Background.

In December 2019, a novel type of pneumonia known as coronavirus disease 2019 (COVID-19) emerged in Wuhan, China [1]. The first patient in Japan was reported on January 16, 2020 [2]. In March 2021, Japan encountered a Delta variant strain B.1.617.2, which swiftly outperformed the previously dominant Alpha variant [3]. The Delta variant played a pivotal role in Japan’s fifth wave, leading to an escalation in severe cases compared to the preceding variant [4, 5]. Another significant variant, Omicron strain B.1.1.529, originally identified in South Africa in November 2021, was confirmed in Japan in December 2021 and was influential in precipitating the seventh wave of the pandemic [6].

Extensive research has been conducted to elucidate the risk factors that contribute to the progression of severe COVID-19. The Centers for Disease Control and Prevention have identified several risk factors for COVID-19, including age ≥ 65 years, malignancies, chronic kidney disease, chronic liver disease, chronic lung disease, cystic fibrosis, neurological conditions (e.g., dementia), type 1 diabetes, type 2 diabetes, Down syndrome, and an array of cardiac conditions, including heart failure, coronary artery disease, cardiomyopathy, and other cardiovascular disorders. Additionally, hypertension, human immunodeficiency virus infection, immunodeficiency, mental health disorders (such as depression and schizophrenia), overweight or obesity, lack of physical activity, pregnancy, thalassemia, smoking (including past smoking), solid organ and hematopoietic stem cell transplantation, stroke or cerebrovascular disease, substance use disorders, and tuberculosis have all been implicated as potential risk factors for the progression to severe conditions [7].

In Japan, the Ministry of Health, Labour and Welfare has identified individuals aged ≥ 65 years; those with dyslipidemia, malignancy, obesity, chronic obstructive pulmonary disease (COPD), chronic kidney disease, diabetes, and hypertension; those who have undergone post-solid organ transplantation; and those with late-stage pregnancy as generally susceptible to developing more severe forms of the disease [8]. Research focused on Japanese subjects has indicated that advanced age, hyperglycemia, and obesity constitute significant risk factors for the progression to severe conditions [9]. Furthermore, older adults and male individuals have been identified as being more prone to such progression in this context [10]. Nonetheless, most of these studies have been confined to single institutions or specific geographical regions, with limitations in terms of sample size. Moreover, only a few studies have addressed the pharmacological treatment of underlying diseases, and the association between the management status of these underlying conditions and the progression of COVID-19 to a more severe state remains inadequately explored.

Beyond the disease-specific factors, additional elements such as smoking, obesity, and pregnancy have been recognized as exacerbating the severity of COVID-19 [11,12,13]. Notably, a study investigating the association between smoking and the progression to severe conditions in 17,666 patients with COVID-19 revealed that comorbidities linked to smoking, rather than smoking itself, were correlated with the heightened risk [14]. Furthermore, the influence of obesity is intertwined with various lifestyle-related ailments, while pregnancy amplifies the susceptibility to severe conditions, particularly during the later stages, especially among patients already suffering from diabetes and hypertension [15].

Against the backdrop of the distinctive characteristics governing the progression of COVID-19 to severe illness, it is imperative to identify risk factors within a broader scope of patient information, transcending the confines of existing reports. This study aimed to utilize an extensive database encompassing hospitalized patients in Japan to examine the association between patients’ underlying diseases and pharmacological interventions, with the aim of attenuating the progression of COVID-19 to a severe state.

Methods.

Study design and data source.

This study utilized the COVID-19 dataset provided by the Medical Data Vision Co. Ltd. (MDV), Tokyo, Japan. The MDV dataset is a comprehensive database incorporating the Diagnosis Procedure Combination (DPC) and health insurance claims data from approximately 40 million patients across 460 acute care hospitals in Japan. This dataset covers all regions of Japan. All personal data in this dataset were anonymized. The dataset encompasses tables such as PatientData (patient information), DiseaseData (disease information), ActData (medical practice information), FF1Data (discharge summary), and Drugs (prescription drugs). ATCCODE was employed to extract patient medications, whereas KUBUNCODE was used to extract medical procedures. Data were extracted using SQL via Snowflake (Snowflake Inc., San Mateo, CA, USA).

FormalPara Ethics approval

and data overview.

This study was approved by the Kitasato University Medical Center Ethics Committee (no. 20222028). The ethics committee confirmed that all methods were performed in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan and relevant regulations. The requirement for informed consent was waived owing to the use of anonymized data. The dataset comprised 854,114 patients diagnosed with or suspected of COVID-19 in Japan from January 15, 2020, to December 31, 2022. Subsequently, 827,476 patients with a confirmed COVID-19 diagnosis (ICD-10 CODE: U071) were selected, and exclusions were made based on specific criteria, resulting in the inclusion of 650,317 patients for the analysis. The exclusion criteria included patients with missing age and sex data, age < 20 years, or suspected COVID-19 (ICD-10 CODE: U072).

Variant analysis.

The Delta variant period spanned from August 16, 2021, to December 6, 2021, while the Omicron variant period extended from January 17, 2022, to December 31, 2022. This analysis included 567,400 patients aged ≥ 20 years who were diagnosed with COVID-19 during these respective periods.

Analysis of obesity, smoking, and pregnancy.

To investigate obesity, smoking, and pregnancy, 236,851 patients aged ≥ 20 years without missing information on COVID-19 diagnosis (ICD-10: U071), sex (male or female), smoking history (smoking history was defined as smoking at least one cigarette per day), body mass index (patients with ≧ 30 kg/m2 were defined as obese), and pregnancy status (analysis for female individuals alone) were included.

Disease and drug definitions in data analysis.

Data on patient background and history of disease, which included sex [male/female], age > 65 years [yes/no], hypertension [ICD-10: I10], COPD [J440, J441, J448, and J449], chronic kidney disease [N181-N185 and N189], type 2 diabetes [E11 and E110-E119], cardiovascular disease (angina pectoris, myocardial infarction, heart failure, or other ischemic heart disease) [I200, I201, I208-I214, I219-I221, I229, I249, I252, I255, I256, I259, I420-I429, I500, I501, and I509], cerebrovascular disease [480-I482, I489-I611, I613-I616, I618, I619, I630-I636, I638, I639, and I64], and dyslipidemia [E780-E785], considered significant risk factors for COVID-19 severity, were extracted from the COVID-19 dataset.

Drugs under concomitant use were defined as follows: adrenergic beta-receptor blockers (ATCCODE: C07A0), calcium channel blockers (C08A0), ACE inhibitors (C09A0), ARBs (C09C0), vitamin K antagonists (B01A0), direct thrombin inhibitors (B01E0), direct factor Xa inhibitors (B01F0), low-dose aspirin (B01C1), other antiplatelet agents (B01C2 and B01C4), metformin (A10J1), sulfonylureas (A10H0), dipeptidyl peptidase 4 (DPP-4) inhibitors (A10N1), glucagon-like peptide-1 (GLP-1) receptor agonists (A10S0), SGLT2 inhibitors (A10P1), Pioglitazone (A10K1), alpha-glucosidase inhibitors (A10L0), glinides (A10M1), insulin preparations (A10C1, A10C3, A10C5, and A10C9), inhaled adrenergic agents (R03A3 and R03A4), inhaled steroids (R03D1 and R03M0), inhaled anticholinergics (R03K1, R03K2, and R03L2), inhaled corticosteroid/long-acting beta stimulant combination drugs (R03F1 and R03L3), statins (C10A1), fibrates (C10A2), and ursodeoxycholic acid (A05A2).

COVID-19 therapeutic agents could not be included in the analysis because of the dissociation between their clinical use and insurance claims data. Lemdecivir, mornupiravir, nilmatorvir/ritonavir, and encytorvir were approved for national health insurance drug price listing in Japan in August 2021, August 2022, March 2023, and March 2023, respectively, and their use was approved by special exception before the insurance data were registered. Because these drugs were listed and started to be used in the middle of the study period, the data before and after insurance coverage were mixed, and the period of use after the launch was short. Therefore, it was decided to conduct the analysis without including these drugs in this study. Moreover, to confirm the validity of the analysis with data that did not include COVID-19 drugs, we used data before these COVID-19 drugs were first approved and used in Japan (up to May 2020) and just before registration in the database (up to June 2021) as a reference.

Definition of progression to critical condition.

Patients who progressed to a critical condition due to COVID-19 were defined as those admitted to the intensive care unit (ICU) (KUBUNCODE: A301, A302, A303) or on a ventilator (KUBUNCODE: C164, J026, J045).

Statistical analyses.

Statistical analyses were performed using Stata MP 16.0 (Stata Corp. LCC., Lakeway, TX, USA). Risk factors for serious conditions, adjusted odds ratios (ORs), and 95% confidence intervals were calculated using multivariate logistic regression analysis. The ratio of the number of patients in the dataset to the age distribution of COVID-19-positive patients reported in Japan [16] was analyzed using a 2 × 3 chi-square test, divided into three age categories: under 20 years, 20–64 years, and 65 years and above. The significance threshold was established at P < 0.05.

Results.

Clinical characteristics.

Table 1 presents patient information for the primary analysis. Among the 650,317 patients, 324,127 (49.8%) were male, 326,190 (50.2%) were female, and 197,144 (30.3%) were aged ≥ 65 years, with an average age of 52.1 ± 20.9 years. A total of 20,738 (3.2%) patients progressed to a serious condition (Fig. 1)

Table 1 Characteristics of patients with COVID-19
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Fig. 1
figure 1

Flowchart of COVID-19 patient selection in this study

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Patients with U071 in the ICD-10 were defined as those diagnosed with COVID-19; those with U072 with suspected COVID-19 were excluded. The period covered was from January 15, 2020, to December 31, 2022, in Japan. “Critical condition” was defined as ICU treatment or ventilator use.

COVID-19, coronavirus disease 2019; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; ICU, intensive care unit.

To determine whether the patient composition in the data set is appropriate for the overall age distribution of Japanese infected patients, the following comparisons were made. Of the 827,476 patients in the study, 177,159 (21.4%), 453,173 (54.8%), and 197,144 (23.8%) were aged under 20, 20–64, and 65 years or older, respectively. The number (percentage) of COVID-19-positive patients by age group in Japan, from patients with no symptoms to those with severe disease, was 7,278,424 (28.0%), 15,666,719 (60.2%) and 3,084,335 (11.8%) for the period January 1 2020 to December 27 2022, respectively. This dataset differed from the overall age distribution of Japanese patients (P < 0.01) and included a large number of older patients.

Analysis of all patients with COVID-19.

Figure 2 shows the results for all patients. The factors that significantly increased the risk of progression to a serious condition included older age (> 65 years), hypertension, COPD, cardiovascular disease, cerebrovascular disease, and the use of adrenergic β-receptor blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors, low-dose aspirin, antiplatelet agents, inhaled anticholinergics, insulin, inhaled antidepressants, sodium-glucose cotransporter 2 (SGLT2) inhibitors, inhaled adrenergic agents, ursodeoxycholic acid, antidepressants, and inhalants. Conversely, female sex, type 2 diabetes, dyslipidemia, and the use of angiotensin II receptor blockers (ARBs), metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, pioglitazone, alpha-glucosidase inhibitors, glinides, and inhaled combination drugs significantly reduced the risk of incidence. Chronic kidney disease and the use of statins, fibrates, and inhaled steroids were not significantly different in incidence between patients infected with the Delta and Omicron variants. Figure 3 presents an analysis based on data from before the COVID-19 drugs were approved and available for use. This data included the information of 4,400 patients (Fig. 3A) and 106,998 patients (Fig. 3B) with COVID-19. The trends in odds ratios for most factors were consistent with the results of the analysis over the entire study period.

Fig. 2
figure 2

Risk analysis of risk factors for serious COVID-19 cases

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The forest plot shows the ORs (diamonds) and 95% CIs (horizontal bars) for serious cases.

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; OR, odds ratio; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.

Fig. 3
figure 3

Risk analysis of risk factors during the pre-approval period of COVID-19 treatment in severe COVID-19 cases

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Before the approval and initial use of COVID-19 drugs in Japan (by May 2020) (a), and just prior to the registration of COVID-19 in this database (by June 2021) (b), the forest plot illustrates the odds ratios (ORs) (diamonds) and 95% confidence intervals (CIs) (horizontal bars) for serious cases.

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; OR, odds ratio; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.

1 Background of each of the patients infected with the Delta and Omicron variants

Table 2 presents patient information on the variant-specific analysis. Of the 567,400 eligible patients, 55,577 were infected with the Delta variant and 511,823 with the Omicron variant. Among the patients infected with the Delta variant, 29,760 (53.5%) were males, 25,817 (46.5%) were females, and 15,079 (27.1%) were aged ≥ 65 years. Among the patients infected with the Omicron variant, 246,296 (48.1%) were males, 265,527 (51.9%) were females, and 157,029 (30.7%) were aged ≥ 65 years. The mean age of patients infected with the Delta variant was 50.7 ± 20.1 years, and that of those infected with the Omicron variant patients was 52.3 ± 21.1 years. Further, 6.3% (3,525) and 2.6% (13,434) of the patients infected with the Delta and Omicron variants, respectively, progressed to a serious condition.

Table 2 Characteristics of patients with infection caused by the Delta and Omicron strains
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2 Risk analysis of patients infected with the Delta and Omicron variants

Factors commonly associated with a significantly increased risk of progression to a serious condition in patients with Delta and Omicron variant infections include age ≥ 65 years, hypertension, COPD, cardiovascular disease, cerebrovascular disease, and the use of adrenergic beta receptor blockers, calcium channel blockers, ACE inhibitors, vitamin K antagonists, direct factor Xa inhibitors, aspirin, antiplatelet agents, SGLT2 inhibitors, insulin, inhaled adrenergic agonists, and ursodeoxycholic acid. Conversely, common factors that reduced risk (P < 0.05, OR < 1) include being female, ARBs, metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, alpha-glucosidase inhibitors, and the use of inhaled combination drugs. The prevalence of chronic kidney disease, type 2 diabetes, dyslipidemia, direct thrombin inhibitors, pioglitazone, glinide, inhaled steroids, inhaled anticholinergics, statins, and fibrate drugs did not differ significantly between patients with Delta and Omicron mutant infections (Fig. 4a and b).

Fig. 4
figure 4

Risk factor analysis for severe infections by Delta and Omicron during the respective epidemic periods

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The Delta variant period (a) was defined as the period from August 16, 2021, to December 6, 2021, and the Omicron variant period (b) was defined as the period from January 17, 2022, to December 31, 2022. The forest plot shows the ORs (diamonds) and 95% CIs (horizontal bars) for serious cases.

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; OR, odds ratio; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.

3 Analysis of obesity, smoking, and pregnancy

Table 3 provides patient information on obesity, smoking, and pregnancy. Among the 236,851 eligible patients, 123,754 (52.2%) were males, 113,097 (47.8%) were females, and 122,871 (51.9%) were aged ≥ 65 years. The mean age was 62.1 ± 20.4 years. Risk analysis for serious conditions related to obesity, smoking, and pregnancy is presented in Table 4, with ORs adjusted for sex. Detailed results are presented in Additional File 1. Obesity and smoking were identified as factors that increased the risk of progression to a serious condition. In a stratified analysis of the two groups, patients aged < 65 and ≥ 65 years, smoking was found to be a risk factor for both men and women aged ≥ 65 years, while obesity was a risk factor for all ages and sexes. In addition, pregnancy significantly elevated the risk of developing a serious condition in female individuals.

Table 3 Characteristics of patients with COVID-19 (smoking history, obesity, and pregnancy)
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Table 4 Risks for serious conditions from obesity, smoking, and pregnancy, adjusted by sex-specific odds ratios and stratified analysis
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4 Discussion

This study focused on the risk of COVID-19 severity rather than the risk of death. The results of this study suggest that the risk of COVID-19 severity is increased in patients with cardiovascular disease and those using antithrombotic or anticoagulant medications, whereas it may be reduced in those using medications for diabetes. Considering the urgent need for medical resources in an infectious disease pandemic, focusing on ways to avoid hospitalization and ICU admission was essential. For these reasons, we believe that it is important to evaluate the risk of COVID-19 becoming severe.

Compared to younger adults, older adults are more likely to have several diseases, to develop infectious diseases, including COVID-19, and to progress to a serious condition because their immunity is weakened by aging [17]. In contrast to male individuals, female individuals were at a lower risk of developing a serious condition. This may be because type 1 interferon, which is important for the initial immune response to viral infection, is more potent in females [18].

Moreover, hypertension, cardiovascular disease, cerebrovascular disease, and COPD increase the risk of progression to a serious condition. Pavey et al. reported that when comparing non-hypertensive patients with COVID-19 with hypertensive patients, the OR of the risk of severe disease in hypertensive patients was 2.33 (95% confidence interval 2.16–2.51) and 1.52 (1.40–1.65) when unadjusted for confounding factors and adjusted for age and sex, respectively, with a significantly increased risk in hypertensive patients [19]. Hypertension is considered a risk factor for progression to a serious condition because it occurs with high frequency with aging and is associated with other diseases such as type 2 diabetes mellitus.

In patients with COPD, the expression of ACE2 receptors, which are a route of viral invasion, and mucus secretion and fibrillary motility are reduced, making it easier for viruses to invade [20]. These findings suggest that COVID-19 is a risk factor for the development of a serious condition.

In a meta-analysis by Harrison et al., the mortality rate due to COVID-19 in patients with coronary heart disease was 3.63 times significantly higher than that in those without coronary heart disease [21]. In addition, the incidence of coagulation abnormalities and thrombotic events is reported to be higher in patients with heart failure [22]. It has been reported that patients with COVID-19 with concomitant cardiovascular disease may have elevated plasma cardiac troponin levels [23], suggesting that they are more prone to myocardial damage than patients with COVID-19 without cardiovascular disease. In other words, patients with cardiovascular disease may be at risk for both exacerbation of pre-existing disease and the development of new cardiovascular events due to COVID-19.

Although the mechanism of progression to severe cerebrovascular disease has not been clarified, the incidence of cerebrovascular disease is higher in patients who have progressed to a severe condition and is believed to be associated with the development of thrombosis, with the use of anticoagulants and antiplatelet agents identified as the key risk factor. The mechanism by which the use of these medications is attributed to progression to a more serious condition is not particularly clear, and, similar to hypertension, it is believed to be a risk factor along with cerebrovascular and cardiovascular disease. However, the most important mechanisms by which patients with COVID-19 develop thromboembolism, including stroke, are endothelial cell damage and inflammation caused by cytokine storms and abnormal coagulation [24].

Regarding the use of hypertension medications, the use of adrenergic beta-receptor blockers, calcium channel blockers, and ACE inhibitors is a factor that increases the risk of COVID-19 severity. As hypertension is a risk factor for progression to a more serious condition, it is believed that the same is true for the drugs used to treat it. The use of ACE inhibitors and ARBs that act on the renin-angiotensin system was found to increase progression to a serious condition, while that of ARBs was found to decrease progression to a serious condition. The use of these drugs has been reported to upregulate the expression of ACE2, an infection receptor of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [25], which may facilitate viral entry and reduce the rapid decrease in ACE2 expression due to infection, thereby reducing lung injury and heart damage. The former factor may have caused the difference in results with the use of ACE inhibitors, whereas the latter may have caused the difference in results with that of ARBs. Conversely, the study was unable to definitively determine whether the change in risk was attributable to the underlying disease or the therapeutic drug. Therefore, further analyses of the underlying disease and drug interactions are required, including detailed examinations of these interactions.

Regarding the use of diabetes medications, that of SGLT2 inhibitors and insulin increased the risk of progression to a serious condition, whereas that of metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, pioglitazone, alpha-glucosidase inhibitors, and glinides decreased the risk of progression to a serious condition. Although type 2 diabetes itself is often reported as a risk factor for progression to a serious condition, type 2 diabetes was a slight risk-reducing factor in this study, and patients with diabetes with glycated hemoglobin (HbA1c) > 7.0% had more severe lung involvement due to novel coronavirus infection than did those with HbA1c < 7.0% and patients without diabetes. The severity of pulmonary involvement, mortality, and ventilator use and the ICU admission rate is higher in patients with diabetes with HbA1c of ≥ 7.0% than in those with HbA1c < 7.0% and without diabetes [26]. Moreover, patients with blood glucose levels > 180 mg/dL on admission have abnormal levels compared with those with concentrations managed within 70–180 mg/dL, indicating that not all patients with type 2 diabetes have a higher risk of developing a serious condition [27]. The risk of progression to a serious condition may not be high; however, it may depend on the patient’s blood glucose and HbA1c levels. It is possible that the group of patients taking these drugs included many individuals with stable glycemic control or relatively mild diabetes, leading to a lower risk of progression to a serious condition. As SGLT2 inhibitors are the only oral hypoglycemic agents that increase the risk of progression to severe disease, the use of these inhibitors is believed to reduce the risk of COVID-19-related death in patients with type 2 diabetes [28].

Regarding the use of respiratory medications, there were no significant differences in factors that increased the risk of progression to a serious condition with respect to the use of inhaled adrenergic agents and inhaled anticholinergics and those that decreased the risk of progression to a serious condition with respect to the use of inhaled combination drugs and inhaled steroids. The use of inhaled steroids has not been consistently reported to reduce progression to critical illness or early recovery from COVID-19 in studies using budesonide [29] and not to reduce the risk of death [30]. Inhaled combination drugs include three beta-stimulant-steroid combination drugs and one beta-stimulant-anticholinergic-steroid combination drug. However, it is difficult to clarify which drug is a risk-reducing factor because of the paucity of literature on this subject.

The use of ursodeoxycholic acid increases the risk of progression to a serious condition. Ursodeoxycholic acid prevents SARS-CoV-2 from binding to its infectious receptor, the ACE2 receptor, suppresses proinflammatory cytokines, has antioxidant and antiapoptotic effects, prevents progression to critical illness by increasing alveolar fluid clearance in acute respiratory distress syndrome (ARDS), and inhibits the progression of ARDS to a severe condition by increasing alveolar fluid clearance [31]. More research should be conducted on liver diseases.

However, the relationship with vaccination was not clear in this study. In our analysis of the Delta variant, most patients may have been unvaccinated or may have received one to two doses of the vaccine; further, the patients were expected to be infected with the Omicron variant after most of them had been vaccinated. Because continued vaccination can prevent severe outcomes even with infection with the Omicron variant, the vaccine is likely effective in this period of analysis [32].

In this study, the Delta and Omicron variants did not differ significantly in terms of their risk factors. The number of patients infected with the Delta and Omicron variants was 55,577 and 511,823, respectively, with a difference of approximately 10-fold. This difference may be because the period studied as the Delta variant epidemic was approximately 4 months, whereas the period studied as the Omicron variant epidemic was approximately 1 year.

The OR for cardiovascular disease increased by approximately 0.5 for the Delta variant to over 2 for the Omicron variant, and the ORs for the use of adrenergic β-receptor blockers and calcium channel blockers exceeded 2 for the Omicron variant by a large margin. The overall trend for the Omicron variant was that the OR for factors that increased the risk of progression to a serious condition was higher than that for the Delta variant, whereas the OR for factors that decreased the risk of progression to a serious condition was lower than that for the Delta variant. In other words, patients with risk factors for progression to a serious condition should be more vigilant because the association with progression to a serious condition is stronger in the Omicron variant. Because only a limited number of patients infected with the Omicron variant progressed to a serious condition, we hypothesized that the risk factors for those who progressed to a serious condition would be more meaningful, leading to an increase in the OR. The comparison of risk factors for each mutant variant should continue in the future.

The smoking rate of the study participants was 33.2%. The percentage of current habitual smokers in Japan is 35% in males and 6% in females [33], a difference of approximately two-fold. Smokers in this study were defined broadly, including all patients who had smoked even one cigarette in the past and those who smoked 20 cigarettes daily. Therefore, it is likely that the smoking rate in this study was much higher than that reported in the original data.

Regarding patients with COPD, the expression of ACE2 receptors, which is a route of viral invasion, is increased in patients who smoke [20], and mucus secretion and lineage movement are decreased, making it easier for viruses to invade [21]. Smoking is a risk factor for progression to a serious condition not only in the overall population but also in older adults, male individuals, and female individuals, suggesting that all smokers, regardless of age or sex, should be aware of progression to a serious condition. More detailed studies that consider the number of years of past smoking and the number of cigarettes currently smoked are warranted.

Obesity was a risk factor for the progression to a serious condition in all patient groups. It has been reported that patients with obesity have abnormal adipokine secretion, which induces inflammation and promotes thrombogenesis and embolic conditions [34]. Improvement in obesity status may have significance in the prevention of progression to severe COVID-19 and may help prevent risk factors for the development of serious conditions, such as cardiovascular disease.

Pregnancy was estimated to be a risk factor for progression to a serious condition. Because cardiopulmonary and endocrine changes and increased blood coagulation may contribute to the progression to a serious condition, pregnant women are at high risk of miscarriage, especially in the second trimester of pregnancy [35]. Although the number of weeks of gestation was not considered in this study, it is believed that an assessment of risk during pregnancy should include the results of an analysis focused on patients in the second trimester of pregnancy.

This study has some limitations. The retrospective nature of this study is one of its limitations. The dataset used in this study was derived from the receipt data of DPC-eligible hospitals, which may not include patients treated at non-eligible hospitals or those receiving home-based care. Furthermore, although patient information was anonymized, individual hospital analysis was hindered by the anonymization of hospital names and locations, precluding the exploration of size, regional variation, and functions. The dataset included a higher proportion of older individuals relative to the general age distribution of COVID-19 positive patients in Japan. This discrepancy may stem from the fact that the patients in this dataset required medical treatment, whereas the overall count of COVID-19-positive patients in Japan encompasses those experiencing only minor symptoms and not necessitating treatment.

Second, this study did not include a risk analysis of malignant tumors. Despite the established connection between malignancy and severe progression, it was excluded because of challenges in collecting complications and patient condition information from the database. Future studies should explore the relationship between malignancy type, stages, and metastasis.

A limited number of immunocompromised patients were available for analysis because of exclusion based on factors such as drug-induced, autoimmune, and post-transplantation conditions. Additionally, vaccination data were not included in the database and could not be analyzed in this study.

Smoking data also had limitations, as the database treated occasional past smokers and long-term heavy smokers in the same manner. Moreover, current and past smoking history, as well as the number of cigarettes smoked, was not factored in. The considerable amount of missing height and weight data in the dataset impeded comprehensive patient analysis. For pregnancy, the number of gestation weeks was not considered, warranting further detailed analyses.

5 Conclusions

The study revealed heightened risks of severe COVID-19 progression in patients aged ≥ 65 years, those with hypertension, COPD, cardiovascular or cerebrovascular disease, smokers, individuals with obesity, pregnant women, and those using specific medications such as antihypertensive agents, anticoagulants, antiplatelet agents, insulin, inhaled adrenergic or anticholinergic agents, and ursodeoxycholic acid. In contrast, women, patients on diabetes medications (except insulin and SGLT2 inhibitors), and users of inhaled combination drugs had lower risks. The use of adrenergic beta-receptor blockers, insulin, and inhaled adrenergic agents was consistently linked to high risks of severe progression, independent of age, sex, or variant (Delta or Omicron). Future research should delve into the mechanisms underlying these factors, considering disease severity, laboratory values, and drug use timing and purpose. Moreover, because the risk factors may vary with future mutant strains, comparative analyses are recommended