerns in chronic obstructive pulmonary disease. Respir Med. 2017;128:7–12. doi:10.1016/j.rmed.2017.04.011

190. T-P N. Depressive Symptoms and Chronic Obstructive Pulmonary Disease. Arch Intern Med. 2007;167(1):60. doi:10.1001/archinte.167.1.60

191. Huang J, Bian Y, Zhao Y, Jin Z, Liu L, Li G. The Impact of Depression and Anxiety on Chronic Obstructive Pulmonary Disease Acute Exacerbations: a prospective cohort study. J Affect Disord. 2021;281:147–152. doi:10.1016/j.jad.2020.12.030

192. Jenkins CR, Celli B, Anderson JA, et al. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J. 2012;39(1):38–45. doi:10.1183/09031936.00194610

193. Almagro P, Hernandez C, Martinez-Cambor P, Tresserras R, Escarrabill J. Seasonality, ambient temperatures and hospitalizations for acute exacerbation of COPD: a population-based study in a metropolitan area. Int J Chron Obstruct Pulmon Dis. 2015;10:899–908. doi:10.2147/COPD.S75710

194. Li X, Wu Z, Xue M, Du W. An observational study of the effects of smoking cessation earlier on the clinical characteristics and course of acute exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med. 2022;22(1):390. doi:10.1186/s12890-022-02187-5

195. Hosking L, Yeo A, Hoffman J, et al. Genetics plays a limited role in predicting chronic obstructive pulmonary disease treatment response and exacerbation. Respir Med. 2021;187:106573. doi:10.1016/j.rmed.2021.106573

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