What is the pathophysiology of Cow's Milk Protein Allergy (CMPA) and Food Protein-Induced Allergic Proctocolitis (FPIAP) that leads to their symptoms?

Pathophysiology of CMPA and FPIAP

Core Immunologic Mechanisms

Both CMPA and FPIAP represent immune-mediated reactions to cow's milk proteins, but they differ fundamentally in their immunologic pathways: CMPA can involve IgE-mediated, non-IgE-mediated (cell-mediated), or mixed mechanisms, while FPIAP is exclusively a non-IgE-mediated condition affecting the distal colon. 1, 2, 3

Non-IgE-Mediated Pathway (Shared by Both Conditions)

The primary mechanism involves antigen-specific T cells, cytokines, and resulting intestinal inflammation that increases intestinal permeability and causes fluid shifts into the gastrointestinal lumen. 4, 5

• T cell-mediated inflammation is the postulated central mechanism, though this requires further validation according to international consensus guidelines 4
• The inflammatory cascade involves infiltration of lymphocytes, plasma cells, and polymorphonuclear leukocytes into the intestinal mucosa 4
• This inflammation directly damages the intestinal epithelium, causing increased permeability 5
• The resulting fluid shift into the gastrointestinal lumen explains the profuse vomiting (in FPIES/acute CMPA) and bloody diarrhea (in FPIAP) 4, 5

IgE-Mediated Component (CMPA Only)

• Immediate-type CMPA involves IgE antibodies that trigger rapid-onset allergic symptoms within minutes to hours 1
• Some patients demonstrate mixed pathophysiology with both IgE and non-IgE mechanisms operating simultaneously 4, 1
• Local intestinal mucosal IgE antibodies can facilitate antigen uptake and contribute to intestinal inflammation even in predominantly non-IgE presentations 4
• TH2 responses similar to classic IgE-mediated allergy have been documented in non-IgE CMPA patients, explaining the high rates of atopy 4

Specific Pathophysiology by Condition

FPIAP (Food Protein-Induced Allergic Proctocolitis)

FPIAP specifically affects the distal colon through non-IgE immune reactions causing localized mucosal inflammation. 2, 3

• Colonoscopic findings reveal loss of vascular pattern, spontaneous and induced friability, and variable degrees of ulceration with spontaneous bleeding 4
• Histology shows polymorphonuclear leukocytic infiltration of the lamina propria or glands, with occasional crypt abscesses and mucus depletion from rectal glands 4
• Surface epithelium destruction can occur, with red, fragile, hemorrhagic mucosa appearing within hours of ingesting the offending food 4
• The inflammation is localized to the rectum and distal colon, explaining why rectal bleeding with mucus is the clinical hallmark 2, 3

CMPA (Broader Spectrum)

Non-IgE CMPA can affect multiple levels of the gastrointestinal tract beyond just the colon. 6, 1

• Small intestinal damage with variable degrees of villous atrophy has been documented in infants with CMPA, causing carbohydrate malabsorption and watery stools positive for reducing substances 4, 6
• Upper endoscopy in chronic presentations reveals gastric edema, erythema, mucosal friability, and gastric antral erosions 4
• Colonic involvement shows severe inflammation with increased eosinophil numbers on biopsy 4
• The extent of gastrointestinal involvement determines symptom severity and presentation pattern 1, 7

Neuroimmune Mechanisms

The successful use of ondansetron to treat vomiting, abdominal pain, and lethargy during FPIES challenges implies neuroimmune mechanism involvement beyond simple intestinal inflammation. 4

• This suggests that inflammatory mediators activate neural pathways contributing to the profuse vomiting characteristic of acute presentations 4
• The 1-4 hour delay before symptom onset likely reflects the time required for antigen processing, T cell activation, and cytokine release to reach threshold levels 8

Phenotypic Variations and Clinical Implications

Acute vs. Chronic Presentations

• Acute presentations occur with intermittent food exposures, allowing the immune system to "reset" between exposures, leading to dramatic reactions upon re-exposure 4, 8
• Chronic presentations develop with daily ingestion, causing ongoing low-grade inflammation manifesting as chronic diarrhea, vomiting, and failure to thrive 4
• The distinction reflects different patterns of immune activation rather than fundamentally different mechanisms 4

Important Caveats

• Some patients with non-IgE CMPA can develop IgE-mediated reactions over time, representing phenotypic shifting that may be associated with more protracted disease course 4, 9
• Casein-specific IgE in particular has been associated with more persistent CMPA 4
• Gross and histologic abnormalities can revert to normal as soon as 2 days after removal of the trigger food, demonstrating the reversible nature of the inflammation 4
• The relationship between IgE and non-IgE mechanisms remains incompletely understood and requires further investigation 4