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Transmission and clinical characteristics of coronavirus disease 2019 in 104 outside-Wuhan patients, China
Abstract
Cases with coronavirus disease 2019 (COVID-19) emigrated from Wuhan escalated the risk of spreading in other cities. This report focused on the outside-Wuhan patients to assess the transmission and clinical characteristics of this illness.
Contact investigation was conducted on each patient who admitted to the assigned hospitals in Hunan Province (geographically adjacent to Wuhan) from Jan 22, 2020 to Feb 12, 2020.
Demographic, clinical, laboratory and radiological characteristics, medication therapy and outcomes were collected and analyzed. Patients were confirmed by PCR test.
Of the 104 patients, 48 (46.15%) were imported cases and 56 (53.85%) were indigenous cases; 93 (89.42%) had a definite contact history with infections. Family clusters were the major body of patients. Transmission along the chain of 3 "generations" was observed. Mean age was 43 (rang, 8-84) years (including 3 children) and 49 (47.12%) were male. Most patients had typical symptoms, 5 asymptomatic infections were found and 2 of them infected their relatives. The median incubation period was 6 (rang, 1-32) days, of 8 patients ranged from 18 to 32 days. Just 9 of 16 severe patients required ICU care. Until Feb 12, 2020, 40 (38.46%) discharged and 1 (0.96%) died. For the antiviral treatment, 80 (76.92%) patients received traditional Chinese medicine therapy. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
hospital-associated infections in Wuhan 2, 6 . Until we know this information about it also hard to assess how bad this novel coronavirus is going to get.
Province geographically adjacent to Wuhan, Hubei Province, high-efficiency transport between the two provinces may lead to a rapid spread of COVID-19
in Hunan Province. This report included the hospitalized patients with COVID-19 to assess the transmission and clinical characteristic of two hospitals, which designated as the treatment center for the NCP in Huaihua and Shaoyang cities, Hunan Province, China. These findings could provide value information to better understand such new illness.
In this study, we recruited confirmed patients with COVID-19 from two hospitals, the First People's Hospital of Huaihua and the Central Hospital of Shaoyang which designated as the treatment center of Huaihua and Shaoyang city, Huanan Province, China from Jan 22, 2020 to Feb 12, 2020 . According to the guidelines of China 7 , patient was confirmed by the positive result from the real-time reverse-transcription-polymerase-chain-reaction (RT-PCR) assay of nasopharyngeal or throat swab. Suspected infectors that did not confirmed by PCR were excluded. For the study population, imported case was defined as an infector who emigrated from Wuhan (who ever lived in or traveled to Wuhan), the rest of study patients were defined as indigenous cases.
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author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint
We carefully surveyed the contact history of every patients, including whether he or she ever lived in or travelled to Wuhan, or had closely contacted with people returning from Wuhan during two months before their illness onset. In addition, the history of contacting with animals and eating game meat was also screened. If necessary, we directly communicated with the attending physician, patients or their family members. Demographic, clinical, laboratory and radiological characteristics, medication therapy (ie, antiviral therapy, antibacterial therapy, corticosteroid therapy and traditional Chinese medicine therapy), underlying comorbidities, symptoms, sign and chest computed tomographic images were obtained from electronic medical records. Outcomes were followed till Feb 12, 2020.
Standard questionnaire and form were used for contact investigation and data collection. The data were independently reviewed by two trained physicians (Ye Deng and Xin Liao) and checked by another two physicians (Hongqiang Wang and Da Long) respectively. Every one signed Data Authenticity Commitment and stamp official seal.
The date of onset symptom was defined as the day when the case firstly developed symptoms related to NCP. Acute respiratory distress syndrome (ARDS) was defined according to the Berlin definition 8 . Acute kidney injury was identified by an abrupt decrease in kidney function including changes in serum creatinine (SCr) (≥0.3mg/dl or 265.5μmol/L) when they occur within a 48-hour period, other diagnostic items according to evaluation, and management of acute kidney injury: a KDIGO summary 9 . Liver function abnormal was All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint defined as abnormal of liver enzymes or bilirubin. Cardiac injury was identified by the serum levels of cardiac biomarkers (eg, troponin I) which is above the 99 th percentile upper reference limit or new abnormalities shown in electrocardiography and echocardiography 2 .
In this study, case confirmation accords to the positive results of PCR. Nasopharyngeal swab was collected from suspected patients. Sample collection and extraction followed the standard procedure. The primers and probe target to open reading frame (ORF1ab) and nucleoprotein (N) gene of COVID-19 were used. The procedure and reaction condition for PCR application was followed by the manufacture's All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
This study was approved by the ethics committee of the First People's Hospital of Huaihua (KY-2020013102) and the Central Hospital of Shaoyang (KY-202000103), China.
Considering the infectious of NCP, we conducted an oral informed consent with every patient instead of written informed consent (www.chictr.org.cn Chi CTR2000029734).
Normally distributed continuous variables were described as mean and standard deviation (SD). For non-normally distributed continuous variables, we used median and interquartile range (IQR) or range. Categorical variables were expressed as ratio and percentages (%).
Differences in means of normally distributed continuous variables were compared using Student's t-test (two groups) and the non-normally distributed continuous variables compared using Mann-Whitney U test. Categorical variables were compared using the χ 2 test or Fisher exact test. A two-sided P-value 0.05 was considered statistically significant. All statistical All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint tests were performed using SPSS version 25.0.
Since China firstly reported the outbreak of a cryptic pneumonia to WHO on December 31, 2019. The causative agent was soon identified as a novel coronavirus on Jan 7, 2020. As the sharply increased number of NCP in Wuhan, China ordered a shutdown of Wuhan city on Jan 23, 2020. Hunan Province, geographically closed to Wuhan, immediately launched a level one emergency response to prevent the infection spreading. The other cities also responded strict control measures in succession. From Jan 22, 2020 to Feb 12, 2020, a total of 104 cases were confirmed in the two centers of Hunan Province, 48 (46.15%) were imported cases and 56 (53.85%) were indigenous cases.
Since Feb 6, 2020, imported case no longer appeared in the two centers (Figure 1 A) .
The cumulative number of confirmed cases increased smoothly in the two centers (Figure 1 B), newly confirmed cases per day ranged from 0 to 11, a slight increase of newly confirmed cases was observed from Jan 22, 2019 to Feb 4, 2020, and then the number turned to a little decline lasted to Feb 12, 2020 (Figure 1 B) . The stable of the two centers was quite different from the sharply growth of patients in Wuhan in recent month.
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The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint
With the aim to better understand the transmission characteristics of COVID-19 in outside-Wuhan cities. We carefully clarified the contact history of each patients. Of the 104 patients, 93 (89.42%) patients had a clear contact history with the infections, 11 (10.53%) were sporadic cases that hardly identified a definite contact history. As showed in Table 1 , All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint cluster infections including couples, relatives, friends and colleagues transmitted through a close domestic life or dinner. Family clusters accounted the most infections of COVID-19 in this study population. Cluster 6 (2 cases) and 14 (7 cases) infected via taking the same public vehicle together. Nosocomial transmission did not happen so far in the two centers.
Six clusters (Table 1, were found in this study. In cluster 5, C89 was infected from his wife C45. With the aim to fast screen the potential infections, their family members took the PCR test. Their son-in-law (C'1) and their grandson (C'2) (C'1 and C'2 not included in this study population) got positive results in another hospital, but till now all of them had never developed any symptoms. In cluster 17, C'3 (not included in this study population) returned Shaoyang city from Wuhan on Jan19, 2020, three relatives of C'3 were identified as COVID-19 infection after several days of closely contacted with C'3. None of them had contacted with the other suspected infectors during those days. Her sister-in-low (C37) was confirmed on Feb 1, 2020, her sister (C44) and mother (C49) were confirmed on Feb 4, 2020. But so far C'3 had never developed any symptoms. Weather C'3 is an asymptomatic infection did not been identified by PCR test, but the same contact history and the similar onset time of her three relatives indicate that C'3 was an asymptomatic COVID-19-carrier. In cluster 19, C'4 (not included in this study population) contacted with her college who traveled from Wuhan, and soon confirmed by PCR positive result. As an asymptomatic patient, C'4 infected C92 (C'4's All rights reserved. No reuse allowed without permission.
author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint mother), C94 (C'4' s father-in-law) and C102 (C'4' s daughter), C102 also had no symptoms with a positive result of PCR test.
As showed in Table 2 palpitation (1[0.96%]) as onset symptoms. The median incubation duration was 6 days, ranged from 1 to 32 days; 8 patients got more longer incubation duration (18, 19, 20, 21, 23, 24 , 24 and 32 days) that more than 14 days. Median time from onset to confirmation was 6 (rang, 0-17) days. There were 16 (15.38%) patients were identified as severe, the ratio of male vs. female was 11:5 and median age was 53 (rang, 18-81); 9 (8.65%) patients required ICU care, the ratio of male vs. female was 4:5 and median age was 59 (rang, 18-84). Of the 9 ICU patients, 3 received invasive ventilation and 4 received noninvasive ventilations. Some patients presented with organ function damage, including 5 (4.81%) with liver function abnormal, 3 (2.14%) developed with cardiac injury and 2 (1.89%) developed with acute kidney injury. ARDS occurred in 13 (12.50%) patients. For the period from admission to All rights reserved. No reuse allowed without permission.
author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint developed ARDS, the median time was 2 (1-8) days. As we followed until Feb 12, 2020, 40 (38.46%) had discharged and 1 (0.96%) died, the rest 63 (60.58%) patients stayed in hospital.
As showed in Table 3 author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint
There were 75 of 94 (79.79%) patients lesions involving both lungs. Data of initial chest thin-section CT imaging findings in two discharged patients (C56, Figure 4 A author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the Yet fundamental information gaps exist on how to accurately assess the transmission efficiency. While the controversy of sharply increased cases and medical shortage in the early and outbreak stage in Wuhan, patients in Wuhan may have limitation to fully reflect the true epidemiological characteristics of this illness. Evidence has suggested person-to-person transmission of COVID-19 via droplets or skin touch 2, 3, 11 . The data of this study showed All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint a notable feature is clustering occurrence, most patients were infected from their family members, relatives or friends through a close contact. Only 11 (10.53%) of this study patients were sporadic cases that hardly identified infector source, suggesting that community transmission of COVID-19 is not developed rapidly in the two cities (Huaihua and Shaoyang); this also matches the smooth growth of total confirmed cases. Of note, strict control measures by the local government produced a powerful effect on the slowing spread.
We are eager to know how infectious the virus is. Except the confirmed cases, whether the asymptomatic COVID-19-carriers has the infectious is unclear. Three cases (C37, C44 and C49) infected from the same person (C'3) who ever traveled to Wuhan. But until now, C'3 did not develop any symptoms. Though we did not take a PCR test to confirm whether C'3 was a virus-carrier, the same contact history and the similar onset time of her three relatives indicate that C'3 was an asymptomatic COVID-19-carrier. Five asymptomatic patients were found in this study, one patients (C'4) who infected three family members (C92, C94 and C102) provide evidence that the asymptomatic transmission risks the spread of COVID-19, which brings more difficult to cut off the epidemic's transmission route. We surveyed eight infected couples, a total of 3 infants were closely lived with their parents, but none of them was infected. Just 3 children were infected from their parents or relatives. These observations further demonstrated that infant and child are not so susceptible as adult, that is consistent with the previous reports 2,3,6,12 . Unlike the other reported populations, no nosocomial transmission was found in the two centers 2 . The safeguard of protective equipment and the strengthen of nosocomial infection control may play key roles in the zero accident of hospital-related infection. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint Unlike some earlier reports 3,6 , here no gender difference was found among this study patients (47.12% patients were male). This is consistent with a recent report of 138 Wuhan patients 2 . This report further provides the evidence that male and female may have the same susceptibility of this illness. This study patients were younger than that of reported patients. It may be related to the patients' job characteristics and social relationship. With the Spring Festival coming, young or middle-aged people are more likely to attend social activity, which results in person-to-person transmission. Common symptoms of onset were similar to the reported patietns [1] [2] [3] . The atypical symptoms such as diarrhea, nausea and runny nose bring us more difficult to diagnose precisely. The incubation duration ranged from 1 to 32 days with the median time of 6 days which was similar to the reported patients 13 . A recent report warned us the incubation duration may extend to 24 days 14 . We also found the incubation duration of 8 patients ranged from 18 to 32 days, indicating that it may exceed 14 days which reported with the initial infections 3 .
Patients who required ICU care just presented 8.65%. With the increased awareness of early discovery and timely treatment, organ function damage was occurred just in few patients, that is quite different from observation of patients in Wuhan patients. The higher rate of discharge (38.46%) and lower mortality (0.96%) of this study population may mainly attribute to the relatively superior treat conditions, including enough healthcare worker and single ward for every patient. In addition, psychological intervention was also performed to patients. Studies suggested that COVID-19 may attacks human's immune system which resulted in cytokine storm 3 . The lymphocyte counts of this study patients were below the normal. Here 17 of 19 patients showed a significant decrease in CD4 cell counts and 9 of 17 All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint patients showed a decrease in CD8 cell counts, it is a pity that rest of the patients did not take the test. We still don't know the pathogenic mechanism of COVID-19, so we should take a route test of the CD4 and CD8 counts for better understanding of this illness.
Though no antiviral treatment for COVID-19 infection has been proves to be effective 15, 16 . Antiviral and supportive treatment are the major therapy for NCP. 103 of 104 patients of this study received one or more antiviral drugs, including Lopinavar/ ritonavir, interferon α atomization and Abidol. Lopinavar/ ritonavir was proved to be substantial clinical benefit against SARS 17 19, 20 . Evidence suggests corticosteroids did not decrease the mortality of patients with SARS and MERS, but rather delayed the clearance of viral 19, 21 . Chinese guideline recommends a short treatment of corticosteroids in server NCP 7 This study has several limitations. First, just two centers of Hunan Province were included, there is limited information based on the data to fully assess the transmission and All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.04.20026005 doi: medRxiv preprint clinical characteristics in outside-Wuhan cities. Second, all patients were confirmed by RT-PCR through nasopharyngeal or throat swab, it could not reflect viral load change in blood or organs. Until now it is confused about whether the severity of NCP is related to changes of viral load in blood. Third, the follow-up period is not long enough to examine the outcomes of all the included patients.
In conclusion, this report gives showed that timely control measures after the Wuhan
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The copyright holder for this preprint (which was not peer-reviewed) is the Notes, C indicates the cases who have been confirmed as COVID-19 pneumonia in the two centers. X indicates the cases who did not included in this study population but have been confirmed as COVID-19 pneumonia or as virus-carrier. C' indicates asymptomatic infections. * The others include the confirmed cases returning from Wuhan but did not infect others. Sporadic cases include the indigenous patients who did not identified the source of infection.
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