Micronutrients and Infection: Interactions and Implications with Enteric and Other Infections and Future Priorities

Abstract

Symposium presentations have focused on the elegant molecular science and the biologic mechanisms by which micronutrients play critical roles in cellular and humoral immune responses, cellular signaling and function, and even in the evolution of microbial virulence. The concluding session examined the practical issues of how best to evaluate the nutritionally at-risk host, especially in the areas of greatest need—an analytical model of nutrient-immune interactions, implications of nutritional modulation of the immune response for disease, and the implications for international research and child health. This overview illustrated how malnutrition may be a major consequence of early childhood diarrhea and enteric infections, as enteric infections may critically impair intestinal absorptive function with potential long-term consequences for growth and development. The potentially huge, largely undefined DALY (disability-adjusted life years) impact of early childhood diarrheal illnesses demonstrates the importance of quantifying the long-term functional impact of largely preventable nutritional and infectious diseases, especially in children in developing areas.

The complexity of the effects of key micronutrients (i.e., vitamins, trace minerals, essential amino acids, and polyunsaturated fatty acids) on host cellular and molecular immunomodulatory responses to infectious agents is matched only by their often overlooked importance in determining health, functionality, and disease. The development of new tools in molecular genetics now enables us to link the basic sciences of immunology and nutrient biochemistry to clinically important infectious diseases and field epidemiology and thus opens new opportunities to bring an understanding of molecular nutritional science to those in greatest need.

Individual and national and international decisions to invest in measures to improve health are based on the availability and cost of effective interventions and on the “value” or health gained by the intervention. The health burden of diseases and injuries is increasingly quantified by the disability-adjusted life year (DALY) calculations that take into account both years of life lost and years lost to disability. The DALY burden of nutrition-related infectious diseases and their interactions, which are now beginning to be quantified, painfully demonstrate the magnitude of our “unfinished agenda” [1, 2].

Nutrition-infection interactions have potentially huge implications not just for traditionally defined overt recognized disease (e.g., diarrhea defined as liquid from one end of a long gastrointestinal canal) but also for subclinical problems (e.g., disrupted intestinal absorptive function from “asymptomatic” enteric infections or micronutrient deficiencies). Either of these overt or covert infectious or nutritional conditions may produce long-term additive or even synergistic effects on physical and cognitive function and thus on full health and productivity. These effects are illustrated by recent studies of intestinal helminths and by ourselves and others of long-term sequelae of early childhood diarrhea.

Long-Term DALY Impact of Intestinal Helminths in School-Age Children

An elegant series of placebo-controlled studies in Kenya and Jamaica revealed that school-age children treated with albendazole literally grew better and had improved physical activity, fitness, and school attendance plus improved cognitive function by several measures 9 weeks to 4 months later [3–13]. These studies enabled Bundy and Chan [14] to recalculate the DALY burden attributable to intestinal helminths and to effectively more than double their global DALYs from 18 to 39 million, a measure that more than doubles the cost-effectiveness calculations for interventions that avert these helminth DALYs and hence the huge importance for defining and applying effective interventions.

Potential Long-Term Burden of Early Childhood Diarrhea

Although a single or brief treatment is less definitively available for childhood diarrhea than it is for intestinal helminths, long-term cohort studies may provide clues about potential lasting consequences of repeated diarrheal illnesses in early childhood. In a prospective cohort of children whom we have followed at least twice weekly from birth as a part of a National Institutes of Health (international collaboration in infectious diseases research project) over the last 9 years, some children are now reaching ages 6–9 years and offer unique opportunities for review of the long-term impact of early childhood illnesses. Table 1 summarizes findings from our initial pilot studies in these cohort children, following their growth (by quarterly anthropometric measurements), their physical fitness and activity (evaluated by the Harvard step test and Kaulins and Willis actometers, respectively), and their cognitive function (by use of the McCarthy Scales Draw-A-Design and Wechsler Intelligence Scale for Children [WISC-III Scaled Coding and Digit Span tests]; Psychological Corp., San Antonio, TX]) [15]. As noted, diarrheal illness burdens in the first 2 years of life (early childhood diarrhea) appear to have profound and lasting effects on impaired growth, impaired physical fitness, and impaired cognitive function at age 6–9 years [15]. Furthermore, these effects on fitness are independent of nutritional status, helminths, respiratory illnesses, hematocrit, activity scores, maternal education, and household income, and on cognitive function (by McCarthy Draw-A-Design test) are independent of hematocrit and early childhood parasitic infections [15].

Table 1

Summary of long-term functional and growth impairment (at age 6–9 years) seen with early childhood diarrhea and parasitic infections.

We have now confirmed and substantially extended our earlier findings in more children and with other tests that show substantial correlations of early childhood diarrhea with prolonged impairments of growth and cognitive function [16]. In fact, these effects are observed even under the best of circumstances: We recently documented the considerable improvements in this community in reduced diarrhea rates and mortality and in improved nutritional status, improvements not seen in nearby communities where surveillance did not take place (Moore SR, Lima AM, Guerrant RL, unpublished data).

The magnitude and potential importance of the effect on fitness is illustrated by the 4%–8% reductions in Harvard step test scores seen with the average-to-maximal diarrheal burdens in children in northeast Brazil [15]. These results were roughly equivalent to those in Zimbabwe sugar cane cutters, who had a 4.3% improvement in Harvard step test scores when treated for schistosomiasis and experienced a corresponding 16.6% increase in work productivity [17]. Early childhood cryptosporidial infections per se are associated with significantly reduced physical fitness at age 6–9 years [15]. Finally, early childhood helminthic infections are also associated with prolonged impairment of growth. These findings extend the findings of previous studies to a much longer impact from much earlier helminthic infections [15, 16]. Thus, the potential long-term impairment in fitness and cognitive function, in addition to growth retardation from early childhood illnesses and diarrheal and other enteric and parasitic infections, may have profound human, economic, and total societal costs that long-term studies have only begun to quantify. Clearly, such documentation and appreciation of long-term effects of early childhood illnesses and infections (likely augmented by micronutrient deficiencies as noted below) will determine the huge potential cost saved (in dollars per DALY averted) by interventions that ameliorate these outcomes.

Malnutrition as a Major Manifestation of Enteric Infections (with or without Diarrhea): The Vicious Cycles with Enteric Infections and Micronutrient Deficiencies

The relationships between early childhood diarrheal illnesses, specific enteric infections, and intestinal helminthic infections and potentially long-term effects on growth, physical fitness, and cognitive impairment are summarized in figure 1 [15, 18, 19]. In addition to the short- and long-term impact of diarrheal illnesses (especially of persistent diarrhea) on impaired growth [20–23], specific enteric infections are increasingly recognized as predisposing to significant growth impairment. Several studies of cryptosporidiosis, enteroaggregative Escherichia coli infections, and Giardia infections (even without overt diarrhea) show they have substantial effects on growth [18, 19, 23, 24]. Thus, malnutrition might appropriately be considered largely as an emerging infectious disease.

Figure 1

The vicious cycle of effects of enteric infections with or without overt diarrhea or persistent diarrhea (PD) on nutritional status and on physical and cognitive development [15, 18, 19].

In addition, many true infectious diseases are largely the consequences of the effects of nutritional or micronutrient diseases [2]. Furthermore, the effects of malnutrition on both the incidence and duration of diarrheal illnesses have been well documented in studies in Brazil and elsewhere [20, 21, 25–28]. Although “catch up” growth may occur in settings in which repeated diarrheal and other illnesses do not occur with frequency [29], repeated diarrheal illnesses during the early development years substantially impair or ablate this critical catch-up growth [21, 22, 30]. The involvement of other childhood infections (e.g., measles, pneumonia, and malaria) plus the nutrient demand by enteric parasites through catabolism, malabsorption, and increased losses further compound this vicious cycle [31].

Micronutrient Roles

The critical role of micronutrient malabsorption in the effects of diarrhea and enteric infections on growth and physical and cognitive development and the potential for micronutrients (including zinc, vitamin A, and perhaps others) in the effects of malnutrition on diarrheal illnesses largely remains to be fully defined. Several studies suggest that zinc and vitamin A may have key roles in determining the duration, frequency, and severity of diarrheal illnesses. Placebo-controlled supplementation trials of specific micronutrients have evaluated their importance in diarrheal diseases in developing areas. Zinc supplementation may reduce diarrhea duration, barrier disruption, and growth faltering in children with diarrhea [32–37]. Similarly, vitamin A deficiency is associated with impaired intestinal barrier function per se [38], and vitamin A may improve outcomes in children with acute or persistent diarrheal illnesses [37, 39–41].

The remarkable potential of micronutrient deficiency to not only impair host physiology and immunology but also to lead to permanently enhanced microbial virulence was shown in an elegant series of studies by Beck and colleagues [42–44]. They demonstrated enhanced coxsackievirus B-3 or A-19 virulence in selenium deficiency in Keshan's disease in China and in epidemic optic and peripheral neuropathy in Cuba, respectively [42–44]. This ability for host micronutrient deficiency to induce permanent mutations to greatly enhanced virulence in the microbial pathogen adds yet another dimension to the disturbing ways that micronutrient deficiencies and infectious diseases of poverty pose new and potentially widespread threats. Add to this the likely, but again poorly quantified, impact of malabsorption of key antimicrobial drugs (e.g., antiretrovirals and antituberculous drugs) on the emergence of drug resistance in impoverished areas of greatest need, and the potentially global magnitude of these threats can begin to be appreciated.

Despite their complexity, these vicious cycles of infection and malnutrition must be critically reexamined and dissected via the new techniques offered by molecular evolution and physiology, so that they can be interrupted to the greatest extent possible. We need to understand the interactions of specific micronutrient deficiencies with diarrheal and other infectious diseases and specific infections with or without overt symptoms in order to evaluate their short- and long-term functional consequences. Only with a concerted effort aimed at correcting host deficiencies as well as acquisition of infections from the environment can these increasingly recognized “vicious cycles” be effectively interrupted. The economic and biologic imperatives to address these micronutrient and infectious diseases of poverty only await the will to direct appropriate resources to their recognition and solution. Sound basic and field data thus become critical to defining these global threats in order to direct our societal priorities.

Commitments for Effective Changes

An indication of the potential huge relevance of micronutrient deficiencies to development is that the US Agency for International Development (USAID) has identified micronutrient deficiencies as a priority. The “USAID is firmly committed to the implementation of programs based on the best scientific evidence. We have identified micronutrient deficiencies as one way to make some inroads into the large and overwhelming problem of malnutrition in low-income countries and its role in disease and mortality particularly in women and children. As a development agency we are concerned with the translation of scientific findings into programs and policies that will benefit vulnerable populations. To this end we need assistance from the participants at this important workshop and appreciate the opportunity to participate here and thank the conveners.”

There is a clear need for good quality research in order to improve policies and programs in all sectors. It is sometimes thought that lack of funding is the main constraint to truly useful research. However, the problem is more complex. Not all researchers aim to have an impact on policy and program decisions or select research questions and conduct studies with program and policy relevance. Even when the research is relevant, it is often ignored by decision-makers. Indeed, many research findings do not reach the population they are intended to benefit.

Research informs policies and programs most effectively when there is a genuine collaboration that links researchers, policy makers, and those most affected by the issues under consideration. This is a departure from the notion that the proper audience for most research is other researchers. If the resulting research products are to be useful to health system managers and policy makers, their information needs must be factored into the research from the start.

Research that clearly defines the dimensions of a problem and identifies its underlying causes can be a catalyst for change, even if the researchers themselves do not recommend a specific course of action. The credibility of the research process also affects the chances for application of research findings. This includes the perceived accuracy and objectivity and appropriateness of the research design and methods. Integral to this is the need for well-developed research hypotheses and clearly defined study cohorts. An important screen for this in low-income countries is the extent to which the research design includes the collaboration of in-country investigators, in order to build indigenous research capability and ensure the dissemination of research results.

Barriers to the practical application of research results need to be identified at the outset of the research. Review of past experience would aid researchers to ensure that their programs do not duplicate previous failures. One solution might be the formal establishment of an international collaborative effort to promote evidence-based scientific investigation for public policy application. Clearly, the identification of barriers is of critical concern to international agencies concerned with improving the health and well being of vulnerable populations. When this is done collaboratively, better decisions can be made about the allocation of funds and evaluation of the relevance of study findings.

In summary, the complex interactions between micronutrient deficiencies and infectious diseases have potentially huge long-term developmental and societal impacts. These effects range from individual long-term functional impairment to effects on microbial virulence or (through drug malabsorption) antimicrobial resistance. Only with a joining of new molecular understanding with careful field epidemiology can we appreciate the magnitude of these challenges or the optimal approach to their solutions.

Priority Directions

Priorities that we have identified to maximize the effects of research on public policy are as follows:

1. Link basic bench molecular mechanistic studies with field work in endemic areas of greatest relevance.

2. Define the role of specific enteric and other infections, with or without overt symptoms (e.g., diarrhea) in contributing to micronutrient deficiencies.

3. Determine the mechanisms of the effects of micronutrient deficiencies on increased susceptibility to infection and when and how they can be reversed.

4. Identify the effects of age on susceptibility to effects of micronutrient deficiencies and on their reversibility by replacement therapy.

5. Quantify, when possible, both short- and potential long-term functional and developmental consequences in humans of micronutrient deficiencies and of micronutrient deficiency-infection interactions.

6. Define potential effects of micronutrient deficiencies on microbial genetics that lead to (potentially irreversible) enhanced virulence or resistance.

Informed consent was obtained from parents and guardians of the children studied. This study was approved by human investigation committees at the Federal University of Ceará, Johns Hopkins University School of Medicine, and the University of Virginia.

Grant support: NIH (AI-30639 and AI-26512).