The spectrum of cow''s milk allergy

Childhood cow's milk allergy is a diagnosis encompassing various syndromes. Antigen-immunoglobulin E (IgE) antibody interaction is classically involved in mast cell degranulation in IgE-mediated food allergy, while non-IgE mediated cow's milk allergy is mostly mediated by cellular mechanisms. The diagnosis of cow's milk allergy largely relies on a good knowledge of the clinical expression of the disease. In this educational review series, we describe three cases of cow's milk allergy, first a 7-yr-old girl with persisting IgE-mediated cow's milk allergy, second a 8-month-old boy with cow's milk induced flares of atopic dermatitis, and third a 6-yr-old boy with sheep and goat milk allergy, in the absence of cow's milk allergy. The cases are discussed and summarized with more general recommendations for the clinical management of cow's milk allergy.     

Correlation between skin prick test using commercial extract of cow''s milk protein and fresh milk and food challenges

The skin prick test (SPT) is regarded as an important diagnostic measure in the diagnostic work-up of cow's milk protein allergy. It is not known whether commercial extracts have any advantage over fresh milk. The aims of the study were to (i) compare the diagnostic capacity of SPTs for the three main cow's milk proteins (alpha-lactalbumin, casein and beta-lactoglobulin) with fresh milk and (ii) determine a cut-off that discriminates between allergic and tolerant children in a controlled food challenge. A study was carried out on 104 children consecutively attending two paediatric allergy clinics for suspected cow's milk allergy. A clinical history, SPTs with fresh cow's milk and commercial extracts of its three main proteins and a challenge test were performed on all the children. A study of the validity of the prick test was also performed by taking different cut-off points for fresh milk and its proteins. Twenty-eight of 104 challenge tests (26.9%) were positive. At a cut-off point of 3 mm, fresh milk showed the greatest negative predictive value (98%), whereas casein showed the greatest positive predictive value (PPV, 85%). Calculation of 95% predicted probabilities using logistic regression revealed predictive decision points of 12 mm for lactalbumin, 9 mm for casein, 10 mm for beta-lactoglobulin and 15 mm for fresh cow's milk. We found that the greater the number of positive SPTs for milk proteins, the more likely the positive response to challenge. Having a positive SPT for all three milk proteins had PPV of 92.3% and would seem more clinically useful than any cut-off. Both fresh milk and cow's milk extract of the three main proteins could be useful in the diagnostic work-up of cow's milk allergy. Finding positivity to all three cow's milk proteins seems to be a simpler and more useful way of avoiding oral food challenges.     

Oral desensitization in children with immunoglobulin E-mediated cow's milk allergy – follow-up at 4 yr and 8 months

Until now, the basic treatment for food allergy has been to avoid the offending item. This approach is difficult in the case of common foods and in the case where there is a risk of severe reaction after consuming the offending food, even inadvertently. This is the follow‐up of a previous study aimed at desensitizing 21 children with immunoglobulin E (IgE)‐mediated cow’s milk (CM) allergy. This protocol was totally or partially successful in 85% of cases, but failed in the remaining 15%. Our aims were to study the long‐term effectiveness and safety of oral CM desensitization, and the prognostic value of Skin Prick Test (SPT) and specific serum CM IgE. The 21 children were called back (one dropped out). The allergic history and other information on CM intake over the last 4–5 yr were recorded. Children underwent SPT, and end‐point SPT, with casein and α‐lactoalbumin. Specific CM IgE was also measured. At follow‐up, 14/20 children totally (n = 13, 65%) or partially (n = 1, 5%) tolerated CM. None of the recalled children reported use of emergency care. SPT positivity to casein and/or α‐lactoalbumin decreased significantly (p < 0.01), and all the negative SPT referred to the tolerant children. Cutaneous sensitivity to both casein and α‐lactoalbumin (end‐point SPT) significantly decreased after the 6‐month desensitization period of the previous study (p < 0.001), but did not decrease significantly at follow‐up. A significant reduction of serum‐specific CM IgE was also observed (p < 0.05). Clinical tolerance induced by oral CM desensitization persists in time. Negativization of SPT and reduction of specific CM IgE could be considered prognostic indicators of CM tolerance. Oral CM desensitization seems to be a promising method to treat CM food allergy. This protocol is time‐consuming but offers the advantage that it can be performed at home. This methodology must only be used by trained staff.     

Follow‐up of patients with uncertain symptoms during an oral food challenge is useful for diagnosis

Background

Uncertain symptoms often emerge during an oral food challenge (OFC), and Open‐OFCs with those uncertain mild symptoms are ordinarily regarded as positive. Double‐blind placebo‐controlled food challenges should be conducted to determine these associations. Nevertheless, studies regarding the diagnosis of uncertain food allergy symptoms are lacking. We examined the diagnostic decision for a food allergy based on uncertain symptoms during an Open‐OFC.

Methods

We conducted an Open‐OFC between August 2005 and April 2012 with 2271 cases who suspected as allergic to hen's eggs, cow's milk, or wheat. For the primary diagnosis, Open‐OFCs with obvious symptoms were classified as “positive,” no symptoms as “negative,” and uncertain, indeterminate symptoms as “uncertain.” We encouraged the children in the uncertain group to consume the causative foods at home more than twice; if any definitive symptoms were induced, children were classified as “intolerant,” and children without any symptoms were classified as “tolerant,” for the final diagnosis.

Results

We analyzed 454 uncertain cases excluding 781 positive cases and 1036 negative cases. The symptoms that occurred for the uncertain cases included slight abdominal pain, localized skin rash, and an isolated cough. Of these cases, 362 (79.7%) were considered tolerant at the final diagnosis. Of the intolerant children at the final diagnosis, the induced symptoms at home were not serious.

Conclusions

Monitoring of recurring symptoms following consumption of causative foods at home by patients with uncertain symptoms improves the diagnostic accuracy of an Open‐OFC.     

Labial food challenge in children with food allergy

The current increase in the prevalence of food allergies appears to have several causes including better screening, improved diagnosis and changes in both the techniques used by food manufacturers and eating habits. Labial food challenge (LFC)is simple, rapid to perform and is associated with only low risks of systemic reaction. It is thus an appealing alternative to the oral food challenge (OFC) for pediatric use.
We report a series of 202 LFC performed over two years in 142 children with food allergy suspected from the case history, positive skin prick tests and specific serum IgE assays: 156 LFC were positive; and 46 negative, followed by positive single-blind, placebo-controlled food challenges (SB-PCFC). The foods provoking reactions were egg white (75 cases), peanut (60 cases), mustard (23 cases), cow's milk (13 cases), cod (8 cases), kiwi fruit, shrimp (4 cases each), chicken, peanut oil (3 cases each), hazel nuts (2 cases), and snails, apple, fennel, garlic, chilli peppers, pepper, and duck (1 case each). LFC positivity was mostly (89. 7% of cases) manifested as a labial edema with contiguous urticaria. There were systemic reactions in 4. 5% of cases: generalized urticaria, hoarseness and rapid-onset and generalized eczema. The 46 infants with negative LFC results had positive SBPCFC. The reactions were in 34 cases generalized urticaria, 10 cases asthma attacks, 2 cases early and generalized eczema, and in one case general anaphylactic shock. The sensitivity of the LFC was 77%. The LFC was easy to perform with children. Positive results indicate the presence of food allergy, but negative results require further investigations preferably double-blind, placebo-controlled food challenge (DBPCFC)     

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??Oral allergy syndrome??OAS?? is an IgE-mediated acute oropharyngeal hypersensitivity to food??which is caused by cross-reactivity between proteins in fresh fruits or vegetables and pollens??with a prevalence of 5% to 24 % in children. A variety of food protein antigens have been implicated in OAS. The most classic of these cross-reactive antigens include birch antigen Betv1??profilin and lipid transfer proteins??LTPs??. Symptoms are usually manifested as numbness??itching or swelling of the lips or mouth??itching or oedema of the lips?? throat??palate or gingiva??erythema of the face and tightness of the throat. OAS can be diagnosed based on clinical history??antigen-specific immunoglobulin E testing??skin prick testing and oral food challenge. If the diagnosis is established??patients should be instructed to avoid the fresh fruits and vegetables that cause symptoms??and emergency administration of epinephrine should be given for severe??generalized reactions.     

Follow-up of children with rhinitis and cough associated with milk allergy

Young children sensitized with foods may develop early respiratory symptoms including nasal symptoms and cough, but not clinical manifestations in the skin or gastrointestinal tract. The long-term outcome of these patients is largely unknown. We studied 36 children sensitized with cow's milk and three different age-matched control groups. The patients were followed from 12 to 18 months of age for at least 5 yr with repeat skin testing and oral food challenge. After 2½ yr, 63.9% (n = 23) of those in the mild allergy group lost sensitivity to foods; after 5 yr, the number was 86.1% (n = 31). However, during the study period of 5 yr, 69.4% (n = 25) simultaneously developed a sensitivity to common indoor airborne allergens. A similar trend was found only in the egg allergy control group. A positive family history and a history of parental smoking significantly increased the relative risk (RR) of sustaining nasal allergy symptoms (RR = 3.33 and 1.79, respectively). We concluded that allergy march from food sensitivity to sensitivity to airborne allergens may occur in a subset of children before 4 yr of age. Genetics and environmental factors might independently contribute to the continuation of these respiratory symptoms.     

Oral immunotherapy and tolerance induction in childhood

Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food‐allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long‐term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy.     

Fetal sensitization to cow''s milk protein and wheat: cow''s milk protein and wheat-specific TNF-α production by umbilical cord blood cells and subsequent decline of TNF-α production by peripheral blood mononuclear cells following dietary intervention

We present a case of fetal sensitization to cow's milk protein (CMP) and wheat, resulting in non-IgE mediated food allergy (NFA). Fetal sensitization was indicated by onset of NFA symptoms shortly after birth and CMP/wheat-specific tumor necrosis factor-alpha (TNF-alpha) production by cord blood mononuclear cells. Following dietary intervention, we observed a decline of TNF-alpha production by peripheral blood mononuclear cells with stimuli of these dietary proteins (DPs) but recurrence of reactivity was observed following viral gastroenteritis, while interleukin-10 production with these DPs persisted during his first 5 yr of life. This finding may indicate active suppressive mechanisms for maintaining oral tolerance.