The Costly Vicious Cycle of Infections and Malnutrition

Abstract

Over a half century ago Leonardo Mata and Nevin Scrimshaw, described how the children of Santa Maria Cauque who had repeated enteric and respiratory tract illnesses progressively fell off their projected normal growth curves [1]. Since then, numerous studies have documented that infectious diseases as diverse as human immunodeficiency virus (HIV), leishmaniasis, trypanosomiasis, shigellosis, and campylobacteriosis, can have detrimental effects on the nutritional status, among other long-term consequences [2–4]. Molecular tools have further revealed how common and problematic infections can be, even without overt acute symptoms [5, 6]. Infectious diseases worsen nutritional status through a plethora of known mechanisms: reduced food consumption due to cytokine production, disrupted intestinal absorption, increased catabolism, urinary excretion of micronutrients, and alterations in nutrient utilization [4].

However, malnutrition is not just a consequence of infectious diseases; it can also be a key determinant. Indeed, malnutrition is the most common cause of secondary immunodeficiency and has been dubbed as nutritionally acquired immunodeficiency syndrome (N-AIDS) [7]. Through its effect on the host's adaptive and innate immune responses, malnutrition can alter the risk of acquiring and spreading pathogens as well as their severity and treatment response. Furthermore, even in the absence of acute symptoms, malnutrition and infections can synergistically have long-term clinical consequences such as stunted growth or impaired cognitive function. This is especially troubling in early childhood, but may also pertain to often “asymptomatic” (or silent) infections in adults [3, 6, 8, 9]. Thus, malnourished states often worsen and can be worsened by infectious diseases; hence creating a vicious cycle.

Tuberculosis is the poster child for the bidirectional relationship between malnutrition and infectious diseases [7]. Weight loss is a cardinal tuberculosis symptom, which is mediated largely through anorexia induced by the inflammatory milieu, increased catabolism due to fevers, and possibly an anabolic block that favors oxidation and excretion of amino acids instead of protein synthesis to generate lean body mass [4, 10]. In a large Indian study, more than half of the persons with tuberculosis (PWTB) were malnourished with body mass indices (BMI) below 18.5 kg/m² [8]. BMIs as low as 10.3 kg/m² were documented in this cohort.

Conversely, malnutrition is the leading risk factor for tuberculosis worldwide; 1 in 5 incident tuberculosis cases in 2021 were attributable to malnutrition—a higher proportion than HIV and smoking combined [4]. The aforementioned Indian study found that PWTB who were severely undernourished (BMI < 16 kg/m²) prior to tuberculosis disease onset, had a 2-fold increased risk of unfavorable outcomes [11]. PWTB who were severely undernourished at the time of diagnosis had a 4-fold increased all-cause mortality. Similar observations have been made in other contexts [7].

Unfortunately, the impact of malnutrition remains underappreciated and epidemiological studies of tuberculosis often do not include nutritional status as a covariate [12]. Not accounting for N-AIDS results in unmeasured confounding in studies of tuberculosis as well as other infectious diseases. This deflates the impact of nutrition, which is a modifiable risk factor and reduces interest in nutritional interventions for infectious diseases.

Nutritional interventions can have dramatic outcomes. The recently published RATIONS trial that demonstrated that providing a food basket costing less than 50 cents per day per person alongside nutritional counseling, successfully reduced incident tuberculosis among household contacts of PWTB by 40% [13]. Participants received rations of rice and lentil that provided 750 Kcal/d, including 23 g of protein daily, as well as multimicronutrient tablets. Further, PWTB who received support in this study had reduced mortality and improved weight gain compared to cohorts that did not receive nutritional support. This randomized trial demonstrated that historical observations on nutritional support in reducing tuberculosis incidence and mortality hold true today [7]. Of note, the RATIONS trial succeeded in reducing incident tuberculosis where other interventions that provided single micronutrients, such as vitamin D, did not [14]. This may speak to the fact that rescuing malnourished individuals from a single nutrient deficiency may be necessary, but not sufficient, for resuscitating their immune function.

To catalyze scientific innovation at the intersection of nutrition and infectious diseases, we must take some key steps (Figure 1). First, we must modernize the tools we use to define malnutrition. Anthropometry provides only a crude picture of body composition and provides no data on micronutrient deficiencies, which also have significant impacts on disease acquisition and outcomes [10]. For instance, even after adjusting for BMI, vitamin A deficiency was associated with a 10-fold increased risk of tuberculosis incidence in a Peruvian cohort [15]. Several micronutrients affect the functioning of the immune system, particularly vitamins A, D, C, E, B6, and B12 as well as folate, zinc, iron, copper, and selenium [16]. Newer tools such as metabolomic testing and inexpensive point-of-care micronutrient testing, such as the NutriPhone platform, can help define malnutrition in a more nuanced way and tailor nutritional interventions to the needs of our patients [17]. As some infectious diseases researchers may have limited experience with nutritional assessment and interventions, partnering with colleagues specializing in nutrition will help advance research on nutrition and infectious diseases.

Figure 1.

Suggested actions to understand and break the vicious cycle of infections and malnutrition.

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Ultimately, we need well-funded and adequately powered clinical studies to investigate the role of antimicrobials, vaccines, beneficial microbiota, and dietary supplementation with micronutrients and macronutrients to disrupt the vicious cycle of malnutrition and infectious diseases. Special attention to social determinants of health will be necessary, such as food security, water, sanitation, breast feeding, and education that clearly underlie both infection and malnutrition risks; hence, offering a potential multipronged approach to these interacting interventions.

These clinical studies should be augmented by molecular tools and models to elucidate pathways, establish causality, and test interventions [9]. Doing so could help identify multiple, potentially synergistic points of potential interventions to break the cycle and prevent potentially devastating acute or long-term outcomes. Clinical research must be complemented by operational studies to identify innovative and efficient delivery designs for nutritional interventions and policy research to assess the cost-effectiveness of these interventions.

Although Mata and Scrimshaw were writing about infections and malnutrition half a century ago, the salience of their findings has only increased. Globally, approximately 735 million people experienced food insecurity and hunger in 2022 [18]. In the coming years, pandemics, armed conflict, and climate change are likely to exacerbate malnutrition, particularly among individuals who are already vulnerable to infectious diseases. It is therefore critical for us as clinicians and researchers to disrupt, through scientific discovery and advocacy, the vicious cycle of microbes and malnutrition that entraps millions in misery.

Notes

Author contributions. R. L. G. conceived the manuscript. P. S. and R. L. G. both contributed to the writing, editing, and revising of the manuscript.

Disclaimer. The funders had no role in study design, analysis, or reporting.

Financial support. This work was supported by the National Institutes of Health (grant number K01AI167733-01A1 to P. S.); the Burroughs Wellcome Fund-American Society of Tropical Medicine and Hygiene (postdoctoral fellowship to P. S.); US Civilian Research and Development Foundation (grant number USB-31150-XX-13 to P. S.); federal funds from the Government of India Department of Biotechnology, the Indian Council of Medical Research, the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, and the Office of AIDS Research and distributed in part by CRDF Global; and the Warren Alpert Foundation (grant to P. S.).

References

Author notes