The outbreak of coronavirus disease 2019 (COVID- 19) , which was caused by the novel coronavirus SARS-CoV-2, has posed tremendous challenges to the international communities [1] [2] [3] [4] [5] [6] [7] [8] .
As of March 18, 2020 , there were 81,116 confirmed cases and 3231 deaths in China 9 ; Globally, 160 counties and territories have reported cases of COVID-19, including 191,127 confirmed cases and 7807 deaths 9 . In response to "the alarming levels of spread and severity", the World Health Organization (WHO) has characterized COVID-19 as a pandemic 10 . This is the first pandemic caused by a coronavirus. Coronaviruses (CoV) are a large family of RNA viruses that cause a variety of mild and severe diseases in humans and animals 11 . Prior to the COVID-19, there were two severe outbreaks of human coronavirus diseases in the past two decades, the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) [12] [13] [14] [15] [16] Super-spreading events, by which an individual patient spread an infection to a large number of susceptible people, were associated with the outbreaks of SARS and MERS [19] [20] [21] [22] . While case clusters with human-to-human transmission of SARS-CoV-2 have been reported [3] [4] [5] [23] [24] [25] , it remains unknown whether super-spreading events occurred in the outbreak of COVID-19. Here, we conducted a retrospective study and identified a super-spreading chain of transmission associated with COVID-19.
This retrospective study was approved by the institutional review board of Renmin Hospital of Wuhan University (No. WDRY2020-K019). Oral consent was obtained from the patients or their family members, whereas written informed consent was waived by the Provincial and National Health Commissions in China under the exceptional circumstances for investigation of an ongoing disease outbreak. In this cohort, we identified a super-spreading chain of transmission involving 52 linked patients with COVID-19 in three . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted March 23, 2020. . https://doi.org/10.1101/2020.03. 19.20026245 doi: medRxiv preprint separate hospitals in Wuhan, the epicenter of an outbreak of COVID-19 across China. The data we retrieved from the electronic medical records included demographic features, comorbidities, clinical presentation, laboratory investigation, RT-PCR testing for SARS-CoV-2, serum specific IgM and IgG antibodies, chest computed tomographic (CT) scan, and the disease outcome. The contact and exposure history were also collected through communications with the patients and/or their family members. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted March 23, 2020. . https://doi.org/10.1101/2020.03. 19.20026245 doi: medRxiv preprint or Fisher's exact test. A two-sided α of less than 0.05 was considered statistically significant.
Statistical analyses were done using the SPSS 22.0 software.
In this report, we conducted a retrospective study and identified a super-spreading chain of transmission involving the index patient, seven cancer patients, 40 health care workers and four family members ( Figure 1 and Table 1 ).
Identification of the index patient (C-1). On January 3, 2020, a male patient in his 50s developed fever (38.8°C), headache, chest pain and myalgias when he visited his relative in a ward room (Ward-X in Figure 1 ) shared by four female cancer patients at Hospital A. He initially thought that he had a "cold" and continued to visit this ward until he was admitted to hospital B on January 10, 2020. His Chest CT-scan findings showed a rapid progression of bilateral infiltrates in the lungs ( Figure 2 ). He received antibiotics treatment for one week but was ineffective. On January 18, he was tested positive for SARS-CoV-2 and diagnosed with COVID-19. He died of severe respiratory failure on January 26, 2020. While the exact exposure history of this patient remained unclear, he did not visit the "Huanan Wet Market", the suspected origin for this outbreak in Wuhan. Of note, the "Huanan Wet Market" is located in the Hankou District of Wuhan city, which is separated from the Wuchang District by the Yangtse River. The two hospitals (A and B) where the index patient visited were located in Wuchang District.
A super-spreading event initiated by the index patient. Eleven people presented fever and abnormal CT-scan findings after close contacts with the index patient C-1 between January 3 and January 10, 2020 ( Figure 1 and Table 1 ). Below was a timeline for the initial transmission events. (1) C-1 visited his relative C-2 in Ward-X that was shared by other three cancer patients (C-3, C4, and C-5) at the Department-I of hospital A when he first developed fever and other symptoms on January 3. All four cancer patients had close contacts with C-1 and subsequently developed fever (38°C-40°C) and abnormal CT-scan findings between January 4 and January 15.
All were RT-PCR positive for SARS-CoV-2, but the assays for the serum specific antibodies
were not available at that time. All four patients did not have other exposure records and epidemiological history before their disease onsets. Three of them died of severe respiratory . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted March 23, 2020. . https://doi.org/10.1101/2020.03. 19.20026245 doi: medRxiv preprint failure within 9-20 days after the onsets. C-2 developed symptoms on January 9 (6 days after the onset of C-1) and died on January 17. C-3 developed symptoms on January 4 (one day after her close contact with C-1) and died on January 24. C-4 developed symptoms on January 15 and transferred to a designated hospital on January 30, where she remained at a stable condition after the treatment. C-5 developed symptoms on January 15 and died on January 29.
(2) On January 3, C-1 also visited the office area of the health care workers at the Department-I of hospital A to discuss the treatment plan for his relative C-2. Four doctors (C-6, C-7, C-8 and C-9) and one nurse (C-10) developed fever and abnormal CT-scan findings between January 9
and January13 (within 10 days after close contacts with C-1). In addition, a cluster of eleven health care workers (C-17 to C-27) from the same department who had close contact with their co-workers (C-6 to C-10) presented fever and abnormal CT-scan findings between January 16 and January 21 (within 3-12 days after their exposure to the secondary cases). All the health care workers were previously healthy and did not have other exposure records and epidemiological history ( Figure 1 and Table 1 ).
(3) On January 10, C-1 was admitted to hospital B, where he was diagnosed with COVID-19.
Two doctors (C-51 and C-52) had close contacts with C-1 when they met with him on a medical consultation meeting to discuss his treatment plan. They presented fever and abnormal CT-scan findings on January 21 and January 26, respectively. Both of them were previously healthy and did not have other exposure records and epidemiological history. Our findings suggested that C-1 was the source patient and considered as a "super-spreader" who initiated this super-spreading chain of transmission.
Between January 14 and January 20, 2020, a total of twelve doctors and nurses (C-29 to C-40) from Department-II in hospital A developed fever and abnormal CT-scan findings ( Figure 1 and Table 1 ). All twelve individuals were previously healthy, and none of them except C-29 had other exposure records and epidemiological history. C-29, a male doctor in his 50s, attended medical consultation meetings between January 3 and January 8 at the Department-I to discuss treatment plans for two lung cancer patients (C-2 and C-3). Of note, Department-I and Department-II were located at two separate buildings in hospital A. C-29 had close contact with . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted March 23, 2020. . https://doi.org/10.1101/2020.03. 19.20026245 doi: medRxiv preprint the health care workers (C-6 to C-10) on the consultation meetings before he developed fever and abnormal CT-scan findings, and was diagnosed with COVID-19 on January 14. All eleven co-workers (C-30 to C-40) had close contacts with C-29 before his disease onset. In addition, C-29's relative (C-41) was diagnosed with COVID-19 on January 25. Our findings indicated that C-29 was likely the source patient who was responsible for introduction of COVID-19 into this cluster, and therefore was considered as a "super-spreader".
A cluster of tertiary cases linked to a gastric cancer patient. C-13, a female with gastric cancer, was initially hospitalized in Ward-Y at Department-I in hospital A. She was transferred to Department-III on January 10 and had surgical operation on January 12. She had close contacts with C-9 and C-10 who were in charge of her treatment at Department-I, However, she did not present fever and other symptoms until January 15 (i.e. 3 days after her surgical operation). She was transferred to a designated hospital after her confirmation with COVID-19 on January 23 and remained at a stable condition. Two Doctors (C-14 and C-15) who conducted the operation procedures were diagnosed with COVID-19 on January 21 and January 22, respectively. In addition, C-16 (C-15's relative) showed fever and other symptoms on January 23 after close contact with C-16 at home.
A cluster of tertiary cases linked to a colon cancer patient. C-42, a female colon cancer patient, was admitted to the same hospital ward room (Ward-Y) as C-13 on January 10 and treated by the same medical team (C-9 and C-10). She developed fever (39.9°C) and other symptoms on January 16, and died of severe respiratory failure on January 18. She did not take CT-scan and RT-PCR testing due to her sudden death. C-43, a male doctor from Department-V examined C-42 on January 15, and was diagnosed with COVID-19 on January 23 (8 days after his close contact with C-42). Moreover, C-44 was accompanying his relative C-42 in hospital A and diagnosed with COVID-19 on January 17 (one day after the disease onset of C-42). Two doctors (C-45 and C-46) who conducted the medical treatment on C-44 at Department-V in hospital A were diagnosed with COVID-19 on January 24 and January 25, respectively. Furthermore, C-44 was transferred to hospital C on January 17. Four doctors (C-47, C-48, C-49, and C-50) at hospital C had close contacts with C-44, and developed fever and other symptoms between January 24 and January 27. Our findings also suggested that C-44 was a potential "super-spreader" since he transmitted the disease to six people who had direct contacts with him.
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The copyright holder for this preprint this version posted March 23, 2020. . https://doi.org/10.1101/2020.03. 19.20026245 doi: medRxiv preprint Additional tertiary cases.
(1) C-11 was diagnosed with COVID-19 after direct contact with his relative C-10 at home. (2) C-12, a male doctor from the Department-VI, conducted medical treatment on C-4 and C-5 on January 14, and was diagnosed with COVID-19 on January 19 (5 days after direct contacts with C-4 and C-5).
(3) C-28, a male liver cancer patient in his 60s (Ward-Z), was diagnosed with COVID-19 on January 20 (4 days after the disease onset of his doctor C-17) and died of respiratory failure on January 23, 2020.
Clinical features and laboratory findings ( Figure 1 , Table 1 , and Table 2 
In this study, we identified a super-spreading chain of transmission associated with COVID-19 at the early stage of the outbreak in Wuhan. In addition, we were able to find the index patient C-1 and C-29 as the presumptive "super-spreaders" who initiated and amplified this chain of transmission, respectively. We understand that "super-spreader" is still a vague term without a strict scientific definition, we followed a definition adopted by the epidemiologists during the SARS outbreak, which defined the "super-spreader" as an individual with transmission of SARS . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted March 23, 2020. . https://doi.org/10.1101/2020.03. 19.20026245 doi: medRxiv preprint to at least eight contacts 19 . Therefore, C-1 and C-29 were considered as the super-spreaders because each of them passed the infection of SARS-CoV-2 on to at least eleven contacts. Since super-spreading events were associated with the outbreaks of SARS and MERS [19] [20] [21] [22] , it would be not a surprise to discover super-spreading events associated with COVID-19.
Our study has a number of unique features. (1) By coincidence, this transmission chain started from a hospital ward shared by four female cancer patients, and the female health care workers (total of 23) outnumbered the male co-workers (total of 17). As a result, there were 60% female (31/52) and 40% (21/52) male patients in this cohort, which were different from other reports 3-5 .
(2) we were able to identify several distinct clusters of cases based on the exposed time and the date of disease onset, which helped connecting all the related activities and events. (3) There were seven cancer patients in this study, and five of them (71%) died of severe respiratory failure within 2-20 days of their disease onsets, suggesting that cancer patients were highly vulnerable to COVID-19 and had rapid disease progression and high mortality rate due to immune suppression and comorbidities. (4) Approximately 13.5% (7/52) of patients were asymptomatic individuals in this study (Table 1) 15% of the RT-PCR positive patients were tested negative for the specific IgM and/or IgG at the convalescent phase. The discrepancy between the results of the RT-PCR assay and serological testing suggested the existence of possible "false negative" and/or "false positive" with these assays. Both scenarios may significantly affect the clinical diagnosis and should be addressed accordingly by additional studies given the fact that strict clinical validation studies were not performed on any of these assays due to the urgent need for screening and diagnosis of COVID-19 during the disease outbreak. In particular, it would be a huge concern if a significant portion of SARS-CoV-2 infected patients were tested negative for the specific IgM and IgG at the convalescent phase.
A large number of health care workers were infected with SARS-CoV-2 in our cohort, which were consistent with a report that 41% of the 138 hospitalized patients at one of the major tertiary hospitals in Wuhan were hospital-related transmission 30 . These findings suggested that . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted March 23, 2020. . In conclusion, we identified a super-spreading chain of nosocomial transmission that occurred in the outbreak of COVID-19 in Wuhan. Given the fact that COVID-19 has been spreading rapidly in many other countries worldwide, it is conceivable that more super-spreading events will be identified in near future, and its impact on the disease outbreak and transmission warrant further investigation. The finding that a significant portion of SARS-CoV-2 infected patients were tested negative for the specific IgM and IgG at the convalescence stage should be addressed by additional studies.
We are extremely grateful to all the patients and their families for participation of this study and providing all the valuable information. We also thank our colleagues for their kind help and strong support.
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Case ID . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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The copyright holder for this preprint this version posted March 23, 2020. M=male. F=female. NA=not available. +=positive. +=negative. GI=gastrointestinal. CT-scan=computed tomographic (CT) scan; of note, the preexisting conditions of the patients were removed and the specific ages were replaced with an age range, e.g. 20s, and 30s, etc. to avoid identifying information. There were five patients (C-6, C-8, C-18, C-22, and C-27), who were tested negative for RT-PCR but positive for the specific IgM and/or IgG at the convalescent phase (highlighted in blue color); There were five patients (C-12, C-15, C-23, C-39, and C-40), who were tested positive for RT-PCR but negative for the specific IgM and/or IgG at the convalescent phase (highlighted in red color).
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The copyright holder for this preprint this version posted March 23, 2020. A. An image taken on 01/10/2020 (the admission day);
B. An image taken on 01/13/2020 (three days after admission);
C. An image taken on 01/16/2020 (6 days after admission).
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