AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Whipple disease is a systemic disease most likely caused by a gram-positive bacterium, Tropheryma whippelii. Although the first descriptions of the disorder described a malabsorption syndrome with small intestine involvement, the disease also affects the joints, CNS, and cardiovascular system. Because fewer than 1000 reported cases have been described, clinical experience with this disorder is sparse.

Pathophysiology

The clinical manifestations of the disease are believed to be caused by infiltration of the various body tissues by T whippelii. 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). 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 whippelii organism. This is diagnostic because a positive polymerase chain reaction (PCR) for T whippelii will be present in the affected tissue.

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. The organisms have been detected in the heart valves of patients with cardiac Whipple disease and in the CNS of patients with neurologic disease. Rarely, the organism can be detected in the lungs of affected patients. In short, although Whipple disease represents a systemic condition, only a few organ systems of the body are affected overtly.

Frequency

International

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.

Mortality/Morbidity

Untreated patients have a poor prognosis. The disease is almost universally fatal after 1 year in patients who do not receive the correct diagnosis and therapy.

Race

Whipple disease is most common in white males and rarely is described in females.

Sex

Males predominate, roughly 8-9:1.

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The classic presentation is that of a wasting illness characterized by arthralgias, arthritis, fever, and diarrhea.
• Lymphadenopathy may be present.
• If the disease affects the small intestine, steatorrhea often is present.
• Approximately 90% of patients present with weight loss, and 70% of patients complain of either diarrhea or arthralgias.
• Occult GI bleeding can be found in 80% of patients, but frank hematochezia is uncommon.
• Cardiac involvement occurs in approximately 30% of cases.

Physical

• Swelling of the joints may occur, but frankly deforming arthritis is quite rare. Sacroileitis, pancarpal narrowing, and cervical epiphyseal fusion has been described in selected patients.
• Patients 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
  • On occasion, hyperpigmentation around the orbital and malar areas of the face
• 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). A recent review noted that supranuclear ophthalmoplegia and cerebellar ataxia were two of the most common neurologic findings.

Causes

• The disease is believed to be due to a disordered host response to the bacterium T whippelii. Interestingly, patients with HIV infection do not acquire the disease.
• Of interest are recent data that suggest that T whippelii DNA may be found in patients who are asymptomatic. The study revealed its presence in saliva in 35% of a sample of 40 healthy patients. 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 whippelii bacteria have been grown successfully in HEL (a human fibroblast line) cells. The production of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies has been shown. The organism has been cultured from affected CSF and vitreous humor of patients with the disease.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

AIDS-related complex
Endocarditis, bacterial and nonbacterial
Human immunodeficiency virus (HIV) enteropathy
Macroglobulinemia
Mycobacterium avium intracellulare infection
Abetalipoproteinemia and hypobetalipoproteinemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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 a CT scan and a small-bowel series also may suggest the presence of malabsorption, but these studies are not specific for Whipple disease.
• Brain 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 changes are not pathognomonic for Whipple disease.

Other Tests

• No tests are specific for diagnosis except determining the presence of T whippelii DNA through PCR.
• • This test is not available universally. 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.

Procedures

• 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 will show expanded villi containing macrophages staining positive with periodic acid-Schiff stain. This finding leads to electron microscopy and then DNA testing for T whippelii.

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. The presence of T whippelii by PCR in patients who are clinically symptomatic is pathognomonic for the disease.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The mainstay of medical treatment is antibiotic therapy.

Surgical Care

Surgery is not part of the therapy for this disease.

Consultations

Consultations with a gastroenterologist, cardiologist, rheumatologist or orthopedist, or 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.

Diet

Usually, no dietary changes are required.

Activity

Usually, no activity restrictions are required.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Antibiotics

Antibiotics are the mainstay of treatment. Because of the tendency of the 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 whippelii is the best way of detecting remission because patients with a clinical relapse have shown histologic improvement but a persistence of T whippelii 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 Whipple disease patients as followed using PCR remain sparse.

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

Drug Name	Penicillin G (Pfizerpen)
Description	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.
Adult Dose	1.2 million U IM qd for 14 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects of penicillin; coadministration of tetracyclines can decrease effects of penicillin
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in impaired renal function

Drug Name	Streptomycin
Description	Alternative to TMP/SMZ therapy but should be followed by TMP/SMZ for 1 year.
Adult Dose	1 g IM for 14 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Narrow therapeutic index; not intended for long-term therapy; caution in patients on renal failure not on dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission

Drug Name	Penicillin VK (Beepen-VK, Betapen-VK, Robicillin VK, Veetids)
Description	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.
Adult Dose	250 mg PO qid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing a decrease in the effectiveness of penicillins when administered concurrently
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal impairment

Drug Name	Amoxicillin (Trimox, Amoxil, Biomox)
Description	Use in patients who are sulfa allergic. Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.
Adult Dose	250 mg PO tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Reduces the efficacy of oral contraceptives
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in renal impairment

Drug Name	Chloramphenicol (Chloromycetin)
Description	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.
Adult Dose	1 g IV qid for 14 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; not recommended for long-term use because of bone marrow toxicity
Interactions	Concurrently with barbiturates, chloramphenicol serum levels may decrease, while barbiturate levels may increase, causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum chloramphenicol levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; chloramphenicol levels may be increased or decreased
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Use only for indicated infections or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (ie, aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; evaluate baseline and perform periodic blood studies approximately every 2 d while in therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Once the diagnosis is established and antibiotics are started, patients may be discharged for continued therapy as outpatients.

Further Outpatient Care

• Patients with clinical Whipple disease should be monitored with a PCR test because it is the most sensitive and specific (in contrast to histology) method to determine if they are responding to antibiotic therapy.
• Recently, T whippelii 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 actually will develop clinical manifestations.

Complications

• Reactions or allergies to antibiotics may occur that could require changing the antibiotic agent.

Prognosis

• If untreated, the prognosis is poor, and mortality approaches 100% after 1 year.
• If treated for a full year, the prognosis usually is good. Clinical remission occurs in approximately 70% of patients.
• Up to 30-40% of patients may relapse, and relapse appears to be more common in patients with CNS Whipple disease.

Patient Education

• No special advice is required.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to carefully explain that patients must comply with follow-up care

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Célard M, de Gevigney G, Mosnier S, Buttard P, Benito Y, Etienne J. Polymerase chain reaction analysis for diagnosis of Tropheryma whippelii infective endocarditis in two patients with no previous evidence of Whipple's disease. Clin Infect Dis. Nov 1999;29(5):1348-9. [Medline].
• Dobbins WO 3d. HLA antigens in Whipple's disease. Arthritis Rheum. Jan 1987;30(1):102-5. [Medline].
• Durand DV, Lecomte C, Cathebras P. Whipple disease. Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Societe Nationale Francaise de Medecine Interne. Medicine (Baltimore). May 1997;76(3):170-84. [Medline].
• Ehrbar HU, Bauerfeind P, Dutly F. PCR-positive tests for Tropheryma whippelii in patients without Whipple's disease [letter]. Lancet. Jun 26 1999;353(9171):2214. [Medline].
• Fleming JL, Wiesner RH, Shorter RG. Whipple's disease: clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc. Jun 1988;63(6):539-51. [Medline].
• Gerard A, Sarrot-Reynauld F, Liozon E, et al. Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine (Baltimore). Nov 2002;81(6):443-57. [Medline].
• Gubler JG, Kuster M, Dutly F. Whipple endocarditis without overt gastrointestinal disease: report of four cases. Ann Intern Med. Jul 20 1999;131(2):112-6. [Medline].
• Keinath RD, Merrell DE, Vlietstra R. Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients. Gastroenterology. Jun 1985;88(6):1867-73. [Medline].
• Kelly CA, Egan M, Rawlinson J. Whipple's disease presenting with lung involvement. Thorax. Mar 1996;51(3):343-4. [Medline].
• Matthews BR, Jones LK, Saad DA, et al. Cerebellar ataxia and central nervous system Whipple disease. Arch Neurol. Apr 2005;62(4):618-20. [Medline].
• O'Duffy JD, Griffing WL, Li CY, Abdelmalek MF, Persing DH. Whipple's arthritis: direct detection of Tropheryma whippelii in synovial fluid and tissue. Arthritis Rheum. Apr 1999;42(4):812-7. [Medline].
• Ramzan NN, Loftus E Jr, Burgart LJ. Diagnosis and monitoring of Whipple disease by polymerase chain reaction. Ann Intern Med. Apr 1 1997;126(7):520-7. [Medline].
• Raoult D, Birg ML, La Scola B, Fournier PE, Enea M, Lepidi H. Cultivation of the bacillus of Whipple's disease. N Engl J Med. Mar 2 2000;342(9):620-5. [Medline].
• Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med. Jul 30 1992;327(5):293-301. [Medline].
• Sheib JS. Whipple disease revisited. Radiographic features of a patient with 35 years of undiagnosed arthritis. J Clin Rheumatol. 2004;10:69-73.
• Street S, Donoghue HD, Neild GH. Tropheryma whippelii DNA in saliva of healthy people [letter]. Lancet. Oct 2 1999;354(9185):1178-9. [Medline].
• Swartz MN. Whipple's disease--past, present, and future. N Engl J Med. Mar 2 2000;342(9):648-50. [Medline].
• Süzer T, Demirkan N, Tahta K, Coskun E, Cetin B. Whipple's disease confined to the central nervous system: case report and review of the literature. Scand J Infect Dis. 1999;31(4):411-4. [Medline].

Article Last Updated: Oct 10, 2006