Clinical Manifestations and Associated Mortality Factors of COVID-19: A Large Population-Based Study in the Northeast of Iran During 2020-2021

Background and aims: The emergence of the coronavirus disease 2019 (COVID-19) has become one of the greatest health problems of the 21st century. The current study was conducted to investigate COVID-19’s clinical manifestation, mortality factors, and their association with each other during the three devastating waves of the pandemic in Razavi-Khorasan province, Iran. Methods: This cross-sectional epidemiological population-based study was performed in Razavi-Khorasan province, Iran from January 21, 2020, to March 20, 2021. The data, including demographic characteristics and clinical presentations of the patients, were extracted from the Medical Care Monitoring System (MCMS), disease management portal in the Deputy of Health and hospital information system (HIS) of the medical universities/faculties of the province. Results: Overall, 80 499 patients were admitted to all hospitals of Khorasan-Razavi with the laboratory/ clinical COVID-19 confirmed disease. The male-to-female ratio and the mean age of our COVID-19 individuals were 1.10:1 and 55.67 ± 23.27, respectively. The most frequently reported presenting symptoms in histories provided at the admission time were respiratory distress (58.2%), fever (36.7%), and cough (34.9%), while the less common ones were abdominal pain (2.7%) and alternation in smell/ taste (0.9%). Male gender (odds ratio [OR] = 1.32, P < 0.001), age over 60 (OR = 2.59, P < 0.001), and presence of at least one comorbidity (OR = 1.32, P < 0.001) were significantly associated with higher mortality rates. Conclusion: Healthcare providers and public health managers can benefit from the findings of this study to detect and emphasize patients with poor prognoses.


Introduction
The coronavirus disease 2019 (COVID-19) has become one of the greatest health crises in the current century. 1 Following the emergence of COVID-19 in Wuhan, Hubei province, China in December 2019, the virus spread all over the world, and in a blink, the World Health Organization (WHO) called it a global pandemic. 2ccording to the official reports of the WHO, more than 200 million individuals were infected with the severe acute respiratory syndrome coronavirus type two (SARS-CoV-2), which has led to more than 4 million deaths in the world. 3n detail, SARS-CoV-2 is a single-stranded positivesense RNA virus of the Coronaviridae family. 4This betacoronavirus is commonly transmitted by respiratory droplets from an infected individual to others, and each person can transmit the virus to an average of 4 people. 5,6lthough many studies indicated that there is no one completely immune from the virus infection, its clinical manifestations are various from asymptomatic infection to severe multisystemic organ failure and death 7 .However, male gender, old age, smoking, and underlying diseases such as diabetes mellitus, hypertension, cardiovascular disease (CVD), chronic obstructive pulmonary disease, cerebrovascular disease, chronic kidney disease, and liver dysfunctions are reported as factors associated with higher disease severity and its mortality rate. 8,9The most common clinical manifestations of COVID-19 include fever, dyspnea, fatigue, non-productive cough, nausea and vomiting, diarrhea, and heart failure, but the disease is not limited to these signs and symptoms; moreover, different variants of the virus can be demonstrated with different manifestations. 7,9,10ased on our current knowledge about the clinical manifestations of COVID-19, anorexia, diarrhea, and nausea are the most common gastrointestinal (GI) manifestations of this infectious disease, respectively. 11owever, recent research indicated various GI signs and symptoms of the infected patients due to the mutant variants that infected them. 12Not only the GI presentations of COVID-19 are going to be changed through the virus genetic changes in new variants, but also some studies demonstrated that the other clinical manifestations and presentations of COVID-19 were changed due to virus mutant variants. 13On the other hand, there is some contradictory evidence of the relationships between patients' clinical manifestation, disease severity, and mortality. 14As there are many gray areas regarding COVID-19's clinical manifestations and their associations with mortality, the current study was designed to evaluate COVID-19's clinical manifestation, mortality factors, and their association during the three devastating waves of the COVID-19 pandemic in Razavi-Khorasan province, Iran.

Study Design
The current cross-sectional epidemiological populationbased study was conducted from January 21, 2020 (first wave) to March 20, 2021

Data Source and Study Population
The data were extracted from the Medical Care Monitoring System (MCMC) of Mashhad University of Medical Sciences.This system was created from the beginning of the COVID-19 pandemic in Iran to monitor COVID-19 patients in the country.The data of the MCMC in Razavi-Khorasan province are collected from six medical universities/faculties of the province and are continuously updated 24 hours a day.Moreover, the recorded information in the MCMC is going to be matched with the patient's information in the disease management portal in the Deputy of Health and hospital information system (HIS) of the medical universities/ faculties.
Hospitalized patients with a definitive diagnosis of coronavirus infection by the reverse transcriptasepolymerase chain reaction (RT-PCR) method or through clinical evaluations and admission to public hospitals affiliated with Mashhad University of Medical Sciences in Razavi-Khorasan province were included in this study.Their information was recorded through MCMC from January 21, 2020, to March 20, 2021.After the extraction of the patients' reports from the MCMC system and before the statistical analysis of the demographics and clinical presentations of patients, data quality control was performed by researchers, and all duplicate reports were excluded from further analysis.

Outcomes
The information and outcomes gathered from the MCMC archive and assessed in this study were demographic data and clinical presentations of COVID-19 at admission.Demographic data included gender, age, hospitalization date and duration, comorbidities (e.g., hypertension, diabetes, CVD, pulmonary diseases, kidney disease, cancer, neurologic disease, liver disease, and hematologic disease), and patients' status (expired or not).In addition, clinical presentations of COVID-19 at admission were respiratory distress, fever, cough, myalgia, neurologic symptoms (e.g., headache, loss of consciousness, seizure, paresis, plegia), anorexia, nausea, vomiting, diarrhea, chest pain, abdominal pain, and anosmia/ageusia.

Statistical Analysis
The analyses were performed based on non-missing data, and missing data were not imputed in the final logistic regression.The Kolmogorov-Smirnov test was applied to check the normality of variables.The age, gender, and disease presentations were analyzed over all of the three waves of COVID-19 epidemics.The total frequency of the above-mentioned variables was also taken into consideration.The male-to-female ratio (gender ratio) and the case fatality rate (CFR) were calculated as well.Continuous and categorical data were presented as mean ± standard deviation (SD), median (interquartile range), and absolute number (percentage) as appropriate.The chi-square and Fisher's exact tests were employed to compare proportions.
A multiple binary logistic regression model evaluated the effect of multiple variables comprised of age, gender, disease presentations, and comorbidities on COVID-19 mortality.The primary outcome was mortality in COVID-19 subjects.The backward selection method was used for variable selection.Different variables were entered in binary logistic regression one by one, and those with a significance value of < 0.2 were imputed in the final logistic regression to identify independent predictors of mortality in both the total population and the stratified random sample.All data were interpreted using IBM SPSS Statistics (version 26), and statistical significance was set at P < 0.05.

Clinical Presentations of COVID-19
In terms of the pattern of COVID-19 presentation, the most frequently reported presenting symptoms in histories provided at the admission time were respiratory distress (58.2%), fever (36.7%), and cough (34.9%), whereas the less common ones included abdominal pain (2.7%) and alternation in smell/taste (0.9%).Table 2 presents the remaining presentation data.
As shown in Figure 1, respiratory distress, fever, cough, myalgia, neurologic, anorexia, and diarrhea were significantly more prevalent in males than females.However, chest pain and dermatitis were slightly more reported in males.Females had higher rates of nausea, vomiting, alternations in smell/taste, and abdominal pain rather than males, and the difference between the presence of stated presentations in males and females was significant (P < 0.001).Age, male gender, and the wave of COVID-19 epidemics, as well as cough, myalgia, respiratory distress, alternations in smell/taste, neurologic symptoms, chest pain, the appearance of at least one GI symptom, abdominal pain, anorexia, presence of at least one comorbidity, hypertension, diabetes, and CVD, were independently associated with the mortality of COVID-19, based on the multiple binary logistic regression model (Table 3).

Factors Associated With COVID-19 Mortality
Age > 60 was a strong predictor of disease mortality.Males had a higher probability of death, compared to females.Among the initially reported presentations of COVID-19, having neurologic symptoms, and reported respiratory distress were prominent predictors of death.Smoking, the presence of cough, myalgia, alterations of smell/taste, chest pain, and abdominal pain were associated, on the other hand, with a lower risk of mortality.However, fever, nausea, and vomiting were accompanied by a lower risk of death, but not significantly (Table 3).

Discussion
The COVID-19 pandemic is a serious public health problem that has so far challenged humankind for about two years. 5According to the weekly report of the WHO, as of 31 August 2021, the cumulative number of COVID-19 cases exceeded 200 million. 9The complete mechanism of pathogenesis and the other aspects of this novel disease are still under study.8][19] Cases from distinct locations and cultures are present with relatively different rates of clinical manifestations and co-morbidities. 20Therefore, population-specific studies are required for prompt management approach, prevention, and treatment in public health policy.The current study investigated the clinical presentations, including GI symptoms, comorbidities, and demographic features of COVID-19 patients, in Khorasan-Razavi province, Iran.In this retrospective study, the prevalence of these characteristics and their association with mortality were evaluated in 80 499 hospital-admitted COVID-19 cases from January 21, 2020, to March 20, 2021.To the best of our knowledge, our epidemiological study demonstrated the largest number of confirmed COVID-19 cases in Khorasan-Razavi province.
The data of 80 499 cases showed that the majority of hospital-admitted patients (63.0%) were above 50 years old, and only 15% of them were younger than 30 years.2][23][24] Some reports from Ecuador and Kazakhstan had a meaningful younger mean age of patients in comparison to our data. 25,26During the three periods of disease surge, the number of admitted children (< 10 years) surprisingly increased from 2.5% in 1 st wave to 8.9% in 3 rd wave.Based on the early report as of February 11 from China, only 0.9% of 44 672 cases were < 10 years old 23 compared to 6.1% (4948) in our study.However, rising patterns in the number of younger patients (0-18) were observed in other countries such as Italy. 27The mean length of hospital stay was 5.50 ± 7.42; the length of stay appears to be related to underlying disease, age, and admission criteria of different territories. 28he main clinical COVID-19 signs and symptoms were respiratory distress, fever, and cough which were observed in 58.2%, 36.7%, and 34.9% of patients, respectively.Respiratory distress was strongly associated with a higher rate of mortality (OR = 2.05, P < 0.001).On the other hand, patients with a cough had a better prognosis (OR = 0.88, P < 0.001).The most common presentation in the younger group (0-20) was fever due to their potent innate immune response. 29Nonetheless, there was a slightly lower risk of death in patients with fever (OR = 0.99, P = 0.525).According to Li et al, not fever per se, but a higher temperature of fever can be associated with COVID-19 severity. 30Consistent with our study, the information of 1083 patients in Tehran revealed that fever, shortness of breath, and cough were the prominent symptoms; cough and fever were associated with lower mortality, while shortness of breath indicated worse outcomes. 31Similarly, a study of 20 133 UK patients reported the mentioned symptoms as the most common presentations and represented a high level of overlap between them. 32he UK cohort study defined another cluster of symptoms called enteric symptoms (abdominal pain, vomiting, and diarrhea).In general, 29% of their patients had GI manifestations on admission. 32Our study evaluated the frequencies of GI symptoms, including anorexia (8.1%), nausea (6.1%), vomiting (4.5%), diarrhea (3.4%), and abdominal pain (2.7%), and the overall prevalence was lower (16.76%).There was significant heterogeneity in the prevalence of GI manifestations among various studies; for instance, ~8.7% 33 or 16% 34 in China, 21.7% (diarrhea) and 13.4% (nausea/vomiting) in Spain, 35 14.6% (diarrhea) and 16.6% (nausea/vomiting), 31 and 25.4% 36 in Tehran.One explanation for this heterogeneity is the different frequencies of enteric symptoms in age groups.Considering that the age distribution of patients was probably not quite similar in various studies, the reports were not similar.Not applying a universal scale for the diagnosis of each GI symptom and small sample sizes of the studies could also cause this diversification.
Comparing the frequency of GI presentations in each age group, it was found that for patients older than 90, anorexia was the prominent symptom, whereas other GI symptoms such as abdominal pain and nausea were more prevalent for the adolescent group [11-20].Vomiting and diarrhea were mostly observed in children [0-10] compared to other ages (P < 0.001).These results match the meta-analysis by Dara et al, reporting the prevalence of diarrhea (12%) and nausea/vomiting (11%) as the most common GI manifestations in children. 37][40] There are conflicting reports about the association between the presence of GI symptoms and the clinical outcome of COVID-19 infection in literature.Several studies found no significant difference in mortality between cases with GI symptoms and those with no GI presentation. 36,41However, a meta-analysis by Mao et al showed a higher prevalence of severe COVID-19 disease in patients having GI symptoms. 42Particularly, the results on diarrhea were also controversial, reporting better 43 or worse prognosis in COVID-19 patients with diarrhea. 44ccording to the comparison of the percentage of expired cases in the group "with diarrhea" (8.5%) versus the "no diarrhea" group (15.7%) in our study, diarrhea may be related to a lower mortality rate, but the results were not meaningful (P = 0.935).Nevertheless, a significant decrease was found in mortality in COVID-19 patients having GI symptoms compared to those with no GI manifestation, which is in conformity with the results of several studies. 45,46arious neurological manifestations related to the central or peripheral nervous system in the COVID-19 infection were discussed in studies. 47The prevalence of neurological symptoms, specifically headache, loss of consciousness, seizure, paresis, and plegia, was 15.1%, and they generally elevated the risk of death based on our data.Impaired consciousness and a higher mortality rate in some studies 48,49 are in line with our results.
Eventually, the overall mortality rate was 15.1%, which is higher than another descriptive study of over 200 000 patients in Tehran (10.0%). 49In both studies, male gender, age > 60, and hypertension were related to weak clinical outcomes, although diabetes was associated with a lower mortality ratio (OR = 0.90, P < 0.001) in our report and not significantly higher death risk in the above-mentioned descriptive study.

Strengths and Limitations
The large number of patients included in our study was a major strength.However, this research had several limitations.First, our data were restricted to admitted cases in hospitals affiliated to Khorasan-Razavi Universities of Medical Sciences.In addition, blood biochemical tests, including liver function tests in GI manifestations, were not analyzed in this study.Finally, the patients were not followed up for further evaluations of post-COVID-19 symptoms and complications.

Conclusion
In general, this investigation was a multi-hospital study of COVID-19 patients in Khorasan-Razavi province.It analyzed the demographics, clinical manifestations, and comorbidities of 80499 cases reported from January 21, 2020 to March 20, 2021.Age over 60, male gender, (third wave) to determine the characteristics of COVID-19 patients, clinical presentations of COVID-19, and COVID-19-associated factors with mortality during the first, second, and third wave in COVID-19 patients who were admitted to the hospitals affiliated to the Mashhad University of Medical Sciences in Razavi-Khorasan province, Iran.

Table 1 .
As of April 21, 2021, 12119 (15.1%) had deceased in our study, following a median of 4 days [IQR: 1-10] of hospitalization.The mean ± SD and the median [IQR] of age were 67.40 ± 18.27 and 70 (59-81) years versus 53.58 ± 23.44 and 57 (37-72), in expired vs. alive subjects, respectively.The gender-based CFR specified that males had a significantly higher rate of mortality (16.6% vs. 13.4%).Based on the results, 72% of deaths occurred in subjects over the age of 60.The highest age-based CFR was observed in patients aged over 90 with a rate of 31.3%Demographic Characteristics of COVID-19 In-patients * Note.COVID-19: Coronavirus disease 19; SD: Standard deviation; IQR: Interquartile range.*Data expressed as N (% within the wave), Mean ± SD and Median [IQR] as appropriate.(30.7% vs. 32.1%:Males vs. females).Instead, patients in the age group of 21-30 years had the lowest rate of mortality (3.4%).Patients with at least one comorbidity expired more frequently (19.8%), whereas patients with no mentioned comorbidity had a CFR of 13.9%.

Table 3 .
Independent Predictors Associated With Mortality: Multivariable Binary Logistic Regression Analysis * Neurologic symptoms comprised of headache, loss of consciousness, seizure, paresis, and plegia.Model: Age, gender, the wave of epidemics, fever, cough, myalgia, respiratory distress, anosmia/ageusia, neurologic symptoms (comprised of headache, loss of consciousness, seizure, paresis, plegia), chest pain, the appearance of at least one GI symptom, abdominal pain, nausea, vomiting, diarrhea, anorexia, presence of at least one comorbidity, diabetes, hypertension, and cardiovascular disease.