Tor Strand 97

Nutritional determinants of infection and immunity



Research interests

1. Childhood diarrheal disease and nutrition - an overview.

2. Diarrheal diseases - the disease spectrum.

3. Micronutrients and diarrhea.

3.1. Zinc.

3.2. Vitamin A.

4. Diarrhea- important causative agents.

5. Preventive interventions against childhood diarrhea.

6. Ongoing research


 


Research interests


1. Childhood diarrheal disease and nutrition - an overview. Diarrheal disease kills approximately 4 million children in developing countries annually. Poor sanitary conditions and hygiene lead to a high microbial load, and protein energy malnutrition as well as other nutritional deficiencies are prevalent. Diarrheal disease and other infectious diseases worsen an already existing nutrient imbalance and impair the resistance to infections. An improvement in public and personal hygiene and increased access to uncontaminated water and clean, nutritious food will reduce the burden of diarrhea disease. While awaiting these changes, more directed measures for disease prevention and case management need to be implemented.

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2. Diarrheal diseases - the disease spectrum. While 25% of the deaths related to diarrhea is caused by dysentery, it was believed that the remaining was caused by acute dehydration. Recent work has shown that as much as 40 - 50% of all diarrhoeal deaths are caused by persistent diarrhea, defined as diarrhea lasting 14 days or more. Forty per cent of persistent diarrhea is associated with growth faltering, a reflection of a severe nutritional insult. During a diarrhoeal episode, micronutrients, e.g. zinc, are lost in the stool, absorption is often reduced and there may be reduced intake of food due to inanition. The secretion of vitamin A, mainly as retinol in the urine, is increased substantially.

An important risk factor for persistent diarrhea, i.e. diarrhea lasting >14 days, is protein energy malnutrition (PEM). Moreover, antecedent PEM substantially increases the risk of death in persistent diarrhea. Recent research indicates that the increased risk of persistent diarrhea encountered by children with PEM may to a large extent be attributed to micronutrient deficiency; vitamin A and zinc having so far received the greatest attention. The mechanisms behind this observation are not clear but may be related to an impaired immune response and/or to a reduced ability of intestinal cell regeneration. Promotion of a well-balanced diet and possibly specific micronutrient supplementation during acute diarrhea may thus prevent persistence.

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3. Micronutrients and diarrhea. Several micronutrients, especially those which have effects on cellular regeneration and differentiation, have an important effect on the resistance to infectious diseases. The cells of the immune system are labile and their half-lives are short, approximately one to two weeks, in body fluids. To mount an immune response it is necessary to generate large populations of immunologically active cells. Another important defense against infections is our cellular lining (epithelial cells), e.g. in skin, respiratory system and digestive system which act as mechanical barriers against microbial pathogens. The cells of this system are also labile and an active cell division is necessary to maintain this barrier. Thus, factors that impair cell division impair our resistance to infectious diseases.

In many developing countries, including India and Nepal, traditional diets offered to children have low vitamin A, folate, vitamin B12 and zinc contents and low zinc bioavailability. Supplementation with zinc and vitamin A has been proven to be of benefit in reducing morbidity of diarrheal diseases in several countries. Meta-analysis of published studies on vitamin A supplementation and mortality has shown a 23 % decline in childhood deaths. More clinical research in the area is a high priority of the World Bank, WHO and most national essential health research programs.

Before recommending large scale programmatic supplementation with micronutrients to prevent persistent diarrhea, extensive research is needed to quantify the effect of such interventions. Furthermore, comprehensive studies are needed to elucidate the biological effects of micronutrient supplementation in malnourished children.

From the perspective of the national programs it is also important to promote practices that will increase the availability of foods rich in micronutrients, identify nutrition related educational messages that are site specific and lead to increased intake and bioavailability of micronutrients.

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3.1. Zinc.
Zinc is normally provided through the mothers milk as well as in other food. Animal products give more zinc than plant products. The mothers milk is rich in zinc but this steadily declines to 6 months after birth, where after it remains relatively low. It is, accordingly, from this point that the children are most susceptible to zinc deficiency. Zinc is usually excreted through the feces and during diarrhea, a child looses substantial amounts of zinc. As zinc deficiency is likely to worsen diarrhea, a vicious cycle of zinc deficiency-diarrhea- zinc deficiency might be established.

Zinc is crucial for the normal function of many organs in the body, it is a cofactor for approximately 300 known enzymes, it is a membrane stabilisator, important for the production of DNA, and therefore for cell division and differentiation. Zinc deficiency has a marked impact on rapidly dividing cells like those in the mucosa, skin, hair and blood. It is crucial for the regeneration of intestinal epithelial structures following an enteric infection. A model for zinc deficiency is the rare disorder Acrodermatitis enterophatica. Children with this inborn error of metabolism, that interferes with zinc absorption, have marked growth retardation, brittle hair and hair loss, chronic diarrhea and immune suppression associated infections. Zinc supplementation results in complete cure.

The most important experimentally induced immunological effects of zinc deficiency are on the cellular immunity and the reduction of t-lymphocytes (especially CD4), as demonstrated in human and animal studies. Thymus involution is frequent in PEM as well as in zinc deficiency, this is reversible upon zinc supplementation.

3.2. Vitamin A. Vitamin A (retinol) can either be ingested as such or synthesized within the body from plant carotenes. The best sources of preformed vitamin A are animal products such as liver, milk and kidney, where it occurs largely in the form of fatty acid esters. The clinical features of vitamin A deficiency are impaired dark adaptation followed by night blindness. Later, dryness of the conjunctiva and the cornea (xerophthalmia) occurs as a result of keratinisation; corneal ulceration and dissolution keratomalacia eventually occurs, superimposed infection is a frequent accompaniment. Vitamin A deficiency is a common cause of blindness in developing countries, affecting 250 000 children per year. The most important effect of subclinical vitamin A deficiency is, however, the impaired resistance to several important infectious diseases, including diarrhea. Large supplementation trials with vitamin A has shown a considerable impact in reducing overall child mortality.

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4. Diarrhea- important causative agents
. Rotavirus and enterotoxigenic Escherichia coli (ETEC) are the most important pathogens causing acute diarrhea. Rotavirus has a high virulence, i.e. most cases are severe with a considerable case fatality ratio (CFR) and occur in epidemics, usually in the cooler/dryer periods of the year. Rotavirus is estimated to be responsible for 20% of all diarrheal deaths and 6% of diarrheal episodes in children under 5 years. ETEC infection is even more common but causes severe illness more rarely. A review from 1986 suggests that, every year, 130 million children (i.e. equivalent to the entire world's birth cohort) develop rotavirus diarrhea, 18 million of whom experience clinically overt dehydration resulting in 850,000 deaths, a figure comparable to those due to ETEC diarrhea, malaria or measles. Most children in developing countries develop rotavirus diarrhea in their first year of life.

Seven main different rotavirus serotypes are known, only three causes disease in humans and the vast majority of these belong to serogroup "A". Very few viral particles are needed to cause disease and they are usually transmitted through polluted water or food. The disease lasts for about five to seven days and dehydration may develop and progresses rapidly, particularly in infants. The virion consists of three shells: an outer capsid, an inner capsid, and a core. The outer capsid consists of two proteins, VP4 and VP7, the inner capsid is formed by VP6, and the core is formed by VP2. The genome segments are contained within the core. VP4 and VP7 are neutralizing antigens, meaning that antibodies directed against these antigens following natural or experimental exposures neutralizes viral infectivity. Neutralizing antibodies to either VP4 or VP7 is sufficient for virus neutralization. VP6 is the major group-specific antigen and is the primary antigen detected by commercial assays for rotaviruses. Previous studies have suggested that the rotavirus vaccines may be less immunogenic in developing countries than in developed countries. Several potential differences in the epidemiology of rotavirus between industrialized and developing countries may explain the variability of results between settings. These include earlier age of rotavirus infection, neutralization of the vaccine strain by breast milk antibodies, host factors (e.g. micronutrient deficiency), and concomitant circulation of atypical rotavirus strains.

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5. Preventive interventions against childhood diarrhea. Until recently, the program strategy of the World Health Organization (WHO) control of diarrheal disease program was focused on wide usage of oral rehydration therapy (ORT). Experience from most countries has shown that, because of logistic problems, physicians reluctance to advocate oral rehydration salts (ORS) and limitations in ORT compliance in the homes, high usage rates are difficult to achieve, and, more importantly, to sustain. Furthermore, from an epidemiological point of view, it is important to realize that ORT has no preventive effect against diarrheal disease and does not limit the spread of the micro-organisms causing diarrhea. Obviously, ORT must be promoted further, but even with a complete coverage, according to WHO's recent estimates, ORT can prevent no more than 30% of diarrheal deaths, as it is ineffective against acute diarrhea with severe dehydration, persistent diarrhea and dysentery. Case management of acute diarrhea must accordingly be expanded to prevent severe episodes (many of which are caused by rotavirus) and prolonged diarrhea and the associated growth faltering. Lastly, effective measures for primary prevention of acute diarrhea and persistent diarrhea need to be developed. An effective means of preventing diarrhea is to develop and adopt vaccines against the most important enteropathogens. However, in contrast to many of the other important infectious diseases of children in DCs, very little progress has been so far made towards the development of effective vaccines against diarrhea.

On this background, the WHO and the international scientific community have established priority areas on which research aimed at reducing the burden of acute diarrhea and persistent diarrhea should focus. These areas encompass both preventive as well as curative approaches to diarrheal disease control. The preventive strategies encompasses a wide range from improved water supply to vaccine development, while curative approaches range from improved ORT to micronutrient replenishment during acute diarrhea. Recently, our collaborators in India, among others, have shown that daily supplementation with zinc given to moderately undernourished children with diarrhea are beneficial in reducing disease severity and duration.

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6.Ongoing research

Animal models of immunity in zinc deficient animals

Interventions studies of zinc supplementation in children where deficiency is suspected.


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