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1.  Extensively hydrolysed casein formula supplemented with Lactobacillus rhamnosus GG maintains hypoallergenic status: randomised double-blind, placebo-controlled crossover trial 
BMJ Open  2012;2(2):e000637.
Objective
To evaluate the hypoallergenicity of an extensively hydrolysed (EH) casein formula supplemented with Lactobacillus rhamnosus GG (LGG).
Design
A prospective, randomised, double-blind, placebo-controlled crossover trial.
Setting
Two study sites in Italy and The Netherlands.
Study participants
Children with documented cow's milk allergy were eligible for inclusion in this trial.
Interventions
After a 7-day period of strict avoidance of cow's milk protein and other suspected food allergens, participants were tested with an EH casein formula with demonstrated hypoallergenicity (control, EHF) and a formula of the same composition with LGG added at 108 colony-forming units per gram powder (EHF-LGG) in randomised order in a double-blind placebo-controlled food challenge (DBPCFC). After absence of adverse reactions in the DBPCFC, an open challenge was performed with EHF-LGG, followed by a 7-day home feeding period with the same formula.
Main outcome measure
Clinical assessment of any adverse reactions to ingestion of study formulae during the DBPCFC.
Results
For all participants with confirmed cow's milk allergy (n=31), the DBPCFC and open challenge were classified as negative.
Conclusion
The EH casein formula supplemented with LGG is hypoallergenic and can be recommended for infants and children allergic to cow's milk who require an alternative to formulae containing intact cow's milk protein.
Trial registration number
http://ClinicalTrials.gov Identifier: NCT01181297.
Article summary
Article focus
Hypoallergenic extensively hydrolysed (EH) cow's milk-based or amino acid-based formulae are recommended for management of cow's milk allergy in formula-fed infants.
Although Lactobacillus rhamnosus GG (LGG) has over 25 years of safe use as a dietary probiotic, the safety and hypoallergenic status of EH casein formula supplemented with LGG has not yet been demonstrated.
Key messages
Supplementing the EH casein formula with LGG to provide additional benefits does not change its hypoallergenic status.
The LGG-supplemented EH formula can be safely used for management of cow's milk allergy in infants and children.
Strengths and limitations of this study
Testing the LGG-supplemented EH formula in a properly designed double-blind placebo-controlled food challenge in accordance with accepted European Society of Pediatric Gastroenterology and Nutrition (ESPGHAN) and American Academy of Pediatrics standards to establish hypoallergenicity is a major strength of this study.
One limitation is the potentially low novelty of our finding. Because LGG is the most used dietary probiotic, accumulated safety data for LGG as a stand-alone dietary supplement in infants and adults are available.
doi:10.1136/bmjopen-2011-000637
PMCID: PMC3298831  PMID: 22396223
Cow's milk protein; cow's milk allergy; extensively hydrolysed formula; double-blind placebo-controlled food challenge; hypoallergenic formula; infant; Lactobacillus GG
2.  Intestinal malrotation with suspected cow’s milk allergy: a case report 
BMC Research Notes  2012;5:481.
Background
Intestinal malrotation is an incomplete rotation of the intestine. Failure to rotate leads to abnormalities in intestinal positioning and attachment that leave obstructing bands across the duodenum and a narrow pedicle for the midgut loop, thus making it susceptible to volvulus. One of the important differential diagnoses for malrotation is an allergy to cow’s milk. Several studies have described infants with surgical gastrointestinal diseases and cow’s milk allergy. However, to our knowledge, no study has reported infants with intestinal malrotation who have been symptomatic before surgery was performed and have been examined by allergen-specific lymphocyte stimulation test and food challenge tests with long-term follow-up.
Case presentation
The patient was a Japanese male born at 39 weeks of gestation. He was breast-fed and received commercial cow’s milk supplementation starting the day of birth and was admitted to our hospital at 6 days of age due to bilious vomiting. Plain abdominal radiography showed a paucity of gas in the distal bowel. Because we demonstrated malpositioning of the intestine by barium enema, we repositioned the bowel in a normal position by laparotomy. The patient was re-started on only breast milk 2 days post surgery because we suspected the presence of a cow’s milk allergy, and the results of an allergen-specific lymphocyte stimulation test showed a marked increase in lymphocyte response to kappa-casein. At 5 months of age, the patient was subjected to a cow’s milk challenge test. After the patient began feeding on cow’s milk, he had no symptoms and his laboratory investigations showed no abnormality. In addition, because the patient showed good weight gain and no symptoms with increased cow’s milk intake after discharge, we concluded that the present case was not the result of a cow’s milk allergy. At 1 year, the patient showed favorable growth and development, and serum allergy investigations revealed no reaction to cow’s milk.
Conclusion
When physicians encounter infants with surgical gastrointestinal disease, including intestinal malrotation, they should consider cow’s milk allergy as a differential diagnosis or complication and should utilize food challenge tests for a definitive diagnosis.
doi:10.1186/1756-0500-5-481
PMCID: PMC3490812  PMID: 22943656
Allergen-specific lymphocyte stimulation test; Cow’s milk allergy; Food challenge test; Infant; Intestinal malrotation
3.  421 Cow's Milk Allergy and Persistent Changes in a Multiple Food Allergy, A Case Report 
Background
Cow's milk allergy (CMA) is the most common food allergy. Clinical manifestations are mediated immediate hypersensitivity and delayed. The allergy study include: specific IgE, prick and patch test. Regarding treatment, this is based on the exclusion diet and the replacement of cow's milk hydrolysates extensive.
Virtually all infants who have cow's milk allergy develop this condition in the first year of life, with clinical tolerance developing in about 80 percent by their fifth birthday.
Methods
Describe the case of a child with CMA, which moves without tolerance and also become sensitized to other foods.
Results
Female with 6 years of age. At 9 months presents watery diarrhea, weight loss and intermittent rash. Initial study (2006): Upper endoscopy: Duodenitis chronic nonspecific, total IgE: 72.60 IU/mL, IgE specific to cow's milk 10.40 IU/mL (Class III) and prick test positive. Exclusion diet starts to cow's milk, its derivatives and beef. Patient improvement. At 2 years, begins with rhinitis and diarrhea reappears with low weight. Colonoscopy (2007): Subacute nonspecific colitis histology. At 3 years old facial angioedema, throat and rash are associated with eating chicken, turkey, carrot and orange juice. New tests: specific IgE cow's milk, 24. 7 IU/mL (class IV), class II chicken. Prick test positive. At 4 years enter kindergarten, restarts with diarrhea and occasional angioedema. Cow's milk specific IgE (January 2009): 66, 6 IU/mL (class V). January 2010: 5 years post anaphylactic shock milk pudding. Besides diarrhea 10 times a day, intermittently throughout the year. Year 2011: intermittent diarrhea and specific IgE to cow's milk is kept in class V.
Conclusions
In this case the patient with CMA which evolved atypically because it has not been able to acquire tolerance. Moreover, awareness is added to other foods during their evolution. A recent study indicated a lower rate of development of clinical tolerance. As assessed by passing a milk challenge, 5 percent were tolerant at age 4 and 21 percent at age 8. Patients with persistent milk allergy have higher cow's milk sIgE levels in the first 2 years of life. Approximately 35 percent developed allergy to other foods.
doi:10.1097/01.WOX.0000412184.40629.eb
PMCID: PMC3512946
4.  Nutritional Status According to Sensitized Food Allergens in Children With Atopic Dermatitis 
Purpose
Food allergies can affect the growth and nutritional status of children with atopic dermatitis (AD). This study was conducted to determine the association between the number of sensitized food allergens and the growth and nutritional status of infants and young children with AD.
Methods
We studied 165 children with AD, aged 5 to 47 months, and who visited the Atopy Clinic of the Seoul Medical Center. We recorded the birth weight, time at which food weaning began, scoring of atopic dermatitis (SCORAD) index, eosinophil counts in peripheral blood, and total serum IgE and specific IgE to six major allergens (egg white, cow's milk, soybean, peanut, wheat, and fish). The height and weight for age and weight for height were converted to z-scores to evaluate their effects on growth and nutritional status. Specific IgE levels ≥0.7 kUA/L, measured via the CAP assay, were considered positive.
Results
As the number of sensitized food allergens increased, the mean z-scores of weight and height for age decreased (P=0.006 and 0.018, respectively). The number directly correlated with the SCORAD index (r=0.308), time at which food weaning began (r=0.332), eosinophil counts in peripheral blood (r=0.266), and total serum IgE (r=0.394). Inverse correlations were observed with the z-scores of weight for age (r=-0.358), height for age (r=-0.278), and weight for height (r=-0.224).
Conclusions
A higher number of sensitized food allergens was associated with negative effects on the growth and nutritional status of infants and young children with AD. Therefore, a thorough evaluation of both growth and nutritional status, combined with adequate patient management, is crucial in pediatric AD patients presenting with numerous sensitized food allergies.
doi:10.4168/aair.2011.3.1.53
PMCID: PMC3005320  PMID: 21217926
Dermatitis atopic; food hypersensitivity; growth; nutritional status
5.  The effect of a partially hydrolysed formula based on rice protein in the treatment of infants with cow’s milk protein allergy 
Pediatric Allergy and Immunology  2010;21(4p1):577-585.
Reche M, Pascual C, Fiandor A, Polanco I, Rivero-Urgell M, Chifre R, Johnston S, Martín-Esteban M. The effect of a partially hydrolysed formula based on rice protein in the treatment of infants with cow’s milk protein allergy. Pediatr Allergy Immunol 2010: 21: 577–585. © 2010 John Wiley & Sons A/S
Infants diagnosed with allergy to cow’s milk protein (CMP) are fed extensively hydrolysed cow’s milk formulas, modified soy formulas or even amino acid-based formulas. Hydrolysed rice protein infant formulas have become available and have been shown to be well tolerated by these infants. A prospective open, randomized clinical study to compare the clinical tolerance of a new hydrolysed rice protein formula (HRPF) with an extensively hydrolysed CMP formula (EHF) in the feeding of infants with IgE-mediated cow’s milk allergy. Ninety-two infants (46 boys and 46 girls, mean age 4.3 months, range 1.1–10.1 months) diagnosed with IgE-mediated cow’s milk allergy were enrolled in the study. Clinical tolerance to the formula products was tested. Clinical evaluation included skin prick tests with whole cow’s milk, soya and rice as well as antigens of CMP (beta-lactoglobulin, alpha-lactalbumin, casein and bovine seroalbumin), HRPF and EHF and specific IgE determinations to CMP using CAP technology. Patients were randomized to receive either an EHF based on CMP or a new HRPF. Follow-up was at 3, 6, 12, 18 and 24 months. Growth parameters were measured at each visit. One infant showed immediate allergic reaction to EHF, but no reaction was shown by any infant in the HRPF group. The number of infants who did not become tolerant to CMP during the study was not statistically different between the two groups. Measurement of IgE levels of infants allergic to CMP during the study showed no significant differences between the two formula groups. Growth parameters were in the normal range and similar between groups. In this study, the HRPF was well tolerated by infants with moderate to severe symptoms of IgE-mediated CMP allergy. Children receiving this formula showed similar growth and development of clinical tolerance to those receiving an EHF. In accordance with current guidelines, this HRPF was tolerated by more than 90% of children with CMP allergy and therefore could provide an adequate and safe alternative to CMP-hydrolysed formulas for these infants.
doi:10.1111/j.1399-3038.2010.00991.x
PMCID: PMC2904490  PMID: 20337976
cow’s milk protein allergy; hydrolysed rice protein formula; extensively hydrolysed cow’s milk protein formula
6.  Diagnosing possible infantile cow’s milk protein allergy in rural Africa, when history and physical examination are the only tools: a case report 
Cases Journal  2009;2:6287.
Introduction
Cow’s milk protein allergy is common in infants from industrialised countries, but is rarely considered in developing countries due to its variable clinical presentation.
Case presentation
We report on a Tanzanian male infant, who developed blood-stained stool when feeding fresh cow’s milk at the age of three months. After an initial diagnosis of amoebiasis, possible cow’s milk protein allergy was suspected. Further diagnostic work-up was not possible due to lack of resources. After elimination of cow’s milk from the diet, the infant recovered soon.
Conclusion
Cow’s milk protein allergy should be considered more frequently in infants from developing countries, especially when they belong to agropastoralist tribes and are fed cow’s milk early.
doi:10.4076/1757-1626-2-6287
PMCID: PMC2740089  PMID: 19829778
7.  Markers of gut mucosal inflammation and cow’s milk specific immunoglobulins in non-IgE cow’s milk allergy 
Background
Allergy to cow’s milk protein (CMP) may cause gastrointestinal (GI) symptoms in the absence of CMP specific IgE. The immunological mechanisms involved in such disease are not fully understood. Therefore we examined markers of gut mucosal inflammation and the immunoglobulin profiles in children with Gl symptoms suspected of cow’s milk protein allergy (CMPA).
Patients and methods
We prospectively recruited infants and young children (n = 57; median age 8.7 months) with gastrointestinal complaints suspected of CMPA. The diagnosis of CMPA was made using the double-blind, placebo-controlled food challenge. Serum and stool samples were collected during CMP-free diet and after both placebo and active challenges. We analyzed the stool samples for calprotectin, human β-defensin 2 and IgA. In serum, we analyzed the levels of β-lactoglobulin and α-casein specific IgA, and IgG antibodies (total IgG and subclasses IgG1 and IgG4). Control group included children with e.g. dermatological or pulmonary problems, consuming normal diets.
Results
Fecal calprotectin levels were higher in the challenge positive group (n = 18) than in the negative (n = 37), with respective geometric means 55 μg/g [95% confidence interval 38–81] and 29 [24–36] μg/g (p = 0.0039), during cow’s milk free diet. There were no significant inter-group differences in the fecal β-defensin and IgA levels. The CMP specific IgG and IgA were not elevated in patients with CMPA, but the levels of β-lactoglobulin-IgG4 (p = 0.0118) and α-casein-IgG4 (p = 0.0044), and total α-casein-IgG (p = 0.0054) and -IgA (p = 0.0050) in all patient samples (regardless of CMPA diagnosis) were significantly lower compared to the control group using dairy products.
Conclusions
Despite cow’s milk elimination in children intolerant to cow’s milk there might be ongoing low-grade inflammation in the gut mucosa. CMP specific IgG or IgA should not be used to diagnose non-IgE CMPA. The observed frequency of impaired CMP specific total IgA, IgG and IgG4 production in patients following cow’s milk free diet warrants further studies.
doi:10.1186/2045-7022-4-8
PMCID: PMC3946153  PMID: 24598281
8.  The Role of Cow's Milk Allergy in Pediatric Chronic Constipation: A Randomized Clinical Trial 
Iranian Journal of Pediatrics  2012;22(4):468-474.
Objective
Cow's milk allergy has different presentations in children and can cause functional bowel symptoms such as chronic constipation. The aims of this study were to investigate the role of cow's milk allergy as a cause of chronic constipation and effect of cow's milk free diet (CMFD) on its treatment in children.
Methods
We performed a randomized clinical study comparing CMFD with cow's milk diet (CMD) in two groups each consisting of 70 patients (age range, 1-13 years) with chronic functional constipation (defined as Rome III criteria). All subjects had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives for at least 3 months without success; also all 140 patients performed skin prick test. The case group received CMFD for 4 weeks. After that they received CMD for 2 extra weeks. The control group received CMD for whole 6 weeks. A response was defined as decreased in signs and symptoms that not fulfilled Rome III criteria after 4 weeks of CMFD and came back to Rome III criteria after 2 weeks of CMD challenge.
Findings
After 4 weeks 56 (80%) patients of the case group responded in comparison to 33 (47.1%) patients in the control group (P=0.0001). In the case group after 2 weeks challenge 24 out of 56 (42.8%) responders developed constipation according to Rome III criteria. With other words, the frequency of cow's milk allergy among constipated patients was 80%. Only one patient had positive skin prick test.
Conclusion
In children, chronic constipation can be a manifestation of cow's milk allergy. At present, although several aspects must be further investigated, a therapeutic attempt with elimination diet is advisable in all children with constipation unresponsive to correct laxative treatment.
PMCID: PMC3533146  PMID: 23429756
Cow's Milk; Milk Allergy; Allergy; Chronic Constipation; Children
9.  End point prick test: could this new test be used to predict the outcome of oral food challenge in children with cow's milk allergy? 
Background
Cow's milk allergy (CMA) is the most frequent food allergy in childhood; the trend of CMA is often characterized by a progressive improvement to achieve tolerance in the first 4 to 5 years of life.
It has been observed that specific IgE (sIgE) towards cow's milk proteins decrease when the age increases.
Although food allergy can be easily diagnosed, it is difficult to predict the outcome of the oral food challenge (OFC), that remains the gold standard in the diagnosis of food allergy, by allergometric tests.
Methods
We considered 44 children with CMA diagnosed through OFC who returned to our Allergy and Immunology Pediatric Department between January to December 2010 to evaluate the persistence of allergy or the achievement of tolerance.
On the basis of the history, we performed both allergometric skin tests and OFC in children that were still following a milk-free diet, whereas only allergometric skin tests those that had already undergone spontaneous introduction of milk protein at home without presenting symptoms.
Objective
The aim of this study was to investigate the relationship between the persistence of CMA or the acquisition of tolerance and the results of the end point prick test (EPT).
Results and Discussion
The OFC with cow's milk was performed on 30 children, 4 children were excluded because of a history of severe reactions to cow's milk, and 10 because they had spontaneously already taken milk food derivates at home without problems. 16/30 (53%) children showed clinical reactions and the challenge was stopped, 14/30 (47%) did not have any reaction.
Comparing the mean wheal diameter of every EPT's dilution between the group of allergic children and the tolerant ones, we obtained a significant difference (p < 0.05) for the first 4 dilutions.
We have also calculated sensitivity (SE), specificity (SP), the positive predictive value (PPV) and the negative predictive value (NPV) for each EPT dilution.
Conclusions
EPT is a safe and cheap test, easy to be executed and that could provide good prediction of the outcome of OFC; so it might be used to avoid OFC-induced anaphylaxis in children affected by CMA. It can also help avoiding dietetic restrictions in tolerant children who show sensitization towards cow's milk proteins.
doi:10.1186/1824-7288-37-52
PMCID: PMC3220633  PMID: 22053846
Cow's milk proteins allergy; end point prick test; food oral challenge; tolerance
10.  Predictive value of the cow’s milk skin prick test in infantile colic 
Annals of Saudi Medicine  2010;30(6):468-470.
BACKGROUND AND OBJECTIVES:
Infantile colic is a common problem among young infants. Cow’s milk allergy has been suggested as one of the causes. We aimed to investigate the value of the cow’s milk skin test for the diagnosis of cow’s milk allergy in exclusively breast-fed infants with infantile colic.
METHODS:
Exclusively breast-fed infants with infantile colic were enrolled in this study. On the first visit, the average hours of crying of the infant in a 24-h period were recorded and the cow’s milk skin test was performed. If the infant had a positive skin test, elimination of cow’s milk from the mothers’ diet was advised. Infants with negative skin tests were divided into case and control groups. Cow’s milk was eliminated from the diet of mothers in the case group. After 2 weeks, the number of hours of crying were recorded again. The reduction in the crying hours was compared between the two groups using the chi-square test.
RESULTS:
Skin tests were positive in 3 of 114 cases (2.6%) of infantile colic. All three cases recovered completely following elimination of cow’s milk from the mother’s diet. Among the 111 patients with negative skin tests, 77 patients completed the study: 35 in the case group and 42 in the control group. The reduction in crying hours in infants in the case group was not significantly different from that in the control group.
CONCLUSION:
Elimination of cow’s milk from the mothers’ diet is not beneficial for infants with a negative skin test. Infants with a positive skin test may benefit from this management.
doi:10.4103/0256-4947.72269
PMCID: PMC2994164  PMID: 21060160
11.  Approach to milk protein allergy in infants 
Canadian Family Physician  2008;54(9):1258-1264.
ABSTRACT
OBJECTIVE
To provide a practical, evidence-based approach to the diagnosis and management of milk protein allergy in infants.
SOURCES OF INFORMATION
MEDLINE was searched from 1950 to March 2008 using the MeSH heading milk-hypersensitivity. Additional sources were derived from reviews found with the initial search strategy. Evidence was levels I, II, and III.
MAIN MESSAGE
Milk protein allergy is a recognized problem in the first year of life; cow’s milk protein allergy is the most common such allergy. Diagnosis is suspected on history alone, with laboratory evaluations playing a supporting role. Confirmation requires elimination and reintroduction of the suspected allergen. Management includes diet modification for nursing mothers and hydrolyzed formulas for formula-fed infants. Assessing the underlying immunopathology can aid in determining prognosis.
CONCLUSION
The therapeutic model presented allows rapid assessment of the presence of allergy, timely management, and surveillance for recurrence of symptoms. Breastfeeding can be continued with attentive diet modification by motivated mothers.
PMCID: PMC2553152  PMID: 18791102
12.  Presence of functional, autoreactive human milk-specific IgE in infants with cow’s milk allergy 
Summary
Background
Occasionally, exclusively breastfed infants with cow’s milk allergy (CMA) remain symptomatic despite strict maternal milk avoidance.
Objective
To determine whether or not persistence of symptoms could be due to sensitization against endogenous human milk proteins with a high degree of similarity to bovine allergens.
Methods
Ten peptides representing known bovine milk IgE-binding epitopes [α-lactalbumin (ALA), β- and κ-casein] and the corresponding, highly homologous human milk peptides were labelled with sera from 15 breastfed infants with CMA, aged 3 weeks to 12 months, and peptide (epitope)-specific IgE antibodies were assessed. Nine of the 15 breastfed infants became asymptomatic during strict maternal avoidance of milk and other major food allergens; six infants remained symptomatic until weaned. Ten older children, aged 5–15 years, with CMA were also assessed. The functional capacity of specific IgE antibodies was assessed by measuring β-hexosaminidase release from rat basophilic leukaemia cells passively sensitized and stimulated with human and bovine ALA. Results A minimum of one human milk peptide was recognized by IgE antibodies from 9 of 15 (60%) milk-allergic infants, and the majority of older children with CMA. Genuine sensitization to human milk peptides in the absence of IgE to bovine milk was occasionally seen. There was a trend towards specific IgE being detected to more human milk peptides in those infants who did not respond to the maternal milk elimination diet than in those who did (P = 0.099). Functional IgE antibody to human ALA was only detected in infants not responding to the maternal diet.
Conclusions and Clinical Relevance
Endogenous human milk epitopes are recognized by specific IgE from the majority of infants and children with CMA. Such autoreactive, human milk-specific IgE antibodies appear to have functional properties in vitro. Their role in provoking allergic symptoms in infants exclusively breastfed by mothers strictly avoiding dietary milk remains unclear.
doi:10.1111/j.1365-2222.2011.03864.x
PMCID: PMC3780604  PMID: 22092935
atopic eczema; autoreactivity; cow’s milk allergy; cross-reactivity; endogenous protein; human milk; IgE antibodies; infants; RBL assay; sensitization; SPOT method
13.  493 The Prevalence of Food Allergy in Children under 2 Years in Three Cities in China 
The World Allergy Organization Journal  2012;5(Suppl 2):S173-S174.
Background
To estimate the prevalence and clinical features of food allergy in children aged 0 to 2 years.
Methods
From January to February, 2009 and January to May, 2010, all well-infants and young children between the age of 0-2 years attending routine health visits at the Department of Primary Child Care, in Chongqing, Zhuhai and Hangzhou were invited to participate the study. Parents completed questionnaires and all children were skin prick tested to a panel of 10 foods (egg white, egg yolk, cow milk, soybean, peanut, wheat, fish, shrimp, orange and carrot). Based on the results of SPT and medical history, the subjects should undergo the suspected food elimination and oral food challenge under medical supervision. Food allergy was confirmed by the food challenge test.
Results
There were 1,687 children recruited by the consent of their parents. Of 1,687 children approached, 1,604 (550 for Chongqing, 573 for Zhuhai and 481 for Hangzhou) fulfilled the study criteria for diagnosing food allergy. 100 children were confirmed to have challenge-proven food allergy in 3 cities (40 for Chongqing, 33 for Zhuhai and 27 for Hangzhou). The prevalence of food allergy in 0 to 2 years old children in Chongqing was 7.3%, in Zhuhai was 5.8% and in Hangzhou was 5.5%. There was no significant difference in the prevalence of food allergy in children under 2 years among the 3 cities, and the average prevalence for food allergy in children under 2 years was 6.2%. Egg was the most common allergen, followed by cow milk.
Conclusions
The prevalence of food allergy in 0 to 2 years old children in China was 5.5% to 7.3%. There was no significant difference in the prevalence of food allergy in children under 2 years among the 3 cities. Egg was the most common allergen, followed by cow milk.
doi:10.1097/01.WOX.0000411608.35185.f5
PMCID: PMC3512627
14.  Milk and Soy Allergy 
SYNOPSIS
Cow’s milk allergy (CMA) affects 2% to 3% of young children and presents with a wide range of immunoglobulin E (IgE-) and non-IgE-mediated clinical syndromes, which have a significant economic and lifestyle impact. Definitive diagnosis is based on a supervised oral food challenge (OFC), but convincing clinical history, skin prick testing, and measurement of cow’s milk (CM)-specific IgE can aid in the diagnosis of IgE-mediated CMA and occasionally eliminate the need for OFCs. It is logical that a review of CMA would be linked to a review of soy allergy, as soy formula is often an alternative source of nutrition for infants who do not tolerate cow’s milk. The close resemblance between the proteins from soy and other related plants like peanut, and the resulting cross-reactivity and lack of predictive values for clinical reactivity, often make the diagnosis of soy allergy far more challenging. This review examines the epidemiology, pathogenesis, clinical features, natural history and diagnosis of cow’s milk and soy allergy. Cross-reactivity and management of milk allergy are also discussed.
doi:10.1016/j.pcl.2011.02.005
PMCID: PMC3070118  PMID: 21453810
cow’s milk; soy; bovine; allergy; cross-reactivity; diagnosis; management; natural history; pediatric; children
15.  Dietary baked-milk accelerates resolution of cow's milk allergy in children 
Background
The majority (∼75%) of cow's milk-allergic children tolerate extensively heated-(baked-) milk products. Long-term effects of inclusion of dietary baked-milk have not been reported.
Objective
We report on the outcomes of children who incorporated baked-milk products into their diets.
Methods
Children evaluated for tolerance to baked-milk (muffin) underwent sequential food challenges to baked-cheese (pizza) followed by unheated-milk. Immunologic parameters were measured at challenge visits. The comparison group were matched to active subjects (using age, sex, and baseline milk-specific IgE) to evaluate the natural history of tolerance development.
Results
Over a median of 37 months (range 8-75 months), 88 children underwent challenges at varying intervals (range 6-54 months). Among 65 subjects initially tolerant to baked-milk, 39 (60%) now tolerate unheated-milk, 18 (28%) tolerate baked-milk/baked-cheese and 8 (12%) chose to avoid milk strictly. Among the baked-milk-reactive subgroup (n=23), 2 (9%) tolerate unheated-milk, 3 (13%) tolerate baked-milk/baked-cheese, while the majority (78%) avoid milk strictly. Subjects who were initially tolerant to baked-milk were 28 times more likely to become unheated-milk-tolerant compared to baked-milk-reactive subjects (P<.001). Subjects who incorporated dietary baked-milk were 16 times more likely than the comparison group to become unheated-milk-tolerant (P<.001). Median casein IgG4 levels in the baked-milk-tolerant group increased significantly (P<.001); median milk IgE values did not change significantly.
Conclusions
Tolerance of baked-milk is a marker of transient IgE-mediated cow's milk allergy whereas reactivity to baked-milk portends a more persistent phenotype. The addition of baked-milk to the diet of children tolerating such foods appears to accelerate development of unheated-milk tolerance compared to strict avoidance.
Clinical implications
Addition of dietary baked-milk is safe, convenient, and well-accepted by patients. Prescribing baked-milk products to milk-allergic children represents an important shift in the treatment paradigm for milk allergy.
Capsule summary
The majority of cow's milk-allergic children tolerate extensively baked-milk products, which is a marker of transient IgE-mediated cow's milk allergy. Dietary baked-milk appears to accelerate development of unheated-milk tolerance compared to strict avoidance.
doi:10.1016/j.jaci.2011.04.036
PMCID: PMC3151608  PMID: 21601913
cow's milk allergy; milk allergy; tolerance; extensively heated; baked; immunotherapy; immunomodulation
16.  Health-related quality of life, assessed with a disease-specific questionnaire, in Swedish adults suffering from well-diagnosed food allergy to staple foods 
Background
Our aim was to investigate the factors that affect health related quality of life (HRQL) in adult Swedish food allergic patients objectively diagnosed with allergy to at least one of the staple foods cow’s milk, hen’s egg or wheat. The number of foods involved, the type and severity of symptoms, as well as concomitant allergic disorders were assessed.
Methods
The disease-specific food allergy quality of life questionnaire (FAQLQ-AF), developed within EuroPrevall, was utilized. The questionnaire had four domains: Allergen Avoidance and Dietary Restrictions (AADR), Emotional Impact (EI), Risk of Accidental Exposure (RAE) and Food Allergy related Health (FAH). Comparisons were made with the outcome of the generic questionnaire EuroQol Health Questionnaire, 5 Dimensions (EQ-5D). The patients were recruited at an outpatient allergy clinic, based on a convincing history of food allergy supplemented by analysis of specific IgE to the foods in question. Seventy-nine patients participated (28 males, 51 females, mean-age 41 years).
Results
The domain with the most negative impact on HRQL was AADR, assessing the patients’ experience of dietary restrictions. The domain with the least negative impact on HRQL was FAH, relating to health concerns due to the food allergy. One third of the patients had four concomitant allergic disorders, which had a negative impact on HRQL. Furthermore, asthma in combination with food allergy had a strong impact. Anaphylaxis, and particularly prescription of an epinephrine auto-injector, was associated with low HRQL. These effects were not seen using EQ-5D. Analyses of the symptoms revealed that oral allergy syndrome and cardiovascular symptoms had the greatest impact on HRQL. In contrast, no significant effect on HRQL was seen by the number of food allergies.
Conclusions
The FAQLQ-AF is a valid instrument, and more accurate among patients with allergy to staple foods in comparison to the commonly used generic EQ-5D. It adds important information on HRQL in food allergic adults. We found that the restrictions imposed on the patients due to the diet had the largest negative impact on HRQL. Both severity of the food allergy and the presence of concomitant allergic disorders had a profound impact on HRQL.
doi:10.1186/2045-7022-3-21
PMCID: PMC3702411  PMID: 23816063
Food allergy; Adults; Health-related quality of life; Instrument; Questionnaire
17.  Growth Parameters Impairment in Patients with Food Allergies 
Journal of Allergy  2014;2014:980735.
Background and Aims. Food allergy (FA) is a common disease that is rapidly increasing in prevalence for reasons that remain unknown. Objective. The aim of this study was to analyze the clinical characteristics and anthropometric data of patients with food allergies followed in a tertiary centre of allergy and immunology. Methods. A retrospective study was performed that assessed the data records of patients with food allergy diagnosis, covering a period from February 2009 to February 2012. Results. 354 patients were evaluated in the period; 228 (69.1%) patients had a confirmed FA diagnosis. The z-scores for weight-for-age, height-for-age, and body mass indices-for-age showed lower significant values in the FA group compared with the non-FA group by Mann-Whitney test, with significance values of P = 0.0005, P = 0.0030, and P = 0.0066, respectively. There were no statistical differences in sex, gestational age, birth type, breastfeeding period, and age of introduction of complementary formulas based on cow milk protein between groups. Conclusion. FA patients had a lower growth rate in comparison with patients without FA. The early recognition of food allergies with the establishment of protein-implicated diet exclusion, in association with an adequate nutrient replenishment, is important to reduce the nutritional impact of food allergies.
doi:10.1155/2014/980735
PMCID: PMC4052520  PMID: 24949021
18.  Cow's milk protein allergy in children: a practical guide 
A joint study group on cow's milk allergy was convened by the Emilia-Romagna Working Group for Paediatric Allergy and by the Emilia-Romagna Working Group for Paediatric Gastroenterology to focus best practice for diagnosis, management and follow-up of cow's milk allergy in children and to offer a common approach for allergologists, gastroenterologists, general paediatricians and primary care physicians.
The report prepared by the study group was discussed by members of Working Groups who met three times in Italy. This guide is the result of a consensus reached in the following areas. Cow's milk allergy should be suspected in children who have immediate symptoms such as acute urticaria/angioedema, wheezing, rhinitis, dry cough, vomiting, laryngeal edema, acute asthma with severe respiratory distress, anaphylaxis. Late reactions due to cow's milk allergy are atopic dermatitis, chronic diarrhoea, blood in the stools, iron deficiency anaemia, gastroesophageal reflux disease, constipation, chronic vomiting, colic, poor growth (food refusal), enterocolitis syndrome, protein-losing enteropathy with hypoalbuminemia, eosinophilic oesophagogastroenteropathy. An overview of acceptable means for diagnosis is included. According to symptoms and infant diet, three different algorithms for diagnosis and follow-up have been suggested.
doi:10.1186/1824-7288-36-5
PMCID: PMC2823764  PMID: 20205781
19.  Adverse reactions to milk in infants 
Aim
To study the age when symptoms of adverse reactions to milk occur, in premature and term children, the debut of various symptoms, immunoglobulin E (IgE)- and non-IgE-mediated reactions and the frequency of tolerance at 1 year.
Methods
Six hundred and eight children, 193 premature and 416 term infants, were followed. Symptomatic children were invited to a clinical examination. The criteria for the diagnosis were: histories of suspected cow's milk allergy (CMA) and proven IgE-mediated reactions to cow's milk or positive elimination/challenge tests.
Results
Twenty-seven out of 555 (4.9%) were diagnosed with adverse reactions to cow's milk. All had symptoms before 6 months of age. The main symptoms were: pain behaviour (13), gastrointestinal symptoms (7), respiratory symptoms, (6) and atopic dermatitis (1). One child had proven IgE to cow's milk. Premature and term infants displayed the same symptoms and age of debut. Thirteen children were tolerant to cow's milk at 1 year.
ConclusionAdverse reactions to milk start early in life, with pain behaviour, gastrointestinal, and respiratory symptoms being the most common, and rarely atopic dermatitis. Non-IgE-mediated reactions were the most frequent. Symptoms and age of debut were the same in premature and term infants. Half of the children tolerated cow's milk at age 1.
doi:10.1111/j.1651-2227.2007.00599.x
PMCID: PMC2253707  PMID: 18254909
Adverse reactions to milk; Infancy; Premature children
20.  441 Patterns of Food Allergens in Kenyan Children 
The World Allergy Organization Journal  2012;5(Suppl 2):S157-S158.
Background
To determine the patterns of food allergens in children presenting to pediatric gastroenterology clinic at the Aga Khan University Hospital, Nairobi.
Methods
This data includes children evaluated from March to November, 2010.All the children presenting for evaluation of various gastrointestinal symptoms and who had positive history of atopy in at least one first degree relative were included. History of reccurent cough was sought and the skin was examined for eczema. Skin Prick Test was perfomed by an expert in allergy and immunology. Prick to Prick Test was done for local foods where commercial antigens were not available. Positive tests were followed by an exclusion and rechallenge progamme but this was excluded from analysis due to poor compliance. Analysis was performed to determine frequencies and associations of the different gastrointestinal symptoms and food allergens. Both skin Prick and Prick to Prick results were analysed together.
Results
The commonest food allergens in order of frequency were cow milk (65%), egg (35%), beef (26%), beans (14%), chicken, corn, wheat, soya and rice (9%), fish (8%) and peanut (5%).Common local infant complementary foods including potatoes, bananas and vegetables all tested positive in 4% of the children. Pumpkin tested positive in one infant who had presented with rectal bleeding. Majority of the children had positive tests to multiple foods. Only 14% of the children had negative tests. The commonest gastrointestinal (GI) symptoms were abdominal pain (38%), constipation (36%), vomiting (14%), diarrhoea (11%), failure to thrive (9%) and colics (3%). Majority of the children had multiple GI symptoms. Eczema and cough were associated symptoms in 9% and 3% of the children respectively.
Conclusions
The prevalence of food allergy as suggested by this study is high in Kenyan children and contributes signficantly towards gastrointestinal morbidity. While cow milk, egg and beef are the commonest allergens, the emerging allergy to local infant complementary foods is also significant. The high frequency of multiple allergens partly contributed to poor compliance in the exclusion rechallenge programme due to lack of options on alternative foods.
doi:10.1097/01.WOX.0000412204.60821.e4
PMCID: PMC3512893
21.  Clinical practice. Diagnosis and treatment of cow’s milk allergy 
European Journal of Pediatrics  2009;168(8):891-896.
Introduction
Cow’s milk allergy (CMA) is thought to affect 2–3% of infants. The signs and symptoms are nonspecific and may be difficult to objectify, and as the diagnosis requires cow’s milk elimination followed by challenge, often, children are considered cow’s milk allergic without proven diagnosis.
Diagnosis
Because of the consequences, a correct diagnosis of CMA is pivotal. Open challenges tend to overestimate the number of children with CMA. The only reliable way to diagnose CMA is by double-blind, placebo-controlled challenge (DBPCFC).
Therapy
At present, the only proven treatment consists of elimination of cow’s milk protein from the child’s diet and the introduction of formulas based on extensively hydrolysed whey protein or casein; amino acid-based formula is rarely indicated. The majority of children will regain tolerance to cow’s milk within the first 5 years of life.
Conclusions
Open challenges can be used to reject CMA, but for adequate diagnosis, DBPCFC is mandatory. In most children, CMA can be adequately treated with extensively hydrolysed whey protein or casein formulas.
doi:10.1007/s00431-009-0955-7
PMCID: PMC2694929  PMID: 19271238
Cow’s milk allergy; Double-blind placebo-controlled food challenge; DBPCFC; Hypoallergenic formula
22.  Basophil Reactivity, Wheal Size and Immunoglobulin Levels Distinguish Degree of Cow’s Milk Tolerance 
Background
In our previous study, about 75% of cow’s milk-allergic children tolerated baked-milk products, which improved their prognosis and quality of life.
Objective
We sought to identify biomarkers of varying degrees of clinical tolerance among a cohort of cow’s milk-allergic children.
Methods
132 subjects were initially classified as baked-milk-reactive, baked-milk-tolerant or “outgrown milk allergy” based on oral food challenges. The baked-milk tolerant group was then divided into 3 groups based upon the amount and degree of heat-denatured milk protein that they could tolerate. Serum was analyzed for allergen-specific IgE and IgG4, basophil reactivity was assessed in whole blood stimulated with serial 10-fold dilutions of milk protein, and prick skin tests were performed to commercial milk extract. Activated basophils were defined using flow cytometry as CD63brightCD203c+CD123+HLA-DRdim/−CD41a− lineage−. Data were analyzed using the Jonckheere-Terpstra test.
Results
Significant differences across the five clinical groups were seen for median casein- and milk-specific IgE, casein-specific IgG4 and casein IgE/IgG4; milk-specific to non-specific basophil activation ratio, median basophil reactivity, and spontaneous basophil activation (CD203c expression following stimulation with RPMI); and milk PST wheal diameters. Casein- and milk-specific IgE, milk-specific basophil reactivity and milk prick skin test wheal diameter are all significantly greater among milk-allergic patients who react to baked-milk than among those who tolerate it.
Conclusions
The majority of milk-allergic patients are able to tolerate some forms of baked-milk in their diets. Different phenotypes of cow’s milk-allergic children can be distinguished by casein- and milk-specific IgE, milk-specific basophil reactivity, and milk prick skin test mean wheal diameters. Spontaneous basophil activation is greater among patients with more severe clinical milk reactivity.
doi:10.1016/j.jaci.2012.06.003
PMCID: PMC3493710  PMID: 22819512
Cow’s milk allergy; tolerance; extensively heated; baked; immunotherapy; immunomodulation; biomarker; basophil activation
23.  Whole cow’s milk in infancy 
Paediatrics & Child Health  2003;8(7):419-421.
Early introduction of whole cow’s milk may lead to iron deficiency anemia. From a nutritional point of view, it is best to delay the introduction of whole cow’s milk until the infant is one year old. While there is no evidence to suggest adverse clinical sequelae associated with the increased renal solute load in healthy infants, feeding with whole cow’s milk would narrow the margin of safety in situations that may lead to dehydration. Early exposure to cow’s milk proteins increases the risk of developing allergy to milk proteins. Because of the possible association between early exposure to cow’s milk proteins and risk for type 1 diabetes mellitus, breast-feeding and avoidance of commercially available cow’s milk and products containing intact cow’s milk protein during the first year of life are strongly encouraged in families with a strong history of insulin dependent diabetes mellitus. The authors suggest that the optimal food in infancy is human breast milk. If human milk is not available, it is preferred that iron-fortified formulas rather than whole cow’s milk be used during the first year of life.
PMCID: PMC2791650  PMID: 20019947
whole cow’s milk; infancy
24.  Double-blind placebo-controlled food challenges in children with alleged cow’s milk allergy: prevention of unnecessary elimination diets and determination of eliciting doses 
Nutrition Journal  2013;12:22.
Background
Children with cow’s milk allergy (CMA) need a cow’s milk protein (CMP) free diet to prevent allergic reactions. For this, reliable allergy-information on the label of food products is essential to avoid products containing the allergen. On the other hand, both overzealous labeling and misdiagnosis that result in unnecessary elimination diets, can lead to potentially hazardous health situations. Our objective was to evaluate if excluding CMA by double-blind placebo-controlled food challenge (DBPCFC) prevents unnecessary elimination diets in the long term. Secondly, to determine the minimum eliciting dose (MED) for an acute allergic reaction to CMP in DBPCFC positive children.
Methods
All children with suspected CMA under our care (Oct’05 - Jun’09) were prospectively enrolled in a DBPCFC. Placebo and verum feedings were administered on two randomly assigned separate days. The MED was determined by noting the ‘lowest observed adverse effect level’ (LOAEL) in DBPCFC-positive children. Based on the outcomes of the DBPCFC a dietary advice was given. Parents were contacted by phone several months later about the diet of their child.
Results
116 children were available for analysis. In 76 children CMA was rejected. In 60 of them CMP was successfully reintroduced, in 2 the parents refused introduction, in another 3 the parents stopped reintroduction. In 9 children CMA symptoms reappeared. In 40 children CMA was confirmed. Infants aged ≤ 12 months in our study group have a higher cumulative distribution of MED than older children.
Conclusions
Excluding CMA by DBPCFC successfully stopped unnecessary elimination diets in the long term in most children. The MEDs form potential useful information for offering dietary advice to patients and their caretakers.
doi:10.1186/1475-2891-12-22
PMCID: PMC3599188  PMID: 23394146
Cow’s milk allergy; Cow’s milk protein; Double-blind placebo-controlled provocation; Milk hypersensitivity; Minimum eliciting dose
25.  Maternal Consumption of Peanut during Pregnancy is Associated with Peanut Sensitization in Atopic Infants 
Background
Peanut allergy is typically severe, life-long and prevalent.
Objective
To identify factors associated with peanut sensitization.
Methods
We evaluated 503 infants 3–15 months of age (mean, 9.4 months) with likely milk or egg allergy but no previous diagnosis of peanut allergy. A total of 308 had experienced an immediate allergic reaction to cow’s milk and/or egg and 204 had moderate to severe atopic dermatitis and a positive allergy test to milk and/or egg. A peanut IgE level of ≥ 5 kUA/L was considered likely indicative of peanut allergy.
Results
A total of 140 (27.8%) infants had PN-IgE levels ≥5 kUA/L. Multivariate analysis including clinical, laboratory and demographic variables showed frequent peanut consumption during pregnancy (OR 2.9, 95% CI 1.7–4.9, p < 0.001), IgE levels to milk (p = 0.001) and egg (p < 0.001), male sex (p = 0.02) and non-white race (p = 0.02) to be the primary factors associated with peanut IgE ≥5 kUA/L. Frequency of peanut consumption during pregnancy and breast feeding showed a dose-response association with peanut IgE ≥ 5 kUA/L, but only consumption during pregnancy was a significant predictor. Among 71 infants never breastfed, frequent consumption of peanut during pregnancy was strongly associated with peanut IgE ≥ 5 kUA/L (OR-4.99, 95% CI-1.69–14.74, p < 0.004).
Conclusions
In this cohort of infants with likely milk or egg allergy, maternal ingestion of peanut during pregnancy was strongly associated with a high level of peanut sensitization.
doi:10.1016/j.jaci.2010.08.036
PMCID: PMC3018157  PMID: 21035177
food allergy; sensitization; atopy; peanut allergy

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