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Background: Cow's milk allergy is common in infancy, and total avoidance of this food is the only effective approach. In alternative, oral immunotherapy has been proposed to achieve tolerance. Once desensitization is achieved, daily intake of milk is recommended to maintain it, but this may be impractical for children/parents. We assessed whether a twice weekly maintenance regimen is effective., Methods: Children who were successfully desensitized with oral immunotherapy were randomized to two maintenance regimens for 1 year: group A had to eat 150-200 ml milk daily, group B had to eat 150-200 ml milk twice weekly. Both regimens were associated to a totally free diet. Maintenance of tolerance and adverse events were recorded during 1 year. Specific IgE, IgG4 and prick-by-prick test to milk were carried out before immunotherapy (T0), before maintenance (T1), and after 1 year (T2)., Results: Recorded episodes included asthma, oral itching, urticaria, rhinitis, abdominal pain variously combined, usually associated with concomitant illness or exercise. The episodes were 8 in group A and 9 in group B, with no difference. None of the children discontinued the feeding maintenance. Specific IgG4 increased at T1 and remained high at T2. Specific IgE and skin reactivity significantly decreased at T2. There was no difference in those parameters between the groups., Conclusion: After achieving desensitization to cow milk with oral immunotherapy, a maintenance regimen with milk given twice weekly is as effective as the daily maintenance., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Patients with chronic constipation due to food hypersensitivity (FH) had an elevated anal sphincter resting pressure. No studies have investigated a possible role of FH in anal fissures (AFs). We aimed to evaluate (1) the effectiveness of diet in curing AFs and to evaluate (2) the clinical effects of a double-blind placebo-controlled (DBPC) challenge, using cow's milk protein or wheat., Methods: One hundred and sixty-one patients with AFs were randomized to receive a "true-elimination diet" or a "sham-elimination diet" for 8 weeks; both groups also received topical nifedipine and lidocaine. Sixty patients who were cured with the "true-elimination diet" underwent DBPC challenge in which cow's milk and wheat were used., Results: At the end of the study, 69% of the "true-diet group" and 45% of the "sham-diet group" showed complete healing of AFs (P<0.0002). Thirteen of the 60 patients had AF recurrence during the 2-week cow's milk DBPC challenge and 7 patients had AF recurrence on wheat challenge. At the end of the challenge, anal sphincter resting pressure significantly increased in the patients who showed AF reappearance (P<0.0001), compared with the baseline values. The patients who reacted to the challenges had a significantly higher number of eosinophils in the lamina propria and intraepithelial lymphocytes than those who did not react to the challenges., Conclusions: An oligo-antigenic diet combined with medical treatment improved the rate of chronic AF healing. In more than 20% of the patients receiving medical and dietary treatment, AFs recurred on DBPC food challenge.

Food allergies are often seen in infancy and usually show the clinical signs in the form of type I hypersensitivity reaction. However, a combination of food allergies can sometimes be found in the same patient. In this report, we present an 11-month-old infant who had a combination of anaphylaxis and eosinophilic esophagitis induced by cow's milk. Diagnosis of eosinophilic esophagitis is done by examination of esophageal biopsy material histologically. This is a very rare combination of food allergy. Improvement in clinical and histological findings of eosinophilic esophagitis was achieved by removal of cow's milk and dairy products from the infant's diet.

Atopy patch tests (APTs) have been proposed for the diagnostic approach in children with non-IgE-mediated cow's milk allergy and gastrointestinal symptoms. We aimed to investigate the benefit of APTs in predicting oral tolerance in these patients. We prospectively evaluated 172 subjects with a sure diagnosis of non-IgE-mediated CMA and gastrointestinal symptoms (97 boys, 56.4%; age, 6.37 m; range, 2-12 m). At diagnosis, 113/172 (65.7%) children had positive APTs to cow's milk proteins (CMP). After 12 months of exclusion, diet APTs were repeated immediately before OFC. APTs significantly correlated (P < 0.001) with the OFC outcome (r 0.579). Diagnostic accuracy was sensitivity of 67.95%, specificity of 88.3%, PPV of 82.81%, NPV of 76.85%, and a +LR of 5.80. APTs are a valuable tool in the follow-up of children with non-IgE-mediated CMA-related gastrointestinal symptoms by contributing in determining whether an OFC can safely be undertaken., (© 2012 John Wiley & Sons A/S.)

Background: Allergic colitis (AC) is an inflammatory condition characterized by eosinophils infiltrating the colonic wall. It can be a benign and/or severe illness among gastrointestinal diseases in infants., Methods: We report five infants who, since January 2009, in whom AC under fibrotic endoscopic examinations has been diagnosed. The criterion for histopathologic diagnosis of AC in this study was five or more eosinophils per high-power field. Patients' clinical symptoms, pathologic findings, and immunologic studies, such as specific antibodies against component of cow's milk protein, were compared with those of allergic children without AC and those of nonatopic control children., Results: Histopathologic examinations of biopsy specimens revealed acute inflammation with characteristic eosinophilic infiltration of lamina propria (5-15 eosinophils per high-power field) in all five patients. They all had strongly positive skin prick tests against milk protein, which were not correlated with in vitro allergen-specific immunoglobulin (Ig) E levels. In contrast, there were significantly higher levels of IgE antibodies, and lower specific IgG4 and IgA levels to components and whole milk proteins in AC, as compared to control children without AC., Conclusion: Endoscopic biopsy specimens of intestine confirm the diagnosis of AC. However, allergen skin prick test and IgE antibody to milk protein components also provide helpful diagnostic tools for this rare disease in children., (Copyright © 2012. Published by Elsevier B.V.)

The aims of this study were to: (1) determine whether replacement of cow's milk protein with soy resolves Chronic Functional Constipation (CFC); and (2) investigate the effects of cow's milk β casein A1 and cow's milk β casein A2 on CFC. Children diagnosed with CFC were recruited to one of two crossover trials: Trial 1 compared the effects of cow's milk and soy milk; Trial 2 compared the effects of cow's milk β casein A1 and cow's milk β casein A2. Resolution of constipation was defined as greater than eight bowel motions during a two week intervention. Thirteen children (18 to 144 months) participated in Trial 1 (6 boys, 7 girls). Nine participants who completed the soy epoch all experienced resolution (p < 0.05). Thirty-nine children (21 to 144 months) participated in Trial 2 (25 boys, 14 girls). Resolution of constipation was highest during the washout epoch, 81%; followed by cow's milk β casein A2, 79%; and cow's milk β casein A1, 57%; however, the proportions did not differ statistically. The results of Trial 1 demonstrate an association between CFC and cow's milk consumption but Trial 2 failed to show an effect from type of casein. Some other component in cow's milk common to both A1 and A2 milk may be causing a problem in these susceptible children.

Background: The recommended formulas for treatments of cow's milk allergy (CMA) in infants are hydrolyzed protein-based and amino acid-based formulas. However they are not always affordable. Furthermore, some patients are still allergic to these formulas. Therefore, chicken-based formula has been innovated and used as an alternative formula to treat CMA in these infants., Objective: To assess the growth of infants with CMA who consumed chicken-based formula compared to normal infants., Material and Method: A prospective study was performed in 34 infants aged 3 to 24 months diagnosed as CMA at Siriraj Hospital. All subjects consumed the chicken-based formula for at least three months. The growth parameters were recorded., Results: Manifestations occurred in dermatological (78.60%), respiratory (67.9%), and gastrointestinal (53.6%) systems. Mean (+/-SD) chicken-based formula intake was 77 (+/-39.6) kcal/kg/d Weight gains are higher (35.7%), equal (10.8%), and lower (53.5%) than those of normal infants. In addition, length gains were higher (38%), equal (5%), and lower (57%) than those of normal infants. However, the difference of weight and length in chicken-basedfed, cow s milk-allergic infants, and normal infants were not statistically significant (p = 0.141, p = 0.192). None of these infants had severe complications., Conclusion: Growth parameters of infants fed with chicken-based formula are not diferent from those of normal infants.

Background and Aims: Functional gastrointestinal disorders (FGIDs) are common in children. Abdominal pain (AP) is the most common gastrointestinal (GI) symptom in children. The severity of AP drives medical consultations and quality of life in adult patients with irritable bowel syndrome (IBS). Thirty-eight percent of 8- to 15-year-old schoolchildren report AP weekly with 24% of those children reporting persistence of AP >8 weeks. Despite the high prevalence of AP, only 2% of school children seek medical attention for AP. Lack of parental knowledge on their child's symptoms may constitute one of the factors affecting the low ratio of consultation in children reporting AP. The aim was to assess parental reports of AP symptoms in a population of healthy community children., Methods: Data of 5 studies with identical methodology to assess GI symptoms in children with celiac disease (CD), cow's milk allergy (CMA), pyloric stenosis (PS), Henoch-Schönlein purpura (HSP), and stem cell transplant (SC) and their healthy siblings were reviewed: a phone questionnaire on GI symptoms and Pediatric Gastrointestinal Symptoms Rome III version questionnaire (QPGS-RIII). Inclusion criteria were healthy children 4 to 18 years of age with a sibling previously diagnosed with CD, CMA, PS, HSP, or SC., Results: Data on 246 healthy children, mean age (9.8 years, range 3-24, 112 girls) were obtained. Parents reported presence of AP in the last 8 weeks before the telephone contact in 20 (8.1%) children (age range 4-18 years, 11 girls). There was no significant difference in AP prevalence between boys and girls (P = 0.64). Six children (2.4%) met QPGS-RIII diagnostic criteria for FGIDs: 3 functional abdominal pain (FAP) and 3 IBS., Conclusions: AP was common in community children. FAP was the most common FGID among healthy community children. The prevalence of AP by parental report is lower than the previously published prevalence of AP reported by children. Lack of awareness of children's symptoms may play a role in the low ratio of consultation for AP in symptomatic children. Future prospective studies should confirm our findings and investigate the factors influencing the medical consultation decision including parental awareness of children's symptoms.

Background: Isolated rectal bleeding in infants is often attributed to the consumption of cow's milk. However, the prevalence of this condition has not been described, and its preferred diagnostic methods and management are controversial., Methods: In a prospective population-based study following 13,019 children from birth, 21 infants with isolated rectal bleeding attributed to cow's milk protein consumption were identified. Following evaluation, parents were encouraged to resume cow's milk protein and infants were followed for reappearance of symptoms and thereafter for 6 yr. In addition, infants with rectal bleeding were compared to a control group of healthy infants., Results: The prevalence of isolated rectal bleeding attributed to cow's milk consumption was 0.16%. All infants were asymptomatic within days of dietary modifications. Eleven of the 14 infants (78.5%) whose parents reintroduced cow's milk protein to their diet following our evaluation tolerated it with no adverse effects. Those 11 infants were significantly younger at initial consumption of cow's milk protein (6.7 ± 1.6 months) compared to those who continued elimination diet (17.7 ± 9.2 months), (p = 0.002) while their 1-yr hemoglobin levels were comparable (p = 0.98). No risk factors for rectal bleeding were identified., Conclusions: The prevalence of isolated rectal bleeding attributed to cow' milk is low. The condition is generally benign and resolves quickly with elimination diet. Reintroduction of cow's milk following resolution of symptoms is often well tolerated and is recommended for confirming the diagnosis and avoiding prolonged unnecessary elimination diets., (© 2012 John Wiley & Sons A/S.)

Background: Probiotics are used in the treatment of allergic diseases. We investigated the safety of probiotics for subjects with food allergy., Material and Methods: Labels of probiotics commercially available in Spain were examined to assess their content of cow's milk or hen's egg. Skin prick tests with these compounds (20 mg/ml) were performed in five children allergic to cow's milk, five children allergic to hen's white egg, and five control subjects non-allergic to food. Three serum pools: I (positive-specific IgE to cow's milk and hen's egg white proteins), II (positive-specific IgE to cow's milk and negative to hen's egg white proteins), and III (negative-specific IgE to cow's milk and positive to hen's egg white proteins) were used to detect cow's milk and hen's egg white allergens in probiotics. ImmunoCAP(®) (Phadia), in-house ELISA, SDS-PAGE immunoblotting, and inhibition studies of these assays were performed. Proteins were quantified by enzyme-immunoassay., Results: Eleven probiotics were studied. No label advertised about egg content, eight labels warned about lactose, lactic acid or cow's milk, one label claimed to be milk-free, and two gave no information. Cow's milk proteins were detected, by at least one lab technique, in 10/11 probiotics, three over 2.5 mg/kg (21, 52, 112 mg/kg). Hen's egg white proteins were detected in 3/11 probiotics, only one had more than 2.5 mg/kg (47 mg/kg)., Conclusion: Probiotic compounds may contain hidden allergens of food and may not be safe for subjects with allergy to cow's milk or hen's egg., (© 2012 John Wiley & Sons A/S.)

Purpose of Review: To provide an overview of clinical manifestations, diagnosis and pathophysiology of food protein-induced enterocolitis syndrome (FPIES), an under-recognized and often misdiagnosed nonimmunoglobulin E-mediated food hypersensitivity. This review will highlight updates on natural history and clinical management., Recent Findings: The main developments in FPIES involve epidemiology, common presentation and variants thereof, and natural history. Improved understanding and recognition of FPIES have influenced changes in clinical management., Summary: A large prospective population-based study reported cow's milk-FPIES cumulative incidence to be 0.34% by 1 year of age; immunoglobulin E-mediated cow's milk allergy was 0.5%. A case report has suggested that FPIES pathophysiology involves Th2 activation, and a shift away from Th2 signalling may be associated with resolution. Appreciation of the frequent incidence of multiple food-FPIES has influenced anticipatory guidance. Two case reports have described FPIES to food proteins in maternal breast milk. The threshold dose for FPIES reactivity may decrease with successive episodes. Reports from different populations indicate that children may outgrow FPIES sooner than previously thought.

Objectives: Cow's-milk protein is one of the food antigens responsible for causing eosinophilic esophageal inflammation in a majority of children. We describe our experience with treating eosinophilic esophagitis (EoE) in children by eliminating only cow's milk from their diets., Methods: This retrospective study assessed the short-term clinical and histological response to eliminating cow's-milk protein from the diet of children with EoE. Only patients undergoing a subsequent upper endoscopy to assess their histological response were included in this analysis., Results: We identified 17 (12 boys and 5 girls) children with EoE who excluded only cow's milk from their diet. Remission was induced in 11 of 17 (65%) patients; within the remission group, 7 (41%) achieved complete histological remission and 4 patients (24%) were in significant histological remission. The mean peak pre- and posttreatment counts for those in remission were 76 ± 40 and 2 ± 4 (P < 0.01), respectively., Conclusions: Elimination of cow's milk-induced clinical and histological remission in 65% (95% confidence interval 42%-88%) of children with EoE in whom it was attempted. This approach offers distinct advantages over other dietary treatment approaches for the initial management of children with EoE. The role of eliminating cow's milk alone for the treatment of EoE warrants further prospective study.

Unlabelled: This study was performed to identify the cause and frequency of food protein-induced proctocolitis (FPIPC) in not-sick neonates with small and fresh rectal bleeding and to verify the effectiveness of oral food elimination and challenge test (ECT) as a diagnostic method of FPIPC. We prospectively analyzed neonates with small and fresh rectal bleeding who were clinically normal. We investigated age at symptom onset, feeding at onset of bleeding, the time of bleeding disappearance, stool smear and culture, endoscopic findings, and histopathologies in the biopsy specimens of 16 not-sick neonates. We performed food ECT in cases with over 4 days of persistent rectal bleeding in the absence of any other etiology. In 16 not-sick neonates with rectal bleeding, the median age at symptom onset was 8.5 (1-43) days. Endoscopic abnormalities were observed in all 16 patients, and in 10 cases satisfying the pathological guidelines for FPIPC, two (12.5 %) were confirmed as FPIPC by food ECT. In the other 14 (87.5 %) cases, rectal bleeding spontaneously disappeared after on average at 4 (1-8) days and thus was diagnosed as idiopathic neonatal transient colitis (INTC)., Conclusions: FPIPC is rare as a cause of small and fresh rectal bleeding in not-sick newborns and most of cases proved to be INTC. Although clinical findings are suspected as its symptoms and histological results satisfy its diagnostic criteria, FPIPC should be carefully confirmed through food ECT.

Background: The pathogenesis of food allergy is not completely understood - animal models suggest hepatic mechanisms may be important for immune tolerance to orally ingested antigens, but there is little direct evidence for this in humans., Objectives: We investigated whether there is an association between liver dysfunction or transplantation in young children and IgE sensitisation to food., Methods: We evaluated paired pre- and post- liver transplant sera from children aged 0-36 months treated at a single centre during 2001-2008. Sera were assayed for total IgE and cow's milk, egg and peanut-specific IgE. We quantified hepatic dysfunction pre-transplant using the Paediatric End-stage Liver Disease (PELD) score. We also assessed 70 children after renal transplant to establish whether any association between liver transplant and food sensitisation was organ specific., Results: Paired sera were available from 50 of 94 children who had a liver transplant during the study period. 35 of 50 (70%) had IgE sensitisation (≥ 0.35 kUa/l) to ≥ 1 food pre-transplant and 18 (36%) post-transplant (p = 0.001). Ten (20%) children had food-specific IgE levels that carry high probability of challenge-confirmed food allergy pre-transplant. Food sensitisation pre-transplant was associated with severity of liver dysfunction [mean (s.d.) pre-transplant PELD score 1.52 (0.13) in food sensitised, 0.77 (0.22) in non-sensitised children p = 0.004]. Total IgE level was raised in 34/42 (81%) pre-transplant and fell significantly post-transplant. Interview assessment of the parents of 40 children revealed that 13 (33%) had a history consistent with food allergy. These findings were not replicated in the renal transplant group., Conclusions: Young children with severe liver dysfunction appear to have a high prevalence of food sensitisation. Hepatic mechanisms may therefore be important for establishing immune tolerance to dietary antigens in humans., (© 2012 John Wiley & Sons A/S.)

Unlabelled: Cow's milk protein allergy (CMPA) may cause gastrointestinal motility disorders. Symptoms of both conditions overlap and diagnostic tests do not reliably differentiate between both. A decrease of symptoms with an extensive hydrolysate and relapse during challenge is not a proof of allergy, because hydrolysates enhance gastric emptying, a pathophysiologic mechanism of gastro-oesophageal reflux (GER). Thickened formula reduces regurgitation, and failure to do so suggests CMPA. A thickened extensive hydrolysate may induce more rapid improvement, but does not always differentiate between CMPA and GER. Different hypotheses are discussed: is the overlap between CMPA and functional disorders coincidence, or do both entities present with identical symptoms, or does the fact that symptoms are identical indicates that there is only one entity involved? Studies on the prevention of CMPA focused on 'at-risk families', and resulted in a decrease of CMPA and atopic dermatitis, but did not provide data on the incidence of GER., Conclusion:   As long as there are no objective diagnostic tools to separate GER from CMPA, the physician has two options: first treat the most likely diagnosis, and switch if after 2-4 weeks there is no improvement, or treat both conditions with one intervention, what will not result in a diagnosis., (© 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.)

Unlabelled: Children treated with a dairy-free diet are in a group of those at risk of nutritional deficiencies, including vitamin D deficiency.THE AIM of this study was to evaluate the vitamin D status in children with cow's milk allergy (CMA) treated with a dairy-free diet., Material and Methods: The study involved 66 children with CMA, aged 2-5 years (mean age 3.9±1.9 yrs). The children were treated with a milk-free diet (high degree of protein hydrolysates or soy formulas/soy products) and remained under the care of the medical and nutritional team. The majority of the children lived in urban areas and their parents have mainly secondary or higher education. The supply of vitamin D in children's daily food rations was evaluated and related to Adequate Intake (AI) as well as the recommendations contained in the Medical Standard (2009) for the prophylaxis of vitamin D deficiency. Fifteen (22.7%) children in the autumn-winter season used vitamin D containing supplements. The serum 25-hydroxyvitamin D [25(OH)D] concentration was measured and related to the recommended levels from Medical Standard (2009). Taking into consideration the possibility of seasonal differences in vitamin D status, blood samples for the 25(OH)D assay were collected from April to September (spring-summer season) in 34 (51.5%) children and from October to March (autumn-winter season) in 32 (48.5%) children., Results: The mean supply of vitamin D in the diets of the children with CMA was 5.9±3.7 μg/d. The mean supply of vitamin D in supplements in the group of children receiving them was 143.6±132.9 IU/d [3.6±3.3 μg/d]. The mean 25 (OH)D serum concentration among the children without taking into account the season for blood withdrawal was 28.7±9.9 ng/ml. Taking into account the season of blood sample collection, the mean 25(OH)D serum concentration in children in spring-summer was 30.1±7.8 ng/ml, while in autumn-winter 27.5±11.2 ng/ml, p>0,05. A positive correlation between the supply of vitamin D in the children's diets and 25(OH)D serum concentration (Spearman correlation coefficient r=0.46, p<0,01) was found. The mean supply of vitamin D in the children's diets and the mean 25(OH)D serum concentration did not differ significantly depending on the place of living and the parents' education., Conclusions: 1. Vitamin D supplied by the diets of the children with CMA remaining under our care was compliant with the Adequate Intake, but lower than the recommendations contained in the Medical Standard. 2. The serum 25(OH) D concentration in these children in the spring-summer as well as autumn-winter season indicated the optimal vitamin D status. 3. Being under constant medical and nutritional care is one of the conditions for an appropriate vitamin D supply in children with CMA.

Objectives: The aim of the present study was to describe the prevalence of childhood constipation, stool characteristics, and their relationship with toilet training and age of introduction of cow's milk., Methods: A total of 4231 children born in 2004, from a birth cohort study, were assessed at 12, 24, and 48 months of age, when their mothers provided information on sociodemographic characteristics, bowel habits, toilet training, and age of introduction of cow's milk and other foods., Results: The prevalence of constipation was 27.3% and 31.0% at 24 and 48 months of age, respectively. Among girls, at 48 months of age, it was 34.4% versus 27.4% in boys (P<0.001). The most common features of constipation were scybalous stools (47.7% and 41.0% at 24 and 48 months, respectively), evacuation difficulty (24.3% and 23.1%), and hard stools (17.8% and 34.1%). Toilet training starting before 24 months was associated with constipation at 24 months and its persistence up to 48 months. Among children who did not receive cow's milk in their first year of life, 22% had constipation at 24 months, 22.6% at 48 months, and 8.3% at 24 and 48 months. Among children who started cow's milk before 30 days of life, the respective proportions of children with constipation was 28.2%, 33%, and 12.4%., Conclusions: The prevalence of constipation increases with age and cannot be detected using only information on evacuation interval. Toilet training before 24 months and introduction of cow's milk before 1 year of age is positively associated with constipation at 24 months and its persistence up to 48 months.

Unlabelled: Cow's milk allergy is the most frequent childhood food allergy. Children older than 5 who have not become tolerant have less probabilities of natural tolerance. Specific oral desensitization methods are being investigated in reference centres. The aims of our study were to assess the efficacy of our guideline of specific oral desensitization to cow's milk in children and to know its suitability for anaphylactic children. Both clinical and specific IgE outcomes were evaluated. Eighty-seven children aged 5 to 16 years with a history of cow's milk allergy were included. Prior to desensitization, skin prick test, specific IgE to cow's milk proteins and a double-blind placebo control food challenge were performed in all. Of the 87 patients, 21 had a negative challenge; they were considered tolerant, and they were told to follow a free diet. Of the positive, 44 were anaphylactic and 22 non-anaphylactic. All of them were included. In non-anaphylactic patients, 6 achieved partial and 16 maximum desensitization after 23.1 weeks. In the anaphylactic group, 7 achieved partial and 35 maximum desensitization after 26.4 weeks. Cow's milk-specific IgE levels and casein-specific IgE levels were significantly lower in the tolerant patients at baseline. One year after desensitization, the medium specific cow's milk levels and casein IgE levels had dropped significantly., Conclusions: Our guideline for specific oral desensitization to cow's milk is efficacious even in patients with anaphylactic reactions to cow's milk and represents a significant life change. Immunological changes in 1 year show a drop in cow's milk protein-specific IgE.

The most frequent symptoms among the manifestations of cow milk allergy (CMA) are gastrointestinal. CMA pathogenesis involves immunological mechanisms with participation of immunocompetent cells, production of immunoglobulin E (IgE) and immunoglobulin G (IgG). We aim to determine whether cow milk-specific IgE antibodies coexist with cow milk-specific IgG antibodies in CMA patients with diarrhea symptom, and if there is any relationship between both antibody types. 65 CMA patients (average age of 17 years, ranging from 2 to 74 years), all of who had diarrhea symptom of CMA, were enrolled in this study. The total cow IgE and IgG subclass in serum were measured by electrochemiluminescence immunoassay and rate immune scatter turbidimetry, respectively. And also the cow milk-specific IgE was determined by enzyme-linked immunosorbent assay. The number of eosinophils in serum was calculated by Sysmex XE-2100 Hematology Analyzer. Our data showed that both cow milk-specific IgG and IgE levels were significantly elevated in CMA patients compared to those of age-matched control subjects. Out of the 65 CMA patients, 40 showed elevated cow milk-specific IgE antibody level, among which, 28 cases presented highly sensitive reaction to cow milk-specific IgG, along with each six of moderate and mild sensitive reaction to cow milk-specific IgG; while 20 showed elevated total IgG levels. The IgG3 positive rate was 16.9%, which was the highest. A moderate correlation between cow milk-specific IgE and cow milk-specific IgG was found in the CMA patients (r=0.415, P=0.001). The results indicated that cow milk-specific IgE antibodies could coexist with cow milk-specific IgG antibodies in patients suffering from CMA. The aberrant changes in the concentration of cow milk-specific IgE antibodies were associated with cow milk-specific IgG antibodies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Acquired delayed-onset hypolactasia is a common autosomal recessive condition. Cow's milk allergies, conversely, are less common conditions that may manifest with equivalent symptoms and are able to simulate and/or aggravate lactose intolerance. This study was designed to evaluate the contribution of IgE-mediated cow's milk sensitization to the symptomatology of adult patients with lactose-free diet refractory lactose intolerance. Forty-six adult patients with lactose intolerance and persistent symptoms despite a lactose-free diet underwent skin-prick test to investigate cow's milk, goat's milk, and soy protein-specific-IgE. SDS-PAGE immunoblotting was used to investigate the presence of cow's milk protein-specific IgE. The percentage of patients who had skin reactions to whole cow's milk, alpha-lactalbumin, beta-lactoglobulin, caseins, goat's milk, and soy was 69.5, 36.9, 56.5, 56.5%, 54.3, and 50%, respectively. The percentage of patients with immunoblot-detected IgE specific for alpha-lactalbumin, beta-lactoglobulin, caseins, and bovine serum albumin was 21.7, 63, 67.3, and 2.1%, respectively. IgE-mediated sensitization to cow's milk is a frequent comorbidity in subjects with lactose-free diet refractory lactose intolerance and is worth consideration in patients with this condition.

Objectives/hypothesis: To explore the relationship between food hypersensitivity and common upper aerodigestive disorders found in children younger than 2 years., Study Design: Case control study., Setting: Tertiary pediatric gastroenterology/otolaryngology clinics., Methods: Two-year retrospective chart review of a common cohort of children younger than 2 years with suspected cow's milk protein allergy (CMPA). Patients were managed in both a tertiary pediatric gastroenterology and otolaryngology clinic and compared with a control study group., Results: One hundred ninety-one children with CMPA were reviewed. One hundred forty-one had aerodigestive complaints, with 101 having sufficient follow-up to participate in the study. Ninety-one percent of this final patient group demonstrated improved symptoms following dairy elimination. Twenty-five patients (27%) had associated otolaryngologic (ear, nose, and throat [ENT]) issues that had been refractory to maximal gastroesophageal reflux therapy. The most common associated upper aerodigestive conditions were persistent upper airway congestion (72%) and oropharyngeal dysphagia (80%). Sixty percent of ENT disease improved with elimination diet. Eosinophilic esophagitis was noted in 36% of the cohort who had mucosal biopsies performed. Otolaryngology intervention was much more common in the cohort of children with CMPA compared with controls (odds ratio, 33.78; 95% confidence interval, 7.55, 151.03)., Conclusions: CMPA is difficult to diagnose because of limited accurate diagnostic tools, especially in young children. This study suggests a relationship between CMPA and otolaryngologic conditions in children younger than 2 years. Some patients in this study showed symptom improvement via an elimination diet. Early recognition of otolaryngologic manifestations of CMPA may help manage this condition in young children.

Cow's milk protein allergy (CMPA) is one of the most prevalent human food-borne allergies, particularly in children. Experimental animal models have become critical tools with which to perform research on new therapeutic approaches and on the molecular mechanisms involved. However, oral food allergen sensitization in mice requires several weeks and is usually associated with unspecific immune responses. To overcome these inconveniences, we have developed a new food allergy model that takes only two weeks while retaining the main characters of allergic response to food antigens. The new model is characterized by oral sensitization of weaned Balb/c mice with 5 doses of purified cow's milk protein (CMP) plus cholera toxin (CT) for only two weeks and posterior challenge with an intraperitoneal administration of the allergen at the end of the sensitization period. In parallel, we studied a conventional protocol that lasts for seven weeks, and also the non-specific effects exerted by CT in both protocols. The shorter protocol achieves a similar clinical score as the original food allergy model without macroscopically affecting gut morphology or physiology. Moreover, the shorter protocol caused an increased IL-4 production and a more selective antigen-specific IgG1 response. Finally, the extended CT administration during the sensitization period of the conventional protocol is responsible for the exacerbated immune response observed in that model. Therefore, the new model presented here allows a reduction not only in experimental time but also in the number of animals required per experiment while maintaining the features of conventional allergy models. We propose that the new protocol reported will contribute to advancing allergy research., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Gastroesophageal reflux (GER) is a challenging clinical entity that has often been associated with a number of negative clinical outcomes. The treatment of this condition lacks evidence and is often based on anecdotal beliefs and myths. This article will define GER and review the recommendations for the diagnosis of GER as well as review the evidence for both pharmacologic and nonpharmacologic treatment of GER.

The aim of this study was to analyze the natural history of atopic dermatitis (AD) and the risk factors associated with the remission of AD in Korean children. We enrolled 597 children with AD that occurred in the first year of life. A variety of factors influencing the prognosis were assessed by medical records and telephone interviews. Their outcome was classified into complete remission, intermittent, and persistent AD. AD had completely disappeared in 422 cases (70.6%), while 149 (25%) and 26 cases (4.4%) showed intermittent and persistent skin symptoms, respectively. The average healing time was 29.6 months in complete remission group and expected healing time of the AD was 60 months. None of risk factors were significant by multivariate analysis. But, in moderate-to-severe AD group, maternal diet restriction during lactation (P = 0.046) and no sensitization to cow's milk (P = 0.017) were significantly associated with remission of AD in the multivariate analysis. In conclusion, AD occurring in the first year of life disappears in a significant proportion of patients. In addition, in Korean children with moderate-to-severe AD, maternal diet restriction of allergenic food during lactation and sensitization to cow's milk seem to predict the prognosis of AD.

Cow's milk protein allergy (CMPA) affects between 1.9 and 4.9% of infants and young children. This food allergy requires the complete elimination of cow's milk and its derivatives, impacting on nutritional status. The risk of having protein energy malnutrition (PEM) in children with CMPA has been well documented. In 2007, the World Health Organisation published guidelines on the dietary management of PEM, which has impacted on the recommendations and composition on specialist feeds for many chronic diseases, but not on CMPA. The main change in management of the child with PEM is the protein energy ratio and energy requirements. The ideal protein energy ratio lies between 8.9 and 11.5%, which would ensure a deposition of about 70% lean and 30% fat mass. In addition, for optimal catch-up growth between 5 and 10 g/kg/day, energy requirements should be between 105 and 126 kcal/kg/day. Although most current hypoallergenic formulas fall well within the recommendation for protein, there is a problem in achieving energy requirements. As a result, modular additions are often made, disturbing the protein energy ratio or feeds are concentrated, which impacts on osmolality. We therefore aimed to review current guidelines on PEM and how these can be applied in the management of the malnourished child with CMPA., (© 2012 John Wiley & Sons A/S.)

Unlabelled: In predisposed individuals dietary intake of cereal products may lead to the development of food allergy or celiac disease. These diseases may also coexist with each other. In recent years, a change in the clinical picture of celiac disease has been observed and the incidence of atypical forms has increased. The disease is currently either diagnosed late or often remains undiagnosed. The article presents a case of an underweight 11- year old girl with height deficiency and recurrent respiratory infections, as well as chronic rhinitis, occurring from the age of three. On the basis of complex differential diagnosis, sensitization to tree pollens, and to cow's milk protein and gluten were identified. Despite the detection of antibodies specific for celiac disease, such as the antibodies against smooth muscle endomysium (IgAEMA) and anti-tissue transglutaminase antibodies (IgAtTGAb), the histological confirmation of the diagnosis was not obtained. Implementation of the gluten and milk protein-free - elimination diet and the use of antihistamines resulted in clinical improvement and the disappearance of markers of both food sensitization and celiac disease. The second food provocation test was negative for previously detected markers of food sensitization but showed the presence of IgAEMA and IgAtTGAb and the histological features of intestinal mucosa typical for celiac disease., Conclusions: The diagnosis of food allergy or other chronic diseases which can cause growth disturbance (short stature and/or impaired weight gain ) should not exempt from the obligation of estimating the markers specific for celiac disease.

Objectives: The aim of the study was to explore pathogenesis and find new serum markers for cow's-milk-sensitive enteropathy (CMSE) and coeliac disease (CD). We assessed the intestinal expression and serum concentration of CD23, IL-15, and FasL. We hypothesised that the serum levels of CD23, a protein expressed in the lymphoid follicles, would be associated with lymphonodular hyperplasia (LNH), a feature characteristic of CMSE. We also presumed that interleukin (IL)-15 and FasL, functionally connected with proliferation and apoptosis of the intraepithelial lymphocytes (IELs), would relate with the increased numbers of IELs present in both CMSE and CD., Methods: Twenty-three children with CMSE, 20 with untreated CD, and 14 controls were studied for CD3, α/β- and γ/δ-expressing IELs, and for duodenal and ileal expression of CD23, FasL, and IL-15 by immunohistochemistry, and for serum concentration of sCD23, sFasL, and sIL-15 by enzyme-linked immunosorbent assay., Results: There was a trend for increase in sCD23 serum levels in untreated CMSE and in CD (P = 0.074; P = 0.077). CD23 was expressed in the mucosal germinal centres, but sCD23 was not related to presence of LNH. In CMSE, there was a trend for increase in serum sFasL (P = 0.07) and high levels associated with LNH (P = 0.025) and correlated with the IEL numbers (P < 0.05). Mucosal high endothelial venules adjacent to lymphoid follicles showed an intensive FasL expression., Conclusions: Serum sCD23 shows a trend of increment in CMSE and CD, and in the latter, sCD23 level may provide information about the severity of villous atrophy. In CMSE, high serum sFasL indicates both LNH and an increase of IELs, suggesting importance of FasL-mediated mechanisms in the pathogenesis of these features characteristic of CMSE. Further studies are necessary to evaluate whether intensive FasL expression in mucosal high endothelial venules presents a regulatory element in mucosal immunity.

It is known that the use of anti-TNF-α drugs is related to an increased incidence of infective diseases. This therapy can not be administered to patients having active infections and it has to be considered with caution in case of acquired or congenital immunodeficiency diseases. We report the case of a 28-years-old man affected by psoriatic arthritis; he developed some infections during treatment with TNF-α blockers. The infections were caused by a selective IgA deficiency, that was not evident before the anti-TNF-α blockers administration and disappeared after withdrawing the biological therapy. This case-report draws our attention to the possibility of cases of subclinical immunodeficiency, unknown by the patients, but important in the prognosis and in the therapeutic approach to these diseases. Therefore, it is important to evaluate carefully the immunologic status of patients during the pre-therapeutic screening for TNF-α blocking therapy.

Background: Atopic dermatitis is a major public health problem, often starting in early childhood and sometimes followed by other allergic diseases. Although hypersensitivity to foods is assumed to play an essential role in the development of atopic dermatitis in some patients, little is known about common food allergens in Iranian children with atopic dermatitis., Objectives: This study was designed to identify probable food allergens in Iranian children with atopic dermatitis and find the relationship between food sensitization and the severity of atopic dermatitis., Methods: This study included 90 children aged 2-48 months with atopic dermatitis. Skin prick tests for cow's milk, hen's egg, almond, potato and soybean were done. Serum specific IgE to 20 food allergens was also screened., Results: Among children with atopic dermatitis, the frequency of food sensitization was 40% by skin prick test and 51% by food-specific IgE. Children with atopic dermatitis were most commonly sensitized to cow's milk (31%), hen's egg (17.7%), tree nuts (17.7%), wheat (12.2%), potato (11.1%), tomato (8.8%) and peanut (8.8%). In 42 children with moderate to severe eczema, sensitivity to food allergens was 78.5% by skin prick test and 88% by serum specific IgE evaluation., Conclusion: Our results showed that cow's milk, hen's egg and tree nuts were the most common food allergens in Iranian children with atopic dermatitis. Sensitization to foods was much higher in patients with moderate to severe atopic dermatitis. Determining specific IgE in children with atopic dermatitis can be helpful in managing these patients.

Background: Skin-prick tests (SPT), food-specific immunoglobulin E level (sIgE) and clinical history have limited value individually in predicting the severity of outcome of the oral food challenge (OFC)., Objectives: To develop a score that accounts for SPT, sIgE and clinical history to predict the risk of severe reaction to the OFC., Methods: A 5 year retrospective chart review was performed on 983 children who underwent OFC to egg, milk and peanut., Results: Using multilogistic regression, four major indicators were found to be independently associated with failed OFC: sIgE (odds ratio = 1.04, P < 0.0001), wheal size of the SPT (OR = 1.23, P < 0.0001), a history of any prior reaction to the food (OR = 1.13, P < 0.01), and a history of a prior non-cutaneous reaction (OR = 1.99, P < 0.01); and three were independently associated with anaphylaxis: wheal size (OR = 1.16, P < 0.001), a history of a prior non-cutaneous reaction (OR = 4.24, P < 0.01), and age (OR = 1.07, P < 0.03). A Food Challenge Score (0-4) was developed which accounted for SPT wheal, sIgE, a history of a prior non-cutaneous reaction, and age. A score of 0-1 had a negative predictive value for multisystem reaction to the OFC: 95% for milk, 91% for egg and 93% for peanut. A score of 3-4 had a positive predictive value for anaphylaxis: 62% for milk, 92% for egg and 86% for peanut., Conclusions: Severe reaction to milk, egg and peanut OFC can be predicted using a simple score that takes into account clinical data that are commonly available prior to the challenges.

Unlabelled: Few studies concerning the occurrence of cow's milk allergy with the use of double-blind, placebo controlled food challenge test in adolescents and adult patients suffering from atopic dermatitis exist., Aim: To evaluate the occurrence of cow's milk allergy in adolescents and adults suffering from atopic dermatitis., Method: Altogether 179 persons suffering from atopic dermatitis were included in the study: 51 men and 128 women entered the study with the average age of 26.2 (s.d. 9.5 years). Complete dermatological and allergological examinations were performed., Results: The positive results in specific IgE and in skin prick tests were recorded in 12% of patients. According to the open exposure tests and double-blind, placebo controlled food challenge tests these patients are only sensitized to cow's milk without clinical symptoms of allergy. Double-blind, placebo controlled food challenge test confirmed food allergy to cow milk only in one patient (worsening of atopic dermatitis), the oral allergy syndrome was observed in another one patient, occurrence of this allergy was altogether 1.1%., Conclusion: Cow's milk allergy rarely plays a role in the worsening of atopic dermatitis in adolescent and adult patients.

Aim: The possible role of serum interleukin 4 (IL-4) and tumor necrosis factor alpha (TNF- α) in pathogenesis of the reflux symptoms in children with primary acid gastroesophageal reflux (GER) and acid GER secondary to cow's milk allergy (CMA)., Material and Methods: Out of 264 children, 76 (28.8%) patients with primary GER and 62 (23.5%) patients with GER secondary to CMA (pH - monitoring) serum IL-4 and TNF- α concentrations were assessed before treatment, 1 and 2 years after the initiation of the periodically administered pharmacotherapy., Results: Children with primary GER had mean IL-4 concentrations 0.17 ± 0.06 pg/ml before treatment, 0.08 ± 0.07 pg/ ml after 1-year and 0.07 ± 0.06 pg/ml after 2-years of treatment. The mean IL-4 concentrations were 1.07 ± 0.24, 0.5 ± 0.22 and 0.44 ± 0.19 pg/ml respectively in children with GER secondary to CMA. The mean serum TNF- α concentrations was 3.62 ± 1.30 pg/ml before treatment , 2.16 ± 1,35 pg/ ml after 1 year and 1.65 ± 1.16 pg/ml after 2 years of treatment in children with primary GER. In group with GER secondary to CMA mean serum TNF- α concentrations were 4.95 ± 1.88, 2.53 ± 0.80 and 2.02 ± 0.78 pg/ml respectively. Statistical analysis of the concentration of both cytokines showed their differentiation between them and in the study groups., Conclusions: The highest mean serum IL-4 and TNF-α concentrations were observed in children with GER secondary to CMA and in children in control group (with cow's milk allergy and/or other food allergy diagnosed - CMA/FA) before the treatment administration.

In this study, specific oral tolerance induction using interferon-gamma (IFN-γ) could successfully treat food allergies. Allergen-specific IL-10-producing regulatory B cell (Br1) responses are characteristic in immune tolerance of food allergies. The in-vivo effects of IFN-γ on allergen-induced changes in Br1 proportion and numbers in food allergies were investigated. Oral food challenges were conducted and 20 allergic patients to cow's milk were selected. Of these 20 patients, five were treated with IFN-γ and milk (SOTI group), five were treated with only milk, five were treated with only IFN-γ, and five did not receive any treatment. In addition, 10 milk-tolerant subjects were involved in this study. Peripheral blood mononuclear cells (PBMCs) were stimulated using casein and stained for CD5, CD19, annexin V, and IL-10 before and after treatment. Allergy tolerance was induced only in the SOTI group along with induction of allergen-induced Br1 changes. Thus, IFN-γ can show tolerogenic effects in vivo when introduced with an allergen, which may be at least partly due to its effect on allergen-induced Br1 responses., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Cow's milk allergy (CMA) can cause functional bowel symptoms. This can lead to confusion and difficulty in managing pediatric surgical patients who also have CMA. We examined CMA's effect on the management of pediatric surgical patients in our institute., Methods: With institutional review board approval, 14 pediatric surgical patients with CMA were reviewed. Cow's milk allergy was diagnosed according to clinical findings and stimulation index (normal range <300%) of the lymphocyte stimulation test., Results: The main symptoms were abdominal distension (n = 10), vomiting (n = 6), constipation (n = 2), and apnea (n = 1). Stimulation index median value was 731% (range, 341%-2132%). Patients were divided into 3 groups. In group 1 (n = 8), persistent postoperative bowel symptoms were initially considered related to surgical diseases. Following CMA diagnosis, CM elimination therapy improved symptoms. In group 2 (n = 4), CMA was diagnosed concurrently with surgical disease, and elimination therapy was continued postoperatively. In group 3 (n = 2), the pathogenesis of bowel symptoms was initially attributed to CMA and later diagnosed as Hirschsprung's disease., Conclusions: A high index of suspicion regarding the possibility of concurrent CMA may be necessary to manage bowel symptoms in pediatric surgical patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This article reports a case of live-threatening respiratory failure during induction of anesthesia. An 18-year-old female was admitted to hospital for an axillary abscess incision on a public holiday. The patient had a history of asthmatic episodes and an allergy to milk protein and 2 years previously an asthmatic attack had possibly been treated by mechanical ventilation. Retrospectively, this event turned out to be a cardiac arrest with mechanical ventilation for 24 h. During induction of anesthesia the patient suddenly developed massive bronchospasms and ventilation was impossible for minutes. Oxygen saturation fell below 80% over a period of 12 min with a lowest measurement of 13%. The patient was treated with epinephrine, prednisolone, antihistamine drugs, ß(2)-agonists, s-ketamine and methylxanthines and 15 min later the oxygen saturation returned to normal values. After mild therapeutic hypothermia for 24 h mechanical ventilation was still required for another 4 days. The patient recovered completely and was discharged home on day 19. Initially propofol was suspected of having caused an anaphylactic shock but in retrospect, the diagnosis of near fatal asthma was more likely. The onset of the event was facilitated by the patient playing down the history of asthmatic episodes due to a strong wish for independency and negation of the severity of the disease.

Objectives: Migraine is a very common headache disorder. Due to the co-occurrence of migraine and allergic disorders, allergic mechanisms have been thought to play a role in migraine pathophysiology. This study aimed to investigate the association between cow's milk allergy and egg-white allergy and migraine-type headache of childhood., Methods: We included 39 children with migraine-type headache and 167 children with no headache who had been evaluated previously in a school screening study program. Egg-white and cow's milk-specific IgE levels were measured for all involved subjects., Results: Specific IgE levels were positive for cow's milk in 4 children and for egg-white in 2 children, respectively. No meaningful relationship was detected between food allergies and migraine. However, specific IgE levels for egg-white were significantly higher in migraineurs (p=0.008)., Conclusion: Childhood migraine does not appear to be associated with cow's milk or egg-white allergy. However, the elevation of egg-white-specific IgE levels in migraine-type headache may signify the possible presence of shared pathogenetic pathways in the development of migraine and food allergies.

Cow's milk is one of the most common food allergens in children with atopic dermatitis (AD). This study was conducted to describe the natural course of cow's milk allergy in children with AD, and to identify factors predictive of outcome. To accomplish this, we reviewed the medical records of 115 children who were diagnosed with AD and cow's milk allergy before 24 months of age to evaluate their clinical characteristics and prognostic factors. During a follow-up period of 24 to 114 months, the median age for tolerance to cow's milk was found to be 67 months. Multivariate analysis using the Cox proportional hazard model revealed that the peak cow's milk-specific IgE level within 24 months after birth was the most important factor for prediction of the outcome of cow's milk allergy. In conclusion, half of the children younger than 24 months of age with AD and cow's milk allergy could tolerate cow's milk at 67 months of age. The peak cow's milk-specific IgE level within the first 24 months of birth is useful to predict the prognosis of cow's milk allergy in children with AD.

Aim: Allergies to hen's egg and cow's milk are the most frequent food allergies in infancy and childhood. Current guidelines recommend safe administration of measles-mumps-rubella (MMR) vaccine in egg allergic patients., Methods: We present three cases of anaphylaxis that we encountered after MMR vaccination in children sensitized to hen's egg and cow's milk., Results: Even though MMR vaccine is generally known to be safe in children with egg allergy, there may still be isolated cases of anaphylaxis., Conclusion: Therefore, we recommend that all children not only those who were sensitized to foods should receive the MMR vaccination in a setting that is equipped to deal with anaphylactic reactions. As stated by WHO in immunization safety surveillance, 'Each vaccinator must have an emergency kit with adrenaline, and be familiar with its dosage and administration'., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Aims/background: Nuclear transit studies (NTS) allow us to follow transit through the stomach and the small and large intestines. We identified children with chronic constipation with rapid proximal colonic transit and characterized their clinical features., Methods: We reviewed NTS from 1998 to 2009 to identify patients with chronic constipation and rapid proximal colonic transit, defined as greater than 25% of tracer beyond hepatic flexure at 6 hour and/or greater than 25% of tracer beyond end of descending colon at 24 hour. This was correlated with clinical symptoms and outcome from patient records., Results: Five hundred twenty children with chronic constipation underwent investigation by NTS, and 64 (12%) were identified with rapid proximal colonic transit. The clinical history, symptoms, and outcome in 55 of 64 available for analysis frequently showed family history of allergy (10.9%) and symptoms associated with food allergy/intolerance: abdominal pain (80%), anal fissure (27.3%), and other allergic symptoms (43.6%). Eighteen children were treated with dietary exclusion, with resolution of symptoms in 9 (50%)., Conclusions: Some children with intractable chronic constipation have rapid proximal colonic transit, have symptoms consistent with possible food allergy/intolerance, and may respond to dietary exclusion. The NTS can identify these patients with rapid proximal transit that may be secondary to food intolerance., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Food allergy is among the most common of the allergic disorders, with a prevalence of 6-8 per cent in children up to the age of three. However, many people self-diagnose, putting their children at risk of malnutrition, possibly as a result of lack of awareness by health professionals of food allergy as a potential cause of conditions such as infantile eczema, chronic diarrhoea, faltering growth and gastrooesophageal reflux. NICE (The National Institute for Health and Clinical Excellence) recently published guidelines, which they hope will help to improve the diagnosis of food allergies within the community. If food allergy or lactose intolerance is suspected, the mainstay of a diagnostic work up should comprise of a detailed allergy-focused clinical history, part of which will involve determining whether the adverse reaction is typically an immediate (IgE mediated) or more delayed-type (non-IgE mediated) allergic reaction, or whether it may be lactose intolerance; a form of non-allergic hypersensitivity.