Cryptococcosis Pre- and Post-Transplant October 13, 2015 John W. Baddley, MD, MSPH University of Alabama at Birmingham Birmingham VA Medical Center

Outline 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%

Pappas et al., Clin Infect Dis Epidemiology in Solid Organ Transplant Recipients TRANSNET

Associated Factors 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 ( 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 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 1 Graybill et al. Clin Infect Dis 2000;30:47-54.

Case Renal transplant patient Tacrolimus, MMF, prednisone CSF culture negative Steroids? Reduction of immunosuppression; AmB + 5’FC, then fluconazole Headache, fever LP: OP 300 mm H20 CSF: 20 WBCs; protein elevated; glucose decreased Culture positive for C. neoformans; CSF CRAG 1:1024 Nausea, vomiting, headache Brain imaging with lesions OP 350 mm H2O CSF with 80 WBCs (protein increased) CSF CRAG 1:128 Antifungals

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 T- cells 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 CharacteristicHIV/AIDS Transplant Incidence10-42% (19.5%*)5-11% ManifestationsAseptic meningitis, lymphadenitis, cryptococcomas, lung nodules, hydrocephalus, pneumonitis, sepsis, optic neuritis Cellulitis, myostitis, aseptic meningitis, cryptococcomas, arachnoiditis, hydrocephalus, lung nodule Time-to-IRIS4-8 weeks4-6 weeks Risk factorsFungemia CD4/baseline HIV RNA not predictive Tacrolimus, mycophenolate, prednisone Disseminated cryptococcosis OutcomesImpacts mortality (?)Allograft loss; no impact on mortality Mortality33%-66% (20.8%*)10% 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 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

Chen at al, CMR 2014 Canavanine-glycine-bromothymol blue (CGB) agar

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