Age Modifies the Association Between Obesity and Mortality in Individuals Hospitalized with Severe Sepsis

To the Editor: Although obesity is strongly associated with several chronic conditions,1 the role of obesity in acute illness is less clear, with some studies describing an "obesity paradox," an apparent protective effect of obesity.2 Preliminary studies suggest that obesity may be associated with lower mortality in individuals with sepsis,3, 4 although some evidence is conflicting.5, 6 Although the incidence and case fatality of sepsis is higher in older adults, it is unknown whether obesity-related immune dysregulation and clinical outcomes differs across the age spectrum. The objective of the current study was to determine whether age modifies the association between obesity and mortality in individuals with sepsis. This was a secondary analysis using data from the 2010 and 2011 California State Inpatient Database (SID), part of the Agency for Healthcare Research and Quality Healthcare Utilization Project (HCUP). Information on hospital visits for adults aged 20 and older hospitalized from the emergency department with an explicit International Classification of Diseases, Ninth Revision (ICD-9) discharge diagnosis of severe sepsis (995.92) or septic shock (785.52) was included. Obesity was defined according to the validated ICD-9-based chronic disease indicator that the HCUP provided. This is a dichotomous (yes/no) variable based on the ICD-9 code for obesity because actual body mass index (BMI) or other body composition measurements were not available. The primary outcome was in-hospital mortality. Demographic covariates included age (analyzed in decades), sex, and race and ethnicity. Other factors, coded as dichotomous (yes/no) variables, included skilled nursing facility residence and comorbidities defined according to the validated ICD-9-based chronic disease indicator provided in HCUP for diabetes mellitus, hypertension, congestive heart failure, chronic pulmonary disease, cancer, and renal failure. Multivariable logistic regression models were constructed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the adjusted association between obesity and in-hospital mortality. Separate adjusted obesity-mortality models stratified according to age category were constructed to evaluate effect modification according to age. Analyses were performed using Stata 12.1 (Stata Corp. LP, College Station, TX). Of the 116,566 visits that met the inclusion criteria, 13,991 (12.0%) were coded as visits by obese individuals. Overall, 30,712 (26.3%) visits resulted in death during the hospital admission. Obesity was associated with substantially lower in-hospital mortality (18.4% vs 27.4%; absolute difference −9.0%, 95% CI = −9.7% to −8.3%). After adjusting for covariates, obesity was inversely associated with in-hospital mortality (OR = 0.74, 95% CI = 0.71–0.77). In the adjusted models stratified according to age, the association between obesity and mortality differed according to age, with a weaker association with younger age (aged 20–29, OR = 0.96, 95% CI = 0.61–1.51; aged 30–39, OR = 1.09, 95% CI = 0.85–1.42; aged 40–49, OR = 0.94, 95% CI = 0.80–1.10) than with older age (aged 50–59, OR = 0.76, 95% CI = 0.68–0.84; aged 60–69, OR = 0.75, 95% CI = 0.68–0.82; aged 70–79, OR = 0.75, 95% CI = 0.68–0.82; aged 80–89, OR = 0.62, 95% CI = 0.55–0.70; aged ≥90, OR = 0.73, 95% CI = 0.51–1.04) (Figure 1). Similar results were observed when age categories were dichotomized to younger than 50 (OR = 0.99, 95% CI = 0.87–1.13) and 50 and older (OR = 0.65, 95% CI = 0.62–0.68, P for interaction <.001). Obesity was inversely associated with in-hospital mortality in individuals hospitalized for severe sepsis, and age modified this association such that obesity was associated with lower mortality in older adults but not in younger adults. These results are consistent with those of other studies that have reported an inverse association between obesity and in-hospital mortality in critically ill individuals.3, 4 Studies demonstrating no association between obesity and mortality included younger individuals,5, 6 whereas those focusing on older adults reported an inverse association between obesity and mortality in individuals with sepsis.4 It is unknown why obesity might protect against mortality in individuals with sepsis, particularly in older adults. CD4-positive T-lymphocytes and B-lymphocytes are depleted in severe sepsis,7 and aging-related immune dysfunction impairs pathogen clearance.8 Adipose tissue is believed to have many functions, including immune modulation. Accordingly, obese older adults may chronically live in an immune-stimulated rather than immune-suppressed state, which might improve pathogen clearance, although this requires further study. One limitation is that obesity status was based on validated ICD-9-based chronic disease indicator and was not calculated from measured or self-reported height and weight. Visits by some obese individuals, particularly those with a BMI toward the lower limit of obese, may not have been classified as obese according to ICD-9 code and thus would have been misclassified as not obese. The nonobese group included underweight individuals who, because of frailty and underlying comorbidity, may have been more likely than normal-weight individuals to die from sepsis (thus modestly increasing the overall mortality of the nonobese group). Nonetheless, this study reports the novel finding that age may modify the association between obesity and mortality in individuals with sepsis. Future studies are needed to elucidate the relationship between obesity and sepsis outcomes and to determine the biological effects of adipose tissue immune function in aging and sepsis. These data were presented as a poster presentation at the American College of Emergency Physicians annual Scientific Assembly, October 2014, Chicago, IL. Conflict of Interest: Dr. Abbate was supported by National Institutes of Health (NIH) Grant T32AG000279, and Dr. Ginde was supported by NIH Grant K23AG040708.