Teklay Gebrecherkos,1 Feyissa Challa,2 Geremew Tasew,3 Zekarias Gessesse,4 Yazezew Kiros,4 Atsbeha Gebreegziabxier,5 Mahmud Abdulkader,1 Abraham Aregay Desta,6 Ataklti Hailu Atsbaha,7 Getachew Tollera,8 Saro Abrahim,5 Britta C Urban,9 Henk Schallig,10 Tobias Rinke de Wit,11,12 Dawit Wolday1,5 1Department of Medical Microbiology and Immunology, College of Health Sciences (CHS), Mekelle University (MU), Mekelle, Tigray, Ethiopia; 2National Reference Laboratory for Clinical Chemistry, Ethiopian Public Health Institute, Addis Ababa, Ethiopia; 3Department of Bacteriology, Parasitology and Zoonosis, Ethiopian Public Health Institute, Addis Ababa, Ethiopia; 4Department of Internal Medicine, College of Health Sciences, Mekelle University, Mekelle, Tigray, Ethiopia; 5HIV/TB Research Directorate, Ethiopian Public Health Institute, Addis Ababa, Ethiopia; 6Public Health Research and Emergency Management, Tigray Health Research Institute, Mekelle, Tigray, Ethiopia; 7Department of Microbiology, Tigray Health Research Institute, Mekelle, Tigray, Ethiopia; 8Research and Technology Transfer Directorate, Ethiopian Public Health Institute, Addis Ababa, Ethiopia; 9Department of Clinical Sciences, Respiratory Clinical Research Group, Liverpool School of Tropical Medicine, Liverpool, UK; 10Department of Medical Microbiology and Infection Prevention, Experimental Parasitology Unit, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; 11Amsterdam Institute of Global Health and Development, Department of Global Health, Amsterdam University Medical Center, Amsterdam, the Netherlands; 12Joep-Lange Institute, Amsterdam, the NetherlandsCorrespondence: Teklay Gebrecherkos, Department of Medical Microbiology and Immunology, Mekelle University, P.O. Box 1871, Mekelle, Tigray, Ethiopia, Email estiftg17@gmail.comPurpose: To evaluate the role of C-reactive protein (CRP) in predicting severe COVID-19 patients.Methods: A prospective observational cohort study was conducted from July 15 to October 28, 2020, at Kuyha COVID-19 isolation and treatment center hospital, Mekelle City, Northern Ethiopia. A total of 670 blood samples were collected serially. SARS-CoV-2 infection was confirmed by RT-PCR from nasopharyngeal swabs and CRP concentration was determined using Cobas Integra 400 Plus (Roche). Data were analyzed using STATA version 14. P-value < 0.05 was considered statistically significant.Results: Overall, COVID-19 patients had significantly elevated CRP at baseline when compared to PCR-negative controls [median 11.1 (IQR: 2.0– 127.8) mg/L vs 0.9 (IQR: 0.5– 1.9) mg/L; p=0.0004)]. Those with severe COVID-19 clinical presentation had significantly higher median CRP levels compared to those with non-severe cases [166.1 (IQR: 48.6– 332.5) mg/L vs 2.4 (IQR: 1.2– 7.6) mg/L; p< 0.00001)]. Moreover, COVID-19 patients exhibited higher median CRP levels at baseline [58 (IQR: 2.0– 127.8) mg/L] that decreased significantly to 2.4 (IQR: 1.4– 3.9) mg/L after 40 days after symptom onset (p< 0.0001). Performance of CRP levels determined using ROC analysis distinguished severe from non-severe COVID-19 patients, with an AUC value of 0.83 (95% CI: 0.73– 0.91; p=0.001; 77.4% sensitivity and 89.4% specificity). In multivariable analysis, CRP levels above 30 mg/L were significantly associated with an increased risk of developing severe COVID-19 for those who have higher ages and comorbidities (ARR 3.99, 95% CI: 1.35– 11.82; p=0.013).Conclusion: CRP was found to be an independent determinant factor for severe COVID-19 patients. Therefore, CRP levels in COVID-19 patients in African settings may provide a simple, prompt, and inexpensive assessment of the severity status at baseline and monitoring of treatment outcomes.Keywords: CRP, COVID-19, SARS-CoV-2, biomarker