Isa HM, Abdulnabi MJ, Naser NS, Lahmda FN, AlAnsari NM, Isa ZH, Mohamed AM. Clinical, laboratory, and therapeutic differences between immunoglobulin E-mediated and non-immunoglobulin E-mediated cow’s milk protein allergy in children. World J Clin Pediatr 2025; 14(1): 100386 [DOI: 10.5409/wjcp.v14.i1.100386]
Corresponding Author of This Article
Hasan M Isa, MBChB, Associate Professor, Consultant Physician-Scientist, Department of Pediatrics, Salmaniya Medical Complex, 2904 Al Salmaniya Area, PO Box 12, Manama 26671, Bahrain. halfaraj@hotmail.com
Research Domain of This Article
Allergy
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Clin Pediatr. Mar 9, 2025; 14(1): 100386 Published online Mar 9, 2025. doi: 10.5409/wjcp.v14.i1.100386
Clinical, laboratory, and therapeutic differences between immunoglobulin E-mediated and non-immunoglobulin E-mediated cow’s milk protein allergy in children
Hasan M Isa, Marwa J Abdulnabi, Nawra S Naser, Fatema N Lahmda, Noor M AlAnsari, Department of Pediatrics, Salmaniya Medical Complex, Manama 26671, Bahrain
Hasan M Isa, Department of Pediatrics, Arabian Gulf University, Manama 26671, Bahrain
Zahra H Isa, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
Afaf M Mohamed, Public Health Directorate, Ministry of Health, Manama 26671, Bahrain
Author contributions: Isa HM was the main contributor in study design, literature review, data analysis, drafting manuscript, and oversight for all phases of the project and the final approval of the version to be published; Abdulnabi MJ was responsible for literature review, data collection, data analysis, drafting and revising manuscript; Naser NS, Lahmeda FN, and AlAnsari NM were responsible for literature review, data collection, drafting and revising manuscript; Isa ZH was responsible for data collection, drafting and revising manuscript; Mohamed AM was responsible for data collection and revising manuscript; all the authors have read and approved the final manuscript.
Institutional review board statement: This study was conducted in accordance with the Principles of Helsinki Declaration and Received Ethical Approval from the Research and Research Ethics Committee at Salmaniya Medical Complex, Government Hospitals, Manama, Bahrain (No. 30036216, December 6, 2016).
Informed consent statement: Consent was not needed as the study was retrospective without exposure to the patient’s data. However, parental consent was obtained to publish the children’s photographs, and patient confidentiality was maintained by covering their eyes to obscure their identities.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Data are available upon reasonable request.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hasan M Isa, MBChB, Associate Professor, Consultant Physician-Scientist, Department of Pediatrics, Salmaniya Medical Complex, 2904 Al Salmaniya Area, PO Box 12, Manama 26671, Bahrain. halfaraj@hotmail.com
Received: August 14, 2024 Revised: October 8, 2024 Accepted: November 12, 2024 Published online: March 9, 2025 Processing time: 127 Days and 10.9 Hours
Abstract
BACKGROUND
Although breast milk is ideal for newborns, in some cases, it is replaced with cow’s milk, which contains proteins that increase the risk of cow’s milk protein allergy (CMPA).
AIM
To evaluate CMPA prevalence in Bahrain and compare clinical characteristics of children with immunoglobulin E (IgE)- and non-IgE-mediated CMPA.
METHODS
This retrospective cohort study examined children with CMPA diagnosed at the pediatric gastroenterology outpatient clinic of the Salmaniya Medical Complex, Bahrain, between 2014 and 2022, and assessed CMPA prevalence. Clinical presentations, laboratory findings, dietary modifications, and outcomes were compared between children with IgE-mediated and non-IgE-mediated CMPA. Categorical variables were compared using Fisher’s exact test or Pearson’s χ2 test, whereas continuous variables were compared using Student’s t-test or the Mann-Whitney U test.
RESULTS
Of 8332 patients, 6022 (72.3%) adhered to their appointment. Of them, 618 (10.3%) were suggested of having CMPA and 595 (96.3%) were included; CMPA prevalence was 2%. Most patients were Bahraini (93.8%) and males (55.3%). Non-IgE-mediated type accounted for 77.3% cases and IgE-mediated type, 22.7%. IgE-mediated CMPA presented more in boys (P = 0.030), and later in life (5.1 months ± 4.5 months vs 4.2 months ± 4.2 months, P = 0.016, 95%CI: 0.08-1.73), had more associated diseases (P < 0.001); and presented with more cutaneous (P = 0.024) and respiratory (P = 0.003) manifestations, severe symptoms [rash/dry skin (P = 0.031), facial swelling/angioedema (P = 0.003), failure to thrive (P = 0.013), apparent life-threatening event (P < 0.001)], and positive physical findings (P = 0.002) than non-IgE-mediated CMPA. Most patients were exclusively fed cow milk formula (50.3%). The amino acid-based formula (AAF) was most prescribed (60.5%) with no difference between the two types (P = 0.173). Although breastfeeding was recommended to 49.6%, only 8.2% were exclusively breastfed. IgE-mediated CMPA was associated with a longer follow-up duration than non-IgE-mediated CMPA (17.3 months ± 14.0 months vs 13.5 months ± 13.4 months, P = 0.005, 95%CI: 1.1-6.3).
CONCLUSION
This study revealed a high CMPA prevalence with clinical differences between both types that can influence treatment. AAF was most prescribed, while breastfeeding with dietary modification is rarely applied.
Core Tip: The prevalence of cow’s milk protein allergy (CMPA) in children in Bahrain and differences between immunoglobulin E (IgE)-mediated and non-IgE-mediated allergies have not been studied previously. In this retrospective cohort study, we found that CMPA, commonly the non-IgE-mediated type, affects 10.3% of children among those visiting outpatient pediatric gastroenterology clinics. IgE-mediated CMPA presents with more severe symptoms and physical findings than non-IgE-mediated CMPA. Despite being common, CMPA diagnosis depends on the clinical presentation. Amino acid-based formulas are frequently prescribed, whereas exclusive breastfeeding and maternal dietary restrictions are underutilized. Therefore, breastfeeding children with CMPA should be encouraged.
Citation: Isa HM, Abdulnabi MJ, Naser NS, Lahmda FN, AlAnsari NM, Isa ZH, Mohamed AM. Clinical, laboratory, and therapeutic differences between immunoglobulin E-mediated and non-immunoglobulin E-mediated cow’s milk protein allergy in children. World J Clin Pediatr 2025; 14(1): 100386
Breast milk is the ideal food for newborns on their first day. However, in some cases, mother’s milk is replaced with cow’s milk, which contains proteins that increase the risk of cow’s milk protein allergy (CMPA)[1-5]. CMPA is an immunological adverse reaction that develops secondary to exposure to specific foods[1,2,4-6]. Although 25 types of proteins are present in cow milk, only few are known to cause CMPA[3]. CMPA can be classified as immunoglobulin E (IgE)-mediated, non-IgE-mediated, or mixed type[7,8]. In IgE-mediated CMPA, reactions occur either upon direct intake of cow’s milk or through the maternal passage of proteins, specially β-lactoglobulin (in whey) and casein, via breastfeeding children aged < 2 years[3,5,7,9]. Moreover, sensitization to cow milk proteins may occur during pregnancy where the placenta plays a role in delivering proteins via fetal circulation, thus leading to IgE sensitization[1,3]. Sensitization to several proteins might develop in around 75% of children[3]. After exposure, cow milk proteins are identified by antigen-presenting cells that then activate naive T cells. Activated T cells differentiate into T helper 2 cells, which can release cytokines such as interleukin (IL)-4 and IL-13 that stimulate B cells. B cells then differentiate into plasma cells that begin producing milk-specific IgE antibodies in large amounts[10]. This IgE response varies in both intensity and specificity[3]. However, in non-IgE-mediated CMPA, destructive lesions and lymphocytic infiltration are involved[11,12]. In some cases, infants may develop mixed manifestations of both IgE-mediated and non-IgE-mediated reactions[3,7,13].
CMPA is a common disease in children[3,14,15], with a prevalence of 1%-5% in the Middle East[7]. CMPA affects the gastrointestinal (GI), respiratory, cutaneous, and nervous systems[4-7,14]. Immediate symptoms like severe anaphylactic reactions, eczema, conjunctivitis, angioedema, asthma, and migraine usually occur with an IgE-mediated reaction[3,7,11,14,16]. Nonetheless, some symptoms, mainly GI manifestations, have a delayed onset and develop after 2 hours to several days[3,7,11,14,16]. They are commonly present with diarrhea, vomiting or gastroesophageal reflux, and colicky cry[2,4,13,17,18]. Moreover, rectal bleeding in infants in their first 6 months of life is caused by allergic proctocolitis[6,9]. In addition, enteropathy, eosinophilic GI diseases, Heiner’s syndrome, type 1 diabetes mellitus, infantile colic, and the most serious form of GI manifestations “food protein-induced enterocolitis syndrome (FPIES)” are examples of delayed reactions[3,7,11,13,19]. These symptoms are usually associated with the non-IgE-mediated type[11,12].
According to the European Society for Pediatric Gastroenterology and Nutrition (ESPGHAN) position paper published in 2024, the gold standard diagnostic method for IgE-mediated CMPA is oral food challenge while for non-IgE-mediated CMPA, it is the reintroduction of cow’s milk[8]. Milk-specific IgE antibody testing and skin prick test are used for further confirmation in IgE-mediated diseases[6,7,11,14,19].
Although several studies about CMPA have been published worldwide[7,16,20-22], those from the Middle East are scarce. Apart from four consensus statements[7,16,23,24], no original studies about CMPA have been published from the Gulf Corporate Counsel countries, including the Kingdom of Bahrain. Therefore, this study aimed to assess the prevalence of CMPA in children from Bahrain and compare clinical presentations, laboratory findings, dietary modifications, and outcomes between children with IgE-mediated and non-IgE-mediated CMPA to help clinicians differentiate between these two types.
MATERIALS AND METHODS
Study design and setting
In this retrospective cohort study, the iSeha electronic medical and dietary records of all children presenting to the outpatient gastroenterology clinic, Department of Pediatrics, Salmaniya Medical Complex (SMC), Bahrain, with clinical symptoms and signs suggestive of CMPA between March 5, 2014, and December 31, 2022, were reviewed. In SMC, we have two pediatric gastroenterology clinics, one immunology clinic, and one dedicated pediatric dietetic clinic. CMPA diagnosis is based on a combination of clinical features, laboratory findings including IgE levels, and elimination diets and rechallenge. The diagnosis is made after a consensus agreement between the pediatric gastroenterologist, immunologist, and dietitian. Dietary modification advice is provided to breastfeeding mothers of children with CMPA, while for mothers who cannot continue breastfeeding, the extensively hydrolyzed formula (EHF) or amino acid-based formula (AAF) is initially prescribed for a trial period of 2 weeks and then continued free of charge up to the age of 1 year.
Study population
Children from birth up to the age of 14 years of both sexes and from all four governorates (Capital, Northern, Southern, and Muharraq) in Bahrain who were suggested of having CMPA were examined. Children who fulfilled the ESPGHAN Working Group diagnostic criteria of CMPA were included in the study[25]. Symptoms such as urticaria, rash, angioedema, wheezing or breathing difficulties, vomiting, abdominal distention, weight loss or gain, diarrhea, and bloody stools suggest CMPA. These can appear immediately within 1 hour of ingestion of cow’s milk or several hours to days after ingestion[25]. However, they disappear after the use of the EHF or AAF milk formula and recur after intake of the standard formula[25]. Patients were classified as having the IgE-mediated or non-IgE-mediated type based on the time from exposure to reaction, severity and duration of symptoms, or results of milk-specific serum IgE testing. Those who presented with symptoms within 2 hours of exposure, had severe reactions that persisted beyond 1 year of age, or had positive milk-specific serum IgE levels were considered of having IgE-mediated CMPA. Patients who developed reactions several hours or days after exposure, had mild-to-moderate severity of symptoms, recurrence of symptoms after rechallenging with standard formula, with symptoms resolved by 1 year or had negative milk-specific serum IgE levels were considered of having non-IgE-mediated CMPA. According to the clinical presentation, non-IgE-mediated CMPA was further classified into FPIES, food protein-induced enteropathy (FPE), and allergic proctocolitis[8,26-28]. FPIES is characterized by vomiting, abdominal pain, and diarrhea[26]. In the acute form, the symptoms develop within 24 hours after food ingestion, while in the chronic form, they develop after repeated ingestion and persist[8]. FPE has a similar presentation to celiac disease presenting with chronic diarrhea, steatorrhea, and failure to thrive (FTT)[8]. Allergic proctocolitis is characterized by the presence of blood and mucus in the stool[26,27]. Patients with infantile colic, lactose intolerance, idiopathic urticaria, toddler diarrhea, infective diarrhea, or missing CMPA-relevant clinical presentation data and milk-specific IgE testing results were excluded.
Data collection
Data on sex, nationality, geographical region (the four governorates), age at presentation, gestational age, type of delivery, birth weight, symptoms at presentation, family history of allergies, associated diseases, and physical findings were collected. Laboratory results, including white blood cell count; serum hemoglobin level; hematocrit percentage; mean cell volume; mean cell hemoglobin; platelet count; eosinophil count; serum albumin; alkaline phosphatase; calcium, phosphorus, iron, ferritin, and vitamin D levels; and milk-specific IgE level, were retrieved. Stool microscopy was performed for analyzing color and consistency and detecting the presence of red blood cells, white blood cells, occult blood, mucus, and fat globules; stool cultures were also conducted. Dietary modifications for breastfeeding mothers and infants, type of special milk formula used, and follow-up durations for CMPA were also recorded.
Statistical analysis
Patients’ data were entered into an Excel spreadsheet and analyzed using the Statistical Package for Social Sciences version 28. Missing data were excluded from the analysis of each variable. Categorical variables are presented as frequency and percentage. Patient age at presentation was categorized into four groups (< 6 months, ≥ 6-12 months, 13-24 months, and > 24 months), age at follow-up into another four groups (< 1 years, 1-3 years, 4-6 years, and > 6 years), and birth weight into two groups (< 2.5 kg and ≥ 2.5 kg). After normality distribution, continuous variables are presented as mean and standard deviation or median and interquartile range (IQR). Children with IgE-mediated CMPA were compared with those with non-IgE-mediated CMPA regarding clinical presentations, laboratory findings, dietary modifications, and outcomes. Categorical variables were compared using the χ2 test (Fisher’s exact test or Pearson’s χ2 test), whereas continuous variables were compared using Student’s t-test or the Mann-Whitney U test. Confidence interval (CI) was set at 95%, and effect size was estimated using Cohen’s d formula where 0.2 indicated small, 0.5 indicated medium, and 0.8 indicated large effect size. P values < 0.05 indicated statistical significance.
Ethical considerations
This study was conducted following the Principles of Helsinki Declaration and received ethical approval from the Research and Research Ethics Committee at SMC, Government hospitals, Manama, Bahrain (No. 30036216, December 6, 2016). Additionally, parental consent was obtained for the publication of the children’s photographs, and patient confidentiality was maintained by covering their eyes to obscure their identities.
RESULTS
Until December 2022, 8332 patients made an appointment at the gastroenterology outpatient clinics, and 6022 (72.3%) of them attended their appointments. Of them, 618 (10.3%) were diagnosed with CMPA. Based on the Statista website updated in 2023, the total population of Bahrain is 1524693, and 307835 (20.2%) are children aged < 14 years[29]. Accordingly, the prevalence of CMPA was estimated at 2% (200.8 patients per 100000). We observed an overall increasing trend in the annual incidence of CMPA with the non-IgE-mediated type as the main contributor (Figure 1). Twenty-three (3.7%) patients were excluded owing to missing data on clinical presentation and IgE test results. The remaining 595 (96.3%) patients were included in the study and were classified into either the IgE-mediated or non-IgE-mediated CMPA group. Most had non-IgE-mediated CMPA (n = 460, 77.3%) with a prevalence of 1.5%, while the remaining 135 (22.7%) had IgE-mediated CMPA with a prevalence of 0.4% (Figure 2). Among the non-IgE-mediated subtypes, allergic proctocolitis was most common (n = 182, 39.7%), followed by FPE (n = 166, 36.1%), chronic FPIES (n = 79, 13.3%), and acute FPIES (n = 33, 5.5%).
Figure 1 Incidence of cow’s milk protein allergy in children attended Pediatric Gastroenterology Clinics, Salmaniya Medical Complex, Kingdom of Bahrain, 2014-2022.
IgE: Immunoglobulin E.
Figure 2 Flow chart of children with suspected cow’s milk protein allergy who attended pediatric gastroenterology clinics, Salmaniya Medical Complex, Kingdom of Bahrain, 2014-2022.
CMPA: Cow’s milk protein allergy; IgE: Immunoglobulin E.
Demographic patient data are presented in Table 1. Most patients were Bahraini (n = 558, 93.8%), while others were non-Bahraini [n = 37, 6.2%; 10 (1.7%) from Pakistan; 8 (1.3%) from Egypt; 5 (0.8%) from India; 4 (0.7%) from Syria and Yemen; 2 (0.3%) from Jordan; and 1 (0.2%) each from the United States, China, Oman, and Tunisia]. Three hundred and twenty-nine (55.3%) patients were boys and 266 (44.7%) were girls. IgE-mediated CMPA was significantly more common in boys than in girls (P = 0.030). The median age at presentation was 3 months (IQR: 2-5 months), and the most common age group was < 6 months (n = 464; 78.0%). Patients with IgE-mediated CMPA presented later than those with non-IgE-mediated CMPA (5.1 months ± 4.5 months vs 4.2 months ± 4.2 months, P = 0.016, 95%CI: 0.08-1.73 and Cohen’s d = 0.211, 95%CI: 0.02-0.40, indicating small-to-medium effect). Associated diseases were noted in 226 (38.0%) patients. Patients with IgE-mediated CMPA had a higher percentage of associated diseases than those with non-IgE-mediated CMPA (51.9% vs 33.9%, P < 0.001). Bronchial asthma was the most frequently associated disease [n = 64 (10.8%)], with no significant difference between the two types of CMPA. Other food allergies, hypoxic-ischemic encephalopathy, and cystic fibrosis were more strongly associated with IgE-mediated CMPA (P < 0.001, P = 0.034, and P = 0.003, respectively; Supplementary Table 1). A family history of allergy was recorded for 222 (37.3%) patients, and 130 (21.8%) had a family history of CMPA.
Table 1 Demographic data in children with cow’s milk protein allergy, n (%).
GI manifestations were most common (n = 567, 95.3%) in both types, followed by cutaneous manifestations (n = 278, 46.7%; Table 2). Specifically, vomiting (n = 282, 47.4%) was followed by rash/dry skin (n = 277, 46.6%). Patients with IgE-mediated CMPA presented with more cutaneous and respiratory manifestations than those with non-IgE-mediated CMPA (P = 0.024 and P = 0.003, respectively). They also had more severe symptoms, including rash/dry skin (P = 0.031), facial swelling/angioedema (P = 0.003), FTT (P = 0.013), and apparent life-threatening events (P < 0.001) than those with non-IgE-mediated CMPA. Regarding symptomatology of the non-IgE-mediated type, some patients had more than one symptom, and some symptoms were overlapping between the various subtypes. Patients with allergic proctocolitis presented mainly with frank blood in stool (n = 104, 57.1%), followed by mucus in stool (n = 80, 43.9%), diarrhea (n = 65, 62.5%), constipation and vomiting (n = 56, 53.8% each), colic (n = 51, 49.0%), and FTT (n = 24, 23.1%); along with cutaneous manifestations (rash/dry skin) (n = 61, 33.5%), and respiratory manifestations (n = 4, 2.2%). Patients with FPE presented mainly with chronic diarrhea (n = 79, 47.6%), followed by vomiting (n = 63, 37.9%), constipation (n = 50, 30.1%), FTT (n = 45, 27.1%), colic (n = 38, 22.9%), and steatorrhea (n = 4, 2.4%); along with cutaneous manifestations (rash/dry skin) (n = 83, 50.0%), and none had respiratory manifestations. Patients with FPIES presented mainly with repetitive vomiting (n = 102, 91.1%), followed by constipation (n = 47, 41.9%), colicky abdominal pain (n = 31, 27.7%), and none reported diarrhea; along with cutaneous manifestations (rash/dry skin) (n = 59, 52.7%), and respiratory manifestations (n = 1, 0.9%). However, their stool analysis revealed loose stool in 31.5% (n = 17/54). Most patients had normal physical examination results (n = 387, 65.7%), with their number higher in the non-IgE-mediated group than in the IgE-mediated group (P = 0.002). The most frequent positive physical finding was signs of eczema (n = 147, 25.0%), which were more frequent in IgE-mediated than in non-IgE-mediated CMPA (54.8% vs 44.1%, P = 0.004). Examples of clinical presentations of infants with CMPA are shown in Figure 3.
Figure 3 Examples of clinical presentation of infants with cow’s milk protein allergy.
A: A four-month-old infant with cow’s milk protein allergy (CMPA) and facial eczema at presentation; B: The same patient after changing to extensively hydrolyzed formula feeding; C: Another four-month-old infant with eczema in the forehead; D: The same infant with peri umbilical erythematous lesion (arrow); E: Stool of an infant with CMPA before treatment; F: Stool of the patient after starting extensively hydrolyzed formula.
Table 2 History and physical examination findings of children with cow’s milk protein allergy, n (%).
Children with IgE-mediated CMPA had lower serum calcium levels (2.45 mmol/L ± 0.13 mmol/L vs 2.51 mmol/L ± 0.15 mmol/L, P = 0.003, 95%CI: -0.09 to -0.02 and Cohen’s d = 0.369, 95%CI: 0.12-0.62, indicating small-to-medium effect) and phosphorus levels (1.83 mmol/L ± 0.27 mmol/L vs 1.90 mmol/L ± 0.28 mmol/L, P = 0.022, 95%CI: -0.14 to -0.01, and Cohen’s d = 0.278, 95%CI: 0.04-0.52, indicating small effect) than those with non-IgE-mediated CMPA (Supplementary Table 2). No other significant laboratory differences were found between the two groups (Table 3). Leukocytosis was found in 41.7% of patients and was higher in non-IgE−mediated than in IgE-mediated CMPA (42.6% vs 39%); however, the difference was not significant (P = 0.520). Most patients were anemic (n = 424, 75.3%), with hypochromic microcytic anemia due to iron deficiency observed in 54.8% of patients. There were no significant differences between the two types in the case percentage of thrombocytosis (47.4%), low vitamin D level (30.3%), hypoalbuminemia (18.4%), high alkaline phosphatase level (13.3%), hypocalcemia (5.9%), eosinophilia (4.2%), and hypophosphatemia (1.5%). High IgE levels were detected in 50.4% (n = 121/240) of patients: (1) 97.6% with IgE-mediated CMPA; and (2) None with non-IgE-mediated CMPA.
Table 3 Laboratory findings in children with cow’s milk protein allergy, n (%).
Stool analysis data are presented in Supplementary Table 3. The most common stool color was brown (n = 139, 46.6%), whereas the most common consistency was formed stool (n = 220, 73.8%). The stool test result was positive for white blood cells, red blood cells, mucus, fat globules, and occult blood in 67 (22.1%), 48 (15.8%), 36 (12.1%), 32 (10.7%), and 17 (21.1%) patients, respectively, with no significant differences between the two types of CMPA.
Nutritional data were available for 586 (98.5%) patients (Table 4). Most patients were exclusively fed cow milk formula (n = 295, 50.3%). While breastfeeding was recommended to 291 (49.6%) patients, only 48 (8.2%) were exclusively breastfed. The median breastfeeding duration was 3 months (IQR: 1.5-8 months). Mothers of the 291 breastfed patients received dietary advice to avoid dairy products while breastfeeding: (1) 241 (82.8%) complied; and (2) 50 (17.2%) discontinued breastfeeding and switched to exclusive formula feeding. On follow-up, it was noted that 202 (69.4%) mothers strictly avoided dairy products per the advice. AAF was most frequently prescribed (n = 322, 60.5%), followed by EHF (n = 300, 56.4%). There were no significant differences in feeding between the two types of CMPA (P = 0.173 and P = 0.301, respectively).
Table 4 Types of feeding in children with cow’s milk protein allergy, n (%).
The follow-up duration was 14.4 months ± 13.6 months. Patients with IgE-mediated CMPA had a longer follow-up duration than those with non-IgE-mediated CMPA (17.3 months ± 14.0 months vs 13.5 months ± 13.4 months, P = 0.005, 95%CI: 1.1-6.3 and Cohen’s d = 0.276, 95%CI: 0.08-0.47, indicating small effect).
DISCUSSION
CMPA prevalence in children is generally high[3,14,15]. This study found that the prevalence in children in Bahrain was 2%. Moreover, CMPA accounts for 10.4% of pediatric gastroenterology outpatient clinic visits; however, Mehaudy et al[22] from Argentina reported a lower prevalence of 0.8%. In contrast, Elmahdy et al[20] from Egypt, Suh et al[30] from Korea, and Irani and Maalouly[31] from Lebanon reported a higher prevalence of CMPA at 3.4%, 4.5%, and 14%, respectively. Nonetheless, underestimation or overestimation of CMPA prevalence is a frequent phenomenon in the literature[8]. This is attributed to the wide spectrum of symptoms and signs at presentation, lack of specific diagnostic biomarkers, overlap with other medical conditions such as gastroesophageal reflux, and variations in study settings[8]. This difference in prevalence can also be attributed to variations in study design and inclusion criteria, environmental exposure, and healthcare accessibility. Moreover, the presence of food allergies in other family members might indicate genetic susceptibility to the disease but with no specific gene detected[21]. AbdulAal and Alalwan[32], from Bahrain, reported that 49.3% of the patients with food allergies were diagnosed by a family member, indicating increased awareness of food allergies among the population in Bahrain, which might also explain the increasing trend in the annual incidence of the disease in this study.
This study had a higher proportion of children with non-IgE-mediated CMPA than with IgE-mediated CMPA. This could be attributed to the fact that children with non-IgE-mediated CMPA were referred to the gastroenterology outpatient clinic, owing to the predominance of GI symptoms, instead of an allergy clinic. Most studies focus on only one type of CMPA, the IgE-mediated type, and do not compare between the two types[33,34].
The current study showed a male predominance (63.7%) among children with CMPA. However, the cause for this has not been extensively studied. A reasonable explanation may be the higher male birth rate in Bahrain. According to Bahrain’s national registry from 2014 to 2020[35], a consistently higher birth rate of males than females was recorded, ranging between 50.5% and 51.7%. Similar to our study, those by Katry et al[21], Toro Monjaraz et al[5], Lozinsky et al[13], and Suh et al[30] revealed male predominance at 51%, 54.5%, 55%, and 66.9%, respectively. Moreover, Elmahdy et al[20] from Egypt reported more affection for males, explained by the higher preference for male sex in Egyptian culture and genetic predisposition. However, other studies reported female predominance[4,6,12,36]. This study also showed that males were more significantly prone to IgE-mediated CMPA, whereas females were more prone to non-IgE-mediated CMPA. Nevertheless, a Spanish study showed a similar percentage of male and female patients with IgE-mediated CMPA[1].
Food allergies are among the most common problems encountered in early childhood[26]. As milk is the first food introduced into one’s diet, the development of allergies to milk begins in early infancy before other types of allergies[37]. In the present study, the median age at the time of diagnosis was 3 months (IQR: 2-5 months), with the age group < 6 months being the most common (78.0%). Comparably, Al-Beltagi et al[26], Martorell et al[1], and Lins et al[38] reported median ages at diagnosis of 3.5 (10 days to 10 months), 5.4 (1-12 months) months, and 5 (2-9 months) months, respectively. Yet, Malekiantaghi et al[36] reported a lower median age at diagnosis of 60 days (IQR: 30-90 days). However, Merras-Salmio et al[12] reported a higher median age of 8.7 months (IQR: 2.4-40.8 months). This difference may be explained by variations in the study population and CMPA type.
Unexpectedly, the current study found that children with non-IgE-mediated CMPA presented earlier than those with IgE-mediated CMPA; however, the IgE-mediated type has more severe symptoms that most probably force parents to promptly seek medical care. Consequently, some of our patients were taken to the emergency department for immediate management or hospital admission. They were referred late to an outpatient clinic after discharge, which might explain their late presentation.
In the present study, a positive family history of allergies was found in 37.3% cases. Similarly, Elmahdy et al[20] reported a positive family history of allergy in 37%. Yet, Suh et al[30] and Meyer et al[39] studies noted a higher percentage of 49.6% and 67.7%, respectively. It is well known that children with a positive family history of allergic diseases are more prone to developing food allergies including CMPA[40].
In this study, GI manifestations were found to be the most common presentation of CMPA, and vomiting (47.4%) was the main symptom. However, Chong et al[34] reported that GI manifestations including vomiting, abdominal pain, and diarrhea were secondary presentations (28.8%). Although Epifanio et al[2] reported a higher percentage of vomiting cases (70%), it was the second presentation after irritability (100%), which accounted for only 5% of our cases. This difference can be explained either by poor documentation of the irritability symptom or owing to prior treatment for infantile colic. Moreover, Malekiantaghi et al[36] reported that the most common manifestation was gastroesophageal reflux disease (47%). Nonetheless, Merras-Salmio et al[12] reported other GI symptoms such as constipation, loose stools, and flatulence, and crying was the main symptom parents noticed in their infants. However, in few cases with confirmed CMPA, blood in stool was the main symptom[2]. In this study, blood in stools was found in 21.2% of patients. This variation in presenting symptoms complicates the clinical diagnosis of CMPA[2]. In the present study, most of the patients with IgE-mediated CMPA presented with GI manifestations (94.8%), followed by cutaneous manifestations (55.6%), and only a few of them had angioedema (3.0%) or urticaria (1.5%). In contrast, Chong et al[34], reported that 92.4% of patients with IgE-mediated type presented to an allergy center with cutaneous manifestations, while only 28.8% presented with GI manifestations. This variation could be attributed to the differences in the study setting as our patients were referred to gastroenterology clinics, and not to allergy clinics. Regarding constipation and blood in stool, although these symptoms are atypical features of the IgE-mediated type, they have been previously reported in both types of CMPA. Romańczuk and Samojedny[41] conducted a large comparative study of 325 children with chronic constipation with or without food allergy, 179 (55.1%) of them had IgE-mediated allergy, and they concluded that food allergy can be clinically presented as constipation and IgE-mediated allergy may significantly prolong total and segmental colonic transit time. Moreover, patients with IgE-mediated CMPA can present with bloody stool[26]. Furthermore, in our study, these findings could also be explained by the coexistence of other food allergies, which were significantly higher in the IgE-mediated group (15.6% vs 5.4%, P < 0.001, see Supplementary Table 1).
The current study showed that rash/dry skin was the second most common presentation (46.6%) and was significantly more frequent in children with the IgE-mediated type. However, 25.0% of our patients showed signs of eczema on physical examination. In the study by Chong et al[34], cutaneous manifestations (rash, angioedema) were the most common symptoms in 92.4%, but their study included only IgE-mediated cases. This difference could be explained by the fact that some of our patients were examined by a general pediatrician and/or dietitian before their presentation to the GI clinic, and their milk formula had changed, which might have subsided the eczema. Nonetheless, the prevalence of eczema was much higher than that in children from Bahrain, which was estimated at 9.8% and 10.8% by Al-Sindi et al[42] and AbdulAal and Alalwan[32], respectively. The study by Meyer et al[39] from the United Kingdom also reported a higher percentage of eczema association (41%). Moreover, Suh et al[30] reported that one-third of patients with atopic dermatitis had CMPA. Notably, most reviewed studies did not mention physical findings in children with CMPA[13,20,39].
In this study, 38.2% of patients had associated diseases, which was significantly more frequent in the IgE-mediated type than in the non-IgE-mediated type. The most common associated disease was bronchial asthma (10.7%); its prevalence is comparable with that reported by Al-Sindi et al[42] in children from Bahrain (10.8%). However, in another study from Bahrain, AbdulAal and Alalwan[32] reported a lower prevalence of asthma (5.9%). This variation could be explained by the difference in age groups included in each study. Nevertheless, Meyer et al[39] reported a higher percentage of bronchial asthma association (32.1%). This might be attributed to including children with all types of food protein-induced GI allergies. Moreover, Irani and Maalouly[31] noted that 51% of patients with a food allergy have other allergic diseases. Furthermore, Katry et al[21] reported that 17% of their patients had other known allergies and atopic tendencies. This association of CMPA with other types of allergic diseases might support the atopic march hypothesis and the possibility of shared pathophysiology of these diseases[43].
Although it might be an unrelated condition to CMPA, we found that hypoxic-ischemic encephalopathy was more strongly associated with IgE-mediated CMPA. However, to the best of our knowledge, no previous studies have shown this association. This association might be explained by ischemia of the GI system, leading to tissue damage and increased intestinal permeability, causing leakage of cow milk protein antigens into the systemic circulation and subsequent synthesis of milk-specific IgE antibodies. However, further research is warranted.
History taking and physical examination are the main steps to diagnose CMPA[3,6,7,14,18]. No laboratory or imaging studies with good sensitivity and specificity exist that can be used for confirmation of this disease[2,6]. The gold standard diagnostic method of a food allergy is the double-blinded, placebo-controlled food challenge (DBPCFC) test[3,6,7,12,30]. Although the DBPCFC test is currently the most standard diagnostic method for food allergies, it is less feasible and most caregivers refrain from consenting to this considering the high disease prevalence[3,6-8,30]. Therefore, CMPA diagnosis in this study was dependent on patient history, physical findings, and basic laboratory testing with or without milk-specific IgE antibody testing. In vitro testing, milk-specific IgE antibody testing, and puncture skin tests are used for further confirming IgE-mediated CMPA[3,6,7,11,14]. While the skin prick test is not preferred, intradermal skin tests should not be used owing to the risk of anaphylaxis in children[7]. In addition, two studies suggested color Doppler ultrasound as a screening tool[2,9]. Nonetheless, most reviewed studies focused only on one type of CMPA, IgE-mediated, and rarely compared the two types[1,30].
Laboratory results are important to differentiate between CMPA types. In our study, positive milk-specific IgE results were detected in 50.4% of tested patients. However, a study from Egypt on 100 patients with suspected CMPA showed that only 15.5% had positive milk-specific IgE[20]. Elevated milk-specific IgE levels indicate IgE-mediated CMPA, while low or undetectable IgE levels indicate non-IgE-mediated CMPA. In this study, a high IgE level was detected in 97.6% of patients with IgE-mediated CMPA and in none with non-IgE-mediated CMPA. In line with our findings, D’Auria et al[27] showed that patients with allergic proctocolitis, a subtype of non-IgE-mediated CMPA, tested negative for milk-specific IgE in 93.7% cases. In our study, the stool test result was positive for white blood cells, red blood cells, mucous, and occult blood in 22.1%, 15.8%, 12.1%, and 21.1% of patients, respectively, with no significant difference between the two types of CMPA. In non-IgE-mediated CMPA, the presence of white and red blood cells in the stool indicates proctocolitis[9,27], which was the most common subtype of non-IgE-mediated CMPA in our study. Other laboratory results can also help assess the impact of CMPA as a disease on the macro- and micronutrient status of affected infants. Compared with the general pediatric population, children with CMPA are more prone to multiple nutritional deficiencies resulting in anemia, iron deficiency, hypocalcemia, and vitamin D deficiency[8,21]. Although this study did not show differences in most laboratory findings between the two types of CMPA, it highlighted the importance of investigating patients with CMPA for micronutrient deficiencies that can be easily overlooked. Early detection of the CMPA type and associated nutrient deficiencies can influence treatment strategies and improve patient outcomes[8,27,33].
Education, supervision, and avoidance (removal) of cow milk protein from the child and breastfeeding mother’s diets are crucial for managing and treating CMPA[2,3,6,7,13]. In formula-fed infants, the best alternatives are EHF or AAF[3,6,7,11,16]. The current study noted that most patients (91.8%) received either milk formula exclusively (50.3%) or a combination of both formula and breastfeeding (41.5%), whereas a minority were exclusively breastfed (8.2%). This reflects the low prevalence of exclusive breastfeeding in Bahrain (5.5%), which might be attributed to the short official childbirth leave (2 months) allowed for working mothers after delivery[44]. These findings support the theory that breastfeeding protects against CMPA development. Toro Monjaraz et al[5] and Elmahdy et al[20] reported that patients with CMPA had lower breastfeeding rates than those without CMPA. This may be attributed to the immunological factors present in breast milk, along with differences in the intestinal microbiota that may play a role in allergy prevention[45].
Despite EHF being cheaper and having a similar efficacy[7], the current study showed that most patients (60.5%) received AAF. Similarly, Meyer et al[39] reported that 53.4% were administered AAF. Conversely, Merras-Salmio et al[12] noted that only 19% were administered AAF. Malekiantaghi et al[36] also reported that only 24.3% were administered AAF, while most (54%) were administered EHF. A recent systematic review by the World Allergy Organization suggested that EHF is most beneficial with respect to patient outcomes[46]. However, the study by Miqdady et al[47] that was conducted in three Gulf Cooperation Council countries (Saudi Arabia, Kuwait, and United Arab Emirates) found that the use of AAF is cheaper from the healthcare payer’s perspective, which might be also applied in Bahrain. This variation in the milk formula type used can be attributed to the study setting, population, and prevalence of IgE-mediated CMPA along with the economic status of the country. Another explanation is that our study was conducted at the main tertiary hospital in Bahrain, where more severe cases are referred for treatment.
Although insignificant, this study showed that the use of a high-energy formula was greater among children with IgE-mediated than with non-IgE-mediated CMPA. This might be explained by their higher presentation with FTT than those with non-IgE-mediated CMPA (24.4% vs 15.0%, P = 0.013). Katry et al[21] also reported FTT in their patients with CMPA, including both IgE and non-IgE types, but with a higher percentage (60.94%). Although IgE-mediated CMPA is an acute reaction, children with this type of allergy can develop FTT even before the dietary restriction. This might be attributed to the severe GI symptoms such as vomiting and diarrhea that may affect the absorption of essential nutrients, leading to growth impairment[28,34]. Moreover, CMPA can lead to aversions to certain foods, making maintaining a balanced diet challenging[2]. Nonetheless, most reviewed studies did not compare FTT between the IgE and non-IgE types. Even after managing CMPA, FTT can develop owing to the dietary restriction of preventing all dairy product intake[12]. Thus, these patients will require regular and long-term nutritional assessment.
The prognosis of CMPA is reasonably good[30]. There is a difference in the rate of resolution according to the type of allergy (IgE, non-IgE, or mixed type)[13,30]. However, by the age of 3 years, most infants will overcome this allergy[3,13,30]. This study showed a mean follow-up duration of 14.4 months, and patients with IgE-mediated CMPA had a significantly longer follow-up duration than those with non-IgE-mediated CMPA (P < 0.005). However, a study by Suh et al[30] reported a longer mean duration of follow-up of 47.0 months ± 20.4 months. This difference might be explained by the inclusion of patients with only CMPA and atopic dermatitis in their study.
This study has some limitations. Regarding generalizability of results to other populations, this study is a single tertiary center study and, subsequently, its results cannot be generalized to the entire population. Despite our hospital being the main tertiary hospital in Bahrain that provides the expensive specialized infant formula free of charge to this group of patients, some patients might be treated in private sectors or other hospitals. This might raise the potential for sample selection bias. Moreover, owing to the retrospective nature of this study, establishing causality was a challenge and some missing laboratory information was expected, leading to information bias. Reliability of the diagnostic methods is also an issue in this study. Although milk-specific IgE level is important to confirm the diagnosis of IgE-mediated CMPA, not all patients were tested for serum IgE levels as this was not a mandatory diagnostic criterion. Moreover, despite the fact that the diagnosis of the IgE-mediated group was based on clinical presentations and laboratory findings including the positive milk-specific IgE testing[25], the presence of patients with mixed type could not be fully guaranteed due to the overlapping symptoms of both types of CMPA. Most of the reviewed studies did not compare the symptoms between the two types, and the mixed type of this disease is particularly underreported. Besides, CMPA studies from the Middle East are extremely limited and most publications were consensus statements or reviews[7,16,23,24]. To the best of our knowledge, no original studies have been reported from countries neighboring Bahrain who share similar dietary habits including Saudi Arabia, Oman, United Arab Emirates, Qatar, Kuwait, or Iraq. This made the comparison of our findings with those of other studies difficult. Despite these limitations, this study is the first report about CMPA in children from Bahrain and, to the best of our knowledge, in this region of the world. Moreover, it covered all aspects of CMPA from prevalence to outcome. Furthermore, our sample size was large considering the small population of Bahrain. The findings of this study will help general practitioners as well as pediatricians by improving their knowledge about this common condition in children and can facilitate their clinical practice, particularly in choosing the best treatment for CMPA. This study shows clinical, laboratory, and therapeutic differences between the two types of CMPA. These findings are important for improving the diagnostic accuracy of each type of CMPA and ensuring appropriate management plans and therapeutic interventions. This study recommends continuing to encourage breastfeeding while treating children with CMPA, starting the appropriate type of milk formula based on the CMPA type, and detecting and correcting earlier any associated nutritional deficiencies to improve patient outcomes. This study encourages future prospective studies on investigating biomarkers to distinguish IgE and non-IgE-mediated CMPA and assessing the long-term outcome and socioeconomic impact of each type of CMPA.
CONCLUSION
This study found that CMPA is a common condition affecting children in Bahrain. Non-IgE-mediated CMPA was more common than IgE-mediated CMPA. The disease can present with a variety of symptoms but most commonly with GI manifestations and, specifically, vomiting. The IgE-mediated type presents with more severe symptoms such as rash/dry skin, facial swelling/angioedema, FTT, and apparent life-threatening events than the non-IgE-mediated type that presents with less severe symptoms such as vomiting, colic, and blood and mucus in the stool. Most patients had normal physical examination findings, more common with non-IgE-mediated CMPA. Children with the IgE-mediated type had more positive physical findings with signs of eczema being the most common. Association with other diseases was also found to be significantly more frequent in IgE-mediated CMPA. Bronchial asthma was the most frequent associated disease. AAF was most prescribed for both types, while breastfeeding with dietary modification is rarely applied. Distinction between IgE-mediated and non-IgE-mediated CMPA can influence physicians’ decision-making on the best treatment modality. Clinicians are encouraged to differentiate between the types of CMPA using their clinical skills and appropriate laboratory investigations. Moreover, they are expected to promote the continuation of breastfeeding while treating infants with CMPA and tailor their therapeutic alternatives based on the child’s assessment via using the right choice of specialized milk formula. A cheaper and better-tasting EHF is an option for non-IgE-mediated CMPA, whereas an expensive AAF should be reserved for IgE-mediated CMPA. Prospective studies are warranted on navigating laboratory biomarkers to differentiate between IgE-mediated and non-IgE-mediated CMPA, focusing on the best method to diagnose each type of CMPA, assessing the utility of the milk ladder technique in inducing tolerance to cow milk proteins, and analyzing long-term outcomes of these patients and their relation to the development of other immunological disease such as diabetes mellitus.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge all those who provide care for children with cow’s milk protein allergy at the Department of Pediatric, Salmaniya Medical Complex, Government Hospitals, Kingdom of Bahrain. The authors also would like to thank staff in the Department of Medical Record for providing the list of outpatient visits.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
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