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      Clinical Characteristics of Hospitalized Patients with SARS-CoV-2 and Hepatitis B Virus Co-infection

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          Abstract

          Dear Editor, Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection was first detected in Wuhan, China in late December 2019. The virus was spreading rapidly to other cities of China and accumulating cases had been reported (Li et al. 2020). On March 11, 2020, WHO declared the outbreak of SARS-CoV-2 as a pandemic. As of June 28, around 10 million COVID-19 cases have been reported in 216 countries or territories and the worldwide death toll has passed 490,000 according to data from WHO (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Until now, there is no effective drug or vaccine available against SARS-Cov-2 infection. In addition to the recent emerged SARS-CoV-2, hepatitis B virus (HBV) is one of the viruses which cause a global infection and threat public health. In worldwide, the prevalence of HBsAg is about 3.9% (Polaris Observatory 2018). According to a nationwide epidemiological survey of population whose ages range from 1 to 59 years in China, 2006, the prevalence of HBsAg was 7.2% (Liang et al. 2009). As SARS-CoV-2 and HBV both can cause liver damage (Fan et al. 2020), further understanding of the risk of SARS-CoV-2 on patients with HBV infection is urgently required in order to design an optimized treatment strategy. However, the impacts of SARS-CoV-2 infection on HBV patients are still not clear. For example, we do not yet know whether the SARS-CoV-2 infection is more severe in HBV patients and we also do not have much knowledge about the impact of SARS-CoV-2 on the course of HBV infection. In this retrospective study, we investigated the clinical characterizes of the patients coinfected with SARS-CoV-2 and HBV by analyzing the clinical records and laboratory tests of 123 COVID-19 patients admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, from January 5 to February 20, 2020. A total of 123 patients with COVID-19 were enrolled in this study, including 50 males and 73 females. The median age of total enrolled patients was 51.0 years (IQR, 35.0–66.0; range, 20–96 years). The most common symptoms at the onset of illness were: fever (37.4–39.1 °C, 69.1%), fatigue (54.5%), cough (50.4%), and myalgia (32.5%) (Table 1). Other symptoms included dyspnea (21.1%), headache (17.1%) and diarrhea (16.3%). Among 123 enrolled patients, thirty-five (28.5%) cases had at least one underlying comorbidity such as hypertension, cardiovascular disease, diabetes, malignancy, COPD or liver cirrhosis. Around 12.2% (15/123) of patients were also suffering from HBV infection. There were more males than females (10:5) co-infected with HBV and SARS-CoV-2 (P = 0.0469, Table 1). The treatment for COVID-19 patients was mainly supportive. Ninety patients were given the antiviral (oral arbidol and/or lopinavir). Seventy-four patients were offered with oxygen support and antibiotic therapy (both orally and intravenous). Sixty-one patients received corticosteroids to suppress an excessive inflammatory activation. There is no significant difference of treatments between patients with and without HBV infection (Table 1). Table 1 Demographics, baseline characteristics, laboratory results, treatment and clinical outcomes of 123 COVID-19 patients with or without HBV infection. Total (n = 123) With HBV infection (n = 15) Without HBV infection (n = 108) P value Sex 0.0469  Female 73 (59.3%) 5 (33.3%) 68 (63.0%)  Male 50 (40.7%) 10 (66.7%) 40 (37.0%) Age, median (IQR), y 51.0 (35.0, 66.0) 54.0 (39.0, 60.0) 51.0 (35.0, 66.0) 0.6127 Comorbidities 35 (28.5%) 4 (26.7%) 31 (28.7%) 1.0000 Hypertension 19 (15.4%) 1 (6.7%) 18 (16.7%) 0.4628 Cardiovascular disease 8 (6.5%) 0 (0.0%) 8 (7.4%) 0.5939 Diabetes 12 (9.8%) 1 (6.7%) 11 (10.2%) 1.0000 Malignancy 5 (4.1%) 3 (20.0%) 2 (1.9%) 0.0724 COPD 5 (4.1%) 0 (0.0%) 5 (4.6%) 1.0000 Liver cirrhosis 3 (2.4%) 2 (13.3%) 1 (0.9%) 0.0390 Signs and symptoms Fever 85 (69.1%) 8 (53.3%) 77 (71.3%) 0.2310 Fatigue 67 (54.5%) 8 (53.3%) 59 (54.6%) 1.0000 Myalgia 40 (32.5%) 3 (20.0%) 37 (34.3%) 0.7604 Cough 62 (50.4%) 4 (26.7%) 58 (53.7%) 0.0582 Dyspnea 26 (21.1%) 6 (40.0%) 20 (18.5%) 0.0859 Diarrhea 20 (16.3%) 2 (13.3%) 18 (16.7%) 1.0000 Headache 21 (17.1%) 2 (13.3%) 19 (17.6%) 1.0000 Days from illness onset to hospital, median (IQR), d 7.0 (4.0, 10.0) 7.0 (4.0, 10.0) 7.0 (4.0, 10.0) 0.9102 Laboratory results (units, normal range) White blood cell Count (×109/L, 3.5–9.5) 4.2 (3.0, 5.7) 4.4 (3.4, 5.6) 4.2 (2.9, 5.7) 0.6484 Lymphocyte count (×109/L, 1.1–3.2) 0.9 (0.6, 1.3)↓ 0.6 (0.4, 1.1) ↓ 0.9 (0.6, 1.3) ↓ 0.0598 Neutrophil count (×109/L, 1.8–6.3) 2.5 (1.6, 3.8) 3.4 (2.3, 5.3) 2.5 (1.6, 3.7) 0.2091 Platelet count (×109/L, 125–350) 179.0 (129.0, 2250) 186.0 (104.0, 225.0) 178.5 (130.3, 225.5) 0.7020 Alanine aminotransferase (ALT) (U/L, 9–50) 22.0 (15.0, 34.5) 25.0 (16.0, 44.0) 21.5 (15.0, 32.8) 0.4418 Aspartate aminotransferase (AST) (U/L, 15–40) 25.0 (19.0, 38.0) 28.0 (19.0, 58.0) 25.0 (19.0, 37.0) 0.6327 Total bilirubin (TBIL) (mmol/L, 5–21) 9.6 (7.8, 12.8) 13.2 (10.0, 17.4) 9.4 (7.6, 12.3) 0.0178 Gamma-glutamyltransferase (GGT) (U/L, 8–57) 22.0 (15.0, 36.0) 20.0 (14.0, 28.0) 22.0 (15.3, 36.8) 0.5110 Alkaline phosphatase (ALP) (U/L, 30–120) 66.0 (54.0, 83.0) 76.0 (52.0, 102.0) 65.0 (54.0, 79.8) 0.2339 Albumin (g/L, 40–55) 38.2 (34.4, 41.0) ↓ 36.0 (30.9, 39.6) ↓ 38.3 (34.6, 41.1) ↓ 0.2309 Prothrombin time (s, 9.4–12.5) 12.7 (11.7, 13.3) ↑ 13.0 (11.5, 13.9) ↑ 12.7 (11.8, 13.3) ↑ 0.2376 Activated partial thromboplastin time (s, 25.1–36.5) 30.7 (28.5, 32.6) 30.6 (27.9, 32.7) 30.9 (28.6, 32.6) 0.4557 International normalized ratio (0.85–1.15) 1.2 (1.1, 1.2) ↑ 1.2 (1.1, 1.3) ↑ 1.2 (1.1, 1.2) ↑ 0.2324 D-dimer (mg/L, 0–500) 204.0 (126.0, 464.0) 270.0 (101.0, 2139.0) 195.5 (128.0, 438.8) 0.4794 Creatinine (µmol/L, 64–104) 62.9 (52.6, 76.9) ↓ 65.4 (59.0, 81.1) 61.9 (52.4, 73.5) ↓ 0.2177 Severe type 33 (26.8%) 7 (46.7%) 26 (24.1%) 0.1152 Treatment Oxygen support 74 (60.2%) 8 (53.3%) 66 (61.1%) 0.5842 Antiviral therapy 90 (73.2%) 8 (53.3%) 82 (75.9%) 0.1152 Antibiotic therapy 123 (100.0%) 15 (100.0%) 108 (100.0%) – Use of corticosteroid 61 (49.6%) 5 (33.3%) 56 (51.9%) 0.2704 Hospital stays, median (IQR), days 14.0 (9.0, 20.0) 14.0 (11.0, 18.0) 14.0 (9.0, 21.0) 0.9383 Clinical outcome Remained in hospital 8 (6.5%) 2 (13.3%) 6 (5.6%) 0.0690 Discharged 110 (89.4%) 11 (73.4%) 99 (91.6%) Death 5 (4.1%) 2 (13.3%) 3 (2.8%) Bold represents the significant difference of P values less than 0.05 The arrow ↓: decrease; ↑: increase Laboratory results indicated that the level of total bilirubin was higher in patients with HBV infection (P = 0.0178, Table 1). The blood counts of the patients with or without HBV infection showed lymphopenia (< 1.3 × 109/L, Table 1). Fifteen COVID-19 patients were examined to be HBsAg positive (5 females and 10 males). The data of anti-HBsAg, HBeAg, anti-HBeAg and anti-HBcAg were available for 11 patients with 10 HBeAg negative and one positive. HBV-DNA was detected in 13 patients. The HBV-DNA level of 10 patients was more than 20 IU/mL. Among the 15 patients, two patients have cirrhosis; three patients were treated with nucleoside analogue (oral entecavir, 0.5 mg, once daily) during the retrospective investigation period (Table 2). Table 2 Hepatitis B serological markers, cirrhosis and nucleoside analogue use of COVID-19 patients co-infected with HBV. Patient Age (years) Sex (female/male) HBsAg Anti-HBs HBeAg Anti-HBe Anti-HBc HBV-DNA Cirrhosis Use of nucleoside analogue (Pos/Neg) (Pos/Neg) (Pos/Neg) (Pos/Neg) (Pos/Neg) (IU/mL, < 20) 1 38 Male Pos NA NA NA NA 100.0 2 54 Male Pos NA NA NA NA NA 3 74 Male Pos Neg Neg Pos Pos < 20 Yes Yes 4 36 Female Pos Neg Neg Neg Pos 211.0 5 48 Male Pos Neg Neg Pos Pos 235.0 6 60 Male Pos Neg Neg Pos Pos < 20 7 72 Female Pos Neg Neg Pos Pos 40,500.0 8 56 Female Pos Neg Neg Pos Pos 40.6 Yes 9 57 Male Pos NA NA NA NA NA 10 39 Male Pos NA NA NA NA 657.0 11 50 Female Pos Neg Neg Pos Pos 2180.0 12 49 Male Pos Neg Neg Pos Pos 89.0 13 59 Male Pos Neg Neg Pos Pos < 20 14 77 Male Pos Neg Neg Pos Pos 166.0 Yes Yes 15 28 Female Pos Neg Pos Neg Pos 1340.0 Bold indicates the value of HBV-DNA >20 IU/mL and is considered as positive NA Data not available, Pos positive; Neg negative Among 15 COVID-19 patients with HBV infection, 11 patients (73.4%) were discharged from the hospital according to the guideline; two patients (13.3%) were still hospitalized and the other two patients (13.3%) were dead. The causes of death are upper gastrointestinal bleeding and Intestinal bleeding respectively (Supplementary Table S1). In the group of 108 COVID-19 patients without HBV infection, ninety-nine patients (91.6%) were discharged from hospital while 6 patients (5.6%) were still hospitalized. Three patients (2.8%) without HBV infection were dead due to respiratory failure (Table 1, Supplementary Table S1). The detailed information of five dead patients was shown in Supplementary Table S1. In line with previous observations (Chen et al. 2020; Guan et al. 2020; Huang et al. 2020; Shi et al. 2020; Wang et al. 2020; Xu et al. 2020; Yang et al. 2020; Zhang et al. 2020), we found that in COVID-19 cases without HBV infection about 50.9% (55/108) patients have the dysfunction of liver symptoms by measuring the level of ALT, AST, TBIL, GGT, and ALP during the disease progress. Furthermore, we uncovered patients with HBV infection had a higher rate of liver cirrhosis (P = 0.0390, Table 1). Seven of 15 patients (46.7%) with HBV infection developed to the severe situation while the percentage of severe cases was much lower (24.1%) in the COVID-19 patients without HBV infection. Two of seven severe HBV and SARS-CoV-2 coinfection patients had cirrhosis whereas the percentage was one out of 26 in the cases of severe COVID-19 without HBV infection. In the enrolled cases, we also discovered that there was a higher incidence of abnormal liver function (27/33, 81.8%) in severe COVID-19 patients than did in mild cases (43.3%, 39/90, data not shown), which agrees with the study that lower incidence of AST abnormality was found in the cases diagnosed by CT scan on the subclinical stage than in the COVID-19 patients who were confirmed after onset of symptom (Shi et al. 2020). Therefore, liver function could be considered as one factor to indicate the progress of COVID-19. In our research, 21.8% of (7/33) COVID-19 severe patients were found to coinfect with HBV infection. It has been suggested that liver impairment in COVID-19 patients could be due to the direct attack of the virus or resulted by other causes such as drug toxicity and systemic inflammation (Zhang et al. 2020). Detecting the viral RNA or viral particles from liver biopsies of COVID-19 patients will be helpful to elucidate if virus can infect liver tissue. Our results pointed out that as high as 47% (7/15) of HBV patients were identified as severe COVID-19 cases. It is more likely that HBV patients would suffer from more severe situation during the disease progress when they were encountered with SARS-CoV-2 infection. In our enrolled cases, two patients with SARS-CoV-2 and HBV coinfection died on admission. One patient died from severe liver disease, haptic sclerosis. And the other died from intestinal hemorrhage, which seems to be associated with the impairment of gastrointestinal tract. More coinfection case analyses are required to further understand whether SARS-CoV-2 infection aggregates the progress of pre-existing disease and thereby cause death. Electronic supplementary material Below is the link to the electronic supplementary material. Supplementary material 1 (PDF 60 kb)

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

             Qun Li,  Xuhua Guan,  Peng Wu (2020)
            Abstract Background The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP. Methods We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number. Results Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9). Conclusions On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.)
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              Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination.

              To determine the prevalence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core anti-body (anti-HBc) in a representative population in China 14 years after introduction of hepatitis B vaccination of infants. National serosurvey, with participants selected by multi-stage random sampling. Demographics and hepatitis B vaccination history collected by questionnaire and review of vaccination records, and serum tested for HBsAg, antibody to anti-HBc and anti-HBs by ELISA. The weighted prevalences of HBsAg, anti-HBs and anti-HBc for Chinese population aged 1-59 years were 7.2%, 50.1%, 34.1%, respectively. HBsAg prevalence was greatly diminished among those age <15 years compared to that found in the 1992 national serosurvey, and among children age <5 years was only 1.0% (90% reduction). Reduced HBsAg prevalence was strongly associated with vaccination among all age groups. HBsAg risk in adults was associated with male sex, Western region, and certain ethnic groups and occupations while risk in children included birth at home or smaller hospitals, older age, and certain ethnic groups (Zhuang and other). China has already reached the national goal of reducing HBsAg prevalence to less than 1% among children under 5 years and has prevented an estimated 16-20 million HBV carriers through hepatitis B vaccination of infants. Immunization program should be further strengthened to reach those remaining at highest risk.
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                Author and article information

                Contributors
                alackcn@126.com
                jinlinli@whu.edu.cn
                znact1936@126.com
                Journal
                Virol Sin
                Virol Sin
                Virologica Sinica
                Springer Singapore (Singapore )
                1674-0769
                1995-820X
                24 August 2020
                : 1-4
                Affiliations
                [1 ]GRID grid.413247.7, Department of Infectious Diseases, , Zhongnan Hospital of Wuhan University, ; Wuhan, 430071 China
                [2 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, , University of Uppsala, ; 75123 Uppsala, Sweden
                [3 ]GRID grid.49470.3e, ISNI 0000 0001 2331 6153, State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, , Wuhan University, ; Wuhan, 430071 China
                [4 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Cell and Molecular Biology, , Karolinska Institute, ; 17165 Stockholm, Sweden
                Article
                276
                10.1007/s12250-020-00276-5
                7444863
                32839868
                © Wuhan Institute of Virology, CAS 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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