Whipple’s disease

  • Rare multisystem disease involving late middle aged to elderly men manifested by fever, abdominal pain, steatorrhea associated with weight loss enlarged lymph nodes and arthritis as a result of infection with Tropheryma whippleii.

Whipple’s disease due to Tropheryma whipplei a systemic chronic infection characterized by chronic diarrhea, hypoproteinemia, abdominal pain, malnutrition, and weight loss due to PLE, as well as migratory, polyarthralgia and enlarged lymph nodes.

T whipplei is a ubiquitous environmental organism, thought to be acquired by fecal-oral transmission.

Transmission of T. whipplei occurs with contact with contaminated soil or sewage or through the fecal oral route.

T whipplei is identified in fecal samples and up to 20% of asymptomatic persons.

T. whipplei is a rod shaped, intracellular, gram-positive actino bacteria found in the natural environment for which humans are the only known host.

Once infected T. whipplei resides within peripheral blood mono nuclear cells or the vacuoles of macrophages in the small intestine were evade host immuunity by creating an anti-inflammatory environment.

Most infected persons clear the infection, but some, 25%, become asymptomatic long-term carriers, and a small minority of less than .01% present with classic or localized Whipples disease.

Clinical manifestations of infection occur in only one case per million persons annually.
The incidence rate is approximately 1 to 6 cases per 10,000,000 persons per year worldwide.
in US there is a higher prevalence among White persons than among Black individuals, among non-Hispanic persons than among Hispanic persons, and among older than 65 years than among those who are 65 years of age or younger.
Immunologic variation may influence the susceptibility to active disease.

The infection shows a male predominance and typically affects persons of European ancestry, suggesting genetic susceptibility.

Only 1000 cases have been reported with a frequency of less than 0.1% in postmortem studies.

Rare annual incidence of less than one per 1 million people.

Occurs more commonly in people of European ancestry.

80% of cases affect typically middle-age men.

Should be considered in patients with seronegative rheumatoid arthritis

Characterized by 2 stages-a prodromal stage and a later steady state stage.

Classic Whipples disease predominantly affects the small intestine and common presentations include weight loss, diarrhea, abdominal pain, seronegative nondestructive migratory arthropathy, fever, and lymphadenopathy: pleural effusion occurs less frequently and extra intestinal lymphoma occurs in rare cases.

Prodromal stage associated with nonspecific complaints and arthritis, may occur years before the onset of other manifestations.

Affects multiple organ systems and has a broad spectrum of signs and symptoms.

Patients classically present with weight loss, steatorrhea, hypoalbuminemia, anemia, diarrhea, lymphadenopathy, arthralgia, abdominal pain, or fever.

Arthralgias and diarrhea occur in 70-80% of patients, and abdominal pain occurs in about 55%.
Weight loss is seen in more than 90% of patients as is hypoalbuminemia, anemia is seen in 85% of cases, and lymphadenopathy in 60%.
Oculomasticatory myorhythmia is seeing in 20% of patients, hyperpigmentation in exposed areas of the body is seen in 40%,  nonnecrotizing granulomas of the lymph nodes in 9% and ascites in 8%.
Up to 50% of patients have CNS disease.

Many clinical features develop over a period of 6-8 years before diagnosis is made.

Arthritis can proceed gastrointestinal symptoms by many years, with the median of 5.5 years.

Can manifest with endocarditis or CNS disease.

CNS disease may be asymptomatic and may require a lumbar puncture for diagnosis.

The steady state stage manifested by weight loss, diarrhea or both, and occasionally other symptoms.

Associated with infiltration of foamy macrophages into the small bowel, resulting in syndrome abdominal pain, diarrhea, and malabsorption that is typically accompanied by joint pain.

Average time between prodromal stage and steady state stage is 6 years.

Associated with polyarthralgias.

Extraintestinal features include fever, lymphadenopathy, CNS abnormalities such as dementia, cerebellar ataxia, and rarely oculomasticatory myorhythmia.

Eye findings include visible cellular infiltrates in the vitreous or aqueous humor.

Patients who have received immunosuppressive therapy including steroids or tumor necrosis factor inhibitors a more rapid clinical progression may occur.

DNA of organism detected in duodenal biopsy and polymerase chain reaction testing is the diagnostic technique of choice.

Diagnostic test for Whipple’s disease include histologic examination for PAS-positive macrophages, a PCR assay for T.whipplei and immuno histochemical binding of T. whipplei specific antibody.

Diagnosis requires at least two of the three above test to be positive.

Duodenal biopsy also shows organism in histiocytes in the lamina propia which cannot be cultured and have intracytoplasmic inclusions that are PAS positive.

PAS positive foamy macrophages are a non-specific finding that occurs with histiocytic and reactive disorders and other infections, including mycobacterium avian and histoplasma infections.

Immunohistochemical examination and PCR assay have high sensitivity and specificity for T. whipplei infection of greater than 90%.

PCR testing of small bowel biopsy specimens has been reported to have the sensitivity of approximately 89% compared with approximately 60% for localized Whipple disease.

Organisms can be identified on electron microscopy of biopsy specimens or with PCR testing of biopsy specimens or peripheral blood.

Small bowel biopsy with periodic acid Schiff staining along with PCR assay of blood or tissue including duodenum, synovial fluid, CSF, or lymph node can make the diagnosis.

Treatment is with antibiotics which typically includes induction with intravenous ceftriaxone for 2 weeks, (four weeks for endocardial involvement) , followed by maintenance therapy with trimethoprim-sulfamethoxazole for one year.

Associated with massive amounts of bacteria in macrophages of the lamina propia of the duodenum suggesting deficient macrophage activation.

Arthritis present in 60-90% of patients and is the most common presenting process.

Can be associated with polyserositis, hypotension, hyperpigmentation, CNS symptoms of personality changes, dementia and paraparesis

Arthritis is intermittent and migratory with spontaneous remissions.

Approximately 15% of patients lack classic signs and symptoms.

Differential diagnosis includes inflammatory rheumatic disease, malabsorption, with small intestinal disease, celiac disease, sarcoidosis lymphoma, Addison’s disease, connective tissue diseases and neurologic diseases.

Synovial fluid has typical inflammatory findings.

The peripheral and mucosal T helper cell response is impaired.

Treated with tetracycline and results in complete resolution of symptoms in 1-4 weeks.

Standard treatment is a 14 day course of ceftriaxone followed by a one-year course of trimethoprim-sulfamethoxazole.

Antibiotic therapy results in a 95% remission rate.

Without antibiotic therapy the disease is fatal.

Diagnosis is often delayed because of the rarity of the entity and many nonspecific symptoms and signs.

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