Didactic Series. Fungal Infections: small bother to big mortality

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1 Didactic Series Fungal Infections: small bother to big mortality Christian B. Ramers, MD, MPH Family Health Centers of San Diego Ciaccio Memorial Clinic 8/8/13 ACCREDITATION STATEMENT: University of California, San Diego School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The University of California, San Diego School of Medicine designates this educational activity for a maximum of one credit per hour AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. Disclosure Statement: Speaker has no personal financial relationship with a commercial interest that produces, markets or distributes health care goods or services 1 discussed in this presentation.

2 Learning Objectives 1) Distinguish oral from esophageal candidiasis by clinical history 2) List four of the most common fungal OI s affecting HIV patients with low CD4+ cells 3) Review clinical, diagnostic, and treatment features of cryptococcal meningitis

3 aidsinfo.nih.gov Updated 5/7/2013

Risk of Opportunistic Infection by CD4 Normal CD4 = 750-1500 Mycobacterium tuberculosis (TB) Bacterial Pneumonia,

jirovecii Pneumonia (PCP), AIDS, Kaposi s OI Sarcoma risk Cryptococcal Meningitis, Toxoplasmosis, Non-Hodgkin s

4 Risk of Opportunistic Infection by CD4 Normal CD4 = Mycobacterium tuberculosis (TB) Bacterial Pneumonia, HSV, Zoster, Diarrhea Oral Candidiasis (Thrush), Molluscum Contagiosum, Dermatitis, Folliculitis Pneumocystis jirovecii Pneumonia (PCP), AIDS, Kaposi s OI Sarcoma risk Cryptococcal Meningitis, Toxoplasmosis, Non-Hodgkin s Lymphoma Mycobacterium avium (MAC), CMV, Histoplasmosis, Coccidiomycosis, PML, Cryptosporidiosis, Primary CNS Lymphoma (EBV)

Risk of OI varies by Region Candida, PCP, MAC, CMV, Toxoplasmosis, Histoplasmosis PCP Candida, Cryptococcosis, Leishmaniasis PCP, Candida, Tuberculosis, Cryptococcosis, Penicillinosis PCP,

5 Risk of OI varies by Region Candida, PCP, MAC, CMV, Toxoplasmosis, Histoplasmosis PCP Candida, Cryptococcosis, Leishmaniasis PCP, Candida, Tuberculosis, Cryptococcosis, Penicillinosis PCP, Tuberculosis, Cryptococcosis, Crypto/Micro/Isosp oridiasis, T. cruzi Tuberculosis, KS, PCP, Salmonella, Malaria, Cryptococcosis, Histoplasmosis Holmes, CID, 2003 Putong, SEA Trop Med, 2002 Marques, Med Mycol, 2000 Amornkul, CID, 2003

6 Endemic Mycoses Crypto: everywhere

7 Case #1: 17 yo female presents to clinic for first visit HIV diagnosed during last pregnancy but she has been poorly engaged in care. Took ART briefly as PMTCT, now off x 9 months Complains of white chalky discharge in mouth and painful swallowing x 3 weeks Has not been engaged in care PEX afebrile OP with thick white exudate No rash

8 Case #1 (cont): What is the diagnosis? Esophageal Candidiasis What is the treatment? Preferred: fluconazole x d Alternative: many other choices What else should be done today? Initiate Prophylaxis for Pneumocystis

highly effective Mostly a clinical diagnosis: odynophagia should treat for esophageal

9 Mucocutaneous Candidiasis Very common OI, but rarely invasive Routine primary prophylaxis not recommended, secondary prophylaxis can be considered Acute treatment is highly effective Mostly a clinical diagnosis: odynophagia should treat for esophageal disease x 21 days Indicates moderate immunosuppression, so should start PJP prophylaxis right away.

10 Oral/Esophageal Candidiasis Esophageal Candidiasis Oral Candidiasis, aka thrush

11 Candidiasis - Treatment Infection Preferred Alternative Comments Oral Fluconazole 100 mg QD (AI) x 7-14 d Itraconazole 200 mg QD (BI) Chronic Azoles may promote resistance Clotrimazole 10 mg troche 5X/day Posaconazole 400 PO BID x 1 QD Higher relapse w/ echinocandins Nystatin susp 5 ml QID (BII) Miconazole QD (BII) Esophageal Fluconazole mg QD x d (AI) Echinocandin: Mica-, Caspo-, Anidulafungin (BI) Suppressive therapy not recommended Itraconazole 200 mg QD x d (AI) Azole: Vori-, Posaconazole (BI) Amphotericin B (BI) MMWR 2009; 58 (RR4): 1-132

12 Pnuemocystis jirovecii Pneumonia Chest X-Ray Sputum Silver Stain PCP Pneumonia (Pneumocystis jiroveci)

Pneumocystis jiroveci Pneumonia Clinical Manifestations: Probably reactivation and inhalation 70-90% of patients have CD4 < 200 Pathophysiology: symptoms caused by inflammation which requires CD4

13 Pneumocystis jiroveci Pneumonia Clinical Manifestations: Probably reactivation and inhalation 70-90% of patients have CD4 < 200 Pathophysiology: symptoms caused by inflammation which requires CD4 cells Diagnosis: Clinical, Chest X-Ray, induced sputum for silver stain, O2 saturation Mortality: Patients may worsen after starting treatment Potential for hypoxic respiratory failure Treatment: Trimethoprim/Sulfamethoxazole (TMP/SMX) mg/kg/day divided Q8 hrs x days Steroids beneficial if PaO2 < 70%

Sax P, et al Clinical Infectious Diseases 2011; Jul 15; 53:197 Pneumocystis: New Diagnostics» 1 3 β D glucan a component of fungal cell wall» Data extracted from ACTG 5164: 282 pts with

14 Sax P, et al Clinical Infectious Diseases 2011; Jul 15; 53:197 Pneumocystis: New Diagnostics» 1 3 β D glucan a component of fungal cell wall» Data extracted from ACTG 5164: 282 pts with acute OI (69% PJP, 14% crypto, 9% bact PNA)» POSITIVE in 92% of pts with confirmed PCP, but also POSITIVE in 35% of those without PCP» Sensitivity 92%, Specificity 65%» PPV 85%, NPV 80%

15 Case #2 A 29 yo male with HIV presents with headache for 7 days. He was diagnosed with HIV this year and tells you he is on anti-retroviral therapy What is the most important historical detail? 1. Toxoplasma Serology 2. HAART Regimen (drugs) 3. HAART Regimen (timing) 4. Nadir (lowest) CD4 count 5. Most Recent CD4 count

16 Case #2 (cont) CD4 count is 58 cells/ 3, HIV VL 280,000 2 wks prior Started Truvada+Darunavir/Ritonavir 4 weeks prior Toxoplasma IgG negative, Initial CD4 35 cells/mm 3 Azithromycin (1200 mg QWk)TMP/SMS (i DS tab QD) What is the most likely diagnosis? 1. Immune Reconstitution Syndrome 2. Common side effect of HAART 3. Bacterial meningitis 4. Fungal meningitis 5. Cerebral Toxoplasmosis

17 Cryptococcosis Pathophysiology Mandell s Principles & Practice of Infectious Diseases, Sixth Ed. Chapter 261:

18 Asymptomatic Carriage Cryptococcosis Pulmonary Manifestations Asymptomatic Carriage Mandell s Principles & Practiced of Infectious Diseases, Sixth Ed. Chapter 261:

19 Cryptococcosis Dissemination Cell-mediated immunity Mandell s Principles & Practice of Infectious Diseases, Sixth Ed. Chapter 261:

20 Cryptococcosis Skin Manifestations

21 Cryptococcus HIV epidemiology Most common serious fungal infection in HIV/AIDS, occurring in % of AIDS patients Highest risk patients with CD4 < 100 cells/mm Peak US incidence 5 per 100,000/year Incidence in US has steadily declined, but 3-month mortality still 10-20% With Global HIV epidemic, burden increased, estimates of 15-45% of advanced HIV patients and 500,000 deaths/year in Sub-Saharan Africa Currie, B. P., and A. Casadevall CID. 19: ; Lortholary O et al AIDS 2006; 20: Park BJ et al AIDS 2009; 23:

Crypto Meningitis Clinical Presentation Subacute: weeks-months, often lacking classic meningeal signs (only 25-33%) Commonly fever, malaise, headache, confusion

22 Crypto Meningitis Clinical Presentation Subacute: weeks-months, often lacking classic meningeal signs (only 25-33%) Commonly fever, malaise, headache, confusion May be subtle personality change, memory loss Rarely preceding respiratory illness recognized Skin manifestations may be present at time of meningitis presentation

23 Crypto Meningitis Clinical Presentation Darras-Joly C et al CID 1996;23:369-76

24 Crypto Meningitis Diagnosis Serum CrAg is sensitive/specific, titer > 1:8 is presumptive evidence of cryptococcal infection CrAg precedes meningitis by median 22 days and in 11% detectable > 100 days before symptoms Most would perform head CT prior to LP in AIDS patients, even with no focal abnormalities Lumbar puncture with opening CSF pressure is essential (both diagnosis & mgmt)

25 Crypto Meningitis CSF Findings CSF Parameter Typical Findings Comment Cell count Acute Leukocyte predominant; > 50% of patients will have < 20 cells glucose protein Decreased Elevated Cryptococcal Ag High positive Positive in 95% of cases, titers may be > 1:2048 Fungal Culture Positive Essential to document response at 2 weeks Young NS and Brown KE N Engl J Med 2004; 350:

26 Crypto Meningitis Induction therapy Anti-fungal Regimen Amphotericin B ( mg/kg) + Flucytosine (100 mg/kg) Lipid Amphotericin B (4-6 mg/kg) + Flucytosine (100 mg/kg) Amphotericin B + Fluconazole 400 mg QD Amphotericin B Fluconazole mg QD + Flucytosine 100 (mg/kg) Comments 5FC: CSF sterilization, relapse Peak 5FC blood levels should be monitored (< 75 ug/ml). Consider if patient has renal dysfunction or high likelihood of renal dysfunction during therapy If Flucytosine not tolerated If 5FC/Fluconazole not tolerated If Amphotericin not tolerated Perfect JR CID 2010; 50: ; MMWR 2009; 58: RR-4

27 EFA early fungicidal activity: Ampho+5FC more fungicidal by 0.23 log CFU/day than Ampho alone (p = 0.001) Brouwer AE et al 2004 Lancet: 363:

28 Crypto Meningitis Subsequent therapy Transition from Induction Consolidation after > 2 weeks + clinical improvement + negative CSF cultures Phase Preferred Alternative Comments Consolidation (8 weeks) Fluconazole (400 mg QD) Itraconazole (200 mg BID) Maintenance Fluconazole (200 mg QD) Itraconazole (200 mg QD) lifelong or until immune reconstitution (CD4 > 200 x 6 months) Perfect JR CID 2010; 50: ; MMWR 2009; 58: RR-4

29 Cryptococcus: Take Home Points Classic presentation in HIV+ patient is sub-acute, listless, HA, confusion. May lack meningismus or even CSF pleiocytosis Treatment: Ampho+5FC fluconazole Induction (2 wks) Consolidation (8 wks) Maintenance (until CD4 > 200 x 6 months) Don t forget to address intracranial pressure

30 Case #3 A 38 yo Mexican-American male presents with fevers, chills, sweats, wt loss, diffuse abdominal pain for 3 weeks. Diagnosed with HIV 1 month prior, not on ART CD4 = 40 cells/mm 3, CBC with WBC 1.8, Hct 27, Plt 117 Which fungal infection is most likely? 1.Disseminated Candidiasis 2.Cryptococcosis 3.Histoplasmosis 4.Mycobacterium avium

31 Sometimes diagnosed in blood or tissue Skin biopsy: Silver stain Giemsa blood smear

Histoplasmosis Etiology: Histoplasma capsulatum Presentation: Acute: febrile

anemia, high LFT s, may have evidence of old disease on CXR Pathophysiology:

Direct visualization of fungus, culture, Serum or Urine Antigen test Mortality:

32 Histoplasmosis Etiology: Histoplasma capsulatum Presentation: Acute: febrile pulmonary infection Reactivation: fever, chills, wt loss, bone marrow failure, anemia, high LFT s, may have evidence of old disease on CXR Pathophysiology: Initially latent disease, with reactivation upon immunosuppresion Diagnosis: Direct visualization of fungus, culture, Serum or Urine Antigen test Mortality: low in immune competent; high in immunosuppressed. Risk Factors: dyspnea, plt < 100K, high LDH

33 Histoplasma Distribution Edwards LB; Am Rev Repir Dis. 1969; 99(4):Suppl: 1-132

34 Histoplasmosis - Treatment Syndrome Preferred Alternative Comments Severe Disseminated Less Severe Disseminated Meningitis Long-term suppression Liposomal Ampho B 3 mg/kg x 14 d (AI) Itraconazole 200 mg TID x 3d BID (AII) Itraconazole 200 mg TID x 3 d BID (AII) Liposomal Ampho B 5 mg/kg x 4-6 wks Itraconazole 200 mg BID/TID x > 1 year Itraconazole 200 mg QD Ampho B ABLC Levels should be obtained (AIII) Duration > 12 mos Treat until CSF normalizes Recommended for CNS disease or any relapse MMWR 2009; 58 (RR4): 1-132

35 Summary: Fungal Infections Oral/Esophageal Candidiasis is easy to manage with azoles or other antifungals, but indicates significant immunosuppression Cryptococcal meningitis should be suspected with indolent CNS symptoms and must be worked up with lumbar puncture with opening pressure Histoplasmosis is a serious systemic febrile disease usually seen in patients with CD4 < 100 cells/ml

Cryptococcosis of the Central Nervous System: Classical and Immune-Reconstitution Disease

Cryptococcosis of the Central Nervous System: Classical and Immune-Reconstitution Disease Assist Prof. Somnuek Sungkanuparph Division of Infectious Diseases Faculty of Medicine Ramathibodi Hospital Mahidol