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 discussed in this presentation.

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

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

aidsinfo.nih.gov

Updated 5/7/2013

Risk of Opportunistic Infection by CD4

“AIDS”, ↑ OI risk

Normal CD4 = 750-1500

Bacterial Pneumonia, HSV, Zoster, Diarrhea

Oral Candidiasis (Thrush), Molluscum Contagiosum, Dermatitis, Folliculitis

Cryptococcal Meningitis, Toxoplasmosis, Non-Hodgkin’s Lymphoma Pneumocystis jirovecii Pneumonia (PCP), Kaposi’s Sarcoma

Mycobacterium avium (MAC), CMV, Histoplasmosis, Coccidiomycosis, PML, Cryptosporidiosis, Primary CNS Lymphoma (EBV)

Mycobacterium tuberculosis (TB)

Risk of OI varies by Region

Holmes, CID, 2003 Putong, SEA Trop Med, 2002

Marques, Med Mycol, 2000 Amornkul, CID, 2003

Tuberculosis, KS, PCP, Salmonella, Malaria, Cryptococcosis, Histoplasmosis

Candida, PCP, MAC, CMV, Toxoplasmosis, Histoplasmosis

PCP, Candida, Tuberculosis, Cryptococcosis, Penicillinosis

PCP, Tuberculosis, Cryptococcosis, Crypto/Micro/Isosporidiasis, T. cruzi

PCP Candida, Cryptococcosis, Leishmaniasis

Crypto: everywhere

Endemic Mycoses

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

Case #1 (cont):

• What is the diagnosis? • Esophageal Candidiasis

• What is the treatment?

• Preferred: fluconazole x 14-21 d • Alternative: many other choices

• What else should be done today?

• Initiate Prophylaxis for Pneumocystis

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.

Oral/Esophageal Candidiasis

Oral Candidiasis, aka thrush

Esophageal Candidiasis

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 1QD

Higher relapse w/ echinocandins

Nystatin susp 5 mL QID (BII)

Miconazole QD (BII)

Esophageal Fluconazole 100-400 mg QD x 14-21 d (AI)

Echinocandin: Mica-, Caspo-, Anidulafungin (BI)

Suppressive therapy not recommended

Itraconazole 200 mg QD x 14-21 d (AI)

Azole: Vori-, Posaconazole (BI)

Amphotericin B (BI)

MMWR 2009; 58 (RR4): 1-132

Pnuemocystis jirovecii Pneumonia – Chest X-Ray

‘PCP’ Pneumonia (Pneumocystis jiroveci)

Sputum Silver Stain

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)

15-20 mg/kg/day divided Q8 hrs x 14-21 days • Steroids beneficial if PaO2 < 70%

Pneumocystis: New Diagnostics

» 13 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%

Sax P, et al Clinical Infectious Diseases 2011; Jul 15; 53:197

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

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/mm3 • 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

Cryptococcosis – Pathophysiology

Mandell’s Principles & Practice of Infectious Diseases, Sixth Ed. Chapter 261: 2997-3012

Cryptococcosis – Pulmonary Manifestations

Asymptomatic Carriage

Asymptomatic Carriage

Mandell’s Principles & Practiced of Infectious Diseases, Sixth Ed. Chapter 261: 2997-3012

Cryptococcosis – Dissemination

Cell-mediated immunity

Mandell’s Principles & Practice of Infectious Diseases, Sixth Ed. Chapter 261: 2997-3012

Cryptococcosis – Skin Manifestations

Cryptococcus – HIV epidemiology

•Most common serious fungal infection in HIV/AIDS, occurring in 6.1-8.5% of AIDS patients

•Highest risk patients with CD4 < 100 cells/mm3

•1992 – 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. 1994. CID. 19:1029-1033; Lortholary O et al AIDS 2006; 20:2183-91Park BJ et al AIDS 2009; 23:525-530

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

Crypto Meningitis – Clinical Presentation

www.hivwebstudy.org; Darras-Joly C et al CID 1996;23:369-76

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)

Crypto Meningitis – CSF Findings

Young NS and Brown KE N Engl J Med 2004; 350: 586-97

CSF Parameter Typical Findings Comment

Cell count Acute Leukocyte predominant; > 50% of patients will have < 20 cells

glucose Decreased protein 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

Crypto Meningitis – Induction therapy

Perfect JR CID 2010; 50:291-322 ; MMWR 2009; 58: RR-4

Anti-fungal Regimen Comments

Amphotericin B (0.7-1.0 mg/kg) + Flucytosine (100 mg/kg)

5FC: ↑ CSF sterilization, ↓ relapse Peak 5FC blood levels should be

monitored (< 75 ug/mL).

Lipid Amphotericin B (4-6 mg/kg) + Flucytosine (100 mg/kg)

Consider if patient has renal dysfunction or high likelihood of renal dysfunction

during therapy

Amphotericin B + Fluconazole 400 mg QD

If Flucytosine not tolerated

Amphotericin B If 5FC/Fluconazole not tolerated

Fluconazole 400-800 mg QD + Flucytosine 100 (mg/kg) If Amphotericin not tolerated

• 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: 1764-67

Crypto Meningitis – Subsequent therapy

Perfect JR CID 2010; 50:291-322 ; MMWR 2009; 58: RR-4

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)

• Transition from Induction Consolidation after > 2 weeks + clinical improvement + negative CSF cultures

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

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/mm3, 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

Sometimes diagnosed in blood or tissue

Giemsa blood smear

Skin biopsy: Silver stain

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

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

Histoplasma Distribution

Histoplasmosis - Treatment

Syndrome Preferred Alternative Comments

Severe Disseminated

Liposomal Ampho B 3 mg/kg x 14 d (AI)

Ampho B ABLC

Itraconazole 200 mg TID x 3d BID (AII)

Levels should be obtained (AIII)

Less Severe Disseminated

Itraconazole 200 mg TID x 3 d BID (AII) Duration > 12 mos

Meningitis Liposomal Ampho B 5 mg/kg x 4-6 wks

Itraconazole 200 mg BID/TID x > 1 year

Treat until CSF normalizes

Long-term suppression

Itraconazole 200 mg QD

Recommended for CNS disease or

any relapse

MMWR 2009; 58 (RR4): 1-132

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