Cow’s milk protein/allergy intolerance

Allergy, General paediatrics, Immunology, Nutrition

A common issue for babies and infants.  But not that common – in EAT study, symptoms (vomiting, colic, eczema) related to milk reported by 13% of parents, but only found in 0.7%!

“Intolerance” suggests that cow’s milk causes adverse effects (generally gastrointestinal) but without committing to an underlying mechanism. 

If there is reason to think the adverse effects are immune mediated (because there are signs/symptoms outside the GI tract, for example) then it is preferable to use “cow’s milk allergy” (which then divides into type 1, non type 1, or mixed). 

Can even affect exclusively breast fed infants if sufficient milk proteins transmitted in breast milk, but probably over diagnosed (as challenge after 2-4 weeks not done).

Not the same as lactose intolerance – lactose is a sugar, intolerance to it is due to malabsorption and effects of undigested sugar in colon eg bloating, diarrhoea.  NOT rash, vomiting.  Usually post-gastroenteritis, transient.  No useful test other than lactose restriction for 2 weeks then rechallenge.

Some parents feel milk leads to more respiratory problems – there is some evidence that milk allergy is associated with more respiratory/GI infections and that an elimination diet (although supplemented by pre/probiotics) lead to reduced infections and less antibiotic use.

Cow’s milk allergy

Can be IgE mediated (immediate, histamine release, potentially anaphylaxis), else non-IgE mediated (typically more chronic, delayed symptoms, predominantly gastrointestinal, possibly a threshold level below which a patient is asymptomatic) but can be both. Non-IgE mediated symptoms include:

  • Eczema
  • Colic
  • Gastro-oesophageal reflux
  • Constipation [NOT green or mucuous stools]
  • Eosinophilic oesophagitis
  • Allergic Proctocolitis (FPIAP – see below)
  • Growth failure
  • Enterocolitis (FPIES)
  • Enteropathy – no blood, and longer recovery time (weeks)

Note that the first 4 problems are very common and cow’s milk protein intolerance may only be a factor in a small proportion of such patients. Best predictor of whether symptoms are due to milk allergy appears to be the background of the health care professional, not the history, age or family history of atopy! See Imperial College review of evidence (Munblit and Perkins 2020).

ESPGHAN 2023 guidance does detail trial of exclusion for reflux. For colic, very strict – only when Rome IV research criteria satisfied (3hrs per day, without obvious cause, cannot be prevented or resolved by care givers, 3 days a week, confirmed with prospective diary) AND suspected on basis of additional symptoms.

In patients with eczema, a mixture of IgE mediated and non-IgE mediated reactions can be seen (and immediate reactions may be seen on re-introduction even when only delayed reactions seen initially).

Food protein induced allergic proctocolitis

Well baby with blood +/- mucus in stool, usually in first few weeks of life. Associated with eczema and family history of food allergies. Mixed feeding appears to protect. Benign – in exclusively breast fed infants, ESPGHAN says no dietary intervention for first month. Even for formula fed babies controversial, as large study in Boston found elimination increased risk of later type 1 milk allergy by factor of 5!

DRACMA 2022 guidelines from WAO quote small Brazilian study showing 80% tolerant by 6 months so earlier reintroduction presumably possible if you do exclude. Calls for more research.

So depends on severity/frequency – and if you eliminate, definitely challenge early.

Diagnosis

Prescriptions for specialist formulas increased massively in early part of century – 10-12x higher than expected in England, for example. Estimated prevalence is 1% in the UK, less than 0.3% in Germany and Greece.

With delayed reactions, diagnosis depends on history, and then dietary exclusion followed by re-challenge after 2-4 weeks. In the case of FPIES, re-challenge may need to be done in hospital. Sometimes the diagnosis is only made at endoscopy.

Dietary exclusion has been shown to affect long term taste preferences. Also significantly restricts diet, with potential impact on calcium intake (and also riboflavin, niacin, zinc).

For immediate reactions, skin prick testing (SPT) more specific than IgE blood testing. 3mm SPT wheal considered positive in infants, but low specificity; when doing IgE/SPT tests, also check egg allergy (high cross-reactivity) and soy (for formula substitution). If IgE/SPT negative, needs challenge (ideally double blind).

Substitute Formulas

  • Breast feeding mothers may need to exclude dairy in their own diet.  Need supplements of 1000mg calcium, 10mcg vit D per day – dietetic advice is recommended.
  • Because of theoretical risk from phyto-oestrogens in soya, use extensively hydrolysed formula (EHF) instead of soya formula if under 6 months. Soya cross reactivity is reported in up to 25% of young infants with non IgE allergy but this varies widely. Soya milk usage is also associated with increased risk of subsequent peanut allergy (RR=2.6)!
  • ESPGHAN says you can also use hydrolysed rice formula – available in UK? Reported arsenic values are within WHO limits.
  • About 10% of infants will not tolerate even extensively hydrolysed formula (eHF) and may require an amino acid based formula; anaphylaxis has been described even with hydrolysed formula.  AA formula should be used first line if:
    • anaphylaxis,
    • severe non IgE (eg PR bleeding leading to haematological disturbance, severe skin disease, FPIES),
    • faltering growth (says ESPGHAN but controversial).
  • eHF potentially better than other types of formula, and potentially added benefit from probiotics – in trial of N=260 (42% IgE mediated, non-randomised) tolerance after 12 months 79% for EHF & Lactobacillus rhamnosus GG (LGG), cf 43% for EHF. 23% soya, 18% AA. Associated with IgE mechanism (negatively, OR 0.12), and EHF (4.41) or EHF & LGG (29) [Canani, European lab for food induced diseases, Naples. PMID 23582142].

Challenge

Cow’s milk must be tried again to prove it is the causal agent, unless type 1 symptoms, or severe non-type 1 (FPIES).  If symptoms return then continue elimination diet for at least 6 months, else 1yr of age, then re-introduce gradually. ESPGHAN says do IgE for milk first if type 1! Highlights that boiling more likely to hydrolyse proteins than baking, but ignores matrix idea. No evidence for further challenges but suggests every 6 months.

Prognosis

Exposure does encourage tolerance. In studies, after 6 months of oral desensitization, 11% had had positive food challenges cf 40% for abstainers. And in the abstainers, the threshold of sensitivity tended to be lower, and symptoms more severe [Eur Ann Allergy Clin Immunol. 2007 39:12-9. PMID 17375736].

Almost all non IgE milk allergy and most type 1 resolves by 1yr after diagnosis.

Reintroduction is typically done according to a “ladder” of 4 or more steps – baked milk, then boiled milk, then yogurt, then fresh raw milk. Baked milk is less allergenic due to the matrix of wheat – if wheat allergic, then gluten free cheese oatcakes (Nairns) or shortbread (Walkers/Asda).

IgE disease less likely to resolve if asthma, rhinitis, severe reactions or strongly positive results.  Median age of tolerance 5yrs.  According to Thermofisher, positive IgE Casein (Bos d 8) means less likely to tolerate baked milk or outgrow, as protein (casein) more heat stable (no consensus on component testing in ESPGHAN 2023).

You could argue for early introduction of weaning foods but this is only briefly mentioned in ESPGHAN 2023 and not yet recommended.

Final adult height has been shown to be reduced in milk allergy – this could be related to co-morbidities (asthma, eczema, steroid use, sleep disruption etc) or feeding difficulties (associated with elimination diets).

Prevention

EAACI task force recommends against use of milk formula top ups in first week of life in breast fed babies. Low certainty, though. Also recommends avoidance of allergens (including milk but not limited to) in pregnancy and during breast feeding!

ESPGHAN discusses too. In a multivariate model, independent factors associated with milk allergy were family history of allergy (OR = 2.83), avoidance of dairy products during pregnancy or breastfeeding (OR = 5.62), and formula given at the maternity hospital (OR = 1.81). In an RCT of daily 10ml formula supplementation (n=504 breast fed) cf only soya formula if required, performed between 1 and 2 months of age, daily formula ingestion prevented nearly 90% of later milk allergy confirmed by OFC at 6 months (RR: 0.12). EAACI neutral on this – and regular top ups would never be supported by breast friendly clinicians. Overall however, ESPGHAN group decided there was insufficient evidence for any of these things.

See also EAT study, and GINI study.

Treatment

66% of kids grow out cow’s milk allergy, even if they completely avoid it. But rate rises to nearly 90% if baked milk introduced. And less restrictive diet good for everyone, of course.

Oral immunotherapy (OIT) for severe milk allergy (IgE >85 or low eliciting dose):  at 1yr 36% tolerated 150ml, 54% 5-150ml (good enough for accidental exposure). 10% could not complete protocol.

DRACMA update on milk immunotherapy mostly fresh milk used in research. Randomized trials looked at kids aged 2-14, mean 8. Non randomized had wider range. 67% tolerated 150ml (cf 2.2% of controls), 78% tolerated 5-150ml (=swig protection) (cf 3.3% of controls). Anaphylaxis rate of 5.5 per person-years (although not always defined, and not always usual definition). 63% used IM adrenaline!?

6.9% developed EOE but rarely biopsy confirmed. No deaths.

2–8 weeks after discontinuation of successful OIT, tolerance of cow’s milk persisted in only 36% (20%–91%). So you have to persevere life long, probably.

Quality of life badly reported – only 5 studies. 1 study found parents reported better QOL in 37%, worse in 26%, and unchanged in 38%! 2 conference abstracts reported improved QOL or at least reduced anxiety in general and reduced fear of unexpected reaction. Some studies found worse QOL! Certainty of evidence overall v low…

Only 1 trial and 2 non randomized studies of baked milk OIT! In the 1 RCT of baked milk, 73% achieved tolerance at 12 months (cf none of control group). 20% required adrenaline! Only some children assessed for QOL, with evidence of benefit – of the parents studied, no improvement in QOL! [Dantzer and Dunlop 2021].

Highlights “a dire need for a standardization in outcome assessment and reporting,” and that successful completion of OFC needs to be validated as a predictor of “real world” success. [Natasha trial will hopefully clarify further…]

Separate article on OIT recommendations – apart from balancing risks and benefits, recommends using omalizumab (monoclonal anti-IgE) in advance and in initial stages of oral immunotherapy with unheated cow’s milk. Inferring from limited evidence (use in other food allergies, mostly) that risk of anaphylaxis reduced (RR0.34 but not significant!). Not really any downside? (But costs at least £256 per dose, maybe double? Lasts a month?). Plus, does not recommend baked milk OIT as very low certainty of benefit. More evidence on effect, risks, QOL benefit obviously required.  

Sublingual/epicutaneous immunotherapy (SLIT) for milk? Low rate of success and high rate of relapse.

[EGPHAN 2023, Frontiers in Pediatrics 2019; BMJ cmpa article sept 2013]

Natasha Trial is looking at Peanut or cow’s milk OIT in UK – groups are Peanut age 6-23yrs, Peanut age 2-3yrs, Cow’s milk age 3-23yrs. Using everyday food products. Final results expected 2027.