A Head-To-Head Comparative Study of Covid-19 Patients Between Epicenter and Peripheral Areas of Pandemic From China

Background: There has been little information on difference of epidemiology, clinical characteristics and outcomes between epicenter and peripheral areas of Covid-19 pandemic. Methods: Based on Sichuan & Wuhan collaboration research group for Covid-19, we established two retrospective cohorts reecting the epicenter and peripheral area of pandemic. Epidemiology, clinical characteristics and outcomes of patients were compared. Multivariate regression analyses were used to estimate adjusted odds ratios (aOR) to identify clinical variables associated with outcomes. Results: Upon March 12, 2020, Wuhan cohort consisted of 710 patients using random sampling, and 474 consecutive cases constituted Sichuan cohort. Sichuan cohort had more upper airway symptoms, while Wuhan cohort is elder, has more lower airway symptoms and comorbidities. Wuhan cohort had higher risk of death (aOR=7.64), ICU admission (aOR=1.66), delayed time from illness onset to hospital and ICU admission (aOR=6.29 and aOR=8.03) and prolonged duration of viral shedding (aOR=1.64). Conclusions: Worse outcomes in the epicenter would be explained by delayed time from illness onset to hospital and ICU admission associated with elevated systemic inammation reecting organ dysfunction and prolonged duration of virus shedding except for age and comorbidities. It indicates potentially clinical implications of Covid-19 that early supportive care would achieve better clinical outcome. the rate of ICU admission, time from illness onset to ICU admission and discharge, hospital length of stay, and duration of viral shedding after Covid-19 onset. The shedding of SARS-CoV-2 was dened as two consecutive negative results with qPCR detection at in interval of 24 hours. The criteria for discharge were absence of fever for at least 3 days, substantial improvement in both lungs in chest CT, clinical remission of respiratory symptoms and comorbidities, and shedding of SARS-Cov-2.

Fever clinics were created to exclusively screen patients with suspected SARS-CoV-2 infection as indicated in the supplementary data.

Study design and subjects
This was a retrospective study based on two cohorts led by the Sichuan and Wuhan Collaboration Research Group for Covid-19, China. The Sichuan cohort Sichuan as the peripheral area of pandemic consisted of SARS-CoV-2 con rmed patients consecutively recruited from 41 designated hospitals until March 12, 2020. Based on the exposure history, we further divided the Sichuan cohort into two sub-cohorts with or without Wuhan exposure history. The Wuhan cohort as the epicenter area of pandemic formed using random sampling method from 2 designated hospitals, namely Wuhan Red Cross Hospital and Renmin Hospital of Wuhan University, Wuhan, China. All patients enrolled in this study were diagnosed as Covid-19 according to the interim guidance issued by the National Health Commission of China and WHO [13]. Cases were con rmed with infection of SARS-CoV-2 by a positive result of real-time reverse-transcriptase-polymerase-chainreaction of nasopharyngeal, pharyngeal, throat-swab or sputum specimens. Some patients had been reported by Wei et al. [14], Xiong et al [15] and Xiong et al. [16], but their study purposes are signi cantly different from this study.

Data collection
The medical records of patients with Covid-19 were reviewed by the trained research team. Epidemiological, demographic, clinical, laboratory, radiological characteristics, treatment and outcome data were collected with standardised data collection forms (modi ed case record form for severe acute respiratory infection clinical characterization shared by International Severe Acute Respiratory and Emerging Infection Consortium [ISARIC] from the electric medical records. The cutoff date was Mar 12, 2020. We collected the exposure history, clinical symptoms and signs, and laboratory ndings on admission. Laboratory examinations were performed according to clinical care needs of the patients. Radiological abnormalities were extracted from the documentation. The patients were excluded if the medical records were not available. A team of trained researchers abstracted the data and entered into structured spreadsheet. All data were crosschecked.

Study outcomes
The primary outcomes included death or the use of mechanical ventilation. Secondary outcomes were the rate of ICU admission, time from illness onset to ICU admission and discharge, hospital length of stay, and duration of viral shedding after Covid-19 onset. The shedding of SARS-CoV-2 was de ned as two consecutive negative results with qPCR detection at in interval of 24 hours. The criteria for discharge were absence of fever for at least 3 days, substantial improvement in both lungs in chest CT, clinical remission of respiratory symptoms and comorbidities, and shedding of SARS-Cov-2.

Statistical analysis
The aim of our study is to report the difference of epidemiological, clinical characteristics and outcomes of Covid-19 patients in peripheral and epicenter areas of pandemic. The detailed statistical analysis was described in supplementary data.

Clinical outcomes
Clinical outcomes are summarized in Table 2. The case fatality rate in Sichuan cohort was obviously lower than that in Wuhan cohort (0.6% vs. 8.3%, P<0.001). However, it had no signi cant difference in the proportion of patients receiving non-invasive mechanical ventilation or invasive mechanical ventilation between two cohorts (5.7% vs. 5.9%, P=0.872 and 1.7% vs. 1.4%, P=0.701). For the secondary outcomes, the proportion of patients who admitted to ICU in Sichuan cohort was signi cantly decreased than that in Wuhan cohort (6.3% vs. 13.6%, P<0.001). Time from illness onset to ICU admission and time from illness onset to discharge in Sichuan cohort were evidently shorter than Wuhan cohort (
Subgroup analyses between Sichuan sub-cohorts with vs. without Wuhan-related exposure As a result, it found almost no difference in clinical characteristics and outcomes between two sub-cohorts with and without Wuhan-related exposure in Sichuan ( Figure 1; Tables S1, S2 and S3). The detailed information was provided in Supplementary Data.
Sichuan sub-cohort with Wuhan-related exposure vs. Wuhan cohort It showed differential clinical characteristics and outcomes between Sichuan sub-cohort with Wuhan-related exposure and Wuhan cohort that were similar to the ndings found between Sichuan and Wuhan cohorts. The results were described in details in Supplementary Data (Tables S4, S5 and S6).

Discussion
To the best of our knowledge, there has been little information on difference of epidemiology, clinical characteristics and outcomes of patients with Covid-19 between epicenter (Wuhan) and peripheral areas of pandemic using comparative study design with a large sample size. This comparative study found some important information as follows. First, the outbreak and transmission of Covid-19 within the region of Sichuan as the peripheral epidemic area has well been of containment within no more than two months using traditional public health outbreak response tactics. Second, Sichuan cohort is characterized by more upper airway symptoms, while Wuhan cohort is elder, has more lower airway symptoms and comorbidities, and has elevated pivotal systemic in ammation re ecting organ dysfunction, and worse clinical outcomes independent of sex, age, smoking and comorbidities. Third, the subgroup analysis indicates that, within Sichuan cohort, the Wuhan-related exposure patients have similar clinical features and outcomes to those with non-Wuhan-related exposure. Fourth, the Wuhan-related exposure patients in Sichuan cohort have improved clinical outcomes in comparison with Wuhan cohort, although these two groups of patients have similar Wuhan-related exposure history.
As indicated in just published studies [8], the Covid-19 patients in Wuhan as the epicenter area of epidemic had elder age, more co-existing conditions assessed by Charlson comorbidity index, extended time from illness onset to hospital admission and severe patients in this study, but Sichuan cohort as the peripheral area had some featured characteristics as follows. Firstly, less health care workers in Sichuan cohort were infected than Wuhan cohort, which would be at least explained by insu cient precautions and overwhelmed health system at an earlier stage of this outbreak in Wuhan. Second, intriguingly, we found Sichuan cohort had more upper-airway symptoms rather than lower airway symptoms featured in Wuhan cohort in the epicenter epidemic, which was similarly found in exported cases in Singapore [18]. Accordingly, the exported patients from epicenter usually esteemed to have "common cold" at the beginning of Covid-19 outbreak. Different population, proliferation location of airway or evolution of SARS-CoV-2 would account for these differential symptoms [18][19][20][21]. Third, within the consecutively recruited cases in Sichuan cohort as a well-de ned population, our subgroup analyses indicated more males and elder age in non-Wuhan-related exposure patients, which supported the propensity of SARS-CoV-2 infection in males and elders [5,22,23].
Recently reported studies from USA and Italy supported that the greater proportion of elder and male Covid-19 patients would result in more critical illness [24,25].
Until now no antiviral treatment for Covid-19 has been proven to be effective, and the mainstay of treatment is supportive care. Compared with the Wuhan cohort, use of antibiotics (i.e. cephalosporin and quinolones) and glucocorticoids in Sichuan cohort, fell by 26.4% and 16.1%, respectively. These results could be possibly explained as following. Firstly, as indicated above, the expert panel from multiple disciplines team established by HCSP together developed and adjusted treatment plan for severe or critically ill patients according to interim guidance from National Health Commission of China and WHO across the 208 designated hospitals in Sichuan via 5G network technique every day. Accordingly, systemic corticosteroids were strictly managed and not routinely given for treatment of Covid-19 patients. Second, the Covid-19 patients in Wuhan cohort would actually be more severe or critically ill, who were supported by increased use of oxygen support if acute hypoxia occurred. In addition, prone position ventilation, physical rehabilitation and a variety of traditional Chinese medicine was used more in Sichuan under the guidance of expert panel, although it needed to be further investigated in randomized controlled trials [11,12].
In terms of clinical outcomes, there were several important ndings indicated by this study. Epidemic outbreak provided an opportunity to gain important information, some of which was associated with a limited window of opportunity. Our study showed that it had a delay from illness onset to hospital admission in Wuhan cohort, which might be an important risk factor for progression of Covid-19. Our multivariate regression analysis proved that the time from illness onset to hospital admission was signi cantly associated with mortality and ICU admission, which suggested some important implications about the pathogenesis of SARS-CoV-2 and may provide a unique window of opportunity for intervention [11]. Liang et al. [8] recently found the Wuhan-related exposure patients have worse clinical outcomes compared with non-Wuhan-related exposure cases, which, they think, would be explained by attenuated disease due to onward transmission of Covid-19. Actually, it is paradoxical in Liang et al.'s study [8] because relationship of Wuhan-related exposure with the prognosis disappears after adjusting for confounders. Our study rstly found that Covid-19 patients in the Wuhan cohort had worse clinical outcomes including case fatality rate, ICU admission and duration of virus shedding independent of sex, age, smoking, comorbidities and even time from illness onset to hospital admission. Severity of Covid-19 and shortage of medical resources would partly account for these worse outcomes. For example, at an earlier stage of outbreak, some patients would not achieve enough oxygen support because of insu cient oxygen pressure.
Duration of infectious virus replication is an important factor in assessing the risk of transmission and guiding decisions regarding isolation of patients, but the duration of SARS-CoV-2 RNA detection has not been well explored. Our study found the Wuhan cohort in epicenter area had the prolonged virus shedding that may contribute to severity of disease and clinical course [26,27]. Further, it rstly found duration of virus shedding was independently associated with age and time from illness onset to hospital admission. Our ndings were supported by other studies. Liu et al. [28] found that viral load of severe cases was higher than that of mild cases who had an early viral shedding. Wolfel et al. [29] found that virus shedding in upper airway where is the location of mild Covid-19, was very high during the rst week of symptoms, but shedding of viral RNA from sputum derived from lower airway where is the region of general to critical illness of Covid-19, outlasted the end of symptoms. Although Xu et al.
[30] found elder cases had a prolonged virial shedding, the correlation of age with duration of viral shedding disappeared after adjusting for confounders, which might be partly explained by small sample size.
Although this head-to-head comparative study provides informative ndings on difference of epidemiology, clinical characteristics and outcomes of patients with Covid-19 between epicenter (Wuhan) and peripheral (Sichuan) areas of pandemic with a large sample size, there are several limitations that need to be addressed. First, due to the retrospective study design, data generation was clinically driven and not all laboratory data were available in all patients. Accordingly, the missing data on patients may have biased the ndings. Second, Sichuan cohort representing peripheral area of Covid-19 pandemic was incomplete, although consecutive patients accounting for 88.1% of total cases with Covid-19 were recruited from 41 designated hospitals across Sichuan. Third, we did not analyze genetic diversity of virus strains and evolutionary history, which may well explain these biological differences between epicenter and peripheral areas of pandemic.

Conclusions
This head-to-head comparative study found that there have signi cant differences of epidemiology, clinical characteristics and outcomes of patients with Covid-19 between epicenter and peripheral areas of pandemic. Worse outcomes in the epicenter of pandemic would be partly explained by overwhelmed health recourses, delayed time from illness onset to hospital admission associated with elevated systemic in ammation re ecting organ dysfunction and prolonged duration of virus shedding except for sex, age, smoking and comorbidities. It indicates potential implications of clinical relevance in intervention of Covid-19 that urgent or early supportive care would achieve improved clinical outcomes including mortality, although no proven effective therapies for this virus currently exist. However, no differences of epidemiology, clinical characteristics and outcomes between the rst generation and secondary generation patients in the peripheral area of pandemic were found. Biological differences accounting for the differences between the Wuhan-related exposure patients in Sichuan cohort and Wuhan cohort need to be further investigated.