key: cord-0792334-zfomom6e authors: Gasalla, M. G.; Ferrer, J. M.; Fraile-Ribot, P. A.; Ferre-Beltran, A.; Rodriguez, A.; Martinez-Pomar, N.; Ramon-Clar, L.; Iglesias, A.; Fanjul, F.; Pou, J. A.; LLompart, I.; Losada, I.; Toledo, N.; Pons, J.; Oliver, A.; Riera, M.; Murillas, J. title: PREDICTIVE IMMUNOLOGICAL, VIROLOGICAL, AND ROUTINE LABORATORY MARKERS FOR CRITICAL COVID-19 ON ADMISSION.Immunocovid study date: 2021-03-20 journal: nan DOI: 10.1101/2021.03.17.21253816 sha: 79a385f58fc89701c7325746a4b762c1e2efdef5 doc_id: 792334 cord_uid: zfomom6e Introduction: Early identification of COVID-19 patients at risk of critical illness is challenging for clinicians. Immunological, virological, and routine laboratory markers to be used in addition to clinical data are needed. Aim and methods: Blood tests to measure neutrophil/lymphocyte ratio (NLR), levels of ferritin, CRP, D-dimer, complement components (C3, C4), lymphocyte subsets, and cytokines, and SARS-Cov2 RT-PCR tests were performed in COVID-19 confirmed cases within 48 hours of admission. Cycle threshold (Ct) values were determined by RT-PCR from oral or nasopharyngeal swabs on the day of admission. Severity of symptoms was categorized as mild (grade 1), severe (grade 2), and critical (grade 3). Results: 120 patients were included. COVID-19 was mild in 49, severe in 32, and critical in 39. Ferritin >370 ng/mL (OR 16.4, 95% CI 5.3-50.8), D-dimer >440 ng/mL (OR 5.45, 95% CI 2.36-12.61), CRP >7.65 mg/dL (OR 11.54, 95% CI 4.3-30.8), NLR >3.77 (OR 13.4, 95% CI 4.3-41.1), IL-6 >142.5 pg/mL (OR 8.76, 95% CI 3.56-21.54), IL-10 >10.8 pg/mL (OR 16.45, 95% CI 5.32-50.81), sIL-2r (sCD25) >804.5 pg/mL (OR 14.06, 95% CI 4.56-43.28), IL-1Ra >88.4 pg/mL (OR 4.54, 95% CI 2.03-10.17), and IL-18 >144 pg/mL (OR 17.85, 95% CI 6.54-48.78) were associated with critical COVID-19 in the univariate age-adjusted analysis. In the multivariate age-adjusted analysis, this association was confirmed only for ferritin, CRP,NLR, IL-10, sIL-2r, and IL-18. T, B, and NK cells were significantly decreased in critical patients. SARS-CoV-2 was undetected in blood except in 3 patients with indeterminate results. Ct values determined by RT-PCR from oral/nasopharyngeal swabs on admission were not related to symptom severity. Conclusion: levels of ferritin, D-dimer, CRP, NLR, and cytokines and cytokine receptors IL-6, IL1-Ra, sCD25, IL-18, and IL-10, taken together with clinical data, can contribute to the early identification of critical COVID-19 patients. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted March 20, 2021. ; https://doi.org/10.1101/2021.03.17.21253816 doi: medRxiv preprint transcription polymerase chain reaction (RT-PCR) from nasopharyngeal swabs, which 79 determines viral load through cycle threshold (Ct) values, with lower Ct values associated 80 with worse outcomes [14] . Moreover, SARS-CoV-2 viremia has been reported in severe 81 cases [15] . 82 The purpose of our study was to identify routine laboratory, immunological and 83 virological biomarkers to be used together with clinical data for early identification of patients 84 at risk of developing critical illness. The severity of signs and symptoms developed during hospitalization was categorized as 94 mild (grade 1), severe (grade 2), and critical (grade 3). Mild disease was established when 95 the patient had symptoms without pneumonia or had mild pneumonia; severe disease was 96 established when dyspnea was associated with a respiratory rate ≥30/min or blood oxygen 97 saturation <93%, or a partial pressure of arterial oxygen to fraction of inspired oxygen ratio 98 <300, and/or lung infiltrates >50% within 24 to 48 hours from admission; critical disease 99 was established for cases with respiratory failure, septic shock, and/or multiple organ 100 dysfunction or failure [1] . The most severe category developed during hospitalization was 101 selected, and it occurred in the first 72h of admission in all cases. 102 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Between 17 April and 20 July 2020, 120 laboratory-confirmed SARS-CoV-2 patients 147 accepted to participate and were included in the study. There were 55 women and 65 men, 148 and median age was 59 years (29-89). COVID-19 was considered mild in 49 patients, severe 149 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in of 2 of them was not related to COVID-19 but to an associated malignancy. Pulmonary 151 embolism (PE) was diagnosed in 15 patients (12.5%), and of these, 9 had critical COVID-19. Demographic characteristics and comorbidities of SARs-COV-2 infected patients with mild, 153 severe, and critical disease are presented in Table 1 . Compared with patients with mild or 154 severe disease, critically ill patients were significantly more likely to be men (p = .00), have 155 older age (p = .036), concomitant hypertension (p = .036), and diabetes mellitus (p = .023). -Laboratory data: Laboratory markers were tested on admission ( perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Levels of IL-6, sIL-2rα (sCD25), IL-1β, IL-1Ra, IL-8, IL-17A, IL-18, IL-22, IFN, IL-10, 174 and TNF-α were analyzed (Table 3) . IL-6, IL-10, sIL-2rα, IL-1Ra, and IL-18 levels were 175 significantly elevated on admission in patients who developed a critical disease. A cut-off 176 value for each of these markers was determined to predict the risk of developing a critical 177 COVID-19 ( Figure 1 ). Values of IL-6 > 142.5 pg/mL, IL-10 > 10.8 pg/mL, IL1β > 4.68pg/ml , 178 sIL-2rα > 804.5 pg/mL, IL-1Ra > 88.4 pg/mL, and IL-18 > 144 pg/mL were associated with 179 the development of critical COVID-19 in the age-adjusted univariate analysis. In the age-180 adjusted multivariate analysis, this association was confirmed only for IL-10, sIL-2rα, and IL-181 18 (Table 4) . perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted March 20, 2021. ; https://doi.org/10.1101/2021.03.17.21253816 doi: medRxiv preprint The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. 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