What are the manifestations and treatment of Whipple disease?

Manifestations and Treatment of Whipple Disease

Whipple disease is a rare, chronic, systemic bacterial infection caused by Tropheryma whipplei that requires long-term antibiotic treatment with doxycycline plus hydroxychloroquine for at least 18 months to prevent potentially fatal outcomes. 1

Clinical Manifestations

Gastrointestinal Manifestations

• Diarrhea, abdominal pain, weight loss, and malabsorption syndrome are the classic gastrointestinal symptoms, though they may be absent in some cases 2, 3
• Periodic acid-Schiff (PAS) positive macrophage infiltration in the lamina propria of the small intestine is a pathognomonic finding 2
• Small bowel biopsy is often diagnostic, though approximately 30% of patients may have no intestinal abnormalities 2

Articular Manifestations

• Migratory arthralgia or arthritis may precede other manifestations by years and can be the only presenting symptom in some cases 2, 4
• Joint symptoms can occur in up to 75% of patients and may evolve intermittently 3
• These symptoms may lead to multiple hospital admissions and misdiagnoses before the correct diagnosis is established 4

Neurological Manifestations

• Central nervous system involvement can present with various neurological abnormalities 2, 4
• Oculofacial-skeletal myorhythmia or oculomasticatory myorhythmia are unique signs that, when present, are diagnostic of Whipple disease 2
• Isolated neurological Whipple disease can occur without gastrointestinal involvement 5

Other Systemic Manifestations

• Low-grade fever, lymphadenopathy, and skin hyperpigmentation 4, 6
• Cardiovascular involvement including endocarditis 6
• Pleuritis, uveitis, and spondylodiscitis 6
• The disease can affect virtually any organ system in the body 2, 6

Diagnostic Approach

Histopathology

• Small intestinal biopsy with PAS staining remains the first choice for diagnosis of classical Whipple disease 5
• PAS-positive macrophages may also be found in peripheral and mesenteric lymph nodes and various other organs 2
• Histological differential diagnoses include histoplasmosis and Mycobacterium avium-intercellulare complex 2

Molecular Testing

• Polymerase chain reaction (PCR) for T. whipplei 16S ribosomal RNA is an important diagnostic test 2, 6
• DNA sequencing from PCR-positive specimens from blood and cerebrospinal fluid is essential, especially in neurological cases 5
• PCR testing is more sensitive than histopathological analysis, particularly for extraintestinal specimens 6

Other Tests

• In patients with only CNS involvement, stereotactic brain biopsy may be necessary 2
• Immunohistochemistry can help identify the agent more specifically 5

Treatment

Antibiotic Regimens

• The recommended treatment for Whipple disease is doxycycline (200 mg/24 h) plus hydroxychloroquine (200-600 mg/24 h) orally for at least 18 months 1
• For central nervous system involvement, sulfadiazine 1.5 g/6 h orally must be added to doxycycline 1
• Alternative therapy options include:
  • Ceftriaxone (2 g/24 h IV) for 2-4 weeks 1
  • Penicillin G (2 million U/4 h) and streptomycin (1 g/24 h) IV for 2-4 weeks followed by cotrimoxazole (800 mg/12 h) orally 1

Treatment Monitoring

• Close monitoring for response to treatment is essential as relapses are common 2
• CNS involvement requires more vigorous treatment due to high recurrence rates after apparently successful treatment 2
• Life-long surveillance for recurrence is essential once primary treatment has been completed 4

Treatment Complications

• Immune reconstitution inflammatory syndrome (IRIS) might complicate the course of treatment and in worst cases can be fatal 5

Special Considerations

Diagnostic Challenges

• The average time to diagnosis is approximately 6 years due to the variable clinical presentation 3
• Diagnosis is often delayed because symptoms can be intermittent and nonspecific 4, 3
• Clinicians should maintain a high index of suspicion for T. whipplei infection in patients with long-term history of arthritis, fever, and diarrhea 4

Epidemiology

• Whipple disease occurs primarily in Caucasian males older than 40 years 6
• Recent data suggest the disease occurs in an older age group than previously described 2

Immunological Aspects

• Various immunological abnormalities have been described in Whipple disease 2
• Cell-mediated immunity in active and inactive Whipple disease has subtle defects that might predispose some individuals to symptomatic infection 5
• T. whipplei DNA has been found in persons without clinical evidence of Whipple disease, suggesting possible asymptomatic carriers or differences in strain virulence 6