Evolution of serious and life-threatening COVID-19 pneumonia as the SARS-CoV-2 pandemic progressed: an observational study of mortality to 60 days after admission to a 15-hospital US health system

Abstract

Objective: In order to predict at hospital admission the prognosis of patients with serious and life-threatening COVID-19 pneumonia, we sought to understand the clinical characteristics of hospitalised patients at admission as the SARS-CoV-2 pandemic progressed, document their changing response to the virus and its variants over time, and identify factors most importantly associated with mortality after hospital admission.

Design: Observational study using a prospective hospital systemwide COVID-19 database.

Setting: 15-hospital US health system.

Participants: 26 872 patients admitted with COVID-19 to our Northeast Ohio and Florida hospitals from 1 March 2020 to 1 June 2022.

Main outcome measures: 60-day mortality (highest risk period) after hospital admission analysed by random survival forests machine learning using demographics, medical history, and COVID-19 vaccination status, and viral variant, symptoms, and routine laboratory test results obtained at hospital admission.

Results: Hospital mortality fell from 11% in March 2020 to 3.7% in March 2022, a 66% decrease (p<0.0001); 60-day mortality fell from 17% in May 2020 to 4.7% in May 2022, a 72% decrease (p<0.0001). Advanced age was the strongest predictor of 60-day mortality, followed by admission laboratory test results. Risk-adjusted 60-day mortality had all patients been admitted in March 2020 was 15% (CI 3.0% to 28%), and had they all been admitted in May 2022, 12% (CI 2.2% to 23%), a 20% decrease (p<0.0001). Dissociation between observed and predicted decrease in mortality was related to temporal change in admission patient profile, particularly in laboratory test results, but not vaccination status or viral variant.

Conclusions: Hospital mortality from COVID-19 decreased substantially as the pandemic evolved but persisted after hospital discharge, eclipsing hospital mortality by 50% or more. However, after accounting for the many, even subtle, changes across the pandemic in patients' demographics, medical history and particularly admission laboratory results, a patient admitted early in the pandemic and predicted to be at high risk would remain at high risk of mortality if admitted tomorrow.

Keywords: Adult intensive & critical care; COVID-19; Public health.

Figure 1

Trends across the pandemic in number and mortality of patients hospitalised for severe and life-threatening COVID-19 pneumonia. Vertical lines demark epochs of dominant SARS-CoV-2 variants: ·Pre-1 April 2021: Alpha B.1.1.7 11 483 (43%) ·1 April 2021 to 1 July 2021: Alpha Q 1560 (5.8%) ·1 July 2021 to 1 December 2021: Delta B.1.617.2 and AY 5280 (20%) ·1 December 2021 to 1 February 2022: Omicron BA.1 6601 (25%) ·1 February 2022 to 21 March 2022: Omicron BA.1.1 785 (2.9%) ·21 March 2022 to 21 May 2022: Omicron BA.2 878 (3.3%) ·21 May 2022 to 1 June 2022: Omicron BA2.12.1 285 (1.1%). (A) Number of cases per week with each symbol a 1-week average. (B) Hospital mortality (per cent) by week with each symbol a 1-week average. Curved line is loess (locally weighted scatterplot) smoother. (C) Actuarial and simulated 60-day mortality. Black symbols represent observed 60-day unadjusted Kaplan-Meier actuarial estimated mortality for patients admitted each month, and black line is a loess smoother. The blue curve represents simulated 60-day mortality if all hospitalised patients across the pandemic were admitted on the same date from 3 January 2020 to 6 January 2022 based on the mortality model.

Figure 2

Time-related mortality after hospital admission for severe and life-threatening COVID-19 pneumonia: overall and according to SARS-CoV-2 variant and vaccination status. (A) Unadjusted mortality to 360 days after admission is depicted by Kaplan-Meier estimates (circles with vertical bars for 68% CIs equivalent to ±1 SE) superimposed on solid parametric estimates enclosed within a 68% confidence band. The number of patients remaining at risk at various intervals is shown beneath horizontal axis. Dash-dot-dash line represents mortality of an age-sex-race-matched US population. (B) Corresponding instantaneous risk of mortality, which peaks and falls to a constant level by about 60 days after hospital admission. (C) Unadjusted Kaplan-Meier estimates for each SARS-CoV-2 variant (see Key), with 68% confidence bars. (D) Unadjusted Kaplan-Meier estimates according to COVID-19 vaccination status with 68% confidence bars. (E) Partial dependency plot of risk-adjusted mortality according to SARS-CoV-2 variant from at-admission model. (F) Partial dependency plot of mortality according to COVID-19 vaccination status from at-admission model. Key: ·Black: Pre-1 April 2021: Alpha B.1.1.7 11 483 (43%) ·Red: 1 April 2021 to 1 July 2021: Alpha Q 1560 (5.8%) ·Orange: 1 July 2021 to 1 December 2021: Delta B.1.617.2 and AY 5,280 (20%) ·Blue: 1 December 2021 to 1 February 2022: Omicron BA.1 6601 (25%) ·Green: 1 February 2022 to 21 March 2022: Omicron BA.1.1 785 (2.9%) ·Purple: 21 March 2022 to 21 May 2022: Omicron BA.2 878 (3.3%) ·Brown: 21 May 2022 to 1 June 2022: Omicron BA2.12.1 285 (1.1%, too few to graph).

Figure 3

Illustration of strength and shape of a sample of risk-adjusted (partial dependency plots) associations with 60-day mortality of older age, higher blood urea nitrogen, lower albumin, higher aspartate aminotransferase, higher CRP and lower lymphocyte count. These are representative of demographics, renal and liver function, inflammatory response and haematological derangements found at hospital admission of patients with COVID-19. Accompanying these partial dependency plots at the foot of the graph is variable importance (VIMP) of each of these and others of the 13 most important variables in the at-admission model of mortality (error=18%). AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; RBCs, red blood cells; RDW, red cell distribution width.

Figure 4

Distribution of seven risk profiles of patients with serious and life-threatening COVID-19 pneumonia across date of hospital admission and observed survival for each profile. (A) Predicted 60-day survival using the at-admission model for mortality for survival profiles 1–7 are as follows: (1) ≥95%, (2) 90% to <95%, (3) 85% to <90%, (4) 80% to <85%, (5) 70% to<80%, (6) 60% to <70%, (7) <60%. Note particularly the gradual reduction in percentage of hospital admissions of the highest risk patients (pink and purple at bottom of graph) and increase in number of patients in lower risk categories at the top of the graph. (B) Survival stratified by predicted risk profile. Each symbol represents an event estimated by the Kaplan-Meier method, and vertical bars are 68% CIs equivalent to ±1 SE. Individual graphs are identified according to predicted survival profile.