1. Whipple’s disease Ana Mae H. Quintal Medical Resident

2. 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

3. General Data
33 year old
Female
Filipino
Single
Manila resident

4. Chief Complaint
diarrhea

5. 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 ( months).
Weight gain noted on the first 3 months,
however started to lose weight again
after the succeeding months

6. 18 mos PTA. Referred to an ID specialist due
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.

7. 18 mos PTA Outpatient work-ups:
Stool for TB culture and Sputum AFB
smears were negative
Thyroid function Tests—normal

8. 3 weeks PTA. Presented with soft, non-bloody, non-
3 weeks PTA Presented with soft, non-bloody, non- mucoid, 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

9. 2 weeks PTA Diarrhea increased in severity to >10 episodes per day.
Day of admission Persistence of diarrhea with generalized body weakness

10. Review of Systems
SKIN No easy bruisability, sores, rashes, pruritus, or hyperpigmentation
HEENT 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 post- nasal drip or sinus pain. No history of frequent sore throats
PULMO No cough, hemoptysis, or dyspnea
CVS No history of orthopnea, PND, palpitations, chest pain, or bipedal edema.

11. 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.

12. 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 normal)

13. 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

14. 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.

15. 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

16. Salient Features 33/ F Previously treated with anti- Koch’s
Previously treated as a case of Tropical sprue
Chronic diarrhea
Weight loss

17. Chronic Diarrhea
To Flow Through

18. Diarrhea AGA definition: Stool >= 200grams/day, or
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

25. 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

26. 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)

27. Time course Acute: < 2 weeks in duration Persistent: > 14 days
Chronic: >4 weeks
Severe: >4 fluid stools/day for > 3 days

28. Small vs. Large Bowel Diarrhea
Small bowel:
secretory & nutrient absorbing functions
Watery, large volume diarrhea
Bloating, gas, cramping, profound weight loss, electrolyte disturbances, malabsorption (D-xylose, B12)
Large bowel:
storage organ, addtitional absorption of water
Frequent, small volume, painful stools
Bloody, mucoid

34. Infectious Non- 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

35. 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).

36. Secretory vs. Osmotic Osmotic gap = 290 – 2x [(stool Na + stool K)]
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)]

37. Secretory Diarrhea Osmotic 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
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)

38. 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

39. Malabsorption: weight loss, abnormal laboratory values, fecal fat > 7- 10 g/ day Causes:
Mucosal – malabsorption
Celiac disease
Tropical sprue
Infection – bacteria, parasites
Whipple’s disease
Intestinal resection –short gut
Abetalipoproteinemia
Crohn’s disease
Intraluminal maldigestion
Pancreatic insufficiency
Bacterial overgrowth
Defective bile secretion

40. 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

41. Case Physical exam History Cachexia Gradual onset Signs of anemia
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
History
Gradual onset
Intermittent, watery, 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)

42. Admitting Impression
Chronic diarrhea probably secondary to GITB (TB Ileitis) vs Inflammatory Bowel Disease vs Tropical Sprue
Hypovolemic Shock sec to GI Loss

43. Course in the Wards

44. Problem#1: HYPOVOLEMIC SHOCK sec to GI Loss
Upon admission, BP / , 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

45. Patient was referred to Nephrology service for fluid and electrolyte management.
On 1st HD, CVP was noted to be at , BP / , HR 120s, afebrile, I and O=3625 vs 1180.
On the 3rd HD, BP stabilized at / , HR
However, later on the 3rd HD, CVP was noted to be elevated at 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

46. 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

47. 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.

48. 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.

49. 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.

50. 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.

51. Impression : Acute Infarct left parietal subcortical white matter.
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.

52. 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

53. 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.

54. 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

55. 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.

56. Pathology Report JEJUNUM BIOPSY
Specimen consists of five pieces of pink-red, soft, ovoid tissues
Measurement : 0.3 to 0.4 cm
Block all

57. LYMPHOCYTES

58. Negative in histiocytes
Control
Test
Negative in histiocytes

59. Final diagnosis CHRONIC INFLAMMATION, MODERATE, JEJUNUM
PERIODIC ACID SCHIFF(PAS) :
NEGATIVE IN HISTIOCYTES

60. 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.

61. Hospital Days Doxycycline Folic Acid, Cyanocobalamin, Depakote
Co-trimoxazole
Ciprofloxacin
Myrin P
Hypersensitivity reaction to Co-tri
Seizure
Whipple’s Disease
Diarrhea
EGD Biopsy
23.4 kg
24.2 kg
23 kg
A 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th 13th 14th 15th 16th
Hospital Days

62. 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.

63. 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

64. 1/06
1/07
1/08
1/09
1/10
1/11
1/13
1/14
1/16
1/17
1/19 Na
134
139
143
145
138
136 K
2--
2.6
3– 2.8 4
3.8
2.8
3.3
3.6
3.5
Chloride
114
Albumin
0.6
1.6
1.9 2
1.8
2.3
Urea 9 7 6 11
Creatinine
0.5
Magnesm
( )
1.5
2.4
1.3
Ion Calcium
( )
5.8
1.01
1.23
1.18
1.11
SGPT 23
SGOT 17
Alka phos
125 TB
1.1
Cholesterol 41

65. 1/06
1/14
1/15
1/17
1/22
Hgb
10.5
6.6
6.7
12.1
11.6 12
Hct 31 22
37.2
36.9 38
RBC
4.6
4.5
MCV
80.4 (82-92)
MCH
24.4 (27- 31)
MCHC
30.3 (32- 36)
WBC
14, 150
7,200
7390
8,380
6400
Eeos 1
Myelo
Meta
Seg 94 90 89 83 70
Lym 3 5 9 7 18
Mono 2 10
Platelet
211, 000
130, 000
136, 000
225, 000
538,000
Retic Ct
1.1% (5-15)

66. 1/12 Blood CS- no growth 1/13 Blood CS- no growth
PTH intact (10- 65)
TSH normal 0.3, FT3 dec ( ), FT4 normal 11
1/10 Lupus panel- negative
1/15 Anti- Cardiolipin antibody- 6 (<15)
1/15 occult blood- positive
1/15 Peripheral Blood Smear-
hypochromic anemia with anisocytosis; few polychromasia; relative neutrophilia; no abnormal cells seen; platelets slightly decreased
1/12 Blood CS- no growth
1/13 Blood CS- no growth
1/04 stool CS- no growth
1/14 Iron studies
Serum iron- 35 ( )
Serum TIBC – 67 ( )
Total Sat- 35/ 67 = 52.23

67. 1/06 ecg- sinus tachycardia, left axis deviation
1/06 Chest Xray- normal
1/09 Chest Xray--
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
1/06 ecg- sinus tachycardia, left axis deviation
1/09 2D- Echo- normal, ejection fraction 61%, mitral regurg- mild, tricuspid regurg- trace; minimal pericardial effusion

68. 1/07 EEG- abnormal eeg due to excess theta waves bilaterally
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

69. Discussion
Whipple’s Disease

70. 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
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

71. 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

72. 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

73. 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%)

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

75. 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:

76. 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

77. GI Features
Weight loss: usually 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.

78. 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
OMM - synchronus rhythmic contractions of masticatory muscles and pendular oscillations of both eyes at 1-2 Hz

79. 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

80. Cognitive dysfunction is the most common abnormality
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

81. 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

82. 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.

83. 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.

84. 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

85. 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

86. 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

87. 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.

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

89. 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)

90. 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

91. 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.

92. 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.

93. 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

94. 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.

95. 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.

96. 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.

97. - induction (first 10- 14 days)
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 days)
-long- term therapy; first line drug; good CNS penet but prone to relapse
-used for many years

98. 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.

99. 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

100. 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

101. 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.

102. Case Outcome Follow- up Feb’08 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

103. Recommendations
Requires a strong index of suspicion, but PCR is a definitive diagnosis