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Food allergy needs to be distinguished from food intolerance, which is a non-immune-medi- ated adverse reaction to food constituents [2] . Examples of food intolerance include lactose malabsorption, fructose malabsorption as well as idiosyncratic reactions to food additives or naturally occurring vasoactive compounds in foods. Lactose malabsorption is the most com- mon food intolerance in non-Caucasian individ- uals. About 70% of adults worldwide suffer from lactose intolerance due to a genetically deter- mined decline in lactase activity (adult-onset hypolactasia) [5] . In children, food intolerances may indicate the presence of an underlying gas- trointestinal condition such as celiac disease or other enteropathies [6] . Due to considerable
overlap between the symptoms of gastrointesti- nal food allergy and intolerances, the diagnostic process can be complex and confusing. For ex- ample, cow’s milk may cause diarrhea due to non-IgE-mediated gastrointestinal allergy to cow’s milk protein, or due to malabsorption of lactose (lactose intolerance).
Pathophysiology
There are two main types of allergic reactions to food, differentiated by the timing of onset in rela- tion to food ingestion ( fig. 1 ). Immediate-onset re- actions occur within minutes after ingestion. In these patients, the reaction is mediated by food-
Food hypersensitivity
Food protein allergy Food intolerance
Immune-mediated (T helper 2 lymphocytes) Non-immune-mediated
• Intolerance to ingested non-protein food ingredients
• Pharmacological reaction, dose dependent
Immediate reactions
(IgE-mediated)
• Onset approximately 30–60 min after food ingestion
• Signs and symptoms:
Oral tingling/itch Urticaria/angioedema Lip swelling Vomiting/diarrhea
Delayed reactions
(Non-IgE-mediated or mixed*)
• Onset several hours to days after food ingestion
• Atopic eczema*
• Eosinophilic esophagitis*
• Anaphylaxis Above plus any:
Upper airway swelling Wheeze/stridor Hypotonia/collapse Cardiorespiratory arrest
• Signs and symptoms:
Feeding difficulties (infant) Vomiting/GER symptoms Persistent diarrhea Failure to thrive Rectal bleeding
• Food protein-induced Enteropathy
Enterocolitis (FPIES) Proctocolitis
• Carbohydrate malabsorption e.g. lactose, fructose, sorbitol, sucrose
• Fat malabsorption e.g. intestinal lymphangi- ectasia, cystic fibrosis
• Inborn errors of metabolism e.g. hereditary fructose intolerance
• Idiosyncratic food reactions e.g. vasoactive amines, food additives and preservatives
Fig. 1. Classification of adverse reactions to foods. GER = Gastroesophageal reflux; FPIES = food protein-induced enterocolitis syndrome.
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 195–202 DOI: 10.1159/000360340
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specific serum IgE antibodies [1] . Delayed-onset reactions occur within several hours to days after ingestion and may involve the gut, skin or respira- tory tract. These reactions are cell mediated (lym- phocytes, eosinophils and mast cells), and individ- uals lack evidence of systemic IgE sensitization (skin prick testing, SPT, and food-specific serum IgE antibodies negative). Finally, some allergic conditions (e.g. atopic eczema or eosinophilic esophagitis) display mixed features of IgE-mediat- ed and non-IgE-mediated immune mechanisms.
An increasing number of major food allergens have been characterized at the molecular level, e.g. β-lactoglobulin in cow’s milk, ovomucin in hen’s egg or Ara h2 in peanut. On each of these proteins, specific epitope regions have been mapped that interact with either specific IgE an- tibodies or T cell receptors. Conformational epi- topes (with a three-dimensional structure) may be inactivated by heating or acidification, while linear epitopes are more resistant to degradation.
For example, egg-allergic patients may tolerate baked egg in cakes, while still reacting to un- cooked egg [7] . By contrast, boiling of cow’s milk or roasting of nuts generally does not reduce their allergenicity.
Clinical Manifestations of Food Allergy Food allergy may present with a diverse range of clinical manifestations ( table 1 ) [1] . Immediate reactions consist of urticaria, angioedema, oral tingling/itch, vomiting or diarrhea within 30–60 min of allergen ingestion. Atopic dermatitis with onset in the first months of life is closely associ- ated with IgE-mediated food allergy [1] . The term
‘anaphylaxis’ is reserved for severe immediate- type reactions with either respiratory compro- mise (wheeze, stridor, cough) or systemic hypo- tension [8] . Anaphylaxis may occur in response to small allergen doses and can be fatal, particu- larly in adolescents and young adults with unsta- ble asthma.
Delayed-onset reactions (non-IgE-mediated food allergy) typically involve the gastrointesti- nal tract or skin. While gastrointestinal food al- lergy is thought to be relatively common in the first 2–3 years of life, population-based preva- lence estimates are scarce. In infants and young children, gastrointestinal food allergies may cause growth failure due to persistent vomiting/
regurgitation, diarrhea and/or poor feeding [6] . The gastrointestinal allergy syndromes can be divided into food protein-induced (1) enteropa- thy, (2) enterocolitis syndrome (FPIES) and (3) proctocolitis ( table 1 ) [6] . Enteropathy and proc- tocolitis may occur in exclusively breastfed in- fants [9] , whereas FPIES seems to require direct ingestion of the allergen by the infant [10] . Re- cently, eosinophilic esophagitis has been recog- nized as a condition associated with food allergy that often responds to dietary elimination of food allergens [11] .
Lactose Intolerance
Lactose is the main disaccharide in mammalian milk. It can only be absorbed after digestion into glucose and galactose by the small intestinal brush border enzyme lactase. Failure to absorb lactase results in bacterial fermentation in the colon, pre- senting as flatulence, diarrhea, acidic stools and perianal skin excoriation [5] . The abundance of lactase activity is genetically regulated and slowly drops after infancy (lactase nonpersistence). This often leads to symptomatic hypolactasia by adult age, particularly in non-Caucasian individuals.
Primary lactose intolerance (congenital absence of lactase) in infants is rare [5] . Secondary forms of lactose intolerance may be transient and re- solve after the underlying gastrointestinal condi- tion (e.g. viral gastroenteritis or celiac disease) has remitted.
Lactase malabsorption can be confused with cow’s milk allergy, and both conditions may co- exist in cow’s milk enteropathy ( table 2 ) [6] .
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Breath hydrogen testing may be used to confirm the diagnosis of lactose malabsorption; however, its correlation with diet response varies [5] . Di- etary avoidance of fresh cow’s milk and dairy products is usually sufficient to control gastro- intestinal symptoms in lactose-intolerant indi- viduals, and small amounts of lactose are gener- ally tolerated. In formula-fed infants, a lactose- reduced formula or soy formula can be used if symptoms are significant. In breastfed infants, low-grade lactose malabsorption is physiologi- cal. In cases of postenteritic lactose malabsorp-
tion, breastfeeding should be continued. Incu- bation of expressed breast milk with lactase drops may be effective if symptoms are severe [5] .
Diagnostic Evaluation
The diagnosis of IgE-mediated food allergy re- quires a typical immediate-type clinical reaction to a food, in conjunction with demonstration of IgE antibodies by either SPT or measurement of
Table 1. Gastrointestinal food allergy
Diagnosis Clinical features Investigations Complications Treatment
Food protein- induced enteropathy
Mainly affects formula- fed infants (cow’s milk or soy formula) Persistent diarrhea Occasional vomiting Failure to thrive
SPT/serum-specific IgE (ImmunoCAP®) negative Intestinal biopsy: evidence of small intestinal villus shortening and crypt hyperplasia
Duodenal disaccharidases:
secondary lactase deficiency
Growth failure Secondary lactose malabsorption
Protein-losing enteropathy Hypoproteinemia and edema
Iron deficiency anemia Hypogammaglobulinemia in severe cases
Strict cow’s milk- and soy-free diet
Extensively hydrolyzed formula as first-line treatment
If not tolerated, change to amino acid-based formula
FPIES Profuse vomiting about 2 h after ingestion of food allergen Does not occur in breastfed infants Common allergens are cow’s milk, soy, grains (rice, oats) and poultry meat (chicken, turkey) Low-grade rectal bleeding may occur after reaction
SPT/serum-specific IgE (ImmunoCAP) negative Negative atopy patch test may predict tolerance on subsequent food challenge, but its clinical usefulness is controversial
FPIES food challenge generally not performed before 2 years of age
Acute dehydration and hypovolemic shock occur in about 20% of first presentations
May be mistaken for sepsis, gastroenteritis or intestinal obstruction
Strict avoidance of offending food item Requires hypoallergenic formula if previous reaction to cow’s milk or soy (extensively hydrolyzed formula considered first-line treatment)
Food protein- induced proctocolitis
May occur in breast- or formula-fed infants within the first weeks of life
Low-grade rectal bleeding, often mixed in with mucus
Infants otherwise well and thriving
SPT/serum-specific IgE (ImmunoCAP) negative Sigmoidoscopy and biopsy not always required, particularly if responding to cow’s milk protein elimination
Rectal biopsy: increased lymphocytes and eosinophils, with focal epithelial erosion
Iron deficiency anemia uncommon
Breastfed infants often respond to maternal elimination diet In formula-fed infants, use extensively hydrolyzed formula If ongoing rectal bleeding, change to amino acid-based formula (rare)
FPIES = Food protein-induced enterocolitis syndrome.
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 195–202 DOI: 10.1159/000360340
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food-specific serum IgE antibodies (Immuno- CAP ® ) [12] . Detection of specific IgE antibodies (sensitization) on its own, in the absence of clin- ical symptoms, is not diagnostic ( table 3 ). A neg- ative SPT or specific IgE test has a high negative predictive value and makes IgE-mediated food allergy unlikely [12, 13] . Conversely, high SPT levels or specific IgE concentrations beyond a defined cutoff (95% predictive decision point) are considered diagnostic [12, 13] . In patients with equivocal results, the diagnosis of IgE-me- diated food allergy needs to be assessed by for- mal food challenge in hospital (due to the poten- tial risk of anaphylaxis) [8] . No useful in vitro
markers for non-IgE-mediated food allergy are currently available. The diagnosis of non-IgE- mediated food allergy relies on recognition of the clinical presentation, demonstration of im- provement after a 2- to 4-week period of food allergen elimination, and relapse of symptoms after a food challenge. The investigation of pos- sible food intolerances follows the same princi- ples. In addition, breath hydrogen testing (lac- tose and fructose) and measurement of disac- charidase levels in duodenal biopsies may be useful in patients with suspected carbohydrate malabsorption syndromes (lactase or sucrase- isomaltase deficiency).
Table 2. Lactose malabsorption and its management Type of
lactose intolerance
Differential diagnosis Treatment Comments
Primary Congenital (rare) Lactose restriction (long-term) Extremely rare
‘Adult-onset’ hypolactasia Lactose restriction (long-term) Common
Genetic polymorphism
Lactase decline may commence in childhood
Secondary Acute gastroenteritis/
postenteritic lactose malabsorption
Short-term lactose restriction (lactose-free formula) In breastfed infants, continue breastfeeding
If not tolerated, incubation of expressed breast milk with lactase may be successful
Mainly occurs in infancy
Typically resolves within 1–2 weeks In very young infants, recovery may be delayed
Celiac disease (untreated) Ongoing strict gluten-free diet Lactose restriction until intestinal mucosa has been restored on gluten-free diet
Beware of false diagnostic labeling as
‘lactose intolerance’ or ‘irritable bowel syndrome’
Food protein-induced enteropathy (non-IgE-mediated cow’s milk or soy allergy)
Extensively hydrolyzed (first-line treatment) or amino acid-based formula (if intolerant to extensively hydrolyzed formula)
Cow’s milk-based, lactose-free formula may control the malabsorptive symptoms but does not allow mucosal repair (due to ongoing exposure to cow’s milk protein)
Intestinal dysplasia syndromes (e.g. microvillus inclusion disease, tufting enteropathy)
Depends on severity of disease May require parenteral nutrition Lactose restriction generally required
Rare
Presents with intestinal failure Intestinal mucosal transporter
defects (e.g. glucose-galactose malabsorption)
Strict avoidance of lactose-, glucose-, galactose- and sucrose-containing foods
Fructose is tolerated
Rare defect of sodium-glucose transporter 1
Presents with profuse osmotic diarrhea and severe dehydration in first weeks of life
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Dietary Management of Food Allergy
Treatment of food allergies is based on strict elimi- nation of specific food proteins until tolerance has developed [1] . As allergens are commonly dis- guised in manufactured food products, this in- volves education of parents and careful reading of ingredient labels [14] . In non-IgE-mediated food allergy, due to the diverse spectrum and underlying mechanisms and the absence of clear diagnostic markers, it may be difficult to define an exact diag- nosis. In these children, empirical treatment with dietary manipulations is common practice. Elimi- nation diets avoiding multiple food allergens should be monitored by a pediatric dietician to safeguard the nutritional adequacy of the diet, and growth parameters should be carefully monitored.
In breastfed infants, a maternal elimination diet may be effective as intact food antigens in
breast milk can elicit allergic manifestations in the infant [9] . The maternal diet should be nor- malized as soon as tolerated by the infant. An ad- equate maternal intake of protein and micro- nutrients needs to be maintained. The maternal calcium intake recommended for breastfeeding mothers is 1.2 g per day (provided as separate portions throughout the day).
Several hypoallergenic formulas are available for the treatment of infants with cow’s milk and/
or soy allergy who are not breastfed ( table 4 ).
These hypoallergenic formulas are tolerated by at least 90% of infants with cow’s milk allergy [15] . There are two main types of hydrolyzed formula, partially and extensively hydrolyzed formulas.
Partially hydrolyzed formulas may have a role in allergy prevention but are not suitable for infants with established clinical signs of cow’s milk al- lergy [16] . Extensively hydrolyzed formulas are
Table 3. Investigation of food allergy
Clinical presentation Diagnostic test Comments
Immediate-onset reaction (IgE-mediated) Urticaria/angioedema Oral allergy syndrome Anaphylaxis
Food-specific serum IgE antibody
(ImmunoCAP) or SPT demonstrate evidence of sensitization
Diagnosis of IgE-mediated food allergy likely if food-specific serum IgE levels or SPT diameter above 95% predictive diagnostic decision points If inconclusive, food challenges in controlled environment (hospital) are required to confirm allergy or tolerance
Home challenges may be indicated if SPT or serum food-specific IgE is negative (requires supervision by trained allergist)
Delayed-onset reaction (non-IgE-mediated) FPIES or proctocolitis
Diagnosis based on symptomatic improvement within 2–4 weeks after allergen elimination and relapse on subsequent food challenge FPIES food challenge generally not performed before 2 years of age
Gastrointestinal biopsy, as clinically indicated (mainly for enteropathy; sometimes required in infantile allergic proctocolitis if atypical presentation)
Food-specific serum IgE antibody and SPT negative
Histological appearance of allergic enteropathy similar to celiac disease
Mixed reaction (IgE-/non-IgE-mediated) Atopic dermatitis Eosinophilic esophagitis
Food-specific serum IgE antibody (ImmunoCAP) or SPT
Esophageal biopsy in patients with suspected eosinophilic esophagitis (severe feeding refusal in infants; gastroesophageal reflux symptoms, dysphagia or food impaction in older children)
Elimination diet, as guided by history and SPT/
specific IgE testing, and empirical elimination of non-IgE food allergens (followed by challenge) Esophageal biopsy reveals increased tissue eosinophils (>15 eosinophils per high-power field in upper and lower esophagus)
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 195–202 DOI: 10.1159/000360340
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the first-line treatment for infants with cow’s milk allergy. Infants with ongoing symptoms while on an extensively hydrolyzed formula, and those with a history of cow’s milk anaphylaxis, require an amino acid-based formula [15, 17] . The role of soy formulas in the treatment of young infants with cow’s milk allergy is controversial.
Concomitant soy allergy occurs in about 15% of infants with IgE-mediated cow’s milk allergy [18] . Because of the risk of soy allergy and con- cerns regarding the phytoestrogen and phytate content of soy formulas, the European Society for Pediatric Gastroenterology, Hepatology and Nu- trition has advised against using soy formulas with infants with cow’s milk allergy under 6 months of age [15, 19] . However, for older infants, soy is a suitable treatment option for cow’s milk allergy, provided tolerance to soy has been estab- lished [19] .
Conclusions
• Hypoallergenic formulas (extensively hydro- lyzed formulas or amino acid-based formulas) are used in the treatment of cow’s milk allergy in formula-fed infants. Soy formulas are also suitable for infants over 6 months of age with- out concomitant soy allergy
• In breastfed infants with food-allergic mani- festations, a maternal elimination diet may control symptoms in the infant. Prolonged maternal elimination diets should be super- vised by a dietician
• Lactose intolerance is the most common food intolerance and is treated with a low-lactose diet. Causes of secondary lactose intolerance, such as celiac disease, should be considered in the differential diagnosis
Table 4. Formulas used in the treatment of infants with food allergies or intolerances Type of formula Features and indications
Partially hydrolyzed cow’s milk-based formula
Contains relatively large cow’s milk protein fragments/peptides Not suitable for treatment of cow’s milk allergy
May have a role in allergy prevention in high-risk infants in the first 6 months of life Extensively hydrolyzed cow’s
milk-based formula (whey-predominant or casein-predominant)
Treatment of choice for formula-fed infants with cow’s milk allergy Contains small cow’s milk peptides
Residual allergenicity due to trace amounts of cow’s milk proteins
Infants with previous cow’s milk anaphylaxis require introduction of extensively hydrolyzed formula under medical observation
Not tolerated by approximately 10–20% of infants with cow’s milk allergy Amino acid-based formula Synthetic formula containing mixture of free amino acids
Nutritionally complete formula
Treatment of choice for infants with intolerance to extensively hydrolyzed formula, multiple food allergy of infancy or history of cow’s milk anaphylaxis
Soy formula Generally not considered first-line treatment formula for infants with cow’s milk allergy under 6 months of age
Has a role in the treatment of cow’s milk allergy in older infants who are tolerant to soy protein
Treatment of lactose malabsorption or galactosemia Lactose-free cow’s
milk-based formula
Contains intact cow’s milk protein (same as in standard cow’s milk-based formula) Useful for infants with transient lactose intolerance (e.g. after acute gastroenteritis) Not suitable for infants with secondary lactose malabsorption due to cow’s milk protein- induced enteropathy
202 Heine 14 Mofidi S: Nutritional management of
pediatric food hypersensitivity. Pediat- rics 2003; 111: 1645–1653.
15 Fiocchi A, Brozek J, Schünemann H, Bahna SL, von Berg A, Beyer K, Bozzola M, Bradsher J, Compalati E, Ebisawa M, Guzman MA, Li H, Heine RG, Keith P, Lack G, Landi M, Martelli A, Rance F, Sampson H, Stein A, Terracciano L, Vieths S; World Allergy Organization Special Committee on Food Allergy: World Allergy Organi- zation (WAO): Diagnosis and Ratio- nale for Action against Cow’s Milk Allergy (DRACMA) Guidelines. Pedi- atr Allergy Immunol 2010; 21(suppl 21):1–125.
16 Osborn DA, Sinn J: Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants.
Cochrane Database Syst Rev 2003; 4:
CD003664.
17 de Boissieu D, Dupont C: Allergy to ex- tensively hydrolyzed cow’s milk proteins in infants: safety and duration of amino acid-based formula. J Pediatr 2002; 141:
271–273.
18 Zeiger RS, Sampson HA, Bock SA, Burks AW Jr, Harden K, Noone S, Martin D, Leung S, Wilson G: Soy allergy in infants and children with IgE-associated cow’s milk allergy. J Pediatr 1999; 134: 614–
622.
19 Agostoni C, Axelsson I, Goulet O, Ko- letzko B, Michaelsen KF, Puntis J, Rieu D, Rigo J, Shamir R, Szajewska H, Turck D: Soy protein infant formulae and fol- low-on formulae: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2006; 42:
352–361.
References
1 Allen KJ, Hill DJ, Heine RG: 4. Food allergy in childhood. Med J Aust 2006;
185: 394–400.
2 Osborne NJ, Koplin JJ, Martin PE, Gurrin LC, Lowe AJ, Matheson MC, Ponsonby AL, Wake M, Tang ML, Dharmage SC, Allen KJ; HealthNuts Investigators: Prevalence of challenge- proven IgE-mediated food allergy using population-based sampling and prede- termined challenge criteria in infants. J Allergy Clin Immunol 2011; 127: 668–
676e2.
3 Prescott S, Saffery R: The role of epigen- etic dysregulation in the epidemic of allergic disease. Clin Epigenetics 2011; 2:
223–232.
4 Heederik D, von Mutius E: Does diver- sity of environmental microbial expo- sure matter for the occurrence of allergy and asthma? J Allergy Clin Immunol 2012; 130: 44–50.
5 Heyman MB; Committee on Nutrition:
Lactose intolerance in infants, children, and adolescents. Pediatrics 2006; 118:
1279–1286.
6 Heine RG: Pathophysiology, diagnosis and treatment of food protein-induced gastrointestinal diseases. Curr Opin Al- lergy Clin Immunol 2004; 4: 221–229.
7 Leonard SA, Sampson HA, Sicherer SH, Noone S, Moshier EL, Godbold J, Nowak-Wegrzyn A: Dietary baked egg accelerates resolution of egg allergy in children. J Allergy Clin Immunol 2012;
130: 473–480e1.
8 Sampson HA, Muủoz-Furlong A, Camp- bell RL, Adkinson NF Jr, Bock SA, Bra- num A, Brown SG, Camargo CA Jr, Cy- dulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM,
Lieberman PL, Metcalfe DD, O’Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW: Second symposium on the definition and management of ana- phylaxis: summary report – Second Na- tional Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Im- munol 2006; 117: 391–397.
9 Jọrvinen KM, Mọkinen-Kiljunen S, Suomalainen H: Cow’s milk challenge through human milk evokes immune responses in infants with cow’s milk allergy. J Pediatr 1999; 135: 506–512.
10 Leonard SA, Nowak-Wegrzyn A: Clini- cal diagnosis and management of food protein-induced enterocolitis syndrome.
Curr Opin Pediatr 2012; 24: 739–745.
11 Liacouras CA, Furuta GT, Hirano I, At- kins D, Attwood SE, Bonis PA, Burks AW, Chehade M, Collins MH, Dellon ES, Dohil R, Falk GW, Gonsalves N, Gupta SK, Katzka DA, Lucendo AJ, Mar- kowitz JE, Noel RJ, Odze RD, Putnam PE, Richter JE, Romero Y, Ruchelli E, Sampson HA, Schoepfer A, Shaheen NJ, Sicherer SH, Spechler S, Spergel JM, Straumann A, Wershil BK, Rothenberg ME, Aceves SS: Eosinophilic esophagitis:
updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128: 3–20e6.
12 Hill DJ, Heine RG, Hosking CS: The di- agnostic value of skin prick testing in children with food allergy. Pediatr Al- lergy Immunol 2004; 15: 435–441.
13 Sampson HA: Utility of food-specific IgE concentrations in predicting symptom- atic food allergy. J Allergy Clin Immunol 2001; 107: 891–896.
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 195–202 DOI: 10.1159/000360340