Whipple’s disease
Ana Mae H. Quintal
Medical Resident
General Objectives
 To present and discuss a case of a 33/F who
presented with chronic diarrhea
 To discuss the diagnostic approach to chronic
diarrhea;
 To discuss Whipple’s disease:






Epidemiology
Pathogenesis
Clinical manifestations
Diagnostic methods
Treatment
Prevention and control
General Data
 33 year old
 Female
 Filipino
 Single
 Manila resident
Chief Complaint
diarrhea
History of Present Illness
 2006 May
Consulted with a gastroenterologist due
to diarrhea, abdominal pain, and weight
loss, treated as a case of TB ilietis with
Econokit (HRZE) until Aug 2007 (15
months).
Weight gain noted on the first 3 months,
however started to lose weight again
after the succeeding months
 18 mos PTA
Referred to an ID specialist due
to recurrent diarrhea despite more
than 1 year of anti- koch’s medication.
Managed as a case of Tropical sprue;
started on folic acid, cyanocobalamin,
vitamin C and ferrous sulfate.
 18 mos PTA
Outpatient work-ups:
Stool for TB culture and Sputum AFB
smears were negative
Thyroid function Tests—normal
 3 weeks PTA
Presented with soft, non-bloody, nonmucoid, loose stools, ~3 episodes per
day, accompanied by bouts of abdominal
pain and flatulence.
No fever or no vomiting; still noted to
have anorexia and progressive weight
loss
 2 weeks PTA
Diarrhea increased in severity to >10
episodes per day.
 Day of admission Persistence of diarrhea with
generalized body weakness
Review of Systems
SKIN
HEENT
PULMO
CVS
No easy bruisability, sores, rashes, pruritus, or
hyperpigmentation
No headaches, dizziness or vertigo. Does not wear
corrective glasses. No history of eye pain, blurring of
vision, excessive tearing, diplopia; gross hearing is
intact. No ear pain, discharge or infection. No postnasal drip or sinus pain. No history of frequent sore
throats
No cough, hemoptysis, or dyspnea
No history of orthopnea, PND, palpitations, chest
pain, or bipedal edema.
Review of systems
URINARY
No history of UTIs, intermittency, decreased
caliber of urine flow, or incontinence.
RHEUMA
Back pain. Generalized myalgia.
No joint pains.
NEURO
Memory lapses
No history of syncope, seizures or tremors. No
numbness or loss of sensation.
HEMA
No history of prolonged bleeding.
ENDOCRINE No history of polyuria, polyphagia, polydipsia.
No excessive sweating.
Past Medical History
 1999- abdominal pain (Status post EGD:
pseudodiverticulum)
 1999- PTB (treated with anti-Koch’s medication for 6
months then was lost to follow- up)
 2001- diffuse non- toxic goiter (no meds taken; last thyroid
test 2004- normal)
Personal/Social and Family
History
 Non- alcoholic beverage drinker; non- smoker
 Denies illicit drug use
 Family history of DM type 2; no other herido-familial
diseases
Physical Exam
VITAL SIGNS BP 80/ 50mm Hg, CR 121bpm, RR 22 cpm
T 36.8C JVP 4 cm H2O
GENERAL
Cachectic, conscious, coherent, oriented to person,
place, and time
Weight 23 kg, Height 1.57 m, BMI 9.3 kg/m2
SKIN
All extremities were warm to touch. No discolorations,
bruises or rashes. No hyperpigmentation
HEENT
Normocephalic; anicteric sclerae, pale conjunctivae; no
naso-aural discharge; dry oral mucosa; no
tonsillopharyngeal congestion; no neck mass; no
cervicolymphadenopathy.
Physical exam
CHEST/LUNGS Equal chest expansion, no retractions, clear breath sounds,
equal tactile and vocal fremitus
CVS
Adynamic precordium, tachycardic, regular rhythm, distinct
S1/S2, no S3 or S4, no murmurs/gallops, PMI and apex beat
at the 5th intercostal space left midclavicular line; full
and equal pulses bilaterally.
ABDOMEN
flat, normoactive bowel sounds, soft; no
guarding, direct tenderness, or rebound tenderness;
no splenomegaly
EXTREMITIES no cyanosis, edema or deformities; no limitation of motion;
pale nail beds
RECTAL
good sphincteric tone, no fissures, no masses, stool on
examining finger
Salient Features
 33/ F
 Previously treated with anti- Koch’s
 Previously treated as a case of Tropical sprue
 Chronic diarrhea
 Weight loss
Chronic Diarrhea
 To Flow Through
Diarrhea
AGA definition:
 Decrease in fecal consistency lasting for >4 weeks
 Stool >= 200grams/day, or
 >3 loose or watery stools/day, or
 Increased water content of stool
 Impaired water absorption,
 Active water secretion
Lab work- ups
 CBC, electrolytes, total protein, albumin, thyroid
function tests, radiologic work- ups, endoscopy
 Stool analysis- stool osmolality, ph, occult blood, fecal
leukocytes, stool fat (quantitative, sudan III)
 Fecalysis, stool culture, C. difficile toxin
 Selective testing for plasma peptides
 Laxative screen
Classification of Diarrhea
 By time course ( acute vs chronic )
 Site ( large vs small )
 Pathophysiology ( secretory vs osmotic )
 Epidemiology ( epidemic vs travel- related vs
immunosuppression- related )
 Stool characteristics ( watery vs fatty vs inflammatory)
Time course
 Acute: < 2 weeks in duration
 Persistent: > 14 days
 Chronic: >4 weeks
 Severe: >4 fluid stools/day for > 3 days
Small vs. Large Bowel Diarrhea
Small bowel:
secretory & nutrient
absorbing functions
 Watery, large volume
diarrhea
 Bloating, gas, cramping,
profound weight loss,
electrolyte disturbances,
malabsorption (Dxylose, B12)
Large bowel:
storage organ,
addtitional absorption of
water
 Frequent, small volume,
painful stools
 Bloody, mucoid
Infectious
 Parasites: Giardia lamblia,




Entamoeba histolytica,
Cyclospora
AIDS-related:
Viral: Cytomegalovirus,
HIV infection (?)
Bacterial: Clostridium
difficile, Mycobacterium
avium complex
Protozoal: Microsporida,
Cryptosporidium, Isospora
belli
Non- infectious
 Primary GI diseases –
IBS, IBD,
malabsorption,celiac,
etc.
 Non-GI disease states –
hyperthyroid, carcinoid,
etc.
 Drugs (laxatives)
 Carbohydrate (Lactose)
intolerance
Principal causes of diarrhea depend
upon the socioeconomic status of the
population.
In developing countries,
 chronic infections,
 although functional
disorders,
malabsorption, and
inflammatory bowel
disease are also common.
In developed countries,
 irritable bowel
syndrome (IBS),
 inflammatory bowel
disease,
 malabsorption
syndromes (as lactose
intolerance and celiac
disease), and
 chronic infections
(particularly in the
immunocompromised).
Secretory vs. Osmotic
 Secretory
 Volumes > 1L/day
 Occurs day and night
 Continues despite
fasting
 Osmotic gap < 50
 Osmotic
 Due to an unabsorbable
solute
 High osmotic pressure > increased water
output
 Stops with fasting
 Osmotic gap > 125
Osmotic gap = 290 – 2x [(stool
Na + stool K)]
Osmotic diarrhea
CLUES: Stool volume
decreases with fasting;
increased stool osmotic gap
1. Medications: antacids,
lactulose, sorbitol
2. Disaccharidase deficiency:
lactose intolerance
3. Factitious diarrhea:
magnesium (antacids,
laxatives)
Secretory
Diarrhea
CLUES: volume ( >1 L/d); little
change with fasting; normal
stool osmotic gap
1. Hormonally mediated:
VIPoma, carcinoid,
medullary carcinoma of
thyroid (calcitonin),
Zollinger-Ellison syndrome
(gastrin)
2. Factitious diarrhea (laxative
abuse): phenolphthalein,
cascara, senna
3. Villous adenoma
4. Bile salt malabsorption (ileal
resection; Crohn's ileitis;
postcholecystectomy)
5. Medications
Inflammatory
 Fever, hematochezia, abdominal pain
1. Ulcerative colitis
2. Crohn's disease
3. Microscopic colitis
4. Malignancy: lymphoma, adenocarcinoma (with
obstruction and pseudodiarrhea)
5. Radiation enteritis
Malabsorption:
weight loss, abnormal laboratory values, fecal fat > 7- 10 g/ day
Causes:
 Intraluminal
maldigestion
 Pancreatic insufficiency
 Bacterial overgrowth
 Defective bile secretion
 Mucosal –
malabsorption
 Celiac disease
 Tropical sprue
 Infection – bacteria,
parasites
 Whipple’s disease
 Intestinal resection –
short gut
 Abetalipoproteinemia
 Crohn’s disease
Motility disorders
 Systemic disease or prior abdominal surgery
1. Postsurgical: vagotomy, partial gastrectomy, blind loop
with bacterial overgrowth
2. Systemic disorders: scleroderma, diabetes mellitus,
hyperthyroidism
3. Irritable bowel syndrome
Case
 History
 Physical exam
 Gradual onset
 Cachexia
 Intermittent, watery,
 Signs of anemia






non- bloody diarrhea
Weight loss
More than 4 wks
duration
Non- diabetic
No history of travel
Non- promiscuous
No family history of
malabsorption (celiac
disease)
 No mouth ulcers, skin
rash, anal fissures/
fistula, no blood on EF
on rectal
 No exolphthalmos, no
thyroid enlargement
 Good sphincteric tone
 No glossitis,
protruberant abdomen,
pedal edema
Admitting Impression
 Chronic diarrhea probably secondary to GITB (TB
Ileitis) vs Inflammatory Bowel Disease vs Tropical
Sprue
 Hypovolemic Shock sec to GI Loss
Course in the Wards
Problem#1: HYPOVOLEMIC SHOCK
sec to GI Loss
 Upon admission, BP 85- 90/ 70- 75, HR 121, cvp 4-
6;
 Impression :


Hypotension secondary to hypovolemia sec to GI Loss;
TB Ileitis vs Inflammatory Bowel disease vs Tropical sprue.
 ER: Fast dripped a total of 900 cc PNSS. IVF rate increased
Patient was referred to Nephrology service for fluid and
electrolyte management.
 On 1st HD, CVP was noted to be at 10- 12, BP 90- 110/ 60-
80, HR 120s, afebrile, I and O=3625 vs 1180.
 On the 3rd HD, BP stabilized at 90- 100/ 60- 70, HR 90100.
 However, later on the 3rd HD, CVP was noted to be elevated
at 15- 16 cm H2O, RR 24, with neck vein distention. Clear
breath sounds by auscultation.
 Chest XRAY : pulmonary congestion.
Lasix 20 mg/SIVP was given ; Aldactone 50 mg/tab
together with Lasix
Problem #2: ELECTROLYTE
IMBALANCE and Hypoalbuminemia
 Upon admission, HYPOKALEMIA was noted.
 K= 2 – 2.6 – 3 – 4
 Central line insertion was done.
 KCL drip started: 40 meq KCl in 100 cc PNSS to run
for 8 hours and Kalium durule 1 tab TID
 On 1st HD, HYPOALBUMINEMIA
 Alb= 0.6 – 1.6
 Albumin 25% infusion.
 On 3rd HD, HYPOCALCEMIA and
HYPOMAGNESEMIA

Calcium gluconate 4 amps + 5 grams MgSO4 in 2500 cc D5W
at 10 cc/ hr. Despite resolution of diarrhea, hypokalemia was
still noted; subsequent potassium correction was done.
Problem #3: DIARRHEA
And Seizure
 Impression on admission was TB Ileitis vs
Inflammatory Bowel disease vs Tropical sprue.

Ciprofloxacin 500 mg/ tab BID, and Isoniazid + Rifampicin
+Pyrazinamide+ Etambutol (Myrin P Forte) 3 tabs once daily
were started upon admission.
 On 1st HD, 4 episodes of generalized tonic- clonic




seizures of both upper and lower extremities, lasting
for 5 secs each, associated with upward rolling of
eyeballs; PE: motor 2/5 in the Right UE/LE.
Referred to Neurology service.
Impression: Hypokalemic Periodic Paralysis;
Seizure, etiology to be determined.
O2 at 2LPM PRN
Diazepam 5 mg IV PRN and started on Epival 250
BID.
 On 2nd HD, still with seizure episode ~6x.
 complained of difficulty moving head to the right,
nape pain, numbness of Left LE. On PE: left- sided
hemiplegia, flaccidity, hyperactive DTR, L.
 Impression: Todd’s paralysis.
 EEG was abnormal due to excess theta waves.
 MRI/ MRA of the brain Small, acute infarct, Left parietal subcortical white matter;
consider low- grade glioma, Right frontal lobe;
 filling defect in the superior sagittal sinus with tortuous
cortical vessels, consider superior sagittal sinus thrombosis
with collateral formation.
 Impression : Acute Infarct left parietal subcortical
white matter.
 On the 3rd HD, Medical Junta was done
 On consensus, impression was Whipple’s Disease.
 Plan : EGD with biopsy and PAS tissue staining,
once patient is hemodynamically and nutritionally
stable, to confirm diagnosis
 Ciproflaxacin and Myrin P Forte were discontinued
 Co- Trimoxazole 800/ 100 mg/ tab I tab BID was
started.
 Cyanocobalamin 1 cc IM every 10 days, Vitamin A
25, 000 units, 2 caps 4x a day for 8 doses, Folic Acid
5 mg/ tab I tab OD, Ferrous sulfate 325 mg/ tab 1 tab
OD.
Epival 250 BID was discontinued;
Depacon 1 amp in 100 cc PNSS in 1 hour every 6 hours was
started and Dexamethasone was discontinued.
 On the 4th HD, diarrhea and seizure resolved.
 However, on the 7th HD, noted to have recurrence of
loose- watery stools~ 5x but resolved the next day.
 Repeat EEG on the 13th HD showed abnormal
EEG due to mild diffuse slowing of background
activity at 7Hz and frequent delta slow waves or
sharp waves R>L frontocentroccipital region
 On the 12th HD, she underwent EGD and biopsy
 Results: mild erythema and friability of gastric especially
antral mucosa;
 mild granularity of jejunal mucosa.
 Histopathology result showed only chronic
inflammation, moderate (jejunum)
 tissue PAS staining negative for histiocytes.
Pathology Report
JEJUNUM BIOPSY
Specimen consists of five pieces of pink-red, soft,
ovoid tissues
Measurement : 0.3 to 0.4 cm
Block all
LYMPHOCYTES
Control
Test
Negative in histiocytes
Final diagnosis
CHRONIC INFLAMMATION,
MODERATE, JEJUNUM
PERIODIC ACID SCHIFF(PAS) :
NEGATIVE IN HISTIOCYTES
 On 13th HD, rashes on neck, abdomen
 Impression : Hypersensitivity Reaction sec to Co-
Trimoxazole.


Bactrim was discontinued;
Doxycycline 100 mg/ tab 1 tab OD was started.
Doxycycline
Diarrhea
23 kg
A
23.4 kg
EGD Biopsy
Seizure
Whipple’s Disease
Ciprofloxacin
Myrin P
Hypersensitivity reaction to Co-tri
Folic Acid, Cyanocobalamin, Depakote
Co-trimoxazole
24.2 kg
1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th 13th 14th 15th 16th
Hospital Days
Problem #5: ANEMIA
 On 8th HD, Hgb 6.6, Hct 22; Repeat Hgb: 6.7,
 2 unit PRBC was transfused.
 Peripheral blood smear, RBC indices were normal.
Serum iron, serum ferritin were slightly decreased
and stool for occult blood was positive.
 On the 9th HD, anemia resolved. Repeat Hgb= 12.
Final Diagnosis:
Whipple’s Disease
On 16th HD, discharged
Home Meds:
 Doxycycline 100 mg/ tab 1
tab OD
 Cyanocobalamin 1cc IM
every 5 days
 Folic Acid 0.5 mg 1 tab TID
 Ferrous Sulfate gr5 1 tab
OD
 Vitamin C 500mg/ tab, 1
tab OD
1/06
1/07
1/08
1/09
1/10
Na
134
139
143
145
143
K
2-2.6
3– 2.8 4
3.8
2.8
3.3
2.8
1.9
2
1.8
2.3
Chloride
114
Albumin
0.6
1.6
1/11
1/13
1/14
1/16
138
1/17
1/19
136
3.6
3.8
3.5
Urea
9
7
6
6
11
9
Creatinine
0.6
0.5
0.5
0.6
0.6
0.5
1.3
Magnesm
(1.8- 2.4)
Ion Calcium
(1.12- 1.32)
1.5
1.5
2.4
5.8
1.01
1.23
SGPT
23
SGOT
17
Alka phos
125
TB
1.1
Cholesterol
41
2.3
1.6
1.18
1.11
Hgb
Hct
RBC
1/06
1/14
1/14
1/15
1/17
1/22
10.5
31
6.6
22
6.7
22
12.1
37.2
4.6
11.6
36.9
4.5
12
38
4.6
7390
8,380
6400
MCV
80.4 (82-92)
MCH
24.4 (27- 31)
30.3 (32- 36)
MCHC
WBC
14, 150
7,200
Eeos
1
Myelo
1
Meta
1
Seg
94
90
89
83
70
Lym
3
5
9
7
18
Mono
3
2
2
9
10
Platelet
211, 000
130, 000
136, 000
225, 000
538,000
Retic Ct
1.1% (5-15)
 PTH intact- 93.8 (10- 65)
 1/12 Blood CS- no growth
 TSH normal 0.3, FT3 dec 3.8
 1/13 Blood CS- no growth
(4.2- 12), FT4 normal 11
 1/10 Lupus panel- negative
 1/04 stool CS- no growth
 1/15 Anti- Cardiolipin
antibody- 6 (<15)
 1/14 Iron studies
 1/15 occult blood- positive
Serum iron- 35 (35- 150)
 1/15 Peripheral Blood Smear-
Serum TIBC – 67 (250450)

hypochromic anemia with
anisocytosis; few
polychromasia; relative
neutrophilia; no abnormal
cells seen; platelets slightly
decreased
Total Sat- 35/ 67 = 52.23
 1/06 Chest Xray- normal
 1/06 ecg- sinus
 1/09 Chest Xray--
tachycardia, left axis
deviation
 1/09 2D- Echo- normal,
ejection fraction 61%,
mitral regurg- mild,
tricuspid regurg- trace;
minimal pericardial
effusion
 veil of haziness in the R
mid to lower
hemithoraces obliterating
the right
hemidiaphragms
compatible with pleural
effusion;
 accentuation of
pulmonary vasculature
due to congestion
 1/08 MRI of brain
Small, acute infarct, Left
parietal subcortical white
matter
Consider low- grade glioma,
Right frontal lobe
Filling defect in the superior
sagittal sinus with tortuous
cortical vessels, consider
superior sagittal sinus
thrombosis with collateral
formation
 1/07 EEG- abnormal eeg
due to excess theta waves
bilaterally
 1/18 EEG- abnormal; eeg
due to diffuse slowing of
background activity, Left
frontocentrooccipital
region
Discussion
Whipple’s Disease
Epidemiology
 a rare infectious disorder caused by Tropheryma whipplei.
first described in1907 (35), 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 (28, 33).
 underlying genetic predisposition that leads to
colonization of T. whipplei throughout the intestinal tract,
lymphoreticular system, and central nervous system
Tropheryma whipplei
 isolated in a cell culture from a patient with endocarditis




(24).
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 (8).
grow slowly in acidic vacuoles of cells
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
 tissue macrophages are unable to kill and clear T.whipplei.
 CD11b on macrophages mediates intracellular
degradation of ingested bacteria
 This deficiency in killing then causes Whipple’s disease
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%)
Clinical Manifestations
 There are four cardinal clinical manifestations of
Whipple's disease
 Arthralgias
 Weight loss
 Diarrhea
 Abdominal pain
Symptoms of 21 patients with Whipple disease
( Hamburg Series 1965 - 1983 )
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%)
von Herbay A, Otto HF (1988). Whipple´s disease. A report of 22 patients. Klin Wochenschr 66: 533-539
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
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.
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
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
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
 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
 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.
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.
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
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
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
 The hallmark of Whipple’s disease is the histopathological
finding of macrophages containing diastase-resistant paminosalicylic acid (PAS)-positive material, which are T.
whipplei bacteria or partly digested remnants thereof.
 Bacilli with a
characteristic trilamellar
wall is specific for
Whipple's disease.
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)
Evaluation
 *** the patient may not have any finding due to suppression
by preceding anti- tuberculous treatment inclusive of
Rifampicin, which has a bactericidal effect on t. whipplei
Definitive 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.
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.
 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
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.
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.
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.
 Pen G 6- 24M U IV OD+
Streptomycin 1g IM OD
 Ceftrixone 2g IV OD
 Co- Trimoxazole 160/ 800
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
 Doxycycline (or
tetracycline) 100 mg PO
BID
-used for many years
The rationale for prolonged therapy is to permit
complete eradication of the organism, thereby
reducing the likelihood of relapse.
No prospective studies are available on the choice or
duration of antibiotic treatment.
 At present, therapy is based on observations in small
patient groups and personal experience.
Conclusions
 Whipple’s disease is a systemic infectious disorder
 The disease requires an immunologic disposition in order for
the disease to manifest itself.
 Although Whipple's disease has a reputation as a great
mimicker of many different illnesses, the difficulty in
diagnosis is probably more a function of its rarity than its
stealth.
 should be considered in all patients with the four cardinal
manifestations mentioned
Conclusions
The diagnosis should be considered in:
 Unexplained malabsorption on a background of
systemic disease
 Unexplained systemic granulomatous disease
resembling sarcoidosis
 Neurological disease characterized by myoclonus,
dementia, and supranuclear ophthalmoplegia
 Unexplained culture negative endocarditis
 Unexplained uveitis
Conclusions
 Diagnosis can be made by PAS staining or PCR
 Biopsies can be taken from the small intestine, lymph
nodes, bone marrow, muscle, synovium, and the spinal
cord.
 Antibiotic treatment options are effective.
 Follow up is important to diagnose relapse.
Case Outcome
Weight upon discharge
Jan22’08: 24.8 kg
Home Meds:
 Doxycycline 100 mg/ tab 1
tab OD
 Cyanocobalamin 1cc IM
every 5 days
 Folic Acid 0.5 mg 1 tab TID
 Ferrous Sulfate gr5 1 tab
OD
 Vitamin C 500mg/ tab, 1
tab OD
 Follow- up Feb’08
 Weight: 29.5 kg
 No recurrence of
diarrhea
Current weight: 35 kg
Recommendations
 Requires a strong index of suspicion, but PCR is a
definitive diagnosis