key: cord-0912631-f6xlfc7d authors: Chen, Min; An, Wei; Xia, Fei; Yang, Ping; Li, Kuangyu; Zhou, Qin; Fang, Shasha; Liao, Yaling; Xu, Xin; Liu, Jialin; Liu, Shiguo; Qin, Tao; Zhang, Jianjun; Wei, Wei; Zhang, Yafang; Zhang, Guowei; Zhang, Mingwei title: Clinical Characteristics of Re‐hospitalized Patients with COVID‐19 in China date: 2020-05-13 journal: J Med Virol DOI: 10.1002/jmv.26002 sha: 1038d500226cb002140588032adeaccbf6db8497 doc_id: 912631 cord_uid: f6xlfc7d BACKGROUND: This study aims to observe the clinical characteristics of recovered patients from Coronavirus Disease 2019 (COVID 19) with positive in RT‐PCR or serum antibody. METHODS: The profile, clinical symptoms, laboratory outcomes and radiologic assessments were extracted on 11 patients, who tested positive for COVID‐19 with RT‐PCR or serum antibody after discharged and was admitted to Hubei No. 3 People's Hospital of Jianghan University for a second treatment in March 2020. RESULTS: The average interval time between the first discharge and the second admission measured 16.00 ± 7.14 days, ranging from 6 to 27 days. In the second hospitalization, 1 patient was positive for RT‐PCR and serum antibody IgM‐IgG, 5 patients were positive for both IgM and IgG but negative for RT‐PCR. 3 patients were positive for both RT‐PCR and IgG but negative for IgM. The main symptoms were cough (54.5%), fever (27.3%) and feeble (27.3%) in the second hospitalization. Compared with the first hospitalization, there were significant decreases in gastrointestinal symptoms (5 vs. 0, P=0.035), elevated levels of both white blood cell count(P=0.036) and lymphocyte count (P=0.002), remarkedly decreases in CRP and SAA (P<0.05) in the second hospitalization. Additionally, 6 patients' chest CT exhibited notable improvements in acute exudative lesions CONCLUSION: There could be the positive results for RT‐PCR analysis or serum IgM‐IgG in discharged patients, even with mild clinical symptoms, however, their laboratory outcomes and chest CT images would not indicate the on‐going development in those patients. This article is protected by copyright. All rights reserved. In December 2019, pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, Hubei Province, China. As of March 7, 2020, a total of 80,695 COVID-19 cases have been confirmed in China. Nevertheless, the number has experienced an obvious decline as the disease has been brought under reasonable control. Till March 17, 2020, there were no new confirmed cases reported for 13 consecutive days in Hubei Province except Wuhan city. By contrast, a total of 69,725 cases were cured and discharged. At present, the disease has quickened its spread in many countries and regions across the world, sparking wide concerns among governments and scientists. This epidemic is a major health risk and sends ripples through national economy, which has infected 100,000 worldwide. [1] [2] In previous studies, epidemiological, clinical, and radiological features of COVID-19 patients have been intensively reported. [3] [4] However, there was less attention on the follow-up of discharged patients. Therefore, this study further investigated the 11 cases of re-hospitalized patients with COVID-19 in Hubei No. 3 People's Hospital of Jianghan University since March 2020 with positive outcomes for RT-PCR or serum antibody. We performed a retrospective review of 11 re-hospitalized patients with WHO interim guidanceand were diagnosed by a Multidisciplinary diagnosis and treatment (MDT) team composed of infectious disease experts, respiratory medicine staff and intensive care unit staff. 5 The clinical symptoms, laboratory outcomess and chest computed tomography(CT) were extracted from electronic medical records. Data were entered into a computerized database and cross-checked. Laboratory assessments consisted of complete blood count, blood chemistry, liver and renal function, erythrocyte sedimentation rate, C-reactive protein, procalcitonin, lactate dehydrogenase and Statistical analysis was performed with SPSS, version 26.0. Continuous variables were directly expressed as mean, median and interquartile range (IQR) values. This article is protected by copyright. All rights reserved. Comparisons between the groups were performed using Mann-Whitney U test. Fisher's exact test between the different groups. All tests were two-sided tests, and P < 0.05 has a statistical significance. As of 11 re-hospitalized patients, there were 3 males and 8 females, at the mean age of 48.45 ± 14.12 years, ranging from 33 to 72 years. The first hospital stay was significantly longer than the second[(22.27 ± 4.85) days vs.(7.00 ± 2.56) days, P<0.001]. The average interval time between the first discharge and the second admission measured 16.00 ± 7.14 days, ranging from 6 to 27 days. The average count of negative results by RT-PCR before discharge was 2.63 ± 0.92 times, in the range of 2 to 5 times. During the second hospitalization, one patient displayed positive outcomes both for RT-PCR analysis and IgM-IgG, five patients were double positive for IgG-IgM but negative for RT-PCR, three patients were positive both for RT-PCR and serum antibody IgG but negative for IgM. The quantitation of IgM and IgG were not available in all patients before April. Three patients had common chronic illness, with two cases of diabetes and one case of hypertension. (Table. 1) The main symptoms of the 11 patients' second admission were cough (6, 54.5%), fever (3, 27.3%) and feeble (3, 27 .3%), respectively. There was no expectoration, pant and muscular soreness during the second hospitalization, and the rate of gastrointestinal symptoms were statistically different between the two hospitalizations (5 vs. 0, P=0.035). (Table. 2) This article is protected by copyright. All rights reserved. The routine blood test, CRP, ESR, SAA and PCT were used to reflect changes of inflammatory response in COVID-19. Compared with the first hospitalization, there was an increase in both white blood cell count and lymphocyte count, a significant fall in CRP and SAA in the second hospitalization, and the difference was statistically significant (P<0.05). There was no difference in biochemical criterion between the two hospitalizations (P>0.05). (Table. 3) The patients' chest CT imaging showed ground-glass opacification or mixed ground-glass opacification and consolidation at onset. In the second hospitalization, chest CT images of the 6 patients showed a substantial improvement of the acute, discharged from the Hubei No. 3 People's Hospital of Jianghan University for the first time. In addition, the chest CT of patient 1, patient 2 and patient 6 showed that the lesions were completely absorbed in the second hospitalization. (Figure.1) For hospital discharge or suspension of quarantine, patients had to meet the following 5 criteria including: (1) normal temperature without fever for over 3 days, re-hospitalized patients were female, at the average age of below 50.The longest interval between the first discharge and the second admission was 27 days whereas 13 days reported by LanLan. 7 One patient was negative in RT-PCR tests for 5 times This article is protected by copyright. All rights reserved. before the first discharge but positive on 8th day after discharge. These findings suggest that at least a proportion of recovered patients were potential virus carriers. Previous study suggested that false-negative RT-PCR test results could have occurred. 8 The nucleic acid testing may be influenced by the different samples. Previous studies suggested the possibility of extended duration of viral shedding in faeces, for nearly 5 weeks after the patients' respiratory samples tested negative for SARS-CoV-2 RNA, may be the delayed clearance of viral RNA in patients' stools. [9] [10] In addition, the results of RT-PCR or serum antibody test of 11 patients were different in the second hospitalization. One patient was positive for both RT-PCR and serum antibody IgM-IgG. To some extent, this patient was still in active phase of infection and had acquired some immunity to SARS-CoV-2 (persistent antibody IgG has been produced). By contrast, five patients were double positive in erum antibody IgG-IgM but negative for RT-PCR. These outcomes suggest a status that those patients were in course of recovery and virus has not been fully eliminated or the RT-PCR results are false negative and the patient was still in the active period of infection. As for the false negatives, there was one possibility that SARS-CoV-2 infection is prone to starts at the lungs, not in the upper respiratory tract, therefore, sampling during the early infection stage using throat swab or sputum may not detect the virus. [11] Three patients were positive in RT-PCR and serum antibody IgG but negative in IgM. These results showed that the patients could be in the middle or late phage of the SARS-CoV-2 infection or in the re-active infection. In some cases, the IgM level might well be below its peak and not detectable by test. A study encouraged more research and development of the COVID 19 IgG-IgM combined antibody test kit to improve the diagnostic sensitivity and specificity for patients. [12] Patients can be diagnosed as recurrent infection when the IgG antibody is increased to 4 times or more in the convalescent compared with the acute phase. Unfortunately, quantification of IgG titer was not available in March. Therefore, this study suggested This article is protected by copyright. All rights reserved. that the patients should take a prolonged quarantine and more reexaminations from varying samples after discharge with COVID-19. The latest diagnosis and treatment of COVID-19 pneumonia in China(7 th ed) issued by the National Health Commission, PRC recommends that patients shall continue to undergo an intensive isolation for 14 days after discharge, and followed by reexamination at 2 and 4 weeks after discharge. 13 In this study, the main clinical symptoms were cough, fever, and feeble. Compared to those in patients' first hospital admission, more of them were mild and relieved, especially the improved gastrointestinal symptoms in five patients with diarrhea or nausea for the first hospitalization. Recent studies have suggested that there was no direct relationship between gastrointestinal symptoms and virus in faecal. 9 Therefore, the discharged patients need reexamination of the virus RNA if asymptomatic. A study showed that in patients recovering from COVID-19 infection, four stages of evolution on chest CT were identified: early stage (0-4 days); progressive stage (5-8 days); peak stage (10-13 days) and absorption stage (≥14 days). 14 In this study, the chest CT indicated that the patients were all in the absorptive stage after first discharge. Together, there were still positive outcomes in RT-PCR analysis or serum IgM-IgG in re-hospitalized COVID-19 patients, though they met the discharge criteria at the end of the first hospitalization. However, in the second hospitalization, there were the shortened hospital stay, relieved clinical symptoms improved laboratory outcomes, and ameliorated CT manifestations on the second admission, which suggest that these re-hospitalized patients were more likely to be in a status of recovery. This study was a single-center, small-sample, retrospective study. A larger cohort of longitudinal studies will help to understand the prognosis of the disease. Min Chen, Wei An, and Fei Xia had the idea for and designed the study and had full access to all data in the study. Mingwei Zhang, Jialin Liu and Yafang Zhang take responsibility for the integrity of the data and the accuracy of the data analysis. Ping The data is expressed as n (%) World Health Organization. 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Diagnosis and treatment of COVID-19 pneumonia in China Time Course of Lung Changes On Chest CT During Recovery From WBC: white blood cells, NEU: neutrophils, N%:neutrophil ratio, LYM: lymphocytes, RBC: red blood cells, Hb: hemoglobin, IL-6:interleukin-6, PLT: blood platelet, CRP:C-reactive protein, ESR: erythrocyte sedimentation rate, SAA: serum amyloid A, PCT: procalcitonin, N/A: Not available, ALT: alanine transaminase, AST: glutamic oxalacetic transaminase, GGT: gamma-glutamyl transpeptidase This research is Supported by the Health Commission Hubei provincial Foundation Authors have no conflict of interest to declare. This article is protected by copyright. All rights reserved.