Definition/General
Introduction:
Whipple disease is a rare systemic infection caused by Tropheryma whipplei
It primarily affects the small intestine
It shows characteristic PAS-positive macrophages
It is a multisystem disease with GI, CNS, cardiac, and articular manifestations.
Origin:
Caused by Tropheryma whipplei, a gram-positive actinomycete
Results from immune system dysfunction allowing bacterial proliferation
Impaired macrophage function and reduced IL-16 production
Genetic predisposition: HLA-DRB1*13 association.
Classification:
Classic Whipple disease: intestinal involvement with systemic features
Localized forms: CNS-only, cardiac-only
Primary CNS Whipple (without GI involvement)
Asymptomatic infection (rare)
Based on organs involved.
Epidemiology:
Very rare disease (annual incidence 1 per million)
Male predominance (8:1 ratio)
Middle-aged Caucasian men (40-60 years)
Extremely rare in non-Caucasians
Farmers and outdoor workers at higher risk.
Clinical Features
Presentation:
Weight loss (most common, 80% cases)
Diarrhea and steatorrhea
Abdominal pain
Polyarthritis (70% cases)
Fever and lymphadenopathy
Neurological symptoms (10-40% cases).
Symptoms:
Chronic diarrhea with steatorrhea
Significant weight loss (average 10-20 kg)
Migratory polyarthritis
Abdominal distension and pain
Neurological manifestations: dementia, ataxia, seizures
Cardiac symptoms: murmurs, heart failure.
Risk Factors:
Male sex (8:1 predominance)
Caucasian ethnicity
Middle age (40-60 years)
Agricultural work or rural environment
HLA-DRB1*13 genetic susceptibility
Immunocompromised states.
Screening:
Upper endoscopy with duodenal biopsy
Small bowel biopsy (definitive diagnosis)
PCR for T
whipplei
CSF analysis (neurological symptoms)
Echocardiography (cardiac involvement)
CT/MRI abdomen.
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Gross Description
Appearance:
Pale, thickened mucosa
Villous atrophy and blunting
Yellow-white discoloration
Enlarged mesenteric lymph nodes
Dilated lacteals
Surface may appear velvety.
Characteristics:
Diffuse small bowel involvement
Duodenum and jejunum most affected
Mucosal thickening without ulceration
Enlarged, pale lymph nodes
Hepatosplenomegaly possible.
Size Location:
Duodenum and proximal jejunum primarily affected
Entire small bowel may be involved
Mesenteric lymphadenopathy characteristic
Retroperitoneal lymph nodes involved
Extraintestinal organs: heart, CNS, joints.
Multifocality:
Diffuse small bowel involvement
Multisystem disease
Lymph node involvement common
CNS involvement (10-40% cases)
Cardiac involvement (endocarditis pattern).
Microscopic Description
Histological Features:
Foamy macrophages in lamina propria
PAS-positive inclusions in macrophages
Villous atrophy
Chronic inflammation
Dilated lacteals
Lymphatic obstruction.
Cellular Characteristics:
Large foamy macrophages with abundant cytoplasm
PAS-positive, diastase-resistant inclusions
Rod-shaped bacteria within macrophages
Lymphocytes and plasma cells
Neutrophils (minimal unless secondary infection).
Architectural Patterns:
Villous shortening and blunting
Crypt hyperplasia
Lamina propria expansion
Lymphatic dilatation
Submucosal involvement
Preserved surface epithelium (usually).
Grading Criteria:
Villous architecture: normal to severe atrophy
Macrophage density: sparse to packed
Bacterial load: light to heavy (PAS stain)
Inflammatory activity: minimal to moderate.
Immunohistochemistry
Positive Markers:
CD68 (macrophages positive)
PAS stain (pathognomonic positive macrophages)
CD3 (T-lymphocytes)
CD20 (B-lymphocytes)
Lysozyme (macrophages).
Negative Markers:
Acid-fast stain (negative, excludes TB)
GMS stain (negative, excludes fungi)
Gram stain (weakly positive or negative)
Von Kossa (negative, excludes calcium).
Diagnostic Utility:
PAS stain: diagnostic hallmark (magenta-colored inclusions)
Confirms macrophage nature of foamy cells
Excludes other infections (TB, fungi, MAC)
Demonstrates bacterial inclusions
Essential for diagnosis.
Molecular Subtypes:
Classic intestinal form: heavy bacterial load, PAS-positive
CNS-predominant: may have fewer GI bacteria
Cardiac form: endocardial involvement pattern
Asymptomatic carriage: minimal bacterial load.
Molecular/Genetic
Genetic Mutations:
HLA-DRB1*13 association (genetic susceptibility)
IRF4 gene variants (immune response)
TLR genes (innate immunity)
Host factors affecting IL-16 production
Macrophage dysfunction genes.
Molecular Markers:
16S rRNA PCR (T
whipplei specific)
Real-time PCR (quantitative bacterial load)
Sequencing confirmation
Reduced IL-16 levels
Impaired Th1 response.
Prognostic Significance:
Early diagnosis: excellent prognosis with treatment
CNS involvement: requires longer treatment
Cardiac involvement: potential complications
Relapse risk: 5-10% cases
Untreated disease: fatal.
Therapeutic Targets:
Antibiotics: trimethoprim-sulfamethoxazole (first-line)
Initial therapy: ceftriaxone or penicillin
Maintenance therapy: 1-2 years minimum
CNS penetration: doxycycline alternative
Monitoring: PCR negativity.
Differential Diagnosis
Similar Entities:
Malabsorption syndrome
Mycobacterium avium complex (MAC)
Histoplasmosis
Celiac disease
Tropical sprue
Lymphoma.
Distinguishing Features:
Whipple: PAS-positive macrophages, T
whipplei PCR+
MAC: acid-fast positive, immunocompromised
Histoplasmosis: GMS-positive fungi
Celiac: villous atrophy, gluten sensitivity
Lymphoma: monoclonal cells.
Diagnostic Challenges:
Recognizing PAS-positive macrophages
Distinguishing from other infections
PCR confirmation availability
Identifying extraintestinal manifestations
Correlation with clinical syndrome.
Rare Variants:
Primary CNS Whipple (without GI involvement)
Isolated cardiac Whipple
Asymptomatic infection
Ocular Whipple disease
Relapsing forms (treatment resistance).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Duodenal/small bowel biopsy, [number] fragments
Diagnosis
Small intestinal biopsy consistent with Whipple disease
Histological Features
Foamy macrophages in lamina propria with villous blunting and chronic inflammation
PAS Stain
PAS stain: strongly positive inclusions in macrophages (pathognomonic)
Villous Architecture
Villous architecture: [normal/mild blunting/moderate atrophy/severe atrophy]
Special Stains
Acid-fast stain: negative, GMS stain: negative
Molecular Studies
T. whipplei PCR: [positive/negative/pending]
16S rRNA sequencing: [result if performed]
Bacterial culture: [typically negative]
Recommendations
Clinical correlation, antibiotic therapy, systemic evaluation for extraintestinal involvement
Final Diagnosis
Small intestinal Whipple disease (Tropheryma whipplei infection)