Predictive criteria of severe cases in COVID‐19 patients of early stage: A retrospective observational study

Abstract Background Patients with coronavirus disease 2019 (COVID‐19) often suffer sudden deterioration of disease around 1‐2 weeks after onset. Once the disease progressed to severe phase, clinical prognosis of patients will significantly deteriorate. Methods This was a multicenter retrospective study on patients of all adult inpatients (≥18 years old) from Tianyou Hospital (Wuhan, China) and the Fourth Affiliated Hospital, Zhejiang University School of Medicine. All 139 patients had laboratory‐confirmed COVID‐19 in their early stage, which is defined as within 7 days of clinical symptoms. Univariate and multivariate logistic regression models were used to determine the predictive factors in the early detection of patients who may subsequently develop into severe cases. Results Multivariable logistic regression analysis showed that the higher level of hypersensitivity C‐reactive protein (OR = 4.77, 95% CI:1.92‐11.87, P = .001), elevated alanine aminotransferase (OR = 6.87, 95%CI:1.56‐30.21, P = .011), and chronic comorbidities (OR = 11.48, 95% CI:4.44‐29.66, P < .001) are the determining risk factors for the progression into severe pneumonia in COVID‐19 patients. Conclusion Early COVID‐19 patients with chronic comorbidities, elevated hs‐CRP or elevated ALT are significantly more likely to develop severe pneumonia as the disease progresses. These risk factors may facilitate the early diagnosis of critical patients in clinical practice.


| Assessment and grouping
Severity of the disease was staged according to the guidelines for diagnosis and treatment of COVID-19 (trial seventh edition) published by the National Health Commission of China on March 4, 2020.
Patients who had any of the following features at the time of, or after admission were classified as severe cases: (a) respiratory distress (≥30 breaths per minute); (b) oxygen saturation at rest ≤ 93%; (c) oxygenation index (artery partial pressure of oxygen/inspired oxygen fraction, PaO 2 /FiO 2 ) ≤300 mm Hg; and (d) Lung imaging showed that the lesion progressed more than 50% within 24 hours and 48 hours.
As a result, there were 93 cases in the severe group and 46 cases in the non-severe group.

| Statistical analysis
Statistical analyses were performed using SPSS 20.0 software. Measurement data were described by median and interquartile ranges (IQR). Differences of measurement data were compared with Mann-Whitney U test. The enumeration data were represented by frequencies and percentages. To compare the enumeration data of different groups, chi-square and Fisher's exact test were used.
Univariate and multivariate logistic regression models were used to analyze the risk factors for severe tendency of early COVID-19 patients. P < .05 was considered statistically significant.

| General clinical data of the COVID-19 patients
As indicated in Table 1, the median age of patients was 60 years (IQR, 47-69; range from 19 to 89 years). The age of the patients in the severe group was older than that in the non-severe group (P < .001). 52% of the patients are male, while no significant correlation between sex and severity of the disease (P = .059) was found. 76 patients were complicated with chronic comorbidities, of which hypertension (32%) was the most common, followed by chronic obstructive pulmonary disease (17%) and diabetes (15%). There was no significant difference in antiviral therapy, antibiotic therapy, oxygen therapy, and traditional Chinese medicine treatment between two groups (P > .05), but patients in the severe group were more likely to receive glucocorticoid therapy (P = .012).

| Radiological and laboratory results
Lymphocyte count was significantly lower in severe group than the non-severe group (0.93 vs 1.2, P = .001), while NLR (neutrophilto-lymphocyte ratio) was higher (4.48 vs 2.54, P = .01) ( Table 2). In addition, the severe group showed the significantly higher levels of hs-CRP (P < .001), D-dimer (P < .035), and ALT (P < .001). Although a statistical difference was observed in the level of LDH between the two groups (P = .01), if we take the upper limit of normal value (250U/L) as a standard, the difference was insignificant (P = .33).
Lung lesions in the chest CT images were detected for all patients.
The imaging manifestation of severe patients and non-severe patients were different (P < .001). In the severe group, bilateral lung lesions were more common (92%).

| Risk factors for the progression into severe cases
Through univariate logistic regression models, we found that advanced age (≥65 years old), chronic comorbidities, lymphocytopenia, elevated hs-CRP, increased D-dimer, and elevated levels of ALT were the key risk factors for the progression of COVID-19 patients into their severe stage (Table 3). And then we analyzed the optimal cutoff values calculated by the ROC analysis, and the ROC curves were presented in Figure 1

| D ISCUSS I ON
Our study provides some important insight into the differentiation of severe cases among the early COVID-19 patients. The presence of chronic comorbidity is a key risk factor of developing into severe state. Recent study demonstrated that presence of hypertension, diabetes, COPD, and coronary artery disease were risk factors of disease progression in mild or moderate COVID-19 patients, which is in accordance with our result. 6 Moreover, patients with two or more comorbidities are prone to poor prognosis compared with those with no or single. 7 The risk of severe predisposition in patients with chronic comorbidities is higher since it may be related to subsequent multiple organ function damage caused by SARS-CoV-2. Principally, increased gene expression of ACE-2 in the airways of COPD patients may explain the susceptibility of SARS-CoV-2 and exacerbation of disease. 8 Also, SARS-CoV-2 facilitated impaired insulin secretion through ACE2 in pancreatic endocrine cells, meanwhile diabetic patients are susceptible to viral infections, causing cytokine storms, and worsening clinical presentation. 9 Our research suggested that the risk of severe illness increased with an elevated level of hs-CRP. It has been noticed that dysregulation of inflammatory cytokines and chemokines contributes to severe COVID-19. And the cytokine storm can induce apoptosis of endothelial cells and epithelial cells, which may cause vascular leakage and alveolar edema and lead to respiratory failure. 10   Multivariate logistic regression analysis demonstrated that patients with an elevated level of ALT had a higher risk of exacerbation. It should be noted that the laboratory data used in our study were from early COVID-19 patients, generally before medication.
And some studies have found that abnormal levels of ALT were not associated with the liver condition. 16   Abbreviations: ALT, alanine transaminase; CK creatine kinase; ESR, erythrocyte sedimentation rate; hs-CRP, hypersensitive C-reactive protein; hs-TNT, high-sensitivity troponin T; LDH, lactate dehydrogenase; PCT, procalcitonin; PT, prothrombin time; WBC, white blood cell count.
the average lymphocyte percentage was significantly decreased. 22 These evidences suggest that liver abnormalities in COVID-19 pa- Lymphocytopenia is one of the most prominent features of patients with COVID-19. Extensive researches have indicated that lymphocytopenia existed in all clinical types of COVID-19 patients, 3,25,26 especially in dead cases. 27 The prognostic role of the NLR has been documented in different studies and NLR is an risk factor of in-hospital mortality in COVID-19 patients. 28,29 Recent evidence suggested that both T cells and NK cells in patients with COVID-19 were reduced, and memory helper T cells and regulatory T cells were significantly decreased in severe patients. 30 Our study also showed that lymphopenia and higher NLR were associated with the severity of the disease, but there was no further analysis of lymphocyte subsets due to the lack of relevant data. The autopsy report demonstrated that lymphocytes were overactivated despite the decreased number of lymphocytes. 31 This suggests that SARS-CoV-2 may overactivate the immune system, destroy lymphocytes, and lead to the abnormal release of various cytokines. Consequently, these pathological changes may result in systemic hyperinflammation and indicate a poor prognosis.
A recent pathological work has established that patients with COVID-19 revealed transparent thrombosis of microvessels. 17 Abnormal blood coagulation was also observed in the course of the disease along with some obvious ischemic changes in certain dead

| CON CLUS ION
Early COVID-19 patients with chronic comorbidities, elevated hs-CRP or increased ALT are significantly more likely to develop severe pneumonia as disease progresses. If a patient's profile fits one of these three criteria, it will become highly important to raise priority for the critical care and surveillance of disease progress of the patient. Our findings may facilitate the early recognition of critical patients in clinical practice in dealing with this unprecedent COVID-10 outbreak.

CO N FLI C T O F I NTE R E S T
There were no conflicts of interest to this work.

AUTH O R CO NTR I B UTI O N S
Zhihao Xu conceived and designed the study. Jinrui Gao designed the study, analyzed the data, and wrote the first draft of the manuscript. Xiu Huang analyzed the data and wrote the first draft of the manuscript. Haibo Gu collected the clinical and CT data. Lingyun Lou did the analysis. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.