Analysis of Protein Biomarkers From Hospitalized COVID-19 Patients Reveals Severity-Specific Signatures and Two Distinct Latent Profiles With Differential Responses to Corticosteroids.

OBJECTIVES: To identify and validate novel COVID-19 subphenotypes with potential heterogenous treatment effects (HTEs) using electronic health record (EHR) data and 33 unique biomarkers. DESIGN: Retrospective cohort study of adults presenting for acute care, with analysis of biomarkers from residual blood collected during routine clinical care. Latent profile analysis (LPA) of biomarker and EHR data identified subphenotypes of COVID-19 inpatients, which were validated using a separate cohort of patients. HTE for glucocorticoid use among subphenotypes was evaluated using both an adjusted logistic regression model and propensity matching analysis for in-hospital mortality. SETTING: Emergency departments from four medical centers. PATIENTS: Patients diagnosed with COVID-19 based on International Classification of Diseases , 10th Revision codes and laboratory test results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomarker levels generally paralleled illness severity, with higher levels among more severely ill patients. LPA of 522 COVID-19 inpatients from three sites identified two profiles: profile 1 ( n = 332), with higher levels of albumin and bicarbonate, and profile 2 ( n = 190), with higher inflammatory markers. Profile 2 patients had higher median length of stay (7.4 vs 4.1 d; p < 0.001) and in-hospital mortality compared with profile 1 patients (25.8% vs 4.8%; p < 0.001). These were validated in a separate, single-site cohort ( n = 192), which demonstrated similar outcome differences. HTE was observed ( p = 0.03), with glucocorticoid treatment associated with increased mortality for profile 1 patients (odds ratio = 4.54). CONCLUSIONS: In this multicenter study combining EHR data with research biomarker analysis of patients with COVID-19, we identified novel profiles with divergent clinical outcomes and differential treatment responses.

Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock.

OBJECTIVES: To identify cytokine signature clusters in patients with septic shock. DESIGN: Prospective observational cohort study. SETTING: Single academic center in the United States. PATIENTS: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Coronavirus Disease 2019 Temperature Trajectories Correlate With Hyperinflammatory and Hypercoagulable Subphenotypes.

OBJECTIVES: Body temperature trajectories of infected patients are associated with specific immune profiles and survival. We determined the association between temperature trajectories and distinct manifestations of coronavirus disease 2019. DESIGN: Retrospective observational study. SETTING: Four hospitals within an academic healthcare system from March 2020 to February 2021. PATIENTS: All adult patients hospitalized with coronavirus disease 2019. INTERVENTIONS: Using a validated group-based trajectory model, we classified patients into four previously defined temperature trajectory subphenotypes using oral temperature measurements from the first 72 hours of hospitalization. Clinical characteristics, biomarkers, and outcomes were compared between subphenotypes. MEASUREMENTS AND MAIN RESULTS: The 5,903 hospitalized coronavirus disease 2019 patients were classified into four subphenotypes: hyperthermic slow resolvers (n = 1,452, 25%), hyperthermic fast resolvers (1,469, 25%), normothermics (2,126, 36%), and hypothermics (856, 15%). Hypothermics had abnormal coagulation markers, with the highest d-dimer and fibrin monomers (p < 0.001) and the highest prevalence of cerebrovascular accidents (10%, p = 0.001). The prevalence of venous thromboembolism was significantly different between subphenotypes (p = 0.005), with the highest rate in hypothermics (8.5%) and lowest in hyperthermic slow resolvers (5.1%). Hyperthermic slow resolvers had abnormal inflammatory markers, with the highest C-reactive protein, ferritin, and interleukin-6 (p < 0.001). Hyperthermic slow resolvers had increased odds of mechanical ventilation, vasopressors, and 30-day inpatient mortality (odds ratio, 1.58; 95% CI, 1.13-2.19) compared with hyperthermic fast resolvers. Over the course of the pandemic, we observed a drastic decrease in the prevalence of hyperthermic slow resolvers, from representing 53% of admissions in March 2020 to less than 15% by 2021. We found that dexamethasone use was associated with significant reduction in probability of hyperthermic slow resolvers membership (27% reduction; 95% CI, 23-31%; p < 0.001). CONCLUSIONS: Hypothermics had abnormal coagulation markers, suggesting a hypercoagulable subphenotype. Hyperthermic slow resolvers had elevated inflammatory markers and the highest odds of mortality, suggesting a hyperinflammatory subphenotype. Future work should investigate whether temperature subphenotypes benefit from targeted antithrombotic and anti-inflammatory strategies.

IL-33-mediated Eosinophilia Protects against Acute Lung Injury.

Pneumonia-induced lung injury and acute respiratory distress syndrome can develop because of an inappropriate inflammatory response to acute infections, leading to a compromised alveolar barrier. Recent work suggests that hospitalized patients with allergies/asthma are less likely to die of pulmonary infections and that there is a correlation between survival from acute respiratory distress syndrome and higher eosinophil counts; thus, we hypothesized that eosinophils associated with a type 2 immune response may protect against pneumonia-induced acute lung injury. To test this hypothesis, mice were treated with the type 2-initiating cytokine IL-33 intratracheally 3 days before induction of pneumonia with airway administration of a lethal dose of Staphylococcus aureus. Interestingly, IL-33 pretreatment promoted survival by inhibiting acute lung injury: amount of BAL fluid proinflammatory cytokines and pulmonary edema were both reduced, with an associated increase in oxygen saturation. Pulmonary neutrophilia was also reduced, whereas eosinophilia was strongly increased. This eosinophilia was key to protection; eosinophil reduction eliminated both IL-33-mediated protection against mortality and inhibition of neutrophilia and pulmonary edema. Together, these data reveal a novel role for eosinophils in protection against lung injury and suggest that modulation of pulmonary type 2 immunity may represent a novel therapeutic strategy.

Temperature Trajectory Subphenotypes Correlate With Immune Responses in Patients With Sepsis.

OBJECTIVES: We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN: Prospective observational study. SETTING: Large academic medical center between 2013 and 2019. SUBJECTS: Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS: Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS: The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS: Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.

A committed precursor to innate lymphoid cells.

Innate lymphoid cells (ILCs) specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair at mucosal barriers. Their diversity and similarities with previously characterized natural killer (NK) cells and lymphoid tissue inducers (LTi) have prompted a provisional classification of all innate lymphocytes into groups 1, 2 and 3 solely on the basis of cytokine properties, but their developmental pathways and lineage relationships remain elusive. Here we identify and characterize a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor previously associated with NK T cell development, by using lineage tracing and transfer studies. PLZF(high) cells were committed ILC progenitors with multiple ILC1, ILC2 and ILC3 potential at the clonal level. They excluded classical LTi and NK cells, but included a peculiar subset of NK1.1(+)DX5(-) 'NK-like' cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZF(high) precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages. These findings establish novel lineage relationships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defining role of PLZF in the differentiation of innate lymphocytes.

Caring for Critically Ill Adults With Coronavirus Disease 2019 in a PICU: Recommendations by Dual Trained Intensivists.

OBJECTIVE: In the midst of the severe acute respiratory syndrome coronavirus 2 pandemic, which causes coronavirus disease 2019, there is a recognized need to expand critical care services and beds beyond the traditional boundaries. There is considerable concern that widespread infection will result in a surge of critically ill patients that will overwhelm our present adult ICU capacity. In this setting, one proposal to add "surge capacity" has been the use of PICU beds and physicians to care for these critically ill adults. DESIGN: Narrative review/perspective. SETTING: Not applicable. PATIENTS: Not applicable. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The virus's high infectivity and prolonged asymptomatic shedding have resulted in an exponential growth in the number of cases in the United States within the past weeks with many (up to 6%) developing acute respiratory distress syndrome mandating critical care services. Coronavirus disease 2019 critical illness appears to be primarily occurring in adults. Although pediatric intensivists are well versed in the care of acute respiratory distress syndrome from viral pneumonia, the care of differing aged adult populations presents some unique challenges. In this statement, a team of adult and pediatric-trained critical care physicians provides guidance on common "adult" issues that may be encountered in the care of these patients and how they can best be managed in a PICU. CONCLUSIONS: This concise scientific statement includes references to the most recent and relevant guidelines and clinical trials that shape management decisions. The intention is to assist PICUs and intensivists in rapidly preparing for care of adult coronavirus disease 2019 patients should the need arise.

Identifying Novel Sepsis Subphenotypes Using Temperature Trajectories.

Rationale: Sepsis is a heterogeneous syndrome, and identifying clinically relevant subphenotypes is essential.Objectives: To identify novel subphenotypes in hospitalized patients with infection using longitudinal temperature trajectories.Methods: In the model development cohort, inpatient admissions meeting criteria for infection in the emergency department and receiving antibiotics within 24 hours of presentation were included. Temperature measurements within the first 72 hours were compared between survivors and nonsurvivors. Group-based trajectory modeling was performed to identify temperature trajectory groups, and patient characteristics and outcomes were compared between the groups. The model was then externally validated at a second hospital using the same inclusion criteria.Measurements and Main Results: A total of 12,413 admissions were included in the development cohort, and 19,053 were included in the validation cohort. In the development cohort, four temperature trajectory groups were identified: "hyperthermic, slow resolvers" (n = 1,855; 14.9% of the cohort); "hyperthermic, fast resolvers" (n = 2,877; 23.2%); "normothermic" (n = 4,067; 32.8%); and "hypothermic" (n = 3,614; 29.1%). The hypothermic subjects were the oldest and had the most comorbidities, the lowest levels of inflammatory markers, and the highest in-hospital mortality rate (9.5%). The hyperthermic, slow resolvers were the youngest and had the fewest comorbidities, the highest levels of inflammatory markers, and a mortality rate of 5.1%. The hyperthermic, fast resolvers had the lowest mortality rate (2.9%). Similar trajectory groups, patient characteristics, and outcomes were found in the validation cohort.Conclusions: We identified and validated four novel subphenotypes of patients with infection, with significant variability in inflammatory markers and outcomes.

Allergic Immune Diseases and the Risk of Mortality Among Patients Hospitalized for Acute Infection.

OBJECTIVES: The immune response during sepsis remains poorly understood and is likely influenced by the host's preexisting immunologic comorbidities. Although more than 20% of the U.S. population has an allergic-atopic disease, the type 2 immune response that is overactive in these diseases can also mediate beneficial pro-resolving, tissue-repair functions. Thus, the presence of allergic immunologic comorbidities may be advantageous for patients suffering from sepsis. The objective of this study was to test the hypothesis that comorbid type 2 immune diseases confer protection against morbidity and mortality due to acute infection. DESIGN: Retrospective cohort study of patients hospitalized with an acute infection between November 2008 and January 2016 using electronic health record data. SETTING: Single tertiary-care academic medical center. PATIENTS: Admissions to the hospital through the emergency department with likely infection at the time of admission who may or may not have had a type 2 immune-mediated disease, defined as asthma, allergic rhinitis, atopic dermatitis, or food allergy, as determined by International Classification of Diseases, 9th Revision, Clinical Modification codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 10,789 admissions for infection, 2,578 (24%) had a type 2 disease; these patients were more likely to be female, black, and younger than patients without type 2 diseases. In unadjusted analyses, type 2 patients had decreased odds of dying during the hospitalization (0.47; 95% CI, 0.38-0.59, p < 0.001), while having more than one type 2 disease conferred a dose-dependent reduction in the risk of mortality (p < 0.001). When adjusting for demographics, medications, types of infection, and illness severity, the presence of a type 2 disease remained protective (odds ratio, 0.55; 95% CI, 0.43-0.70; p < 0.001). Similar results were found using a propensity score analysis (odds ratio, 0.57; 95% CI, 0.45-0.71; p < 0.001). CONCLUSIONS: Patients with type 2 diseases admitted with acute infections have reduced mortality, implying that the type 2 immune response is protective in sepsis.

Distinct T-helper cell responses to Staphylococcus aureus bacteremia reflect immunologic comorbidities and correlate with mortality.

BACKGROUND: The dysregulated host immune response that defines sepsis varies as a function of both the immune status of the host and the distinct nature of the pathogen. The degree to which immunocompromising comorbidities or immunosuppressive medications affect the immune response to infection is poorly understood because these patients are often excluded from studies about septic immunity. The objectives of this study were to determine the immune response to a single pathogen (Staphylococcus aureus) among a diverse case mix of patients and to determine whether comorbidities affect immune and clinical outcomes. METHODS: Blood samples were drawn from 95 adult inpatients at multiple time points after the first positive S. aureus blood culture. Cox proportional hazards modeling was used to determine the associations between admission neutrophil counts, admission lymphocyte counts, cytokine levels, and 90-day mortality. A nested case-control flow cytometric analysis was conducted to determine T-helper type 1 (Th1), Th2, Th17, and regulatory T-cell (Treg) subsets among a subgroup of 28 patients. In a secondary analysis, we categorized patients as either having immunocompromising disorders (human immunodeficiency virus and hematologic malignancies), receiving immunosuppressive medications, or being not immunocompromised. RESULTS: Higher neutrophil-to-lymphocyte count ratios and higher Th17 cytokine responses relative to Th1 cytokine responses early after infection were independently associated with mortality and did not depend on the immune state of the patient (HR 1.93, 95% CI 1.17-3.17, p = 0.01; and HR 1.13, 95% CI 1.01-1.27, p = 0.03, respectively). On the basis of flow cytometric analysis of CD4 T-helper subsets, an increasing Th17/Treg response over the course of the infection was most strongly associated with increased mortality (HR 4.41, 95% CI 1.69-11.5, p < 0.01). This type of immune response was most common among patients who were not immunocompromised. In contrast, among immunocompromised patients who died, a decreasing Th1/Treg response was most common. CONCLUSIONS: The association of both increased Th17 responses and increased neutrophil counts relative to lymphocyte counts with mortality suggests that an overwhelming inflammatory response is detrimental. However, the differential responses of patients according to immune state suggest that immune status is an important clinical indicator that should be accounted for in the management of septic patients, as well as in the development of novel immunomodulatory therapies.

PLZF expression maps the early stages of ILC1 lineage development.

Among the variety of tissue-resident NK-like populations recently distinguished from recirculating classical NK (cNK) cells, liver innate lymphoid cells (ILC) type 1 (ILC1s) have been shown to represent a distinct lineage that originates from a novel promyelocytic leukaemia zinc finger (PLZF)-expressing ILC precursor (ILCP) strictly committed to the ILC1, ILC2, and ILC3 lineages. Here, using PLZF-reporter mice and cell transfer assays, we studied the developmental progression of ILC1s and demonstrated substantial overlap with stages previously ascribed to the cNK lineage, including pre-pro-NK, pre-NK precursor (pre-NKP), refined NKP (rNKP), and immature NK (iNK). Although they originated from different precursors, the ILC1 and cNK lineages followed a parallel progression at early stages and diverged later at the iNK stage, with a striking predominance of ILC1s over cNKs early in ontogeny. Although a limited set of ILC1 genes depended on PLZF for expression, characteristically including Il7r, most of these genes were also differentially expressed between ILC1s and cNKs, indicating that PLZF together with other, yet to be defined, factors contribute to the divergence between these lineages.

Intrinsic functional defects of type 2 innate lymphoid cells impair innate allergic inflammation in promyelocytic leukemia zinc finger (PLZF)-deficient mice.

BACKGROUND: The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response. OBJECTIVE: We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF(-/-) mice and mixed wild-type:PLZF(-/-) bone marrow chimeras. METHODS: PLZF(-/-) mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2-derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines. RESULTS: PLZF-deficient lung ILC2s exhibit a cell-intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired. CONCLUSIONS: PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice.

COVID-19 Hospitalization in Hawai'i and Patterns of Insurance Coverage, Race and Ethnicity, and Vaccination.

Importance: The people of Hawai'i have both high rates of health insurance and high levels of racial and ethnic diversity, but the degree to which insurance status and race and ethnicity contribute to health outcomes in COVID-19 remains unknown. Objective: To evaluate the associations of insurance coverage, race and ethnicity (using disaggregated race and ethnicity data), and vaccination with outcomes for COVID-19 hospitalization. Design, Setting, and Participants: This retrospective cohort study included hospitalized patients at a tertiary care medical center between March 2020 and March 2022. All patients hospitalized for acute COVID-19, identified based on diagnosis code or positive results on polymerase chain reaction-based assay for SARS-CoV-2, were included in analysis. Data were analyzed from May 2022 to May 2023. Exposure: COVID-19 requiring hospitalization. Main Outcome and Measures: Electronic medical record data were collected for all patients. Associations among race and ethnicity, insurance coverage, receipt of at least 1 COVID-19 vaccine, intensive care unit (ICU) transfer, in-hospital mortality, and COVID-19 variant wave (pre-Delta vs Delta and Omicron) were assessed using adjusted multivariable logistic regression. Results: A total of 1176 patients (median [IQR] age of 58 [41-71] years; 630 [54%] male) were hospitalized with COVID-19, with a median (IQR) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 30 (25-36) and Sequential Organ Failure Assessment score of 1 (0-2). The sample included 16 American Indian or Alaska Native patients, 439 Asian (not otherwise specified) patients, 15 Black patients, 66 Chinese patients, 246 Filipino patients, 76 Hispanic patients, 107 Japanese patients, 10 Korean patients, 299 Native Hawaiian patients, 523 Pacific Islander (not otherwise specified) patients, 156 Samoan patients, 5 Vietnamese patients, and 311 White patients (patients were able to identify as >1 race or ethnicity). When adjusting for age, BMI, sex, medical comorbidities, and socioeconomic neighborhood status, there were no differences in either ICU transfer (eg, Medicare vs commercial insurance: odds ratio [OR], 0.84; 95% CI, 0.43-1.64) or in-hospital mortality (eg, Medicare vs commercial insurance: OR, 0.85; 95% CI, 0.36-2.03) as a function of insurance type. Disaggregation of race and ethnicity revealed that Filipino patients were more likely to die in the hospital (OR, 1.79; 95% CI, 1.04-3.03; P = .03). When considering variant waves, mortality among Filipino patients was highest during the pre-Delta time period (OR, 2.72; 95% CI, 1.02-7.14; P = .04), when mortality among Japanese patients was lowest (OR, 0.19; 95% CI, 0.03-0.78; P = .04); mortality among Native Hawaiian patients was lowest during the Delta and Omicron period (OR, 0.35; 95% CI, 0.13-0.79; P = .02). Patients with Medicare, compared with those with commercial insurance, were more likely to have received at least 1 COVID-19 vaccine (OR, 1.85; 95% CI, 1.07-3.21; P = .03), but all patients, regardless of insurance type, who received at least 1 COVID-19 vaccine had reduced ICU admission (OR, 0.40; 95% CI, 0.21-0.70; P = .002) and in-hospital mortality (OR, 0.42; 95% CI, 0.21-0.79; P = .01). Conclusions and Relevance: In this cohort study of hospitalized patients with COVID-19, those with government-funded insurance coverage (Medicare or Medicaid) had similar outcomes compared with patients with commercial insurance, regardless of race or ethnicity. Disaggregation of race and ethnicity analysis revealed substantial outcome disparities and suggests opportunities for further study of the drivers underlying such disparities. Additionally, these findings illustrate that vaccination remains a critical tool to protect patients from COVID-19 mortality.

Using Trajectories of Bedside Vital Signs to Identify COVID-19 Subphenotypes.

BACKGROUND: Trajectories of bedside vital signs have been used to identify sepsis subphenotypes with distinct outcomes and treatment responses. The objective of this study was to validate the vitals trajectory model in a multicenter cohort of patients hospitalized with COVID-19 and to evaluate the clinical characteristics and outcomes of the resulting subphenotypes. RESEARCH QUESTION: Can the trajectory of routine bedside vital signs identify COVID-19 subphenotypes with distinct clinical characteristics and outcomes? STUDY DESIGN AND METHODS: The study included adult patients admitted with COVID-19 to four academic hospitals in the Emory Healthcare system between March 1, 2020, and May 31, 2022. Using a validated group-based trajectory model, we classified patients into previously defined vital sign trajectories using oral temperature, heart rate, respiratory rate, and systolic and diastolic BP measured in the first 8 h of hospitalization. Clinical characteristics, biomarkers, and outcomes were compared between subphenotypes. Heterogeneity of treatment effect to tocilizumab was evaluated. RESULTS: The 7,065 patients with hospitalized COVID-19 were classified into four subphenotypes: group A (n = 1,429, 20%)-high temperature, heart rate, respiratory rate, and hypotensive; group B (1,454, 21%)-high temperature, heart rate, respiratory rate, and hypertensive; group C (2,996, 42%)-low temperature, heart rate, respiratory rate, and normotensive; and group D (1,186, 17%)-low temperature, heart rate, respiratory rate, and hypotensive. Groups A and D had higher ORs of mechanical ventilation, vasopressors, and 30-day inpatient mortality (P < .001). On comparing patients receiving tocilizumab (n = 55) with those who met criteria for tocilizumab but were admitted before its use (n = 461), there was significant heterogeneity of treatment effect across subphenotypes in the association of tocilizumab with 30-day mortality (P = .001). INTERPRETATION: By using bedside vital signs available in even low-resource settings, we found novel subphenotypes associated with distinct manifestations of COVID-19, which could lead to preemptive and targeted treatments.