• Weight loss, diarrhea, and abdominal discomfort are present in 85–90% of patients at time of diagnosis.
  
• An intermittent, migratory oligoarthritis occurs early in the disease course, preceding gastrointestinal symptoms by an average of 6–8 years.
  
• Inflammatory polyarthritis and sacroiliitis can develop in the chronic phase of disease.
  
• Neurologic involvement is present in 90% of cases.
  
• Diagnosis is based on demonstration of characteristic periodic acid–Schiff (PAS)–positive intracellular inclusions and identification of Tropheryma whipplei by polymerase chain reaction (PCR) in biopsies of involved tissues or in fluids.

Whipple disease, a chronic multisystem disease caused by infection with T whipplei, was first described in 1907 by George H. Whipple who noted the presence of rod-shaped organisms in the vacuoles of foamy macrophages in the intestinal tissue of a 36-year-old man during autopsy. Over 40 years later, these cells were found to stain positively with PAS and, in 1961, electron microscopy facilitated the recognition of bacterial components in these tissues. Identification of the bacillus was reported in 1992 with the aid of the PCR technique, which enabled the amplification of specific gene segments. In 2000, the organism T whipplei was successfully cultivated in vitro, thereby facilitating developments in the pathogenesis, diagnosis, and treatment of this disease.

Whipple disease is rare, with an estimated incidence of 1 per million. It has been most commonly reported in middle-aged white men with an occupational exposure to soil, animals, or sewage. There are two recognized phases of Whipple disease. In the initial stage, symptoms and signs are nonspecific and are marked predominantly by fatigue and joint pains, with or without synovitis. In the later phase, weight loss, diarrhea, and neurologic or psychiatric symptoms may prevail. Although the average interval between these stages is 6–8 years, the initiation of immunosuppressive treatment for presumed inflammatory arthritis may unmask the diagnosis by allowing proliferation of the organism, resulting in more acute symptoms.

T whipplei can be found in the general environment, in sewage plant effluent, and in the stool in asymptomatic human carriers. It has also been isolated from the saliva, blood, stool and duodenal samples from healthy individuals, although it is unclear if this represents environmental contamination, preclinical infection, or the inconsequential presence of commensal organisms. No link with specific genetic factors has been identified.

There is a striking absence of inflammation in tissues infected with T whipplei. The organism does not provoke a local cytotoxic reaction, and large numbers of bacilli accumulate at areas of infection. These observations suggest that aberrations of the host immune response may contribute to the clinical manifestations of disease.

The diagnosis of Whipple disease requires evidence of infection with T whipplei. The test of choice usually is upper gastrointestinal endoscopy and the acquisition of multiple biopsies from the duodenum and jejunum. The tissue should be stained with PAS, which yields a 78% positivity rate for detection of characteristic intracellular inclusions in patients with untreated Whipple disease. PCR analysis is recommended for confirmation. If gastrointestinal biopsies are negative, other symptomatic areas should be examined, such as synovial fluid, pleural fluid, skin, and lymph nodes. Examination of the cerebrospinal fluid is recommended in all confirmed cases to investigate for asymptomatic neurologic involvement.

Because of the systemic nature of Whipple disease, the wide variety of possible clinical presentations, and the chronicity of the illness, a high index of suspicion is essential in order to make the diagnosis in a timely manner before the onset of permanent or life-threatening sequelae. Approximately 15% of patients with Whipple disease have atypical signs. However, the presence of gastrointestinal symptoms with or without neurologic features on the background of an unusual seronegative arthropathy should trigger appropriate investigations. Ideally, however, the diagnosis should be made in the prodromal stage of unexplained, intermittent oligoarthritis or polyarthritis.

Symptoms and Signs

Articular Manifestations

Articular symptoms occur in up to 90% of patients with Whipple disease. Joint involvement is characteristically an intermittent, migratory oligoarthritis, predominantly affecting the large joints, such as the knees, wrists, and ankles. Less frequently, the hips, elbows, and shoulders may be symptomatic. It is rare for small joints to be involved. Attacks usually last several hours to a few days and resolve spontaneously with complete remission between episodes. The average duration of joint symptoms is 6–8 years before the diagnosis of Whipple disease is made.

Chronic polyarthritis is less common but has been described in association with Whipple disease. It tends to show the features of an inflammatory arthritis, with prolonged early morning stiffness. Joint damage does not develop in most patients, but ankylosis of the wrists, ankles, and spine may occur in a minority. Furthermore, sacroiliitis and the radiographic changes of hypertrophic osteoarthropathy have been reported in patients with Whipple disease.

Gastrointestinal Manifestations

The most common gastrointestinal symptom of Whipple disease is profound weight loss. Diarrhea is a frequent complaint and abdominal pain may be present. In advanced cases, evidence of chronic malabsorption is present, with edema, ascites, and muscle wasting. However, 10–15% of patients have no gastrointestinal symptoms at diagnosis. During upper gastrointestinal endoscopy, pale yellow mucosa punctuated with erosions may be observed.

Skin Lesions

A variety of skin lesions have been described in association with Whipple disease. The most common of these is hyperpigmentation or melanoderma that develops in up to 46% of patients in the later stages of the illness. Other characteristic skin abnormalities include subcutaneous nodules; erythema nodosum–like lesions; and inflammatory rashes that may mimic cutaneous lupus, dermatomyositis, psoriasis, or eczema. Urticaria and vasculitic lesions have also been reported. Consequences of severe malnutrition may also affect the skin, leading to petechiae, purpura, and edema.

Central Nervous System and Eye Disease