Tropheryma Whippelii
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The Disease


What is it?

Whipple's disease is a rare, multi-visceral, and chronic condition. The clinical presentation is typically dominated by a symptom triad of diarrhea, weight loss, and abdominal pain. Digestive symptoms are often preceded for months or years by other symptoms, the most common being arthralgia, although cardio-vascular, neurologic or pulmonary involvement may be more prominent at times.

Allchin and Hebb reported the first Whipple's disease case in 1895, however, they did not realize that their patient had a unique disease. George Hoyt Whipple in 1907 recognized the first case of the disease that now bears his name, when he reported the results of the autopsy on a 36-years old physician, serving as a missionary in Constantinopole. The next case reported in the literature was in 1923. In 1949, Black-Schaffer demonstrated that the macrophages found in the intestinal mucosa of a patient with Whipple's disease stained vividly by the periodic acid-Schiff (PAS) method.

In 1961, Yardley et al. using electronic microscope, revealed that these same rod shaped structures in the intestinal macrophages were bacteria. Peroral small bowel biopsy was used in 1947 to make the first pre-mortem diagnosis of this condition. In 1952 Paulley was the first to use antibiotics successfully to treat Whipple's disease, but it was recognized only subsequently that Whipple's disease is systemic in nature and can respond to a variety of antibiotics. Although the disease was recognized as an infectious disease for decades, it was not until the 1990-s that the causative organism was definitely identified and classified as Tropheryma whippelii.

In 1991, Willson et al. used a gene that encodes for a 16 S ribosomal RNA in bacteria to characterize the nucleotide sequence of the bacteria from a patient with Whipple's disease. Relman et al. subsequently confirmed Willson's observation on five other patients and classified the organism as a gram-positive actinomycete not closely related to any other known species.

In 1999, a team of French researchers, led by Dr. Raoult, for the first time, have isolated and cultured Tropheryma whippelii from a heart valve. The ability to grow the bacteria may help in finding the most effective antibiotic against the disease.


How do you get it?

Although the source of transmission is unknown and the pathogenesis is obscure, direct bacterial invasion has been found in numerous cases in various sites, including the eye. The bacteria most commonly invades the intestinal lamina propria and the vacuoles of “foaming” macrophages. Less frequently, they are found in other intestinal mucosal structures, such as polymorphonuclear cells, smooth muscle, capillaries, lymphocytes, plasma cells, and mast cells. The route of invasion is via the lamina propria and basal intercellular spaces, rather than intestinal lumen. There may be little or no injury to cells that take up bacteria. To date there is little evidence that bacteria remain viable and reproduce intracellularly. The altered host immune system and cell-mediated immunity may play an important role in developing of Whipple's disease. The possibility remains, however, that patients with Whipple's disease have normal immune systems that are subverted by Tropheryma whippelii infection, by promoting IL-4 release or blocking macrophage-activating cytokines.


Clinical Symptoms

Although primarily considered as a gastrointestinal disorder, Whipple's disease is a chronic, relapsing multi-system illness. The presentation therefore is quite variable and may include any number of signs and symptoms. Because there can be rheumatologic, neurologic, ophtalmologic, and cardiopulmonary involvement anywhere in the course of the disease, patients may seek help from a variety of different specialists.

Weight loss, seen in nearly all patients, is the most common presenting symptom. Watery or fatty diarrhea is noted in 75% of patients. Abdominal pain is usually located the epigastric area and is non specific in character. The pain is associated with a sense of abdominal fullness and is often more severe postprandially.

Arthralgia typically is the first symptom experienced. It is generally migratory involving most joints but most often the ankles, knees, shoulders and wrists in a symmetric fashion. The affected joints may be swollen with edema and effusion. There is an association with spondyloarthritis, observed in 19% of patients in one series.

Pleural and pericardial pain have been reported in patients with Whipple disease . In 50% of patients, a non productive cough may be present, which may represent pneumonic or pleuritic involvement.

Central nervous system manifestations are present in up to 10% of patients and include headache, ataxia, deafness, muscle weakness, lethargy, sensory deficits, visual changes, progressive dementia, seizures, personality changes, and meningitis. Hypothalamic involvement causing insomnia, polydipsia, or hyperphagia has also been observed. A commonly described triad includes dementia, ophtalmoplegia, and myoclonus. The neurologic involvement may occur in the absence of intestinal manifestations or may appear as a form of relapse, again possibly without recurrence of intestinal symptoms.

Physical findings differ in patients with Whipple 's disease depending on the duration and the severity of the disease. The most common signs found usually are: relative hypotension, peripheral lymphadenopathy, hyperpigmentation, low-grade fever, abdominal tenderness, peripheral edema, cardiac murmurs, pleural and pericardial friction rubs, ascites, splenomegaly and glossitis.

The clinical course of untreated Whipple's disease is divided into three stages. Vague and nonspecific symptoms, like migratory polyarthralgia, anorexia, abdominal fullness, cough, pleuritic chest pain, and low-grade fever, characterize the first stage. The second stage can occur at any time up to 20 years and manifest itself with weight loss, weakness, diarrrhea, and abdominal pain. The third stage is characterized by steatorrhea, cachexia, lymphadenopathy, hyperpigmentation, and neurologic or ocular dysfunction.

Currently, survival is much improved as a result of effective antibiotic treatment.


Laboratory Diagnosis

The diagnosis of Whipple's disease is made by demonstrating the characteristic lesions in any affected tissue. This is best accomplished via small bowel biopsy performed during upper endoscopy. Endoscopic findings of Whipple's disease include areas of thickened folds with the typical granular, yellow-white shaggy covering. A biopsy specimen revealing infiltration of the lamina propria of the small bowel with PAS-positive macrophages containing gram-positive, AFB-negative bacilli and lymphatic dilation is specific and diagnostic of Whipple disease.

The polymerase chain reaction (PCR) method has been used to amplify DNA unique to Tropheryma whippelii extracted from various tissue samples of patients with Whipple disease. PCR method can be used to confirm the diagnosis of Whipple's disease when the diagnosis cannot be confirmed histologically. It is highly sensitive and specific and is useful in suspicious, inconclusive cases.

It is suggested that a negative PCR result after therapy might predict a low clinical relapse rate, whereas a persistently positive PCR result despite treatment may be associated with disease recurrence. Since most, if not all, patients with Whipple's disease have central nervous system infection, but only some develop clinical or radiologic evidence of the disease and that PCR analysis of the cerebrospinal fluid can be added to the diagnostic evaluation to detect those with cerebral Whipple's disease.

Currently, PCR has an undefined role in monitoring disease activity with treatment.


Treatment/Recovery

For many years Whipple's disease was considered a fatal primary metabolic disorder.

Antibiotics now are the mainstay of treatment, often providing dramatic life-saving improvement of symptoms. Antibiotic regimens include penicillin with or without streptomycin, erythromycin, ampicillin, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole. Relapses are common and can occur months or even years after initial treatment. Many of the relapses occur in the central nervous system, and thus, antibiotics should have adequate blood-brain barrier penetration.

Because of the rarity of the disease, controlled and prospective evaluations of different treatment regimens will probably never be possible. Recommendations are based on case reports, retrospective reviews, and antibiotic characteristics. Treatment with trimethoprim-sulfamethoxazole for 6 to 12 months is recommended both for initial therapy and for relapses of the disease. Other antibiotic regimens reported may be associated with a higher relapse rate and are considered to be second-line agents.

With effective treatment, the small intestinal mucosa reverts toward normal. Bacilli disappear within a few days, and after 1 to 2 months, only dying organisms may be seen. The number of PAS-positive macrophages decreases, and the mucosa regains its normal villous architecture. for some patients, however, it may take years to obtain a normal histologic appearance.

Other considerations, not specific for Tropheryma whippelii infection, are extremely important to patient outcome. Proper fluid and electrolyte replacement in patients with intestinal malabsorption is vital. Iron or folate supplements may be required to correct anemia. Vitamin D, calcium, and magnesium may be necessary to maintain calcium homeostasis. Vitamin K is used to correct coagulopathy. The diet should be appropriately high in calories, protein, and other vitamins because most of the patients are malnourished. Long-term hyperalimentation is rarely indicated.

Immunologic studies have shown reduced production of interleukin-12 and interferon-gamma in patients with Whipple's disease. It is not yet determined whether the immunoregulatory defect is a primary or secondary result of the infection. The addition of interferon-gamma may be an option in the treatment of patients with refractory Whipple's disease but further studies are needed to clarify benefit of their therapy.


Statistics

Whipple's disease may appear in 1 out of 100,000 people, but there have been reports that between 3-5% of the population carries the bacteria in their saliva and gut, apparently without ill effect.

It is found that the systemic incidence rate is between 18 to 30 new cases per year, and the age range is 13 and 83 years. The age of diagnosis increases progressively until the 5-th decade and then diminishes in males , whereas it is uniform in the 4-th to 6-th decade with the maximal rate of diagnosis in the 7-th decade in females. There is an well-known but unexplained male predominance. The male to female ratio is 8:1.

The majority of patients (98%) are caucasians, they work more as farmers, construction workers or machinists. It is relatively uncommon in African-Americans and reported only rarely in Africans, Asians, and Native Americans. It occurs in the central parts of Europe and North America, with relatively few cases in northern and southern Europe, Canada, Mexico.

The presence of genetic factors in Whipple's disease would gain additional support by the occurrence of familial cases, but to date only two pairs of brothers and a brother-sister pair with disease have been reported.

There is no accurate estimate of prevalence on death rate due to the low incidence rate. Deaths from Whipple's disease are usually a result of central nervous system or cardiac complications, failure to diagnose the disease , and irreversible relapse.


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Copyright 1999-2007 Department of Microbiology, Mount Sinai Hospital, Toronto, Canada. All rights reserved.