key: cord-336546-wcxqn5z2 authors: Xi, Aiqi; Zhuo, Ma; Dai, Jingtao; Ding, Yuehe; Ma, Xiuzhen; Ma, Xiaoli; Wang, Xiaoyi; Shi, Lianmeng; Bai, Huanying; Zheng, Hongying; Nuermberger, Eric; Xu, Jian title: Epidemiological and clinical characteristics of discharged patients infected with SARS‐CoV‐2 on the Qinghai plateau date: 2020-05-21 journal: J Med Virol DOI: 10.1002/jmv.26032 sha: doc_id: 336546 cord_uid: wcxqn5z2 Since the outbreak of coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was first reported in Wuhan, a series of confirmed cases of COVID‐19 were found on the Qinghai‐Tibet plateau. We aimed to describe the epidemiological, clinical characteristics, and outcomes of all confirmed cases in Qinghai, a province at high altitude. The region had no sustained local transmission. Of all 18 patients with confirmed SARS‐CoV‐2 infection, 15 patients comprising 4 transmission clusters were identified. Three patients were infected by direct contact without travel history to Wuhan. Of 18 patients, 10 patients showed bilateral pneumonia and 2 patients showed no abnormalities. Three patients with comorbidities such as hypertension, liver diseases or diabetes developed severe illness. High C‐reactive protein levels and elevations of both ALT and AST were observed in 3 severely ill patients on admission. All 18 patients were eventually discharged, including the 3 severe patients who recovered after treatment with non‐invasive mechanical ventilation, convalescent plasma and other therapies. Our findings confirmed human‐to‐human transmission of SARS‐CoV‐2 in clusters. Patients with comorbidities are more likely to develop severe illness. This article is protected by copyright. All rights reserved. Coronavirus disease 2019 , caused by infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, Hubei, China in December 2019 [1] [2] [3] [4] and rapidly spread worldwide. 5 The outbreak spread to 209 countries and the global number of reported cases surpassed 1,210,000 as of April 6, 2020. 6 With evidence that SARS-CoV-2 is spread by human-to-human transmission, 7-9 the increasing number of cases and widening geographical spread of the disease raise a global health concern. 10 So far, several studies have described the epidemiological and clinical features of COVID-19, but the data mainly came from Wuhan. 4, 11 Qinghai province, located on the Qinghai-Tibet plateau with Accepted Article an average altitude of more than 3000 meters above sea level and a population of 6.03 million, reported a total of 18 confirmed cases by April 6. During the outbreak, Qinghai rapidly instituted a number of strict control measures to lower transmission, including the enforcement of quarantine measures, early detection, reducing passenger flow, and strong social messaging. By April 6, 2020, no new confirmed cases had been found in Qinghai Province for 60 consecutive days since Feb 6, 2020. More importantly, all 18 patients including 3 severely ill cases had been discharged after treatment by Feb 21, 2020 ( Figure 1 ). In this study, we report the epidemiological and clinical characteristics, and outcomes of all 18 confirmed COVID-19 patients in Qinghai including family clusters who returned to Qinghai from Wuhan, and family members who did not travel to Wuhan. For this retrospective study, we enrolled all 18 patients infected with SARS-CoV-2 from the hospitals designated for treatment by the Health Commission of Qinghai Province from Jan 21 to April 6, 2020. 15 patients were from the Fourth People's Hospital of Qinghai Province and 3 patients were from the Third People's Hospital of Xining. All confirmed patients enrolled in this study were diagnosed with COVID-19 according to World Health Organization interim guidance 12 . A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay from nasopharyngeal swab specimens. Under the condition of tertiary protection, nasopharyngeal swabs of patients were collected in the isolation ward for SARS-CoV-2 nucleic acid detection. All biological samples were sealed and transferred to the laboratory of Qinghai Center for Diseases Prevention and Control in strict accordance with the standard process. Total RNA was extracted using RNA isolation kit (Tianlong Science Technology, Xi'an, China). In order to target the nucleocapsid (N) gene and open reading frame lab (ORF1ab) gene, a SARS-Cov-2 real-time PCR kit (Bio-germ, Shanghai, China) was used in fluorescent PCR method. Both internal controls and negative controls were routinely performed with each batch of tests. Incubation period was defined from the first point of contact with a symptomatic case to illness onset. This study was approved by the ethics commissions of the two hospitals. Oral consent was obtained from patients. The epidemiological, demographic, clinical, laboratory and radiological characteristics and treatment and outcomes data were obtained from patients' medical records. Information recorded included demographic data, exposure history, comorbidities, symptoms, laboratory findings and Mild cases: clinical symptoms were mild without pneumonia manifestation through image results. Moderate cases: having fever and other respiratory symptoms with pneumonia manifestation through image results. Severe cases: meeting any one of the following: respiratory distress, RR> 30/min; SpO2 ≤90% at rest in Xining adjusted according to altitude; PaO2/FiO2≤ 300mmHg needed to be corrected according to altitude as mentioned above. All treatment measures were collected during the hospitalization, such as antiviral therapy, antibacterial therapy, corticosteroid therapy, traditional Chinese medicine therapy, immune support therapy, convalescent plasma therapy, and respiratory support. Discharge criteria were based on COVID-19 Guidelines (5th version) by NHCC as follows: body temperature normal for more than 3 days, respiratory symptoms and pulmonary imaging improved significantly, and respiratory tract Accepted Article specimen nucleic acid amplification test negative on two consecutive occasions at least 24 hours apart. Categorical variables were described as proportions and percentages, and continuous variables were described using median and range (min-max) values. Statistical analyses were done using the Graphpad Prism software, version 8.02, unless otherwise indicated. For unadjusted comparisons, a 2-sided α of less than 0.05 was considered statistically significant. Median values were compared by Mann-Whitney test. All 18 patients identified as confirmed SARS-CoV-2 cases were included in this study from January 25 to February 5, 2020 ( Figure 1 ). Among them, 3 (17%), 13 (72%) and 2 (11%) patients were categorized into severe, moderate and mild groups, respectively, during hospitalization. Of 3 severe patients, 2 were initially classified as moderate and then changed to severe as disease progressed. In total, 15 patients returned from Wuhan, Hubei Province of China. Of the 3 remaining cases, 2 patients had contact with a confirmed case and 1 patient had contact with a family member who returned from Wuhan with a negative result on nucleic acid amplification test. In total, 4 clusters of SARS-CoV-2 infection were identified, involving 15 cases. The median age was 32 years (range, 7-47 years), and 12 (67%) were men. Five (28%) patients, including 3 severe patients, had chronic diseases, including hypertension, hyperlipidemia, diabetes, liver injury and polymyositis (Table 1 and 2). On admission, the most common symptoms were cough (9 [50%]), sputum production (6 [33%]), chest tightness (6 [33%]), fever (3 [17%] ) and fatigue (3 [17%] ). All and showed fever, cough and fatigue when they contacted. Two second-generation patients contacted with one source patient for 2 days and the incubation periods were 14 days and 15 days separately. The third second-generation patient contacted with the other source patient for 5 days and the incubation periods was 5 days. Therefore, three second-generation cases had incubation periods of 5, 14 and 15 days, respectively. The median time from departure from Wuhan to admission was 8 days (range, 1-16). Chest X-ray or CT examination was performed on all patients on admission. Of 18 patients, 10 (56%) patients showed bilateral pneumonia while 6 (33%) patients showed unilateral pneumonia, and 2 (11%) patients showed no abnormalities ( Table 1 ). The most common abnormalities were ground-glass opacities (12 [67%]) and patchy shadows ( Figure 2 ). On admission, 3 (17%), 3 (17%), 4 (22%) and 5 (28%) patients had leucopenia, lymphopenia, neutropenia and eosinophilia, respectively (Table 3 ). Hemoglobin was above the normal range in 6 (33%) patients, which may be attributed to high altitude. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations were elevated in 4 patients including 3 severe patients ( Table 2 ). Elevated levels of lactate dehydrogenase (LDH) and creatine kinase were found in 6 (40%) and 2 (13%) cases, respectively. One patient with polymyositis showed abnormal (Table 4) . With supportive care, the condition of all 18 patients improved significantly and CT images showed obvious regression of ground glass opacities ( Figure 2 ). All patients including 3 severe cases were discharged. The median time for conversion of nucleic acid amplification test from positive to negative was 9 days (range, 5-18) and the median length of hospital stay was 13.5 days respectively. The remaining one had fever several hours before admission but no pneumonia symptoms on CT imaging. According to COVID-19 Guidelines made by the National Health Commission of the People's Republic of China at that time, they were admitted before February 5. It is worth noting that one second-generation patient (47 years old, male) had contact with, and presumably contracted COVID-19 from, his son who returned from Wuhan withnegative nucleic acid test. His son had mild symptoms including fever, cough and fatigue at the next day after returning from Wuhan. However, the nucleic acid tests for SARS-CoV-2 were negative at four different time points and CT imaging showed normal. So his son was quarantined at home and only contacted with him for 5 days. Then the second-generation patient showed cough, fatigue and sore throat and was confirmed of COVID-19 by nucleic acid test. We observed a greater number of men than women among the 18 cases of SARS-CoV-2 infection, consistent with a previous study 15 . Additionally, 3 children were infected with SARS-CoV-2 and showed mild or moderate symptoms. All 3 severe cases had comorbidities such as hypertension, liver disease or diabetes. SARS-CoV-2 infects host cells through angiotensin-converting enzyme 2 (ACE2) receptors. 2 ACE2 is highly expressed in the heart and lungs, which is involved in heart function and the development of hypertension and diabetes. 16 Liver injury in patients with SARS-CoV-2 infections might be also directly caused by the viral infection of liver cells. 17 Elevation of both ALT and AST was observed in 4 patients including 3 severe cases and 1 case with polymyositis on admission. Therefore, liver damage is more prevalent in severe cases than in mild and moderate cases of COVID-19 consistent with previous reports. 4, 14 As the elevated amount of C-reactive protein may be associated with the inflammatory response and cytokine storms caused by the virus in the blood vessels 18 , a previous study showed that the C-reactive protein level was positively correlated with the severity of the pneumonia. 19 Similarly, we found that the amount of C-reactive protein was higher in 3 severe patients than the other 15 mild and moderate patients. Qinghai is located on an elevated plateau with lower ambient oxygen levels. Compared to those living at lower altitudes, patients at high altitude are less tolerant to hypoxia and lung diseases are more likely to cause respiratory failure. 20 Therefore, oxygen supply is important for patients with COVID-19, especially severe patients. Our study has several limitations. First, there was no detailed collection of symptom data at different phases of illness. There is no detailed serial RT-PCR sampling depicted to show the viral dynamics in this small cohort. Second, with the limited number of cases in Qinghai, the results should be interpreted with caution. Third, there was no control group for any of the treatments given, so no conclusion can be drawn about their role in recovery. At the time of convalescent plasma transfusion, the antibody level test (IgG, IgM et al) had not yet been routinely introduced at the hospital and no treatment guideline for using convalescent plasma was released. We did not measure the antibody concentrations in severe patients before and after convalescent plasma transfusion, so it is difficult to accurately evaluate the efficacy related to convalescent plasma. In summary, all 18 patients including 3 severely ill patients with COVID-19 were discharged after treatment on Qinghai plateau. Patients with comorbidities are more likely to develop severe illness. High C-reactive protein levels and elevations of both ALT and AST were observed in 3 severely ill patients on admission. The strategies of early detection, early diagnosis, early isolation, and early treatment of COVID-19 in Qinghai are useful to prevent the transmission and improve the cure rate. All authors declare no competing interests of this study. 4 -J a n -2 0 2 0 2 5 -J a n -2 0 2 0 2 6 -J a n -2 0 2 0 2 7 -J a n -2 0 2 0 2 8 -J a n -2 0 2 0 2 9 -J a n -2 0 2 0 3 0 -J a n -2 0 2 0 3 1 -J a n - This article is protected by copyright. All rights reserved. A new coronavirus associated with human respiratory disease in China A pneumonia outbreak associated with a new coronavirus of probable bat origin A Novel Coronavirus from Patients with Pneumonia in China Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention WHO. Coronavirus disease 2019 (COVID-19) Situation Report -77 A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges A novel coronavirus outbreak of global health concern Clinical Characteristics of 138 Hospitalized Patients With Novel Coronavirus-Infected Pneumonia in Wuhan, China Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance (ncov)-infection-is-suspected Acute respiratory distress syndrome: the Berlin Definition Clinical Characteristics of Coronavirus Disease 2019 in China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study COVID-19 and the cardiovascular system Liver injury in COVID-19: management and challenges This study was funded by Science and Technology Department of Qinghai Province (number 2020-SF-158). We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Qinghai. We thank all patients involved in the study. We thank Qinghai Center for Provincial People's Hospital for detection of coronavirus antibody. This article is protected by copyright. All rights reserved.