Malnutrition syndromes of childhood are especially important for host defense since long-term effects may occur due to the continuing interaction of the immune system with potentially infectious pathogens. In addition, there are long-term implications for response to immunization and duration of protection. A general outline of how nutrients affect immune function is shown in Table 2.
Low birth weight infants are classified as SGA (small for gestational age), which can also occur in full-term infants, or as AGA (appropriate for gestational age), which is the more common presentation of prematurity. Intrauterine growth retardation (IUGR) is usually associated with placental insufficiency, congenital infection, maternal smoking, exposure to toxins, or a combination of factors. In developing countries, IUGR can be caused by a prenatal deficiency of calcium, vitamin A, B1, and E; and folate. Clinically, low birth weight infants, including AGA premature infants with no evidence of infection, have impaired cell-mediated immunity, diminished cytokine responses, and reduced phagocyte function [94-96]. SGA infants have smaller thymic glands and deficient cytokine responses relative to the AGA infants. It is not surprising that IUGR is linked to poor future health, postnatal infections, sudden infant death syndrome, hypertension, ischemic heart disease, insulin resistance and diabetes. Zinc supplements given to SGA infants have been shown to reduce infectious mortality .
Failure to thrive (FTT) can be caused by primary malnutrition, malignancy, and toxin exposure, congenital anomalies (i.e., Bloom's syndrome, Russell Silver syndrome, immune deficiency, GI disorders, and psychosocial/eating disorders. For most cases of FTT, the causes can be found with a comprehensive history/physical, and limited laboratory studies. Some cases of true FTT have an unknown etiology, with simple under-nutrition due to behavioral abnormalities and inadequate parenting the most common cause. Infants require nutrient rich diets to sustain growth and development. Although rare, exclusively breast fed infants can show signs of growth abnormalities. One cause can be a maternal genetic abnormality in zinc transport into milk, resulting in severe zinc deficiency in the infant . It is widely appreciated that many so-called health food diets and beverages that may be harmless for adults are not appropriate for infants due to their need to maintain continued growth and their unique requirement for additional nutrients. Cases of severe nutritional deficiency, even kwashiorkor, can be caused by consumption of "health food beverages" as an alternative nutrient source for children with perceived food allergies .
Table 2. Mechanisms of nutrient action
Deficiency causes cytokine shifts, activation of the HPA axis, T cell apoptosis
Antioxidant vitamins, C, E, and carotenoids
Saturated/ unsaturated fatty acid ratio
Essential fatty acids n-6, n-3
T, B, NK cells, Deficiency increases
GALT (gas- infection, impairs lym-
trointestinal- phopoiesis associated lymphoid tissue)
Monocytes, Deficiency causes oxi- Anti-inflammatory effects
T cells, dative stress, increases Decreases PGE2 production neutrophils, reactive oxygen species, Increases IFN-y, IL-4 production
NK cells DNA damage Enhances phagocytosis
Monocytes, Deficiency leads to neutrophils, infections, morbidity, T, B, NK cells, mortality GALT
T cells, monocytes,
T cells, NK, monocytes
Monocytes, neutrophils T cells
Monocytes, T, and NK cells
Monocytes, T cells
Increased thymus weight, T cell response, IgA, autoimmunity?
Increased immune response thymic weight, phagocytosis and killing
NK, T cells response, phagocytosis
Decreased Th-2 cytokine and IgA response, NK, B cells, Decreased cilia, microvilli, mucin, abnormal keratin
Increases lymphocyte proliferation, cytokine response, phagocytosis, MHC class II expression
Increases thymocyte proliferation, modulates TNF-a production, increases production of ROS. phagocyte function
Regulation of adhesion molecules, membrane fluidity
Deficiency or excess: decreases chemotaxis, phagocytosis, NK activity
High levels decrease IL-2, IFN-y, ICAM-1, superoxide production
Anti-inflammatory Signal transduction MHC class II
Short bowel syndrome (congenital atresia or surgical resection), and inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn's disease (CD) are commonly associated with chronic malnutrition due to poor GI absorption. Bacterial infections may contribute to intestinal inflammation in genetically susceptible hosts. Malabsorption due to lactose intolerance and gluten-sensitive enteropathy are common causes of GI disease. Prolonged parenteral nutrition, while essential, often correlates with impaired immune responses due to loss of antigenic stimuli, caloric and micronutrient insufficiency. Change in normal flora can result in micro-
infections of the GI tract, which provokes inflammation, motility abnormalities and worsening of malabsorption.
Both UC and CD appear to be multigenic disorders with evidence of familial segregation. Recent studies show that the development of oral tolerance is defective in both UC and CD. In UC patients, clinical investigators have reported that failure to induce tolerance to a neo antigen is associated with disease expression . Inflammatory cytokines have been implicated in the pathogenesis of UC, possibly linked with gene polymorphism of the IL-1 receptor antagonist. Antibodies to neutrophil cytoplasmic antigens (ANCAs) and to mucin are often present in UC, with generalized hyper reactivity to cow's milk protein, either cellular or antibodies, often present.
CD is associated with increased numbers of circulating memory CD4+ T cells and activated mucosal T cells with defective proliferative responses. An abnormal immune response towards endogenous bacteria may be causative. A genetic defect in tolerance induction in CD has been identified . Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to CD . Altered taste and anorexia can cause inadequate dietary intake and lead to zinc deficiency.
Celiac disease is a genetically determined chronic inflammatory intestinal disease induced by an environmental precipitant, gluten, that often presents without clear GI symptoms. Celiac disease may be characterized by damage to the small intestinal mucosa caused by the gluten fraction of wheat proteins and similar alcohol-soluble proteins (prolamines) of barley and rye in genetically susceptible subjects . Clinical severity varies from silent to severe. FTT is the most frequent presentation in the pediatric age group. Increased frequency of other diseases such as type 1 diabetes or autoimmune thyroiditis, Down's syndrome, Turner's syndrome, or IgA deficiency, is found in family members of celiac patients. In developed countries, the prevalence of celiac disease among children and adults with type 1 diabetes exceeds the prevalence in the general population . Reduced levels of vitamin E have also been reported . Exclusively breastfed children with biopsy-proven celiac disease are significantly less likely to present with FTT .
Severity of pulmonary infection often correlates with the degree of intestinal involvement and nutritional status. Lung function correlates with nutritional status . One large study has shown that levels of specific antioxidants vitamin A, vitamin E, carotenoids, and glutathione were lower in CF patients than in controls, decreasing during acute exacerbation, and increasing after antibiotic treatment. Antioxidant levels were decreased with bronchial infection . Only vitamin A and carotenoid were linked with body mass index (BMI). Intestinal inflammation may be a fundamen tal feature of CF. Inflammatory markers such as soluble IL-2 receptor and eosinophilic cationic protein are often increased. Infections are worsened by diminished immune responsiveness, possibly related to abnormal zinc turnover, reduced thymulin activity, and reduced IL-2 and NK activity. Both copper and zinc are reduced in CF [105, 106]. Nutritional therapy includes dietary supplements, increased fat and protein absorption with oral pancreatic enzymes, supplemental fat-soluble vitamins (vitamin K), and omega-3 long-chain polyunsaturated fatty acids, such as docosahexaenoic acid. Evaluation of growth requires a specialized approach .
Development of immune tolerance towards food and environmental antigens is a central requirement for gut homeostasis. The neonate encounters food, environmental antigens and microbes after birth. A functional relationship between the composition of normal commensal microflora and presence or absence of allergies and atopic disease in children has been recently shown by several groups. These findings include a report of reduced colonization with lactobacilli and higher counts of aerobic bacteria in a large study of allergic children  and the demonstration that characteristic differences in neonatal gut flora precede development of allergic responses . A Th2-skewed immune response prevails systemically in the neonate, and contact with microbial antigens acts to repolarize this orientation gradually during the first months of life . Studies strongly suggest that absence of exposure to appropriate microbial signals and lack of a Th2 to Th1 switch is associated with allergic disease in high-risk children. The primary mediators now appear to be regulatory T cells and dendritic cells, which down-regulate inflammatory response through production of IL-10 and transforming growth factor (TGF)-p1. Milk intolerance can be associated with failure to develop immune tolerance mediated by T regulatory cells .
Food intolerance is defined as a reproducible adverse reaction to the ingestion of food or any of its components, i.e., proteins, carbohydrates, fats, and additives. Such adverse reactions include toxic, metabolic, and allergic reactions. Common forms of food intolerance include cow's milk allergy (CMA), lactose intolerance that causes carbohydrate malabsorption, and gluten-sensitive enteropathy (celiac disease). CMA and other food allergies of childhood are often transient; more than 85% of children lose their sensitivity to most allergenic foods within the first 3-5 years of life. Most common allergenic foods in childhood include egg, cow's milk, wheat, and soy. In the case of infants and toddlers, milk and egg are important source of calcium and protein, and dietary restriction may have long-term effects on growth and development. CMA may cause acute diarrhea . Human milk also contains a number of immune-modifying substances, such as IgA antibodies toward bacteria, fungi, foods, and inhalants, and even inhalant allergens, as well as cytokines and chemokines. The protective effect for infection and prevention of atopy development is promoted both by specific immunologically active elements in milk and prebiotic oligosaccharides [113, 114].
Milk allergy is associated with IgA deficiency . A low IgA content in maternal milk may lead to defective exclusion of food antigens and thus predispose an offspring to develop food allergies . In addition, levels of TGF-p, a regulator of the mucosal immune system, may be important. TGF-p induces IgA production and oral tolerance. Inadequate production of TGF-p has been reported in children with CMA alone, and as part of multiple-food allergy presentations. This was associated with increased systemic pro-allergenic IL-4 responses on intestinal antigen contact .
Lactose intolerance is most common cause of carbohydrate malabsorption, with unabsorbed carbohydrate undergoing bacterial fermentation in the colon, producing gas and fluid. Maturational lactose deficiency may occur in premature infants. Both early and late onset congenital defects may occur at any age, with increased incidence in certain populations. Lactose intolerance may be associated with infection or develop in chronic infection such as HIV or parasitic infection [118-121].
Infantile anorexia was first described in a series of case studies, and was initially thought to be a separation disorder . These children exhibit extreme food refusal and frequently fail to take in sufficient calories to sustain growth, and as a result display acute and/or chronic malnutrition. Eating disorders, such as bulimia (BN) and anorexia nervosa (AN), in childhood are characterized by a seriously undernourished state. In contrast, changes in the immune system have been less clear-cut and do not appear to follow the more typical types of malnutrition, such as PEM. In general, adaptive immunity seems to be preserved over long periods and susceptibility to viral infection is not common outside the advanced stages of disease. However, altered cell-mediated immunity in AN and BN is reflected in lymphocyte subset balance and poor response to delayed hypersensitivity tests . A recent study compared healthy women to both underweight AN and normal-weight BN patients and reported that both patient groups had decreased plasma levels of leptin, prolactin, and 17p-estradiol. Plasma levels of cortisol were increased in AN, but not in BN, women. In bulimics, circulating leptin was inversely correlated with the duration of the illness and the frequency of bingeing/vomiting .
Obesity develops when energy intake exceeds expenditure. Human obesity often becomes a permanent condition, and is thought to involve changes in the neural-endocrine network, which regulates energy intake, expenditure and storage . Plasma leptin and insulin are signals in this system. Obesity-prone individuals may have an inborn reduction in their catabolic responses to glucose, leptin and insulin . Involvement of immune pathways in obesity is also likely, as suggested by the role of leptin signaling in immune regulation. One study has revealed a possible relationship between a common inherited IL-6 promoter single-nucleotide polymorphism (174 G/ C), serum leptin and BMI . Obesity is usually characterized by elevated circulating leptin levels, which may contribute significantly to the reported low-grade systemic inflammation. One hypothesis is that obesity involves altered metabolism secondary to changes in microflora. The gut microbiota as a whole is essential for production of short chain fatty acids from polysac-charides, and has been shown to regulate host metabolism through direct effects on fat storage . Leptin secretion is linked to the functions of the hypothalamic-pituitary-adrenal axis and the immune system in response to infection, as shown by a study of leptin and cortisol response in acute sepsis in which survivors had higher levels of leptin . Congenital leptin deficiency is a rare cause of severe early onset obesity characterized by absence of leptin, and carries a high risk of death due to infection in childhood [25, 129]. Generally, the incidence and severity of specific types of infectious illnesses are higher in obese persons and may also be linked to poor antibody responses to antigens in overweight subjects. A direct role for viral infection in obesity has also been proposed . In vitro studies have shown that weight loss in obesity may be associated with improved immune function .
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