What causes blood in stool in Cow's Milk Protein Allergy (CMPA)?

Why Blood Appears in Stool in Cow's Milk Protein Allergy (CMPA)

Blood in stool occurs in CMPA because cow's milk proteins trigger a non-IgE-mediated immune response that causes direct inflammatory damage to the intestinal mucosa, particularly in the colon, resulting in mucosal edema, friability, ulceration, and spontaneous bleeding. 1

Underlying Immunologic Mechanism

The pathophysiology centers on T cell-mediated inflammation rather than classic IgE-mediated allergic reactions 1, 2:

• Antigen-specific T cells, cytokines, and inflammatory mediators infiltrate the intestinal wall when cow's milk proteins are ingested 1, 2
• This triggers an inflammatory cascade involving lymphocytes, plasma cells, and polymorphonuclear leukocytes that infiltrate the lamina propria and epithelium 1
• The inflammation causes increased intestinal permeability and fluid shift into the gastrointestinal lumen 1, 2

Direct Mucosal Damage Causing Bleeding

The inflammatory process produces visible pathologic changes that directly cause bleeding 1:

Colonoscopic Findings

• Loss of vascular pattern with spontaneous and induced friability 1
• Variable degrees of ulceration with spontaneous bleeding 1
• Red, fragile, hemorrhagic mucosa appearing within hours of ingesting the offending food 1
• Mucosal edema with infiltration of eosinophils in the epithelium and lamina propria 1

Histologic Changes

• Polymorphonuclear leukocytic infiltration of the lamina propria or glands 1
• Occasional crypt abscesses and depletion of mucus from rectal glands 1
• Destruction of the surface epithelium in severe cases 1
• In severe lesions with crypt destruction, both eosinophils and neutrophils are prominent 1

Clinical Presentation Patterns

Food Protein-Induced Allergic Proctocolitis (FPIAP)

This is the most common presentation causing bloody stools 1:

• Manifests as mucoid, blood-streaked stools in an otherwise healthy-appearing infant 1
• Typically occurs in breast-fed infants in the first weeks to months of life 3, 4
• The infant appears well and thriving despite the bleeding 1
• Symptoms resolve within 48-72 hours following elimination of cow's milk protein 4

Food Protein-Induced Enterocolitis Syndrome (FPIES)

A more severe presentation that can also include bloody stools 1:

• Presents as blood-streaked or hemoccult-positive stools in young infants 1
• Accompanied by profuse vomiting, diarrhea, and potential shock 1, 5
• Symptoms occur 1-4 hours after ingestion of the causative food 1, 5
• Can involve small intestinal damage with villous atrophy in addition to colonic inflammation 1

Key Clinical Distinctions

Important caveat: In preterm infants, CMPA with bloody stools can be easily confused with necrotizing enterocolitis (NEC) 6, 7:

• Both conditions present with bloody stools and abdominal distension 6
• CMPA infants typically appear systemically well, unlike NEC patients who show systemic instability 6
• The distinction is critical because treatment approaches are completely different 6
• Most preterm infants with CMPA were exposed to bovine-based formulas before symptom development 7

Diagnostic Approach

IgE testing (skin prick tests and serum IgE) is typically negative because this is a non-IgE-mediated process 1, 4:

• Diagnosis relies on clinical history, symptom resolution with elimination, and recurrence with re-challenge 1
• Endoscopy is not routinely required for diagnosis 1
• When performed, colonoscopy confirms the inflammatory changes described above 1
• Stool tests should not be used to make the diagnosis of FPIES, though occult blood or frank blood may be present 1

Resolution Timeline

The inflammatory damage and bleeding resolve rapidly with appropriate management 4:

• Gross and histologic abnormalities can revert to normal as soon as 2 days after removal of the trigger food 1
• Most infants with FPIAP achieve tolerance by 1-2 years of age 1
• FPIES typically resolves within a few years 1

Critical pitfall to avoid: While most cases resolve favorably, some infants with initial non-IgE-mediated CMPA can develop severe, persistent IgE-mediated cow's milk allergy with anaphylaxis later in childhood 8. This phenotypic shift, though uncommon, warrants continued monitoring even after apparent resolution.