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

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.

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). 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, 2020, Zeberg and Pääbo, 2020). 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., 2021).

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 (World Health Organization, 2020).

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 1.

Characteristics of 1674 patients with COVID-19 in Japan

Parameters	Number of patients with data	Subcategories	n (%) or median and IQR
Severity
classification	1674
		Asymptomatic	51 (3.0)
		Mild	933 (55.7)
		Severe	459 (27.4)
		Most severe	231 (13.8)
Death at discharge	1633		52 (3.2)
Age, years	1674		59 (45–71)
Sex	1674
		Male	1109 (66.2)
		Female	565 (33.8)
Population	1674
		Japanese	1629 (97.3)
		Others	45 (2.7)
BMI, kg/m2	1525		23.9 (21.6–26.9)
Smoking history	1547
		Never	840 (54.3)
		Previously or currently	707 (45.7)
Chronic medical conditions
Hypertension	1643		569 (34.6)
Diabetes mellitus	1654		379 (22.9)
Coronary artery disease	1657		164 (9.9)
Malignancy	1640		97 (5.9)
Autoimmune disease	1653		61 (3.7)
COPD	1651		67 (4.1)
Chronic liver disease	1592		53 (3.3)
Chronic kidney disease	1579		110 (7.0)
Symptoms at referral
Fever (≥37.5°C)	1653		1311 (79.3)
Cough	1648		959 (58.2)
Sputum	1642		405 (24.7)
Sore throat	1628		387 (23.8)
Rhinorrhea	1634		232 (14.2)
Dysgeusia	1635		305 (18.7)
Dysosmia	1634		278 (17.0)
Shortness of breath	1616		496 (30.7)
Fatigue	1642		811 (49.4)
Laboratory tests
WBC [cells/μL]	1613		5200 (4100–6700)
LDH [IU/L]	1634		237 (190–314)
Ferritin [ng/mL]	1269		376 (171–711)
KL-6 [U/mL]	1213		234 (178–350)
PCT [ng/mL]	1165		0.06 (0.04–0.11)
CRP [mg/dL]	1628		2.69 (0.51–6.87)
Radiographic imaging
Chest radiography findings	1556	Bilateral thoracic opacities	834 (53.6)
		Unilateral thoracic opacities	180 (11.6)
	1539	Bilateral thoracic consolidation	305 (19.8)
		Unilateral thoracic consolidation	121 (7.9)
Chest CT findings	1480	Bilateral GGO	1055 (71.3)
		Unilateral GGO	148 (10.0)
	1445	Bilateral consolidation	465 (32.2)
		Unilateral consolidation	110 (7.6)
Complications after referral
Bacterial infection	1653		196 (11.9)
Heart failure	1641		36 (2.2)
Thrombosis	1623		59 (3.6)
COVID-19 treatment
ICU admission	1650		314 (19.0)
Intubation	1649		183 (11.1)
ECMO	1641		37 (2.3)
Antiviral drugs
	1657	Favipiravir	595 (35.9)
	1645	Ritonavir	7 (0.4)
	1648	Remdesivir	311 (18.9)
Hydroxychloroquine	1647		18 (1.1)
Tocilizumab	1643		118 (7.2)
Systemic corticosteroid	1663		680 (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.

Coronavirus 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, 2020; Matsunaga N et al., 2020). 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., 2020). 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., 2020). 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., 2021), we believe that the lower fatality rate in this study and in the previous report (Matsunaga N et al., 2020) 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., 2021). 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, 2021). 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 Hiki^5,6, Yasushi Matsushita⁷, Haruhi Takagi³, Ryousuke Aoki⁸, Ai Nakamura³, Sonoko Harada^3,9, 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 Nishimura^2,14, 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 Edahiro^45,46, Yuya Shirai^45,46, Kyuto Sonehara^46,47, 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 Kishikawa^46,48,50, Shuhei Yamada⁴⁹, Shuhei Kawabata⁴⁹, Noriyuki Kijima⁴⁹, Masatoshi Takagaki^49,54, Noa Sasa^46,48, Yuya Ueno⁴⁸, Motoyuki Suzuki⁴⁸, Norihiko Takemoto⁴⁸, Hirotaka Eguchi⁴⁸, Takahito Fukusumi⁴⁸, Takao Imai⁴⁸, Munehisa Fukushima^48,53, Haruhiko Kishima⁴⁹, Hidenori Inohara⁴⁸, Kazunori Tomono⁵¹, Kazuto Kato⁵², Haruhiko Hirata⁴⁵, Yoshito Takeda⁴⁵, Atsushi Kumanogoh^45,47,54,55, 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 Mochimaru^72,73, Shigenari Nukaga⁷², Ryosuke Satomi^72, 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 Nishikawa^98, Ayumi Yoshifuji⁹⁹, Kazuto Ito⁹⁹, Saeko Takahashi¹⁰⁰, Kota Ishioka¹⁰⁰, Yusuke Chihara¹⁰¹, Mayumi Takeuchi¹⁰¹, Keisuke Onoi¹⁰¹, Jun Shinozuka¹⁰¹, Atsushi Sueyoshi¹⁰¹, Yoji Nagasaki¹⁰², Masaki Okamoto^103,104, Sayoko Ishihara¹⁰⁵, Masatoshi Shimo¹⁰⁵, Yoshihisa Tokunaga^103,104, 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 Kanehiro^123,124, 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 Okada^46,47,55,151, Ryuji Koike¹⁵², Yuko Kitagawa¹⁵³, Katsushi Tokunaga¹⁴⁹, Akinori Kimura¹⁵⁴, Seiya Imoto¹⁴⁶, Satoru Miyano²³, Seishi Ogawa^145,155,156, Takanori Kanai¹³, Koichi Fukunaga¹

• 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
• 2Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
• 3Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
• 4Department of General Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
• 5Department of Emergency and Disaster Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
• 6Department of Cardiovascular Biology and Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
• 7Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
• 8Department of Nephrology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
• 9Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
• 10Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo, Japan
• 11Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.
• 12Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan
• 13Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
• 14Keio University Health Center
• 15Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.
• 16Department of Respiratory Medicine, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan.
• 17Department of Infection Control, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan.
• 18JCHO (Japan Community Health Care Organization) Saitama Medical Center, Internal Medicine, Saitama, Japan.
• 19Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Kumagaya, Japan.
• 20Department of Respiratory Medicine, Tokyo Women's Medical University, Tokyo, Japan.
• 21Department of General Medicine, Tokyo Women's Medical University, Tokyo, Japan.
• 22Department of Emergency and Critical Care Medicine, Kansai Medical University General Medical Center, Moriguchi, Japan.
• 23M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan.
• 24Clinical Research Center, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
• 25Department of Medical Informatics, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
• 26Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
• 27Clinical Laboratory, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
• 28Department of Insured Medical Care Management, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
• 29Fukujuji Hospital, Kiyose, Japan.
• 30Kawasaki Municipal Ida Hospital, Department of Internal Medicine, Kawasaki, Japan.
• 31Department of Infectious Diseases, Tosei General Hospital, Seto, Japan.
• 32Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan.
• 33Department of Respiratory Medicine, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
• 34School of Veterinary Medicine, Kitasato University, Towada, Japan.
• 35Laboratory of Viral Infection I, Department of Infection Control and Immunology, Ōmura Satoshi Memorial Institute & Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
• 36Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
• 37Department of Infectious Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
• 38Saiseikai Utsunomiya Hospital, Utsunomiya, Japan.
• 39Department of Pulmonary Medicine, Saitama City Hospital, Saitama, Japan.
• 40Department of Infectious Diseases, Saitama City Hospital, Saitama, Japan.
• 41Department of General Thoracic Surgery, Saitama City Hospital, Saitama, Japan.
• 42Department of Pulmonary Medicine, Eiju General Hospital, Tokyo, Japan.
• 43Division of Infection Control, Eiju General Hospital, Tokyo, Japan.
• 44Department of Hematology, Eiju General Hospital, Tokyo, Japan.
• 45Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
• 46Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
• 47Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
• 48Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
• 49Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan
• 50Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
• 51Division of Infection Control and Prevention, Osaka University Hospital, Suita, Japan.
• 52Department of Biomedical Ethics and Public Policy, Osaka University Graduate School of Medicine, Suita, Japan.
• 53Department of Otolaryngology and Head and Neck Surgery, Kansai Rosai Hospital, Hyogo, Japan
• 54Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
• 55The Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan.
• 56Department of Respirtory Medicine, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan.
• 57Department of Clinical Laboratory, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan.
• 58Internal Medicine, Internal Medicine Center, Showa University Koto Toyosu Hospital, Tokyo, Japan.
• 59Internal Medicine, Sano Kosei General Hospital, Sano, Japan.
• 60Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
• 61Tachikawa Hospital, Tachikawa, Japan.
• 62Department of Emergency and Critical Care Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
• 63Department of Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
• 64Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
• 65Japan Community Health care Organization Kanazawa Hospital, Kanazawa, Japan.
• 66Department of Respiratory Medicine, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, Kawasaki, Japan.
• 67Department of Generai Internal Medicine, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, Kawasaki, Japan.
• 68Sapporo City General Hospital, Sapporo, Japan.
• 69Department of Emergency and Critical Care Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
• 70Department of Infection Control, Fukuoka University Hospital, Fukuoka, Japan.
• 71Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.
• 72Department of Respiratory Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
• 73Department of Allergy, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
• 74Department of General Internal Medicine and Infectious Diseases, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
• 75Department of Respiratory Medicine, Toyohashi Municipal Hospital, Toyohashi, Japan.
• 76Keiyu Hospital, Yokohama, Japan.
• 77Division of Respiratory Medicine, Social Welfare Organization Saiseikai Imperial Gift Foundation, Inc., Saiseikai Kumamoto Hospital, Kumamoto, Japan.
• 78KKR Sapporo Medical Center, Department of respiratory medicine, Sapporo, Japan.
• 79Division of General Internal Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
• 80Departmet of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
• 81Japanese Red Cross Medical Center, Tokyo, Japan.
• 82Matsumoto City Hostpital, Matsumoto, Japan.
• 83Department of Rheumatology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan.
• 84Department of Respiratory Medicine, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan.
• 85Department of Emergency and Critical Care Medicine, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan.
• 86NHO Kanazawa Medical Center, Kanazawa, Japan.
• 87Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.
• 88Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
• 89Nihon University School of Medicine, Department of Internal Medicine, Division of Respiratory Medicine, Tokyo, Japan.
• 90Musashino Red Cross Hospital, Musashino, Japan.
• 91Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
• 92Ome Municipal General Hospital, Ome, Japan.
• 93Fukuoka Tokushukai Hospital, Department of Internal Medicine, Kasuga, Japan.
• 94Fukuoka Tokushukai Hospital, Respiratory Medicine, Kasuga, Japan.
• 95National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.
• 96Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan.
• 97Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
• 98Department of Respiratory Medicine, Fujisawa City Hospital, Fujisawa, Japan.
• 99Department of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
• 100Department of Pulmonary Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
• 101Uji-Tokushukai Medical Center, Uji, Japan.
• 102Department of Infectious Disease and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka Japan.
• 103Department of Respirology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
• 104Division of Respirology, Rheumatology, and Neurology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.
• 105Department of Infectious Disease, National Hospital Organization Kyushu Medical Center, Fukuoka Japan.
• 106Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.
• 107Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
• 108Department of Emergency and Critical Care Medicine, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
• 109Departmentof Hematology, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
• 110Department of Nephrology, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
• 111Department of Cardiovascular Surgery, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan.
• 112Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
• 113Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
• 114Daini Osaka Police Hospital, Osaka, Japan.
• 115Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara, Japan.
• 116Department of Anesthesiology and Intensive Care Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
• 117Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
• 118Department of Respiratory Internal Medicine, St. Marianna University School of Medicine, Yokohama-City Seibu Hospital, Yokohama, Japan.
• 119Gifu University School of Medicine Graduate School of Medicine, Emergency and Disaster Medicine, Gifu, Japan.
• 120KINSHUKAI Hanwa The Second Hospital, Osaka, Japan.
• 121Department of Respiratory Medicine, Tokyo Medical University Hospital, Tokyo, Japan.
• 122JA Toride medical hospital, Toride, Japan.
• 123Okayama Rosai Hospital, Okayama, Japan.
• 124Himeji St. Mary's Hospital, Himeji, Japan.
• 125Emergency & Critical Care, Niigata University, Niigata, Japan.
• 126Emergency & Critical Care Center, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
• 127National Hospital Organization Tokyo National Hospital, Kiyose, Japan.
• 128Fujioka General Hospital, Fujioka, Japan.
• 129Department of General Medicine, School of Medicine, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
• 130Department of Pharmacology, School of Pharmacy, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
• 131Department of Respiratory Medicine, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
• 132Department of Clinical Laboratory, International University of Health and Welfare Shioya Hospital, Ohtawara Japan.
• 133Department of General Medicine, School of Medicine, International University of
• 134Health and Welfare, Narita Japan.
• 135Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.
• 136Kansai Electric Power Hospital, Osaka, Japan.
• 137Department of Infectious Diseases, Kumamoto City Hospital, Kumamoto, Japan.
• 138Department of Respiratory Medicine, Kumamoto City Hospital, Kumamoto, Japan.
• 139Tokyo Medical University Ibaraki Medical Center, Inashiki, Japan.
• 140Department of Emergency and Critical Care Medicine, Tokyo Metropolitan Police Hospital, Tokyo, Japan.
• 141Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
• 142National hospital organization Saitama Hospital, Wako, Japan.
• 143Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan.
• 144Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
• 145Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
• 146Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
• 147Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
• 148Department of Neurosurgery, Faculty of Medicine, the University of Tokyo, Tokyo, Japan.
• 149Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
• 150Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan.
• 151Department of Biomolecular Engineering, Graduate School of Tokyo Institute of Technology, Tokyo, Japan.
• 152Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
• 153Medical Innovation Promotion Center, Tokyo Medical and Dental University, Tokyo, Japan.
• 154Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
• 155Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan.
• 156Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
• 157Department 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.