Cryptococcal meningitis Melicent Peck MD, PhD Stanford University Department of Medicine Case One HPI: 73 y/o male admitted for 3-week h/o acute memory loss. Per pt’s wife, pt getting lost, repeating same story over and over, unable to recall details of recent events. No F/C, no HA, no recent illness. Patient had acute-onset aphasia in 07/09 and 09/09 with resolution over several weeks. Found to have L temporal stroke on MRI brain. PMHx: IDDM, HLD, HTN, vertigo (x 2 years, attributed to Meniere's disease) Meds: Metformin, Lantus, Nicardipine, Citicholine SR SHx: No etoh, tobacco. Retired administrator, lives in Bangalore, India but travels to US ~ 1x/year to see family. No rural contacts, no hiking, no pets. FHx: NC PE: VSS. AAO x 3. Exam unremarkable. Labs: Na 133, CRP < 0.2, ESR 38, HIV negative, serum CrAg 1:4 LP: OP 22cm, 116 wbc ((N28L66M6)), 12,625 rbc, xanthochromia, g glucose 69, TP 536, CrAg g 1:4 Gram Stain: small number polys, small number PMNs, small number rbc, no organisms, Cx: NGTD MRI brain: new temporal lobe CVA Case Two HPI: 55 y/o male with h/o HIV (CD4+ 2 cells/l, VL 1850 copies/ml) not on HAART with OI disseminated KS and Candidiasis, homeless admitted for abdominal pain, SOB. Pt found to have SBO s/p lysis of adhesions, PNA 2/2 KS vs CAP. +HA primarily in morning, diffuse. PMHx: HIV (1990), disseminated KS (lung, skin), Candidiasis (esophageal), polysubstance abuse Meds: Atazanavir, Truvada, Ritonovir, Bactrim, Fluconazole, Azithromycin SHx: Homeless, + etoh, + crack cocaine FHx: NC PE: VS: RR 24 Chronically ill-appearing male, cachectic OP: oral thrush, areas of mild ulceration on hard palate, CV: RRR no mrg Lung: diffuse coarse crackles, decreased BS in RLL Abd: TTP RLQ with voluntary guarding Skin: 2 x 2 cm violaceous macule on dorsum of L foot Neuro: non-focal Labs: Hct 29, Na 132, albumin 2 BCx +Cryptococcemia, CrAg 1:256 LP <1 LP: 1 wbc, b <1 1 rbc, b Glucose Gl 66, 66 TP 24 24,CrAg C A 1:8 18 GS: no polys, no orgs Cx: NGTD Fungal Cx: Cryptococcus neoformans (liquid media, not on plate) CT Head: unremarkable DDX: Chronic Meningitis  Bacteria     Mycobacterium Tb Syphilis Lyme disease Nocardiosis  Parasites   Cysticercosis y Acanthamebiasis  Fungal      • Cryptococcosis Coccidiomycosis Histoplasmosis Candidiasis Aspergillosis Viral • • HSV VZV •Sarcoid •Tumor Cryptococcal Meningitis  Signs/Symptoms  HA,, F,, nuchal rigidity, g y, p photophobia p  Decreased vision, unsteady gait, CN palsies  Confusion, lethargy, memory loss over several weeks  Seizure or strokes in multiple vascular territories  Causative Agent Strain Global Distribution Environmental Reservoir C. neoformans Global Temperate climates Pigeon droppings/ guano/ birds nests Rotting g vegetation g Epidemiology  Occurs O in i ~ 1 million illi people l per year  ~600,000 deaths annually  3-month mortality rate ~20% in developed countries, ~70% in Africa  Primarily seen in immunocompromised patients  Newly diagnosed HIV patients   Most common OI in AIDS (CD4+ < 50 cells/l)  Incidence 0.04%-12% per year Look for co-morbid CNS processes (Toxoplasma, Nocardia, lymphoma)  Solid organ transplant patients   Median time to disease onset 21 months after transplantation g transplant p recipients p Documented in 2.8% of sold-organ  High dose CS, monoclonal Abs, other immunosuppressants  Global disease burden  Sub-Saharan Sub Saharan Africa > S and SE Asia > Latin America > E Europe and Central Asia > > N America > N Africa and Middle East> W and Central Europe  95% of cryptococcal meningitis cases in developing countries are HIV associated i t d  Account for 10-20% of all deaths in HIV infected patients in Africa (> Tb) Pathogenesis g  Virulence Factors  Capsule  Antiphagocytosis barrier, depletes complement, dysregulates cytokine secretion  Melanin  Antioxidant (UV light, toxic free radicals), interferes with T-cell response  Growth at high-temperature (37o C) Mechanism of Infection  Yeast spores enter host through lungs via inhalation  Spores deposited in alveoli  Phagocytosed by macrophages  Granulomatous inflammation  CD4, CD8, NK cells inhibit growth  Immunosuppressed Yeast proliferates/ disseminates Immunocompetent Yeast produce small Yeast eliminated lung-lymph node complex Remain dormant (latency) Host asymptomatic y p Clinical Manifestations  Lung   1/3 pts asymptomatic (abnormal CXR with single or multiple pulmonary nodules) PNA (F, chest pain, SOB, productive cough)  CXR: lobar infiltrate, hilar LAD, pleural effusions, lung cavitations  CNS  Subacute meningitis or meningoencephalitis  Skin  Ulceration, cellulitis, abscess  Prostate   Usually asymptomatic Can serve as reservoir of infection  Eye   Ocular p palsies,, p papilledema p Can lead to blindness   Optic neuritis Cerebral edema 2/2 elevated ICPs  Bone/joint (osteolytic lesion) Diagnosis  CSF  Elevated opening pressure  Mononuclear pleocytosis  Elevated protein  Decreased glucose (< 40mg/dl)  Cryptococcal antigen  Direct detection (India Ink)  Spherical, narrow based, budding, encapsulated yeast  50% of non non-AIDS AIDS pts, 80% of AIDS pts CNS positive  Culture  Growth 48-72 hours on laboratory media at 20-37o C  Routine R ti blood bl d culture lt can d detect t t cryptococcemia t i (3 (3-7 7 days) d )  CSF fungal culture Diagnosis  Serology  Cryptococcal polysaccharide antigen (sera and CSF)  Latex agglutination and enzyme immunoassay >90% sensitive and specific CSF titer ≥ 1:4 positive Titer ≥ 1:1024 -High burden of yeasts, poor host immunity, greater chance of therapeutic h ffailure l Serial titers imprecise but can be used for disease follow-up Can be negative in pulmonary disease  Radiology  No pathognomonic scan  CT brain: cryptococcomas (single/multiple), hydrocephalus, gyral enhancement  50% of CT scans normal  MRI brain: hyperintense clustered foci in basal ganglia or midbrain  Follow-up scans may show worsening of lesions  Represents enhancement by inflammation as yeast being eliminated  Not necessarilyy treatment failure Treatment: Drugs  Amphotericin B  Amphotericin B deoxycholate (0.7 mg/kg/day)  Nephrotoxic  Acute infusion rxn (F/C, N/V, SOB)  Liposomal amphotericin B (Ambisome:3-6 mg/kg/day)  Amphotericin B lipid complex (Abelcet:3-6 (Abelcet:3 6 mg/kg/day)  Flucytosine (100 mg/kg/day) (FC)  MIC ≥ 128 g/ml associated with treatment failure  Drug resistance as monotherapy  Monitor for cytopenias  2hr post-dose level 30-80 g/ml 3-5 days after initiation of treatment  Fluconazole (200-1200 mg/day)  MIC ≥ 16 g/ml g/ml associated with treatment failure  Resistance emerging problem when used as monotherapy (Africa) Treatment: HIV  Induction phase  Amphotericin B + FC x 2 weeks  Continue up to 6 weeks if pt sx (AMS), (AMS) persistent increased ICP, CSF culture remains positive  Consolidation phase p  Fluconazole 400 mg Qday (6 mg/kg) x 8 weeks  Suppressive phase  Fluconazole 200 mg Qday  Initiate HAART 2-10 weeks after commencement of initial antifungal treatment  Stop if CD4+ > 100 cells/l, VL ND x ≥ 3 months, CrAG negative, minimum 12 mos of antifungal therapy  Reinstitute maintenance therapy if CD4+ < 100 cells/l or C A iincreases CrAg  Primary antifungal prophylaxis not recommended IDSA Guidelines, 2010 Treatment: Organ Transplant  Induction phase  Amphotericin B + FC x 2 weeks  Consolidation phase  Fluconazole 400 mg-800 mg Qday (6 mg/kg) x 8 weeks  Suppressive phase  Fluconazole 200-400 mg Qday x 6-12 months  Reduce immunosuppressants  Lower prednisone to < 20 mg/day IDSA Guidelines, 2010 Treatment: Normal  Induction phase  Amphotericin B + FC x 4 weeks  No neurological l l complications l  CSF culture results negative after 2 weeks of treatment  Extend treatment to 6 weeks if neurological complications  If low-risk for therapeutic failure can shorten treatment to 2 weeks  Consolidation phase  Fluconazole 400 mg Qday (6 mg/kg) x 8 weeks  Suppressive phase  Fluconazole 200 mg Qday x 6-12 months IDSA Guidelines, 2010 Elevated ICP  Seen in ~ 50% of HIV infected patients  Linked to high burden of yeast in CSF  Opening CSF pressure ≥ 25 cm H2O + symptoms  CSF drainage to reduce OP by 50% or to ≤ 20 cm H2O  Repeat LP daily until CSF pressure and sx stabilized for > 2 days  Consider placement of temporary CSF shunt or lumbar drain IDSA Guidelines, 2010 Treatment in Resource-Limited S tti Settings  Induction/Consolidation  Amphotericin B (1 mg/kg/day) x 2 weeks -> fluconazole (800 mg/day) x 8 weeks  Amphotericin B (0.7 mg/kg/day) + fluconazole (800 mg/day) x 2 weeks -> fluconazole (800 mg/day) x 8 weeks  Fluconazole (1200 mg/day) + FC (100 mg/kg/day) x 2-10 weeks  Fluconazole (1200 mg/day) x 10-12 weeks  Maintenance M i t  Fluconazole 200-400 mg/day  Open-labeled p RCT in Malawi ((2008))  HIV positive adults (mean CD4+ count 21 cells/l, VL 99,000 cells/ml) with first episode of cryptococcal meningitis  Patients with ANC < 500, plt < 50K, ALT > 200, or on ART excluded  Randomized to fluconazole (1200 mg/day) (n (n=20) 20) vs fluconazole + FC (100 mg/kg/day) (n=21) x 14 days -> 800 mg fluconazole Qday  ART started after 4 weeks of antifungal therapy  Monitored LP at t =0, 1, 3, 7, 14 days  More frequent LP if OP > 30 cm H2O (mean OP at baseline 34 cm H2O)  Followed LFTs, creatinine, CD4+ cells, HIV VL at baseline, LFTS and cbc at weeks 1,2,4,6,10.  Primary outcome: mean rate of decrease in CSF cryptococcal counts  Secondary S d outcomes: t serious i adverse d events, t d drug S/E S/E, mortality t lit att 2 & 10 weeks Results/Conclusions Fungicidal Activity: High-dose fluconazole + FC > than high high-dose dose fluconazole alone (p< 0.001). Four patients in combination arm and one in monotherapy arm had sterile cultures lt att D14 D14. 10% 37% 43% 58% Survival: Trend toward improved survival at 2 and 10 weeks among patients who received combination therapy. Results/Conclusions Safety: Combination regimen safe w/o monitoring g FC levels Limitations: -FC not available in most of developing world, including Africa -Underpowered to detect mortality benefit References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 10. 11. 12. Buchanan K & Murphy p y J ((1998)) What makes Cryptococcus yp neoformans a p pathogen? g Emerging Infectious Diseases 4(1):71-83. Idnurm A, et al. (2005) Deciphering the model pathogenic fungus Cryptococcus neoformans. Nat Rev Microbiol 3(10):753-764. Longley N, et al. (2008) Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. 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