Cow milk protein allergy is considered to be the most common type of food allergy in infancy and childhood. The challenging point is the absence of a specific test for an accurate diagnosis of CMPA. OFC, with the elimination of cow milk protein for 4 weeks and then reintroduction with meticulous observation for resolution of symptoms after elimination and recurrence after reintroduction is still the gold standard test for diagnosis of CMPA. Our study showed that sociodemographic characteristics were significantly associated with CMPA. The male gender was more affected by CMPA than females. This agreed with Selbuz et al. who reported a significant male predominance in the CMPA among the male group. This can probably be explained by a genetic predisposition. An X-linked recessive trait associated with the allergic disease would be more likely to be unmasked in males (XY) and could explain why food allergies in males are more common at a very young age [13].
Regarding the age of presentation, this study showed that CMPA was more common in infants less than 6 months of age. Infants usually presented with CMPA during the first few months of life. CMPA most probably occurs at the time of addition of feeding (whatever its type) and decreases up to 1 year of age. Breastfed infants are more liable to food protein-induced allergic proctocolitis [14], whereas food protein-induced enterocolitis syndrome commonly occurs with artificial feeding [15].
Moreover, consanguinity and positive family history of allergic diseases play a crucial role. Our study showed that the incidence of CMPA was higher in infants with positive consanguinity and positive family history of allergic diseases. This finding agreed with various studies that found that a family history of atopy was significant in cases with CMPA, and the risk of atopy increases if a parent or sibling has an atopic disease. Furthermore, if both parents are atopic, the risk is even higher [16, 17]. As we have discussed before, allergy is an X-linked recessive trait, so CMPA was more prevalent among our studied infants with positive consanguinity and family history of allergic diseases. This is specifically important in countries such as Egypt, where parental consanguinity is common. A recent study conducted in South Sinai (Egypt) showed that 21 to 33% of the married couples were relatives and rural settings showed higher rates than urban settings [18].
Regarding the frequency of GI manifestations, the most frequent was regurgitation, then comes diarrhea, colic, vomiting, and least common presentation was constipation. Our study came in line with Dominguez-Ortega et al. who demonstrated that the majority of affected children with CMPA had other symptoms involving one or more organ systems, usually the gastrointestinal tract and/or skin [10]. Maksoud et al. reported that infants with suspected CMPA usually present with GI manifestations [12]. Additionally, Selbuz et al. reported a significant difference in the clinical presentation between infants with CMPA(+) and (−), with 60.4% of CMPA(+) infants reporting more than 5 episodes of regurgitation per day, which suggests that the severity of regurgitation may be a factor in determining whether to test the infant for CMPA [13]. ESPGHAN GI Committee practical guidelines stated that dysphagia, frequent regurgitation, colic, abdominal pain, vomiting, anorexia, refusal of food, diarrhea (with or without malabsorption or protein loss due to enteropathy), and constipation with or without perianal rash are common but nonspecific GI signs of CMPA in infants and toddlers [9].
Breastfeeding remains to prove that it is the best type of infant feeding, its protective effect against CMPA was pronounced in our study, where infants who were artificially fed exceeded infants who were breastfed. Jakaitis & Denning also stated that infants who were fed breast milk were found to have a reduced incidence of allergic disease [14]. The short-chain fatty acid produced by the degradation of breast milk oligosaccharides by colonizing bacteria, which has a function in strengthening tight-junctions integrity, can be used to explain this protective action of breast milk against infectious diseases and atopic disorders [15, 16].
Meanwhile, exclusive breastfeeding was shown to be protective against CMPA. Our study clearly showed a clear difference between the time of introduction of complementary food and the occurrence of CMPA that was statistically significant. The protective effect of exclusive breastfeeding was highlighted in previous studies who also reported that the risk of Allergy to cow milk protein was reduced in exclusively breastfed infants [12, 17]. CMPA was observed in infants who began complementary food after 6 months of age in our studied cases. According to Du Toit et al. 2015 study “the Learning Early About Peanut study (LEAP)” and the Enquiring About Tolerance study results, we found an agreement with our findings [18,19,20]. The introduction of complementary foods between the ages of 4 and 6 months is the best time to reduce the incidence of allergy, as advised by the majority of international guidelines, including The American and European allergy expert committee guidelines, as both have suggested that early complementary food introduction may be protective against allergy [21, 22].
This study was conducted in one of the largest university hospitals in Upper Egypt, and during recruitment of our cases, we notice the marked extremes in the diagnosis of CMPA with clearly obvious over and under-diagnosis. Many cases were misdiagnosed to have CMPA based on clinical criteria of persistent or recurrent GI manifestations and sometimes depending on some investigations, that proved to be irrelevant in the diagnosis of CMPA, like the occult blood in stool, fecal calprotectin level in the stool, skin prick test, or serum IgE food panel. On other hand, many of our cases proved to have CMPA by OFC test were misdiagnosed as lactose intolerance, persistent gastroenteritis, dysentery, pyloric stenosis, GERD, functional constipation, or anal fissure. A high index of suspicion, proper application of CoMiSS, and OFC are the cornerstones for early diagnosis and management of CMPA.
