Tuberculosis-Related Malnutrition: Public Health Implications

To the Editor—With great interest, we read the recent article by Sinha et al regarding public health implications of undernutrition and tuberculosis (TB) [1]. Indeed, nutritional status is a significant factor in the development, reactivation, and treatment of TB, and the authors rightfully point out that the prevention and treatment outcomes of TB can benefit from increased awareness on this topic. Malnutrition has been defined as “a state resulting from lack of intake or uptake of nutrition that leads to altered body composition (decreased fat free mass) and body cell mass leading to diminished physical and mental function and impaired clinical outcome from disease” [2]. In patients with TB, 2 different types of undernutrition/malnutrition (we prefer the term “malnutrition” as it is well-established in the context of disease [2]) can be present: (1) hunger-related malnutrition before being actively infected; and (2) disease-related malnutrition with established infection, due to a combination of loss of appetite, malabsorption, and inflammation-driven catabolism [2]. A low body mass index (BMI) is a characteristic of chronic malnutrition such as hunger-related malnutrition [2]. However, disease-related malnutrition leads to loss of fat-free mass in all individuals, including those who are overweight or obese [2]. Therefore, even TB patients with either normal or high BMI may be malnourished, resulting in negative changes in body composition (ie, significant loss of muscle mass). A better understanding of the concept of malnutrition and its relation to TB may contribute to the World Health Organization (WHO) goal of ending the TB epidemic [3]. Malnutrition can detrimentally affect the treatment of TB, but there is more to explore regarding the complex interactions between malnutrition and TB. We hypothesize that malnutrition in relation to treatment outcome may be an underestimated factor because of both malabsorption of TB drugs and a different volume of distribution related to changes in body composition, that is, loss of fat-free mass. We suggest adding changes in pharmacokinetics to the proposed future research topics associated with malnutrition and treatment outcome of TB. Pharmacokinetic variability resulting from changes in malabsorption and body composition can influence both efficacy and toxicity, and needs to be studied in more detail. Bioavailability of anti-TB drugs largely depends on solubility and the intestinal permeability capacity of the digestive tract [4]. Patients with TB may suffer from malabsorption because of malnutrition and/or comorbidities such as diabetes and human immunodeficiency virus/AIDS [5]. Subsequently, decreased absorption of anti-TB drugs is likely to result in low drug exposure. This may lead to unfavorable outcome by treatment failure and development of drug resistance [6]. Whereas there is the risk of low drug exposure, malnutrition may also induce a risk for overdosing. An important hallmark of malnutrition is decreased fat-free mass [2]. Therefore, unmet nutritional needs in the context of disease often lead to substantial loss of fat-free mass, even in individuals with overweight or obesity. Because bodyweight and body length do not provide information on body composition, food intake, or functional ability, as also alluded to by Sinha et al, BMI as a measure for nutritional status does not enhance recognition of malnutrition. Thus, malnutrition may remain unidentified in overweight and obese patients. For TB drugs with volume of distribution reflected by fat-free mass (eg, ethambutol, aminoglycosides), decreased fat-free mass may result in overdosing, with inherent increased toxicity and concentration-dependent adverse effects. As an example, we have reported that with total body weight being used for dosing, obese patients are at risk of ethambutol overdosing [7]. Clearly, there is a need to increase our knowledge and awareness of nutritional status regarding pharmacokinetics. As stated by Sinha et al, the WHO has stressed that all patients with active TB should receive individualized nutritional assessment and management, including dietary counseling and nutritional interventions, to prevent treatment failure [8]. Nutritional status and anti-TB drug exposure should both be assessed and monitored over time, as both nutritional status and pharmacokinetics change [9]. The risk for both inadequate drug exposure resulting from malabsorption and decreased fat-free mass should be taken into account, and until better predictive models for drug exposure are developed, we will need therapeutic drug monitoring (TDM) [5], combined with drug susceptibility testing, to improve outcomes and reduce drug toxicity by tailoring treatment [10]. Exploration of a TDM program for malnourished TB patients may be helpful to assess the relationship between malnutrition and bioavailability of TB drugs. Research exploring nutritional assessment and monitoring as an integrated part of TB treatment is ready for prime time. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.