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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 2  |  Page : 55-63

Risk factors of delayed tolerance in children with cow milk protein allergy attending gastroenterology clinic in Alexandria University Children’s Hospital


Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission11-Feb-2020
Date of Decision15-Apr-2020
Date of Acceptance18-Apr-2020
Date of Web Publication5-Oct-2020

Correspondence Address:
MD, PhD Ahmed F Khalil
Lecturer of Pediatrics and Pediatric Gastroenterology, Department of Pediatrics, Alexandria University, Alexandria, 2164655
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJOP.AJOP_18_20

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  Abstract 


Background Cow’s milk protein allergy (CMPA) is the most common type of food allergy. The prevalence is increasing in both developing and developed countries. The clinical presentations are variable in intensity and may involve many different organ systems. The diagnosis depends on positive response to an elimination diet, with recurrence of the symptoms upon re-challenge. CMPA usually resolves during early childhood, but some factors may delay the acquisition of tolerance.
Aim The aim was to investigate the possible risk factors that may be associated with delayed tolerance to cow’s milk in patients with CMPA.
Patients and methods The study included 95 patients aged 1 month to 3 years with proved CMPA attending the Gastroenterology Clinic at Alexandria University Children Hospital. Cases were recruited for 6 months, starting from January 1, 2018, to the end of June 2018. The demographic data, age at onset, clinical presentations, nutritional history, and family history of atopy were reported. The diagnosis was confirmed through elimination-re-challenge trial. All patients were treated by a milk-free diet with the use of appropriate milk substitutes according to the age. After a 6–9-month period of elimination, gradual re-introduction of milk was attempted, and the development of tolerance to milk was evaluated. Factors associated with delayed tolerance were compared in both the tolerant and intolerant groups.
Results At their initial visit, the mean age of the studied patients was 8.5±4.9 months, and 17.9% were underweight. The mean age at onset of symptoms was 2.2±2.2 months, whereas the mean duration before diagnosis was 3.3±2.8 months. Overall, 85.3% were born via cesarean section. Chronic or delayed symptoms were reported in 93.7%. All patients had gastrointestinal symptoms. Chronic diarrhea was the commonest symptoms (90.53%) followed by vomiting (42%). In addition, 28.4% had cutaneous symptoms. Moreover, 81% were formula fed. Food protein-induced proctocolitis was the most common syndrome among patients with chronic symptoms. Overall, 85.26% of them were born via cesarean section. Early introduction of dairy products was encountered in 37.9%. In addition, 10% of the patients had cross-reaction to soy and 14.5% had multiple food allergy (MFA). Additionally, 56.8% had a family history of atopy. Overall, 68.42% tolerated cow milk after gradual re-introduction. Delayed diagnosis of CMPA symptoms, delayed introduction of complementary food, rural residence, family history of atopy, cross-reactivity to soya or MFA were associated with delayed tolerance to cow’s milk. Patients with immediate symptoms [immunoglobulin (Ig)E mediated] or food protein-induced enterocolitis syndrome or those with CMPA-associated eosinophilic gastrointestinal disorders showed delayed tolerance. Tolerance was achieved more frequently in patients with delayed (non-IgE mediated) symptoms, in patients with exclusive gastrointestinal symptoms, and in patients with food protein-induced proctocolitis.
Conclusion The tolerance rate after 6–9 months of elimination was 63.2%, which is comparable to the international rates. IgE-mediated CMPA, food protein-induced enterocolitis syndrome, CMPA-associated eosinophilic gastrointestinal disorders, and MFA have delayed tolerance.

Keywords: cow’s milk allergy, delayed tolerance, food protein-induced proctocolitis, food protein-induced enterocolitis syndrome and eosinophilic gastrointestinal disorders


How to cite this article:
Khalil AF, Abdel Gawad MM, Mokhtar N. Risk factors of delayed tolerance in children with cow milk protein allergy attending gastroenterology clinic in Alexandria University Children’s Hospital. Alex J Pediatr 2020;33:55-63

How to cite this URL:
Khalil AF, Abdel Gawad MM, Mokhtar N. Risk factors of delayed tolerance in children with cow milk protein allergy attending gastroenterology clinic in Alexandria University Children’s Hospital. Alex J Pediatr [serial online] 2020 [cited 2020 Oct 20];33:55-63. Available from: http://www.ajp.eg.net/text.asp?2020/33/2/55/297240




  Introduction Top


Over the past decade, the incidence of food allergy has increased significantly to be a major health problem worldwide [1]. Cow’s milk protein allergy (CMPA) is the most common type of food allergy in infants and young children [2]. The increased incidence of CMPA is attributed to the excessive use of cow milk-based infant formulae as a replacement for human milk. Increasing rates of cesarean sections and urbanized lifestyle may also contribute to the global increase in the incidence of CMPA [3],[4]. Although the pathogenesis of CMPA involves immunoglobulin E (IgE)-mediated, non-IgE-mediated, or mixed immune reactions to one or multiple cow milk proteins, CMPA is most frequently caused by a non-IgE-mediated mechanism [5]. In developed countries, the incidence of CMPA is variable among different populations and ranges from 2 to 6% [6]. CMPA usually develops in early infancy, most commonly before the age of 6 months and rarely after 12 months of age. The onset of symptoms in most cases is closely related to the time of introduction of cow milk products [7].

The clinical spectrum of CMPA includes a range of symptoms of variable intensity that involves many different organ systems. Non-IgE-mediated gastrointestinal symptoms are usually the main presentation, especially in the first year of life. Infants usually present with diarrhea, vomiting, excessive colic, constipation, gastrointestinal bleeding, or combination of two or more symptoms [7]. Atopic dermatitis is the commonest skin manifestation and usually has a chronic relapsing course [8].

The diagnosis of CMPA is a challenging task, especially in infants with delayed gastrointestinal manifestations because the symptoms are usually non-specific and may be caused by other disorders like GERD, infant colic, lactose intolerance, or gastrointestinal infections [5]. The cornerstone of diagnosis is a positive response to an elimination diet with improvement of the presenting symptoms and recurrence of the same symptoms upon re-challenge with cow’s milk [9].

The mainstay of treatment is a milk-free diet with the use of appropriate milk substitutes. Cow milk-based formula and supplementary foods containing cow’s milk or other unmodified animal milk proteins (e.g. goat’s milk and sheep’s milk) should be strictly avoided. In breast-fed infants, milk and any milk products are eliminated from the mother’s diet, and breastfeeding is continued. In formula-fed infants, an extensively hydrolyzed formula or amino acid-based formula is recommended [5],[9],[10]. The natural history of CMPA is to resolve during early childhood or at least before adolescence. The tolerance is achieved in 87% of cases before the age of 3 years. Overall, the chances of tolerance are better for non-IgE-mediated type, whereas those with IgE-mediated symptoms or patients with mixed reaction CMPA [CMPA-associated eosinophilic gastrointestinal disorders, (EGID)] usually have delayed acquisition of tolerance to CMPs. Children with respiratory symptoms at onset, multiple food allergy (MFA), or positive family history of atopy have a higher risk of a prolonged intolerance to cow’s milk [9],[11],[12]. The prognosis of CMPA has been studied in different populations; however, the results were inconsistent. Old studies reported that CMA is transient and always has a good prognosis [13],[14]. However, the more recent studies have shown less optimistic results, with persistence of CMPA in more patients [15],[16]. It is possible that the same factors responsible for the increase in the incidence of food allergy in the last decade account for the persistence of CMPA until older ages, contributing to the global increase in its prevalence [16],[17].


  Aim Top


The aim of the present study was to investigate the possible risk factors that may be associated with delayed tolerance to cow milk protein in infants and children with CMPA after a period of its complete elimination from their diet.


  Patients and methods Top


The study included 95 infants and toddlers aged 1 month to 3 years with proved CMPA attending the Gastroenterology Clinic at Alexandria University Children Hospital. Cases were recruited for 6 months, starting from January 1, 2018, to the end of June 2018. Patients with nonimmunological hypersensitivity reactions to milk such as lactose intolerance were excluded. A written consent was taken from the parents or caregivers of all included children. The study was approved by the Ethics Committee, Faculty of Medicine, Alexandria University. The following steps were done for all patients included in the study.

Clinical evaluation

Full medical history was obtained from all the patients including demographic data, age at onset of symptoms, type of presenting gastrointestinal symptoms, nutritional history, other symptoms suggestive of atopy, and any family history of atopic disease in the parents or siblings. Thorough clinical examination was performed with stress on anthropometric measurements and nutritional assessment.

Diagnosis and classification of CMPA

In patients with delayed or chronic symptoms suggestive of non-IgE mediated CMPA, a trial of milk elimination for 2–6 weeks was performed. If the symptoms improved after elimination, re-challenge with milk was done. If the same symptoms recurred, then the diagnosis of non-IgE mediated CMPA was confirmed. If the patient’s symptoms did not improve after 6 weeks of elimination, other diseases with similar presentations were excluded through further workup according to the clinical scenario. In patients with immediate symptoms, a trial of milk elimination for 1–2 weeks was performed. If the symptoms improved after elimination, the diagnosis was confirmed in this group of patients by measurement of serum-specific IgE to cow’s milk proteins. In this group with IgE-mediated CMPA, re-challenge was not attempted for fear of acute severe symptoms or anaphylaxis [9]. Food allergen panel was done also in patients with IgE-mediated CMPA with suspected MFAs and in patients with EGID [18].

Treatment and follow-up

Both groups were treated by a milk-free diet with the use of appropriate milk substitutes. In breast-fed infants, milk and any milk products were eliminated from the mothers’ diet, and mothers were encouraged to continue breastfeeding. If formula feeds were used, the formula was changed to an amino acid-based formula in all cases, as extensively hydrolyzed formulae were not available during the whole period of the study. Complementary feeding was started at 4–6 months of age for infants. Verbal and written advice was provided on the avoidance of dairy‐based solids and foods with cow milk proteins as hidden ‘ingredients’ and measures to avoid contamination, so as to minimize accidental cow milk ingestion. All patients were followed up in the clinic for a minimum of 6 months before the re-challenge step. Patients with EGID were given the recommended medical therapy in addition to the elimination of milk and any other associated allergens if present [18].

Milk re-introduction trial

After a 6–9-month period of elimination, depending on the rate of symptoms improvement, age at onset of symptoms, and type of CMPA, the development of tolerance to milk was evaluated. In the non-IgE group, gradual introduction of milk was done in a step-like approach (Milk ladder) over a period of at least six weeks. In the IgE group, specific serum IgE levels to milk were repeated; if the tests were negative, a gradual re-introduction of cow’s milk was attempted by the same method [19]. Children were assessed twice during the re-introduction phase (at week 2, week 4, and week 8) to observe for the occurrence of any symptoms. Introduction of milk was stopped whenever the patients developed significant symptoms and were advised to repeat the process of re-introduction after a period of 3–4 months again.

Determination of short-term prognosis and risk factors associated with delayed tolerance

Based on the response of the previous step, the patients were divided into two groups according to acquisition of tolerance to cow’s milk: the tolerant and intolerant groups. Factors associated with delayed tolerance to cow’s milk were compared in both groups.

The minimum sample size required was 91 patients. Statistical analysis was carried out using SPSS statistics software version 23 (IBM SPSS Statistics for Windows, Version 23 Armonk, NY: IBM Corp). Data were expressed as percentage of the total for categorical variables, as mean with SD for normally distributed continuous variables, or as median with interquartile range for skewed distributed variables. Comparisons were carried out between two studied independent normally distributed variables using independent sample t test. χ2 test was used to test association between qualitative variables. Yates’ correction for continuity or Monte Carlo correction was used when indicated.


  Results Top


A total of 100 children with confirmed CMPA were recruited; however, five children were lost during follow-up or had incomplete compliance on milk-free diet and were excluded. At the end of the study, 95 infants and toddlers were included.

Demographic and clinical characteristics

No sex difference was found between the children in the studied group, with a mean age of 8.55±4.97 months at their initial visit. Most of the infants were born via cesarean section (85.3%) ([Table 1]).
Table 1 Demographic and clinical characteristics of the study population

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The mean age at onset of symptoms was 2.18±2.23 months, whereas the mean duration before diagnosis was 3.36±2.85 months. Chronic or delayed symptoms were reported in most patients (n=84, 88.4%).

All the patients included in the study had gastrointestinal symptoms. Almost two-thirds of the patients experienced isolated gastrointestinal symptoms (67.4%). Chronic diarrhea was the commonest symptoms reported (70.5%), and the majority of them had mucoid diarrhea or mucoid bloody diarrhea (79%). Vomiting was reported in 42% of the patients. The vomitus was associated with hematemesis in 18% of them. Acute GI symptoms were manifested in the form of immediate oral itching, burning, swelling, and erythema (oral allergy syndrome, 6.3%) after exposure to milk antigens.

A total of 27 (28.4%) patients had cutaneous symptoms. Chronic eczema was present in 66.6% of them (n=18), whereas 33.4% had acute urticaria±angioedema (n=9). Respiratory symptoms were observed in 11.6% of the patients (n=11).

At the initial visit, 17.9% (n=17) of the studied children were underweight (weight-for-age Z score <−2 SD), and one of them also was short (height-for-age Z score <−2 SD). Perianal erythema associated with chronic diarrhea was detected in 26% of the patients and skin changes owing to chronic eczema in 18% of them. All these findings were reported in patients with chronic symptoms.

The majority of infants were formula fed (72.6%), either in the form of mixed feeding (n=56) or exclusive formula feeding (n=13). The mean age of complementary feeding was 5.67±1.74 months. Early introduction of dairy products before the recommended age (<10–12 months) was encountered in 37.9% of the patients. Almost 10% of the patients had cross-reaction to soy, and 14.5% had allergy to multiple food items.

Family history of allergy was found in 56.84% of the patients’ families (n=54). History of multiple allergies was positive in 48% of infants’ relatives with atopy. Allergic rhinitis was the most common type of allergy reported by 34% of infants’ relatives, whereas food allergy was reported in 14%.

Most patients presented with chronic symptoms (n=84, 88.4%), and their diagnosis was confirmed by elimination and re-challenge trial in most of them. Anemia and hypoalbuminemia were detected in 36 and 19%, respectively. They were reported in patients with prolonged chronic diarrhea. Fecal calprotectin was performed in 35 patients, either before referral to our clinic or because of persistent mucoid or bloody diarrhea on milk-free diet. The levels of calprotectin ranged between 7 and 880 μg/g, whereas the mean was 285.4±261 μg/g. GI endoscopy was done in 10 (10.5%) cases because they did not improve on elimination after 6 weeks of elimination and six of them had an allergic EGID attributed to CMPA. Serum specific IgE for milk and casein were positive in all the patients with acute symptoms (IgE mediated CMPA group) and in two thirds of the EGID group. Food protein-induced allergic proctocolitis (FPIAP) was the most common syndrome among patients with chronic symptoms (47.36% of all patients) ([Table 2]).
Table 2 Diagnosis of the CMPA patients with chronic GI symptoms

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After a period of 6–9 months of milk elimination, reevaluation of the patients was done. All patients were symptoms free on milk-free diet including the group with EGIDs. The weight-for-age scores improved; only 4.21% of the infants had Z score <−2 SD.

Tolerance to milk after milk re-introduction trial

After trial of gradual milk re-introduction in the patients’ diet, 60 (63.16%) patients acquired tolerance to cow milk proteins (tolerant group), whereas 35 (36.84%) patients did not acquire tolerance with reappearance of clinical symptoms after re-introduction of cow’s milk in their diet (intolerant group) ([Table 3]).
Table 3 Comparison of demographic and clinical characteristics between the intolerant and tolerant groups

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No significant statistical difference was found between the two groups regarding their sex, consanguinity, and mode of delivery or type of feeding. The following parameters were associated with intolerance: delayed diagnosis, delayed introduction of complementary food, rural residence, and family history of atopy. Patients with cross-reactivity to soya or with MFA had also delayed tolerance to cow’s milk.

Tolerance was achieved more frequently in patients with exclusive gastrointestinal symptoms when compared with patients with involvement of two or multiple body systems. However, in patients presented with chronic GI symptoms, this did not differ statistically in relation to the type of presenting symptom (diarrhea, colics, GERD, vomiting, or constipation). Most patients with FPIAP acquired tolerance to cow’s milk, whereas 70% of the patients with food protein-induced enterocolitis (FPIES) did not acquire tolerance (P=0.000). High levels of fecal calprotectin at presentation was found to have no statistical difference between both groups in acquisition of tolerance, whereas the need of GIT endoscopy was associated with delayed acquisition of tolerance (P=0.000). Patients with immediate GIT symptoms like oral allergy syndrome showed delayed tolerance (P=0.045).

Urticaria was associated with delayed tolerance. There was no statistical difference between the group of infants who experienced eczema or different acute or chronic respiratory symptoms and those who did not in acquisition of tolerance to cow’s milk later on.

Children with non-IgE-mediated CMPA had the highest rate of tolerance (75%) when compared with children with the other two types of CMPA (IgE mediated or mixed types) (P=0.000).


  Discussion Top


CMPA is common in infants in both developing and developed countries [20],[21]. It is the first form of food allergy in childhood and sometimes precedes the development of other types of allergies. The overall prognosis of CMPA is good, with a total recovery of 56% at 1 year, 77% at 2 years, 87% at 3 years, and 92% at 5 years [12],[22],[23]. There are scant published data on the clinical characteristics and prognosis of CMPA in Egypt. This study investigated the possible risk factors associated with delayed tolerance to cow’s milk protein in infants and children with CMPA after a 6–9-month period of elimination.

The study included a total number of 95 children who were confirmed to have CMPA. The mean age of the onset of CMPA symptoms was 2.18±2.2 months. This was similar to what was reported in many similar studies. The symptoms of CMPA can develop as early as the neonatal period or any time during the first year of life, and it tends to remit in early childhood [16],[22],[24].

A high cesarean section rate (85.3%) was observed among the studied group. Similar findings were reported (55.9%) by Yang et al. [25] in infants proven to have CMPA. This association is not precisely understood but may be related to infant’s gut microbiota composition. Cesarean section delivery is associated with dominance of skin-derived bacterial populations in the gut microbiota, which is associated with alterations in the gut microbiota or dysbiosis early in life that may be associated with development of atopy [4],[26],[27],[28]. The families of our patients were more commonly living in urban communities (55.7%). More urbanized lifestyle is associated with reduced microbial exposure, more antibiotic use, changes in diet, and vitamin D insufficiency, which may be responsible for the recent rise in food allergy. In the current study, we found a strong positive family history of food allergy or other atopic diseases in our patients (56.84%). Multiple studies confirmed that genetic predisposition and other shared environmental risk factors may play a significant role in the pathogenesis of CMPA [25],[29],[30].

In the present study, most of infants were formula fed (72.6%). Multiple researchers reported that formula feeding is an important risk factor for the development of CMPA. CMPA developed even in breast-fed infants who were just exposed few artificial feeds in the first three days of life [4],[25]. The potential for CM proteins to prime allergic sensitization underlies the hypothesis that early short-term exposure may initiate the development of CMPA. Moreover, the type of formula consumed in early life can determine the composition and diversity of the gut microbiota and influence food allergy resolution later [31]. Exclusive breastfeeding is the best primary prevention against the development of CMPA [24],[32]. In our cohort, early introduction of dairy milk products or unmodified Cow’s milk was observed in 37.9% of the infants. In this group, there was more rapid development or exaggeration of the clinical symptoms. Early introduction of dairy milk products triggers the sensitization to CM antigens in genetically susceptible infants. Early exposure to CM is a risk factor for the development of CMA. This relationship has been illustrated in many epidemiological and immunological studies [4],[32],[33].

In the present study, most patients presented with chronic symptoms (88.7%). The spectrum of clinical presentation was variable. Diarrhea was the commonest symptom (70.5%). Excessive regurgitation and vomiting were the second common symptoms reported (42.1%). Similarly, multiple studies reported that digestive symptoms were the most common, including regurgitation and vomiting, colic, diarrhea, and blood in stools [9],[10],[25]. Cutaneous and respiratory symptoms were less frequent (28.4 and 11.6%, respectively) in our cohort. Other researchers reported that most of their patients presented with cutaneous manifestations [16],[34]. Although the predominant type of clinical manifestation may depend on the type of specialty care where the study patients are enrolled and/or the ethnicity of the study population, there is a consensus that gastrointestinal or cutaneous symptoms are the predominant forms of presentation of cow’s milk allergy [9],[10],[23],[24]. In the current study, 17.89% of the studied children presented with malnutrition at the time of diagnosis. These patients had prolonged diarrhea, vomiting, and/or feeding refusal. Other surveys found that eczema, IgE-mediated reaction, and EE are also associated with slower growth rates in affected children [8],[34]. This can be attributed to the potential loss of nutrients caused by chronic inflammation and/or abnormal intestinal permeability and finally the higher protein and energy needs of children with moderate to severe eczema [35],[36].

After a period of 6–9 months of elimination diet, infants with CMPA were re-challenged by re-introduction of cow milk products into their diet. Children with CMPA should be challenged with CM proteins after 6–12 months of elimination and not before 12 months of age according to the symptoms [1],[9],[12]. However, no definite age was recommended for the process of re-challenge, rather than a range was advised because children vary in their tolerability to CMP according to the age of diagnosis, immunological status, and degree of sensitization to CMP. Guidelines also recommend against prolonged unnecessary dietary avoidance which can lead to nutritional inadequacies, affection of the quality of life of the whole family and unnecessary expenses [37],[38]. The rate of tolerance to CM in our cohort was 63.2%, which is comparable to the international rates. In Europrevall birth cohort study, 69% of children with confirmed CMA tolerated cow’s milk within 12 months of diagnosis (up to age 30 months) [6]. In another two studies, the tolerance was tested after a longer duration of elimination (12–18 months), and the rate of tolerance ranged between 65.2 and 77.3% [25],[34]. The variability in the rate of tolerance can be explained by differences regarding the ethnic and genetic background of the studied population, the setting and sub-specialty of the study, different patients’ demographics and clinical characteristics, the duration of elimination, and the process of re-challenge itself. The patients were referred to our tertiary center after a long period of undiagnosed symptoms. Many cases were using inappropriate formula, and many were even fed raw cow milk. Despite these unfavorable conditions, the rate of tolerance in our patients is comparable to the studies performed in more developed countries.

No significant statistical difference was encountered between the tolerant and intolerant groups regarding their sex, consanguinity, and mode of delivery. Similarly, no difference in these parameters was observed between subjects with persistent CMPA and the other subjects in the similar studies [15],[16],[34]. Family history of atopy in one of the first-degree relatives may be associated with persistence of CMPA in affected children [15],[16]. Similarly, in our study, positive family history of allergic diseases was more common in children with intolerance to milk on re-introduction after the period of elimination.

Infants with delayed diagnosis of CMPA showed a significant higher rate of intolerance to CM. The diagnosis of CMPA remains a clinical challenge as many symptoms are non-specific. Non-IgE-mediated CMPA is particularly difficult to diagnose as the time between contact with the offending protein and onset of allergic symptoms is delayed [5],[23]. This may be attributed to prolonged and repeated exposure to the offending allergens with more sensitization of the immune system causing a state of chronic gut inflammation resulting in malnutrition and associated co-morbidities. Approximately 62.9% of the intolerant infants were from rural areas. Rural residency was associated with delayed tolerance owing to lower socioeconomic and educational levels, which lead to delayed recognition of symptoms and delayed diagnosis.

Involvement of multiple body systems in the allergic response to milk is usually associated with more severe course and persistence of CMPA. Other similar studies reported that an allergic reaction to CMPA that included skin and respiratory symptoms was associated with persistence of CMPA, especially acute reactions like urticaria [16],[34],[39]. Infants who initially presented with isolated gastrointestinal symptoms and with low serum total IgE levels at the time of diagnosis had a better recovery rate [40]. Similarly, a higher rate of tolerance was achieved in our patients with exclusive gastrointestinal symptoms, whereas patients with involvement of the 3 body systems and/or had urticaria had delayed tolerance to CM. In the current work, infants with cross-reaction to soya or MFAs showed delayed tolerance to CMPA, which correlates with other studies [16],[34]. MFA is usually associated with elevated positive specific IgE and/or EGID; both of them are indicators of severe atopy with increased risk of persistent allergies.

Most infants with food protein-induced proctocolitis acquired tolerance to CMPA, whereas nearly half the infants with food protein-induced enterocolitis did not acquire tolerance to CMPA. Our results were parallel to other several studies, which showed that patients with proctocolitis were more likely to develop tolerance at the age of one year, whereas FPIES was associated with more severe forms of enteropathy, prolonged sensitization, and delayed tolerance [16],[34],[41],[42]. In our cohort, non-IgE CMPA had the highest rate of tolerance, whereas infants with IgE-mediated and mixed (eosinophilic) type of CMPA had lower rates. Our results are consistent with other studies, which showed that a non-IgE-mediated CMPA is associated with the earlier tolerance, and IgE-mediated reaction increased the probability of CMPA persistence with positive inverse relation to the level of serum-specific IgE to cow’s milk proteins [16],[17],[39],[43].

There are limited data about the factors that predict the development of tolerance in infants with CMPA in our community. To our best knowledge, this study is the first to highlight these factors in Egypt. This work was conducted as a prospective study which involved diagnostic and therapeutic interventions for 95 patients with CMPA. In conclusion, the tolerance rate after 6–9 months of elimination in our cohort was 63.2%, which is comparable to the international rates. IgE-mediated CMPA, FPIES, and CMPA-associated EGID have a poor prognosis when compared with other types of CMPA. Regardless of the mechanism of CMPA, delayed diagnosis, family history of atopy, cross-reactivity to soya, MFA, multiple involved body systems, and MFAs are associated with delayed tolerance and persistent CMPA to older age. A 6–9-month duration of milk avoidance was proved by this study to be safe in most of the infants and children with CMPA especially in infants and children with no risk factors for delayed tolerance. The elimination period should thus be tailored to every patient’s scenario, putting into consideration the mechanism of allergy, duration and type of symptoms, the presence of other food allergies, and the compliance to milk-free diet.

This work was limited by the short duration of follow-up. Other studies are needed to study the long-term clinical course and prognosis of patients with persistent CMPA. These studies will identify when the tolerance to cow’s milk protein will develop and what are prognostic factors. Recognitions of these predictive factors will definitely improve the management guidelines in infants and children with CMPA in our developing communities. Exclusive breastfeeding and vaginal delivery are associated with lower rates of allergy in childhood and both are highly recommended to fight against the global rising tide of atopy.

Acknowledgements

The research was supported by Alexandria Faculty of Medicine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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