Whipple's disease

What is Whipple's disease?

A chronic, relapsing multisystem disease first described in 1907 by George Hoyt Whipple, an American pathologist.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.

Whipple hypothesised that the condition was due to an infectious agent, but this was only fully identified in 1992. It is now thought to be due to infection with the actinomycete Tropheryma whipplei, combined with defective cell-mediated immunity.² 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.^{3 4}

Traditionally, Whipple's disease has presented a diagnostic challenge, both to clinicians and to pathologists.^{5 6}

How common is Whipple's disease? (Epidemiology)

Whipple's disease is an extremely rare condition. Incidence is estimated as between 1 to 6 cases per 1,000,000 people, per annum, globally. Its prevalence is estimated as 1.1 per million.⁷

Risk factors⁷

Upon infection with T whipplei, most people clear the infection completely, a small number become asymptomatic carriers, and only a discrete group of people go on to develop Whipple's disease. Whipple's disease is more common in:

• Middle-age and older individuals (mean age at diagnosis is 55 years).

• Men (85% of cases are in men).

• White people.

• Family clusters (suggesting an immunogenetic component).

• Certain geographic locations: most cases of Whipple's disease are diagnosed in Western Europe and North America.

• HLA-B27 antigen; HLA-DRB1*13 and DQB1*06 alleles.⁸

• Sewage plant workers, farmers and agricultural workers.

Symptoms of Whipple's disease (presentation)^{5 97}

Not everyone with infection develops symptoms, supporting the thought that a defect in cellular immune response may predispose certain individuals.³

Whipple's disease may cause many different issues, due to the involvement of several organs. These include:

• Polyarthralgia - transient and episodic (often a prodromal symptom).

• Gastrointestinal symptoms - resembling other malabsorption syndromes:
  

  • 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 and erythema nodosum.¹⁰

Differential diagnosis¹¹

• AIDS with Mycobacterium avium complex infection of the small intestine.

• Coeliac disease.

• Sarcoidosis.

• Reactive arthritis.

• Familial Mediterranean fever.

• Behçet's disease.

• Intestinal lymphoma.

• Inflammatory bowel disease.

• Tuberculosis.

Investigations ^{7 12}

Given its rarity, wide spectrum of symptoms, and an absence of pathognomic clinical signs, diagnosis is very challenging, and 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. Supplementary staining with anti-T whipplei antibodies or Ziehl-Neelsen staining is recommended, as other bacteria, such as Mycobacterium avium, also stain PAS-positive.

• 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.¹³

Management of Whipple's disease⁹

• Antibiotics are the main treatment.¹⁴ Expert microbiological advice will be needed. Prolonged treatment for 1-2 years is usually advised.

• Repeat PCR at the end of treatment.

Prognosis

• Insidious progression and fatal if untreated.

• Locomotor and gastrointestinal symptoms may improve very rapidly with treatment but histological and microbiological remission can take several years.

• Follow up closely for signs of recurrence - there is relapse in about 40%.⁹