Cow's Milk Oral Immunotherapy Research Articles

Cow's milk oral immunotherapy has differentially better long-term adherence than peanut or sesame

Cow's milk oral immunotherapy has differentially better long-term adherence than peanut or sesame

Efficacy and safety of oral immunotherapy for peanut, cow's milk, and hen's egg allergy: A systematic review of randomized controlled trials.

Oral immunotherapy (OIT) is a promising treatment for food allergies; however, safety is a concern. We synthesized evidence from the best randomized controlled trials (RCTs) on efficacy/safety of OIT for desensitization (DS) and remission (sustained unresponsiveness (SU)) in IgE mediated allergy to peanut, hen's eggs, and cow's milk. BODY: We searched Pubmed, EMBASE, and Cochrane databases (Until Oct 22) identifying 16 eligible RCTs published in English measuring food allergy by food challenge at the beginning and at the end of the study. The Cochrane Risk of Bias tool was used to assess study quality. We found 18 eligible studies. There was evidence of efficacy for DS for all allergens: peanut (RR 11.32; 95% CI 5.93, 21.60, I2 49%, 8 studies); hen's egg (RR 4.67; 2.66, 8.21, I2 0%, 5 studies); cow's milk (RR 13.98; 3.51, 55.65, I2 0%, 4 studies) and evidence for SU for peanut (RR 7.74; 2.90, 20.69, I2 0%, 3 studies) and hen's egg (RR 6.91; 1.67, 28.57, I2 0%, 2 studies). Allergic events were increased with intervention, and risk of adrenaline use increased for peanut RR 2.96; 1.63, 5.35, I2 0%, 8 studies; egg RR 1.71; 0.42, 6.92, I2 0%, 6 studies; and milk RR 8.45; 2.02, 35.27, I2 0%, 4 studies. We found strong evidence that peanut, hen's egg, and cow's milk OIT can induce DS and some evidence for remission. There was a high risk of allergic reactions. Generalizability to the entire food allergic population is not known.

Could Age and Oral Challenge Outcomes Identify High-Risk Patients During Cow's Milk Oral Immunotherapy?

Objective: Severe immunglobuline E (IgE)-mediated reactions during oral immunotherapy (OIT) are major obstacles to treatment. The present study aimed to evaluate and identify clinical and laboratory biomarkers of adverse events during OIT among children with cow's milk (CM) allergy. Study Design: Eighty-six children older than 36 months who had undergone OIT with milk were enrolled. Clinical data, oral food challenge (OFC) test results, and laboratory data were recorded retrospectively. Results: The median duration of the build-up phase of OIT was 19 weeks (min 10-max 40) and the duration of the maintenance phase was 86.5 (min 1-max 132) months. A total of 11,767 CM doses were administered during the build-up phase and adverse reactions were seen in 62 (73.8%) patients with reactions registered for 157 doses among 11,767 (1/75 doses). The number of reactions during the maintenance phase was 41 (47.6%) in 24 (27.9%) patients. There was a significant reduction in the number of reactions (P = 0.000) between the build-up phase and maintenance phase. Adverse reactions and anaphylaxis were higher for patients who had cough during OFC (P = 0.003, P = 0.002, respectively) during the build-up phase and also during the maintenance phase too (P = 0.000). Evaluation for all reactions and anaphylaxis (during build-up and maintenance) with Kaplan-Meier and Cox regression analysis showed class IV-VI of CM-specific immunoglobulin E (sIgE), casein-sIgE and cough during OFC were significantly associated with increased probability of reaction and anaphylaxis. Younger age at onset of OIT was associated with risk reduction (0.017). Conclusion: Laboratory data and reactions during the OFC (especially cough) can help to identify high-risk patients during OIT.

Oral immunotherapy in severe cow's milk allergic patients treated with omalizumab: Real life survey from a Spanish registry.

Oral immunotherapy is a frequent treatment for the management of food allergies, but adverse events (AE) are common. This study assessed the outcome of cow's milk oral immunotherapy (MOIT) in severe cow`s milk-allergic patients treated with omalizumab in a real-life setting. OmaBASE was a national, multicenter, open, and observational registry that collected clinical, immunologic, and treatment from patients with food allergy receiving omalizumab. Data derived from 58 patients aged 10.3years (IQR 6.3-13.2) and median milk-specific IgE 100kUA /L at the start of omalizumab treatment. Most had experienced anaphylaxis by accidental exposures (70.7%) and had asthma (81.0%). Omalizumab in monotherapy induced tolerance to ≥6000mg of cow's milk protein (CMP) to 34.8% of patients tested by oral food challenge. Omalizumab combined with MOIT conferred desensitization to ≥6000mg of CMP to 83.0% of patients. Omalizumab withdrawal triggered more AE (P=.013) and anaphylaxis (P=.001) than no discontinuation. Anaphylaxis was observed in 36.4% of patients who discontinued omalizumab, and more in those with sudden (50.0%) rather than progressive (12.5%) discontinuation. At database closure, 40.5% of patients who had completed follow-up tolerated CMP without omalizumab (7.2% 1500-4500mg; 33.3% ≥6000mg). Milk oral immunotherapy initiated under omalizumab allows the desensitization of subjects with severe cow's milk allergy even after omalizumab discontinuation. However, discontinuation of omalizumab can lead to severe AE and should be carefully monitored.

Precision medicine in cow's milk allergy.

The aim of this review is to describe the role of precision medicine in the diagnosis, treatment, and monitoring of cow's milk allergy. The development of 'omics' sciences in the field of food allergy has led to a better understanding of the allergenicity of cow's milk proteins and significant advances in the knowledge of the pathogenesis and mechanisms of cow's milk allergy. Omics-based technologies allow the practitioner to better differentiate cow's milk allergy subtypes and to predict cow's milk allergy (CMA) persistence over time. Precision medicine extends the role of the oral food challenge, to determine the individual's threshold doses, and to establish tolerance to baked milk products. Other than symptom relief, dietary strategies are currently being investigated for the potential to induce tolerance. Oral immunotherapy offers a treatment option for patients with severe and persistent IgE-mediated CMA. Individual baseline-immune profiles may be predictive of cow's milk oral immunotherapy safety and efficacy.Patient data derived from current technology, in combination with the patient's history, can be translated into treatments targeted at patient-tailored interventions. The identification of novel biomarkers may improve diagnostic accuracy and also predict patient responsiveness to treatments. Integration of patient data will become increasingly important as omics technologies become more widely used in the clinical setting.

Cross-desensitization to goat and sheep milk following cow's milk oral immunotherapy

Cross-desensitization to goat and sheep milk following cow's milk oral immunotherapy

Adverse Events in Oral Immunotherapy for the Desensitization of Cow's Milk Allergy in Children: A Randomized Controlled Trial

This study focuses on the side effects of cow's milk oral immunotherapy (CM-OIT) using consensus definitions of food-induced anaphylaxis. To evaluate the risk of allergic reactions (ARs) and to identify risk factors associated with higher risk of anaphylactic ARs (AARs) during CM-OIT in children. Clinical charts of children receiving CM-OIT were carefully reviewed. ARs were defined as single-organ ARs, and AARs were defined as involvement of 2 organ systems and/or hypotension in response to CM protein. Descriptive statistics were used to represent demographics, occurrence, reaction characteristics, and comorbidities. Poisson analysis was performed to evaluate risk factors associated with AARs. Among 41 children undergoing CM-OIT, 11 discontinued the treatment (N= 26.8%). The mean age at challenge was 12.1 years (standard deviation [SD], 3.6) and half were male (56.1%). The mean number of AARs per patient was 6.0 (SD, 3.5) versus a mean of 17.4 (SD, 11.9) non-AARs per patient. Among withdrawals from OIT, the mean number of AARs per patient was 8.3 versus 5.1 in nonwithdrawals. AARs were more frequent in children with higher specific IgE (sIgE) for α-lactalbumine and casein at baseline (1.11 [95% confidence interval (CI): 1.01, 1.22] and 1.01 [1.0, 1.03], respectively). Children with resolved eczema and higher sIgE for β-lactoglobuline at baseline (0.13 [95% CI: 0.04, 0.46] and 0.96 [95% CI: 0.94, 0.99], respectively) were less likely to develop AARs. Although the majority of ARs during OIT are nonanaphylactic, AARs occur frequently. Children with higher sIgE for α-lactalbumine and casein at baseline seem to be at higher risk for AARs during OIT.

Serological Profile of Children Undergone Cow's Milk Oral Immunotherapy

Serological Profile of Children Undergone Cow's Milk Oral Immunotherapy

Cow's milk oral immunotherapy in real life: 8-year long-term follow-up study.

BackgroundOral immunotherapy (OIT) has been recognized as a promising treatment for severe and long-lasting cow's milk (CM) allergy. Once maintenance has been achieved, patients should maintain daily intake of CM to ensure desensitization. Clinical experience concerning long-term follow-up is scarce.ObjectiveThe authors aimed to assess long-term efficacy and safety of a maintenance phase of OIT in real life.MethodsProspective study of all children and adolescents, who underwent CM-OIT and were subsequently followed at our allergy center on maintenance dose (200 mL daily) for at least 36 months after reaching the maintenance phase (from 2009 to 2016).ResultsForty-two patients were enrolled: 60% male, 36% with history of anaphylaxis and 57% with asthma. The median time of follow-up was 69 months (range, 39–105 months) and the median age at the last clinical evaluation was 13 years (range, 6–23 years). Regarding adherence to the protocol: 92% are on free diet (at least 200 mL of CM daily; 7-g protein); 14% had transient interruptions and 7% definitely withdrawn with loss of tolerance. During maintenance, 45% developed mild to severe allergic reactions, and 7% had more than 3 episodes. A positive correlation between the occurrence of allergic reactions and history of anaphylaxis (p < 0.001) was found. The coexistence of asthma was risk factor for the occurrence of allergic reactions during maintenance.ConclusionThis real-life study supports long-term efficacy and safety of CM-OIT. Despite daily intake, 41% had symptoms at some moment during the complete follow-up period; a total of 33 symptomatic days in patients with mean follow-up time of 67.5 months. Clinical tolerance depends on daily intake. The protective effect reached can be lost after CM withdrawal. History of anaphylaxis was a risk factor for the occurrence of allergic reactions during the maintenance phase.

Identification of novel peptide biomarkers to predict safety and efficacy of cow's milk oral immunotherapy by peptide microarray.

Cow's milk oral immunotherapy (CM-OIT) is still an experimental treatment. The development of novel biomarkers to predict the safety and efficacy of CM-OIT is crucial to translate this treatment to common clinical practice. To analyse long-term changes in IgE and IgG4 epitope binding profile induced by CM-OIT to identify safety and efficacy biomarkers. We studied 25 CM-allergic children who underwent CM-OIT and seven non-treated CM-allergic children as controls. CM-OIT patients were classified as low, moderate, and high risk according to the number of allergic reactions (safety), time required to achieve desensitization (efficacy) and need of premedication. IgE and IgG4 peptide microarray immunoassay was performed using a library of overlapping peptides of CM proteins at baseline, after oral desensitization, and 6, 12, and 24months of follow-up. Cow's milk oral immunotherapy induced a rapid increase of IgG4-binding epitopes and a slow decrease in IgE-binding epitopes. High-risk patients recognized a statistically significant higher number of IgE peptides in caseins at all the times studied. Similar but less pronounced changes were observed for IgG4-positive peptides. Clustering analysis grouped together the high-risk patients, and we identified 13 regions of caseins significantly differed between groups of patients. Bioinformatics analysis selected two sets of 16 IgE-binding peptides at baseline that predicted safety (R(2) =0.858) and efficacy (R(2) =0.732), respectively, of CM-OIT. We found two sets of IgE-binding peptides that can be used as novel biomarkers to predict the safety and efficacy of CM-OIT before starting treatment.

Identification of biomarkers to predict safety and efficacy of cow's milk oral immunotherapy by peptide microarray

Methods We studied 25 CM-allergic children at baseline, after oral desensitization, and at 6, 12 and 24 months of follow-up. Seven patients who refused CM-OIT were used as controls. Patients were classified as low, moderate, and high risk according to the number of allergic reactions (safety), time required to achieve tolerance (efficacy), and requirement of premedication. IgE and IgG4 peptide microarray immunoassay was performed using a library of overlapping peptides of CM proteins.

Debut of Crohn's disease in a child desensitised to cow's milk

Specific oral immunotherapy (OIT) is a proven therapeutic option in children with persistent food allergy. Several cases of eosinophilic esophagitis have been reported during the long term follow-up, but not inflammatory bowel diseases. The role of food allergy in the pathogenesis of these diseases is unknown. We present an 11 year-old girl who developed cow's milk allergy (CMA) at the age of 5 months followed by mild asthma in her early childhood. Due to persistent CMA she started cow milk OIT at the age of 8. After a long induction phase - 10 months - in which she presented repeated systemic reactions and abdominal pain, tolerance of 200 ml of cow's milk was reached, and serum levels of cow's milk specific IgE and its components decreased (pre-OIT whole milk sIgE 97.9 kUIA/L, casein 97.5 kUIA/L; post-OIT whole milk sIgE 27.2 kUIA/L, casein 22.7 kUIA/L). After 4 months of daily maintenance treatment, she complained about recurrent abdominal pain related to any food ingestion. A pediatric gastroenterologist ruled out the diagnosis of eosinophilic esophagitis, and she was treated with proton pump inhibitors during 18 months while maintaining daily cow’s milk intake. Although the patient improved partially, abdominal pain was not solved. At age 11 an emergency appendectomy was performed because of an acute abdomen caused by a suspected appendicitis. She was advised to maintain a milk-free diet at discharge. One month later she was readmitted for abdominal pain and diarrhea with weight loss. She underwent an exploratory laparotomy with ileum resection upon obtaining macroscopic evidence of Crohn's disease and pathological results which confirmed the diagnostic. Treatment with corticosteroids, azathioprine and 3 cycles of infliximab was initiated, yielding a good response. At present her symptoms are under control using azathioprine 50 mg daily, while tolerating foods containing trace amounts of cow’s milk. In conclusion, we present a case of a girl who developed Crohn’s disease during the maintenance phase of cow milk OIT. At present we have no rationale for the role of OIT in the development of her Crohn’s disease.

Specific Antibodies in Oral Immunotherapy for Cow's Milk Allergy: Kinetics and Prediction of Clinical Outcome

Background: Methods for predicting the clinical outcome of specific oral immunotherapy (OIT) would improve the safety of the therapy. Methods: We investigated 40 children aged 6-17 years with IgE-mediated cow's milk allergy (CMA) who either successfully completed OIT (n = 32) or discontinued the therapy due to adverse reactions (n = 8). From sera drawn before and after OIT, we analyzed specific IgA, IgG, IgG1 and IgG4 to cow's milk (CM), casein, β-lactoglobulin and ovalbumin (with enzyme-linked immunosorbent assay) and IgE to CM and hen's egg white [with enzymatic fluoroimmunoassay (Phadia ThermoFisher Scientific CAP system)]. As a reference, we also analyzed serum samples from 8- to 9-year-old children who either had no history of CMA (n = 76) or who had spontaneously recovered from IgE-mediated CMA (n = 56). Results: Levels of specific IgA, IgG, IgG1 and IgG4 to CM and casein, and CM-specific IgE prior to OIT were higher in children who discontinued the therapy than in those who achieved desensitization (p < 0.05). Adverse reactions in the entire population were associated with low IgG and IgG4, but high IgG1 levels to ovalbumin (p < 0.05). Specific IgA, IgG, IgG1 and IgG4 to CM proteins significantly increased and IgE to CM decreased during OIT in children who achieved desensitization (p < 0.01). In those who discontinued OIT, only IgG, IgG1 and IgG4 to CM increased significantly (p < 0.03) and CM IgE remained unchanged. Conclusions: High specific IgE, IgA and IgG-class antibodies to CM proteins appear to predict failure to achieve desensitization in CM OIT. Specific IgA and IgG-class antibodies to CM increase and CM IgE decreases during desensitization.

PD28 ‐ Is other bovid mammals milk tolerated by children who have been submitted to cow's milk oral immunotherapy?

Caseins cross-reactivity rises up to 90% between cow’s milk (CM) and other bovid milks. There are few studies on tolerance to other mammals milk in patients submitted to cow’s milk oral immunotherapy (CMOIT). AIMS: To determine the percentage of patients whom after CMOIT tolerate water buffalo (WB), goat and sheep’s milk proteins (MP). To describe immunologic features which can predict allergy.

Use of IgE and IgG4 epitope binding to predict the outcome of oral immunotherapy in cow's milk allergy

Oral immunotherapy (OIT) with cow's milk (CM) has been reported to induce a number of specific antibody responses, but these remain to be fully characterized. Our objective was to explore whether IgE and IgG4 epitope binding profiles could predict the risk of side effects during CM OIT. The study population consisted of 32 children (6-17 yr of age) with CM allergy: 26 children who successfully completed OIT and six children who discontinued therapy due to adverse reactions. We investigated sera drawn before and after OIT. We analyzed specific IgE and IgG4 binding to CM protein-derived peptides with a microarray-based immunoassay. Antibody binding affinity was analyzed with a competition assay where CM proteins in solution competed with peptides printed on the microarray. IgE binding to CM peptides decreased and IgG4 binding increased following the OIT in children who attained desensitization. Compared with children who successfully completed OIT, those who discontinued OIT due to adverse reactions developed increased quantities and affinity of epitope-specific IgE antibodies and a broader diversity of IgE and IgG4 binding, but less overlap in IgE and IgG4 binding to CM peptides. Detailed analysis of IgE and IgG4 binding to CM peptides may help in predicting whether CM OIT will be tolerated successfully. It may thus improve the safety of the therapy.

Long-term follow-up of oral immunotherapy for cow's milk allergy

Long-term follow-up of oral immunotherapy for cow's milk allergy

Safety and predictors of adverse events during oral immunotherapy for milk allergy: severity of reaction at oral challenge, specific IgE and prick test

Strict avoidance is the only accepted management for cow's milk (CM) allergy. CM oral immunotherapy (CM-OIT) is under investigation. To evaluate long-term safety of CM-OIT. To identify clinical/immunological predictors of adverse events. Prospective longitudinal epidemiological intervention study. CM-allergic children aged 5-18 underwent a Spanish-approved CM-OIT protocol without premedication. Clinical data, skin prick test (SPT) and specific IgE (sIgE) at baseline and 1 year after OIT were registered. All dose-related reactions, treatments needed and cofactors involved were recorded. Through survival analysis, we studied the cumulative probability of reactions resolution over time and clinical/immunological risk factors of reactions persistence. 81 children were recruited. Mean follow-up was 25 months. 95% of children suffered reactions, 91% of which affected a single organ. Reactions were heterogeneously distributed: (a) 60 children (75%) had occasional symptoms which ceased over time. 86% of them reached complete desensitization (200 mL). (b) 20 children (25%) suffered frequent (78% of total reactions), more severe and unpredictable reactions, which persisted during follow-up or led to withdrawal (6 cases). Reactions persistence was associated with a higher frequency and severity. Kaplan-Meier estimate revealed a cumulative probability of reactions resolution of 25% at 3 months (95% CI: 1.9-4.1) and 50% (95% CI: 6.1-9.9) at 8 months based on all patients. Cox proportional hazards multivariate regression model identified 3 variables (CM-sIgE ≥ 50 KU L(-1) , CM-SPT ≥ 9 mm and Sampson's severity grades 2, 3 and 4 at baseline food challenge) as independent risk factors of reactions persistence. The combination of 2 or 3 of these factors involved hazard ratios to develop persistent reactions of 2.26 (95% CI: 1.14-4.46; P = 0.019) and 6.06 (95% CI: 2.7-13.7; P < 0.001), respectively. CM-OIT was insufficiently safe in 25% of children. The above-mentioned clinical and immunological parameters would help clinicians to identify highly reactive patients before CM-OIT. In them, individualized schedules and premedication should be considered.

Allergy to goat’s and sheep’s milk in a population of cow’s milk–allergic children treated with oral immunotherapy*

Cow's milk oral immunotherapy (CMOIT) is a recognized treatment for persistent cow's milk (CM) allergy. However, further data are necessary on tolerance to milk from other mammals. To describe the clinical and immunologic features of goat's and sheep's milk (GSM) allergy in patients who tolerated CM after CMOIT. Fifty-eight CM-allergic patients who successfully underwent CMOIT in our department were evaluated using skin prick test (SPT), specific immunoglobulin (Ig) E determination, enzyme-linked immunoassay (ELISA), and controlled oral challenge to assess allergy to GSM. Statistical analysis was carried out to identify markers of allergy to GSM. Fifteen of 58 (25.9%) patients were allergic to either goat's or sheep's milk or to both, as confirmed by a controlled positive oral challenge. Forty-seven percent of all positive oral challenges were classified as anaphylactic reactions. Specific IgE to CM casein, goat's whole milk, and sheep's whole milk was 13.2, 18.0, and 21.4 kU(A)/l in the group of GSM-allergic patients and 6.6, 6.5, and 6.5 kU(A) /l in the GSM-non-allergic patients (p < 0.05). Decision-making cut-off points based on sIgE for diagnosing symptomatic GSM allergy could not be determined. ELISA inhibition assays showed limited cross-reactivity (up to 77.2%) between CM casein and GSM casein in the group of GSM-allergic patients in contrast with almost 100% in GSM-not-allergic patients. We found a high prevalence (26%) of allergy to GSM in our population of CM-allergic children treated with oral immunotherapy. Therefore, tolerance to GSM should be assessed in order to provide accurate nutritional advice and minimize life-threatening accidental intake. Specific IgE to CM casein, goat's and sheep's whole milk is a good marker of this allergy. Although CM oral immunotherapy is a specific treatment for CM allergy, it may not be effective against allergy to the milk of other mammals.

Oral desensitization for milk allergy in children

The purpose of this review is to research current evidence on cow's milk oral immunotherapy for the treatment of cow's milk allergy (CMA). The specific, active treatment for IgE-mediated food allergy included CMA, which is currently being investigated in human trials. Allergen-specific approaches include oral, sublingual and epicutaneous immunotherapy. Reports on oral immunotherapy (OIT) for the treatment of milk allergy have been more extensive and carried out mostly with native proteins. The aim of OIT with cow's milk is the achievement of desensitization or tolerance by patients suffering from CMA. Desensitization state can be achieved by approximately 36-92% of the children treated with specific immunotherapy; the rate of permanent tolerance is unknown. Longer duration of desensitization may result in permanent tolerance. The possibility of adverse events or reactions during OIT is quite frequent. Side-effects have been reported by patients in all published studies. OIT as an active treatment for CMA represents an emerging reality. Before this treatment can be used in clinical practice, additional studies are needed. Currently, many issues remain unanswered: severity and type of food allergy responsive to specific immunotherapy, degree of protection, 'shared schedules' of desensitization(s) in research settings and well established risk-to-benefit ratio. However the field of specific, active treatment of food allergy is poised for clinically important advances.

Narcolepsy–cataplexy induced by a cow milk oral immunotherapy protocol?

Narcolepsy–cataplexy induced by a cow milk oral immunotherapy protocol?