K-Means Clustering Identifies Diverse Clinical Phenotypes in COVID-19 Patients: Implications for Mortality Risks and Remdesivir Impact

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Abstract

Introduction

The impact of remdesivir on mortality in patients with COVID-19 is still controversial. We aimed to identify clinical phenotype clusters of COVID-19 hospitalized patients with highest benefit from remdesivir use and validate these findings in an external cohort.

Methods

We included consecutive patients hospitalized between February 2020 and February 2021 for COVID-19. The derivation cohort comprised subjects admitted to Hospital Clinic of Barcelona. The validation cohort included patients from Hospital Universitari Mutua de Terrassa (Terrassa) and Hospital Universitari La Fe (Valencia), all tertiary centers in Spain. We employed K-means clustering to group patients according to reverse transcription polymerase chain reaction (rRT-PCR) cycle threshold (Ct) values and lymphocyte counts at diagnosis, and pre-test symptom duration. The impact of remdesivir on 60-day mortality in each cluster was assessed.

Results

A total of 1160 patients (median age 66, interquartile range (IQR) 55–78) were included. We identified five clusters, with mortality rates ranging from 0 to 36.7%. Highest mortality rate was observed in the cluster including patients with shorter pre-test symptom duration, lower lymphocyte counts, and lower Ct values at diagnosis. The absence of remdesivir administration was associated with worse outcome in the high-mortality cluster (10.5% vs. 36.7%; p < 0.001), comprising subjects with higher viral loads. These results were validated in an external multicenter cohort of 981 patients.

Conclusions

Patients with COVID-19 exhibit varying mortality rates across different clinical phenotypes. K-means clustering aids in identifying patients who derive the greatest mortality benefit from remdesivir use.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40121-024-00938-x.

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Most cited references 22

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Remdesivir for the Treatment of Covid-19 — Final Report

John H. Beigel, Kay Tomashek, Lori Dodd … (2022)

Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)

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Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): Explanation and Elaboration

Karel Moons, Douglas G. Altman, Johannes Reitsma … (2015)

The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) Statement includes a 22-item checklist, which aims to improve the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. This explanation and elaboration document describes the rationale; clarifies the meaning of each item; and discusses why transparent reporting is important, with a view to assessing risk of bias and clinical usefulness of the prediction model. Each checklist item of the TRIPOD Statement is explained in detail and accompanied by published examples of good reporting. The document also provides a valuable reference of issues to consider when designing, conducting, and analyzing prediction model studies. To aid the editorial process and help peer reviewers and, ultimately, readers and systematic reviewers of prediction model studies, it is recommended that authors include a completed checklist in their submission. The TRIPOD checklist can also be downloaded from www.tripod-statement.org.

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Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Jennifer Hammond, Heidi Leister-Tebbe, Annie Gardner … (2022)

Background Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M pro ) inhibitor with potent pan–human-coronavirus activity in vitro. Methods We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. Results A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log 10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. Conclusions Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202 .)

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Author and article information

Contributors

Carolina Garcia-Vidal:

ORCID: http://orcid.org/0000-0002-8915-0683

cgarciav@clinic.cat

Tommaso Francesco Aiello: tfaiello@recerca.clinic.cat

Journal

Journal ID (nlm-ta): Infect Dis Ther

Journal ID (iso-abbrev): Infect Dis Ther

Title: Infectious Diseases and Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 2193-8229

ISSN (Electronic): 2193-6382

Publication date (Electronic): 15 March 2024

Publication date PMC-release: 15 March 2024

Publication date (Print): April 2024

Volume: 13

Issue: 4

Pages: 715-726

Affiliations

[1 ]Infectious Disease Department, Hospital Clinic of Barcelona-IDIBAPS, University of Barcelona, ( https://ror.org/021018s57) C/ Villarroel 170, 08036 Barcelona, Spain

[2 ]CIBERINF, Barcelona, Spain

[3 ]GRID grid.84393.35, ISNI 0000 0001 0360 9602, Respiratory Department, Hospital Universitari La Fe, ; Valencia, Spain

[4 ]Infectious Disease Department, Hospital Universitari Mutua de Terrassa, ( https://ror.org/011335j04) Terrassa, Barcelona, Spain

[5 ]Universitat Internacional de Catalunya, ( https://ror.org/00tse2b39) Barcelona, Spain

[6 ]GRID grid.414875.b, ISNI 0000 0004 1794 4956, CATLAB. Hospital Universitari Mútua de Terrassa, ; Terrassa, Barcelona, Spain

[7 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Microbiology Department, , Hospital Clinic, University of Barcelona, ISGLOBAL, ; Barcelona, Spain

[8 ]GRID grid.413328.f, ISNI 0000 0001 2300 6614, Emergency Department, , Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, ; Paris, France

Author information

Carolina Garcia-Vidal http://orcid.org/0000-0002-8915-0683

Article

Publisher ID: 938

DOI: 10.1007/s40121-024-00938-x

PMC ID: 11058153

PubMed ID: 38489118

SO-VID: cdb5f96b-0404-4a60-a44e-e7ed78cdc448

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 12 December 2023

Date accepted : 5 February 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;

Award ID: FIS PI21/01640

Award Recipient : Carolina Garcia-Vidal

Funded by: FundRef http://dx.doi.org/10.13039/501100003030, Agència de Gestió d'Ajuts Universitaris i de Recerca;

Award ID: SGR 01324 Q5856414G

Award Recipient : Carolina Garcia-Vidal

Funded by: FundRef http://dx.doi.org/10.13039/501100004099, Ligue Contre le Cancer;

Award ID: AAPMRC 2022/OP

Award Recipient : Olivier Peyrony

K-Means Clustering Identifies Diverse Clinical Phenotypes in COVID-19 Patients: Implications for Mortality Risks and Remdesivir Impact

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Abstract

Introduction

Methods

Results

Conclusions

Supplementary Information

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 22

Remdesivir for the Treatment of Covid-19 — Final Report

Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): Explanation and Elaboration

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

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