Infectious Diseases Case Conference

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Infectious Diseases Case Conference

• Robin Trotman, D.O.
• November 22, 2004

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Case 1-Presentation

• 63 yo wm with a history of colon cancer, RA, and
  CKD transferred from OSH on 10/15/04 with FUO.
• July-cough, leukocytosis, treated for RMSF and
  aspiration PNA with clindamycin and doxycycline.
• September-_at_ return visit he had a temperature of
  104-treated for sinusitis with levofloxacin.
• Oct. 11, admitted to OSH with fever, cough, and
  malaise. Also with night sweats, anorexia,
  malaise.

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Presentation

• At the OSH he had extensive W/U-bcx, CT
  chest/ab/pelvis, Indium scan, and was treated for
  the duration with clindamycin and ceftriaxone.
• Transferred to WF for eval of FUO.

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Past Medical History

• 1. RA
• 2. Colon CA-s/p colectomy and subsequent bowel
  infarction with resection/ileostomy/takedown.
• 3. Depression
• 4. Hx of resolved lung abscess
• 5. Remote Hx of PE
• 6. CKD-secondary to NSAIDS
• 7. Nephrolithiasis and previous staghorn calculi

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Medications

• Ceftriaxone and clindamycin
• Hydroxychloroquine
• Prednisone 5mg a day
• Sertraline
• Sodium Bicarbonate
• Pantoprazole
• Atropine/diphenoxylate
• Infliximab every eight week since Dec 2003

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Social History

• Assistant Athletic Director at small college
• Previous extensive smoking history
• No alcohol or illicit drugs
• Married with 3 children

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Review of Systems

• Other positive-mild urinary hesitancy, cough with
  occ. large sputum, chronic loose stools, remote
  hx of TB exposure

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Physical Exam

• 121/71_at_79, temp 97.5, SpO2 98 on RA, wt 155
• Alert and oriented X4, NAD
• HEENT exam wnl
• Lungs-RUL rales, otherwise clear
• CV-Regular, 2/6 SEM at left sternal border,
  pulses brisk and symmetric
• Ab-rt flank tenderness with multiple well healed
  ab scars, otherwise unremarkable
• GU-guaiac positive,
• Remainder of exam unremarkable

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Admission Labs
Seg-60 Lymph-20 Mono-12
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5.2
108
33
42
ALP-395 Bili-1.1 Alb-2.5 Ca-7.8 AST/ALT-30/32 CRP-
7.5 ESR-17 LDH-206 GGT-518
103
139
108
25
4.9
3.2
AG11
Micro BCX-neg UCx-neg
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Hospital Course

• Admitted, antibiotics were held
• Recultured, radiographs repeated.
• Bronchoscopy 10/20-neg cytology and no cultures
  were sent.
• Remained febrile with pancytopenia.
• Wbc 3, h/h 9/28, plts 120, lymphos-900
• Renal function improved
• Bone Marrow Bx done 10/26

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Admission CXR 10/16
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CT Chest 10/27
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PET scan 10/25
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PET-10/25

• 13.7 mCi F18-FDG
• (fluorodeoxyglucose)Approximately 60 minutes
  after the injection of the radiopharmaceutical,
  images were obtained from the mid-calvarium
  through the proximal thighs. Blood glucose at
  the time of injection was 87 mg/dl.
• FINDINGS Multiple foci of intense FDG uptake
  noted throughout the mediastinum corresponding to
  a large prevascular, right paratracheal, right
  hilar, subcarinal and right cardiophrenic lymph
  nodes, as well as a mass in the right middle
  lobe. No abnormal activity is noted below the
  diaphragm.
• CONCLUSION Multiple hypermetabolic foci seen
  throughout the mediastinum and right
  supraclavicular region, consistent with
  lymphadenopathy seen on CT.

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Hospital Course

• Based on Histopathology and clinical scenario
  suggestive of disseminated histoplasmosis, the
  patient was started on amphotericin b lipid
  complex.
• He had drenching sweats for the first 2 nights,
  and as the infusions were slowed he began to
  tolerate them well.
• He was discharged to home to complete 2 weeks of
  liposomal amphotericin b at local hospital
  infusion center.
• He tolerated 13/14 days and due to rising
  creatinine, he was switched to itraconazole.

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Follow Up

• Report to FDAs Adverse Event Reporting System
  (AERS)
• Urinary and serum histo antigen were positive
• Blood and bone marrow culture both growing mold
• No more TNF drugs
• Back to work-The Great Game

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Discussion

• 1. TNF inhibiting drugs
• -infections with which they are associated
• 2. Disseminated Histoplasmosis
• -review
• 3. Treating disseminated Histoplasmosis

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Background

• Recent review in CID analyzing the FDA AERS
  database for granulomatous infections associated
  with infliximab and etanercept from approval to
  the end of 2002.
• -3 TNF drugsetanercept is a soluble TNF
  receptor, adalimunab and infliximab are
  monoclonal antibodies
• -most notable culprit is infliximab
• -use in Crohn disease, psoriatic arthritis, and
  RA
• -239/100K receiving infliximab developed
  granulomatous infections (17/100K developed
  histoplasmosis)
• -74/100K receiving etanercept developed
  granulomatous infections (3/100K developed
  histoplasmosis)
• -about one-half of these were TB
• R. S. Wallis, M. S. Broder, J. Y. Wong, M. E.
  Hanson, and D. O. Beenhouwer. Granulomatous
  Infectious Diseases Associated with Tumor
  Necrosis Factor Antagonists. Clin Infect Dis
  200438 (1 May) 1261-5

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Background

• Infection risk was 3.25 fold higher for patients
  receiving infliximab than etanercept, and both
  were clustered within the first 3 months
• FDA recommends skin testing for TB and subsequent
  treatment of latent TB prior to initiating
  therapy with infliximab and adalimumab.
• False positive PPD in RA patients
• Other OI in endemic areas should be considered
• R. S. Wallis, M. S. Broder, J. Y. Wong, M. E.
  Hanson, and D. O. Beenhouwer. Granulomatous
  Infectious Diseases Associated with Tumor
  Necrosis Factor Antagonists. Clin Infect Dis
  200438 (1 May) 1261-5

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Histoplasma capsulatum

• Dimorphic fungus
• Missouri and Ohio river valleys
• The most prevalent cause of pulmonary fungal
  disease in humans.
• 95 of infections are clinically unapparent-XR
  findings only.
• Appearance inside of macrophages resembled
  encapsulated protozoa-hence was named H.
  capsulatum
• Epi. was pinned down during skin test surveys
  for TB in the 1940s.

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Histoplasma capsulatum

• Thermally dimorphic--
• _at_ temps lt35 it grows as brown or white mold
• _at_ temps of 37 it grows as yeast with small yellow
  heaped colonies
• Slow grower
• Mold colonies can grow after 1-2 weeks
• Clinical specimens can require up to 8-12 weeks
  to grow.
• Produces both microconidia and macroconidia _at_
  tempslt35
• These micorconidia are easily aerosolized and
  transmit infection.

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Histoplasm capsulatum

• The large thick-walled macroconidia have
  projections
• _at_ tempsgt 37, the mold converts to yeast-can be
  enhanced by brain-heart infusion agar-cysteine
  dependence
• Heterothallic, requires 2 opposite mating types
  and the - type is more infectious
• Epi-MO/OH river valley, and in South America is
  associated with chicken coops

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Histoplasma capsulatum-mycelial form Hyaline
septate branching hyphae with micro and
scherical macroconydia
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Histoplasma capsulatum-small yeast cells inside
of macrophages
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Histoplasma capsulatum

• Pathophysiology-microconidia are inhaled,
  penetrate alveoli, convert to small budding yeast
  (essential for pathogenicity), live in
  yeast-laden alveolar macrophages, either elicit
  tissue rxn., or disseminate to RE system.
• They then multiply in protected phagolysosome
  (acid neutralized).
• Dx. with microscopy on blood, csf, sputa, tissue.
  Wright or Giemsa stains

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Histoplasma capsulatum

• Culture the nonsterile fluids with Sarourauds
  agar with abx. And incubate 12 weeks
• Lysis-centrifugation of blood.
• Skin test-mainly for epi., conversion and
  negative test without anergy can be helpful, and
  a positive test in infants is useful
• RIA for antigenemia/antigenuria
• Can test CSF and BAL fluid

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Cutaneous Histoplasmosis in AIDS patient
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Histoplasma capsulatum

• Disseminated histoplasmosis-Lung-RE system,
  liver, LN, BM.
• Granulomatous lesions in these organs, even
  adrenal glands
• Acute Progressive is opportunistic and rapidly
  fatal and usually reactivation ds.
• Chronic Pulmonary histoplasmosis-older males with
  emphysema-centrilobular and apical.

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Histoplasma capsulatum

• Treatment-IDSA guidelines 2000
• Acute localized pulmonary histoplasmosis in
  typical patient. No treatment needed
• But if no improvement after one
  month-rxitraconazole 200 daily for 6-12 weeks.
• Diffuse pulmonary histoplasmosis-in
  immunocompetent host-amphotericin B 0.7mg/kg/d
  for total of 35mg/kg in severely ill patients and
  /- steroids. Then itraconazole 200 daily for 12
  weeks.
• 3. Chronic pulmonary histoplasmosis-itraconazole
  200mg once or twice daily for 12-24 months

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Histoplasma capsulatum

• Treatment-IDSA guidelines 2000
• Disseminated histoplasmosis-fever and weight loss
• Dissemination to almost anywhere-adrenals, GI
  tract, skin,
• oropharyngeal. CNS in 5-20 of cases.
• -Treatment in immunocompetent hosts and those
  without
• AIDSAmphotericin B .7-1mg/kg/d-switch to
  itraconazole 200 once or twice daily for 6-18
  months.

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Histoplasma capsulatum

• Treatment-IDSA guidelines 2000
• -Treatment in patients with AIDS-Induction with
• amphotericin B then itraconazole for 12 week
  induction.
• -monitor antigen levels in the blood or urine
  every 6
• months.
• -prophylaxis with itraconazole only
• -guidelines have further recommendations for
  other
• Manifestations of disseminated histoplasmosis

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Histoplasma capsulatum

• Can you ever stop ?
• -Goldman, M., et al. CID 200438(15 May) 1485-9
• 32 subjects with median CD4 of 289, all on ART
  for more than 24 weeks, and the same regimen for
  more than 8 weeks. 59 had undetectable viral
  loads. They were effectively treated for
  disseminated histoplasmosis for more than12
  months.
• They discontinued maintenance therapy at entry.
• Good follow at 24 months-up, no CD4 drops below
  100, and 81 had undetectable viral loads.
• 0 relapse for 65 person-years of observation, no
  histo antigen over 4.1