Cow milk protein allergy mimics in infancy

Abstract

Cow milk protein allergy (CMPA) is a prevalent food allergy in infancy. It often presents with symptoms that overlap with other conditions, such as gastroesophageal reflux disease, lactose intolerance, food protein-induced enterocolitis syndrome, and eosinophilic esophagitis. This diagnostic overlap makes distinguishing CMPA from its mimics difficult, resulting in potential misdiagnoses and unnecessary dietary restrictions. This review aims to comprehensively analyze CMPA and its mimicking conditions, highlighting their clinical presentations, diagnostic approaches, and management strategies to enhance diagnostic accuracy and optimize patient care. A systematic literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar, focusing on studies published within the last 20 years. Articles addressing CMPA and its mimicking conditions were selected, with data synthesized into comparative analyses of diagnostic methods and management strategies. Accurate differentiation between CMPA and its mimics requires a thorough clinical evaluation supported by diagnostic tests such as skin prick tests, serum-specific IgE, and oral food challenges. Misdiagnosis can lead to nutritional deficiencies, psychological stress, and increased healthcare costs. Emerging diagnostic technologies, including component-resolved diagnostics and cytokine profiling, offer promising avenues for improving accuracy. A multidisciplinary approach involving pediatricians, allergists, and dietitians is essential for precise diagnosis and effective management. Ongoing research and education are crucial to enhancing clinical outcomes and reducing the burden on families.

Key Words: Cow milk protein allergy; Diagnostic challenges; Mimicking conditions; Gastroesophageal reflux disease; Lactose intolerance; Food protein-induced enterocolitis syndrome; Eosinophilic esophagitis

Core Tip: This review emphasizes the diagnostic challenges of cow milk protein allergy and its mimicking conditions in infancy, including gastroesophageal reflux disease, lactose intolerance, food protein-induced enterocolitis syndrome, and eosinophilic esophagitis. Accurate differentiation between these conditions is essential for appropriate management and preventing unnecessary dietary restrictions that can lead to nutritional deficiencies and psychological stress. A comprehensive diagnostic approach, combining clinical history, diagnostic tests, and exclusion diets, is crucial. Emerging technologies such as component-resolved diagnostics and cytokine profiling show promise in improving diagnostic accuracy. Healthcare providers must adopt a multidisciplinary approach to ensure timely, precise diagnosis and effective management for optimal patient outcomes.

INTRODUCTION

Cow’s milk is a complex nutritional fluid composed primarily of water, carbohydrates, fats, proteins, vitamins, and minerals. The protein content, which constitutes about 3.2% of milk, is divided into two main categories: Casein (approximately 80%) and whey (about 20%)[1]. Casein proteins, including alpha-S1- and S2- casein, beta-casein, and kappa-casein, form micelles that provide milk with its white appearance and are essential for transporting calcium and phosphate. Whey proteins, such as beta-lactoglobulin, alpha-lactalbumin, bovine lactoferrin, bovine seroalbumin, and immunoglobulins, remain soluble in milk after casein coagulation and are rich in essential amino acids[2]. Cow’s milk whey and casein proteins have more than 20 potentially allergenic proteins, such as bovine immunoglobulins, α-lactalbumin, β-lactoglobulin, and caseins[3]. Cow milk protein allergy (CMPA) is an immune-mediated adverse reaction to proteins found in cow's milk. It occurs due to an abnormal immune response, which can be either IgE-and non-IgE-mediated. IgE-mediated CMPA involves immediate hypersensitivity reactions caused by IgE antibodies, while non-IgE-mediated delayed reactions caused by other immune pathways, often involving the gastrointestinal system[4]. CMPA typically presents in infancy, often within the first year of life, when cow’s milk or cow’s milk-based formula is introduced. It may affect multiple organ systems, including vomiting, diarrhea, bloody stools, constipation, colic, urticaria, eczema, angioedema, wheezing, chronic cough, and nasal congestion[5]. CMPA is one of the most common food allergies in infants, with a reported prevalence of 2%-2.8% in developed countries. Prevalence may vary based on geographic regions, dietary practices, and diagnostic criteria. It is more common in formula-fed infants than exclusively breastfed infants, as breast milk naturally excludes cow’s milk proteins unless the mother consumes cow’s milk in her diet[6]. Understanding the prevalence and clinical variability of CMPA is crucial for differentiating it from other mimicking conditions in infancy.

Diagnosing CMPA is often challenging because its symptoms overlap significantly with other conditions, particularly in infancy. CMPA can present with symptoms affecting the gastrointestinal, respiratory, or dermatological systems, which are not unique to CMPA. Gastrointestinal symptoms like vomiting, diarrhea, or abdominal discomfort may also occur in lactose intolerance, gastroesophageal reflux disease (GERD), or food protein-induced enterocolitis syndrome (FPIES)[7]. Dermatological symptoms like eczema or urticaria can be mistaken for atopic dermatitis unrelated to food allergies. Respiratory symptoms like wheezing or nasal congestion may mimic viral respiratory infections or asthma[8]. CMPA symptoms may overlap with common infantile disorders. Conditions such as GERD, colic, and functional gastrointestinal disorders are prevalent in infancy and share symptoms with CMPA, often leading to diagnostic confusion. In addition, symptoms like irritability, regurgitation, and feeding difficulties are frequently attributed to CMPA without confirmatory tests, resulting in potential overdiagnosis[9].

It is also important to differentiate IgE-mediated from non-IgE-mediated CMPA (Table 1). IgE-mediated CMPA presents with immediate symptoms, such as hives or anaphylaxis, making identification easier. Non-IgE-mediated CMPA, on the other hand, involves delayed symptoms, such as chronic diarrhea, failure to thrive, or blood in stools, which are harder to attribute directly to CMPA. Standard diagnostic tools (e.g., skin prick tests (SPT), serum-specific IgE) are reliable for IgE-mediated allergies but have limited utility for non-IgE-mediated CMPA[7]. In non-IgE-mediated cases, diagnosis often relies on exclusion diets and reintroduction challenges, which can be time-consuming and stressful for families. The frequent attribution of non-specific symptoms to CMPA may lead to misdiagnosis, resulting in the unnecessary elimination of cow’s milk from the infant’s diet. This can impose emotional and financial burdens on families and increase the risk of nutritional deficiencies if alternative formulas or diets are not adequately managed. Infants may have CMPA alongside other conditions, such as GERD or lactose intolerance, further complicating diagnosis and management[10].

Table 1 Differentiation between IgE-mediated and non-IgE-mediated cow milk protein allergy.

Feature	IgE-mediated CMPA	Non-IgE-mediated CMPA
Mechanism of allergy	Allergic reactions mediated by IgE antibodies binding to allergens, mast cells, and basophils, triggering mast cell degranulation and histamine release	T-cell mediated immune response leading to inflammation without IgE involvement
Pathophysiology	Immune response involving IgE antibodies	Immune response without IgE involvement
Onset of symptoms	Rapid onset, usually within minutes to hours after ingesting cow’s milk protein	Delayed onset, typically hours to days after ingestion
Common presentation age	It is more common after initial exposure to cow’s milk protein through formula or food introduction	It often occurs early in infancy, even in exclusively formula-fed infants
Symptoms	Urticaria, angioedema, anaphylaxis; Respiratory symptoms (wheezing, nasal congestion); Immediate gastrointestinal symptoms (vomiting)	Chronic diarrhea, constipation, blood-streaked stools; Gastroesophageal reflux-like symptoms; Poor feeding, colic, and failure to thrive
Systemic involvement	Systemic reactions, including anaphylaxis, are common	Limited to localized inflammation, primarily in the gastrointestinal tract
Severity	It can be life-threatening (e.g., anaphylaxis)	Symptoms are generally less acute but may lead to chronic complications
Duration of symptoms	Symptoms resolve quickly once exposure ceases	Symptoms persist until the trigger is eliminated for an extended period
Diagnostic tools	Skin prick test; Serum-specific IgE testing; Food challenge (confirmation)	Diagnosis of exclusion; Elimination diet and reintroduction challenge; No reliable specific tests available
Management	Strict avoidance of cow’s milk protein and use of emergency medication (e.g., epinephrine for anaphylaxis)	Strict avoidance of cow’s milk protein, ensuring nutritional adequacy of alternatives
Resolution	It may persist longer, though some children outgrow it by school age	Often resolves by 1-3 years of age

This table shows the underlying mechanisms of allergy, providing a more comprehensive comparison of IgE-mediated and non-IgE-mediated cow milk protein allergy. CMPA: Cow milk protein allergy.

The purpose of this review is to explore conditions that mimic CMPA in infancy, such as lactose intolerance, GERD, FPIES, eosinophilic esophagitis (EoE), and non-allergic reactions to milk proteins. By examining the clinical presentations, diagnostic criteria, and management strategies of these mimics, the review aims to enhance diagnostic accuracy among healthcare providers. Accurate differentiation between CMPA and its mimicking conditions is crucial to reducing diagnostic errors, preventing unnecessary dietary restrictions, and ensuring timely and appropriate interventions. Misdiagnosis of CMPA often results in unwarranted elimination diets that may lead to nutritional deficiencies, increased healthcare costs, and parental anxiety. This review serves as an educational resource for clinicians, providing practical insights to improve patient outcomes while highlighting gaps in current knowledge to guide future research and awareness in the field.

LITERATURE REVIEW

A comprehensive literature search was conducted to identify studies addressing conditions that mimic CMPA in infancy. The search was performed using PubMed, Scopus, Web of Science, and Google Scholar, employing keywords such as "cow milk protein allergy", "CMPA mimics", "lactose intolerance in infants", "GERD in infants", "FPIES", "eosinophilic esophagitis in infancy", "casomorphin disorders", and "casein A1 intolerance". Articles published over the last 20 years were prioritized, focusing on recent systematic reviews, clinical guidelines, and key trials. Studies were included if they focused on CMPA and conditions with similar presentations in infants, while those involving non-infant populations or unrelated topics were excluded. Titles, abstracts, and full texts were screened for relevance, and data from eligible studies were synthesized to comprehensively analyze the clinical presentations, diagnostic approaches, and management strategies for CMPA mimics in infancy.

CMPA OVERVIEW

CMPA is a common food allergy in infancy, affecting 2%-7% of infants worldwide. It results from an immune-mediated hypersensitivity to cow’s milk proteins, such as casein and whey. It typically manifests within the first year of life, often upon the introduction of cow’s milk into the diet[11]. The etiology of CMPA involves genetic predisposition, with a strong association with familial atopy, environmental factors such as early exposure to cow’s milk proteins, altered gut microbiota, and reduced breastfeeding duration. Immaturity of the immune and gastrointestinal systems also plays a critical role[4]. The pathophysiology is classified into IgE-mediated, non-IgE-mediated, and mixed mechanisms. In IgE-mediated CMPA, mast cell degranulation triggered by allergen-bound IgE results in rapid onset symptoms, such as urticaria, angioedema, vomiting, and anaphylaxis. Non-IgE-mediated CMPA involves T-cell-mediated inflammation, leading to delayed gastrointestinal symptoms like diarrhea, blood-streaked stools, and reflux-like presentations. Mixed mechanisms may exhibit overlapping features[12]. CMPA presents with a broad spectrum of gastrointestinal, dermatological, respiratory, and systemic symptoms, ranging from colic and eczema to severe anaphylaxis or failure to thrive. IgE-mediated reactions typically occur within minutes to two hours of ingestion, while non-IgE-mediated symptoms develop over hours to days[13]. Understanding the etiology, pathophysiology, and clinical manifestations is essential for accurate diagnosis, as CMPA's diverse presentations often mimic other conditions, complicating management and care.

The diagnosis of CMPA involves a combination of clinical history, physical examination, and confirmatory tests. IgE-mediated CMPA is diagnosed through the rapid onset of symptoms following milk ingestion, with confirmation using SPT, which detect allergen-specific IgE reactions, serum-specific IgE testing to quantify antibody levels, and the oral food challenge (OFC), considered the gold standard. However, false positives can occur in sensitized but non-allergic individuals[14]. Therefore, a detailed history is essential to correlate test results with clinical symptoms. Diagnostic options for non-IgE-mediated CMPA include an elimination diet followed by reintroduction to observe symptom resolution and recurrence. While endoscopy and biopsy may be used in severe cases, these are not routine[15]. The diagnosis of non-IgE-mediated CMPA relies heavily on clinical observation and parental reporting, which can lead to subjective bias. Mixed CMPA, involving both mechanisms, presents with overlapping immediate and delayed symptoms, requiring a combination of diagnostic approaches[16]. Differentiating between these types is critical, as IgE-mediated CMPA benefits from objective tests, while non-IgE-mediated CMPA relies heavily on clinical observation and dietary trials (Table 1). A comprehensive diagnostic strategy ensures appropriate management, avoiding unnecessary dietary restrictions or delayed treatment. Accurate diagnosis is crucial to differentiate CMPA from other conditions with similar presentations, ensuring appropriate management and preventing unnecessary dietary restrictions or delayed treatment in affected infants.

CONDITIONS MIMICKING CMPA

Lactose intolerance

Lactose intolerance results from a deficiency or reduced activity of the enzyme lactase, produced by the small intestine's brush border. Lactase is responsible for hydrolyzing lactose, the primary sugar in milk, into glucose and galactose for absorption. When lactose is not adequately digested, it accumulates in the intestinal lumen, where it undergoes fermentation by gut bacteria, producing gases like hydrogen and methane[17]. This process also creates osmotic gradients, drawing water into the intestine and leading to diarrhea and bloating. Lactase activity is highest at birth and tends to decline with age. Still, in some individuals, particularly those of non-European descent, this decline may occur earlier, leading to symptoms in infancy. The primary symptoms of lactose intolerance include abdominal pain, bloating, flatulence, diarrhea, and sometimes nausea, typically appearing within 30 minutes to 2 hours after consuming lactose-containing foods. These symptoms are dose-dependent, with smaller lactose amounts often causing less severe reactions[18].

Diagnosing lactose intolerance involves several tools designed to identify reduced lactase activity or confirm the inability to digest lactose properly. The hydrogen breath test is one of the most commonly used methods. It measures the amount of hydrogen in the breath after the patient consumes a lactose-containing solution. When lactose is not digested, it ferments in the gut, producing hydrogen that enters the bloodstream and is exhaled[19]. Elevated hydrogen levels indicate lactose malabsorption. The test requires an overnight fast and regular breath sampling after ingestion. However, false positives may occur in conditions like small intestinal bacterial overgrowth or rapid intestinal transit times[20].

The stool acidity test is often preferred in infants and young children due to its noninvasive nature. This test detects lactic acid and other fermentation byproducts in stool, produced when undigested lactose ferments in the gut. A stool pH below 5.5 and the presence of reducing substances indicate lactose intolerance[21]. While easy to perform, this test is less specific and can be influenced by dietary factors. The lactose tolerance test is another diagnostic method that measures blood glucose levels after ingesting a lactose solution. A minimal rise in glucose suggests inadequate lactose digestion and absorption. While useful, this test is less commonly employed due to the need for multiple blood draws and its susceptibility to false positives or negatives[22].

Genetic testing can identify polymorphisms associated with lactase non-persistence in patients with a genetic predisposition. This is particularly useful in populations where primary lactase deficiency is prevalent. However, genetic tests cannot assess secondary lactose intolerance caused by gut injury or inflammation[23]. A more practical approach, especially in young children, is the elimination and reintroduction diet. This involves removing lactose from the diet for a few weeks and monitoring symptom improvement. Lactose is then reintroduced to confirm symptom recurrence[24]. While simple and cost-effective, this approach requires careful dietary adherence and observation. These diagnostic tools, individually or in combination, confirm lactose intolerance while differentiating it from other conditions, such as CMPA, ensuring appropriate management.

Lactose intolerance and CMPA differ significantly in their underlying mechanisms, clinical presentations, and diagnostic approaches (Table 2). Lactose intolerance is not immune-mediated, whereas CMPA involves immune responses, either IgE-mediated or T-cell-mediated. Symptoms of lactose intolerance typically occur after ingesting significant amounts of lactose and are generally confined to the gastrointestinal system, presenting as bloating, diarrhea, or abdominal discomfort[18]. In contrast, CMPA can involve a broader range of symptoms, including gastrointestinal, respiratory, dermatological, or systemic reactions. Lactose intolerance is confirmed through diagnostic tools like the hydrogen breath test or stool acidity test. At the same time, CMPA requires immunological testing, such as SPT or specific IgE testing, and elimination diets with OFCs[7]. Additionally, lactose intolerance is rare in infancy due to high lactase activity in early life, whereas CMPA commonly manifests within the first year of life. Recognizing these distinctions is critical for accurate diagnosis and management, as mistaking lactose intolerance for CMPA could result in unnecessary dietary restrictions or inappropriate treatment[18].

Table 2 Differentiating cow milk protein allergy from its mimics.

Feature	CMPA (IgE & non-IgE)	Lactose intolerance	GERD	FPIES	EoE	Casomorphin-induced disorders
Pathophysiology	Immune-mediated (IgE/non-IgE) reaction to milk proteins	Enzyme deficiency (lactase) leading to lactose malabsorption	Acid reflux due to lower esophageal sphincter immaturity	Non-IgE-mediated immune reaction to food proteins	Chronic Th2-mediated inflammation with eosinophil infiltration	Opioid-like activity of BCM-7
Primary triggers	Cow’s milk proteins (casein, whey)	Lactose-containing dairy products	Overfeeding, positional factors, immature lower esophageal sphincter	Cow’s milk, soy, grains (e.g., rice, oats)	Food allergens (including cow’s milk), environmental triggers	A1 beta-casein from certain cow breeds (e.g., Holstein, Friesian)
Primary symptoms	Gastrointestinal (diarrhea, vomiting), skin (eczema, urticaria), respiratory (wheezing, anaphylaxis)	Bloating, diarrhea, gas, abdominal pain	Regurgitation, vomiting, irritability, poor weight gain	Severe vomiting, diarrhea, dehydration, lethargy	Feeding difficulties, vomiting, failure to thrive	Constipation, bloating, colic, abdominal pain
Onset of symptoms	Immediate (IgE) or delayed (non-IgE) after milk ingestion	30 min–2 hours after lactose consumption	Typically post-feeding; worsens when lying down	1-4 hours after ingestion	Chronic, develops over weeks/months	Dose-dependent after consuming A1 milk
Age of onset	Typically within the first year of life	Rare in infancy; more common in older children and adults	Common in infancy, peaks at 4-6 months	Usually presents in infancy, often within the first few months	Infancy to early childhood	More common in older infants and children, rare in newborns
Diagnosis	Skin prick test, serum IgE, elimination diet, oral food challenge	Hydrogen breath test, stool acidity test	Clinical evaluation, pH monitoring, endoscopy	Clinical history, symptom resolution after food elimination	Endoscopy with biopsy (≥ 15 eosinophils/HPF)	Clinical observation, symptom resolution with A2 milk
Treatment	Elimination of cow’s milk proteins, hypoallergenic formula	Lactose-free diet or lactase enzyme supplementation	Positional therapy, thickened feeds, acid suppressants (PPIs, H2 blockers)	Avoid trigger food, supportive care for acute episodes	Elimination diet (milk and other allergens), topical steroids	Switch to A2 milk or eliminate cow’s milk
Systemic Involvement	Possible (especially in IgE-mediated cases)	No systemic symptoms	No systemic symptoms	Severe systemic effects (hypovolemia, shock)	Limited to the esophagus, no systemic effects	No systemic involvement
Nutritional Impact	Risk of deficiencies in calcium, vitamin D, and protein if improperly managed	Minimal if alternative lactose-free dairy is included	Generally no direct nutritional impact	Risk of malnutrition if multiple food eliminations are required	Risk of poor growth if untreated	Minimal if A2 milk or other dairy substitutes are used
Prognosis	Most outgrow by 3-5 years	Symptoms persist if lactose is consumed	Often resolves by 1 year	Tolerance develops by 3-5 years	Chronic, requiring long-term management	Symptoms resolve with dietary modification

Casomorphin-induced disorders: Conditions resulting from the opioid-like effects of beta-casomorphin-7, a peptide released during the digestion of A1 beta-casein, leading to gastrointestinal symptoms. Cow milk protein allergy: An immune-mediated response to cow’s milk proteins, which can be IgE-mediated (immediate) or non-IgE-mediated (delayed). Eosinophilic esophagitis: A chronic allergic condition characterized by eosinophilic inflammation of the esophagus, often triggered by food allergens like cow’s milk. Food protein-induced enterocolitis syndrome: A non-IgE-mediated immune reaction that leads to severe gastrointestinal symptoms like vomiting and diarrhea, typically after food ingestion. Gastroesophageal reflux disease: A condition where stomach contents reflux into the esophagus, causing regurgitation, vomiting, and feeding difficulties. Lactose intolerance: A non-immune reaction due to lactase enzyme deficiency, leading to malabsorption of lactose and gastrointestinal symptoms. BCM-7: Beta-casomorphin-7; CMPA: Cow milk protein allergy; EoE: Eosinophilic esophagitis; FPIES: Food protein-induced enterocolitis syndrome; GERD: Gastroesophageal reflux disease; HPF: High-power field; PPI: Proton pump inhibitor.

GERD

GERD is a common condition in infancy caused by the backward flow of stomach contents into the esophagus. The primary symptoms include regurgitation, irritability during or after feeding, vomiting, feeding difficulties, and poor weight gain. In severe cases, GERD may cause esophagitis, leading to discomfort and crying during feeding[25]. GERD shares several overlapping symptoms with CMPA, particularly gastrointestinal symptoms such as regurgitation, vomiting, and irritability. Both conditions can also present with failure to thrive in severe cases, complicating the diagnostic process. Unlike GERD, CMPA may involve additional systemic manifestations such as eczema, wheezing, or bloody stools, which are not typical of GERD[9]. However, in some cases, CMPA may exacerbate GERD symptoms, as an allergic response to cow's milk proteins can trigger esophageal inflammation and worsen reflux. This overlap highlights the importance of careful clinical assessment, including a detailed feeding history and associated symptom evaluation[26]. Diagnostic tools such as pH monitoring for GERD or elimination diets for CMPA can help distinguish between the two conditions and guide appropriate management strategies[27].

GERD in infants is primarily diagnosed through clinical evaluation, focusing on symptoms such as regurgitation, irritability during or after feeding, and poor weight gain. These symptoms often overlap with conditions like CMPA, making accurate diagnosis crucial[28]. In some cases where GERD is suspected to lead to complications such as esophagitis or poor growth, additional diagnostic tools may be employed. The gold-standard diagnostic test for GERD is esophageal pH monitoring, which measures the frequency and duration of acid reflux episodes over 24 hours[29]. For a more comprehensive assessment, multichannel intraluminal impedance-pH monitoring can detect acidic and non-acidic reflux episodes. In cases where there is a concern for structural abnormalities or esophageal damage, an upper gastrointestinal endoscopy may be performed, allowing for visual examination and biopsy[30]. A barium swallow study may also detect anatomical issues, such as hiatal hernia, that could contribute to reflux. Sometimes, an empiric trial with acid suppressants, such as proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs), can help confirm the diagnosis if symptoms improve with treatment[31].

Therapeutic approaches for GERD include lifestyle and dietary modifications, such as keeping the infant upright during and after feedings, offering smaller and more frequent feedings, and thickening feeds for formula-fed infants. Pharmacological treatment with PPIs, such as omeprazole, effectively reduces acid production and treats esophagitis[32]. At the same time, H2RAs like ranitidine may be used in milder cases or as a first-line option. In certain instances, prokinetic agents may be prescribed to enhance gastric motility, although their use is limited due to potential side effects[33]. For severe or refractory cases of GERD, surgical intervention, such as Nissen fundoplication, may be considered, especially in cases with life-threatening complications like aspiration. Early diagnosis and appropriate management of GERD are essential to prevent complications. Still, careful differentiation from conditions like CMPA is crucial to avoid unnecessary treatments and ensure optimal care for the infant[34]. While GERD and CMPA share some symptoms, the underlying mechanisms, symptom spectrum, and diagnostic approaches differ significantly. Accurate differentiation between the two conditions is critical for appropriate management and to avoid unnecessary treatments or dietary restrictions[9]. Table 2 shows the differences between CMPA and GERD.

FPIES

FPIES is a non-IgE-mediated food allergy that primarily affects infants and young children. Due to its unique clinical presentation and pathophysiology, it is distinct from other food allergies, such as CMPA[35]. FPIES is characterized by delayed gastrointestinal symptoms, typically occurring 1-4 hours after ingesting the trigger food. Common symptoms include profuse vomiting, diarrhea, lethargy, pallor, and in severe cases, dehydration, hypovolemia, or even shock[36]. Unlike IgE-mediated allergies, FPIES does not involve hives, wheezing, or anaphylaxis, and it cannot be detected through traditional allergy tests like SPT or serum IgE measurements. The most common triggers for FPIES are cow’s milk, soy, and certain grains such as rice and oats, but any food protein can potentially cause reactions[37]. The condition is often resolved by 3-5 years old, but re-exposure to trigger foods should be carefully monitored under medical supervision. Diagnosis of FPIES relies on clinical history and symptom resolution after eliminating the trigger food from the diet. OFCs are sometimes conducted in a controlled clinical setting to confirm the diagnosis. The absence of IgE-mediated markers and the delayed onset of symptoms are key differentiators from other food allergies[38]. Management involves strict avoidance of the identified triggers and supportive care during acute episodes, such as fluid resuscitation or antiemetics for severe vomiting. Nutritional guidance is also essential to ensure adequate growth and development while avoiding trigger foods. Understanding the unique features of FPIES is crucial for prompt recognition and appropriate management of this potentially serious condition[39].

FPIES and non-IgE-mediated CMPA share similarities with non-IgE-mediated immune conditions but have distinct characteristics that help differentiate them. FPIES is a delayed hypersensitivity reaction primarily involving the gastrointestinal system, triggered by various food proteins, including cow’s milk, soy, and grains like rice and oats[40]. In contrast, non-IgE-mediated CMPA is specifically triggered by cow’s milk proteins[4]. The onset of symptoms in FPIES typically occurs 1-4 hours after ingestion of the trigger food, presenting with severe vomiting, diarrhea, lethargy, pallor, dehydration, and, in some cases, hypovolemic shock. These systemic effects are not characteristic of non-IgE-mediated CMPA, which manifests as gastrointestinal symptoms such as vomiting, diarrhea, abdominal pain, and, sometimes, blood or mucus in the stool, along with dermatological issues like eczema[36].

Diagnosis for both conditions relies on the clinical history and the resolution of symptoms after eliminating the suspected trigger. However, in FPIES, OFCs may be conducted under medical supervision to confirm the diagnosis, particularly when acute episodes are involved[41]. Laboratory tests, such as SPT or serum IgE levels, are negative in both conditions[38]. FPIES typically resolves spontaneously in early childhood, with tolerance developing at 3-5 years old. On the other hand, non-IgE-mediated CMPA also tends to resolve in early childhood but can persist longer in some cases[42]. Treatment for FPIES focuses on strict avoidance of trigger foods and supportive care during acute episodes, such as fluid resuscitation and antiemetics[41]. At the same time, non-IgE-mediated CMPA management involves eliminating cow’s milk proteins from the diet, using hypoallergenic formulas, or maternal dietary adjustments during breastfeeding[43]. Recognizing these key differences is crucial for accurate diagnosis and effective management, ensuring appropriate interventions for affected infants (Table 2).

EoE

EoE is a chronic, immune-mediated inflammatory condition of the esophagus characterized by the infiltration of eosinophils into the esophageal mucosa[44]. The pathogenesis of EoE involves an interplay of genetic, environmental, and immune factors. Food allergens are a primary trigger, leading to a Th2-dominated immune response. This response involves the release of cytokines like interleukin-5 and interleukin-13, promoting eosinophil recruitment and activation. These eosinophils release cytotoxic proteins that cause tissue damage, remodeling, and fibrosis, resulting in esophageal dysfunction[45,46]. Genetic predisposition, such as mutations in the CAPN14 gene, and environmental factors, including early antibiotic use or disrupted microbiota, may further increase susceptibility[47]. In infancy, EoE presents with nonspecific and age-dependent symptoms that overlap significantly with other conditions, including CMPA. Common clinical features include feeding difficulties, failure to thrive, vomiting, irritability, and regurgitation. Infants may also show signs of food aversion or display discomfort during feeding[48]. Unlike older children or adults, where dysphagia and food impaction are hallmark symptoms, these are less apparent in infants due to their liquid-based diet[49]. The chronic nature of EoE often leads to delayed growth and nutritional deficiencies if untreated[50]. The variability in presentation makes early recognition challenging, underscoring the need for clinicians to consider EoE in differential diagnoses for infants presenting with persistent gastrointestinal symptoms unresponsive to standard treatments for reflux or CMPA[51].

Endoscopy and biopsy are essential tools in diagnosing EoE, particularly when clinical features suggest esophageal inflammation but overlap with other conditions such as GERD or CMPA[52]. Endoscopy allows for direct visualization of the esophageal mucosa and can reveal characteristic findings indicative of EoE. These include linear furrows, concentric rings (also known as trachealization), white exudates or plaques (representing eosinophilic microabscesses), and edema[53]. In some cases, the esophagus may appear normal despite active disease, making histological examination crucial for confirmation[54]. A biopsy involves obtaining multiple tissue samples from different esophageal segments, as eosinophilic infiltration can be patchy. Histological analysis reveals a dense eosinophilic infiltration, with a threshold of ≥ 15 eosinophils per high-power field (HPF) in the esophageal mucosa being diagnostic of EoE. Additional findings may include basal cell hyperplasia, elongation of papillae, and lamina propria fibrosis[55]. These changes distinguish EoE from GERD, which typically exhibits fewer eosinophils and lacks the architectural changes seen in EoE. Endoscopy with biopsy confirms the diagnosis and helps exclude other pathologies, such as infections or structural abnormalities, that may mimic EoE[56]. Furthermore, repeat endoscopy after dietary elimination or medical therapy (e.g., PPIs or corticosteroids) can assess treatment efficacy. Integrating endoscopy and biopsy findings with clinical features remains the gold standard for diagnosing EoE, enabling targeted interventions to manage this chronic condition effectively[57].

EoE and CMPA differ significantly in their diagnostic approaches due to their distinct pathophysiologies. EoE is diagnosed through upper endoscopy with esophageal biopsies, revealing eosinophilic infiltration (≥ 15 eosinophils per HPF), which is absent in CMPA[58]. In contrast, CMPA diagnosis relies on a combination of clinical history, elimination diets, and testing for serum-specific IgE or skin prick testing for IgE-mediated cases. Non-IgE-mediated CMPA is confirmed through elimination and reintroduction challenges, as no definitive biomarkers exist[11]. While EoE may involve esophageal eosinophilia triggered by various allergens, including cow's milk, CMPA does not show such histological findings and is primarily linked to systemic immune responses. These diagnostic differences underscore the need for distinct investigations tailored to each condition's underlying mechanisms[59]. Table 2 shows the differences between CMPA and EOE.

Non-allergic reactions to milk proteins

Non-allergic reactions to milk proteins refer to adverse responses to components of milk that do not involve the immune system. These reactions differ from CMPA as IgE antibodies or T-cells do not mediate them and do not trigger hypersensitivity reactions. Instead, they arise due to intolerance, enzymatic deficiencies, or pharmacologically active compounds in milk. Key types of non-allergic reactions include casomorphin-induced gastrointestinal disorders and intolerance to casein A1[60].

Casein A1 intolerance

Beta-casein, a major protein in cow’s milk, accounts for about 30% of its total protein content and exists in two primary genetic forms: A1 and A2. A2 beta-casein is considered the original variant, with A1 beta-casein arising from a genetic mutation (proline67 to histidine67) in certain European cattle populations approximately 5000–10000 years ago[61]. When milk or milk products containing A1 beta-casein are digested, enzymes in the gut produce a bioactive peptide called beta-casomorphin-7 (BCM-7). This peptide, which has opioid-like properties, can bind to μ-opioid receptors in the gut, influencing gastrointestinal function. The digestion of A1 beta-casein has been linked to gastrointestinal disorders[62]. BCM-7 can affect gut motility, slow gastrointestinal transit, and increase Bristol stool values, and it is associated with symptoms such as constipation, abdominal pain, and bloating. Additionally, BCM-7 has been implicated in increasing intestinal permeability, which can exacerbate gastrointestinal discomfort and contribute to inflammation[63]. In contrast, A2 beta-casein generates minimal amounts of BCM-7 under normal digestive conditions, potentially making it less likely to cause these adverse effects. However, under specific laboratory conditions not typical of the human gut, A2 beta-casein has been shown to release small amounts of BCM-7, though its clinical significance remains unclear[64]. In human milk, beta-casein belongs to the A2 type, characterized by a proline residue at the corresponding position in the beta-casein protein chain. The BCM-7 derived from human beta-casein differs from bovine BCM-7 in its amino acid composition, sharing homology in five of the seven amino acids while differing at positions four and five. Notably, human-derived BCM-7 exhibits significantly weaker opioid activity compared to its bovine counterpart[65].

Symptoms of casein A1 intolerance typically present as gastrointestinal disturbances without systemic manifestations, distinguishing these disorders from CMPA (Tables 2 and 3). Unlike CMPA, these reactions are not immune-mediated but result from biochemical processes during digestion[66]. The onset of symptoms in A1-induced disorders is dose-dependent and occurs after consuming milk or dairy products containing A1 β-casein. Diagnosis relies on clinical observation and symptom resolution following dietary changes, as no specific tests exist to confirm BCM-7 activity[67]. Eliminating A1 β-casein from the diet by switching to A2 milk—produced by breeds like Guernsey and Jersey cows, which lack A1 β-casein—can provide relief. In infants, hypoallergenic formulas may be used when breastfeeding is not an option, though these are not typically required unless other milk sensitivities coexist[68].

Table 3 Comparison between casein A1–induced intolerance and cow milk protein allergy.

Aspect	Casein A1–induced intolerance	CMPA
Mechanism	Non-immune-mediated; caused by the release of BCM-7 during digestion of A1 β-casein	Immune-mediated response to milk proteins (e.g., casein, whey) via IgE or T-cell pathways
Primary trigger	A1 β-casein found in milk from breeds like Holstein and Friesian cows	Any cow’s milk protein, including casein and whey
Symptoms	Gastrointestinal symptoms: Constipation, bloating, abdominal pain. No systemic manifestations	Wide range: Gastrointestinal (vomiting, diarrhea), skin (eczema, rash), respiratory (wheezing), or systemic reactions (anaphylaxis)
Onset	Dose-dependent; occurs after consuming significant amounts of A1 β-casein	It can occur after small amounts of milk protein; onset may be immediate (IgE-mediated) or delayed (non-IgE-mediated)
Age of onset	It is more common in older infants and children and rare in newborns	Typically manifests in infancy, often within the first year of life
Diagnosis	Clinical observation with symptom resolution following a switch to A2 milk. No specific diagnostic tests were available	Based on clinical history, specific IgE tests, skin prick tests, and elimination diets with oral food challenges
Management	Substituting with A2 milk, there is no need for hypoallergenic formulas unless other sensitivities coexist	Avoid all cow’s milk proteins; use extensively hydrolyzed or amino acid-based formulas for infants
Systemic involvement	Absent; symptoms are limited to the gastrointestinal system	Possible, particularly in IgE-mediated cases (e.g., respiratory or skin involvement)
Prognosis	Symptoms resolve with dietary modification, such as switching to A2 milk	Many children outgrow CMPA by 3-5 years; strict dietary management is required until the resolution is reached
Nutritional impact	Minimal if A2 milk or suitable dietary alternatives are included	Risk of nutritional deficiencies if dietary restrictions are not appropriately managed

This comparison underscores the distinct mechanisms, symptoms, and management strategies for casein A1–induced intolerance and cow milk protein allergy. Accurate diagnosis is critical to avoid unnecessary treatments or dietary restrictions and to ensure optimal care. A2 milk: Milk containing only A2 beta-casein. BCM-7: Beta-casomorphin-7; CMPA: Cow milk protein allergy.

Recognition of casein A1-induced disorders is essential to differentiate them from CMPA and lactose intolerance. Effective management involves dietary modification without unnecessary restrictions, ensuring proper nutrition while addressing symptoms. Current research continues to explore the broader health implications of BCM-7, including its potential impact on conditions beyond the gastrointestinal system, such as neurological and cardiovascular health[60].

Casomorphin-induced gastrointestinal disorders

Casomorphin-induced gastrointestinal disorders are associated with the production of bioactive peptides called casomorphins during the digestion of milk proteins, particularly β-casein. These peptides, especially BCM-7, exhibit opioid-like activity by binding to μ-opioid receptors in the gastrointestinal tract and the central nervous system[63]. This interaction can slow gut motility, potentially causing constipation, increase intestinal permeability ("leaky gut"), and influence the gut-brain axis. These effects are especially significant in infants and young children, who may have immature digestive systems that are more sensitive to these peptides[69]. Clinically, casomorphin-induced disorders primarily present with gastrointestinal symptoms, including constipation, abdominal discomfort, and bloating. In infants, these issues can manifest as feeding difficulties, irritability, or colicky behavior following milk consumption[64]. Importantly, systemic symptoms such as skin rashes or respiratory issues—hallmarks of CMPA—are absent. Symptoms of casomorphin sensitivity are dose-dependent, typically worsening with increased milk intake[70].

Diagnosis is based on clinical observation, as no standardized tests exist to measure the effects of casomorphins directly. Symptom resolution following dietary modifications, such as switching from A1 milk (which produces BCM-7) to A2 milk or eliminating milk proteins altogether, can help clarify the role of casomorphins in symptom development[71]. Management strategies focus on dietary adjustments, such as replacing A1 milk with A2 milk, which does not release BCM-7 during digestion. For infants, hypoallergenic formulas, such as extensively hydrolyzed or amino acid-based formulas (AAF), may be necessary[62]. Ensuring adequate nutritional intake from alternative sources, particularly calcium and protein, is also critical. While evidence linking casomorphins to gastrointestinal disorders is still emerging, recognizing this condition can prevent unnecessary treatments for CMPA or lactose intolerance[72]. Proper dietary adjustments can alleviate symptoms without imposing overly restrictive measures, ensuring optimal growth and development in infants and children.

DIAGNOSTIC APPROACHES FOR CMPA AND ITS MIMICS

Due to the overlap in clinical presentations, diagnosing CMPA and distinguishing it from other conditions that mimic its symptoms can be challenging. A thorough approach involving clinical history, specific diagnostic tests, and using elimination diets is essential for accurate diagnosis and effective management[6].

Clinical history

The first step in diagnosing CMPA involves taking a detailed clinical history. This should include a description of symptoms, their onset, and the timing relative to cow’s milk exposure. CMPA symptoms can be immediate or delayed and may involve a range of systems, including the gastrointestinal, respiratory, and dermatological systems[14]. Common symptoms include vomiting, diarrhea, eczema, urticaria, and respiratory distress. The age of onset is an important factor, as CMPA typically manifests in the first year of life, often within the first few months after the introduction of cow's milk[73]. A family history of atopic diseases (asthma, eczema, or rhinitis) can increase the likelihood of CMPA, particularly in IgE-mediated cases. In contrast, many other conditions mimicking CMPA, such as GERD and lactose intolerance, may present overlapping symptoms like vomiting and abdominal discomfort but do not involve an immune response[74]. FPIES, EoE, and casomorphin-induced gastrointestinal disorders also share symptoms but differ in their pathophysiology, allowing for further differentiation based on clinical history. Table 4 highlights how clinical history can be instrumental in distinguishing CMPA from other conditions that might present with similar symptoms[75].

Table 4 How clinical history can help differentiate cow milk protein allergy from other mimicking conditions.

Condition	Key features in clinical history	How clinical history helps differentiate from CMPA
CMPA (IgE-mediated and non-IgE-mediated)	Symptoms often begin in the first few months after cow's milk introduction; Can present with gastrointestinal (vomiting, diarrhea), dermatological (eczema, urticaria), respiratory (wheezing, coughing), and systemic (anaphylaxis) symptoms	Symptoms directly linked to cow's milk exposure; May involve multiple systems (gastrointestinal, skin, respiratory) simultaneously; Family history of atopic diseases increases the likelihood of CMPA
GERD	Common in infants, often linked with post-feeding regurgitation, vomiting, irritability, & back arching; Often exacerbated by overfeeding, positional changes, or lying down	GERD symptoms are primarily gastrointestinal (vomiting, regurgitation) and often responsive to anti-reflux treatments (H2 blockers or proton pump inhibitors); No skin, respiratory, or systemic involvement
Lactose intolerance	Usually present after the introduction of dairy (often after weaning) or with high-lactose-containing formula or milk; Symptoms mainly gastrointestinal (bloating, diarrhea, abdominal cramping)	Symptoms occur specifically after lactose ingestion and are not associated with other systemic reactions (e.g., skin rashes or respiratory symptoms); Rare in infants but can occur in older children
FPIES	Presents with delayed gastrointestinal symptoms (vomiting, diarrhea, lethargy) after ingestion of a trigger protein (cow's milk, soy); Episodes often occur hours after ingestion	Symptoms typically emerge hours after milk ingestion (delayed reaction); No allergic (IgE-mediated) symptoms like urticaria or anaphylaxis; Symptoms resolve with dietary elimination of the trigger
EoE	Chronic symptoms of reflux, vomiting, dysphagia, or food impaction; History of food allergies or atopic diseases is common; Symptoms may persist despite reflux treatments	EoE often presents with chronic vomiting or feeding difficulties, but without systemic allergic manifestations; No immediate or IgE-mediated reactions; Requires biopsy for diagnosis
Casomorphin-induced gastrointestinal disorders	May include symptoms like bloating, diarrhea, and abdominal pain after milk consumption; History may show improvement with dairy-free diet	Symptoms are generally isolated to gastrointestinal issues, unlike CMPA, which involves a broader spectrum (e.g., skin, respiratory); No immediate allergic response or anaphylaxis

The table shows that each condition has distinct features in terms of symptom timing, response to dietary changes, and involvement of multiple organ systems, all of which can guide the clinician toward the correct diagnosis. H2 blockers: Histamine-2 receptor antagonists. CMPA: Cow milk protein allergy; EoE: Eosinophilic esophagitis; FPIES: Food protein-induced enterocolitis syndrome; GERD: Gastroesophageal reflux disease.

SPT

SPT is a widely used diagnostic tool for identifying IgE-mediated CMPA. During the test, small amounts of allergens, including cow's milk proteins, are introduced into the skin via a needle, and the resulting local reaction is monitored[76]. A positive result, characterized by a wheal and flare response, indicates sensitization to milk proteins, which suggests an allergic reaction. However, a positive SPT result alone does not confirm clinical allergy, as it merely indicates sensitization and cannot differentiate between a true allergy and a mild hypersensitivity[77]. Negative SPT results typically rule out IgE-mediated CMPA, although non-IgE-mediated forms of CMPA may still be present. SPT is essential for distinguishing CMPA from other conditions with similar symptoms, as it identifies IgE-mediated immune responses. In CMPA, SPT usually shows a positive result for cow's milk proteins, indicating an immediate hypersensitivity reaction[16]. In contrast, conditions such as lactose intolerance, GERD, FPIES, and casomorphin-induced gastrointestinal disorders do not involve IgE-mediated immune mechanisms, and therefore, SPT results are negative, helping to exclude CMPA[78]. In EoE, SPT may be negative even though food triggers are present, further distinguishing EoE from IgE-mediated CMPA. Thus, SPT is a valuable tool for confirming IgE-mediated CMPA and differentiating it from non-IgE-mediated and non-allergic conditions by revealing the underlying immune mechanism[79].

Serum-specific IgE testing

Serum-specific IgE testing is a key diagnostic tool used to identify IgE-mediated CMPA by measuring the concentration of IgE antibodies specific to cow's milk proteins. In CMPA, elevated levels of specific IgE against cow's milk proteins, such as casein and whey, are typically detected, confirming an IgE-mediated allergic response[80]. This test helps differentiate CMPA from non-IgE-mediated conditions, such as lactose intolerance, GERD, FPIES, and casomorphin-induced gastrointestinal disorders, as these conditions do not involve IgE antibodies and thus show negative results on serum-specific IgE testing[81]. However, while a positive result strongly suggests CMPA, it is important to note that serum-specific IgE testing cannot distinguish between a clinically relevant allergy and simple sensitization, meaning a positive result does not always correlate with the severity of symptoms or clinical allergy[82]. Additionally, some conditions like EoE may trigger immune responses without elevated specific IgE levels, making it crucial to integrate serum IgE results with clinical history and other diagnostic tools. Despite its utility, serum-specific IgE testing has limitations, including potential false positives in sensitized individuals without clinical allergy, and its inability to detect non-IgE-mediated forms of CMPA[83]. Therefore, while serum-specific IgE is a valuable tool for confirming IgE-mediated CMPA, its results must be interpreted alongside other clinical and diagnostic findings.

OFC

OFC is considered the gold standard for diagnosing CMPA, particularly when the diagnosis is unclear based on clinical history and other tests such as SPT or serum-specific IgE[84]. During the OFC, the patient is gradually exposed to increasing amounts of cow's milk protein under controlled medical supervision, allowing for the observation of any allergic reactions, which may include gastrointestinal, dermatological, or respiratory symptoms[11]. A positive reaction during the OFC, such as hives, vomiting, or anaphylaxis, confirms an IgE-mediated CMPA, while the absence of symptoms suggests the patient is not allergic to milk[42]. This test is highly valuable in differentiating CMPA from other conditions that mimic its symptoms, such as lactose intolerance, GERD, and FPIES, as these conditions do not typically trigger the same immune-mediated responses observed in CMPA[85]. However, while the OFC is a highly sensitive and specific test for diagnosing CMPA, it has limitations. The OFC can carry a risk of severe allergic reactions, including anaphylaxis, requiring careful monitoring in a clinical setting. Additionally, it may not be suitable for infants with a history of severe or immediate allergic reactions, as it could pose a danger[86]. Moreover, the OFC is less effective in diagnosing non-IgE-mediated forms of CMPA, such as delayed-type hypersensitivity or conditions like EoE, where immune responses are not mediated by IgE[87]. Therefore, while the OFC is an essential tool in confirming CMPA, its results must be interpreted in conjunction with the patient's clinical history and other diagnostic tests, considering the potential risks and limitations of the procedure.

Elimination diet and reintroduction

The elimination diet and reintroduction process are pivotal diagnostic strategies for distinguishing CMPA from other conditions that mimic its symptoms. In this approach, cow's milk and its derivatives are completely removed from the infant's diet for a specified period, usually two to four weeks. If the symptoms resolve during the elimination phase and recur upon reintroduction of milk proteins, this strongly indicates CMPA[15]. This method is particularly useful for diagnosing both IgE-mediated and non-IgE-mediated forms of CMPA, as it evaluates symptom resolution and recurrence in a controlled, natural setting. Unlike OFC, which involves supervised, incremental exposure to milk protein, the elimination diet and reintroduction focus on identifying triggers through dietary observation over time[88]. The elimination diet is less risky than the OFC, as it avoids immediate allergen exposure, making it suitable for infants with severe or non-IgE-mediated reactions. However, it has limitations, including the need for strict adherence to dietary restrictions, which may be challenging for families[89]. Additionally, it requires longer observation periods and may fail to distinguish CMPA from other conditions with fluctuating symptoms, such as GERD or FPIES, that might improve coincidentally during the elimination phase[43]. Furthermore, unlike the OFC, which can directly demonstrate IgE-mediated hypersensitivity through an immediate reaction, the elimination diet does not confirm the immune mechanism involved. Thus, while elimination diets and reintroduction are invaluable tools for CMPA diagnosis, they should be integrated with clinical history and other diagnostic methods for comprehensive evaluation[90].

Other tests for mimicking conditions

Additional tests may be required to differentiate CMPA from other conditions with similar clinical presentations. For example, lactose intolerance is confirmed through the hydrogen breath test, which measures the amount of hydrogen in the breath after lactose ingestion. High levels indicate lactose malabsorption[91]. For conditions like GERD, esophageal pH monitoring or a barium swallow may be used to evaluate acid reflux. EoE can be diagnosed through endoscopy and biopsy, revealing eosinophils in the esophageal lining[92]. For FPIES, diagnosis is clinical, often based on history and symptom patterns after ingesting cow’s milk or other proteins, with supportive evidence from the elimination diet and reintroduction challenge[40]. Table 5 summarizes the potential biases in each diagnostic method for CMPA, highlighting false positives, false negatives, and other limitations of these tools.

Table 5 The potential for bias in the diagnostic tools for cow milk protein allergy.

Diagnostic tool	Potential for bias	False positives	False negatives	Limitations/considerations
SPT	Inaccurate representation of clinical allergy; positive result indicates sensitization, not clinical allergy	Positive results may occur in sensitized individuals without clinical allergy	False negatives may occur due to antihistamine use or insufficient IgE production in infants	Cannot differentiate between sensitization and clinical allergy; sensitivity may be reduced in young infants or due to medication interference (e.g., antihistamines)
Serum-specific IgE testing	Positive result indicates sensitization, but not severity of clinical allergy	Positive results in sensitized individuals without clinical allergy	False negatives may occur if IgE production is insufficient or if the patient has non-IgE-mediated CMPA	Cannot distinguish between clinically relevant allergy and simple sensitization; may not detect non-IgE-mediated CMPA or EoE
OFC	Potential for overdiagnosis if patient reacts to low doses or testing is not closely supervised	Rare in non-IgE mediated conditions, though some allergic reactions may be overlooked	High risk of severe allergic reactions, including anaphylaxis	Requires controlled medical supervision; not suitable for infants with severe allergic reactions; may not diagnose non-IgE-mediated forms of CMPA
Elimination diet and reintroduction	Limited by subjective reporting; dependent on strict adherence to dietary changes	Positive result may be due to coincidental improvement (e.g., GERD or FPIES improvement)	Symptom recurrence may be delayed, leading to false negatives or difficulty in confirming diagnosis	Requires long observation periods and careful monitoring; does not confirm IgE-mediated immune mechanism; subjective reports may lead to bias
Lactose intolerance testing (hydrogen breath test)	Confounding variables (e.g., gastrointestinal disorders) may affect results	Rare but possible due to non-lactose-related gastrointestinal issues	May fail in detecting lactose intolerance in some infants with undetectable hydrogen levels	Requires cooperation from patient; less useful in younger infants; may not detect milk protein allergies or CMPA
EoE testing (endoscopy/biopsy)	Diagnostic procedure complexity; may not show food triggers in some cases	False positive due to eosinophils' presence in other esophageal conditions	False negative if eosinophil count is low or in the absence of endoscopic evidence	Highly invasive; may not detect food triggers in every case of EoE; expensive and time-consuming
FPIES	Clinical history-based diagnosis may be subjective and lead to overdiagnosis or misdiagnosis	Misdiagnosis with other gastrointestinal conditions (e.g., gastroenteritis, GERD)	False negative if symptoms are subtle or only occur with larger quantities of the trigger	Diagnosis largely based on clinical history and symptoms; may not detect non-IgE-mediated CMPA or other gastrointestinal disorders

This table summarizes how diagnostic tools for cow milk protein allergy might introduce bias in their results and what factors should be considered for a more accurate diagnosis. SPT: Skin prick tests; CMPA: Cow milk protein allergy; EoE: Eosinophilic esophagitis; OFC: Oral food challenge; FPIES: Food protein-induced enterocolitis syndrome; GERD: Gastroesophageal reflux disease.

A comprehensive diagnostic approach is crucial to accurately diagnose CMPA and differentiate it from other conditions with overlapping symptoms. Clinical history, appropriate testing (including skin prick testing, serum IgE, and OFCs), and elimination diets are essential to the diagnostic process[93]. Understanding the similarities and differences between CMPA and its mimics, such as GERD, lactose intolerance, FPIES, and EoE, ensures that infants receive the appropriate treatment and avoid unnecessary dietary restrictions or mismanagement. Accurate diagnosis leads to better clinical outcomes and enhances the quality of life for infants and their families[18].

MANAGEMENT STRATEGIES FOR CMPA

Evidence-based approaches

Managing CMPA involves evidence-based strategies to alleviate symptoms, promote optimal nutrition, and prevent complications. The cornerstone of CMPA management is the complete elimination of cow's milk proteins from the infant's diet, which includes both direct and indirect milk sources[94]. For exclusively breastfed infants, maternal elimination of cow's milk from her diet and calcium and vitamin D supplementation are recommended to prevent maternal deficiencies[95]. Formula-fed infants typically require hypoallergenic formulas such as extensively hydrolyzed protein formulas (eHF) or AAF in cases of severe allergy or failure to tolerate eHF, which should continue for at least six months or up to the age of 9–12 months, whichever comes first[96]. In non-IgE-mediated CMPA, symptom resolution is often achieved with dietary elimination, though a longer period may be needed compared to IgE-mediated cases[11]. For IgE-mediated CMPA, dietary avoidance remains critical, but additional measures, such as emergency management plans for accidental exposures, including the use of adrenaline autoinjectors, may be necessary. Reintroducing cow's milk protein under medical supervision is periodically considered to assess tolerance development, particularly after 6–12 months of elimination or based on clinical guidance. This is particularly important because most children outgrow CMPA by 3-5 years[97].

Emerging therapeutic approaches, such as oral immunotherapy, aim to induce cow's milk protein tolerance through gradual exposure. However, these approaches are still under investigation and not widely adopted due to potential risks and variable outcomes[98]. Parental education is a critical component of CMPA management, recognizing hidden sources of cow's milk, ensuring balanced nutrition, and preparing for emergencies[72]. Additionally, interdisciplinary collaboration between pediatricians, dietitians, and allergists ensures comprehensive care tailored to the infant's specific needs. These evidence-based strategies emphasize symptom resolution while supporting growth, development, and quality of life for infants with CMPA[99].

Specific treatments for mimicking conditions

Effective management of conditions mimicking CMPA requires accurate diagnosis and targeted interventions tailored to the underlying pathology. Each mimicking condition has distinct treatment strategies that differ significantly from the elimination-based approach for CMPA[93]. For lactose intolerance, the primary treatment involves reducing or eliminating lactose from the diet. Lactose-free formulas or lactase enzyme supplementation can effectively alleviate symptoms. Unlike CMPA, completely avoiding cow's milk is unnecessary, as the issue lies with lactose, not the milk proteins[24]. GERD management focuses on reducing reflux and its associated symptoms. First-line treatments include dietary adjustments, such as smaller, more frequent feedings and positional changes to minimize reflux episodes. In severe cases, pharmacological interventions, such as PPIs or H2RAs, may be prescribed. GERD does not require milk elimination unless cow's milk exacerbates the reflux[100,101]. Management of FPIES involves strictly avoiding the offending food protein, often cow's milk or soy. Acute reactions are treated with rehydration therapy, and severe cases may require intravenous fluids or corticosteroids. Nutritional support ensures adequate caloric and nutrient intake while avoiding trigger foods[102]. Dietary management is a key component in EoE, with elimination diets (often removing the top allergens, including cow's milk) commonly employed. Elemental diets may be necessary in severe cases. Pharmacological treatment involves topical corticosteroids (e.g., swallowed fluticasone or budesonide) to reduce esophageal inflammation. Endoscopic monitoring is often required to evaluate therapeutic efficacy[103,104]. Dietary modification can manage non-allergic reactions, such as casomorphin-induced gastrointestinal disorders or casein A1 intolerance. Switching to casein-free or A2 milk may alleviate symptoms without completely eliminating dairy products[68,105]. Unlike CMPA, these conditions do not involve immune mechanisms, and symptom resolution focuses on specific protein avoidance rather than immunological desensitization. Tailoring treatment to the specific mimicking condition resolves symptoms and prevents unnecessary dietary restrictions, ensuring infants receive appropriate nutrition[106]. A multidisciplinary approach involving pediatricians, allergists, dietitians, and gastroenterologists is essential to optimizing outcomes and addressing each infant's unique needs.

Addressing unnecessary dietary restrictions

Unnecessary dietary restrictions in infants suspected of having CMPA can lead to adverse outcomes, including nutritional deficiencies, impaired growth, and increased caregiver stress[107]. Addressing these unnecessary restrictions is critical to effective management and requires a nuanced approach to diagnosis and treatment. For infants falsely diagnosed with CMPA, avoiding cow’s milk-based formulas or dairy products can result in inadequate intake of essential nutrients, such as calcium, vitamin D, and protein, vital for growth and development[108]. Reintroducing cow's milk under controlled conditions—using OFCs or guided reintroduction protocols—can help confirm tolerance and safely re-establish milk in the diet when CMPA is ruled out[15]. Healthcare professionals should emphasize the importance of accurate diagnosis through evidence-based tests, such as skin prick testing, serum-specific IgE testing, and OFCs. These tools distinguish true CMPA from conditions with similar symptoms, reducing the risk of misdiagnosis and the resultant dietary over-restrictions.

For CMPA-mimicking conditions like lactose intolerance or GERD, targeted management strategies can avoid the unnecessary elimination of all dairy products. For instance, individuals with lactose intolerance can consume lactose-free dairy products, which retain the nutritional benefits of milk without triggering symptoms[24]. Similarly, GERD treatment does not inherently require milk elimination unless cow’s milk exacerbates reflux[31]. Caregiver education is paramount to dispel misconceptions about CMPA and ensure they understand the importance of not unnecessarily restricting the child’s diet. Engaging dietitians in the management process provides caregivers with practical guidance on ensuring balanced nutrition while avoiding unnecessary exclusions[109]. Addressing unnecessary restrictions also includes monitoring for signs of nutritional inadequacies in cases where elimination diets are implemented temporarily. Re-evaluating the need for dietary restrictions as the child grows can prevent prolonged avoidance of milk, particularly when immune tolerance develops in CMPA cases or when mimicking conditions resolve[42]. A multidisciplinary approach that combines diagnostic accuracy, tailored management strategies, and caregiver education is essential to prevent over-restriction risks while ensuring optimal health outcomes for infants with allergy-like symptoms.

IMPLICATIONS OF MISDIAGNOSIS AND INAPPROPRIATE MANAGEMENT

Misdiagnosis of CMPA or its mimicking conditions can lead to significant and far-reaching consequences, spanning clinical, nutritional, psychological, and economic domains. Inappropriate management strategies rooted in misdiagnosis exacerbate these issues, posing risks to the health and well-being of infants and their families[110]. Misdiagnosis can delay the identification and appropriate treatment of the true underlying condition[111]. For instance, diagnosing CMPA in a child with GERD or lactose intolerance may result in unnecessary dietary changes without addressing the actual pathology. This can lead to persistent symptoms like irritability, poor feeding, and growth failure, which continue to impair the infant’s health[9]. On the other hand, failure to recognize CMPA may expose the infant to continued allergen exposure, increasing the risk of recurrent gastrointestinal distress, atopic dermatitis, and potentially life-threatening anaphylactic reactions[7].

Unnecessary dietary restrictions, such as eliminating cow’s milk from the infant’s diet, can lead to nutritional deficiencies, particularly in calcium, vitamin D, and high-quality protein, essential for growth and bone health. Infants placed on restrictive diets without adequate nutritional substitutes may experience growth retardation, developmental delays, or bone demineralization[112,113]. Over-reliance on hypoallergenic formulas or plant-based milk alternatives may fail to meet the infant’s caloric and micronutrient needs if these substitutes are not properly fortified or consumed in adequate quantities[114]. Misdiagnosis of CMPA often creates a heightened sense of fear and anxiety among caregivers, who may go to great lengths to avoid perceived allergens in the child’s environment. This can lead to stress within the family, disruptions to daily routines, and increased social isolation[115]. The financial burden of purchasing specialized formulas or hypoallergenic diets further exacerbates caregiver stress[116]. Over time, unnecessary dietary restrictions can negatively impact the child’s quality of life, limit food diversity, and hinder the development of oral tolerance to milk proteins. Inappropriate management resulting from misdiagnosis places a financial strain on both families and healthcare systems[42]. Families may incur significant expenses for diagnostic tests, specialized formulas, or dietary alternatives, which may not be reimbursed. Additionally, healthcare systems face increased costs due to repeated consultations, unnecessary diagnostic procedures, and prolonged treatments for incorrectly identified conditions[117].

The long-term outcomes of CMPA and its mimics vary based on accurate diagnosis and timely intervention. In true CMPA cases, most children develop tolerance by 3-5 years of age. Infants misdiagnosed with CMPA are often placed on long-term avoidance diets. While necessary in true cases of CMPA, prolonged avoidance in misdiagnosed cases may delay the natural development of tolerance to cow’s milk proteins[110]. This increases the risk of persisting food allergies into later childhood and adulthood, further complicating management and dietary planning. Persistent cow’s milk allergy beyond childhood is associated with increased risks of other allergic diseases, including asthma, allergic rhinitis, and EoE. Also, prolonged dietary avoidance without proper nutritional supplementation can lead to long-term calcium, vitamin D, and protein deficiencies, impacting bone health and growth[118].

For conditions misdiagnosed as CMPA, such as lactose intolerance or GERD, inappropriate dietary restrictions may result in unnecessary elimination of dairy, leading to reduced dietary diversity and potential micronutrient deficiencies. In contrast, failure to diagnose GERD properly can contribute to long-term complications such as esophagitis, feeding aversion, and poor weight gain, while untreated EoE may result in esophageal strictures and dysphagia in later life[29]. The psychological and social effects of CMPA misdiagnosis are also significant. Parents who unnecessarily restrict their child’s diet may experience heightened anxiety, increased healthcare expenses, and reduced quality of life. Children subjected to restrictive diets may develop disordered eating behaviors, food aversions, and social difficulties related to meal restrictions. Additionally, misdiagnosis contributes to increased healthcare costs due to repeated specialist consultations, unnecessary diagnostic testing, and prolonged dietary interventions[119].

The multifaceted impact of misdiagnosis underscores the importance of accurate diagnostic approaches. A comprehensive clinical history, combined with evidence-based diagnostic tools such as skin prick testing, serum-specific IgE assays, OFCs, and elimination diets with structured reintroduction, is crucial in distinguishing CMPA from its mimics[120]. Standardized diagnostic protocols and enhanced clinician awareness are essential to prevent inappropriate management. Addressing these implications through early and accurate identification of CMPA or its mimics will improve clinical outcomes and reduce the emotional and financial burden on families and healthcare systems[6]. Tailored management strategies and ongoing monitoring ensure optimal care while avoiding unnecessary interventions, promoting affected infants' overall health and well-being.

CASE STUDIES: CLINICAL APPLICATION OF CMPA AND ITS MIMICS

To enhance the practical application of the discussed diagnostic and management strategies, the following case studies illustrate real-world scenarios involving CMPA and its mimics.

Case 1: CMPA misdiagnosed as GERD

A 4-month-old infant presented with frequent regurgitation, irritability, and poor weight gain. The initial diagnosis was GERD, and the infant was started on PPIs. Despite treatment, symptoms persisted. Further evaluation revealed atopic dermatitis and eosinophilia. An elimination diet trial confirmed CMPA, leading to symptom resolution after switching to an extensively hydrolyzed formula.

Case 2: Lactose intolerance confused with CMPA

A 1-year-old child developed bloating, diarrhea, and gas after consuming dairy products. Suspecting CMPA, the child was placed on a dairy-free diet. However, symptoms persisted despite the removal of cow’s milk proteins. A hydrogen breath test confirmed lactose intolerance, and dietary modifications with lactose-free dairy resolved the symptoms.

Case 3: FPIES presenting as acute gastroenteritis

A 6-month-old infant was brought to the emergency department with severe vomiting and lethargy 2 hours after ingesting a formula containing cow’s milk protein. Initially diagnosed with viral gastroenteritis, the infant continued to have episodic vomiting after formula intake. A clinical history review led to a diagnosis of FPIES, and complete cow’s milk avoidance resulted in resolution of symptoms.

Case 4: EoE misdiagnosed as feeding aversion

A 3-year-old child with chronic feeding difficulties, vomiting, and failure to thrive was suspected of behavioral feeding aversion. However, endoscopic biopsy showed eosinophilic infiltration of the esophagus, leading to a diagnosis of EoE. Dietary elimination and swallowed corticosteroids improved the child's symptoms.

These case studies illustrate the importance of accurate diagnosis and differentiation between CMPA and its mimics. They highlight the need for a thorough clinical history, appropriate diagnostic tests, and a structured approach to dietary elimination and reintroduction.

Enhancing patient and caregiver education

Educating patients and caregivers is crucial in ensuring the effective management of CMPA and its mimics. Many misconceptions about food allergies and intolerances contribute to unnecessary dietary restrictions, parental anxiety, and improper nutrition. Healthcare professionals should provide evidence-based information about CMPA, its mimics, and the importance of an accurate diagnosis. Clear instructions on when to seek medical attention, how to monitor symptoms, and when to consider reintroducing cow’s milk should be emphasized[14].

Structured educational materials such as printed booklets, online resources, and visual aids can reinforce verbal explanations. Infographics and video tutorials explaining common symptoms, diagnostic methods, and dietary management can further enhance understanding[121]. Additionally, personalized nutritional counseling led by dietitians can help caregivers understand alternative food sources to prevent nutritional deficiencies. Families should receive guidance on fortified dairy alternatives, calcium and vitamin D intake, and maintaining adequate protein balance[122]. Hands-on training and support groups can also be beneficial. Practical workshops on reading food labels, preparing hypoallergenic meals, and introducing dairy substitutes can empower caregivers. Peer support groups provide opportunities for parents to share experiences, reducing stress and misinformation[123]. Additionally, families should receive guidance on safe dietary reintroduction. Structured OFCs, where appropriate, should be explained to caregivers so they can recognize signs of tolerance development and differentiate between adverse reactions and normal food-related symptoms[124].

The psychological and social aspects of food allergies should not be overlooked. Parents should be reassured about the natural history of CMPA and the likelihood of their child outgrowing the condition[125]. Counseling can help caregivers manage anxiety related to dietary restrictions and potential allergic reactions. Moreover, addressing the financial and emotional burden is essential. Families should be informed about cost-effective dietary options and potential insurance coverage for hypoallergenic formulas. Healthcare providers should acknowledge and help mitigate the economic impact of managing food allergies[126]. By implementing these educational strategies, healthcare providers can empower caregivers with the knowledge and confidence to manage their child's condition effectively. Comprehensive education reduces unnecessary dietary restrictions, improves adherence to management plans, and enhances the overall well-being of both the child and family.

EMERGING TRENDS AND FUTURE RESEARCH: ADVANCES IN CMPA DIAGNOSIS AND MANAGEMENT

The field of allergy diagnostics is evolving, with growing interest in identifying reliable biomarkers to differentiate CMPA from conditions that mimic it, such as lactose intolerance, GERD, EoE, and FPIES. Traditional diagnostic methods, including clinical history, elimination diets, and OFCs, remain the cornerstone of CMPA diagnosis but are limited by subjectivity, invasiveness, and the potential for misinterpretation[127]. Advances in biomarker research hold promise for more precise, non-invasive, and reproducible diagnostic approaches.

Serum-specific IgE tests for milk proteins, such as casein and whey, commonly diagnose IgE-mediated CMPA. Recent advances in component-resolved diagnostics (CRD) allow identifying IgE against individual milk protein components, such as alpha-S1-casein, beta-lactoglobulin, and alpha-lactalbumin. These tests provide deeper insights into the sensitization profile of patients and help predict the severity of allergic reactions[128]. For example, sensitization to casein is often associated with more persistent and severe CMPA, while beta-lactoglobulin sensitization may indicate transient allergy. Researchers are investigating novel biomarkers for non-IgE-mediated CMPA, where traditional IgE tests fail to detect the immune response[129]. These include cytokines such as interleukin-10 and tumor necrosis factor-alpha, which are elevated during allergic inflammation, and fecal biomarkers like calprotectin and eosinophil-derived neurotoxin (EDN), which indicate gastrointestinal inflammation. These markers may help differentiate non-IgE-mediated CMPA from other gastrointestinal disorders like GERD or lactose intolerance[130,131].

MicroRNAs (miRNAs) are emerging as potential biomarkers for food allergies, including CMPA. These small, non-coding RNA molecules regulate gene expression and are involved in immune responses. Studies have identified distinct miRNA profiles in children with CMPA compared to healthy controls, suggesting their potential in non-invasive diagnostic tests[132]. Fecal markers, such as secretory IgA and fecal calprotectin[133,134] and salivary markers, including specific IgE and inflammatory cytokines, are being explored for their diagnostic utility in differentiating CMPA from its mimics[135]. These non-invasive methods could be particularly useful in infants, minimizing the need for blood tests or invasive procedures.

Genomics and proteomics are rapidly advancing fields with transformative potential for diagnosing and managing CMPA. These disciplines offer insights into the molecular and genetic mechanisms underlying allergic responses, enabling the development of personalized diagnostic and therapeutic strategies[127,136]. Genomics focuses on understanding genetic predispositions to CMPA. Variants in genes related to immune regulation, such as those encoding interleukins, toll-like receptors, and major histocompatibility complex proteins, have been associated with an increased risk of food allergies, including CMPA[137]. Genome-wide association studies have identified genetic polymorphisms linked to IgE-mediated allergies and non-IgE-mediated immune responses[138]. For instance, genetic variations in the IL-4 and IL-13 genes, which regulate IgE production, are implicated in atopic disorders, including CMPA[139]. Genomic data can also predict disease severity and persistence. For example, certain HLA haplotypes are linked to long-lasting food allergies, while others suggest a higher likelihood of tolerance development[140]. This information can guide clinicians in prognosis and monitoring, enabling more tailored management strategies. Table 6 shows some of the biomarkers that can predict the persistence and severity of CMPA.

Table 6 Some of the biomarkers that are associated with the severity and persistence of cow milk protein allergy.

Biomarker	Type	Associated with severity	Associated with persistence	Comments
SPT	Clinical test	≥ 8 mm indicates high reaction risk during OFC	Related to milk allergy persistence	Predictive of OFC outcomes, useful for identifying high-risk patients
EPT	Clinical test	High risk of anaphylaxis during food challenges	Marker for milk allergy persistence	Described as more useful than SPT for identifying severe milk allergy risk
sIgE	Serum biomarker	Severe allergic reactions in peanut and milk	Higher levels linked with persistent allergies	sIgE cutoffs can predict OFC outcomes
BAT	Cellular biomarker	High CD63 ratio linked to severe reactions	Associated with severe clinical milk reactivity	High proportions of activated basophils indicate severe allergic reactions
Cytokines (interleukin-13, interleukin-10)	Immune biomarker	Higher levels during allergic inflammation	Linked to persistent milk and egg allergies	Elevated in both milk and egg allergy studies, indicating immune dysregulation
Calprotectin	Fecal biomarker	Not specified	Associated with persistent gastrointestinal inflammation	Useful for differentiating non-IgE-mediated allergies from other GI conditions
EDN	Fecal biomarker	Not specified	Associated with persistent gastrointestinal inflammation	Indicates eosinophilic inflammation in the gastrointestinal tract

This table illustrates the growing complexity of allergy diagnostics and highlights emerging biomarkers that may improve the differentiation and management of cow milk protein allergy. SPT: Skin prick tests; OFC: Oral food challenge; EPT: Endpoint test; sIgE: Specific IgE; BAT: Basophil activation test; EDN: Eosinophil-derived neurotoxin.

Proteomics, the study of the full range of proteins expressed in a biological system, has become instrumental in identifying novel biomarkers for CMPA. Unlike traditional diagnostic tools that rely on single markers, proteomics provides a comprehensive view of protein interactions and changes associated with allergic responses[141]. For CMPA, proteomic analysis has identified unique protein signatures in biological samples, such as blood, feces, and saliva, which distinguish CMPA from conditions like lactose intolerance, GERD, and EoE[7]. For example, elevated levels of allergen-specific proteins and inflammatory mediators, such as EDN and calprotectin, have been detected in children with CMPA[142]. Proteomics also sheds light on milk protein allergens themselves. Casein and whey proteins, particularly beta-lactoglobulin and alpha-lactalbumin, are well-known triggers of IgE-mediated responses[143]. Proteomic studies have identified structural features of these allergens that drive immune sensitization, paving the way for developing hypoallergenic milk substitutes through molecular engineering[144]. Integrating genomics and proteomics allows for a systems-level understanding of CMPA, linking genetic predisposition to protein-level expression changes[145]. This approach enables the identification of gene-protein networks involved in allergic inflammation and tolerance development, which can guide targeted therapies.

Genomics and proteomics are also revolutionizing treatment approaches. Personalized allergen-specific immunotherapy, guided by genetic and proteomic profiles, is emerging as a potential treatment for CMPA[146]. This strategy involves gradually exposing specific milk proteins tailored to the individual's immune profile, reducing allergic sensitivity over time[147]. Additionally, proteomics is aiding the development of novel therapeutic agents. Anti-IgE monoclonal antibodies, such as omalizumab and cytokine inhibitors, are being investigated for their ability to modulate immune responses in severe CMPA cases[148]. Despite these promising advancements, their routine clinical application requires validation through large, diverse cohorts and cost-effectiveness analyses. Future research should focus on combining biomarkers into diagnostic panels to improve accuracy and on investigating correlations between biomarker levels, clinical severity, and tolerance development. Integrating genomics, proteomics, and microbiomics offers an exciting, multidisciplinary approach to CMPA management, ultimately aiming to improve patient outcomes while minimizing unnecessary interventions.

RECOMMENDATIONS

Accurate differentiation between CMPA and its mimicking conditions is crucial for effective management. Healthcare providers should employ a comprehensive diagnostic approach, incorporating a thorough clinical history, SPT, serum-specific IgE tests, and OFC when necessary. For non-IgE-mediated CMPA, diagnostic strategies should focus on exclusion diets and reintroduction challenges alongside careful clinical observation. Given the symptom overlap with conditions like GERD, lactose intolerance, FPIES, and EoE, clinicians must use a differential diagnosis strategy, utilizing tools like hydrogen breath tests for lactose intolerance and endoscopy with biopsy for EoE. Early recognition of CMPA and its mimics is essential to prevent unnecessary dietary restrictions and ensure appropriate interventions. For CMPA, completely avoiding cow's milk proteins is key, with hypoallergenic formulas for formula-fed infants and maternal dietary modifications for breastfed infants. In contrast, conditions like GERD and lactose intolerance should be managed with targeted strategies without eliminating cow’s milk entirely, and FPIES requires strict avoidance of trigger foods. At the same time, EoE may need dietary changes and corticosteroid treatment.

Moreover, unnecessary dietary restrictions can lead to nutritional deficiencies and psychological stress for both infants and their families. Clinicians must educate families on the risks of misdiagnosing CMPA and the importance of avoiding unnecessary dietary exclusions. Ensuring adequate calcium, vitamin D, and protein intake is crucial, particularly when restrictive diets are used. Clear communication with families can help alleviate anxiety and reduce the emotional and financial burden of unnecessary dietary changes. Multidisciplinary care involving pediatricians, dietitians, allergists, and gastroenterologists is critical to providing holistic support to families. Additionally, emerging diagnostic tools like CRD and cytokine profiling offer promising alternatives for more precise and less invasive diagnosis, and healthcare providers should stay informed about these advancements. Research into these emerging technologies could enhance the diagnostic process and help distinguish CMPA from other conditions more effectively.

Ongoing research should focus on improving diagnostic protocols and management guidelines, ensuring that they reflect the latest evidence and best practices. Large-scale studies are needed to assess the long-term effects of misdiagnosis, including impacts on growth, development, and quality of life in affected infants. Standardized diagnostic and management protocols could ensure consistent care across various clinical settings, minimizing the risk of misdiagnosis and unnecessary interventions. Finally, effective patient and caregiver education is paramount in managing CMPA and its mimics. Healthcare providers must proactively educate families about symptoms, diagnostic approaches, and available management strategies, ensuring that information is clear and accessible. By offering comprehensive education, clinicians can help families confidently manage the condition, reduce stress, and ensure that children receive optimal care. By implementing these recommendations, healthcare providers can improve diagnosis, reduce misdiagnosis-related burdens, and enhance the overall health outcomes for infants with CMPA and related conditions.

LIMITATIONS

This review highlights the complexities of diagnosing and managing CMPA and its mimicking conditions in infancy. However, several limitations must be acknowledged. First, the diagnostic methods discussed, including SPT, serum-specific IgE tests, and OFC, have inherent limitations. While they provide valuable insights, these tools are not foolproof, and false positives or negatives can occur, particularly with non-IgE-mediated CMPA, where diagnostic tests are less reliable. The reliance on clinical history and exclusion diets for non-IgE-mediated cases can lead to subjectivity and potential misinterpretation, especially in infants who may not yet present with clear symptom patterns. Furthermore, the diagnostic strategies for conditions such as GERD, FPIES, and EoE overlap with CMPA, making the differentiation process challenging and prone to diagnostic uncertainty.

Another limitation of this review is the generalization of the diagnostic and management approaches, which may vary depending on geographical location, access to healthcare resources, and clinician experience. The prevalence of CMPA and its mimicking conditions may also differ across populations, affecting the applicability of certain diagnostic tools or treatment regimens. Additionally, the evolving nature of allergy diagnostics, including the potential for new biomarkers and emerging technologies, means that the findings presented here may soon be outdated as research advances. While emerging tools such as CRD and cytokine profiling offer promise, they are still under investigation and not yet widely available in clinical practice, limiting their current utility in routine diagnostic settings.

Moreover, the review predominantly focuses on the clinical aspects of diagnosis and management, with less emphasis on the long-term follow-up and outcomes for infants diagnosed with CMPA or its mimics. The psychological and nutritional impacts of misdiagnosis and unnecessary dietary restrictions are briefly addressed, but further exploration of these effects, particularly over time, is needed. The role of caregivers in managing these conditions is also critical, yet more emphasis on the challenges they face, including the burden of managing complex dietary changes and dealing with healthcare costs, could enhance understanding of the broader impact on families. Finally, while the review provides a comprehensive overview, it is important to note that the absence of large-scale, long-term studies on the misdiagnosis of CMPA and its mimics leaves gaps in our understanding of the true impact of these conditions. Further research is needed to fill these gaps and provide more robust evidence for optimal diagnostic and management strategies.

CONCLUSION

CMPA and its mimicking conditions present significant diagnostic challenges, especially in infancy, where symptoms often overlap with those of other gastrointestinal, dermatological, and respiratory disorders. Accurate diagnosis requires a multifaceted approach that includes a detailed clinical history, diagnostic testing such as SPT and serum-specific IgE assays, and, when necessary, OFCs. For non-IgE-mediated CMPA, exclusion diets, and reintroduction challenges play a crucial role, although they are not without limitations. The differentiation between CMPA and conditions such as lactose intolerance, GERD, FPIES, and EoE remains complex, requiring clinicians to adopt a careful and systematic diagnostic strategy. Misdiagnosis and unnecessary dietary restrictions can lead to significant nutritional, psychological, and financial burdens for families. Therefore, healthcare providers must clearly understand the diagnostic tools and management strategies for CMPA and its mimics, ensuring that infants receive the most appropriate care. Furthermore, emerging diagnostic technologies, such as CRD and cytokine profiling, offer exciting prospects for enhancing diagnostic accuracy and reducing the reliance on subjective clinical evaluation. The importance of interdisciplinary collaboration and effective patient and caregiver education cannot be overstated. A collaborative approach between pediatricians, allergists, dietitians, and gastroenterologists is essential for providing holistic care to families while ensuring that diagnostic and management practices are based on the latest evidence. With continued research into the pathophysiology of CMPA and its mimics and the development of new diagnostic and therapeutic tools, the clinical understanding of these conditions will continue to improve, leading to better patient outcomes and reduced burdens on affected families.