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Cryptococcosis Pre- and
Post-Transplant
October 13, 2015
John W. Baddley, MD, MSPH
University of Alabama at Birmingham
Birmingham VA Medical Center
[email protected]
Outline
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Case
Epidemiology
Treatment
C. gattii
Complications
Pre- and post-transplant cryptococcosis
Case
• 58-year-old man who received a heart transplant in 2001 was
admitted for pacemaker implantation in April. A CT following
secondary to polycys procedure identified a 1.5 x 1.5 cm left
upper lobe lung nodule. He complained of dyspnea and left arm
pain upon exertion. No fever, chills or cough.
• Past Medical History:
-allograft vasculopathy (stents), bradycardia, hyperlipidemia
- heavy smoker prior to transplant
- Lives on a farm
• Relevant Medications:
-Sirolimus
-Tacrolimus
-Mycophenolate
• Referred to Pulmonary clinic and seen in July. He was
asymptomatic
Cryptococcosis
• Caused by the encapsulated, budding yeasts
Cryptococcus neoformans or Cryptococcus gattii
• These saprophytic fungi are distributed worldwide and
are particularly abundant in soil contaminated by
pigeon droppings
• Pulmonary infection results from inhalation of the
organism from an environmental source, and the
organism has a propensity to metastasize to the
central nervous system
• Rare cause of pneumonia, with incidence of <0.1%
• A major cause of meningoencephalitis in transplant.
Cryptococcosis affects up to 5% of transplant patients.
• Mortality approximately 15%
TRANSNET
Epidemiology in Solid Organ Transplant Recipients
Pappas et al., Clin Infect Dis. 2010
Associated Factors
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HIV/AIDS
Corticosteroids
Organ transplantation
Malignancy
CD4 T-cell lymphopenia
Connective tissue disease
Renal failure
Cirrhosis
Chronic lung disease
Immunosuppressive agents
Diabetes mellitus
Pregnancy
Sarcoidosis
Systemic lupus erythematosus
Rheumatoid arthritis
Geography (Southern US)
Diagnosis of Cryptococcosis
• Definitive diagnosis is made by culture. Best yields
will occur from BAL, transbronchial biopsy or open
lung biopsy
• Cryptococcus is recognized by its oval shape and
narrow-based budding. With use of the mucicarmine
stain, the cryptococcal capsule will stain rose to
burgundy in color
• Transplants:
-CSF cryptococcal antigen positive in > 95%
-Pulmonary: serum CRAG is positive in 25-56%
Mucicarmine staining
Treatment
Transplant Patient
-Asymptomatic or mild to moderate disease
Fluconazole 400mg daily for a minimum of 6-12 months
Alternatives: Itraconazole 400 mg/d
-Severe, progressive disease, or suspected or proven dissemination
Induction: Amphotericin B (0.5-0.7 mg/kg/d) or lipid preparations
of amphotericin B with flucytosine (100mg/kg/d) for 2-4 weeks
Consolidation: Fluconazole 400 mg/d for 8-10 weeks, then fluconazole
200mg/d for a minimum of 6-12 months
Alternatives: Itraconazole may be substituted for fluconazole
Maintenance therapy: Fluconazole 200 mg/d as lifelong therapy or until
immune reconstitution is attained*
Baddley and Forrest, AJT 2013; Perfect et al, Clin Infect Dis 2010
Intracranial Pressure
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Increased intracranial pressure (ICP) is an important
complication of cryptococcal meningitis
Approximately half of transplant patients have opening
pressure > 25 cm. Elevated ICP is associated with poor
outcomes (death, impaired mentation)1
Evaluation and treatment of elevated ICP:
1) Recognition of the patient’s opening pressure. Re-analysis during
treatment if symptoms of increased ICP develop
2) Frequent lumbar punctures (Rolfes et al., Clin Infect Dis 2014)
3) Medical therapy (antifungal therapy, corticosteroids, mannitol,
acetazolamide)
4) Consideration of lumbar drain, ventriculostomy or ventriculoperitoneal
(VP) shunt placement in patients with increased ICP refractory to other
measures
1Graybill
et al. Clin Infect Dis 2000;30:47-54.
Case
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Renal transplant patient
Tacrolimus, MMF,
prednisone
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Headache, fever
LP: OP 300 mm H20
CSF: 20 WBCs;
protein elevated;
glucose decreased
Culture positive for C.
neoformans;
CSF CRAG 1:1024
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Nausea, vomiting, headache
Brain imaging with lesions
OP 350 mm H2O
CSF with 80 WBCs (protein increased)
CSF CRAG 1:128
Antifungals
Reduction of
immunosuppression;
AmB + 5’FC, then
fluconazole
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CSF culture negative
Steroids?
What is Immune Reconstitution
Inflammatory System (IRIS)?
• An exaggerated immune response to persisting
microbial antigens despite microbiologic treatment
success
• Associated with improved immune system function
(decreased immunosuppressives, increasing CD4 Tcells or TNF-α)
• Most common in HIV infection (tuberculosis,
cryptococcosis, NTM, CMV)
• Paradoxical or new presentation of infection
• Emerging among transplant recipients
Definition (Transplant)
1. New or worsening appearance of any of the following
manifestations:
a) CNS: Clinical or radiographic manifestations consistent with
inflammatory process, such as contrast enhancing lesions on
neuroimaging studies (CT or MRI); CSF pleocytosis, defined as >5
white blood cells; or increased intracranial pressure (with or without
hydrocephalus)
b) Lymph nodes, skin or soft tissue lesions (cellulitis or abscesses)
c) Pulmonary (nodular, cavitary, mass lesions, pleural effusions)
detected by chest radiography or CT).
d) Other focal tissue involvement with histopathology showing
granulomatous lesions, and
2. Symptoms occurred during receipt of appropriate antifungal
therapy and could not be explained by a newly acquired infection,
and
3. Negative results of cultures for C. neoformans during the
diagnostic workup for the inflammatory process
Singh and Perfect, Lancet ID 2007 ; Baddley and Forrest, Am J Transplant 2013; Singh et al, Transplantation 2005; Haddow et
al, Lancet Infect Dis 2010.
Epidemiology of IRIS
HIV/AIDS
Transplant
10-42% (19.5%*)
5-11%
Aseptic meningitis, lymphadenitis,
cryptococcomas, lung nodules,
hydrocephalus, pneumonitis, sepsis,
optic neuritis
Cellulitis, myostitis, aseptic
meningitis, cryptococcomas,
arachnoiditis, hydrocephalus, lung
nodule
Time-to-IRIS
4-8 weeks
4-6 weeks
Risk factors
Fungemia
CD4/baseline HIV RNA not predictive
Tacrolimus, mycophenolate,
prednisone
Disseminated cryptococcosis
Outcomes
Impacts mortality (?)
Allograft loss; no impact on
mortality
Mortality
33%-66% (20.8%*)
10%
Characteristic
Incidence
Manifestations
Sun and Singh, Clin Infect Dis 2011, Bouleware et al, PloS Medicine 2010, Singh et al., Clin Infect Dis 2005
*Muller et al., Lancet ID 2010; Singh et al, Clin Infect Dise 2014
Treatment of IRIS
Drugs:
• Steroids (prednisolone 1mg/kg/d; prednisone 0.5-1.0 mg/kg;
dexamethasone 8-16 mg/kg/d) over a 2-6 week period
• NSAIDs
• TNF-α inhibitors (adalimumab, infliximab, etanercept)
• Pentoxifylline
• Montelukast
• Thalidomide
• Hydroxychloroquine
• Statins (promote Th2 and Tregs; block TH17 development)
• Other immunomodulators (IL-6; IL-17 antagonists?)
Other:
• *Discontinuation of CNIs associated with IRIS
• Monitoring of CSF pressure
*Sun et al, Clin Infect Dis 2014
C. gatti Infection
• C. gattii infection has been described throughout the world
but endemnicity has primarily been limited to tropical and
subtropical regions.
• Emergence of C. gattii in Vancouver, Canada and the
Pacific Northwest United States in the since 1999
• C. gattii typically causes disease in people with apparently
normal immune systems
• Key molecular types: VGI, VGII, VGIII, VGIV
• VGII strains often have high MICs to fluconazole
• Transplant:
-11/62 cases on Oregon in transplants (time-to-crypto 17.8 months)
-More likely to have disseminated disease and higher mortality
-VGII strain in 11/12; elevated fluconazole MICs (2-32 ug/ml)
Forrest G et al, Trans Infest Dis 2015; Datta et al., EID 2009
Canavanine-glycine-bromothymol blue (CGB) agar
Chen at al, CMR 2014
• Can transplant candidates with cryptococcosis safely undergo
liver transplant?
• Multi-center study in patients with cirrhosis
• 112 patients identified (48% CNS, 37.5% pulmonary; fungemia 46.5%)
• 90-day mortality was 57% (attributable to cryptococcosis in 56%)
• Advanced liver disease, renal disease, MELD predicted mortality
• 46 were listed for transplant; 8 were transplanted
• Antifungal therapy before transplantation ( median 42 days)
• NO patients developed progression or recurrence after transplantation
Singh et al., Transplantation 2015