key: cord-0970737-yx0lofn7 authors: Kim, Misun; Yoo, Jeong Rae; Heo, Sang Taek; Lee, Hyang Ran; Oh, Hyunjoo title: Clinical Characteristics and Risk Factors for Severe Disease of Coronavirus Disease 2019 in a Low Case Fatality Rate Region in Korea date: 2021-12-16 journal: Infect Chemother DOI: 10.3947/ic.2021.0104 sha: bc10e4c1c9f86b956e0c30073ce50bfdf699f810 doc_id: 970737 cord_uid: yx0lofn7 BACKGROUND: Jeju island had the seventh highest incidence rate of coronavirus disease 2019 (COVID-19) but showed the lowest case fatality rate among 17 provinces of Korea, which may be associated with comorbidities and geographic differences. This study aimed to analyze the epidemiological and clinical characteristics of patients with COVID-19 and evaluate the risk factors for severe COVID-19 in Jeju island, Korea. MATERIALS AND METHODS: All patients with COVID-19 admitted between February 20, 2020, and June 19, 2021, at a single center were retrospectively enrolled in this study. The severity of illness was defined using five categories (asymptomatic, mild, moderate, severe, and critical) according to the National Institute of Health criteria. Then, patients with severe and critical illness were grouped into a severe group, whereas patients with asymptomatic, mild, and moderate illness were grouped into a non-severe group. Multivariate logistic regression analysis was performed using risk factors that were found to be significantly associated with the severe group. RESULTS: This study included 348 patients with a median age was 57 years, and 37.5% were aged 60 or older. Among them, 43.4% were male and 10.9% were asymptomatic, whereas 41.4%, 33.9%, 12.9%, and 1.1% had mild, moderate, severe, and critical illness. The all-cause mortality of patients with COVID-19 was 0.28% (1/348). Among confirmed patients with COVID-19, exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was mainly within Jeju island (75.9%). The mean body mass index was 24.09 ± 4.04 kg/m(2), the median comorbidity index score was low in each group (0 in asymptomatic; 1 in mild; 1 in moderate; 1 in severe; and 2 in critical group, P <0.548). In the multivariable analysis, male sex [odds ratio (OR), 6.37; 95% confidence interval (CI), 2.69 – 15.13; P <0.001], ≥65 years of age (OR, 2.68; 95% CI, 1.18 – 6.10; P <0.019), chronic pulmonary disease (OR, 6.10; 95% CI, 1.40 – 26.61; P = 0.016), and length of fever duration (OR, 1.33; 95% CI, 1.19 – 1.49; P <0.001) were independently associated with severe COVID-19. CONCLUSION: The most relevant risk factors of COVID-19 severity were male sex, older age, underlying chronic lung diseases, and duration of fever during hospitalization. The risk factors for severe COVID-19 were not significantly different from those reported in other studies. However, a lower proportion of the older population among confirmed SARS-CoV-2 cases might contribute to the lower fatality rate than the national rate. The novel coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 transmission mainly occurs through saliva droplets of an infected individual as well as through direct contact with an infected individual or contact with contaminated inanimate objects [1, 2] . Since its emergence, the disease has rapidly spread worldwide. As of September 18, 2021, 226 million confirmed cases, including 4 million deaths, have been reported worldwide, with more than 500,000 new cases diagnosed per day even after the introduction of vaccines for COVID-19 [3] . In Korea, 289,263 cases of COVID-19 were confirmed as of September 20, 2021 , and four nationwide outbreaks -first outbreak (February 2020 -May 2020), second outbreak (August 2020 -November 2020), third outbreak (November 2020 -January 2021), and fourth outbreak (June 2021)-had occurred in Korea (Supplementary Fig. 1A ) [4] . On Jeju island, the first outbreak occurred in December 2020, and the second and third outbreaks occurred in May 2021 -June 2021 and July 2021 -August 2021, respectively, which corresponds to the period when the third and fourth nationwide outbreaks occurred ( Supplementary Fig. 1B) . The trend of confirmed COVID-19 cases on Jeju Island changed as the COVID-19 epidemic continued. Jeju island had its first COVID-19 cases in the spring of 2020 which resulted in a local outbreak; they were two young foreign patients with SARS-CoV-2 (one was asymptomatic, while the other was mild) exposure either from outside Jeju island or abroad. Since November 2020, the patients diagnosed with COVID-19 were mainly inhabitants of Jeju island, and the proportion of seriously ill patients increased. Despite reduction in the sporadic cases in Jeju, the number of patients with COVID-19 in Jeju island increased rapidly in May 2021, with an increase in the number of visitors, resulting in outbreak events in the region. Although the emergence of confirmed patients on the island was initially caused by an influx of infected people from overseas, cases were detected among the inhabitants due to an influx of people from the mainland or due to unknown sources of infection in the community during the first and second outbreaks in Jeju Island [5] . Since the outbreak of COVID-19 on Jeju island, 2,782 cases have been confirmed, and the region had the seventh highest incidence rate in Korea [4] . However, this region had the lowest case fatality rate compared with that of the entire Korea on September 20, 2021 (0.2% for Jeju Island vs. 0.8% for Korea) (Supplementary Fig. 2 , last updated September 20, 2021) [4] . Various factors can be considered to have contributed to the low fatality rate of COVID-19 on Jeju island. In previous studies, patients with advanced age, obesity, and comorbidities (such as hypertension, diabetes, respiratory system disease, and cardiovascular disease) were at a higher risk of developing severe COVID-19 [6, 7] . The prevalence of comorbidities and chronic diseases, such as hypertension and diabetes, was lower among the inhabitants of Jeju island than that among the general population in Korea [8] . Our hospital has been designated to treat high-risk COVID-19 patients. According to the COVID-19 triage protocols of the Jeju local government, regardless of disease severity, SARS-CoV-2-confirmed patients with underlying comorbidities, those aged ≥65, or those with severe COVID-19 are classified as high-risk patients and should be admitted to our hospital. This study aimed to analyze the epidemiological and clinical characteristics of patients with COVID-19 and evaluate factors for low case fatality rate in patients in this region. We performed a retrospective study on patients with COVID-19 at the Jeju National University Hospital in Jeju island, a nationally designated negative pressure isolation ward responsible for treating patients with high-risk COVID-19 in Jeju Province. The analysis was conducted using data from the electronic medical records of the included patients. The study was approved by the Institutional Review Board (IRB) at the Jeju National University Hospital (IRB file no. 2020-10-019). Patients who were admitted for confirmed SARS-CoV-2 infection between February 20, 2020, and June 19, 2021, were eligible to participate in the study. During the study period, 1,230 cases were confirmed to be positive for SARS-CoV-2 through a reverse transcriptase polymerase chain reaction (RT-PCR) on Jeju island. Of these, 827 SARS-CoV-2-confirmed patients were admitted to other hospitals or residential treatment centers, whereas 403 SARS-CoV-2confirmed patients were admitted to our hospital. A total of 348 patients with COVID-19 (≥18 years old) were analyzed in the present study. Patients aged <18 years and those who were admitted to other clinics or residential treatment centers were excluded (Fig. 1) . Demographic and clinical characteristic data, which included the patients' demographics (age, sex, and body mass index), past medical history and comorbidity index score (CCI), source of exposure risk to SARS-CoV-2, symptom presentation, type of oxygen therapy, hospital treatment (inotropics, extracorporeal membrane oxygenation), duration of hospitalization, and mortality, were retrospectively obtained from the registry database. Jeju island (33°0 N, 126°0 E) is the largest island located off the coast of the Korean Peninsula. It has a humid subtropical climate and is warmer than the rest of Korea (daily mean temperature: 15.8 -16.6°C). As of August 2021, the total population of Jeju was 697,108, with 675,883 Korean and 21,225 foreigner residents [8] . There is no land route that connects the Korean Peninsula and Jeju island, and it is only possible to enter and exit by air and sea. SARS-CoV-2 infection was confirmed using nasal and/or oropharyngeal swab RT-PCR. The severity of illness was classified into the following five groups according to the National Institute of Health criteria based on the patient's worst condition during hospitalization: asymptomatic, mild, moderate, severe, and critical [10] . The severe and critical groups were then combined as the severe group, whereas the asymptomatic, mild, and moderate groups were combined as the non-severe group, and the risk factors for the severe group were analyzed. The level of comorbidities for each patient was assessed using the CCI for each previously diagnosed disease. Influx case from outside Jeju Island (mainland) was defined as those patients who had visited other cities in Korea or had contact with confirmed cases in other cities. Patients who had unidentifiable source of infection or had contact with confirmed cases which occurred in large-scale clusters were categorized to have an unknown source of infection [4, 11] . Categorical variables were compared using the chi-square test, and continuous variables were compared using the two-sample t-test and ANOVA. Data for continuous variables are presented as means ± standard deviations or medians and interquartile ranges. Multivariate logistic regression analysis was performed using the risk factors that were found to be significantly associated with the non-severe or severe groups in the univariate analysis. P <0.05 was considered statistically significant in the multivariate analysis. Statistical analyses were performed using SPSS (version 20.0; IBM Corp., Armonk, NY, USA). Overall, 348 patients were included in the study. Duration of fever, median (IQR), days 17 (17 -17 [12, 13] . The monthly percentages of medication used is shown in Fig. 2A . The median hospitalization duration was 10 days (IQR, 10 -14) . There was only one (0.28%) overall and in-hospital case fatality. The mean SARS-CoV-2 RT-PCR cycle threshold (Ct) value was 23.07 ± 6.25, and there was no significant difference between the five groups. There were differences in the mean lymphocyte counts (P <0.001), platelet counts (P <0.001), and levels of aspartate aminotransaminase (P <0.001), alanine aminotransferase (P = 0.016), and C-reactive protein (CRP) (P <0.001) between the groups. Comparisons of laboratory findings between the groups are presented in Table 2 . Until July 2020, our hospital accommodated all confirmed COVID-19 cases in Jeju island. However, as the number of confirmed cases gradually increased from the end of August 2020, the capacity of our hospital became insufficient, and the confirmed cases were distributed to other facilities. Our hospital was assigned to first prioritize high-risk COVID-19 patients, such as patients aged ≥65 with underlying chronic diseases and patients with more severe COVID-19 symptoms. Therefore, the proportion of patients with chronic diseases and with severe or critical COVID-19 is increasing at our hospital. During the study period, no severe or critical cases occurred until July 2020, but increased from August 2020 in Jeju island. The proportion of high-risk groups and patients with severe or critical COVID-19 has increased 723 https://icjournal.org https://doi.org/10.3947/ic.2021.0104 since November 2020. The percentage of severe or critical cases among the COVID-19 confirmed cases admitted at our hospital was 13.3% in August 2020, 21.7% in January 2021, and 18.8% in June 2021. The monthly trend in the COVID-19 case severity is shown in Fig. 2B . In addition, the proportion of the older age group in our hospital became higher than that of the whole Jeju island among COVID-19 confirmed cases. The detailed proportion of each age group nationwide, the whole Jeju island, and our hospital is shown in Fig. 3. Univariable logistic regression analysis with non-severe and severe groups is summarized in Table 3 . Overall, 49 patients were classified into the severe group. In the univariable analysis, the proportion of males (71.4%), patients aged ≥65 years (51.0%), and patients with BMI ≥25 kg/m 2 (56.2%) was higher in the severe group, and the unadjusted odds ratios (OR) were 3.94 (95% CI, 2.03 -7.64), 3.17 (95% CI, 1.70 -5.88), and 1.92 (95% CI, 1.04 -3.56), respectively. The mean BMI was 24.4 kg/m 2 in the non-severe group and 26.4 kg/m 2 in the severe group (P = 0.299). There were significant differences in the signs and symptoms associated with severity, presence of fever (39.8% in the non-severe group vs. 75.5% in the severe group, P <0.001), dyspnea (3.7% in the non-severe group vs. 55.1% in the severe group, P <0.001), cough or sputum (54.8% in the non-severe group vs. 75.5% in the severe group, P <0.001), and duration of fever during hospitalization (1.60 ± 2.68 days in the non-severe group vs. 4.00 ± 3.76 days in the severe group, P <0.001). The SARS-CoV-2 RT-PCR Ct value was not significantly different between the non-severe and severe groups (23.07 ± 6.32 in non-severe group vs. 23.06 ± 5.80 in severe group, P = 0.299). The lymphocyte counts were significantly decreased in the severe group (P = 0.002) compared with that in the non-severe group. The CRP levels and the proportion of patients who used antibiotics were higher in the severe group (P <0.001, respectively) than in the non-severe group. In the multivariable analysis, male sex (OR, 6.37; 95% CI, 2.69 -15.13; P <0.001), age ≥65 years (OR, 2.68; 95% CI, 1.18 - 6.10; P <0.019), and chronic pulmonary disease (OR, 6.10; 95% CI, 1.40 -26.61; P = 0.016) were independently associated with the severe group (Table 4) . However, there were no differences in other underlying comorbidities, exposure and risk of transmission, whether the patients were inhabitants of Jeju island, and BMI. This study details the epidemiological and clinical features of patients with COVID-19 at a single teaching hospital on an isolated island in Korea with low case fatality rate. This study also identified the risk factors of severe symptoms. Of all the patients who were diagnosed with COVID-19 in Jeju island in 2020, 6.1% were from overseas and 31.7% were from areas in Korea other than the Jeju Province. In addition, there was an increase in the incidence 726 https://icjournal.org https://doi.org/10.3947/ic.2021.0104 rate due to unknown sources from the third wave of the nationwide outbreak [11] . In this study, the proportion of native residents of Jeju island and patients exposed to SARS-CoV-2 within Jeju island was 77.1% and 75.9%, respectively. In addition, the percentage of patients aged ≥60 years among the COVID-19 confirmed cases was higher in our hospital than in the whole Jeju island. (37.5% and 19.9%, respectively). These results are thought to be due to the hospitalization of the high-risk COVID-19 patients at our hospital according to the patient assignment policy of Jeju Province, and the older population who were at high-risk was more likely to be Jeju island's residents. Previous studies have reported that COVID-19 is characterized by various clinical manifestations, including common symptoms such as fever, dry cough, dyspnea, muscle ache (myalgia), confusion, headache, sore throat, rhinorrhea, chest pain, diarrhea, nausea/vomiting, conjunctival congestion, nasal congestion, sputum production, fatigue (malaise), hemoptysis, and chill [14] [15] [16] . Moreover, anosmia or ageusia (loss of taste) have been reported as symptoms of COVID-19. The clinical manifestations of the patients in our study are similar to those reported in the previous studies. The risk of COVID-19 is associated with possible comorbidities such as diabetes, osteoporosis, rheumatoid arthritis, substance use, and schizophrenia in Korea [17] , whereas diabetes, hypertension, chronic lower respiratory disease, and chronic kidney disease are associated with severe COVID-19 [6, 7, [18] [19] [20] . A previous large study of 7,590 patients has reported that the most common comorbidity was hypertension (19.3%), followed by chronic pulmonary disease (12.6%) and diabetes (11.9%) [18] , which was also observed in our study; however, the proportion of patients with COVID-19 and comorbidities was lower in our study than that reported in other studies [14, 15, 17, 18] . In a previous study, angiotensin-converting enzyme 2 level was found to be increased in patients with hypertension, diabetes, and chronic obstructive pulmonary disease (COPD), which can increase both the risk and severity of COVID-19 [21] [22] [23] . Recent meta-analyses have identified that cardiovascular diseases and COPD can greatly affect the severity of COVID-19 [20] . In our study, hypertension and diabetes were not significantly associated with severe COVID-19, but chronic pulmonary disease showed a significant association with the severe group. Age of ≥65 years was also a risk factor of severe COVID-19. The proportion of patients aged ≥65 years was 28.4%, which is inconsistent with that reported in other studies (26.6% in Korea vs. 35.2% in Daegu-Gyeongbuk cohort) [14, 15, 19] . However, the percentage of patients aged ≥60 years among SARS-CoV-2 confirmed cases was 19.9% in the whole Jeju island, 25.4% nationwide, and 37.5% at our hospital during the study period (Fig. 3) . The national case fatality rate of Korea during the corresponding period was 1.32%, and 95.1% of case fatalities occurred in the ≥60 years age group [24]. Although not analyzed using statistical methods, the lower number of confirmed cases in the older population are likely to contribute to the lower fatality rate relative to the national rate During the study period, the only COVID-19 mortality in Jeju island occurred at our hospital, and all high-risk and severe COVID-19 confirmed cases in Jeju island were admitted to our hospital. Therefore, it might be meaningful to describe the epidemiologic and clinical characteristics and evaluate the risk factors for severe COVID-19 at our hospital. Furthermore, the results of this study might enable the estimation of risk factors for severe COVID-19 across Jeju island. This study has some limitations. First, this was a retrospective single-center study; therefore, the generalizability of the study findings is limited. Second, the various laboratory values for the analysis of risk for mortality and SARS-CoV-2 Ct values were not serially examined. Third, data for the surge period of the delta variant of SARS-CoV-2 and the completion of full vaccination were not included. Fourth, although we additionally aimed to analyze the factors contributing to the low case fatality rate of COVID-19 in Jeju island, we could not compare the risk factors with those in other areas, except for comparison of age groups. Although this study was conducted among patients admitted at a single hospital, the results of this study regarding the risk factors related to COVID-19 severity and case fatality could be reflective of the entire Jeju island; since all high-risk and severe COVID-19 confirmed cases are assigned to be admitted to our hospital, and the comorbidity and severity of our hospital are higher than that of all patients in Jeju island. In conclusion, this study reports the epidemiology and characteristics of patients with COVID-19 in an isolated region in Korea. The case fatality rate was 0.2% (1/348), and the risk factors for severe and critical COVID-19 were male sex, older age, chronic pulmonary disease, and fever duration during hospitalization. COVID-19: A review on the novel coronavirus disease evolution, transmission, detection, control and prevention Clinical characteristics of COVID-19 Coronavirus disease 2019 (COVID-19) situation report. 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ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19 Comparison of comorbidities in relation to critical conditions among coronavirus disease 2019 patients: A network meta-analysis Current status of COVID-19 outbreaks and vaccinations in Korea We sincerely appreciate the team of the department of infection control unit in Jeju National University Hospital. The outbreaks in nationwide (A) and in Jeju Island (B). The figure was produced based on the Jeju Center for Infection Control, the Jeju Provincial Office press release, and the Korea Disease Control and Prevention Agency press release.