Risk Factors for Mortality of Patients with COVID-19 in Korea: A Nationwide Population-Based Study

Se Jun Park NHIC Ilsan Hospital: National Health Insurance Corporation Ilsan Hospital Hyungkook Lee NHIC Ilsan Hospital: National Health Insurance Corporation Ilsan Hospital Tae Mi Youk NHIC Ilsan Hospital: National Health Insurance Corporation Ilsan Hospital Han Ho Jeon (  fortune22c@nhimc.or.kr ) NHIC Ilsan Hospital: National Health Insurance Corporation Ilsan Hospital https://orcid.org/0000-00023393-3304


Conclusion
Male, elderly patients 65 years old, Medical Aid bene ciaries, higher CCI (≥3), and living in a large outbreak area might have a greater risk of mortality and comorbidities such as hypertension, COPD, CHF, and ESRD could also greatly affect the mortality in COVID-19 patients.

Background
The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rst reported in Wuhan, China in December, 2019 has rapidly spread worldwide and has become a public health emergency (1). Since there are no available vaccines and effective treatments, increasing the number of COVID-19 patients and mortality is a major challenge to public health.
Compared with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), COVID-19 has a lower mortality among diagnosed COVID-19 patients. However, previous studies have shown the risk factors for poor outcomes, such as 65 years old, male, hypertension, diabetes mellitus (DM), and cardiovascular diseases (2)(3)(4). Lai et al. reported that mortality was correlated with country health care resources (5). In many countries, there were undiagnosed COVID-19 cases by reverse transcription polymerase chain reaction (RT-PCR) test and the limitation in availability of health care services, such as lack of intensive care units and ventilators for adequate treatment of severe patients.
Republic of Korea (hereafter 'Korea'), like other countries, has had a COVID-19 outbreak since the rst patient on January 3, 2020. Social distancing and the use of facial masks have been recommended since the beginning of the COVID-19, and most populations have followed these recommendations well. In addition, early detection through active diagnostic tests, contact tracing, and quarantine were performed during the initial outbreak of COVID-19 (6). If patients were con rmed to have COVID-19, the patients were classi ed into mild, moderate, severe, and extremely severe cases by the public health center. All patients were admitted to a hospital or Living and Treatment Center for proper management, classi ed according to severity. Mild cases are isolated at the Living and Treatment Centers and monitored by health care staff at least twice a day. If the patient's symptoms were aggravated, patients were transported to the hospital. When symptoms improved, the patients were discharged based on isolation release standards.
That is, the health care services in Korea are maintained, so the degree of mortality and the risk factors related to mortality may be different from those in previous studies. Therefore, we aimed to identify the clinical risk factors for mortality in the COVID-19 patients without health system disruption.

Data collection
The Ministry of Health and Welfare and the Health Insurance Review and Assessment Service (HIRA) of Korea have shared the nationwide data of COVID-19 for global research collaboration on COVID-19. The HIRA dataset was based on insurance bene t claims and comprised all cases con rmed as COVID-19 in Korea. This dataset contains various health-related variables such as socio-demographic information, health care utilization including diagnosis, and survival status. This study was approved by the Institutional Review Board of the National Health Insurance Service of Ilsan Hospital, and the study adhered to the tenets of the Declaration of Helsinki (NHIMC 2020-05-002). The need for written informed consent was waived as the patient identi cation data were deleted from the database used.

De nition
Patients with COVID-19 were de ned by the following diagnostic codes using the HIRA dataset: corona virus infection (B342); coronavirus as the cause of diseases classi ed into other chapters (B972); domestic temporary designation or emergency use of new diseases (B18); novel coronavirus infection (U181); coronavirus disease 2019 (U071). All patients with COVID-19 were con rmed by RT-PCR test.
The clinical characteristics of the population were obtained when the COVID-19 diagnosis was con rmed.

Statistical analysis
Descriptive statistics were performed for all variables. Differences between the two groups were assessed using the chi-squared test for categorical variables. Multiple logistic regression analysis was performed to estimate the odds ratio (OR) and 95% con dence intervals (CIs) for factors that independently related mortality. A p-value < 0.05 was considered statistically signi cant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results
Baseline characteristics of the population tested for COVID-19.
Between January 3 and June 1, 2020, a total of 7,333 patients were diagnosed with COVID-19. Of these, 2,966 (40.4%) were male patients ( Table 1). The median age of the patients was 48.0 years (min, max; 19, 98). The most common age group was 18-35 years, and 18.3% of the patients were 65 years old. The number of patients living in Daegu and Gyeongsangbuk-do province, which had a large outbreak of COVID-19, was 4,025 (54.9 %), and the number of Medical Aid bene ciaries was 619 (8.4%). A total of 2,472 (33.7%) patients had CCI=0 and 1,799 (24.5%) had CCI ≥3. Among the comorbidities, the most common medical history in patients was hypertension (26.0%), followed by DM (23.0%) and asthma (21.3%).

Comparison between survivor and non-survivor
The comparison of socio-demographic and clinical factors between survivor and non-survivor of patients with COVID-19 is shown in Table 2. In all, 227 (3.1%) patients died. The non-survivor group showed the following characteristics: older age, higher percentage of males, patients con rmed in Daegu and Gyeongsangbuk-do province, and more Medical Aid bene ciaries than in the negative group (P < 0.001).
The non-survivor group also had a higher CCI score compared to the negative group (P < 0.001). All underlying diseases except liver cirrhosis and IBD were more common in the non-survivor group.
Risk factors for mortality of COVID-19 A multivariate logistic regression analysis was performed to identify the risk factors for mortality in patients with COVID-19 (

Discussion
Our study is a nationwide study using the Korean HIRA database to evaluate several risk factors for mortality in adults in patients with COVID-19 in Korea. The mortality rate of patients with COVID-19 was 3.1%. Particularly, male, older age (>65 years), patients diagnosed with a large outbreak area, Medical Aid bene ciaries, higher CCI (≥3), hypertension, COPD, CHF, and ESRD were associated with high odds of mortality.
Previous studies have found that women are less susceptible to viral infection than men (9). Because Xchromosome and sex hormone in uence the innate and adaptive immune responses to a pathogen.
Simultaneously, men are more likely to have underlying diseases. As a result, the proportion of men with mortality is greater than that of women. Old age was a signi cant clinical predictor of mortality in SARS and MERS (10,11). This study con rmed that old age was also associated with death in patients with COVID-19. The age-dependent defects in immunity function and the overproduction of type 2 cytokines could cause a de ciency in control of viral replication and prolonged pro-in ammatory responses and more likely to develop to poor outcomes (12). Daegu and Gyeongsangbuk-do province had the rst large outbreak of COVID-19 in Korea (13). Korea is one of the countries with large outbreak to atten the curve of the newly developed COVID-19. Although it has been performed without block strict speci c areas and shutting down the economy, during this time, a shortage of inpatient beds, healthcare workers, and personal protective equipment in these areas might cause higher mortality rates than in other parts of Korea. In Korea, the Medical Aid system is a public assistance program that provides healthcare bene ts to low-income patients. Medical Aid bene ciaries accounted for 2.9% of all Korea, whereas other Koreans were bene ciaries of National Health Insurance (14). In Korea, the cost of treatment is free of charge after the patients are diagnosed with COVID-19 regardless of the insurance status. In other words, Medical Aid bene ciaries, even if unrelated to the economic status of receiving treatment, fully implicated a risk factor of mortality in this study. Several studies reported that Medical Aid bene ciaries were possibly related to household poverty and had poor health status and a higher risk of chronic diseases compared to National Health Insurance bene ciaries (15). For these reasons, it is thought that Medical Aid Bene ciaries are a risk factor for the mortality Circulatory, endocrine, and respiratory comorbidities were common among patients with COVID-19 in this study. Our ndings have re ected recently published studies in terms of the similarity of comorbidities in patients with COVID-19(16-18). Consistent with previous reports, the percentage of patients with malignancy, ESRD, and IBD was low. These ndings provide further objective evidence, with a larger sample size to consider baseline underlying diseases to evaluate prognosis among patients with COVID-19.
Several existing studies have reported risk factors for poor outcomes (age 65 years, male, hypertension, DM, COPD, malignancy, smoking, and cardiovascular diseases) among patients with COVID-19 admitted to the hospital (2)(3)(4). In our study, some risk factors were the same as those of previous studies, but DM, malignancy, and liver cirrhosis were not risk factors for mortality. Perhaps due to the characteristics of Korean medical services (easy accessibility and National Health Insurance Corporation Checkup), most patients with underlying diseases are diagnosed early and receive treatment; thus, there are many patients with COVID-19 who have less complications or have stable conditions of underlying diseases. In addition, this difference in risk factors is thought to have occurred because all patients diagnosed with COVID-19 were able to receive proper management according to severity free of charge after active rapid testing in Korea.
The clinical signi cance of our study is as follows. First, since large outbreaks become a risk factor for mortality, it is important to prevent large outbreaks in the area by social distancing, wearing masks, early detection through active diagnostic tests, contact tracing, and quarantine. Second, in the case of lowincome patients, the mortality rate is relatively high, therefore, more active social support and interest are required. Third, in general, comorbidity may not exist alone, but two or more comorbidities may exist simultaneously in a patient. A recent study reported that patients with a greater number of comorbidities correlated with poorer clinical outcomes among patients with COVID-19(4). In this study, it was also con rmed that the mortality was signi cantly increased in patients with CCI ≥3.
This study had several limitations. First, all patients did not reach the study outcome or were discharged by the end of the study period. Second, due to the retrospective study design using the Korean HIRA database, all clinical data (symptoms, smoking history, BMI, and laboratory tests) were not available. In addition, the severity of comorbidities at the time of con rmation of COVID-19 could not be evaluated. Third, the diagnosis of comorbidities was based on the ICD-10 code. Therefore, the diagnosis of some comorbidities might not be optimal. Fourth, the Korean health care system was not disrupted, so it is free to use the health care system. ICU and ventilator capacity were not exceeded during the study period. Because the health care system and strategy of COVID-19 in each county are different, the above must be considered when interpreting our ndings.

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In conclusion, this study analyzed the risk factors for progression to mortality in COVID-19 patients. More attention to these risk factors and more personalized and speci c approach are needed to reduce mortality.