Identification of Distinct Clinical Subphenotypes in Critically Ill Patients With COVID-19

Abstract

Background: Subphenotypes have been identified in patients with sepsis and ARDS and are associated with different outcomes and responses to therapies.

Research question: Can unique subphenotypes be identified among critically ill patients with COVID-19?

Study design and methods: Using data from a multicenter cohort study that enrolled critically ill patients with COVID-19 from 67 hospitals across the United States, we randomly divided centers into discovery and replication cohorts. We used latent class analysis independently in each cohort to identify subphenotypes based on clinical and laboratory variables. We then analyzed the associations of subphenotypes with 28-day mortality.

Results: Latent class analysis identified four subphenotypes (SP) with consistent characteristics across the discovery (45 centers; n = 2,188) and replication (22 centers; n = 1,112) cohorts. SP1 was characterized by shock, acidemia, and multiorgan dysfunction, including acute kidney injury treated with renal replacement therapy. SP2 was characterized by high C-reactive protein, early need for mechanical ventilation, and the highest rate of ARDS. SP3 showed the highest burden of chronic diseases, whereas SP4 demonstrated limited chronic disease burden and mild physiologic abnormalities. Twenty-eight-day mortality in the discovery cohort ranged from 20.6% (SP4) to 52.9% (SP1). Mortality across subphenotypes remained different after adjustment for demographics, comorbidities, organ dysfunction and illness severity, regional and hospital factors. Compared with SP4, the relative risks were as follows: SP1, 1.67 (95% CI, 1.36-2.03); SP2, 1.39 (95% CI, 1.17-1.65); and SP3, 1.39 (95% CI, 1.15-1.67). Findings were similar in the replication cohort.

Interpretation: We identified four subphenotypes of COVID-19 critical illness with distinct patterns of clinical and laboratory characteristics, comorbidity burden, and mortality.

Keywords: COVID-19; coronavirus; latent class analysis; phenotypes; subphenotypes.

Figure 1

Heatmap displaying the standardized mean values for each variable across COVID-19 subphenotypes in the discovery and replication cohorts. The heatmap is divided into two sections: latent class-defining variables (top) and baseline characteristics that were not used to define class membership (bottom). Within each section, variables are ordered by standardized mean values, lowest to highest, among patients in the discovery cohort assigned to subphenotype 1 (SP1). The same order of variables is maintained in the replication cohort to facilitate comparison across cohorts. Within each cohort, variables were standardized by scaling to a mean = 0 and an SD = 1 and are represented graphically using a continuous color scale. A variable with value + 1 represents a mean value for that subphenotype, which is 1 SD more than the mean value for the entire cohort population. ACEI = angiotensin converting enzyme inhibitor; ALT = alanine aminotransferase; ARB = angiotensin receptor blocker; AST = aspartate aminotransferase; CRP = C-reactive protein.

Figure 2

A, B, Graphs showing the cumulative incidence of mortality in the discovery (A) and replication (B) cohorts stratified by subphenotype. No patients were censored before mortality determination at 28 days. Patients discharged alive before 28 days were assumed to be alive at day 28. Numbers of at-risk individuals are displayed in the corresponding table, and 95% CIs are shown for each survival curve. SP1, SP2, SP3, SP4 = subphenotype 1, subphenotype 2, subphenotype 3, subphenotype 4.

Figure 3

Diagram showing summary of class-defining variables, baseline characteristics, and clinical outcomes for each subphenotype of COVID-19. Overall cumulative 28-day mortality and the class prevalence, across both cohorts, are shown as percentages. AKI = acute kidney injury; CRP = C-reactive protein. SP1, SP2, SP3, SP4 = subphenotype 1, subphenotype 2, subphenotype 3, subphenotype 4.