Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study

Kensuke Nakagawara; Shotaro Chubachi; Ho Namkoong; Hiromu Tanaka; Ho Lee; Shuhei Azekawa; Shiro Otake; Takahiro Fukushima; Atsuho Morita; Mayuko Watase; Kaori Sakurai; Tatsuya Kusumoto; Takanori Asakura; Katsunori Masaki; Hirofumi Kamata; Makoto Ishii; Naoki Hasegawa; Norihiro Harada; Tetsuya Ueda; Soichiro Ueda; Takashi Ishiguro; Ken Arimura; Fukuki Saito; Takashi Yoshiyama; Yasushi Nakano; Yoshikazu Mutoh; Yusuke Suzuki; Ryuya Edahiro; Koji Murakami; Yasunori Sato; Yukinori Okada; Ryuji Koike; Yuko Kitagawa; Katsushi Tokunaga; Akinori Kimura; Seiya Imoto; Satoru Miyano; Seishi Ogawa; Takanori Kanai; Koichi Fukunaga

doi:10.1186/s12931-022-02222-3

. 2022 Nov 15;23:315. doi: 10.1186/s12931-022-02222-3

Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study

Kensuke Nakagawara ¹, Shotaro Chubachi ^1,^✉, Ho Namkoong ^2,^✉, Hiromu Tanaka ¹, Ho Lee ¹, Shuhei Azekawa ¹, Shiro Otake ¹, Takahiro Fukushima ¹, Atsuho Morita ¹, Mayuko Watase ¹, Kaori Sakurai ¹, Tatsuya Kusumoto ¹, Takanori Asakura ^1,^3,⁴, Katsunori Masaki ¹, Hirofumi Kamata ¹, Makoto Ishii ^1,⁵, Naoki Hasegawa ², Norihiro Harada ⁶, Tetsuya Ueda ⁷, Soichiro Ueda ⁸, Takashi Ishiguro ⁹, Ken Arimura ¹⁰, Fukuki Saito ¹¹, Takashi Yoshiyama ¹², Yasushi Nakano ¹³, Yoshikazu Mutoh ¹⁴, Yusuke Suzuki ⁴, Ryuya Edahiro ¹⁵, Koji Murakami ¹⁶, Yasunori Sato ¹⁷, Yukinori Okada ^18,^19,^20,^21,^22,²³, Ryuji Koike ²⁴, Yuko Kitagawa ²⁵, Katsushi Tokunaga ²⁶, Akinori Kimura ²⁷, Seiya Imoto ²⁸, Satoru Miyano ²⁹, Seishi Ogawa ^30,^31,³², Takanori Kanai ³³, Koichi Fukunaga ¹

¹Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582 Japan

²Department of Infectious Diseases, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582 Japan

³Department of Clinical Medicine (Laboratory of Bioregulatory Medicine), Kitasato University School of Pharmacy, Tokyo, Japan

⁴Department of Respiratory Medicine, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan

⁵Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

⁶Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan

⁷Department of Respiratory Medicine, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan

⁸Department of Internal Medicine, JCHO (Japan Community Health Care Organization) Saitama Medical Center, Saitama, Japan

⁹Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Kumagaya, Japan

¹⁰Department of Respiratory Medicine, Tokyo Women’s Medical University, Tokyo, Japan

¹¹Department of Emergency and Critical Care Medicine, Kansai Medical University General Medical Center, Moriguchi, Japan

¹²Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan

¹³Department of Internal Medicine, Kawasaki Municipal Ida Hospital, Kawasaki, Japan

¹⁴Department of Infectious Diseases, Tosei General Hospital, Seto, Japan

¹⁵Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan

¹⁶Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

¹⁷Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan

¹⁸Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

¹⁹Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan

²⁰The Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan

²¹Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan

²²Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

²³Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

²⁴Medical Innovation Promotion Center, Tokyo Medical and Dental University, Tokyo, Japan

²⁵Department of Surgery, Keio University School of Medicine, Tokyo, Japan

²⁶Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan

²⁷Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan

²⁸Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, the University of Tokyo, Tokyo, Japan

²⁹M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan

³⁰Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan

³¹Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan

³²Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden

³³Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

^✉

Corresponding author.

PMCID: PMC9665023 PMID: 36380316

Abstract

Background

Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients.

Methods

This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death.

Results

Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11–0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43–4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course.

Conclusions

Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12931-022-02222-3.

Keywords: SARS-CoV-2 infection, COVID-19, Upper respiratory tract symptoms, Lower respiratory tract symptoms, Primary care

Background

The most common symptoms of coronavirus disease 2019 (COVID-19) are cough, myalgia, and headache [1]. Additionally, various symptoms including gastrointestinal symptoms (diarrhea), dysgeusia, and dysosmia have been reported in COVID-19 patients [2, 3]. Of the 1.3 million patients reported by the Centers for Disease Control and Prevention (CDC) at the end of May 2020, 14% were hospitalized, 2% were treated in the intensive care unit (ICU), and 5% died [2, 4]. In recent years, several predictive tools have been proposed and used to identify patients prone to severe disease based on epidemiological, clinical, and laboratory characteristics [5, 6]. Primary physicians need to identify patients prone to severe outcomes based on limited clinical information and direct them to the appropriate higher-level medical facilities. Data on respiratory symptoms can be easily obtained during patient visits and could be crucial for primary care physicians.

Upper respiratory symptoms were reported to be present more frequently in COVID-19 than in the influenza virus infection [7, 8]. While sore throat and nasal discharge were reported in approximately 14.4% and 7.7% of the cases [9], respectively, dysgeusia or dysosmia were observed in 62% of the cases and were considered typical upper respiratory symptoms [8, 10]. Angiotensin-converting enzyme 2 (ACE2) receptors are highly expressed in the nasal epithelium, acting as entry and replication points for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [11], causing dysfunction of the olfactory neurons and taste buds and resulting in dysgeusia or dysosmia [12], although the exact mechanism is still unknown [13]. Additionally, dysosmia and dysgeusia were associated with the medical history of COVID-19 patients [12–15], with a higher incidence in younger adults and women with no comorbidities [12]. Dysosmia and dysgeusia occur in more than half of COVID-19 patients [8, 10]; however, previous studies have revealed an incidence of 4% in hospitalized patients [12, 16]. Thus, there could be an inverse association between dysosmia/dysgeusia and favorable clinical outcomes [13–15].

In the context of lower respiratory symptoms, a systematic review of 152 previous studies suggested cough as the most common symptom of COVID-19, occurring in approximately 50% of the cases [9]. Other lower respiratory symptoms such as sputum production and dyspnea were observed in approximately 25–30% of the cases [9]. Lower respiratory symptoms of cough and dyspnea indicate pneumonia and are associated with severe clinical outcomes [2, 6, 17, 18]. Additionally, some studies have suggested that cough and sputum production during the clinical course were caused by secondary bacterial infections [19, 20].

Hence, we hypothesized that these respiratory symptoms could be related to the clinical outcomes. However, no reports have compared the effect of both upper and lower respiratory symptoms on clinical outcomes. The aim of this present study was to investigate the impact of respiratory symptoms on the clinical outcomes of patients hospitalized with COVID-19.

Methods

Study design and settings

In this retrospective cohort study, data were collected from the Japan COVID-19 Task Force database from February 2020 to November 2021. The Japan COVID-19 Task Force collected clinical information on patients with COVID-19 aged > 18 years and diagnosed by polymerase chain reaction test or antigen test from 78 hospitals nationwide in Japan [21, 22]. Of the 3431 patients identified, 117 patients were excluded due to unknown respiratory symptoms, and thus, 3314 patients were included in the analysis (Additional file 1: Fig. S1). This study was approved by the Ethics Committee of Keio University School of Medicine (ID: 20200061), and written or oral informed consent was obtained. The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.

Definition of respiratory symptoms

Sore throat, nasal discharge, dysosmia, and dysgeusia were categorized as upper respiratory symptoms, while cough, sputum production, and dyspnea were categorized as lower respiratory symptoms. Based on the presence of upper or lower respiratory symptoms, the enrolled patients were classified into four groups as follows: Group 1: patients with no respiratory symptoms at all during the clinical course; Group 2: patients with only upper respiratory symptoms; Group 3: patients with only lower respiratory symptoms; and Group 4: patients with both upper and lower respiratory symptoms. The presence of all symptoms was reported subjectively by the patients, and the corresponding data were collected by the health care provider through medical interviews.

Data collection

The following patient data were obtained from the electronic case record form: age, sex, body mass index, number of days in the hospital, comorbidities, clinical symptoms and signs, laboratory and radiographic findings, complications after hospitalization, and medications administered during hospital stay (remdesivir, antibiotics, steroids, tocilizumab, baricitinib, and anti-coagulant drugs). In this study, poor clinical outcomes were defined as the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) or death [22, 23]. All laboratory tests and radiography were performed within 48 h of the initial visit or admission based on the clinical care needs of the patients. The primary outcome was the percentage of patients with poor clinical outcomes.

Statistical analysis

For baseline variables, we reported categorial variables as frequencies and proportions and continuous variables as mean and standard error. Data were compared among the four groups using the chi-square test, ANOVA, and Dunnett’s test. In Dunnett’s tests, Group 1 was used as a control and was compared with the other groups. To assess the association between respiratory symptoms and poor clinical outcomes, we performed univariate analysis and calculated the odds ratio (OR). Data are presented as OR with 95% confidence interval (95% CI). Statistical significance was set at p < 0.05. To investigate the relationship between each group and poor prognosis, we performed a multivariable logistic regression analysis to adjust for previously reported factors [24–30]. Specifically, the models were adjusted for patient characteristics, such as age, sex, body mass index (BMI), smoking history, and comorbidities (hypertension, diabetes, cardiovascular disease and chronic kidney disease). We presented the adjusted odds ratio (aOR) with a 95% CI. Statistical significance was set at p < 0.05. All data were analyzed using the JMP 16 program (SAS Institute Japan Ltd., Tokyo, Japan).

Results

Comparison of baseline characteristics between the four groups stratified by respiratory symptoms

Table 1 shows the clinical characteristics of each group. Among the 3314 COVID-19 patients, 605 patients had no respiratory symptoms (Group 1). There were 2709 COVID-19 patients with respiratory symptoms, including 331 patients with only upper respiratory symptoms (Group 2), 1229 patients with only lower respiratory symptoms (Group 3), and 1149 patients with both upper and lower respiratory symptoms (Group 4). On comparing the clinical characteristics of patients in the four groups, parameters such as age and the incidence of hypertension, diabetes, cardiovascular disorders, and chronic kidney disease, generally associated with the severity of COVID-19 [24–28], were significantly lower in Groups 2 and 4 than in Group 1 (p < 0.05). The proportion of males and patients with a higher BMI, considered factors associated with severe outcomes of COVID-19 [29, 30], was significantly higher in Group 3.

Table 1.

Main clinical characteristics of each group

	All (n = 3314)	Group 1 (n = 605)	Group 2 (n = 331)	Group 3 (n = 1229)	Group 4 (n = 1149)	p value
Age, years	56.5 ± 17.5	62.0 ± 18.6	48.2 ± 19.2	60.2 ± 15.7	52.1 ± 16.3	< 0.0001^{a = /c = }
Sex (Male), %	67	65.5	59.8	71.3	65.4	0.0001 ^{b= **}
BMI	24.8 ± 4.8	23.9 ± 4.9	23.5 ± 4.1	25.2 ± 4.9	25.2 ± 4.8	< 0.0001^{b = /c = }
Days of onset	5.74 ± 4.0	4.35 ± 3.8	4.64 ± 3.3	6.29 ± 4.1	6.18 ± 4.0	< 0.0001^{b = /c = }
Smoker, %	14.8	12.2	16.2	13.3	17.5	0.0090^{c = **}
Hypertension, %	33.5	41.3	21	40.4	25.8	< 0.0001^{a = /c = }
Diabetes, %	21	22.2	15.2	25.8	16.8	< 0.0001 ^{a = /c = }
Cardiovascular disorders, %	10.2	13.7	4.9	13	6.9	< 0.0001 ^{a = /c = }
COPD, %	4.1	3.9	3.1	5.7	2.8	0.0031
Chronic kidney disease, %	7	9.4	4.6	8.8	4.4	< 0.0001^{a = /c = *}
Cancer, %	6.6	9.4	5.2	5.8	6.4	0.0175^{a = /b = /c = }
Hyperuricemia, %	9.9	11.2	7.3	10.8	9.1	0.1456
Chronic liver disease, %	4.3	4.8	3.1	4.6	4.2	0.6131
Asthma, %	7.2	5.3	5.8	7.6	8.2	0.1056
Fever, %	80.7	72.3	71.5	81.7	86.7	< 0.0001^{b = /c = }
WBC (/μL)	5771.8 ± 2873.8	5560.0 ± 2495.1	5371.8 ± 2604.4	6266.3 ± 3406.3	5466.4 ± 2399.6	< 0.0001^{b = **}
Neutrophil (/μL)	4584.2 ± 10,509.2	3916.2 ± 2282.4	3648.2 ± 2204.4	5530.7 ± 1494.3	4190.8 ± 4190.8	0.0013^{b = **}
Lymphocytes (/μL)	1145.2 ± 2342.1	1126.0 ± 556.0	1250.0 ± 595.8	1127.0 ± 3326.0	1145.3 ± 1920.1	0.8689
Neutrophil lymphocyte ratio	6.13 ± 17.0	4.85 ± 7.0	3.64 ± 3.6	7.27 ± 11.0	6.29 ± 25.9	0.0018 ^{b = *}
Eosinophil (/μL)	42.3 ± 184.9	57.1 ± 153.5	58.2 ± 188.7	36.8 ± 258.9	36.1 ± 65.5	0.0429
AST (IU/L)	43.0 ± 58.5	38.9 ± 76.9	36.1 ± 98.5	47.1 ± 49.1	42.7 ± 37.3	0.0040^{b = *}
ALT (IU/L)	39.6 ± 71.5	32.9 ± 38.2	39.9 ± 190.5	42.1 ± 45.9	40.4 ± 38.5	0.0755^{b = *}
T-B (mg/dL)	0.7 ± 0.4	0.7 ± 0.4	0.7 ± 0.3	0.7 ± 0.5	0.6 ± 0.3	0.1603
γ-GTP (IU/L)	69.0 ± 87.5	55.7 ± 67.5	47.5 ± 63.1	75.7 ± 90.1	74.7 ± 97.5	< 0.0001^{b = /c = }
Alb (mg/dL)	3.7 ± 0.6	3.8 ± 0.6	4.1 ± 0.5	3.5 ± 0.6	3.8 ± 0.6	< 0.0001^{a = /b = }
BUN (mg/dL)	16.9 ± 11.8	18.1 ± 12.8	14.4 ± 8.8	18.9 ± 13.1	14.9 ± 9.9	< 0.0001^{a = /c = }
Cr (mg/dL)	1.1 ± 1.3	1.1 ± 1.6	1.0 ± 1.7	1.1 ± 1.4	1.0 ± 1.0	0.0220^{c = *}
LDH (IU/L)	292.2 ± 153.2	255.9 ± 131.1	222.6 ± 91.5	333.8 ± 176.0	286.3 ± 138.2	< 0.0001^{a = /b = /c = **}
UA (mg/dL)	4.9 ± 1.8	5.2 ± 1.9	4.8 ± 1.7	4.9 ± 1.9	4.7 ± 1.6	0.0002^{a = /c = }
HbA1c (%)	6.4 ± 1.3	6.3 ± 1.4	6.0 ± 1.0	6.6 ± 1.4	6.2 ± 1.2	< 0.0001^{a = /b = *}
CRP (mg/dL)	5.7 ± 27.7	3.8 ± 5.1	2.7 ± 4.0	6.8 ± 6.9	6.4 ± 46.5	0.0286
Procalcitonin (ng/mL)	0.6 ± 17.2	0.2 ± 1.1	0.2 ± 0.8	1.4 ± 28.5	0.2 ± 0.6	0.3982
D-dimer (μg/mL)	2.2 ± 7.9	2.3 ± 8.4	1.2 ± 2.1	3.1 ± 11.0	1.4 ± 3.5	< 0.0001
Ferritin (ng/mL)	628.0 ± 760.1	518.0 ± 880.4	390.9 ± 497.7	758.1 ± 768.4	611.2 ± 722.5	< 0.0001^{b = **}
BNP (pg/mL)	54.8 ± 287.4	55.5 ± 146.3	21.8 ± 51.3	89.1 ± 436.1	25.0 ± 91.4	0.0004
KL-6 (IU/L)	328.7 ± 326.3	300.9 ± 337.6	235.1 ± 116.2	393.5 ± 402.2	299.1 ± 249.1	< 0.0001^{a = /b = *}

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Data are shown as mean ± standard Deviation (SD)

BMI body mass index, COPD chronic obstructive pulmonary disease, WBC white blood cell, AST aspartate aminotransferase, ALT alanine aminotransferase, T-B total bilirubin, Alb albumin, BUN blood urea nitrogen, Cr creatinine, LDH lactate dehydrogenase, UA uric acid, CRP C-reactive protein, BNP brain natriuretic peptide, KL-6 Krebs von den Lungen-6

^aComparison of patients in group 1 versus group 2

^bComparison of patients in group 1 versus group 3

^cComparison of patients in group 1 versus group 4

*p < 0.05 ** p < 0.01

Laboratory results of the patients in the four groups

The clinical laboratory findings of the enrolled patients are presented in Table 1. Patients in Group 3 had higher levels of white blood cells, neutrophils, aspartate aminotransferase (AST), alanine aminotransferase (ALT), HbA1c, and ferritin; neutrophil lymphocyte ratio (NLR); and Krebs von den Lungen-6 values (all p < 0.05) than the patients in Group 1. Conversely, albumin (Alb), blood urea nitrogen, uric acid, HbA1c, and Krebs von den Lungen-6 levels (all p < 0.05) of Group 2 patients were significantly lower than those of Group 1 patients. The lactate dehydrogenase (LDH) levels in Group 2 patients were significantly lower than those of Group 1 patients, whereas LDH levels were significantly higher in Group 3 and 4 patients than in Group 1 patients.

Upper and lower respiratory symptoms of the patients in the four groups

In Group 2, most patients (58.9%) suffered from only one upper respiratory symptom. The frequency decreased as the number of symptoms increased, with only four patients (1.2%) developing all four upper respiratory symptoms (Fig. 1a). The most common upper respiratory symptom was sore throat (149 cases), followed by dysgeusia (145 cases) and dysosmia (134 cases). The incidence of nasal discharge was the lowest (74 cases) (Fig. 1b). The details of lower respiratory symptoms were as follows: 549 (44.6%) patients developed only one lower respiratory symptom, 464 (37.8%) developed two symptoms, and 216 (17.6%) patients developed all lower respiratory symptoms (Fig. 1c). Among these, cough was the most frequent symptom (988 cases), followed by dyspnea (695 cases) and sputum production (443 cases) (Fig. 1d). The most common symptoms in all groups, excluding respiratory presentations, were fever, fatigue, and diarrhea (Additional file 1: Table S1). In Group 4 patients, all systemic symptoms, except bloody stools, were significantly more frequently noted than in Group 1 patients. In contrast, only fever and fatigue were more prevalent in Group 3 patients.

Fig. 1 — Details of upper and lower respiratory symptoms. a Ratio of upper respiratory symptoms in Group 2. Of 331 patients in Group 2, 136 patients (41.1%) developed two or more upper respiratory symptoms at the same time. b Number of patients with each upper respiratory symptom in Group 2. Of 331 patients in Group 2, 149 patients developed sore throat, the most frequent upper respiratory symptom. Dysosmia and dysgeusia were also as common as sore throat. c Ratio of lower respiratory symptoms in Group 3. Of 1229 patients in Group 3, 549 patients (44.6%) developed a single lower respiratory symptom. d Number of patients with each lower respiratory symptom in Group 3. Of 1229 patients in Group 3, 988 patients presented with cough and 695 patients with dyspnea. The frequency of sputum production was the lowest

Radiographic findings of the patients in the four groups

In chest X-ray images, ground-glass opacities (GGO) and infiltrated shadows were significantly more frequent in Group 3 and 4 patients than in Group 1 patients (all p < 0.01), whereas these were less frequent in Group 2 patients than in Group 1 patients (p < 0.01). Additionally, GGO and infiltrated shadows in chest CT scans were more frequent in Group 3 and 4 patients than in Group 1 patients (Fig. 2).

Fig. 2 — Comparison of chest images among the four groups. **a, b** Proportions of patients with ground-glass opacities and infiltrative shadows on chest X-ray images among the four groups. **c, d** Proportions of patients with ground-glass opacities and infiltrative shadows on chest computed tomography scans among four the groups

Treatment of the patients in the four groups

The summary of the therapeutic agents (remdesivir, antibiotics, steroids, tocilizumab, baricitinib, and anti-coagulant drugs) used in each group during the hospital stay is presented in Table 2. The patients in Group 2 were administered drugs less frequently than those in Group 1, with the exception of tocilizumab and baricitinib, whereas the patients in Group 3 received all drugs more frequently than those in Group 1. The patients in Group 4 were administered therapeutic agents, except antibiotics and baricitinib, more frequently than those in Group 1.

Table 2.

Treatment of each respiratory symptoms group

	All (n = 3314)	Group 1 (n = 605)	Group 2 (n = 331)	Group 3 (n = 1229)	Group 4 (n = 1149)	p value
Remdesivir, %	35.8	24	16.4	46.9	35.9	< 0.0001^{a = /b = /c = **}
Antibiotics, %	23.2	20.3	12.7	30.6	20.1	< 0.0001^{a = /b = }
Steroids, %	50.4	38.1	24.6	64.7	49.2	< 0.0001^{a = /b = /c = **}
Tocilizumab, %	9.8	5	3.3	15.2	8.5	< 0.0001^{b = /c = }
Baricitinib, %	5.2	31.4	14.3	53.6	42.9	0.0014^{b = *}
Anti-coagulant drugs, %	29.3	21	14	41.3	25.4	< 0.0001^{a = /b = /c = *}

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Data are shown as mean ± standard deviation

^aComparison of patients in group 1 versus group 2

^bComparison of patients in group 1 versus group 3

^cComparison of patients in group 1 versus group 4

*p < 0.05 **p < 0.01

Impact of respiratory symptoms on clinical outcomes

Poor clinical outcomes (using high-flow oxygen therapy, invasive mechanical ventilation (IMV), ECMO, or death) were observed in 321 cases (9.8%) in Group 1, 11 cases (3.3%) in Group 2, 321 cases (26.1%) in Group 3, and 161 cases (14.0%) in Group 4 (Fig. 3a). Compared to Group 1 in univariate analysis, Group 2 had a significantly lower severity rate, and Groups 3 and 4 had a significantly higher severity rate. While Group 2 was associated with a better prognosis [OR (95% CI) = 0.21 (0.11–0.39)], Group 3 and 4 patients had the highest risk for severe disease [OR (95% CI) = 3.27 (2.43–4.40) and 1.51 (1.10–2.07)] (Fig. 3b). However, in the multivariate logistic regression analysis, which adjusted for patient characteristics and comorbidities, the significant difference between the prognosis of Group 1 and Group 2 disappeared [aOR = 0.65 (0.31–1.34)]. In contrast, Groups 3 and 4 remained significantly associated with a poor prognosis in the multivariate analysis [aOR (95% CI) = 4.53 (3.12–6.59) and 2.62 (1.76–3.90)] (Fig. 3c). In univariate analysis of treatments among the four groups, percentage of high-flow oxygen therapy was significantly lower in Group 2 and significantly higher in Groups 3 and 4 as compared to that in Group 1. Group 2 patients had a significantly lower rate of IMV use, and Group 3 patients were associated with increased rates of IMV and ECMO use as compared to those in Group 1. In a similar analysis, no significant differences were found for mortality among the four groups (Additional file 1: Fig. S2). Analysis of complications showed that percentages of bacterial infections were lower in Group 2 and higher in Group 3, when compared to Group 1. Moreover, Group 2 patients had a significantly lower frequency of acute kidney injury, and Group 3 patients had a significantly higher incidence of thrombosis than Group 1 patients (Fig. 3d–g).

Fig. 3 — Relevance to clinical prognosis and percentage of complications in each group during in-patient treatment of COVID-19. a Univariate analysis of the proportion of poor prognosis cases in each group. b Comparison of odds ratios for poor clinical outcomes in each group. c Multivariate logistic regression analysis of the relationship between respiratory symptoms and critical outcomes in the whole cohort (adjusted for age, sex, BMI, smoking history and comorbidities (hypertension, cardiovascular disease, chronic kidney disease and chronic liver disease). d Univariate analysis of the proportion of patients with bacterial infection in each group. e Univariate analysis of the proportion of patients with heart failure in each group. f Univariate analysis of the proportion of patients with acute kidney injury in each group. g Univariate analysis of the proportion of patients with thrombosis in each group

Relevance of clinical outcomes and respiratory symptoms

In the univariate analysis of the association of respiratory symptoms and clinical prognosis, all of the upper respiratory symptoms were good prognostic factors, whereas all of the lower respiratory symptoms were poor prognostic factors. Dysosmia (OR = 0.32 [0.23–0.46]) was the most favorable clinical factor, and dyspnea (OR = 5.56 [4.53–6.81]) was the worst risk factor associated with poor outcomes among respiratory symptoms. Interestingly, as the number of upper respiratory symptoms increased, the clinical course became better. Conversely, a higher incidence of lower respiratory symptoms was associated with a poorer prognosis (Fig. 4).

Fig. 4 — Relevance of symptoms in clinical prognosis. a Forest plot of odds ratios associated with poor clinical prognosis among respiratory symptoms. b Forest plot of odds ratios associated with poor clinical prognosis among numbers of respiratory symptoms

Discussion

This is a large-scale study of the association between the clinical outcomes of COVID-19 and respiratory symptoms. In this study, we characterized the clinical course of patients and classified them into four groups based on their respiratory symptoms. We report that upper respiratory symptoms are favorable prognostic factors, and lower respiratory symptoms are poor factors, similarly to previous studies [2, 13, 15, 17]. Additionally, our study provided two novel findings with clinical relevance. First, we identified that patients with only lower respiratory symptoms had a worse clinical course than those with both upper and lower respiratory symptoms. Second, this study is the first to show the association between the numbers and types of respiratory symptoms and clinical outcomes in COVID-19 patients. This study suggests better clinical outcomes with upper respiratory symptoms and worse clinical outcomes with lower respiratory symptoms. This study demonstrated the importance of conducting a respiratory symptoms interview in the primary care of COVID-19.

The appearance of symptoms in COVID-19 is known to be influenced by age and sex, with otorhinolaryngological symptoms being more common in younger patients; systemic symptoms such as fever, malaise, and anorexia being more common in older patients; and dysosmia, headache, nasal obstruction, and fatigue more common in women [31]. Moreover, several previous studies have revealed that upper respiratory symptoms are associated with favorable clinical outcomes [13, 15]. Similar to previous studies, our study suggested that all upper respiratory symptoms were favorable prognostic factors. Upper respiratory symptoms have been reported to be highly common in mild outpatient cases of COVID-19 [32, 33]. Additionally, in the Delta and Omicron variants, mild upper respiratory symptoms, for instance nasal discharge and sneezing, appear more frequently [34]. In our study, upper respiratory symptoms were less frequent than those in the previous studies [32–34]. This is because this study focused on hospitalized patients and excluded the period after November 2021, when infections with Omicron variants were common. Moreover, this study suggested that olfactory dysfunction was associated with the best prognosis among upper respiratory symptoms. In summary, conducting a medical interview of patients with respect to their respiratory symptoms can be useful for clinicians in primary care to predict the disease severity.

Among the lower respiratory symptoms of COVID-19 evaluated in this study, cough occurred most frequently, and all symptoms of the lower respiratory tract were associated with a severe clinical prognosis, similar to the results of previous studies [2, 4, 17, 18]. There are two reasons for this. First, patients in Groups 3 and 4 showed GGO and infiltrated shadows on chest X-ray images and CT scans more frequently. Several studies have shown a relationship between the extent of pneumonia on chest X-ray images or CT scans and the clinical prognosis [35–39]. Lower respiratory symptoms were considered to reflect the presence of pneumonia as a poor prognostic factor. It would be useful to predict pneumonia based on only medical interviews of the respiratory symptoms observed. Second, patients in Group 3 had bacterial infections and embolism more frequently than those in other groups. Both bacterial infections and embolism with COVID-19 were reported to worsen clinical outcomes [40–43], and these complications may affect the prognosis of patients with lower respiratory symptoms alone. Additionally, patients in Groups 2 and 4 had a significantly lower incidence of comorbidities associated with severe outcomes such as diabetes, hypertension, and cardiovascular disease. However, patients in Group 3, with the worst prognosis, had a significantly different incidence of comorbidities associated with severe outcomes, except sex and BMI, as compared to that of Group 1 patients. As Fig. 3c shows, lower respiratory symptoms were a poor prognostic factor, independent of comorbidities associated with poor clinical outcome, and lower respiratory symptoms were useful markers in predicting the severity of COVID-19. In contrast, our multivariate analysis showed that upper respiratory symptoms were not an independent risk factor for poor outcomes in patients with COVID-19, and the better prognosis in Group 2 may have resulted from the lower incidence of comorbidities associated with severe disease, as suggested by previous studies [12, 13].

In the laboratory data, NLR, AST, ALT, and ferritin levels associated with poor clinical outcomes were significantly elevated in patients in Group 2, consistent with previous reports [44–47]. In addition, Alb, LDH, and HbA1c values improved in Group 2 patients with good prognosis, whereas they worsened in Group 3 patients with poor prognosis. [47, 48]

Several studies have confirmed that SARS-CoV-2 uses human ACE2 as a receptor to enter host cells [49, 50]. These proteins were highly expressed in the nasal epithelium, and their levels were downregulated throughout the lower respiratory tract and type II alveolar cells in the lung [51]. Thus, SARS-CoV-2 may enter through the nasal epithelium followed by entry into the lungs by inhalation, triggering pneumonia. Additionally, elevated ACE2 expression is expected to increase the viral load. Some studies have shown that a high viral load is associated with death and disease severity [52, 53]; thus, increased expression of ACE2 could lead to poor prognosis. Moreover, ACE2 expression is higher in the lungs of males than of females as shown by single cell RNA-seq [54]. Thus, the significantly higher proportion of males in Group 3 with poor prognosis may have been due to a higher ACE2 expression. In addition, obesity and smoking significantly increase ACE2 expression in the lungs and bronchial epithelium [55, 56]; this could further explain the higher rates of obesity and smoking in Groups 3 and 4 with lower respiratory symptoms. The lower frequency of these comorbidities in Groups 2 and 4 may be because SARS-CoV-2 accumulated and proliferated in the upper respiratory tract, where ACE2 expression was the highest. Interestingly, patients in Group 3 had a worse prognosis than patients in Group 4. Thus, elevated ACE2 expression in the lower respiratory tract could prevent the restriction of SARS-CoV-2 to the upper respiratory tract, resulting in poor prognosis. However, the association of ACE2 expression and COVID-19 severity has not been reported [57], and various complex factors are assumed to be involved in the severity of COVID-19.

Our study has several limitations. First, this study included only hospitalized patients with COVID-19, which might have resulted in a biased sample due to the high severity of the disease. Patients with only upper respiratory symptoms were often treated as mild cases. Therefore, the population in Group 2 may not adequately reflect the clinical characteristics of COVID-19 patients with only upper respiratory symptoms. Second, several previous studies used objective scoring tools to assess olfactory and taste disorders [58, 59], but this study included information from only medical interviews, which may be less accurate for symptoms. Additionally, in COVID-19, there are some cases of rapid and severe respiratory failure without dyspnea characterized by silent hypoxia [60]. Although the prognosis of asymptomatic cases was relatively better, clinicians should not solely rely on interviews and use biomarkers such as those measured using pulse oximetry. Further studies are needed to address these limitations and develop optimal treatment strategies in the near future.

Conclusions

Based on the stratification of respiratory symptoms into upper and lower respiratory symptoms using medical interviews, clinicians may be able to predict the presence of pneumonia, clinical course, and complications of COVID-19. Especially in primary care, this easily obtained information is considered an important clinical tool.

Supplementary Information

12931_2022_2222_MOESM1_ESM.docx^{(308.7KB, docx)}

Additional file 1. Supplemental Figure 1. Study flow chart of patient identification and selectionStudy flow chart of patient identification and selection. A total of 117 records were excluded from the 3431 cases registered in the coronavirus disease 2019 (COVID-19) taskforce database owing to lack of essential clinical information. Ultimately, 3314 patients met the eligibility criteria, of which 2709 had respiratory symptoms. Supplemental Figure 2. Frequency of assisted respiration therapy and death in all four groups (a) Univariate analysis of the proportion of high-flow oxygen therapy with COVID-19 in each group. (b) Univariate analysis of the proportion of use of invasive mechanical ventilation (IMV) with COVID-19 in each group. (c) Univariate analysis of the proportion of use of extracorporeal membrane oxygenation (ECMO) with COVID-19 in each group. (d) Univariate analysis of the proportion of death with COVID-19 in each group. Supplemental Table 1.　Common non-respiratory symptoms in each group.

Acknowledgements

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

Kazuhisa Takahashi⁶, Toshio Naito³⁴, Makoto Hiki^35,36, Yasushi Matsushita³⁷, Haruhi Takagi⁶, Ryousuke Aoki³⁸, Ai Nakamura⁶, Sonoko Harada^6,39, Hitoshi Sasano⁶, Shinnosuke Ikemura¹, Satoshi Okamori¹, Hideki Terai¹, Junichi Sasaki⁴⁰, Hiroshi Morisaki⁴¹, Yoshifumi Uwamino⁴², Kosaku Nanki³³, Yohei Mikami³³, Sho Uchida², Shunsuke Uno², Rino Ishihara³³, Yuta Matsubara³³, Tomoyasu Nishimura^2,43, Takunori Ogawa¹, Toshiro Sato⁴⁴, Masanori Azuma⁷, Ryuichi Saito⁷, Toshikatsu Sado⁷, Yoshimune Miyazaki⁷, Ryuichi Sato⁷, Yuki Haruta⁷, Tadao Nagasaki⁷, Yoshinori Yasui⁴⁵, Yoshinori Hasegawa⁷, Ai Tada⁸, Masayoshi Miyawaki⁸, Masaomi Yamamoto⁸, Eriko Yoshida⁸, Reina Hayashi⁸, Tomoki Nagasaka⁸, Sawako Arai⁸, Yutaro Kaneko⁸, Kana Sasaki⁸, Taisuke Isono⁹, Shun Shibata⁹, Yuma Matsui⁹, Chiaki Hosoda⁹, Kenji Takano⁹, Takashi Nishida⁹, Yoichi Kobayashi⁹, Yotaro Takaku⁹, Noboru Takayanagi⁹, Etsuko Tagaya¹⁰, Masatoshi Kawana⁴⁶, Yasushi Nakamori¹¹, Kazuhisa Yoshiya¹¹, Tomoyuki Yoshihara¹¹, Daiki Wada¹¹, Hiromu Iwamura¹¹, Syuji Kanayama¹¹, Shuhei Maruyama¹¹, Takanori Hasegawa²⁹, Kunihiko Takahashi²⁹, Tatsuhiko Anzai²⁹, Satoshi Ito²⁹, Akifumi Endo⁴⁷, Yuji Uchimura⁴⁸, Yasunari Miyazaki⁴⁹, Takayuki Honda⁴⁹, Tomoya Tateishi⁴⁹, Shuji Tohda⁵⁰, Naoya Ichimura⁵⁰, Kazunari Sonobe⁵⁰, Chihiro Tani Sassa⁵⁰, Jun Nakajima⁵⁰, Masumi Ai⁵¹, Ken Ohta⁵², Hiroyuki Kokuto⁵², Hideo Ogata⁵², Yoshiaki Tanaka⁵², Kenichi Arakawa⁵², Masafumi Shimoda⁵², Takeshi Osawa⁵², Yukiko Nakajima¹³, Ryusuke Anan¹³, Ryosuke Arai¹³, Yuko Kurihara¹³, Yuko Harada¹³, Kazumi Nishio¹³, Tomonori Sato⁵³, Reoto Takei⁵³, Satoshi Hagimoto⁵³, Yoichiro Noguchi⁵³, Yasuhiko Yamano⁵³, Hajime Sasano⁵³, Sho Ota⁵³, Sohei Nakayama⁴, Keita Masuzawa⁴, Tomomi Takano⁵⁴, Kazuhiko Katayama⁵⁵, Mitsuhiro Yamada¹⁶, Hisatoshi Sugiura¹⁶, Hirohito Sano¹⁶, Shuichiro Matsumoto¹⁶, Nozomu Kimura¹⁶, Yoshinao Ono¹⁶, Hiroaki Baba⁵⁶, Rie Baba⁵⁷, Daisuke Arai⁵⁷, Takayuki Ogura⁵⁷, Hidenori Takahashi⁵⁷, Shigehiro Hagiwara⁵⁷, Genta Nagao⁵⁷, Shunichiro Konishi⁵⁷, Ichiro Nakachi⁵⁷, Hiroki Tateno⁵⁸, Isano Hase⁵⁸, Shuichi Yoshida⁵⁸, Shoji Suzuki⁵⁸, Miki Kawada⁵⁹, Hirohisa Horinouchi⁶⁰, Fumitake Saito⁶¹, Keiko Mitamura⁶², Masao Hagihara⁶³, Junichi Ochi⁶¹, Tomoyuki Uchida⁶³, Yuya Shirai^15,18, Kyuto Sonehara^18,19, Tatsuhiko Naito¹⁸, Kenichi Yamamoto¹⁸, Shinichi Namba¹⁸, Ken Suzuki¹⁸, Takayuki Shiroyama¹⁵, Yuichi Maeda¹⁵, Takuro Nii¹⁵, Yoshimi Noda¹⁵, Takayuki Niitsu¹⁵, Yuichi Adachi¹⁵, Takatoshi Enomoto¹⁵, Saori Amiya¹⁵, Reina Hara¹⁵, Toshihiro Kishikawa^18,64,66, Shuhei Yamada⁶⁵, Shuhei Kawabata⁶⁵, Noriyuki Kijima⁶⁵, Masatoshi Takagaki^65,70, Noa Sasa^18,64, Yuya Ueno⁶⁴, Motoyuki Suzuki⁶⁴, Norihiko Takemoto⁶⁴, Hirotaka Eguchi⁶⁴, Takahito Fukusumi⁶⁴, Takao Imai⁶⁴, Munehisa Fukushima^64,69, Haruhiko Kishima⁶⁵, Hidenori Inohara⁶⁴, Kazunori Tomono⁶⁷, Kazuto Kato⁶⁸, Haruhiko Hirata¹⁵, Yoshito Takeda¹⁵, Atsushi Kumanogoh^15,19,70,20, Naoki Miyazawa⁷¹, Yasuhiro Kimura⁷¹, Reiko Sado⁷¹, Hideyasu Sugimoto⁷¹, Akane Kamiya⁷², Naota Kuwahara⁷³, Akiko Fujiwara⁷³, Tomohiro Matsunaga⁷³, Yoko Sato⁷³, Takenori Okada⁷³, Takashi Inoue⁷⁴, Toshiyuki Hirano⁷⁴, Keigo Kobayashi⁷⁴, Hatsuyo Takaoka⁷⁴, Koichi Nishi⁷⁵, Masaru Nishitsuji⁷⁵, Mayuko Tani⁷⁵, Junya Suzuki⁷⁵, Hiroki Nakatsumi⁷⁵, Hidefumi Koh⁷⁶, Tadashi Manabe⁷⁶, Yohei Funatsu⁷⁶, Fumimaro Ito⁷⁶, Takahiro Fukui⁷⁶, Keisuke Shinozuka⁷⁶, Sumiko Kohashi⁷⁶, Masatoshi Miyazaki⁷⁶, Tomohisa Shoko⁷⁷, Mitsuaki Kojima⁷⁷, Tomohiro Adachi⁷⁷, Motonao Ishikawa⁷⁸, Kenichiro Takahashi⁷⁹, Kazuyoshi Watanabe⁸⁰, Yoshihiro Hirai⁸¹, Hidetoshi Kawashima⁸¹, Atsuya Narita⁸¹, Kazuki Niwa⁸², Yoshiyuki Sekikawa⁸², Hisako Sageshima⁸³, Yoshihiko Nakamura⁸⁴, Kota Hoshino,⁸⁴ Junichi Maruyama⁸⁴, Hiroyasu Ishikura⁸⁴, Tohru Takata⁸⁵, Takashi Ogura⁸⁶, Hideya Kitamura⁸⁶, Eri Hagiwara⁸⁶, Kota Murohashi⁸⁶, Hiroko Okabayashi⁸⁶, Takao Mochimaru^87,88, Shigenari Nukaga⁸⁷, Ryosuke Satomi^87, Yoshitaka Oyamada⁸⁸, Nobuaki Mori⁸⁹, Tomoya Baba⁹⁰, Yasutaka Fukui⁹⁰, Mitsuru Odate⁹⁰, Shuko Mashimo⁹⁰, Yasushi Makino⁹⁰, Kazuma Yagi⁹¹, Mizuha Hashiguchi⁹¹, Junko Kagyo⁹¹, Tetsuya Shiomi⁹¹, Kodai Kawamura⁹², Kazuya Ichikado⁹², Kenta Nishiyama⁹², Hiroyuki Muranaka⁹², Kazunori Nakamura⁹², Satoshi Fuke⁹³, Hiroshi Saito⁹³, Tomoya Tsuchida⁹⁴, Shigeki Fujitani⁹⁵, Mumon Takita⁹⁵, Daiki Morikawa⁹⁵, Toru Yoshida⁹⁵, Takehiro Izumo⁹⁶, Minoru Inomata⁹⁶, Naoyuki Kuse⁹⁶, Nobuyasu Awano⁹⁶, Mari Tone⁹⁶, Akihiro Ito⁹⁷, Toshio Odani⁹⁸, Masaru Amishima⁹⁹, Takeshi Hattori⁹⁹, Yasuo Shichinohe¹⁰⁰, Takashi Kagaya¹⁰¹, Toshiyuki Kita¹⁰¹, Kazuhide Ohta¹⁰¹, Satoru Sakagami¹⁰¹, Kiyoshi Koshida¹⁰¹, Morio Nakamura¹⁰¹, Koutaro Yokote¹⁰², Taka-Aki Nakada¹⁰³, Ryuzo Abe¹⁰³, Taku Oshima¹⁰³, Tadanaga Shimada¹⁰³, Kentaro Hayashi¹⁰⁴, Tetsuo Shimizu¹⁰⁴, Yutaka Kozu¹⁰⁴, Hisato Hiranuma¹⁰⁴, Yasuhiro Gon¹⁰⁴, Namiki Izumi¹⁰⁵, Kaoru Nagata¹⁰⁵, Ken Ueda¹⁰⁵, Reiko Taki¹⁰⁵, Satoko Hanada¹⁰⁵, Naozumi Hashimoto⁵, Keiko Wakahara⁵, Koji Sakamoto⁵, Norihito Omote⁵, Akira Ando⁵, Yu Kusaka¹⁰⁶, Takehiko Ohba¹⁰⁶, Susumu Isogai¹⁰⁶, Aki Ogawa¹⁰⁶, Takuya Inoue¹⁰⁶, Nobuhiro Kodama¹⁰⁷, Yasunari Kaneyama¹⁰⁷, Shunsuke Maeda¹⁰⁷, Takashige Kuraki¹⁰⁸, Takemasa Matsumoto¹⁰⁸, Masahiro Harada¹⁰⁹, Takeshi Takahashi¹⁰⁹, Hiroshi Ono¹⁰⁹, Toshihiro Sakurai¹⁰⁹, Takayuki Shibusawa¹⁰⁹, Yusuke Kawamura¹¹⁰, Akiyoshi Nakayama¹¹⁰, Hirotaka Matsuo¹¹⁰, Yoshifumi Kimizuka¹¹¹, Akihiko Kawana¹¹¹, Tomoya Sano¹¹¹, Chie Watanabe¹¹¹, Ryohei Suematsu¹¹¹, Makoto Masuda¹¹², Aya Wakabayashi¹¹², Hiroki Watanabe¹¹², Suguru Ueda¹¹², Masanori Nishikawa^112, Ayumi Yoshifuji¹¹³, Kazuto Ito¹¹³, Saeko Takahashi¹¹⁴, Kota Ishioka¹¹⁴, Yusuke Chihara¹¹⁵, Mayumi Takeuchi¹¹⁵, Keisuke Onoi¹¹⁵, Jun Shinozuka¹¹⁵, Atsushi Sueyoshi¹¹⁵, Yoji Nagasaki¹¹⁶, Masaki Okamoto^117,118, Sayoko Ishihara¹¹⁹, Masatoshi Shimo¹¹⁹, Yoshihisa Tokunaga^117,118, Masafumi Watanabe¹²⁰, Sumito Inoue¹²⁰, Akira Igarashi¹²⁰, Masamichi Sato¹²⁰, Nobuyuki Hizawa¹²¹, Yoshiaki Inoue¹²², Shigeru Chiba¹²³, Kunihiro Yamagata¹²⁴, Yuji Hiramatsu¹²⁵, Hirayasu Kai¹²⁴, Satoru Fukuyama¹²⁶, Yoshihiro Eriguchi¹²⁷, Akiko Yonekawa¹²⁷, Keiko Kan-o¹²⁶, Koichiro Matsumoto¹²⁶, Kensuke Kanaoka¹²⁸, Shoichi Ihara¹²⁸, Kiyoshi Komuta¹²⁸, Koichiro Asano¹²⁹, Tsuyoshi Oguma¹²⁹, Yoko Ito¹²⁹, Satoru Hashimoto¹³⁰, Masaki Yamasaki¹³⁰, Yu Kasamatsu¹³¹, Yuko Komase¹³², Naoya Hida¹³², Takahiro Tsuburai¹³², Baku Oyama¹³², Yuichiro Kitagawa¹³³, Tetsuya Fukuta¹³³, Takahito Miyake¹³³, Shozo Yoshida¹³³, Shinji Ogura¹³³, Minoru Takada¹³⁴, Hidenori Kanda¹³⁴, Shinji Abe¹³⁵, Yuta Kono¹³⁵, Yuki Togashi¹³⁵, Hiroyuki Takoi¹³⁵, Ryota Kikuchi¹³⁵, Shinichi Ogawa¹³⁶, Tomouki Ogata¹³⁶, Shoichiro Ishihara¹³⁶, Arihiko Kanehiro^137,138, Shinji Ozaki¹³⁷, Yasuko Fuchimoto¹³⁷, Sae Wada¹³⁷, Nobukazu Fujimoto¹³⁸, Kei Nishiyama¹³⁹, Mariko Terashima¹⁴⁰, Satoru Beppu¹⁴⁰, Kosuke Yoshida¹⁴⁰, Osamu Narumoto¹⁴¹, Hideaki Nagai¹⁴¹, Nobuharu Ooshima¹⁴¹, Mitsuru Motegi¹⁴², Akira Umeda¹⁴³, Kazuya Miyagawa¹⁴⁴, Hisato Shimada¹⁴⁵, Mayu Endo¹⁴⁶, Yoshiyuki Ohira¹⁴⁷, Hironori Sagara¹⁴⁷, Akihiko Tanaka¹⁴⁷, Shin Ohta¹⁴⁷, Tomoyuki Kimura¹⁴⁷, Yoko Shibata¹⁴⁸, Yoshinori Tanino¹⁴⁸, Takefumi Nikaido¹⁴⁸, Hiroyuki Minemura¹⁴⁸, Yuki Sato¹⁴⁸, Yuichiro Yamada¹⁴⁹, Takuya Hashino¹⁴⁹, Masato Shinoki¹⁴⁹, Hajime Iwagoe¹⁵⁰, Hiroshi Takahashi¹⁵¹, Kazuhiko Fujii¹⁵¹, Hiroto Kishi¹⁵¹, Tomoo Ishii¹⁵², Masayuki Kanai¹⁵³, Tomonori Imamura¹⁵³, Tatsuya Yamashita¹⁵³, Masakiyo Yatomi¹⁵⁴, Toshitaka Maeno¹⁵⁴, Shinichi Hayashi¹⁵⁵, Mai Takahashi¹⁵⁵, Mizuki Kuramochi¹⁵⁵, Isamu Kamimaki¹⁵⁵, Yoshiteru Tominaga¹⁵⁵, Mitsuyoshi Utsugi¹⁵⁶, Akihiro Ono¹⁵⁶, Toru Tanaka¹⁵⁷, Takeru Kashiwada¹⁵⁷, Kazue Fujita¹⁵⁷, Yoshinobu Saito¹⁵⁷, Masahiro Seike¹⁵⁷, Masahiro Kanai¹⁵⁸, Ryunosuke Saiki³⁰, Takayoshi Hyugaji²⁸, Eigo Shimizu²⁸, Kotoe Katayama²⁸, Satoru Miyawaki¹⁵⁹, Meiko Takahashi¹⁶⁰, Fumihiko Matsuda¹⁶⁰, Yosuke Omae²⁶, Yasuhito Nannya³⁰, Takafumi Ueno¹⁶¹

³⁴Department of General Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan. ³⁵Department of Emergency and Disaster Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan. ³⁶Department of Cardiovascular Biology and Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan. ³⁷Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan. ³⁸Department of Nephrology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan. ³⁹Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan. ⁴⁰Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo, Japan. ⁴¹Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan. ⁴²Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan. ⁴³Keio University Health Center, Keio University School of Medicine, Tokyo, Japan. ⁴⁴Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan. ⁴⁵Department of Infection Control, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan. ⁴⁶Department of General Medicine, Tokyo Women's Medical University, Tokyo, Japan. ⁴⁷Clinical Research Center, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan. ⁴⁸Department of Medical Informatics, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan. ⁴⁹Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan. ⁵⁰Clinical Laboratory, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan. ⁵¹Department of Insured Medical Care Management, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan. ⁵²Fukujuji Hospital, Kiyose, Japan. ⁵³Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan. ⁵⁴School of Veterinary Medicine, Kitasato University, Towada, Japan. ⁵⁵Laboratory of Viral Infection I, Department of Infection Control and Immunology, Ōmura Satoshi Memorial Institute & Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan. ⁵⁶Department of Infectious Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan. ⁵⁷Saiseikai Utsunomiya Hospital, Utsunomiya, Japan. ⁵⁸Department of Pulmonary Medicine, Saitama City Hospital, Saitama, Japan. ⁵⁹Department of Infectious Diseases, Saitama City Hospital, Saitama, Japan. ⁶⁰Department of General Thoracic Surgery, Saitama City Hospital, Saitama, Japan. ⁶¹Department of Pulmonary Medicine, Eiju General Hospital, Tokyo, Japan. ⁶²Division of Infection Control, Eiju General Hospital, Tokyo, Japan. ⁶³Department of Hematology, Eiju General Hospital, Tokyo, Japan. ⁶⁴Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan. ⁶⁵Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan. ⁶⁶Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan. ⁶⁷Division of Infection Control and Prevention, Osaka University Hospital, Suita, Japan. ⁶⁸Department of Biomedical Ethics and Public Policy, Osaka University Graduate School of Medicine, Suita, Japan. ⁶⁹Department of Otolaryngology and Head and Neck Surgery, Kansai Rosai Hospital, Hyogo, Japan. ⁷⁰Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan. ⁷¹Department of Respirtory Medicine, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan. ⁷²Department of Clinical Laboratory, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan. ⁷³Internal Medicine, Internal Medicine Center, Showa University Koto Toyosu Hospital, Tokyo, Japan. ⁷⁴Internal Medicine, Sano Kosei General Hospital, Sano, Japan. ⁷⁵Ishikawa Prefectural Central Hospital, Kanazawa, Japan. ⁷⁶Tachikawa Hospital, Tachikawa, Japan. ⁷⁷Department of Emergency and Critical Care Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan. ⁷⁸Department of Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan. ⁷⁹Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan. ⁸⁰Japan Community Health care Organization Kanazawa Hospital, Kanazawa, Japan. ⁸¹Department of Respiratory Medicine, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, Kawasaki, Japan. ⁸²Department of Generai Internal Medicine, Japan Organization of Occupational Health and Safety, Kanto Rosai Hospital, Kawasaki, Japan. ⁸³Sapporo City General Hospital, Sapporo, Japan. ⁸⁴Department of Emergency and Critical Care Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan. ⁸⁵Department of Infection Control, Fukuoka University Hospital, Fukuoka, Japan. ⁸⁶Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan. ⁸⁷Department of Respiratory Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. ⁸⁸Department of Allergy, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. ⁸⁹Department of General Internal Medicine and Infectious Diseases, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. ⁹⁰Department of Respiratory Medicine, Toyohashi Municipal Hospital, Toyohashi, Japan. ⁹¹Keiyu Hospital, Yokohama, Japan. ⁹²Division of Respiratory Medicine, Social Welfare Organization Saiseikai Imperial Gift Foundation, Inc., Saiseikai Kumamoto Hospital, Kumamoto, Japan. ⁹³KKR Sapporo Medical Center, Department of respiratory medicine, Sapporo, Japan. ⁹⁴Division of General Internal Medicine, Department of Internal Medicine, StMarianna University School of Medicine, Kawasaki, Japan. ⁹⁵Departmet of Emergency and Critical Care Medicine, StMarianna University School of Medicine, Kawasaki, Japan. ⁹⁶Japanese Red Cross Medical Center, Tokyo, Japan. ⁹⁷Matsumoto City Hostpital, Matsumoto, Japan. ⁹⁸Department of Rheumatology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan. ⁹⁹Department of Respiratory Medicine, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan. ¹⁰⁰Department of Emergency and Critical Care Medicine, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan. ¹⁰¹NHO Kanazawa Medical Center, Kanazawa, Japan. ¹⁰²Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan. ¹⁰³Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. ¹⁰⁴Nihon University School of Medicine, Department of Internal Medicine, Division of Respiratory Medicine, Tokyo, Japan. ¹⁰⁵Musashino Red Cross Hospital, Musashino, Japan. ¹⁰⁶Ome Municipal General Hospital, Ome, Japan. ¹⁰⁷Fukuoka Tokushukai Hospital, Department of Internal Medicine, Kasuga, Japan. ¹⁰⁸Fukuoka Tokushukai Hospital, Respiratory Medicine, Kasuga, Japan. ¹⁰⁹National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan. ¹¹⁰Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan. ¹¹¹Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan. ¹¹²Department of Respiratory Medicine, Fujisawa City Hospital, Fujisawa, Japan. ¹¹³Department of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan. ¹¹⁴Department of Pulmonary Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan. ¹¹⁵Uji-Tokushukai Medical Center, Uji, Japan. ¹¹⁶Department of Infectious Disease and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka Japan. ¹¹⁷Department of Respirology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan. ¹¹⁸Division of Respirology, Rheumatology, and Neurology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. ¹¹⁹Department of Infectious Disease, National Hospital Organization Kyushu Medical Center, Fukuoka Japan. ¹²⁰Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan. ¹²¹Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. ¹²²Department of Emergency and Critical Care Medicine, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan. ¹²³Departmentof Hematology, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan. ¹²⁴Department of Nephrology, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan. ¹²⁵Department of Cardiovascular Surgery, Facualty of Medicine, University of Tsukuba, Tsukuba, Japan. ¹²⁶Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ¹²⁷Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. ¹²⁸Daini Osaka Police Hospital, Osaka, Japan. ¹²⁹Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara, Japan. ¹³⁰Department of Anesthesiology and Intensive Care Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. ¹³¹Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. ¹³²Department of Respiratory Internal Medicine, StMarianna University School of Medicine, Yokohama-City Seibu Hospital, Yokohama, Japan. ¹³³Gifu University School of Medicine Graduate School of Medicine, Emergency and Disaster Medicine, Gifu, Japan. ¹³⁴KINSHUKAI Hanwa The Second Hospital, Osaka, Japan. ¹³⁵Department of Respiratory Medicine, Tokyo Medical University Hospital, Tokyo, Japan. ¹³⁶JA Toride medical hospital, Toride, Japan. ¹³⁷Okayama Rosai Hospital, Okayama, Japan. ¹³⁸Himeji StMary's Hospital, Himeji, Japan. ¹³⁹Emergency & Critical Care, Niigata University, Niigata, Japan. ¹⁴⁰Emergency & Critical Care Center, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. ¹⁴¹National Hospital Organization Tokyo National Hospital, Kiyose, Japan. ¹⁴²Fujioka General Hospital, Fujioka, Japan. ¹⁴³Department of General Medicine, School of Medicine, International University of Health and Welfare Shioya Hospital, Ohtawara Japan. ¹⁴⁴Department of Pharmacology, School of Pharmacy, International University of Health and Welfare Shioya Hospital, Ohtawara Japan. ¹⁴⁵Department of Respiratory Medicine, International University of Health and Welfare Shioya Hospital, Ohtawara Japan. ¹⁴⁶Department of Clinical Laboratory, International University of Health and Welfare Shioya Hospital, Ohtawara Japan. ¹⁴⁷Department of General Medicine, School of Medicine, International University of Health and Welfare, Narita Japan. ¹⁴⁸Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan. ¹⁴⁹Kansai Electric Power Hospital, Osaka, Japan. ¹⁵⁰Department of Infectious Diseases, Kumamoto City Hospital, Kumamoto, Japan. ¹⁵¹Department of Respiratory Medicine, Kumamoto City Hospital, Kumamoto, Japan. ¹⁵²Tokyo Medical University Ibaraki Medical Center, Inashiki, Japan. ¹⁵³Department of Emergency and Critical Care Medicine, Tokyo Metropolitan Police Hospital, Tokyo, Japan. ¹⁵⁴Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan. ¹⁵⁵National hospital organization Saitama Hospital, Wako, Japan. ¹⁵⁶Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan. ¹⁵⁷Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. ¹⁵⁸Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. ¹⁵⁹Department of Neurosurgery, Faculty of Medicine, the University of Tokyo, Tokyo, Japan. ¹⁶⁰Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. ¹⁶¹Department of Biomolecular Engineering, Graduate School of Tokyo Institute of Technology, Tokyo, Japan.

Author contributions

Conceptualization: KN, SC, HN, TA, KM, HK, MI, NH, and KF. Data curation: KN, HT, HL, SO, TF, AM, MW, and TK. Formal analysis: KN, SC, and HN. Methodology: KN, SC, and HN. Supervision: KN, SC, NH, TA, KM, HK, MI, NH, NH, TU, SU, TI, KA, FS, TY, YN, YM, YS, RE, KM, YS, YO, RK, YK, KT, AK, SI, SM, SO, TK, and KF. Visualisation: KN, SC, and HN. Writing—original draft: KN, SC, and HN. Writing—review and editing: KN, SC, NH, TA, KM, HK, MI, NH, NH, TU, SU, TI, KA, FS, TY, YN, YM, YS, RE, KM, YS, YO, RK, YK, KT, AK, SI, SM, SO, TK, and KF. All authors read and approved the final manuscript.

Funding

This study was supported by AMED (JP20nk0101612, JP20fk0108415, JP21jk0210034, JP21km0405211, JP21km0405217, and JP21wm0325031), JST CREST (JPMJCR20H2), JST PRESTO (JPMJPR21R7), MHLW (20CA2054), Takeda Science Foundation, Mitsubishi Foundation, and Bioinformatics Initiative of Osaka University Graduate School of Medicine, Osaka University.

Availability of data and materials

The datasets generated during and/or analyzed during the current study available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of Keio University School of Medicine (20200061) and affiliated institutes. Written informed consent was obtained from all patients. All aspects of the study conformed to the principles of the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflicts of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Shotaro Chubachi, Email: bachibachi472000@live.jp.

Ho Namkoong, Email: hounamugun@gmail.com.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

12931_2022_2222_MOESM1_ESM.docx^{(308.7KB, docx)}

Data Availability Statement

The datasets generated during and/or analyzed during the current study available from the corresponding author on reasonable request.

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PERMALINK

Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study

Kensuke Nakagawara

Shotaro Chubachi

Ho Namkoong

Hiromu Tanaka

Ho Lee

Shuhei Azekawa

Shiro Otake

Takahiro Fukushima

Atsuho Morita

Mayuko Watase

Kaori Sakurai

Tatsuya Kusumoto

Takanori Asakura

Katsunori Masaki

Hirofumi Kamata

Makoto Ishii

Naoki Hasegawa

Norihiro Harada

Tetsuya Ueda

Soichiro Ueda

Takashi Ishiguro

Ken Arimura

Fukuki Saito

Takashi Yoshiyama

Yasushi Nakano

Yoshikazu Mutoh

Yusuke Suzuki

Ryuya Edahiro

Koji Murakami

Yasunori Sato

Yukinori Okada

Ryuji Koike

Yuko Kitagawa

Katsushi Tokunaga

Akinori Kimura

Seiya Imoto

Satoru Miyano

Seishi Ogawa

Takanori Kanai

Koichi Fukunaga

Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Background

Methods

Study design and settings

Definition of respiratory symptoms

Data collection

Statistical analysis

Results

Comparison of baseline characteristics between the four groups stratified by respiratory symptoms

Table 1.

Laboratory results of the patients in the four groups

Upper and lower respiratory symptoms of the patients in the four groups

Fig. 1.

Radiographic findings of the patients in the four groups

Fig. 2.

Treatment of the patients in the four groups

Table 2.

Impact of respiratory symptoms on clinical outcomes

Fig. 3.

Relevance of clinical outcomes and respiratory symptoms

Fig. 4.

Discussion

Conclusions

Supplementary Information

Acknowledgements

Author contributions

Funding

Availability of data and materials

Declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Footnotes