Whipple disease (ORPHA:3452)
A rare chronic infectious disorder in which almost all organ systems can be invaded by the rod-shaped bacterium Tropheryma whipplei (TW).
Epidemiology
The annual incidence in Central European countries is estimated to be approximately 1/1,000,000.
Clinical description
The disease may occur at any age with diagnosis most frequently made between 50 to 60 years of age. The clinical picture is variable. The following symptoms are frequent but not necessarily observed in each patient: weight loss, polyarthritis, diarrhea/malabsorption, fever, lymphadenopathy, cardiac valvular disease, culture-negative endocarditis, pleuritis, ocular inflammatory disease, and relapsing tenosynovitis. In some cases, complex cerebral manifestations (such as cognitive dysfunction, ophthalmoplegia and myoclonus) can be observed. TW polyarthritis is typically palindromic; however, atypical courses may also occur.
Etiology
TW has been found in sewage plant influx and efflux, and can be excreted in the stool of healthy carriers, of sewage plant workers and of people living in precarious hygienic conditions. The circumstances facilitating infection and disease are unknown, but a genetic or acquired immunological predisposition is suspected.
Diagnostic methods
The gold standard for diagnosis was the histological recognition by an experienced pathologist of free or phagocytised rod-shaped bacteria with periodic-acid-SCHIFF (PAS) staining in macrophages from the duodenal mucosa. However, the combination of PAS staining in an intestinal mucosal biopsy plus a validated specific real time polymerase chain reaction (PCR) for TW will raise sensitivity and specificity of the diagnosis. Cooperation with a laboratory, certified for PCR in Whipple's disease and routinely sequencing the amplification product of the PCR is recommended. Specific immunohistochemistry should be available. An isolated positive PCR in an intestinal mucosal biopsy or in a stool specimen is not sufficient for diagnosis. The diagnosis in extraintestinal tissue is always made by PCR. Immunohistochemistry can be very useful. A positive PCR in pulmonary alveolar lavage or from the oral cavity may mean colonization with TW and not necessarily infection. As the majority of patients with infected cerebrospinal fluid (CSF) are asymptomatic at the time of diagnosis, CSF should be examined with PCR in every patient before antibiotic treatment. Synovial fluid or synovial tissue should be examined by PCR for TW in patients with rheumatic symptoms as the intestinal mucosa is not always involved. Positive PAS staining in cerebral tissues should never be accepted as sole diagnostic tool.
Differential diagnosis
The differential diagnosis includes inflammatory bowel disease, malabsorption syndrome, infectious diarrhea, mesenteric lymphadenitis, seronegative polyarthritis, soft tissue rheumatism, culture-negative endocarditis, vasculitis, lymphoma, cerebrovascular disease, demential processes, HIV infection, atypical mycobacteriosis, sarcoidosis, unclear cutaneous symptoms, exophthalmos and many others.
Management and treatment
According to the only available prospective randomized trial, treatment should consist in: 2 g Ceftriaxon daily intravenously for 14 days, followed by Cotrimoxazol twice daily for 12 months. Control examination of CSF, when initially positive, after termination of treatment is strongly suggested. In recurrent or resistant cerebral infection, contact with a TW. specialist is recommended. Expert advice concerning treatment is indispensable in patients who have received immunosuppressive treatment prior to the diagnosis, including oral steroids, or when a clinical response to Ceftriaxone is not apparent within a few days. In such cases, the occurrence of an immune reconstitution inflammatory syndrome in Whipple's disease (IRIS) must be considered. Treatment with immunosuppressive agents may be lifesaving. Lifelong clinical, non-invasive observation is advised in effectively treated patients, as late recurrences or de novo infections can occur.
Prognosis
Untreated, the disease is relentlessly progressive and leads to death either by wasting or by central nervous system involvement. The treatment schedule and follow up, detailed above, is mostly successful. Fatal courses can occur in patients with advanced cerebral involvement and in patients with the Immune Reconstitution Inflammatory Syndrome (IRIS).

                            Last update: 
                            October 2019


                            - Expert reviewer(s): 
                            Pr Gerhard FEURLE