A chronic, relapsing multisystem disease first described by George Hoyt Whipple, an American pathologist, in 1907.¹ He described the disease as an intestinal lipodystrophy characterised by:

• Weight loss.
• Chronic cough.
• Fat accumulation in the intestine, mesenteric lymph nodes and stool.

It is now thought to be due to infection with actinomycete Tropheryma whipplei combined with defective cell-mediated immunity.^2,3 It is probably acquired as an enteric infection as this organism is commonly found in sewage effluent. It has also been detected in soil and is presumed to be ubiquitous.^4,5

Traditionally, Whipple's disease has presented a diagnostic challenge to both clinicians and pathologists.^6,7

Epidemiology

Whipple's disease is an extremely rare condition.³ Incidence is estimated as less than 1 per 1,000,000 per annum.^2,8

Risk factors³

Incidence is increased in:

• Middle-age and older individuals.
• Males more than females.
• Caucasian patients.
• Family clusters (suggesting an immunogenetic component).
• HLA-B27 antigen; HLA-DRB1*13 and DQB1*06 alleles.⁹
• Sewage plant workers, farmers and agricultural workers.

Presentation^6,8

Not everyone with infection develops symptoms, supporting the thought that a defect in cellular immune response may predispose certain individuals.⁴ There may be many different forms of presentation with the common ones being:

• Polyarthralgia - transient and episodic (often a prodromal symptom).
• Gastrointestinal symptoms:
  • Abdominal pain.
  • Diarrhoea.
  • Anorexia and weight loss.
  • Distension.
  • Flatulence.
  • Steatorrhea (due to malabsorption).
  • Gastrointestinal bleeding.
• Intermittent low-grade fever.
• Chronic cough.
• Hyperpigmentation (occurs in 50%).

There may also be:

• Generalised lymphadenopathy.
• Anaemia and, more rarely, clotting abnormalities.
• Cardiac involvement - pericarditis, myocarditis, valve lesions.
• Central nervous system (CNS) involvement in 10% - headache, confusion, dementia, ophthalmoplegia, myoclonus, oculomasticatory movements (convergent eye movements with simultaneous chewing movements), gait abnormalities, seizures, coma.
• Ocular involvement - uveitis, vitritis, keratitis, retinitis, retinal haemorrhages.
• Pulmonary involvement - pleural effusion, mediastinal widening (due to lymphadenopathy).
• Protein-losing enteropathy with hypoalbuminaemia and oedema (due to protein loss).
• Skin involvement - very rare; may be due to malnutrition or an immune reaction to T. whipplei leading to conditions including eczematous plaques, psoriasis, erythema nodosum.¹⁰

Differential diagnosis

• AIDS with Mycobacterium avium complex infection of the small intestine.
• Coeliac disease.
• Sarcoidosis.
• Reiter's syndrome.
• Familial Mediterranean fever.
• Behçet's disease.
• Intestinal lymphoma.

Investigations¹¹

Diagnosis requires a high index of clinical suspicion:

• Routine blood and malabsorption tests are nonspecific.
• Imaging will confirm involvement of different organs but is not diagnostic.
• Biopsy of affected tissue, usually the duodenum, shows infiltration of the lamina propria with periodic acid-Schiff stain (PAS)-positive macrophages with intracellular clumps of T. whipplei.
• PCR of bacterial RNA (unique 16s rRNA sequence) is increasingly used in diagnosis and can be done from peripheral blood, CSF and other tissue samples.

Management

• Antibiotics are the main treatment.¹² Expert microbiological advice will be needed. Prolonged treatment for up to one year is usually advised.³
• Repeat PCR at the end of treatment.

Prognosis

• Insidious progression and fatal if untreated.³
• Locomotor and gastrointestinal symptoms may improve very rapidly with treatment but histological remission can take several years.
• Follow up closely for signs of recurrence - there is relapse in about 30%.³

Document references

1. Fenollar F, Puechal X, Raoult D; Whipple's disease. N Engl J Med. 2007 Jan 4;356(1):55-66.
2. Desnues B, Ihrig M, Raoult D, et al; Whipple's disease: a macrophage disease.; Clin Vaccine Immunol. 2006 Feb;13(2):170-8.
3. Roberts IM; Whipple Disease, Medscape, Aug 2008
4. Deriban G, Marth T; Current concepts of immunopathogenesis, diagnosis and therapy in Whipple's Curr Med Chem. 2006;13(24):2921-6. [abstract]
5. Schneider T, Moos V, Loddenkemper C, et al; Whipple's disease: new aspects of pathogenesis and treatment. Lancet Infect Dis. 2008 Mar;8(3):179-90. [abstract]
6. Rakshit RC, Mackay JD; A diagnostic conundrum.; Postgrad Med J. 2003 Sep;79(935):540, 545-6.
7. Mahnel R, Marth T; Progress, problems, and perspectives in diagnosis and treatment of Whipple's disease.; Clin Exp Med. 2004 Sep;4(1):39-43. [abstract]
8. Oxford textbook of medicine, 4th edition. Ed. D. Warrel et al. OUP Feb 2004 ISBN 0198529988
9. Martinetti M, Biagi F, Badulli C, et al; The HLA alleles DRB1*13 and DQB1*06 are associated to Whipple's disease. Gastroenterology. 2009 Jun;136(7):2289-94. Epub 2009 Jan 27. [abstract]
10. Schaller J, Carlson JA; Erythema nodosum-like lesions in treated Whipple's disease: signs of immune J Am Acad Dermatol. 2009 Feb;60(2):277-88. [abstract]
11. Marth T, Raoult D; Whipple's disease.; Lancet. 2003 Jan 18;361(9353):239-46. [abstract]
12. Basagiannis CS, Panagoulias GS, Tentolouris N, et al; Whipple disease. South Med J. 2010 Apr;103(4):353-6. [abstract]

Internet and further reading

• Sackmann M, Vehling V, Schmidt KD, et al; Persistent diarrhea. J Gastrointestin Liver Dis. 2008 Sep;17(3):327-8. [abstract]

Acknowledgements