key: cord-0895483-gyq6cpc9
authors: Wang, Chang‐Zheng; Hu, Shun‐Lin; Wang, Lin; Li, Min; Li, Huan‐Tian
title: Early risk factors of the exacerbation of Coronavirus disease 2019 pneumonia
date: 2020-05-29
journal: J Med Virol
DOI: 10.1002/jmv.26071
sha: ba9fbe2ffbb41fa0eb08649517f4ef1412feaf07
doc_id: 895483
cord_uid: gyq6cpc9

The purpose of this study was to investigate the early risk factors for the exacerbation of coronavirus disease 2019 (COVID‐19) pneumonia. Restrospective analysis of clinical data of 85 patients infected with SARS‐CoV‐2, including gender, age, comorbidities, symptoms, blood routine, clotting profile, biochemical examination, albumin, myocardial enzyme profile, inflammatory markers, and chest CT. All laboratory examination were measured within first 24 hours after admission, and chest CT were performed before admission. 56 (65.9%) patients had a history of exposure to Huanan seafood market in Wuhan. Fever and dry cough accounted for the highest percentage of all symptoms. Male COVID‐2019 patients were more likely to develop severe pneumonia. Patients with severe and critical conditions are older and have higher rates of hypertension (p=0.003) and coronary heart disease (p=0.017). All severe and critical patients infected with SARS‐CoV‐2 showed bilateral lung involvement and have more multiple lobes involvement than common patients (p<0.001). Severe and critical patients showed higher WBC count (p=0.006), NEU count (p=0.001), NEU% (p=0.002), PCT (p=0.011), CRP (p=0.003), PT (p=0.035), D‐dimer (p=0.025), AST (p=0.006), and lower LYM count (p=0.019), LYM% (p=0.001), ALB (p<0.001). Logistic regression analysis showed NEU count is a independent risk factor for deterioration, with the threshold of 6.5×10(9)·L(‐1). We concluded that the laboratory independent risk factor for the progression of COVID‐19 pneumonia is NEU count. In addition, COVID‐19 patients with bilateral lung involvement or multiple lobes involvement should be taken seriously and actively treated to prevent deterioration of the disease. This article is protected by copyright. All rights reserved.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease with significant morbidity and mortality, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 . In January 2020, the WHO Emergency Committee announced "a public health emergency of international concern". As of March 18, 2020, SARS-CoV-2 has swept through 151 countries worldwide, causing 114,428 infections and 4,655 deaths. At present, the virus is spreading rapidly in many countries, with outbreaks in Italy, Iran, Spain, Germany and South Korea causing the most concern.

The main manifestations of the disease are fever, dry cough and fatigue 2 . A small number of patients have symptoms such as stuffy nose, runny nose, sore throat, myalgia and diarrhea 3 .

Severe patients often develop dyspnea and/or hypoxemia one week after onset, and may even rapidly progress to acute respiratory distress syndrome (ARDS), septic shock, hard-to-correct metabolic acidosis, bleeding and coagulation dysfunction, and multiple organ failure 2 . To date, the worldwide mortality rate for patients infected with SARS-CoV-2 is about 4.1%.

Early identification of patients with possible deterioration of the disease is particularly important for controlling the proportion of severe patients and reduce the mortality. Therefore in this study, we aimed to analyze the early clinical features of COVID-19 and investigate the early risk factors for exacerbation.

The clinical data of 85 patients diagnosed by COVID-19 were collected, including 39 common patients in department of infectious diseases from January 10, 2020 to February 15, 2020 and 46 severe and critical patients in intensive care unit (ICU) from January 10, 2020 to February 28, 2020. All patients were collected continuously. The collection and use of relevant information can fully protect the privacy of patients and the study conformed to ethical norms. The diagnosis of COVID-19 referred to the "diagnosis and treatment of novel coronavirus pneumonia (trial version 7)" issued by the National Health Commission of the People's Republic of China 4 . The confirmed patient should satisfy sputum, pharynx swab or lower respiratory tract secretions and other specimens to receive real-time qPCR to show positive viral nucleic acid 3 . Influenza virus, adenovirus, respiratory syncytial virus and other known viral infections and mycoplasma pneumoniae infection were excluded in all patients.

At present, the clinical classification of the disease is: common type: with fever, respiratory symptoms, imaging manifestations of pneumonia; severe type, one of the following:1.

Respiratory distress, RR≥30 times/min; 2. In resting state, oxygen saturation is less than 93%; 3. Partial arterial oxygen pressure (PaO2)/oxygen absorption concentration (FiO2)≤300 mmHg (1 mmHg = 0.133kPa); 4. Chest imaging showed that the lesion significantly progressed to >50% within 24 to 48 hours; critical type: one of the following: 1. Respiratory failure, requiring mechanical ventilation; 2. Shock; 3. Combined with other organ failure, intensive care unit is required 5 .

All patients underwent CT examination before admission. GE discovery and Siemens Somatom Sensation were used for spiral CT scanning. The patient was supine and scanned at the end of inspiration with a conventional dose scan ranging from the tip of the lung to the base of the lung. The thin-slice CT image was evaluated by two radiologists who did not know the results of nucleic acid. were measured for all enrolled patients within first 24 hours after admission.

The normal distribution measurement data were presented as the mean ± standard deviation (SD), and Student's t-test were employed to compare the mean of two groups. The non-normal distribution measurement data were described as median (quartile spacing), and the Mann-whitney rank-sum test was used for the nonparametric analysis. The counting data were compared by chi-square test or Fisher's exact test. Multiple Logistic regression was used for the regression analysis. Statistical significance was set as P<0.05. SPSS13.3 was used for statistical analysis.

A total of 85 patients were included in this study, including 39 common patients and 46 severe and critical patients. Among them, 45 (52.9%) were males and 40 (47.1%) were females, and males were more likely to develop severe pneumonia (27 vs 12, p=0.006). In addition, severe and critical patients were older than common patients (53.6±13.7 vs 65.1±15.1, p=0.002). 56 (65.9%) patients had a history of exposure to Huanan seafood market in Wuhan. The most common symptoms at onset were fever (89.4%) and dry cough (76.5%); while the less common symptoms were fatigue or muscle aches (42.4%), expectorant (18.8%), dizziness or headeche (12.9%), dyspnea (9.4%), and diarrhea (7.1%). There were no statistically significant differences in symptoms between the two groups. In addition, in terms of comorbidities, compared with common patients, the proportion of severe and critical patients with hypertension (13.0% vs 41.0%, p=0.003) and coronary heart disease (2.2% vs 20.5%, p=0.017) were higher. However, there were no statistically significant differences in other comorbidities and vital signs between the two groups (Table 1) .

All patients presented abnormal chest CT findings before admission. Of the 85 patients, 77 (90.6%) had bilateral involvement. All severe and critical patients showed bilateral lung involvement. In addition, the rate of bilateral involvement was higher in severe and critical patients than in common patients (80.4% vs 100.0%, p=0.010). Typical features of chest CT images were ground-glass changes, grid-form shadow and paving stone sign. Other manifestations included multiple patches, infiltration and even consolidation. The distribution characteristics of lesions in all included patients were shown in Table 2 . The lesions involved one lobe (7 vs 0 cases), two lobes (9 vs 0 cases), three lobes (7 vs 1 cases), four lobes (10 vs 2 cases) and bilateral whole lung (13 vs 36 case). Apparently severe and critical patients have more lobes damage than common patients (p＜0.001).

The results of blood routine showed that WBC count (4.58×10 9 ·L -1 vs 7.13×10 9 ·L -1 , p=0.006), NEU% (67.7% vs 79.3%, p=0.002), and NEU count (3.2×10 9 ·L -1 vs 5.71×10 9 ·L -1 , p=0.001) in severe and critical patients were significantly higher than those in common patients.

Furthermore, the proportion of WBC count (p=0.035) and NEU count (p=0.001) above the normal upper limit was significantly higher in severe and critical patients. However on the contrary, LYM% (18.5% vs 11%, p=0.001) and LYM count (0.96×10 9 ·L -1 vs 0.67×10 9 ·L -1 , p=0.019) were lower in severe and critical patients. Besides, the proportion of severely ill patients with LYM counts less than 1 ×10 9 ·L -1 is lower than that of common patients (52.2% vs 74.4%, p=0.035). There were no significant difference in HGB (127.1g/L vs 129g/L, p=0.926) and PLT count (157×10 9 ·L -1 vs 175×10 9 ·L -1 , p=0.865) between the two groups. In terms of clotting profile, PT (12.7s vs 13.2s, p=0.035) and D-dimer (211ug·mL -1 vs 365ug·mL -1 , p=0.025) were significantly elevated in severe and critical patients, while the level of APTT (30.6s vs 29.5s, p=0.140) did not differ obviously. In addition, CRP (30.5mg·L -1 vs 58.71mg·L -1 , p=0.003) and PCT (0.05ng·mL -1 vs 0.07ng·mL -1 , p=0.011) were higher in severe and critical patients. For biochemical indicators, the values of AST (36IU·L -1 vs 50IU·L -1 , p=0.006) in severe and critical patients were significantly higher than those in common patients, and 45 IU·L -1 may be the threshold. Besides, the level of ALB (38g·L -1 vs32.1g·L -1 , p＜0.001) was significantly lower in common patients. Although the value of creatinine in the severe group was significantly higher than that in the common group (p=0.027), there was no significant difference when threshold was set at 133umol·L -1 (p=0.265). Lastly, there were no significant differences in other biochemical indicators and myocardial injury markers (Table 3) . Multivariate Logistic regression analysis between NEU, LYM, PCT, CRP, ALB, AST and severe and critical covid-19 found that NEU is a independent risk factor for deterioration, with the threshold of 6.5×10 9 ·L -1 (p=0.039)( Table   4 ).

Since SARS-CoV-2 was found in Wuhan City, Hubei Province in December 2019, it has spread rapidly all over the country and the world 5 . The virus transmission through fecal-oral, prolonged exposure in closed field, aerosol transmission in high concentration environment, and indirect transmission of conjunctiva are not excluded 6 . The clinical features are fever, dry cough, persistent high fever in severe cases, and acute respiratory distress syndrome, sepsis, bleeding and coagulation dysfunction in critical cases 3 .

The detection of viral nucleic acid in respiratory tract or blood samples is the main method for the diagnosis of COVID-19, which can be combined with epidemiology and imaging to improve the accuracy 5 . The treatment principle of the disease is, on the basis of symptomatic treatment, to actively prevent and cure complications, to prevent secondary infection, and to provide timely organ function support 5 . There are no specific drugs for this infected disease, while some antiviral drugs that may be effective are recommended in China, such as interferon-alpha, lopiravir/ritonavir, ribavirin, chloroquine phosphate and abidor 5 In this study, we collected a cohort of 85 patients with viral RNA-confirmed SARS-CoV-2 infection. The ratio of male to female was 45:40, indicating that men and women are generally susceptible to SARS-CoV-2. However compared with female patients, male patients accounted for a higher proportion of severe and critical cases. Older patients were at higher risk for disease progression. In addition, clinical data suggested that severe and critical patients often incorporated more basic diseases, such as hypertension and coronary heart disease. This suggests that COVID-19 patients with hypertension and coronary heart disease may require ICU care later. Chest CT before admission suggested that COVID-19 patients with bilateral involvement or multiple lobes involvement were more likely to deteriorate to severe pneumonia. We observed greater increase in NEU count, PCT level, CRP level and greater decrease in lymphocyte count in critically ill patients. This suggests that disease progression in covid-19 patients may be associated with bacterial infection and impaired cellular immunity. In addition, AST was significantly increased and albumin levels were significantly reduced in severe and critical patients, suggesting that SARS-CoV-2 virus may damage liver cells and impair the synthesis function of the liver. Logistic regression analysis showed that NEU is a independent risk factor for deterioration, with the threshold of 6.5×10 9 ·L -1 , suggesting that combination of bacterial infections may be the most important factor in worsening the condition.

In conclusion, a significant number of patients infected with SARS-CoV-2 may progress to severe illness or even death. In early stage of COVID-19, we can predict a patient's risk of progression by combining laboratory tests with chest CT. We concluded that the laboratory independent risk factor for the progression of COVID-19 pneumonia is NEU count, with the threshold of 6.5×10 9 ·L -1 . In addition, COVID-19 patients with bilateral lung involvement or multiple lobes involvement should be taken seriously and actively treated to prevent deterioration of the disease.

The author declare no conflict of interests.

Writing: CW. Data collection: SH, LW, and ML. Data analysis: CW and HL. 

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ALB present neutrophil, lymphocyte, procalcitonin, c-reactive protein, aspertate aminotransferase, albumin, respectively