What is Whipple's disease?

What is Whipple's Disease

Whipple's disease is a rare, chronic, systemic bacterial infection caused by Tropheryma whipplei that can affect multiple organ systems and requires prolonged antibiotic therapy to prevent potentially fatal outcomes. 1, 2

Causative Organism and Epidemiology

• The disease is caused by Tropheryma whipplei, a Gram-positive actinomycete bacterium that was successfully cultured only in recent years 2, 3
• Whipple's disease predominantly affects middle-aged Caucasian males (typically 40-60 years old), with only approximately 1,000-1,500 cases reported in the literature 2, 4, 3, 5
• The actual incidence and prevalence remain uncertain due to underdiagnosis and the rarity of the condition 5
• Patients with certain HLA types (particularly HLA-B27) may have genetic predisposition to symptomatic infection 5

Clinical Manifestations

Classic Presentation

• Gastrointestinal symptoms are most common and include chronic diarrhea, abdominal pain, malabsorption syndrome with steatorrhea, weight loss, and anorexia 2, 4, 3
• Arthralgia is frequently the earliest manifestation, often presenting as migratory polyarthralgias that may precede other symptoms by years or even decades 4, 5
• Constitutional symptoms include low-grade fever, progressive weakness, and cachexia 4, 5

Systemic Involvement

The disease can affect virtually any organ system 3, 6:

• Lymphatic system: Generalized lymphadenopathy is common 5
• Cardiovascular: Endocarditis and valvular involvement can occur 7, 3
• Neurological: Central nervous system manifestations include nystagmus, ophthalmoplegia, cranial nerve defects, sensory and motor polyneuropathy, and cognitive changes 4, 5, 6
• Other manifestations: Skin hyperpigmentation, pleuritis, uveitis, spondylodiscitis, and pulmonary involvement 3, 5

Clinical Stages

Untreated Whipple's disease progresses through three stages 5:

1. Prodromal stage: Non-specific migratory polyarthralgias
2. Classic abdominal stage: Weight loss, weakness, chronic diarrhea, abdominal pain
3. Generalized stage: Steatorrhea, cachexia, lymphadenopathy, hyperpigmentation, and multi-organ dysfunction

Diagnostic Approach

Standard Diagnostic Methods

• Small bowel biopsy remains the gold standard, showing mucosal infiltration with large foamy histiocytes containing periodic acid-Schiff (PAS)-positive granules representing intact or partially degraded bacteria 2, 4, 3, 6
• Lymph node biopsy can demonstrate characteristic granulomatous inflammation with PAS-positive material 5

Advanced Diagnostic Techniques

• PCR testing for T. whipplei DNA is more sensitive than histopathology and can be performed on various specimens including cerebrospinal fluid, blood, and tissue samples 7, 3, 6
• Immunohistochemistry provides specific identification of the organism 2, 6
• Electron microscopy can identify bacteria with characteristic trilaminar cell wall ultrastructure 2, 3

Important Diagnostic Caveats

• T. whipplei DNA has been detected in asymptomatic individuals without clinical or histological evidence of disease, suggesting possible carrier states 3
• The diagnosis is often delayed by years or decades due to the variable and non-specific presentation 4, 3
• Culture-negative endocarditis workup should include consideration of T. whipplei as a fastidious organism 7

Treatment Recommendations

Standard Therapy

• First-line treatment: Doxycycline 200 mg/24 hours plus hydroxychloroquine 200-600 mg/24 hours orally for at least 18 months 1
• This prolonged duration is essential to prevent relapse and achieve complete bacterial eradication 1, 2

CNS Involvement

• When CNS disease is present: Add sulfadiazine 1.5 g every 6 hours orally to the doxycycline regimen 1
• CNS involvement carries a poorer prognosis and requires more aggressive therapy 2, 6

Alternative Regimens

• Ceftriaxone 2 g/24 hours IV for 2-4 weeks can be used as alternative therapy 1
• Penicillin G 2 million units every 4 hours plus streptomycin 1 g/24 hours IV for 2-4 weeks, followed by trimethoprim-sulfamethoxazole 800 mg every 12 hours orally 1, 3

Prognosis and Follow-up

• Most patients respond well to prolonged antibiotic treatment when diagnosed early 2, 6
• Life-long surveillance for recurrence is essential after completing primary treatment 4
• Patients with relapsing disease or CNS manifestation may have poor prognosis despite treatment 2, 6
• Immune reconstitution inflammatory syndrome (IRIS) can complicate treatment and may be fatal in worst cases 6
• Untreated Whipple's disease is progressive and lethal 6

Pathophysiology

• Subtle defects in cell-mediated immunity exist in both active and inactive Whipple's disease, which may predispose certain individuals to symptomatic infection 2, 6
• The exact mechanisms determining why some individuals develop symptomatic disease while others remain asymptomatic carriers remain unclear 3
• Different T. whipplei subtypes have been identified, though their clinical significance regarding virulence and variable manifestations requires further study 3