A Case of Cryptococcal Meningitis DOUGLAS FISH ALBANY MEDICAL COLLEGE JUNE 4, 2013 History Patient transferred from Columbia Memorial Hospital with lethargy, shortness of breath, chest pains and failure to thrive. HIV was newly diagnosed there CD4 4 cells/cmm VL 33,000 copies/ml Transferred with: 1. Pancytopenia. 2. Splenomegaly. 3. Coagulopathy with elevated bilirubin and INR, and very low serum albumin. 4. She was also found, later during her hospital stay there, to have non-anion gap metabolic acidosis, with a normal serum creatinine of 0.6 to 0.8 mg/dl. 5. Positive serum cryptococcal antigen 1
Social History Never used drugs; former smoker. Married 23 years No extramarital relations reported Husband tested HIV negative One son, age 22 Donated blood on several occasions, and was never contacted by Red Cross Two former partners, with whom she had lost contact 12/18/12 Admission Physical Exam Temp 37C; Tmax 39C; P 89; BP 100/58; R 20; Pulse oximetry 97% on room air. General: Chronically ill appearing Pharynx clear; mildly icteric sclerae Chest clear Cardiac: Regular rate and rhythm, with SEM Abdomen: Hepatosplenomegaly Extremities: No edema Neuro: Cognitively slowed. Oriented x 3. Nonfocal. 2
Labs WBC 1300 with 40% segs and 40% lymphs Hgb 9.5 g/dl; Hct 27%; Plts 44K Na+ 131; K+ 3.8 Cl- 101; HCO3 14 BUN 5; Creatinine 0.8 mg/dl Alb 1.3 g/dl; Bilirubin 1.4 mg/dl; ALT 26 IU/L PT 15.6; PTT 53 seconds Hepatitis C Ab +; PCR + Urinalysis 4.o urobilinogen; no protein. ABG: 7.45/pCO2 19/ po2 75/ HCO3 13/ 94% RA CSF and Micro Results Opening pressure 27 cm; CP 17 cm; OP 1 wk later 18 Positive CSF CRAG 1:100 Gram stain negative 82 WBCs/hpf; 0 RBCs; 76% lymphs, 20% monos; 2% polys Glucose 37 mg/dl; Protein 81 mg/dl CSF culture positive for C. neoformans Blood culture positive for C. neoformans Bone marrow with yeast forms (from Columbia Memorial) 3
Hospital Course Received 2 weeks of liposomal Ampho B 5-FC not used due to pancytopenia Fluconazole used concomitantly 400 mg daily (initially given 800 mg daily) Creatinine peaked at 2.1 mg/dl Bilirubin slowly rose to 22 mg/dl Deeply jaundiced PT 18.6 seconds ALT 32 IU/L Creatinine 1.3 mg/dl HIV OI Treatment Guidelines The addition of flucytosine to amphotericin B during acute treatment is associated with more rapid sterilization of CSF (595,596). The combination of amphotericin B deoxycholate with fluconazole, 400 mg daily (BII), is inferior to amphotericin B combined with flucytosine for clearing Cryptococcus from CSF, but is more effective than amphotericin B alone (BII) (597). MMWR Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents April 2009. 4
Concomitant Meds Atovaquone for PJP prophylaxis Azithromycin for MAC prophylaxis started, and held after bilirubin started rising Valacyclovir for positive HSV PCR from tongue ulcer Esomeprazole for GI prophylaxis Darbepoetin for anemia of chronic disease Spironolactone 50 mg daily for cirrhosis, hypokalemia and edema Folate, potassium, magnesium and bicarbonate replaced HAART not yet started due to risk for IRIS, and now bilirubin problem Imaging Head CT negative CXR negative No obstruction by hepatic ultrasound Small, nodular liver with splenomegaly HIDA scan not helpful due to cirrhosis 5
Clinical Impact of New Data From Atlanta 2013: Coinfections and Comorbidities clinicaloptions.com/hiv COAT: Early vs Delayed ART in Tx-Naive Pts With Cryptococcal Meningitis Optimal timing of ART initiation after diagnosis of CM remains uncertain Early ART associated with increased mortality in recent trials in resource-limited settings [1,2] Earlier study showed improved outcomes with immediate vs delayed ART during acute OIs [3] COAT study compared 26-wk survival in tx-naive pts with first episode of CM who received early vs deferred ART initiation [4] ART-naive, HIV-infected pts with first episode of CM; study entry at 7-11 days after initiation of antifungal therapy (N = 177) Stratified by treatment site and mental status (altered vs not) Early ART Initiation ART started < 48 hrs after study entry, before hospital discharge (n = 88) Deferred ART Initiation ART started 4 wks after study entry, after hospital discharge (outpatient) (n = 89) 1. Makadzange AT, et al. Clin Infect Dis. 2010;50:1532-1538. 2. Bisson GP, et al. Clin Infect Dis. 2013; [Epub ahead of print]. 3. Zolopa A, et al. PLoS One. 2009;4:e5575. 4. Boulware D, et al. CROI 2013. Abstract 144. Clinical Impact of New Data From Atlanta 2013: Coinfections and Comorbidities clinicaloptions.com/hiv COAT: Increased Mortality With Early ART During CM Induction Therapy Significantly lower 6-mo OS with early vs deferred ART [1] Survival Probability Enrollment halted early by NIAID Africa DSMB 1.0 0.8 0.6 0.4 OS 70% 55% Deferred ART Early ART P =.03 0 1 2 4 6 8 10 12 Mos From Randomization Pts at Risk, n Mortality associated with Altered mental status at study entry (Glasgow Coma Scale score < 15; HR: 3.0; P =.05) Patients with CSF WBC counts < 5 cells/mm 3 at randomization (HR: 3.3; P =.01) In separate analysis of COAT data, reduced interferon gamma secretion associated with increased risk of IRIS or death [2] Multivariate analysis of death or CM-IRIS risk: OR per 2-fold increase 0.806 (95% CI: 0.684-0.958; P =.014) Deferred 89 71 65 60 60 58 57 Early 88 54 51 47 47 45 44 1. Boulware D, et al. CROI 2013. Abstract 144. 2. Weisner D, et al. CROI 2013. Abstract 861. Reproduced with permission. 6
Points to Remember 1) Consider Cryptococcus in the differential diagnosis of patients with CD4 < 200 cell/cmm, and FUO, failure to thrive, or headache 2) 5-Flucytosine plus Amphotericin B associated with more rapid CSF clearing, though not all patients will be able to tolerate it. 3) HAART should probably be delayed by 4 or more weeks after the diagnosis of Cryptococcal infection. Other References 595. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710 8. 596. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15 21. 597. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004;363:1764 7. 598. Larsen RA, Bozzette SA, Jones BE, et al. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994; 19:741 5. 7