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The essay discusses the professional advises for the parents of a child who has cows' milk allergy. It also compares between the available management tools, whatever the underlying mechanism of the allergy is it igE or non igE mediated reaction. In addition, it reveals how are these differences could influence the psychological aspects of the parents and child's life?
Definition of Food Allergy and CMA:
The European Academy of Allergology and Clinical Immunology (EAACI) gives the names of food hypersensitivity (FA) to any adverse reactions related to food and classifies it to toxic and non toxic reactions. Furthermore, the non toxic reactions would be allergic if the immunity system implicated or non allergic (e.g food intolerance). Moreover, allergic reactions can be classified to igE mediated if ige highlighted, or non igE if there is no role for igE but anaphylaxis is a generalized allergic reactions to food.(1)
Cow's milk allergy is a complex entity and sometimes causes misunderstood disorders. In general public, sometimes it is confused with lactose milk intolerance. In CMA, CMP sensitizes the immune system and giving allergy symptoms, which are resulted from damage of tissues caused by immune system's inflammatory response. This could happen, even with a little amount of milk. (2) Whereas, lactose intolerance occurs due to the deficiency of the lactase enzyme in the body, due to lactose is not metabolized in the body. (3) Cow milk hypersensitivity may occur due to ingestion of preservatives or additives in milk or colored fruits milk products as well. (4)
Prevalence of cow's milk allergy:
Around fifth of population assume that they are having some sort of food allergy. However, the true percentage is around 1 % (4). This is applicable for CMA as well, because the self diagnosed prevalence in the community is ten -fold higher than the clinically diagnosed prevalence which supported by randomized controlled, food challenges studies.(2) Worldwide, the prevalence of cow 's milk allergy is variable. For example, in UK milk allergy affects 2-6 % of infants and children and declines by age to reach to 0.1-0.5 % in adults.(5) Non-igE mediated represents around 50% of paediatrics CMA.(6) CMA prevalence varies between studies due to difficulties in accurate diagnosis, variation in age of patients and different clinical criteria used.(7)
Natural history of CMA:
Cow's milk is the most famous member of the food allergen's list, which includes egg,Ñ•oy ,whÐµÐ°t, pÐµÐ°nutÑ•, trÐµÐµ nutÑ•, fiÑ•h Ð°nd Ñ•hÐµll fiÑ•h. In terms of prÐµvÐ°lÐµncÐµ, It is the most frequent diary allergen during infancy because of the immaturity and sensitivity of immune the immune system and whey proteins are implicated in the allergic responses plus more than 30 cow's milk protein as well. EpitopÐµ mapping of Ð° number of milk protein show shows Ð°llÐµrgÐµnic ÐµpitopÐµÑ• within ÐµÐ°ch protein.The immuno- dominant epitopes in Î²- and Îº-casein is important for understanding the path of physiology and natural history of CMA. (9)
The reasons for why few people develop CMÐ are still not well understood. There might be Ð° hereditary predisposition, but the phenotypic ÐµxprÐµÑ•Ñ•ion of allergy depends on Ð° complex interaction bÐµtwÐµÐµn gÐµnÐµtic Ð°nd ÐµnvironmÐµntÐ°l fÐ°ctorÑ•. However, the fundamental mechanisms of Ñ•ÐµnÑ•itizÐ°tion still remain unclÐµÐ°r(10) Inspite of, some similarities between cow's protein and human milk protein; however, some of the differences in types and homologies are there. In most people the immune system can recognize that the milk protein is a foreign protein and tolerate it, while in the allergic individuals, it sensitized and reacts by a damaging inflammatory response.(11) However ,there is a sort of cross reactions, between human milk and sensitization to cow milk.
So, IgE reactivity to human milk in milk-allergic patients can be due to either cross- sensitization or genuine sensitization to human milk (12)
Clinical presentation and immune-pathology of CMA
An allergic disease symptom is hyper responsiveness in the target organs .e.g. skin, nose, lung and gastrointestinal tract (GIT),it including igE and non-igE reactions. However, In IgE mediated allergy more than one system is affected in contrast to symptoms of non IgE allergy, which confined to one organ (4). Immunoglobulin E (IgE) was discovered in 1966 by two separate research teams. Both teams demonstrate a clear connection between allergic symptoms and IgE antibodies in atopic patients. (13)
Any allergic response, whether the mechanism IgE or non IgE needs antigenic stimulus, genetic background and microenvironment. In food allergy, food is the antigen and gastrointestinal tract (GIT) is the microenvironment. GIT epithelium surface with its tight junctions between cells' acts as a physical barrier plus the Lamina Propria; the underlying loose connective tissue which is rich in immunology cells(e.g. activated T cells B cells, dendertic, macrophages, and plasma cells )plays as an immunological barrier as well . In normal situation cow's milk antigens are digested and cannot enter the underlying tissues. However, when the antigens pay- passes these barriers they are presented by conventional presenting cells to be native T helper cells (th-0). After activation, the (th-0) cells release cytokines, which induce cell-mediated hypersensitivity and inflammation or igE -mediated hypersensitivity and inflammations depending on their types. Even though, If these cells secrete IL-10 and TGF_B they may support the development of oral tolerance (14)
In IgE mediated reactions, IgE normally present in a very small amount in plasma in non atopic persons. The switching of B cells by cytokines released by T cells leads to the release of igE in the plasma with short half life .e.g less than1-2 days. However, it can be fixed to mast cells in tissues for weeks or months waiting to come into contact with allergen. When the patient has cow's milk for the second time and penetrate the mucosal barrier and the epitopes of cow's milk protein attach to IgE antibodies, which bound to FC e receptors on the surface of mast cells or basophils causing degranulations of the mast cells and releasing of vasoactive and chemotactic mediators (e.g. histamine, leukotrienes tryptase chemotactic factors ), and other mediators (leukotrienes, prostaglandin, thromboxane, platelet-activating factor, adenosine, bradykinin, and cytokines ). This causes vasodilation, smooth muscle contraction, mucus secretion, which resulted in symptoms of IGE mediated allergy.e.g. in skin leads to urticaria,eczema,,angiodema.In GIT causing the oral allergy syndrome; nausea; vomiting; diarrhea. In the respiratory system leads to respiratory manifestations such as rhino-conjunctivitis and asthma. All these symptoms could be happened with minutes . In very rare case life threatening anaphylactic reactions to cow's milk have also been observed (14). IGE antibodies gave their biological function through the high affinity to FCER I receptor and with low affinity towards receptor CD23 on macrophages, monocytes, lymphocytes, eosinophilias and platelets on mast cells and basophiles (15)
In addition, mast cells may release a variety of cytokines, which form the late IGE mediated reaction. During the first 4-6 hours, primary neutrophils and eosinophils invade the site of the reaction and become activated. Then, releases a variety of mediators e.g. platelet activating factor, peroxidase, eosinophil major basic protein and eosinophil catatonic protein.. After 24-48 hours, lymphocytes and monocytes infiltrate the response area establishing the chronic inflammatory response. By repeating ingestion of CMP mononuclear cells secrete a cytokine named histamine releasing factor (HRF) which interact with IGE molecules bound to basophiles and mast cells increasing its degranulation thus increasing the bronchial reactivity in the asthmatic patients and increasing the skin irritation in atopic dermatitis patients as well.The direction of B cells switching is under control of cytokines secreted by T cells. The immature T cells (TH0) differentiate into (Th1) and (Th2) type cell, in the presence of IL-12 and interferon Gamma Th0 will develop to Th1 but in the presence of IL-4 Th2 will be induced, Th2 is responsible about the B cells switching to introduce igE(16)
The mechanism involves the pinocytosis of milk proteins by antigen presenting cells (APC). The principal APC are macrophages, B cellsdendritic cells (Langerhans cells), and. Dendritic cells which resopisible about antigen processing and presentation in CMP. These cells are mainly found in skin where they ingest antigens by pinocytosis and transport antigens to the lymph nodes and spleen. They are capable of presenting the antigens to native T cells. Macrophages and B cells are not as effective as the dendritic cells in antigen presentation. Macrophages ingest antigen by phagocytosis or pinocytosis while B cells bind antigen via their surface Ig and ingest antigens by pinocytosis. Both these cells are strong activators of memory T cells. Then, the Th2 effectors T cells are activated after interaction with activated dendritic cells. These cells produce IL 4 which in turn stimulates the B cell to more class switching production of allergenic milk protein-specific IgE.(14)
Here in the table 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
Eosinophil chemotactic factor of anaphylaxis(ECF-A )
Attracts eosinophils and neutrophils to the site of the reaction
leukotriene C4, D4
Incraese the effects of histamine
cause odema plus pain
Platelet aggregation Factor (PAF)
Platelet aggregation and release of heparin release
PAF causes increased platelet aggregation and release of inflammatory mediators. (ECF-A) and neutrophil chemotactic factors attract Eosinophils and Neutrophils to the site of the reactions .These cells release various hydrolytic enzymes which resopisible about tissue necrosis.In addtion, Eosinophils regulates the release of, histamine, phospholipids-D and prostaglandin-E which aggravate the allergic reactions. (17)
Non-ige mediated CMA immune-pathological mechanisms are still unclear.
However, T lymphocytes and monocytes or macrophages have been identified as chief mediators. The path physiology of the allergic response involves that macrophages and monocytes engulf the milk protein antigen. The processing and presentation of the antigen is similar to that in "immediate hypersensitivity" and these APCs present antigen to T cells. In addition, macrophages secrete interleukin (IL)-1, IL-2, IL-6, and in turn recruit cytotoxic T cells and more macrophages. The recruited macrophages form giant cells. Unlike the immediate hypersensitivity; the non IgE mediated allergy is mediated by Th1 helper T cells which secrete cytokines such as interferon-gamma and in turn activate cytotoxic T cells. They also recruit and activate monocytes and macrophages forming a loop, which along with cytotoxic cells causing direct damage to the cells. Monocyte chemo tactic factor(MCT) , IL -2,Interferon-gamma are some of chemokines which involved in delayed hypersensitivity reaction.(18)
In spite of, gastrointestinal anaphylaxis and oral allergy syndrome are
IgE-mediated gastrointestinal disorders and plus non-IgE-mediated
gastrointestinal allergic disorders include food protein-induced enter colitis,
proctocolitis and enteropathy. However, some gastrointestinal diseases, such as
eosinophilic esophagitis and gastroenteritis including both mechanisms (19)
Differential diagnoses of CMA include:
Metabolic disorders, anatomical abnormalities, celiac disease, pancreatic insufficiency and cystic fibrosis. In addition, it must be differentiated from both inhalants and food allergens or other adverse reactions to food such as lactose intolerance. Other medical conditions should be in mind such as malignancy, and infectious gastrointestinal and urinary tract diseases as well.
IgE mediated allergy can be diagnosed by good history, it would be the first and important step. The accurate diagnosis of food allergy is critically dependant on good history taking through a structured prompts questions covering present ,atopic family history ,triggering factors ,occupational and past medical history(14)
Unfortunately, false results could be happened with demographic skin or eczema patients or non specific Skin sensitivity. In addition, Specific IGE Tests are helpful .e.g Radioimmunoassay (RAST), Enzyme-linked immunoassay (ELISA) , and chemo-immunoassay .All have a significance role in allergy testing If related to the history and clinical presentation of the disease . Food Challenges or (Double-blind, placebo-controlled food challenge, DBPCFC) .It is the gold standard for food allergy testing, it needs special precautions, resuscitation facilities must be available, we could use active ingredient or placebo in different days. The use of a define skin weal diameter in SPT could increase the specificity of the, DBPCFC and can reduce the number of patient whose formally need DBPCFC. (16)
Moreover, other tests could be used such as, basophiles histamine release test, serum tryptase.
In contrast, the non- IgE mediated CMA is difficult to diagnose, because of the absence of circulating milk protein-specific IgE and negative skin prick tests. However, history, clinical presentation, obsevations, exclusions and DBPCFC test.
GIT symptoms could be confirmed or excluded by complete blood count(CBC) to detect esonpophilia and anemia .In addition ,Stool analysis to exclude other causes of diarrohea ,Jejunal biopsy specimens and IL-2 production, lactose intolerance could be helpful .Skin reaction could be diagnosed by by patch test. In spite of ,skin patch test has a little clinical importance in CMA .It might be having a role in atopic dermatitis and the new patch testing have a significance role in CMA in comparison the to the conventional patch testing.(20)
Cow's milk hypersensitivity reactions
Non toxic reactions
Cows milk allergic disorders
Cows milk non -allergic disorders
Classical milk allergy
Ingestion milk or milk products or products containing milk
Ingestion milk or milk products or products containing milk
Ingestion milk or milk products or products containing milk
Ingestion milk or milk products or products containing milk
Milk proteins (possible contribution of other components as preservatives, and additives
Onset of symptoms
Within minutes to 4 hours
From 24-48 hors
Within minutes to hours
It depends on the individual amount ,age
-Itching of soft plate, tingling of the tongue, swelling of lips.hoarsness ,laryngeal oedema
(oral allergy syndrome
Nausea, abdominal pain, vomiting ,diarrhea, poor appetite,
Infantile colic, Esinophilic gastroenteritis ,oestiohagitis, Gastritis Colitis, gastrointestinal reflux ,constipation,
abdominal pain, vomiting ,diarrhoea
abdominal pain, vomiting ,diarrhea.fever
Urticaria and angiodema
Oral, gastrointestinal, ,respiratory plus hyoptention, dissress,collapse and cardiac arrethmias
Hypotension, distress Sometimes with Toxic shock,(bacterial or pharmacological )
Sneezing, rhino rhea ,nasal obstruction, itchy nose, wheezing ,cough,seous `otitis media,asthma
Gustatory rhinitis ,thickness of nasal secretions, food induced heamosiderosis(heines syndrome ,peripheral blood esinophilia
- IgE (Th2 mediated)
- cell-mediated (th1 mediated)
- immune complex
metabolic disorder - intestinal lactase deficiency
Bacterial toxins reactions
History,SPT RAST ELISA DBPCFC
lactose tolerance test; breath test; stool acidity test; intestinal biopsy
History and exclusions of other reactions
Goat milk and beef
Breast-feeding. Milk protein avoidance in infancy(0-4) months
Avoid intact milk proteins
Avoid intact milk proteins
Remove allergenic epitopes. Milk protein hydrolysis Remove allergenic epitopes.
No suitable products. Available
Lactose hydrolysis or chromatographic lactose removal
Professional advices to the parents:
Having a child with food allergy is a big problem for any family. But, if this food is milk, the situation would be worse. Because, it means that the child will face a lot of problems for all his life. Many questions will be aroused. Such as, what type of food could replace the cows' milk? How can we prevent the child from having milk or milk products? Should we give multivitamins for the child?
In addition, the psychological stress aspects of food allergy, because it could have bad effects on patient's emotions ether direct thought its effects of allergy mediators on central nervous system (CNS) or indirect impacts of fear from eating and stress from family members such as parents .(21)
The advices can be classified to:
This is the basic principle for management of both types CMA.The following measurements should be performed:
(A) Dietary elimination of the cow milk proteins. The child has to avoid any food containing cow's milk ,even in other forms ,such as dried ,skim, , solid, evaporated,condensed, cheese, yogurt, ice cream, butter. Morever,any soy products containing cow's milk. In addtion , any products containing powdered cow's milk , casein and cereals containing whey.
(B) Breastfeeding (BF) mothers of CMA diagnosed infants are encouraged to continue on breast feeding.BF is the gold standard for infant nutrition for the first 4 months of life (22).
(C)We have to switch the patient diet plan to the soy-based or hydrolysed hypoallergenic substances based. However, it is possible that persistence of symptoms despite strict CMP elimination may occur, because of unrecognised co-existing food allergies (e.g. egg, peanut, wheat) as well. The Ð•urÐ¾pÐµÐ°n Ð…Ð¾ciÐµty Ð¾f PÐµdiÐ°tric ÐllÐµrgy and Clinical Immunology (Ð•Ð…PÐCI) recommend a labelled milk formula thÐ°t fulfillÑ• thÐµ criteria Ð¾f 90 percent clinical tÐ¾lÐµrÐ°ncÐµ in infÐ°ntÑ• with proven IgÐ•-mÐµdiÐ°tÐµd milk allergy. However,extensively hydrolyzed formula, shows more decres in the prevalence of CMA than the partially hydrolyzed one(23) )Infants and childern who can not tolerate dfferent milk formula,they could be benifit from amino acid formula in both parmeters of decresing sumptps and groth as well (24)
D) The child should always hold an allergy notification card, which includes all information about him or her allergy status.
E)At nursery or school ,class teachers and school nursesshould know the exact type of allergy that the child has and what type of food can he/she eat In addition, they sould know what the initial step that they should do to manage such cases.
These prevention measures of FA significantly affects meal preparation at home and family social activity . (25)
2- Management of the current clinical presentations,
After confirming the diagnosis of CMA IgE mediated milk allergy, special medications are prescribed in addition to a dairy-free diet which includes antihistamines or epinephrine Adrenalin Auto Injector (Epipen or Anapen) at least 2 injectors with long expiry dates, especially when they dining out .In addition, they should learn how to use it in case of anaphylaxis and when they should to give the second dose.
.Antihistamines and local nasal corticosteroid are effective in allergic rhinitis. In case of wheezing and confirmed asthmatic children; we can follow GINA (guidelines in management of Asthma) by giving short or long acting Beta -agonist plus inhalant corticosteroids or Leukotrine inhibitors.
In contrast, if the patient is having symptoms of non-igE allergy .e.g nausea, vomiting and gastroenteritis, then the treatment will aim to stop the symptoms and prevent dehydration. For Atopic Dermatitis cases we should concentrate to treat the skin .By using Emollients, local corticosteroid and antihistamines. The patient should be informed about importance and the safety of local corticosteroid and oral antihistamines, for example Cetirizine is very safe for long term use in infants. (26). All these measure should be followed by regular appointments with clinicians, that would increase the family stress as well.
4- Long term prognosis and management.
For the long term prognosis in both types of CMA patients, parents should keep these points in their mind:
(A)-Quality of life of the child is very important. So, advising the parents to keep their child healthy most of the time, giving him the regular vaccinations, treatment any other co-morbidity diseases as Diabetes or Cardiovascular disorders .In addition, fast medical care of any upper respiratory infections.
(B)-Balanced diet is very important because the lack of milk in food means that the child will lose important source of calcium, vitamin D and fat soluble vitamins (phosphorus and magnesium) which are very important for growth. Regular assessment and monitoring of growth curve and education parameters is curial in children with food allergy.
(c)- The prognosis of the disease:
It recognized that the long-term prognosis of CMA is good, it is reached to 80-90% of the affected infants naturally acquiring tolerance to the milk proteins by the age of 5 years .However, its prognosis depending on the atopic status of the child with sensitization rate of (53%) in asthmatic patients at the age of10 years. (10) In addition, IgE level and age of the child can predict the clinical reactivity and tolerance to CMP (27)
In contrast, non-igE symptoms can be limited to mild procitis or pancolitis or extend to esophagitis , entropathy and colitis ,however most of infants can outgrow the allergy by age 2-3 and some maintain this allergy later in their childhood.(28)
4-Future prospect are:
A)Use of CMA immunotherapy, recent study shows some increase in tolerance to CMP for IgE mediated allergy patient. (29)
B) - The re-introduction of milk products into the diet of the affected child can only be done after assessing whether a tolerance towards these proteins has developed. (30)
Management of the psychological aspects:
A) Psychological impacts and its related somatoform disorders should be identified early to decrease unnecessary and costly investigations of allergy. (31)
B) By using well design questioner for history taking and follow up, including quality of life of the child plus parental burden impacts would be a useful tool in the treatment of allergy child patient. (32)
C) Health care providers should understand their role in managing the psychological impacts of food allergy of family members to achieve positive adaptation of the family with their child problem .In addition; they should know when to encourage families to seek psycho- educational guidance. (33)
D) Fears can be decreased by teaching patient and all the family members how to learn reading food labels, adapt recipes. In addition, educate other members outside the family, child care providers, plus teachers and nurses how to recognize the allergic symptoms and what to do when happened (34).
E) Introducing the patient and his/her family to any support group ,even online groups, In UK there some of organizations.(35) These websites serve the parents and the patients by giving educational material, conducting many meetings and provide telephone numbers in case of any emergency
Cows' milk allergy is a big challenge for the clinicians and researchers. And it is still under debate and discussion in all aspects, especially in the natural history of epidemiology diagnosis and treatment. More studies are needed to clarify the differences between IGE and non IGE mediated reactions. For the patients and their parents, more services are in need to fill the gap between them and clinician. Moreover, more time in consultation room, after consultation and follow up to involve the parents more in each detail in the management process.