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Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nationwide Consortium to Investigate Host Genetics of COVID-19

Open AccessPublished:September 30, 2021DOI:https://doi.org/10.1016/j.ijid.2021.09.070

      Highlights

      • Patients with COVID-19 were recruited from more than 70 institutes in Japan.
      • Japan experienced 3 waves of COVID-19 during the first year of the pandemic.
      • The case fatality rate of 3.2% was relatively low.
      • The data will be used for a genome-wide association study.

      Abstract

      Background and design

      The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19.
      The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date.

      Results

      The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45–71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%.

      Conclusions

      Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.

      Keywords

      The coronavirus disease (COVID-19) pandemic has had a devastating effect worldwide, including in Japan (see https://www.mhlw.go.jp/stf/covid-19/kokunainohasseijoukyou.html)(

      Ministry of Health, Labour and Welfare. 2021 "Situation Report." from https://www.mhlw.go.jp/stf/covid-19/kokunainohasseijoukyou.html. [Accessed June 2021].

      ). Host genome differences between populations may influence disease severity. This may explain why Asians, including Japanese, may have a lower risk of death (
      • Price-Haywood EG
      • et al.
      Hospitalization and mortality among Black patients and White patients with Covid-19.
      ,
      • Zeberg H
      • Pääbo S.
      The major genetic risk factor for severe COVID-19 is inherited from Neanderthals.
      ). The Japan COVID-19 Task Force was established in early 2020 as a nationwide multicenter consortium. We collected and analyzed clinical specimens from patients in more than 70 institutions nationwide since February 2020 and reported the results of a genome-wide association study (

      Namkoong H, et al. "Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan." medRxiv 2021. 10.1101/2021.05.17.21256513

      ).
      This cross-sectional study aimed to determine the clinical characteristics of Japanese patients with COVID-19. The study facilities provide coverage for the most populous prefectural capital cities in Japan. We included 1645 (98.3%) patients with reverse transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19, 10 (0.6%) patients with rapid antigen test-confirmed COVID-19, and 19 (1.1%) patients who were considered as highly suspicious for COVID-19 by the physician. We collected information on patient demographics, laboratory test data, radiographic imaging, treatment, comorbidities, and outcomes for 1674 cases to construct a database for the Japan COVID-19 Task Force. The cases were not limited to inpatients; however, 1668 (99.6%) patients were hospitalized patients. All the patients in this study provided appropriate informed consent, which was approved by the ethics committee of the affiliated institutes. Symptoms and signs included not only those reported on referral or admission but also those observed during hospitalization. Laboratory and radiographic data were collected within 48 hours of the initial visit or admission. Disease outcome during hospitalization was assessed for fatality rate. We obtained information regarding any support using oxygen devices, invasive mechanical ventilation (IMV), and extracorporeal membrane oxygenation (ECMO) during the clinical course to determine the disease severity. In this report, disease severity was defined as follows: most severe, patients requiring support using high-flow oxygen devices, IMV, ECMO, or death; severe, patients requiring support using low-flow oxygen devices; mild, symptomatic patients not requiring oxygen support; asymptomatic, asymptomatic patients not requiring oxygen support ().
      The patients’ clinical characteristics are shown in Table 1. Their median (interquartile range) age was 59 (45–71) years, 66.2% were male, and most patients were Japanese. Comorbidities included hypertension (34.6%), diabetes mellitus (22.9%), coronary artery disease (9.9%), and chronic kidney disease (7.0%). Moreover, 231 cases were categorized as most severe (13.8%), 459 cases as severe (27.4%), 933 cases as mild (55.7%), and 51 cases as asymptomatic (3.0%). The most common symptom was fever (≥37.5°C), which was observed in 79.3% of patients. Cough, sputum, shortness of breath, dysgeusia, and dysosmia were observed in 58.2%, 24.7%, 30.7%, 18.7%, and 17.0% of patients, respectively. Most patients were enrolled in April 2020 (first wave), August 2020 (second wave), and December 2020 (third wave) (Figure 1). Supplementary Table 1 shows the patients’ characteristics in each epidemic. There was a high prevalence of elderly males among patients in the third epidemic. They also had a higher prevalence of comorbidities such as hypertension, diabetes, and chronic kidney disease, and a low prevalence of dysgeusia and dysosmia.
      Table 1Characteristics of 1674 patients with COVID-19 in Japan
      ParametersNumber of patients with dataSubcategoriesn (%) or median and IQR
      Severity
      classification1674
      Asymptomatic51 (3.0)
      Mild933 (55.7)
      Severe459 (27.4)
      Most severe231 (13.8)
      Death at discharge163352 (3.2)
      Age, years167459 (45–71)
      Sex1674
      Male1109 (66.2)
      Female565 (33.8)
      Population1674
      Japanese1629 (97.3)
      Others45 (2.7)
      BMI, kg/m2152523.9 (21.6–26.9)
      Smoking history1547
      Never840 (54.3)
      Previously or currently707 (45.7)
      Chronic medical conditions
      Hypertension1643569 (34.6)
      Diabetes mellitus1654379 (22.9)
      Coronary artery disease1657164 (9.9)
      Malignancy164097 (5.9)
      Autoimmune disease165361 (3.7)
      COPD165167 (4.1)
      Chronic liver disease159253 (3.3)
      Chronic kidney disease1579110 (7.0)
      Symptoms at referral
      Fever (≥37.5°C)16531311 (79.3)
      Cough1648959 (58.2)
      Sputum1642405 (24.7)
      Sore throat1628387 (23.8)
      Rhinorrhea1634232 (14.2)
      Dysgeusia1635305 (18.7)
      Dysosmia1634278 (17.0)
      Shortness of breath1616496 (30.7)
      Fatigue1642811 (49.4)
      Laboratory tests
      WBC [cells/μL]16135200 (4100–6700)
      LDH [IU/L]1634237 (190–314)
      Ferritin [ng/mL]1269376 (171–711)
      KL-6 [U/mL]1213234 (178–350)
      PCT [ng/mL]11650.06 (0.04–0.11)
      CRP [mg/dL]16282.69 (0.51–6.87)
      Radiographic imaging
      Chest radiography findings1556Bilateral thoracic opacities834 (53.6)
      Unilateral thoracic opacities180 (11.6)
      1539Bilateral thoracic consolidation305 (19.8)
      Unilateral thoracic consolidation121 (7.9)
      Chest CT findings1480Bilateral GGO1055 (71.3)
      Unilateral GGO148 (10.0)
      1445Bilateral consolidation465 (32.2)
      Unilateral consolidation110 (7.6)
      Complications after referral
      Bacterial infection1653196 (11.9)
      Heart failure164136 (2.2)
      Thrombosis162359 (3.6)
      COVID-19 treatment
      ICU admission1650314 (19.0)
      Intubation1649183 (11.1)
      ECMO164137 (2.3)
      Antiviral drugs
      1657Favipiravir595 (35.9)
      1645Ritonavir7 (0.4)
      1648Remdesivir311 (18.9)
      Hydroxychloroquine164718 (1.1)
      Tocilizumab1643118 (7.2)
      Systemic corticosteroid1663680 (40.9)
      Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease; CRP, C-reactive protein; CT, computed tomography; ECMO, extracorporeal membrane; GGO, ground glass opacity; ICU, intensive care unit; IQR, interquartile range; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; PCT, procalcitonin; WBC, white blood cell.
      Figure 1
      Figure 1Coronavirus disease (COVID-19) epidemic trend in Japan, from February 2020 to February 2021. The epidemic curve shows the three epidemic waves during 1 year in Japan. Red bar shows the first wave including 89 patients in this study; from April 1 to 28, 2020. Blue bar shows the second wave including 468 patients in this study; from July 1 to September 1, 2020. Green bar shows the third wave including 564 patients in this study; from November 18, 2020 to February 9, 2021. ■ Black bar shows the number of new patients during the period not included in the three epidemic waves. We created this figure using GraphPad Prism 9 (GraphPad Software, San Diego, California).
      Laboratory findings showed an elevated inflammatory response, with median ferritin and C-reactive protein levels of 376 ng/mL and 2.69 mg/dL, respectively. Regarding radiographic findings, 81.3% of patients had ground glass opacity (GGO), and 39.8% had consolidation on chest computed tomography. The bilateral spread of GGOs was generally present during the acute phase of COVID-19.
      A total of 19.0% of patients were admitted to the intensive care unit, 11.1% were intubated, and 2.3% required ECMO. The fatality rate was 3.2%. Complications included bacterial infection and thrombosis in 11.9% and 3.6% of patients, respectively. The most commonly used antivirals were favipiravir and remdesivir, which were used in 35.9% and 18.9% of patients, respectively. Systemic corticosteroids were used in 40.9% of patients, especially in 58.9% of patients in the third epidemic.
      Clinical characteristics of patients in this study were similar to those of other previously reported large-sample studies in Asian populations (
      • Guan WJ
      • et al.
      Clinical characteristics of Coronavirus disease 2019 in China.
      ;
      • Matsunaga N
      • et al.
      Clinical epidemiology of hospitalized patients with COVID-19 in Japan: Report of the COVID-19 REGISTRY JAPAN.
      ). The proportion of male patients was higher in this study than in other studies, which may be due to the relatively high disease severity in males (
      • Chen N
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ). The proportion of patients with comorbidities such as hypertension, diabetes, and chronic kidney disease was higher than that reported in another registry in Japan (
      • Matsunaga N
      • et al.
      Clinical epidemiology of hospitalized patients with COVID-19 in Japan: Report of the COVID-19 REGISTRY JAPAN.
      ). We believe that this finding is due to a large number of patients registered in the third epidemic, unlike the situation in the previously reported registry. Our study suggests that the number of hospitalized older male patients with more comorbidities has gradually increased in Japan during the past year. Compared with the recent meta-analyses in other countries (
      • Macedo A
      • et al.
      COVID-19 fatality rates in hospitalized patients: systematic review and meta-analysis.
      ), we believe that the lower fatality rate in this study and in the previous report (
      • Matsunaga N
      • et al.
      Clinical epidemiology of hospitalized patients with COVID-19 in Japan: Report of the COVID-19 REGISTRY JAPAN.
      ) may be explained by reasons specific to Japan. We consider the possibility that many inpatient cases of our study would have been treated as outpatients in other countries, because in Japan, the public health centers coordinated the hospitalization of many patients, including those with mild disease. The low fatality rate may also reflect the unique genetic characteristics of the Japanese. For example, the effect of DOCK2 on disease severity of COVID-19 has been reported (

      Namkoong H, et al. "Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan." medRxiv 2021. 10.1101/2021.05.17.21256513

      ). Our study had a large group of patients treated with remdesivir, especially in the third epidemic. A relatively high proportion of patients were treated with systemic corticosteroids, based on the results of the RECOVERY trial (
      • Horby P
      • et al.
      Dexamethasone in hospitalized patients with Covid-19.
      ). These treatments may have resulted in a lower fatality rate in this study than that in previous reports.
      With this clinical information, characterization of the host genomic factors in a representative sample of Japanese patients may provide insights into new treatment approaches.

      Funding Source

      This study was supported by AMED (JP20nk0101612, JP20fk0108415, JP21jk0210034, JP21km0405211, and JP21km0405217), JST CREST (JPMJCR20H2), MHLW (20CA2054), Takeda Science Foundation, the Mitsubishi Foundation, and Bioinformatics Initiative of Osaka University Graduate School of Medicine, Osaka University.

      Ethics Approval

      This study was approved by the ethics committee of Keio University School of Medicine (20200061) and affiliated institutes.

      Author Information

      Japan COVID-19 Task Force are composed of more than 70 institutions nationwide in Japan. The members who contributed to the collection and analysis of cases at each institution are shown as coauthors in the following list.
      Hiromu Tanaka1, Ho Lee1, Atsuho Morita1, Ho Namkoong2, Shotaro Chubachi1, Hiroki Kabata1, Hirofumi Kamata1, Makoto Ishii1, Naoki Hasegawa2, Kazuhisa Takahashi3, Norihiro Harada3, Toshio Naito4, Makoto Hiki5,6, Yasushi Matsushita7, Haruhi Takagi3, Ryousuke Aoki8, Ai Nakamura3, Sonoko Harada3,9, Hitoshi Sasano3, Katsunori Masaki1, Shinnosuke Ikemura1, Satoshi Okamori1, Hideki Terai1, Takanori Asakura1, Junichi Sasaki10, Hiroshi Morisaki11, Yoshifumi Uwamino12, Kosaku Nanki13, Yohei Mikami13, Sho Uchida2, Shunsuke Uno2, Rino Ishihara13, Yuta Matsubara13, Tomoyasu Nishimura2,14, Takunori Ogawa1, Toshiro Sato15, Tetsuya Ueda16, Masanori Azuma16, Ryuichi Saito16, Toshikatsu Sado16, Yoshimune Miyazaki16, Ryuichi Sato16, Yuki Haruta16, Tadao Nagasaki16, Yoshinori Yasui17, Yoshinori Hasegawa16, Soichiro Ueda18, Ai Tada18, Masayoshi Miyawaki18, Masaomi Yamamoto18, Eriko Yoshida18, Reina Hayashi18, Tomoki Nagasaka18, Sawako Arai18, Yutaro Kaneko18, Kana Sasaki18, Takashi Ishiguro19, Taisuke Isono19, Shun Shibata19, Yuma Matsui19, Chiaki Hosoda19, Kenji Takano19, Takashi Nishida19, Yoichi Kobayashi19, Yotaro Takaku19, Noboru Takayanagi19, Etsuko Tagaya20, Masatoshi Kawana21, Ken Arimura20, Yasushi Nakamori22, Kazuhisa Yoshiya22, Fukuki Saito22, Tomoyuki Yoshihara22, Daiki Wada22, Hiromu Iwamura22, Syuji Kanayama22, Shuhei Maruyama22, Takanori Hasegawa23, Kunihiko Takahashi23, Tatsuhiko Anzai23, Satoshi Ito23, Akifumi Endo24, Yuji Uchimura25, Yasunari Miyazaki26, Takayuki Honda26, Tomoya Tateishi26, Shuji Tohda27, Naoya Ichimura27, Kazunari Sonobe27, Chihiro Tani Sassa27, Jun Nakajima27, Masumi Ai28, Takashi Yoshiyama29, Ken Ohta29, Hiroyuki Kokuto29, Hideo Ogata29, Yoshiaki Tanaka29, Kenichi Arakawa29, Masafumi Shimoda29, Takeshi Osawa29, Yasushi Nakano30, Yukiko Nakajima30, Ryusuke Anan30, Ryosuke Arai30, Yuko Kurihara30, Yuko Harada30, Kazumi Nishio30, Yoshikazu Mutoh31, Tomonori Sato32, Reoto Takei32, Satoshi Hagimoto32, Yoichiro Noguchi32, Yasuhiko Yamano32, Hajime Sasano32, Sho Ota32, Yusuke Suzuki33, Sohei Nakayama33, Keita Masuzawa33, Tomomi Takano34, Kazuhiko Katayama35, Koji Murakami36, Mitsuhiro Yamada36, Hisatoshi Sugiura36, Hirohito Sano36, Shuichiro Matsumoto36, Nozomu Kimura36, Yoshinao Ono36, Hiroaki Baba37, Rie Baba38, Daisuke Arai38, Takayuki Ogura38, Hidenori Takahashi38, Shigehiro Hagiwara38, Genta Nagao38, Shunichiro Konishi38, Ichiro Nakachi38, Hiroki Tateno39, Isano Hase39, Shuichi Yoshida39, Shoji Suzuki39, Miki Kawada40, Hirohisa Horinouchi41, Fumitake Saito42, Keiko Mitamura43, Masao Hagihara44, Junichi Ochi42, Tomoyuki Uchida44, Ryuya Edahiro45,46, Yuya Shirai45,46, Kyuto Sonehara46,47, Tatsuhiko Naito46, Kenichi Yamamoto46, Shinichi Namba46, Ken Suzuki46, Takayuki Shiroyama45, Yuichi Maeda45, Takuro Nii45, Yoshimi Noda45, Takayuki Niitsu45, Yuichi Adachi45, Takatoshi Enomoto45, Saori Amiya45, Reina Hara45, Toshihiro Kishikawa46,48,50, Shuhei Yamada49, Shuhei Kawabata49, Noriyuki Kijima49, Masatoshi Takagaki49,54, Noa Sasa46,48, Yuya Ueno48, Motoyuki Suzuki48, Norihiko Takemoto48, Hirotaka Eguchi48, Takahito Fukusumi48, Takao Imai48, Munehisa Fukushima48,53, Haruhiko Kishima49, Hidenori Inohara48, Kazunori Tomono51, Kazuto Kato52, Haruhiko Hirata45, Yoshito Takeda45, Atsushi Kumanogoh45,47,54,55, Naoki Miyazawa56, Yasuhiro Kimura56, Reiko Sado56, Hideyasu Sugimoto56, Akane Kamiya57, Naota Kuwahara58, Akiko Fujiwara58, Tomohiro Matsunaga58, Yoko Sato58, Takenori Okada58, Takashi Inoue59, Toshiyuki Hirano59, Keigo Kobayashi59, Hatsuyo Takaoka59, Koichi Nishi60, Masaru Nishitsuji60, Mayuko Tani60, Junya Suzuki60, Hiroki Nakatsumi60, Hidefumi Koh61, Tadashi Manabe61, Yohei Funatsu61, Fumimaro Ito61, Takahiro Fukui61, Keisuke Shinozuka61, Sumiko Kohashi61, Masatoshi Miyazaki61, Tomohisa Shoko62, Mitsuaki Kojima62, Tomohiro Adachi62, Motonao Ishikawa63, Kenichiro Takahashi64, Kazuyoshi Watanabe65, Yoshihiro Hirai66, Hidetoshi Kawashima66, Atsuya Narita66, Kazuki Niwa67, Yoshiyuki Sekikawa67, Hisako Sageshima68, Yoshihiko Nakamura69, Kota Hoshino69, Junichi Maruyama69, Hiroyasu Ishikura69, Tohru Takata70, Takashi Ogura71, Hideya Kitamura71, Eri Hagiwara71, Kota Murohashi71, Hiroko Okabayashi71, Takao Mochimaru72,73, Shigenari Nukaga72, Ryosuke Satomi72, Yoshitaka Oyamada73, Nobuaki Mori74, Tomoya Baba75, Yasutaka Fukui75, Mitsuru Odate75, Shuko Mashimo75, Yasushi Makino75, Kazuma Yagi76, Mizuha Hashiguchi76, Junko Kagyo76, Tetsuya Shiomi76, Kodai Kawamura77, Kazuya Ichikado77, Kenta Nishiyama77, Hiroyuki Muranaka77, Kazunori Nakamura77, Satoshi Fuke78, Hiroshi Saito78, Tomoya Tsuchida79, Shigeki Fujitani80, Mumon Takita80, Daiki Morikawa80, Toru Yoshida80, Takehiro Izumo81, Minoru Inomata81, Naoyuki Kuse81, Nobuyasu Awano81, Mari Tone81, Akihiro Ito82, Toshio Odani83, Masaru Amishima84, Takeshi Hattori84, Yasuo Shichinohe85, Takashi Kagaya86, Toshiyuki Kita86, Kazuhide Ohta86, Satoru Sakagami86, Kiyoshi Koshida86, Morio Nakamura86, Koutaro Yokote87, Taka-Aki Nakada88, Ryuzo Abe88, Taku Oshima88, Tadanaga Shimada88, Kentaro Hayashi89, Tetsuo Shimizu89, Yutaka Kozu89, Hisato Hiranuma89, Yasuhiro Gon89, Namiki Izumi90, Kaoru Nagata90, Ken Ueda90, Reiko Taki90, Satoko Hanada90, Naozumi Hashimoto91, Keiko Wakahara91, Koji Sakamoto91, Norihito Omote91, Akira Ando91, Yu Kusaka92, Takehiko Ohba92, Susumu Isogai92, Aki Ogawa92, Takuya Inoue92, Nobuhiro Kodama93, Yasunari Kaneyama93, Shunsuke Maeda93, Takashige Kuraki94, Takemasa Matsumoto94, Masahiro Harada95, Takeshi Takahashi95, Hiroshi Ono95, Toshihiro Sakurai95, Takayuki Shibusawa95, Yusuke Kawamura96, Akiyoshi Nakayama96, Hirotaka Matsuo96, Yoshifumi Kimizuka97, Akihiko Kawana97, Tomoya Sano97, Chie Watanabe97, Ryohei Suematsu97, Makoto Masuda98, Aya Wakabayashi98, Hiroki Watanabe98, Suguru Ueda98, Masanori Nishikawa98, Ayumi Yoshifuji99, Kazuto Ito99, Saeko Takahashi100, Kota Ishioka100, Yusuke Chihara101, Mayumi Takeuchi101, Keisuke Onoi101, Jun Shinozuka101, Atsushi Sueyoshi101, Yoji Nagasaki102, Masaki Okamoto103,104, Sayoko Ishihara105, Masatoshi Shimo105, Yoshihisa Tokunaga103,104, Masafumi Watanabe106, Sumito Inoue106, Akira Igarashi106, Masamichi Sato106, Nobuyuki Hizawa107, Yoshiaki Inoue108, Shigeru Chiba109, Kunihiro Yamagata110, Yuji Hiramatsu111, Hirayasu Kai110, Satoru Fukuyama112, Yoshihiro Eriguchi113, Akiko Yonekawa113, Keiko Kan-o112, Koichiro Matsumoto112, Kensuke Kanaoka114, Shoichi Ihara114, Kiyoshi Komuta114, Koichiro Asano115, Tsuyoshi Oguma115, Yoko Ito115, Satoru Hashimoto116, Masaki Yamasaki116, Yu Kasamatsu117, Yuko Komase118, Naoya Hida118, Takahiro Tsuburai118, Baku Oyama118, Yuichiro Kitagawa119, Tetsuya Fukuta119, Takahito Miyake119, Shozo Yoshida119, Shinji Ogura119, Minoru Takada120, Hidenori Kanda120, Shinji Abe121, Yuta Kono121, Yuki Togashi121, Hiroyuki Takoi121, Ryota Kikuchi121, Shinichi Ogawa122, Tomouki Ogata122, Shoichiro Ishihara122, Arihiko Kanehiro123,124, Shinji Ozaki123, Yasuko Fuchimoto123, Sae Wada123, Nobukazu Fujimoto124, Kei Nishiyama125, Mariko Terashima126, Satoru Beppu126, Kosuke Yoshida126, Osamu Narumoto127, Hideaki Nagai127, Nobuharu Ooshima127, Mitsuru Motegi128, Akira Umeda129, Kazuya Miyagawa130, Hisato Shimada131, Mayu Endo132, Yoshiyuki Ohira133, Hironori Sagara133, Akihiko Tanaka133, Shin Ohta133, Tomoyuki Kimura133, Yoko Shibata134, Yoshinori Tanino134, Takefumi Nikaido134, Hiroyuki Minemura134, Yuki Sato134, Yuichiro Yamada135, Takuya Hashino135, Masato Shinoki135, Hajime Iwagoe136, Hiroshi Takahashi137, Kazuhiko Fujii137, Hiroto Kishi137, Tomoo Ishii138, Masayuki Kanai139, Tomonori Imamura139, Tatsuya Yamashita139, Masakiyo Yatomi140, Toshitaka Maeno140, Shinichi Hayashi141, Mai Takahashi141, Mizuki Kuramochi141, Isamu Kamimaki141, Yoshiteru Tominaga141, Mitsuyoshi Utsugi142, Akihiro Ono142, Toru Tanaka143, Takeru Kashiwada143, Kazue Fujita143, Yoshinobu Saito143, Masahiro Seike143, Masahiro Kanai144, Ryunosuke Saiki145, Takayoshi Hyugaji146, Eigo Shimizu146, Kotoe Katayama146, Satoru Miyawaki147, Meiko Takahashi148, Fumihiko Matsuda148, Yosuke Omae149, Yasuhito Nannya145, Takafumi Ueno150, Yukinori Okada46,47,55,151, Ryuji Koike152, Yuko Kitagawa153, Katsushi Tokunaga149, Akinori Kimura154, Seiya Imoto146, Satoru Miyano23, Seishi Ogawa145,155,156, Takanori Kanai13, Koichi Fukunaga1
      • 1
        Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
      • 2
        Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
      • 3
        Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
      • 4
        Department of General Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
      • 5
        Department of Emergency and Disaster Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
      • 6
        Department of Cardiovascular Biology and Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
      • 7
        Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
      • 8
        Department of Nephrology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
      • 9
        Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
      • 10
        Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo, Japan
      • 11
        Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.
      • 12
        Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan
      • 13
        Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
      • 14
        Keio University Health Center
      • 15
        Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.
      • 16
        Department of Respiratory Medicine, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan.
      • 17
        Department of Infection Control, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan.
      • 18
        JCHO (Japan Community Health Care Organization) Saitama Medical Center, Internal Medicine, Saitama, Japan.
      • 19
        Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Kumagaya, Japan.
      • 20
        Department of Respiratory Medicine, Tokyo Women's Medical University, Tokyo, Japan.
      • 21
        Department of General Medicine, Tokyo Women's Medical University, Tokyo, Japan.
      • 22
        Department of Emergency and Critical Care Medicine, Kansai Medical University General Medical Center, Moriguchi, Japan.
      • 23
        M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan.
      • 24
        Clinical Research Center, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
      • 25
        Department of Medical Informatics, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
      • 26
        Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
      • 27
        Clinical Laboratory, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
      • 28
        Department of Insured Medical Care Management, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
      • 29
        Fukujuji Hospital, Kiyose, Japan.
      • 30
        Kawasaki Municipal Ida Hospital, Department of Internal Medicine, Kawasaki, Japan.
      • 31
        Department of Infectious Diseases, Tosei General Hospital, Seto, Japan.
      • 32
        Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan.
      • 33
        Department of Respiratory Medicine, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
      • 34
        School of Veterinary Medicine, Kitasato University, Towada, Japan.
      • 35
        Laboratory of Viral Infection I, Department of Infection Control and Immunology, Ōmura Satoshi Memorial Institute & Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
      • 36
        Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
      • 37
        Department of Infectious Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
      • 38
        Saiseikai Utsunomiya Hospital, Utsunomiya, Japan.
      • 39
        Department of Pulmonary Medicine, Saitama City Hospital, Saitama, Japan.
      • 40
        Department of Infectious Diseases, Saitama City Hospital, Saitama, Japan.
      • 41
        Department of General Thoracic Surgery, Saitama City Hospital, Saitama, Japan.
      • 42
        Department of Pulmonary Medicine, Eiju General Hospital, Tokyo, Japan.
      • 43
        Division of Infection Control, Eiju General Hospital, Tokyo, Japan.
      • 44
        Department of Hematology, Eiju General Hospital, Tokyo, Japan.
      • 45
        Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
      • 46
        Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
      • 47
        Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
      • 48
        Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
      • 49
        Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan
      • 50
        Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
      • 51
        Division of Infection Control and Prevention, Osaka University Hospital, Suita, Japan.
      • 52
        Department of Biomedical Ethics and Public Policy, Osaka University Graduate School of Medicine, Suita, Japan.
      • 53
        Department of Otolaryngology and Head and Neck Surgery, Kansai Rosai Hospital, Hyogo, Japan
      • 54
        Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
      • 55
        The Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan.
      • 56
        Department of Respirtory Medicine, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan.
      • 57
        Department of Clinical Laboratory, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan.
      • 58
        Internal Medicine, Internal Medicine Center, Showa University Koto Toyosu Hospital, Tokyo, Japan.
      • 59
        Internal Medicine, Sano Kosei General Hospital, Sano, Japan.
      • 60
        Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
      • 61
        Tachikawa Hospital, Tachikawa, Japan.
      • 62
        Department of Emergency and Critical Care Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
      • 63
        Department of Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
      • 64
        Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
      • 65
        Japan Community Health care Organization Kanazawa Hospital, Kanazawa, Japan.
      • 66
        Department of Respiratory Medicine, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, Kawasaki, Japan.
      • 67
        Department of Generai Internal Medicine, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, Kawasaki, Japan.
      • 68
        Sapporo City General Hospital, Sapporo, Japan.
      • 69
        Department of Emergency and Critical Care Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
      • 70
        Department of Infection Control, Fukuoka University Hospital, Fukuoka, Japan.
      • 71
        Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.
      • 72
        Department of Respiratory Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
      • 73
        Department of Allergy, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
      • 74
        Department of General Internal Medicine and Infectious Diseases, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
      • 75
        Department of Respiratory Medicine, Toyohashi Municipal Hospital, Toyohashi, Japan.
      • 76
        Keiyu Hospital, Yokohama, Japan.
      • 77
        Division of Respiratory Medicine, Social Welfare Organization Saiseikai Imperial Gift Foundation, Inc., Saiseikai Kumamoto Hospital, Kumamoto, Japan.
      • 78
        KKR Sapporo Medical Center, Department of respiratory medicine, Sapporo, Japan.
      • 79
        Division of General Internal Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
      • 80
        Departmet of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
      • 81
        Japanese Red Cross Medical Center, Tokyo, Japan.
      • 82
        Matsumoto City Hostpital, Matsumoto, Japan.
      • 83
        Department of Rheumatology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan.
      • 84
        Department of Respiratory Medicine, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan.
      • 85
        Department of Emergency and Critical Care Medicine, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan.
      • 86
        NHO Kanazawa Medical Center, Kanazawa, Japan.
      • 87
        Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.
      • 88
        Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
      • 89
        Nihon University School of Medicine, Department of Internal Medicine, Division of Respiratory Medicine, Tokyo, Japan.
      • 90
        Musashino Red Cross Hospital, Musashino, Japan.
      • 91
        Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
      • 92
        Ome Municipal General Hospital, Ome, Japan.
      • 93
        Fukuoka Tokushukai Hospital, Department of Internal Medicine, Kasuga, Japan.
      • 94
        Fukuoka Tokushukai Hospital, Respiratory Medicine, Kasuga, Japan.
      • 95
        National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.
      • 96
        Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan.
      • 97
        Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
      • 98
        Department of Respiratory Medicine, Fujisawa City Hospital, Fujisawa, Japan.
      • 99
        Department of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
      • 100
        Department of Pulmonary Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
      • 101
        Uji-Tokushukai Medical Center, Uji, Japan.
      • 102
        Department of Infectious Disease and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka Japan.
      • 103
        Department of Respirology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
      • 104
        Division of Respirology, Rheumatology, and Neurology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.
      • 105
        Department of Infectious Disease, National Hospital Organization Kyushu Medical Center, Fukuoka Japan.
      • 106
        Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.
      • 107
        Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
      • 108
        Department of Emergency and Critical Care Medicine, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
      • 109
        Departmentof Hematology, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
      • 110
        Department of Nephrology, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
      • 111
        Department of Cardiovascular Surgery, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
      • 112
        Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
      • 113
        Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
      • 114
        Daini Osaka Police Hospital, Osaka, Japan.
      • 115
        Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara, Japan.
      • 116
        Department of Anesthesiology and Intensive Care Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
      • 117
        Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
      • 118
        Department of Respiratory Internal Medicine, St. Marianna University School of Medicine, Yokohama-City Seibu Hospital, Yokohama, Japan.
      • 119
        Gifu University School of Medicine Graduate School of Medicine, Emergency and Disaster Medicine, Gifu, Japan.
      • 120
        KINSHUKAI Hanwa The Second Hospital, Osaka, Japan.
      • 121
        Department of Respiratory Medicine, Tokyo Medical University Hospital, Tokyo, Japan.
      • 122
        JA Toride medical hospital, Toride, Japan.
      • 123
        Okayama Rosai Hospital, Okayama, Japan.
      • 124
        Himeji St. Mary's Hospital, Himeji, Japan.
      • 125
        Emergency & Critical Care, Niigata University, Niigata, Japan.
      • 126
        Emergency & Critical Care Center, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
      • 127
        National Hospital Organization Tokyo National Hospital, Kiyose, Japan.
      • 128
        Fujioka General Hospital, Fujioka, Japan.
      • 129
        Department of General Medicine, School of Medicine, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
      • 130
        Department of Pharmacology, School of Pharmacy, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
      • 131
        Department of Respiratory Medicine, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
      • 132
        Department of Clinical Laboratory, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
      • 133
        Department of General Medicine, School of Medicine, International University of
      • 134
        Health and Welfare, Narita Japan.
      • 135
        Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.
      • 136
        Kansai Electric Power Hospital, Osaka, Japan.
      • 137
        Department of Infectious Diseases, Kumamoto City Hospital, Kumamoto, Japan.
      • 138
        Department of Respiratory Medicine, Kumamoto City Hospital, Kumamoto, Japan.
      • 139
        Tokyo Medical University Ibaraki Medical Center, Inashiki, Japan.
      • 140
        Department of Emergency and Critical Care Medicine, Tokyo Metropolitan Police Hospital, Tokyo, Japan.
      • 141
        Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
      • 142
        National hospital organization Saitama Hospital, Wako, Japan.
      • 143
        Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan.
      • 144
        Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
      • 145
        Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
      • 146
        Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
      • 147
        Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
      • 148
        Department of Neurosurgery, Faculty of Medicine, the University of Tokyo, Tokyo, Japan.
      • 149
        Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
      • 150
        Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan.
      • 151
        Department of Biomolecular Engineering, Graduate School of Tokyo Institute of Technology, Tokyo, Japan.
      • 152
        Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
      • 153
        Medical Innovation Promotion Center, Tokyo Medical and Dental University, Tokyo, Japan.
      • 154
        Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
      • 155
        Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan.
      • 156
        Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
      • 157
        Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      We would like to thank all the participants involved in this study, and all the members of Japan COVID-19 Task Force engaging in clinical and research work on COVID-19 every day. All these members contributed to the accumulation of cases in this study.

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