Epidemic of the 2019 severe acute respiratory syndrome coronavirus 2 outside of Wuhan, China

Background The 2019 severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) responsible for coronavirus disease 2019 (COVID-19) appeared in Wuhan, Hubei in December 2019. Beside from Hubei Province, no large-scale epidemiological data are available. The purpose of the study is to investigate the epidemiology of the patients diagnosed with COVID-19 in Shandong province, China. Methods Data were obtained from the Epidemic Daily Report Network. Confirmed patients and suspected cases in Shandong were included in the analysis. Data including age, sex, address, time of disease onset, time of diagnosis, and sources of transmission were collected.

them, China was the epicenter of the spread, with 72,528 confirmed cases and 1870 deaths [1]. The World Health Organization declared the SARS-Cov-2 an international public health emergency [2].
Whole-genome sequencing demonstrated that the infection agent at the disease origin was caused by a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily [3], and was later named SARS-Cov-2 by the World Health Organization [1]. Different from the Middle East Respiratory Syndrome (MERS)-CoV but similar to SARS-CoV, SARS-Cov-2 is the seventh member of the family of coronaviruses that has infected humans [3,4]. Additionally, SARS-Cov-2 was confirmed in the bronchoalveolar lavage fluid of patients with confirmed diagnoses [3].
The exact origin and source of the virus are still unclear, but previous investigations suggested the virus may be associated with the illegal sale of wild animals in the Huanan Seafood Wholesale Market [5]. Huang et al. [6,7] reported that a majority of the initial SARS-Cov-2 patient population had a history of visiting this market. Currently, it is confirmed the SARS-Cov-2 is transmitted by human-tohuman contact [3,6,[8][9][10][11]. Chen et al. [5] reported SARS-Cov-2 infection clustered within groups of individuals in close contact, and with a higher frequency of men with comorbidities. The symptoms of COVID-19 are similar with those of SARS-CoV and MERS-CoV [12], including fever, non-productive cough, dyspnea, myalgia, fatigue, normal or decreased leukocytes, and imaging suggestive of pneumonia [6]. Severe cases developed shock, acute respiratory distress syndrome (ARDS), acute cardiomyopathy, and acute renal injury leading to death [5,6]. No effective targeted drugs or vaccines are available to date, but several clinical studies are currently ongoing. Nevertheless, important mobilization and preparation efforts were undertaken in Chinese hospitals [13]. To accelerate triage in emergency rooms and guide appropriate preventive methods, a scoring system was designed [13][14][15].
To date, most studies about SARS-Cov-2 and COVID-19 are case reports or case series [5,6,10,[16][17][18][19][20]. Large-scale epidemiological studies are only available for the Hubei Province, the origin of the epidemic [6]. Therefore, this study aimed to investigate the epidemiology (including the population distribution, temporal trend, and transmission methods of the disease) of patients confirmed with SARS-Cov-2 in Shandong province (China), which has a population of over 100 million. The results could provide new evidence regarding the mode of transmission and natural history of SARS-Cov-2 infection in areas outside of Hubei Province.

Methods
The study protocol was in accordance with the ethics standards and gained approval from Shandong Critical Care Quality Control Administration Ethics Committee. Due to the nature of this epidemiological data study it was exempt from obtaining informed consent by the Ethics Committee.

Statistical analysis
All statistical analyses were carried using SPSS 16.0 (IBM, Armonk, NY, USA). Only descriptive statistics were used. The continuous data were presented as means ± standard deviation and as medians (range). The categorical data were presented as numbers and percentages.

Distribution of the patients
According the Epidemic Daily Report Network, 596 patients in Shandong province were either confirmed or suspect cases with SARS-Cov-2 by February 13th, 2020. Among them, 518 patients in Shandong province were formally confirmed with SARS-Cov-2. These patients were distributed in 106 counties (municipalities or districts) in 15 prefecture-level cities. In addition, there were 78 suspected cases in 11 prefecture-level cities in Shandong.
The highest frequency of confirmed patients and suspected cases were found in the 30-39 age group ( Table 2). Most of the confirmed patients were young or middle-aged individuals, and only 5.4% (32/596) patients were ≥ 70 years of age. The percentage of males was higher in confirmed patients (male-to-female ratio of 1.26:1) compared to suspected cases (male-to-female ratio was 0.85:1). Figure 1 shows the distribution of the confirmed patients according to age groups. The highest frequency in males was in the 30-34 age group, while the highest frequency in females was in the 60-64 age group. Temporal distribution of SARS-Cov-2 The first case of SARS-Cov-2 in Shandong province occurred on January 14th, 2020 and was confirmed on January 21st, 2020. The number of confirmed patients with SARS-Cov-2 increased with time, and the number of the confirmed cases was higher after January 28th, 2020, which was mainly due to the patients confirmed from previously performed laboratory screening. Nevertheless, the diagnoses were associated with stricter screening and could not reflect the actual status of the infection. Figure 2 shows the delays between symptom onset and diagnosis. The delays were longer in the early period of the epidemic with high frequencies of patients with delays > 7 days.

Epidemic characteristics of SARS-Cov-2
Initially, patients were primarily characterized by histories of traveling in Hubei and other areas, but in the later period, the patients were mainly local individuals with close contacts to virus carriers ( Fig. 3)

Clinical severity
The clinical manifestations of the confirmed patients and suspected cases were primarily comparative to regular pneumonia. Among the confirmed patients, 3.3% (17/518) and 6.9% (36/518) of patients had critical or severe pneumonia, respectively (Table 3). There was no death case by February 13th, 2020. The proportion of patients with severe pneumonia increased with time, as well as with the changes of disease courses and delayed diagnosis.

Discussion
The results of this study show that by February 13th, 2020, in Shandong, there were 518 patients confirmed with SARS-Cov-2 and 78 suspected cases (10th in China). Among them, there was no death case. Most patients were middle-aged or young, and the proportion of males was higher than that of females. Additionally, male patients were younger than females. The mode of transmission seems to favor cluster transmission. The onset-diagnosis was reduced as time progressed, probably due to the implemented public health prevention and control measures.
Compared with a previous study by Wang et al. [16], the confirmed patients in the present study were younger (43 vs. 56 years), but similar to patients from Zhejiang Province (41 years) [4]. The percentage of male patients was higher in confirmed patients (similar between the two studies, at 56% and 54%), and the male-to-female ratio was 1.26:1. In contrast, the male-to-female ratio was 0.85:1 in suspected cases. The sex distribution was different between the confirmed patients and suspected patients, which could be associated with the fact that males have more outdoor activities than females, and thus the risk of exposure was higher, while more females received examinations because of having been in close contacts with carriers.
As time progressed, the cause of the disease changed from a history of traveling in Hubei and other high-prevalence areas [3,6,8,9,16,19] to local individuals who were in close contact with the virus carriers. In addition, in accordance with the human-to-human transmission mode of SARS-Cov-2 [3,6,[8][9][10][11], the virus was mainly transmitted among individuals living, working, or traveling together, and there were 99 cluster outbreaks in Shandong province. Li et al. reported in Zhejiang that no patient was ever exposed to the Huanan Seafood Market, and all were due to human-to-human transmission, indicating protective measures should be taken to prevent direct human contact transmission [4].
The delay between onset and diagnosis dimension with time, which may be due to enhanced awareness and knowledge of the disease, as well as to the strict preventive measures and reporting policies that were implemented in China to face the epidemic [13][14][15].
Similarly to SARS-CoV, fever and cough were the dominant symptoms, accompanied by chest imaging suggestive of pneumonia [5,6], but the gastrointestinal symptoms were rare, which is different from SARS-CoV, MERS-CoV, and influenza [23][24][25]. Of note, the absence of fever is much higher with SARS-Cov-2 than with SARS-CoV and MERS-CoV, [26] suggesting many cases may have been missed since public health surveillance relied heavily on fever detection [27]. In the present study, a small percentage of patients with confirmed infection were in a critical state, but no deaths were reported.
The 62 patients from Zhejiang reported in February 2020 were showing relatively mild symptoms [4]. This is lower than the official death toll of 2.01% in China [1,22]. Nevertheless, since the first case of SARS-Cov-2 was reported relatively late compared with Hubei, the appropriate detection, prevention, and control methods were already implemented [13,14], which probably led to a reduction in disease severity and mortality due to early diagnosis and management.

Limitations
There were several limitations to this study. For instance, the asymptomatic cases or cases with mild symptoms that stayed in their homes may not have been accounted for and included in this study.
Additionally, we only analyzed the data of the patients from Shandong province, which cannot accurately reflect the data in China, especially in Hubei province. The data were from an electronic database, making it possible for patients seen in outpatient settings or community clinics were not included. There was no comparator group, and only descriptive statistics were completed. Finally, we only analyzed the data by February 13th, 2020.

Conclusion
Considering the collective confirmed and suspected cases of SARS-Cov-2 in Shandong by February 13th, 2020, males and the young and middle-aged populations were more frequently affected by the virus, which was most commonly transmitted through cluster outbreaks. Since the initial case of SARS-Cov-2 was identified, the onset-diagnosis delay was reduced with time, which coincides with the implementation of guidelines for prevention, diagnosis, and treatment of infected patients. Availability of data and materials: All data generated or analyzed during this study are included in this published article. The datasets generated during and/or analyzed during the current study are available in the Epidemic Daily Report repository. No administrative permissions were required to access raw data from the epidemic daily reporting network.

Figure 1
Age distribution of patients confirmed with SARS-Cov-2 according to sex.

Figure 2
Time between onset and diagnosis of patients confirmed with SARS-Cov-2 in Shandong province.

Figure 3
Distribution of the sources of patients confirmed with SARS-Cov-2 in Shandong province.