Post-acute COVID-19 condition in Saudi Arabia: A national representative study

Background Many survivors of COVID-19 have developed symptoms and diseases similar to those observed after severe acute respiratory syndrome (SARS). Therefore, this study aimed to characterize the symptoms that appear after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been eradicated and to determine their relationship with COVID-19 severity. Methods This multicenter, retrospective cross-sectional study was conducted in all eligible confirmed cases of SARS-CoV-2 infection from Saudi Arabia. Study participants were randomly selected using computerized random sampling from a population of 314,821 patients. Descriptive statistics were used to describe baseline demographic data and clinical characteristics. Categorical variables were presented as counts and percentages, while continuous variables were presented as means and standard deviations. Results Approximately 70% of patients were found to have five or fewer symptoms simultaneously. Late symptoms (in the ongoing symptomatic COVID-19) occurred in 225 (22·5%) patients with the most common late symptoms being loss of smell, loss of taste, fatigue, shortness of breath, and cough (52·4%, 31·1%, 11·5%, 10·2%, and 8·9% of patients with late symptoms, respectively). We also found that the presence of acute symptoms of COVID-19 and admission to the hospital were significant independent predictors of the post-COVID-19 condition. Conclusion Saudi patients with COVID-19 develop a wide range of symptoms, similar to those observed and reported in other countries. The loss of smell, the loss of taste, shortness of breath, and fatigue were the main persistent symptoms. Regular follow-up of COVID-19 survivors is highly recommended to minimize the burden of the post-acute COVID-19 condition and improve the quality of life of patients.


Introduction
The novel coronavirus disease 2019 (COVID-19) is a serious respiratory disease that results from infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been declared as a global pandemic by the World Health Organization (WHO) [1][2][3]. At the beginning of 2022, approximately 304,513,000 individuals were infected with SARS-CoV-2, and 5483,562 lives have been lost worldwide (1). The disease affects the physical and mental health of individuals who become infected. Economic and social difficulties markedly increase every day due to the distress and fear faced by combating this rampant virus [4].
Saudi Arabia is one of the countries that battled the pandemic in its early phases [5]. The first case of COVID-19 was discovered in March 2020, and once the first wave of COVID-19 had ended, 557,082 individuals had been infected with SARS-CoV-2 and 8878 deaths were reported at the end of 2021 (1). The second COVID-19 wave is currently in its early stages in Saudi Arabia, while the fourth wave has already started in some countries. This rapid progression has been driven by emerging variants of the virus, which have required new preventive and corrective measures to combat the emergence of each variant [6]. According to the WHO, COVID-19 has many variants; the variants of concern (VOCs) are Alpha, Beta, Gamma, Delta, and Omicron, and the variants of interest (VOIs) are Lamda and Mu [7]. 7 VOCs may be associated with any of the following: increased transmissibility; increased virulence; detrimental changes in the epidemiology or presentation of COVID-19; and decreased effectiveness of preventive measures, diagnostics, vaccines, or therapeutics. VOIs are also associated with genetic changes that are predicted or known to affect virus characteristics such as transmissibility, disease severity, and immune, diagnostic or therapeutic escape [7,8].
Patients present with symptoms such as fever, dry cough, and fatigue, which are moderate in around 80% of cases, but severe cases of the disease might proceed to respiratory distress, respiratory failure, or multi-organ failure (MOF), necessitating admission to an intensive care unit (ICU) [9,10]. The long-term effects of acquiring SARS-CoV-2 remain unclear given the novelty of the outbreak. Most individuals infected with COVID-19 recover completely; however, a small percentage of patients infected with SARS-CoV-2 experience recurring difficulties years later, and exhibit symptoms associated with the so-called "post-COVID-19 syndrome" or "post-COVID-19 condition" [11].
The post-acute COVID-19 condition is characterized by a wide range of new, returning, or chronic health problems that present 4 weeks or more after being infected with SARS-CoV-2 [12]. The postacute COVID-19 condition consists of subacute/ongoing COVID-19 and chronic or post-COVID-19 syndrome. Subacute/ongoing COVID-19 includes symptoms that appear 4-12 weeks after the onset of acute COVID-19, while chronic or post-COVID-19 syndrome includes symptoms that persist or appear beyond 12 weeks after the onset of acute COVID-19 and are not attributable to other diagnoses [13,14]. Individuals often report experiencing different combinations of the following symptoms: rash, fever, diarrhea, sleep disorders, dizziness, cough, chest or stomach pain, tiredness or fatigue, difficulty breathing, difficulty thinking or concentrating, mood changes, changes in menstrual period cycles, and changes in smell or taste [15]. Furthermore, post-acute COVID-19 conditions can be associated with MOF, including cardiovascular, pulmonary, renal, and neuropsychiatric organ systems [16]. Although extremely rare, some patients, especially children, develop multisystem inflammatory syndrome (MIS) during or shortly after contracting COVID-19 [17]. Various areas of the body can become inflamed due to MIS, which may eventually lead to MOF. Therefore, this study aimed to investigate and characterize the post-acute COVID-19 condition and its relationship with the severity of the disease.

Study design
This national cross-sectional study was conducted over a sixmonth period from March 2020 to August 2020, as authors collaborated from the Saudi Ministry of Health and Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The study participants were randomly selected from a population of 314,821 patients registered at the Ministry of Health Database. All participants were informed about their enrollment in the study and oral consents were obtained through phone interviews. During the collection, handling, and storage of data, the ethical standards of the Declaration of Helsinki were followed, and all precautions were taken to ensure participant confidentiality. The study protocol was approved by the Institutional Review Board (IRB) of Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia (No: 21-0172).

Inclusion and exclusion criteria
The study included all patients diagnosed with COVID-19 who were at least 18 years old. We excluded patients who died during acute illness and patients who refused to consent for participation and provide all requested information.

Sample size calculation
Raosoft ® software was used to determine the sample size calculation; to obtain a 95% confidence interval, a response distribution of 50%, and a 5% margin of error, the target sample size was estimated to be 371 participants. Adjusting the calculation for the projected 10% attrition, the final sample size was estimated to be 415 participants.

Data collection
Two public health specialists and two family physicians evaluated the questionnaire before and after it was translated into Arabic. Eight health practitioners (trained by the experts in the field), interviewed all participants and recorded all information using a designated data collection form. Oral consents and interviews were obtained by phone through the "937" Ministry of Health call center.
An independent reviewer resolved any discrepancies between the collected data and medical records. The questionnaire included sociodemographic data such as age; sex and occupation; questions about the medical history related to COVID-19, including a history of medical illness, hospital or ICU admission; history of smoking; questions about the ongoing symptomatic COVID-19; and questions about the post-COVID-19 condition. Acute SARS-CoV-2 infection was defined as signs and symptoms of COVID-19 lasting for up to 4 weeks. Ongoing symptomatic COVID-19 was defined as signs and symptoms of COVID-19 from 4 weeks to 12 weeks. Post-COVID-19 condition was defined as signs and symptoms that developed during or after an infection consistent with COVID-19, continuing for more than 12 weeks, and not explained by an alternative diagnosis. 15 .

Statistical analysis
Descriptive statistics were used to describe the baseline demographic data and clinical characteristics. Categorical variables were presented as counts and percentages, whereas continuous variables were presented as means and standard deviations (SDs). The t-test was used for continuous variables, and the chi-squared test was used for categorical variables. Simple and multiple logistic regression analyses were performed to identify factors associated with the appearance of COVID-19 symptoms 4 weeks after the diagnosis; odds ratios (OR), adjusted odds ratios (aORs) and 95% confidence intervals (CI) were calculated. A p-value of less than 0.05 was considered significant. Statistical analyses were performed using the Statistical Package of Social Science (SPSS vers. 24; IBM Corp., Armonk, NY, USA).

Baseline characteristics of the study population
A total of 1000 participants with confirmed SARS-CoV-2 infection were included in the study, with a mean age of 36.9 ± 11.9 years. Most of the participants (85.9%) were < 50 years of age. The male to female ratio was 1·5:1. More than half of the participants were workers (56.5%), while 29.2% were unemployed, 6.7% were retired, and 2.4% were students. Regarding smoking status, 20.1% currently smoked, and 7.9% formally smoked, and 71.9% had never smoked (Table 1). Comorbid conditions were prevalent in 247 (24.7%) participants ( Fig. 1). In terms of associated comorbidities, 24.7% of the participants had comorbidities; of these, 16.3% had one comorbidity and 8.2% had two or more comorbidities. The most prevalent comorbidity was diabetes (9.7%), followed by hypertension (7.9%), asthma (5.7%), hyperparathyroidism (2.3%), and allergic disorders (1.8%). Fig. 1 summarizes the recorded comorbidities.

Discussion
Persistent post-COVID-19 symptoms have a negative impact on health-related quality of life and exert increased burden on health systems [18,19]. The extent of those symptoms, their predictors, and possible alleviating and aggravating factors were not studied and reported previously for the population of Saudi Arabia.
This study identified that late symptoms (beyond 4 weeks of diagnosis) occurred in 22.5% of participants. Similar results were reported in a population representative study done in the UK, where 21% of the included cases had late symptoms lasting beyond 5 weeks of infection [20]. In contrast, Sudre et al. reported a lower percentage of 13% with symptoms lasting 28 days after symptom onset in another cohort in the UK [21]. In the Netherlands and Belgium, Goertz et al. reported that over 99% of infected cases did not fully recover within 12 weeks after symptom onset. The huge number of persistent late symptoms could be explained by the fact that the sample was from a Facebook group of patients with persistent complaints [22]. Nehme et al., reported 33% of cases with symptoms 30-45 days after diagnosis in hospital outpatient settings in Switzerland [23]. A large-scale observational study involving 38 participants in Michigan, USA also showed similar results where 32·6% of their participants experienced chronic symptoms [24].
The most common late symptoms in our population were loss of smell, loss of taste, fatigue, shortness of breath, and cough. Fatigue and shortness of breath were also commonly reported in different studies [14,[22][23][24].
Only 5.5% of participants continued to have symptoms more than 12 weeks after diagnosis in this study, compared with 10% and 2% in different studies in the UK [20,21]. The following symptoms were reported: loss of smell, loss of taste, fatigue, shortness of breath, and fever (32.6%, 15.8%, 7.4%, 5.3% and 5.3% of post-COVID-19 symptomatic patients respectively). Loss of smell continued to be the top persistent complaint in our population. This should direct the focus of public education toward the course of olfactory inflammation and set recovery expectations [15].
Hospital admission, female sex and the presence of early symptoms were found to be top predictors for the occurrence of late symptoms in our population. Similarly, a Chinese post-acute COVID-19 investigation identified sex-based differences, with females more likely to experience fatigue and anxiety/depression at 6 months of follow-up [25].
A concerning percentage of those who had the late symptoms beyond 4 weeks (31%), reported that the symptoms affected their social and work-related activities. The majority of patients who had late symptoms (beyond 4 weeks) reported no alleviating (72.7%) or aggravating factors (94.8%).
Our study had limitations due to the nature of a retrospective, cross-sectional design where only a sample of participants was Table 2 The distribution of acute SARS-CoV-2 infection symptoms (N = 1000.  assessed at a certain time. However, the results of this study are valid due to the careful representative sampling methodology.

Conclusions
Saudi patients with the post-acute COVID-19 condition experience a wide range of symptoms, which is consistent with what has been documented in other countries. Loss of smell, loss of taste, shortness of breath, and fatigue are among the persistent symptoms. These symptoms substantially influence social and work-related activities. The impact of this condition should be one of the focus areas for future COVID-19-related research. Regular follow-up of COVID-19 survivors is highly recommended to minimize the burden of the post-acute COVID-19 condition and improve the quality of life of patients.

Funding
This work was supported by the Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R290), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Ethical approval
This study was approved by Princess Nourah bint Abdulrahman University IRB log no. 21-0172 on 11 March 2021. All participants were clearly informed about their enrollment in the study and oral consents were obtained. Privacy and confidentiality of patient data were assured throughout the study and only accessed by study primary investigator without identifiers.

Data sharing statement
Data are available upon reasonable request.

Declaration of interests
None declared.