Association Between Body Mass Index and Severe Infection in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Cohort in Japan

Background: Although previous studies have evaluated risk factors for the incidence of severe infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), the relationship between body mass index (BMI) and severe infection in AAV has not been elucidated. We hypothesized that elderly AAV patients with a low BMI would be at a higher risk of infection. To evaluate this hypothesis, we investigated the association between underweight at AAV diagnosis and subsequent severe infection in elderly AAV patients. Methods: This single-center retrospective cohort study included 98 consecutive elderly AAV patients treated at the Aichi Medical University Hospital in Japan between 2004 and 2018. The relationships between BMI at diagnosis and subsequent rst severe infection were assessed using multivariate Cox proportional hazards models. Results: During the entire follow-up period (median, 22 months; interquartile range, 7 ‒ 52 months), 32 (32.7%) patients developed at least one severe infection. Low BMI (< 18.5 kg/m 2 compared with normal BMI [18.5 ‒ 23.0 kg/m 2 ], adjusted hazard ratio [HR] = 2.70, 95% condence interval [CI]: 1.18–6.17; P = 0.018) and use of methylprednisolone pulse therapy (adjusted HR = 3.09, 95% CI: 1.37–6.99; P = 0.007) were the signicant predictors of severe infection. Furthermore, an interaction effect between unintentional body weight loss (> 10%) within 6 months before diagnosis and low BMI was observed (P < 0.001). Conclusions: Low BMI was associated with a higher risk of severe infection in elderly AAV patients, suggesting that careful management may be required to prevent the development of infection in patients with a low BMI. Further studies are needed to elucidate the optimal treatment strategy for these patients. Data are the HR, 95% CI, and P value from Cox proportional hazard regression analyses. The multivariate model was adjusted for the baseline characteristics, including age, sex, lung involvement, serum creatinine level, diabetes mellitus, use of mPSL pulse therapy, and BMI groups (low, normal, and high BMI). “Normal BMI” was used as the reference category.

Body mass index (BMI) has been regarded as an indicator of nutritional issues; malnutrition can lead to underweight, while overnutrition can lead to overweight [19]. To date, although the association between BMI and the incidence of infection has been evaluated in several general population-based observational studies [19][20][21][22][23][24][25][26][27][28], the results, according to the participants' characteristics, were inconsistent. Furthermore, no previous studies have focused on patients who are immunocompromised due to immunosuppressive treatment, including patients with AAV. Therefore, the clinical impact of BMI on the incidence of infection in AAV patients receiving immunosuppressive therapy remained unknown.
In the present study, we hypothesized that elderly AAV patients with a low BMI would be at a higher risk of development of infection. To evaluate this hypothesis, we investigated the association between underweight at the diagnosis of AAV and subsequent severe infection in elderly AAV patients, using a single-center, retrospective cohort from Japan.

Study population
The present study included 126 adult patients who were diagnosed with AAV, including GPA, MPA, and EGPA, based on the classi cation of the AAV by the European Medicines Agency algorithm [29], at Nephrology and Rheumatology centers in the Aichi Medical University in Japan between 2004 and 2018.
The study protocol was approved by the Ethics Committees of Aichi Medical University (approval number 2018-H350, date November 3, 2019). The need to obtain patients' informed consent was waived due to the retrospective nature of the study.

Data collection
Baseline characteristics, at the start of immunosuppressive therapy, were collected retrospectively from patients' medical records and included the following: age; sex; BMI; body weight loss > 10% within 6 months before diagnosis; serum creatinine level; serum albumin level; C-reactive protein level; serum IgG level; presence of diabetes mellitus; Birmingham Vasculitis Activity Score (BVAS) 2003 [30]; organ involvement; anti-myeloperoxidase (MPO) and anti-proteinase 3 (PR3) ANCA levels; use of immunosuppressive treatment, such as induction immunosuppressive therapy; methylprednisolone pulse therapy (0.5 or 1.0 g/day for 3 consecutive days); intravenous cyclophosphamide (CYC) or rituximab (RTX) use, and maintenance therapy; oral CYC use, azathioprine (AZA) use, methotrexate use, and RTX use.

Outcomes
The primary exposure of interest was the BMI at the diagnosis of AAV. BMI was de ned according to the World Health Organization Asian Standard [32]; underweight was de ned as BMI < 18.5 kg/m 2 , normal weight as BMI 18.5-22.9 kg/m 2 , overweight as BMI 23.0-24.9 kg/m 2 , obesity I (moderate obesity) as BMI 25.0-29.9 kg/m 2 , and obesity II (severe obesity) as BMI ≥ 30 kg/m 2 . Because of the small number of overweight, obesity I and II patients, we combined these three groups into a "high BMI" group. Accordingly, we strati ed patients into three BMI categories: low BMI (BMI < 18.5 kg/m 2 ), normal BMI (BMI 18.5-23 kg/m 2 ), and high BMI (BMI > 23 kg/m 2 ).
The main outcome of interest was the development of severe infection, which was de ned as infection requiring hospitalization for any causes. Remission was de ned as the absence of clinical signs and symptoms of active vasculitis (BVAS = 0) for more than 2 months. Relapse was de ned as clinical signs of vasculitic activity in any organ system, followed by an increase in corticosteroid dosing and/or add-on use of immunosuppressive agents after development of remission, as previously described [33]. Other outcome data, including information about end-stage renal disease (ESRD) requiring dialysis, death, and hospitalization due to causes other than infection, was collected. Patients were followed up until December 2019 and data were censored at death or on the last day of attending examination in our hospital before December 2019.

Statistical analyses
Baseline patient characteristics were summarized according to the three BMI categories, and are presented as a percentage for categorical variables and as median (interquartile range) for continuous variables with both normal and skewed distributions.
The associations of BMI with outcomes were assessed using univariate and multivariate Cox proportional hazards (CPH) models. The multivariate models were adjusted for the following potential confounding factors; age, sex, lung involvement, diabetes mellitus, serum creatinine level, use of methylprednisolone therapy, and BMI (low, normal, and high BMI), based on the clinical experience and theoretical considerations.
Furthermore, we assessed the effect of changes in body weight loss (> 10%) within 6 months before diagnosis and low BMI for the primary outcome in a multivariate model, adjusted for age, sex, lung involvement, diabetes mellitus, serum creatinine level, and use of methylprednisolone therapy.
The proportional hazard assumption for covariates was tested using scaled Schoenfeld residuals. For continuous variables, the Wilcoxon rank-sum test was used to evaluate the signi cance of intergroup differences. Categorical variables are expressed as percentages and were compared using the Fisher's exact test. The cumulative probability of the development of a rst severe infection was calculated using the Kaplan-Meier method and log-rank test.
The level of statistical signi cance was set at P < 0.05. All statistical analyses were performed using JMP, version 14.0.0 (SAS Institute, Cary, NC, USA) and STATA version 13.0 (StataCorp LP, College Station, TX, USA).

Predictors of severe infections
Predictors of severe infection were evaluated using the clinical data, including age, sex, BMI, serum creatinine level, and use of methylprednisolone pulse therapy on the basis of previous reports [15][16][17][18]. Univariate CPH analyses identi ed several statistically signi cant predictors of increased infection risk, namely, older age, use of methylprednisolone pulse therapy, and low BMI (  (Table 2). Furthermore, an interaction effect between unintentional body weight loss (> 10%) within 6 months before diagnosis and low BMI was observed (P < 0.001).

Discussion
The present study revealed that low BMI at diagnosis is signi cantly associated with subsequent development of severe infection in elderly AAV patients in a single-center, retrospective cohort from Japan. Our results suggested that malnutrition at diagnosis might increase vulnerability to infection during immunosuppressive treatment in elderly patients, in particular. No previous study has focused on the clinical impact of underweight on infection risk in elderly AAV patients, and our results may provide a basis for identifying elderly AAV patients requiring more careful management to reduce severe infection risk.
Previously, the relationship between BMI and infection risk has been evaluated in several general population-based cohort studies; however, these studies did not yield consistent results according to the participant's characteristics [20]. First, in children and adolescents, underweight is considered a signi cant risk factor for infection in developing countries, probably re ecting malnutrition and poor hygiene standards [21]. On the other hand, data from industrialized countries suggest that infection rate is increased in obese children and adolescents [22]. For adults, several studies have suggested a Ushaped increase in the infection rate for both underweight and obese participants, in industrialized countries [23][24][25].
In terms of elderly populations, Thomas et al. studied 619 inpatient geriatric patients (≥ 75 years) and showed that both underweight (BMI < 20 kg/m 2 ) and overweight (BMI > 28 kg/m 2 ) increased the risk for overall infection, including pneumonia, urinary tract infection (UTI), diarrhea, and others (incidence risk  [26]. However, their study showed that men experienced UTIs more frequently than did women, although, among the older adults, women are usually more susceptible to UTIs than are men [27]. Although the study ascribed this to the fact that more men than women were supplied with urinary catheters, their study participants might not re ect the general population and the results should be interpreted with caution.
Additionally, a meta-analysis that included a large number of cohort studies, including 19538 nursing However, no previous studies had focused on the association between BMI and incidence of infection in immunocompromised patients who are on immunosuppressive treatment. Therefore, it is essential to assess the clinical effect of BMI on infection risk in patients receiving immunosuppressive treatment. In the present study, we focused on elderly AAV patients who are at high risk for infection due to immunosuppressive therapy, and found that underweight at diagnosis was a signi cant predictor of the risk of severe infection.
Furthermore, previous studies [19,26,27] did not assess body weight change as an important factor for diagnosing malnutrition [34]. We here assessed the impact of body weight loss in the 6 months preceding diagnosis on subsequent severe infection. We found a signi cant effect interaction between unintentional body weight loss exceeding 10% in the 6 months prior to diagnosis and of low BMI (< 18.5 kg/m 2 ) on the development of severe infection, suggesting that patients who were severely malnourished due to unintentional weight loss might be more vulnerable to immunosuppressive treatment, increasing their risk for developing severe infection.
Although the precise mechanism of the in uence of BMI on the immune system is unresolved, in undernourished subjects, depleted leucocyte, lymphocyte, and T-cell counts, increased CD4/CD8 ratios, and decreased CD2/CD19 ratios have been found [35,36]. In addition, several factors with immunomodulatory effects, including physical activity [37], nutritional aspects (dietary composition or supplements) [38], and well-being [39] might modulate the infection risk.
The present study had several limitations. First, because of the retrospective, observational nature of the present study, evaluation of the clinical consequences of an altered immune response could not fully adjust for confounding factors, such as the underlying immune condition or co-morbidities of each patient. In addition, the various immunomodulatory factors mentioned above could not be assessed in the present study. Further studies should investigate the impact of these factors. Second, most of our patients were elderly MPA patients from Japan; hence, the results may not be generalizable to young or middle-aged or GPA patients from other geographic areas. Third, we were unable to assess the effect of the lifetime duration of BMI and its status over the entire follow-up period on the outcomes; hence, the impact of change in BMI after starting immunosuppressive treatment could not be assessed. We believe that the potential preventive measures focusing on improving the nutritional intake of these high-risk patients should be evaluated in further studies.
In conclusion, the present study identi ed a lower BMI as a signi cant predictor of the risk of severe Availability of data and material: All data were fully anonymized (Table S1).

Competing interests:
There are no con icts of interest to declare.  Cumulative probability of the rst severe infection

Supplementary Files
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