Molecularly defined adult-type hypolactasia in school-aged children with a previous history of cow＇s milk allergy

AIM: To assess the role of lactase non-persistence/persistence in school-aged children and their milk-related symptoms. METHODS: The genotypes for the C/T-13910 variant associated with lactase non-persistence/ persistence were determined using PCR-minisequencing in a group of 172 children with a mean age of 8.6 years (SE = 0.02, 93 boys) participating in a follow-up study for cow's milk allergy. The parents were asked to assess their children's milk consumption and abdominal symptoms. RESULTS: The presence of allergy to cow's milk was not associated with the C/C-13910 genotype related with a decline of lactase enzyme activity during childhood (lactase non-persistence). The frequency of the C/C-13910 genotype (16%) was similar to published figures for the prevalence of adult-type hypolactasia in Finland. The majority of the children (90%) in this series consumed milk but 26% of their families suspected that their children had milk-related symptoms. Forty-eight percent of the children with the C/C-13910 genotype did not drink milk at all or consumed a low lactose containing diet prior to the genotyping (P< 0.004 when compared to the other genotypes). CONCLUSION: Analysis of the C/T-13910 polymorphism is an easy and reliable method for excluding adult-type hypolactasia in children with milk-related symptoms. Genotyping for this variant can be used to advise diets for children with a previous history of cow's milk allergy.     

In vitro methods for specific IgE detection in cow's milk allergy

BackgroundA new method for determining serum specific IgE (IMMULITE^® 2000 3gAllergy) has recently become available.ObjectiveTo evaluate the clinical performance of IMMULITE 2000 in the diagnosis of cow's milk allergy compared with that of UniCAP^®. Additionally, we verified the behavior of both methods at two diagnostic decision points proposed by other authors.MethodsThe study population consisted of 31 children with cow's milk allergy (group A) and a control group of 19 atopic children without food allergy (group B). A blood sample from each child was tested using both methods and the results were compared.ResultsIn group A, the values for cow's milk IgE ranged from 0.35 kU/L (the lowest common detection limit) to above 100 kU/L. In group B, the values were less than 1.1 kU/L for IMMULITE 2000 and less than 1.6 kU/L for UniCAP. An agreement of 90 % in IgE classes was obtained. Both methods demonstrated exactly the same diagnostic performance (sensitivity: 100 %; specificity: 78.9 %; negative predictive value: 100 %; positive predictive value: 84.6%; efficiency: 90.2 %). The evaluation of the two methods at the two different decision points proposed in the literature showed a better positive predictive value with UniCAP, but we obtained equivalent performance with IMMULITE 2000 by choosing higher cutoff values.ConclusionsWe conclude that IMMULITE 2000 is as effective as UniCAP in the diagnosis of cow's milk allergy. Both methods can be used to obtain site-specific decision points that are population, age and disease dependent.     

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 3-5?years, 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.     

Mechanisms of cholinergic dysfunction in rabbits following recurrent aspiration of cow's milk.

Recurrent aspiration of cow's milk has been shown to alter neural control of airways in young rabbits (Gelfand et al., 1997). The purpose of this study was to define the mechanisms responsible for in vitro cholinergic hyperresponsiveness in this model. Beginning at 1 week of age, rabbits received either 0.5 mL/kg whole cow's milk or sterile saline intranasally while under light anesthesia. This was repeated each weekday for 2 weeks. At 8 weeks of age, rabbits were sacrificed. Portions of lungs underwent lavage with sterile saline. Tracheal smooth muscle (TSM) segments were also removed. Segments were assessed for acetylcholine (ACh) release by high-performance liquid chromatography ( HPLC) with electrochemical detection or acetylcholinesterase (AChE) kinetic activity by spectrophotometry. Substance P (SP), a neuropeptide that can increase ACh release from nerves, was also assessed using an enzyme immunoassay to define the content in lavage and TSM segments. Immunohistochemistry for SP within airways was also assessed. We found that recurrent aspiration of milk led to statistically significant alterations in many parameters. Acetylcholine release was significantly greater in segments of airways from rabbits that had aspirated cow's milk (27.5 +/- 1.7 vs. 20.1 +/- 1.6 pmol/min/g tissue) than saline. At the same time, AChE activity was less in the group that aspirated milk (8.7 +/- 0.4 vs. 10.2 +/- 0.5 nmol/min/mg protein) compared to saline. The amount of SP within both lavage as well as tissue homogenates was greater in the group that had aspirated the foreign protein (159.1 +/- 28.9 vs. 41.9 +/- 5.2 pmol/mg protein in lavage; 158.7 +/- 31.9 vs. 80.5 +/- 7.8 pmol/mg protein in tissues) than saline controls. While total cholinergic nerve density as assessed by choline acetyltransferase was not significantly different between groups, SP-positive immunoreactive nerves were easily identified in the group that aspirated cow's milk. This study suggests that cholinergic hyperresponsiveness caused by repeated aspiration of milk is due to several abnormalities, including prejunctional (increase in ACh release) as well as junctional (decrease in AChE) mechanisms within the airways. In addition, an upregulation of SP within airways is part of this process.     

Is oral food challenge test useful for avoiding complete elimination of cow's milk in Japanese patients with or suspected of having IgE-dependent cow's milk allergy?

BackgroundCow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known.MethodsAfter setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events.ResultsForty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%).ConclusionsThis analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.     

Multiple bone fractures in an 8-year-old child with cow's milk allergy and inappropriate calcium supplementation

The case of an 8-year-old boy with severe bone mass reduction and 4 fractures as a result of an unsupervised diet established to treat cow's milk allergy is presented. Endocrine, genetic and orthopedic pathologies were excluded. While vitamin D intake had always been appropriate, his calcium intake had been inadequate for many years. This clinical report suggests that both vitamin D and calcium supplementation are necessary when a cow's milk protein-free diet is prescribed, even when a hypo- or non-allergenic formula is provided.     

Use of an amino-acid-based formula in the treatment of cow's milk protein allergy and multiple food allergy syndrome

Food allergy to cow's milk proteins (APLV) is frequently found in young infants. Treatment is by starting an elimination diet. Different substitution products have been proposed: soya milk, partial hydrolysate of the proteins of lactoserum, powdered casein hydrolysate, hydrolysed soya and pork collagen. Allergic reactions to soya milk, hydrolysates of lactoserum proteins, powdered casein hydrolysates and hydrolysates of soya have been described. The study that we present evaluates the effect on the natural development of these allergies of a formula based on amino-acids (Neocate) in 26 patients who presented a syndrome of multiple allergies one of which was a food allergy to milk. Twenty-five of them had a severe atopic dermatitis, isolated (14 cases), or associated with gastro-intestinal troubles (6) break in the growth curve (5), anaphylactic reactions (2), one asthma (1). One child had a chronic diarrhoea associated with a weight plateau. Evaluation 2 or 3 months later showed a significant improvement of the atopic dermatitis. Return of the stature-weight growth was noted in 4 children from 5, the check in one was reported as due to a initially unrecognised allergy to gluten. The recovery of the APLV was shown by double-blind oral provocation test in 20/23 children between 11 and 37 months (22 +/- 9). Duration of administration of Neonate was between 6 to 19 months (12 + 5) months. This study confirmed the beneficial effect of the amino-acid formula on weight gain, gastro-intestinal troubles and development of atopic dermatitis. The level of recovery of APLV of 86% at the age of 2 years is better than that reported in the syndrome of multiple food allergies of 22%. The influence of this diet on the development of other food allergies remains to be evaluated.     

Increased serum antibody levels against cow's milk proteins in children with chronic liver disease

We measured IgG, IgM and IgA antibodies to cow's milk proteins: alpha-casein, alpha-lactalbumin, bovine serum albumin, beta-lactoglobulin-a and beta-lactoglobulin-b in the sera of 29 pediatric patients with liver disease. IgG antibodies to bovine serum albumin, beta-lactoglobulin-a and beta-lactoglobulin-b and IgA antibodies to alpha-casein were elevated in most of the patients compared to age-matched controls. We postulate that, in patients with liver disease either increased intestinal uptake resulting in increased humoral response, or decreased hepatic clearance of food antigens intensifying a humoral response to these foreign antigens, may occur.     

Acute pancreatitis associated with milk allergy.

We are reporting the case of a 23-yr-old patient who had recurring episodes of acute pancreatitis characterized by the typical abdominal pain, elevated serum levels of pancreatic enzymes, and enlargement of the pancreas and edema on sonogram. These episodes were accompanied by facial erythema with conjunctival injection, generalized pruritus, diarrhea, and eosinophilia, and they were induced by the consumption of milk. The serum levels of IgE specific to cow milk proteins and to beta-lactoglobulin were increased. We suggest that these episodes are caused by a milk allergy (milk), that has been described as an unusual cause of acute pancreatitis.     

Hidden presence of cow's milk proteins in foods.

Cow's milk is one of the first foreign proteins ingested by infants and is one of the most common and potent food allergens. The presence of cow's milk is widespread due also to its unlabelled inclusion as an ingredient, or to errors in cooking, processing and preparation, and in restaurant food. As several foods may contain cow's milk in a hidden form, foods for allergic babies should be prepared at home or with food items with all their ingredients listed on the label. Parents should be provided with appropriate material and instructed how to detect potential sources of hidden cow's milk by judiciously reading food labels to avoid possible untoward reactions. A study on products with potential hidden forms of cow's milk or its proteins is reported herein.     

Transfer of cow's milk beta-lactoglobulin to human serum after a milk load: a pilot study.

A sensitive and specific enzyme linked immunosorbent assay (ELISA) was developed for the quantification of cow's milk beta-lactoglobulin in human serum. The assay had a sensitivity of 80 pg/ml (2 standard deviations from zero) and did not cross react significantly with any other tested milk proteins. The absorption of cow's milk beta-lactoglobulin and beta-lactoglobulin immunoglobulin G antibody levels after a milk load was investigated in eight healthy non-allergic individuals. There was a significant variation in the circulating beta-lactoglobulin antigen levels during the six hour period after feeding (p < 0.01) for the combined data. A biphasic absorption pattern was seen in all subjects except one subject who had undetectable levels. No significant variation with time was observed for the beta-lactoglobulin IgG antibody levels and no correlation was found between the beta-lactoglobulin antigen levels and the beta-lactoglobulin IgG antibody levels. This pilot study offered information on the quantity of immunogenic cows' milk protein transferred to the blood after a milk load in non-allergic healthy adults and confirmed a biphasic profile of antigen transfer. The sensitivity of the assay used has shown that transfer of food antigen does occur in the majority of healthy nonallergic subjects.     

Disaccharidase deficiency in infants with cow's milk protein intolerance. Response to treatment

7 infants, aged 5 weeks to 11 months, with clinically documented intolerance to cow's milk protein, chronic diarrhea, and failure to thrive, underwent small intestinal (peroal, suction) biopsy before and after withdrawal of milk proteins. Mucosal specimens were examined by light microscopy and assayed for disaccharidase activities. In all patients, moderate to severe mucosal changes were presented, associated with marked inflammation of lamina propria and damages to the brushborder. Disaccharidase activities (lactase, sucrase, maltase and palatinase) were markedly depressed in all. Follow-up biopsies were obtained in 6 infants, after 3-5 months on a milk-protein-free diet. At the time of the second biopsy, the disaccharidase activities had risen significantly and histologic improvement had occurred in each instance. In infancy, intestinal mucosal lesions due to intolerance to cow's milk protein are histologically indistinguishable from those seen in gluten-sensitive enteropathy and are associated with marked secondary disaccharidase deficiencies. Following therapy, the activity of the disaccharidases become normal or near normal prior to the complete morphologic recovery of the small intestinal mucosa.     

Small intestinal intraepithelial lymphocyte levels in cow's milk protein intolerance.

The mean small intestinal intraepithelial lymphocyte count in seven children with untreated cow's milk protein intolerance (CMPI) on a milk-containing diet was significantly higher than 22 control children also having a milk-containing diet. Ten milk-intolerant children on a milk-free diet had a mean intraepithelial lymphocyte count which was significantly lower than the level in the 22 control children on a milk-containing diet. When these 10 children were challenged with cow's milk they relapsed clinically, and in every case the intraepithelial lymphocyte count rose, although it remained within normal limits. Nineteen children on milk-free diets who had recovered from CMPI had a mean lymphocyte count which was also significantly lower than controls on normal diets, suggesting that when milk is remo-ed from the diet the lymphocyte count is low regardless of whether the child is milk sensitive or not. The reaction of intraepithelial lymphocytes to milk in CMPI is markedly different from their response to gluten in coeliac disease.     

IgE cross reactivity between reindeer and bovine milk beta-lactoglobulins in cow's milk allergic patients.

BACKGROUND: Allergic reactions to cow's milk are common in small children. One of the main protein allergens found in cow's milk is beta-lactoglobulin (beta-Lg). Reindeer and bovine milk both contain related beta-Lg proteins, but the allergenicity of reindeer beta-Lg has not previously been studied. The purpose of this study was to analyze the immunological cross-reactivity of IgE antibodies from children with cow's milk allergy to reindeer and bovine beta-Lg. METHODS: Sera from 17 children and a serum pool of 4 patients with elevated cow's milk-specific IgE were investigated. Beta-Lg from bovine and reindeer milk was isolated in native form and an enzyme-linked immunosorbent inhibition assay was developed. Bovine beta-Lg was used as a capturing antigen and the inhibiting effects of reindeer and bovine beta-Lg on the IgE binding were measured. RESULTS: Cross-reactivity patterns of bovine milk beta-Lg specific IgE to reindeer beta-Lg varied among patients. In general, reindeer beta-Lg showed significantly lower inhibition (mean 43%) of IgE binding to the capturing antigen than did bovine beta-Lg (mean 89%). In some patients, even high concentrations of reindeer beta-Lg only partly eliminated the IgE binding to bovine beta-Lg. CONCLUSIONS: The partial cross-reactivity of human anti-bovine IgE with reindeer beta-Lg suggests that it lacks important bovine epitopes and those that are recognized are only weakly bound.     

Pilot study: tendency of increasing iodine content in human milk and cow's milk.

The iodine supply in Germany has improved throughout the last decade, albeit with enormous differences between individuals and regions. In the Thuringian city of Jena, analyses of the iodine content of human milk have been undertaken regularly since 1982. Significantly increasing iodine concentrations in human and cow's milk have been found. Therefore, the current situation and the effectiveness of measures to prevent iodine deficiency demands re-evaluation. The iodine content of human milk from 32 lactating mothers was analysed on the 5th day (mean) postpartum and mothers' dietary iodine intake during the last two months of pregnancy was assessed by means of a food frequency questionnaire. To corroborate the assumption that the increasing iodine levels of cow's milk are one of the main reasons for the improved iodine supply, the iodine concentration of 34 cow's milk bulk-samples was also determined. Both human and cow's milk samples were analysed by the ICP-MS method. Twenty women took iodine supplements (mean daily intake = 175 microg). The average daily iodine intake of the 20 supplemented and 12 non-supplemented women was 258 microg and 116 microg, respectively. Daily iodine intake from food and beverages was significantly lower in supplemented women (83 microg/day). The average iodine content of human milk was 169 +/- 88 microg/l with a range of 33 - 348 microg/l. This content is two times higher than levels from 1994 in the same area. There was no difference in the human milk iodine content between mothers taking supplements and those who did not. Cow's milk samples showed a mean iodine concentration of 178 +/- 131 microg/l (range 48 - 661 microg/l).