Clinical Case Conference Monday March 10, 2003

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Clinical Case ConferenceMonday March 10, 2003

• Caryn Gee Morse, MD
• Senior Fellow in Infectious Disease

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Case 1 JH

• 65 year old white male
• PMH HTN, CVA, MI, CRI (baseline Cr 1.7)
• 4 month hx of intermittent fever, chills, sweats,
  malaise and colds
• OSH evaluation revealed marked leukocytosis,
  anemia, thrombocytopenia

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Case JH Presentation

• Admitted 12/29/02 with presumed AML
• BM bx confirmed AML, myelomonocytic, M4
• Induction chemotherapy initiated 12/31 with
  dauorubicin/VP16/ara-C 7/3/3
• F/U BM bx 1/13 revealed residual disease and
  underwent re-induction with above agents 5/2/2

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Case JH Presentation

• Febrile on admission to 102o
• Empiric broad spectrum coverage initiated with
  V/cefepime/cipro
• Prophylactic fluconazole, acyclovir
• For persistent fever in face of worsening
  neutropenia, cefepime ?d to pip/tazo 1/9/03 and
  ampho B added at 0.5mg/kg 1/12/03

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Case JH Presentation

• Defervesced with addition of ampho B
• On 1/17, patient noted erythema on dorsal aspect
  of L 5th toe just below base of nail
• Initially area non-tender and without associated
  soft-tissue swelling
• Over 2-3 days, erythema extended spreading up
  the foot with increased swelling and pain

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Case JH Presentation

• Ampho B ?d to 1mg/kg 1/17/03 and then ?d up to
  1.5mg/kg 1/19/03
• Erythematous lesions continued to spread
  proximally towards ankle
• Dermatology and infectious disease consults
  obtained 1/20/03

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Case JH Hospital Course

• Dermatology consult team performed punch biopsy
  of lesions

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Case JH ID Consult

• On evaluation by ID consult team,
• Medications Vanc 1g IV q18h (day 18,) pip/tazo
  3.375g IV q4h (day 12,) cipro 750mg IV q12h (day
  17,) amphotericin 105mg IV q24h (day 10,)
  amiloride, captopril, HCTZ, Benadryl and
  Solu-Cortef (pre-meds)
• NKDA

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Case JH Physical Examination

• GEN Pleasant cachetic elderly wm NAD
• HEENT Conj pale Non-icteric OP clr Multiple
  ulcerated lesions on upper and lower lips and
  intra-orally c/w HSV Post-pharynx clear
• NECK Supple FLAD
• CHEST CTA
• CV RRR F aud m/g/r Pulses full and symmetric
• ABD BS NT/ND liver edge palp 2cm below CM
• EXT Fc/c/e

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Case JH Physical Examination

• SKIN
• L 5th toe swollen, erythematous, painful with
  palpable erythematous nodules extending to
  dorsal/lateral aspect of L foot. Violaceous
  streaks near ankle. Non-blanchable. No palpable
  local LAD.

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Case JH Laboratory Studies
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Case JH Studies cont.
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Case JH ID Consult

• Differential diagnosis?

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Case JH ID Consult

• Consult team recommended continuing current
  antibiotic coverage including amphotericin at
  1.5mg/kg while awaiting skin bx and cx results
• Suggested addition of voriconazole if clinical
  picture should worsen

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Case JH Hospital Course

• Foot cx (swab) fungal smear (-), cx 2 colonies
  fusarium
• Skin biopsy
• Path sparse perivascular dermatitis with
  extravasated RBC no organisms seen
• Micro (-)

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Case JH Hospital Course

• ID consult team recommended
• D/C ampho B
• Start voriconazole at 400mg PO q12h x 2 followed
  by 200mg q12h
• Increase acyclovir to treatment dose for oral HSV

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Case JH Hospital Course

• With the addition of voriconazole, L foot lesions
  appeared to initially stabilize
• Two days after initiation of therapy, painful,
  red nodules appeared at ankle with subsequent
  spread proximally
• Fever continued
• Neutropenia persisted
• Trial of WBC transfusion unsuccessful

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Case JH Hospital Course

• Progressive clinical decline with increasing
  pleural effusions, pulmonary edema and hypoxia
  worsening transaminitis
• Transferred to BMT
• Subsequently dxd with nosocomial pneumonia
• Developed AFIB with RVR
• Expired 2/1/03

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Case 2 JS

• 50 year old AAF
• ESRD secondary to glomerulonephritis
• s/p cadaveric renal transplant 6/2000, failed
  secondary to arterial thrombosis
• s/p second cadaveric transplant 6/26/01 with
  post-transplant course complicated by nocardiosis
• Maintenance immunosuppression with Prednisone
  10mg QD, Prograf 6mg BID and CellCept 500mg BID

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Case 2 JS

• Developed a small ulcer at the base of her L 4th
  toe in late 12/02 which progressed over 6-8
  weeks, extending across the dorsum of the foot to
  form a larger, non-healing ulcer 2/02
• Initial wound cx, derm bx unrevealing
• Subsequently admitted in early 3/02 for surgical
  debridement
• OR cx revealed mold?fusarium

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Case 2 JS

• Admitted 3/11/02 for anti-fungal therapy and
  aggressive wound management
• CellCept and Prograf both held on admit 3/11/02
  Prednisone continued with stress dosing for
  surgical procedures
• Initially placed on Abelcet 350mg IV q24h
• Despite antifungal therapy and repeated operative
  debridement, ulceration continued to expand
  proximally

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Case 2 JS

• MRI 3/15/2002 cortical breakdown of 3rd and 4th
  metatarsals c/w multifocal osteomyelitis diffuse
  soft tissue swelling c/w cellulitis
• Plain film L foot 3/20/2002 destruction of the
  3rd metatarsal c/w osteomyelitis

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JS Plain Film
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JS MRI
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Case 2 JS

• Voriconazole obtained through compassionate
  access and added 3/21/02
• Ulceration appeared to stabilize but healing poor
• F/U MRI L foot 4/1/02 revealed progressive boney
  and soft-tissue involvement

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Case 2 JS

• After discussion between the renal transplant
  team, orthopedic surgery, infectious disease and
  the patient, decision made to amputate L foot.
• JS underwent L BKA 4/5/02. Post-operative course
  marked by slow wound healing and small area of
  breakdown at stump.
• F/U aspirations, wound cxs (-) for fungus

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Fusarium

• Fusarium sp. can be isolated from most soils,
  insects, running water and from roots, seeds and
  other tissues of a wide variety of herbaceous and
  woody plants, both wild and domesticated.
• Also found in normal mycoflora of commodities,
  such as corn, rice, beans, soybeans, and other
  crops.
• Fusarium spp. may cause various infections in
  humans. Fusarium is one of the emerging causes of
  opportunistic mycoses.

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Corn attacked by Fusarium graminearum, source of
zearalenone and vomitoxin
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Hole-in-the-head disease" of horses
Leucoencephalomalacia caused by toxins of
Fusarium moniliforme.
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Fusariosis

• Disease in humans is rare and usually follows
  traumatic inoculation in the healthy host.
• Inhalation or minor trauma ? fusariosis in
  immunocompromised patients.
• Most common cause of fungal keratitis
• Described cause of endophthalmitis,
  onychomycosis, and skin and musculoskeletal
  infections (including septic arthritis,
  osteomyelitis and mycetoma).

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Fusarium Keratitis
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Fusarium keratitis
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Fusarium corneal ulcer scraping demonstrating
branching fungal hyphae
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Fusarium fungus balls seen on removed globe
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Fusariosis

• Since the early 1970s, disseminated infection
  increasingly common in persons with hematologic
  malignancy and other immunocompromising disorders
  (including HIV/AIDS).
• Rare cases of dissemination also described in the
  severe burns and heat stroke.
• Most commonly occurs in patients with acute
  leukemia (70 to 80 of cases) and prolonged
  neutropenia (more than 90 of cases). (Martino et
  al. Clinical patterns of Fusarium infections in
  immunocompromised patients. J Infect.
  199428(Suppl 1)7)
• Increasingly reported in patients undergoing BMT

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Fusariosis

• In one review of 43 patients, the median duration
  of neutropenia was greater than 3 weeks. (Boutati
  and Anaissie. Fusarium, a significant emerging
  pathogen in patients with hematologic malignancy
  Ten years' experience at a cancer center and
  implications for management. Blood.
  199790999-1008.)

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Fusariosis

• Portal of entry in disseminated infection is
  often not known.
• Inhalation, ingestion, and entry through skin
  trauma have been suggested.
• Described assocations with onychomycosis,
  sinusitis, indwelling intravascular catheters
  (Anaissie et al. The emerging role of Fusarium
  infections in patients with cancer. Medicine.
  19886777-83.)

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FusariosisClinical Presentation

• Fever and myalgias unresponsive to broad-spectrum
  antibacterial antibiotics during periods of
  profound neutropenia.
• Disseminated fusariosis has been recognized in
  patients who have been receiving empirical or
  prophylactic antifungal therapy.

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FusariosisClinical Presentation

• Skin lesions occur in 60 to 80 of infections,
  usually appearing as multiple papules or deeply
  set, painful nodules. Most common on the
  extremities, reported on the trunk and face as
  well.
• Rash usually initially macular with central
  pallor with progress to ecthyma gangrenosum-like
  necrotic lesions with a surrounding thin rim of
  erythema.

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Nucci M and Anaissie E. Cutaneous infection by
Fusarium species in healthy and
immuno-compromised hosts implications for
diagnosis and management. CID 2002 Oct
1535(8)909-20.

• Literature review and case series
• Identified a total of 259 patients (232
  immunocompromised and 27 immunocompetent)
• Skin involvement was present in 70 of patients,
  particularly in immunocompromised patients (72
  vs. 52 P .03)

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Nucci and Anaissie. Cutaneous infection by
Fusarium species

• Skin lesions were the single source of diagnosis
  of fusarial infection in the majority of patients
  (100 55 of 181), including in the 148 patients
  whose skin lesions were disseminated.
• Of these 148 patients, 78 had blood cultures
  negative for Fusarium species, and the skin was
  the only source of diagnostic material in all
  except 2 patients (sinus was the source in 2
  patients).

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Nucci and Anaisse

• Overall death rate 66 (170/259)
• 100 mortality among persistently neutropenic
  patients
• 30 among those who ultimately recovered from
  immunosuppression (P lt .0001)
• A higher mortality was observed among patients
  with skin lesions (70 vs. 56 P .04),
  particularly among those whose lesions were
  disseminated (76 vs. 39 P lt .0001).

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Nucci and Anaissie Conclusions

• 1. Skin lesions represent a frequent
  manifestation (gt50) of infection by Fusarium
  species, especially among immunocompromised
  patients, in contrast to the rare cutaneous
  involvement (lt10) in infection with other
  opportunistic fungi, such as Candida species or
  Aspergillus species.
• 2. Skin is the primary site of disseminated and
  life-threatening infections among a subset of
  highly immunocompromised patients.
• 3. Skin is the most common source of diagnostic
  material (and frequently the only one).

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Nucci and Anaissie Conclusions

• 4. Distinct patterns of skin involvement by
  Fusarium species exist, depending on the immune
  status of the host.
• 5. Mortality rate among neutropenic patients is
  high, regardless of whether fusarial skin lesions
  are localized or disseminated. This is in
  contrast to the immunocompromised patients with
  adequate neutrophil count and in whom localized
  skin lesions are associated with a lower
  mortality rate.

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Fusariosis Diagnosis

• Recovery of the fungus from the blood and biopsy
  of suspicious skin lesions are the two most
  common and effective ways to diagnose this
  infection.
• Although nonspecific for Fusarium, finding
  septate hyphal elements in a skin biopsy specimen
  should aid in making rapid therapeutic decisions.
• Fusarium can usually be recovered in culture of
  skin biopsy tissue and seen in histopathologic
  studies.
• Hyphae resemble Aspergillus. And like
  Aspergillus, Fusarium has a predilection for
  small blood vessels, resulting in angioinvasion
  and associated thrombosis.

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Fusarium

• Septate hyphae of Fusarium species difficult to
  visualize with routine HE staining but easily
  identified when tissue is prepared with
  methenamine silver or periodic acid-Schiff
  stains.
• Fusarium spp. grow easily and rapidly within two
  to five days on Sabouraud dextrose agar producing
  downy, cottony colonies that are lavender to
  purple-red in color. Microscopically, the
  characteristic feature is sickle- or
  banana-shaped multi celled macroconidia
• F. solani is the most common species recovered
  (when speciated), followed by F. oxysporum, and
  F. moniliforme.

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Fusarium oxysporum
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Fusarium oxysporum
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Fusarium and antifungal susceptibility

• Fusarium spp. resistant to most antifungal agents
  in vitro.
• Most isolates resistant to ampho B and frequently
  resistant to flucytosine, itraconazole and
  fluconazole.
• Some isolates susceptible to ketoconazole and
  miconazole. (Speeleveld et al. Susceptibility of
  clinical isolates of Fusarium to antifungal
  drugs. Mycoses 1996 3937.)

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Fusarium and antifungal susceptibility

• Newer agents including voriconazole and
  posaconazole have limited activity against
  Fusarium
• Two studies have shown that caspofungin also
  lacks activity against Fusarium species.
• No data in literature about susceptibility to
  combination therapy.

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Fusarium sp.

• Fusarium known to produce toxic metabolites.
• Not known whether toxins are produced in human
  infection, though it has been suggested these
  toxins could possibly prolong myelosuppression or
  contribute to myalgias. (Anaissie et al. The
  emerging role of Fusarium infections in patients
  with cancer. Medicine. 19886777-83.)

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Fusariosis Therapy

• Optimal treatment for disseminated disease not
  established.
• Amphotericin B has been included in the regimens
  of most successfully treated patients and thus
  high-dose amphotericin B was formerly the drug of
  choice.
• Lipid-based amphotericin B formulations and
  combinations of other antifungal agents with
  amphotericin B have been reported all with mixed
  success.

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Voriconazole and Fusarium

• Voriconazole is approved for treatment of
  Fusarium infections in patients intolerant of or
  with infection refractory to other drugs.
• For Fusarium species, MICs of voriconazole are
  substantially lower than MICs of itraconazole,
  but they are higher than those noted for other
  molds.

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From Johnson and Kaufman. Voriconazole A New
Triazole Antifungal Agent, CID 2003 Mar
136(5)630-7.
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Voriconazole and Fusarium

• Reports of the use of voriconazole therapy for
  Fusarium infections are limited.
• A case of keratitis due to F. solani was cured
  with surgery, topical voriconazole therapy, and 8
  weeks of high-dose, orally administered
  voriconazole therapy (Reis et al. Successful
  treatment of ocular invasive mould infection
  (fusariosis) with the new antifungal agent
  voriconazole. Br J Ophthamol 2000 84932-3)
• In data presented to the FDA, 9 (43) of 21
  patients with fusariosis had a complete or
  partial response to voriconazole, which was
  provided on a compassionate-use basis.

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Fusariosis Therapy

• Addition of colony-stimulating factors (GCSF or
  GMCSF) or granulocyte transfusions to specific
  antifungal therapy described.
• Benefit not currently known.

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Immune Modulating Therapies and Invasive Fungal
Infection Leukocyte Transfusion

• Limited case reports suggest that administration
  of G-CSF primed leukocytes can be beneficial for
  patients with Aspergillus and Candida tropicalis
  infections.

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Peters et al. Leucocyte transfusions from rhG-CSF
or prednisolone stimulated donors for treatment
of severe infections in immunocompromised
neutropenic patients. Br J Haematol 1999
106689- 96.

• Phase 1/2 trial of leukocyte transfusion used
  cells from donors primed with G-CSF and
  prednisolone to treat patients with severe
  neutropenia and bacterial or fungal infections.
• Low toxicity (12)
• Fungal infection was cleared in 5 of 13 patients.
  Notably, infections were cleared in 5 of 9
  patients with aspergillosis.

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Price TH et al. Phase I/II trial of neutrophil
transfusions from donors stimulated with G-CSF
and dexamethasone for treatment of patients with
infections in hematopoietic stem cell
transplantation. Blood 2000 953302 9.

• Leukocyte transfusions from G-CSF treated donors
  to 20 patients who had undergone SCT
• Demonstrated the migration of transfused PMNL to
  peripheral tissues and demonstrated
  microbiological resolution of candidemia in 4 of
  7 transfusion recipients.
• Only 1 patient with candidemia was alive 30 days
  after diagnosis of infection, suggesting that
  despite a possible anti-candidal effect of
  donor-primed PMNL, therapy did not affect
  outcome.

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Fusariosis Outcome

• Overall mortality from fusarial infections is
  60-80
• Survival almost universally associated with
  recovery of neutrophil counts

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Fusariosis Outcome

• Boutati and Anaissie noted an association between
  survival and
• remission of hematologic malignancy (100 versus
  10 percent)
• recovery of adequate neutrophil count (100 versus
  0 percent)
• lack of significant graft-versus-host-disease (0
  versus 66 percent)
• (Boutati, EI, Anaissie, EJ. Fusarium, a
  significant emerging pathogen in patients with
  haematological malignancy Ten years experience
  at a cancer centre and implications for
  management. Blood 1997 90999.)