Cardiovascular drugs and COVID-19 clinical outcomes: a living systematic review and meta-analysis

ABSTRACTOBJECTIVETo continually evaluate the rapidly evolving evidence base on the role of cardiovascular drugs in COVID-19 clinical outcomes (susceptibility to infection, hospitalization, hospitalization length, disease severity, and all-cause mortality).DESIGNLiving systematic review and meta-analysis.DATA SOURCESEligible publications identified from >500 databases indexed through 31st July 2020 and additional studies from reference lists, with planned continual surveillance for at least two years.STUDY SELECTIONObservational and interventional studies that report on the association between cardiovascular drugs and COVID-19 clinical outcomes.DATA EXTRACTIONSingle-reviewer extraction and quality evaluation (using ROBINS-I), with half the records independently extracted and evaluated by a second reviewer.RESULTSOf 23,427 titles screened, 175 studies were included in the quantitative synthesis. The most reported drug classes were angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) with ACEI/ARB exposure being associated with higher odds of testing positive for COVID-19 (pooled unadjusted OR 1.15, 95% CI 1.02 to 1.30). Among patients with COVID-19, unadjusted estimates showed that ACEI/ARB exposure was associated with being hospitalized (OR 2.25, 1.70 to 2.98) and having severe disease (OR 1.50, 1.27 to 1.77) but not with the length of hospitalization (mean difference −0.45, −1.33 to 0.43 days) or all-cause mortality (OR 1.25, CI 0.98 to 1.58). However, after adjustment, ACEI/ARB exposure was not associated with testing positive for COVID-19 (pooled adjusted OR 1.01, 0.93 to 1.10), being hospitalized (OR 1.16, 0.80 to 1.68), having severe disease (1.04, 0.76 to 1.42), or all-cause mortality (0.86, 0.64 to 1.15). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with being hospitalized (OR 0.84, 0.58 to 1.22), disease severity (OR 0.88, 0.68 to 1.14) or all-cause mortality (OR 0.77, 0.54 to 1.12) while it decreased the length of hospitalization (mean difference −0.71, −1.11 to −0.30 days). After adjusting for relevant covariates, other cardiovascular drug classes were mostly not found to be associated with poor COVID-19 clinical outcomes. However, the validity of these findings is limited by a high level of heterogeneity in terms of effect sizes and a serious risk of bias, mainly due to confounding in the included studies.CONCLUSIONOur comprehensive review shows that ACEI/ARB exposure is associated with COVID-19 outcomes such as susceptibility to infection, severity, and hospitalization in unadjusted analyses. However, after adjusting for potential confounding factors, this association is not evident. Patients on cardiovascular drugs should continue taking their medications as currently recommended. Higher quality evidence in the form of randomized controlled trials will be needed to determine any adverse or beneficial effects of cardiovascular drugs.PRIMARY FUNDING SOURCENoneSYSTEMATIC REVIEW REGISTRATIONPROSPERO (CRD42020191283)

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Cardiovascular drugs and COVID-19 clinical outcomes: a living systematic review and meta-analysis

10.22541/au.161452914.41833841/v1 ◽

2021 ◽

Author(s):

Innocent Asiimwe ◽

Sudeep Pushpakon ◽

Richard Turner ◽

Ruwanthi Kolamunnage-Dona ◽

Andrea Jorgensen ◽

...

Keyword(s):

Clinical Outcomes ◽

Disease Severity ◽

Enzyme Inhibitors ◽

Angiotensin Receptor Blockers ◽

Meta Analysis ◽

Angiotensin Converting Enzyme Inhibitors ◽

Cardiovascular Drugs ◽

Mean Difference ◽

Converting Enzyme Inhibitors ◽

All Cause Mortality

Aims: To continually evaluate the role of cardiovascular drugs in COVID-19 clinical outcomes. Methods: Eligible publications were identified from >500 databases on 1-Nov-2020. One reviewer extracted data with 20% of the records independently extracted/evaluated by a second reviewer. Results: Of 52,735 screened records, 429 and 390 studies were included in the qualitative and quantitative syntheses, respectively. The most-reported drugs were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) with ACEI/ARB exposure having borderline association with positive COVID-19 status (OR 1.14, 95% CI 1.00–1.31). Among COVID-19 patients, unadjusted estimates showed that ACEI/ARB exposure was associated with hospitalization (OR 1.76, 1.34–2.32), disease severity (OR 1.41, 1.27–1.56) and all-cause mortality (OR 1.22, 1.12–1.33) but not hospitalization length (mean difference -0.27, -1.36; 0.82 days). After adjustment, ACEI/ARB exposure was not associated with positive COVID-19 status (OR 0.92, 0.71–1.19), hospitalization (OR 0.93, 0.70–1.24), disease severity (OR 1.05, 0.81–1.38), or all-cause mortality (OR 0.85, 0.71–1.01). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with positive COVID-19 status (OR 0.93, 0.79–1.09), hospitalization (OR 0.84, 0.58–1.22), hospitalization length (mean difference -0.14, -1.65; 1.36 days), disease severity (OR 0.92, 0.76–1.11) while it decreased the odds of dying (OR 0.76, 0.65–0.88). A similar trend was observed for other cardiovascular drugs. However, the validity of these findings is limited by a high level of heterogeneity and serious risk of bias. Conclusion: Cardiovascular drugs are not associated with poor COVID-19 outcomes in adjusted analyses. Patients should continue taking these drugs as prescribed.

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Association Between SARS-CoV-2 Cycle Threshold Values and Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab453 ◽

2021 ◽

Vol 8 (9) ◽

Author(s):

Vishal P Shah ◽

Wigdan H Farah ◽

James C Hill ◽

Leslie C Hassett ◽

Matthew J Binnicker ◽

...

Keyword(s):

Systematic Review ◽

Clinical Outcomes ◽

Disease Severity ◽

Meta Analysis ◽

Severe Disease ◽

Sample Type ◽

Sample Collection ◽

Cycle Threshold ◽

Significant Difference ◽

Polymerase Chain

Abstract Cycle threshold (CT) values are correlated with the amount of viral nucleic acid in a sample and may be obtained from some qualitative real-time polymerase chain reaction tests used for diagnosis of most patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, CT values cannot be directly compared across assays, and they must be interpreted with caution as they are influenced by sample type, timing of sample collection, and assay design. Presently, the correlation between CT values and clinical outcomes is not well understood. We conducted a systematic review and meta-analysis of published studies through April 19, 2021, that reported an association between CT values and hospitalization, disease severity, and mortality in patients ≥18 years old with SARS-CoV-2. A meta-analysis of 7 studies showed no significant difference in mean CT values between hospitalized and nonhospitalized patients. Among hospitalized patients, those with CT values <25 had a high risk of more severe disease and mortality than patients with CT values >30 (odds ratio [OR], 2.31; 95% CI, 1.70 to 3.13; and OR, 2.95; 95% CI, 2.19 to 3.96; respectively). The odds of increased disease severity and mortality were less pronounced in patients with CT values of 25–30 compared with >30.

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Effect of timing of intubation on clinical outcomes of critically ill patients with COVID-19: a systematic review and meta-analysis of non-randomized cohort studies

Critical Care ◽

10.1186/s13054-021-03540-6 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Eleni Papoutsi ◽

Vassilis G. Giannakoulis ◽

Eleni Xourgia ◽

Christina Routsi ◽

Anastasia Kotanidou ◽

...

Keyword(s):

Systematic Review ◽

Mechanical Ventilation ◽

Clinical Outcomes ◽

Critically Ill ◽

Critically Ill Patients ◽

Meta Analysis ◽

Mortality And Morbidity ◽

Icu Admission ◽

All Cause Mortality ◽

Detectable Difference

Abstract Background Although several international guidelines recommend early over late intubation of patients with severe coronavirus disease 2019 (COVID-19), this issue is still controversial. We aimed to investigate the effect (if any) of timing of intubation on clinical outcomes of critically ill patients with COVID-19 by carrying out a systematic review and meta-analysis. Methods PubMed and Scopus were systematically searched, while references and preprint servers were explored, for relevant articles up to December 26, 2020, to identify studies which reported on mortality and/or morbidity of patients with COVID-19 undergoing early versus late intubation. “Early” was defined as intubation within 24 h from intensive care unit (ICU) admission, while “late” as intubation at any time after 24 h of ICU admission. All-cause mortality and duration of mechanical ventilation (MV) were the primary outcomes of the meta-analysis. Pooled risk ratio (RR), pooled mean difference (MD) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO (CRD42020222147). Results A total of 12 studies, involving 8944 critically ill patients with COVID-19, were included. There was no statistically detectable difference on all-cause mortality between patients undergoing early versus late intubation (3981 deaths; 45.4% versus 39.1%; RR 1.07, 95% CI 0.99–1.15, p = 0.08). This was also the case for duration of MV (1892 patients; MD − 0.58 days, 95% CI − 3.06 to 1.89 days, p = 0.65). In a sensitivity analysis using an alternate definition of early/late intubation, intubation without versus with a prior trial of high-flow nasal cannula or noninvasive mechanical ventilation was still not associated with a statistically detectable difference on all-cause mortality (1128 deaths; 48.9% versus 42.5%; RR 1.11, 95% CI 0.99–1.25, p = 0.08). Conclusions The synthesized evidence suggests that timing of intubation may have no effect on mortality and morbidity of critically ill patients with COVID-19. These results might justify a wait-and-see approach, which may lead to fewer intubations. Relevant guidelines may therefore need to be updated.

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Serum albumin concentrations are associated with disease severity and outcomes in coronavirus 19 disease (COVID-19): a systematic review and meta-analysis

Clinical and Experimental Medicine ◽

10.1007/s10238-021-00686-z ◽

2021 ◽

Author(s):

Panagiotis Paliogiannis ◽

Arduino Aleksander Mangoni ◽

Michela Cangemi ◽

Alessandro Giuseppe Fois ◽

Ciriaco Carru ◽

...

Keyword(s):

Systematic Review ◽

Serum Albumin ◽

Disease Severity ◽

Meta Analysis ◽

Severe Disease ◽

Geographic Area ◽

Adverse Outcomes ◽

Poor Outcome ◽

Standard Mean Difference ◽

Meta Regression Analysis

AbstractCoronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the most threatening pandemic in modern history. The aim of this systematic review and meta-analysis was to investigate the associations between serum albumin concentrations and COVID-19 disease severity and adverse outcomes. A systematic literature search was conducted in PubMed, from inception to October 30, 2020. Sixty-seven studies in 19,760 COVID-19 patients (6141 with severe disease or poor outcome) were selected for analysis. Pooled results showed that serum albumin concentrations were significantly lower in patients with severe disease or poor outcome (standard mean difference, SMD: − 0.99 g/L; 95% CI, − 1.11 to − 0.88, p < 0.001). In multivariate meta-regression analysis, age (t = − 2.13, p = 0.043), publication geographic area (t = 2.16, p = 0.040), white blood cell count (t = − 2.77, p = 0.008) and C-reactive protein (t = − 2.43, p = 0.019) were significant contributors of between-study variance. Therefore, lower serum albumin concentrations are significantly associated with disease severity and adverse outcomes in COVID-19 patients. The assessment of serum albumin concentrations might assist with early risk stratification and selection of appropriate care pathways in this group.

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Renin-angiotensin system blocker and outcomes of COVID-19: a systematic review and meta-analysis

Thorax ◽

10.1136/thoraxjnl-2020-215322 ◽

2021 ◽

pp. thoraxjnl-2020-215322

Author(s):

Hyun Woo Lee ◽

Chang-Hwan Yoon ◽

Eun Jin Jang ◽

Chang-Hoon Lee

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Severe Disease ◽

Renin Angiotensin System ◽

Angiotensin Ii Receptor ◽

Angiotensin System ◽

Risk Of Mortality ◽

Increased Risk ◽

All Cause Mortality ◽

Receptor Blockers

BackgroundThe association of ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) with disease severity of patients with COVID-19 is still unclear. We conducted a systematic review and meta-analysis to investigate if ACEI/ARB use is associated with the risk of mortality and severe disease in patients with COVID-19.MethodsWe searched all available clinical studies that included patients with confirmed COVID-19 who could be classified into an ACEI/ARB group and a non-ACEI/ARB group up until 4 May 2020. A meta-analysis was performed, and primary outcomes were all-cause mortality and severe disease.ResultsACEI/ARB use did not increase the risk of all-cause mortality both in meta-analysis for 11 studies with 12 601 patients reporting ORs (OR=0.52 (95% CI=0.37 to 0.72), moderate certainty of evidence) and in 2 studies with 8577 patients presenting HRs. For 12 848 patients in 13 studies, ACEI/ARB use was not related to an increased risk of severe disease in COVID-19 (OR=0.68 (95% CI=0.44 to 1.07); I2=95%, low certainty of evidence).ConclusionsACEI/ARB therapy was not associated with increased risk of all-cause mortality or severe manifestations in patients with COVID-19. ACEI/ARB therapy can be continued without concern of drug-related worsening in patients with COVID-19.

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Clinical characteristics, treatment and outcomes of paediatric COVID-19: a systematic review and meta-analysis

Archives of Disease in Childhood ◽

10.1136/archdischild-2020-321385 ◽

2021 ◽

pp. archdischild-2020-321385

Author(s):

Omar Irfan ◽

Fiona Muttalib ◽

Kun Tang ◽

Li Jiang ◽

Zohra S Lassi ◽

...

Keyword(s):

Systematic Review ◽

Disease Severity ◽

World Bank ◽

Low Income ◽

Meta Analysis ◽

Severe Disease ◽

Income Level ◽

Clinical Findings ◽

Middle Income ◽

Middle Income Countries

ObjectiveCompare paediatric COVID-19 disease characteristics, management and outcomes according to World Bank country income level and disease severity.DesignSystematic review and meta-analysis.SettingBetween 1 December 2019 and 8 January 2021, 3350 articles were identified. Two reviewers conducted study screening, data abstraction and quality assessment independently and in duplicate. Observational studies describing laboratory-confirmed paediatric (0–19 years old) COVID-19 were considered for inclusion.Main outcomes and measuresThe pooled proportions of clinical findings, treatment and outcomes were compared according to World Bank country income level and reported disease severity.Results129 studies were included from 31 countries comprising 10 251 children of which 57.4% were hospitalised. Mean age was 7.0 years (SD 3.6), and 27.1% had a comorbidity. Fever (63.3%) and cough (33.7%) were common. Of 3670 cases, 44.1% had radiographic abnormalities. The majority of cases recovered (88.9%); however, 96 hospitalised children died. Compared with high-income countries, in low-income and middle-income countries, a lower proportion of cases were admitted to intensive care units (ICUs) (9.9% vs 26.0%) yet pooled proportion of deaths among hospitalised children was higher (relative risk 2.14, 95% CI 1.43 to 3.20). Children with severe disease received antimicrobials, inotropes and anti-inflammatory agents more frequently than those with non-severe disease. Subgroup analyses showed that a higher proportion of children with multisystem inflammatory syndrome (MIS-C) were admitted to ICU (47.1% vs 22.9%) and a higher proportion of hospitalised children with MIS-C died (4.8% vs 3.6%) compared with the overall sample.ConclusionPaediatric COVID-19 has a favourable prognosis. Further severe disease characterisation in children is needed globally.

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Factors Associated with Disease Severity and Mortality among Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis

10.1101/2020.08.07.20166868 ◽

2020 ◽

Author(s):

Vignesh Chidambaram ◽

Nyan Lynn Tun ◽

Waqas Haque ◽

Marie Gilbert Majella ◽

Ranjith Kumar Sivakumar ◽

...

Keyword(s):

Systematic Review ◽

Disease Severity ◽

English Language ◽

Clinical Decision Making ◽

Clinical Laboratory ◽

Data Extraction ◽

Meta Analysis ◽

Severe Disease ◽

Factors Associated ◽

Risk Of Mortality

Background: Understanding the factors associated with disease severity and mortality in Coronavirus disease (COVID19) is imperative to effectively triage patients. We performed a systematic review to determine the demographic, clinical, laboratory and radiological factors associated with severity and mortality in COVID-19. Methods: We searched PubMed, Embase and WHO database for English language articles from inception until May 8, 2020. We included Observational studies with direct comparison of clinical characteristics between a) patients who died and those who survived or b) patients with severe disease and those without severe disease. Data extraction and quality assessment were performed by two authors independently. Results: Among 15680 articles from the literature search, 109 articles were included in the analysis. The risk of mortality was higher in patients with increasing age, male gender (RR 1.45; 95%CI 1.23,1.71), dyspnea (RR 2.55; 95%CI 1.88,2.46), diabetes (RR 1.59; 95%CI 1.41,1.78), hypertension (RR 1.90; 95%CI 1.69,2.15). Congestive heart failure (OR 4.76; 95%CI 1.34,16.97), hilar lymphadenopathy (OR 8.34; 95%CI 2.57,27.08), bilateral lung involvement (OR 4.86; 95%CI 3.19,7.39) and reticular pattern (OR 5.54; 95%CI 1.24,24.67) were associated with severe disease. Clinically relevant cut-offs for leukocytosis(>10.0 x109/L), lymphopenia(< 1.1 x109/L), elevated C-reactive protein(>100mg/L), LDH(>250U/L) and D-dimer(>1mg/L) had higher odds of severe disease and greater risk of mortality. Conclusion: Knowledge of the factors associated of disease severity and mortality identified in our study may assist in clinical decision-making and critical-care resource allocation for patients with COVID-19.

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Laboratory Tests and Outcome for Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis

The Journal of Applied Laboratory Medicine ◽

10.1093/jalm/jfaa098 ◽

2020 ◽

Vol 5 (5) ◽

pp. 1038-1049 ◽

Cited By ~ 1

Author(s):

Anne Alnor ◽

Maria B Sandberg ◽

Charlotte Gils ◽

Pernille J Vinholt

Keyword(s):

Systematic Review ◽

Disease Severity ◽

Laboratory Tests ◽

Evidence Synthesis ◽

Meta Analysis ◽

Severe Disease ◽

Risk Of Bias ◽

Mean Difference ◽

Routine Laboratory ◽

Standard Mean Difference

Abstract Background Severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019 (COVID-19) and poses substantial challenges for healthcare systems. With a vastly expanding number of publications on COVID-19, clinicians need evidence synthesis to produce guidance for handling patients with COVID-19. In this systematic review and meta-analysis, we examine which routine laboratory tests are associated with severe COVID-19 disease. Content PubMed (Medline), Scopus, and Web of Science were searched until March 22, 2020, for studies on COVID-19. Eligible studies were original articles reporting on laboratory tests and outcome of patients with COVID-19. Data were synthesized, and we conducted random-effects meta-analysis, and determined mean difference (MD) and standard mean difference at the biomarker level for disease severity. Risk of bias and applicability concerns were evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. Summary 45 studies were included, of which 21 publications were used for the meta-analysis. Studies were heterogeneous but had low risk of bias and applicability concern in terms of patient selection and reference standard. Severe disease was associated with higher white blood cell count (MD, 1.28 ×109/L), neutrophil count (MD, 1.49 ×109/L), C-reactive protein (MD, 49.2 mg/L), lactate dehydrogenase (MD, 196 U/L), D-dimer (standardized MD, 0.58), and aspartate aminotransferase (MD, 8.5 U/L); all p < 0.001. Furthermore, low lymphocyte count (MD −0.32 × 109/L), platelet count (MD −22.4 × 109/L), and hemoglobin (MD, −4.1 g/L); all p < 0.001 were also associated with severe disease. In conclusion, several routine laboratory tests are associated with disease severity in COVID-19.

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Abstract 118: Right Bundle Branch Block and Clinical Outcomes in Patients with Heart Failure: A Systematic Review and Meta-analysis

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.7.suppl_1.118 ◽

2014 ◽

Vol 7 (suppl_1) ◽

Author(s):

Ahmad Hazem ◽

Sunita Sharma ◽

Amit Sharma ◽

Cameron Leitch ◽

Roopalakshmi Sharadanant ◽

...

Keyword(s):

Heart Failure ◽

Systematic Review ◽

Clinical Outcomes ◽

Cardiovascular Mortality ◽

Observational Studies ◽

Meta Analysis ◽

Bundle Branch Block ◽

Increased Risk ◽

Patients With Heart Failure ◽

All Cause Mortality

Importance: Right bundle branch block (RBBB) is observed in approximately 5-14% of patients with heart failure (HF). Multiple observational studies have reported the association of RBBB with clinical outcomes in patients with HF. We performed a systematic review and meta-analysis to determine the prognostic significance of RBBB for patients with HF. Data Sources: We have systematically searched MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science and Scopus through January 2014. Study Selection: Reviewers working independently and in duplicate screened all eligible abstracts that described all cause or cardiovascular mortality in patients with RBBB and HF. We excluded studies that reported unadjusted outcome, i.e.: unadjusted event rates. Knowledge synthesis: We pooled reported risk ratio and hazard ratio. Main Outcomes: All-cause mortality and cardiovascular mortality (death). Results: We found 12 relevant observational studies enrolling over 38,000 patients. Risk of bias was assessed using the Newcastle-Ottawa Scale. Included studies had at least a moderate quality. Seven of those evaluated prognosis of patients with RBBB and heart failure. After a mean follow up period of 2.5 years (range: 1-5 years), RBBB was associated with a statistically significant increased risk of all-cause mortality compared to patients with heart failure but no BBB, RR 1.27, 95% CI (1.08-1.50), Figure 1. The other 5 studies evaluated CHF patients receiving cardiac resynchronization therapy (CRT), comparing outcomes of patients with RBBB to those with LBBB. After a mean f/u period of 3 years, patients with RBBB were once again found to have an increased risk of all-cause mortality, RR 1.45, 95% CI 1.12-1.89. Conclusion and Relevance: RBBB in patients with HF is associated with higher all-cause mortality in comparison to patients without inter-ventricular conduction defects, as well as LBBB patients in patients undergoing CRT setting.

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A Systematic Review and Meta-analysis of D-Dimer Levels in Patients Hospitalized with Coronavirus Disease 2019 (COVID-19)

10.1101/2020.06.24.20139600 ◽

2020 ◽

Author(s):

Agam Bansal ◽

Achintya D Singh ◽

Vardhmaan Jain ◽

Manik Aggarwal ◽

Samiksha Gupta ◽

...

Keyword(s):

Systematic Review ◽

Clinical Outcome ◽

Clinical Outcomes ◽

Outcome Measure ◽

Meta Analysis ◽

Icu Admission ◽

End Point ◽

Cochrane Database ◽

All Cause Mortality ◽

D Dimer

AbstractAimTo determine if the d-dimer levels are elevated in individuals with COVID 19 having worse clinical outcomes including all-cause mortality, ICU admission or ARDSMethodsWe conducted a systematic review and meta-analysis of published literature in Pubmed, Embase and Cochrane database through April 9, 2020 for studies evaluating the d-dimer levels in patients with and without a worse clinical outcome (all-cause mortality, ICU admission and ARDS). A total of 6 studies included in the meta-analysis.ResultsThe values of d-dimer were found to be significantly increased in patients with the composite clinical end point than in those without (SMD, 1.67 ug/ml (95% CI, 0.72-2.62 ug/ml). The SMD of the studies (Tang et al, Zhou et al, Chen et al), which used only mortality as an outcome measure was 2.5 ug/mL (95% CI, 0.62-4.41).ConclusionThe results of this concise meta-analysis suggest that d-dimer is significantly increased in patients having a worse clinical outcome (all-cause mortality, ICU admission or ARDS).

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