Micronutrients as an adjuvant to the mitigation of infections:

On the therapeutic side, extensive research and meta-analysis largely confirms a survival advantage and reduction in morbidity for complicated measles in hospitalised children with high-dose vitamin A supplementationReference Hussey and Klein^6–Reference Huiming, Chaomin and Meng⁸. Similarly, supplementation with oral zinc in diarrhoea, treated with oral rehydration therapy, reduces the duration and severity of episodes, and has been officially recommended by the WHO⁹.

Micronutrients in the prevention of infections:

Ensuring adequate micronutrient status is important for the prevention of certain infections. Although vitamin A has been termed the “anti-infective nutrient,” there is little evidence that it prevents the incidence of new infectionsReference Underwood^10, Reference Semba¹¹. It is more likely that the effect of vitamin A supplementation on preventing death from childhood diseaseReference Sommer, Tarwotjo, Hussaini and Susanto^12, Reference Sommer, Tarwotjo, Djunaedi, West, Loeden, Tilden and Mele¹³ is one of reducing the severity of infectious illnesses. The one area in which this vitamin has actually been strongly suggested to prevent infections is in small premature infantsReference Darlow and Graham¹⁴.

Similarly, although iron supports components of the host defence system such as phagocytosis, there is no evidence of it preventing infectionsReference Iannotti, Tielsch, Black and Black^15, Reference Gera and Sachdev¹⁶. In contrast, zinc is emerging as a nutrient whose supplementation can reduce the risk of infectionsReference Roy, Tomkins, Haider, Behren, Akramuzzaman, Mahalanabis and Fuchs¹⁷ and re-infectionReference Baqui, Black, El Arifeen, Yunus, Chakraborty, Ahmed and Vaughan¹⁸. Vitamin D and infection is a recently emerging area of interest with promise for prophylactic application in epidemic viral diseases such as influenza and diverse microbial infectionsReference Tremezaygues, Sticherling and Pfohler^19, Reference Cannell, Vieth and Umhau²⁰.

Malnutrition, protozoa and multicellular parasites:

One classical scenario of pathogens depleting nutritional stores of the host is the blood loss caused by intestinal hookworms. The biology of protozoa and multicellular parasites is much more complex than that of viruses or bacteria, having a more intricate interaction with host nutritional status. The influence of human nutritional status on the success of parasitic infection has intrigued investigatorsReference Solomons and Keusch²¹. One particular such example is the interaction of host vitamin A status and certain filarial nematodes which have evolved elaborated retinoid receptor systems to access the vitamin A of their hostReference Sani and Comley²².

Human immunodeficiency virus:

The HIV/AIDS pandemic began with the discovery of the syndrome in 1981. A large body of experience from experimental micronutrient interventions, aimed at potentially enhancing immune function, viral counts and disease outcomes in mothers and their offspring, is available for reviewReference Mehta, Finkelstein and Fawzi²³. One paradoxical finding stands out: except for infants, in which vitamin A supplementation can be lifesaving, high-dose vitamin A often has adverse consequences for HIV. On the other hand, a multi-micronutrient supplement has produced benefits in mothers and infantsReference Mehta, Finkelstein and Fawzi²³. The effect of Vitamin D on HIVReference Villamor²⁴ is currently under inquiry, based on a series of theoretical considerations.

With the advent of AIDS, we observe that, in addition to the physiological, the social aspects of the infection can be detrimental to an individual's nutritional well being. The social stigma surrounding AIDS, as well as the loss of working and earning capacity, compromises the food security of the household, contributing further to nutritional deficienciesReference Gillespie, Haddad and Jackson^25, Reference Solomons and O'Donnell²⁶. In retrospect, a similar social dynamic of marginalisation undoubtedly occurred with other infections of chronic evolution, such as leprosy and the white plague (tuberculosis) in the past, but they were not recognised in the infection-malnutrition context.

Other emerging infectious diseases:

AIDS is considered an emerging infectious disease, having only been recognised in 1981. It is, however, not alone in this category of diseases which have emerged, often by zoonotic transmission, to the human population. Table 1 provides a list of selected organisms or infectious syndromes in the emerging category for which virtually nothing is known of the nutritional influences – synergistic, antagonistic or nil – which offer opportunities for new discoveries of potential public health importance. Among the reasons for the emergence of new human pathogens are: migration and changing demographics, rapid international travel, microbial adaptations, altered land use and human behaviourReference Leiby²⁷.

Table 1 A non-exhaustive listing of infectious agents and conditions in the domain of emerging and re-emerging infectious diseases

Overweight and infectious disease risk:

As far back as 25 years ago it occurred to EdelmanReference Edelman³⁵ to ask the question of whether obesity modulates infectious disease and immunity. It is surprising how few investigative responses this call received. In the realm of common consensus, it is suggested that obese individuals are more susceptible to infection than lean subjects. For reasons related to the anatomical distortions of overweight, clinical wisdom accepts as a fact that obese individuals have greater risk of bacteremia and a prolonged wound healing time after surgical operations. There is documentation that the fatty liver of obesity may also favour persistence of the hepatitis C virusReference McCullough³⁶. In addition, obesity increases the incidence of cutaneous infections of interest to the dermatology community; including candidiasis, intertrigo, furunculosis, erythrasma, tinea cruris, and folliculitis. Less common infections include cellulitis, necrotising fascitis, and gas gangreneReference Scheinfeld³⁷.

Antagonistic interactions of iron status and infection:

WeinbergReference Weinberg³⁸ has coined the term “nutritional immunity” to denote the situation in which the deficiency of a nutrient might provide protective advantage to the host by restricting the access to a nutrient required for the proliferation of a specific pathogen. The most common example of an antagonistic interaction arises in the context of iron excess and overload states. In 1949, Elsdon-DewReference Elsdon-Dew³⁹ noted that fulminant amoebiasis was selective to certain ethnic groups in South Africa, namely Bantu males who have an excess of iron due to consumption of an iron-laden brew. Diamond et al Reference Diamond, Harlow, Phillips and Keister⁴⁰ provided a mechanistic context for this phenomenon by showing in an animal model (the hamster) that the iron status of the animal conditions the systemic virulence of Entamoeba histolytica. In further experimental work, Beck et al Reference Beck, Shi, Morris and Levander⁴¹ showed that a normally benign murine coxsackie virus damages heart muscle in vitamin E-deficient mice when overloaded with iron. In related clinical observations in pediatric patients, Brocks et al Reference Brocks⁴² documented an increased risk of gram negative sepsis with parenteral injection of iron dextran supplements.

Malaria has taken centre stage in the contemporary consideration of the antagonistic effects of iron and plasmodial infections. Pregnant women taking iron-containing prenatal supplements in Plasmodium vivax-endemic areas have increased susceptibility to malarial attacks. More dramatically, a major field intervention trial on the island of Pemba in Zanzibar, Tanzania, an area holo-endemic for the more lethal Plasmodium falciparum, was suspended. In-study monitoring revealed adverse effects such as increased hospitalisation and excess mortality in children under 36 months of age who had been randomised to receive 12·5 mg of iron daily, along with 50 μg of folic acidReference Sazawal, Black and Ramsan⁴⁴.

Molecular biology of the immune system:

The examples of discoveries concerning the role of the immune host defence at the molecular biology levels are too numerous and complex to summarise here. The insights began to emerge when immunologists with an interest in nutrition adopted and adapted the emerging tools of molecular biology. A case in point involving zinc is the work performed in Pamela Fraker's laboratoryReference Fraker, Gershwin, German and Keen⁴⁷ in the late 1990 s. She and her colleagues suggested the effects on lymphocyte glucocorticoid receptors from zinc restriction in laboratory rodents as a mechanism for immunosuppression. Emerging from the same era was the work of Melinda Beck and coworkersReference Beck, Nelson and Shi⁴⁸, which showed in a mouse model that the pulmonary damage due to an influenza virus is greater in a selenium deficient animal. At the molecular and cellular basis, the lack of oxidative protection led to an increased oxidative response, which directly spurred on the local inflammation.

Nutrients, nutritional status and immunisations:

It has been considered whether simultaneous delivery of vitamin A and key immunisations (e.g. measles, polio) has any influence of the efficacy of the latter. The consensus was that no interference occurred⁴⁹. More recently, a similar question of nutrient-vaccination interactions has been raised with respect to zinc and a cholera vaccine. Studies in Bangladesh have shown that seroconversion and production of antibodies after an oral cholera vaccine were improved after zinc supplementation, whereas high-dose vitamin A had no enhancing effectReference Albert, Qadri and Wahed⁵⁰.

Manipulation of the immune response:

The manipulation of the immune response takes on a number of creative formats. It has been speculated that early hunter-gatherers' penchant for grazing on the roots of foraged plants introduced anaerobic microbes that protected evolutionary man from infections. The contemporary equivalent of this is the attempts to take advantage of probiotics (live anaerobic fermentation bacteria) to treat or prevent infectious human and animal diseases. This has been explored most with regard to gastrointestinal infectionsReference Penner, Fedorak and Madsen⁵¹. Meta-analyses of published trials indicate the effectiveness of prophylactic use of probiotics to prevent traveler's diarrhoeaReference McFarland⁵² and to avert antibiotic-associated infections with Clostridium dificile Reference Szajewska, Ruszczynski and Radzikowski⁵³. When a more comprehensive view of all the explored applications is taken, diverse efficacy trials have provided more mixed resultsReference Michail, Sylvester, Fuchs and Issenman⁵⁴.

The earliest mammalian milk (colostrum) contains an abundance of immune factors. Since all of the passive immunity for ruminant newborns is passed on through the colostrum, the efficacy of bovine colostrum for treating and preventing human infections has been of clinical and public health interest. Reviews of the topic show that bovine colostrum immunoglobulins survive the passage through the human gastrointestinal tract intact and can have both therapeutic and prophylactic effects against selected pathogensReference Lilius and Marnila^55, Reference Solomons⁵⁶.

A bold gambit for immunology has been therapeutic application of biological response modifiers, notably anti-cytokine therapyReference Buchwald and Pirofski⁵⁷. Dampening down the systemic effects of the acute-phase response by antibodies to suppress inflammatory cytokines was pioneered in the treatment of inflammatory rheumatoid conditionsReference Hochberg, Lebwohl, Plevy, Hobbs and Yocum⁵⁸. Its application to systemic inflammation caused by infectious pathogens is the next frontierReference Dinarello⁵⁹.

Dietary pattern for infections disease resistance:

To what extent the dietary pattern, per se, influences the risk of illness was first explored in the 1980 s in the U.S. National Research Council report Diet and Health ⁶⁰. Since then, dietary guidelines for long-term health and prevention of chronic disease have evolved. For the U.S. population, these are currently set out in MyPyramid⁶¹.

The paradigm of an interaction between food, diet and acute disease has been explored to a much lesser extent. However, in the instance of infant feeding, a strong association between the exclusive or predominant consumption of maternal milk and protection from infections in the infant and toddler years has been documentedReference Villalpando and Hamosh^{62, 63}.

Some interesting observations of diet-infection associations in somewhat older children (preschoolers) came from a field study in TanzaniaReference Fawzi, Herrera, Willett, Nestel, el Amin, Lipsitz and Mohamed^64, Reference Fawzi, Herrera, Willett, Nestel, el Amin and Mohamed⁶⁵. This was part of a vitamin A supplementation intervention, which failed to reveal any benefit in morbidity or mortality. However, the total intake of vitamin A from the diet was protective against childhood infections. Insofar as total dietary vitamin A in rural Tanzania may be a proxy measure for consumption of carotene-rich foods, e.g. herbs, vegetables and pigmented fruits, the disease resistance observed may be attributable to constituents of these pigmented foods.

Pathogen virulence and the nutritional status of the host:

Keshan disease was a progressive and fatal pulmonary disease in East Asia, which was found to be associated with low selenium status in the populationReference Jackson⁶⁶. Beck et al Reference Beck, Kolbeck, Shi, Rohr, Morris and Levander⁶⁷ looked at murine models of pulmonary infections using a usually benign mouse coxsackie virus which produced a self-limited, mild respiratory infection in well-nourished mice. The same virus, however, turned virulent when selenium deficient mice were inoculated; the mutated virus isolated from the selenium-restricted host was also now lethal when passed into selenium-sufficient animals. This observation points towards a new departure in nutrition:infection interactions - where the micronutrient status of the host could determine the virulence of pathogens across a whole societyReference Beck and Levander⁶⁸.