47 y/o man with 5 months of diarrhea Interhospital ID Conference June 7, 2005

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47 y/o man with 5 months of diarrheaInterhospita
l ID ConferenceJune 7, 2005

• Jonathan Sellman, MD
• Regions Hospital, HPMG
• University of Minnesota

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HPI

• 47 y/o man presents with 5 month history of GI
  symptoms.
• He describes initial Sx of nausea starting the
  2nd week of September, 1999.
• Nausea progressed over 2 months.
• Nausea induced after eating only a couple bites.
• Also, occasional diarrhea which he treated with
  loperamide.

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HPI (cont)

• After two months of progressive nausea and
  occasional diarrhea, he presented to his PCP.
• Dxd with gastroenteritis and prescribed
  prochlorperazine and a bland diet.

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HPI (cont)

• In December, his diarrhea became progressively
  more diarrheal.
• By 12/12, he was having stools every two hours.
• Stools were loose to watery with rare formed
  portions, greasy and foul smelling.
• Diarrhea awakened him from sleep.
• Diarrhea continued despite fasting.
• Associated crampy lower abd pain.

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HPI (cont)

• The patient took Lomotil prescribed for a
  relative, and the frequency of his stools
  decreased to every 8 hours.

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ROS

• No melena, BRBPR.
• Emesis x 1 on Dec 12th (after eating cherry
  yogurt).
• Weight loss (205 to 145 ).
• No fevers, chills, rigors.
• No CP, SOB.
• No GU Sx.
• arthritis in neck.
• occasional palpitations lightheadedness.

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PMH

• s/p Bilateral carpal tunnel release.
• Umbilical herniorraphy 1990.
• Walking pneumonia treated with amoxicillin,
  April, 1999.
• Anemia.
• MEDS
• Ranitidine 150 mg po bid
• Fe Gluconate 325 mg po bid.
• NKDA

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Social Hx

• Divorced x 7 years (previously married 10 yrs).
• No tobacco, IV drug use.
• Occasional marijuana.
• No EtOH x 20 years.
• Works at Science Museum.
• He associates onset of illness to the move to the
  new Science Museum.
• No travel outside St. Paul since 1995 (traveled
  to Des Moines).
• Never traveled outside US.

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Social Hx (cont)

• Has a pet cat
• Cat is healthy.
• Obtained the cat at age 1½ yrs from pound Oct
  98.
• No HIV risk factors.
• No known TB exposures.
• PPD negative in 1991
• (Obtained when he volunteered at Gillette
  Childrens Hospital.)

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Family Hx

• Mother DM, CAD, s/p CABG at age 60.
• Father MI.
• Brother Mono while in Army, developed blood
  disease (hemophagia?). Died 1992.
• Sister Died of CML 1998.
• Other sister healthy.
• 1 daughter. She has asthma psoriasis.

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Thoughts?
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More History

• December 19, 1999, he was admitted for
  dehydration.
• Flexible sigmoidoscopy grossly c/w colitis.
• Colonic Biopsy No inflammation.
• C. difficile toxin assay .
• Pt. was prescribed Metronidazole Prednisone.
• Discharged with Dx C. difficile colitis vs. IBD.

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More History (cont)

• Patients symptoms markedly improved.
• Until
• Beginning in January, started to feel un-well.
• Jan 17th diarrhea started again.
• Jan 20th underwent outpatient endoscopy.
• Jan 21st admitted for dehydration.

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PE (January 21, 2000)

• Cachectic, male in NAD.
• T 97.9 HR 91 BP 119/75 RR 20 Sats 99 RA
• PERRL. EOMI. Sclerae clear. Conjunctiva pale.
  Fundi nl.
• O/P dry mucus membranes.
• Neck without LAD.
• Lungs clear.
• C/V RRR without MRG.
• Abd Soft, NT, ND. No HSM.
• DRE Normal tone. No mass. Guaiac negative.
• Ext
• Neuro Normal

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Work-Up?
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Work-Up

• LFTs
• Alk Phos 81
• ALT 13
• AST 29

11.6
8.2
Adequate
Normal Diff
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Colonoscopy 1/20/00

• Terminal ileum- erythematous, very inflamed and
  fragile.
• Colon unremarkable.
• Diagnostic Impression Enteritis?!

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Next?

• GI recommendations
• Await Pathology
• Proceed with EGD

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EGD 1/20/00

• Diagnostic impression
• Candida esophagitis
• Enteritis
• Lymphoma vs Enteritis
• Recommendations
• Await pathology
• Nystatin swish swallow
• Mesalamine (Pentasa) 500 mg po bid
• Ensure 4- 5 cans/ day

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Pathology
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Pathology

• Final Pathologic Diagnosis
• Biopsies from terminal ileum
• Subacute histiocytic ileitis.
• Biopsies from Duodenum
• Subacute histiocytic inflammation.
• Comments
• AFB stains are negative.
• PAS stains are strongly positive for
  intracytoplasmic granular particles in the
  histiocytes.

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Diagnosis?

• Pathological Differential Diagnosis of PAS
  histiocytic infiltration of the lamina propria
• AIDS with MAC infection
• Systemic histoplasmosis
• Macroglobulinemia
• Whipples disease

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Whipple's Disease

• Intestinal lipodystrophy.
• Systemic disease involving
• multiple organ systems
• GI tract 100
• C/V system 55
• Resp system 50
• CNS 25
• Eye 10

Figure Lancet 363 654 (2004)
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Whipple's Disease History

• 1907 First described by George Hoyt Whipple.
• 1949 Black-Schaffer describe PAS stain.
• 1961 Electron microscopy demonstrates
  "bacillary bodies."
• 1992 PCR amplification of 16S ribosomal RNA
• New genus
• Tropheryma whippelii
• trophe "Nourishment"
• eryma "Barrier"
• Phylogenetically, an actinomycete.
• 1997 1st report of successful culture of
  organism in PBMs.

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Whipple's Disease Epidemiology

• Rare Only 696 cases reported between 1907- 1987
• Annual incidence 30 cases per year since 1980.
• Predilection for males of European ancestry.
• 81 MenWomen.
• Mean age 50 years.
• Majority have occupational exposure to soil or
  animals.

Lancet 361 239 (2003) Clin Microbiol Rev 14 561
(2001)
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Genome sequenced, 2003. Unexpectedly small
genome 926 kb Pronounced deficiencies in
energy metabolism genes. Apparent requirement
for external aminoacids. Large amount of coding
capacity dedicated to synthesis of cell surface
proteins.
Lancet 361 637 (2003)
Lancet 361 637 (2003)
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Tropheryma whippelii
Clin Micro Rev 14 561
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Lancet 363 654 (2004)
Figure Lancet 363 654 (2004)
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Lancet 361 239 (2003)
Lancet 361 239 (2003)
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Whipple's Disease Presentation

• Major Clinical Features
• Weight loss 80- 90
• Arthropathy 70- 90
• Diarrhea 70- 85
• Abdominal Pain 50- 90
• Fever 40- 60
• Low grade, intermittent
• Lymphadenopathy 40- 60

Clin Micro Rev 14 561
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Whipple's Disease Presentation

• Less Frequent Clinical Features
• Cardiac Signs 35- 65
• Murmurs, Friction Rub, EKG changes
• CNS Signs 20- 30
• Cognitive Changes
• Supranuclear Gaze Palsy
• Altered MS
• Oculomasticatory myorhythmia
• Ocular Signs 5- 15
• Visual disturbances
• Uveitis
• Retinitis
• Splenomegaly 5- 10

Clin Micro Rev 14 561
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Clinical Situations in which to Consider
Whipples Disease

• Unexplained malabsorption with systemic disease.
• Unexplained systemic granulomatous disease
  resembling sarcoid.
• Neurological disease characterized by myoclonus,
  dementia, and supranuclear ophthalmoplegia.
• Unexplained uveitis.

Lancet 363 654 (2004)
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Whipple's Disease Diagnosis

• Histology of small bowel biopsy specimens
• Foamy histiocytes infiltrating the lamina
  propria.
• PAS inclusions.
• Diagnosis is Confirmed by one of two methods
• Electron microscopy
• Or,
• PCR

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Whipple's Disease Treatment

• Prior to the 1950s, Whipple's was uniformly
  fatal.
• Initial IV Therapy
• Ceftriaxone 2 gms IV BID
• Streptomycin 1 gm IV QD
• Then PO Therapy for 1 year with
• TMP-SMX 1 ds tab PO BID, or
• Cefixime 400 mg PO QD
• Follow clinically and with duodenal biopsies.

Lancet 361 239 (2003) Sanford Guide (2005)
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Whipple's Disease Treatment
Lancet 361 239 (2003)
Lancet 361 239 (2003)
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Whipple's Disease References

• Bentley, SD, et al. 2003. Sequencing and
  analysis of the genome of the Whipples disease
  bacterium Tropheryma whipplei. Lancet 361 637.
• Dutly, F M Altwegg. 2001. Whipples disease
  and Tropheryma whippelii. Clin Microbiol Rev
  14 561.
• Maiwald, M DA Relman. 2001. Whipples disease
  and Tropheryma whippelii Secrets slowly
  revealed. Clin Infect Dis 32 457.
• Marth, T D Raoult. 2003. Whipples disease.
  Lancet 361 239.
• Misbah, SA, et al. 2004. Whipples disease.
  Lancet 363 654.
• Ramaiah, C RF Boynton. 1998. Whipples
  disease. Gastro Clin N Am 27(3) 683.
• Ratnaike, RN. 2000. Whipples disease.
  Postgrad Med 76 760.
• Relman, DA. 1992. Identification of the
  uncultured bacillus of Whipples disease. NEJM
  327 293.
• Relman, DA. 1997. Editorial The Whipple
  bacillus lives (ex vivo)! JID 176 752.
• Schoedon, G, et al. 1997. Deactivation of
  macrophages with Interleukin-4 is the key to the
  isolation of Tropheryma whippelii. JID 176 672.

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