Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a Long-term Care Facility during Covid-19 Outbreak

Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a Long-term Care Facility during Covid-19 Outbreak | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a Long-term Care Facility during Covid-19 Outbreak Peter Sabaka, Alena Koščálová, Igor Straka, Julius Hodosy, Robert Lipták, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-42503/v3 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Mar, 2021 Read the published version in BMC Infectious Diseases → Version 3 posted 3 You are reading this latest preprint version Show more versions Abstract Background: Covid-19 is a disease with high morbidity and mortality among elderly residents of long-term care facilities (LTCF). During an outbreak of SARS-CoV-2 infection in the LTCF an effective screening tool is essential to identify the patients at risk for severe illness and death. We explored the role of interleukin 6 (IL-6) as a predictor for severe disease during the outbreak of Covid-19 in one LTCF in Slovakia. Methods: We conducted a retrospective data analysis of cases of COVID-19, diagnosed during the outbreak in one LTCF in Slovakia between April 11, 2020, and May 5, 2020. Within 24 hours after the diagnosis of Covid-19, clinical and laboratory screening was performed in the LTCF to identify patients in need of hospitalization. Patients with oxygen saturation below 90% were immediately referred to the hospital. Patients staying in the LFTC were monitored daily and those that developed hypoxemia were transferred to the hospital. We analyzed the association between the IL-6 at the initial assessment and development of hypoxemia during follow up and determined the cut-off of the IL-6 able to predict the development of hypoxemia requiring oxygen therapy. Results : Fifty-three patients (11 men, 42 women) with diagnosed Covid-19 were included in the analysis. 19 (53%) patients developed hypoxemia during the disease. Patients with hypoxemia had significantly higher concentrations of IL-6, C-reactive protein, procalcitonin, fibrinogen, total bilirubin, aspartate aminotransferase and alanine aminotransferase at initial screening. ROC analyses identified IL-6 as the most robust predictor of hypoxemia. The concentration of IL-6 > 24 pg/mL predicted the development of hypoxemia with the sensitivity of 100% and specificity of 88.9%. The positive and negative predictive values were 76.9%, and 100% respectively. Conclusions : The concentration of IL-6 > 24 pg/mL at initial assessment predicted the development of hypoxemia requiring hospitalization with excellent sensitivity and good specificity. IL-6 appears as a potential predictor for the development of the severe Covid-19 and might serve for early identification of patients in need of hospitalization. Further studies are needed to evaluate the robustness of the use of IL-6 as an effective screening tool for the severe course of Covid-19. Infectious Diseases Covid-19 Long-term care facility Interleukin 6 hypoxemia Background Coronavirus disease 2019 (Covid-19) is a disease caused by the zoonotic novel Coronavirus called SARS-CoV-2 [1]. Covid-19 quickly spread across the globe from a place of its origin in Hubei China and pandemic was declared by WHO on March 11, 2020 [2]. Most patients with Covid-19 experience mild self-limiting disease. However, up to 20% of known cases of Covid-19 are complicated by severe pneumonia which might result in acute respiratory distress syndrome (ARDS) which causes acute hypoxemic respiratory failure [1,3]. The overall infection fatality ratio is estimated to be below 1% [4]. It should be noted that fatal outcome may occur at any age including children and young adults [5]. Also, physiologic condition, pregnancy is associated with higher risk of severe disease [7]. However, the risk of death in Covid-19 is increasing with age and a presence of comorbidities, especially cardiovascular diseases, diabetes mellitus and obesity [3]. According to data from the early China epidemic, the case-fatality ratio in the patients over 80 is up to 15% [7]. Elderly and highly comorbid residents of long-term care facilities (LTCF) are at high risk of Covid-19 associated morbidity and mortality [8, 9, 10]. In one well-documented outbreak in LTCF in Washington, USA, more than half of the infected residents required hospitalization and more than one third died [10]. On the background of the ongoing pandemic, the spreading of Covid-19 in LTCF might significantly burden the local health care system and markedly contributes to mortality. Timely and effective intervention is essential to reduce morbidity and mortality during the Covid-19 outbreak in the LTCF. Such intervention consists of quick identification of cases, immediate introduction of infection control measures, initial triage, and daily monitoring of patients. An effective screening tool is essential to identify the patients at risk for severe illness and death [11]. Such patients need close monitoring and early transfer to the hospital. Various biomarkers, especially inflammatory markers like C-reactive protein (CRP), ferritin, fibrinogen, D-dimer and Interleukin 6 (IL-6) are associated with Covid-19 progression [12, 13]. According to known evidence, IL-6 is superior to CRP and other markers of inflammation in predicting respiratory failure in Covid-19 [18, 19]. IL-6 appears to be the most important driver of immune dysregulation and ARDS in Covid-19 [20, 21, 22, 23]. The role of systematic measurement of IL-6, CRP, and other markers of inflammation at the initial assessment during Covid-19 outbreak in LTCF and its ability to predict the severe course of disease is yet to be determined. Methods We conducted a retrospective data analysis of laboratory-confirmed cases of COVID-19, diagnosed during the outbreak in one LTCF in Slovakia between April 11, 2020, and May 5, 2020. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase–polymerase-chain-reaction assay of nasopharyngeal swab specimens for SARS-CoV-2. In our analysis, we aimed to identify laboratory markers predicting the severe course of the disease at the initial assessment. Intervention Within 24 hours after the diagnosis of COVID-19, clinical and laboratory screening was performed in the LTCF by trained clinicians to identify patients in need of hospitalization. The clinical initial assessment consisted of measurement of vital signs (blood pressure, heart rate respiratory rate) and measurement of oxygen saturation by pulse oximetry. Additionally, the venous blood was drawn to measure concentrations of serum glucose, creatinine, urea, sodium, potassium, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), CRP, D-dimer, IL-6 and complete blood count. The blood samples were immediately transported to laboratory. The results were obtained and evaluated from 4 to 6 hours after last blood drawn. After an initial assessment, daily monitoring consisting of measurement of vital signs and measurement of oxygen saturation by pulse oximetry was performed by the same clinician. The development of hypoxemia with oxygen saturation below 90% was considered as the criteria for severe disease with the need for hospitalization. Patients with oxygen saturation below 90% at the initial screening or during the daily monitoring were immediately referred to the hospital. Biochemical analysis: Concentrations of serum glucose, creatinine, urea, sodium, potassium, bilirubin, ALT, AST, were measured using spectrophotometry (Cobas Integra 400, Roche Diagnostics, Rotkreuz, Switzerland). CRP and D-dimer were measured using immunoturbidimetry (Cobas Integra 400, Roche Diagnostics, Rotkreuz, Switzerland). Serum IL-6 concentrations were measured using an immunoassay (Elecsys, Roche Diagnostics, Rotkreuz, Switzerland). Statistical analysis: Quantitative variables are expressed as medians and 25th and 75th percentiles. Data in our cohort according to the Kolmogorov-Smirnov test were non-parametric. Medians of quantitative variables between groups were compared using the Mann-Whitney nonparametric test. Effect sizes were assessed using Cohen's d. Receiver operating characteristic curve (ROC) analysis was used to compare markers of hypoxemia. Only the biomarkers with different medians between groups were evaluated in ROC analysis. Optimal cut off values were also determined using ROC analysis. Sensitivity was calculated as the number of true positive divided by true positive + false negative. Specificity was calculated as the number of true negative divided by true negative + false positive. Association of baseline serum concentration of IL-6 > 24 pg/mL with the probability of development of hypoxemia requiring oxygen therapy (HRO) was assessed using multivariate logistic regression. For statistical analysis, SPSS version 26 (International Business Machines Corporation, Armonk, NY, USA) was used. Ethics : This study was carried out in concordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans and was approved by the local Ethical Committee of University Hospital Bratislava. The participants signed informed consent. The investigators preserved the full anonymity of all participants. Results During the intervention in the LTCF, 78 subjects were screened for COVID-19 and 59 patients (47 women, 12 men) had positive pharyngeal swabs for SARS-CoV-2 RNA by RT-PCR and were diagnosed with Covid-19. 53 patients (90%) had blood sampling during the initial screening phase. In 6 patients, blood sampling was not performed because of technical difficulties. These patients were excluded from the study. In 53 patients (11 men, 42 women) in which blood sampling was performed, the clinical variables and the results of biochemical and blood count analysis were available for evaluation and were included in the study. 7 patients (1 man, 6 women) were diagnosed with severe disease in initial triage and were immediately transferred to a hospital within the first two days of intervention. Remaining 45 patients (10 men, 36 women) remained under observation in LTCF and were screened for severe disease and triaged on a daily basis by the intervention team. Overall, 32 patients (6 men, 26 women) were admitted. Among these patients, 19 (2 men, 17 women) had hypoxemia required oxygen therapy, 16 patients (2 men, 14 women) were admitted to ICU, and 13 patients (2 men, 12 women) died. In 11 patients (1 man, 10 women) initially suffering from hypoxemia requiring oxygen therapy, the disease progressed, and they required intubation and mechanical ventilation. All these patients died because of severe ARDS. 1 male, initially suffering from hypoxemia requiring oxygen therapy died because of severe gastrointestinal bleeding from gastric adenocarcinoma. 1 female, initially suffering from hypoxemia requiring oxygen therapy suddenly died after short period of clinical improvement. An autopsy revealed pulmonary embolism. In hospitalized patients, various severe complications were observed. 6 patients developed deep vein thrombosis, 6 developed congestive heart failure, 3 patients developed new atrial fibrillation and 5 developed acute renal failure. Baseline characteristics of patients are provided in table 1. Major clinical findings of all enrolled patients are provided in supplementary table. The baseline serum concentrations of IL-6, CRP, procalcitonin, urea, creatinine, fibrinogen, AST, ALT, fasting glucose, total bilirubin and neutrophil count were significantly higher, and lymphocyte and eosinophil count was significantly lower in patients who developed hypoxemia. All patients included in our study seroconverted and developed IgG antibodies within 1 month of diagnosis. The median of baseline serum concentrations of D-dimer and ferritin and a median total count of leukocytes were not significantly different among groups of patients with and without hypoxemia requiring oxygen therapy. Patients who developed hypoxemia requiring oxygen therapy were also significantly more comorbid according to the higher median Charlson Comorbidity Index (tab. 1). In the ROC analysis, IL-6 was identified as more robust marker of hypoxemia development than CRP, procalcitonin, CRP, fibrinogen, ALT, AST and total bilirubin and lymphocyte, neutrophil and eosinophil blood count. However, all of these variables were associated with hypoxemia (tab. 2). The cut-off of 24 pg/mL for IL-6 showed the best combination of sensitivity and specificity. In the group of all screened LTCF residents, baseline IL-6 concentration > 24 pg/mL predicted the development of hypoxemia with a sensitivity of 88% and specificity of 89%. PPV of 83%, and NPV of 93%. After excluding the 7 patients diagnosed with severe Covid-19 and transferred to the hospital after the initial assessment, baseline IL-6 concentration over 24 pg/mL predicted the development of hypoxemia during the daily monitoring in the LTCF with the sensitivity of 100%, specificity 89, PPV of 77%, and NPV 100% (tab. 3). Baseline CRP concentration with cut-off of 24 mg/L showed sensitivity and especially specificity inferior to IL-6 (tab. 4). In multivariate analysis, baseline IL-6 concentration > 24 pg/mL was positively associated with the risk of hypoxemia development during follow up in LTCF residents after adjustment for CRP, age, gender, and glomerular filtration rate (tab. 5). Discussion Our retrospective data analysis evaluated the potential role of biomarkers of inflammation, IL-6, CRP, procalcitonin, D-dimer and fibrinogen in the prediction of severe disease and need for oxygen therapy in residents of LTCF during Covid-19 outbreak. It suggests that IL-6 is a most robust predictor of hypoxemia requiring oxygen therapy. The concentration of IL-6 > 24 pg/mL at the initial assessment is showing the best combination of sensitivity and specificity in predicting the hypoxemia requiring oxygen therapy. There is a substantial body of evidence linking the IL-6 concentration to the severity of disease and unfavorable outcome of Covid-19 [13, 14, 15, 16, 17, 18, 20, 21, 22]. However, to our knowledge, this study is the first study which evaluated the ability of IL-6 to predict the need for supplementary oxygen administration as a surrogate marker of severe Covid-19 requiring hospital admission in the population of high risk elderly patients. It also suggests clinical implications for intervention procedures for Covid-19 outbreak in LTCF. Han et al. examined the predictive value of various cytokines and concluded that IL-6 is the best predictor of severe Covid-19 [18]. A metanalysis of 9 studies concluded that increased IL-6 is highly associated with severe disease. In this study, patients with severe Covid-19 had mean IL-6 58 pg/mL compared to 17 pg/mL in mild disease [16]. A study by Herold et al. found that IL-6 > 80 pg/mL the predicts respiratory failure and need for mechanical ventilation in Covid-19. Like in our study, IL-6 was superior to CRP in ROC analysis. Chen et al. found cut-off 80 pg/mL of IL-6 differentiates the survivors from the non-survivors [17]. We suggest that we found much lower optimal cut-off value (24 pg/mL compared to 80 pg/mL) because we choose less severe endpoint (need for supplementary oxygen). Overall, we can conclude that our study is in concordance with previous studies and adds new aspects to the known body of evidence. Clinical significance and implications: The residents of LTCF are one of the most vulnerable populations of the Covid-19 pandemic [8, 9, 10]. The outbreak of Covid-19 in LTCF might significantly burden the local health care system. Timely and effective intervention is essential to reduce morbidity and mortality during such outbreak. According to the proposed guideline by Kim et al., the first phase of response should include broad testing a quick identification of cases and their clinical assessment and triage. In the next phase, monitoring of patients should be implemented in order to quickly identify the patients in need of hospital care [11]. Identification of patients at high risk of deterioration during the initial assessment may significantly improve the monitoring process by allocating the resources to high-risk patients more effectively. Especially in the case of limited human resources, the focus on high-risk patients is might contribute to mortality reduction and improve the overall outcome of the outbreak. In our study, all patients that developed hypoxemia requiring oxygen therapy during the follow up had the baseline concentration of IL-6 over 24 pg/mL. As a screening tool, it provides excellent sensitivity with an acceptable specificity over 88%. It may be used to identify the patients with a high risk of hypoxemia. It also identifies the patients with low risk for hypoxemia with great negative predictive value. This might help in the decision making for admission during the initial triage. Baseline CRP concentration with cut-off of 24 mg/L showed sensitivity and especially specificity inferior to IL-6, however, might be used as cheaper alternative in low resource setting. For the purposes of our study, we defined that the residents that developed hypoxemia requiring oxygen therapy are the cases that needed close monitoring and early transfer to the hospital. The rationale is that patients who developed hypoxemia requiring oxygen therapy are those that might benefit from the early pharmacological treatment in order to reduce mortality. According to the body of evidence on remdesivir and dexamethasone, these drugs significantly improves the outcome in the patients needing conventional oxygen therapy [24, 25, 26]. Thus, the patients with early disease but in the high risk of development of hypoxemia are those patients who will profit from close observation and rapid initiation of remdesivir and dexamethasone in case of progression of Covid-19. IL-6 and development of severe Covid-19 : IL-6 is produced by stromal cells and virtually all immune system cells in the lungs and its secretion is stimulated by proinflammatory cytokines, especially interleukin 1β (IL-1β) and tumor necrosis factor α (TNFα). In the early stages of the infection, it is produced by lung macrophages after stimulation of toll-like receptors [27]. An important trait of IL-6 upregulation in Covid-19 is that it precedes the development of acute lung injury that implicates its usability as an early marker of severe disease [16]. However, there is controversy if excessive IL-6 synthesis is true a cornerstone of the pathogenesis of respiratory failure in Covid-19 or is just an epiphenomenon of increased IL-1β and TNFα in the cytokine storm [20]. Predominant theory is that overexpression of IL-6 have a crucial role in the incitement and propagation of the so-called cytokine storm leading to lung injury and ARDS [20, 21]. It is believed that IL-6 increases the permeability of lung capillaries driving the ARDS development and also stimulates the coagulation pathway leading to microthrombi in lung circulation and increases the risk of thrombotic event [27]. A study by Giamarellos-Bourboulis et al. suggests that patients with severe respiratory failure in Covid-19 suffer from distinct types of immune dysregulation which are mediated by IL-6 upregulation. This dysregulation is characterized by high production of proinflammatory cytokines by monocytes and macrophages and CD4 lymphocyte depletion that contributes to the progression of inflammation of lung parenchyma [21]. The direct role of IL-6 in Covid-19 pathogenesis is further supported by findings that IL-6 inhibition improves the prognosis of severe Covid-19 [29, 27]. Other markers of severe disease: In our study, patients who developed hypoxemia had significantly higher serum concentrations of AST, ALT, CRP, serum glucose, creatinine, procalcitonin, and fibrinogen. They also had significantly higher blood count of neutrophils and lower count of lymphocytes and eosinophils. These variables were identified as markers of severe disease by the previous studies [13]. Medians of other well-established markers of serious disease, D-dimer and ferritin were higher in patients who developed hypoxemia, however, the differences were not statistically significant. Using ROC analysis, we concluded that IL-6 is better marker of hypoxemia than CRP or other evaluated variables. Other proinflammatory cytokines, like IL-1β or TNF-α are also associated with severity of Covid-19 and might also serve as biomarkers [30, 32]. However, because the primary goal of our study was to improve the practical algorithm for intervention in LTCF, we focused on examination of biomarkers that are well established in clinical practice and are available for evaluation in most commercial biochemical laboratories in Slovakia. Prognosis of LTCF residents suffering from Covid-19: According to an epidemiologic study by McMichael et al., during the outbreak in one LTCF in Washington, USA, 54.5% of residents required hospitalization and required hospital admission and 33.7% of infected residents died [8]. In our study, we identified 59 residents with positive swabs for SARS-CoV-2. Of these patients. 32 patients (54%) were admitted to hospital which is similar to the study by McMichael et al. In our study, 13 patients (22%) died. That is less than in the study by McMichael et al., however, this difference of proportion might be attributed to potentially different age and comorbidity status of residents. Limitations: The limitations of our study are the relatively low sample size and retrospective design. Larger prospective studies are needed to obtain more robust data and to evaluate if the examination of IL-6 during the initial assessment leads to better prognosis of LTCF residents and improves the management of the Covid-19 outbreaks in the LTCFs. Because of the retrospective design of the study, there might be a concern of bias in the sensitivity of the diagnosis of hypoxemia between groups of hospitalized and outpatient residents. The hospitalized patients were naturally more closely monitored and therefore might be more likely to be diagnosed with hypoxemia. However, we regard this potential bias as insignificant because the outpatient residents were daily monitored for the symptoms and signs of respiratory failure, and patients suffering from dyspnea and patients with tachypnea and/or SpO2 below 90% were transferred to hospital. In normoxic patients, the bias of pulse oximetry comparing to SaO2 is regarding to be insignificant. It reliably identifies the patients with SaO2 below 90% and is a reliable screening tool for hypoxemia with very high negative predictive value [31]. Another limitation is that we did not evaluate the IL-1β as a possible biomarker of hypoxemia. IL-1β is believed to contribute to the cytokine storm in Covid-19. It is the cytokine which stimulates the IL-6 production and therefore is on the level above the IL-6 in the cascade of cytokine storm [30]. The theory that IL-1β have an important role in the pathogenesis of Covid-19 is widely accepted [32]. However, recent study by Mandel et al found that baseline concentration of IL-1β is not significantly higher in non-survivors [22]. Giamarellos-Bourboulis et al. concluded that immune dysregulation in severe Covid-19 is directly driven by IL-6, not IL-1β upregulation [21]. Our study included more females than males. This proportion reflects the LTCF population in which female to male ratio was three to one and is not a result of deliberate selection. Conclusions Baseline IL-6 concentrations over 24 pg/mL in LTCF residents suffering from Covid-19 predicts the development of hypoxemia requiring oxygen therapy with excellent sensitivity and good specificity. Patients with the IL-6 above 24 pg/m at initial assessment seems to be at high risk of development of respiratory failure and might benefit from early hospitalization and close follow-up. Further studies are needed to evaluate the real benefits of systematic examination of IL-6 during the initial assessment and its use as predictive factor of severe disease. Abbreviations ALT: alanine aminotransferase ARDS: acute respiratory distress syndrome AST: aspartate aminotransferase AUC: area under curve BBC: basophil blood count CCI: Charlson Comorbidity Index Covid-19: Coronavirus disease 2019 EBC: eosinophil blood count IL-6: interleukin 6 IL-1β: interleukin 1β LBC: lymphocyte blood count LTCF: long term care facility MBC: monocyte blood count NBC: neutrophil blood count p: probability TNF-α: tumor necrosis factor α ROC: receiver operating characteristic curve SARS-CoV-2: severe acute respiratory distress syndrome coronavirus 2 SaO2: oxygen saturation from arterial blood SpO2: oxygen saturation by pulse oximetry WBC: white blood cell blood count. Declarations Ethics approval and consent to participate This study was carried out in concordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans and was approved by the local Ethical Committee of University Hospital Bratislava. All patients or their legally authorized representatives had provided written informed consent prior to participation in this study. The investigators preserved the full anonymity of all participants. Consent for publication Not applicable. Availability of data and materials The dataset used and analyzed during this study is available from the corresponding author upon request. Competing interests The authors declare that they have no competing interests. Funding None. Authors' contributions PS drafted the manuscript, co-developed the study design, and participated in the data gathering and analysis and interpretation of results. AK co-drafted the manuscript, planned the intervention, developed the study design, and participated in the data gathering and analysis and interpretation of results. JH planned the intervention and participated in the data gathering and analysis and interpretation of results. IS and RL co-drafted the manuscript and participated in the data gathering and analysis and interpretation of results. MK, BK, and AK participated in data gathering and analysis and interpretation of results. All authors have read and approved the final manuscript. Acknowledgments The authors would like to thank all personnel of the University Hospital in Bratislava that contributed to the intervention in LTCF and to this study. References Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648. 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Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954. doi:10.1016/j.ijantimicag.2020.105954Jubran A. Pulse oximetry. Crit Care. 2015;19(1):272. Published 2015 Jul 16. doi:10.1186/s13054-015-0984-8 Kohyama T, Moriyama K, Kanai R, et al. Accuracy of pulse oximeters in detecting hypoxemia in patients with chronic thromboembolic pulmonary hypertension [published correction appears in PLoS One. 2015;10(10):e0141944]. PLoS One. 2015;10(5):e0126979. Published 2015 May 15. doi:10.1371/journal.pone.0126979 Conti P, Caraffa A, Gallenga CE, et al. IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra) [published online ahead of print, 2020 Aug 3]. J Biol Regul Homeost Agents. 2020;34(4):10.23812/20-34-4EDIT-65. doi:10.23812/20-34-4EDIT-65 Tables Table 1: Baseline characteristics of patients. Variables are provided as median (25th percentile, 75th percentile). No hypoxemia requiring oxygen therapy (n = 26) Hypoxemia requiring oxygen therapy (n = 19) p (Mann-Whitney) Cohen d Age (years) 81 (73, 87) 87 (80.5, 90) 0.056 0.522 SpO2 0.96 (0.95, 0.97) 0.91 (0.86, 0.94) < 0.0001 1.563 CCI 5 (4, 6) 7 (6, 8) < 0.05 1.038 CRP (mg/L) 8.92 (3.223, 17.943) 70.69 (29.59, 142.46) < 0.0001 1.398 IL-6 (pg/mL) 12.3 (7.3, 20.5) 43.1 (26.3, 116.7) < 0.0001 1.880 D-dimer (mg/L) 1.215 (0.558, 2.625) 1.58 (0.78, 3.43) 0.198 0.366 Fibrinogen (g/L) 3.6 (3.3, 4.18) 4.45 (3.825, 5.825) < 0.05 0.869 Procalcitonine (ng/mL) 0.02 (0.02, 0.03) 0.132 (0.048, 0.313) < 0.0001 1.791 Ferritin (ug/L) 175.9 (94.13, 429.3) 295.18 (149.79, 778.02) 0.125 0.465 AST (ukat/L) 0.355 (0.29, 0.533) 0.755 (0.403, 1.12) < 0.0001 1.214 ALT (ukat/L) 0.25 (0.16, 0.37) 0.35 (0.26, 0.54) < 0.05 0.613 Sodium (mmol/L) 140.9 (137.45, 142.675) 139 (133.6, 145.6) 0.830 0.06 Potasium (mmol/L) 4.09 (3.85, 4.36) 3.71 (3.235, 4.503) 0.184 0.386 Glucose (mmol/L) 4.8 (4.2, 5.4) 5.9 (5.1, 7.1) < 0.01 0.861 Urea (mmol/L) 6.2 (5.4, 7.5) 11 (6, 21.5) < 0.01 0.794 Creatinine (umol/L) 74.5 (59.25, 101.25) 110.9 (73, 264) < 0.05 0.729 Total bilirubin (umol/L) 8.75 (6.55, 11.75) 11.95 (9.8, 15.4) < 0.0001 0.728 WBC (cells/mL) 4880 (4100, 6515) 5640 (4420, 8640) 0.167 0.395 LBC (cells/mL) 1565 (1045, 2083) 860 (580, 1300) < 0.0001 1.035 NBC (cells/mL) 2680 (2015, 3800) 3890 (2950, 7450) < 0.05 0.816 MBC (cells/mL) 490 (370, 615) 440 (250, 680) 0.712 0.107 EBC (cells/mL) 110 (30, 190) 10 (0, 30) < 0.05 1.373 BBC (cells/mL) 20 (10, 37) 10 (10, 20) 0.155 0.398 ALT - alanine aminotransferase, AST - aspartate aminotransferase, BBC – basophil blood count, CCI - Charlson Comorbidity Index, CRP – C-reactive protein, EBC – eosinophil blood count, IL-6 - interleukin 6, LBC - lymphocyte blood count, MBC – monocyte blood count, NBC – neutrophil blood count, p - probability, SpO2 - oxygen saturation, WBC - white blood cell blood count. Table 2: AUC and optimal cut-offs for evaluated markers of hypoxemia requiring oxygen therapy by receiver operating characteristic curve analysis. marker AUC 95% CI of AUC Asymptotic significance IL-6 0.911 0.819 - 1 0.0001 CRP 0.887 0.777 – 0.996 0.0001 Fibrinogen 0.788 0.640 – 0.936 0.001 D-dimer 5.777 0.409 – 0.745 0.392 PCT 0.886 0.767 - 1 0.0001 Total bilirubin 0.712 0.535 – 0.888 0.036 Creatinine 0.644 0.443 – 0.846 0.152 AST 0.838 0.701 – 0.975 0.001 ALT 0.675 0.491 – 0.858 0.083 LBC 0.777 0.642 - 0. 912 0.001 NBC 0.728 0.582 - 0.783 0.007 EBC 0.841 0.730 – 0.953 0.0001 ALT - alanine aminotransferase, AST - aspartate aminotransferase, AUC – area under curve, 95% CI – 95% confidence interval, CRP – C-reactive protein, EBC – eosinophil blood count, IL-6 - interleukin 6, LBC - lymphocyte blood count, NBC – neutrophil blood count, PCT – procalcitonine, Asymptotic significance below 0.5 is regarded as statistically significant. Table 3: Test evaluation of baseline concentration of IL-6 > 24 pg/mL for predicting the development of hypoxemia requiring oxygen therapy during follow up after excluding patients admitted to hospital during initial triage. Statistic Value 95% confidence interval Sensitivity 100.00% 69.15% - 100.00% Specificity 88.89% 70.84% - 97.65% Disease prevalence 27.03% 13.79% - 44.12% Positive Predictive Value 76.92% 53.42% - 90.64% Negative Predictive Value 100.00% Accuracy 91.89% 78.09% - 98.30% Table 4: Test evaluation of baseline concentration of CRP > 24 mg/L for predicting the development of hypoxemia requiring oxygen therapy during follow up after excluding patients admitted to hospital during initial triage. Statistic Value 95% CI Sensitivity 90.91% 58.72% to 99.77% Specificity 79.41% 62.10% to 91.30% Disease prevalence 24.44% 12.88% to 39.54% Positive Predictive Value 58.82% 41.84% to 73.94% Negative Predictive Value 96.43% 80.52% to 99.44% Accuracy 82.22% 67.95% to 92.00% Table 5. Multivariate binary logistic regression analysis of the association of IL-6 > 24 pg/mL, CRP, glomerular filtration rate, gender, and age with the probability of development of hypoxemia requiring oxygen therapy during follow up. p OR 95% CI of OR IL-6 > 24 pg/mL < 0.05 39.741 1.838 - 859.426 CRP 0.203 1.028 0.985 - 1.072 age 0.187 1.133 0.943 - 1.364 gender (male) 0.175 0.088 0.003 - 2.944 GFR 0.773 0.979 0.850 - 1.128 CRP - C-reactive protein, GFR - glomerular filtration rate, 95% CI - 95% confidence interval, IL-6 - interleukin 6, OR-odds ratio, p - probability Supplementary Files Supplementarytable1.docx Cite Share Download PDF Status: Published Journal Publication published 29 Mar, 2021 Read the published version in BMC Infectious Diseases → Version 3 posted Editor assigned by journal 23 Oct, 2020 Submission checks completed at journal 22 Oct, 2020 Editor invited by journal 22 Oct, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Kušnírová","email":"","orcid":"","institution":"Faculty of Medicine, Comenius University in Bratislava","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alica","middleName":"","lastName":"Kušnírová","suffix":""}],"badges":[],"createdAt":"2020-07-13 19:34:19","currentVersionCode":3,"declarations":"","doi":"10.21203/rs.3.rs-42503/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-42503/v3","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-021-05945-8","type":"published","date":"2021-03-29T19:10:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":13607875,"identity":"d474fb39-2133-4ed9-b5f0-1d3763ccb4e8","added_by":"auto","created_at":"2021-09-17 06:13:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":366714,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-42503/v3/e77c0bcc-f9f2-4575-82eb-897b21baa9ee.pdf"},{"id":3282628,"identity":"c3333d26-cb53-47b4-b921-d9fd08272c55","added_by":"auto","created_at":"2020-10-30 01:20:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29435,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-42503/v3/809183f2c96159c14b49a983.docx"}],"financialInterests":"","formattedTitle":"Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a Long-term Care Facility during Covid-19 Outbreak","fulltext":[{"header":"Background","content":"\u003cp\u003eCoronavirus disease 2019 (Covid-19) is a disease caused by the zoonotic novel Coronavirus called SARS-CoV-2 [1]. Covid-19 quickly spread across the globe from a place of its origin in Hubei China and pandemic was declared by WHO on March 11, 2020 [2]. Most patients with Covid-19 experience mild self-limiting disease. However, up to 20% of known cases of Covid-19 are complicated by severe pneumonia which might result in acute respiratory distress syndrome (ARDS) which causes acute hypoxemic respiratory failure [1,3]. The overall infection fatality ratio is estimated to be below 1% [4]. It should be noted that fatal outcome may occur at any age including children and young adults [5]. Also, physiologic condition, pregnancy is associated with higher risk of severe disease [7]. However, the risk of death in Covid-19 is increasing \u0026nbsp;with age and a presence of comorbidities, especially cardiovascular diseases,\u0026nbsp; diabetes mellitus and obesity [3]. According to data from the early China epidemic, the case-fatality ratio in the patients over 80 is up to 15% [7]. Elderly and highly comorbid residents of long-term care facilities (LTCF) are at high risk of Covid-19 associated morbidity and mortality [8, 9, 10]. In one well-documented outbreak in LTCF in Washington, USA, more than half of the infected residents required hospitalization and more than one third died [10]. On the background of the ongoing pandemic, the spreading of Covid-19 in LTCF might significantly burden the local health care system and markedly contributes to mortality. Timely and effective intervention is essential to reduce morbidity and mortality during the Covid-19 outbreak in the LTCF. Such intervention consists of quick identification of cases, immediate introduction of infection control measures, initial triage, and daily monitoring of patients. An effective screening tool is essential to identify the patients at risk for severe illness and death [11]. Such patients need close monitoring and early transfer to the hospital. Various biomarkers, especially inflammatory markers like C-reactive protein (CRP), ferritin, fibrinogen, D-dimer and Interleukin 6 (IL-6) are associated with Covid-19 progression [12, 13]. According to known evidence, IL-6 is superior to CRP and other markers of inflammation in predicting respiratory failure in Covid-19 [18, 19]. IL-6 appears to be the most important driver of immune dysregulation and ARDS in Covid-19 [20, 21, 22, 23].\u0026nbsp; The role of systematic measurement of IL-6, CRP, and other markers of inflammation at the initial assessment during Covid-19 outbreak in LTCF and its ability to predict the severe course of disease is yet to be determined.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe conducted a retrospective data analysis of laboratory-confirmed cases of COVID-19, diagnosed during the outbreak in one LTCF in Slovakia between April 11, 2020, and May 5, 2020. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase\u0026ndash;polymerase-chain-reaction assay of nasopharyngeal swab specimens for SARS-CoV-2. In our analysis, we aimed to identify laboratory markers predicting the severe course of the disease at the initial assessment.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWithin 24 hours after the diagnosis of COVID-19, clinical and laboratory screening was performed in the LTCF by trained clinicians to identify patients in need of hospitalization. The clinical initial assessment consisted of measurement of vital signs (blood pressure, heart rate respiratory rate) and measurement of oxygen saturation by pulse oximetry. Additionally, the venous blood was drawn to measure concentrations of serum glucose, creatinine, urea, sodium, potassium, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), CRP, D-dimer, IL-6 and complete blood count. The blood samples were immediately transported to laboratory. The results were obtained and evaluated from 4 to 6 hours after last blood drawn. After an initial assessment, daily monitoring consisting of measurement of vital signs and measurement of oxygen saturation by pulse oximetry was performed by the same clinician. The development of hypoxemia with oxygen saturation below 90% was considered as the criteria for severe disease with the need for hospitalization. Patients with oxygen saturation below 90% at the initial screening or during the daily monitoring were immediately referred to the hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiochemical analysis:\u003c/strong\u003e Concentrations of serum glucose, creatinine, urea, sodium, potassium, bilirubin, ALT, AST, were measured using spectrophotometry (Cobas Integra 400, Roche Diagnostics, Rotkreuz, Switzerland). CRP and D-dimer were measured using immunoturbidimetry (Cobas Integra 400, Roche Diagnostics, Rotkreuz, Switzerland). Serum IL-6 concentrations were measured using an immunoassay (Elecsys, Roche Diagnostics, Rotkreuz, Switzerland).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis: \u003c/strong\u003eQuantitative variables are expressed as medians and 25th and 75th percentiles. Data in our cohort according to the Kolmogorov-Smirnov test were non-parametric. Medians of quantitative variables between groups were compared using the Mann-Whitney nonparametric test. Effect sizes were assessed using Cohen's d. Receiver operating characteristic curve (ROC) analysis was used to compare markers of hypoxemia. Only the biomarkers with different medians between groups were evaluated in ROC analysis. Optimal cut off values were also determined using ROC analysis. Sensitivity was calculated as the number of true positive divided by true positive + false negative. Specificity was calculated as the number of true negative divided by true negative + false positive. Association of baseline serum concentration of IL-6 \u0026gt; 24 pg/mL with the probability of development of hypoxemia requiring oxygen therapy (HRO) was assessed using multivariate logistic regression. For statistical analysis, SPSS version 26 (International Business Machines Corporation, Armonk, NY, USA) was used.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e: This study was carried out in concordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans and was approved by the local Ethical Committee of University Hospital Bratislava. The participants signed informed consent. The investigators preserved the full anonymity of all participants.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the intervention in the LTCF,\u0026nbsp;78 subjects were screened for COVID-19 and 59 patients (47 women, 12 men) had positive pharyngeal swabs for SARS-CoV-2 RNA by RT-PCR and were diagnosed with Covid-19. 53 patients (90%) had blood sampling during the initial screening phase. In 6 patients, blood sampling was not performed because of technical difficulties. These patients were excluded from the study. In 53 patients (11 men, 42 women) in which blood sampling was performed, the clinical variables and the results of biochemical and blood count analysis were available for evaluation and were included in the study. 7 patients (1 man, 6 women) were diagnosed with severe disease in initial triage and were immediately transferred to a hospital within the first two days of intervention. Remaining 45 patients (10 men, 36 women) remained under observation in LTCF and were screened for severe disease and triaged on a daily basis by the intervention team. Overall, 32 patients (6 men, 26 women) were admitted. Among these patients, 19 (2 men, 17 women) had hypoxemia required oxygen therapy, 16 patients (2 men, 14 women) were admitted to ICU, and 13 patients (2 men, 12 women) died. In 11 patients (1 man, 10 women) initially suffering from hypoxemia requiring oxygen therapy, the disease progressed, and they required intubation and mechanical ventilation. All these patients died because of severe ARDS. 1 male, initially suffering from hypoxemia requiring oxygen therapy died because of severe gastrointestinal bleeding from gastric adenocarcinoma. 1 female, initially suffering from hypoxemia requiring oxygen therapy suddenly died after short period of clinical improvement. An autopsy revealed pulmonary embolism. In hospitalized patients, various severe complications were observed. 6 patients developed deep vein thrombosis, 6 developed congestive heart failure, 3 patients developed new atrial fibrillation and 5 developed acute renal failure. Baseline characteristics of patients are provided in table 1. Major clinical findings of all enrolled patients are provided in supplementary table. The baseline serum concentrations of IL-6, CRP, procalcitonin, urea, creatinine, fibrinogen, AST, ALT, fasting glucose, total bilirubin and neutrophil count were significantly higher, and lymphocyte and eosinophil count was significantly lower in patients who developed hypoxemia. All patients included in our study seroconverted and developed IgG antibodies within 1 month of diagnosis. The median of baseline serum concentrations of D-dimer and ferritin and a median total count of leukocytes were not significantly different among groups of patients with and without hypoxemia requiring oxygen therapy. Patients who developed hypoxemia requiring oxygen therapy were also significantly more comorbid according to the higher median Charlson Comorbidity Index (tab. 1). In the ROC analysis, IL-6 was identified as more robust marker of hypoxemia development than CRP, procalcitonin, CRP, fibrinogen, ALT, AST and total bilirubin and lymphocyte, neutrophil and eosinophil blood count. However, all of these variables were associated with hypoxemia (tab. 2). The cut-off of 24 pg/mL for IL-6 showed the best combination of sensitivity and specificity. In the group of all screened LTCF residents, baseline IL-6 concentration \u0026gt; 24 pg/mL predicted the development of hypoxemia with a sensitivity of 88% and specificity of 89%.\u0026nbsp; PPV of 83%, and NPV of 93%. After excluding the 7 patients diagnosed with severe Covid-19 and transferred to the hospital after the initial assessment, baseline IL-6 concentration over 24 pg/mL predicted the development of hypoxemia during the daily monitoring in the LTCF with the sensitivity of 100%, specificity 89, PPV of 77%, and NPV 100% (tab. 3). Baseline CRP concentration with cut-off of 24 mg/L showed sensitivity and especially specificity inferior to IL-6 (tab. 4). \u0026nbsp;In multivariate analysis, baseline IL-6 concentration \u0026gt; 24 pg/mL was positively associated with the risk of hypoxemia development during follow up in LTCF residents after adjustment for CRP, age, gender, and glomerular filtration rate (tab. 5).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur retrospective data analysis evaluated the potential role of biomarkers of inflammation, IL-6, CRP, procalcitonin, D-dimer and fibrinogen in the prediction of severe disease and need for oxygen therapy in residents of LTCF during Covid-19 outbreak. It suggests that IL-6 is a most robust predictor of hypoxemia requiring oxygen therapy. The concentration of IL-6 \u0026gt; 24 pg/mL at the initial assessment is showing the best combination of sensitivity and specificity in predicting the hypoxemia requiring oxygen therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere is a substantial body of evidence linking the IL-6 concentration to the severity of disease and unfavorable outcome of Covid-19 [13, 14, 15, 16, 17, 18, 20, 21, 22].\u0026nbsp;However, to our knowledge, this study is the first study which evaluated the ability of IL-6 to predict the need for supplementary oxygen administration as a surrogate marker of severe Covid-19 requiring \u0026nbsp;hospital admission in the population of high risk elderly patients. It also suggests clinical implications for intervention procedures for Covid-19 outbreak in LTCF. Han et al. examined the predictive value of various cytokines and concluded that IL-6 is the best predictor of severe Covid-19 [18]. A metanalysis of 9 studies concluded that increased IL-6 is highly associated with severe disease. In this study, patients with severe Covid-19 had mean IL-6 58 pg/mL compared to 17 pg/mL in mild disease [16]. A study by Herold et al. found that IL-6 \u0026gt; 80 pg/mL the predicts respiratory failure and need for mechanical ventilation in Covid-19. Like in our study, IL-6 was superior to CRP in ROC analysis. Chen et al. found cut-off 80 pg/mL of IL-6 differentiates the survivors from the non-survivors [17]. We suggest that we found much lower optimal cut-off value (24 pg/mL compared to 80 pg/mL) because we choose less severe endpoint (need for supplementary oxygen). Overall, we can conclude that our study is in concordance with previous studies and adds new aspects to the known body of evidence.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical significance and implications:\u003c/strong\u003e The residents of LTCF are one of the most vulnerable populations of the Covid-19 pandemic [8, 9, 10]. The outbreak of Covid-19 in LTCF might significantly burden the local health care system. Timely and effective intervention is essential to reduce morbidity and mortality during such outbreak. According to the proposed guideline by Kim et al., the first phase of response should include broad testing a quick identification of cases and their clinical assessment and triage. In the next phase, monitoring of patients should be implemented in order to quickly identify the patients in need of hospital care [11]. Identification of patients at high risk of deterioration during the initial assessment may significantly improve the monitoring process by allocating the resources to high-risk patients more effectively. Especially in the case of limited human resources, the focus on high-risk patients is might contribute to mortality reduction and improve the overall outcome of the outbreak.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our study, all patients that developed hypoxemia requiring oxygen therapy during the follow up had the baseline concentration of IL-6 over 24 pg/mL. As a screening tool, it provides excellent sensitivity with an acceptable specificity over 88%. It may be used to identify the patients with a high risk of hypoxemia. It also identifies the patients with low risk for hypoxemia with great negative predictive value. This might help in the decision making for admission during the initial triage.\u0026nbsp;Baseline CRP concentration with cut-off of 24 mg/L showed sensitivity and especially specificity inferior to IL-6, however, might be used as cheaper alternative in low resource setting.\u003c/p\u003e\n\u003cp\u003eFor the purposes of our study, we defined that the residents that developed hypoxemia requiring oxygen therapy are the cases that needed close monitoring and early transfer to the hospital.\u0026nbsp; The rationale is that patients who developed hypoxemia requiring oxygen therapy are those that might benefit from the early pharmacological treatment in order to reduce mortality. According to the body of evidence on remdesivir and dexamethasone, these drugs significantly improves the outcome in the patients needing conventional oxygen therapy [24, 25, 26]. Thus, the patients with early disease but in the high risk of development of hypoxemia are those patients who will profit from close observation and rapid initiation of remdesivir and dexamethasone in case of progression of Covid-19.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIL-6 and development of severe Covid-19\u003c/strong\u003e: IL-6 is produced by stromal cells and virtually all immune system cells in the lungs and its secretion is stimulated by proinflammatory cytokines, especially interleukin 1\u0026beta; (IL-1\u0026beta;) and tumor necrosis factor \u0026alpha; (TNF\u0026alpha;). In the early stages of the infection, it is produced by lung macrophages after stimulation of toll-like receptors [27]. An important trait of IL-6 upregulation in Covid-19 is that it precedes the development of acute lung injury that implicates its usability as an early marker of severe disease [16]. However, there is controversy if excessive IL-6 synthesis is true a cornerstone of the pathogenesis of respiratory failure in Covid-19 or is just an epiphenomenon of increased IL-1\u0026beta; and TNF\u0026alpha; in the cytokine storm [20]. Predominant theory is that overexpression of IL-6 have a crucial role in the incitement and propagation of the so-called cytokine storm leading to lung injury and ARDS [20, 21]. \u0026nbsp;It is believed that IL-6 increases the permeability of lung capillaries driving the ARDS development and also stimulates the coagulation pathway leading to microthrombi in lung circulation and increases the risk of thrombotic event [27]. A study by Giamarellos-Bourboulis et al. suggests that patients with severe respiratory failure in Covid-19 suffer from distinct types of immune dysregulation which are mediated by IL-6 upregulation. This dysregulation is characterized by high production of proinflammatory cytokines by monocytes and macrophages and CD4 lymphocyte depletion that contributes to the progression of inflammation of lung parenchyma [21].\u0026nbsp;The direct role of IL-6 in Covid-19 pathogenesis is further supported by findings that IL-6 inhibition improves the prognosis of severe Covid-19 [29, 27].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOther markers of severe disease:\u003c/strong\u003e In our study, patients who developed hypoxemia had significantly higher serum concentrations of AST, ALT, CRP, serum glucose, creatinine, procalcitonin, and fibrinogen. They also had significantly higher blood count of neutrophils and lower count of lymphocytes and eosinophils. These variables were identified as markers of severe disease by the previous studies [13]. Medians of other well-established markers of serious disease, D-dimer and ferritin were higher in patients who developed hypoxemia, however, the differences were not statistically significant.\u0026nbsp;Using ROC analysis, we concluded that IL-6 is better marker of hypoxemia than CRP or other evaluated variables. Other proinflammatory cytokines, like IL-1\u0026beta; or TNF-\u0026alpha; are also associated with severity of Covid-19 and might also serve as biomarkers [30, 32]. However, because the primary goal of our study was to improve the practical algorithm for intervention in LTCF, we focused on examination of biomarkers that are well established in clinical practice and are available for evaluation in most commercial biochemical laboratories in Slovakia.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognosis of LTCF residents suffering from Covid-19:\u003c/strong\u003e According to an epidemiologic study by McMichael et al., during the outbreak in one LTCF in Washington, USA, 54.5% of residents required hospitalization and required hospital admission and 33.7% of infected residents died [8]. In our study, we identified 59 residents with positive swabs for SARS-CoV-2. Of these patients. 32 patients (54%) were admitted to hospital which is similar to the study by McMichael et al. In our study, 13 patients (22%) died. That is less than in the study by McMichael et al., however, this difference of proportion might be attributed to potentially different age and comorbidity status of residents.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations:\u003c/strong\u003e The limitations of our study are the relatively low sample size and retrospective design. Larger prospective studies are needed to obtain more robust data and to evaluate if the examination of\u0026nbsp;IL-6 during the initial assessment leads to better prognosis of LTCF residents and improves the management of the Covid-19 outbreaks in the LTCFs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBecause of the retrospective design of the study, there might be a concern of bias in the sensitivity of the diagnosis of hypoxemia between groups of hospitalized and outpatient residents. The hospitalized patients were naturally more closely monitored and therefore might be more likely to be diagnosed with hypoxemia. However, we regard this potential bias as insignificant because the outpatient residents were daily monitored for the symptoms and signs of respiratory failure, and patients suffering from dyspnea and patients with tachypnea and/or SpO2 below 90% were transferred to hospital. In normoxic patients, the bias of pulse oximetry comparing to SaO2 is regarding to be insignificant. It reliably identifies the patients with SaO2 below 90% and is a reliable screening tool for hypoxemia with very high negative predictive value [31].\u003c/p\u003e\n\u003cp\u003eAnother limitation is that we did not evaluate the IL-1\u0026beta; as a possible biomarker of hypoxemia. IL-1\u0026beta; is believed to contribute to the cytokine storm in Covid-19. It is the cytokine which stimulates the IL-6 production and therefore is on the level above the IL-6 in the cascade of cytokine storm [30]. The theory that IL-1\u0026beta; have an important role in the pathogenesis of Covid-19 is widely accepted [32]. However, recent study by Mandel et al found that baseline concentration of IL-1\u0026beta; is not significantly higher in non-survivors [22]. Giamarellos-Bourboulis et al. concluded that immune dysregulation in severe Covid-19 is directly driven by IL-6, not IL-1\u0026beta; upregulation [21].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study included more females than males. This proportion reflects the LTCF population in which female to male ratio was three to one and is not a result of deliberate selection.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eBaseline IL-6 concentrations over 24 pg/mL in LTCF residents suffering from Covid-19 predicts the development of hypoxemia requiring oxygen therapy with excellent sensitivity and good specificity. Patients with the IL-6 above 24 pg/m at initial assessment seems to be at high risk of development of respiratory failure and might benefit from early hospitalization and close follow-up.\u0026nbsp; Further studies are needed to evaluate the real benefits of systematic examination of IL-6 during the initial assessment and its use as predictive factor of severe disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALT: alanine aminotransferase\u003c/p\u003e\n\u003cp\u003eARDS: acute respiratory distress syndrome\u003c/p\u003e\n\u003cp\u003eAST: aspartate aminotransferase\u003c/p\u003e\n\u003cp\u003eAUC: area under curve\u003c/p\u003e\n\u003cp\u003eBBC: basophil blood count\u003c/p\u003e\n\u003cp\u003eCCI: Charlson Comorbidity Index\u003c/p\u003e\n\u003cp\u003eCovid-19: Coronavirus disease 2019\u003c/p\u003e\n\u003cp\u003eEBC: eosinophil blood count\u003c/p\u003e\n\u003cp\u003eIL-6: interleukin 6\u003c/p\u003e\n\u003cp\u003eIL-1\u0026beta;: interleukin 1\u0026beta;\u003c/p\u003e\n\u003cp\u003eLBC: lymphocyte blood count\u003c/p\u003e\n\u003cp\u003eLTCF: long term care facility\u003c/p\u003e\n\u003cp\u003eMBC: monocyte blood count\u003c/p\u003e\n\u003cp\u003eNBC: neutrophil blood count\u003c/p\u003e\n\u003cp\u003ep: probability\u003c/p\u003e\n\u003cp\u003eTNF-\u0026alpha;: tumor necrosis factor \u0026alpha;\u003c/p\u003e\n\u003cp\u003eROC: receiver operating characteristic curve\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2: severe acute respiratory distress syndrome coronavirus 2\u003c/p\u003e\n\u003cp\u003eSaO2: oxygen saturation from arterial blood\u003c/p\u003e\n\u003cp\u003eSpO2: oxygen saturation by pulse oximetry\u003c/p\u003e\n\u003cp\u003eWBC: white blood cell blood count.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was carried out in concordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans and was approved by the local Ethical Committee of University Hospital Bratislava. All patients or their legally authorized representatives had provided written informed consent prior to participation in this study. The investigators preserved the full anonymity of all participants.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset used and analyzed during this study is available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePS drafted the manuscript, co-developed the study design, and participated in the data gathering and analysis and interpretation of results. AK co-drafted the manuscript, planned the intervention, developed the study design, and participated in the data gathering and analysis and interpretation of results. JH planned the intervention and participated in the data gathering and analysis and interpretation of results. IS and RL co-drafted the manuscript and participated in the data gathering and analysis and interpretation of results. MK, BK, and AK participated in data gathering and analysis and interpretation of results. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all personnel of the University Hospital in Bratislava that contributed to the intervention in LTCF and to this study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWu Z, McGoogan JM. 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Lancet. 2020; 20(6): 669-677. doi:10.1016/S1473-3099(20)30243-7.\u003c/li\u003e\n\u003cli\u003eLai CC, Wang JH, Ko WC, et al. COVID-19 in long-term care facilities: An upcoming threat that cannot be ignored. J Microbiol Immunol Infect. 2020;53(3):444‐ doi:10.1016/j.jmii.2020.04.008.\u003c/li\u003e\n\u003cli\u003eAbrams HR, Loomer L, Gandhi A, Grabowski DC. Characteristics of U.S. Nursing Homes with COVID-19 Cases [published online ahead of print, 2020 Jun 2]. J Am Geriatr Soc. 2020;10.1111/jgs.16661. doi:10.1111/jgs.16661\u003c/li\u003e\n\u003cli\u003eMcMichael TM, Currie DW, Clark S, et al.\u0026nbsp; Epidemiology of Covid-19 in a Long-Term Care Facility in King County, Washington. N Engl J Med. 2020;382(21):2005‐ doi:10.1056/NEJMoa2005412\u003c/li\u003e\n\u003cli\u003eKim G, Wang M, Pan H, et al. A Health System Response to COVID-19 in Long-Term Care and Post-Acute Care: A Three-Phase Approach [published online ahead of print, 2020 Apr 28]. J Am Geriatr Soc. 2020;10.1111/jgs.16513. doi:10.1111/jgs.16513\u003c/li\u003e\n\u003cli\u003ePonti G, Maccaferri M, Ruini C, Tomasi A, Ozben T. Biomarkers associated with COVID-19 disease progression [published online ahead of print, 2020 Jun 5]. Crit Rev Clin Lab Sci. 2020;1-11. doi:10.1080/10408363.2020.1770685\u003c/li\u003e\n\u003cli\u003eVelavan TP, Meyer CG. Mild versus severe COVID-19: Laboratory markers. Int J Infect Dis. 2020;95:304-307. doi:10.1016/j.ijid.2020.04.061\u003c/li\u003e\n\u003cli\u003eLiu T, Zhang J, Yang Y, et al. The role of interleukin-6 in monitoring the severe case of coronavirus disease 2019 [published online ahead of print, 2020 May 19]. \u003cem\u003eEMBO Mol Med\u003c/em\u003e. 2020;e12421. doi:10.15252/emmm.202012421.\u003c/li\u003e\n\u003cli\u003eUlhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. 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SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the 'culprit lesion' of ARDS onset? What is there besides Tocilizumab? SGP130Fc [published online ahead of print, 2020 May 14]. Cytokine X. 2020;2(2):100029. doi:10.1016/j.cytox.2020.100029\u003c/li\u003e\n\u003cli\u003eGiamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3. doi:10.1016/j.chom.2020.04.009\u003c/li\u003e\n\u003cli\u003eMandel M, Harari G, Gurevich M, Achiron A. Cytokine prediction of mortality in COVID19 patients [published online ahead of print, 2020 Jul 10]. Cytokine. 2020;134:155190. doi:10.1016/j.cyto.2020.155190.\u003c/li\u003e\n\u003cli\u003eHan H, Ma Q, Li C, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123-1130. doi:10.1080/22221751.2020.1770129\u003c/li\u003e\n\u003cli\u003eBeigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report [published online ahead of print, 2020 May 22]. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2020;NEJMoa2007764. doi:10.1056/NEJMoa2007764\u003c/li\u003e\n\u003cli\u003eCao YC, Deng QX, Dai SX. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence [published online ahead of print, 2020 Apr 2].\u003cem\u003e Travel Med Infect Dis. \u003c/em\u003e2020;101647. doi:10.1016/j.tmaid.2020.101647\u003c/li\u003e\n\u003cli\u003eHorby P, Shen Lim W, Emberson J, et al. 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Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954. doi:10.1016/j.ijantimicag.2020.105954Jubran A. Pulse oximetry. Crit Care. 2015;19(1):272. Published 2015 Jul 16. doi:10.1186/s13054-015-0984-8\u003c/li\u003e\n\u003cli\u003eKohyama T, Moriyama K, Kanai R, et al. Accuracy of pulse oximeters in detecting hypoxemia in patients with chronic thromboembolic pulmonary hypertension [published correction appears in PLoS One. 2015;10(10):e0141944]. PLoS One. 2015;10(5):e0126979. Published 2015 May 15. doi:10.1371/journal.pone.0126979\u003c/li\u003e\n\u003cli\u003eConti P, Caraffa A, Gallenga CE, et al. IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra) [published online ahead of print, 2020 Aug 3]. J Biol Regul Homeost Agents. 2020;34(4):10.23812/20-34-4EDIT-65. doi:10.23812/20-34-4EDIT-65\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eTable 1: Baseline characteristics of patients. Variables are provided as median (25th percentile, 75th percentile).\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-left: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eNo hypoxemia requiring oxygen therapy (n = 26)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-left: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eHypoxemia requiring oxygen therapy (n = 19)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-left: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003ep\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e(Mann-Whitney)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-left: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121;\"\u003eCohen d\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eAge (years)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e81 (73, 87)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e87 (80.5, 90)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.056\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.522\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eSpO2\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.96 (0.95, 0.97)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.91 (0.86, 0.94)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.563\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eCCI\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e5 (4, 6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e7 (6, 8)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.038\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eCRP (mg/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e8.92 (3.223, 17.943)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e70.69\u0026nbsp;\u0026nbsp;\u0026nbsp; (29.59, 142.46)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.398\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eIL-6 (pg/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e12.3 (7.3, 20.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e43.1 (26.3, 116.7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.880\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 27.0pt;\"\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eD-dimer (mg/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.215\u0026nbsp;\u0026nbsp;\u0026nbsp; (0.558, 2.625)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.58 (0.78, 3.43)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.198\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.366\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 27.0pt;\"\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eFibrinogen (g/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e3.6 (3.3, 4.18)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e4.45 (3.825, 5.825)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 27.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.869\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eProcalcitonine (ng/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.02 (0.02, 0.03)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.132\u0026nbsp;\u0026nbsp;\u0026nbsp; (0.048, 0.313)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.791\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eFerritin (ug/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e175.9\u0026nbsp;\u0026nbsp;\u0026nbsp; (94.13, 429.3)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e295.18 (149.79, 778.02)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.125\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.465\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eAST (ukat/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.355\u0026nbsp;\u0026nbsp;\u0026nbsp; (0.29,\u0026nbsp;\u0026nbsp;\u0026nbsp; 0.533)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.755 (0.403, 1.12)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.214\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eALT (ukat/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.25 (0.16, 0.37)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.35 (0.26, 0.54)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.613\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eSodium (mmol/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e140.9\u0026nbsp;\u0026nbsp;\u0026nbsp; (137.45, 142.675)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e139 (133.6, 145.6)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.830\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.06\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003ePotasium (mmol/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e4.09 (3.85, 4.36)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e3.71 (3.235, 4.503)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.184\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.386\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eGlucose (mmol/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e4.8 (4.2, 5.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e5.9 (5.1, 7.1)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.01\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.861\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eUrea (mmol/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e6.2 (5.4, 7.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e11 (6, 21.5)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.01\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.794\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eCreatinine (umol/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e74.5 (59.25, 101.25)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e110.9 (73, 264)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.729\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eTotal bilirubin (umol/L)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e8.75 (6.55, 11.75)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e11.95\u0026nbsp;\u0026nbsp;\u0026nbsp; (9.8, 15.4)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.728\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 24.0pt;\"\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 24.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eWBC (cells/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 24.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e4880 (4100, 6515)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 24.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e5640 (4420, 8640)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 24.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.167\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt; height: 24.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.395\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eLBC (cells/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1565 (1045, 2083)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e860 (580, 1300)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.035\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eNBC (cells/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e2680 (2015, 3800)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e3890 (2950, 7450)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.816\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eMBC (cells/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e490 (370, 615)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e440 (250, 680)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.712\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.107\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eEBC (cells/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e110 (30, 190)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e10 (0, 30)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.373\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eBBC (cells/mL)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e20 (10, 37)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e10 (10, 20)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.155\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.398\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eALT - alanine aminotransferase, AST - aspartate aminotransferase, BBC \u0026ndash; basophil blood count, CCI - Charlson Comorbidity Index, CRP \u0026ndash; C-reactive protein, EBC \u0026ndash; eosinophil blood count, IL-6 - interleukin 6, LBC - lymphocyte blood count, MBC \u0026ndash; monocyte blood count, NBC \u0026ndash; neutrophil blood count, p - probability, SpO2 - oxygen saturation, WBC - white blood cell blood count.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026nbsp;Table 2: AUC and optimal cut-offs for evaluated markers of hypoxemia requiring oxygen therapy by receiver operating characteristic curve analysis.\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003emarker\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border: solid windowtext 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eAUC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border: solid windowtext 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e95% CI of AUC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border: solid windowtext 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"text-align: center; line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eAsymptotic significance\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eIL-6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.911\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.819 - 1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eCRP\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.887\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.777 \u0026ndash; 0.996\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eFibrinogen\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.788\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.640 \u0026ndash; 0.936\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eD-dimer\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e5.777\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.409 \u0026ndash; 0.745\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.392\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003ePCT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.886\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.767 - 1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eTotal bilirubin\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.712\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.535 \u0026ndash; 0.888\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.036\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eCreatinine\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.644\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.443 \u0026ndash; 0.846\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.152\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eAST\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.838\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.701 \u0026ndash; 0.975\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eALT\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.675\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.491\u0026nbsp;\u0026ndash; 0.858\u0026nbsp; \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.083\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eLBC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.777\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.642 - 0. 912\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eNBC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.728\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.582 - 0.783\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.007\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 90.6pt; border: solid windowtext 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"121\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eEBC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 107.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"143\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.841\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 127.6pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"170\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.730 \u0026ndash; 0.953\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.5pt; border-top: none; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"161\"\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.0001\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eALT - alanine aminotransferase, AST - aspartate aminotransferase, AUC \u0026ndash; area under curve, 95% CI \u0026ndash; 95% confidence interval, CRP \u0026ndash; C-reactive protein, EBC \u0026ndash; eosinophil blood count, IL-6 - interleukin 6, LBC - lymphocyte blood count, NBC \u0026ndash; neutrophil blood count, PCT \u0026ndash; procalcitonine, \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eAsymptotic significance below 0.5 is regarded as statistically significant.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 150%; margin: 12.0pt 0in 12.0pt 0in;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eTable 3: Test evaluation of baseline concentration of IL-6 \u0026gt; 24 pg/mL for predicting the development of hypoxemia requiring oxygen therapy during follow up after excluding patients admitted to hospital during initial triage.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 34.5pt;\"\u003e\n\u003ctd style=\"width: 148.35pt; border: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"198\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eStatistic\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.25pt; border: solid #A0A0A0 1.0pt; border-left: none; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"132\"\u003e\n\u003cp style=\"text-align: center; line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eValue\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 198.45pt; border: solid #A0A0A0 1.0pt; border-left: none; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"265\"\u003e\n\u003cp style=\"text-align: center; line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e95%\u0026nbsp; confidence interval\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 34.5pt;\"\u003e\n\u003ctd style=\"width: 148.35pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"198\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eSensitivity\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.25pt; border: none; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"132\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e100.00%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 198.45pt; border: none; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"265\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e69.15% - 100.00%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 34.5pt;\"\u003e\n\u003ctd style=\"width: 148.35pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"198\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eSpecificity\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.25pt; border: none; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"132\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e88.89%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 198.45pt; border: none; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"265\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e70.84% - 97.65%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 34.5pt;\"\u003e\n\u003ctd style=\"width: 148.35pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"198\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eDisease prevalence\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.25pt; border: none; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"132\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e27.03%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 198.45pt; border: none; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"265\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e13.79% - 44.12%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 34.5pt;\"\u003e\n\u003ctd style=\"width: 148.35pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"198\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003ePositive Predictive Value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.25pt; border: none; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"132\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e76.92%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 198.45pt; border: none; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"265\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e53.42% - 90.64%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 34.5pt;\"\u003e\n\u003ctd style=\"width: 148.35pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"198\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eNegative Predictive Value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.25pt; border: none; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"132\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e100.00%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 198.45pt; border: none; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"265\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 34.5pt;\"\u003e\n\u003ctd style=\"width: 148.35pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"198\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eAccuracy\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.25pt; border: none; border-bottom: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"132\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e91.89%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 198.45pt; border-top: none; border-left: none; border-bottom: solid #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: white; padding: 2.0pt 6.0pt 1.0pt 6.0pt; height: 34.5pt;\" width=\"265\"\u003e\n\u003cp style=\"line-height: 150%; margin: 9.0pt 0in 9.0pt 0in;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e78.09% - 98.30%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eTable 4: Test evaluation of baseline concentration of CRP \u0026gt; 24 mg/L for predicting the development of hypoxemia requiring oxygen therapy during follow up after excluding patients admitted to hospital during initial triage.\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"background: white; border-collapse: collapse; border: none;\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: .25in;\"\u003e\n\u003ctd style=\"width: 148.45pt; border: solid #A0A0A0 1.0pt; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt; height: .25in;\" width=\"198\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eStatistic\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: solid #A0A0A0 1.0pt; border-left: none; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt; height: .25in;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eValue\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border: solid #A0A0A0 1.0pt; border-left: none; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt; height: .25in;\" width=\"255\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003e95% CI\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 148.45pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"198\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eSensitivity\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e90.91%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border: none; border-right: solid #A0A0A0 1.0pt; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"255\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e58.72% to 99.77%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 148.45pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"198\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eSpecificity\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e79.41%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border: none; border-right: solid #A0A0A0 1.0pt; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"255\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e62.10% to 91.30%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 148.45pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"198\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eDisease prevalence\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e24.44%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border: none; border-right: solid #A0A0A0 1.0pt; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"255\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e12.88% to 39.54%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 148.45pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"198\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003ePositive Predictive Value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e58.82%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border: none; border-right: solid #A0A0A0 1.0pt; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"255\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e41.84% to 73.94%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 148.45pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"198\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eNegative Predictive Value \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e96.43%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border: none; border-right: solid #A0A0A0 1.0pt; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"255\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e80.52% to 99.44%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 148.45pt; border-top: none; border-left: solid #A0A0A0 1.0pt; border-bottom: dotted #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; background: transparent; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"198\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif;\"\u003eAccuracy\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.3pt; border: none; border-bottom: solid #A0A0A0 1.0pt; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"142\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e82.22%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 191.4pt; border-top: none; border-left: none; border-bottom: solid #A0A0A0 1.0pt; border-right: solid #A0A0A0 1.0pt; padding: 1.5pt 6.0pt .75pt 6.0pt;\" width=\"255\"\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: black;\"\u003e67.95% to 92.00%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: 12.0pt; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eTable 5. Multivariate binary logistic regression analysis of the association of IL-6 \u0026gt; 24 pg/mL, CRP, glomerular filtration rate, gender, and age with the probability of development of hypoxemia requiring oxygen therapy during follow up.\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width: 451.3pt; border-collapse: collapse;\" width=\"602\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-left: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-left: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eOR\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-left: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e95% CI of OR\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eIL-6 \u0026gt; 24 pg/mL\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026lt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e39.741\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.838 - 859.426\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eCRP\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.203\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.028\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.985 - 1.072\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eage\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.187\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e1.133\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.943 - 1.364\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003egender (male)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.175\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.088\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.003 - 2.944\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"border: solid black 1.0pt; border-top: none; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eGFR\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.773\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.979\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid black 1.0pt; padding: 5.0pt 5.0pt 5.0pt 5.0pt;\"\u003e\n\u003cp style=\"margin-bottom: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e0.850 - 1.128\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003eCRP - C-reactive protein, GFR - glomerular filtration rate, \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e95% CI - 95% confidence interval,\u003c/span\u003e\u003cspan style=\"font-size: 12.0pt; line-height: 150%; font-family: 'Arial',sans-serif; color: #212121; background: white;\"\u003e\u0026nbsp;IL-6 - interleukin 6, OR-odds ratio, p - probability\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Covid-19, Long-term care facility, Interleukin 6, hypoxemia","lastPublishedDoi":"10.21203/rs.3.rs-42503/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-42503/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Covid-19 is a disease with high morbidity and mortality among elderly residents of long-term care facilities (LTCF). During an outbreak of SARS-CoV-2 infection in the LTCF an effective screening tool is essential to identify the patients at risk for severe illness and death. We explored the role of interleukin 6 (IL-6) as a predictor for severe disease during the outbreak of Covid-19 in one LTCF in Slovakia. \u003c/p\u003e\u003cp\u003eMethods: We conducted a retrospective data analysis of cases of COVID-19, diagnosed during the outbreak in one LTCF in Slovakia between April 11, 2020, and May 5, 2020. Within 24 hours after the diagnosis of Covid-19, clinical and laboratory screening was performed in the LTCF to identify patients in need of hospitalization. Patients with oxygen saturation below 90% were immediately referred to the hospital. Patients staying in the LFTC were monitored daily and those that developed hypoxemia were transferred to the hospital. We analyzed the association between the IL-6 at the initial assessment and development of hypoxemia during follow up and determined the cut-off of the IL-6 able to predict the development of hypoxemia requiring oxygen therapy. \u003c/p\u003e\u003cp\u003eResults : Fifty-three patients (11 men, 42 women) with diagnosed Covid-19 were included in the analysis. 19 (53%) patients developed hypoxemia during the disease. Patients with hypoxemia had significantly higher concentrations of IL-6, C-reactive protein, procalcitonin, fibrinogen, total bilirubin, aspartate aminotransferase and alanine aminotransferase at initial screening. ROC analyses identified IL-6 as the most robust predictor of hypoxemia. The concentration of IL-6 \u0026gt; 24 pg/mL predicted the development of hypoxemia with the sensitivity of 100% and specificity of 88.9%. The positive and negative predictive values were 76.9%, and 100% respectively. \u003c/p\u003e\u003cp\u003eConclusions : The concentration of IL-6 \u0026gt; 24 pg/mL at initial assessment predicted the development of hypoxemia requiring hospitalization with excellent sensitivity and good specificity. IL-6 appears as a potential predictor for the development of the severe Covid-19 and might serve for early identification of patients in need of hospitalization. Further studies are needed to evaluate the robustness of the use of IL-6 as an effective screening tool for the severe course of Covid-19.\u003c/p\u003e","manuscriptTitle":"Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a Long-term Care Facility during Covid-19 Outbreak","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2020-10-30 01:20:13","doi":"10.21203/rs.3.rs-42503/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2020-10-23T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-10-22T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-10-22T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2020-08-14 21:29:20","doi":"10.21203/rs.3.rs-42503/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-10-17T12:00:00+00:00","index":4,"fulltext":"Recommendation: Accept after discretionary revisions\nForm responses:\n---\n\nComments to Author:\n---\nDear Authors,\nThank you for your contribution. The manuscript is the about IL-6 and COVID-19. I recommend following suggestions to reconsider your manuscript. Please answer pointwise and incorporate all the changes, discussion, and references in suitable places for us to be clear about the revised/edited manuscript. Thank you for your contribution.\n1. BACKGROUND: Please ensure that in your write up in background, we are mentioning that COVID-19 has not left any age group (children to elderly) or physiological conditions like pregnancy. It is recommended to discuss them briefly before focusing the paper specifically on the long-term care facilities residents. See the following paper to refer to: [Rathore V, Galhotra A, Pal R, Sahu KK. COVID-19 Pandemic and Children: A Review. J Pediatr Pharmacol Ther. 2020;25(7):574-585]\n2. INTERVENTIONS: Change heart to heart rate and breath frequency to respiratory rate\n3. RSEULTS: Any specific reason why women are too many compared to men? Or it is just by chance.\n4. How much time it took average from point of sending IL-6 sample to it being reported? Please mention.\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **'I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"decision","content":"Minor revision","date":"2020-10-17T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-09-27T12:00:00+00:00","index":3,"fulltext":"Recommendation: Reject\nForm responses:\n---\n\nComments to Author:\n---\nI agree that the study is well written and well designed. However, the relationship between COVID-19 and IL-6 is well known and there are many publications in the literature. According to previous studies, the number of individuals of the authors is also low (doi: 10.1016/j.ijid.2020.07.023). I suggest the authors enrich the study with some cytokines.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-09-24T12:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-24T12:00:00+00:00","index":4,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-09-08T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-08T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-08T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-09-08T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\nPlease include all comments for the authors in this box rather than uploading your report as an attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting materials or other aspects of your report which cannot be included in a text format.\nPlease overwrite this text when adding your comments to the authors.\n\nThe authors adreesed all questions\n\n\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing or interest confict .**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-09-08T12:00:00+00:00","index":2,"fulltext":"Recommendation: Accept after discretionary revisions\nForm responses:\n---\n\nComments to Author:\n---\nAuthors have performed all critical changes. I have only one remaining request. In supplementary table, numeric parameters are presented with commas instead of dots, separating number (example: 0,8 instead of 0.8). Please correct.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **The answer is no to all questions.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorAssigned","content":"","date":"2020-08-11T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-08-10T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-08-10T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-07-28 16:59:01","doi":"10.21203/rs.3.rs-42503/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-08-06T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThis work aimed by retrospective analysis evaluates the Il-6 as a predictor of severe course in patients with Covid-19 infection.\nThe manuscript is well writing, with defined objectives. However, some comments must be pointed out.\n\n1. casuistic and methods. How the diagnosis of COVID was made: RT-PCR and serology?\n2. Others have evaluated the role of IL-6 as a marker of severity, so the author must improve the discussion\n3. I think that just IL-6 do not bring new facts to IL-6 in COVID; however, this study could evaluate IL-1β together with IL-6, since the production of this cytokine is increased by IL-1β, per ex.,\n4. So an increase of IL-6 in cytokine storm is an epiphenomenon or primarily involved.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no conflict of interest considering all of 6 question above .\n1. NO\n2. No\n3. No\n4. No\n5. No\n6. No**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"decision","content":"Major revision","date":"2020-08-06T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-07-29T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-07-29T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nThe study shows that IL6 could be a good early marker to predict severe COVID-19 in elder patients. As a whole, 53 patients were evaluated; there was a 100% sensitivity and 88% specificity for IL6 levels greater than 24pg/ml in blood samples collected within 24h of COVID19 diagnosis. Authors propose that early screening for IL6 could improve the detection of patients in need of hospitalization. This could provide an early intervention and potentially reduce morbidity and mortality.\nIn general, the text is very well written, the rational is clear and the approach is appropriate.\n\nIn introduction, authors should expand on their choice for IL6, only. What about other important inflammatory cytokines?\nAuthors should include a supplementary Table with major clinical findings of all patients enrolled in the study (individually).\nA Table with the blood counts of monocytes, neutrophils, eosinophils and basophils could be included.\nIn results section, data on other complications, except for the need of supplementary oxygen, should be presented, such as cardiovascular instability, renal abnormalities, and coagulation abnormalities.\nIn discussion the section of clinically significant and implications is too long. Authors should be more specific.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **No conflict of interest**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewersInvited","content":"","date":"2020-07-27T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-07-27T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-07-15T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-07-14T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-07-14T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-07-13T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b33522da-204f-4a9e-8042-5210a246b9e3","owner":[],"postedDate":"October 30th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":300881,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2021-08-18T19:30:06+00:00","versionOfRecord":{"articleIdentity":"rs-42503","link":"https://doi.org/10.1186/s12879-021-05945-8","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2021-03-29 19:10:12","publishedOnDateReadable":"March 29th, 2021"},"versionCreatedAt":"2020-10-30 01:20:13","video":"","vorDoi":"10.1186/s12879-021-05945-8","vorDoiUrl":"https://doi.org/10.1186/s12879-021-05945-8","workflowStages":[]},"version":"v3","identity":"rs-42503","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-42503","identity":"rs-42503","version":["v3"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}