Clinical Mycology Scott G. Filler, M.D. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

Invasive Fungal Infections in the USA Endemic Fungi Endemic Fungi Coccidioides Coccidioides Histoplasma capsulatum Histoplasma capsulatum Blastomyces dermatitidis Blastomyces dermatitidis

Invasive Fungal Infections in the USA Opportunistic fungi Opportunistic fungi Candida Candida Aspergillus Aspergillus Cryptococcus Cryptococcus Pneumocystis jirovecii Pneumocystis jirovecii Molds Molds

Superficial Diseases Caused by Candida Part of the normal flora of the oropharynx, GI and GU tract Part of the normal flora of the oropharynx, GI and GU tract Oropharyngeal candidiasis (thrush) Oropharyngeal candidiasis (thrush) Esophageal candidiasis Esophageal candidiasis Vulvovaginal candidiasis (yeast infection) Vulvovaginal candidiasis (yeast infection) Dermatitis (diaper rash) Dermatitis (diaper rash) Onychomycosis (nail infection) Onychomycosis (nail infection) ~80% of infections caused by Candida albicans ~80% of infections caused by Candida albicans

Diseases Caused by Candida: Oropharyngeal Candidiasis

Epithelial Cell Invasion during Oropharyngeal Candidiasis

Risk Factors for Oropharyngeal and Esophageal Candidiasis Antibiotics Antibiotics Diabetes mellitus Diabetes mellitus Corticosteroids Corticosteroids Dentures Dentures Dry mouth Dry mouth AIDS AIDS

Diseases Caused by Candida: Hematogenously Disseminated Candidiasis Bloodstream infection via translocation across gut or via indwelling vascular catheter Bloodstream infection via translocation across gut or via indwelling vascular catheter Organism carried by the bloodstream to all organs in the body Organism carried by the bloodstream to all organs in the body Microabscesses in almost all tissues Microabscesses in almost all tissues 25-50% mortality, even with treatment 25-50% mortality, even with treatment

Diseases Caused by Candida: Hematogenously Disseminated Candidiasis Nadir. NEJM 2005;353:e9

Diseases Caused by Candida: Hematogenously Disseminated Candidiasis

Distribution of Species Kao. Clin Infect Dis 1999;29:1164 Hajjeh. J Clin Micro 2004;42:1519

Colonization Broad spectrum antibiotics Prolonged ICU (hospital) stay Central line Intravenous feeding Major Risk Factors for Candidemia GI surgery (cardiac surgery) Neutropenia Burns Premature infants

Host Defense Mechanisms against Disseminated Candidiasis Neutrophils Neutrophils ?Lymphocytes? ?Lymphocytes? Type I immune response Type I immune response Normal bacterial flora Normal bacterial flora Anatomic barriers Anatomic barriers Antimicrobial peptides Antimicrobial peptides

Diagnosis of Disseminated Candidiasis Blood culture (insensitive) Blood culture (insensitive) Biopsy (rarely) Biopsy (rarely) Emperic therapy (common) Emperic therapy (common) Non-culture based diagnostic tests (still experimental) Non-culture based diagnostic tests (still experimental)

Treatment of Candidal Infections Azoles Azoles Inhibition of 14 α -demethylase Inhibition of 14 α -demethylase Eichinocandins Eichinocandins Inhibition of 1,3 β –glucan synthase Inhibition of 1,3 β –glucan synthase Polyenes Polyenes Bind to ergosterol Bind to ergosterol

Pathogenesis of Aspergillosis

Aspergillus fumigatus Spores are Ubiquitous Millner. Compost Sci Utilization 1994;2:6

The Type of Aspergillosis is Determined by the Extent of Host Inflammatory Response Host Inflammatory Response Tissue Damage Allergic bronchopulmonary aspergillosis AspergillomaInvasive pulmonary aspergillosis Disseminated aspergillosis

Allergic Bronchopulmonary Aspergillosis Usually pre-existing airway disease Usually pre-existing airway disease Aspergillus colonization Aspergillus colonization Allergic response (high Aspergillus IgE) Allergic response (high Aspergillus IgE) Pulmonary infiltrates with progressive airway damage Pulmonary infiltrates with progressive airway damage Treated with corticosteroids ± oral antifungal drugs Treated with corticosteroids ± oral antifungal drugs

Copyright ©Radiological Society of North America, 2001 Franquet, T. et al. Radiographics 2001;21: Allergic bronchopulmonary aspergillosis in a 43-year-old asthmatic man

Aspergilloma Fungus ball in a pre-existing cavity in the lung Fungus ball in a pre-existing cavity in the lung Usual symptom is hemoptysis Usual symptom is hemoptysis Treated with lung resection Treated with lung resection

Aspergilloma

Copyright ©Radiological Society of North America, 2000 Harisinghani, M. G. et al. Radiographics 2000;20: Cavitary tuberculosis associated with aspergilloma

Invasive Aspergillosis Invasive pulmonary aspergillosis Invasive pulmonary aspergillosis Progressive necrotizing pneumonia Progressive necrotizing pneumonia Disseminated aspergillosis Disseminated aspergillosis Infections in all organs Infections in all organs ~90% mortality ~90% mortality

Increasing Incidence of Invasive Aspergillosis in Hematopoietic Cell Transplant Patients Marr. Clin Infect Dis 2002;34:909 Allogenic Autologous

Survival after Invasive Aspergillosis is Improving, But Remains Poor Upton. Clin Infect Dis 2007;44:531 Crude Mortality Attributable Mortality

Microbiology fumigatus 56% Stem Cell TransplantsSolid Organ Transplants Morgan. Med Mycol 2005;43 suppl 1:S49

Risk Factors for Invasive Pulmonary Aspergillosis Transplantation Transplantation Hematopoietic Hematopoietic Solid organ Solid organ Pegues. Infect Control Hosp Epidemiol 2001;22:370 Patterson. Medicine 2000;79:250 Others Others Corticosteroids Corticosteroids HIV HIV Chemotherapy Chemotherapy Chronic pulmonary disease Chronic pulmonary disease Chronic granulomatous disease Chronic granulomatous disease TNF-inhibition TNF-inhibition

Interaction of A. fumigatus with Host Cells During Invasive Pulmonary Aspergillosis Filler. PLoS Pathog 2006;2:e129

Angioinvasion and Invasive Aspergillosis A characteristic feature of invasive aspergillosis is fungal invasion of the blood vessels A characteristic feature of invasive aspergillosis is fungal invasion of the blood vessels Angioinvasion results in: Angioinvasion results in: Intravascular thrombosis Intravascular thrombosis Tissue infarction Tissue infarction Reduced entry of leukocytes and antifungal drugs into areas of infection Reduced entry of leukocytes and antifungal drugs into areas of infection

Angioinvasion

Halo Sign

Diagnosis of Invasive Pulmonary Aspergillosis Culture (insensitive and not specific) Culture (insensitive and not specific) Biopsy Biopsy Antigen testing Antigen testing Galactomanan Galactomanan β -glucan β -glucan

Treatment of Invasive Aspergillus Voriconazole Voriconazole Alone Alone In combination with an eichinocandin or polyene In combination with an eichinocandin or polyene

Cryptococcus spp. Environmental sources of Cryptococcus neoformans Environmental sources of Cryptococcus neoformans Found in soil world-wide Found in soil world-wide Bird guano Bird guano Trees Trees Eucalyptus Eucalyptus Cedar Cedar Douglas fir Douglas fir

Pathogenesis of Cryptococcal Disease

Cryptococcal Diseases Meningitis Meningitis Most common Most common Pneumonia Pneumonia Less common Less common

C. neoformans varieties

Risk Factors for Cryptococcal Meningitis Weakened cell-mediated immunity Weakened cell-mediated immunity AIDS AIDS Organ transplantation Organ transplantation Hematologic malignancy Hematologic malignancy Corticosteroids Corticosteroids

Cryptococcal Meningitis

Symptoms of Cryptococcal Meningitis Persistent headache Persistent headache Fever Fever Altered mental status Altered mental status Gradual onset Gradual onset

Diagnosis of Cryptococcal Disease Cryptococcal antigen testing Cryptococcal antigen testing Culture Culture India ink India ink

Treatment of Cryptococcal Meningitis 100% fatal if untreated 100% fatal if untreated Polyene (ampotericin B) Polyene (ampotericin B) Followed by an azole (fluconazole) Followed by an azole (fluconazole) 10-20% mortality 10-20% mortality Some survivors with permanent neurological problems Some survivors with permanent neurological problems