Atkinson, Andrew

Baumgartner, Christine

Exadaktylos, Aristomenis K

Hammann, Felix

Hautz, Wolf E

Liakoni, Evangelia

Schöning, Verena

Journal of Translational Medicine

English

PubMed

Verena Schöning

Evangelia Liakoni

Christine Baumgartner

Aristomenis K. Exadaktylos

Wolf E. Hautz

Andrew Atkinson

Felix Hammann

Crossref

Revalidating the prognostic COVID-19 severity assessment (COSA) score for variants of concern

Exadaktylos, Aristomenis K.

Hautz, Wolf E.

PubMed Central

Bern Open Repository and Information System (BORIS)

Schöning et al. Journal of Translational Medicine          (2022) 20:427  https://doi.org/10.1186/s12967-022-03634-xLETTER TO THE EDITORRevalidating the prognostic COVID-19 severity assessment (COSA) score for variants of concernVerena Schöning1, Evangelia Liakoni1, Christine Baumgartner2, Aristomenis K. Exadaktylos3, Wolf E. Hautz3, Andrew Atkinson4,5 and Felix Hammann1*  © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits 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:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Dear Editor,Many prediction models have been published for Coro-navirus disease 2019 (COVID-19) to support clinical decision-making for either diagnosis, prediction of mor-tality risk, or disease progression. An ongoing review concluded that most of these were poorly reported and had a high risk of bias, casting doubt over their real-world predictive value [1]. Additionally, dominant strains are no longer the ancestral type but variants of concern (VOCs) with different pathogenicity, and vaccinations and herd immunity can influence individual outcomes. We aimed to assess the performance of our previously published COSA (COVID-19 Severity Assessment) score on admitted patients in the twelve months following its development, a time during which the score was used clinically for risk stratification.The COSA score was developed using data from patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse-tran-scriptase polymerase chain reaction (RT-PCR) between February 1st and November 16th, 2020 (1st and 2nd waves in Switzerland, i.e. the original cohort) [2]. The revalidation cohort consisted of patients who tested posi-tive for SARS-CoV-2 between November 17th, 2020 and November 16th, 2021. The primary outcome was dis-ease severity, as determined by the worst outcome at any point after diagnosis:– Non-severe outcome: no intensive care unit (ICU) admission or death of any cause during the observa-tional period– Severe outcome: ICU admission at any stage and / or death of any causeAll patients were discharged or had died by the time the revalidation was performed.The COSA score (Table  1) was calculated for each patient using the most extreme laboratory values within 3 days prior to 1 day after the positive SARS-CoV-2 test. The results of the original and the revalidation cohort were then compared.Data wrangling, analysis, and visualization were per-formed in GNU R (version 4.0.2, [3]). Statistical sig-nificance levels were defined at a p-value of < 0.05, and determined with the Wilcoxon rank sum test for con-tinuous variables, and the Chi-square test for categori-cal variables using the stats package (version 4.0.2). The area under the receiver operating characteristic curve (AUROC) and the 95% confidence intervals (CI) were Open AccessJournal of Translational Medicine*Correspondence:  Felix.Hammann@insel.ch1 Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandFull list of author information is available at the end of the articlePage 2 of 5Schöning et al. Journal of Translational Medicine          (2022) 20:427 Table 1 COVID-19 severity assessment (COSA) score (from Ref. [2])The COSA score was calculated for each patient using the most extreme values within 3 days prior to 1 day after the positive SARS-CoV-2 test, with a score of 6 or higher indicating a high risk (> 50%) for a severe progressionParameter Value Score pointsSex Male 1CRP  ≥ 25 mg/L 3Sodium  ≥ 144 mmol/L 2Hemoglobin  ≤ 100 g/L 1eGFR according to CKD-EPI  ≤ 75 mL/min 1Glucose  ≥ 8.6 mmol/L 1Leucocytes  ≥ 10 G/L 1Table 2 General demographics and laboratory parameters of the original and revalidation cohortLaboratory parameters were considered from three day prior to until 1 day after the first positive SARS-CoV-2 PCR test resultIQR interquartile rangeBold numbers indicate significant differences (p < 0.05) between severe and non-severe cases.Non-severe (N = 758) Severe (N = 512)Original(N = 457)Revalidation(N = 301)P value Original(N = 171)Revalidation(N = 208)P valueDemographics Age (years)  Median(IQR)64.00 (49.00, 76.00) 72.00 (59.00, 82.00)  < 0.002 68.00 (57.00, 78.00) 72.00 (59.75, 82.25) 0.058 Sex  Female, n (%) 188 (41.05) 125 (41.81) 0.895 45 (26.32) 63 (30.29) 0.460 Hospitalization  Inpatients, n (%) 319 (69.58) 299 (100.00)  < 0.002 163 (95.27) 208 (100.00) 0.005 Deaths  Deceased, n (%) 0 (0.00) 0 (0.00) – 51 (29.82) 120 (57.69)  < 0.002 Weight (kg)  Median(IQR)77.90 (66.23, 88.00) 76.30 (65.62, 88.00) 0.526 81.00 (70.40, 93.70) 75.20 (65.20, 90.00) 0.026 Height (cm)  Median(IQR)170.00 (165.00, 176.00) 170.00 (163.00, 177.00) 0.241 170.00 (165.00, 176.00) 170.00 (165.00, 176.75) 0.883 Body Mass Index (BMI, kg/m2)  Median(IQR)25.98 (23.38, 29.74) 26.20 (23.29, 30.32) 0.489 28.07 (25.20, 31.20) 26.87 (23.28, 29.81) 0.018Laboratory parameters Maximum C-reactive protein (CRP) levels  Median (IQR) 37.00 (10.00, 78.00) 60.00 (21.00, 107.50)  < 0.002 106.00 (59.00, 175.00) 125.50 (62.00, 202.50) 0.300 Maximum sodium levels  Median (IQR) 139.00 (137.00, 141.00) 139.00 (137.00, 142.00) 0.262 142.00 (139.00, 145.00) 142.00 (138.00, 146.00) 0.901 Minimum hemoglobin levels  Median (IQR) 132.00 (118.00, 144.00) 126.00 (111.00, 142.00) 0.004 113.00 (89.50, 125.00) 107.50 (84.75, 124.25) 0.372 Minimum glomerular filtration rate (GFR) values  Median (IQR) 82.00 (61.00, 97.00) 75.00 (52.00, 93.00) 0.007 64.00 (39.50, 87.00) 56.00 (31.75, 84.25) 0.158 Minimum glucose values  Median (IQR) 6.40 (5.67, 7.90) 6.90 (6.00, 8.46) 0.002 9.50 (7.46, 12.55) 9.45 (7.18, 11.80) 0.393 Minimum leukocytes values  Median (IQR) 6.32 (4.70, 8.61) 6.41 (4.91, 9.09) 0.235 8.92 (6.65, 13.70) 10.90 (7.03, 15.12) 0.072Page 3 of 5Schöning et al. Journal of Translational Medicine          (2022) 20:427  calculated to assess the discriminatory power of the COSA score to predict a severe outcome. The COSA score was considered validated if the 95% CI of the AUROC from fitting the original and the revalidation data set were overlapping.The original cohort consisted of 626 patients (457 non-severe and 169 severe outcomes), and 508 patients were included in the revalidation cohort (301 non-severe and 208 severe outcomes). A comparison of the demograph-ics and laboratory parameters of both cohorts is provided in Table 2. The patients in the original non-severe cohort were significantly younger with a lower share of inpa-tients than in the non-severe revalidation cohort. The latter had significantly higher peak C-reactive protein (CRP) and glucose, and lower minimal hemoglobin and estimated glomerular filtration rate values. For severe patients, we noted a higher proportion of inpatients and deaths, and significantly lower body weights and body mass index in the revalidation cohort. There was no sig-nificant difference in laboratory parameters.The AUROC was 0.85 (95% CI 0.82–0.88) and 0.80 (95% CI 0.76–0.84) for the original and revalidation cohort, respectively (Fig.  1). A closer look at the sever-ity distribution per score value (Fig. 2) revealed a greater share of severe cases with low score values (0–4 points) in the revalidation cohort than in the original cohort. No major differences are noticeable for score points greater than 4.Patients in the revalidation cohort presented with over-all worse laboratory markers and a greater likelihood of severe outcomes compared to the original cohort (69.1% vs. 37.4%). This could be due to more selective labora-tory testing for hospitalized patients only and differences in circulating variants. Although no sequencing data is available for either cohort, national surveys indicate that the dominant strain during the 1st and 2nd waves (original cohort) was the ancestral type, whereas the 3rd and 4th waves (revalidation cohort) were driven by the more transmissible and virulent VOCs Alpha (B.1.1.7) and Delta (B.1.617.2) [4]. Vaccination campaigns and an emerging population-level immunity likely mitigated the individual disease severity [5].While the performance of the score remains robust with strong positive discriminative ability we did note a decrease in specificity towards the lower end of the scale (Fig.  2). This suggests that readjustment of the cut-offs might be beneficial for a better separation of the severity classes as new variants emerge.Despite changes in the viral landscape and population immunity, the COSA score still delivered good predictions of disease progression one year after its development. We attribute this to the simple set of covariates and the rigor-ous internal and external validation in the original model-building process. Adaptations to the score could become necessary in the near future as vaccination effects begin to wane and if drastically different VOCs appear.Fig. 1 Area under the receiver operating characteristic (AUROC) of the COVID-19 severity assessment (COSA) score. Original (red) and revalidation cohort (blue)Page 4 of 5Schöning et al. Journal of Translational Medicine          (2022) 20:427 Fig. 2 Percentage amount of patients with severe and non-severe COVID-19 in relation to score points in the original (A) and revalidation (B) cohortPage 5 of 5Schöning et al. Journal of Translational Medicine          (2022) 20:427  • fast, convenient online submission •  thorough peer review by experienced researchers in your field•  rapid publication on acceptance•  support for research data, including large and complex data types•  gold Open Access which fosters wider collaboration and increased citations  maximum visibility for your research: over 100M website views per year •  At BMC, research is always in progress.Learn more biomedcentral.com/submissionsReady to submit your research ?  Choose BMC and benefit from: AbbreviationsAUROC: Area under the receiver operating characteristic; BMI: Body mass index; COSA: COVID-19 severity assessment; COVID-19: Coronavirus disease 19; CRP: C-reactive protein; eGFR: Estimated glomerular filtration rate; ICU: Intensive Care Unit; RT-PCR: Reverse-transcriptase polymerase chain reaction; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; VOC: Variants of concern.AcknowledgementsWe thank Noel Frey, Myoori Wijayasingham, and the Insel Data Coordination Lab for database and infrastructure support.Author contributionsFH and VS conceptualized this study. VS and FH performed the data analysis and drafted the manuscript. AA assessed the machine learning models and statistics, EL, CB, AE, and WH assessed the clinical score. All authors read and approved the final manuscript.FundingNone to declare.Availability of data and materialsThe source code and corresponding input file are available on GitHub: https:// github. com/ cptbe rn/ COSAs core. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.DeclarationsEthics approval and consent to participateThe study was approved by the Cantonal Ethics Committee of Bern (Project-ID 2020–00973). Participants either agreed to a general research consent or, for participants with no registered general research consent status (neither agree-ment nor rejection), a waiver of consent was granted by the ethics committee.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Author details1 Clinical Pharmacology and Toxicology, Department of General Internal Medi-cine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 2 Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 3 Department of Emergency Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 4 Pediatric Pharmacology and Pharmacometrics Research Group, University Children’s Hospital, Basel, Switzerland. 5 Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Received: 8 September 2022   Accepted: 10 September 2022References 1. Wynants L, Van Calster B, Collins GS, Riley RD, Heinze G, Schuit E, Bonten MMJ, Dahly DL, Damen JA, Debray TPA, et al. Prediction models for diag-nosis and prognosis of covid-19: systematic review and critical appraisal. BMJ. 2020;369: m1328. 2. Schöning V, Liakoni E, Baumgartner C, Exadaktylos AK, Hautz WE, Atkin-son A, Hammann F. Development and validation of a prognostic COVID-19 severity assessment (COSA) score and machine learning models for patient triage at a tertiary hospital. J Trans Med. 2021;19:56. 3. R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2022. 4. Covid-19 Schweiz: Epidemiologischer Verlauf, Schweiz und Liechten-stein, Virusvarianten. https:// www. covid 19. admin. ch/ de/ epide miolo gic/ virus- varia nts? time= total & varia nts= Varia ntB11 529,Varia ntB16 172,Varia ntP1,Varia ntB13 51,Varia ntB11 7,Varia ntC37 ,Varia ntB16 171,Varia ntP2,Varia ntB15 25,Varia ntB15 26. Accessed 5 July 2022. 5. Zeng B, Gao L, Zhou Q, Yu K, Sun F. Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern: a systematic review and meta-analysis. BMC Med. 2022;20:200.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in pub-lished maps and institutional affiliations.

Revalidating the prognostic COVID-19 severity assessment (COSA) score for variants of concern.

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Revalidating the prognostic COVID-19 severity assessment (COSA) score for variants of concern.

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