In this large US cohort of inpatients with COVID-19 followed to hospital discharge, we observed prolonged hospital stays and 17.7% hospital mortality during the first pandemic wave. Most patients developing critical illness were admitted to the ICU by hospital day 4, and mortality increased substantially when respiratory failure was complicated by shock or the need for dialysis. Increasing age had an exponential association with mortality. Male sex, comorbidity burden, hypoxemia, and abnormalities of vital signs and laboratory test results on hospital day 1 were also associated with increased odds of dying. Among survivors, 18.1% were discharged with respiratory support that was new or higher in intensity than at baseline. Nearly 1 in 4 survivors admitted from home received new at-home or facility-based health care services at discharge.
Hospital mortality in our cohort was lower than in some contemporaneous cohorts in China and the United States[1,20,21] but higher than the 10% mortality observed in a systematic review of studies performed through April 20, 2020. Heterogeneous mortality rates across studies may be due to differing follow-up duration as well as between-hospital differences in admission thresholds, patient mix, management strategies, resource strain, and hospital-level operational modifications.[5,6,23–25] We captured data through hospital discharge for all cohort patients, including the nearly 10% who remained in the hospital for more than 4 weeks, thus avoiding the potential for misestimation of hospital mortality.[20,26] The geographic heterogeneity of this cohort should also mitigate the effects of regional-level and hospital-level variation, yielding a more generalizable estimate of COVID-19 hospital mortality early in the pandemic. However, current mortality rates may differ from our estimates in the face of shifting SARS-CoV-2 infection rates and COVID-19 treatment.[27,28]
Mortality correlated with the number of organ failures, reaching 66% among intubated patients who also required vasopressors and dialysis.
Our data also highlight the high inpatient morbidity and prolonged hospitalizations experienced by patients with COVID-19. Shock and renal failure were common among nonsurvivors, corroborating reports suggesting that COVID-19–related critical illness and death often result from multiorgan dysfunction rather than isolated respiratory failure.[5,29,30] Adding to this prior work, we found that ICU admission, when required, was likely to occur early in the hospitalization. Together, these findings suggest that efforts to reduce the incidence of COVID-19 critical illness should consider the multiorgan effects of SARS-CoV-2 infection and focus on the prehospital and early hospital settings.
The number of patients who received new postdischarge health care services or respiratory support suggests that substantial impairment relative to baseline health status and function is common among survivors of a hospitalization related to COVID-19. However, characterization of the severity, patterns, and duration of symptoms and disability after outpatient SARS-CoV-2 infection and hospitalization for COVID-19 remains preliminary.[31–34] Future studies are needed to better characterize the posthospital trajectory in COVID-19 survivors as well as predictors, mechanisms, trajectory, management, and prevention of persistent impairment in this population.
We evaluated a comprehensive and generalizable array of demographic and clinical characteristics as potential risk factors for COVID-19 mortality and respiratory failure. Men made up a disproportionately large fraction of hospitalized patients with COVID-19 and experienced poorer outcomes than women, confirming the results of prior studies.[3,5,35,36] Drivers of sex-based disparities in clinical outcomes warrant further study and may include differences in angiotensin-converting enzyme 2 receptor expression, immune response, and other mechanisms.[37,38] However, as with any other multivariable analysis, the parameters chosen and their estimated effect sizes are conditional on the other variables in the model. This is particularly important when interpreting our data suggesting that, for a given level of demographic and clinical risk at a given hospital, COVID-19 outcomes in our cohort were similar across race/ethnicity categories once patients were hospitalized. This finding is consistent with prior reports and suggests that higher COVID-19 mortality among minority patients does not indicate a biological difference in risk but rather reflects underlying health disparities leading to worse baseline health status, higher illness severity on presentation, and delayed hospital presentation combined with disparities in SARS-CoV-2 infection rates,[40–43] admission thresholds, and potentially differences in care quality at hospitals treating a greater proportion of minority patients.[44,45]
Our study has important strengths and several notable limitations. Leveraging the resources and personnel of an experienced clinical trials network, we collected a rich body of carefully curated data for a cohort representative of the underlying population of all patients with COVID-19 hospitalized early in the pandemic at 57 geographically diverse US hospitals. Follow-up to hospital discharge and identification of new health support needs among survivors yielded a comprehensive portrait of the sickest patients' hospital trajectories. Our patient cohort was enrolled early in the COVID-19 pandemic, allowing us to contribute to collaborative international efforts to describe and study the epidemiology of COVID-19 and substantively inform clinical trial design for national and international efforts such as Operation Warp Speed's ACTIV-3 studies. Pharmacologic and organ support management strategies, however, have continued to evolve with emerging evidence, new therapeutic options, and clinicians' increasing experience managing this disease. For instance, treatment with repurposed drugs (hydroxychloroquine and azithromycin) shown in subsequent trials to lack efficacy was common in our cohort,[48–52] although corticosteroids—which now appear beneficial—were rarely used.[53,54] Our definition of respiratory failure included receipt of high-flow oxygen therapy as well as invasive or noninvasive positive pressure ventilation, increasing the likelihood that identified risk factors are unaffected by shifting management practices. However, additional studies are needed to validate the risk factors we identified and evaluate how new therapeutic strategies affect the observed associations.
Our study has several additional limitations. First, our data do not include deaths or readmissions occurring after study hospital discharge. Second, although collection of patients' clinical histories (including symptoms) by manual review of clinical documentation has advantages over claims-based or automated analyses, our findings may be vulnerable to recall bias, underreporting dependent on patients' illness severity, and incomplete clinician documentation in times of strain. Third, most study sites were academic referral hospitals, so complex, severely ill patients with COVID-19 may be overrepresented relative to a population-based sample. Fourth, our analysis did not directly evaluate potential effects on patient management and outcomes due to variations in patient volumes and resource strain between hospitals and across the enrollment period. Inclusion of a site-level random effect in our risk factor analyses mitigated the effect of such differences. Finally, because of the selection procedure used to identify important risk factors, reported CIs may underestimate the imprecision for the effect size estimates. The impact of this selective inference is substantially mitigated by the relatively small collection of candidate variables and the relatively strong prognostic value of the included risk factors.
Efforts to reduce COVID-19 critical illness should focus on prehospital and early inpatient treatment.
Am J Crit Care. 2022;31(2):146-157. © 2022 American Association of Critical-Care Nurses