key: cord-0819846-xan96t7l
authors: Lim, Zheng Jie; Subramaniam, Ashwin; Ponnapa Reddy, Mallikarjuna; Blecher, Gabriel; Kadam, Umesh; Afroz, Afsana; Billah, Baki; Ashwin, Sushma; Kubicki, Mark; Bilotta, Federico; Curtis, J. Randall; Rubulotta, Francesca
title: Case Fatality Rates for Patients with COVID-19 Requiring Invasive Mechanical Ventilation. A Meta-analysis
date: 2021-01-01
journal: Am J Respir Crit Care Med
DOI: 10.1164/rccm.202006-2405oc
sha: d20fea94cc40b5e645ae1fb8a2c81b4117302a9c
doc_id: 819846
cord_uid: xan96t7l

Rationale: Initial reports of case fatality rates (CFRs) among adults with coronavirus disease (COVID-19) receiving invasive mechanical ventilation (IMV) are highly variable. Objectives: To examine the CFR of patients with COVID-19 receiving IMV. Methods: Two authors independently searched PubMed, Embase, medRxiv, bioRxiv, the COVID-19 living systematic review, and national registry databases. The primary outcome was the “reported CFR” for patients with confirmed COVID-19 requiring IMV. “Definitive hospital CFR” for patients with outcomes at hospital discharge was also investigated. Finally, CFR was analyzed by patient age, geographic region, and study quality on the basis of the Newcastle-Ottawa Scale. Measurements and Results: Sixty-nine studies were included, describing 57,420 adult patients with COVID-19 who received IMV. Overall reported CFR was estimated as 45% (95% confidence interval [CI], 39–52%). Fifty-four of 69 studies stated whether hospital outcomes were available but provided a definitive hospital outcome on only 13,120 (22.8%) of the total IMV patient population. Among studies in which age-stratified CFR was available, pooled CFR estimates ranged from 47.9% (95% CI, 46.4–49.4%) in younger patients (age ≤40 yr) to 84.4% (95% CI, 83.3–85.4%) in older patients (age >80 yr). CFR was also higher in early COVID-19 epicenters. Overall heterogeneity is high (I(2) >90%), with nonsignificant Egger’s regression test suggesting no publication bias. Conclusions: Almost half of patients with COVID-19 receiving IMV died based on the reported CFR, but variable CFR reporting methods resulted in a wide range of CFRs between studies. The reported CFR was higher in older patients and in early pandemic epicenters, which may be influenced by limited ICU resources. Reporting of definitive outcomes on all patients would facilitate comparisons between studies. Systematic review registered with PROSPERO (CRD42020186997).

The novel coronavirus disease (COVID- 19) pandemic, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has severely burdened healthcare system capacities in many parts of the world (1) . The World Health Organization reports the global crude mortality rate to be 3.9% (2) .

The care of critically ill patients with COVID-19 has been rapidly evolving (3) . Although there have been promising therapies such as remdesivir (4) and dexamethasone (5) , mechanical ventilation continues to be the mainstay of management of severe COVID-19 (6) . Hypoxemia (Pa O 2 ,60 mm Hg) has been commonly reported in hospitalized patients with COVID-19 (7) . Early invasive mechanical ventilation (IMV) was promoted early in the pandemic because of concerns of aerosol generation from noninvasive oxygenation therapies facilitating nosocomial viral transmission (8) (9) (10) .

The case fatality rate (CFR) is defined as the proportion of a population with a disease that dies during a specific period (11) . The reported CFRs of critically ill patients with COVID-19 receiving IMV have been observed to be highly variable (12) . Causes of this inconsistency likely include the heterogeneity in the management of these patients and in the presentation of outcome data (12, 13) . Addressing this knowledge gap will assist in intensive care resource planning and public health strategies.

The aim of this systematic review and meta-analysis was to report the CFR of critically ill adult patients with COVID-19 who received IMV based on the available evidence. The variability in CFR by patient age, geographic region, and study quality was also analyzed in this study.

This systematic review and meta-analysis was reported using the preferred reporting items for systematic reviews and meta-analyses framework (14) and has been registered on PROSPERO (CRD42020186997). The majority of patients receiving IMV are admitted to the ICU; however, not all ICU patients receive IMV. We therefore included studies explicitly reporting on patients receiving IMV to limit heterogeneity in illness severity. The review process is illustrated in a flow diagram ( Figure 1 ).

Only studies reporting on consecutive adult patients (>18 yr of age) with laboratoryconfirmed COVID-19 receiving IMV were included. Studies were excluded if 1) the sample size of the cohort was less than 10, 2) they did not report the results of original research, or 3) the cohort consisted only of deceased patients. Studies were also excluded if a significant overlap in patient cohorts was identified.

Two authors (Z.J.L. and A.S.) independently searched on the publicly available COVID-19 living systematic review. This dynamic systematic review contains a daily updated list of preprint and published articles relating to COVID-19 obtained from PubMed, EMBASE, medRxiv, and bioRxiv (15) . The workflow for obtaining these articles is freely available and has been used previously during the Zika virus epidemic (16) . This living platform has been recently validated against an Ovid search relating to COVID-19 (17) . Two authors (Z.J.L. and M.P.R.) independently extracted the content of this living systematic review and national registry databases between January 1, 2020, and July 8, 2020. Conflicts in data extraction were resolved by discussion between the reviewers or adjudication by a third author (A.S.). Corresponding authors for all the selected papers were contacted by e-mail for outcome data for patients who were still in the hospital at the time the manuscript was published. The search terms "mortality," "fatality," "ICU," "characteristic," "invasive," "mechanical," "ventilation," "death," and "died" were used within the title and abstract columns of the systematic review list. The searching criteria were combined with the Boolean operator "OR." All studies, including preprint and non-English language articles, were considered. A separate search for COVID-19 national registries was also conducted. Study period and location were analyzed as part of the data collection process.

Reported CFR. "Reported CFR" was defined as the CFR among all patients who received IMV, before accounting for patients who were still receiving care in hospital.

Author Contributions: Z.J.L. conceived the project idea, conducted the systematic review and statistical analysis, assisted with data analysis, wrote the initial drafts of the manuscript, created tables and figures, and finalized the manuscript. A.S. conceived the project idea, conducted the systematic review, assisted with data analysis, wrote the initial drafts of the manuscript, and finalized the manuscript. M.P.R. conducted the systematic review, assisted with data analysis, wrote the initial drafts of the manuscript, and finalized the manuscript. G.B. analyzed the data, wrote the initial drafts of the manuscript, and finalized the manuscript. U.K. conducted the systematic review, assisted with data analysis, wrote the initial drafts of the manuscript, and finalized the manuscript. A.A. conducted the statistical analysis and created the tables and figures. B.B. conducted the statistical analysis and wrote the statistical section in the METHODS. S.A. assisted with data collection and analysis and finalized the manuscript. M.K. analyzed the data, wrote the initial drafts of the manuscript, and finalized the manuscript. F.B. analyzed the data and finalized the manuscript. J.R.C. provided oversight for analysis of the data and edited the manuscript. F.R. analyzed the data and edited the manuscript. All authors critically reviewed the manuscript and approved the final version before submission. Of 57,420 adult patients in 69 studies who met the inclusion criteria for this systematic review and meta-analysis of patients with severe COVID-19, the overall estimate for the reported CFR was 45% (95% confidence interval, 38-52%). Definitive hospital outcomes were only available for 13,120 (36.6%) patients. Significant variability in CFR was also present by age of patients and geographic location of the study.

Range of estimates for CFR. We also provided a sensitivity analysis of the best possible and worse possible CFRs, assuming all remaining hospitalized patients either lived (lowest possible) or died (highest possible) in the subset of studies that reported the number of patients who received IMV who were still hospitalized at the time of study conclusion.

Definitive CFR. We examined the number of patients receiving IMV who died divided by the number of patients with a known hospital outcome (died or discharged alive) to calculate the definitive CFR.

The Newcastle-Ottawa Scale (NOS) is a quality assessment tool used to evaluate nonrandomized studies on the basis of an eight-item score divided into three domains. The NOS has been selected for the purpose of this study because these domains assess selection, comparability, and ascertainment of the outcome of interest. The NOS is the most suitable for the purpose of comparing both reported and definitive CFR values. The NOS was used by the two reviewers (Z.J.L. and U.K.) to independently evaluate the quality of included studies and assess for risk of bias (18) . The same set of decision rules was used by each reviewer to score the studies. Any discrepancies from the NOS were reviewed and resolved by two additional authors (A.S. and M.P.R.).

The primary outcome was the reported CFR for patients with COVID-19 receiving IMV based on the published studies. However, multiple methods of reporting CFR existed across different studies. Studies have reported the CFR of patients receiving IMV out of all patients receiving IMV, including those still hospitalized, whereas other studies have reported the CFR among patients who have completed their hospital course. This variance in reporting methods therefore resulted in variance in the CFRs reported by authors. As a secondary outcome, we examined the "definitive hospital CFR" for the subgroup of studies for whom we were able to ascertain hospital discharge outcomes. For all studies, we also present a sensitivity analysis that includes all patients showing "lowest possible" CFR for each study (assuming all patients still hospitalized lived) and a "highest possible" CFR (assuming all patients still hospitalized died). Within the appendix, the definitive hospital CFR is calculated by excluding patients who were still hospitalized to report the CFR only among patients with a known hospital outcome. Studies were also stratified based on geographical location (continent), economy (based on United Nations classification 2020), mean age, and study quality.

Statistical analyzes were performed using the statistical software package Stata, version 16.1 (StataCorp). Mean and SD were used for numerical data and proportion was used for categorical data. The random-effects model and the Hartung-Knapp-Sidik-Jonkman method for meta-analysis (19) were used for the pooled prevalence of CFR because these demonstrate better properties in the presence of heterogeneity, accounting for both within-study and between-study variances (20) . Results were presented in forest plots. Heterogeneity was tested by using the x 2 test on Cochran's Q statistic, which was calculated by means of H and I 2 indices. The I 2 index estimates the percentage of total variation across studies on the basis of true between-study differences rather than on chance. Conventionally, I 2 values of 0-25% indicate low heterogeneity, values of 26-75% indicate moderate heterogeneity, and values of 76-100% indicate substantial heterogeneity. Authors conducted subgroup analyzes to identify the possible causes of substantial heterogeneity (21) . Univariable metaregression was used, symmetry of the funnel plots was evaluated, and the Egger's regression test was used to examine for publication bias (22) . Confidence interval (CI) was used to evaluate whether differences in CFRs were statistically significant. The 95% CI of prevalence including 0.0% and 100% were calculated using the standard equation (23) . As prevalence cannot fall below 0% or above 100%, the CI is trimmed at 0% and 100% (20) .

We also examined the reported CFR based on age stratification for the subset of studies that reported outcomes by patient age. In addition, we compared the CFRs in studies from different geographic regions and examined difference between reports from cities with an early and dramatic pandemic outbreak, such as Hubei, China, and New York, United States, compared with studies from other cities in the same country.

A total of 5,322 studies were obtained from the living systematic review with 662 unique studies assessed for eligibility via full-text screening ( Figure 1 ). Sixty-nine studies across 23 countries with reported CFRs were included in the final analysis (13, , including publicly available national registry data from seven countries (29, 56, 59, 65, 66, 80, 90) . A summary of the reported CFRs for adult patients receiving IMV is outlined in Table 1 Figure 2 . Individual study NOS score is illustrated in Table E1 in the online supplement. There was no significant difference in CFR when studies were analyzed based on NOS score ( Figure  E1 ). 

A simple regression (univariate) analysis and multivariate regression analysis were conducted across the 46 studies with definitive hospital outcome (Table E3 ). Studies were analyzed by common variables, including geographical location (continent), study quality (NOS score), mean age, and economic status. Poor-quality studies reported significantly lower CFRs compared with good-quality studies (P = 0.035). Multivariate regression did not yield any further statistical significance in study quality. A univariate analysis of studies from earlier epicenters (Wuhan and New York) showed significantly higher CFRs within these epicenters compared with nonepicenter studies in the same country (P = 0.010 for Wuhan vs. other studies in China and P = 0.002 for New York vs. other studies in the United States).

This is a large international systematic review and meta-analysis to examine global reports of CFRs for adult patients with COVID-19 receiving IMV. The reported CFR was 45% across all 69 studies, but this included patients still in the hospital. Among all 54 studies, lowest possible to best possible hospital CFR ranged from 43% to 

67%. Among patients with a known hospital outcome, the definitive hospital CFR was 56%. We observed no statistical difference between continents. Older patients had a higher CFR, and the CFR was higher in the early COVID-19 epicenters of Wuhan and New York compared with that of other studies from the same country. The CFR observed in this review of patients with COVID-19 is similar to that of previous outbreaks of severe respiratory infections. Studies from SARS-CoV in 2003 reported a CFR of 45-48% in patients receiving IMV (93, 94) , and more recent studies from the Middle East respiratory syndrome reported a 60-74% CFR in critically ill patients (95, 96) . In contrast, the CFR is lower in critically ill patients suffering from H1N1 influenza A, in which the CFR of patients receiving IMV was 24.2-26.5% (97) . The reported CFR from severe acute respiratory distress syndrome before COVID-19 was lower at 45% (98, 99) when compared with the definitive CFR from COVID-19.

The CFR of patients receiving IMV among studies from Wuhan and New York was significantly higher than that of studies from other regions in China and the United States, respectively. This finding may reflect of the significant challenges faced in the initial stages of the COVID-19 outbreak (100, 101) . Reports suggest that prone positioning was infrequent in the initial phase (41) , with one Wuhan study reporting only 12% of patients receiving IMV were managed with prone positioning. Variable provider:patient ratios may also have contributed to higher CFR (102) (103) (104) .

Several factors may account for the large variance in CFRs between studies. ICUs outside of outbreak epicenters may have had the opportunity of time to obtain equipment and consolidate resources before the pandemic (71) . This has enabled ICUs to continue at standard patient:provider ratios (71) . Closer monitoring and early intensive care for critically ill patients potentially improved patient prognosis (31) . Differences in hospital facilities, patient preferences (for which limitations of care may have been in place), and indications for IMV may have also influenced the CFR (12) . Finally, the change in triage process considering comorbidities, age, and frailty status in allocating ICU beds and ventilators during the pandemic Despite stratifying studies on the basis of location and NOS score, high heterogeneity continued to exist across our meta-analysis. This has been reported in other meta-analyzes studying COVID-19 mortality (109-113). Heterogeneity was the lowest at 83.4% among definitive outcomes from Wuhan ( Figure E6 ). Although the reasons for this are not clear, we believe that studies originating from the same geographical location may provide a less heterogeneous cohort, and hence, the I 2 value was lower. Other potential factors influencing heterogeneity could be differences in illness severity, thresholds for IMV, admission criteria to the ICU, and regional differences in ICU care.

As demonstrated in a recent editorial, the CFR is substantially higher among older patients, with more than 70% of patients over 60 years of age receiving IMV dying (12) . It has also been reported that the CFR for patients in their 80s and 90s receiving IMV with comorbidities has been higher (114) . Our findings also suggest that older patients receiving IMV had significantly higher mortality.

There are several limitations to this systematic review. First, most of the included studies had very small numbers of patients; only 17 of 69 studies reported on more than 100 patients receiving IMV. Given the available evidence, we conducted a metaanalysis to account for this variability in sample size. Second, multiple studies may have covered similar patient cohorts. However, each study's time period, hospital, and location were considered in the final inclusion of studies to minimize overlap in patient cohorts. Third, 14 studies were not peer reviewed, as they were prepublication articles. However, these studies still provided meaningful data on the CFR of the subgroup of patients with COVID-19 who receive IMV. Fourth, the overall heterogeneity was very high (I 2 .90%), which may preclude a valid conclusion from pooled results. Although we performed various sensitivity and metaregression analyses, the heterogeneity could not be minimized. This is most likely due to the case mix and the structure of age within included populations. Finally, we were unable to examine the influence of timing in the pandemic because timing and region were highly correlated.

The reported CFR for existing studies of adult patients with COVID-19 receiving IMV was 45%, but many of these reports included patients still in the hospital at the time of publication. Accounting for patients still in the hospital, we found a best possible CFR of 43% and a worst possible CFR of 64%. The CFR increased exponentially in the elderly. Although CFRs did not vary between continents, higher CFRs were noted in early COVID-19 epicenters such as Wuhan and New York compared with other regions in the same country. Additional studies examining long-term CFRs beyond hospital discharge are needed. n Author disclosures are available with the text of this article at www.atsjournals.org.

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The authors thank the