Clinical Manifestation of Cow’s Milk Protein Allergy as a Complex Disorders

Clinical Manifestation of cow’s milk protein allergy

Cow’s milk is a leading cause of food allergy especially in infants and children. Symptoms of cow’s milk allergy are non-specific; as a result, suspected cow’s milk allergy is far more common than proven allergy to cow’s milk. Cow’s milk allergy in infants is therefore most probably a fairly uncommon clinical picture; cow’s milk allergy is estimated to occur in less than one per cent of infants. The only valuable additional diagnostic tool is food challenge, preferably double blind.

A significant association between early neonatal exposure to cow’s milk formula feeding and subsequent development of CMPA/CMPI has been documented. The small amounts of ‘foreign’ protein in human milk may rather induce tolerance than allergic sensitization. The findings of specific IgE to individual cow’s milk proteins in cord blood of the majority of infants who later develop CMPA/CMPI suggests a prenatal sensitization may play a role in the pathogenesis of CMPA/CMPI. Perhaps a weak intrauterine education of low IgE-response may need to ‘boosted’ neonatally in order to cause clinical disease. The prognosis of CMPA/CMPI is good with a recovery of about 45-56% at one year, 60-77% at two years and 71-87% at three years. Associated adverse reactions to other foods, especially egg, soy, peanut and citrus develop in about 41-54%. Allergy to potential environmental inhalant allergens has been reported in up to 28% by three years and up to 80% before the age of puberty. Especially, infants with an early increased IgE response to cow’s milk protein have an increased risk of persisting CMPA, development of persistent adverse reactions to other foods and development of allergy against environmental inhalant allergens. Cow’s milk protein/intolerance (CMPA/CMPI), meaning reproducible adverse reactions to cow’s milk protein(s) may be due to the interaction between one or more milk proteins and one or more immune mechanisms, possible any of the four basic types of hypersensitivity reactions. Immunologically mediated reactions are defined as CMPA. Mostly, CMPA is caused by IgE-mediated (type I) reactions, but evidence for type III (immune complex) reactions and type IV (cell mediated reactions) have been demonstrated. Non immunologically reactions against cow’s milk protein(s) are defined as CMPI. However, it should be stressed that many studies on ‘cow’s milk allergy’ have not investigated the immunological basis of the clinical reactions. In most instances of cow’s milk protein hypersensitivity only diagnostic investigations such as skin prick test and RAST indicative of IgE-mediated reactions are performed. In fact, CMPA cannot be ruled out unless extensive diagnostic tests for type II-III-IV reactions have proved negative. Thus, the classification of adverse reactions to cow’s milk proteins depends on the extent and the quality of performed diagnostic tests for immune mediated reactions. At present, no single laboratory test is diagnostic of CMPA/CMPI, and differentiation between CMPA and CMPI cannot be based solely on clinical symptoms. Therefore the diagnosis has to be based on strict well-defined elimination and milk challenge procedure. Preferably, double-blind placebo-controlled challenges (DBPCFC) should be carried out in children older than 1-2 years of age. In infants open controlled challenges have been shown to be reliable when performed under professional observation in a hospital setting

Between 5% and 15% of infants show symptoms suggesting adverse reactions to cow’s milk protein (CMP),1 while estimates of the prevalence of cow’s milk protein allergy (CMPA) vary from 2% to 7.5%.2 Differences in diagnostic criteria and study design contribute to the wide range of prevalence estimates and underline the importance of an accurate diagnosis, which will reduce the number of infants on inappropriate elimination diets. CMPA is easily missed in primary care settings and needs to be considered as a cause of infant distress and diverse clinical symptoms. Accurate diagnosis and management will reassure parents. CMPA can develop in exclusively and partially breast-fed infants, and when CMP is introduced into the feeding regimen. Early diagnosis and adequate treatment decrease the risk of impaired growth

Cow’s milk protein (CMP) is usually one of the first complementary foods to be introduced into the infant’s diet and is commonly consumed throughout childhood as part of a balanced diet. CMP is capable of inducing a multitude of adverse reactions in children, which may involve organs like the skin, gastrointestinal (GI) tract or respiratory system. The diagnosis of CMP-induced adverse reactions requires an understanding of their classification and immunological basis as well as the strengths and limitations of diagnostic modalities. In addition to the well-recognised, immediate-onset IgE-mediated allergies, there is increasing evidence to support the role of CMP-induced allergy in a spectrum of delayed-onset disorders ranging from GI symptoms to chronic eczema. The mainstay of treatment is avoidance of CMP; this requires dietetic input to ensure that this does not lead to any nutritional compromise.

EVALUATION OF AN INFANT WITH SUSPECTED CMPA

A comprehensive history (including a family history of atopy) and careful physical examination form the foundation of both algorithms. The risk of atopy increases if a parent or sibling has atopic disease (20–40% and 25–35%, respectively), and is higher still if both parents are atopic (40–60%). In comparison to cow’s milk formula-fed infants, exclusive breast feeding during the first 4–6 months of life reduces the risk for CMPA and most severe allergic manifestations during early infancy. The distinction between breast-fed and formula-fed infants reflects the importance of ensuring an adequate duration of breast feeding. Management principles also differ. The management of breast-fed infants depends on reducing the maternal allergen load and strict avoidance of CMP in supplementary feeding. It is recommended that exclusive or partial breast feeding is continued, unless alarm symptoms require a different management.The earlier CMPA develops, the greater the risk of growth retardation

Clinical manifestations of CMA

I. Gastrointestinal reactions
• Oral allergy syndrome (rare in pediatric patients) • Lip swelling is a commonly observed manifestation during food challenge procedures.
Immediate gastrointestinal allergy
• Vomiting (described in children both isolated and as part of allergic/anaphylactic reactions) • Diarrhea (usually in, but not limited to, delayed reactions)
CMA in short bowel syndrome
• Greater than 50% of these patients are also allergic to cow’s milk, according to 1 case study.
II. IgE-mediated respiratory reactions
• Rhinitis occurs in ±70% of patients during oral cow’s milk challenge, and asthma occurs in less than 8%. • Reactions rarely occur in isolation. • Reactions correlate with severe CMA. • Asthma makes for the worst prognosis in children with anaphylaxis. • Asthma in patients with CMA is of particular severity. • Respiratory symptoms in patients with CMA can progress to respiratory allergy. • Inhalation of milk vapor has been associated with severe respiratory tract reactions.
III. IgE-mediated skin reactions
Acute urticaria or angioedema
• Urticaria is a feature of most anaphylactic reactions to cow’s milk. • Urticaria with inhalation or accidental skin contact is often severe.
Contact urticaria
• Pattern varies from irritant to allergic contact dermatitis. • Generalized eczematous rash (systemic contact dermatitis) is present. • Contact reactions are frequent in patients with AD.
IV. Late-onset reactions
• Symptoms not IgE mediated • Mostly localized in the gastrointestinal tract • Typically develop 1 to several hours or even days after ingestion • No reliable laboratory tests to diagnose late-onset CMA: IgE test results are negative
Skin • AD
Gastrointestinal tract • Gastroesophageal reflux disease
• Allergic eosinophilic esophagitis
• Food protein–induced enterocolitis syndrome
• Cow’s milk protein–induced enteropathy
• Constipation
• Severe irritability (colic)
• Food protein–induced gastroenteritis and proctocolitis
Respiratory system • Milk-induced chronic pulmonary disease
• Heiner syndrome
V. AD
• AD is most often present as an eczematous lesion (after ingestion or contact). • AD can involve both IgE-mediated and non–IgE-mediated skin responses. • Less than 30% of children with moderate-to-severe AD have food allergy, and CMA is the second most common food allergy in this population. • The earlier the age of onset, the greater the severity and frequency of high of cow’s milk sIgE levels.67 • Appropriate diagnosis and elimination diets frequently lead to symptom improvement.
VI. Gastrointestinal syndromes
Symptoms frequently include nausea, vomiting, abdominal pain, diarrhea, and, with chronic disease, malabsorption and failure to thrive or weight loss.
• Food protein–induced enterocolitis syndrome, the primary cause of which is CMA • Cow’s milk–induced enteropathy syndrome and secondary lactose malabsorption • Cow’s milk–induced proctocolitis syndrome (relatively benign disorder) • Gastroesophageal reflux disease–like symptoms • Eosinophilic esophagitis • Constipation • Irritable bowel syndrom
VII. Milk-induced chronic pulmonary disease
• Heiner syndrome is a very rare form of pulmonary hemosiderosis caused by CMA. • Young children typically present with recurrent pulmonary infiltrates associated with chronic cough, tachypnea, wheezing, rales, recurrent fevers, and failure to thrive. • Milk-precipitating antibodies are found in the serum. • Symptoms generally resolve after an elimination diet.
.
Organ involvement Symptoms
Gastrointestinal tract Frequent regurgitation
Vomiting
Diarrhoea
Constipation (with/without perianal rash)
Blood in stool
Iron deficiency anaemia
Skin Atopic dermatitis
Swelling of lips or eye lids (angio-oedema)
Urticaria unrelated to acute infections, drug intake or other causes
Respiratory tract Runny nose (otitis media)20 21
(unrelated to infection) Chronic cough
Wheezing
General Persistent distress or colic (wailing/irritable for ⩾3 h per day) at least 3 days/week over a period of >3 weeks
  • *Infants with CMPA in general show one or more of the listed symptoms.

Alarm symptoms and findings indicating severe CMPA as the possible cause

Organ involvement Symptoms and findings
Gastrointestinal tract Failure to thrive due to chronic diarrhoea and/or refusal to feed and/or vomiting
Iron deficiency anaemia due to occult or macroscopic blood loss
Hypoalbuminaemia
Endoscopic/histologically confirmed enteropathy or severe colitis
Skin Exudative or severe atopic dermatitis with hypoalbuminaemia or failure to thrive or iron deficiency anaemia
Respiratory tract Acute laryngoedema or bronchial
(unrelated to infection) obstruction with difficulty breathing
General Anaphylaxis

Unusual clinical presentations of CMA

Unusual clinical presentations are as much a feature of CMA as one might expect from such a ubiquitous allergen source in food and the environment as milk

Unusual clinical manifestations and routes of exposure

Manifestation
Constipation See Table I Iacono et al
Heiner syndrome Moissidis et al
Unusual routes of exposure
Skin contact Direct or indirect contact in bathtub into which a few drops of milk were spilled by a younger brother Liccardi et al
Mucous membrane contact Kiss Hallett et al
Vaginal contact Liccardi et al
Inhalation Milk vapor or casein powder Bonadonna et al,Vargiu et al
Environmental exposure
Poor food labeling Labeling of commercially prepared foods might not be accurate Joshi et al
Hidden or contamination in other foods Contamination in restaurants or factories Ignorance of catering personnel Muñoz-Furlong et al
Hidden or contamination in medications In lactose Nowak-Wegrzyn et al
In dermatologic preparations or injectable corticosteroids Eda et al

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