Prevalence and Epidemiological Trends in Mortality Due to COVID-19 in Saudi Arabia


 Background: Coronavirus disease of 2019 (COVID-19) created a major public health emergency and an international concern. It is an infectious respiratory illness caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The international mortality rates due to COVID-19 reached 2,748,763 on March 24, 2021. We describe the prevalence, case fatality rate, and epidemiological trends of COVID-19 mortality in Saudi Arabia in this paper.Method: A systematic approach of evaluating COVID-19 related mortalities was established in Saudi Arabia. A scientific committee that evaluated all reported cases with suspicious or confirmed COVID-19 disease using a standardized electronic form. A data registry of all deaths with all clinical parameters was built based on active reporting from all healthcare facilities in Saudi Arabia. Analysis of data using national and regional crude case fatality rate (cCFR) and death per 100,000 population was carried. Descriptive analysis of age, gender, nationality, and comorbidities. Mortality trend was plotted per week and compared to international figures.Results: The total reported number of deaths between March 23rd until April 9, 2021 was 6,737. cCFR was reported as 1.70%, and death per 100,000 population was reported as 19.24 which compared favourably to figures reported by several developed countries. Highest percentages of deaths were among individuals aged between 60-69 years, males (74%), individuals with diabetes (60%), and Hypertension (50%). Conclusion: Case fatality rate and death per 100,000 population in Saudi Arabia is among the lowest in the world due to multiple factors. Several comorbidities have been identified namely diabetes, hypertension, obesity, and cardiac arrhythmias.

The first case of COVID-19 had emerged in Wuhan, China, in late December of 2019. Cases continued to mount around the world, with the first confirmed case announced in Saudi Arabia in early March 2020. (3) COVID-19 was declared as a pandemic by the World Health Organization (WHO) in March of 2020. By mid-April 2021, approximately 135 million confirmed cases with COVID-19 were reported worldwide, with 2,917,830 thousand related deaths. (1,2) Several risk factors for negative outcomes have been identified. Specific minority ethnic groups are disproportionally affected by severe COVID-19 outcomes. (4) However, whether this is linked to genetic predisposition, socio-economic vulnerabilities, access to care, or other associated factors, have yet to be determined. Regarding gender, it has been well-established that males are at nearly 1.7-fold higher risk of death due to COVID-19 than females. (5) The elderly population is at a higher risk of death (5,6) , but this might be attributed to their pre-existing medical conditions such as cardiovascular diseases, diabetes, respiratory diseases, or cancer independently associated with increased risk of death related to COVID-19. (5)(6)(7) Obesity has also been shown to contribute to disease severity (8,9) .
To properly evaluate the impact of COVID-19 on society, excess deaths have been recognized as an essential and meaningful measure. It was reported as the third leading death in the US right after heart diseases and cancer. (10) It has been suggested that the mortality rate due to COVID-19 could be under or overestimated depending on reporting mechanism and definition of COVID-19 direct cause of mortality. (7,11) Excess mortality estimates the degree to which currently measured mortality exceeds baseline levels estimated using historical data. Rapid mortality surveillance (RMS), "a system that generates daily or weekly counts of total mortality by age, sex, date of death, place of death" was proposed to inform decision-makers about the trajectory and magnitude of the pandemic, with excess mortality being the main focal point. (11) The World Health Organization (WHO) defined death due to COVID-19 as "A death resulting from a clinically compatible illness, in a probable or confirmed COVID-19 case, unless there is a clear alternative cause of death that cannot be related to COVID disease (e.g., trauma). ", the death caused by COVID-19 may not be credited to another disease and should be counted freely of prior conditions that are associated with triggering a severe course of COVID-19. (12) Kingdom of Saudi Arabia (KSA) is divided into 13 regions covered by 20 health directorates. Each directorate has its own autonomy in managing its health affairs according to policies and guidelines set by the Ministry of Health (MOH). (13) The study aimed to report prevalence and epidemiological trends of mortality due to COVID-19 disease.
We also aimed to quantify the extent to which having comorbidities increases the chance of death from COVID-19.

Methods
This study was performed in accordance with the Declaration of Helsinki and was approved by the central IRB of the Saudi Ministry of Health (log No: 20-168M). All methods were carried out in accordance with relevant guidelines and regulations of the Kingdome of Saudi Arabia. Informed consent was not required by the IRB as this was not an interventional study and exempt was granted.
Daily death data for the 20 health directorates were studied and obtained from the MOH and non-MOH public and private hospitals from March 23, 2020, through April 9, 2021. The analysis included all direct causes of death due to  According to the WHO definition, the Saudi Ministry of Health registers COVID-19 as a possible cause of death under three categories. First, direct death, in which death resulted from a clinical illness compatible with COVID-19 infection for confirmed or suspected cases. Second, indirect death, death resulted from another disease (e.g., diabetes, cardiovascular diseases, emphysema, etc.), and the patient's condition worsened due to a confirmed or suspected COVID-19. The last scenario is death unrelated to COVID-19, which is any death in a confirmed or suspected case with COVID-19, but COVID-19 was not a direct or indirect cause of death. (3) (Figure 1) The COVID-19 mortality scientific committee was established by the Minister of Health to determine the causes of deaths during the COVID-19 pandemic, report COVID-19 mortalities, and evaluate the quality of care provided to patients with COVID-19. The committee meets daily to assess and evaluate each case and decide whether mortality is direct, indirect, or unrelated to COVID-19.
Any mortality case with confirmed or suspected COVID-19 must be reported to the COVID-19 mortality scientific committee using the approved electronic form within 3 hours from the time of death. The form contains all needed information to assess and evaluate the cause of death (demographics, symptoms, comorbidities, co-infections, vital signs and laboratory values, all reported investigations, medications, ventilation setting and requirements, and complications during hospital stay) (supplement 1). Analysis of all reports is sent to the statistics department, whereas only direct COVID-19 related mortalities are announced.
The objective of this report is to describe the prevalence of COVID-19 death in Saudi Arabia, including trends of mortality, risk factors of death, and population estimates for the prevalence of the various comorbidities. Additionally, we report the association between comorbidities and death from COVID-19.

Statistical Analysis:
National and regional crude case fatality rate (cCFR), defined as the number of mortality cases divided by the number of confirmed COVID-19 cases, and the number of mortality cases per 100,000 population were reported. (14) Descriptive statistics using numbers and percentages were used to describe the categorical variables such as nationality, age, gender, comorbidities, and geographical location of case fatalities.
Weekly mortality trends were reported as the number of deaths per time period. The mortality trend was plotted per week and compared to international figures.
Relative and absolute measures of association between comorbidities and death were calculated using odds ratios, attributable risk, and attributable risk percent. Population estimates for the prevalence of the various comorbidities were used to calculate population attributable risk estimates for comorbidities.
Conventionally measures of association were derived from data for which each observation is classified along two dimensionsexposure and outcome, and for each dimension is binary. The exposure is comorbidity (yes or no), and the outcome is death from COVID-19 (yes or no). As this study did not include subjects not dying, emphasis was placed on cause-specific death and with death from COVID-19 versus death from another cause as the outcome of interest.
Comorbidities were analyzed individually as well as in combinations (e.g., diabetes and obesity together).
Furthermore, the unexposed group was regarded in two different ways. We considered the unexposed to be those with no comorbidity and then investigated the extent to which the comorbidity (or combination of comorbidities) was associated with COVID-19 death versus no comorbidity. The second way to consider the unexposed was as those simply without the comorbidity, but possibly with a variety of other comorbidities. The former type of unexposed definition would reflect the isolated association of the comorbidity, whereas the latter would reflect the association of the comorbidity versus the set of other comorbidities seen in the population. In order to calculate the attributable risk and attributable risk percent associated with comorbidities, the risk of death from COVID-19 for the exposed and unexposed was calculated as follows: Given these risk values, then the attributable risk and the attributable risk percent are: Finally, the number needed to harm (NNH), defined as the number of subjects infected with SARS-CoV2 who need to be exposed to comorbidity in order for one subject to die from COVID-19, was calculated as Measures of association were calculated together with 95% confidence intervals. Analyses were carried out using SAS/JMP version 15.0.

Results
Between March 23, 2020, and April 9, 2021, among the 7,761 subjects were studied, 1,025 had died from causes unrelated to COVID-19, and 6,737 had died from causes directly related to COVID-19 from a total of 395,854 infected patients by COVID-19.
Compared to cCFR with Brazil, China, Germany, Italy, South Korea, and the United States, Saudi Arabia's cCFR was 1.70%. (Figure 2). Among the 20 health directorates in KSA, Taif Province accounted for the highest cCFR (4.85%), while Qunfotha reported only five deaths during this period with a cCFR of 0.22 % ( Table 1).
The national number of deaths per 100,000 population was 19.24 (Table 2) province. Males accounted for 74% of total deaths, and the highest percentage of deaths per age group was between the age of 60 -69 years ( Figure 5). The most common comorbidities associated with death were diabetes (60%), hypertension (50%), chronic renal impairment, and obesity (10%) ( Table 3). The highest number of reported mortalities was reached on week 12, which was then plateaued until week 16 and started to decline thereafter. (Figure 6) Across the whole cohort of subjects who were analyzed, there were 271 distinct comorbidity profiles.  8). Table   5 shows the attributable risk of death and needed number to be hard as measures of absolute measure of the risk of death for each comorbidity.

Discussion
This is the first report on the prevalence and epidemiological trends of COVID-19 mortality in Saudi Arabia. Several countries have published the prevalence of mortalities related to COVID-19. The crude case Fatality rate among European countries was the highest in Italy (3%). (15) Italy defines death related to COVID-19 in a broader term due to the lack of clear criteria for COVID-19 deaths. Death is recorded as related to COVID-19 in individuals who tested positive by Real-Time-Polymerase Chain Reaction (RT-PCR) for SARS-CoV-2 regardless of pre-existing conditions that might have contributed to their death. (16) In China, the case fatality rate reached 5.1% of confirmed cases. (5,14) while in the UK, 12,6980 (2.91%) of deaths were recorded as related to COVID-19 (14) . The Center for Disease Control and Prevention (CDC) in the United States has reported 573,856 COVID-19 cases in the United States (US). The total fatality rate was estimated to be 1.8%. (15,19) The CDC reported no data on serious pre-existing conditions. Due to missing key patients' characteristics, the fatality rate was estimated as a range having the lower bound estimated by using all cases among age group and upper bound estimated by using only cases with known key characteristics. (19) Saudi Arabia has lower cCFR and deaths per 100,000 compared to many developed countries. This could be due to several factors, including multiple strategies of early preventive measures by the government and early lockdown that took place before the first COVID-19 mortality was reported. Intensive care unit (ICU) bed expansion from 6,360-beds to 10,401-beds (increased by 164%) during the pandemic period played a significant role in accommodating more critical patients. In addition, early outpatient intervention through the creation of "fever clinics" in primary healthcare centers around the Kingdome. These clinics aimed to treat patients with early symptoms to prevent hospital admissions and decongest emergency departments in hospitals. Finally, MOH developed multiple protocols for COVID-19 that are continuously updated. More than 32 protocols covered different aspects of COVID-19-disease, including but not limited to radiology preparedness, guidelines for BLS and ACLS for COVID-19 patients, COVID-19 in pregnancy, ICU admission criteria, Mechanical ventilation, high flow nasal cannula and helmet use in covid-19, and COVID-19 treatment protocol.
The number of cases in Italy has reached 112,861 in early April 2021. (17) In China, the prevalence of COVID-19 between men and women was also nearly the same (51.4% vs. 48.6%). However, fatality rate among men was significantly higher than women (RR = 1.67, 95%CI = 1.47-1.89, p < 0.001). (5) In the UK, mortality was also higher in men than women (fully adjusted HR 1.59, 1.53-1.65). (18) This is similar to our findings, as males accounted for more than two-thirds of mortalities. This could be explained by the presence of different social and occupational factors among both genders. Biologicals differences cannot be excluded as well. (20) An increase in age was strongly associated with an increased risk of severe COVID-19 outcomes. In the US, individuals aged ≥65 years accounted for 30% of the cases, half of the ICU admissions, and 80% of deaths with the highest case-fatality rate (10.4-27.3 %) in adults aged 85 years or older. (21) In the UK, patients above 80 years of age accounted for 1,131,680 (6.5%) of total recorded mortalities, and 6,474 (0.57%) of mortalities were related to COVID-19. Overall cumulative incidence of death 90 days after study start in patients aged above 80 was found to be rising to 0.67% and 0.44% in men and women, respectively aged ≥80 years. (18) In Italy, the case-fatality rate was exceptionally high in individuals aged 80 years or older reaching 20.2%. (17) Patients aged above 80 years old in China (5) accounted for 14.8% of fatalities. Our study showed that most mortalities occurred in patients aged between 60-69 years old.
Minorities ethnic groups have been especially affected by COVID-19, with an increase in fatality rate in the US and UK than most populations. (22,23) In the Bronx, New York City, an area known to have a high poverty rate compared to the national US average (22) , deceased Black patients accounted for 24% of total deaths (n= 160), and Hispanic accounted for 68%. The remaining deaths (8%) were for other unspecified ethnicities. However, minimal representation of other ethnicities limited the ability to draw a proper assessment of ethnicity and its relation to severe COVID-19 outcomes in the US. (22) In the UK, (23) registered hospital deaths related to COVID-19 (per 100,000) were the highest in Black Caribbean ethnicity, three times the White British majority. Age has established a crucial role in the severity of COVID-19 outcomes. However, even after adjusting for age and geography, minorities still comprise the majority of deaths related to COVID-19 in the UK, making Black African deaths the highest (3.7 times the White British group), followed by Pakistani deaths (2.9 times the White British group) and Bangladeshi deaths at twice the deaths of White British group. (23) Individuals with pre-existing conditions are at an exceptionally high risk of death due to COVID-19. Death from non-respiratory causes had a significant proportional increase in 5 US states with the highest excess deaths related to COVID-19. (7) Deaths in individuals with diabetes are increasing by 96% and having the most significant increase in New York City by 356%. Heart diseases related deaths increased by 89% and 398% in New York City. Other non-respiratory diseases that resulted in deaths were also noted. Alzheimer disease-related deaths increased by 64%, and cerebrovascular diseases by 35%. (7) Diabetes has also been noted to increase the risk of death in both China and UK patients (RR = 4.43, 95%CI = 3.49-5.61, p < 0.001. HbA1c >= 58 mmol/mol had greatest Hazard Ratio, fully adjusted HR 1.95, 1.83-2.07. respectively). (5,18) our study suggests that diabetes is one of the most important comorbidities associated with COVID-19 mortality. This is particularly concerning knowing that diabetes prevalence in Saudi Arabia is about 20%.
China and UK have also established an association of increased risk of severe COVID-19 outcomes with respiratory disease (Excluding asthma in both. RR = 3.43, 95%CI = 2.42-4.87, p < 0.001. Fully adjusted HR 1.63, 1.55-1.71. respectively). (5,18) Severe asthma was associated with the risk of death in Chinese patients (Asthma with Oral Corticosteroid use had greatest HR, fully adjusted HR 1.13, 1.01-1.26). (18) This is similar to our findings as respiratory diseases were three times more likely to result in death due to covid-

19.
Other pre-existing conditions that increased the risk of death in a patient with COVID-19 in our study included cardiovascular diseases, renal impairment, obesity, thromboembolic disorders, thyroid dysfunction, and neurological disorders. A study from China found cardiovascular disease (RR = 6.75, 95%CI = 5.40-8.43, p < 0.001), and hypertension (RR = 4.48, 95%CI = 3.69-5.45, p < 0.001) among the most common comorbidities associated with COVID-19 mortality. (5) Another study in the UK showed that obesity was associated with an increased risk of death (BMI >40 fully adjusted HR 1.92, 95% CI 1.72-2.13). (18) 16), were also associated with increased risk of death. (18) It is important to note that we reported the association of different comorbidities, which does not necessarily mean correlation or causality. Furthermore, two critical assumptions are necessary for the validity of the measures of association in this study. Firstly, it must be assumed that the presence or absence of comorbidity is independent of the likelihood of getting infected by the COVID-19 virus.
Secondly, the distribution of the comorbidities among the study subjects who died from unrelated causes matches the distribution of the comorbidities in the population of interest.

Conclusion:
Case fatality rate and death per 100,000 population in Saudi Arabia is among the lowest in the world due to multiple factors. Several comorbidities have been identified, namely diabetes, hypertension, obesity, and cardiac arrhythmias. Data from this study could be used to help in public health decision-making and preparedness efforts.       Week 24 Week 25 Week 26 Week 27 Week 28 Week 29 Week 30 Week 31 Week 32 Week 33 Week 34 Week 35 Week 36 Week 37 Week 38 Week 39 Week 40 Week 41 Week 42 Week 43 Week 44 Week 45 Week 46 Week 47 Week 48 Week 49 Week 50 Week 51 Week 52