Whipple disease is a rare systemic chronic infectious disease. It is caused by the bacterium Tropheryma whipplei, which is ubiquitous in the environment and is transmitted through contact with contaminated soil or sewage or through the fecal-oral route. The most common symptoms are gastrointestinal, but the disease can affect multiple body systems. There is a higher prevalence of Whipple disease in middle-aged white males of European ancestry, and so a genetic predisposition has been postulated. However, no definitive association has been demonstrated, and the mechanism of infection is unknown.
Signs / Symptoms: Physical examination findings for Whipple disease are generally nonspecific, and diagnosis is thus often delayed. Many of these features develop over a period of 6-8 years before diagnosis.
Gastrointestinal – Gastrointestinal symptoms are most common and include weight loss, diarrhea, and abdominal pain and often lead to hypoalbuminemia and anemia. Malabsorption can progress to a wasting syndrome, and abdominal lymphadenopathy may occur.
Joints – Joint involvement occurs in 60%-90% of cases, typically with intermittent migratory polyarthritis, predominately of the large joints. Rarely, a chronic destructive seronegative polyarthritis can occur that may be mistaken for rheumatoid arthritis.
Central nervous system – Central nervous system (CNS) symptoms are seen in approximately one-half of cases. Headache is a common symptom. Other manifestations include cognitive impairment, altered level of consciousness, encephalopathy, depression, and personality changes. Disturbances of ocular movement with progressive supranuclear ophthalmoplegia with oculomasticatory myorhythmia or oculofacial-skeletal myorhythmia are pathognomonic. Prognosis is particularly poor for those with CNS involvement. Isolated neurological manifestations may occur without histologic evidence of intestinal involvement.
Ocular – Anterior or posterior uveitis is the most common ocular manifestation; optic neuritis and retinitis may also occur.
Cardiac – Pericarditis occurs in up to 40% of cases, and blood-culture negative endocarditis may be seen; the latter may occur in isolation without other manifestations.
Pulmonary – Pulmonary symptoms are rare, but a chronic cough can be a central feature of the disease. If there is pulmonary involvement, symptoms may include dry, chronic cough, dyspnea, pleural effusions, and other findings on chest imaging such as interstitial patterns and/or mediastinal lymphadenophy.
Microbiology: Tropheryma whipplei is a rod-shaped gram-positive bacteria with a trilamellar plasma membrane typically found within macrophages of the lamina propria of the small intestine of patients with Whipple disease. The bacterium's cell wall contains an unusual inner layer comprised mainly of polysaccharides. On periodic acid-Schiff (PAS) stain, macrophages have characteristic foamy intracellular inclusions representing components of the degraded bacterial cell wall.
PAS-positive macrophages can also be detected from other involved sites including the cerebrospinal fluid (CSF), brain tissue, lymph nodes, synovium, heart valves, and bone marrow. The organism is one of the slowest growing human pathogenic bacteria, with an estimated generation time of 18 days, slower than some mycobacteria.
ICD10CM: K90.81 – Whipple's disease
SNOMEDCT: 41545003 – Whipple's disease
Differential Diagnosis & Pitfalls
Because Whipple disease can affect many organ systems, the differential diagnosis is broad:
Autoimmune disorders including Addison disease and connective tissue diseases – Cortisol, adrenocorticotropic hormone (ACTH), antinuclear antibodies (ANA), anti-dsDNA antibodies.
Neurological disorders such as atypical parkinsonism, metabolic disorders such as mitochondrial diseases, and degenerative diseases such as progressive supranuclear palsy – Magnetic resonance imaging (MRI) of brain, lumbar puncture.
Syphilis, sarcoidosis, and vasculitis can cause similar ophthalmic symptoms, unexplained weight loss, diarrhea, and migratory arthralgia – Funduscopic examination, rapid plasma reagin (RPR), ANA, angiotensin-converting enzyme (ACE) level.
Crohn disease with reactive arthritis – Cannot clinically distinguish gastrointestinal symptoms from Whipple disease; duodenal biopsy does not show PAS-positive cells.
Celiac disease – Gastrointestinal symptoms are alleviated by gluten-free diet and often have coexisting dermatologic manifestations such as dermatitis herpetiformis; serology for anti-transglutaminase antibodies is usually positive; duodenal biopsy shows flattened and blunted villi, crypt hyperplasia, and lymphocyte infiltration but no PAS-positive cells.
Sarcoidosis – Typically there is lung involvement, in contrast to Whipple disease; lymph node biopsy shows noncaseating granulomas with no PAS-positive cells (although noncaseating granulomas can be seen with Whipple disease; see Best Tests).
Seronegative rheumatoid arthritis – Isolated joint symptoms cannot be clinically distinguished from Whipple disease; biopsy of synovium or of duodenum does not reveal PAS-positive cells.