eMedicine Specialties > Gastroenterology > Intestine

Whipple Disease

Ingram M Roberts, MD, MBA, Associate Clinical Professor of Medicine, University of Connecticut School of Medicine; Program Director of Internal Medicine Residency, Vice Chairman, Department of Medicine, St Vincent's Medical Center

Updated: Aug 14, 2008

Introduction

Background

Whipple disease is a systemic disease most likely caused by a gram-positive bacterium, Tropheryma whippelii.^1,2 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).^3,4 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.^5,6,7

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.⁸ The organisms have been detected in the heart valves of patients with cardiac Whipple disease^9,10 and in the CNS of patients with neurologic disease.¹¹ Rarely, the organism can be detected in the lungs of affected patients.¹² 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.¹³ The incidence has been estimated to be less than 1 per 1,000,000.¹⁴

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.^15,16,17

Race

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

Sex

Whipple disease is more predominant in males than in females, roughly 8-9:1.

Age

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

Clinical

History

• The classic presentation of Whipple disease is that of a wasting illness characterized by arthralgias, arthritis, fever, and diarrhea.
• 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.
• Occult 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

• Swelling of the joints may occur, but frankly deforming arthritis is quite rare.¹⁸ Sacroileitis, pancarpal narrowing, and cervical epiphyseal fusion has 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).¹⁹ One review noted that supranuclear ophthalmoplegia and cerebellar ataxia were two of the most common neurologic findings.²⁰

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 data that suggest that T whippelii DNA may be found in patients who are asymptomatic.²¹ The study revealed its presence in saliva in 35% of a sample of 40 healthy patients.²² 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.² 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 Whipple disease.

Differential Diagnoses

Abdominal Angina
Celiac Sprue
Malabsorption
Sprue, Tropical

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

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 a CT scan and a small-bowel series, may suggest the presence of malabsorption, but these imaging 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 abnormalities 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 StanfordUniversity.
• 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.
• IgG antibody for T whippelii should not be used diagnostically, as up to 70% of control subjects demonstrate the antibody. IgM antibody is more specific but not easily available.

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 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

Medical Care

The mainstay of medical treatment is antibiotic therapy.

Surgical Care

Surgery is not part of the therapy for Whipple disease.

Consultations

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.

Diet

No dietary changes are usually required.

Activity

No activity restrictions are usually required.

Medication

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

Antibiotics

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 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 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.

Dosing

Adult

160 mg TMP/800 mg SMZ PO bid for 1-2 y, with folate supplementation

Pediatric

Not established

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenic purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency

Precautions

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

Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, long-term alcoholics, elderly persons, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in individuals who are G-6-PD deficient; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

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.

Dosing

Adult

1.2 million U IM qd for 14 d

Pediatric

Not established

Interactions

Probenecid can increase effects of penicillin; coadministration of tetracyclines can decrease effects of penicillin

Contraindications

Documented hypersensitivity

Precautions

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

Streptomycin

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

Dosing

Adult

1 g IM for 14 d

Pediatric

Not established

Interactions

Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics

Contraindications

Documented hypersensitivity; non–dialysis-dependent renal insufficiency

Precautions

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

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.

Dosing

Adult

250 mg PO qid

Pediatric

Not established

Interactions

Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing a decrease in the effectiveness of penicillins when administered concurrently

Contraindications

Documented hypersensitivity

Precautions

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

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.

Dosing

Adult

250 mg PO tid

Pediatric

Not established

Interactions

Reduces the efficacy of oral contraceptives

Contraindications

Documented hypersensitivity

Precautions

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

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.

Dosing

Adult

1 g IV qid for 14 d

Pediatric

Not established

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

Contraindications

Documented hypersensitivity; not recommended for long-term use because of bone marrow toxicity

Precautions

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

Further Inpatient Care

• Once the diagnosis of Whipple disease 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.
• 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 will actually develop clinical manifestations.

Complications

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

Prognosis

• If Whipple disease is 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

Medicolegal Pitfalls

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

References

1. Relman DA, Schmidt TM, MacDermott RP, et al. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med. Jul 30 1992;327(5):293-301. [Medline].

2. Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipple's disease. N Engl J Med. Mar 2 2000;342(9):620-5. [Medline].

3. Dray X, Vahedi K, Delcey V, et al. Mycobacterium avium duodenal infection mimicking Whipple's disease in a patient with AIDS. Endoscopy. Feb 2007;39 Suppl 1:E296-7. [Medline].

4. Patel SJ, Huard RC, Keller C, et al. Possible Case of CNS Whipple's Disease in an Adolescent With AIDS. J Int Assoc Physicians AIDS Care (Chic Ill). Jun 2008;7(2):69-73. [Medline].

5. Ramzan NN, Loftus E Jr, Burgart LJ, et al. Diagnosis and monitoring of Whipple disease by polymerase chain reaction. Ann Intern Med. Apr 1 1997;126(7):520-7. [Medline].

6. Marth T, Schneider T. Whipple disease. Curr Opin Gastroenterol. Mar 2008;24(2):141-8. [Medline].

7. Schneider T, Moos V, Loddenkemper C, et al. Whipple's disease: new aspects of pathogenesis and treatment. Lancet Infect Dis. Mar 2008;8(3):179-90. [Medline].

8. O'Duffy JD, Griffing WL, Li CY, et al. Whipple's arthritis: direct detection of Tropheryma whippelii in synovial fluid and tissue. Arthritis Rheum. Apr 1999;42(4):812-7. [Medline].

9. Celard M, de Gevigney G, Mosnier S, et al. 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].

10. Gubler JG, Kuster M, Dutly F, et al. Whipple endocarditis without overt gastrointestinal disease: report of four cases. Ann Intern Med. Jul 20 1999;131(2):112-6. [Medline].

11. 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].

12. Kelly CA, Egan M, Rawlinson J. Whipple's disease presenting with lung involvement. Thorax. Mar 1996;51(3):343-4. [Medline].

13. Dobbins WO 3rd. HLA antigens in Whipple's disease. Arthritis Rheum. Jan 1987;30(1):102-5. [Medline].

14. Fenollar F, Puéchal X, Raoult D. Whipple's disease. N Engl J Med. Jan 4 2007;356(1):55-66. [Medline].

15. Durand DV, Lecomte C, Cathebras P, et al. Whipple disease. Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Société Nationale Française de Médecine Interne. Medicine (Baltimore). May 1997;76(3):170-84. [Medline].

16. Keinath RD, Merrell DE, Vlietstra R, et al. Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients. Gastroenterology. Jun 1985;88(6):1867-73. [Medline].

17. 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].

18. Sheib JS. Whipple disease revisited. Radiographic features of a patient with 35 years of undiagnosed arthritis. J Clin Rheumatol. 2004;10:69-73.

19. 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].

20. Süzer T, Demirkan N, Tahta K, et al. 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].

21. Ehrbar HU, Bauerfeind P, Dutly F, et al. PCR-positive tests for Tropheryma whippelii in patients without Whipple's disease. Lancet. Jun 26 1999;353(9171):2214. [Medline].

22. Street S, Donoghue HD, Neild GH. Tropheryma whippelii DNA in saliva of healthy people. Lancet. Oct 2 1999;354(9185):1178-9. [Medline].

23. Swartz MN. Whipple's disease--past, present, and future. N Engl J Med. Mar 2 2000;342(9):648-50. [Medline].

Keywords

Whipple disease, Whipple's disease, Tropheryma whippelii, T whippelii, intestinal lipodystrophy, WD, polyarthralgias, chronic diarrhea, Whipple disease with symptomatic CNS involvement, fever of unknown origin

Contributor Information and Disclosures

Author

Ingram M Roberts, MD, MBA, Associate Clinical Professor of Medicine, University of Connecticut School of Medicine; Program Director of Internal Medicine Residency, Vice Chairman, Department of Medicine, St Vincent's Medical Center
Ingram M Roberts, MD, MBA is a member of the following medical societies: American College of Gastroenterology, American College of Physician Executives, American College of Physicians, American Gastroenterological Association, American Medical Informatics Association, American Society for Gastrointestinal Endoscopy, and Association of Program Directors in Internal Medicine
Disclosure: Nothing to disclose.

Medical Editor

Marco G Patti, MD, Professor of Surgery, Director, Center for Esophageal Diseases, University of Chicago Pritzker School of Medicine
Marco G Patti, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Surgeons, American Gastroenterological Association, American Medical Association, American Surgical Association, Association for Academic Surgery, Pan-Pacific Surgical Association, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Southwestern Surgical Congress, and Western Surgical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Noel Williams, MD, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
Noel Williams, MD is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

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