Whipple’s disease: Pathophysiology, Symptoms, Evaluation and Treatment

It is a rare and infectious disease, caused by the bacterium  Tropheryma whipplei. The general incidence is from one to three in every million people.

Worldwide, Whipple’s disease is a rare disorder with the majority of reports published in North America and Europe. The disorder is associated with the HLA B27 haplotype.

It is much more frequent in men than in women with a 4: 1 ratio. The average age of onset of symptoms is 55 years.

The organism seems to be in the soil, which explains the higher prevalence in farmers.

Pathophysiology of whipple’s disease

The majority of individuals who develop Whipple’s disease are asymptomatic carriers or develop a limited infection with the subsequent development of protective humoral and cellular immunity.

The inflammatory response to the organism is silenced and consists mainly of macrophages. The Whipple bacillus shares antigenic similarity with groups B and G of Streptococcus and with Shigella flexneri.

There is clear evidence that a patient has clinically well altered cellular immunity, including lymphocytopenia and diminished factors in the pathogenesis of the disease.

Host factors play an important pathogenic role as suggested by the two to three fold increase in the frequency of the HLA-B27 antigen among affected individuals.

There is some evidence of altered macrophage function and activation and an altered type 1 T cell response.

Symptoms

Whipple’s disease is characterized by a myriad of findings attributable to the infectious involvement of various organ systems.

The typical presentation includes surprising gastrointestinal symptoms that resemble other diseases with generalized malabsorption.

Prominent symptoms are weight loss, diarrhea, arthralgia , fever and abdominal pain. Diarrhea has the usual characteristics of steatorrhea, but it can be watery.

Hidden gastrointestinal bleeding is common (up to 80% of patients) and occasional heavy bleeding is seen.

Peripheral edema that reflects hypoproteinemia by protein losing enteropathy and poor nutrition are common.

Arthralgias are migratory, non-destructive and involve large joints. Often they precede intestinal manifestation. Joint attacks are usually acute at the beginning and last for hours or days. Sacroilitis is common (20 to 30%), but ankylosing spondylitis is rare.

Fever is also present in 30% to 50% of patients.

At some point, at least one third of patients will have heart involvement. Pericarditis and endocarditis are common (50% to 75%) but rarely produce significant symptoms. The apical systolic murmurs are detected in 25% of patients.

Frictional friction and congestive heart failure occur in up to 10% of patients.

Patients who develop central nervous system (CNS) involvement may show signs of frontal release, ataxia, or clonus. Supranuclear ophthalmoplegia has also been reported in many series.

Other neurological characteristics described in these patients include confusion, seizures, delirium, cognitive deterioration, abnormal body movements, hypersomnia and extrapyramidal symptoms.

The post-mortem examination reveals that the CNS is affected in 90% of patients, but clinical participation is evident in only 10% to 40% of patients. Neurological dysfunction may be the presenting symptom in 5% of patients with Whipple’s disease.

The examination of the patients will reveal inflammation of the joints, but even after a prolonged period there is no deforming arthritis.

Other skeletal disorders described in these patients include sacroiliitis and pancarpal narrowing. Nonspecific findings on a physical examination include the following:

  • Weight loss, cachexia, hypotension.
  • Low-grade fever (in 40% to 50% of patients).
  • Peripheral lymphadenopathy (50% of patients).
  • Hyperpigmentation around the malar and orbital areas.
  • Hiperqueratosis.
  • The joint exam rarely shows any spills, swelling or heat.
  • Abdominal distension.
  • Glossitis
  • Queilitis.
  • Gingivitis.
  • Sign of Chovstek or Trousseau.
  • Night blindness.

Evaluation

Anemia is present in 90% of cases and is the result of chronic diseases, iron deficiency and deficiency of folate or vitamin B12. Neutrophilia is present in one third of patients.

Mild lymphocytopenia is common. Eosinophilia and thrombocytopenia rarely occur. Hypoalbuminemia (average 2.7g / dL) is prevalent, while serum globulin levels are normal. The prothrombin time is prolonged. Steatorrhea occurs in 93% of cases.

The diagnosis of Whipple’s disease is made by a bowel biopsy and identification of the organism.

The current diagnostic criteria require two of the following three:

  • PAS staining showing foamy macrophages in the biopsy sample of the affected tissues.
  • Detection of Whipple’s disease or detection of bacteria-specific 16S rRNA from brain material or CSF by PCR.
  • Immunohistochemical staining with antibodies against Whipple’s disease from intestinal samples or other tissues.

If only one test is positive for Whipple’s disease, the diagnosis is possible but not definitive.

It is important to know that Whipple’s disease quickly becomes negative after the start of therapy, which can lead to false negatives since many patients receive antibiotics before undergoing extensive diagnostic tests for this condition.

Treatment of Whipple’s Disease

Once Whipple’s disease is diagnosed, the treatment is with antibiotics, even in the absence of symptoms, it is desirable to use antibiotics that cross the blood-brain barrier.

A recommended regimen is Ceftriaxone two grams a day for two weeks, followed by trimethoprim twice a day 160 mg-sulfamethoxazole 800 mg.

An alternative regimen is the exclusive use of trimethoprim-sulfamethoxazole. Long courses are usually necessary to prevent relapse.

Unfortunately, relapse can occur even years after treatment and central nervous system symptoms may be the first sign of relapse.