Whipple Disease

Etiology

Tropheryma whipplei was described in 1992. It was named Tropheryma whippelii until 2001, when its name was modified to conform with the proper spelling of Dr. George Hoyt Whipple's name. It is a gram-positive bacillus, periodic acid-Schiff-positive (PAS), and acid-fast negative. Electron microscopy showed that the bacillus core is enclosed within a plasma membrane, which is surrounded by a three-layered cell wall. The inner layer contains polysaccharides that stain positive with PAS. The outer layer resembles a plasma membrane and may be of host origin, which possibly accounts for the failure of the host to mount a humoral antibody response to the infection.

Epidemiology

Globally, Whipple disease is a rare disorder with most reports published in North America and Europe. The disorder is associated with the HLA B27 haplotype. The overall incidence of Whipple disease is about one to three in every one million people. The mean age of onset of symptoms is age 55. It is much more frequent in males than in females, with a ratio of 4:1. The organism seems to be soil-dwelling which explains the increased prevalence in farmers.[4]

Pathophysiology

The detailed pathogenesis remains unclear, but there is enough evidence to believe that host immunity plays an important role. Most individuals who contract T. whippelii are asymptomatic carriers or develop a limited infection with subsequent development of protective humoral and cellular immunity. In diseased individuals, the inflammatory response to the organism is muted. It consists primarily of altered macrophage function and activation and an impaired type 1 T-cell response. Whipple bacillus shares antigenic similarity with Streptococcal groups B and G and with Shigella flexneri. Host factors play an important pathogenic role as suggested by the two to threefold increase in the frequency of HLA-B27 antigen among affected individuals.[5]

The organism is ingested by macrophages which can be observed PAS. Unfortunately, PAS-stained macrophages are not pathognomonic for Whipple disease. Electron microscopy may reveal coccobacillus bodies that reflect the organism.

The malabsorption seen is due to disruption of the normal villus function. If systemic disease develops, the organism can be found in many tissues.

History and Physical

Whipple disease is characterized by myriad findings related to the infectious involvement of several organ systems. The typical presentation includes gastrointestinal symptoms that resemble other malabsorption syndromes. The prominent symptoms are weight loss, diarrhea, arthralgias, fever, and abdominal pain. Diarrhea has the usual features of steatorrhea but may be watery. Occult gastrointestinal bleeding is common (up to 80% of patients). Gross bleeding can also be present sometimes.

Peripheral edema reflects hypoproteinemia from protein-losing enteropathy and poor nutrition. Arthralgias are migratory, nondestructive, and involve large joints. They often precede intestinal manifestation. The articular attacks are usually acute in onset and last for hours to days. Sacroiliitis 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 involvement of the heart. Pericarditis and endocarditis are common (50% to 75%) but rarely produce significant symptoms. Apical systolic murmurs are detected in 25% of patients. Friction rubs and congestive heart failure develop in up to 10% of patients. Patients who develop central nervous system (CNS) involvement may have signs of frontal release, ataxia, or clonus. Supranuclear ophthalmoplegia has also been reported in the medical literature.

Other neurological features described in these patients include confusion, seizures, delirium, cognitive impairment, abnormal body movements, hypersomnia, and extrapyramidal symptoms. Post-mortem examination reveals that the central nervous system is affected in 90% of patients, but clinical involvement becomes evident in only 10% to 40% of patients. Physical examination of patients will reveal peripheral lymphadenopathy in about 50% of the cases. Hyperpigmentation around the malar and orbital areas, hyperkeratosis, purpura, abdominal distension, glossitis, cheilitis, gingivitis, Chovstek or Trousseau sign can also be seen. [6]

Evaluation

The diagnosis of Whipple disease is made by a biopsy of the intestine and identification of the organism. Current diagnostic criteria require positive results for PAS-positive foamy macrophages in the small bowel biopsy. If it is negative, the diagnosis can also be made by showing positive results in for two of the following:

• PAS staining showing foamy macrophages in a biopsy specimen of involved tissues
• PCR Detection of T. whippelii or detection of the specific 16S rRNA of the bacterium
• Immunohistochemical staining with T. whippelii antibodies

It is important to know that T. whippelii quickly becomes negative after the initiation of therapy, which may lead to false negatives since many patients receive antibiotics before undergoing extensive diagnostic testing for this condition. Other lab findings include anemia in 90% of cases and results from chronic disease, iron deficiency, and folate or vitamin B12 deficiency. Neutrophilia is present in one-third of patients. Mild lymphocytopenia is common. Eosinophilia and thrombocytopenia rarely occur. Hypoalbuminemia is prevalent, whereas serum globulin levels are normal. The prothrombin time is prolonged. Steatorrhea occurs in 93% of cases.[3]

Treatment / Management

The mainstay of treatment for Whipple disease is antibiotic therapy. Because of the possibility of CNS involvement, even in the absence of symptoms, the use of antibiotics that penetrate the blood-brain barrier is desirable. One recommended regimen for the initial phase is Ceftriaxone two grams daily or Penicillin G two million units every four hours. The usual duration for the initial phase is two weeks, followed by the maintenance phase with Trimethoprim 160 mg- Sulfamethoxazole 800 mg twice daily for twelve months. Meropenem can also be used for the initial phase in patients with penicillin allergy. Long courses are usually necessary to prevent relapse. Unfortunately, relapse can occur even years after treatment. Often, CNS symptoms may be the first sign of relapse.[7][8]

It is important to note that after the initial parenteral treatment, at least 12 months of treatment is required with oral trimethoprim-sulfamethoxazole.

Body fluids must be evaluated for the organism to ensure a complete cure, which can take 1 to 2 years.

Differential Diagnosis

The differential diagnoses of Whipple disease include:

• HIV
• Tuberculosis
• Inflammatory bowel disease with arthropathy
• Connective tissue disorder
• Hyperthyroidism.

Prognosis

Usually, the prognosis is good with prompt diagnosis and treatment of Whipple disease. The patients feel a lot better within two to three weeks of initiation of the treatment.[9]

Untreated patients have a poor prognosis.

Complications

Whipple disease is a progressively debilitating disease if it gets undiagnosed and untreated. Complications from untreated Whipple disease are mainly due to nutritional deficiencies as it interferes with the absorption process of the small intestine. Few disseminated cases of Whipple disease sepsis have also been reported. Irreversible brain damage and potential death can also occur.