Kochar B, Cai W, Cagan A, Ananthakrishnan AN
Gastroenterology 2020 Feb 25;S0016-5085(20)30243-2. doi: 10.1053/j.gastro.2020.02.032. Online ahead of print.
© Raphael Luber
The growing arsenal of therapies available for Inflammatory Bowel Disease (IBD) is improving IBD physicians’ ability to target remission. However, risk of infectious complications associated with immunosuppression is a reality that weighs in the minds of physicians and patients alike, affecting the acceptability of these treatments . Both treatment- and patient-related risk factors for infection have been identified in observational studies. Systemic steroids and combination anti-tumour necrosis factor (anti-TNF) and immunomodulator therapy are particularly associated with increased risk of infection, while non-modifiable patient factors include older age and non-IBD comorbidities [2–4]. Accordingly, this perceived risk results in reduced use of effective therapies in older people, despite risk of disease progression and a need for surgery similar to that in young people [5,6].
As explained by Kochar et al., however, chronological age does not capture the physiological heterogeneity in older populations, possibly leading to treatment being unnecessarily conservative in some. Furthermore, reliance on chronological age may lead to underappreciation of risk in younger people. Accordingly, more accurate tools for risk stratification of patients in the setting of immunosuppressive therapies are required.
In this context, Kochar et al. explored frailty, an emerging multifactorial measure of general health reserve, as a potentially more comprehensive tool in the assessment of infection risk in immunosuppressed IBD patients. They performed a large retrospective cohort study in which frailty was defined using a series of International Classification of Disease (ICD) codes adapted from the previously validated Frailty Risk Score . Factors included protein-calorie malnutrition, delirium or dementia, mobility difficulty, falls, and urinary or faecal incontinence, among others; presence of at least one of these factors in the two years prior to commencing immunosuppression classed a patient as frail.
Patients were stratified according to frailty (fit versus frail) and by treatment (immunodulators and anti-TNF). The primary and secondary outcomes assessed were, respectively, occurrence of a serious infection and infection requiring hospitalisation, both within a year of commencing treatment.
Among 1299 patients treated with an anti-TNF, 68 (5%) were frail. The median (IQR) age of frail anti-TNF patients was 41 (28–53) years, compared with 35 (25–50) years among fit patients (p=0.02). Of patients in whom anti-TNF treatment was commenced at >60 years of age, 8% were classed as frail. Frail patients had a higher median C-reactive protein pre-anti-TNF (48 mg/L vs 12 mg/L, p=0.01) and a higher median number of comorbidities (6 vs 2, p<0.01); they were also more likely to have had IBD-related hospitalisation and surgery pre-treatment.
A total of 2676 patients commenced immunomodulators, 19% as combination therapy, with 212 (8%) classed as frail. Frail immunomodulator patients had a median age of 44 (32–61) years, compared with 38 (26–53) years among fit patients. Similar trends to anti-TNF patients were noted in terms of number of comorbidities and pre-treatment IBD-related hospitalisation and surgery. Interestingly, frail patients were more likely to receive combination anti-TNF immunomodulator therapy (25% vs 18%, p<0.03).
Frail patients commencing anti-TNF treatment were more likely to experience an infection within a year (19% vs 9%, p=0.01, OR 2.32, 95% CI 1.23–4.37), and frailty remained an independent predictor even after adjusting for age, comorbidities, steroid use and combination therapy (aOR 2.05, 95% CI 1.07–3.93). Other significant predictors included ≥1 co-morbidity (aOR 3.21, 95% CI 1.79–5.76) and concomitant immunomodulation (aOR 1.76, 95% CI 1.21–2.57).
There were similar findings in those commenced on immunomodulators. Frailty was a predictor of infection within the first year of starting an immunomodulator (17% vs 7%, p<0.01, OR 2.59, 95% CI 1.74–3.83), even after adjusting for confounders (aOR 1.81, 95% CI 1.22–2.70).
Interestingly, frail patients under the age of 60 years had higher odds of infection in both anti-TNF (aOR 2.28, 95% CI 1.17–4.44) and immunomodulator (aOR 1.89, 95% CI 1.17–3.03) groups compared with those over 60 years. .
The commencement of systemic immunosuppression requires an individualised evaluation of risk and benefit, with caution applied in patients at greatest risk. While age and comorbidities are commonly used as risk factors in clinical practice, they underappreciate the heterogeneity of function and physiological reserve across the spectrum of ages. The results of this study indicate frailty to be a novel, more nuanced risk factor for infection in IBD patients, independent of age and co-morbidities. Assessment of frailty may be used to better risk stratify particularly older patients who may benefit from either avoidance or delivery of immunosuppression.
The concept of frailty, both in research and in clinical practice, is poorly defined . This study used a frailty risk tool based on ICD codes developed and validated in older (>75 years) people . However, the median age of patients meeting the criteria of “frail” was 41–44 years, considerably younger than the validation cohort. This had the potential to nullify group differences, and yet increased risk of infection was still displayed in the frail cohort. While not addressed in Kochar et al.’s study, this begs the question as to what factors most commonly categorised patients as frail. Given the high prevalence of malnutrition in IBD patients , it is plausible that this potentially correctible factor contributed significantly, particularly among the younger patients.
Frailty, malnutrition and IBD are interrelated [10,11]. Malnutrition contributes to the frailty syndrome and was found to be independently correlated with infectious complications in a general population of older patients . As the authors note, in addition to predisposing to malnutrition, IBD may result in a syndrome with similar characteristics to frailty, including sarcopenia, weight loss and fatigue, possibly due to chronically elevated inflammatory mediators. As such, frailty is relevant to both old and young IBD patients.
While data with regard to improvement of frailty, by nutritional or other means, to prevent infection is sparse , correction of nutritional status pre-surgery in order to reduce postoperative complications, including infection, is well accepted in IBD . Accordingly, addressing malnutrition and frailty may be important pre-immunosuppression in IBD patients. As malnutrition is a potentially correctible factor, a low threshold for nutritional intervention may serve to reduce infectious complications in the setting of immunosuppression. This requires future studies. On the other hand, absence of frailty or malnutrition in older patients may offer reassurance when commencing immunosuppressive therapy in this population.
Raphael Luber completed his gastroenterology training in Melbourne, Australia, and is currently undertaking an IBD clinical fellowship at Guy’s and St Thomas’ Hospitals in London. He has a particular interest in therapeutic drug monitoring, intestinal ultrasound and the role of diet in IBD.