key: cord-0816048-znw26ofs authors: Liu, Cai-xia; Liu, Zhi-hui; Sun, Lu-yao; Zhang, Kai-yu; Sun, Yi-zhe title: A familial cluster of COVID-19 infection in a northern Chinese region date: 2021-07-18 journal: J Infect Public Health DOI: 10.1016/j.jiph.2021.07.011 sha: 3d8cc3076ff85657e878c12ff6f38d8eaa53b6f8 doc_id: 816048 cord_uid: znw26ofs OBJECTIVE: Currently, coronavirus disease 2019 (COVID-19) has spread worldwide and become a global health concern. Here, we report a familial cluster of six patients infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) in a northern Chinese region and share our local experience with regard the control of COVID-19. METHODS: The demographic data, clinical features, laboratory examinations, and epidemiological characteristics of enrolled cases were collected and analyzed. Two family members (Cases 1 and 2) had Hubei exposure history and were admitted to the hospital with a confirmed diagnosis of COVID-19; eight familial members who had contact with them during the incubation period underwent quarantine in a hospital. We closely followed up all the family members and analyzed their clinical outcome. RESULTS: Case 3 had negative SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) results but was suspected to have COVID-19 because of radiographic abnormalities. Cases 4 and 5 developed symptomatic COVID-19. Case 6 was considered an asymptomatic carrier as his SARS-CoV-2 RT-PCR result was positive. The other four family members with close contacts to COVID-19 patients had no evidence of SARS-CoV-2 infection. CONCLUSIONS: Our findings suggest that COVID-19 has infectivity during the incubation period and preventive quarantine is effective for controlling an outbreak of COVID-19 infection. In December 2019, a number of cases with viral pneumonia of unknown cause were reported in Wuhan, Hubei Province, China Currently, accumulating evidence has indicated person-to-person transmission. 3 In most cases, respiratory and direct contact with contaminated surfaces is the two main infection routes of COVID-19. 4 Recently, COVID-19 nucleic acid was detected in fecal samples, and in an epidemiological and clinical investigation of childhood COVID-19, which raised the possibility of fecal-oral transmission. 5 Hence, we report a familial cluster of COVID-19 infection in Jilin, a northern The study protocol adhered to the declaration of Helsinki and was approved by the ethic committee of the Gongzhuling Central Hospital of Jilin Province (Jilin, China). Written informed consent was obtained for this prospective study. Between January 20, 2020 and February 23, 2020, a familial cluster of six patients infected with SARS-CoV-2 and four close contacts were included for analysis. The demographic data, clinical features, laboratory examinations, and epidemiological characteristics of enrolled cases were collected and analyzed. Guideline for New Coronavirus Pneumonia (7th edition), issued by the National Health Commission of China. 7 All patients with COVID-19 pneumonia were confirmed by performing reverse transcription-polymerase chain reaction (RT-PCR)on their samples (e.g., pharyngeal swab and fecal sample) for SARS-CoV-2. A cluster of SARS-CoV-2 infection was defined as two or more cases reported from the same address (e.g., family, school, and office) and diagnosed within a 2-week interval. Table 1 shows the clinical and epidemiological characteristics of confirmed and suspected COVID-19 cases. Timeline of exposure and chronology of symptom onset in the family cluster of SARS-CoV-2 infection are depicted in Figure 1 . The relationship of relatives to cases is shown in Figure 2 . Case 1 was a 50-year-old woman, who lived in Hubei Province. On January 16, 2020, she took the train, returned from Xiantao (Hubei Province), and stopped in Wuhan (Hubei Province) before arriving in Gongzhuling (Jilin Province). On January 25, she had a fever (37.8°C). Two days later, she was admitted to our hospital for fever, J o u r n a l P r e -p r o o f cough, and sore throat. RT-PCR for the detection of SARS-CoV-2 was performed and COVID-19 was confirmed. Laboratory examination revealed decreased levels of white blood cells (WBCs) (2.15×10 9 /L, reference: 3.5-9.5×10 9 /L), lymphocytes (0.46×10 9 /L reference: 1.1-3.2×10 9 /L), and neutrophils (1.64×10 9 /L, reference: 1.8-6.3×10 9 /L); and increased levels of C-reactive protein (CRP) (>10 mg/L, reference: 2-10 mg/L; Table 1 ) and erythrocyte sedimentation rate (ESR) (55 mm/h, reference: 0-20 mm/h). Computed tomography (CT) images showed patchy ground-glass opacities in the lungs (Fig. 3A) . Case 2 was the husband of Case 1; he arrived in Gongzhuling together with Case 1. On January 30, 2020, he had a temporary fever. Chest CT showed lung infection; the radiological findings are shown in Figure 3B . One day later, he was diagnosed with COVID-19 because of the positive SARS-CoV-2 RT-PCR results. He was given an anti-viral and also treated for his symptoms. On March 2, his clinical condition significantly improved, as revealed by CT findings. After Case 1 was confirmed to have COVID-19 on January 27, 2020, close contacts were identified, immediately isolated, and screened for SARS-CoV-2 in the fever clinic of our hospital. Respiratory samples were collected and tested using RT-PCR for detection of SARS-CoV-2. Case 3 had dinner with Cases 1,2, and 4 on January 20. On January 31, she became ill with fatigue and cough. Chest CT scan was performed and multiple patchy shadows were observed (Fig. 3C ). Although RT-PCR for detection of SARS-CoV-2 was performed several times, the results were all negative. Due to the COVID-19 contact history, clinical symptoms, and abnormal radiographic findings, the patient was diagnosed with suspected COVID-19. Case 4 presented with mild symptoms of fatigue. On February 2, COVID-19 was confirmed by RT-PCR. Chest CT revealed multiple patchy, flocculent, fuzzy, and high-density shadows in the lungs (Fig. 3D ). Case 5 had contact with Cases 1 and 2 on January 18 and 23, respectively. She became ill on February 4, presenting with fever, transcutaneous oxygen saturation 86% at rest, and patchy consolidation on CT images (Fig. 3E ). Subsequently, COVID-19 was confirmed by RT-PCR. Case 6 had contact with Cases J o u r n a l P r e -p r o o f 1 and 2 on January 19, and no symptoms were observed. On February 6, pharyngeal swabs, including fecal samples, were tested for SARS-CoV-2 and positive results were confirmed. In addition, a chest CT scan was done and appeared normal. Hence, the patient was considered to have asymptomatic infection. The remaining four cases, who had close contact with the two index cases, were not found to have COVID-19. The detailed investigation was follows. C1D (daughter of Cases 1 and 2) lived with Case 1 between January 17 and 19, reporting no symptoms, and had persistently negative RT-PCR for SARS-CoV-2, and normal radiographic appearance. C5H Moreover, an asymptomatic carrier was also suspected of being a source for transmission of COVID-19, 9 and this key point was proved by Zhang et al. 10 Although these new findings make the prevention and control of COVID-19 more complicated, they will lead to improved and more effective strategies. To avoid acquiring COVID-19, specific attention should be paid to factors such as environmental, direct contact, and social distance. 7, 11 Person-to-person transmission has been confirmed. It is unclear if during the incubation period, the virus is infective. A previous study by Yu et al. 12 showed possible transmission of COVID-19 during the incubation period. Similarly, our data also supported that the virus remains infective during the incubation period. In this study, before the onset of symptoms of Case 1 (January 25), Cases 3 and 4 only had dinner with Case 1, as well as a dinner party, and Case 5 had another social contact with Case 1. Three cases were all infected with COVID-19. This special characteristic mentioned above is different from the transmission of SARS infection. In our study, the incubation period was relatively long and ranged from 9 to 17 days. Remarkably, although the incubation period of Case 1 was estimated at 9 days, the possibility remained of it being extended to longer than 9 days because of her residential location (Xiantao, Hubei). The incubation periods of Cases 5 and 6 were estimated from the first contact with Case 1, with the longest period being 17 days. Likewise, the incubation period of a secondary case has been reported over 14 days, 13 even reaching up to 20 days. 14 Hence, a longer quarantine period, such as 2 or 3 weeks, may be required. Usually, patients with COVID-19 present with fever, cough, or lung infiltrates. 15 In some cases, they may also have mild respiratory symptoms. More recently, asymptomatic infection has been reported. In Japan, the prevalence of asymptomatic infection is estimated at 41.6% (95% confidence interval: 16.7%, 66.7%) among COVID-19-infected individuals. 16 However, in China, a study of 72, 314 COVID-19 patients showed that asymptomatic carriers comprised 1.2% of all COVID-19 cases. 17 The difference in the prevalence of asymptomatic infection may be caused by sample size estimated and different subjects included between the two studies (highrisk vs. confirmed). In our study, due to positive SARS-CoV-2 RT-PCR results from fecal and pharyngeal samples, Case 6 was considered asymptomatic infection, the time of viral shedding was 8 days, longer than the time for Cases 4 and 5. We believe that asymptomatic infection is common. A similar result was reported in another familiar cluster of COVID-19 infection. Due to SARS-CoV-2 RT-PCR (+) and IgM assays (+), four cases without clinical symptoms were considered asymptomatic infection. 18 Hence, on one hand, good personal hygiene is emphasized; on the other hand, due to no clinical symptoms and normal radiography, asymptomatic infection could be easily neglected. Hence, more attention should be given to improving the diagnostics and management of asymptomatic carriers, this would improve the prevention and control of the COVID-19 epidemic. 19 For the diagnosis of COVID-19 patients, the sensitivities of IgM and IgG assays were 77.3%, and 83.3%, respectively, 20 and RT-PCR for detection of COVID-19 has a lower sensitivity of 35%. 21 It was then concluded that a significant proportion of COVID-19 would be diagnosed as suspected cases. Case 3, as a suspected COVID-19 case, presented with mild respiratory symptoms and abnormal radiography. Although RT-PCR for SARS-CoV-2 detection was performed several times, the case was not confirmed. However, due to contact history with the index case, Case 3 was identified, isolated, and treated as a suspected case. Fortunately, until now, several new assays, such as an automated chemiluminescent immunoassay, a reverse transcription loop-mediated isothermal amplification assay, and antibody detection assay for the diagnosis of COVID-19, have been evaluated and good performance has J o u r n a l P r e -p r o o f been confirmed. 20, [22] [23] [24] [25] These new assays may improve the diagnostic dilemma of current assays for COVID-19. Accumulated evidence suggests that SARS-CoV-2 is more infectious than SARS-CoV and MERS-CoV. 18 However, this study of a familiar cluster of COVID-19 infection demonstrated a differential susceptibility. Although C1D and C5S lived with Cases 1 and 2, it remains to be found without COVID-19 infection. The result suggests a difference in the susceptibility to COVID-19 among individuals. The SARS-CoV-2 has preferential tropism to human airway epithelial cells through the same cellular receptor as that for SARS, angiotensin-converting enzyme 2 (ACE2), which is a central body receptor for the surface glycoprotein S of the virus. 26 Therefore, the down regulation of ACE2 expression is thought to explain the lower susceptibility to COVID-19. In addition, the differential susceptibility suggested by the study implicated that interventions, such as vaccine trials and preventive measures, for the COVD-19 control should be evaluated their feasibility. China is one of the countries hard-hit by COVID-19 at the beginning of its outbreak. After the impose of strict quarantine measures, we successfully stopped the exacerbation of the condition 27 . After that, COVID-19 only occurred as sporadic cases across China, in response to which, quarantine and close follow up of individuals with close contact with COVID-19 patients were implemented. All these measures play an critical role in stifle the wide spread of COVID-19. Currently, vaccination against COVID-19 is widely carried out all over the world, which would decrease the incidence of COVID-19 28, 29 . Sporadic cases may be more common during the vaccination era. Effective quarantine measures can help to accelerate the eradication of the COVID-19. In terms of the control of sporadic clusters of COVID-19 infection, several recommendations can be made as a result of the study. 1) Cases who are exposed to COVID-19 patients during the incubation period should also be included as close contacts. 2) The diagnosis of COVID-19 infection could not reasonably rely on RT-PCR and antibody detection and all suspected cases should be treated as confirmed patients. Moreover, further research should be performed to look for a rapid, accurate, J o u r n a l P r e -p r o o f economic diagnostic assay for COVID-19. 3) A differential susceptibility to COVID-19 between individuals exists. Further investigation for the mechanism of the difference may be helpful to improve the management of the susceptible population. 4) Finally, it is better that all close contacts are isolated and observed in a centralized setting. 30 Otherwise, home isolation and observation are required and a community supervision mechanism is needed. Our study enhance our knowledge with regard the epidemiology characteristics of COVID-19 especially the characteristics of clustering infection, and highlighted the importance of quarantine for the COVID-19. It's true that transmission of COVID-19 had been well characterized by previous studies, and the information in our study is a little bit dated. However, few case reports emphasize the importance of preventive quarantine for COVID-19 control, especially when sporadic cases remain prevalent. We believe our findings will help to better guide strategy of COVID-19 controlling and accelerate the termination of pandemic. The authors declare that they have no conflict of interest. The study protocol adhered to the declaration of Helsinki and was approved by the ethic committee of the Gongzhuling Central Hospital of Jilin Province (Jilin, China). Written informed consent was obtained for this prospective study. All data published here are under the consent for publication. The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request. Notification of novel coronavirus pneumonia temporarily named by the national health and Health Commission Novel Coronavirus(2019-nCoV) Situation Report-22 A novel coronavirus outbreak of global health concern The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak Washington State 2019-nCoV Case Investigation Team. First Case of 2019 Novel Coronavirus in the United States Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding New coronavirus pneumonia prevention and control program Asymptomatic SARS-CoV-2 infected case with viral detection positive in stool but negative in nasopharyngeal samples lasts for 42 days Presumed Asymptomatic Carrier Transmission of COVID-19 Familial cluster of COVID-19 infection from an asymptomatic Zhonghua liu xing bing xue za zhi A familial cluster of infection associated with the 2019 novel coronavirus indicating potential person-to-person transmission during the incubation period Clinical features of patients infected with Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19) The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases Zhonghua liu xing bing xue za zhi Analysis of the first cluster of cases in a family of novel coronavirus Zhonghua liu xing bing xue za zhi Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Patients with Positive RT-PCR; a Diagnostic Accuracy Study. Archives of academic emergency medicine 2020 Rapid and visual detection of 2019 novel coronavirus (SARS-CoV-2) by a reverse transcription loop-mediated isothermal amplification assay. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients Development of a reverse transcription-loop-mediated isothermal amplification as a rapid early-detection method for novel SARS-CoV-2. Emerging microbes & infections 2020 Diagnostic accuracy of an automated chemiluminescent immunoassay for anti-SARS-CoV-2 IgM and IgG antibodies: an Italian experience A Novel Coronavirus Emerging in China -Key Questions for Impact Assessment Management and Treatment of COVID-19: The Chinese Experience COVID-19 vaccines: The status and perspectives in delivery points of view The Long Road Toward COVID-19 Herd Immunity: Vaccine Platform Technologies and Mass Immunization Strategies None.J o u r n a l P r e -p r o o f patchy shadows (C); Case 4: multiple patchy, flocculent, fuzzy, and high-density shadows in the lungs (D); Case 5: patchy consolidation (E).