key: cord-0838754-mng4ajwn
authors: Yi, Bo; Fen, Gaoke; Cao, Dedong; Cai, Yuli; Qian, Li; Li, Wei; Wen, Zhongyuan; Sun, Xuan
title: Epidemiological and clinical characteristics of 214 families with COVID-19 in Wuhan, China
date: 2021-02-10
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.02.021
sha: 839844741c778cb44388b35900ca629bdb4e8e6b
doc_id: 838754
cord_uid: mng4ajwn

Objective To investigated the epidemiological dynamics, transmission patterns and the clinical outcomes of Coronavirus disease 2019 (COVID-19) in familial cluster patients in Wuhan, China. Methods Between January 22, 2020 and February 4, 2020, we enrolled 214 families for this retrospective study. The COVID-19 cases were diagnosed using Real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Number of COVID-19 subjects in a family, their relationship with index patients, the key time-to-event, exposure history, and the clinical outcomes were obtained through telephone calls. Results Overall 96 families (44.9%) met the criteria of a familial cluster, which is at least one confirmed case in addition to the index patient in the same household. The secondary attack rate was 42.9%, and nearly 95% of index patients transmitted the infection to ≤2 other family members. High transmission pattern was noted between couples (51.0%) and among multi-generations (27.1%). The median serial interval distribution in familial clusters was 5 days (95% CI, 4 to 6). The case fatality rate was 8.7% in index patients and 1.7% in non-familial clusters patients (p = 0.023). Conclusions There is an related higher attack rate and the worse clinical outcomes in COVID-19 family clusters.

Renmin Hospital of Wuhan University, Wuhan 430060, China; Email: 515356928@qq.com; Tel: +86-027-88041911

Emerging evidence highlights the distribution of the disease at household level and the risk factors associated with secondary infection (3) (4) (5) (6) (7) (8) . Given the limited health facilities in Wuhan at the beginning of the COVID-19 outbreak, most patients with mild to moderate COVID-19 have had to quarantine at home (9, 10) . This predisposed close contacts of the COVID- 10 

This was a retrospective study conducted at the fever clinics of Renmin Hospital of Wuhan University, one of the major designated hospitals in Wuhan, J o u r n a l P r e -p r o o f Hubei province, China. After the COVID-19 outbreak, the fever clinics was designated by the government to provide more highly effective medical care including meticulous interrogation, necessary examination, and nucleic acid tests of patients presenting with fever, defined as a temperature of 37.3°C or higher.

We reviewed suspected COVID-19 cases from January 22, 2020, to The suspected cases were defined as illness accompanied with a fever, with or without respiratory symptoms, and/or had an exposure to live animal market or close contact with confirmed or probable cases within 14 days before illness onset. According to WHO, a confirmed case was definitively positive for SARS-COV-2 after real-time reverse-transcriptase polymerase chain reaction (RT-PCR) test or by high-throughput sequencing. Probable patient was person only with the clinical symptoms or the radiological findings of COVID-19 (12) .

Only laboratory-confirmed COVID-19 patients with certain medical records were enrolled in the follow-up survey.

The primary outcomes were the incidences of laboratory confirmed COVID-19 cases in a household after disease exposure from a family member. The secondary outcomes included the rate of death and hospitalization and the proportion of individuals quarantined in centralized isolation center or at home.

Familial clusters of COVID-19 cases were defined as at least one confirmed cases in addition to the index patients in the same household within 14 days from the illness onset of index patient. The non-familial cluster was the family with only one confirmed COVID-19 patient. An index patient was defined as the first laboratory-confirmed cases in a familial cluster. Secondary patients were classified in the laboratory-confirmed cases who closely interacted with index J o u r n a l P r e -p r o o f patients for a maximum of 2 weeks. Self-protective measures by family members and strict quarantine of index patients were defined as wearing of surgical masks and separate dining at home. If that fails, we deem it to unshielded or without intense quarantine.

Laboratory confirmation of the SARS-COV-2 RNA was performed by RT-PCR at Renmin Hospital of Wuhan University (13) . Briefly, the nucleic acid was extracted from sputum and throat swab samples based on the Viral Nucleic Acid Kit (Health, Ningbo, China) following the manufacturer's instructions. A COVID-19 detection kit (Bioperfectus, Taizhou, China) was used in detecting the ORF1ab and the N genes. The procedure used for RT-PCR assay was adopted from the WHO protocol (14) . A positive test was defined as a cycle threshold value (Ct value) less than 37, while a negative test was defined by Ct value more than 40. The Ct value more than 37 were replicated twice within 48 hours. Laboratory confirmation of COVID-19 was based on the positive results for both ORF1ab and the N genes.

The epidemic plot of familial clusters was constructed by the day of illness onset. The serial interval distribution (the times of illness onset between index J o u r n a l P r e -p r o o f patients and secondary patients) was estimated by fitting a three-parameter lognormal distribution after Anderson-Darling test.

Continuous data were presents as mean ± standard deviation (SD) or median (interquartile range [IQR]) values, categorical data were described as percentages. To analyze the differences between index or secondary patients from familial clusters and non-clusters patients, we used the Mann-Whitney U test or t-test depending on parametric or nonparametric data for continuous variables and the  2 test or Fisher's exact test for categorical variables, as appropriate. A two-tailed p-value 0.05 was considered statistically significant. At the end of study, secondary outcomes were only evaluated in 118 nonclusters, 92 index patients, and 118 secondary patients because of the lack of some data (Table 1) Key time-to-event intervals of familial clusters

The epidemic plot showed that incidences of familial clusters occurred before Jan 20, 2020 ( Figure 2A ). Subsequently, they gradually increased, particularly between January 20 and February 3. The median serial interval distribution in familial clusters was estimated to be 5 days (95% CI, 4 to 6) ( Figure 2C ). There was showed no substantial difference in the key time-toevent intervals between index and non-clusters patients. For secondary patients, the median times from illness onset to laboratory confirmation was shorter than that of non-clusters cases (3 days vs. 8 days, p 0.001), and the median days from illness onset to hospitalization (7 days vs 9 days, p 0.001) ( Figure 2B ).

There were 3 family members in both non-familial clusters (range from 2 to 6) and familial clusters (range from 2 to 10) (p=0.3661). However, the proportion of exposure to positively COVID-19 cases was higher in index patients (20. Compared with the patients from non-familial clusters, index patients in familial cluster was older, generally above 70years old (21.1% vs 11.0%, p=0.044). On the other hand, the secondary patients were generally younger, with majority being males. There were 51.1% index patients with at least one underlying comorbidities, such as hypertension (32.2%), coronary heart disease (12.2%), diabetes (10.0%) and pulmonary diseases (1.1%). Table 2 presents clinical characteristics of patients in various group clusters.

In the full cohort, the most common initial symptoms were fever (75.5-84.9%), Previous reports indicate that the spouses were at risk of contracting the J o u r n a l P r e -p r o o f virus from their partners (6) . Notably, we also found that Model 1 was the most common means of transmission between husband and wife (51.0%). On the other hand, 13.5% families were more likely to transmit SARS-COV-2 virus from single-parent to siblings (Model 2), for example, a 67yr mother transmitted the disease to her adult daughter. These phenomena can be explained by the structure of the home-based care system. In China, the spouse or an adult child primarily provide cares for the elderly in case of an illness (15) . In stem families, grandparent assume the homecare responsibility for their grandchildren as their adult children fend for the family (15)，which also potentially increases the risk of COVID-19 transmission (Model 4, 27.1%).

It has been reported that the duration of home care, poor hand hygiene practices, and poor use of masks rather than the family size are associated with higher secondary household risk of SARS (16) . However, in this study, there was no substantial difference in the number of family members, days of home isolation after the onset of illness, the proportion of individuals wearing a surgical mask and isolated eating between index and non-familial clusters patients ( Figure 2 and Table 1) (Table 2) , lower than other proportions reported outside Wuhan (14.1%) (6) and outside Hubei (20.0%) (18) . The most common symptoms COVID-19 symptoms at the onset of the disease were fever (temperature of more than 37.3°C), dry cough, and fatigue, consistent with earlier studies (17, 19) . However, more than 20% of patients from familial clusters exhibited dyspnea and/or pant, whereas 22.9% of non-familial clusters cases present with gastrointestinal symptoms, such as vomiting, diarrhea, and nausea. Additionally, less than half of COVID-19 patients exhibited hematologic abnormalities. Also, index patients were more likely to suffer from neutropenia and lower hemoglobin level. Although the characteristic appearances of chest CT are ground-glass opacity (17, 19) , 1.9% of index patients presented with J o u r n a l P r e -p r o o f normal chests, with only 8.3% of the cases exhibited patch shadows and/or linear opacities. Therefore, this study underscores the significant role of family setting in studying the natural history of COVID-19.

To our knowledge, this is the first study reporting worse clinical outcomes (the rate of death and hospitalization at the time of data cutoff) for COVID-19 patients in familial clusters. We found that the case fatality rate in index patients was 5 times that of non-cluster subjects (8.7% vs 1.7%, p=0.023), and as well higher than the overall fatality ratio in China (5.0%) (1). Particularly, old age and elevated respiratory rate (dyspnea) are risk factors for COVID-19 associated mortalities (20) , as demonstrated in familial clusters (Table 1 and 2). There were 28.3% index and 45.8% secondary patients still hospitalized at the end of the study, this implies that additional medical care is needed.

Our findings notwithstanding, this cohort steady has several notable limitations. First, the small sample sizes may cast doubt on the credibility of our findings. Second, the relatively higher non-response rate (22.9%) recorded in this study presents a potential non-respondent bias. Some people were apprehensive of sharing critical information having been dissatisfied with the medical care they received at the beginning of the outbreak. Third, the laboratory-confirmed cases were exclusively identified by the RT-PCR test, which may have missed few positive cases, particularly the asymptomatic carriers. Fourth, although we employed best principles and methodologies for 

We declare no competing interests. 

We are grateful to all patients and their relatives who participated in the study.

Sincere gratitude to the entire medical staff at the fever clinics for their relentless effort in managing COVID-19 patients. 

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