Epidemiology and Clinical Characteristics of the First 500 Positive Cases of COVID-19. A Multicenter Retrospective Study across the Najran Region of the Kingdom of Saudi Arabia (KSA)

Introduction: Coronavirus Disease 2019 (COVID-19) is a viral infection that was first reported in Wuhan, China on 31 December 2019. This study aimed to clarify the epidemiology and clinical characteristics of 500 first COVID-19 in the Najran region, Saudi Arabia. Material and Methods: A multi-center retrospective study design was employed to study the first 500 confirmed COVID-19 positive cases in Najran province, Kingdom of Saudi Arabia (KSA). Data were collected from 1 March 2020 until 1 July 2020 and provided by the Infection Prevention and Control (IPC) department from the hospitals. Included cases were confirmed using real-time reverse transcrip-tase-polymerase chain reaction (RT-PCR). Demographic, vital signs, symptoms, incubation period, travel or exposure history medical history, and comorbidities were collected. Logistic regression analysis was used to explore the association between potential risk factors associated with symptoms occurrence of COVID-19. Results: The median age of 500 COVID-19 patients was 31 years; 333 (66.6%) males. A total of 34 (6.8%) were Healthcare Workers (HCWs). Out of the 500 patients, 180 (36%) had at least one comorbid disease. The most common symptoms on admission were fever 281 (56.2%), cough 266 (53.2%), shortness of breath 166 (33.2%), and malaise 113 (22.6%). Most of the patients presented with mild disease severity 310 (62%). Natio-How nality, age, and Diabetes Miletus (DM) were independently and significantly associated with being symptomatic (P < 0.05). Compared to Saudi nationals, other nationality patients were most likely to have symptoms (β = 2.968, CI = 2.002 - 4.400, P = 0.0010). For every 1 year increase in age, the risk of being symptomatic increased by 5.8% (β = 1.045, CI = 1.033 - 1.058, P = 0.001). Compared with non-DM patients, DM patients had a 4.05 times higher risk (β = 4.05, CI = 2.188 - 7.507, P = 0.001) of getting symptoms. Conclusions: The study concluded that the majority of the COVID-19 patients were symptomatic or had mild disease severity. Age, nationality, and DM were the important risk factors in being symptomatic.


Introduction
In 1965, the first human coronavirus (HCoV) was identified by Tyrrell and Bynoe as they had isolated the virus from a nasal swab taken from a child patient [1]. By 1968, the term "Coronavirus" was endorsed for this group of viruses describing their unique characteristics [2].
Around six species of HCoVs have been identified, that causes infections in human; 229E, OC43, NL63, and HKU1, and presenting symptoms are similar to the common cold [7] [10]. On the other hand, the other two species are considered zoonotic that provoke a severe acute respiratory syndrome (SARS-CoV), which was linked to the outbreak that occurred in Guangdong Province, the Republic of China in 2002 and 2003. SARS-CoV, may in some cases lead to systemic infection and eventually death (about 10% of cases) [6] [11] [12] [13].
Another outbreak of coronavirus was notified in the Middle East, known as the Middle East respiratory syndrome coronavirus (MERS-CoV) [14] [15] [16].
On 31 December 2019, the local World Health Organization (WHO) office was alarmed with several pneumonia cases of etiology not known before, emerging in Wuhan, Hubei Province of China [17]. On 7 January 2020, the Chinese health authorities confirmed that this cluster was associated with a novel coronavirus, and it was called 2019-nCoV [18]. Subsequently, the task of experts of the International Committee on Taxonomy of Viruses named it severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [19] owing to similari-Open Journal of Epidemiology ties to SARS-CoVs that caused the SARS outbreak in 2003. In February 2020, WHO named the disease caused by SARS-CoV-2 as COVID-19, which stands for coronavirus disease 2019 [20]. Further, on 11 March 2020, WHO declared COVID-19, a global pandemic [21].
Initial cases were proposed to be linked to a seafood wholesale market in Wuhan [22] [23]. Clinical presentation ranged from asymptomatic/mild symptoms to severe illness and death. The main symptoms are fever, cough, fatigue, shortness of breath, anorexia, and the presence of invasive lesions in bilateral lungs. Some patients may develop complete respiratory failure requiring intensive care for mechanical ventilation [24] [32].
Since the introduction of COVID-19 in the Najran region and until 2 June 2020, there has been only one study that had evaluated the knowledge of HCWs about this new disease [33]. Therefore, this study aims to identify the epidemiology and clinical characteristics of the first 500 positive cases of COVID-19 in Najran province, KSA, and to explore the association of potential risk factors with symptoms occurrence of COVID-19.

Study Design and Participants
This investigation employed a retrospective design study. The study included  [34]. A suspected case presented with one or more of the following symptoms; fever or history of fever, cough/dyspnea, and a travel history to known areas, currently identified as having an epidemic, or direct contact with a confirmed case of COVID-19.
In this study, we classified patients with COVID-19 as asymptomatic (a con-firmed case with no symptoms) and symptomatic (a confirmed case with symptoms). The severity of symptomatic cases was categorized as mild, moderate, severe, and critical as per the therapeutic protocol for COVID-19 patients issued by Saudi MOH (version 1.1). Disease severity was considered mild or moderate if mechanical ventilation was not required; while severe if the patient condition met at least one of the following criteria; respiratory distress with respiratory rate ≥ 30/min, blood oxygen saturation (SPO 2 ) ≤ 93% at rest, the arterial partial pressure of oxygen/inspired oxygen fraction ratio, (PaO 2 /FiO 2 ) ≤ 300 mm Hg and lung infiltration > 50% of the lung field within 24 -48 hours of admission. The case was classified as critical, if at least one or more symptoms of acute respiratory distress syndrome (ARDS), sepsis, altered consciousness, and multi-organ failure were present. Patient with cytokine release syndrome (criteria for patients at high risk for developing cytokine storm [1 or more of the following: Serum IL-6 ≥ 3x upper normal limit, Ferritin > 300 μg/L (or surrogate) with doubling within 24 hours, Ferritin > 600 μg/L at presentation and LDH > 250 and Elevated D-dimer (>1 mcg/mL)].

Data Collection
For confirmation, a naso/oropharyngeal swab specimen was collected from all the suspected cases by a trained healthcare worker (HCW). Following collection, the specimens were sent to regional laboratories, either in Jeddah or Asir. The shipping condition of the samples was maintained by the carrier companies assuring the stability of the specimens during transportation. IPC department in each hospital had provided the patient data. The collected data included demographic, vital signs, clinical signs/symptoms, incubation period, travel or exposure history, etc.

Statistical Analysis
Statistical analysis was performed using the statistical packages IBMSPSS (version 20). Data in this study has been expressed as percentages (%) and percentiles (25 th Q1 & 75 th Q3). Factors associated with being symptomatic were identified by using logistic regressions. The univariate model was used to find significant associative factors independently and later all the significant factors were analyzed collectively in a multivariate model. A probability (P) value less than 0.05 was considered significant.

Results
A total of 500 COVID-19 positive cases were included in the study. The demographic and historical characteristics of cases are shown in In terms of the clinical course of the COVID-19, Figure 1 displays the median incubation period, which was 5 days (4 -6). The median of the symptomatic period was 4 days (3 -6), the latent period was 4 days (3 -5) while the median of the positivity period was 11 days (9 -14).
From Figure 2, the analysis of disease severity showed that the majority 310 (62%) of the cases presented with mild disease. Roughly, 160 (32%) of patients reported moderate disease, and only a small minority 20 and 10 (4% and 2%) of the cases presented with severe and critical disease, respectively.
Factors associated with being symptomatic are presented in Table 3. According to logistic regression, in univariate analysis, nationality, age, and DM were significantly associated factors (P < 0.05). In multivariate analysis, nationality,

Discussion
Early identification studies, via next-generation sequencing and culture isolates of respiratory tract samples, have revealed that the genome of SARS-CoV-2 is 79% and 50% identical to SARS-CoV and MERS-CoV respectively [35]. Data from the epidemiological, clinical characteristics and therapeutic outcomes of patients of COVID-19 need an evaluation. To the best of our knowledge, the current study is the first to investigate the epidemiological and clinical characteristics of 500 patients with COVID-19 in the south region of the KSA.
Since the introduction and until 1 June 2020, 137 cases were reported by the appropriate authorities in the Najran region. But there had been an exponential increase in the number of cases since lockdown measures were removed and as of June 26, 2020, a total of 881 cases have been reported.
Similar to previously published studies, the findings in this study indicate the high contagiousness of this novel virus either via direct or indirect contact [29] [36] [37]. Nearly all of the patients included in the study had no recent travel history ( Further, the study confirms that people from all age groups are equally susceptible to the COVID-19 infection, with a median age of 31 years in this study. Infection was more common in males (N = 333, 66.6%) compared to females (N = 167, 33.4%) and this trend has been reported previously in many published studies [29] [36] [37] [39]. This might be due to differences among males and females rooted in their anatomy, physiology, biochemistry, genetics, and lifestyle, specifically with the increased pieces of evidence concerning health and health outcomes [40]. For example, men tend to use all tobacco products at higher rates than women [41], smoking may help increase the expression of angiotensin-converting enzyme 2 in lung tissue, which plays a key role in SARS-CoV-2 infection [42] [43]. This might also explain the higher number of infections among middle or elderly-aged males who are more likely to be smokers. Of all cases, 34 (6.8%) were HCWs, which supports the rapid transmissibility of the novel disease across health care settings [42].  [48], Patients with any comorbidity yield poorer clinical outcomes than those without any [19] [44].
Interestingly, our study revealed that people from other nationalities developed symptoms at a higher frequency than Saudi nationals, which might be interpreted to the immunity acquired previously from MERS-CoV but it needs further evaluation [48]. Gender, nationality, and health status can pose both a challenge and an opportunity during the outbreak, as well as potent predictors for disease risk [49] [50].
Results revealed the median time between known exposure and becoming infected was around 4 days. While the median duration from onset of symptoms to admission to a hospital was 4 days and the incubation period median was 5 days, which is in agreement with existing results elsewhere [24] [38].

Strengths and Limitations
Nonetheless, our study had certain limitations, specifically in study design. First, we could include only 500 confirmed cases, which are relatively small sample size. Second, the issue of recall bias could not have been eliminated, with patients giving inaccurate information on the date/mode of exposure or travel or onset of symptoms and their identification. The strengths of this study include detailed demographical data and clinical presentation of cases, and the use of multivariate analyses to identify the fundamental factors associated with the existence of symptoms. Novel findings of the study included confirmation of the risk factors among specific gender, age groups, and nationalities.

Conclusion
The most frequent symptoms in the study were fever, cough, short breath, and malaise. The severity of the disease was low in the Najran region, which requires further evaluation. Age, nationality, and DM were found as the main risk factors linked with SARS-CoV-2 symptomatic infection in the Najran region. Further studies are needed to explore the reasons behind the low severity of COVID-19 infection in the Najran region, KSA.