Whipple disease

1. Whipple’s Disease

2. INTRODUCTION
In 1907, George H Whipple described a 36-year-old clinician with
"gradual loss of weight and strength, stools consisting chiefly of
neutral fat and fatty acids, indefinite abdominal signs, and a
peculiar multiple arthritis" . The patient died of this progressive
illness; Whipple called it intestinal lipodystrophy since he
observed accumulation of "large masses of neutral fats and fatty
acids in the lymph spaces."
It was renamed Whipple's disease in 1949 upon description of
the sine qua non of this disorder, accumulation of macrophages
in the lamina propria with intensely periodic acid-Schiff (PAS)-
positive intracellular material . An infectious etiology was
suspected as early as Whipple's initial report; however,
successful treatment with antibiotics was not reported until
1952

3. Scientific understanding of the histology, immunology, and
treatment of Whipple's disease has improved since the initial
description, and the etiologic agent was identified in 1991.
The cause is now known to be Tropheryma whipplei (from the
Greek "trophe," nourishment, and "eryma," barrier, in
reference to the nutrient malabsorption characteristic of the
disease)

4. Epidemiology
• a rare infectious disorder caused by Tropheryma whipplei. first
described in1907 , only 696 cases reported between 1907 and
1987,
• annual incidence of approximately 30 cases per year since
1980.
• chronic, systemic infection affecting mostly middle-aged
males .
• underlying genetic predisposition that leads to colonization of
T. whipplei throughout the intestinal tract, lymphoreticular
system, and central nervous system

5. Tropheryma whipplei
 aerobic, rod-shaped, gram-positive, non- acid fast,
periodic acid-Schiff (PAS) positive bacillus
 member of the Actinomycetes (placed between the genus
Cellulomonas and the Actinomycetes clade)
 found both intracellularly and extracellularly .
 grow slowly in acidic vacuoles of cells

6. Pathogenesis /Immunology
 host immune deficiency and possibly secondary immune
downregulation are reponsible
 source of transmission is unknown - likely per oral
 The bacteria most commonly invades the intestinal lamina propria
and the vacuoles of "foamy" macrophages
 There may be a defect in host mononuclear cells,
manifested by persistent deficiency in the expression of
complement receptor type 3 (CD11b) , persistently
diminished ability to degrade intracellular organisms, and
impaired production of interleukin-12, an important
stimulator of T-cell function
 This deficiency in killing then causes Whipple’s disease

7. Pathogenesis
• The route of invasion is via the lamina
propria and basal intercellular spaces,
rather than the intestinal lumen
• accumulation of massive numbers of organisms within the
intestinal tract, subsequent impaired nutrient absorption.
• Noncaseating granulomas are found in
surprisingly few patients (less than 10%)

8. Clinical Manifestations
• There are four cardinal clinical manifestations
of Whipple's disease
• Arthralgias
• Weight loss
• Diarrhea
• Abdominal pain

9. Symptoms of 21 patients with Whipple disease
( Hamburg Series 1965 - 1983 )
von Herbay A, Otto HF (1988). Whipple´s disease. A report of 22 patients. Klin Wochenschr 66: 533-539
Weight Loss 14 (67%)
Chronic Diarrhea 13 (62%)
Arthralgias/Arthritis 13 (62%)
Abdominal Pain 11 (52%)
Skin Hyperpigmentation 8 (38%)
Myalgia 6 (28%)
Lymphadenopathy 3 (14%)
Fever 2 (10%)
Abdominal Tumor 1 ( 5%)
Sleeping Disorder 1 ( 5%)
Cerebral Syncope 1 ( 5%)
Gastric Ulcer 1 ( 5%)
Dyspnea 1 ( 5%)

10. Less common symptoms include
• fever and skin hyperpigmentation
• symptoms or signs related to cardiac disease
(dyspnea, pericarditis, culture-negative
endocarditis),
• pleuropulmonary (pleural effusion),
• mucocutaneous disease; nonthrombocytopenic
purpura can also occur

11. GI Features
• Weight loss: usually 20-30 lbs. May present years before
diagnosis.
• Early GI symptoms are nondescript, often diagnosed as IBD.
• Diarrhea: steatorrhea, but may be watery.
• Abdominal pain tends to be epigastric and exacerbated
following meals.

12. CNS Features
• 21–43% of cases of Whipple's disease have neurologic
symptoms
• 43% - 100% have central nervous colonization
• Characteristic triad:
– Dementia
– External opthalmoplegia
– Facial myoclonus
• Oculomasticatory myorhythmia (OMM) is diagnostic.
• CNS colonization may serve as a repository for bacteria
and a mechanism for CNS relapse

13. CNS Features
• Imaging:
– generalized cerebral atrophy, scattered small
chalky nodules in cortical and subependymal
gray matter (true granulomas that contain PAS-
positive foamy macrophages)
– Areas of intense demylination resembling MS
– Micro-infarcts

14. CNS disease —
• Cognitive dysfunction is the most common
abnormality
• but two findings, at least one of which is present
in approximately 20 percent of such patients, are
considered pathognomonic for Whipple's
disease:
– oculomasticatory myorhythmia (continuous rhythmic
movements of eye convergence with concurrent
contractions of the masticatory muscles), and
– oculo-facial-skeletal myorhythmia

15. • A variety of other neurologic findings have
been described in case series, including
dementia, myoclonus, hemiparesis, peripheral
neuropathy, seizures, and upper motor neuron
disorders
• supranuclear ophthalmoplegia, nystagmus,
and myoclonus occur more frequently (21
percent in one series) in the later stages of the
disease

16. • Endocarditis — Whipple endocarditis has
been described in a small number of patients.
Affected patients may have no clinical or
histologic evidence of gastrointestinal disease
or arthralgias. Endocarditis caused by T.
whipplei may not be associated with the
classical clinical presentation of Whipple's
disease.

17. Common clinical syndromes that suggest the possible
diagnosis of Whipple's disease include
• fever of unknown origin, chronic serositis, progressive
central nervous system disease with myoclonus or
ophthalmoplegia, migratory polyarthropathy, and
generalized lymphadenopathy.
Vitamin or iron deficiency anemia, hypoalbuminemia, and
relative lymphopenia should increase the level of
suspicion.

18. Among the disorders which should be excluded
prior to making a diagnosis of Whipple's disease
are:
• Hyperthyroidism
• Connective tissue disease
• Inflammatory bowel disease with migratory
polyarthropathy
• AIDS

19. Diagnosis
• Periodic acid schiff:
– PAS-positive, diastase-resistant inclusions on light
microscopy
– Confirmed by characteristic trilaminar cell wall
• Polymerase Chain reaction:
– PCR-sequenced bacterial 16sRNA
– PCR can be applied to duodenal tissue, lymph node, pleural-
fluid cells, and peripheral blood
• Abnormal Labs:
– ESR, CRP
– anaemia of chronic disease
– hypoalbuminaemia

20. Diagnosis
The diagnosis of Whipple's disease is usually
readily apparent upon Periodic Acid- Fast
Schiff Stain (PAS)staining of jejunal biopsies
• extensive PAS-positive material (granular foamy
macrophages stained purple with PAS)
• and villous atrophy

21.  The hallmark of Whipple’s disease is the histopathological
finding of macrophages containing diastase-resistant p-
aminosalicylic acid (PAS)-positive material, which are T.
whipplei bacteria or partly digested remnants thereof.

22. • Bacilli with a
characteristic trilamellar
wall is specific for
Whipple's disease.

24. List of organisms that stain positively with the
periodic acid Schiff reagent
• Actinomycetes
• Atypical mycobacteria
• Mycobacterium avium intracellulare55
• Mycobacterium genavense
• Bacillus cereus56
• Corynebacterium spp
• Fungi
• Histoplasma
• Rhodococcus equi57 (Corynebacterium equi)

25. Diagnosis
includes immunohistochemistry and PCR assays for various
target genes on biopsy samples
The PCR assay has become an important diagnostic tool for the
diagnosis of Whipple’s disease, especially :
– in patients with unusual presentations and
• in patients in which the diagnosis cannot be confirmed
histologically.
• The mere presence of DNA of T. whipplei, as demonstrated by
PCR, without a demonstration of the macrophages harboring
it, is not Whipple’s disease.

26. The diagnosis of Whipple's disease can be made with the
classic finding of PAS-positive macrophages from a small
bowel biopsy .
In the absence of this finding, the diagnosis is made when
two different T. whipplei tests (PAS, PCR, or
immunohistochemistry) from the same specimen or two T.
whipplei tests from different specimens are positive (eg,
with positive PAS staining and PCR from a synovial specimen
or with positive PCR from both a small bowel biopsy and a
synovial specimen).

27. Treatment
• Tetracycline became the mainstay of therapy
for many years.
– high relapse rate of 35 percent among patients
treated primarily with tetracycline. Even more
alarming was a high rate of CNS relapse, and a
dismal response (five percent) to retreatment of
CNS relapse with tetracycline.

28. • A combination of streptomycin (1 g) and benzylpenicillin
(penicillin G; 1.2 million units) for 14 days and thereafter
• oral cotrimoxazole (trimethoprim-sulfamethoxazole; 160
mg/800 mg twice daily) for 1 year
With this treatment regimen, however, relapses have been
reported after cessation of antibiotic therapy (5, 11, 17).
may be because trimethoprim-sulfamethoxazole is
only bacteriostatic despite the high intracellular
concentrations

29. These observations led the authors to
recommend an initial course of
• parenteral ceftriaxone
• followed by maintenance therapy with oral
trimetophrim- sulfamethoxazole (TMP-SMX,
one double-strength tablet twice daily) for
one year.

30. These observations led the authors to
recommend an initial course of
• parenteral ceftriaxone
• followed by maintenance therapy with oral
trimetophrim- sulfamethoxazole (TMP-SMX,
one double-strength tablet twice daily) or oral
doxycycline (100 mg twice daily) for 1 year.

31. Doxycycline, rifampin, macrolides, and aminoglycosides have
been shown to be highly active against strict intracellular
bacteria such as T. Whipplei, Rickettsia spp., C. burnetii,
and Ehrlichia spp.
• combination of doxycycline and hydroxychloroquine was
bactericidal.

32. • Pen G 6- 24M U IV OD+
Streptomycin 1g IM OD
• Ceftrixone 2g IV OD
• Co- Trimoxazole 160/ 800
PO BID
• Doxycycline (or tetracycline)
100 mg PO BID
• - induction (first 10- 14
days)
• - induction (first 10- 14
days)
• -long- term therapy; first
line drug; good CNS penet
but prone to relapse
-used for many years

33. Evaluation of clinical response — Most adequately treated
patients do well. Clinical improvement is often dramatic, occurring
within 7 to 21 days .
However, neurological symptoms are occasionally irreversible.
The response to treatment can be monitored by following the
patient's hematocrit, weight, and symptom resolution.
There are no clear data to guide repeat T. whipplei testing as a way
to monitor response. It is suggested to repeat small bowel biopsy
each year for the first five years, then every three to five years
unless new symptoms prompt an earlier evaluation.
PCR testing of small bowel biopsy may have some predictive value
for future relapse;

34. IRIS — In the first few weeks following initiation of antibiotic
treatment, some patients develop high fever or other symptoms
that mimic relapse or disease progression . In contrast to disease
relapse, PCR testing of the relevant specimen is often negative.
IRIS reflects an inflammatory process that occurs despite successful
therapy of the organism. Those at risk for developing IRIS after
starting therapy for Whipple's disease include:
●Patients who have been treated with immunosuppressive therapy
for presumed rheumatic disease for an extended period prior to
the diagnosis of Whipple's disease, whose immunosuppressive
therapy is discontinued at the start of antibiotic treatment.
●Patients with CNS involvement of Whipple's disease.
In these circumstances, corticosteroid therapy may be beneficial;
further study is needed.

35. Relapse —
Clinical failure is suggested by a positive PCR in the relevant specimen
from patients who fail to respond clinically to adequate therapy or have
recurrence of symptoms after initial improvement.
Clinical relapses have been reported in as many as 17 to 35 percent of
patients and, as noted above, in 7 of 12 patients who remained PCR-
positive on small bowel biopsy obtained after initial therapy .
However, many patients with suspected relapse in these studies may have
actually had IRIS. It is assumed that relapses reflect incomplete eradication
of the organism with initial therapy.

36. Treatment Relapse —
For patients who fail to respond to initial therapy or relapse, we suggest
penicillin G (4 MU IV every 4 hours) or ceftriaxone (2 g IV twice daily) for
four weeks followed by oral doxycycline (100 mg twice daily) in
combination with hydroxychloroquine (200 mg PO thrice daily)
OR
TMP-SMX (one double-strength tablet [160 mg TMP/800 mg SMX] twice a
day) for one year .
If a CNS relapse occurs after a lower dose of ceftriaxone, a higher dose (2
g IV twice daily) may be more effective . Occasional patients have required
chronic intravenous ceftriaxone therapy for control of CNS symptoms [