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.
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
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
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
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
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,
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
Currently, PCR has an undefined role in monitoring disease
activity with treatment.
For many years Whipple's disease was considered a fatal primary
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
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.
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
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
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