key: cord-1004194-fwvlgdqk
authors: Saito, Takafumi; Yamaguchi, Tetsuo; Kuroda, Shunsuke; Kitai, Takeshi; Yonetsu, Taishi; Kohsaka, Shun; Torii, Sho; Node, Koichi; Matsumoto, Shingo; Matsue, Yuya; Kodama, Takahide
title: Impact of Body Mass Index on the Outcome of Japanese Patients with Cardiovascular Diseases and/or Risk Factors Hospitalized with COVID-19 Infection
date: 2021-09-28
journal: J Cardiol
DOI: 10.1016/j.jjcc.2021.09.013
sha: b26033f2fd6d16b71643efbc7d4e28e33e8af70d
doc_id: 1004194
cord_uid: fwvlgdqk

BACKGROUND: Obesity is reported to be a predictor of adverse clinical events in coronavirus disease 2019 (COVID-19) in Western countries. However, there are limited data reported regarding the prognostic impact of obesity in Asian patients. We investigated the relationship between body mass index (BMI) and in-hospital outcomes in 580 Japanese patients with cardiovascular disease and/or risk factors and who were admitted for COVID-19 infection using data from 49 hospitals in Japan. METHODS: We analyzed data from the Clinical Outcomes of COVID-19 Infection in Hospitalized Patients with Cardiovascular Disease and/or Risk Factors (CLAVIS-COVID) registry. BMI was classified into four groups accordance with the definition of the Japan Society for the Study of Obesity, as follows: underweight, <18.5 kg/m(2); normal range, 18.5 to <25 kg/m(2); pre-obese, 25 to 30 kg/m(2); and obese, ≥30 kg/m(2). RESULTS: In-hospital death occurred in 15.0% (n=87) of the patients and intubation was performed for 139 (24.0%) patients. In a multivariate analysis, we found a significant association between higher BMI and in-hospital mortality [underweight: hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.23-0.97; p=0.041; pre-obese: HR 1.46, 95%CI 0.84-2.55; p=0.18; and obese: HR 3.28, 95%CI 1.34-8.02; p=0.009 vs. normal range]. In contrast, the association between BMI and the intubation rate was not statistically significant. CONCLUSIONS: Obesity was associated with a stepwise increase in the risk of in-hospital mortality in Japanese patients with COVID-19 infection. The threshold BMI for the increased risk of a worse outcome was 30, which was much lower in comparison to Western countries.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been pervasive in recent years [1] [2] [3] . Patients who have hypertension, diabetes mellitus, dyslipidemia, and history of cardiovascular diseases are more likely to develop critical illness if infected with coronavirus disease 2019 (COVID-19) [4, 5] . A previous report showed that obesity was also associated with poor outcomes in patients with infection in Western countries [6] . In addition, this association has been seen with other respiratory virus infections, including influenza [7] . Obese patients with influenza have a higher risk of hospitalization and death, a longer duration of hospital stay, and a higher risk of requiring mechanical ventilation in comparison to normal weight individuals with influenza infection [8] . Although there are a few reports regarding the prognostic impact of obesity in Asian patients with COVID-19 infection [9, 10] , the results were inconsistent. A previous report from China showed that obesity was linearly associated with severity of COVID-19 only in men but not in women [9] . However, this study was a single centered and the median age was almost 50 years old. In addition, the mortality rate was only 0.8% (3/383). On the contrary, a nationwide epidemiological study in Korea showed a non-linear (U-shaped) relationship between body mass index (BMI) and mortality [10] . However, this study mostly included outpatients and the mortality was only 3.0% (126/4141). Thus, we consider it important to clarify the impact of obesity on outcomes in Japanese populations who were hospitalized with COVID-19 infection because Japanese patients are older than those in other countries and they are generally leaner in comparison to Western populations. In the present analysis, we investigated the relationship between the BMI and in-hospital mortality in Japanese patients with cardiovascular disease and/or risk factors (CVDRF) who were admitted due to COVID-19 infection using the data from a Japanese multicenter registry.

This study was a sub-analysis of the Clinical Outcomes of COVID-19 Infection in Hospitalized Patients with Cardiovascular Disease and/or Risk Factors (CLAVIS-COVID) registry. Detailed information on the CLAVIS-COVID registry has been published elsewhere [11] . Briefly, CLAVIS-COVID was a nationwide multicenter retrospective study that was sponsored by the Japanese Circulation Society. It enrolled Japanese patients with COVID-19 infection who were ≥20 years of age and who were hospitalized at 49 participating hospitals in Japan from January 2020 to May 2020 as the first infection wave in Japan. The diagnosis of COVID-19 was determined by a positive nucleic acid amplification test for SARS-CoV-2. From these registry data, our study used the data of all adults with CVDRF and for whom all BMI data were available. The definition of CVDRF was described in a previous study [11] . We collected the background characteristics, status at admission, treatments, and outcomes of these patients from the database. BMI was classified into four groups, according to the definitions of the Japan Society for the Study of Obesity (JASSO), as follows: underweight, <18.5 kg/m 2 ; normal range, 18.5 to <25 kg/m 2 ; pre-obese, 25 to 30 kg/m 2 ;

and obese, ≥30 kg/m 2 [12] . Hypertension was defined as a history of antihypertensive medication, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg. Dyslipidemia was defined as a history of anti-cholesterol medication, low-density lipoprotein cholesterol ≥140 mg/dl, high-density lipoprotein cholesterol <40 mg/dL, or triglycerides ≥ 150 mg/dL. Diabetes was defined as history of antidiabetic medication or hemoglobin A1c ≥ 6.5%. In-hospital mortality was the primary outcome of this study, and the intubation rate and other adverse outcomes were also analyzed.

The present study was approved by the Institutional Review Board of the Toranomon Hospital. The requirement for informed consent was waived because of the anonymized nature of the data. All participants were notified through homepages or posters at each hospital of their participation in the study, and they were free to opt out of participation at any time. Our study complies with the Declaration of Helsinki and baseline and maximum brain natriuretic peptide, and higher D-dimer. In addition, the median length of hospitalization was significantly longer in lower BMI groups ( Table   1) .

There were no significant differences with respect to the treatments among the groups ( Table 2) . Antibiotics or antiviral treatments were administered to almost half of the patients. Anti-coagulation therapy was administered to almost 20% of the patients.

In-hospital outcomes

The in-hospital outcomes are summarized in Table 3 

We investigated the clinical impact of obesity on in-hospital outcomes for Japanese patients with CVDRF who were hospitalized with COVID-19 infection.

Obesity was associated with a stepwise increase in the risk of in-hospital mortality Infection with SARS-CoV-2 generally causes mild disease; however, in some individuals it progresses to severe respiratory illness characterized by hyperinflammatory syndrome, multiorgan dysfunction, and death [13, 14] . A previous study reported that the risk of COVID-19-related death was strongly associated with higher BMI [15] . In general, obesity is associated with a higher prevalence of cardiometabolic diseases, such as hypertension, hyperlipidemia, and diabetes, which are thought to be linked to worse outcomes [15, 16] . Indeed, in-hospital mortality of our study (15.0%) was much higher than those in previous reports from China (0.8%) [9] and Korea (3.0%) [10] . Although there were differences between previous reports and our study (older, hospitalized population in our study), cardiovascular comorbidities may play an important role for poor outcomes.

We found a linear association between increasing BMI and in-hospital mortality, even after adjustment for covariates. This result was consistent with a report from the Western countries [6] but inconsistent with one from Korea that showed non-linear (U-shaped) association [10] . We consider that the difference derives from differences in patients' backgrounds and mortality rates. Because our study included hospitalized patients with COVID-19, the median age was 67 years old, and the mortality rate was 15.0%. On the contrary, a previous report from Korea included mainly outpatients and mortality was much lower (3.0%) than that in our study.

Our result clarified that the threshold of BMI for increased mortality in Japan was much smaller than that in Western countries. In a previous study [6] , the adjusted HR for death was reported to significantly increase with class III obesity (BMI ≥40.0 kg/m 2 ) in Western countries. In contrast, in our database, the obese group according to the Japanese definition (BMI ≥30 kg/m 2 ) only accounted for 12.1% of the population and showed a significantly higher HR for in-hospital mortality.

The risk of requiring invasive mechanical ventilation is reported to increase over the full range of BMIs, possibly due to impairment of the lung function in association with higher BMI values [17] . Obesity has become a well-recognized risk factor for hospitalization and adverse outcomes in patients with COVID-19 [15] .

However, our results did not show a statistically significant relationship between higher BMI and a higher intubation rate, contrary to the previous report [6] . One of the possible reasons for this discrepancy is that almost half (44/87) of the patients died without intubation. Among the 42 of these patients for whom the cause of death was known, 67% (28/42) died due to respiratory failure. We hypothesize that these patients were likely to have been amenable to intubation. Indeed, the median age of death without intubation (86.5 years) was significantly higher than death with intubation (74.0 years). Although we did not clarify the reason for non-intubation, high age seems to be associated with non-intubation. In the real-world treatment setting, several factors, such as old age and the patient's wishes, may have affected the intubation rate. For the younger generation, efforts towards achieving a healthy weight would help to reduce the rate of adverse events in COVID-19 infection [18] . In addition, we have to clarify better management practices for this population.

Contrary to the results of the multivariate analysis, the low BMI group showed higher in-hospital mortality in a univariate analysis. We consider that this discrepancy occurred due to the fact that elderly individuals comprised the majority of the low BMI group. The low BMI group showed significantly higher median age (80 years old) than those in other groups (55-71 years old) ( Table 1) . From the multivariate analysis (Fig. 1) , age was a significant predictor for in-hospital mortality in our dataset (it showed a 9%

increase in risk of in-hospital mortality as a 1-year increase in age). Thus, we consider that higher in-hospital mortality in the low BMI group could be mainly explained by their old age. In general, the risk of a poor outcome is greater in elderly people with infectious diseases. In fact, in a previous report, old age was associated with a higher mortality rate after COVID-19 infection [11] . In addition, vascular endothelial cell dysfunction, inflammation-associated myocardial depression, stress cardiomyopathy, direct viral infection of the heart and its vessels, or the host response may cause or worsen heart failure, demand-related ischemia, and arrhythmias in this population [19] .

These factors may underlie the associations that have been observed between cardiovascular events and COVID-19 infection [20] .

The present study was associated with some limitations. First, this was a sub-analysis of a retrospective multicenter registry. Thus, a selection bias could not be avoided. In addition, although this study was a large multicenter registry, the sample 

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