Food hypersensitivity is a common name for any adverse reactions related to food. These reactions classified into toxic or nontoxic reactions. The nontoxic reactions are allergic if the immunity system implicated. The allergic reactions classified to IgE mediated, or non-IgE mediated. However, anaphylaxis is a generalized allergic reaction to food (1)
Cow's milk has cow milk protein (CMP), water, carbohydrates, minerals and vitamins. CMP found to cause of cow's milk allergy (CMA).
CMA is one of the crucial and complex entities of FH reactions and sometimes a misunderstood disorder. General public often confused it with lactose milk intolerance. In CMA, CMP sensitizes the immune system and gives allergic symptoms, which resulted from damage of tissues caused by the immune system's inflammatory response, which can occur, even with a little amount of milk (2)Whereas, lactose intolerance occurs due to the deficiency of the lactose enzyme in the body (3).
CMA is the regular dairy allergen during infancy because of the immaturity of the immune system. Casein and Whey proteins implicated in the allergic reaction among more than thirty cows' milk protein (4)
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The prevalence of CMA is inconsistent. It affects 2-7.5 % of infants and children and declines by time to reach 0.1-0.5 % in adults (4). Non-IgE mediated represents around 50% of Paediatrics CMA(5) CMA prevalence varies between studies due to difficulties in accurate diagnosis, difference in age of patients and different clinical criteria used (6)
This report compares and contrasts between IgE mediated and non-IgE mediated CMA protein allergy, with specific references to the clinical presentation, Immunopathology, diagnostic tests and long-term prognosis for the patient. Through the report, the clinical manifestations will be linked to the underlying immunological processes.
Methods of research; a literature search on MEDLINE done by using the search titles: food hypersensitivity, cow milk protein allergy, IgE mediated, non-IgE mediated, immunopathology of cow milk allergy, clinical presentations, allergy tests, long term prognosis.
The research outcome; out of a total of 598 publications identified, 40 papers selected which published in primer Journals, plus two books.
-288 papers excluded because of no relevance to IgE and non-IgE mediated CMA.
-189 papers were duplicated.
- 60 were not in English Language.
- 21 related to non Human.
Immunopathology and clinical presentation of CMA :
Any allergic response, whatever, the mechanism needs an antigenic stimulus plus genetic conditions and micro-environment. In CMA, CMP is the antigen and gastrointestinal tract (GIT) is the micro-environment. GIT epithelium surface, with its tight junctions between cells acts as a physical barrier. In addition to the presence, the Lamina Propria; the underlying loose connective tissue is rich in immune cells .e.g. activated T cells, B cells, dendritic macrophages, and plasma cells, all play as an immunological barrier. These barriers prevent CMP to reach the underlying tissues. However, after ingestion of milk and when the CMP pay- passes these barriers they presented by presenting cells to be native T helper cells (Th-0). After activation, the T cells release cytokines, which differentiates (Th-0) into (Th-1) or (Th-2). If these cytokines interlukin (IL)-12 and interferon (IFN) -y), it will evolve into (Th-1) inducing the cell-mediated hypersensitivity(non-IgE mediated reaction). However, In the presence of (IL-4) it will develop into (Th-2) which induce IgE mediated hypersensitivity. Even though, if these cells secrete IL-10 and transforming growth factor-beta (TGF-B) they may promote the development of oral tolerance (seven holigate)
CMA classified into IgÐ• mediated and non IgE mediated reactions(7)
1-IgÐ• mediated CMÐ (ImmÐµdi°tÐµ hypÐµrÑ•ÐµnÑ•itivity):
After ingestion of milk for the second time, and penetration of the mucosal barrier, the epitopes of cow's milk protein adhere to IgE antibodies, which bound to FCe receptors on the surface of mast cells or basophiles. This causes degranulations of the mast cells, and release of vasoactive and chemotactic mediators.(table 1) These Releasing mediators, causes vasodilatation, smooth muscle contraction, mucus secretion and starting IgE mediated reactions (nine holigate).
The table (1): shows a List of mediators and their effects:
Causes bronco-constriction, mucus secretion, vasodilatation, vascular permeability
Causes extensive proteolysis
Production of kinins; increased vasodilatation and vascular permeability, edema
Always on Time
Marked to Standard
Eosinophil chemo tactic factor of anaphylaxis(ECF-A)
Attracts eosinophils and neutrophils to the site of the reaction
leukotriene C4, D4
Increase the effects of histamine
cause edema plus pain
Platelet aggregation Factor (PAF)
Platelet aggregation and release of heparin release
Diagnosis of CMP IgE mediated reactions:
The accurate diagnosis of CMA is critically dependent on proper history taking through structured prompts questions. These should include the current, atopic family history, triggering factors, occupational and past medical history(seven holigate). The questionnaire should include; the onset of the reaction after having milk, the quantity of milk, type of milk and any material mixed with it. In addition, we should ask the child's parents about the frequency of symptoms, its relationship to exercise and history of anaphylaxis.
2-clinical presentation of CMP IgE mediated:
The increase in histamine release, in plasma, associated with all signs and symptoms of IgE mediated reactions in different body systems.
Urticareia and angioedema are the common reactions with a very rapid onset within minutes. In addition, flare of acute atopic dermatitis (AD), the pathogenesis of AD characterized by the infiltrating T cells predominately express IL-5 and IL-13.
B-Oral and GIT:
An itching of the soft palate, pruritis, tingling and angioedema can involve lips, tongue, palate and throat or vomiting and diarrhoea. The mast cell degranulation is responsible mainly about these symptoms, so, are usually having been short lived.
C. Upper and lower respiratory:
Rhinoconjunctivitis symptoms include; sneezing, rhinorrhoea, blocked nose, itching of the nose, throat, eye and watery eyes. Chest symptoms occur in the form of wheezing and cough.
Rare reaction, the patient may develop an extremely fast form of onset for one or more symptoms of oral, GIT, skin, respiratory reactions and at the same time he develops of a cardiovascular symptom in the form of hypotension, vascular collapse and cardiac arrhythmia. These symptoms are mainly due to massive mast cell mediators' release.
A-Skin Prick Tests (SPT):
It is necessary in CMA to exclude the other inhalants' allergens and differentiates IgE from non-IgE mediated reactions. Unfortunately, false positive results could be happened with demographic or sensitive skin and Eczema or use of non-standardised extracts or poor selection of extract panel. However, a false negative can be happened with using antihistamines or small weal in infants below one year.
B-Specific IgE Tests:
There is radioallergosorbant test (RAST), enzyme-linked immune-sorbent assay (ELISA), and chemo-immunoassay; all have a role in allergy testing. However, it is less sensitive and not too accurate than SPT because it depends on quality control of the laboratory and different types of the assays.
The elimination of CMP from child food and try using a different formula .e.g. soya, rice or use other food for two weeks, leads to resolution of symptoms.
D-Food challenges tests :
Open, single or Double- blind, placebo-controlled food challenge (DBPCFC), are the gold standard for food allergy diagnosis. The test should conduct after taking history, doing SPT /specific IgE and diets elimination (8) Because of the risk of anaphylaxis, the need for specific precautions and resuscitation facilities is essential. Interpretation of symptoms may be difficult, depending on the kind, onset and progression of the symptoms. A negative oral food challenge permits the introduction of the food, whereas avoidance of the food is the first advice after a positive oral food challenge result (9)
2- Non-IgÐ•-mÐµdi°tÐµd CMÐ (delayed hypÐµrÑ•ÐµnÑ•itivity reaction):
The non-IgE mediated CMA immunopathological mechanisms are poorly understood and still uncertain. The pathophysiology of non-IgE reaction involves macrophages and monocytes which engulf the milk protein antigen. This process mediated by T helper cells (Th1) which secrete cytokines such as interferon-gamma and in turn activates cytotoxic T cells. They also recruit and activate monocytes and macrophages forming a circle, which along with cytotoxic cells causing direct damage to the cells. Monocyte chemo tactic factors (MCT), IL -2, Interferon-gamma are some of the chemokines which involved in the delayed hypersensitivity reaction. In addition, macrophages secrete (IL-1, IL-2 and IL-6) and in turn recruit cytotoxic T cells and more macrophages (david male book)
Diagnosis of non-IgE mediated CMA :
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It depends on history, clinical presentation and diagnostic tests, which varies according to the affected systems.
A-G°Ñ•trointÐµÑ•tin°l (GIT) symptoms, these are the most common symptoms and present in the type of allergic eosinophilic oesophagitis, gastritis and gastroenteritis syndromes. The eosinophilic oesophagitis presents with abdominal pain, food refusal, intermittent emesis, and sleep disturbance, dysphagia and gastro esophageal reflux. While the eosinophilic gastritis, and gastroenteritis presents with abdominal pain, vomiting, anorexia haematemisis and failure to thrive.
Infantile colic could be happened with a short period. In addition, CMP can cause enterocolitis, which presents with protracted vomiting and diarrhoea. The mechanism is still not sure, however; the inflammatory changes suggested that the tumor necrosis factor alpha (TNF-a) could be responsible for the secretary diarrhoea.
CMP also, causes CMP induced colitis, this presents with no symptom and only may be discovered with the presence of blood in the stools. Blood loss could lead to anemia.
-Negative SPT and RAST.
-Endoscopy and biopsy showed a swelling of intestinal mucosa after ingestion of milk.
-Serum eosinophilia and stool examination to exclude other causes of GIT symptoms.
Diagnosis of CMP eosinophilic induced esophagitis based on SPT, specific IgE and food challenges, because it has both IgE and non-IgE mediated mechanisms (19),
B-Cutaneous Reactions in the form of chronic Atopic Dermatitis (AD); the chronic lesions promote the delayed hypersensitivity reactions. The symptoms arise from 24-48 hours after ingestion of milk. The underlying mechanism involves the sensitized T cells which react with CMP to produce cytokines, which mobilise non-sensitized cells to fight the antigen, causing inflammation, tissue damage and formation of epithiliod and giant cells. The skin lesions show INF-Y and IL-12.
- DBPCFC: can be useful, and the observation period should be 48 h (10)(Niggemann B 2004.)
-Patch test: Evaluation of eczematous skin lesions with an atopy patch test (APT) can be used as a diagnostic tool in food-triggered Atopic dermatitis(11). 2006EAACI/GA2LEN). (turjanmaa,)
C-Respiratory Symptoms :
CMP-induced pulmonary hemosiderosis (Heiners Syndrome):
The symptoms are coughing, wheezing, haemoptysis, and nasal congestion and may be in the form of dyspnoea. The diagnosis could be achieved by positive milk precipitin test and milk elimination. In this syndrome, the peripheral blood shows eosinophilia and multiple serum precipitates (milk specific IgG). The underlying mechanism is still not clear. (12) (Moissidis I 2005)
Rhinitis symptoms presented along with an increase the production, thickness of the nasal secretions and obstruction.
-Negative skin and RAST tests.
The recovery or tolerance of IgE mediated has reached 56% at one year, and has improved to reach about 90 % at age five. While, at age of 15 years it has reached 97 %. However, its prognosis has reached (53%) in asthmatic patients at the age of 10 years because of their atopic background (13)In addition, IgE level plus the age of the child can play a role in the prediction of the clinical reactivity and tolerance to CMP (14)
Patient of IgE mediated CMA has higher chances to develop asthma, atopic dermatitis and other food allergies than non-IgE mediated (15) (Saarinen km 2005).
The prognosis of non IgE reactions is promising. The GIT non-IgE mediated reactions can be limited to mild procitis or pancolitis or extend to esophagitis, enteropathy and colitis. However, most of the infants can outgrow the allergy by age 2-3 years, and some maintain this allergy later in their childhood years (16)remission of esionphilic esoohagitis (17)
Future outlook on CMA is the use of CMA immunotherapy; recent research shows an increase in tolerance to CMP for IgE mediated allergy after desensitisation(18) (Robert wood). In addition, anti-IL-5 therapy may be a promising therapeutic option for eosinophilic esophagitis. (19) ( Chehade M 2007).
Table (2): summarises the most notable differences of Cows milk allergic reactions:
Cow's milk protein allergy
Ingestion of milk or milk products
Ingestion of milk or milk products
Prevalence and incidence
Cow's milk protein
Cow's milk protein
Age of onset
Infancy and childhood
Infancy and childhood
One or more of skin of GIT and respiratory
Mainly GIT and/or respiratory or skin
Could be happen
-IgE (Th2 -mediated)
Onset of action after cow's milk ingestion
From minutes to 2hours
From hours to days
- elimination diets
-endoscopy and biopsy
-breast-feeding during first 6 months of life
breast-feeding during first 6 months of life
-amino acid formula
amino acid formula
Outgrows at age of 5
outgrows at 2-3 years
Professional advices to the parents:
Having a child with a food allergy is a trouble for any family. However, if this food is milk, the situation is more difficult. Many questions could be aroused in the parents' mind, such as; should they stop milk for the child? What food could replace the cows' milk? Should they allow other milk formula for the child? What should they do if anaphylaxis happens?
The advices to parents are:
Avoidance of CMP is the basic principle for management of both types of IgE and non-IgE mediated CMA. We encourage parents to avoid any food containing cow's milk, even in other forms, such as skimmed, dried, solid, evaporated, condensed, cheese, yoghurt, ice cream and butter and any soy products containing cow's milk. In addition, any products which contains powdered cow's milk, casein and cereals containing whey. Moreover, the child should not receive any food from other children unless he knows its content.
Avoidance of milk has a psychological impact on the parents, because the lack of milk in food means that the child would lose a valuable source of calcium, vitamin D and fat soluble vitamins (Phosphorus and Magnesium) which are particularly beneficial for growth. We can accomplish this fear by:
1-The mothers should be advised to continue on exclusive breast feeding for 4-6 months, because it is the gold standard for nutrition for the first 4 months of life and has a lower incidence of atopic dermatitis and wheezing than other formulas. (20)However, there is a cross reaction, between human milk and sensitization to cow milk. The IgE reactivity to human milk can be expected to either cross- sensitization or direct sensitization to it (21)The recommendations for IgE mediated patient are to stop breast feeding and switch him/her to another formula if allergic reactions occur with exclusive breast feeding.
2- Switching the patient diet's plan to other milk formulas. Extensively hydrolyzed formula (eHF) shows further reduction in the prevalence of CMA than the partially hydrolyzed one (22)Infants and children who cannot tolerate different milk formula, they may obtain benefits from an amino acid formula (AAF) in both parameters of symptoms and growth (23)Moreover, an exclusive amino acid formula has more than 90% improvement in children with eosinophilic oesophagitis. (17)(Chehade M 2010)
The parents should know that soy milk is a cheaper option than eHF and AAF, but it has a cross reaction with cow's milk with 10-35 %.(24)(nowak 2009). It recommended beyond 6 months only (25)(agostini 2006) .
However, the symptoms could be happened, despite strict CMP elimination, because of other food allergens in meals .e.g. egg, peanut and wheat. Egg avoidance recommended in CMA patient with atopic dermatitis. (26) (schoetzau 2002).
In addition, goat milk has about 90% cross reaction with cow's milk,.It is not recommended for the child (27). Furthermore, parents must realize that raw beef has 10% cross reaction with cow's milk, however; sensitisation to raw beef can be reduced by heat or freeze treatment and advice is no need to eliminate beef meat from child diet (28)
3- A written dietary programme should be given to the nursery or school which obtained from the dietician.
4- Arranging a perfect follow up appointments with clinician and dietician, who will do regular assessment, monitoring of growth curve and quality of life of the child. In addition, parents should use a food -symptom card to record each symptom and its relationship to milk or other food. Patient-clinician relationship plays a role in managing the psychological impacts of food allergy in family members, to achieve positive adjustment of the family with their child problem and encourage them to seek psycho- educational guidance (29)
5-By giving The child routine vaccinations and treating any other co-morbidity diseases as diabetes or cardiovascular disorders, this will keep their child fit most of the time,. In addition, asking for immediate medical care of any upper respiratory infections
6- Introducing the patient and his/her family to any support group, even on-line groups, In UK, there are some of the organizations e.g. www.anaphylaxis.org.uk and www.allergyuk.org,www. They can help by giving educational material, conducting several meetings and providing telephone numbers in case of emergency
Although, an anaphylaxis (severe generalized reactions) is a tremendous fear for the family of a child with IgE mediated CMA, in contrast, child with non-IgE mediated reactions has no probabilities for that.
The advices in case of anaphylaxis are:
1-If a child has a history of anaphylaxis; he/she should carry an adrenalin auto injector (Epipen) all the times.
2- Parents should keep at home and contribute to the nursery or school a written allergy management plan, in understandable language, which should be obtained from the doctor. It includes; the triggers of his allergy, medications and contact information of child. When anaphylaxis or collapse symptoms appeared, they should call for emergency service, and give emergency medication (Epipen) In addition, a second dose of Epipen could be administered if no obvious recovery after 5-10 min(30). (EAACI)
3- Teaching patient and all the family members how to learn to read food labels, and adapt recipes. The guidance notes on food labels, and best practice on allergen and various labelling provisions is available on the UK governmental website, http://www.food.gov.uk.
4- The child should always hold an allergy notification card which includes all information about his or her allergy status.
The advice for IgE and non-IgE mediated respiratory symptoms (mild and moderate reactions) is to give antihistamines or local nasal corticosteroids, short or long acting Beta-antagonist plus inhalant corticosteroids or Leukotrienes inhibitors. We should teach the patient how can use these inhalers devices. While, in urticaria and angioedema and acute atopic dermatitis (IgE mediated type) the advice is to give an oral antihistamine, local corticosteroids and local antibiotic in case if infected skin. However,nd calcineurin inhibitors s and181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818in chronic atopic dermatitis (non-IgE mediated) emollients should be added and the child should temporarily discontinue or reduce swimming pool exposure and apply emollient after physical exe.(30)
Fear of using these medications can be decreased by giving the parents all information about the importance, doses, safety and possible side effects of them. For example, Cetirizine (an antihistamine) is remarkably safe for a long-term use in atopic dermatitis infants (31)
Regarding to IgE and non-IgE mediated GIT reactions, the guidance is to check for any source of milk in the child's food, control the symptoms and prevent dehydration by regular intake of fluids.
The advice for parents if they have a plan for another child is to know that no specific genes associated with CMA (32). However, if there is an atopic family history of asthma or rhinitis, we counsel parents to seek clinician suggestion for doing the required investigations to exclude other atopic diseases.
Assurance of parents that CMA is mostly a self-limited disease; for that reason, reintroduction of cow milk could be achieved under clinician recommendation by regular assessment to recheck the tolerability to CMP by doing SPT, RAST and DBPCFC.
CMA is a monumental challenge for clinicians and researchers. In spite of, we have a lot of information. However, it is still under discussion, especially in the natural history, epidemiology, diagnosis and treatment of non-IgE mediated type. More researches are needed to clarify the differences between IgE and non-IgE mediated reactions. Up till now, prevention resources constitute the most effective means for the management. However, a new hope of CMA immunotherapy could be the solution, but it is still under investigation.
The psychological aspects of CMA are extremely influential when we deal with the patient and his/her family. This could be managed by various tools, especially in milk avoidance advices or in case of a child who could suffer from anaphylaxis. By working in an allergy team and doing their best efforts to maintain a cooperative relationship with the patient's family, the clinicians can manage CMA medically and psychologically, as well. Moreover, more time needed in the consultation room, after consultation and follows up, to involve the parents more in each detail in the management process.