Clinical and Biologic Profiles of Patients with Acute Respiratory Distress Syndrome by Prevalence of Chronic Obstructive Pulmonary Disease or Emphysema; A Cohort Study

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Kitsios, William Bain, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4803327/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Nov, 2024 Read the published version in Respiratory Research → Version 1 posted 13 You are reading this latest preprint version Abstract Introduction: Acute respiratory distress syndrome (ARDS) is a critical care disorder characterized by diffuse lung injury. The impact of pre-existing chronic obstructive pulmonary disease (COPD) or emphysema on ARDS pathogenesis is not well characterized. Methods: Secondary analysis of ARDS patients enrolled in the Acute Lung Injury Registry and Biospecimen Repository at the University of Pittsburgh between June 2012 and September 2021. Patients were categorized into two mutually exclusive groups by the prevalence of COPD or emphysema at the time of ARDS diagnosis. The COPD/emphysema group comprised ARDS patients with radiological evidence of emphysema, chart diagnosis of COPD, or both. Demographics, lung mechanics, and clinical outcomes were obtained from the electronic medical record. Host-response biomarkers known to have validated associations with ARDS were previously measured in plasma and lower respiratory tract samples using a customized Luminex assay. Continuous and categorical variables were compared between groups with and without COPD/emphysema. Results: 217 patients with ARDS were included in the study, 57 (27%) had COPD/emphysema. Patients with COPD/emphysema were older (median 62 [interquartile range 55-69] versus 53 [41-64] years, p<0.01), more likely to be male (62% vs 44%, p=0.02) and had a higher prevalence of congestive heart failure (25% vs 4%, p<0.01) compared to patients without COPD/emphysema. Baseline demographics, laboratory parameters, and mechanical ventilatory characteristics were otherwise similar between the two groups. No difference in 90-day mortality was observed between groups; however, patients with COPD/emphysema had shorter duration of intensive care unit (ICU) stay (median 10 [7-18] versus 16 [9-28] days, p=0.04) and shorter duration of mechanical ventilation (median 7 [4-16] vs 12 [6-20] days, p=0.01). Host response biomarkers in serum and lower respiratory tract samples did not significantly differ between groups. Conclusion: ARDS patients with COPD or emphysema had similar respiratory mechanics, host response biomarker profiles, and mortality compared to those without COPD or emphysema but with a shorter median duration of mechanical ventilation and ICU length of stay. Future studies should address differences in clinical and biological responses by disease severity, and should investigate the impact of severity of COPD and emphysema on mechanical ventilation and targeted therapeutic strategies in ARDS. acute respiratory distress syndrome chronic obstructive pulmonary syndrome systemic host immune response emphysema Figures Figure 1 Figure 2 Introduction Acute respiratory distress syndrome (ARDS) is a common and potentially fatal condition characterized by diffuse lung injury in response to a direct or indirect insult, with an estimated prevalence of 10% among critically ill patients and with a 28-day in-hospital mortality rate approaching 40% (1). The incidence of ARDS increased sharply during the Coronavirus-19 (COVID-19) pandemic, highlighting the need to better understand pathogenesis and management. Effective clinical treatments for ARDS remain limited, with numerous preclinical interventions yielding minimal success in clinical trials (2)(3). Notably, preclinical in vivo models of ARDS are often conducted in young and healthy mice, contrasting the clinical ARDS patient population, which is characterized by multiple chronic comorbidities (4). Understanding the relationship between chronic comorbidities and ARDS pathogenesis is essential for tailoring therapeutic strategies. Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease globally and is the sixth leading cause of death in the United States (5). The impact of pre-existing COPD on ARDS pathogenesis is not well characterized. Patients with COPD have a higher risk of severe community-acquired pneumonia, the most common cause of ARDS, and once hospitalized with severe pneumonia in the intensive care unit (ICU), have higher mortality and need for mechanical ventilation (6)(7). COPD is common in ARDS patients as the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG-SAFE) study encompassing 459 ICUs in 50 countries demonstrated that approximately one in five ARDS patients had underlying COPD (1). The LUNG-SAFE study did not characterize differences in clinical outcomes based on pre-existing COPD and additionally based the diagnosis of COPD on chart reviews. Systematic assessment of radiologic imaging may uncover the presence of anatomic emphysema which may impact clinical and biologic responses in ARDS. We performed this study to investigate the impact of COPD and emphysema on ARDS pathogenesis. Our specific objectives were (1) to determine the prevalence of COPD and emphysema in ARDS using both chart review and systemic review of radiologic testing, and (2) to investigate differences between ARDS patients by prevalence of COPD or emphysema in mechanical ventilation parameters, host response biomarkers, and clinical outcomes. Methods Description of cohort : We performed a secondary analysis of patients prospectively enrolled in the Acute Lung Injury and Biospecimen Repository (ALIR) at the University of Pittsburgh between June 2012 to September 2021. Details of the ALIR have previously been published, and all patients were enrolled after obtaining informed consent (8,9). ALIR protocols have been approved by the Human Research Office at the University of Pittsburgh (protocol# STUDY19050099). ALIR enrolls adult patients with acute respiratory failure with most requiring invasive mechanical ventilation. For this study, we included patients with a diagnosis of ARDS as determined by a consensus committee meeting of at least three board-certified pulmonary and critical care physicians following a review of all available clinical and radiographic data and adjudicated based on Berlin Criteria (10) We classified patients in our study cohort into two mutually exclusive groups based on the prevalence or absence of COPD or emphysema (COPD/emphysema). All ARDS patients with a chart diagnosis of COPD were included in the COPD/emphysema group. Chart diagnosis was based on review of history and physical examination notes on admission to the intensive care unit and was not dependent on specific diagnosis or procedure codes. ARDS patients with a chart diagnosis of COPD underwent review of computed tomography (CT) chest reports and/or imaging, if available, during the incident admission or within the 2 years preceding admission to determine presence and extent of anatomic emphysema as described below. ARDS patients without a chart diagnosis of COPD were only included in our study if a CT chest had been performed during or in the 2 years prior to admission— if review of chest imaging revealed anatomic emphysema, then patients were classified in the COPD/emphysema group, if not, then patients were classified in the ARDS without COPD/emphysema group. Emphysema scoring : Electronic records of all ARDS patients were reviewed for the presence of CT chest imaging with or without intravenous contrast performed as part of their clinical care up to 2 years prior to the incident hospitalization. All CT scans had previously been interpreted by a board-certified radiologist. All CT images that were available in the electronic record were independently reviewed by a board-certified pulmonologist (SN) for visual assessment of the presence of emphysema without knowledge of the radiologist’s report. The extent of emphysema was graded from 0 to 3, using a semiquantitative visual scoring system to define emphysema severity (0 none; 1 mild; 2 moderate; 3 severe), which corresponded to 0%, less than 25%, 26–50%, and greater than 75% visual emphysema respectively (11). For this study, patients with a score ≥ 1 were classified as having anatomic emphysema. In patients with multiple CT scans of the chest available for review, the CT scan most proximal to the day of admission for respiratory failure due to ARDS was used for emphysema assessment. Agreement between the radiology report and independent review for the visual assessment of emphysema was assessed by the κ coefficient for interrater reliability. In cases of discrepancy, images were independently reviewed and scored by a second reviewer (FS). In a subset of patients, a CT chest had been performed but images were not available for independent review. In this subset, the radiologist’s interpretation was used to determine the presence or absence of emphysema. Clinical data collection : Baseline demographics, chronic comorbidities, parameters of mechanical ventilation, laboratory variables, and calculated sequential organ failure assessment (SOFA) scores were abstracted from the electronic medical record. Driving pressure (ΔP) on the day of study enrollment was calculated as the difference between the positive end-expiratory pressure (PEEP) and the plateau pressure (Pplat) during volume-controlled ventilation or between PEEP and the maximum airway pressure (Pmax) during pressure-controlled ventilation. Ventilatory ratio (VR) was calculated by using the formula VR = [minute ventilation (ml/min) × PaCO2 (mmHg)]/(predicted body weight(kg) × 100 × 37.5). Respiratory system compliance (CRS) was calculated by dividing the tidal volume(ml) by ΔP(cmH20)(12). Host response biomarkers : Biospecimens are collected from ALIR patients within 72 hours of intubation, including blood samples and endotracheal aspirates (ETA), and processed as previously described(8,9). Ten host-response biomarkers shown to have validated associations with ARDS were previously characterized in blood and ETA samples with a customized Luminex assay (R&D Systems, Minneapolis)(13). Host-response biomarkers included markers of innate immune response (interleukin (IL)-6, IL-8, IL-10, fractalkine, soluble tumor necrosis factor receptor-1 [sTNFR-1], suppressor of tumorigenicity-2 [ST-2]); epithelial injury (receptor of advanced glycation end-products [RAGE]); endothelial injury (angiopoietin-2 [Ang-2]); and response to bacterial infections (procalcitonin and pentraxin-3). Host response subphenotype assignments : We classified patients into host response subphenotypes (hyperinflammatory versus hypoinflammatory) using a parsimonious logistic regression model based on plasma levels of Ang-2, procalcitonin, sTNFR1, and bicarbonate that have been previously validated in this cohort (14). Statistical analyses : In our primary analyses, we compared continuous and categorical variables between ARDS patients with and without COPD/emphysema by nonparametric tests (Kruskal-Wallis or Fisher’s tests, as appropriate). We report variables as median and interquartile range [IQR] for continuous variables and number (proportion) for categorical variables. We constructed Kaplan Meier survival curves to visually investigate differences in the duration of mechanical ventilation and 90-day survival and compared between groups. We compared differences in 90-day mortality in logistic regression analyses adjusted for age, history of congestive heart failure by review of the electronic medical record, and COVID-19 diagnosis. Since ARDS patients with COPD/emphysema in our cohort may have had a chart diagnosis of COPD or evidence of anatomic emphysema on a CT scan (or both), we performed two sensitivity analyses to ensure the robustness of the results. First, we compared differences between ARDS patients with no COPD to the subset of patients who had a documented diagnosis of COPD on chart review. Second, we compared differences between ARDS patients with no COPD to the subset of patients who had evidence of emphysema on CT imaging. We performed all analyses with STATA version 17 and considered a p-value of less than 0.05 as statistically significant. Analyses were not adjusted for multiple testing. All findings are reported consistent with the STROBE statement for observational studies. Results Cohort Description : From January 2012 to January 2022, 783 patients with acute respiratory failure were prospectively enrolled from medical ICUs in the UPMC Health System in Western Pennsylvania in the Acute Lung Injury Registry and Biospecimen Repository. In our study, we excluded patients who did not have a CT scan of the chest within 2 years prior to hospitalization for respiratory failure unless they had a chart review diagnosis of COPD (n=258) and we excluded patients without ARDS (n=308) (Figure 1). The remaining ARDS patients (n=217) were classified into two mutually exclusive groups: those with COPD/emphysema (n=57) and without COPD/emphysema (n=160). The COPD/emphysema group comprised 28 patients with radiologic evidence of emphysema and 41 patients with a preexisting diagnosis of COPD; 12 ARDS patients had both evidence of emphysema and a chart diagnosis of COPD. Emphysema severity was assessed in ARDS patients with COPD who had images available for independent review (n=43) and revealed most patients had no anatomic emphysema (n=15, 35%) or mild emphysema (n=14, 33%). Fewer ARDS patients with COPD had moderate emphysema (n=10, 23%) or severe emphysema (n=4, 9%) on review of CT imaging. The agreement between the radiology report and independent review for the visual assessment of emphysema was excellent, with a κ coefficient for interrater reliability of 0.93. Baseline clinical characteristics: In our cohort, ARDS patients with COPD/emphysema were older (median age 62 [interquartile range: 55-69] versus 53 [41-64] years, p<0.01) and were more likely to be male (62% versus 44%, p=0.02) compared to ARDS patients without COPD (Table 1). BMI did not differ significantly between ARDS patients with or without COPD (30.5 [24.9-35.9] versus 31.2 [26.4-36.1], p=0.29). ARDS patients with COPD/emphysema had a higher prevalence of congestive heart failure (25% versus 4%, p<0.01), but otherwise, comorbid conditions were similar between COPD and no COPD groups. The cause of ARDS was similar as 59% of ARDS patients with COPD/emphysema had direct pulmonary injury (primary insult caused by pneumonia, aspiration event, or inhalation injury) compared to 56% without COPD (p=0.32). In our cohort, 23% of ARDS patients with COPD/emphysema had COVID-19 infection compared to 36% in patients without COPD, though this difference did not reach statistical significance (p=0.06). As determined by the modified SOFA score, the severity of illness was also similar in both groups (p=0.29) (Table 1). Ventilator characteristics on the day of study enrollment: We compared baseline ventilator parameters between groups on the day of study enrollment. Several parameters did not differ significantly, including minute ventilation, positive end-expiratory pressure (PEEP), tidal volume, peak inspiratory pressures, plateau pressure, driving pressures, and static compliance (Figure 2). The ventilatory ratio was higher in ARDS patients with COPD/emphysema compared to ARDS patients without COPD/emphysema (2.1 vs. 1.9, p=0.02), potentially reflecting higher dead space in the COPD/emphysema group. ARDS severity, as determined by the P/F ratio, did not differ significantly between groups (120 in the ARDS with COPD/emphysema group versus 126 in the ARDS without COPD/emphysema group, p=0.56). Serum and lower respiratory tract host-response biomarker profiles: We compared host-response biomarkers at study enrollment between ARDS patients with and without COPD/emphysema. Most had biomarker data available (eTable 1). Serum biomarkers assessing systemic inflammation, endothelial injury, epithelial injury, and host response to bacterial infection did not significantly differ between groups (Table 2). Membership to a hyperinflammatory host response subphenotype did not differ between ARDS patients with (28%) or without COPD/emphysema (24%, p=0.65). In exploratory analyses, we investigated host response biomarkers in lower respiratory tract samples in a subset of patients (ARDS without COPD/emphysema n=48; ARDS with COPD/emphysema n=9) and similarly did not detect significant differences (eTable 2). Clinical outcomes: Median duration of mechanical ventilation (7 [4-16] versus 12 [6-20] days, p=0.04) and ICU length of stay (10 [7-18] versus 17 [9-28] days, p=0.01) were shorter in ARDS patients with COPD/emphysema versus ARDS patients without COPD/emphysema. We hypothesized this may be due to differences in the prevalence of COVID-19 between groups. In the subgroup of patients without COVID, the duration of mechanical ventilation was 5 [3-9] and 6 [3-13] days in the ARDS patients with and without COPD/emphysema respectively (p=0.29), and ICU length of stay was 8 [5-12] and 10 [6-18] days respectively (p=0.09). In the subgroup of patients with COVID, the duration of mechanical ventilation was 11 [7-18] and 19 [10-29] days with and without COPD/emphysema respectively (p=0.73), and ICU length of stay was 10 [8-19] and 27 [13-38] days respectively (p=0.28). Kaplan-Meier curves of unadjusted time to liberation from mechanical ventilation (eFigure 1A) demonstrate an initial separation between both groups between 3 and 14 days, but the overall number liberated appears equivalent by 30 days. Mortality did not differ significantly between ARDS patients with or without COPD/emphysema (90-day mortality 40% with COPD/emphysema and 37% without COPD/emphysema, p=0.64). Mortality at 90 days did not differ between groups in unadjusted analyses (odds ratio [OR] 1.16, 95% CI 0.62-2.15, p=0.64) or in analyses adjusted for age, history of congestive heart failure, and COVID-19 status (OR 0.87, 95% CI 0.43-1.76, p=0.69). Sensitivity analyses: First, when the subgroup of ARDS patients was restricted only to patients with a documented history of COPD in the electronic medical record (n=41), differences between groups in baseline demographics, comorbidities, and laboratory values were consistent with the primary analyses, as were the lack of significant differences in mechanical ventilation parameters, host response biomarkers, and mortality (eTables 3-5). Second, when the subgroup of ARDS patients was restricted to only patients with anatomic emphysema on CT imaging (n=28), differences in age, race, and history of congestive heart failure were no longer significantly different. Body mass index was lower in ARDS patients with emphysema compared to those without COPD (median 31.2 [IQR 26.4-36.1] versus 26.7 [23.7-33.9], p=0.01). Other comorbidities, laboratory values, host response biomarkers, and mortality were otherwise similar in ARDS patients with emphysema compared to those without COPD (eTables 6-8). Discussion We performed a detailed assessment of the differences in baseline demographics, comorbid conditions, mechanical ventilation parameters, systemic and pulmonary host responses, and clinical outcomes in ARDS patients with and without COPD or emphysema. We found that, generally, pre-existing COPD or emphysema did not impact ARDS pathogenesis. ARDS patients with COPD or emphysema were older, more likely to be male, and had a higher prevalence of heart failure compared to ARDS patients without COPD or emphysema, but other comorbidities and severity of illness were similar. The ventilatory ratio was higher on study enrollment in ARDS patients with COPD or emphysema, suggesting a higher fraction of dead space, but otherwise, ventilator parameters were comparable. Host response biomarker profiles did not differ between groups in serum or in lower respiratory tract samples. Median duration of mechanical ventilation and ICU length of stay were slightly shorter in ARDS patients with COPD or emphysema, but overall mortality at 90 days did not differ between groups. COPD is a common comorbidity in critically ill patients, and the prevalence of COPD or emphysema in our ARDS cohort was ~26%. While our prevalence is slightly higher than the ~20% reported in LUNG-SAFE, prior studies investigating COPD in ARDS relied on a review of the medical record for diagnosis. By performing a systematic investigation into radiologic evidence of anatomic emphysema, our study likely grouped more ARDS patients into the COPD or emphysema group and less into the no COPD or emphysema group. Consistent with prior reports, our study demonstrates that the mechanical ventilation delivered to ARDS patients with COPD or emphysema is similar to patients without COPD (15). We hypothesized that the respiratory mechanics and gas exchange characteristics in ARDS patients with COPD or emphysema at baseline would be characterized by lower elastance (or higher compliance), worse gas exchange, and dynamic hyperinflation (16). We found both groups had similar static compliance of the respiratory system and similar gas exchange. Since both groups of ARDS patients had severe acute hypoxemic respiratory failure, baseline differences in groups may have been overcome by the severity of illness and lung injury. Our findings are consistent with findings from the PRoVENT-COVID study (a multicenter, observational cohort study done in patients with COPD and COVID ARDS in the Netherlands) and do not support the theoretical notion that ARDS with COPD is a separate clinical phenotype distinct with a “low-elastance” ARDS phenotype (15). Despite our findings, in patients with severe COPD and ARDS, several unanswered questions remain regarding nuances of PEEP titration and the impact of low tidal volume ventilation on gas exchange in the setting of severe obstruction. Many landmark ARDS trials have excluded patients with severe chronic lung disease (3). To the best of our knowledge, our study is the first to investigate differences in host response biomarkers in the plasma and lower respiratory tract samples of patients with ARDS with and without COPD or emphysema. In the outpatient setting, COPD patients exhibit higher circulating levels of IL-6 and IL-8 and lower levels of sRAGE than healthy controls (17). However, ARDS is characterized by a much more severe and acute inflammatory lung response (18). Our finding of the similarity in plasma and lower respiratory tract biomarker profiles could potentially be attributed to the fact that both groups experienced an acute insult leading to ARDS, had similar rates of pulmonary insults, and exhibited comparable severity of illness, overwhelming any differences in baseline local or systemic host responses. We acknowledge two caveats in the interpretation of the host response. First, we recognize that most patients in our ARDS with COPD or emphysema group had no or minimal anatomic emphysema. Higher severity of anatomic emphysema may alter lung and systemic host responses, but the low prevalence of severe emphysema in our cohort prevented an in-depth study. Second, we did not have spirometry data available for participants in our study and recognize that both that currently spirometry and not emphysema is required for diagnosis of COPD and that differences in biologic responses may emerge based on the severity of obstruction. We noted that ARDS patients with COPD or emphysema in our study had shorter ICU stay and shorter duration of mechanical ventilation compared to ARDS patients without but similar 90-day mortality. Our findings contrast the results of prior studies in COVID patients with ARDS, which showed higher 28-day and 90-day mortality in patients with COPD (15,19,20). Our study included a mix of COVID and non-COVID ARDS patients and lacked adequate power to detect differences in mortality, specifically in COVID patients. However, the differences in COVID prevalence may explain the differences in ventilator and ICU length of stay duration. ARDS patients with COPD or emphysema in our study had a median of 7 days of mechanical ventilation and 10 days of ICU stay, similar to findings in LUNG-SAFE (1). We hypothesize that the higher incidence of COVID-19 in the group of ARDS patients without COPD or emphysema contributed to the longer ventilator and ICU length of stay (21). Our cohort may also have a lower prevalence of participants with rapidly improving ARDS (a clinical phenotype of ARDS characterized by rapid resolution of lung injury) compared to prior observational studies such as LUNG-SAFE (22), as such patients may improve before recruitment efforts are successful. Our study does have several additional limitations to acknowledge. First, our study included primarily ARDS patients requiring mechanical ventilation. Newer definitions of ARDS may include patients on high-flow nasal cannula oxygen but not on mechanical ventilation. We hypothesize that such modalities may be preferred for ARDS patients with chronic lung diseases such as COPD when possible and may have been missed in our cohort. Second, we did not have detailed information on the severity of baseline hypoxia in our COPD patients. We hypothesize that the need for home oxygen may impact gas exchange in COPD patients with ARDS. Third, we investigated host response biomarkers and mechanical ventilation parameters on study enrollment but acknowledge that the time from hospitalization to time of study enrollment, as the use of other modalities such as high flow oxygen or non-invasive ventilation, may have differed between groups and will be a focus of future studies. Conclusion In conclusion, our findings suggest that ARDS patients with COPD or emphysema are similar to ARDS patients without COPD or emphysema in several key clinical, physiologic, and biologic parameters, but further study is warranted. Personalization of ARDS care is a research priority, and consideration should be given to the impact of chronic conditions alongside strategies guided by biologic responses or clinical signatures on presentation (9,23,24). The clinical and biological heterogeneity within COPD underscores the importance of larger studies to understand the difference in pathogenesis, recovery, and effect on quality of life in patients with COPD who develop ARDS. Abbreviations ARDS Acute respiratory distress syndrome COPD Chronic obstructive pulmonary disease COVID-19 Coronavairus-19 ALIR Acute Lung Injury and Biospecimen Repository IL Interleukin sTNFR-1 Soluble tumor necrosis factor receptor-1 ST-2 Suppressor of tumorigenicity-2 RAGE Receptor of advanced glycation end-products Ang-2 Angiopoietin-2 SOFA Sequential organ failure assessment ΔP Driving pressure PEEP Positive end-expiratory pressure Pplat Plateau pressure Pmax Maximum airway pressure VR Ventilatory ratio PaCO2 Partial pressure of carbon dioxide in arterial blood CRS Respiratory system compliance Declarations Ethics approval and consent to participate: All research was conducted consistent with standards set in the Declaration of Helsinki. All participants in this study were enrolled in the Acute Lung Injury Registry and Biospecimen Repository (ALIR) at the University of Pittsburgh after obtaining informed consent from patients or legally authorized representatives. ALIR protocols have been approved by the Human Research Office at the University of Pittsburgh under protocol number STUDY19050099. Consent for publication: All authors reviewed the final version of the manuscript and consented to submission and publication. Availability of data and materials: Data from this study can be made available to qualified investigators through collaboration with ALIR investigators. Requests can be made through the Pulmonary Translational Research Core at the University of Pittsburgh through https://paccm.pitt.edu/ptrc/supportrequest.html . Authors' contributions: SN, JB, JE, and FAS conceived and designed the study. SN, HQ, and FAS performed the acquisition of data, performed statistical analyses, and drafted the initial manuscript. FAS, GDK, WB, and BJM provided resources for the completion of the study. All authors contributed to the interpretation of data, reviewed the manuscript, provided significant contributions to the writing and editing of the manuscript, and agreed to the submission of the final version. Acknowledgments: None Conflicts of Interest: GDK has received research funding from Karius, Inc., Pfizer, Inc., and Genentech, Inc, unrelated to this work. BJM has received grant funding from Genentech and consulting fees from BioAegis, Beohringer Ingelheim, and Synairgen Research. Funding Information: This manuscript is supported by grants from the National Institutes of Health: K23GM122069 (FAS); P01HL114453 (BJM). References Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. 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Tables Table 1 Characteristics of the Study Cohort Variable No COPD or emphysema COPD or emphysema p-value N 160 57 Demographics Age, years 53 (41–64) 62 (55–69) < 0.01 Sex, male 99 (61.8%) 25 (43.8%) 0.02 Race, Caucasian 143 (89.3%) 49 (85.9%) 0.63 Body mass index, kg/m 2 31.2 (26.4–36.1) 30.5 (24.9–35.9) 0.29 Comorbidities Diabetes mellitus 49 (30.6%) 20 (35.0%) 0.53 Chronic renal failure 20 (12.5%) 7.0 (12.8%) 0.97 Congestive heart failure 7.0 (4.3%) 14 (24.5%) < 0.01 Active neoplasm 8.0 (5.0%) 10 (1.7%) 0.29 Immune suppression 48 (30.0%) 13 (22.8%) 0.30 Pulmonary fibrosis 6.0 (3.7%) 2.0 (3.5%) 0.93 Severity of illness Pulmonary injury 222 (59%) 111 (56%) 0.32 COVID-19 infection 58 (36.2%) 13 (22.8%) 0.06 Modified SOFA score 8 ( 5 – 10 ) 7 ( 5 – 8 ) 0.08 Laboratory results White blood cell count, 10 9 /L 12.1 (8.7–17.6) 11.2 (9.0-15.1) 0.30 Hemoglobin g/dL 10.3 (8.7–12.1) 9.9 (8.7–11.4) 0.22 Platelets, 10 9 /L 187 (119–259) 213 (134–272) 0.63 Creatinine, mg/dL 1.1 (0.8–2.1) 1.5 (0.8–2.5) 0.34 Bicarbonate, mEq/L 25 (22–29) 24 (20–28) 0.26 Blood urea nitrogen mg/dL 31 (21–43) 35 (17–49) 0.83 Blood glucose mg/dL 143 (114–183) 143 (122–171) 0.95 Data are presented as median (interquartile range) or n (%) as appropriate. Participants in the “COPD” group have a preexisting diagnosis of chronic obstructive pulmonary disease (COPD), presence of anatomic emphysema on computational tomography (CT) imaging of the chest, or both. Participants in the “No COPD” group have neither a chart diagnosis of COPD and have an absence of anatomic emphysema on CT imaging. Pulmonary insult indicates presence of at least one direct risk factor for acute respiratory distress syndrome determined by consensus and includes pneumonia, aspiration, and inhalational injury. SOFA score is modified to exclude the neurologic component as Glasgow Coma Scale were not routinely collected on patients in our study. p-values represent differences between groups compared by Mann-Whitney U test or by chi-squared analysis as appropriate. Abbreviations : COPD- chronic obstructive pulmonary disease; COVID-19- Coronavirus Disease-19; SOFA- Sequential Organ Failure Assessment. Table 2 Plasma host response biomarkers measured on study enrollment compared between ARDS patients with and without COPD or emphysema. Variable No COPD or emphysema COPD or emphysema p-value Angiopoetin-2 (pg/mL) 6883 [3761–13735] 8935 [4153–19008] 0.22 Interleukin-8 (pg/mL) 24 [14–40] 27 [14–54] 0.40 Interleukin-6 (pg/mL) 118 [30–413] 111 [37–198] 0.43 Interleukin-10 (pg/mL) 1.7 [1.0-8.6] 3.4 [1.3–11.8] 0.17 Procalcitonin (pg/mL) 670 [305–2885] 853 (193–4510) 0.42 Suppressor of tumorigenicity-2 (pg/mL) 161171 [809997 − 350891] 189618 [90955–422669] 0.77 Fractalkine (pg/mL) 2302 [1198–4024] 2133 [1179–3815] 0.48 Pentraxin-3 (pg/mL) 7833 [3669–20785] 8076 [3604–15562] 0.74 Soluble receptor for advanced glycation endproducts (pg/mL) 5212 [2760–9811] 5275 [2260–7866] 0.66 Beta-D-glucan (pg/mL) 24 [14–35] 28 [15–41] 0.35 Data are presented as median [interquartile range]. Biomarker data at baseline was available for a subset of participants (n = 207 total; no COPD: n = 154; COPD: n = 53). p-values represent differences between groups compared by Mann-Whitney U test. Additional Declarations Competing interest reported. GDK has received research funding from Karius, Inc., Pfizer, Inc., and Genentech, Inc, unrelated to this work. BJM has received grant funding from Genentech and consulting fees from BioAegis, Beohringer Ingelheim, and Synairgen Research. Supplementary Files ARDSCOPDsuppupdated.docx Cite Share Download PDF Status: Published Journal Publication published 08 Nov, 2024 Read the published version in Respiratory Research → Version 1 posted Editorial decision: Revision requested 24 Aug, 2024 Reviews received at journal 12 Aug, 2024 Reviews received at journal 02 Aug, 2024 Reviewers agreed at journal 01 Aug, 2024 Reviewers agreed at journal 01 Aug, 2024 Reviewers agreed at journal 29 Jul, 2024 Reviewers agreed at journal 27 Jul, 2024 Reviewers agreed at journal 27 Jul, 2024 Reviewers agreed at journal 26 Jul, 2024 Reviewers invited by journal 26 Jul, 2024 Editor assigned by journal 26 Jul, 2024 Submission checks completed at journal 26 Jul, 2024 First submitted to journal 25 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4803327","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":339764246,"identity":"545e29aa-8def-406f-9298-902fd800af7b","order_by":0,"name":"Sridesh Nath","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, and Critical Care Medicine, Downstate Health Sciences University, Brooklyn, NY","correspondingAuthor":false,"prefix":"","firstName":"Sridesh","middleName":"","lastName":"Nath","suffix":""},{"id":339764248,"identity":"9740aa14-bb0a-4b52-b00b-1b835e9a2d93","order_by":1,"name":"Hafiz Qurashi","email":"","orcid":"","institution":"Department of Medicine, UPMC Health Systems","correspondingAuthor":false,"prefix":"","firstName":"Hafiz","middleName":"","lastName":"Qurashi","suffix":""},{"id":339764249,"identity":"83e37520-ab62-46fe-8916-6b530696b4ef","order_by":2,"name":"Georgios D. Kitsios","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"Georgios","middleName":"D.","lastName":"Kitsios","suffix":""},{"id":339764250,"identity":"aafaea03-4609-4117-a641-65d9aea8fcd8","order_by":3,"name":"William Bain","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Bain","suffix":""},{"id":339764251,"identity":"d2ca0ebd-3bfe-4178-a427-4b3fe3d903a5","order_by":4,"name":"Tomeka Suber","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"Tomeka","middleName":"","lastName":"Suber","suffix":""},{"id":339764252,"identity":"371037e0-b814-4a67-bd83-1171884eb1ce","order_by":5,"name":"Niall Prendergast","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"Niall","middleName":"","lastName":"Prendergast","suffix":""},{"id":339764253,"identity":"68fb1bbe-c277-4a6d-93bb-33b9e157caca","order_by":6,"name":"Matthew Hensley","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Hensley","suffix":""},{"id":339764254,"identity":"be1a78dd-54d9-48a9-8e9b-c05f9f0155b1","order_by":7,"name":"Caitlin Schaefer","email":"","orcid":"","institution":"Acute Lung Injury and Infection Center of Excellence, University of Pittsburgh, Pittsburgh, PA.","correspondingAuthor":false,"prefix":"","firstName":"Caitlin","middleName":"","lastName":"Schaefer","suffix":""},{"id":339764255,"identity":"13da00b0-94e9-463f-b231-ce655831f85a","order_by":8,"name":"Yingze Zhang","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"Yingze","middleName":"","lastName":"Zhang","suffix":""},{"id":339764256,"identity":"1763966f-b791-48c4-b597-a1c632c667e9","order_by":9,"name":"Jessica Bon","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Bon","suffix":""},{"id":339764257,"identity":"30b19696-45da-4e51-96ac-ebc188c70e2b","order_by":10,"name":"Bryan J. McVerry","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"Bryan","middleName":"J.","lastName":"McVerry","suffix":""},{"id":339764258,"identity":"76c6a4ea-a4d5-4777-8caf-6f627e36d3b7","order_by":11,"name":"John Evankovich","email":"","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Evankovich","suffix":""},{"id":339764259,"identity":"cecc47af-182e-45d6-9058-3a30422a49d1","order_by":12,"name":"Faraaz Ali Shah","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYDACCQY2hgoGGyiPjVgtZxjSSNdymAQt8rObnz04UHM+cbvY4QcMH8oOE9ZicOeYucGBY7cTd85OM2CccY4YLRIJZtIf2G4nbridw8DM20aEFvkZ6d8kDvw7B9HylxgtDDdyzCQOth2AaGEkRovBjZwyiYN9ycYgvxzsOZdOlMO2SRz4Zie7XTr54YMfZdZEOAxuHRAfIEE9VMsoGAWjYBSMAqwAADBJQBou0KfrAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA","correspondingAuthor":true,"prefix":"","firstName":"Faraaz","middleName":"Ali","lastName":"Shah","suffix":""}],"badges":[],"createdAt":"2024-07-25 16:32:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4803327/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4803327/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12931-024-03027-2","type":"published","date":"2024-11-08T15:56:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":63420573,"identity":"d204d514-3f8d-4492-a5ca-230066ad3a36","added_by":"auto","created_at":"2024-08-28 02:40:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":391816,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow chart\u003c/strong\u003e. Patients previously enrolled in the Acute Lung Injury and Biospecimen Repository (ALIR) at the University of Pittsburgh were included in the current study if and if a diagnosis of acute respiratory distress syndrome (ARDS) by the Berlin criteria had been reached by consensus of at least three board-certified intensivists, and if either a diagnosis of chronic obstructive pulmonary disease (COPD) was present on chart review prior to ARDS diagnosis or if computed tomography (CT) of the chest had been performed within 2 years preceding the incident hospitalization to assess presence or absence of anatomic emphysema. ARDS patients in the current study were classified into two mutually exclusive groups: those with COPD or emphysema (defined by the presence of a chart diagnosis of COPD, radiologic evidence of anatomic emphysema, or both) and those without COPD (no chart diagnosis of COPD or emphysema on CT imaging).\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4803327/v1/e766378fd86b46999f70f23c.jpg"},{"id":63420569,"identity":"8340eec6-4b79-4973-bf50-654e5b16e2b0","added_by":"auto","created_at":"2024-08-28 02:40:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":265944,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eVentilatory parameters compared in ARDS patients by presence or absence of COPD or emphysema. \u003c/strong\u003eCOPD in figures denotes the COPD or emphysema group. Data\u003ca href=\"#_msocom_1\"\u003e[QHMS1]\u003c/a\u003e\u0026nbsp; are presented as violin plots with medians and 25\u003csup\u003eth\u003c/sup\u003e and 75\u003csup\u003eth\u003c/sup\u003e percentiles demarcated. Each dot represents an individual patient. * denotes significance at p\u0026lt;0.05 by Kruskal-Wallis test. Abbreviations: COPD = chronic obstructive lung disease; PEEP = positive end-expiratory pressure\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4803327/v1/d8b472435ba91942127b1de8.jpg"},{"id":68749722,"identity":"179c19aa-9431-4479-907d-0a253d95ac3c","added_by":"auto","created_at":"2024-11-11 16:01:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1144969,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4803327/v1/67acc30a-3443-44b8-974b-24b343b1bf15.pdf"},{"id":63420574,"identity":"26c931a5-f5e6-4f7c-8296-2805222e8652","added_by":"auto","created_at":"2024-08-28 02:40:14","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":163182,"visible":true,"origin":"","legend":"","description":"","filename":"ARDSCOPDsuppupdated.docx","url":"https://assets-eu.researchsquare.com/files/rs-4803327/v1/5860694b0159f3d51bc1a3ec.docx"}],"financialInterests":"Competing interest reported. GDK has received research funding from Karius, Inc., Pfizer, Inc., and Genentech, Inc, unrelated to this work. BJM has received grant funding from Genentech and consulting fees from BioAegis, Beohringer Ingelheim, and Synairgen Research.","formattedTitle":"Clinical and Biologic Profiles of Patients with Acute Respiratory Distress Syndrome by Prevalence of Chronic Obstructive Pulmonary Disease or Emphysema; A Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute respiratory distress syndrome (ARDS) is a common and potentially fatal condition characterized by diffuse lung injury in response to a direct or indirect insult, with an estimated prevalence of 10% among critically ill patients and with a 28-day in-hospital mortality rate approaching 40% (1). The incidence of ARDS increased sharply during the Coronavirus-19 (COVID-19) pandemic, highlighting the need to better understand pathogenesis and management. Effective clinical treatments for ARDS remain limited, with numerous preclinical interventions yielding minimal success in clinical trials (2)(3). Notably, preclinical in vivo models of ARDS are often conducted in young and healthy mice, contrasting the clinical ARDS patient population, which is characterized by multiple chronic comorbidities (4). Understanding the relationship between chronic comorbidities and ARDS pathogenesis is essential for tailoring therapeutic strategies.\u003c/p\u003e\n\u003cp\u003eChronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease globally and is the sixth leading cause of death in the United States\u0026nbsp; (5). The impact of pre-existing COPD on ARDS pathogenesis is not well characterized. Patients with COPD have a higher risk of severe community-acquired pneumonia, the most common cause of ARDS, and once hospitalized with severe pneumonia in the intensive care unit (ICU), have higher mortality and need for mechanical ventilation (6)(7). COPD is common in ARDS patients as the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG-SAFE) study encompassing 459 ICUs in 50 countries demonstrated that approximately one in five ARDS patients had underlying COPD (1). The LUNG-SAFE study did not characterize differences in clinical outcomes based on pre-existing COPD and additionally based the diagnosis of COPD on chart reviews. Systematic assessment of radiologic imaging may uncover the presence of anatomic emphysema which may impact clinical and biologic responses in ARDS.\u003c/p\u003e\n\u003cp\u003eWe performed this study to investigate the impact of COPD and emphysema on ARDS pathogenesis. Our specific objectives were (1) to determine the prevalence of COPD and emphysema in ARDS using both chart review and systemic review of radiologic testing, and (2) to investigate differences between ARDS patients by prevalence of COPD or emphysema in mechanical ventilation parameters, host response biomarkers, and clinical outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cu\u003eDescription of cohort\u003c/u\u003e: We performed a secondary analysis of patients prospectively enrolled in the Acute Lung Injury and Biospecimen Repository (ALIR) at the University of Pittsburgh between June 2012 to September 2021. Details of the ALIR have previously been published, and all patients were enrolled after obtaining informed consent (8,9). ALIR protocols have been approved by the Human Research Office at the University of Pittsburgh (protocol# STUDY19050099).\u003c/p\u003e\n\u003cp\u003eALIR enrolls adult patients with acute respiratory failure with most requiring invasive mechanical ventilation. For this study, we included patients with a diagnosis of ARDS as determined by a consensus committee meeting of at least three board-certified pulmonary and critical care physicians following a review of all available clinical and radiographic data and adjudicated based on Berlin Criteria (10) We classified patients in our study cohort into two mutually exclusive groups based on the prevalence or absence of COPD or emphysema (COPD/emphysema). All ARDS patients with a chart diagnosis of COPD were included in the COPD/emphysema group. Chart diagnosis was based on review of history and physical examination notes on admission to the intensive care unit and was not dependent on specific diagnosis or procedure codes. ARDS patients with a chart diagnosis of COPD underwent review of computed tomography (CT) chest reports and/or imaging, if available, during the incident admission or within the 2 years preceding admission to determine presence and extent of anatomic emphysema as described below. ARDS patients without a chart diagnosis of COPD were only included in our study if a CT chest had been performed during or in the 2 years prior to admission\u0026mdash; if review of chest imaging revealed anatomic emphysema, then patients were classified in the COPD/emphysema group, if not, then patients were classified in the ARDS without COPD/emphysema group.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eEmphysema scoring\u003c/u\u003e: Electronic records of all ARDS patients were reviewed for the presence of CT chest imaging with or without intravenous contrast performed as part of their clinical care up to 2 years prior to the incident hospitalization. All CT scans had previously been interpreted by a board-certified radiologist. All CT images that were available in the electronic record were independently reviewed by a board-certified pulmonologist (SN) for visual assessment of the presence of emphysema without knowledge of the radiologist\u0026rsquo;s report. The extent of emphysema was graded from 0 to 3, using a semiquantitative visual scoring system to define emphysema severity (0 none; 1 mild; 2 moderate; 3 severe), which corresponded to 0%, less than 25%, 26\u0026ndash;50%, and greater than 75% visual emphysema respectively (11). For this study, patients with a score \u0026ge; 1 were classified as having anatomic emphysema. In patients with multiple CT scans of the chest available for review, the CT scan most proximal to the day of admission for respiratory failure due to ARDS was used for emphysema assessment. Agreement between the radiology report and independent review for the visual assessment of emphysema was assessed by the \u0026kappa; coefficient for interrater reliability. In cases of discrepancy, images were independently reviewed and scored by a second reviewer (FS). In a subset of patients, a CT chest had been performed but images were not available for independent review. In this subset, the radiologist\u0026rsquo;s interpretation was used to determine the presence or absence of emphysema.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eClinical data collection\u003c/u\u003e: Baseline demographics, chronic comorbidities, parameters of mechanical ventilation, laboratory variables, and calculated sequential organ failure assessment (SOFA) scores were abstracted from the electronic medical record. Driving pressure (\u0026Delta;P) on the day of study enrollment was calculated as the difference between the positive end-expiratory pressure (PEEP) and the plateau pressure (Pplat) during volume-controlled ventilation or between PEEP and the maximum airway pressure (Pmax) during pressure-controlled ventilation. Ventilatory ratio (VR) was calculated by using the formula VR = [minute ventilation (ml/min)\u0026thinsp;\u0026times;\u0026thinsp;PaCO2 (mmHg)]/(predicted body weight(kg)\u0026thinsp;\u0026times;\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;37.5). Respiratory system compliance (CRS) was calculated by dividing the tidal volume(ml) by \u0026Delta;P(cmH20)(12).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHost response biomarkers\u003c/u\u003e: Biospecimens are collected from ALIR patients within 72 hours of intubation, including blood samples and endotracheal aspirates (ETA), and processed as previously described(8,9). Ten host-response biomarkers shown to have validated associations with ARDS were previously characterized in blood and ETA samples with a customized Luminex assay (R\u0026amp;D Systems, Minneapolis)(13). Host-response biomarkers included markers of innate immune response (interleukin (IL)-6, IL-8, IL-10, fractalkine, soluble tumor necrosis factor receptor-1 [sTNFR-1], suppressor of tumorigenicity-2 [ST-2]); epithelial injury (receptor of advanced glycation end-products [RAGE]); endothelial injury (angiopoietin-2 [Ang-2]); and response to bacterial infections (procalcitonin and pentraxin-3).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eHost response subphenotype assignments\u003c/u\u003e: We classified patients into host response subphenotypes (hyperinflammatory versus hypoinflammatory) using a parsimonious logistic regression model based on plasma levels of Ang-2, procalcitonin, sTNFR1, and bicarbonate that have been previously validated in this cohort (14).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStatistical analyses\u003c/u\u003e: In our primary analyses, we compared continuous and categorical variables between ARDS patients with and without COPD/emphysema by nonparametric tests (Kruskal-Wallis or Fisher\u0026rsquo;s tests, as appropriate). We report variables as median and interquartile range [IQR] for continuous variables and number (proportion) for categorical variables. We constructed Kaplan Meier survival curves to visually investigate differences in the duration of mechanical ventilation and 90-day survival and compared between groups. We compared differences in 90-day mortality in logistic regression analyses adjusted for age, history of congestive heart failure by review of the electronic medical record, and COVID-19 diagnosis.\u003c/p\u003e\n\u003cp\u003eSince ARDS patients with COPD/emphysema in our cohort may have had a chart diagnosis of COPD or evidence of anatomic emphysema on a CT scan (or both), we performed two sensitivity analyses to ensure the robustness of the results. First, we compared differences between ARDS patients with no COPD to the subset of patients who had a documented diagnosis of COPD on chart review. Second, we compared differences between ARDS patients with no COPD to the subset of patients who had evidence of emphysema on CT imaging.\u003c/p\u003e\n\u003cp\u003eWe performed all analyses with STATA version 17 and considered a p-value of less than 0.05 as statistically significant. Analyses were not adjusted for multiple testing. All findings are reported consistent with the STROBE statement for observational studies.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cu\u003eCohort Description\u003c/u\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFrom January 2012 to January 2022, 783 patients with acute respiratory failure were prospectively enrolled from medical ICUs in the UPMC Health System in Western Pennsylvania in the Acute Lung Injury Registry and Biospecimen Repository. In our study, we excluded patients who did not have a CT scan of the chest within 2 years prior to hospitalization for respiratory failure unless they had a chart review diagnosis of COPD (n=258) and we excluded patients without ARDS (n=308) (Figure 1). The remaining ARDS patients (n=217) were classified into two mutually exclusive groups: those with COPD/emphysema (n=57) and without COPD/emphysema (n=160). The COPD/emphysema group comprised 28 patients with radiologic evidence of emphysema and 41 patients with a preexisting diagnosis of COPD; 12 ARDS patients had both evidence of emphysema and a chart diagnosis of COPD. Emphysema severity was assessed in ARDS patients with COPD who had images available for independent review (n=43) and revealed most patients had no anatomic emphysema (n=15, 35%) or mild emphysema (n=14, 33%). Fewer ARDS patients with COPD had moderate emphysema (n=10, 23%) or severe emphysema (n=4, 9%) on review of CT imaging. The agreement between the radiology report and independent review for the visual assessment of emphysema was excellent, with a \u0026kappa; coefficient for interrater reliability of 0.93.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eBaseline clinical characteristics:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIn our cohort, ARDS patients with COPD/emphysema were older (median age 62 [interquartile range: 55-69] versus 53 [41-64] years, p\u0026lt;0.01) and were more likely to be male (62% versus 44%, p=0.02) compared to ARDS patients without COPD (Table 1). BMI did not differ significantly between ARDS patients with or without COPD (30.5 [24.9-35.9] versus 31.2 [26.4-36.1], p=0.29). ARDS patients with COPD/emphysema had a higher prevalence of congestive heart failure (25% versus 4%, p\u0026lt;0.01), but otherwise, comorbid conditions were similar between COPD and no COPD groups. The cause of ARDS was similar as 59% of ARDS patients with COPD/emphysema had direct pulmonary injury (primary insult caused by pneumonia, aspiration event, or inhalation injury) compared to 56% without COPD (p=0.32). In our cohort, 23% of ARDS patients with COPD/emphysema had COVID-19 infection compared to 36% in patients without COPD, though this difference did not reach statistical significance (p=0.06). As determined by the modified SOFA score, the severity of illness was also similar in both groups (p=0.29) (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eVentilator characteristics on the day of study enrollment:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eWe compared baseline ventilator parameters between groups on the day of study enrollment. Several parameters did not differ significantly, including minute ventilation, positive end-expiratory pressure (PEEP), tidal volume, peak inspiratory pressures, plateau pressure, driving pressures, and static compliance (Figure 2). The ventilatory ratio was higher in ARDS patients with COPD/emphysema compared to ARDS patients without COPD/emphysema (2.1 vs. 1.9, p=0.02), potentially reflecting higher dead space in the COPD/emphysema group. ARDS severity, as determined by the P/F ratio, did not differ significantly between groups (120 in the ARDS with COPD/emphysema group versus 126 in the ARDS without COPD/emphysema group, p=0.56).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSerum and lower respiratory tract host-response biomarker profiles:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eWe compared host-response biomarkers at study enrollment between ARDS patients with and without COPD/emphysema. Most had biomarker data available (eTable 1). Serum biomarkers assessing systemic inflammation, endothelial injury, epithelial injury, and host response to bacterial infection did not significantly differ between groups (Table 2). Membership to a hyperinflammatory host response subphenotype did not differ between ARDS patients with (28%) or without COPD/emphysema (24%, p=0.65). In exploratory analyses, we investigated host response biomarkers in lower respiratory tract samples in a subset of patients (ARDS without COPD/emphysema n=48; ARDS with COPD/emphysema n=9) and similarly did not detect significant differences (eTable 2).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eClinical outcomes:\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eMedian duration of mechanical ventilation (7 [4-16] versus 12 [6-20] days, p=0.04) and ICU length of stay (10 [7-18] versus 17 [9-28] days, p=0.01) were shorter in ARDS patients with COPD/emphysema versus ARDS patients without COPD/emphysema. We hypothesized this may be due to differences in the prevalence of COVID-19 between groups. In the subgroup of patients without COVID, the duration of mechanical ventilation was 5 [3-9] and 6 [3-13] days in the ARDS patients with and without COPD/emphysema respectively (p=0.29), and ICU length of stay was 8 [5-12] and 10 [6-18] days respectively (p=0.09). In the subgroup of patients with COVID, the duration of mechanical ventilation was 11 [7-18] and 19 [10-29] days with and without COPD/emphysema respectively (p=0.73), and ICU length of stay was 10 [8-19] and 27 [13-38] days respectively (p=0.28). Kaplan-Meier curves of unadjusted time to liberation from mechanical ventilation (eFigure 1A) demonstrate an initial separation between both groups between 3 and 14 days, but the overall number liberated appears equivalent by 30 days. Mortality did not differ significantly between ARDS patients with or without COPD/emphysema (90-day mortality 40% with COPD/emphysema and 37% without COPD/emphysema, p=0.64). Mortality at 90 days did not differ between groups in unadjusted analyses (odds ratio [OR] 1.16, 95% CI 0.62-2.15, p=0.64) or in analyses adjusted for age, history of congestive heart failure, and COVID-19 status (OR 0.87, 95% CI 0.43-1.76, p=0.69).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSensitivity analyses:\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eFirst, when the subgroup of ARDS patients was restricted only to patients with a documented history of COPD in the electronic medical record (n=41), differences between groups in baseline demographics, comorbidities, and laboratory values were consistent with the primary analyses, as were the lack of significant differences in mechanical ventilation parameters, host response biomarkers, and mortality (eTables 3-5). Second, when the subgroup of ARDS patients was restricted to only patients with anatomic emphysema on CT imaging (n=28), differences in age, race, and history of congestive heart failure were no longer significantly different. Body mass index was lower in ARDS patients with emphysema compared to those without COPD (median 31.2 [IQR 26.4-36.1] versus 26.7 [23.7-33.9], p=0.01). Other comorbidities, laboratory values, host response biomarkers, and mortality were otherwise similar in ARDS patients with emphysema compared to those without COPD (eTables 6-8).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe performed a detailed assessment of the differences in baseline demographics, comorbid conditions, mechanical ventilation parameters, systemic and pulmonary host responses, and clinical outcomes in ARDS patients with and without COPD or emphysema. We found that, generally, pre-existing COPD or emphysema did not impact ARDS pathogenesis. ARDS patients with COPD or emphysema were older, more likely to be male, and had a higher prevalence of heart failure compared to ARDS patients without COPD or emphysema, but other comorbidities and severity of illness were similar. The ventilatory ratio was higher on study enrollment in ARDS patients with COPD or emphysema, suggesting a higher fraction of dead space, but otherwise, ventilator parameters were comparable. Host response biomarker profiles did not differ between groups in serum or in lower respiratory tract samples. Median duration of mechanical ventilation and ICU length of stay were slightly shorter in ARDS patients with COPD or emphysema, but overall mortality at 90 days did not differ between groups.\u003c/p\u003e\n\u003cp\u003eCOPD is a common comorbidity in critically ill patients, and the prevalence of COPD or emphysema in our ARDS cohort was ~26%. While our prevalence is slightly higher than the ~20% reported in LUNG-SAFE, prior studies investigating COPD in ARDS relied on a review of the medical record for diagnosis. By performing a systematic investigation into radiologic evidence of anatomic emphysema, our study likely grouped more ARDS patients into the COPD or emphysema group and less into the no COPD or emphysema group.\u003c/p\u003e\n\u003cp\u003eConsistent with prior reports, our study demonstrates that the mechanical ventilation delivered to ARDS patients with COPD or emphysema is similar to patients without COPD (15). We hypothesized that the respiratory mechanics and gas exchange characteristics in ARDS patients with COPD or emphysema at baseline would be characterized by lower elastance (or higher compliance), worse gas exchange, and dynamic hyperinflation (16). We found both groups had similar static compliance of the respiratory system and similar gas exchange. Since both groups of ARDS patients had severe acute hypoxemic respiratory failure, baseline differences in groups may have been overcome by the severity of illness and lung injury. Our findings are consistent with findings from the PRoVENT-COVID study (a multicenter, observational cohort study done in patients with COPD and COVID ARDS in the Netherlands) and do not support the theoretical notion that ARDS with COPD is a separate clinical phenotype distinct with a \u0026ldquo;low-elastance\u0026rdquo; ARDS phenotype (15). Despite our findings, in patients with severe COPD and ARDS, several unanswered questions remain regarding nuances of PEEP titration and the impact of low tidal volume ventilation on gas exchange in the setting of severe obstruction. Many landmark ARDS trials have excluded patients with severe chronic lung disease (3).\u003c/p\u003e\n\u003cp\u003eTo the best of our knowledge, our study is the first to investigate differences in host response biomarkers in the plasma and lower respiratory tract samples of patients with ARDS with and without COPD or emphysema. In the outpatient setting, COPD patients exhibit higher circulating levels of IL-6 and IL-8 and lower levels of sRAGE than healthy controls (17). However, ARDS is characterized by a much more severe and acute inflammatory lung response (18). Our finding of the similarity in plasma and lower respiratory tract biomarker profiles could potentially be attributed to the fact that both groups experienced an acute insult leading to ARDS, had similar rates of pulmonary insults, and exhibited comparable severity of illness, overwhelming any differences in baseline local or systemic host responses. We acknowledge two caveats in the interpretation of the host response. First, we recognize that most patients in our ARDS with COPD or emphysema group had no or minimal anatomic emphysema. Higher severity of anatomic emphysema may alter lung and systemic host responses, but the low prevalence of severe emphysema in our cohort prevented an in-depth study. Second, we did not have spirometry data available for participants in our study and recognize that both that currently spirometry and not emphysema is required for diagnosis of COPD and that differences in biologic responses may emerge based on the severity of obstruction.\u003c/p\u003e\n\u003cp\u003eWe noted that ARDS patients with COPD or emphysema in our study had shorter ICU stay and shorter duration of mechanical ventilation compared to ARDS patients without but similar 90-day mortality. Our findings contrast the results of prior studies in COVID patients with ARDS, which showed higher 28-day and 90-day mortality in patients with COPD (15,19,20). Our study included a mix of COVID and non-COVID ARDS patients and lacked adequate power to detect differences in mortality, specifically in COVID patients. However, the differences in COVID prevalence may explain the differences in ventilator and ICU length of stay duration. ARDS patients with COPD or emphysema in our study had a median of 7 days of mechanical ventilation and 10 days of ICU stay, similar to findings in LUNG-SAFE (1). We hypothesize that the higher incidence of COVID-19 in the group of ARDS patients without COPD or emphysema contributed to the longer ventilator and ICU length of stay (21). Our cohort may also have a lower prevalence of participants with rapidly improving ARDS (a clinical phenotype of ARDS characterized by rapid resolution of lung injury) compared to prior observational studies such as LUNG-SAFE (22), as such patients may improve before recruitment efforts are successful.\u003c/p\u003e\n\u003cp\u003eOur study does have several additional limitations to acknowledge. First, our study included primarily ARDS patients requiring mechanical ventilation. Newer definitions of ARDS may include patients on high-flow nasal cannula oxygen but not on mechanical ventilation. We hypothesize that such modalities may be preferred for ARDS patients with chronic lung diseases such as COPD when possible and may have been missed in our cohort. Second, we did not have detailed information on the severity of baseline hypoxia in our COPD patients. We hypothesize that the need for home oxygen may impact gas exchange in COPD patients with ARDS. Third, we investigated host response biomarkers and mechanical ventilation parameters on study enrollment but acknowledge that the time from hospitalization to time of study enrollment, as the use of other modalities such as high flow oxygen or non-invasive ventilation, may have differed between groups and will be a focus of future studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our findings suggest that ARDS patients with COPD or emphysema are similar to ARDS patients without COPD or emphysema in several key clinical, physiologic, and biologic parameters, but further study is warranted. Personalization of ARDS care is a research priority, and consideration should be given to the impact of chronic conditions alongside strategies guided by biologic responses or clinical signatures on presentation (9,23,24). The clinical and biological heterogeneity within COPD underscores the importance of larger studies to understand the difference in pathogenesis, recovery, and effect on quality of life in patients with COPD who develop ARDS.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eARDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcute respiratory distress syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOVID-19\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCoronavairus-19\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALIR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcute Lung Injury and Biospecimen Repository\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterleukin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003esTNFR-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSoluble tumor necrosis factor receptor-1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eST-2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSuppressor of tumorigenicity-2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRAGE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eReceptor of advanced glycation end-products\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAng-2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAngiopoietin-2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSOFA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSequential organ failure assessment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eΔP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDriving pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePEEP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePositive end-expiratory pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePplat\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePlateau pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePmax\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMaximum airway pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVentilatory ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePaCO2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePartial pressure of carbon dioxide in arterial blood\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRespiratory system compliance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthics approval and consent to participate:\u003c/u\u003e All research was conducted consistent with standards set in the Declaration of Helsinki. All participants in this study were enrolled in the Acute Lung Injury Registry and Biospecimen Repository (ALIR) at the University of Pittsburgh after obtaining informed consent from patients or legally authorized representatives. ALIR protocols have been approved by the Human Research Office at the University of Pittsburgh under protocol number\u0026nbsp;STUDY19050099.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent for publication:\u003c/u\u003e All authors reviewed the final version of the manuscript and consented to submission and publication.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAvailability of data and materials:\u003c/u\u003e Data from this study can be made available to qualified investigators through collaboration with ALIR investigators. Requests can be made through the Pulmonary Translational Research Core at the University of Pittsburgh through\u0026nbsp;\u003ca href=\"https://paccm.pitt.edu/ptrc/supportrequest.html\"\u003ehttps://paccm.pitt.edu/ptrc/supportrequest.html\u003c/a\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors\u0026apos; contributions:\u003c/u\u003eSN, JB, JE, and FAS conceived and designed the study. SN, HQ, and FAS performed the acquisition of data, performed statistical analyses, and drafted the initial manuscript. FAS, GDK, WB, and BJM provided resources for the completion of the study. All authors contributed to the interpretation of data, reviewed the manuscript, provided significant contributions to the writing and editing of the manuscript, and agreed to the submission of the final version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAcknowledgments:\u003c/u\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConflicts of Interest:\u003c/u\u003e \u0026nbsp;GDK has received research funding from Karius, Inc., Pfizer, Inc., and Genentech, Inc, unrelated to this work. BJM has received grant funding from Genentech and consulting fees from BioAegis, Beohringer Ingelheim, and Synairgen Research.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding Information:\u003c/u\u003e This manuscript is supported by grants from the National Institutes of Health: K23GM122069 (FAS); P01HL114453 (BJM).\u0026nbsp;\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788\u0026ndash;800.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePham T, Rubenfeld GD. Fifty years of research in ARDS. the epidemiology of acute respiratory distress syndrome. A 50th birthday review. 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J Appl Physiol. 2009;107(1):309\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStockley RA, Halpin DMG, Celli BR, Singh D. Chronic obstructive pulmonary disease biomarkers and their interpretation. Am J Respir Crit Care Med. 2019;199(10):1195\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJabaudon M, Blondonnet R, Ware LB. Biomarkers in acute respiratory distress syndrome. Curr Opin Crit Care. 2021;27(1):46\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoreno-Martos D, Verhamme K, Ostropolets A, Kostka K, Duarte-Sales T, Prieto-Alhambra D, et al. Characteristics and outcomes of COVID-19 patients with COPD from the United States, South Korea, and Europe. Wellcome Open Res. 2022;7:22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerayeli FV, Milne S, Cheung C, Li X, Yang CWT, Tam A, et al. COPD and the risk of poor outcomes in COVID-19: A systematic review and meta-analysis. EClinicalMedicine. 2021;33:100789.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBain W, Yang H, Shah FA, Suber T, Drohan C, Al-Yousif N, et al. COVID-19 versus Non-COVID-19 Acute Respiratory Distress Syndrome: Comparison of Demographics, Physiologic Parameters, Inflammatory Biomarkers, and Clinical Outcomes. Ann Am Thorac Soc. 2021;18(7):1202\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchenck EJ, Oromendia C, Torres LK, Berlin DA, Choi AMK, Siempos II. Rapidly improving ARDS in therapeutic randomized controlled trials. Chest. 2019;155(3):474\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinha P, Delucchi KL, McAuley DF, O\u0026rsquo;Kane CM, Matthay MA, Calfee CS. Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials. Lancet Respir Med. 2020;8(3):247\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinha P, Churpek MM, Calfee CS. Machine learning classifier models can identify acute respiratory distress syndrome phenotypes using readily available clinical data. Am J Respir Crit Care Med. 2020;202(7):996\u0026ndash;1004.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":" \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eCharacteristics of the Study Cohort\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eVariable\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eNo COPD or emphysema\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eCOPD or emphysema\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003ep-value\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eN\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e160\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e57\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eDemographics\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAge, years\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e53 (41\u0026ndash;64)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e62 (55\u0026ndash;69)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.01\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSex, male\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e99 (61.8%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e25 (43.8%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.02\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eRace, Caucasian\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e143 (89.3%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e49 (85.9%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.63\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBody mass index, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e31.2 (26.4\u0026ndash;36.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e30.5 (24.9\u0026ndash;35.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.29\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eComorbidities\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eDiabetes mellitus\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e49 (30.6%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e20 (35.0%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.53\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eChronic renal failure\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e20 (12.5%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e7.0 (12.8%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.97\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCongestive heart failure\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e7.0 (4.3%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e14 (24.5%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.01\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eActive neoplasm\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e8.0 (5.0%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e10 (1.7%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.29\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eImmune suppression\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e48 (30.0%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e13 (22.8%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.30\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePulmonary fibrosis\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e6.0 (3.7%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2.0 (3.5%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.93\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eSeverity of illness\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePulmonary injury\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e222 (59%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e111 (56%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.32\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCOVID-19 infection\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e58 (36.2%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e13 (22.8%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.06\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eModified SOFA score\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e8 (\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e7 (\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.08\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eLaboratory results\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eWhite blood cell count, 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e12.1 (8.7\u0026ndash;17.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e11.2 (9.0-15.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.30\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHemoglobin g/dL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e10.3 (8.7\u0026ndash;12.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9.9 (8.7\u0026ndash;11.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.22\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePlatelets, 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e187 (119\u0026ndash;259)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e213 (134\u0026ndash;272)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.63\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCreatinine, mg/dL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.1 (0.8\u0026ndash;2.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.5 (0.8\u0026ndash;2.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.34\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBicarbonate, mEq/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e25 (22\u0026ndash;29)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e24 (20\u0026ndash;28)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.26\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBlood urea nitrogen mg/dL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e31 (21\u0026ndash;43)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e35 (17\u0026ndash;49)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.83\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBlood glucose mg/dL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e143 (114\u0026ndash;183)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e143 (122\u0026ndash;171)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.95\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as median (interquartile range) or n (%) as appropriate. Participants in the \u0026ldquo;COPD\u0026rdquo; group have a preexisting diagnosis of chronic obstructive pulmonary disease (COPD), presence of anatomic emphysema on computational tomography (CT) imaging of the chest, or both. Participants in the \u0026ldquo;No COPD\u0026rdquo; group have neither a chart diagnosis of COPD and have an absence of anatomic emphysema on CT imaging. Pulmonary insult indicates presence of at least one direct risk factor for acute respiratory distress syndrome determined by consensus and includes pneumonia, aspiration, and inhalational injury. SOFA score is modified to exclude the neurologic component as Glasgow Coma Scale were not routinely collected on patients in our study. p-values represent differences between groups compared by Mann-Whitney U test or by chi-squared analysis as appropriate. \u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eAbbreviations\u003c/span\u003e: COPD- chronic obstructive pulmonary disease; COVID-19- Coronavirus Disease-19; SOFA- Sequential Organ Failure Assessment.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003cbr/\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003ePlasma host response biomarkers measured on study enrollment compared between ARDS patients with and without COPD or emphysema.\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eVariable\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eNo COPD or emphysema\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eCOPD or emphysema\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003ep-value\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAngiopoetin-2 (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e6883 [3761\u0026ndash;13735]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e8935 [4153\u0026ndash;19008]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.22\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eInterleukin-8 (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e24 [14\u0026ndash;40]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e27 [14\u0026ndash;54]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.40\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eInterleukin-6 (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e118 [30\u0026ndash;413]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e111 [37\u0026ndash;198]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.43\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eInterleukin-10 (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.7 [1.0-8.6]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3.4 [1.3\u0026ndash;11.8]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.17\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eProcalcitonin (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e670 [305\u0026ndash;2885]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e853 (193\u0026ndash;4510)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.42\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSuppressor of tumorigenicity-2 (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e161171 [809997\u0026thinsp;\u0026minus;\u0026thinsp;350891]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e189618 [90955\u0026ndash;422669]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.77\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eFractalkine (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e2302 [1198\u0026ndash;4024]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2133 [1179\u0026ndash;3815]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.48\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePentraxin-3 (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e7833 [3669\u0026ndash;20785]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e8076 [3604\u0026ndash;15562]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.74\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSoluble receptor for advanced glycation endproducts (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e5212 [2760\u0026ndash;9811]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e5275 [2260\u0026ndash;7866]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.66\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBeta-D-glucan (pg/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e24 [14\u0026ndash;35]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e28 [15\u0026ndash;41]\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.35\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as median [interquartile range]. Biomarker data at baseline was available for a subset of participants (n\u0026thinsp;=\u0026thinsp;207 total; no COPD: n\u0026thinsp;=\u0026thinsp;154; COPD: n\u0026thinsp;=\u0026thinsp;53). p-values represent differences between groups compared by Mann-Whitney U test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003cbr/\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"acute respiratory distress syndrome, chronic obstructive pulmonary syndrome, systemic host immune response, emphysema","lastPublishedDoi":"10.21203/rs.3.rs-4803327/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4803327/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eIntroduction:\u003c/u\u003e \u0026nbsp;Acute respiratory distress syndrome (ARDS) is a critical care disorder characterized by diffuse lung injury. The impact of pre-existing chronic obstructive pulmonary disease (COPD) or emphysema on ARDS pathogenesis is not well characterized.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMethods:\u003c/u\u003e Secondary analysis of ARDS patients enrolled in the Acute Lung Injury Registry and Biospecimen Repository at the University of Pittsburgh between June 2012 and September 2021. Patients were categorized into two mutually exclusive groups by the prevalence of COPD or emphysema at the time of ARDS diagnosis. The COPD/emphysema group comprised ARDS patients with radiological evidence of emphysema, chart diagnosis of COPD, or both. Demographics, lung mechanics, and clinical outcomes were obtained from the electronic medical record. Host-response biomarkers known to have validated associations with ARDS were previously measured in plasma and lower respiratory tract samples using a customized Luminex assay. Continuous and categorical variables were compared between groups with and without COPD/emphysema.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eResults:\u003c/u\u003e 217 patients with ARDS were included in the study, 57 (27%) had COPD/emphysema. Patients with COPD/emphysema were older (median 62 [interquartile range 55-69] versus 53 [41-64] years, p\u0026lt;0.01), more likely to be male (62% vs 44%, p=0.02) and had a higher prevalence of congestive heart failure (25% vs 4%, p\u0026lt;0.01) compared to patients without COPD/emphysema. Baseline demographics, laboratory parameters, and mechanical ventilatory characteristics were otherwise similar between the two groups. No difference in 90-day mortality was observed between groups; however, patients with COPD/emphysema had shorter duration of intensive care unit (ICU) stay (median 10 [7-18] versus 16 [9-28] days, p=0.04) and shorter duration of mechanical ventilation (median 7 [4-16] vs 12 [6-20] days, p=0.01). Host response biomarkers in serum and lower respiratory tract samples did not significantly differ between groups.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConclusion:\u003c/u\u003e ARDS patients with COPD or emphysema had similar respiratory mechanics, host response biomarker profiles, and mortality compared to those without COPD or emphysema but with a shorter median duration of mechanical ventilation and ICU length of stay. Future studies should address differences in clinical and biological responses by disease severity, and should investigate the impact of severity of COPD and emphysema on mechanical ventilation and targeted therapeutic strategies in ARDS.\u003c/p\u003e","manuscriptTitle":"Clinical and Biologic Profiles of Patients with Acute Respiratory Distress Syndrome by Prevalence of Chronic Obstructive Pulmonary Disease or Emphysema; A Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-28 02:40:09","doi":"10.21203/rs.3.rs-4803327/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-24T19:36:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-12T23:29:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-02T04:54:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17888938977553386849983548446931900576","date":"2024-08-01T14:00:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97971981640109671400017252470260465028","date":"2024-08-01T08:02:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44366669120337587794019502919745368327","date":"2024-07-29T13:33:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"149549671935092511312231757438777922799","date":"2024-07-27T17:16:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267214638181619996457788372599292109578","date":"2024-07-27T11:37:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208458559254302151411253942507817590527","date":"2024-07-26T20:36:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-26T15:59:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-26T15:46:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-26T05:37:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Respiratory Research","date":"2024-07-25T16:31:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"respiratory-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"rere","sideBox":"Learn more about [Respiratory Research](http://respiratory-research.biomedcentral.com/)","snPcode":"12931","submissionUrl":"https://submission.nature.com/new-submission/12931/3","title":"Respiratory Research","twitterHandle":"@RespiratoryBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"773c9fd6-3842-4429-b48b-0242c96a65b7","owner":[],"postedDate":"August 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-11T15:58:42+00:00","versionOfRecord":{"articleIdentity":"rs-4803327","link":"https://doi.org/10.1186/s12931-024-03027-2","journal":{"identity":"respiratory-research","isVorOnly":false,"title":"Respiratory Research"},"publishedOn":"2024-11-08 15:56:52","publishedOnDateReadable":"November 8th, 2024"},"versionCreatedAt":"2024-08-28 02:40:09","video":"","vorDoi":"10.1186/s12931-024-03027-2","vorDoiUrl":"https://doi.org/10.1186/s12931-024-03027-2","workflowStages":[]},"version":"v1","identity":"rs-4803327","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4803327","identity":"rs-4803327","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}