key: cord-0825368-sttoaj3l authors: Li, Jinzhong; Gong, Xiaobing; Wang, Zhigang; Chen, Renzhou; Li, Taoyuan; Zeng, Dongyu; Li, Minran title: Clinical features of familial clustering in patients infected with 2019 novel coronavirus in Wuhan, China date: 2020-06-02 journal: Virus Res DOI: 10.1016/j.virusres.2020.198043 sha: 67ec398364b75a3f79bcebe5b0f6d1e2bcb16a1a doc_id: 825368 cord_uid: sttoaj3l An epidemic caused by SARS-Coronavirus-2 (SARS-CoV-2) infection has appeared in Wuhan City in December 2019 and subsequently spread in China. The disease has shown a "clustering epidemic" pattern, and family-clustered onset has been the main characteristic. We collected data from 130 cases from 35 cluster-onset families (COFs) and 41 cases from 16 solitary-onset families (SOFs). The incidence 2019 coronavirus disease (COVID-19) in COFs was significantly higher than that of SOFs. Our study also showed that patients with exposure to high-risk factors (respiratory droplets and close contact), advanced age, and comorbidities were more likely to develop COVID-19 in the COFs. In addition, advanced age and elevated neutrophil/lymphocyte ratio (NLR) were risk factors for death in patients with SARS-CoV-2 infection in the COFs. Since December 2019, cases of SARS-Coronavirus-2 (SARS-CoV-2) infected pneumonia have been found in Wuhan, Hubei Province, China. Since the start of the epidemic, a total of 80,958 people have been diagnosed with 2019 coronavirus disease in China as of March 11, 2020 . SARS-CoV-2 is highly infectious, and mainly transmitting via respiratory aerosols or droplets; most people are generally susceptible to it. The clinical manifestations are mainly fever, fatigue and dry cough [1, 2] . In contrast to SARS, SARS-CoV-2 infection has had a "clustering epidemic" pattern, and family clustering of disease is the main characteristic [3] . According to China-WHO statistics, the 344 clusters reported in Guangdong and Sichuan provinces involved a total of 1308 cases, most (78%-85%) of which occurred in family members [4] . However, the transmission path, persistent transmission rate, clinical characteristics, and prognostic outcomes of cluster-onset families (COFs) are currently unknown. Therefore, this article retrospectively analyzed the epidemiological and clinical characteristics and prognosis of 35 COF patients diagnosed with COVID-19. A preliminary study was conducted to evaluate the relationship between epidemiological factors, such as exposure route and incidence sequence, and the incidence, clinical manifestation and prognosis of patients in COF to provide a strong basis for epidemic control. A retrospective epidemiological investigation and analysis of COVID-19 cases was conducted in accordance with the National Epidemiological Survey Program for New Coronavirus Infected Pneumonia Cases [5] by mainly collecting data from cases with clustered onset in the family; data from some solitary-onset families, where only one person was infected, were also collected as a control. Full-time investigators conducted in-depth epidemiological investigations on the patients one-by-one, and the incidence of some family members was obtained through history collection or telephone follow-up. The main contents of the data collected included general information of the J o u r n a l P r e -p r o o f patients and their close contact family members, epidemiological history (incidence, exposure history), clinical manifestation, previous history, medical treatment, degree of illness, laboratory results, CT diagnosis, length of hospital stay, and prognosis. The data were relatively complete, accurate, true and reliable. COVID-19 data were collected from January 1, 2020, to March 11, 2020 . COVID-19 was diagnosed according to the Chinese New Coronavirus Pneumonia Diagnosis and Treatment Program (trial version 7) [4] . COVID-19 cases includes confirmed cases and clinically diagnosed cases. Clinically diagnosed cases were defined as those with a clear epidemiological history and clinical manifestations that met any two of the following three criteria: (1) fever and/or respiratory symptoms; (2) imaging features of COVID-19 [6] ; (3) normal or decreased white blood cell count and normal or decreased lymphocyte count in early onset. A confirmed case was defined as one with the following etiology or serology evidence based on clinical diagnosis: (1) positive for SARS-CoV-2 by the real-time PCR nucleic acid test in respiratory or blood samples [7] ; (2) viral gene sequencing was highly homologous to known new coronaviruses; or (3) positive detection of SARS-CoV-2-specific IgM antibodies and IgG antibodies. Familial clustered onset referred to two or more confirmed cases or asymptomatic infections found in a single family, with the possibility of interpersonal transmission due to close contact or the possibility of infection due to co-exposure, within 14 days. Close contact mainly started 2 days before symptoms appeared in suspected and confirmed cases or 2 days before samples of asymptomatic infected patients were collected in people who do not take effective protection and had close contact with them [8] . Categorical variables were expressed as counts and percentages, and they were analyzed using the χ2 or Fisher's exact test. Continuous variables are presented as the mean and standard deviation (±SD). Student's t test or one-way ANOVA were used for statistical comparisons, where appropriate. Multinomial (binary) logistic regression was applied to evaluate factors associated with deaths in COFs. Two-sided P values <0.05 were considered statistically significant. Statistical analyses were performed using SPSS 19.0 software (SPSS, Chicago, IL, USA). By March 11, 2020, a total of 130 people from 35 COF were admitted at Hankou Hospital of Wuhan City, including 35 new-onset patients, 59 secondary patients and 36 non-infected family members (Table 1 ). There were also 16 SOFs with 41 people, including 16 new-onset patients and 25 non-infected family members. The average age of the onset in the COF patients was 58.7±16.0 years old, and 46.9% were females, while the average age of onset in the SOF patients was 61.6±10.2 years old, and females accounted for 37.5%. There was no significant difference J o u r n a l P r e -p r o o f between the two groups. Of the onset members of the COFs, 76.6% had fever symptoms, while 68.8% of SOFs had fever symptoms. The next most common symptom in COFs was cough (52.1%), while chest tightness (9.6%) and diarrhea (13.8%) were less common. The most common "other" symptoms in COFs were anorexia (20.2%) and expectoration (13.8%). Among COF patients, 41.5% had at least one comorbidity (such as hypertension and diabetes), compared with 56.3% in SOF patients. At the time of admission, the proportion of severe cases and critical cases in COF patients was 41.5% and 14.9%, respectively; the respective proportions in SOF patients was 62.5% and 6.3%, indicating that the proportion of severe and critical cases in the enrolled patients was high. A total of 68.9% of inpatients in the COFs had lymphopenia, and 17.8% had leukopenia. In addition, 81.3% of inpatients in the SOFs had lymphopenia, and 12.5% had leukopenia. In terms of diagnosis, the positive rate on the nucleic acid test in COF patients (67%) was higher than that in SOF patients (53.3%), but the difference was not statistically significant (P> 0.05). There were 3 (4.8%) patients with positive nucleic acid and normal chest CT and 23 (28%) patients with multiple negative nucleic acid tests and chest CT with typical features of COVID-19, suggesting that the false negative rate for nucleic acid detection was relatively high. Among the self-reported causes of infection in new-onset patients in the COFs (Figure 1 ), the most common was cross-infection in the community (45.7%), followed by hospital exposure history (14.3%), vegetable market or supermarket exposure (11.4%), and a history of seafood or fruit market exposure in south China for a few (8.6%). In COFs, the transmission rates of respiratory droplets in secondary and non-infected patients were 11.9% and 66.7%, respectively, while the transmission rates of respiratory droplets with close contacts were 88.1% and 33.3%, respectively. In SOFs, the proportion of respiratory droplet and respiratory droplet transmission with close contacts was 40% and 60%, respectively ( Figure 2 ). In COFs, the incidence of COVID-19 was as high as 72.3%, with was significantly higher than the 39.0% COVID-19 incidence in the SOFs. Statistic analysis found that the proportion of exposure to high-risk factors (respiratory droplets + close contact) in the secondary group (88.1%) was significantly higher than that in the non-infected group (33.3%), and the difference was statistically significant (P<0.001). The average age of the secondary infection group was 54.9±16.7 years, which was much older than that in the non-infected group (36.3±20.8 years), and the difference was statistically significant (P <0.001). In addition, 33.9% of patients in the secondary infection group had comorbidities, which was higher than 5.6% of patients in the non-infected group that had comorbidities, and the difference was statistically significant (P= 0.001) ( Table 2) . J o u r n a l P r e -p r o o f The mortality rate in the COFs was 10%, while the mortality rate for all affected people is as high as 13.8%. Statistical analysis found that the average age of the patients who died was 72.0±9.8 years, which was much older than that of the patients who did not die (56.6±15.8 years), and the difference was statistically significant (P=0.001). The proportion of patients with shortness of breath or dyspnea in the patients who died (92.3%) was higher than that in the patients who did not die (29.6%), and the difference was statistically significant (P<0.001). A total of 69.2% of patients who died had comorbidities, which was higher than that among those who did not die, and the difference was statistically significant (P=0.03). In addition, the neutrophil/lymphocyte ratio (NLR) in the patients who died was higher than that in the patients who did not die, and the difference was statistically significant (P<0.001). Whereas multiple logistic regression analysis identified that age (OR=1.18, 95%CI: 1.01-1.37, Wald=4.18, P=0.04) and NLR (OR=1.31, 95%CI: 1.06-1.62, Wald=6.26, P=0.01) were associated with deaths in COFs (Table 3 ). With the development of the COVID-19 epidemic, the proportion of the incident cases occurring in clusters continues to increase; the virus has spread to the community through the people who come into contact with the seafood market, forming community transmission, and person-to-person and clustered transmission has been occurring in many communities and families in Wuhan [9] [10] [11] [12] [13] . In this study, a total of 130 people from 35 COFs admitted to Hankou Hospital of Wuhan City were collected. According to the analysis of the self-reported cause of infection in the new-onset patients, most of the reasons reported were cross-infection in the community, history of hospital exposure, and visits to densely populated places (supermarkets and various bazaars), which were related to the significant increase in the flow of people around the Spring Festival in China [14] . The incidence of COVID-19 was higher in the COFs than in the SOFs. The reasons include the following. 1. The included families were from local designated hospitals for infectious diseases, and the proportion of cases with critical illness was high. 2. The exposure to risk factors, such as respiratory droplets and close contact, was higher in COFs, and the possibility of aerosol or contact transmission caused by the presence of feces and urine in families was not excluded [15] . Consistent with the results of other recent studies [6, 13, 16] , the most common symptoms in COFs were fever (76.6%), cough (52.1%), and fatigue (38.3%). However, the proportion of patients with cough and other symptoms as the first symptoms (without fever) was not low, especially for elderly and critically ill patients, which reminds us that screening of high-risk groups should be more comprehensive. At the same time, some atypical or uncommon symptoms also appeared in the COFs, such as anorexia (20.2%) and diarrhea (13.8%). At present, nucleic acid detection in nasal or pharyngeal swabs is still the main method to J o u r n a l P r e -p r o o f diagnose COVID-19, but the positive rate was only 40%-60%. Our study also found that there were 23 COF patients (28%) whose chest CT showed typical COVID-19 characteristics despite multiple negative nucleic acid tests, suggesting a higher false negative rate for the nucleic acid tests. Nucleic acid screening alone will cause a large number of imaging-suspected SARS-CoV-2 infectious pneumonia patients to be unable to obtain timely diagnosis and treatment, thus further delaying the control of the virus transmission pathway. Therefore, it is more practical to conduct detailed screening of suspected patients by adopting multiple methods, including detection of novel coronavirus serum-specific antibodies. The proportion of severe and critical patients in the COFs was as high as 56.4%, and the mortality rate in this group was as high as 13.8%. Our statistical analysis found that advanced age and an elevated NLR were high risk factors for death in patients with COVID-19. The NLR has proven to be a useful indicator of systemic inflammation [17] . In addition, the NLR is associated with mortality in critically ill patients [18] . Neutrophils and lymphocytes are an important part of the innate immune system. Neutrophils, whose count mainly reflects the function of innate immune cells, release a large number of cytokines and chemokines, promoting the formation of a cytokine storm [19] . Studies have shown that neutrophils can be used as antigen-presenting cells of anti-virus CD8+ T cells [20] . Our study found that, on the one hand, lymphopenia was not statistically significant different between the patients who died and those who survived; on the other hand, many critically ill patients experienced an increase in leukocytes and neutrophils with a decrease in lymphocytes. We further suggested the possibility of bacterial infection as a result of procalcitonin. Mixed infection may be another risk for patients with COVID-19, and the NLR can be used as a predictor of infection and prognosis in patients with COVID-19 [21] . This study has some limitations. First, because some family members could only be accessed through medical history collection or telephone interviews, their laboratory or imaging examination records were incomplete. At the same time, a few cases were diagnosed in an outpatient department, so the corresponding medical information was relatively brief and the laboratory examination was not comprehensive. Second, case data were collected mainly in respiratory wards, where the majority of patients were in severe or critical condition, so our study may represent a subset of patients with more severe COVID-19. Furthermore, the number of cases included in this study was not very large, and the results need to be further verified by expanding the sample size. In summary, compared with SOFs, COFs have higher infectivity and pathogenicity. In addition to the increased exposure to high-risk factors such as respiratory droplets and close contact, older patients, especially those with comorbidities, were more likely to be infected. The clinical symptoms of COFs were mainly fever, cough, fatigue, shortness of breath or dyspnea; some patients also manifested as anorexia and diarrhea. COVID-19 patients with advanced age and elevated NLR are at high risk for poor prognosis in COFs. 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The New England journal of medicine2020 Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia Ratio of neutrophil to lymphocyte counts-rapid and simple parameter of systemic inflammation and stress in critically ill The association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study Monocyte/lymphocyte ratio as a better predictor of cardiovascular and all-cause mortality in hemodialysis patients: a prospective cohort study Neutrophil-lymphocyte ratio as an early new marker in AIV-H7N9-infected patients: a retrospective study Role of neutrophil to lymphocyte and monocyte to lymphocyte ratios in the diagnosis of bacterial infection in patients with fever Not applicable.J o u r n a l P r e -p r o o f Minran Li and Jinzhong Li searched the literature, conceived the study, Xiaobing Gong designed the study, Minran Li and Jinzhong Li interpreted the results, and drafted the report. Zhigang Wang 2 , Renzhou Chen 3 , and Dongyu Zeng collected the data. Taoyuan Li analyzed the data. The authors have no competing of interest nor any financial interest in any product mentioned in this paper. Parts of the data that support the findings of this study are available from Clinical Trial Management Public Platform, but restrictions apply to the availability of these data, which were used under license for the present study and so are not publicly available. This study was approved by the Ethics Committee of Hankou Hospital of Wuhan City, China. Informed consent was obtained from all the patients or their guardians. Not applicable. Not applicable.