NNIW59 - Nutrition Support for Infants and Children at Risk

Editor(s): R.J. Cooke, Y. Vandenplas and U. Wahn. vol. 59


The Development of Atopic Phenotypes: Genetic and Environmental Determinants

Author(s): U. Wahn, E. Von Mutius, S. Lau, R. Nickel

Atopic manifestations may be present from infancy to adolescence. Atopic dermatitisrepresents the first clinical manifestation followed by allergic symptoms of theupper or lower airways. IgE responses to alimentary or environmental allergens arehallmarks of atopy in childhood. Characteristically infantile IgE responses to cow’smilk and hen’s egg are the first immunological markers of atopy. In many cases theyare followed by IgE responses to indoor or outdoor allergens, which suggests a highrisk for the development of persistent asthma in childhood. During recent years a varietyof genes for both asthma and atopic dermatitis have been described. Infantile diet,early exposure to environmental allergens and a variety of environmental and lifestylefactors may act as strong modulators of atopy during the first decade of life.

Food Allergy to Proteins

Author(s): A. Nowak-Wegrzyn

Food allergy is defined as an immune system-mediated adverse reaction to foodproteins. Class 1 food allergens are represented by peanut, egg white, and cow’s milk;they are heat- and acid-stable glycoproteins that induce allergic sensitization via gastrointestinaltract and cause systemic reactions. Class 2 food allergens are homologousto proteins in birch tree pollen and class 2 food allergy develops as a consequence ofrespiratory sensitization to the cross-reactive pollen. Class 2 food allergens are veryheat-labile and tend to induce reactions limited to oral allergy symptoms. In contrast,plant nonspecific lipid transfer proteins are resistant to heating and tend to inducesystemic reactions. Analysis of IgE-binding epitopes with SPOT membranes revealedthat cow’s milk-, egg- and peanut-allergic subjects without IgE antibodies against certainsequential epitopes of the major allergens were more likely to achieve tolerancethan subjects whose IgE antibodies were directed against those epitopes. Subsequently,peptide microarray showed a correlation between reaction severity and the intensityof IgE binding and the number of epitopes recognized of patients’ immune responsesagainst peanut allergens. Taken together, these data suggest that the epitope recognitionpattern and intensity of IgE binding are important determinants of severity andduration of food allergy.

Hypoallergenicity: A Principle for the Treatment of Food Allergy

Author(s): K. Beyer

Food allergy is a common disease with the treatment of choice being completeavoidance of the incriminated food. In cow’s milk allergy a hypoallergenic milk substituteis necessary during infancy and childhood. Hypoallergenic formulas are producedthrough enzymatic hydrolysis of different sources such as bovine casein or whey followedby further processing such as heat treatment and/or ultrafiltration. Accordingto the degree of protein hydrolysis the resulting products have been classified into‘extensively’ or ‘partially’ hydrolyzed. Reduction of allergenicity should be assessed invitro and in vivo. Hypoallergenic formulas might also be based on amino acid mixtures.These elementary diets can be considered as nonallergenic. Several novel therapiesare currently being explored in food allergy. One of the most promising approaches isthe immunotherapy with mutated proteins. For this approach, alteration of the IgEbindingsites through single amino acid substitution is performed resulting in reducedto complete loss of IgE binding. For the major peanut allergens such mutations wereintroduced into the cDNA sequences and successfully expressed as hypoallergenicrecombinant proteins. In peanut-sensitized mice, the use of these modified proteinsco-administered with adjuvant such as heat-killed Escherichia coli showed promisingresults for future therapeutic approaches.

The Concept of Hypoallergenicity for Atopy Prevention

Author(s): A. Von Berg

Infancy represents the period in which an individual may be at the highest risk ofsensitization. During the first year of life around 2.5% of neonates experience hypersensitivityreactions to cow’s milk protein, which is highly associated with early exposureto cow’s milk. Attempts to avoid sensitization in this very early period of life andto prevent allergic diseases focus on diets with reduced allergenicity and possibly onthe induction of oral tolerance. Hydrolyzed infant formulas are characterized by areduced allergenicity and thus recommended as substitute or supplementary tobreastfeeding during the first 4–6 months of life for infants at high risk of developingatopic diseases. This concept of hypoallergenicity has been shown effective in clinicalstudies. Both partially and extensively hydrolyzed formulas have demonstrated apotential in protecting from allergic diseases, mainly atopic eczema and food allergy.The in vitro characterization of allergenicity by the degree of hydrolyzation and peptidesize, however, does not necessarily predict the immunogenic effect in humans, asit could be shown that the preventive effect seems to be dependent on the processrather than on the degree of hydrolyzation, which could be best explained by a possibleproduction of tolerogenic epitopes.

The Concept of Oral Tolerance Induction to Foods

Author(s): G. Lack

The conventional wisdom is that early exposure to allergenic food proteins duringpregnancy, lactation, or infancy leads to food allergies, and that prevention strategiesshould therefore aim to eliminate allergenic food proteins during pregnancy, breastfeeding,and early childhood. Prolonged exclusive breastfeeding and delayed weaningonto solid foods is therefore seen as an effective public health policy to prevent allergies.However, there is little epidemiological data to support this belief. Interventionalstudies on dietary elimination have failed to reduce IgE-mediated food allergies.Conversely, there is preclinical data and some clinical data to suggest that early cutaneousexposure to food protein through inflamed skin leads to allergic sensitizationand that early oral exposure results in the induction of tolerance. New strategies toprevent food allergy in infants need to be put to test in randomized controlled interventionalstudies.

Chronic Enteropathy: Molecular Basis

Author(s): F.M. Ruemmele

Major advances in the understanding of the pathophysiology of chronic andintractable diarrhea of infancy allow a new conceptual view of this heterogeneousgroup of disorders. Two major types of chronic ‘intractable’ enteropathies can bedistinguished. (1) Congenital-constitutive forms are characterized by intrinsic enterocytedefects. To date three different types have been identified on a morphologicalhistologicalbasis: microvillous inclusion disease, intestinal epithelial dysplasia and theso-called syndromatic diarrhea. These disorders are characterized by a high degree ofconsanguinity in the affected families. An autosomal recessive transmission was suggested,but the genes involved have not yet been identified. (2) Immunoinflammatoryenteropathies starting within the first months of life, such as autoimmune enteropathies,can share the clinical picture of constitutive enteropathies; however, mostoften there are associated extraintestinal symptoms. A loss of function mutation in theFOXP3 gene located on Xp11.23-q13.3 causes a distinct X-linked form of severeautoimmune enteropathy. The functional consequences of FOXP3 mutations whichpoint to a defect of regulatory T cells are currently under investigation. With theincreasing understanding of the molecular basis of these distinct diarrheal disorders,new treatment strategies will emerge within the next years, giving new hope to thesecritically ill children and their families.

Chronic Enteropathy: Clinical Aspects

Author(s): T. Gibbons, G.J. Fuchs

Diarrheal disease is a major cause of childhood morbidity and mortality worldwide.Chronic enteropathy with subsequent persistent diarrhea and associated viciouscycles of malnutrition, increased gut permeability and secondary immunodeficiencyare particularly devastating in the childhood population. The major causes of chronicenteropathy differ significantly between developed countries and developing countries.In developed countries, infectious and postinfectious diarrhea as well as abnormalitiesin immune response including celiac disease, food-induced allergic enteropathyand idiopathic inflammatory bowel disease account for most cases of chronicenteropathy. In developing countries, syndromic persistent diarrhea associated withmalnutrition and secondary immunodeficiency due to human immunodeficiency virus(HIV) infection predominate as the major causes of chronic enteropathy. These lattertwo causes account for a disproportionate share of the more than 2.5 million deaths ofchildren under 5 years of age due to diarrhea each year worldwide. From a practicalperspective, diagnostic evaluation of chronic enteropathy in developing countries isoften limited to identifying potential causative enteropathogens and antimicrobialtreatment. Proper management with an emphasis on fluid homeostasis and protocolizednutritional therapy and rehabilitation is essential to successful treatment of syndromic persistent diarrhea.

Transition from Parenteral to Enteral Nutrition

Author(s): P.J. Milla

Children are unique as their food intake must provide sufficient nutrients notonly for the maintenance of body tissues but also for growth. Improvements intechniques for nutritional support has resulted in very long term parenteral nutritionbeing available for those with chronic intestinal failure in addition to those whorequire short term parenteral feeding either following surgery or whilst treatmentfor an underlying enteric disease becomes effective. Parenteral nutrition isrequired whenever insufficient nutrients cannot be provided enterally to prevent orcorrect malnutrition or to sustain appropriate growth. Somatic growth is fastest ininfancy and puberty but other organs such as the brain may only grow and differentiateat one particular time. When a period of more liberal feeding intervenescatch-up of growth and function occurs. In adolescence the risk is of not achievinggrowth potential. Timing and methods of weaning from parenteral to normal nutritionremain controversial. In infants and children it is essential to consider carefullywhether gastrointestinal function is sufficient for enteral nutrition to adequatelysupport them. Thus the time when the infant and child can be weaned from parenteralnutrition will depend both on the activity of the underlying disease and theage and size of the infant or child.

Chronic Enteropathy and Feeding

Author(s): S. Salvatore, B. Hauser, Y. Vandenplas

Enteropathy defines abnormalities of the small intestinal mucosa, visible with thelight microscope, of various etiologies, that can be separated into acute versus chronicconditions. This review focuses on these areas in which recent progress has beenmade. Severe infections increase mucosal permeability and induce local expression ofco-stimulatory molecules allowing antigen penetration in the mucosa, T cell activationand possible disruption of oral tolerance. Biotherapeutics are of importance in theprevention and treatment of (chronic) enteropathy of infectious origin. Celiac diseaseand cow’s milk protein allergy are key examples of chronic enteropathy. The dietaryapproach to allergy has evolved to include active stimulation of the immature immunesystem in order to support the establishment of tolerance. Supplementation with probioticsmay provide maturational signals for the lymphoid tissue and improve the balanceof pro- and anti-inflammatory cytokines. Enteral polymeric feeding is effective inCrohn’s disease. Dietary nucleotides may improve growth and immunity, optimizematuration, recovery and function of rapidly dividing tissue. Adequate dietary lipidsare important not just for caloric value but also for immune-modulatory effects. Lipidsmay prevent allergic sensitization by downregulating inflammatory response (n-3 butnot n-6 fatty acids) whilst protecting the epithelial barrier, regulating immune functionand modifying the adherence of microbes to the mucosa, thereby contributing tohost-microbe interactions.

Stressed Mucosa

Author(s): G. Davidson, S. Kritas, R. Butler

Stress has been defined as an acute threat to the homeostasis of the organism. Themucosal lining of the gastrointestinal tract, a single layer of epithelial cells heldtogether by tight junctions, provides a barrier between the external environment andthe body’s internal milieu. Any mechanism that breaches the tight junction exposesthe body to foreign material be it protein, microorganisms or toxins. Stresses includephysiological (exercise), psychological, disease-related or drug-induced factors.Stress associated gastrointestinal disorders include functional dyspepsia irritablebowel syndrome (IBS), gastroesophageal reflux disease peptic ulcer disease, andinflammatory bowel disease (IBD). Some disease states disrupt gastrointestinal barrierfunction, e.g. infectious diarrhea, IBD, or celiac disease, whilst in others such aseczema it can be indirectly related to antigenic disruption of the barrier. Drugs, e.g.chemotherapy agents and nonsteroidal anti-inflammatory drugs, also disrupt barrierfunction. Malnutrition and nutritional deficiencies (zinc, folic acid, vitamin A) alsopredispose to mucosal damage. Assessment of gastrointestinal mucosal health hasproved problematic as invasive techniques, whilst useful, provide limited data and nofunctional assessment. Noninvasive tests particularly breath tests do provide functionalassessment and many can be used together as biomarkers to improve our abilityto define a stressed mucosa. Therapeutic options include pharmacotherapies,immunomodulation or immunotherapy.

Nutrition for Children with Cholestatic Liver Disease

Author(s): E. Leonie Los, S. Lukovac, A. Werner, T. Dijkstra, H.J. Verkade, E.H.H.M. Rings

Cholestatic liver disease (CLD) in children negatively affects nutritional status,growth and development, which all lead to an increased risk of morbidity and mortality.This is illustrated by the fact that the clinical outcome of children with CLD awaitinga liver transplantation is in part predicted by their nutritional status, which isintegrated in the pediatric end-stage liver disease model. Preservation of the nutritionalstatus becomes more relevant as the number of patients waiting for liver transplantationincreases and the waiting time for a donor organ becomes prolonged.Nutritional strategies are available to optimize feeding of children with CLD. Patientswith CLD, however, form a heterogeneous group and the clinical manifestations oftheir disease vary. This makes a tailor-made approach for these children crucial. Notall aspects of nutrient metabolism and absorption in children with CLD are well understoodand studied. Experiments with stable isotope-labeled triglycerides and fattyacids have provided essential information about fat absorption under physiologicaland cholestatic conditions in animal models and humans. We expect that in the future,tests using other isotope-labeled macronutrients, i.e. carbohydrates and proteins, canbe used to further assess nutritional status of children with CLD, thereby creatingtailor-made nutritional therapies.

Nutrient Requirements of Premature Infants

Author(s): E.E. Ziegler

Exact knowledge of the nutrient requirements of premature infants is criticallyimportant for the prevention of postnatal growth failure and for improved neurodevelopmentaloutcome. Methods whereby nutrient requirements can be estimatedfall into two categories, factorial methods and empirical methods. Each have theiradvantages and disadvantages. The factorial methods provide estimates of requirementsfor protein, energy and a number of other nutrients. The exact methods usedcan vary but still yield fairly similar results. Factorial methods also permit estimationof the extra nutrients needed for a given degree of catch-up growth, but cannotindicate the extent to which catch-up growth is actually possible. Empirical methodsyield estimates of the requirements for protein and energy but not for othernutrients. They often give an indication of what degree of catch-up growth is possible,in addition to providing estimates of the requirements for protein and energy.The advantages of catch-up growth outweigh any possible disadvantages associatedwith it. The nutrients needed for catch-up growth should therefore always beprovided.

Nutritional Assessment in Preterm Infants

Author(s): I.J. Griffin

If the aim of nutritional assessment of preterm infants is to identify suboptimal (orexcessive) provision of protein, energy and micronutrients, most currently availablemethods perform poorly. Assessment of body weight is limited by the confoundingeffect of fluid status especially in the first few days of life, and measurements of lineargrowth are relatively imprecise and slow to respond to nutritional changes. Growthassessment is hampered by the lack of an adequate reference standard. Comparisonsto historical cohorts of preterm babies are inadequate. As most very low birth weightinfants leave hospital below the 10th centile, use of these charts as ‘standards’ almostguarantees that preterm infants will have poor growth. Growth centiles based on datafrom newborn preterm infants have certain advantages. However, this is hardly normativedata as preterm birth is always an abnormal event. Methods of assessing bodycomposition are largely limited to the research setting, and it remains unclear whetherthe optimum composition of postnatal growth is one that mimics fetal growth or postnatalgrowth of the term infant. Biochemical nutritional assessments are of limitedutility except in the highest-risk preterm infants, when nutritional inadequacy is likely(severe fluid restriction) or where intake is difficult to assess (use of human milk).

Early Aggressive Nutrition in Very Preterm Infants

Author(s): P.J. Thureen

Despite numerous advances in the nutrition of preterm infants, the increasing survivalat lower birth weights is resulting in a new frontier of extrauterine nutritionalsupport of these vulnerable infants. The extremely low birth weight infant has endogenousenergy to maintain energy balance for only 3–4 days without an exogenousenergy supply. Nevertheless, many clinicians are still hesitant to introduce substratesat high rates early in life secondary to concerns of intolerance and toxicity. Currentfeeding practices appear to be resulting in significant postnatal growth failure in verypreterm neonates. Optimizing nutritional support in these infants is critical to avoidingadverse growth and neurological outcomes. There is a need for scientifically basedfeeding strategies to achieve normal in utero growth rates postnatally. Important areasfor research include determination of safe and efficacious upper limits of energy andamino acid intake, identification of markers for protein toxicity, better characterizationof the effect of various neonatal illnesses and the neonatal stress response onnutritional metabolism, development of enteral feeding strategies that will allow formore rapid enteral feeding advance while reducing the risk of necrotizing enterocolitis,and understanding the benefits and risks of both over- and undernutrition in theextremely low birth weight infant.

Postdischarge Nutrition of Preterm Infants: More Questions than Answers

Author(s): Ri.J. Cooke

Postnatal growth retardation is inevitable in preterm infants, the more immaturethe infant the greater the degree of postnatal growth retardation at hospital discharge.After hospital discharge, several studies have shown that growth is poorer inpreterm infants fed a standard term formula than those fed a nutrient-enrichedinfant formula. This is not surprising because term formulas are designed to meet therequirements of the term infant, not the more rapidly growing preterm infant. Afterhospital discharge, breastfed infants do not grow as well as their formula-fed counterparts.Yet, there are no randomized controlled trials comparing growth in breastfedinfants who did and did not receive nutrient supplementation. If mature humanmilk is designed to meet the needs of the term infant then breastfed preterm infantsmay also benefit from nutrient supplementation. Questions persist about nutritionalsupport of preterm infants after discharge. What is the ideal composition of a postdischargeformula? Given the wide heterogeneity in nutritional status of preterminfants at hospital discharge and the difference in growth rates and compositionbetween girls and boys, it is not clear that one formula can or will meet the nutritionalneeds of all infants. Studies in which infants were fed a nutrient-enriched formulato 6 months’ corrected age show the most consistent advantage while those inwhich the nutrient-enriched formula was fed to 2 months’ corrected age had noeffect on growth. Whether this is a reflection of the duration of feeding or not isunclear. Further studies are needed to examine this issue. To date, little attention hasfocused on the role and/or effects of complimentary feeds these infants.Complimentary feeds will confound the effects of any study examining postdischargegrowth in preterm infants. However, they may also be an important adjunct in meetingnutritional needs of these high-risk infants. Further studies are also ne