title: Clinical course of cow's milk protein allergy/intolerance and atopic diseases in childhood. A synbiotic-containing amino-acid-based formula improves gut microbiota in non-IgE-mediated allergic infants Markers of gut mucosal inflammation and cow’s milk specific immunoglobulins in non-IgE cow’s milk allergy The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Clinical course and prognosis of cow's milk allergy are dependent on milk-specific IgE status. Lactobacillus GG improves recovery in infants with blood in the stools and presumptive allergic colitis compared with extensively hydrolyzed formula alone. Synbiotics in Children with Cow's Milk Allergy: A Randomized Controlled Trial Nutritional Value of a Rice-Hydrolysate Formula in Infants with Cows' Milk Protein Allergy: A Randomized Pilot Study Natural course and risk factors for persistence of IgE-mediated cow's milk allergy. Extensively hydrolyzed casein formula containing Lactobacillus rhamnosus GG reduces the occurrence of other allergic manifestations in children with cow's milk allergy: 3‐year randomized controlled trial An extensively hydrolysed casein-based formula for infants with cows' milk protein allergy: tolerance/hypo-allergenicity and growth catch-up. Synbiotics-supplemented amino acid-based formula supports adequate growth in cow's milk allergic infants. Long-term effects of hydrolyzed protein infant formulas on growth--extended follow-up to 10 y of age: results from the German Infant Nutritional Intervention (GINI) study. Probiotic Bacteria in the Management of Atopic Disease: Underscoring the Importance of Viability Lack of Effect of Lactobacillus GG in Breast-fed Infants With Rectal Bleeding: A Pilot Double-blind Randomized Controlled Trial The acquisition of tolerance toward cow's milk through probiotic supplementation: a randomized, controlled trial.
abstract: A cohort of 1,749 newborns from the municipality of Odense , born during 1995 at the Odense University Hospital , were followed up prospect ively for the development of cow 's milk protein allergy/intolerance ( CMPA/I ) during the first year of life . Once a diagnosis of CMPA/I was confirmed , a milk-free diet was continued until a new milk challenge had shown development of tolerance . All infants with CMPA/I were rechallenged at 12 months of age and , in the event of continued clinical sensitivity to cow 's milk protein , controlled rechallenges were performed every 6 months up to 3 years of age ; and thereafter every 12 months until the age of 15 years . From the same birth cohort , 276 infants were r and omly selected at birth for prospect i ve non-interventional follow-up in order to investigate the natural course of sensitization and development of atopic disease during childhood . St and ardized question naires on atopic heredity , environmental factors and presence of atopic symptoms were answered at 0 , 6 , 12 and 18 months and at 5 , 10 and 15 years of age . Interviews on atopic history and environmental factors as well as physical examination were carried out at 18 months , 5 , 10 and 15 years of age . Skin prick test and specific sIgE ( Pharmacia CAP ) testing were performed at 18 months , 5 , 10 and 15 years of age against a panel of inhalant allergens ( birch , grass , mugwort , dog , cat , horse , Dermatophagoidespteronyssinus , Dermatophagoides farinae , alternaria and cladosporium herbarum ) . Furthermore , lung function measurements were performed in children when 10 and 15 years of age . Based on controlled milk elimination and challenge procedures , the diagnosis of CMPA/I was confirmed in 39 out of 117 infants , with symptoms suggestive of CMPA/I , thus result ing in a 1-year incidence of CMPA/I of 2.2 % . The overall prognosis of CMPA/I was good , with a total recovery of 56 % at 1 year , 77 % at 2 years , 87 % at 3 years , 92 % at 5 and 10 years and 97 % at 15 years of age . In children younger than 10 years of age , 41 % developed asthma and 31 % rhinoconjunctivitis . Children with non-IgE-mediated CMPI had a good prognosis , whereas children with IgE-mediated CMPA in early childhood had a significantly increased risk for persistent CMPA , development of other food allergies , asthma and rhinoconjunctivitis . During early infancy , recurrent wheezing was the most prevalent disease ( 20 % ) , followed by atopic dermatitis ( 14 % ) and food allergy ( 7 % ) at 18 months of age . Physician diagnosed asthma increased from 2 % at 1.5 years of age to 9 % at 10 years of age .  Rhinoconjunctivitis  increased from < 1 % at 1.5 years of age to 9 % at 10 years of age . Overall , the current prevalence of any atopic disease was 20 % at 1.5 years of age , declining to 14 % at 5 years of age and followed by an increase to 25 % at 10 years of age . Sensitization to inhalant and /or food allergens ( specific IgE of > or = class 2 ; CAP RAST ) showed a low rate of sensitization among asymptomatics ( 3 % , 10 % and 12 % ) compared with higher rates of sensitization of 8 % , 39 % and 30 % among symptomatic atopics at 1.5 , 5 and 10 years of age respectively . The highest rate of sensitization ( 53 % ) was found among children with current asthma at 10 years of age Background Prebiotics and probiotics ( synbiotics ) can modify gut microbiota and have potential in allergy management when combined with amino-acid-based formula ( AAF ) for infants with cow ’s milk allergy ( CMA ) . Methods This multicenter , double-blind , r and omized controlled trial investigated the effects of an AAF-including synbiotic blend on percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group ( ER/CC ) in feces from infants with suspected non-IgE-mediated CMA . Feces from age-matched healthy breastfed infants were used as reference ( healthy breastfed reference ( HBR ) ) for primary outcomes . The CMA subjects were r and omized and received test or control formula for 8 weeks . Test formula was a hypoallergenic , nutritionally complete AAF including a prebiotic blend of fructo-oligosaccharides and the probiotic strain Bifidobacterium breve M-16V . Control formula was AAF without synbiotics . Results A total of 35 ( test ) and 36 ( control ) subjects were r and omized ; HBR included 51 infants . At week 8 , the median percentage of bifidobacteria was higher in the test group than in the control group ( 35.4 % vs. 9.7 % , respectively ; P<0.001 ) , whereas ER/CC was lower ( 9.5 % vs. 24.2 % , respectively ; P<0.001 ) . HBR levels of bifidobacteria and ER/CC were 55 % and 6.5 % , respectively . Conclusion AAF including specific synbiotics , which results in levels of bifidobacteria and ER/CC approximating levels in the HBR group , improves the fecal microbiota of infants with suspected non-IgE-mediated CMA 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 prospect ively 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 sample s were collected during CMP-free diet and after both placebo and active challenges . We analyzed the stool sample s 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 sample s ( 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Large , prospect i ve population -based studies on clinical course , development of tolerance , and risk for other atopy in children with cow 's milk allergy ( CMA ) are lacking . OBJECTIVE We investigated the development of tolerance and the risk for asthma , rhinoconjunctivitis , atopic dermatitis , and sensitization in children with CMA followed to school age . METHODS We followed 118 children with CMA until recovery and repeatedly measured their sensitization to cow 's milk ( CM ) . At age 8.6 years , 94 allergic subjects and 80 control subjects from the same cohort were studied for atopic diseases and sensitization . In addition , the parents of 12 allergic subjects and 26 control children returned a question naire on atopy , respectively . RESULTS IgE-mediated CMA was detected in 86 ( 73 % ) children ; at age 8.6 years , 13 ( 15 % ) had persistent CMA . All children with IgE-negative CMA were tolerant by age 5.0 years ( P < .0001 ) . Risk factors for persistent CMA at age 2.0 years were sensitization to CM at age 1.6 years ( odds ratio , 6.3 ; 95 % CI , 2.6 - 15.2 ) , urticaria at diagnostic challenge ( odds ratio , 3.3 ; 95 % CI , 1.4 - 7.8 ) , CM exposure at the maternity hospital ( odds ratio , 3.2 ; 95 % CI , 1.4 - 7.8 ) , and early sensitization to egg ( odds ratio , 2.8 ; 95 % CI , 1.2 - 6.6 ) . By age 8.6 years , children with IgE-positive CMA more frequently had asthma ( 31 % vs 13 % , P < or = .01 ) , rhinoconjunctivitis ( 66 % vs 21 % , P < or = .001 ) , atopic eczema ( 81 % vs 26 % , P < or = .001 ) , and sensitization to any allergen ( 88 % vs 39 % , P < or = .001 ) than control subjects . CMA and family history of atopy were independent risk factors for atopic diseases , and CMA was also a risk factor for sensitization to inhalant allergens . CONCLUSION IgE-mediated CMA often persists to school age and is a risk factor for other atopy ; non-IgE-mediated CMA , by contrast , is a benign infantile condition OBJECTIVES To determine the benefits of Lactobacillus rhamnosus GG ( LGG ) in an extensively hydrolyzed casein formula ( EHCF ) in improving hematochezia and fecal calprotectin over EHCF alone . STUDY DESIGN Fecal calprotectin was compared in 30 infants with hematochezia and 4 weeks after milk elimination with that of a healthy group . We also compared fecal calprotectin and hematochezia on 26 formula-fed infants r and omly assigned to EHCF with LGG ( Nutramigen LGG ) ( EHCF + LGG ) or without ( Nutramigen ) ( EHCF - LGG )  and on 4 breastfed infants whose mothers eliminated dairy . RESULTS Fecal calprotectin in those with hematochezia was significantly higher than in comparisons ( mean + /- SD 325.89 + /- 152.31 vs 131.97 + /- 37.98 microg/g stool , t = 6.79 , P < .0001 ) . At 4 weeks , fecal calprotectin decreased to 50 % of baseline but was still significantly higher than in comparisons ( 157.5 + /- 149.13 vs 93.72 + /- 36.65 microg/g , P = .03 ) . Fecal calprotectin mean decrease was significantly larger among EHCF + LGG compared with EHCF - LGG ( -214.5 + /- 107.93 vs -112.7 + /- 105.27 microg/g , t = 2.43 , P = .02 ) . At 4 weeks , none of the EHCF + LGG had blood in stools , and 5/14 on EHCF - LGG did ( P = .002 ) . CONCLUSION Fecal calprotectin is elevated in infants with hematochezia and possible allergic colitis . EHCF + LGG result ed in significant improvement of hematochezia and fecal calprotectin compared with the EHCF alone Objective : Cow`s milk protein allergy usually occurs in infants within the first months of life . It can affect several organs , but gastrointestinal symptoms are the most clinical symptoms observed . The most effective treatment is restricting the cow ` s milk protein in mother and infant`s diet . Lactobacillus GG supplementation in infant could be effective through modulation of the immune system and the gut microflora . Methods : Thirty two breastfed infants with cow`s milk protein allergy were enrolled in a double-blinded r and omized controlled trial in which they received Synbiotic ( n=16 ) or placebo ( n=16 ) once a day for one month , simultaneously with cow`s milk protein restriction in mother and infant`s diet . Clinical gastrointestinal symptoms ( vomiting , colic , rectal bleeding and diarrhea ) , head circumference , body length and weight were recorded at the beginning , the end of the first and third month of study . Findings : Percentage of increment in head circumference and weight were statistically more in synbiotic group compared with placebo group at the end of the first and third month of study . There was no significant difference in resolution of clinical gastrointestinal symptoms ( vomiting , colic , rectal bleeding or diarrhea ) and percentage of increment in body length . Conclusion : Synbiotic supplementation in infants may improve increment of head circumference and weight gain , but has no effect on resolution of clinical symptoms This study was design ed to assess whether a rice-hydrolysate formula allows normal growth and adequate metabolic balance in infants with cows ' milk protein allergy . Infants ( seven females , nine males ; aged 6–14 months ) were r and omly assigned to receive a rice-hydrolysate formula ( n = 8) or a soy formula ( control group , n = 8) . St and ardized growth indices ( Z scores ) and biochemical parameters were evaluated during a 6-month treatment period . Infants in both groups showed normal growth patterns during the study , and no adverse reactions were seen . Mean plasma biochemical parameters were within the normal ranges , and did not differ between groups . In conclusion , rice-hydrolysate formula may be a nutritionally suitable alternative for infants with cows ' milk protein allergy . Larger studies , with satisfactory power , should be undertaken to confirm these findings OBJECTIVE 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 . STUDY DESIGN In a prospect i ve 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 . RESULTS 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 ) . CONCLUSIONS 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 Background Children with cow 's milk allergy ( CMA ) have an increased risk of other allergic manifestations ( AMs ) . Objective We performed a parallel‐arm r and omized controlled trial to test whether administration of an extensively hydrolyzed casein formula ( EHCF ) containing the probiotic Lactobacillus rhamnosus GG ( LGG ) can reduce the occurrence of other AMs in children with CMA . Methods Children with IgE‐mediated CMA were r and omly allocated to the EHCF or EHCF+LGG groups and followed for 36 months . The main outcome was occurrence of at least 1 AM ( eczema , urticaria , asthma , and rhinoconjunctivitis ) . The secondary outcome was tolerance acquisition , which was defined as the negativization of a double‐blind food challenge results at 12 , 24 , and 36 months . AMs were diagnosed according to st and ardized criteria . Tolerance acquisition was evaluated every 12 months . Results A total of 220 children ( 147 boys [ 67 % ] ) with a median age of 5.0 months ( interquartile range , 3.0‐8.0 months ) were r and omized ; 110 children were placed in the EHCF group , and 110 children were placed in the EHCF+LGG group . In the complete case analysis the absolute risk difference for the occurrence of at least 1 AM over 36 months was −0.23 ( 95 % CI , −0.36 to −0.10 ; P < .001 ) , and the absolute risk difference for the acquisition of cow 's milk tolerance was 0.20 ( 95 % CI , 0.05‐0.35 ; P < .01 ) at 12 months , 0.24 ( 95 % CI , 0.08‐0.41 ; P < .01 ) at 24 months , and 0.27 ( 95 % CI , 0.11‐0.43 ; P < .001 ) at 36 months . In the sensitivity analysis the effect size of the main outcome was virtually unchanged when the occurrence of AMs was assigned to all 27 missing children . Conclusions EHCF+LGG reduces the incidence of other AMs and hastens the development of oral tolerance in children with IgE‐mediated CMA Children with cows ' milk protein allergy ( CMPA ) are at risk of insufficient length and weight gain , and the nutritional efficacy of hypo-allergenic formulas should be carefully assessed . In 2008 , a trial assessed the impact of probiotic supplementation of an extensively hydrolysed casein-based formula ( eHCF ) on acquisition of tolerance in 119 infants with CMPA . First analysis of the study results showed that the studied formula allowed improvement of food-related symptoms . The scoring of atopic dermatitis ( SCORAD ) index was assessed at r and omisation and after 6 months of feeding . A post hoc analysis was performed using WHO growth software 's nutritional survey module ( WHO Anthro version 3.2.2 ) . All infants who were fed the study formula tolerated it well . The SCORAD index significantly improved from r and omisation to 6 months of feeding with the study formula . Anthropometric data indicated a significant improvement in the weight-for-age , length-for-age and weight-for-length z scores , as well as in the restoration of normal BMI . The probiotic supplementation did not show any impact on these parameters . The present data showed that this eHCF was clinical ly tolerated and significantly improved the SCORAD index and growth indices BACKGROUND Children with cow 's milk allergy ( CMA ) are at risk for inadequate nutritional intake and growth . Dietary management of CMA , therefore , requires diets that are not only hypoallergenic but also support adequate growth in this population . This study assessed growth of CMA infants when using a new amino acid-based formula ( AAF ) with prebiotics and probiotics ( synbiotics ) and evaluated its safety in the intended population . METHODS In a prospect i ve , r and omized , double-blind controlled study , full-term infants with diagnosed CMA received either an AAF ( control ; n = 56 ) or AAF with synbiotics ( oligofructose , long-chain inulin , acidic oligosaccharides , Bifidobacterium breve M-16V ) ( test ; n = 54 ) for 16 wk . Primary outcome was growth , measured as weight , length and head circumference . Secondary outcomes included allergic symptoms and stool characteristics . RESULTS Average age ( ±SD ) of infants at inclusion was 4.5 ± 2.4 months . Both formulas equally supported growth according to WHO 2006 growth charts and result ed in similar increases of weight , length and head circumference . At week 16 , differences ( 90 % CI ) in Z-scores ( test-control ) were as follows : weight 0.147 ( -0.10 ; 0.39 , p = 0.32 ) , length -0.299 ( -0.69 ; 0.09 , p = 0.21 ) and head circumference 0.152 ( -0.15 ; 0.45 , p = 0.40 ) . Weight-for-age and length-for-age Z-scores were not significantly different between the test and control groups . Both formulas were well tolerated and reduced allergic symptoms ; the number of adverse events was not different between the groups . CONCLUSIONS This is the first study that shows that an AAF with a specific synbiotic blend , suitable for CMA infants , supports normal growth and growth similar to the AAF without synbiotics . This clinical trial is registered as NCT00664768 BACKGROUND Previous analysis in a prospect i ve , population -based cohort reported reduced weight gain in children fed extensively hydrolyzed casein ( eHF-C ) formula during the first year of life but showed no effect on growth between 1 and 6 y of life . No studies have been conducted in children up to the age of 10 y. OBJECTIVE The objective was to investigate potential differences in body mass index ( BMI ) over the first 10 y of life between infants fed within the intervention period of the first 16 wk of life with partially hydrolyzed whey ( pHF-W ) , extensively hydrolyzed whey ( eHF-W ) , eHF-C , or cow-milk formula ( CMF ) and infants exclusively breastfed ( BF ) within the intervention period . DESIGN This was a prospect i ve , r and omized , double-blind trial in full-term neonates with atopic heredity in the German birth cohort German Infant Nutritional Intervention ( GINI ) followed through the first 10 y of life . Analyses of absolute and World Health Organization (WHO)-st and ardized BMI trajectories for 1840 infants [ pHF-W ( n = 253 ) , eHF-W ( n = 265 ) , eHF-C ( n = 250 ) , CMF ( n = 276 ) , and BF ( n = 796 ) ] were conducted according to intention-to-treat principles . RESULTS Except for the previously reported slower BMI gain in infants fed with eHF-C formula within the first year of life , no significant differences in absolute or WHO-st and ardized BMI trajectories were shown between the pHF-W , eHF-W , eHF-C , CMF , and BF groups thereafter up to the age of 10 y. CONCLUSIONS Extension of the follow-up period from 6 to 10 y for this r and omized controlled trial showed no long-term consequences on BMI for the 4 infant formulas considered . These data need to be confirmed in future studies Objectives The aim of this study was to assess the efficacy of oral supplementation of viable and heat-inactivated probiotic bacteria in the management of atopic disease and to observe their effects on the composition of the gut microbiota . Methods The study population included 35 infants with atopic eczema and allergy to cow 's milk . At a mean age of 5.5 months , they were assigned in a r and omized double-blind manner to receive either extensively hydrolyzed whey formula ( placebo group ) or the same formula supplemented with viable ( viable LGG group ) or heat-inactivated Lactobacillus GG ( heat-inactivated LGG group ) , respectively . The changes in symptoms were assessed by the SCORAD method and the presence of some predominant bacterial genera in the feces detected with 16S rRNA-specific probes . Results The treatment with heat-inactivated LGG was associated with adverse gastrointestinal symptoms and diarrhea . Consequently , the recruitment of patients was stopped after the pilot phase . Within the study population , atopic eczema and subjective symptoms were significantly alleviated in all the groups ; the SCORAD scores ( interquartile range ) decreased from 13 ( range , 4–29 ) to 8 ( range , 0–29 ) units in the placebo group , from 19 ( range , 4–47 ) to 5 ( range , 0–18 ) units in the viable LGG group , and from 15 ( range , 0–29 ) to 7 ( range , 0–26 ) units in the heat-inactivated LGG group . The decrease in the SCORAD scores within the viable LGG group tended to be greater than within the placebo group . The treatments did not appear to affect the bacterial numbers within the genera enumerated . Conclusions Supplementation of infant formulas with viable but not heat-inactivated LGG is a potential approach for the management of atopic eczema and cow 's milk allergy Objectives : For breast-fed infants with rectal bleeding , maternal restriction of dietary protein such as cow 's milk proteins is often recommended ; however , poor response to dietary protein restriction is of concern . This pilot study was design ed to assess the effectiveness of Lactobacillus GG ( LGG ) in breast-fed infants with rectal bleeding . Patients and Methods : Breast-fed infants < 6 months of age with rectal bleeding ( defined as the presence of visible specks or streaks of blood mixed with mucus in the stool in otherwise healthy infants ) were enrolled in a double-blind r and omized controlled trial in which they received LGG 3 × 109 colony-forming units ( n = 14 ) or placebo ( n = 15 ) twice daily for 4 weeks as an adjunct to cow 's milk restriction in the mother 's diet . Analyses were based on allocated treatment and included data from 26 infants . Results : Mean duration of rectal bleeding was similar in the LGG and control groups ( 17.3 ± 10.6 vs 15.4 ± 11 days ; mean difference −1.9 ( 95 % confidence interval [ CI ] −4 to 7 ) . No difference was found in the number of infants with clinical resolution of rectal bleeding within 72 hours and no relapse afterward ( 2/11 vs 3/15 , relative risk [ RR ] 0.9 , 95 % CI 0.2–3.9 ) and the number of infants with clinical resolution of rectal bleeding within 72 hours followed by relapse of symptoms ( 5/11 vs 5/15 , RR 1.4 , 95 % CI 0.5–3.5 ) . Breast-feeding cessation was not needed in any infant . Conclusions : These results do not support the use of LGG as an adjunct to maternal cow 's milk restriction in breast-fed infants with rectal bleeding BACKGROUND Cow 's milk allergy ( CMA ) is the most frequently diagnosed food allergy in infancy . In general , patients have a good prognosis because the majority acquire tolerance within the first years . Interventions have been proposed to accelerate tolerance and reduce morbidity . Probiotic supplementation could be effective through modulation of the immune system . OBJECTIVE We sought to determine whether supplementation with a combination of probiotics ( Lactobacillus casei CRL431 and Bifidobacterium lactis Bb-12 ) accelerates tolerance to cow 's milk ( CM ) in infants with CMA . METHODS We performed a double-blind , r and omized , placebo-controlled trial in 119 infants with CMA . Infants received CRL431 and Bb-12 supplemented to their st and ard treatment of extensively hydrolyzed formula for 12 months . Primary outcome was clinical tolerance to CM at 6 and 12 months of treatment . Furthermore , we analyzed T- and B-lymphocyte subsets ( CD3(+ ) , CD3(+)CD4(+ ) , CD3(+)CD8(+ ) , and CD20(+ ) ) in peripheral blood at r and omization and at 12 months with flow cytometry and examined the presence of viable probiotic strains in fecal sample s. RESULTS The cumulative percentage of tolerance to CM at 6 and 12 months was similar in both groups : 56 ( 77 % ) in the probiotics group versus 54 ( 81 % ) in the placebo group . Infants in the placebo group had higher percentages of CD3(+ ) and CD3(+)CD4(+ ) lymphocytes compared with those seen in probiotic-treated infants . Probiotic intake was confirmed because probiotics were isolated from feces more often in treated infants than in the placebo group . CONCLUSION Supplementation of CRL431 and Bb-12 to extensively hydrolyzed formula does not accelerate CM tolerance in infants with CMA
target: Conclusion : Limited low- quality evidence indicates that probiotic supplementation may be associated with earlier acquisition of tolerance to CMP in children with CMPA .
  CMPA is associated with significant socioeconomic burden.• Elimination diet and extensively hydrolyzed formula is the mainstay of the management of CMPA.What is New:• This first systematic review of r and omized controlled trials shows that probiotics as an adjuvant can lead to earlier acquisition of tolerance to CMP  in children at 36 months of age .
  However , the evidence is low quality and influenced by data from one large study .• Probiotic supplementation was not associated with earlier resolution of hematochezia
background: Cow ’s milk protein allergy ( CMPA ) is the commonest food allergy in infancy and is associated with significant health burden .
  Given their immune modulatory properties , probiotics have been proposed as a strategy for management of CMPA .
  We aim ed to systematic ally review efficacy and safety of probiotics in the management of CMPA .
  Large well- design ed trials are essential to confirm these findings .What is Known:• Cow ’s milk protein allergy ( CMPA ) is one of the commonest food allergies in children .