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Background: Severe α₁-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α₁-antitrypsin, but whether they have an increased risk of COPD is uncertain.Methods: We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease.Results: PI MZ was associated with a 3.5% lower FEV₁/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV₁/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies.Conclusions: Compared with PI MM individuals, PI MZ heterozygotes had lower FEV₁/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is common in patients with COPD, but its prevalence and progression are not well characterized. Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids (ICSs) on bone density in this population. Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study.Methods: A randomized, double-blind, parallel-group, placebo-controlled study conducted at 88 US centers involving 658 patients (a subset of 6,184 international subjects in TORCH). Therapy with placebo, SAL (50 microg), FP (500 microg), or SFC (SAL 50 microg/FP 500 microg) twice daily was administered for 3 years. Baseline and yearly measurements of BMD at the hip and lumbar spine were performed. The incidence of traumatic and nontraumatic bone fractures was recorded.Results: At baseline, 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia based on BMD assessments. Forty-three percent of subjects completed all testing. The changes in BMD at the hip and lumbar spine over 3 years were small. No significant differences were observed between treatment arms (adjusted mean percent change from baseline at hip was -3.1% for placebo, -1.7% for SAL, -2.9% for FP, and -3.2% for SFC therapy, respectively; while, the corresponding changes for the lumbar spine were 0, 1.5%, -0.3%, and -0.3% for placebo, respectively, SAL, FP, and SFC therapy). The incidence of fractures was low and was similar for all treatments (5.1% to 6.3%).Conclusions: Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. In the TORCH study, no significant effect on BMD was detected for ICS therapy compared with placebo.Trial Registration: ClinicalTrials.gov Identifier: NTC00268216. [ABSTRACT FROM AUTHOR]

Background: The varied treatment response to inhaled corticosteroids (ICS) in COPD, and the increased risk of pneumonia necessitate a personalised ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment., Research Question: Does BEC measured on or off ICS treatment or the change in BEC during ICS treatment, best predict treatment response to ICS in COPD?, Study Design and Methods: FLAME, a 52-week, double-blind RCT compared LABA/LAMA versus LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing pre- and post-run-in period BEC to represent BEC on and off ICS, respectively. In this post-hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS containing regimen., Results: Our study confirms that LABA/LAMA combination is superior, or at least non-inferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off and BEC on ICS and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of exacerbation rate, time-to-first exacerbation, and time-to-first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment (≥200 cells/μL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC were not predictive of treatment effects on lung function and health status., Interpretation: This exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response., Clinical Trial Registration: NCT01782326., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: COPD is a leading cause of mortality., Research Question: We hypothesized that applying machine learning to clinical and quantitative CT imaging features would improve mortality prediction in COPD., Study Design and Methods: We selected 30 clinical, spirometric, and imaging features as inputs for a random survival forest. We used top features in a Cox regression to create a machine learning mortality prediction (MLMP) in COPD model and also assessed the performance of other statistical and machine learning models. We trained the models in subjects with moderate to severe COPD from a subset of subjects in Genetic Epidemiology of COPD (COPDGene) and tested prediction performance in the remainder of individuals with moderate to severe COPD in COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared our model with the BMI, airflow obstruction, dyspnea, exercise capacity (BODE) index; BODE modifications; and the age, dyspnea, and airflow obstruction index., Results: We included 2,632 participants from COPDGene and 1,268 participants from ECLIPSE. The top predictors of mortality were 6-min walk distance, FEV 1 % predicted, and age. The top imaging predictor was pulmonary artery-to-aorta ratio. The MLMP-COPD model resulted in a C index ≥ 0.7 in both COPDGene and ECLIPSE (6.4- and 7.2-year median follow-ups, respectively), significantly better than all tested mortality indexes (P < .05). The MLMP-COPD model had fewer predictors but similar performance to that of other models. The group with the highest BODE scores (7-10) had 64% mortality, whereas the highest mortality group defined by the MLMP-COPD model had 77% mortality (P = .012)., Interpretation: An MLMP-COPD model outperformed four existing models for predicting all-cause mortality across two COPD cohorts. Performance of machine learning was similar to that of traditional statistical methods. The model is available online at: https://cdnm.shinyapps.io/cgmortalityapp/., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: There is insufficient evidence about the long-term course of depressive symptom trajectories and their impact among patients with COPD., Methods: We analysed 3-year data obtained from patients with COPD participating in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study. Patients were split into four groups on the basis of Center for Epidemiologic Studies Depression Scale score (< 16 vs ≥ 16) and antidepressant use (yes vs no) at baseline and at 3 years: never depressed, new onset, remittent, and persistent depression. Baseline characteristics were used to assess factors associated with the group by using logistic regression., Results: A total of 1,589 patients with COPD completed the 3-year follow-up. Of these, 55% (n = 869) were classified as never depressed, 24% (n = 377) were classified as persistently depressed, 14% (n = 226) developed new onset of depression, and 7% (n = 117) had depression that remitted. Female sex and history of stroke were associated with substantial increases in the odds of persistent depression (OR, 2.95; 95% CI, 2.05-4.24 and OR, 3.09; 95% CI, 1.43-6.67, respectively). Odds of new onset depression increased with worse health status (OR, 1.10; 95% CI, 1.04-1.17 per 4-point increase in St. George's Respiratory Questionnaire score) and moderate to severe dyspnea (OR, 1.57; 95% CI, 1.07-2.31 for modified Medical Research Council score ≥ 2 vs 0 or 1). During follow-up, patients with persistent or new-onset depression experienced more exacerbations and more pronounced loss in performance as assessed by reduction in the 6-min walk distance (6MWD) test score., Conclusions: About one in four patients with COPD had persistent depressive symptoms over 3 years. Clinicians should be aware of the characteristics of persistent and new onset depressive symptoms, which are associated with risk of exacerbations and loss of performance on the 6MWD test. Interventions that ameliorate the course of depression are needed., Trial Registry: ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Despite massive investments in the development of novel treatments for heterogeneous diseases such as COPD, the resources spent have only benefited a fraction of the population treated. Personalized health care to guide selection of a suitable patient population already in the clinical development of new compounds could offer a solution. This review discusses past successes and failures in drug development and biomarker research in COPD, describes research in COPD phenotypes and the required characteristics of a suitable biomarker for identifying patients at higher risk of progression, and examines the role of extracellular matrix proteins found to be upregulated in COPD. Novel biomarkers of connective tissue remodeling that may provide added value for a personalized approach by detecting subgroups of patients with active disease suitable for pharmacologic intervention are discussed.

Objective: Exacerbations of COPD requiring hospital admission have important clinical and societal implications. We sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD exacerbations requiring hospital admission compared with those without hospital admission during 3-year follow-up. Patients with COPD (N = 2,138) were identified from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) observational cohort., Methods: An analysis of time to first event of hospital admission was performed using Kaplan-Meier curves and Cox proportional hazard regression adjusting for possible confounders., Results: Of the 2,138 patients, 670 (31%) reported a total of 1,452 COPD exacerbations requiring hospital admission during the study period; 313 patients (15%) reported multiple events. A prior history of exacerbation of COPD requiring hospital admission was the factor associated with the highest risk of a new hospitalization for exacerbation (hazard ratio, 2.71; 95% CI, 2.24-3.29; P < .001). Other risk factors included more severe airflow limitation, poorer health status, older age, radiologic evidence of emphysema, and higher WBC count. Having been hospitalized for exacerbation significantly increased the risk of mortality (P < .001)., Conclusions: Exacerbations of COPD requiring hospital admission occur across all stages of airflow limitation and are a significant prognostic factor of reduced survival across all COPD stages. Patients with COPD at a high risk for hospitalization can be identified by their past history for similar events, and other factors, including the severity of airflow limitation, poor health status, age, presence of emphysema, and leukocytosis., Trial Registry: ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov.

Background: We wished to characterize undertreatment in COPD., Methods: Among 5,812 individuals with COPD defined by FEV1/FVC &lt; 0.7 participating in the Copenhagen General Population Study, we identified 920 individuals with FEV1 &lt; 60% predicted. Prescriptions were identified in an all-inclusive nationwide registry. For each individual, we examined treatment with medication in the year before the day of the baseline examination, as well as treatment in the first year after the examination. Multivariable logistic regression analyses were applied in individuals with FEV1 &lt; 60% predicted to identify predictors of treatment in the first year after baseline., Results: Only 30% of individuals with COPD and FEV1 &lt; 60% predicted were treated with medication in the year before the examination, whereas 42.2% were treated with medication in the first year after. Reporting six to 10 previous respiratory infections during the preceding 10 years that required consulting a doctor and/or staying home from work was the strongest predictor of treatment with medication (OR, 7.9; 95% CI, 3.5-19.8; P &lt; .001). Breathlessness, low FEV1, previous admissions with a discharge diagnosis of COPD, and former smoking were also predictors of treatment with medication, whereas comorbidity predicted lack of treatment. In subgroup analysis, among individuals with FEV1 &lt; 50% predicted, visits to the general practitioner and age were additional predictors of treatment, whereas male sex and being a widow/widower predicted lack of treatment., Conclusions: In this study, we observed important characteristics of a major undertreatment in individuals with COPD in the general population. Previous reported respiratory infections were the strongest predictors of treatment with medications, which indicates that most COPD treatment is initiated because of acute exacerbations.

Background: The authors of previous reports have suggested that women are more susceptible to cigarette smoke and to an airway-predominant COPD phenotype rather than an emphysema-predominant COPD phenotype. The purpose of this study was to test for sex differences in COPD phenotypes by using high-resolution CT (HRCT) scanning in male and female smokers with and without COPD., Methods: All subjects completed spirometry and answered an epidemiologic respiratory questionnaire. Inspiratory HRCT scans were obtained on 688 smokers enrolled in a family-based study of COPD. Emphysema was assessed by using a density mask with a cutoff of -950 Hounsfield units to calculate the low-attenuation area percentage (LAA%) and by the fractal value D, which is the slope of a power law analysis defining the relationship between the number and size of the emphysematous lesions. Airway wall thickness was assessed by calculating the square root of the airway wall area (SQRTWA) and the percentage of the total airway area taken by the airway wall (WA%) relative to the internal perimeter., Results: Women had a similar FEV(1) (women, 65.5% +/- 31.9% predicted; men, 62.1% +/- 30.4% predicted; p = 0.16) but fewer pack-years of cigarette smoking (women, 37.8 +/- 19.7 pack-years; men, 47.8 +/- 27.4 pack-years; p < 0.0001). Men had a greater LAA% (24% +/- 12% vs 20% +/- 11%, respectively; p < 0.0001) and larger emphysematous spaces than women, and these differences persisted after adjusting for covariates (weight, pack-years of smoking, current smoking status, center of enrollment, and FEV(1) percent predicted; p = 0.0006). Women had a smaller SQRTWA and WA% after adjusting for covariates (p < 0.0001)., Conclusion: Male smokers have more emphysema than female smokers, but female smokers do not show increased wall thickness compared with men.

COPD is one of the most common causes of morbidity and mortality. Perhaps paradoxically, COPD also should be an orphan disease. Importantly, this could advance the development of treatments for COPD. There are two criteria for orphan status in the United States. Most widely known is the criterion of < 200,000 affected individuals; however, secondarily, is the impossibility for development costs to be recovered during the patent life of a product. COPD should qualify for the first criterion if the various conditions that comprise COPD are regarded separately. The subphenotyping of COPD into separate groups based on mechanism sets the stage for the rational development of therapeutics. In addition, many candidate treatments may alter the natural history of COPD. Testing them, however, will require large studies for a duration that will compromise the commercial life of any resulting product. Orphan status, therefore, could facilitate the development of treatments for both phenotypic subsets of COPD patients as well as aid the development of agents to alter the natural history of the disease. Post-drug approval regulations could require that agents approved under the orphan provisions are prospectively monitored, assuring that rigorous longitudinal data are generated. This approach could encourage the pharmaceutical industry to stratify studies based on a more detailed characterization of study subjects at baseline, thus approaching "many small COPDs" instead of a single large and heterogeneous COPD. This strategy may help to address the increasing burden that COPD presents and for which no novel clinical class of treatment has been introduced for 30 years.

Background: Respiratory tract infections are a frequent complication of COPD, but little is known about the incidence, association, and risk of infectious diseases related to impaired lung function., Methods: Participants in the Copenhagen City Heart Study had lung function measured at baseline, and were followed for up to 25 years. All hospitalizations due to any infection were identified through registry linkage. Impaired lung function was defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system., Main Results: A total of 3,333 infectious disease hospitalizations (IDHs) occurred during 230,653 person-years of follow-up (PY), corresponding to an overall incidence of 145 IDHs (95% confidence interval [CI], 139 to 149) per 10,000 PY. The incidence increased with GOLD stage, from 131 (95% CI, 126 to 136) for normal COPD, to 170 (95% CI, 146 to 193) for mild COPD, to 230 (95% CI, 207 to 253) for moderate COPD, and 394 (95% CI, 330 to 459) for severe/very severe COPD. The trend in risk persisted after the control of background characteristics using Cox proportional hazards analysis (adjusted relative risks: 1.06 [95% CI, 0.92 to 1.23], 1.39 [95% CI, 1.24 to 1.56], and 2.21 [95% CI, 1.84 to 2.64], respectively; p=0.001). In subgroup analysis, the increased risk was associated with lower and upper respiratory tract infections, pyothorax, and tuberculosis, but not with influenza, sepsis, skin infections, urinary tract infections, diarrheal disease, or other infectious diseases., Conclusions: The presence of obstructive lung disease is a significant predictor of IDH caused by respiratory tract infections, but not of hospitalizations due to infections outside the respiratory system.

Background: The numbers of airway CD8 and B lymphocytes are increased in COPD patients, suggesting an autoimmune process. CD4-regulatory T cells control autoimmunity but have not been studied in patients with COPD., Objective: To compare T-regulatory cell numbers in the BAL from COPD patients, smokers with normal lung function, and healthy nonsmokers (HNS)., Methods: BAL and peripheral blood mononuclear cell (PBMC) samples were obtained from 26 COPD patients, 19 smokers, and 8 HNS. Flow cytometry was performed for regulatory phenotypic markers., Results: COPD patients had increased BAL CD8 numbers compared to smokers and HNS. CD4 numbers were similar between groups. There was increased BAL CD4CD25(bright) expression in smokers (median 28.8%) and COPD patients (median 23.1%) compared to HNS (median 0%). Increased FoxP3 expression was confirmed in BAL CD4CD25(bright) cells. BAL CD4CD25 cells expressed less CD27 compared to PBMCs, suggesting weaker functional regulatory ability., Clinical Implications: Chronic cigarette smoke exposure up-regulates airway CD4 regulatory cell numbers. Their function may be to control pulmonary inflammation.

Background: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV(1)., Methods: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >/= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV(1) decline in COPD patients, and whether this relationship is modified by gender and smoking., Results: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV(1) of 2.42 +/- 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV(1) decline (-0.01 +/- 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV(1) during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV(1) with ICS therapy than did male ex-smokers., Conclusions: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV(1) among those who completed these randomized clinical trials.

Objective: Pneumocystis carinii pneumonia is the most common and serious of the pulmonary complications of AIDS. Despite this, many basic aspects in the pathogenesis of HIV-associated P carinii pneumonia are unknown. We therefore undertook a light and electron microscopic study of transbronchial biopsy specimens to compare pathologic features of P carinii pneumonia and other HIV-related lung diseases., Design and Patients: Thirty-seven consecutive HIV-infected patients undergoing a diagnostic bronchoscopy., Results: P carinii pneumonia was characterized by an increase in inflammation, edema, exudate, fibrosts, type II pneumocyte proliferation, and cellular infiltration of the alveolar wall when compared with other lung diseases (all p < 0.05). Electron microscopy showed apposition of the trophozoite to the type I pneumocyte. Erosion of type I pneumocytes was observed in 13 of 15 patients with P carinii pneumonia, whereas none without P carinii pneumonia had this finding (p < 0.05). Erosion of the type II pneumocyte was not observed., Conclusion: Inflammation, interstitial fibrosis, and alveolar epithelial erosion are characteristic features of P carinii pneumonia. The changes may form the pathologic basis for the respiratory failure seen in patients with P carinii pneumonia. Electron microscopy did not show any diagnostie advantage over conventional light microscopy using routine stains.

Objective: To examine the importance of cytomegalovirus (CMV) in bronchoalveolar lavage (BAL) fluid of patients with HIV-associated Pneumocystis carinii pneumonia (PCP) treated with adjunctive corticosteroids (CS)., Design: Analysis of clinical data during a 5-year period., Setting: Department of infectious diseases where clinical and paraclinical data on patients suspected of having PCP have been sampled prospectively., Patients: 148 consecutive patients with a first episode of PCP in a 5-year period., Main Outcome Measure: Vital status 3 months after diagnosis of PCP., Results: Patients with PCP treated with adjunctive CS who had CMV cultured from BAL fluid had a two times higher mortality within 3 months from bronchoscopy than others (p = 0.08). This difference could not be explained by differences in CD4 count, PO2 or PCO2 at time of bronchoscopy., Conclusion: With the accepted usage of adjunctive CS in severe PCP, the role of CMV as a pulmonary copathogen may have changed. Active CMV infection may be an important cause of failing treatment of severe PCP in those treated with adjunctive CS.

Correlations between semiquantitative amounts of Pneumocystis carinii (PC), the degree of inflammation, and the severity of pneumonia were analyzed in 58 patients with PC pneumonia (PCP). Material from both transbronchial biopsies (TBBs; n = 39) and bronchoalveolar lavage fluid (BALF; n = 57) was examined. In the TBB the amount of PC correlated strongly with overall inflammation in the interstitium (Kendall correlation coefficient [Kcc] = 0.59; p < 0.0001), type 2 pneumocyte proliferation, and edema formation. The amount of PC in the TBB also correlated with interstitial accumulation of neutrophils (Kcc = 0.54; p = 0.0001), lymphocytes, and macrophages. In BALF the amount of PC correlated with edema formation and type 2 pneumocyte proliferation in the TBB but not with the percentage of neutrophils, lymphocytes, or macrophages in BALF. The amount of PC in the BALF and the percentage of neutrophils in the BALF correlated significantly with Po2 and the serum lactate dehydrogenase (LDH) level. Neither short-term nor long-term survival was affected by the amount of PC, inflammatory markers in the TBB, inflammatory cells in BALF, Po2, or the serum LDH levels. In conclusion, the amount of PC is associated with the extent of the acute inflammatory reaction in the lung in PCP associated with human immunodeficiency virus (HIV).