Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

Predictors of discharge disposition and mortality following hospitalization with SARS-CoV-2 infection.

IMPORTANCE: The SARS-CoV-2 pandemic has overwhelmed hospital capacity, prioritizing the need to understand factors associated with type of discharge disposition. OBJECTIVE: Characterization of disposition associated factors following SARS-CoV-2. DESIGN: Retrospective study of SARS-CoV-2 positive patients from March 7th, 2020, to May 4th, 2022, requiring hospitalization. SETTING: Midwest academic health-system. PARTICIPANTS: Patients above the age 18 years admitted with PCR + SARS-CoV-2. INTERVENTION: None. MAIN OUTCOMES: Discharge to home versus PAC (inpatient rehabilitation facility (IRF), skilled-nursing facility (SNF), long-term acute care (LTACH)), or died/hospice while hospitalized (DH). RESULTS: We identified 62,279 SARS-CoV-2 PCR+ patients; 6,248 required hospitalizations, of whom 4611(73.8%) were discharged home, 985 (15.8%) to PAC and 652 (10.4%) died in hospital (DH). Patients discharged to PAC had a higher median age (75.7 years, IQR: 65.6-85.1) compared to those discharged home (57.0 years, IQR: 38.2-69.9), and had longer mean length of stay (LOS) 14.7 days, SD: 14.0) compared to discharge home (5.8 days, SD: 5.9). Older age (RRR:1.04, 95% CI:1.041-1.055), and higher Elixhauser comorbidity index [EI] (RRR:1.19, 95% CI:1.168-1.218) were associated with higher rate of discharge to PAC versus home. Older age (RRR:1.069, 95% CI:1.060-1.077) and higher EI (RRR:1.09, 95% CI:1.071-1.126) were associated with more frequent DH versus home. Blacks, Asians, and Hispanics were less likely to be discharged to PAC (RRR, 0.64 CI 0.47-0.88), (RRR 0.48 CI 0.34-0.67) and (RRR 0.586 CI 0.352-0.975). Having alpha variant was associated with less frequent PAC discharge versus home (RRR 0.589 CI 0.444-780). The relative risks for DH were lower with a higher platelet count 0.998 (CI 0.99-0.99) and albumin levels 0.342 (CI 0.26-0.45), and higher with increased CRP (RRR 1.006 CI 1.004-1.007) and D-Dimer (RRR 1.070 CI 1.039-1.101). Increased albumin had lower risk to PAC discharge (RRR 0.630 CI 0.497-0.798. An increase in D-Dimer (RRR1.033 CI 1.002-1.064) and CRP (RRR1.002 CI1.001-1.004) was associated with higher risk of PAC discharge. A breakthrough (BT) infection was associated with lower likelihood of DH and PAC. CONCLUSION: Older age, higher EI, CRP and D-Dimer are associated with PAC and DH discharges following hospitalization with COVID-19 infection. BT infection reduces the likelihood of being discharged to PAC and DH.

Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery.

Rationale: Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach; 2) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P < 0.001) and more had a comorbidity (84% vs. 70%; P < 0.001). Of 170 discordant participants, 106 (62%) had postdischarge events captured by the TICO approach. Conclusions: Among patients hospitalized with COVID-19, 20% had clinically significant postdischarge events within 90 days after randomization in patients who would be considered "recovered" using the hospital discharge approach. Using the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should use follow-up times up to 90 days to assess clinical recovery more accurately.

Impact of SARS-CoV-2 vaccination and booster on COVID-19 symptom severity over time in the COVID-OUT trial.

BACKGROUND: SARS-CoV-2 vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe COVID-19. The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < 0.001). Individual symptoms were least severe in the vaccine-boosted group including: cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over delta and omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19 which abated the quickest over time.

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 : A Randomized Controlled Trial.

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep). LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome. CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified. PRIMARY FUNDING SOURCE: National Institutes of Health.

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Predictors of Postacute Sequelae of COVID-19 Development and Rehabilitation: A Retrospective Study.

OBJECTIVE: To examine the frequency of postacute sequelae of SARS-CoV-2 (PASC) and the factors associated with rehabilitation utilization in a large adult population with PASC. DESIGN: Retrospective study. SETTING: Midwest hospital health system. PARTICIPANTS: 19,792 patients with COVID-19 from March 10, 2020, to January 17, 2021. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Descriptive analyses were conducted across the entire cohort along with an adult subgroup analysis. A logistic regression was performed to assess factors associated with PASC development and rehabilitation utilization. RESULTS: In an analysis of 19,792 patients, the frequency of PASC was 42.8% in the adult population. Patients with PASC compared with those without had a higher utilization of rehabilitation services (8.6% vs 3.8%, P<.001). Risk factors for rehabilitation utilization in patients with PASC included younger age (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.98-1.00; P=.01). In addition to several comorbidities and demographics factors, risk factors for rehabilitation utilization solely in the inpatient population included male sex (OR, 1.24; 95% CI, 1.02-1.50; P=.03) with patients on angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers 3 months prior to COVID-19 infections having a decreased risk of needing rehabilitation (OR, 0.80; 95% CI, 0.64-0.99; P=.04). CONCLUSIONS: Patients with PASC had higher rehabilitation utilization. We identified several clinical and demographic factors associated with the development of PASC and rehabilitation utilization.

RAGE has potential pathogenetic and prognostic value in nonintubated hospitalized patients with COVID-19.

BackgroundThe value of the soluble receptor for advanced glycation end-products (sRAGE) as a biomarker in COVID-19 is not well understood. We tested the association between plasma sRAGE and illness severity, viral burden, and clinical outcomes in hospitalized patients with COVID-19 who were not mechanically ventilated.MethodsBaseline sRAGE was measured among participants enrolled in the ACTIV-3/TICO trial of bamlanivimab for hospitalized patients with COVID-19. Spearman's rank correlation was used to assess the relationship between sRAGE and other plasma biomarkers, including viral nucleocapsid antigen. Fine-Gray models adjusted for baseline supplemental oxygen requirement, antigen level, positive endogenous anti-nucleocapsid antibody response, sex, age, BMI, diabetes mellitus, renal impairment, corticosteroid treatment, and log2-transformed IL-6 level were used to assess the association between baseline sRAGE and time to sustained recovery. Cox regression adjusted for the same factors was used to assess the association between sRAGE and mortality.ResultsAmong 277 participants, baseline sRAGE was strongly correlated with viral plasma antigen concentration (ρ = 0.57). There was a weaker correlation between sRAGE and biomarkers of systemic inflammation, such as IL-6 (ρ = 0.36) and CRP (ρ = 0.20). Participants with plasma sRAGE in the highest quartile had a significantly lower rate of sustained recovery (adjusted recovery rate ratio, 0.64 [95% CI, 0.43-0.90]) and a higher unadjusted risk of death (HR, 4.70 [95% CI, 2.01-10.99]) compared with participants in the lower quartiles.ConclusionElevated plasma sRAGE in hospitalized, nonventilated patients with COVID-19 was an indicator of both clinical illness severity and plasma viral load. Plasma sRAGE in the highest quartile was associated with a lower likelihood of sustained recovery and higher unadjusted risk of death. These findings, which we believe to be novel, indicate that plasma sRAGE may be a promising biomarker for COVID-19 prognostication and clinical trial enrichment.Trial RegistrationClinicalTrials.gov NCT04501978.FundingNIH (5T32GM008440-24, 18X107CF6, HHSN261201500003I, R35HL140026, and OT2HL156812).

Vaccination Against SARS-CoV-2 Is Associated With a Lower Viral Load and Likelihood of Systemic Symptoms.

Background: Data conflict on whether vaccination decreases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load. The objective of this analysis was to compare baseline viral load and symptoms between vaccinated and unvaccinated adults enrolled in a randomized trial of outpatient coronavirus disease 2019 (COVID-19) treatment. Methods: Baseline data from the first 433 sequential participants enrolling into the COVID-OUT trial were analyzed. Adults aged 30-85 with a body mass index (BMI) ≥25 kg/m2 were eligible within 3 days of a positive SARS-CoV-2 test and <7 days of symptoms. Log10 polymerase chain reaction viral loads were normalized to human RNase P by vaccination status, by time from vaccination, and by symptoms. Results: Two hundred seventy-four participants with known vaccination status contributed optional nasal swabs for viral load measurement: median age, 46 years; median (interquartile range) BMI 31.2 (27.4-36.4) kg/m2. Overall, 159 (58%) were women, and 217 (80%) were White. The mean relative log10 viral load for those vaccinated <6 months from the date of enrollment was 0.11 (95% CI, -0.48 to 0.71), which was significantly lower than the unvaccinated group (P = .01). Those vaccinated ≥6 months before enrollment did not differ from the unvaccinated with respect to viral load (mean, 0.99; 95% CI, -0.41 to 2.40; P = .85). The vaccinated group had fewer moderate/severe symptoms of subjective fever, chills, myalgias, nausea, and diarrhea (all P < .05). Conclusions: These data suggest that vaccination within 6 months of infection is associated with a lower viral load, and vaccination was associated with a lower likelihood of having systemic symptoms.

Characterizing COVID-19 clinical phenotypes and associated comorbidities and complication profiles.

PURPOSE: Heterogeneity has been observed in outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19). Identification of clinical phenotypes may facilitate tailored therapy and improve outcomes. The purpose of this study is to identify specific clinical phenotypes across COVID-19 patients and compare admission characteristics and outcomes. METHODS: This is a retrospective analysis of COVID-19 patients from March 7, 2020 to August 25, 2020 at 14 U.S. hospitals. Ensemble clustering was performed on 33 variables collected within 72 hours of admission. Principal component analysis was performed to visualize variable contributions to clustering. Multinomial regression models were fit to compare patient comorbidities across phenotypes. Multivariable models were fit to estimate associations between phenotype and in-hospital complications and clinical outcomes. RESULTS: The database included 1,022 hospitalized patients with COVID-19. Three clinical phenotypes were identified (I, II, III), with 236 [23.1%] patients in phenotype I, 613 [60%] patients in phenotype II, and 173 [16.9%] patients in phenotype III. Patients with respiratory comorbidities were most commonly phenotype III (p = 0.002), while patients with hematologic, renal, and cardiac (all p<0.001) comorbidities were most commonly phenotype I. Adjusted odds of respiratory, renal, hepatic, metabolic (all p<0.001), and hematological (p = 0.02) complications were highest for phenotype I. Phenotypes I and II were associated with 7.30-fold (HR:7.30, 95% CI:(3.11-17.17), p<0.001) and 2.57-fold (HR:2.57, 95% CI:(1.10-6.00), p = 0.03) increases in hazard of death relative to phenotype III. CONCLUSION: We identified three clinical COVID-19 phenotypes, reflecting patient populations with different comorbidities, complications, and clinical outcomes. Future research is needed to determine the utility of these phenotypes in clinical practice and trial design.

Review of clinical characteristics and laboratory findings of COVID-19 in children-Systematic review and Meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis to assess the prevalence of various clinical symptoms and laboratory findings of COVID-19 in children. METHODS: PubMed, MEDLINE, and SCOPUS databases were searched to include studies conducted between January 1, 2020, and July 15, 2020 which reported data about clinical characteristics and laboratory findings in laboratory-confirmed diagnosis of COVID-19 in pediatric patients. Random effects meta-analysis using generalized linear mixed models was used to estimate the pooled prevalence. RESULTS: The most prevalent symptom of COVID-19 in children was 46.17% (95%CI 39.18-53.33%), followed by cough (40.15%, 95%CI 34.56-46.02%). Less common symptoms were found to be dyspnea, vomiting, nasal congestion/rhinorrhea, diarrhea, sore throat/pharyngeal congestion, headache, and fatigue. The prevalence of asymptomatic children was 17.19% (95%CI 11.02-25.82%). The most prevalent laboratory findings in COVID-19 children were elevated Creatinine Kinase (26.86%, 95%CI 16.15-41.19%) and neutropenia (25.76%, 95%CI 13.96-42.58%). These were followed by elevated LDH, thrombocytosis, lymphocytosis, neutrophilia, elevated D Dimer, Elevated CRP, elevated ESR, leukocytosis, elevated AST and leukopenia. There was a low prevalence of elevated ALT and lymphopenia in children with COVID- 19. CONCLUSIONS AND RELEVANCE: This study provides estimates of the pooled prevalence of various symptoms and laboratory findings of COVID-19 in the pediatric population.

Characterizing COVID-19 Clinical Phenotypes and Associated Comorbidities and Complication Profiles.

BACKGROUND: There is limited understanding of heterogeneity in outcomes across hospitalized patients with coronavirus disease 2019 (COVID-19). Identification of distinct clinical phenotypes may facilitate tailored therapy and improve outcomes. OBJECTIVE: Identify specific clinical phenotypes across COVID-19 patients and compare admission characteristics and outcomes. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective analysis of 1,022 COVID-19 patient admissions from 14 Midwest U.S. hospitals between March 7, 2020 and August 25, 2020. METHODS: Ensemble clustering was performed on a set of 33 vitals and labs variables collected within 72 hours of admission. K-means based consensus clustering was used to identify three clinical phenotypes. Principal component analysis was performed on the average covariance matrix of all imputed datasets to visualize clustering and variable relationships. Multinomial regression models were fit to further compare patient comorbidities across phenotype classification. Multivariable models were fit to estimate the association between phenotype and in-hospital complications and clinical outcomes. Main outcomes and measures: Phenotype classification (I, II, III), patient characteristics associated with phenotype assignment, in-hospital complications, and clinical outcomes including ICU admission, need for mechanical ventilation, hospital length of stay, and mortality. RESULTS: The database included 1,022 patients requiring hospital admission with COVID-19 (median age, 62.1 [IQR: 45.9-75.8] years; 481 [48.6%] male, 412 [40.3%] required ICU admission, 437 [46.7%] were white). Three clinical phenotypes were identified (I, II, III); 236 [23.1%] patients had phenotype I, 613 [60%] patients had phenotype II, and 173 [16.9%] patients had phenotype III. When grouping comorbidities by organ system, patients with respiratory comorbidities were most commonly characterized by phenotype III (p=0.002), while patients with hematologic (p<0.001), renal (p<0.001), and cardiac (p<0.001) comorbidities were most commonly characterized by phenotype I. The adjusted odds of respiratory (p<0.001), renal (p<0.001), and metabolic (p<0.001) complications were highest for patients with phenotype I, followed by phenotype II. Patients with phenotype I had a far greater odds of hepatic (p<0.001) and hematological (p=0.02) complications than the other two phenotypes. Phenotypes I and II were associated with 7.30-fold (HR: 7.30, 95% CI: (3.11-17.17), p<0.001) and 2.57-fold (HR: 2.57, 95% CI: (1.10-6.00), p=0.03) increases in the hazard of death, respectively, when compared to phenotype III. CONCLUSION: In this retrospective analysis of patients with COVID-19, three clinical phenotypes were identified. Future research is urgently needed to determine the utility of these phenotypes in clinical practice and trial design.