IgE-mediated Cow's Milk Allergy Research Articles

Natural Course and Risk Factors for Persistence of IgE-Mediated Cow's Milk Allergy

To describe the natural course of IgE-mediated cow's milk allergy (IgE-CMA) and to determine risk factors for its persistence in a population-based cohort. In a prospective cohort study, 54 infants with IgE-CMA were identified from a population of 13 019 children followed from birth. Diagnosis of IgE-CMA was based on history, skin prick test (SPT), and an oral food challenge (OFC) when indicated. Allergic infants were followed for 48-60 months. Families were contacted by telephone every 6 months and asked about recent exposures to milk. OFC was repeated to evaluate for recovery. Clinical characteristics, SPT, and OFC outcomes were compared between infants with persistent IgE-CMA and infants who recovered. Thirty-one infants (57.4%) recovered from IgE-CMA during the study period. Most infants (70.9%) recovered within the first 2 years. Risk factors for persistence on multivariate analysis included a reaction to <10 mL of milk on OFC (or on first exposure as estimated by the guardian, if OFC was not performed) (P = .01), a larger wheal size on SPT (P = .014), and age of ≤30 days at time of first reaction (P = .05). Resolution occurs in most infants with IgE-CMA. Infants reacting to <10 mL of milk or in the first month of life, and those with a larger wheal size on SPT, are at increased risk for persistence.

Oral immunotherapy for IgE‐mediated cow's milk allergy: a systematic review and meta‐analysis

Cow's milk is a common cause of food allergy in children. Children usually outgrow cow's milk allergy by the age of 3-5years, but some will have persistent symptoms beyond childhood. We performed a systematic review of randomized controlled trials (RCTs) and observational studies to assess the evidence supporting the use of oral immunotherapy in IgE-mediated cow's milk allergy to inform the World Allergy Organization guidelines. Of 1034 screened articles published until May 2011, five RCTs and five observational studies fulfilled a priori specified inclusion criteria. RCTs including 218 patients showed that oral immunotherapy, compared to elimination diet alone, increased the likelihood of achieving full tolerance of cow's milk [relative risk: 10.0 (95% CI: 4.1-24.2)]. Adverse effects of immunotherapy include frequent local symptoms (16% of doses), mild laryngospasm [relative risk: 12.9 (1.7-98.6)], mild asthma [rate ratio: 3.8 (2.9-5.0)], reactions requiring oral glucocorticosteroids [relative risk: 11.3 (2.7-46.5)] or intramuscular epinephrine injection [rate ratio 5.8 (1.6-21.9)]. Results of observational studies were consistent with those of RCTs. Despite the availability of RCTs, the overall low quality of evidence leaves important uncertainty about anticipated effects of immunotherapy due to very serious imprecision of the estimates of effects and the likelihood of publication bias for some of the critical outcomes. A potentially large benefit of oral immunotherapy in patients with cow's milk allergy may be counterbalanced by frequent and sometimes serious adverse effects. Additional, larger RCTs measuring all patient-important outcomes are still needed.

Double-blind, placebo-controlled food challenges in Brazilian children: Adaptation to clinical practice

BackgroundA double-blind, placebo-controlled food challenge (DBPCFC) is considered the gold standard for diagnosing food allergy, but because of methodological difficulties it is rarely conducted in clinical practice, especially in paediatric patients. The purpose of the study was to propose a DBPCFC protocol that is adapted to our conditions for the diagnosis of an IgE-mediated cow's milk allergy (CMA) in a Brazilian reference centre for paediatric allergies. MethodsThis study includes the experimental phase (choice of materials, adjustments made to protocols described in the literature) and the test execution phase. DBPCFCs were performed in 58 patients aged 1–15years who were separated into two groups: Group 1 (n=39), sex 1.6 M:F, 5.3years median age, suggestive history of IgE-mediated CMA; and Group 2 (n=19), sex 1.4 M:F, 8.3years median age with symptoms not associated with milk ingestion and laboratory data not compatible with IgE-mediated CMA. ResultsThe materials were standardised for testing: containers and disposable products, low-lactose cow's milk (CM) and vehicles, such as natural fruit juice, vegetable soup and soybean-based beverages. Each DBPCFC was performed in a single day with two blind, randomised phases with a 2-h interval between them. The milk doses were gradually increased and offered in regular intervals of 15–30min. Following negative or inconclusive results, patients underwent an open oral challenge test with 200mL of low-lactose CM. ConclusionsThe proposed adaptation for the DBPCFC allowed to implement this important test for the diagnosis of IgE-mediated CMA in a reference centre for paediatric allergies. It was considered feasible and safe if performed in an appropriate setting with physician supervision.

Reaction in the First Month of Life and a Lower Eliciting Dose are Risk Factors for Persistence of IgE-Mediated Cow's Milk Allergy

Reaction in the First Month of Life and a Lower Eliciting Dose are Risk Factors for Persistence of IgE-Mediated Cow's Milk Allergy

Peripheral Blood Immune Response Elicited by Beta-Lactoglobulin in Childhood Cow's Milk Allergy

Several studies analyzing the immune responses in patients with cow's milk allergy (CMA) have used T-cell lines or T-cell clones that require prolonged in vitro cell culturing and may result in a switched cell phenotype and function. We investigated immune responses to beta-lactoglobulin (b-LG) in peripheral blood mononuclear cells after a short in vitro antigen stimulation in children with acute CMA (both IgE-mediated and non-IgE-mediated forms) and in those who outgrew an IgE-mediated CMA. Healthy controls were also investigated. Peripheral blood mononuclear cells were assayed for IL-13, IFN-γ, IL-4, and IL-10. Although b-LG induced a cytokine production and/or cell proliferation almost in all children, included healthy controls, differences were observed among the four groups. Children with IgE-mediated CMA had a marked Th2-response, with high IL-13 production and proliferation, but low IFN-γ; by contrast, children with non-IgE-mediated CMA produced no, or very low, IL-13 and cell proliferation. Children, who outgrew CMA, showed a shift to a Th1-response, with reduced IL-13 and increased IFN-γ. IL-10-responses were high in all groups, with the highest level in healthy children; by contrast, IL-4 was undetectable in all children. This study highlights the use of shortly stimulated peripheral blood cells to investigate the food-induced immune responses.

Intérêt des prick-tests aux hydrolysats dans l’allergie IgE-dépendante aux protéines du lait de vache de l’enfant

Allergy to cow's milk is the first allergy to appear in new born babies as soon as they are introduced to their first feeding bottles. There are two main immune forms of allergy to cow's milk: the immediate form known as “IgE-mediated”, when symptoms appear quickly after the allergen intake and the delayed form, or “not IgE-mediated”, when symptoms appear several hours after the allergen intake. A study was carried out at the Children's hospital in Toulouse to evaluate the use of hydrolysate prick tests when IgE-mediated milk allergy is present. The sample concerned 12 infants; 10 boys, on average aged four-months-old when symptoms first appeared, and aged nine months when seen for the first time at the hospital for an allergy check-up. For one child who showed no change on taking Nutramigen ®, it was decided to replace the hydrolysate formula with an amino-acid formula. The infants who showed positive results to the hydrolysate prick tests were prescribed another extensive protein hydrolysate formula. This study validates the guidelines which recommend that neither goat's milk nor sheep's milk should be used (positive results on eight of the 12 infants tested). It seems to be interesting to perform skin prick test with hydrolysate formulas in infants with IgE-mediated cow's milk allergy with aim of the hydrolysate choice.

Dietary baked milk accelerates the resolution of cow’s milk allergy in children

The majority (approximately 75%) of children with cow's milk allergy tolerate extensively heated (baked) milk products. Long-term effects of inclusion of dietary baked milk have not been reported. We report on the outcomes of children who incorporated baked milk products into their diets. 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 was matched to active subjects (by using age, sex, and baseline milk-specific IgE levels) to evaluate the natural history of development of tolerance. 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, and 3 (13%) tolerate baked milk/baked cheese, whereas 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 with 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 IgG(4) levels in the baked milk-tolerant group increased significantly (P< .001); median milk IgE values did not change significantly. 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 the development of unheated milk tolerance compared with strict avoidance.

The pendulum between food protein–induced enterocolitis syndrome and IgE‐mediated milk allergy

The transition from milk protein-induced enterocolitis syndrome to IgE-mediated milk allergy is uncommon. Herein, we describe three infants that suffered from recurrent vomiting and restlessness in response to cow's milk formula with negative skin prick to milk and therefore diagnosed as milk protein-induced enterocolitis syndrome. After recovering and reintroducing cow's milk formula, they developed disseminated urticaria and positive skin prick test to cow milk compatible with IgE-mediated milk allergy. An infant that recovers from cow milk food-induced enterocolitis syndrome might develop afterward IgE-mediated cow milk allergy.

The prevalence and natural course of food protein–induced enterocolitis syndrome to cow’s milk: A large-scale, prospective population-based study

The prevalence and natural history for food protein-induced enterocolitis syndrome (FPIES) have not been determined. We sought to determine the prevalence, clinical manifestations, and rate of recovery for FPIES in a large-scale, population-based prospective study. In a prospective study the feeding history of 13,019 infants was obtained. Infants with probable adverse reactions to cow's milk protein (CMP) were clinically examined, skin prick tested, and challenged orally. Diagnostic criteria for CMP-induced FPIES included age less than 9 months, delayed recurrent vomiting (usually with nausea), and lethargy after exposure to CMP in the absence of other IgE-mediated symptoms, such as rash, urticaria, and respiratory symptoms. In addition, a positive challenge response to milk resulted in the above-mentioned gastrointestinal symptoms, removal of milk from the diet resulted in the resolution of those symptoms, or both. Ninety-eight percent of the cohort participated in the study. The cumulative incidence for FPIES was 0.34% (44/13,019 patients). The most common symptoms were recurrent vomiting (100%), lethargy (77%) diarrhea (25%), pallor (14%), and bloody diarrhea (4.5%). All patients had FPIES within the first 6 months of life. By the age of 3 years, 90% of the patients had recovered. We did not detect any concomitant reaction to soy. Eight patients with FPIES had IgE-mediated cow's milk allergy (IgE-CMA). The prevalence of FPIES is significant, and its clinical presentation is distinct from that of IgE-CMA. Most patients with FPIES recover, although a proportion might convert to IgE-CMA. The likelihood for a cross-reactivity to soy in this population was less than previously estimated.

Milk Oral Immunotherapy (MOI): Interim Results of the First Hundred Patients

RATIONALE: Mortalities due to accidental ingestion of cow's milk protein (CMP)-contaminated products highlights the need for food oral immunotherapy (OIT) programs. METHODS: IgE-mediated cow's milk allergy (IgE-CMA) patients >age 4 were enrolled in an individualized, escalating four-round OIT protocol. Each round consisted of an initial four days in an ambulatory-care hospital setting to determine the maximal tolerated dose (MTD). This dose was then administered at home twice daily for 24 days. All patients and caregivers were instructed on the use of Epipen®, antihistamines and bronchodilators. In addition, each patient was required to report daily. RESULTS: To date, 41/103 patients have completed the treatment program. Their ages range from 4-26 years. Nineteen patients achieved full tolerance (ingestion >7.2gram CMP), 13 achieved partial tolerance (>2.0gram), and 41 patients reached beyond a level protective against incidental exposure (PIE) to contaminated non-dairy products (>150mg). Most of those who didn't reach a PIE level have not entered their second round. The progress of 11 participants was hindered by non-anaphylactic type reactions, albeit most of them still reached a PIE level. Three patients failed to pass the first induction phase. During the 2,453 induction doses given, adverse reactions required 40 injections of adrenaline (1.6%) and 88 treatments with either antihistamines, bronchodilators or both (3.6%). Most of these adverse reactions occurred during the first day of induction. CONCLUSIONS: Patients with IgE-CMA can reach full tolerance with MOI. While the procedure is not without risk, it can be safely carried out in an equipped environment in the presence of experienced personnel.

Associated Factors for the Persistence of IgE-mediated Cow's-milk Allergy

Associated Factors for the Persistence of IgE-mediated Cow's-milk Allergy

Predictive factors for the persistence of cow’s milk allergy

Cow's milk allergy (CMA) is usually transient, but recent studies have shown a later acquisition of tolerance to CM. Our aims were to characterize a population of Portuguese children with CMA and to identify predictive factors for the persistence of this food allergy. Children with CMA observed in our Paediatric Allergy Clinic between 1997 and 2006 were selected. Demographic and clinical data were collected from medical records. The group of children who tolerated CM before the age of 2 was compared with the group of children who tolerated CM beyond that age or persisted with CMA until the end of the study. Multivariate logistic regression analysis was used to investigate independent predictive factors for the persistence of CMA beyond the age of 2. In the subgroup of children with IgE-mediated CMA, the acquisition of tolerance was analysed using Cox regression. In this population of 139 children, the majority presented more than one symptom (73%) affecting more than one organ (51%), with cutaneous (81%), gastrointestinal (55%), respiratory (16%) manifestations and/or anaphylaxis (3%). Thirty-two per cent developed asthma, 20% atopic eczema, 20% rhinoconjunctivitis and 19% other food allergies over time. The acquisition of tolerance was different in the whole population versus the subgroup with IgE-mediated CMA: 34%versus 0% at the age of 2, 55%versus 22% at the age of 5 and 68%versus 43% at the age of 10. Immediate allergic symptoms, asthma and other food allergies were independent factors for the persistence of CMA beyond the age of 2. Higher maximum weal diameter on skin prick test to CM and higher maximum level of specific IgE to CM were associated with reduced likelihood of acquiring tolerance in the subgroup of children with IgE-mediated CMA. In conclusion, children with IgE-mediated CMA acquire tolerance to CM at older age. Clinical parameters and allergy tests may be helpful in defining prognosis. CM-allergic children tend to develop other atopic conditions and need specialized follow-up in the long term.

The role of food allergy in the atopic march

Cite this as: K. J. Allen and S. C. Dharmage, Clinical &amp; Experimental Allergy, 2010 (40) 1439–1441.

Oral immunotherapy for cow's milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study

Cow's milk allergy (CMA) in children is a important problem in medical practice. Oral desensitization has been proposed as a therapeutic approach, but current protocols are time-consuming and impractical. To establish a patient-friendly desensitization regimen with weekly up-dosing and to evaluate it in a randomized controlled trial. Thirty children with IgE-mediated CMA confirmed by double-blind placebo-controlled food challenge were equally randomized to desensitization with CM or soy milk as control. The weekly up-dosing lasted 18 weeks. The occurrence and severity of reactions after each dose was evaluated, and the desensitization was stopped if severe reactions occurred. Specific IgE and IgG4 levels to CM were measured at baseline, after 8 weeks, and at the end of the study. The double-blind food challenge was repeated once the desensitization was completed or after premature discontinuation. Two active and 1 control patient dropped out. Full tolerance to CM (200 mL) was achieved in 10 active patients and partial tolerance in 1. Two active patients discontinued the desensitization after experiencing severe reactions, whereas no reactions occurred in controls, whose sensitivity to CM remained unchanged. A significant increase in specific IgG4 levels was found only in the active group. This weekly up-dosing desensitization protocol for CMA performed under medical supervision was effective and reasonably safe and induced consistent immunologic changes.

Early exposure to cow's milk protein is protective against IgE-mediated cow's milk protein allergy

The diversity in the perceived prevalence, recovery, and risk factors for cow's milk allergy (CMA) necessitated a large-scale, population-based prospective study. We sought to determine the prevalence, cross-reactivity with soy allergy, and risk factors for the development of CMA. In a prospective study the feeding history of 13,019 infants was obtained by means of telephone interview (95.8%) or questionnaire (4.2%). Infants with probable adverse reactions to milk were examined, skin prick tested, and challenged orally. Ninety-eight percent of the cohort participated in the study. The cumulative incidence for IgE-mediated CMA was 0.5% (66/13,019 patients). The mean age of cow's milk protein (CMP) introduction was significantly different (P < .001) between the healthy infants (61.6 +/- 92.5 days) and those with IgE-mediated CMA (116.1 +/- 64.9 days). Only 0.05% of the infants who were started on regular CMP formula within the first 14 days versus 1.75% who were started on formula between the ages of 105 and 194 days had IgE-mediated CMA (P < .001). The odds ratio was 19.3 (95% CI, 6.0-62.1) for development of IgE-mediated CMA among infants with exposure to CMP at the age of 15 days or more (P < .001). Sixty-four patients with IgE-mediated CMA tolerated soy, and none had a proved allergy to soy. IgE-mediated CMA is much less common than generally reported. Early exposure to CMP as a supplement to breast-feeding might promote tolerance. Finally, soy is a reasonable feeding alternative in patients with IgE-mediated CMA.

Early recovery from cow's milk allergy is associated with decreasing IgE and increasing IgG4 binding to cow's milk epitopes

The dynamics and balance of allergen-specific IgE, IgG4, and IgA binding might contribute to the development of tolerance in patients with cow's milk allergy (CMA). Profiling of antibody binding to cow's milk (CM) protein epitopes might help in predicting the natural history of allergy. We sought to investigate differences in IgE, IgG4, and IgA binding to CM epitopes over time between patients with early recovery or with persisting CMA. We studied serum samples at the time of diagnosis (mean age, 7 months), 1 year later, and at follow-up (mean age, 8.6 years) from 11 patients with persisting IgE-mediated CMA at age 8 to 9 years and 12 patients who recovered by age 3 years. We measured the binding of IgE, IgG4, and IgA antibodies to sequential epitopes derived from 5 major CM proteins with a peptide microarray-based immunoassay. We analyzed the data with a novel image-processing method together with machine learning prediction. IgE epitope-binding patterns were stable over time in patients with persisting CMA, whereas binding decreased in patients who recovered early. Binding patterns of IgE and IgG4 overlapped. Among patients who recovered early, the signal of IgG4 binding increased and that of IgE decreased over time. IgE and IgG4 binding to a panel of alpha(s1)-, alpha(s2)-, beta-, and kappa-casein regions predicted outcome with significant accuracy. Attaining tolerance to CM is associated with decreased epitope binding by IgE and a concurrent increase in corresponding epitope binding by IgG4.

Specific antibodies to cow’s milk proteins in infants: effect of early feeding and diagnosis of cow’s milk allergy

To investigate whether specific IgA, IgG, IgG1 and IgG4 responses to cow's milk proteins differ between infants with cow's milk allergy and infants with cow's milk related symptoms (control subjects), and whether early feeding affects these responses as well as specific IgE. A cohort of 6,209 healthy, full-term infants in a double-blind randomized trial received, as supplementary feeding at maternity hospitals (mean duration 4days), either cow's milk formula, extensively hydrolyzed whey formula or donor breast milk. Infants who developed cow's milk associated symptoms (n=223) underwent an open oral cow's milk challenge (mean age 7months), which confirmed cow's milk allergy in 111 and was negative in 112. We measured in sera cow's milk specific IgE levels with UniCAP (Phadia, Uppsala, Sweden), and β-lactoglobulin and α-casein specific IgA, IgG1, IgG4 and IgG levels with enzyme-linked immunosorbent assay. Infants with IgE-mediated cow's milk allergy had lower β-lactoglobulin and α-casein specific IgG1, IgG4 and IgG levels (p<0.05) than infants with non-IgE-mediated cow's milk allergy or control subjects. Within the group of infants with cow's milk allergy, exposure to cow's milk during the first few days after birth led to higher β-lactoglobulin and α-casein specific IgG4 levels (p<0.005) compared to infants fed with either breast milk or extensively hydrolyzed formula. Subdued IgG class responses to cow's milk proteins characterized IgE-mediated cow's milk allergy. In infants who developed cow's milk allergy early exposure to cow's milk resulted in a heightened specific IgG4 response.

The effect of a partially hydrolysed formula based on rice protein in the treatment of infants with cow’s milk protein allergy

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/SInfants 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.

Specific oral tolerance induction (SOTI) in pediatric age: Clinical research or just routine practice?

Specific Oral Tolerance (SOTI) is a promising therapy of food allergy, specially for IgE-mediated cow milk allergy (CMA) in pediatric age. Randomized controlled trials have reported that about 35% of children, at least 5 years of age, became full tolerant to cow milk proteins after SOTI. Regard to the safety, literature describes about 200 children who underwent SOTI, with no fatal events. Nevertheless, a considerable percentage of those children (15%-20%) had to stop SOTI, because of important adverse effects. Numerous protocols have been described, some audacious and other prudent, however all demand an intense commitment either of the doctors and of the families. The information about the follow up of the children who underwent SOTI are still insufficient. For these reasons, we think that SOTI is still an experimental therapy.

Is There A Specific Profile Of Patients With Persistent Ige-mediated Cow'S Milk Allergy?

RATIONALE: Cow's milk allergy (CMA) is the most common food allergy in infants and most patients developing tolerance by age 3. From 89 Brazilian patients with IgE mediate CMA, 55% presented symptoms after 5 years. The aim of this study is to determine a clinical, laboratorial and IL10 genotype profile for persistent IgE-mediated CMA in Brazilian patients.