Whipple Disease 

Updated: Oct 24, 2019
Author: Ingram M Roberts, MD, MBA; Chief Editor: Burt Cagir, MD, FACS 

Overview

Background

Whipple disease is a systemic disease most likely caused by a gram-positive bacterium, Tropheryma whipplei (formerly T whippelii).[1, 2] Although the first descriptions of the disorder described a malabsorption syndrome with small intestine involvement, the disease also affects the joints, central nervous system, and cardiovascular system. T whipplei infection is recognized to be a major cause of culture-negative endocarditis.[3] Because fewer than 1000 reported cases have been described, clinical experience with this disorder is sparse.[4]

Pathophysiology

Whipple disease is a rare multisystem inflammatory disease. The clinical manifestations of the disease are believed to be caused by infiltration of the various body tissues by T whipplei. The patient's immune system reacts by incorporating the organisms into tissue macrophages.

These macrophages can be easily observed infiltrating the tissues using conventional light microscopy. The macrophages are easily observed when periodic acid-Schiff stain is used for the histologic sections. However, positive periodic acid-Schiff–stained macrophages infiltrating body tissues are not pathognomonic for Whipple disease. These microphages also can be detected in infection due to Mycobacterium avium intracellulare, cryptococcosis, or other parasitic organisms (usually observed in patients who are immunosuppressed with HIV disease).[5, 6] Stains for fungal organisms and acid-fast bacilli are helpful in ruling out Whipple disease.

Diagnostic electron microscopy reveals coccobacillary bodies that represent the T whipplei organism. This is diagnostic because a positive polymerase chain reaction (PCR) for T whipplei will be present in the affected tissue.[7, 8, 9]

The malabsorption observed in the small bowel that is associated with this condition is believed to be secondary to the disruption of normal villous function due to infiltration of the lamina propria of the small bowel. Patients with arthralgias have been found to have the organism in the synovial tissues.[10] The organisms have been detected in the heart valves of patients with cardiac Whipple disease[11, 12] and in the CNS of patients with neurologic disease.[13] Rarely, the organism can be detected in the lungs of affected patients.[14] In short, although Whipple disease represents a systemic condition, only a few organ systems of the body are affected overtly.

Etiology

Whipple disease is believed to be due to a disordered host response to the bacterium T whipplei.[15] Of note, patients with human immunodeficiency virus (HIV) infection do not acquire the disease.

Data that suggest that T whipplei DNA may be found in patients who are asymptomatic.[15, 16, 17] One study revealed its presence in saliva in 35% of a sample of 40 healthy patients.[18] This suggests that Whipple disease is a manifestation of an abnormal host response to a microorganism that may occur frequently in humans (perhaps in a similar manner to that observed with Helicobacter pylori).

To date, Koch's postulates have not been fulfilled completely (infection of an animal model and isolation of the organism from the animal). However, T whipplei bacteria have been grown successfully in HEL (a human fibroblast line) cells.[2] The production of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies has been shown. The organism has been cultured from affected cerebrospinal fluid (CSF) and vitreous humor of patients with Whipple disease.

Epidemiology

International statistics

Whipple disease is extremely rare worldwide; only several hundred clinical cases have been reported, mostly from North America and western Europe. The disease appears to be associated with the human leukocyte antigen B27 (HLA-B27) haplotype.[19] The incidence has been estimated to be less than 1 per 1,000,000.[20]

Race-, sex-, and age-related demographics

Whipple disease is most common in white males[15] and rarely is described in females (male-to-female ratio: approximately 8-9:1). The route of disease transmission is not known but may be associated with occupational exposure to animals and soil.

Whipple disease is usually observed in middle-aged[15] and elderly persons (older than 40 y).

Prognosis

If Whipple disease is untreated, the prognosis is poor, and mortality approaches 100% after 1 year in patients who do not receive the correct diagnosis and therapy.[21, 22, 23]

If this condition is treated for a full year, the prognosis usually is good. Clinical remission occurs in approximately 70% of patients.

Complications

Up to 30-40% of patients may relapse, and relapse appears to be more common in patients with central nervous system (CNS)–related Whipple disease.

A potential complication is a reaction or allergy to antibiotics that could require changing the antibiotic agent.

 

Presentation

History

Whipple disease was first described by Dr. George H. Whipple in 1907.[24] The classic presentation of Whipple disease is that of a wasting illness characterized by arthralgias, arthritis, fever, and diarrhea; however, this form is rare.[15, 25] Lymphadenopathy may be present.

If Whipple disease affects the small intestine, steatorrhea often is present.

Approximately 90% of patients with Whipple disease present with weight loss, and 70% of patients with Whipple disease complain of either diarrhea or arthralgias. In about three quarters of patients, the joint manifestations are followed by weight loss and diarrhea, with a mean time of 6 years from onset of the joint symptoms to diagnosis of Whipple disease.[26]

Whipple disease may mimic chronic inflammatory rheumatic disorders and present with atypical manifestations.[27, 28, 29] Case reports exist in which patients with Whipple disease were diagnosed in the context of an inflammatory disease that was refractory to treatment with anti-tumor necrosis factor alpha (anti-TNF-a).[27, 28] The joint manifestations of Whipple disease are nondeforming.

Occult gastrointestinal (GI) bleeding can be found in 80% of patients of Whipple disease, but frank hematochezia is uncommon.

Cardiac involvement occurs in approximately 30% of cases.

Physical Examination

Swelling of the joints may occur, but frankly deforming arthritis is quite rare.[30] Sacroiliitis, pancarpal narrowing, and cervical epiphyseal fusion have been described in selected patients.

Patients with Whipple disease may have any of the physical findings associated with malabsorption. These findings are nonspecific but include the following:

  • Cachexia

  • Distended abdomen

  • Glossitis

  • Perlèche (angular cheilitis)

  • Chvostek or Trousseau sign (secondary to hypocalcemia)

  • Gingivitis and parafollicular hemorrhages (secondary to vitamin C deficiency)

  • Night blindness (secondary to vitamin A deficiency)

  • Visible peristalsis with borborygmi

  • Hyperpigmentation around the orbital and malar areas of the face (occasionally)

When the CNS is involved, patients may demonstrate signs of frontal release (as seen with dementia), meningoencephalitis, or ataxia and clonus (if the cerebellum is affected).[31, 32, 33] One review noted that supranuclear ophthalmoplegia and cerebellar ataxia were two of the most common neurologic findings.[34]

In a retrospective study, neurologic symptoms in 18 patients with Whipple disease and CNS infection (median follow-up, 6 y) included the following: confusion or coma related to meningoencephalitis or status epilepticus (17%); delirium (17%); cognitive impairment (memory loss, attention defects, typical frontal lobe syndrome) (61%); hypersomnia (17%); abnormal movements (eg, myoclonus, choreiform movements, oculomasticatory myorhythmia) (39%); cerebellar ataxia (11%); upper motor neuron symptoms (44%); extrapyramidal symptoms (33%); and ophthalmoplegia, with/without progressive supranuclear palsy (17%).[35]

 

DDx

Diagnostic Considerations

Maintain a high clinical suspicion for Whipple disease in patients diagnosed with chronic inflammatory rheumatism that is partially or not controlled by treatment with anti-tumor necrosis factor-alpha (anti-TNF-a) agents, and whose condition worsens after such therapy.[28]

A recent, single-center retrospective study reviewed seven patients with suspected seronegative rheumatoid arthritis who had inappropriate treatment response and were ultimately diagnosed with Whipple disease.[36] All patients had no gastrointestinal symptoms, increased levels of C-reactive protein, while absent rheumatoid factor and anti-CCP-antibodies. These patients were unresponsive to treatment with steroids, methotrexate and biologic agents. T whipplei was identified in synovial fluid and all patients responded positively with antibiotic therapy.[36]

The following conditions should also be considered in the differential diagnosis of patients with suspected Whipple disease:

  • Acquired immunodeficiency (AIDS)–related complex

  • Endocarditis, bacterial and nonbacterial

  • Human immunodeficiency virus (HIV) enteropathy

  • Macroglobulinemia

  • Mycobacterium avium intracellulare infection

  • Abetalipoproteinemia and hypobetalipoproteinemia

Differential Diagnoses

 

Workup

Approach Considerations

Biopsy of the appropriate tissue is essential for establishing a diagnosis. These tissues may include small bowel, brain, endocardial, and synovial. Biopsies of tissue samples from the small bowel show expanded villi containing macrophages staining positive with periodic acid-Schiff stain. This finding leads to electron microscopy and then DNA testing for T whipplei.

A baseline lumbar puncture to obtain cerebrospinal fluid (CSF) analysis for T whipplei should be obtained in newly diagnosed patients, even if the patient has a normal neurologic examination.

Laboratory Studies

Basic laboratory studies that suggest the presence of malabsorption may be useful screening tests, as follows:

  • Sudan stain of stool

  • Serum carotene

  • Serum albumin

  • Prothrombin time

The definitive test for the presence of malabsorption is the 72-hour fecal fat determination.

Abnormalities in any of these laboratory test results suggest that malabsorption is present, but they are not specific for Whipple disease.

Imaging Studies

Imaging studies, such as computed tomography (CT) scanning and a small-bowel series, may suggest the presence of malabsorption, but these imaging studies are not specific for Whipple disease.

Brain magnetic resonance imaging (MRI) may demonstrate T1, T2, and fluid-attenuated inversion recovery abnormalities in the cerebellar peduncles, vermis, medulla, and foci of enhancement in the subcortical white matter, but these abnormalities are not pathognomonic for Whipple disease.

Other Tests

No tests are specific for diagnosis except determining the presence of T whipplei DNA through PCR.[37] However, this test is not available universally. Polymerase chain reaction (PCR) currently is performed only at a few centers, including the Mayo Clinic and Stanford University.

Availability and cost are prohibitive to obtaining this test. Check for availability with the medical laboratory and for cost approval with each hospital or office laboratory used by the practice.

Immunoglobulin G (IgG) antibody for T whipplei should not be used diagnostically, as up to 70% of control subjects demonstrate the antibody. IgM antibody is more specific but not easily available.

A real-time PCR assay that targets a segment of the rpoB gene specific to T whippeli has been reported to be highly sensitive for the detection of T whipplei.[38]

Histologic Findings

For intestinal disease, a small-bowel biopsy may show the lamina propria of the small bowel full of periodic acid-Schiff–positive macrophages. Endocardial, brain, or synovial biopsies may show similar changes for Whipple endocarditis, CNS Whipple disease, or synovial Whipple disease, respectively.[39] The presence of T whipplei by PCR in patients who are clinically symptomatic is pathognomonic for the disease.

 

Treatment

Approach Considerations

The mainstay of medical treatment for management of Whipple disease is antibiotic therapy. Surgery is not part of the therapy for Whipple disease. Once the diagnosis of Whipple disease is established and antibiotics are started, patients may be discharged for continued therapy as outpatients.

Consultations with a gastroenterologist, cardiologist, rheumatologist, orthopedist, and neurosurgeon (who will ask for a small biopsy, especially when there are no GI symptoms) may be necessary for obtaining the appropriate tissue biopsy in selected patients.

Outpatient monitoring

Patients with clinical Whipple disease should be monitored with a polmerase chain reaction (PCR), because it is the most sensitive and specific (in contrast to histology) method to determine if they are responding to antibiotic therapy.

T whipplei has been detected through PCR in normal saliva, gastric juice, and intestinal tissue. Whether its presence in otherwise healthy patients reflects a pathological state is unclear. Host factors may be important (as in the case of other GI conditions, such as H pylori infection) in determining which patients will actually develop clinical manifestations.

Balducci et al describe a case of a 76-year old woman presenting with rhombencephalitis who was receiving immunosuppressive treatment for rheumatoid arthritis. Leukocytes were slightly elevated; C-reactive protein and brain angio-CT scan were normal. The patient experienced rapid consciousness deterioration with cranial nerve deficits and ataxic paresis of the right upper limb. Brain MRI was performed, showing multiple contrast-enhancing lesions involving the pons, medulla and cerebellum, suggestive for rhombencephalitis. The patient improved on wide-spectrum antibiotic therapy. CSF analysis performed after 4 weeks of antibiotic therapy was positive for T whipplei. The patient experienced complete resolution of ocular and cranial nerve disorders; a 12-month follow-up lumbar puncture revealed normal CSF with negative T. whipplei-PCR. Follow-up is ongoing in order to monitor for possible relapses.[40]

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate the infection.

The standard initial treament regimen is either (1) intravenous (IV) ceftriaxone 2 g once daily OR (2) 2 million units of penicillin G IV every 4 hours, both for 14 days' duration. After the initial treatment is completed, 1 year of maintenance therapy is with oral double-strength trimethoprim-sulfamethoxazole twice daily. In a recent case report, patients' gastrointestinal symptoms improved with prolonged antibiotic therapy, but macrophage infiltration of duodenal mucosa persisted years after the therapy.[41]

As seen in other infectious disease with antibiotic or antiviral therapies, immune reconstitution inflammatory syndrome may occur with Whipple Disease during treatment and may be confused with relapse of the disease. Polymerase chain reaction (PCR) testing is useful in these cases to rule out disease relapse. True relapse (as documented by positive PCR testing) may respond to 2 g ceftriaxone IV twice daily OR 4 million U penicillin G IV every 4 hours, both for 4 weeks' duration, followed by 1 year of oral double strength trimethoprim-sulfamethoxazole twice daily.

Antibiotics

Class Summary

Antibiotics are the mainstay of treatment. Because of the tendency of Whipple disease to relapse on short courses of antibiotics (2 wk to several mo), most authorities suggest a prolonged course (as long as 1 y). Preliminary data suggest that the PCR test for T whipplei is the best way of detecting remission because patients with a clinical relapse have shown histologic improvement but a persistence of T whipplei through PCR. If the PCR test results become negative after therapy, this suggests a true clinical remission and, possibly, cure. However, PCR has been available for only a few years, so data on the long-term clinical course of patients with Whipple disease as followed using PCR remain sparse.

Patients who have a relapse usually are treated for another 1-2 years and should receive one of the 14-day parenteral regimens listed below.

Trimethoprim-sulfamethoxazole (Bactrim, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Lowest incidence of relapse.

Penicillin G (Pfizerpen)

Alternative therapy to that of TMP/SMZ, but should be followed by TMP/SMZ for 1 year. Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Streptomycin

Alternative to TMP/SMZ therapy but should be followed by TMP/SMZ for 1 year.

Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK, Veetids)

Use in patients who are sulfa allergic. Penicillins inhibit the biosynthesis of cell wall mucopeptide. They are bactericidal against sensitive organisms when adequate concentrations are reached, and they are most effective during the stage of active multiplication. Inadequate concentrations may produce only bacteriostatic effects.

Amoxicillin (Trimox, Amoxil, Biomox)

Use in patients who are sulfa allergic. Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Chloramphenicol (Chloromycetin)

Binds to 50 S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria. Alternative to TMP/SMZ therapy but should be followed by TMP/SMZ for 1 year.

 

Questions & Answers