Cow’s Milk Protein Allergy

A hypersensitivity reaction to cow’s milk protein ( CMP ) involving the immune  system can be called CMPA ( European Academy for Allergy and Clinical Immunology and World Allergy Organization )

IgE Medicated –Reactions are acute Frequently have rapid onset From minutes- up to 2 hrs after allergen ingestion

Non IgE Mediated –Generally delayed Non-acute Type 4 type delayed hypersensitivity Up to 48 hrs and up to  1 week after consuming cow’s milk protein

Mixed- Mixed IgE and Non-IgE Mixed reponses

How common –Most common childhood food allergy in children is CMPA second to egg allergy Highest prevalence in 1st year- seen less commonly in older children and adults  ( often outgrown ) Prevalence of 2-3 % in the infant population which falls to < 1% in children 6 yrs and older Prevalence of food allergy and food intolerance is increasing Parents perceive CMA in their children far more than can be proven by oral food challenge Exclusively breast fed infants may also develop clinically significant CMA via dairy protein transfer into human breast milk ( uncommon )

Pathophysiology- Important to note that CMPA is an immune mediated disorder whereas food intolerance(s) is/are non-immunological and can be caused by enzyme deficiencies , pharmacological agent and naturally occurring substances ( NICE 2011 ) Immunological processes that lead to development of CMPA are not still clarified – various mechanisms contribute and the two main described refer to IgE and Non-IgE reactions Cow’s milk contains more than 20 protein fractions The significant allergens are  ◘ casein protein-several isoforms ( alpha-s1-alpha-s-2, beta-, and kappa-casein) ◘ whey proteins ( alpha- lactalbumin and beta-lactoglobulin ) Recent advances have shown circulating casein specific T cells were more prevalent in children suffering from CMA , compared to non-CMA subjects – indicating that T-cell response can be a promising tool to improve CMA diagnosis 

Presentation of Suspected Cow’s Milk Allergy ( CMA ) in the 1st year of life  Having taken an Allergy-focused Clinical History and Physically Examined

UK Adaptation of IMAP guidelines for Primary Care and First Contact Clinicians

Diagnosis –CMA is a clinical diagnosis based on history and examination Currently no lab tests available that can accurately and specifically diagnose – primarily because of the lack of a reliable test for non-IgE reactions Skin prick and IgE show high sensitivity but low specificity – ie can be + ve in non-allergic subjects CoMiSS scoring – can be used to assess symptoms related to CMA- this is available from https://www.nestlehealthscience.com/health-management /food-allergy/documents/comiss%20scoring%20form.pdf

GERD ( GORD )/ Food allergy presentation may overlap one may predispose to another – for e.g it is thought that GORD/ GERD may not only be associated with CMA but can also be induced by it

  Mild to Moderate Non IgE-mediated CMA  Mostly 2-72 hrs after ingestion of Cow’s Milk Protein ( CMA )  Usually formula fed , at onset of formula feeding. Rarely in exclusively breast fed infants  Usually several of these symptoms will be present. Symptoms persisting despite first line measures are more likely to be allergy related e.g atopic dermatitis or reflux. Visit gpifn.org for advice about other infant feeding issues   Gastrointestinal Persistent irritability- Colic Vomiting – ‘ Reflux ‘- GORD Food refusal or aversion Diarrhoea – like stools – abnormally loose +/ more frequent Constipation – especially soft stools , with excess straining Abdominal discomfort , painful flatus Blood and / or mucus in stools in otherwise well infant  Skin  Pruritus ( itching ) Erythema ( flushing ) Non-specific rashes Moderate persistent atopic dermatitis  

The symptoms above are very common in otherwise well infants or those with other diagnoses , so clinical judgement is required. Trial exclusion diets must only be considered if history & examination strongly suggest CMA , especially in exclusively breast fed infants , where measures to support continued breast feeding must be taken.

Cow’s Milk Free diet Exclusively breast feeding mother Trial exclusion of all Cow’s Milk Protein from her own diet and to take  daily calcium and vit D  Formula fed or ‘ Mixed Feeding ‘ If mother unable to revert to fully breastfeeding , trial of Extensively Hydrolysed Formula -eHF-  see management algorithm

non-IgE Mediated –Severe Non-IgE-mediated CMA  Mostly 2-72 hrs , after ingestion of Cow’s Milk Protein ( CMP ) Usually formula fed , at onset of mixed feeding  One but usually more of these severe , persisting & treatment  resistant symptoms : Gastrointestinal Diarrhoea , vomiting , abdominal pain , food refusal or food aversion , significant blood and/ or mucus in stools , irregular or uncomfortable stools +/- Faltering growth Skin Severe atopic dermatitis , + / – Faltering growth  

Cow’s Milk Free Diet  Exlcusively breast feeding mother *  If symptomatic , trial exclusion of all Cow’s Milk Protein from her own diet and to take daily Calcium and Vit D  Formula fed or Mixed feeding *  If mother unable to revert to fully breast feeding , trial of replacement Cow’s Milk Formula with Amino Acid Formula ( AAF ) . If infant asymptomatic , on breast feeding alone , do not exclude cow’s milk from maternal diet  Ensure  Urgent referral to local paediatric allergy srvice  Urgent dietetic referral

Mild to Moderate IgE-mediated CMA   Mostly within minutes ( may be up to 2 hrs ) after ingestion of Cow’s Milk Protein ( CMP ) Mostly occurs in formula fed or at onset of mixed feeding  One or more of these symptoms :  Skin – one or more usually present  Acute pruritus , erythema , urticaria , angiodema Acute ‘ flaring ‘ of persisting atopic dermatitis  Gastrointestinal Vomiting , diarrhoea , abdominal pain / colic  Respiratory- rarely in isolation of other symptoms Acute rhinitis and / or conjunctivitis

Cow’s Milk free Diet  Support continued breast feeding where possible If infant symptomatic on brast feeding alone , trial exclusion of all Cow’s Milk Protein from maternal diet with daily maternal Calcium & Vit D as per local guidance.  If infant asymptomatic on breast feeding alone , do not exclude cow’s milk from maternal diet.  Formula fed or ” Mixed feeding “ If mother unable to revert to fully breast feeding 1st choice-Trial of Extensively Hydrolysed Formula -eHF Infant soy formula may be used for over 6 months of age if not sensitised on IgE-testing  If diagnosis confirmed ( by IgE testing or supervised Challenge in minority of cases ) : Follow-up with serial IgE testing and later planned Challenge to test for acquired tolerance  Dietetic referral required  UK NICE Guidance – If competencies to arrange and interpret testing are not in place – early referral to local paediatric allergy service advised

Severe IgE CMA  ANAPHYLAXIS  Immediate recation with severe respiratory and / or CVS signs and symptoms  ( Rarely a severe gastrointestinal presentation )  Emergency Treatment and Admission

Less than 2 % of UK infants have CMA There is a risk of overdiagnosis of CMA if mild, transient or isolated symptoms are over-interpreted or if milk exclusion diets are not followed up by diagnostic milk reintroduction. Such situations should be avoided. There should be increased suspicion of CMA in infants with multiple , persistent , severe or treatment-resistant symptoms IMAP primarily guides on early recognition of CMA emphasizing , the need for confirmation of the diagnosis , either by allergy testing ( IgE ) or exclusion them reintroduction of dietary cows milk ( Non-IgE ) Breast milk is the ideal nutrition for infants with CMA and any decision to initiate a diagnostic elimination diet trial must include measures to ensure that breast feeding is actively supported. Refer to accompanying leaflet for details of supporting ongoing breast feeding in milk allergic infant. Firststepnutrition.org is a useful information resource on formula composition

References Diagnosis of Cow’s Milk Protein Allergy Among Infants and Children in Assuit University Children’s Hospital NIH Clinical Trials Cow’s Milk-Protein Allergy un Ifancy : A risk Factor for Fuctional Gastrointestinal Disorders in Children ? Licia Pensabene et al Nutrients 2018 , 10, 1716 ; doi : 10.3390 / nu10111716 Cow Milk Allergy Christopher W Edwards ; Mohammad A Younus StatPearls November 2019 iMAP guideline from www.gpifn.org Cow’s milk protein allergy in children CKS NHS June 2015

Links and Resources

COMIS score – Nestle did not respond to a request to reproduce this very useful questionnaire, but I will strongly advise that you consider using it in suspected CMP cases https://www.nestlehealthscience.com/health-management/food-allergy/documents/comiss%20scoring%20form.pdf

GPIFN is a very useful resource and the IMAP guideline has been reproduced from this website with permission https://gpifn.org.uk/imap/

Allergy UK has a very useful section for parents https://www.allergyuk.org/information-and-advice/conditions-and-symptoms/469-cows-milk-allergy

Another very useful resource for patient education Is it Cows Milk Allergy https://www.isitcowsmilkallergy.co.uk/

Reflux in infants certainly seems to be increasing in prevalence – Living with reflux – is a useful patient resource and has guidelines which can be downloaded available via http://www.livingwithreflux.org/

I hope these are enough to see you through this complex topic – if you find any other useful link- just drop a line!

iMAP guideline has been reproduced unedited under open source license from the GPIFN ( GP Infant feeding network ) website www.gpifn.org  GPIFN is a valuable clinical resource for GPs and is highly recommended.  For hospital doctors – visit the site by GPIFN counterpart network called HIFN

Medical Topics