Predictors of illness severity in COVID-19 cases

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Background
In late December 2019, a cluster of pneumonia of unknown etiology emerged in Wuhan, China [1] that was believed to be a zoonotic disease [2,3] linked to a local animal market [4]. Few weeks later the disease showed a sustained transmissibility among human [5] and the etiology was identi ed as a novel member of the Coronaviridae named later as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to its genetic homology (82%) to the previously identi ed member of the coronavirus family, SARS-CoV [4]. Rapidly thereafter, the virus started to spread beyond China signaling an impending pandemic. On January 30th, the World Health Organization declared the novel coronavirus outbreak as a Public Health Emergency of International Concern (PHEIC).
The disease caused by the virus was called coronavirus disease-2019 (COVID-19) [6]. Individuals infected with SARS-CoV-2 can be asymptomatic, or more commonly present with a wide spectrum of clinical manifestations ranging from mild illness to life-threatening pneumonia with a median incubation period of 6.4 days [7].
Symptomatic patients commonly present with fever, cough, fatigue, and shortness of breath [8], and sometimes gastrointestinal manifestations in the form of diarrhea, anorexia, nausea, vomiting and abdominal pain [9].
Children have been shown to manifest mild features of the disease compared to adults [10] although certain studies suggested an increase in the incidence of multisystem in ammatory disease in children with COVID-19 [11,12]. In addition, pregnant women and their newborns seems to be mildly affected by COVID-19 with no reports of teratogenicity or severe illness [13]. On the 26th of November 2020, the World Health Organization indicated that COVID − 19 cases exceeded 59.8 million cases and multiple studies reported that the virus evolved gradually [14,15] and this genetic evolution was thought to impact the severity and infectivity of COVID-19 [16,17].
This study describes the epidemiological and clinical features of COVID-19 of the rst 341 cases diagnosed in a university teaching hospital in the Eastern Province of Saudi Arabia over the rst three months period of the pandemic in the country, and identify the spectrum of clinical presentation in different age groups. In addition, demographic data and comorbidities were analyzed and correlated to identify predictors of severity and prognosis.

Methods
A combined retrospective and prospective single-centered observational study was conducted at a university teaching hospital, which is a 550-bed hospital, which serves patients from the Eastern Province of Saudi Arabia and was authorized, among other hospitals, by the Saudi Ministry of Health to hospitalize and manage COVID-19 patients. The study describes the epidemiological and clinical features of COVID-19 for the rst 341 SARS-CoV-2 positive cases diagnosed in the hospital since the start of the spread of the pandemic in the Eastern Province for three months (March 10th -June 13th).
During the study period, 3146 individuals were tested for SARS-CoV-2 infection using nucleic acid detection tests, of which 341 were positive. The indications for testing included clinical suspicion of symptomatic COVID-19, contact with con rmed cases, health care worker screening, and screening for all elective admissions to the hospital.
Testing for SARS-CoV-2 infection was done using either the RealStar SARS-CoV-2 RT-PCR kit (Altona diagnostics, Hamburg, Germany) or the Xpert Xpress SARS-CoV-2 kit (Cepheid, California, USA) according to the availably and following the manufacture's recommendations. Samples from all positive cases were sent to the National Health Laboratory for con rmation. Cycle thresholds were retrieved from the instruments software as shown in the nal report.
All laboratory con rmed COVID-19 cases were included in the study. Clinical, demographic, and SARS-CoV-2 test results for all patients were obtained from the computerized hospital data system. Patients were strati ed by age groups into infants (≤ 1 year), children (> 1years-19 years), adults (20-65 years) and senior adults (> 65 years) for analysis according to the WHO classi cation. In addition, patients were also grouped based on clinical presentation as described by the Saudi Ministry of health into 4 groups: asymptomatic, mild to moderate, severe, and critical cases [18]. Serial RT-PCR results were recorded for all con rmed cases which were followed up for clearance using a test-based strategy. Clearance duration was de ned by the duration between the rst positive RT-PCR and the rst negative RT-PCR samples when the negative sample was con rmed by another negative RT-PCR sample collected ≥ 24 hours later.

Statistical analysis:
All data were tabulated in Excel spread sheets to calculate frequencies. Data grouping and calculation of chi square for linear trend were performed by the IBM SPSS software version 26. Graphpad software was used to calculate the correlation between Ct values and the disease severity. P value of less than 0.05 was considered signi cant.

Epidemiological features of COVID-19
The total number of patients with laboratory con rmed COVID-19 infection was 341. The male to female ratio was 2:1 (225:116) (p value < 0.0001). The mean age of patients was 44.19 ± 18.03 years (median = 45 years and range = 4 months to 96 years). There was no signi cant difference in mean age between males and females (p value= 0.958).
With regards to mode of acquisition of infection, 67.2 % of patients (n = 229) did not report contact with a suspected or a con rmed COVID-19 case nor was there any clear epidemiological link with the source of infection. On the other hand, 20.2 % (n = 69) reported positive household contact with COVID-19 cases, and 3.2% (n=11) reported contact with suspected cases not con rmed by laboratory test, while only 7.3% (n=25) and 2.1% (n=7) of patients reported positive contact at work or travel history, respectively.

Clinical features of COVID-19
Out of the 341 COVID-19 cases, 52 (15.2%) were completely asymptomatic. Of the majority symptomatic cases, 153 (44.9%) had mild to moderate disease, 74 (21.7%) had severe disease and 62 (18.2%) were critically ill ( Figure.1). Symptomatic patients presented with a wide variety of clinical manifestations including systemic manifestations in the form of fever, headache, and myalgia in addition to respiratory symptoms such as cough, shortness of breath, rhinorrhea and 3 patients reported loss of smell and taste. In addition, patients also reported gastrointestinal manifestation in the form of nausea, vomiting, anorexia and diarrhea. The most common clinical features were fever, shortness of breath, cough, myalgia, vomiting, sore throat, and headache (Table 1). The COVID-19 was found to be more severe in males, senior adults, and patients of Bangladeshi nationality while less severe in females, infants, children, and Saudi and Egyptian nationalities (Table 2). Furthermore, patient with diabetes mellitus, hypertension and dyslipidemia were more likely to have severe illness (Table 2).
No signi cant association was found between bronchial asthma, heart disease, cancer, and sickle cell disease with severity of COVID-19 (   During the three-months study period, three pregnant women were diagnosed as SARS-CoV-2 positive. Two cases were 32 and 29 years old, at 36 and 40 weeks of gestation, respectively. Both reported household contact with COVID-19 cases. The rst patient was gravida 2 para 1, asymptomatic case presented at the time of labor, had uneventful vaginal delivery and discharged home with her baby in good conditions. The second lady was primigravida, who reported runny nose 5 days prior to presentation, was discharged home and readmitted 10 days later with labor which was also uneventful with a healthy newborn baby. Both newborns were isolated in single cribs, initially tested by nasopharyngeal PCR twice, 24 hours apart, and closely monitored in the neonatal intensive care unit for 14 days as per the institution policy followed by a 3rd PCR prior to discharge. The third case was 27 years old primigravida at 11th gestational week who presented with fever and cough after acquiring the infection from a household contact. The lady was sent home for home isolation and care with no complications. The newborns were kep under observation for 14 days during which serial PCR testing was performed; none of the three cases was infected.

Viral shedding dynamics and Predictors of severe COVID-19
Of the 341 cases, one hundred and thirty-ve (39.6%) con rmed cases underwent clearance following a testbased strategy with other cases being followed on a time-based clearance. The duration of viral shedding ranged between 9 and 36 days, with a median of 13.5 days ± 5.66 ( Figure 2). Association between duration of shedding and severity of illness was not possible because asymptomatic cases were following time-based clearance with no repeated testing. No association was found between cycle threshold (Ct values) of Xpert Xpress SARS-CoV2 test and severity of illness ( Figure 3)

Discussion
This study of the rst COVID-19 cases diagnosed in a university teaching hospital in eastern Saudi Arabia showed that out of 3,146 individuals tested for SARS-CoV-2, 341 were positive with an overall 10.8% detection rate. Majority of COVID-19 cases were adults (19-65 years) followed by senior adults (> 65 years), which most probably re ects the frequency of Covid-19 diagnosis in the described settings rather than an incidence in various age groups. Furthermore, males were more commonly affected than females and this is consistent with a recent multi-variate analysis study that identi ed male gender as an independent risk factor for acquisition of Covid-19 infection [19]. However, this could also be attributed to local social factors with males being more exposed by leaving homes to ful l their work and family commitments during the lockdown periods.
The mode of acquisition was not known for most cases indicating a huge impact of asymptomatic spreaders of the disease and the need to improve contact tracing measures. This also may indicate the possibility of contacting the virus with means other than close contact such as the long distance migrating micro-aerosols, which is getting a growing acceptance among experts in the eld [20]. The later hypothesis is supported by the fact that only one fth of the cases in our study reported household contact with COVID-19 con rmed cases and 3% reported contact with suspected cases. Population-level studies are still limited for comparisons and most data available to date regarding the source of infection represent institutional experiences.
Case fatality rates (CFR) was found to be 10%, which is double that reported from Wuhan, China (5.6%) the epicenter of the pandemic [21]. This could be explained by multiple reasons including the study settings, a university hospital that was authorized to receives COVID-19 cases from other regional hospitals, which might lead to selection bias in the severity of cases included. Additionally, heterogenicity in the ethnicity and other demographics might also contribute to this difference in the case fatality across different studies. Most importantly, that case fatality rate does not take into consideration all individuals affected by SARS-CoV2 infection but only considers those cases who presented for testing as symptomatic, contact, or health care workers. This is also evident by the proportion of asymptomatic cases (15.2%) in our cohort that is less than that described in many similar studies [22]. Thus, the overall infection mortality rate among individuals with Covid-19 infections is likely to be considerably lower as it has been estimated by the CDC and WHO to be around 0.5-1% [23,24]. On the other hand, the reported case fatality rates may have been underestimated considering that several fatal Covid-19 infections remain undiagnosed [25].
In our study, case-fatality was signi cantly associated with male gender, which can be explained by a possible genetic predisposition and also justi ed by the random and heterogenous nature of the study sample where nationality being a signi cant confounding factor similar to earlier reports [26,27]. In addition, fatality was also found to be affected by the ethnic origin, being higher in Asian particularly Bengalis compared to Arabs (17.9-6%) (p = value 0.002), and also by the age factor, with higher rates in older age groups [28].
Clinically, COVID-19 con rmed patients were classi ed into four categories of severity, based on the local national protocol [18]. These categories include asymptomatic, mild to moderate, severe, and critical. This classi cation was made based on the clinical features, evidence of pneumonia, oxygen requirements, and the presence of serious complications. In addition to respiratory symptoms, patients also reported gastrointestinal symptoms in the form of vomiting, diarrhea, abdominal pain, nauseas, and anorexia which is in line with other reports from different countries [29]. Fever also was reported in 100% of infants, a feature that was well documented in other studies, despite the low number of cases in our study [30]. It is interesting that only three patients reported the lack of smell/taste in the study. Whether this is a feature of the disease in the region or a lack of reporting needs further investigation.
Severe and critical COVID-19 illness was signi cantly higher in male gender, senior adults age groups, and Bengali ethnicity. On the other hand, severe and critical illness was signi cantly lower in Saudis and Egyptians (Arab ethnic groups) compared to other groups. The severity of the disease in various patient populations needs to be interpreted with cautions taking account for the full burden of the pandemic including delayed care and social determinants of health. Severity was also affected by co-morbidities, particularly diabetes mellitus, hypertension, and dyslipidemias as it was found in other studies [31]. The study included three pregnant cases in whom the disease was mild to moderate in severity since pregnancy has not been identi ed as a risk factor for acquiring SARS-CoV-2 infection or worsening the prognosis [32][33]. . Therefore, the time-based strategy for clearance has been widely adopted in various institutions. Nonetheless, recent reports described the transmission of infectious virus later than 10 days from severely infected patients and therefore caution should be considered for vulnerable patient populations [35,40]. Further data are needed to conclude the period of infectivity in cases of critical and severe illness.
Our study is not without limitations, nevertheless, it contributes to the growing evidence of variable Covid-19 presentation and illness severity in relation to other factors and provided an insight about the lack of usefulness of Ct values as a predictive clinical tool.

Conclusions
Patients with COVID-19 manifest wide range of clinical presentations ranging from asymptomatic infection to severe and critical cases. Adult males were found to be twice as affected as females, and severity of COVID-19 was signi cantly associated with male gender, senior age group, and Asian ethnicity particularly Bengali ethnicity. On the other hand, for the rst time, milder form of the disease was found to be signi cantly associated with Arab ethnic groups (Saudi and Egyptian), demonstrating the impact of ethnicity on disease severity. Furthermore, CFR was also found to be three times higher in Asian compared to Arabs. Cycle threshold (Ct) of Xpert Xpress SARS-CoV2, a surrogate measure of viral load, was not found to correlate with severity of illness and therefore is not recommended to be used as a predictor tool.
Declarations Figure 1 The spectrum of the severity of illness among the 341 COVID-19 cases Frequency of cycle threshold (Ct) values for the E and N2 gene targets relative to COVID-19 severity (p value 0.65).