key: cord-0941473-zghlogmr authors: Vultaggio, Alessandra; Vivarelli, Emanuele; Virgili, Gianni; Lucenteforte, Ersilia; Bartoloni, Alessandro; Nozzoli, Carlo; Morettini, Alessandro; Berni, Andrea; Malandrino, Danilo; Rossi, Oliviero; Nencini, Francesca; Pieralli, Filippo; Peris, Adriano; Lagi, Filippo; Scocchera, Giulia; Spinicci, Michele; Trotta, Michele; Mazzetti, Marcello; Parronchi, Paola; Cosmi, Lorenzo; Liotta, Francesco; Fontanari, Paolo; Mazzoni, Alessio; Salvati, Lorenzo; Maggi, Enrico; Annunziato, Francesco; Almerigogna, Fabio; Matucci, Andrea title: Prompt predicting of early clinical deterioration of moderate-to-severe COVID-19 patients: usefulness of a combined score using IL-6 in a preliminary study date: 2020-06-19 journal: J Allergy Clin Immunol Pract DOI: 10.1016/j.jaip.2020.06.013 sha: 2c4dcd8db9204760173ddd388484ea61c2727f22 doc_id: 941473 cord_uid: zghlogmr Abstract Background The early identification of patients at risk of clinical deterioration is of interest considering the timeline of COVID-19 after the onset of symptoms. Objective The aim of our study was to evaluate the usefulness of testing serum IL-6 and other serological and clinical biomarkers, to predict a short-term negative clinical course of non critical COVID-19 patients. Methods 208 patients with non critical COVID-19 pneumonia at admission were consecutively enrolled. Clinical and laboratory findings obtained upon admission were analyzed by using survival analysis and stepwise logistic regression for variable selection. Three-day worsening as outcome in a logistic model to generate a prognostic score was used. Results Clinical worsening occurred in 63 patients (16=died; 39=transferred to Intensive Care Unit; 8 worsening of respiratory failure). Forty-five of them worsened within 3 days after admission. The risk of clinical worsening was progressively enhanced along with increasing quartiles of IL-6 levels. Multivariate analysis showed that IL-6 (p=0.005), CRP (p=0.003) and SaO2/FiO2 (p=0.014) and were the best predictors for clinical deterioration in the first 3 days after admission. The combined score yielded an AUC=0.88 (95% CI 0.83–0.93). A nomogram predicting the probability of 3-day worsening was generated. The score also showed good performance for 7-day and 14-day or 21-day worsening and in predicting death occurring during all the follow-up. Conclusions Combining IL-6, CRP and SaO2/FiO2 in a score, may help clinicians to identify upon admission those patients with COVID-19 who are at high risk for a further 3-day clinical deterioration. In December 2019, a novel coronavirus disease (COVID-19) was reported in China caused by 89 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of infected patients 90 has increased rapidly worldwide and at the end of January 2020, the first two cases in Italy were 91 recorded. More than 140.000 cases have been confirmed in Italy, so far, with an high case fatality Statistical analysis 167 We used survival analysis to investigate the prognostic value of basal IL-6, both as a linear term and 168 as quartiles in a Cox model. We computed Harrell's C as an overall measure of discrimination for 169 all candidate covariates as linear continuous variables. A 3-day worsening as a response variable in a logistic model to generate a prognostic score, was 171 used because most patients worsened within 3 days following admission. We used stepwise logistic 172 regression for variable selection, with a forward procedure and an entry probability of 0.1. Model-based discrimination was assessed using the Area Under the Curve (AUC) and calibration 174 was assessed using the Hosmer and Lemeshow goodness-of-fit test. Finally we generated a nomogram to calculate an overall score and the corresponding probability of 176 3-day worsening, with the main purpose of presenting graphically the impact of each predictive 177 variable. Continuous variables were summarized using mean and standard error and compared using 179 Student's t-test. All tests were two-sided and a P value of <0.05 was considered significant. All 180 calculations were done using Stata 16.1 software (StataCorp, College Station, TX). 186 We first investigated IL-6 serum levels in all enrolled patients. 131/208 patients (62.9%) displayed 187 IL-6 serum levels higher than the positive cut-off (10 pg/ml), with a mean value (±SD) of 27±40.9. No significant differences (p=0.158) in IL-6 serum levels were noted between males (29.9±45.6) 189 and female (21.5±29.9). It is important to note that baseline IL-6 was weakly but significantly 190 associated with age (Spearman r=0.24, p<0.001). In a small proportion of our cases, an increase of TNF-α and /or IL-10 was observed. Specifically, The predictive value of IL-6 was maintained when age and sex were added to the Cox model (Table 217 2; LR test for overall effect of IL-6 quartiles p=0.008), with age (p=0.028) but not sex (p=0.073) 218 crossing the threshold of nominal statistical significance. Relationship between IL-6 and other serological measures 221 Taking into account that IL-6 is essential for CRP synthesis in the liver and many other laboratory Table 1 ). Predictive performance of a combined score including IL-6, CRP and SF ratio 230 In logistic regression models, several variables were strongly associated with 3-day worsening patients in order to more appropriately allocate them into low-or medium-intensity care settings. To our knowledge, this is the first study that combines clinical parameters (SF ratio) and serological 276 biomarkers (IL-6 and CRP) in the prediction of clinical deterioration of moderate-to-severe 277 COVID-19 patients. It is important to note that our suggested combined score is predictive of disease evolution patients to the appropriate care setting. Although, older age and comorbidities were significantly associated with higher risks of the 297 development of acute respiratory distress syndrome, 5 an overall comorbidity measure such as the 298 age-adjusted Charlson Comorbidity Index did not improve our predictive model. The identification of patients at risk as early as possible would also allow more appropriate anti- produced during immune-mediated inflammatory processes, is the main driver for CPR production 316 by hepatocytes, 21 therefore, we might speculate a rise in serum IL-6 before the increase of CRP. Therefore IL-6 serum levels could be considered as a very early biomarker in COVID-19 patients. This biological relationship between IL-6 and CRP synthesis, may explain why both IL-6 and CRP 319 maintain higher significant predictive power in comparison to the other parameters in our step-wise 320 statistical analysis. Thromboembolism is rapidly emerging as a key clinical concern in COVID-19 in addition to Pathogenic human coronavirus infections: causes and severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell 419 therapy Biomarkers of cytokine release syndrome and neurotoxicity related to 421 CAR-T cell therapy COVID-19 and its implications for thrombosis and 423 anticoagulation Tocilizumab treatment in COVID-19: a single 425 center experience Weathering the cytokine storm in 427 susceptible patients with severe SARS-CoV-2 infection We thank Mrs Jane Griffith for English language revision.