Avoid Overdiagnosis of Cow’s Milk Protein Allergy in Primary Care

Dr Toni Hazell Covers the Diagnosis of Cow’s Milk Protein Allergy (CMPA) in Children, and Asks: Is the Prevalence of CMPA Really Rising, or Is There Another Explanation?

Cow’s milk protein allergy (CMPA), also known as cow’s milk allergy (CMA), is defined by NICE as ‘a reproducible immune‑mediated allergic response to one or more proteins in cow’s milk.’¹ CMPA is broadly classified as immunoglobulin E (IgE) mediated or non-IgE mediated, based on the mechanism underlying the allergy.¹

This article will briefly discuss CMPA in general, then focus on the question of whether CMPA is overdiagnosed in children, explaining how this issue is more nuanced than may be initially obvious. More background information on CMPA is available in a previous article, Top Tips: Cow’s Milk Protein Allergy.

The Pathophysiology of CMPA

To understand CMPA, it is essential to revisit some of that medical school immunology—which many doctors probably forget the day after the exam! The symptoms that people commonly associate with allergy (such as rash or anaphylaxis) are usually caused by an IgE-mediated allergy.² IgE is bound to the outside of mast cells via Fc receptors. When an antigen such as a cow’s milk protein binds to two IgE molecules, it causes crosslinkage between the Fc receptors and the mast cell degranulates, releasing mediators such as histamine and causing symptoms that usually start within minutes of exposure to the antigen.³ IgE-mediated CMPA is relatively straightforward to diagnose—there is a clear temporal relationship between exposure to an allergen and any subsequent reaction, and blood tests can be performed for the specific IgE.⁴ Skin-prick tests will also diagnose IgE‑mediated allergies.⁴

In contrast, the mechanism of non‑IgE‑mediated allergy is less clear, but likely involves antigen‑sensitised T cells that cause a slower inflammatory response.^1,5 This kind of allergy is harder to diagnose because the reaction can occur hours or days after exposure to the allergen,¹ and there are no simple diagnostic tools.⁶ Symptoms may be related to the skin (usually chronic eczema rather than an immediate rash or an acute flare up of pre-existing eczema, both of which are seen with IgE‑mediated allergy), but can also be gastrointestinal (reflux, vomiting, blood or mucus in stools, diarrhoea) or systemic (faltering growth, tiredness, pallor).² The concerns that have been raised about overdiagnosis focus on non‑IgE‑mediated CMPA.⁷

The iMAP Guideline

The International Milk Allergy in Primary Care (iMAP) guideline, and its precursor—the Milk Allergy in Primary Care (MAP) guideline—separate their recommendations on CMPA into two flowcharts (see Figures 1 and 2).⁷ For any children with suspected IgE-mediated CMPA, which usually presents with typical allergy symptoms that come on rapidly (certainly no more than 2 hours after exposure to cow’s milk protein), the guidelines follow the standard medical strategy of history, examination, and investigation—usually by IgE testing.⁷ The use of a serum-specific IgE blood test greatly reduces the likelihood of false-positive diagnoses, especially in situations where skin-prick testing and history can lead to ambiguous results.⁴

There is no such test for those with suspected non-IgE-mediated CMPA, so the diagnosis must be made based on the patient’s history: the clinician should determine whether symptoms disappear when a child is given a cow’s-milk-free diet, and whether they reappear when the child is rechallenged with cow’s milk.⁷ If the patient is a breastfed baby, this challenge can be done via the total exclusion of cow’s milk products from the mother’s diet, making sure that she receives calcium and vitamin D supplementation for her own health.⁷ For formula-fed babies whose mothers are unable to revert to breastfeeding, the challenge can be conducted using a hypoallergenic formula.⁷

Figure 1: Presentation of Suspected CMA in the First Year of Life⁷

Figure 2: Management of Mild-to-moderate Non-IgE CMA⁷

Conducting a Trial of Hypoallergenic Formula

Each integrated care board is likely to have its own rules about prescribing hypoallergenic formulas in primary care in advance of a paediatric assessment. It is common for GPs to prescribe a hypoallergenic formula as part of the diagnostic process or while a child is awaiting paediatric assessment, but all long‑term prescribing requires the child to be under the care of paediatric professionals. The board may also have a view on which brands should be prescribed. Basic principles for prescribing hypoallergenic formulas are covered in the NICE Clinical Knowledge Summary on this topic.⁴

Extensively hydrolysed formulas (eHFs), which are based on whey or casein, are usually used first line and are generally well tolerated.⁴ In these formulas, the cow’s milk protein has been broken down into much smaller peptides that most children with CMPA can tolerate.⁸ For those children who continue to react on an eHF, an amino acid formula (AAF) can be used;⁴ in AAFs, the peptides that trigger CMPA have been broken down into amino acids.⁸ AAFs should also be used first line for those with severe symptoms or a history of anaphylaxis.⁴ The disadvantages of AAFs are that they are often less well tolerated by children (because of their bitter taste),⁸ and are generally more expensive than eHFs.

Parents may ask if they can buy a different milk alternative for their child, but they should generally be dissuaded from this if the child is young. Soya‑based formulas should not be given to a baby aged under 6 months because they contain isoflavones, whose oestrogenic action may affect the reproductive system, and because the absorption of minerals and trace elements is likely to be lower.^4,7,9 There is also significant crossover between CMPA and soya allergy: up to 60% of people with non-IgE-mediated CMPA, and up to 14% of those with IgE‑mediated CMPA, are also allergic to soya.⁴ Other alternatives—including almond, oat, coconut, or rice drinks, as well as other mammalian milks such as goat’s, sheep’s, or buffalo’s milk—have insufficient nutritional value to be suitable as an infant’s sole food source.⁴ In particular, rice‑based milk alternatives should not be given to children under the age of 4‑and‑a‑half years, as they contain arsenic.⁴ There is also a risk of crossover allergy between cow’s milk and milk from other mammals.⁴

Is CMPA Overdiagnosed?

In 2018, an article was published that criticised MAP, iMAP, and other CMPA guidelines for contributing to the overdiagnosis of CMPA.¹⁰ The article based its criticisms on the fact that prescription of hypoallergenic formulas increased by nearly 500% between 2006 and 2016, with no clear data to suggest a true increase in prevalence.¹⁰ In fact, prescription of hypoallergenic formulas started to rise in 2003, 10 years before the publication of the first MAP guideline in 2013, and 4 years before there was any official guidance on CMPA in the UK.⁷ Criticisms of CMPA guidance were discussed in the 2019 iMAP update;⁷ the most prominent are discussed in more detail in the following sections.

Concerns about overdiagnosis are often raised when the treatment of a condition increases significantly in a short period of time. Possible reasons for an increase in prescription of hypoallergenic formulas not related to overdiagnosis of CMPA include:^7,9,11

• a true increase in prevalence
• better recognition of previously underdiagnosed non-IgE-mediated CMPA
• reduced prescribing of soya-based formulas.

Soya-based formulas were widely used in the UK until guidance was issued in 2003 advising against their use.^7,9,11 Those infants who would have been given soya-based formulas were likely to have been switched to hypoallergenic formulas instead; indeed, prescribing data show that prescriptions for soya‑based formulas fell steeply between 2003 and 2008, in line with a rise in prescribing of hypoallergenic formulas.⁷

There is overlap between the symptoms of CMPA and fluctuations in gastrointestinal functioning that are normal in babies.⁷ It is a very lucky parent whose baby has never had experienced occasional vomiting, diarrhoea, or colic! Given that there is no clear diagnostic test for CMPA, this overlap of nonspecific symptoms is a risk factor for overdiagnosis, so it is important that clinicians do not leap straight to a diagnosis of CMPA for symptoms that are mild,⁷ or that respond to simple changes recommended for reflux in infants, such as giving smaller volumes of feed more often or a short trial of alginates.¹² 

Understanding the prevalence of CMPA (1.8–7.5% in the first year of life according to NICE, although there are variations in the literature¹³) may help to provide some perspective on how likely it is that gastrointestinal symptoms are caused by CMPA. A trial of an exclusion diet is most sensible for those patients in whom the symptoms are persistent, severe, and resistant to treatment.⁷

To guard against overdiagnosis, the iMAP guideline is very clear that, if a child’s symptoms appear to improve after a trial of dairy, the dairy must then be reintroduced; a diagnosis of CMPA can only be made if symptoms return on the reintroduction of dairy, and resolve when it is again removed from the diet.⁷ It is extremely unlikely that symptoms not caused by CMPA will wax and wane in line with the removal, reintroduction, and further removal of dairy from the diet. The updated iMAP guideline also stresses that clinical judgement must be used when interpreting these symptoms because of their overlap with normal variation in gastrointestinal functioning.⁷

Most of the authors of the iMAP guideline had received funding from infant formula manufacturers—for example, research grants or consultancy fees—all of which were stated using the usual system of declarations of interest.^7,10 The issue raised as a result of this is whether this funding, even when declared, introduces unconscious bias in favour of the formula industry—a concern reinforced by the fact that formula manufacturers have used the iMAP flowcharts in their promotional materials.¹⁰ These flowcharts are open access, which increases the reach of the guidance to as many healthcare professionals as possible in primary care.⁷ However, open access status means that there is less control over how the flowcharts are used.

To guard against any possibility of unconscious bias, the 2019 iMAP update received unfunded input from a variety of parent and professional groups without industry ties.⁷ Every version of the MAP and iMAP guidance has also been peer reviewed, which should mitigate the potential for bias.^7,10 

Breastfeeding rates in the UK are poor: according to data from 2010, although 81% of women breastfed their babies after birth, only 24% were exclusively breastfeeding at 6 weeks (and only 55% were doing any breastfeeding at all at this point).¹⁴ By 6 months, only 1% were exclusively breastfeeding, with 34% giving some breast milk to their baby.¹⁴ The fact that the most recent data come from a 2010 survey,¹⁴ which has not been repeated, perhaps shows how little importance is given to breastfeeding in the UK.

There are many reasons underlying poor breastfeeding rates in the UK, including a lack of support from family, society, and healthcare professionals, and a lack of fully funded maternity leave for many women.⁷ Most GPs will have experienced the frustration of seeing a patient who wants to breastfeed, but being unable to find local NHS lactation specialists for rapidly accessible advice.⁷ The criticisms of iMAP in this area are twofold: firstly, suggesting that breastfeeding women remove dairy from their diet is too restrictive, and that this will discourage breastfeeding; and secondly, the guidance does not emphasise breastfeeding enough.⁷ 

To mitigate against these criticisms, the 2019 iMAP guideline makes it clear that exclusive breastfeeding is recommended up to 6 months; it advises that mothers should be actively supported to breastfeed, and includes a patient information leaflet that signposts to resources for women who are breastfeeding and want to try cutting out dairy.⁷ It is much less likely for a baby to have symptomatic CMPA triggered by cow’s milk protein in breast milk than by a cow’s-milk‑based formula,⁴ but a prospective study has shown that this is possible,¹⁵ so it is important that breastfeeding women are supported to find out whether or not their babies have CMPA, and act accordingly.

Summary

As the aphorism goes: medicine is not only a science; it is also an art. It is taught that taking a careful history will lead to the correct diagnosis 80% of the time,¹⁶ but in recent years we have become accustomed to backing up our instincts with a formal test or two. When that is not possible, as is the case for non-IgE-mediated CMPA, we must be confident enough to rely on our experience and common sense to see a diagnosis when it is there to be made, and not to see it when it is not there. If you listen to the parent, examine the child, consider all differential diagnoses, and rechallenge with dairy before confirming a diagnosis, you probably won’t go wrong.