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.
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.
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.
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
Neurologic involvement is common, particularly in long-standing disease and may be present in up to 90% of cases. Whipple disease causes a broad spectrum of symptoms, including cognitive impairment, psychiatric illness (such as depression), headaches, seizures, and ataxia. A pathognomonic sign of Whipple disease is oculomasticatory myorhythmia, where involuntary blinking occurs when the patient is talking or eating. Approximately 50% of patients have evidence of supranuclear ophthalmoplegia at presentation. Symptoms of hypothalamic involvement, such as insomnia, polydipsia, and hyperphagia develop in one third of patients. The most common ocular manifestation is anterior or posterior uveitis, which is often bilateral. Optic neuritis has also been described.
Up to 55% of patients with Whipple disease have cardiac involvement. Pericarditis is the most common manifestation and occurs in more than 50% of patients. Myocarditis may present with unexplained heart failure or sudden death. Blood culture–negative endocarditis, often involving native heart valves, has been described, typically occurring in middle-aged men with a preceding history of joint pains. Fever and a history of valvular heart disease are frequently absent in these cases, contributing to a delayed diagnosis.
Uncommonly, patients with Whipple disease may have fever and lymphadenopathy. Intra-abdominal adenopathy is more common than involvement of the peripheral lymph nodes. Kidney disease, hepatosplenomegaly, pleural effusions, pulmonary infiltrates, epididymitis, and orchitis have been reported in Whipple disease.
Routine Laboratory Testing
A neutrophil leukocytosis may be present and, rarely, eosinophilia. A normocytic or macrocytic anemia is a common finding because of disease chronicity or nutritional deficiency. Ferritin levels may be elevated, in keeping with the underlying inflammatory process. There usually is a robust acute phase response, with erythrocyte sedimentation rates typically >100 mm/hour. Evidence of malabsorption may include hypoalbuminemia, clotting abnormalities, and low levels of vitamin B12 and folate. Serologic tests for rheumatoid factor, antibodies to cyclic citrullinated peptides, and antinuclear antibodies are usually negative. An absence of the normal circadian rhythm that characterizes cortisol, growth hormone, melatonin, and thyroid-stimulating hormone may suggest hypothalamic dysfunction.
Examination of Fluid and Tissue
Fluid aspiration or tissue biopsy is recommended to confirm the diagnosis of Whipple disease. If the initial area of examination is negative, further samples from other regions should be obtained if possible. Synovial fluid shows a predominance of neutrophils and mononuclear cells, with a cell count ranging from 4000–100,000/mcL. Cerebrospinal fluid examination is recommended, even in the absence of symptoms, since a positive PCR result influences both treatment and prognosis.
Examination of involved tissue may demonstrate a mild inflammatory cell infiltrate and occasional noncaseating granuloma formation. The characteristic histologic finding in Whipple disease is the presence of PAS-positive macrophages in the involved tissue. The PAS-positive intracellular inclusions correspond to the bacterial cell wall of T whipplei. Multiple biopsies should be obtained in order to avoid sampling errors. Although PAS-positive cells are classically found in the duodenum, they may also be present in cerebrospinal fluid, brain tissue, synovial fluid, synovial tissue, lymph nodes, muscles, skin, bone marrow, and other involved areas. However, false-positive results may occur in tissues infected with mycobacteria, Histoplasma, and Actinomyces. Immunohistochemistry using specific antibodies directed against T whipplei is more sensitive than PAS staining and can be used in cases where added confirmation is required.
Polymerase Chain Reaction
The identification of the nucleotide sequence of T whipplei has facilitated the use of PCR in the detection of the organism. PCR is highly sensitive and specific and may help confirm the diagnosis when the PAS staining is negative. However, false-positive results may arise from environmental contamination or the presence of another bacterium with a similar genome sequence.
Cultivation of T Whipplei from Fluid or Tissue
In specialized laboratories, T whipplei may be cultured from involved tissue and has been isolated from blood, cerebrospinal fluid and tissue derived from the joint, heart, duodenum, and lymph node, suggesting active infection of these areas.
Plain radiography of symptomatic joints is frequently normal. However, in some cases, marked articular damage occurs with subchondral cyst formation and ankylosis of involved areas. Sacroiliitis and syndesmophyte formation of the spinal column have been described in patients with Whipple disease who are HLA-B27 negative. Changes of hypertrophic osteoarthropathy are rare.
Because of the presence of chronic inflammation and malabsorption, low bone mineral density scores are commonly found on dual x-ray absorptiometry scanning.
Computed tomography (CT) of the thorax and pelvis may reveal enlarged lymph nodes, particularly in the mesenteric area. Mediastinal adenopathy has also been described. In patients with central nervous system involvement, single or multiple enhancing lesions in the brain or spinal cord may be observed on CT or MRI.