- CMA is common in infants under 3 years of age and is often undetected
- CMA should be confirmed with specific IgE RAST testing or skin-prick testing, using fresh milk
- Extensively hydrolysed milk formulas are the mainstay of treatment in CMA
- There are no reliable diagnostic tests for non-IgE mediated CMPI
- Suspect CMPI when infants present with protracted colic, blood-stained stools, and persistent feeding problems
- The natural history of all cow’s milk hypersensitivities is resolution and tolerance of cow’s milk protein by the time the child is aged 3 to 5 years
- Primary lactose intolerance is uncommon in infants but they may develop secondary intolerance.
CMA=cow’s milk allergy; IgE=immunoglobulin E; RAST=radioallergosorbent; CMPI=cow’s milk protein intolerance
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According to the World Allergy Organization, cow's milk allergy (CMA) affected 1.9% to 4.9% of children globally in 2007.1 National research from 2008 showed that 2.3% of UK children aged 1–3 years were allergic to cow's milk;2 however, this is probably an underestimate.
The true prevalence of this disease is unknown as many children with food and cow’s milk hypersensitivity still 'slip through the net' because they are never tested or documented and CMA and cow's milk protein intolerance (CMPI) usually resolve naturally by the time the child is 3 years of age.1,2
There are now numerous published guidelines and algorithms on diagnosing and managing food allergy and CMA in infants.2,3 The net result can be an overwhelming array of algorithms that replaces simple old definitions. Current international allergy nomenclatures tend to adopt a 'one-hat-fits-all' approach by dividing food-related reactions into these categories:4,5
- immediate allergic immunoglobulin E (IgE)-mediated
- delayed or non-IgE-mediated
- non-allergic hypersensitivities.
Algorithms certainly have their place but my practical approach is to break down cow’s milk hypersensitivity reactions into three clinically distinct entities:
- lactose intolerance.
Cow’s milk allergy
True CMA presents with immediate onset (within minutes) of:1
- respiratory symptoms
True CMA is associated with infantile eczema, asthma, and a family predisposition to atopy (the allergy genome).
There are strong clinical associations between severe infantile eczema and CMA, as well as concomitant hen’s egg and peanut allergy.1 Whether these food allergies are implicated in exacerbating eczema, or are merely co-morbid manifestations, is still a source of furious academic debate.6 The 'allergic march' (the chronological progression from infantile eczema and food allergy, to asthma and rhinitis) is strongly associated with a family history of atopy.
Testing and prognosis
Allergy tests for specific IgE antibodies to milk proteins, such as radioallergosorbent (RAST) testing and skin-prick testing using fresh cow’s milk, are reliable confirmatory indicators of CMA.1 Specific IgE antibody testing for casein is helpful in predicting which infants will have severe and persistent CMA (see Figure 1).1
Children allergic to the whey (beta-lactoglobulin and alpha-lactalbumin) fraction of cow’s milk tend to tolerate UHT 'long-life' or 'heat-treated' cow's milk and goat's milk, and are more likely to outgrow CMA at an early age. In contrast, CMA is likely to persist in those infants allergic to curd (casein) protein.
Usually, extensively hydrolysed formulas (eHF) are sufficient to provide symptom control, but in children severely affected by CMA, expensive zero-milk-protein-content amino acid-based formulas (AAFs) are needed.2
Recent studies have suggested that children on eHFs tend to develop tolerance to cow’s milk earlier and outgrow their cow's milk allergy more quickly than those infants on AAFs. The hypothesis is that eHFs still contain traces of cow’s milk protein and these traces lead to clinical desensitisation and induce tolerance to the milk proteins.2
Soya and rice milk
Ten per cent of infants severely affected by CMA, and 60% of those with CMPI, will also react to soya milk. Rice milk, which is much cheaper than hypoallergenic formulas, may be an acceptable alternative but must be accompanied by calcium supplementation.2
Cow’s milk protein intolerance
Cow's milk protein intolerance has been increasingly recognised in infants with feeding problems and presents as a delayed reaction, 2–72 hours after the child has ingested cow’s milk protein.
Signs of CMPI in infants may be less acute and specific than those of CMA, ranging from gastro-oesophageal reflux disease (GORD) and colic, to debilitating eosinophilic oesophagitis with diarrhoea and blood-stained stools.7
The differential diagnosis includes candidal oesophagitis, a great mimic of eosinophilic oesophagitis, especially when symptoms persist or are exacerbated by use of fluticasone (see under heading ‘Treatment’, below).
The diagnostic process for CMPI is severely hampered by the following difficulties:
- a lack of reliable diagnostic blood and other tests
- eosinophilia may occasionally be seen on stool microscopy and in the peripheral blood examination
- eosinophilic infiltrates are also sometimes detected in oesophageal and gastric washings or biopsy specimens following the ingestion of cow’s milk.
Treatment of CMPI involves a trial of complete avoidance of cow’s milk protein (including elimination of all dairy products from the maternal diet if the mother is breastfeeding) and use of AAFs for the infant. Symptom control can be achieved with:7,8
- proton pump inhibitors (e.g. omeprazole) if reflux is the predominant feature
- swallowed puffs of fluticasone to reduce oesophageal inflammation if upper GI obstruction and dysphagia are features. NB at the current time, fluticasone does not have marketing authorisation for use in young children for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices for further information.9
Some useful information for patients can be found at: www.allergy.org.au/patients/food-other-adverse-reactions/eosinophilic-oesophagitis8
Although unrelated to allergy, lactose malabsorption is included in the differential diagnosis for CMA. Primary lactose intolerance is more common in adults of Southern European, North African, and Asian descent. Infants of all racial groups, however, may develop secondary lactose intolerance of a temporary nature following gastroenteritis due to denudation of upper GI villi and a lack of lactase (beta-galactosidase).
Lactose intolerance symptoms occur within 30 minutes to 2 hours after ingesting dairy products and are restricted to the GI tract with bloating, flatulence, pain, and diarrhoea. The condition never presents with respiratory symptoms, eczema, or rashes.1
In my own practice, diagnostic testing for unabsorbed disaccharide sugars following a lactose-containing meal includes:
- checking a watery stool for reducing sugars
- the hydrogen-breath test (not practical in small children)
- blood lactose tolerance testing (akin to a glucose tolerance test).
A commercially available lactase enzyme formulation can be added to cow’s milk, or expressed breast milk, to compensate for a possible lactase deficiency.10 Lactose-free formulas are also available.
In my experience, true CMA is often missed and infants are never allergy tested or changed to hypoallergenic milk formulas. Cow's milk intolerance, presenting with delayed eosinophil-driven gastrointestinal disease, should be considered in infants with persistent feeding problems and failure to thrive. Lactose intolerance is less common than many parents suspect, is of a temporary nature, and usually follows a bout of gastro-enteritis (secondary lactose intolerance).
- Fiocchi A, Brozek J, Schünemann H et al. World Allergy Organization (WAO) diagnosis and rationale for action against cow’s milk allergy (DRACMA) guidelines. World Allergy Organ J 2010; 3 (4): 57–161.
- Venter C, Brown T, Shah N et al. Diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy—a UK primary care practical guide. Clin Transl Allergy 2013; 3 (1): 23. Available at: www.ctajournal.com/content/3/1/23.
- NICE. Food allergy in children and young people: diagnosis and assessment of food allergy in children and young people in primary care and community settings. NICE, 2011. Available at: www.nice.org.uk/guidance/CG116
- Koletzko S, Niggemann B, Arato A et al. Diagnostic approach and management of cow’s-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatric Gastroenterol Nutr 2012: 55 (2): 221–229.
- Vandenplas Y, Koletzko S, Isolauri E et al. Guidelines for the diagnosis and management of cow’s milk protein allergy in infants. Arch Dis Child 2007; 92 (10): 902–908.
- Allen K, Davidson G, Day A et al. Management of cow’s milk protein allergy in infants and young children: an expert panel perspective. J Paediatr Child Health 2009; 45 (9): 481–486.
- Sopo M, Giorgio V, Dello Iacono I et al. A multicentre retrospective study of 66 Italian children with food protein-induced enterocolitis syndrome: different management for different phenotypes. Clin Exp Allergy 2012; 42 (8): 1257–1265.
- Australasian Society of Clinical Immunology and Allergy website. Eosinophilic oesophagitis. www.allergy.org.au/patients/food-other-adverse-reactions/eosinophilic-oesophagitis (accessed 11 February 2014).
- General Medical Council. Good practice in prescribing and managing medicines and devices. London: GMC, 2013. Available at: www.gmc-uk.org/guidance/ethical_guidance/14316.asp (accessed 27 November 2013).
- Monthly Index of Medical Specialities. MIMS online. Available at: mims.co.uk (accessed 6 February 2014). G