Prognostic Factors for Severe Coronavirus Disease 2019 in Daegu, Korea

Jong Geol Jang; Jian Hur; Eun Young Choi; Kyung Soo Hong; Wonhwa Lee; June Hong Ahn

doi:10.3346/jkms.2020.35.e209

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Jang, Hur, Choi, Hong, Lee, and Ahn: Prognostic Factors for Severe Coronavirus Disease 2019 in Daegu, Korea

Original Article

Infectious Diseases, Microbiology & Parasitology

Journal of Korean Medical Science 2020; 35(23): e209.

Published online: 2 June 2020

DOI: https://doi.org/10.3346/jkms.2020.35.e209

Prognostic Factors for Severe Coronavirus Disease 2019 in Daegu, Korea

Jong Geol Jang¹

, Jian Hur²

, Eun Young Choi¹

, Kyung Soo Hong¹

, Wonhwa Lee³

, June Hong Ahn¹

¹Division of Pulmonology and Allergy, Department of Internal Medicine, Regional Center for Respiratory Diseases, Yeungnam University Medical Center, College of Medicine, Yeungnam University, Daegu, Korea.

²Division of Infection, Department of Internal Medicine, Yeungnam University Medical Center, College of Medicine, Yeungnam University, Daegu, Korea.

³Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

Address for Correspondence: Wonhwa Lee, PhD. Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea. wonhwalee@kribb.re.kr

June Hong Ahn, MD, PhD. Division of Pulmonology and Allergy, Department of Internal Medicine, Regional Center for Respiratory Diseases, Yeungnam University Medical Center, College of Medicine, Yeungnam University, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea. fireajh@gmail.com

Received 2 May 2020 Accepted 28 May 2020

The Korean Academy of Medical Sciences

(open-access, https://creativecommons.org/licenses/by-nc/4.0/):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Since its first detection in December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infection has spread rapidly around the world. Although there have been several studies investigating prognostic factors for severe COVID-19, there have been no such studies in Korea.

Methods

We performed a retrospective observational study of 110 patients with confirmed COVID-19 hospitalized at a tertiary hospital in Daegu, Korea. Demographic, clinical, laboratory, and outcome data were collected and analyzed. Severe disease was defined as a composite outcome of acute respiratory distress syndrome, intensive care unit care, or death.

Results

Diabetes mellitus (odds ratio [OR], 19.15; 95% confidence interval [CI], 1.90–193.42; P = 0.012), body temperature ≥ 37.8°C (OR, 10.91; 95% CI, 1.35–88.36; P = 0.025), peripheral oxygen saturation < 92% (OR, 33.31; 95% CI, 2.45–452.22; P = 0.008), and creatine kinase-MB (CK-MB) > 6.3 (OR, 56.84; 95% CI, 2.64–1,223.78, P = 0.010) at admission were associated with higher risk of severe COVID-19. The likelihood of development of severe COVID-19 increased with an increasing number of prognostic factors.

Conclusion

In conclusion, we found that diabetes mellitus, body temperature ≥ 37.8°C, peripheral oxygen saturation < 92%, and CK-MB > 6.3 are independent predictors of severe disease in hospitalized COVID-19 patients. Appropriate assessment of prognostic factors and close monitoring to provide the necessary interventions at the appropriate time in high-risk patients may reduce the case fatality rate of COVID-19.

Graphical Abstract

Keywords: COVID-19, Severe Disease, Prognostic Factor, Korea

INTRODUCTION

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 in Wuhan, Hubei Province, China.1 This disease has spread rapidly to other regions around the world, including the Western Pacific, Europe, Eastern Mediterranean, Americas, and Southeast Asia. The World Health Organization declared COVID-19 a pandemic on March 12, 2020. By April 19, 2020, approximately 2.28 million cases had been diagnosed with 155,124 deaths worldwide.

Although 81% of COVID-19 cases are mild, 14% are severe, and 5% are critical. The fatality rate is about 50.0% in critical cases.2 A number of factors associated with severe COVID-19 have been identified from China. Older age, male sex, presence of comorbidities, low oxygen saturation, and abnormal lab findings (high lactate dehydrogenase [LDH], high procalcitonin, low CD4 cell count, low albumin level) were shown to be risk factors for severe COVID-19.3 4 5 6 7 8

However, patient- and disease-related factors vary from region to region, and these factors may be associated with the clinical severity of COVID-19. There have been no studies regarding prognostic factors for severe disease in COVID-19 patients in Korea. This study was performed to identify prognostic factors for severe disease in patients with COVID-19 in Daegu, Korea.

METHODS

Study design and participants

This was a retrospective observational study of 110 patients with confirmed COVID-19 at Yeungnam University Medical Center, Daegu, Korea, from February 19, 2020 to April 15, 2020. During the study period, all adult patients (age ≥ 18 years) with COVID-19 who were hospitalized via the emergency room or outpatient department were eligible for inclusion.

Data collection and definitions

Demographic, clinical, laboratory, treatment, and outcome data were collected from the electronic medical records of the participants. Demographic and clinical data included age, sex, comorbidities, symptoms and vital signs on admission, and treatment in the hospital. Laboratory data consisted of complete blood count, blood biochemistry, and infection-related biomarkers. Peripheral oxygen saturation was measured by pulse oximetry immediately on hospitalization of the patient. In-hospital case fatality rate was monitored until the final date of follow-up. The data were collected and analyzed by all authors.

Severe disease was defined as a composite outcome of acute respiratory distress syndrome (ARDS), intensive care unit care, or death. ARDS was diagnosed according to the Berlin definition.9 SARS-CoV-2 infection was confirmed by real-time reverse transcription polymerase chain reaction assay of nose and/or throat swap samples.

Statistical analysis

Continuous variables are expressed as means ± standard deviation and were compared by Student's t-test or the Mann-Whitney U test. Categorical variables are described as number (%) and were compared by the χ² test or Fisher's exact test. Univariable logistic regression analysis was performed to identify prognostic factors of severe COVID-19. Multivariable logistic regression analysis was conducted with variables that showed P < 0.05 in univariable analysis. We excluded variables from the univariable analysis if the number of events was too small for calculation and if there was no marked difference between two groups. In all analyses, two-tailed P < 0.05 was taken to indicate statistical significance. All statistical analyses were performed using SPSS software (ver. 24.0; SPSS Inc., Chicago, IL, USA).

Ethics statement

This study was conducted in accordance with the tenets of the Declaration of Helsinki and was reviewed and approved by the Institutional Review Board (IRB) of Yeungnam University Hospital (YUH IRB 2020-03-057). The requirement for informed consent was waived because of the retrospective study design. The final follow-up date was April 15, 2020.

RESULTS

Demographic and clinical characteristics

After excluding seven patients who were transferred to other hospitals, 110 hospitalized patients with confirmed COVID-19 were included in this study (Fig. 1). Baseline characteristics of all patients are summarized in Table 1. The mean age was 56.9 ± 17.0 and 62 patients (56.4%) were women. Forty-nine patients (44.5%) had comorbidities, of which hypertension was the most common (33.6%) followed by diabetes mellitus (26.4%). The most frequently presenting symptoms were fever (56.4%) and cough (52.7%).

Fig. 1

Flow chart.

COVID-19 = coronavirus disease 2019.

Table 1

Baseline characteristics of the study participants with COVID-19

Characteristics		All patients (n = 110)	Severe patients (n = 23)	Non-severe patients (n = 87)	P value
Age, yr		56.9 ± 17.0	68.0 ± 11.9	53.9 ± 17.0	< 0.001
Sex					0.051
	Male	48 (43.6)	14 (60.9)	34 (39.1)
	Female	62 (56.4)	9 (39.1)	53 (60.9)
Comorbidities		49 (44.5)	13 (57)	36 (57)	0.144
	Cardiovascular disease	10 (9.1)	1 (4.3)	9 (10.3)	0.352
	Cerebrovascular disease	4 (3.6)	1 (4.3)	3 (3.4)	0.614
	Chronic lung disease	4 (3.6)	2 (8.7)	2 (2.3)	0.192
	Dementia	4 (3.6)	2 (8.7)	2 (2.3)	0.614
	Diabetes mellitus	29 (26.4)	14 (60.9)	15 (17.2)	< 0.001
	Hypertension	37 (33.6)	12 (52.2)	25 (28.7)	0.033
	Connective tissue disease	1 (0.9)	0 (0)	1 (1.1)	0.791
	Liver disease	1 (0.9)	0 (0)	1 (1.1)	0.192
	Malignancy	6 (5.5)	1 (4.3)	5 (5.7)	0.633
	Parkinson's disease	1 (0.9)	0 (6.7)	1 (1.1)	0.209
Symptoms on admission
	Fever	62 (56.4)	14 (60.9)	48 (55.2)	0.402
	Cough	58 (52.7)	10 (43.4)	48 (55.2)	0.222
	Sputum	38 (34.5)	6 (26.1)	32 (36.8)	0.241
	Dyspnea	37 (33.6)	13 (56.5)	24 (27.6)	0.010
	Diarrhea	11 (10.0)	1 (4.3)	10 (11.5)	0.453
	Nausea/vomiting	3 (2.7)	1 (4.3)	2 (2.3)	0.509
	Sore throat	13 (11.8)	0 (0)	13 (14.9)	0.066
	Chest pain	5 (4.5)	0 (0)	5 (5.7)	0.582
	Altered smell or taste loss	0 (0)	0 (0)	0 (0)	1.000
	Skin lesion	1 (0.9)	1 (4.3)	0 (0)	0.209
Vital signs on admission
	Body temperature, °C	37.2 ± 0.7	37.9 ± 1.0	37.3 ± 0.7	0.002
	Heart rate, beats/min	86.0 ± 13.8	87.6 ± 12.7	85.5 ± 14.1	0.532
	Respiratory rate	21.0 ± 2.8	23.1 ± 4.7	20.4 ± 1.7	0.013
	Systolic BP, mmHg	128.1 ± 18.6	134.9 ± 18.6	126.3 ± 18.4	0.058
	Peripheral oxygen saturation, %	94.1 ± 5.7	87.7 ± 7.4	95.8 ± 3.6	< 0.001
Radiologic findings
	Chest X-ray only	34 (30.9)	6 (26.1)	28 (32.2)
	Chest X-ray and CT	76 (69.1)	17 (73.9)	59 (67.8)
	Unilateral pneumonia	17 (15.5)	1 (4.3)	16 (18.4)	0.078
	Bilateral pneumonia	46 (41.8)	13 (56.5)	33 (37.9)
	Multiple ground-glass opacity	39 (35.5)	9 (39.1)	30 (34.5)
Treatment in hospital
	Antibiotics	108 (98.2)	23 (100)	85 (97.7)	0.624
	Lopinavir/ritonavir	106 (96.4)	22 (95.7)	84 (96.6)	0.614
	Hydroxychloroquine	91 (82.7)	23 (100)	68 (78.2)	0.011
	Glucocorticoid	21 (19.1)	15 (65.2)	6 (16.6)	< 0.001
Clinical outcomes
	Death	8 (7.3)	8 (34.8)	0 (0)	1.000
Causes of mortality
	Respiratory failure	4 (3.6)	4 (17.4)	0 (0)	1.000
	Septic shock	4 (3.6)	4 (17.4)	0 (0)	1.000

Data are presented as the mean ± standard deviation or number (%).

COVID-19 = coronavirus disease 2019, BP = blood pressure, CT = computed tomography.

The patients in the severe group were significantly older than the patients in the non-severe group (68.0 ± 11.9 vs. 53.9 ± 17.0, respectively, P < 0.001). The severe group was significantly more likely to have diabetes mellitus (60.9% vs. 17.2%, respectively, P = 0.001) and hypertension (52.2% vs. 28.7%, respectively, P = 0.033). On admission, body temperature (37.9°C ± 1.0°C vs. 37.3°C ± 0.7°C, respectively, P = 0.002) and respiration rate (23.1 ± 4.7 vs. 20.4 ± 1.7 breaths per minute, respectively, P = 0.013) were significantly higher in the severe group than the non-severe group. Peripheral oxygen saturation was significantly lower in the severe group than the non-severe group (87.7 ± 7.4 vs. 95.8 ± 3.6, respectively, P < 0.001). It was difficult to detect meaningful differences in radiologic findings between patients in the severe group and those who were not.

Laboratory findings

Laboratory findings on hospital admission are summarized in Table 2. In complete blood counts, white blood cell count (8.2 ± 3.4 vs. 6.3 ± 3.2, respectively, P = 0.017) and neutrophil count (7.1 ± 3.4 vs. 4.1 ± 3.0, respectively, P < 0.001) were higher in the severe group than the non-severe group. Lymphocyte count (0.7 ± 0.3 vs. 1.6 ± 0.7, respectively, P < 0.001) and platelet count (184.7 ± 75.3 vs. 259.8 ± 104.6, respectively, P = 0.002) were significantly lower in the severe group than the non-severe group. With regard to blood chemistry, albumin level was significantly lower in the severe group than the non-severe group (3.1 ± 0.4 vs. 3.9 ± 0.5 g/dL, respectively, P < 0.001). Concentrations of aspartate aminotransferase, total bilirubin, blood urea nitrogen, LDH, and creatine kinase-MB (CK-MB) were significantly higher in the severe group than the non-severe group. With regard to infection-related markers, C-reactive protein level was significantly higher in the severe group than the non-severe group (15.5 ± 8.8 vs. 3.3 ± 6.2 mg/L, respectively, P < 0.001), although procalcitonin level was not significantly different between the two groups (2.2 ± 5.6 vs. 0.1 ± 0.1 ng/mL, respectively, P = 0.094). Three cases of bacterial co-infection (2 cases of Klebsiella pneumonia, 1 case of Clostridium difficile) were identified in the non-severe group. Duration of viral shedding was not different between the two groups.

Table 2

Laboratory findings on admission in patients with COVID-19

Variables			All patients (n = 110)	Severe group (n = 23)	Non-severe group (n = 87)	P value
Complete blood count (normal range)
	White blood cell count, ×10⁹/L (4–10)		6.7 ± 3.3	8.2 ± 3.4	6.3 ± 3.2	0.017
		< 4	16 (14.5)	1 (4.3)	15 (17.2)	0.007
		4–10	81 (73.6)	15 (65.2)	66 (75.9)
		> 10	13 (11.8)	7 (30.4)	6 (6.9)
	Neutrophil count, ×10⁹/L (1.8–6.3)		4.7 ± 3.3	7.1 ± 3.4	4.1 ± 3.0	< 0.001
		> 6.3	24 (21.8)	13 (56.5)	11 (12.6)	< 0.001
	Lymphocyte count, ×10⁹/L (1.1–3.2)		1.4 ± 0.7	0.7 ± 0.3	1.6 ± 0.7	< 0.001
		< 0.8	24 (21.8)	15 (65.2)	9 (10.3)	< 0.001
	Hemoglobin, g/dL (12–16)		13.0 ± 1.5	13.2 ± 1.8	12.9 ± 1.4	0.385
		< 12	22 (20.0)	4 (17,4)	18 (20.7)	0.491
	Platelets, ×10⁹/L (140–440)		244.1 ± 103.5	184.7 ± 75.3	259.8 ± 104.6	0.002
		< 140	19 (17.3)	10 (43.5)	9 (10.3)	< 0.001
Blood chemistry (normal range)
	Albumin, g/dL (3.5–5)		3.7 ± 0.6	3.1 ± 0.4	3.9 ± 0.5	< 0.001
		< 3.5	38 (35.2)	20 (87)	18 (21.2)	< 0.001
	Alanine aminotransferase, IU/L (0–40)		36.6 ± 46.6	54.5 ± 84.1	31.9 ± 28.9	0.215
		> 40	31 (28.2)	13 (56.6)	18 (20.7)	0.001
	Aspartate aminotransferase, IU/L (10–35)		45.1 ± 47.8	81.3 ± 83.3	35.5 ± 26.0	0.016
		> 35	29 (26.4)	6 (26.1)	23 (22.9)	0.973
	Total bilirubin, mg/dL (0.1–1.2)		0.9 ± 0.5	1.1 ± 0.6	0.8 ± 0.4	0.014
		> 1.2	18 (16.8)	7 (30.4)	11 (13.1)	0.054
	Blood urea nitrogen, mg/dL (8–23)		15.6 ± 9.0	21.7 ± 15.6	13.9 ± 5.4	0.027
		> 23	13 (11.8)	8 (34.8)	5 (5.7)	0.001
	Creatinine, mg/dL (0.5–0.9)		0.9 ± 0.5	1.1 ± 0.9	0.8 ± 0.2	0.174
		> 0.9	36 (32.7)	11 (47.8)	25 (28.7)	0.083
	Creatinine phosphokinase, IU/L (1–145)		108.4 ± 155.2	152.2 ± 182.0	95.0 ± 145.0	0.150
		> 145	9 (10.6)	4 (20.0)	5 (7.7)	0.127
	Lactate dehydrogenase, IU/L (150–550)		625.9 ± 331.7	996.7 ± 497.3	527.7 ± 171.9	< 0.001
		> 550	51 (48.6)	21 (95.5)	30 (36.1)	< 0.001
	CK-MB, ng/mL (0.6–6.3)		3.2 ± 3.3	5.3 ± 4.1	1.9 ± 1.8	0.003
		> 6.3	7 (15.6)	6 (33.3)	1 (3.7)	0.012
Coagulation function
	Prothrombin time, sec (10.4–13.3)		13.0 ± 17.4	16.3 ± 26.7	10.7 ± 4.2	0.278
		> 13.3	10 (20.4)	7 (35.0)	3 (10.3)	0.068
	D-dimer, μg/mL (0–0.5)		4.4 ± 16.5	8.6 ± 25.3	1.4 ± 1.8	0.029
		> 0.5	29 (76.3)	16 (100.0)	13 (59.1)	0.005
Infection biomarkers (normal range)
	C-reactive protein, mg/dL (0–0.5)		5.8 ± 8.4	15.5 ± 8.8	3.3 ± 6.2	< 0.001
		> 0.5	68 (66.7)	21 (100)	47 (58.0)	< 0.001
	Procalcitonin, ng/mL (0–0.5)		0.49 ± 2.6	2.2 ± 5.6	0.1 ± 0.1	0.094
		> 0.5	7 (6.5)	6 (27.3)	1 (1.2)	< 0.001
	Co-infection
		Bacteria	3 (2.7)	0 (0)	3 (3.4)	1.000
		Other viruses	0	0	0	1.000
	Viral shedding
		Duration of viral shedding, days	33.1 ± 10.0	34.2 ± 10.1	32.9 ± 10.0	0.659

Data are presented as the mean ± standard deviation or number (%).

COVID-19 = coronavirus disease 2019, CK-MB = creatine-kinase MB.

Prognostic factors for severe COVID-19

Multivariable analysis using variables with P < 0.05 in univariable analysis (Table 3) and the final logistic regression model demonstrated that diabetes mellitus (odds ratio [OR], 19.15; 95% confidence interval [CI], 1.90–193.42; P = 0.012), body temperature ≥ 37.8°C (OR, 10.91; 95% CI, 1.35–88.36; P = 0.025), peripheral oxygen saturation < 92% (OR, 33.31; 95% CI, 2.45–452.22; P = 0.008), and CK-MB > 6.3 (OR, 56.84; 95% CI, 2.64–1,223.78; P = 0.010) on admission were associated with greater risk of severe COVID-19 (Table 4). The rates of severe disease increased for patients with diabetes mellitus, body temperature ≥ 37.8°C, peripheral oxygen saturation ≤ 92%, and CK-MB > 6.3 (Fig. 2). The likelihood of development of severe COVID-19 increased with increasing number of prognostic factors (P < 0.001, test for trend) (Fig. 3).

Table 3

Univariable analysis of prognostic factors for severe COVID-19

Prognostic factors		OR (95% CI)	P value
Age, yr		1.07 (1.03–1.11)	0.001
	0–39	Reference
	40–49	0.00 (0.0–0.0)	1.000
	50–59	0.40 (0.03–4.70)	0.463
	60–69	3.46 (0.65–18.29)	0.145
	≥ 70	8.14 (1.57–42.33)	0.013
Male, sex		2.43 (0.95–6.22)	0.065
Diabetes mellitus		7.47 (2.73–20.40)	< 0.001
Hypertension		2.71 (1.06–6.93)	0.038
Body temperature, °C		2.54 (1.35–4.78)	0.004
	< 37.8	Reference
	≥ 37.8	6.36 (2.32–17.43)	< 0.001
Respiratory rate		1.42 (1.14–1.76)	< 0.001
	≤ 20	Reference
	> 20	8.11 (2.94–22.36)	< 0.001
Peripheral oxygen saturation, %		0.75 (0.66–0.85)	< 0.001
	≥ 92	Reference
	< 92	17.71 (5.82–53.87)	< 0.001
Albumin		0.03 (0.01–0.13)	< 0.001
	≥ 3.5	Reference
	< 3.5	24.82 (6.63–92.92)	< 0.001
Total bilirubin		3.19 (1.22–8.35)	0.018
	≤ 1.2	Reference
	> 1.2	2.71 (1.05–7.00)	0.040
CK-MB		1.52 (1.12–2.01)	0.007
	≤ 6.3	Reference
	> 6.3	13.0 (1.41–120.27)	0.024

COVID-19 = coronavirus disease 2019, OR = odds ratio, CI = confidence interval, CK-MB = creatine-kinase MB.

Table 4

Multivariable logistic regression analysis of prognostic factors for severe COVID-19

Prognostic factors		Multivariable model 1^a		Multivariable model 2^b
Prognostic factors		OR (95% CI)	P value	OR (95% CI)	P value
Age, yr
	≥ 70			3.37 (0.26–43.58)	0.352
Male, sex				2.98 (0.23–38.81)	0.404
Diabetes mellitus		6.53 (2.26–18.87)	0.001	19.15 (1.90–193.42)	0.012
Hypertension		1.44 (0.49–4.26)	0.508	1.00 (0.09–10.78)	0.999
Body temperature ≥ 37.8°C		8.27 (2.62–26.09)	< 0.001	10.91 (1.35–88.36)	0.025
Peripheral oxygen saturation < 92%		15.39 (4.83–48.98)	< 0.001	33.31 (2.45–452.22)	0.008
Albumin < 3.5		27.21 (6.98–106.10)	< 0.001	5.36 (0.49–59.32)	0.171
Total bilirubin > 1.2		2.53 (0.92–6.97)	0.073	5.92 (0.69–51.01)	0.106
CK-MB > 6.3		13.00 (1.41–120.27)	0.024	56.84 (2.64–1,223.78)	0.010

COVID-19 = coronavirus disease 2019, OR = odds ratio, CI = confidence interval, CK-MB = creatine-kinase MB.

^aAdjusted for age, sex; ^bAdjusted for age, sex, diabetes mellitus, hypertension, body temperature, peripheral oxygen saturation, albumin, total bilirubin, and CK-MB.

Fig. 2

Comparison of rates of severe COVID-19 using categorical variables.

DM = diabetes mellitus, COVID-19 = coronavirus disease 2019, CK-MB = creatine-kinase MB.

Fig. 3

Rate of patients with severe COVID-19 according to the presence of prognostic factors.

COVID-19 = coronavirus disease 2019.

DISCUSSION

Among the 110 patients with COVID-19, 23 (20.9%) had severe disease and the in-hospital case fatality rate was 7.3% in this study. We showed that the presence of diabetes mellitus, body temperature ≥ 37.8°C, peripheral oxygen saturation < 92%, and CK-MB > 6.3 were independent predictors of severe disease in hospitalized COVID-19 patients. To our knowledge, this is the first study to evaluate the prognostic factors of severe COVID-19 in Korea.

Diabetes mellitus is a major public health issue, with an estimated global prevalence of 9.3% in 2019.10 A population-based cohort study showed that type 2 diabetes increased the risk of death associated with pneumonia, and hyperglycemia on admission was associated with increased mortality for both diabetic and nondiabetic patients with community-acquired pneumonia.11 Yang et al.12 reported that diabetes and ambient hyperglycemia are independent risk factors for death and morbidity in SARS patients. Diabetes also results in immune dysregulation and more severe and prolonged lung pathology in Middle East respiratory syndrome.13 The main mechanisms underlying the poorer clinical outcomes in cases of infections associated with diabetes mellitus are as follows: 1) decreased T lymphocyte response; 2) decreased neutrophil function; 3) disorders of humoral immunity; and 4) depression of the antioxidant system.14 In a recent study, COVID-19 patients without other comorbidities but with diabetes were shown to be at greater risk of severe disease as assessed by organ damage, inflammatory factors, and hypercoagulability. In addition, COVID-19 patients with diabetes are at high risk for disease progression.15 The results of the present study suggested that the progression of COVID-19 is influenced by diabetes mellitus. Physicians should pay close attention to whether diabetic patients with COVID-19 show rapid clinical deterioration.

Body temperature is one of the variables included in the pneumonia severity index16 and systemic inflammatory response syndrome (SIRS),17 which can predict clinical outcomes in pneumonia. The febrile response is thought to be mediated by endogenous factors, called endogenous pyrogens. Pyrogenic cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and interferons (IFNs), are released in response to exogenous stimuli, such as bacterial or viral products and toxins.18 In COVID-19, the levels of the proinflammatory cytokines IL-1β, IL-4, IL-6, IL-10, IFN-γ, and TNF-α are significantly higher in severe cases than in mild cases.19 The results of the present study suggested that critical COVID-19 patients have elevated levels of inflammatory cytokines, which increase body temperature.

Low peripheral oxygen saturation was shown to be an independent prognostic factor for severe COVID-19.8 Many COVID-19 patients experience rapid respiratory failure and hypoxemia without any signs of dyspnea, which is referred to as silent hypoxemia.20 This unique characteristic of COVID-19 makes it difficult to predict clinical deterioration accurately using traditional scores, such as quick sequential organ failure assessment and SIRS. As COVID-19 is a highly contagious infectious disease, medical staff tend to have less contact with patients. Therefore, the discovery of a worsening condition in patients may be delayed. From this viewpoint, peripheral oxygen saturation measured immediately upon hospitalization through pulse oximetry can be used as a convenient and accurate marker for the prediction of clinical deterioration in COVID-19.

Cardiac injury is associated with death, and severity of COVID-19 is associated with acute cardiac injury. In the systemic review of the 28 studies with 4,189 confirmed COVID-19 patients, severe COVID-19 infection was associated with high cardiac injury related markers, such as troponin, CK-MB, and myoglobin. And also cardiac injury in COVID-19 were related with higher mortality (OR, 3.85; 95% CI, 2.13–6.96; P < 0.001).21 It has been known that, the SARS-CoV-2 invades human cells via the receptor angiotensin converting enzyme II (ACE2). ACE2 is expressed in the lung, heart, esophagus, kidney, bladder, and ileum. Thus, organs that express ACE2 are vulnerable to SARS-CoV-2 infection.22 Therefore, the measurement of cardiac damage markers on admission is needed in patients with COVID-19, which predict the prognosis of COVID-19.

There are several Chinese studies demonstrating the risk factors for severity of COVID-19. Li et al.5 reported that elder age, hypertension, high cytokine levels, and high LDH levels were associated with severe COVID-19 inpatients in Wuhan. A study in Anhui, China revealed that low fingertip oxygen saturation, and decreased CD4 cell count were independent risk factors for severe COVID-19 patients.8 Diabetes, and maximum body temperature admission were risk factors for progression of COVID-19.15 23 The predictors of severe disease progression on Korean patients and those in Chinese patients were not much different.

This study had several limitations. First, this was a retrospective study conducted in a single center in Korea, which subjected only hospitalized patients. Therefore, these results cannot be generalized to all COVID-19 patients. Second, antiviral agents and corticosteroid usage were not included as variables in this study. Our research focused on the baseline clinical characteristics and laboratory findings related to worsening of the patients' condition due to severe disease and not on treatment. Third, selection bias could not be avoided because population-based data were not used. The disease severity of patients may vary between hospitals in the same region. Fourth, proinflammatory cytokines and early CD8+ T-cell response that can be associated with disease severity, were not measured in this study.

In conclusion, we found that the presence of diabetes mellitus, body temperature ≥ 37.8°C, peripheral oxygen saturation < 92%, and CK-MB > 6.3 are independent predictors of severe disease in hospitalized COVID-19 patients. The likelihood of progression to severe COVID-19 increased with an increasing number of prognostic factors. Appropriate assessment of prognostic factors and close monitoring to provide the necessary interventions at the appropriate time in high-risk patients may reduce the case fatality rate of COVID-19.

Notes

Funding: This study was supported by a research grant from the Daegu Medical Association COVID-19 Scientific Committee in 2020.

Disclosure: The authors have no potential conflicts of interest to disclose.

Author Contributions:

Conceptualization: Jang JG, Ahn JH.
Data curation: Jang JG, Hur J, Choi EY, Hong KS, Lee W, Ahn JH.
Investigation: Jang JG, Ahn JH.
Supervision: Hur J, Choi EY, Hong KS, Lee W.
Writing - original draft: Jang JG, Ahn JH.
Writing - review & editing: Jang JG, Ahn JH.

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