Whipple's Disease

A chronic, relapsing multisystem disease first described by GH 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 whippelii combined with defective cell-mediated immunity.² It is probably acquired as an enteric infection as this organism is commonly found in sewage effluent.

Traditionally, Whipple's disease has presented a diagnostic challenge to both clinicians and pathologists.^3,4

This is a rare condition. Incidence is estimated as less than 1 per 1,000,000 per annum.

Risk factors

Incidence is increased in:

• Middle-age and older
• Males>females
• Caucasian patients
• Family clusters (suggesting an immunogenetic component)
• HLA-B27 haplotype

Many different forms of presentation with the common ones being:

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

May also be:

• Generalised lymphadenopathy
• Anaemia and more rarely clotting abnormalities
• Cardiac involvement - pericarditis, myocarditis, valve lesions
• CNS involvement in 10% - 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)

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

Diagnosis requires a high index of clinical suspicion:

• Routine bloods and malabsorption tests are non-specific.
• Imaging will confirm involvement of different organs but is not diagnostic.
• Biopsy of affected tissue, usually the duodenum, shows infiltration of the laminae propria with PAS(periodic acid Schiff stain)-positive macrophages with intracellular clumps of T.Whippelii. This test is negative in about 30%, more commonly those without GI involvement and biopsy of other organs or lymph nodes may be indicated.
• 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.

• Oral Co-trimoxazole for at least one year or, if allergic, ceftriaxone or chloramphenicol.
• Some have argued for an alternative regimen - long-term doxycycline and hydroxychloroquine in patients without neurological involvement, adding high dose of sulfamethoxazole or sulfadiazine only in those with neurological involvement.⁸
• Repeat PCR at the end of treatment.
• With neurological involvement, treatment often commences with IV cephalosporin and aminoglycoside.

• Insidious progression and fatal if untreated
• Locomotor and GI symptoms may improve very rapidly with treatment but histological remission can take several years.
• Follow up closely for signs of recurrence - relapse in about 35%.