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See“Pretreatment frailty is independently associated with increased risk of infections after immunosuppression in patients with inflammatory bowel diseases,” by Kochar B, Cai W, Cagan A, et al, onpage 2104.
Although immunosuppressive therapy is the mainstay of treatment for patients with moderate to severe inflammatory bowel disease (IBD), side effects, including infection risk, can limit the use of these medications.
patients with IBD on immunosuppression who were >50 years old were found to have a 3 times higher odds of developing an opportunistic infection as compared with patients with IBD ≤24 years old. Later studies, however, have suggested that age itself may be an insufficient predictor of infectious risk. When disease activity and comorbidity were controlled for, Kirchgesner et al
found that, although older age was associated with a higher absolute risk of opportunistic infections, it was not associated with an increase in relative risk.
As a result, over the last several years focus has shifted away from absolute age, and more toward the concept of frailty as a predictor of adverse outcomes. Frailty, defined as a loss of physiologic reserve, represents a composite risk of age and disease-associated deficits that, through synergy, cause dysfunction of multiple physiologic systems.
and demonstrated that frailty, independent of comorbidity and disability, was a significant predictor of hospitalization and death in older community dwellers. Since then, frailty has been applied to a number of different patient populations, including those undergoing surgery, with similar results seen. More specifically, within a population of patients awaiting liver transplantation, Lai et al
found that frailty was found to be an independent predictor of waitlist mortality. On the whole, these studies underscore the notion that, although advancing age is a risk factor for frailty, they remain distinct entities.
tested this concept in patients with IBD by examining whether pretreatment frailty was associated with infection risk within the first year of starting anti-TNF or immunomodulator therapy. Given the retrospective nature of the study design, frailty was assessed using International Classification of Diseases (ICD) codes that were previously constructed and validated within a population of hospitalized patients ≥75 years of age (ICD codes including but not limited to malnutrition, difficulty walking, and urinary incontinence).
Among 1299 patients initiating anti-TNF therapy, the authors found that 5% of patients (68) had an ICD code relating to frailty within 2 years of beginning therapy. On multivariable analysis, when adjusting for age, comorbidities, corticosteroid use, and combination therapy, pretreatment frailty was found to be an independent predictor of infection risk within the first year of therapy. More specifically, frail patients had a >2 times higher odds of infection after anti-TNF use (adjusted odds ratio, 2.05; 95% confidence interval, 1.07–3.93). Although 56% of these infections were perianal and intestinal abscesses, a sensitivity analysis excluding IBD-related infections yielded similar results (adjusted odds ratio, 2.12; 95% confidence interval, 1.32–3.72). Of note, disease severity was not adjusted for in the analysis.
When examining the 2676 patients on immunomodulator therapy, 212 or 8% of patients were identified as being frail before treatment. After adjusting for the same variables, the authors found that frail patients initiating immunomodulators had 1.81 (95% confidence interval, 1.22–2.70) times the odds of developing an infection within the first year as compared with those who were not frail. Analogous to the anti-TNF cohort, when excluding IBD-related infections, similar results were noted. Additionally, even when stratified by age, frailty remained an independent predictor of infection risk among patients with IBD <60 years of age.
As a result of these findings, should we be assessing frailty within patients with IBD initiating immunosuppression? Although frailty will likely have important implications in IBD disease course and outcomes, there remains work to be done before implementation. Although this study has shown frailty to be an independent predictor of infectious risk associated with immunosuppressive therapy, its retrospective nature is an inherent limitation. Defining frailty by ICD codes includes those who have had adverse outcomes as a result of frailty, and thus likely underrepresents the true population of frail and prefrail patients.
Additionally, patients with IBD represent a unique population given the wide spectrum of age, chronicity of disease, and frequency of malnutrition, which may limit the usefulness of these previously defined measures. As such, prospective studies specifically validating frailty assessments within the IBD patient population are needed.
How frailty will specifically play into our clinical decision-making models remains unknown at this time. The findings represented in this study suggest that frailty may play an important role in determining adverse outcomes within patients with IBD, and as a result this should serve as a springboard for future studies: (1) Are validated prospective measures of frailty able to accurately predict adverse outcomes among patients with IBD? (2) Is frailty more prevalent within the IBD patient population as compared with the general patient population? (3) How does frailty impact response to therapy? (4) Can presurgical assessments of frailty predict postoperative outcomes? and (5) Can targeted interventions in frail patients improve these outcomes? Future translational studies should also focus on investigating biological mechanisms leading to the frailty phenotype.
As we move toward improved risk stratification models within IBD, this study supports the adage that age is just a number. More specifically, among patients with IBD initiating immunosuppressive therapy, frailty, and comorbidities, rather than age alone seem to be better predictors of infectious risk. Although these first data are promising, prospective studies are needed to further explore the relationship between the frailty phenotype and IBD-related outcomes.
Comparative risk of serious infections with biologic and/or immunosuppressive therapy in patients with inflammatory bowel diseases: a systematic review and meta-analysis.
Conflicts of interest The authors have made the following disclosures: ASF has previously published work with Dr. Ananthakrishnan. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltrion, Eli Lilly, Enterome, Ferring Pharmaceuticals, Genentech, Janssen Pharmaceuticals, Landos, Ipsen, Medimmune, Merck, Novartis, Pfizer, Shire, Takeda, Tigenix, Viela bio; and hold stock options in Intestinal Biotech Development and Genfit.
Infections are an important adverse effect of immunosuppression for treatment of inflammatory bowel diseases (IBDs). However, risk of infection cannot be sufficiently determined based on patients’ ages or comorbidities. Frailty has been associated with outcomes of patients with other inflammatory diseases. We aimed to determine the association between frailty and risk of infections after immunosuppression for IBD.