Advertisement

Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study

Published:September 10, 2020DOI:https://doi.org/10.1016/j.jinf.2020.08.052

      Keywords

      Lu and colleagues recently reviewed mortality-related risk factors of COVID-19.
      • Lu L.
      • Zhong W.
      • Bian Z.
      • Li Z.
      • Zhang K.
      • Liang B.
      • et al.
      A comparison of mortality-related risk factors of COVID-19, SARS, and MERS: a systematic review and meta-analysis.
      COVID-19 was first reported in Wuhan, China, in December 2019 and subsequently spread globally, leading to a pandemic;
      • Wiersinga W.J.
      • Rhodes A.
      • Cheng A.C.
      • Peacock S.J.
      • Prescott H.C.
      Pathophysiology, transmission, diagnosis, and treatment of coronavirus Disease 2019 (COVID-19): a Review.
      as of August 25, 2020, more than 23 million people worldwide had been confirmed to have COVID-19 infections, and more than 810,000 patients had died.
      Johns Hopkins University and Medicine
      COVID-19 map.
      Although approximately 80% of COVID-19 cases are classified as mild or asymptomatic, 15% of adults infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) developed severe illness and required oxygen supplementation, and an additional 5% progressed to a critical state.
      • Wiersinga W.J.
      • Rhodes A.
      • Cheng A.C.
      • Peacock S.J.
      • Prescott H.C.
      Pathophysiology, transmission, diagnosis, and treatment of coronavirus Disease 2019 (COVID-19): a Review.
      An increasing number of literature indicated the specific risk factors for the progression of severe illness and poor outcomes resulting from COVID-19.
      • Lu L.
      • Zhong W.
      • Bian Z.
      • Li Z.
      • Zhang K.
      • Liang B.
      • et al.
      A comparison of mortality-related risk factors of COVID-19, SARS, and MERS: a systematic review and meta-analysis.
      For example, a recent large-scale study demonstrated that older age and certain clinical conditions (diabetes, respiratory diseases, and heart, kidney, and autoimmune conditions) are risk factors for death from COVID-19.
      • Williamson E.J.
      • Walker A.J.
      • Bhaskaran K.
      • Bacon S.
      • Bates C.
      • Morton C.E.
      • et al.
      OpenSAFELY: factors associated with COVID-19 death in 17 million patients.
      Although there is a limited number of effective therapies to date, the identification of risk factors for disease progression and clinical outcomes is crucial, because it means appropriate care and the proper allocation of medical resources can be timely provided.
      Japan is characterized by a rapidly aging population, with the highest proportion (28.4%) of elderly citizens (65 years and older) worldwide.

      The Japan Times. Elderly citizens accounted for record 28.4% of Japan's population in 2018, data show. 15 September 2019. https://www.japantimes.co.jp/news/2019/09/15/national/elderly-citizens-accounted-record-28-4-japans-population-2018-data-show/(assessed August 25, 2020).

      In Japan, the first case of COVID-19 was reported in mid-January 2020. The first outbreak in Japan occurred on the Diamond Princess cruise ship in February 2020. Since then, the number of COVID-19 patients has increased exponentially. A state of emergency was declared in Tokyo on April 7 and was subsequently lifted on May 25, 2020, due to the decreased number of newly diagnosed COVID-19 cases. Subsequently, the number of COVID-19 cases quickly increased again; more than 63,000 people had been diagnosed with COVID-19, and more than 1200 people had died of COVID-19 in Japan as of August 25, 2020.
      Johns Hopkins University and Medicine
      COVID-19 map.
      A few studies have shown the clinical features or the risk factors for the progression of severe illness and death, in a large number of COVID-19 patients in Japan affected by community transmission, other than the Diamond Princess cruise ship.
      • Tabata S.
      • Imai K.
      • Kawano S.
      • Ikeda M.
      • Kodama T.
      • Miyoshi K.
      • et al.
      Clinical characteristics of COVID-19 in 104 people with SARS-CoV-2 infection on the Diamond Princess cruise ship: a retrospective analysis.
      • Sakurai A.
      • Sasaki T.
      • Kato S.
      • Hayashi M.
      • Tsuzuki S.I.
      • Ishihara T.
      • et al.
      Natural history of asymptomatic SARS-CoV-2 Infection.
      • Kato H.
      • Shimizu H.
      • Shibue Y.
      • Hosoda T.
      • Iwabuchi K.
      • Nagamine K.
      • et al.
      Clinical course of 2019 novel coronavirus disease (COVID-19) in individuals present during the outbreak on the Diamond Princess cruise ship.
      For this retrospective multicenter study, we evaluated the characteristics and prognostic factors of 345 patients with COVID-19, who were admitted to either Keio University Hospital or one of 13 community hospitals located in the Greater Tokyo Area from February 1 to June 19, 2020, to investigate the similarity in these risk factors to those previously reported in an aging country such as Japan. All patients were followed up until June 19, 2020 in the hospital or were discharged before June 19.
      The median age of these patients was 54 years; 198 (57.4%) of the patients were male, and 327 (94.8%) were Japanese (Table 1). Additionally, 167 (48%) had at least one comorbidity, and 17 (6.1%) were obese (defined as a BMI (body mass index) of ≥30 kg/m2). Among various comorbidities, hypertension was the most common (26.1%), followed by diabetes (13.9%) and hyperuricemia (8.1%). The median duration of illness before diagnosis was 5 days. The most common symptoms reported during the observation period were fever (3.0%), followed by cough (48.3%), which were consistent with previous report.
      • Wiersinga W.J.
      • Rhodes A.
      • Cheng A.C.
      • Peacock S.J.
      • Prescott H.C.
      Pathophysiology, transmission, diagnosis, and treatment of coronavirus Disease 2019 (COVID-19): a Review.
      Table 1Clinical characteristics of 345 patients based on the severity of SARS-CoV-2 infection.
      Severity at the end of observationp-valueOutcomesp-value
      Totalnon-severeseverealive at the end of observationdied in hospital
      N345233 (67.5%)112 (32.5%)322 (93.3%)23 (6.7%)
      Age, median (IQR), y54 (32–68)41 (28–58)67 (56–79)<0.000152 (31.25–63)80 (72.5–85)<0.0001
       0–1713130130
       18–2959572590
       30–49826715811
       50–6911067431073
       70–897226465715
       90-93654
      Sex
       Female147 (42.6%)112 (76.2%)35 (23.8%)0.0031139 (94.6%)8 (5.4%)0.516
       Male198 (57.4%)121 (61.1%)77 (38.9%)183 (92.4%)15 (7.6%)
      Current or former smoker117 (38.0%)61 (52.1%)56 (47.9%)<0.0001107 (91.5%)10 (8.5%)0.2523
      Commodities
       Any167 (48.4%)81 (48.5%)86 (51.5%)<0.0001146 (87.4%)21 (12.6%)< 0.0001
       Hypertension90 (26.1%)34 (37.8%)56 (62.2%)<0.000180 (88.9%)10 (11,1%)0.0493
       Diabetes48 (13.9%)21 (43.7%)27 (56.3%)0.000139 (81.3%)9 (18.8%)0.0003
       Cardiovascular disease23 (6.7%)6 (26.1%)17 (73.9%)<0.000117 (73.9%)6 (26.1%)0.0001
       Active malignant disease27 (7.8%)17 (63.0%)10 (37.0%)0.597123 (85.2%)4 (14.8%)0.0771
       Immune-related disease9 (2.6%)4 (44.4%)5 (55.6%)0.13387 (77.8%)2 (22.2%)0.058
      Chronic obstructive pulmonary disease15 (4.3%)1 (6.7%)14 (93.3%)<0.000111 (73.3%)4 (26.7%)0.0015
       Bronchial asthma22 (6.4%)14 (63.6%)8 (36.4%)0.686422 (100%)0 (0%)0.1951
       Hyperuricemia28 (8.1%)10 (35.7%)18 (64.3%)0.000221 (75.0%)7 (25.0%)<0.0001
       Chronic liver disease14 (4.1%)7 (50.0%)7 (50.0%)0.152511 (78.6%)3 (21.4%)0.0238
       Chronic kidney disease17 (4.9%)4 (23.5%)13 (76.5%)<0.000110 (58.8%)7 (41.2%)<0.0001
      Symptoms reported
       Consciousness disorder15 (4.3%)3 (20.0%)12 (80.0%)<0.000110 (66.7%)5 (33.3%)<0.0001
       Fever252 (73.0%)151 (59.9%)101 (40.1%)<0.0001233 (92.5%)19 (7.5%)0.2846
       Cough166 (48.3%)109 (65.7%)57 (34.3%)0.4278156 (94.0%)10 (6.0%)0.635
       Sputum71 (20.6%)43 (60.6%)28 (39.4%)0.146966 (93.0%)5 (7.0%)0.8927
       Sore throat61 (18.2%)48 (88.7%)13 (21.3%)0.034160 (98.4%)1 (1.6%)0.0858
       Rhinorrhoea36 (10.5%)35 (97.2%)1 (2.8%)<0.000136 (100%)0 (0%)0.0969
       Taste disorder69 (21.2%)56 (81.2%)13 (18.8%)0.006869 (100%)0 (0%)0.0141
       Olfactory disorder55 (16.9%)47 (85.5%)8 (14.5%)0.001155 (100%)0 (0%)0.0328
       Shortness of breath95 (28.0%)39 (41.1%)56 (58.9%)<0.000184 (88.4%)11 (11.6%)0.0285
       Diarrhea46 (13.3%)28 (60.9%)18 (39.1%)0.299642 (91.3%)4 (8.7%)0.5535
       Nausea, vomiting16 (4.7%)7 (43.7%)9 (56.3%)0.039214 (87.5%)2 (12.5%)0.3494
       General fatigue133 (39.5%)70 (52.6%)63 (47.4%)<0.0001123 (92.5%)10 (7.5%)0.6834
      Data are expressed as N (%) or median (interquartile range [IQR]). Data were analyzed by χ2 test or by Mann-Whitney U test where appropriate.
      Next, we compared the severe (those who required oxygen supplementation) and non-severe patient groups as well as the living and deceased groups. The number of patients with COVID-19 who required oxygen supplementation was 112 (32.5%), and the number of patients who died in the hospital was 23 (6.7%) (Table 1).
      The risk factors that increased the need for oxygen supplementation were older age, male sex, history of smoking, various comorbidities (hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease [COPD], hyperuricemia, and chronic kidney disease), and specific disease symptoms (consciousness disorder, fever, shortness of breath, nausea/vomiting, and general fatigue) (Table 1).
      Table 1 shows the positive risk factors for COVID-19-related death. We performed univariate analysis of risk factors for severe illness in patients with COVID-19 (not shown). Older age, male sex, a history of smoking, comorbidities (hypertension, diabetes, cardiovascular disease, COPD, hyperuricemia, and chronic kidney disease), and specific disease symptoms (consciousness disorder, fever, shortness of breath, nausea/vomiting, and general fatigue) were positively associated with the need for oxygen supplementation. Subsequently, we performed multivariate analysis of risk factors affecting the need for oxygen supplementation in COVID-19 patients (Table 2). Factors, including COPD (odds ratio [OR] 19.13), consciousness disorder (OR 9.23), shortness of breath (OR 4.74), and general fatigue (OR 3.74), were independently associated with the need for oxygen therapy in COVID-19 patients.
      Table 2Impact of risk factors for patients requiring oxygen therapy and after SARS-CoV-2 infection.
      Risk factors (Oxygen therapy requirement)Odds ratio (95% CI)p-value
      Mulitivariate logistic regression analysis was performed. 95% CI; 95% confidence interval.
      Age group2.24 (1.47–3.43)< 0.001
      Hypertension3.34 (1.54–7.23)0.006
      Chronic obstructive pulmonary disease19.13 (2.14–170.76)0.008
      Consciousness disorder9.23 (1.52–56.18)0.016
      Rhinorrhoea0.05 (0.01–0.44)0.008
      Shortness of breath4.74 (2.31–9.73)<0.001
      General fatigue3.74 (1.84–7.59)<0.001
      Risk factors (death)Odds ratio (95%CI)p-value
      Mulitivariate logistic regression analysis was performed. 95% CI; 95% confidence interval.
      Age group5.43 (2.68–11.01)<0.001
      Hyperuricemia3.60 (1.07–12.09)0.038
      Chronic kidney disease5.74 (1.56–21.07)0.009
      low asterisk Mulitivariate logistic regression analysis was performed.95% CI; 95% confidence interval.
      Univariate analysis of risk factors for death resulting from COVID-19 was performed (not shown). Older age, comorbidities (diabetes, cardiovascular disease, COPD, hyperuricemia, chronic liver disease, and chronic kidney disease), and specific symptoms (consciousness disorder and shortness of breath) were associated with death resulting from COVID-19. We further performed multivariate analysis of risk factors for death associated with SARS-CoV-2 infection (Table 2), and factors, including chronic kidney disease (OR 5.74), older age (OR 5.43), and hyperuricemia (OR 3.60), were independently associated with death resulting from COVID-19.
      Our results demonstrate that chronic kidney disease (CKD), followed by older age and hyperuricemia, are the most common independent risk factors for COVID-19-related death in this study (Table 2). CKD and older age have been previously reported as risk factors for in-hospital death;
      • Williamson E.J.
      • Walker A.J.
      • Bhaskaran K.
      • Bacon S.
      • Bates C.
      • Morton C.E.
      • et al.
      OpenSAFELY: factors associated with COVID-19 death in 17 million patients.
      this is consistent with our data. However, preexisting hyperuricemia has not been previously reported as a risk factor for death resulting from COVID-19; to our knowledge, this is the first study demonstrating that hyperuricemia is an independent risk factor for death in COVID-19 patients. Hyperuricemia is a well-established risk factor for diabetes and CKD;
      • Bardin T.
      • Richette P.
      Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options.
      however, the mechanism underlying the relationship between hyperuricemia and COVID-19-related mortality is unclear. As inflammation and oxidative stress (key status in COVID-19 patients) have been reported as potential causes of higher mortality risks associated with hyperuricemia,
      • Chen P.H.
      • Chen Y.W.
      • Liu W.J.
      • Hsu S.W.
      • Chen C.H.
      • Lee C.L.
      Approximate mortality risks between hyperuricemia and diabetes in the United States.
      the inflammation and oxidative stress induced by SARS-CoV-2 infections likely contributed to this process.
      In conclusion, we have shown the real-world clinical characteristics and risk factors for COVID-19 in the Greater Tokyo Area. Hyperuricemia is a novel risk factor for COVID-related death.

      Declaration of Competing Interest

      None.

      Acknowledgments

      We would like to thank all the members of the K-CORC who participated in this study, including those in Saitama City Hospital, Tokyo Saiseikai Central Hospital, Kawasaki Municipal Ida Hospital, Federation of National Public Service Personnel Mutual Aid Associations Tachikawa Hospital, National Hospital Organization Tokyo Medical Center, Saitama Medical Center, Tokyo Dental College Ichikawa General Hospital, Kitasato Institute Hospital, Keiyu Hospital, Nihon Koukan Hospital, Hino Municipal Hospital, Sano Kousei General Hospital, and Saiseikai Utsunomiya Hospital. We also acknowledge all of the staff who supported us at the 13 hospitals, especially Dr. Shuichi Yoshida, Dr. Shoji Suzuki, Dr. Isano Hase, Dr. Kota Ishioka, Dr. Yasushi Nakano, Dr. Yohei Funatsu, Dr. Tadashi Manabe, Dr. Yoshitaka Oyamada, Dr. Aoi Kuroda, Dr. Akihiro Tsutsumi, Dr. Sohei Nakayama, Dr. Keita Masuzawa, Dr. Tetsuya Shiomi, Dr. Keigo Kobayashi, Dr. Rie Baba, Dr. Takahiro Fukushima, Dr. Taro Shinozaki, Dr. Hiromu Tanaka, Dr. Atsushi Morita, Dr. Shingo Nakayama, Dr. Shuhei Azekawa, Dr. Kensuke Nakagawara, and at Keio University Global Research Institute (KGRI).

      Funding

      This work was supported by the Keio University Global Research Institute (KGRI) COVID-19 Pandemic Crisis Research Grant (to M.I.).

      References

        • Lu L.
        • Zhong W.
        • Bian Z.
        • Li Z.
        • Zhang K.
        • Liang B.
        • et al.
        A comparison of mortality-related risk factors of COVID-19, SARS, and MERS: a systematic review and meta-analysis.
        J Infect. 2020;
        • Wiersinga W.J.
        • Rhodes A.
        • Cheng A.C.
        • Peacock S.J.
        • Prescott H.C.
        Pathophysiology, transmission, diagnosis, and treatment of coronavirus Disease 2019 (COVID-19): a Review.
        JAMA. 2020;
        • Johns Hopkins University and Medicine
        COVID-19 map.
        Johns Hopkins Coronavirus Resource Centre, 2020 (accessed August 25)
        • Williamson E.J.
        • Walker A.J.
        • Bhaskaran K.
        • Bacon S.
        • Bates C.
        • Morton C.E.
        • et al.
        OpenSAFELY: factors associated with COVID-19 death in 17 million patients.
        Nature. 2020;
      1. The Japan Times. Elderly citizens accounted for record 28.4% of Japan's population in 2018, data show. 15 September 2019. https://www.japantimes.co.jp/news/2019/09/15/national/elderly-citizens-accounted-record-28-4-japans-population-2018-data-show/(assessed August 25, 2020).

        • Tabata S.
        • Imai K.
        • Kawano S.
        • Ikeda M.
        • Kodama T.
        • Miyoshi K.
        • et al.
        Clinical characteristics of COVID-19 in 104 people with SARS-CoV-2 infection on the Diamond Princess cruise ship: a retrospective analysis.
        Lancet Infect Dis. 2020;
        • Sakurai A.
        • Sasaki T.
        • Kato S.
        • Hayashi M.
        • Tsuzuki S.I.
        • Ishihara T.
        • et al.
        Natural history of asymptomatic SARS-CoV-2 Infection.
        N Engl J Med. 2020;
        • Kato H.
        • Shimizu H.
        • Shibue Y.
        • Hosoda T.
        • Iwabuchi K.
        • Nagamine K.
        • et al.
        Clinical course of 2019 novel coronavirus disease (COVID-19) in individuals present during the outbreak on the Diamond Princess cruise ship.
        J Infect Chemother. 2020; 26: 865-869
        • Bardin T.
        • Richette P.
        Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options.
        BMC Med. 2017; 15: 123
        • Chen P.H.
        • Chen Y.W.
        • Liu W.J.
        • Hsu S.W.
        • Chen C.H.
        • Lee C.L.
        Approximate mortality risks between hyperuricemia and diabetes in the United States.
        J Clin Med. 2019; 8