Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown.Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up.Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events. Measurements and Main Results:In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline.Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease.Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

OBJECTIVES: Prone position ventilation is a potentially life-saving ancillary intervention but is not widely adopted for coronavirus disease 2019 or acute respiratory distress syndrome from other causes. Implementation of lung-protective ventilation including prone positioning for coronavirus disease 2019 acute respiratory distress syndrome is limited by isolation precautions and personal protective equipment scarcity. We sought to determine the safety and associated clinical outcomes for coronavirus disease 2019 acute respiratory distress syndrome treated with prolonged prone position ventilation without daily repositioning. DESIGN: Retrospective single-center study. SETTING: Community academic medical ICU. PATIENTS: Sequential mechanically ventilated patients with coronavirus disease 2019 acute respiratory distress syndrome. INTERVENTIONS: Lung-protective ventilation and prolonged protocolized prone position ventilation without daily supine repositioning. Supine repositioning was performed only when Fio 2 less than 60% with positive end-expiratory pressure less than 10 cm H2O for greater than or equal to 4 hours. MEASUREMENTS AND MAIN RESULTS: Primary safety outcome: proportion with pressure wounds by Grades (0–4). Secondary outcomes: hospital survival, length of stay, rates of facial and limb edema, hospital-acquired infections, device displacement, and measures of lung mechanics and oxygenation. Eighty-seven coronavirus disease 2019 patients were mechanically ventilated. Sixty-one were treated with prone position ventilation, whereas 26 did not meet criteria. Forty-two survived (68.9%). Median (interquartile range) time from intubation to prone position ventilation was 0.28 d (0.11–0.80 d). Total prone position ventilation duration was 4.87 d (2.08–9.97 d). Prone position ventilation was applied for 30.3% (18.2–42.2%) of the first 28 days. Pao 2:Fio 2 diverged significantly by day 3 between survivors 147 (108–164) and nonsurvivors 107 (85–146), mean difference –9.632 (95% CI, –48.3 to 0.0; p = 0·05). Age, driving pressure, day 1, and day 3 Pao 2:Fio 2 were predictive of time to death. Thirty-eight (71.7%) developed ventral pressure wounds that were associated with prone position ventilation duration and day 3 Sequential Organ Failure Assessment. Limb weakness occurred in 58 (95.1%) with brachial plexus palsies in five (8.2%). Hospital-acquired infections other than central line–associated blood stream infections were infrequent. CONCLUSIONS: Prolonged prone position ventilation was feasible and relatively safe with implications for wider adoption in treating critically ill coronavirus disease 2019 patients and acute respiratory distress syndrome of other etiologies.

Background: Lung transplant is an effective therapy, however, long-term survival is currently limited due to the high rate of bronchiolitis obliterans syndrome (BOS). The longitudinal biological changes that occur as a patient progresses to BOS are not well understood. The objective of this study was to evaluate the bronchoalveolar lavage fluid (BALF) proteome, seeking to identify proteins and their representative biological functions that have coherent changes in the development of BOS. Methods: Isobaric tag for relative and absolute quantification(iTRAQ ® ) with LC MS/MS were performed on BALF enriched for medium and low abundance proteins from three time points (range 699 days pre-BOS to 83 days post-BOS) taken from four patients that developed BOS. Controls consisted of pooled samples from nine patients who did not develop BOS within five years of sample acquisition. We investigated how the protein profiles changed longitudinally as the patient progressed towards BOS using Short Time-series Expression Miner, (STEM), analysis and identified gene ontology terms associated with these protein clusters. Results: We identified 871 unique proteins at a 5% FDR. STEM analysis revealed three models that met statistical significance.Gene ontology revealed three biological processes that associated with these models and included: sequestering of actin monomers, cytoskeletal organization and an inflammatory or defense response. Conclusion: Longitudinal and gene cluster models reveal coherent changes in BALF proteins as patients approach BOS.

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