What Proteins Cause Cow’s Milk Protein Allergy?

Patient Presentation
A 5-month-old female came to clinic because of blood in her stool x 2 the evening before. The blood was mixed in with soft, pudding-like, yellow, fecal material that was not malodorous. The mother said there was no mucous in the stool. She had another stool in the morning that did not have blood in it. The mother did not think there had been any change in the stool color, consistency or frequency over the past few days. The mother described no hard stools. The infant was acting normal with multiple wet diapers and a good appetite. She was exclusively breast fed except that the mother had started some rice cereal about 2 weeks previously without any problems. She had traveled to her grandparents farm 2 weeks previously but had been well as had everyone else who had been there. The past medical history was negative for eczema or rashes, breathing problems, or any gastrointestinal problems. She had an upper respiratory infection at age 3 months when she started child care. She was fully immunized. The review of systems was negative for nausea, emesis, rashes, urticaria, breathing problems, rhinorrhea or fever. There also was no other bleeding or bruising noted.

The pertinent physical exam showed a smiling infant with normal vital signs. Her weight was 25% and length was 50% and tracking along her growth curves. She had no rashes including no diaper rash. Her abdomen was soft, non-tender without organomegaly or masses. Her anus was patent without fissures. A rectal examination found normal tone with a small amount of yellow stool in the vault without obvious blood. The stool was guaiac positive.

The diagnosis of a well-appearing infant with a history of blood in her stool was made. The pediatrician considered that the cause of the blood could be an internal fissure, infection, or allergic cow’s milk protein colitis. She discussed with the mother about these possibilities and they agreed to monitor the infant. The mother was given some guaiac cards to test stools that had any signs of blood, or if she wasn’t seeing blood to test a couple of random stools. “She hasn’t had other signs of allergy before, and eliminating cow’s milk protein from your diet can be hard and I’m not sure at this time we need to do that. I think we can safely watch her and if it continues then we can think about if you would need to stop cow’s milk in your diet,” she counseled. The patient’s clinical course over the next 2 weeks, showed 1 stool that was guaiac positive one day after the visit, and 4 other stools that were negative after that time. No stools had frank blood in them and the infant continued to do well.

Cow’s milk protein allergy (CMPA) is one of the most common food allergies. It is estimated to have an incidence of 2-7.5% in infants and a prevalence of 0.5% in breastfeed infants. The prevalence decreases with age at 1% in children > or = 6 years.
CMPA does not have a laboratory test and therefore is a clinical diagnosis. It is defined as a “hypersensitivity reaction brought on by specific immunologic mechanisms to cow’s milk.” Generally symptoms present within the first month of life and involve 2 of more systems with 2 or more symptoms. Systems are dermatologic (including atopic dermatitis, urticaria, oral pruritis), respiratory (including asthma, stridor, wheezing, rhinoconjunctivitis) and gastrointestinal (including emesis, diarrhea, constipation, malabsorption, gastroestophageal reflux disease) and other symptoms may include colic, irritability, failure to thrive or food aversion. IgE-mediated CMPA (Type 1 hypersensitivity reaction, ~50% of children) has symptoms that occur within minutes to 2 hours of ingestion of the CMP. Non-IgE mediated CMPA (Type 4 delayed hypersensitivity reaction) has symptoms that occur 4 or more hours (even up to 1 week) after exposure to CMP.

Allergic colitis can have blood mixed into stools that are usually non-foul smelling, mucousy or foamy. Blood can be hematochezia or melanotic or insidious. The mechanism for rectal bleeding is felt to be ulceration of thinned mucosa that is stretched over enlarged hyperplastic submucosal lymphatic tissue of the colon.

If the infant is suspected of having IgE mediated CMPA, then a specific blood IgE level or skin prick test in a clinical setting is often used to aid diagnoses. If positive, then CMP should be eliminated from the infant’s diet, or if the mother is breastfeeding, the mother’s diet. If the testing is negative, then a food challenge in a clinical setting can help. Usually CMP is eliminated from the diet for 12-18 months and then the patient is rechallenged in a clinical setting. If the patient still has reactivity, the elimination diet is continued for another 6-12 months and the patient again is rechallenged.

If non-IgE mediated CMPA is suspected, testing is not done, but elimination diets are implemented for 2-8 weeks and the patient should improve if CMPA is truly the cause of the symptoms. If with reintroduction of CMP, the symptoms reoccur then CMPA is assumed to be the cause, and the elimination diet is continued for 6 months (infant age 9-12 months). At that time, an oral food challenge can be tried at home. If the patient continues to react, then the diet is continued for another 6-12 months and again rechallenged. Patients with allergic colitis generally have cessation of frank blood by 3 weeks after the elimination diet is begun but occult blood can be detected until 6-12 weeks. Bleeding after 12 weeks is an indication for referral to a specialist as other causes of bleeding must be reconsidered and potentially other investigations such as sigmoidoscopy are indicated.

For formula fed infants, extensively hydrolyzed formula or an amino acid formula are usually used for elimination diets as there is a high rate of cross reactivity with soy. Plant protein juices (e.g. almond milk, rice milk, coconut) are not recommended as they are inadequate nutritionally for infants. Other mammalian milks (e.g. sheep, goat, etc.) are also not recommended as they are not nutritionally adequate and have an ~80% cross-reactivity rate. Other foods such as beef, veal, eggs, fish and wheat should not be avoided unless there is a documented specific allergy to the specific food. For breast-feeding mothers it can be difficult to follow a completely CMP-free diet, as CMP is used in many foods either as a major or minor component, and also as a binding or stabilizing agent in food manufacturing. Mothers following this diet need to have Vitamin D (400 IU) and calcium (1000 mg/day) supplementation.

Tolerance to CMP is developed over time in most patients. By age 5, 80-90% of children develop tolerance.

Learning Point
The causative proteins in CMPA differ by exposure. For infants and children drinking milk or cow’s milk based formulas the causative protein are thought to be casein or whey. For exclusively breast-fed infants, β-lactoglobulin in the breast milk 4-6 hours after maternal consumption of milk is thought to be the causative protein.

Questions for Further Discussion
1. How do you counsel breastfeeding mothers to do a CMP elimination diet?
2. What are indications for referral to an allergist or gastroenterologist for potential CMPA?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Food Allergy and Gastrointestinal Bleeding.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Vandenplas Y, Marchand J, Meyns L. Symptoms, Diagnosis, and Treatment of Cow’s Milk Allergy. Curr Pediatr Rev. 2015;11(4):293-7.

Nowak-Wegrzyn A, Katz Y, Mehr SS, Koletzko S. Non-IgE-mediated gastrointestinal food allergy. J Allergy Clin Immunol. 2015 May;135(5):1114-24.

Martín-Munoz MF, Pineda F, Garcia Parrado G, Guillen D, Rivero D, Belver T, Quirce S. Food allergy in breastfeeding babies. Hidden allergens in human milk. Eur Ann Allergy Clin Immunol. 2016 Jul;48(4):123-8.

Mousan G, Kamat D. Cow’s Milk Protein Allergy.
Clin Pediatr (Phila). 2016 Oct;55(11):1054-63.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa