Liise-anne Pirofski, M.D. Albert Einstein College of Medicine Fungal update http://clicks.robertgenn.com/miss-potter.php http://letterfromhere.blogspot.com/2007/06/beatrix-potters-jog-trot-through.html
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Patient 1: Pregnant woman in the intensive care unit on antibacterial therapy for 10 days http://www.moffitt.org/moffittapps/ccj/v3n5/dept6.html NB: Not actual patient
What is the treatment of choice? A. Echinocandin B. Fluconazole C. Amphotericin B formulation
SUMMARY: IDSA guidelines on treatment of candidemia and candidiasis * Candidemia Suspected candidiasis CNS disease Endopthalmitis Neutropenic Non-neutropenic All patients Caveat/s Echinocandin or LAmB LAmB, caspofungin or voriconazole Fluconazole 800, then 400 or echinocandin Fluconazole 800, then 400 or echinocandin LAmB +/- 5FC then fluconazole 400-800 AmB + 5FC; fluconazole 400-800; surgery Endocarditis LAmB 3-5 mg/kg +/- 5FC; Am-b +/- 5FC; echinocandin Oropharyngeal Fluconazole 100-200 Esophageal Fluconazole 200-400; echinocandin; AmB Prophylaxis Fluconazole 400; posaconazole Liver tx: fluconazole 200-400 or LAmB x 7-14d post surgery Remove catheter C. parapsilosis fluconazole Pregnancy: AmB AmB- renal toxicity 50% Evidence-based recommendations adapted from:
Candida drug susceptibility Fluconazole Itraconazole Voriconazole Posaconazole Flucytosine (5FC) Amphotericin B (AmB) C. albicans S S S S S S S C. tropicalis S S S S S S S Candins C. parapsilosis S S S S S S S to R C. glabrata S (DD) to R S (DD) to R S (DD) to R S (DD) to R S S to I S C. krusei R S (DD) to R S (DD) to R S (DD) to R I to R S to I S C. lusitaniae S S S S S S to R S I intermediately susceptible; R resistant; S susceptible; S-DD susceptible dose-dependent Redrawn from:
Considerations in treating Candida Candidemia Look for a source Restore barrier Remove catheter/s Treat early Treatment choice Severity of illness» Severe versus less severe» Neutopenic versus not neutropenic Candida species» C. parapsilosis - use fluconazole» C. glabrata use an echinocandin» Unknown use an echinocandin Challenge Early diagnostic tools lacking Caveat Pseudohyphae - 37 o C www.mycology.adelaide.edu.au/fungal_descriptions/yeasts/candida/ Disease reflects a disruption in the normal host-microbe relationship
Candida infection and disease Invasive candidiasis Disseminated candidiasis Hepatosplenic candidiasis Oro-pharyngeal candidiasis Surgery; Radiation Catheters; Antibiotics Immune impairment Vaginitis Mucocutaneous candidiasis Asymptomatic Colonization Disease WEAK Loss of barrier Immunodeficiency Immune response STRONG Excess inflammation Inappropriate response
Patient 2: HIV-infected patient, recently begun on ART Provided by Peter Pappas, UAB
Patient 3: Patient on steroids with acute onset of fever, cough, headache Can J Infect Dis Med Microbiol. 2009 Spring; 20(1): 23 28. NB: Not actual patient
Which fungus is responsible? A. B. XX C. XX
Cryptococcosis HIV Non-HIV IRIS C. neoformans Risk: profound CD4 deficiency (<50) Clinical features: presentation can be indolent; CSF can lack inflammatory features C. gattii Risk: increased (HIV) in recent study (Cao, Emerg Infect Dis (2011)) Risk: SOT*, steroids; XHIM Clinical features: high CSF OP, protein, CSF cell count (Chau BMC Infect Dis (2010)) Risk: Oral steroids; smoking; invasive cancer; lung disease (Cao, Emerg Infect Dis (2011)) Clinical features: fever, cough, headache ART-associated: no previous CN; apparent worsening HIV; evidence of CN (pulmonary; CNS; skin) Unmasking (paradoxical): previous CN; inflammatory manifestations (painful adenopathy; >50 cells CSF; expanding CNS or pulmonary lesions) (Haddow, Lancet Infect Dis (2010)) Provided by Peter Pappas, UAB * Early post-transplant disease unrecognized disease or donor-related infection (Sun, CID, 2020))
Cryptococcus: treatment HIV-infected Non-HIVinfected SOT IRIS Pregnancy CNS AmB + 5FC x 2 weeks (can use LAmB or ABLC), then Fluconazole 400 for 8 weeks, then 200 (until CD4>100 and undetectable VL for 3 mos) Start ART 2-10 weeks Consider immune modulators: Interferon (Pappas, JID (2004); Armstrong-James, Am J Transplant (2010)) AmB + 5FC x 4 weeks, then Fluconazole 200 for 6-12 months LAmB (or ABLC) + 5FC x 2 weeks, then Fluconazole 400-800 x 8 weeks, then 200-400 for 6-12 months Same as CNS; consider steroids for increased ICP, CNS inflammation AmB or LFAmB +/- 5FC (Category C); fluconazole after delivery Non- CNS Dissemination - like CNS No dissemination Fluconazole 400 (6-12 mos Fluconazole 400 (6-12 mos); consider steroids Same as CNS; consider steroids for increased ICP, CNS inflammation
Cryptococcus SOT-associated disease HIV-associated disease IRIS Asthma C. gattii C. neoformans normal patient Asymptomatic Latency Disease WEAK Immunodeficiency Immune response STRONG Reconstitution
Patient 4: Patient with rheumatoid arthritis on TNF inhibitor with fever and confusion NB: Not actual patient
Where did the patient visit? A. XXX B. XXXX C. XXX
Histoplasma Endemic, dimorphic fungus Yeast in tissue; mould in environment Temperate zones Ohio & Mississippi River valleys Species H. capsulatum var capsulatum (U.S.) H. capsulatum var duboisii (Africa) Disease syndromes Pneumonia Acute (often resolves without therapy) Chronic Disseminated disease Blood smear http://www.photomacrography.net/forum/viewtopi c.php?p=61749&sid=221a774c2bdfa7ba5ef8798ffc6 aa857 http://en.wikipedia.org/wiki/histoplasmosis Risk factors Being in endemic area Caves Chicken coops Immune impairment HIV/AIDS TNF inhibitors
Histoplasma Diagnosis Culture Bone marrow Serology Skin testing (epidemiology) Treatment Discontinue immunomodulator Amphotericin B Itraconazole BAL Bone marrow aspirate Peripheral blood smear Images provided by Peter Pappas, UAB
Patient 5: Patient 10 months after liver transplant with flu-like illness after travel to Los Cabos CDC/Dr. Lucille K. Georg http://radiology.casereports.net/index.php/rcr/article/viewarticle/237/552 NB: Not actual patient
What is this? KOH sputum Liver biopsy
Coccidioides Endemic, dimorphic fungus Potential agent of bioterror: Category C Disease syndromes Pulmonary Pneumonia (often self-limited) Cavitary Fever, arthralgia (Valley Fever) Disseminated Bone, skin CNS Pneumonitis Diagnosis Histopathology Culture Serology Treatment Amphotericin B Azoles Risk factors Being in endemic area HIV/AIDS Transplant Species C. immitis: California C. posadasii: Arizona, Texas, South America, Northern Mexico http://commons.wikimedia.org/wiki/file:ge ographic_distribution_of_coccidioidomycosi s_02.png http://www.saber.ula.ve/tropical/contenido/ca pitulo20/capitulo70/contenidocapitulo-en.html
Patient 6: HIV-infected child with skin lesions NB: Not actual patient
Which is the most likely vector? A. XXXX B. XXXX C. XXXX
Penicillium Dimorphic fungus Yeast in tissue, mould in environment Southeast Asia Bamboo rat Disease syndromes Pulmonary Cutaneous Disseminated Diagnosis Histopathology Culture Treatment Amphotericin B Itraconazole (caveat: IRIS after ARV) Risk factors for disease Being in endemic area HIV/AIDS Species Penicilllium marneffei http://www.ajtmh.org/cgi/content/full/7 8/1/11
Dimorphic fungi Disseminated disease HIV-associated disease Pulmonary disease Cutaneous manifestations Asymptomatic Latency Disease WEAK Reactivation latency STRONG Immunological response Immune response
Patient 7: Patient with stem cell transplant and pneumonia http://www.mevis-research.de/~hhj/lunge/xsammlunginf2fr.html http://www.surgeryreview.com/samples.html NB: Not actual patient
Aspergillus Environmental mould Ubiquitous (everywhere) Decaying matter Nosocomial sites Disease syndromes Allergic Aspergilloma Invasive sinus Invasive pulmonary Species A. fumigatus (85-90%) A. nidulans (5-10%) A. niger, A. terreus, A. nidulans (< 5%) Diagnosis Imaging Histopathology Antigen detection -glucan, galactomannan Most useful in following HSCT recipients Need better early detection Risk factors Neutropenia Neutrophil defects (CGD) Corticosteroids Organ transplantation Bone marrow Lung > liver HIV/AIDS Marta Feldmesser, Einstein, Infect Immun 73 (2005): cover art http://www.cytology-asc.com/cec/respiratory/resp83.html
Aspergillus: treatment Treatment Restore immune status IDSA guidelines - http://www.idsociety.org/organism/#fungi Antifungal therapy Voriconazole Amphotericin B Echinocandins Considerations and caveats When invasive disease is suspected, therapy should be initiated while diagnostic evaluation is undertaken Treat for a long time Prophylaxis recommended in high risk patients Future directions Earlier diagnosis advancing, but not there yet Prognosis is improving Adjunctive immunotherapy with interferon- is a consideration (IDSA guidelines)
Aspergillus pathogenesis Invasive sinus disease Invasive pulmonary CNS aspergillosis Sinusitis Allergic alveolitis Cutaneous manifestations Allergic bronchopulmonary aspergillosis Asymptomatic Colonization Disease WEAK Hyphae Tissue damage from microbe STRONG Immune response Tissue damage from inflammation Immune response
Patient 8: Diabetic patient with sinusitis http://radiographics.rsna.org/content/27/5/1283/f15.expansion http://www.accessmedicine.net/search/searchamresultim g.aspx?searchstr=maxillary+sinusitis&searchtype=2&fullte xtstr=maxillary+sinusitis&resourceid=505&narrowing=yes NB: Not actual patient
The same fungus might be identified in which patient? A. A clean-up crew member working in the San Fernando Valley after the earthquake B. A clean-up crew member working in Joplin, Missouri after the tornado C. A tree cutter working in the Pacific Northwest D. A construction worker in Arizona
Zygomycetes Environmental moulds Soil, decaying matter, debris Inhaled Ingested trauma Disease syndromes Cutaneous Pulmonary Gastric Rhinocerebral Disseminated Diagnosis Clinical suspicion Histopathology Culture Treatment http://ats.ctsnetjournals.org/cgi/content/full /78/4/1449 Amphotericin B, debridement Posaconazole under investigation Risk factors for disease Neutropenia (ANC < 1000) Corticosteroids Organ transplantation Desferoxamine therapy Ketoacidosis Trauma Malnutrition Prognosis Dismal Species Mucoraceae Mucor Rhizopus Cuninghamellaceae Cunninghamella
Another important mould Mould Fusarium spp. Ubiquitous, decaying soil Risk for disease Immune impairment Contact lens paraphernalia Disease Keratitis (2006 outbreak) Pulmonary Disseminated» Skin lesions Diagnosis Blood cultures (30-50%) Treatment Voriconazole http://dermatology.cdlib.org/1510/case_reports/fusari um/eisen.html
Summary 1: Basic groups of fungi Yeasts Ubiquitous Cryptococcus Candida Dimorphic Histoplasma Cocciodiodes Blastomycetes (Penicillium) Moulds Aspergillus Zygomycetes Mucor Rhizopus Fusarium
Summary 2: Fungal acquisition Environment (nearly all) Epidemiology reflects environmental distribution Important exceptions Organ-related transplant-associated disease Reactivation of (long) latent state Person to person (an exception) Candida albicans
Summary 3: Fungal disease Infection is common Disease is rare Epidemics can follow natural disasters Earthquakes Tsunamis Tornados Hurricanes Most often occurs in those with: Intravenous catheters (impaired barrier immunity) Broad-spectrum antibiotics Intensive care units Cytotoxic chemotherapy HIV/AIDS Bottom line Most with disease have impaired immunity
Summary 4: Antifungal therapy Restore barrier Reverse immunosuppression Treat for a (very) long time New directions Combination therapy Immune-based therapy Polyenes act on membrane Amphotericin B Echinocandins act on cell wall Pneumocandins Azoles act on membrane Flucytosine acts on nucleus (DNA & RNA)
IDSA guidelines for fungi http://www.idsociety.org/organism/#fungi
Additional slides of fungi to know for the boards
Another dimorphic mycosis (1) Sporothrix shenkii Ubiquitous Disease Occupational Gardening Lymphocutaneous Osteoarticular Treatment Local iodide Systemic Amphoterin B itraconazole http://missinglink.ucsf.edu/lm/ids_105_skinilm/sporotrichosis.htm http://en.academic.ru/dic.nsf/enwiki/4768647
Another dimorphic fungus (2) Blastomyces dermatitidis Endemic, dimorphic fungus Risk factors Being in endemic region Contact with soil, debris Disease syndromes Dogs; humans Pulmonary Disseminated Cutaneous (skin lesions) Treatment Amphotericin B (severe, disseminated disease) Itraconazole http://www.dog-health-guide.org/dogskinsores.html Image provided by Peter Pappas, UAB
Something else to think about
The future: Immunotherapy for fungal disease INCREASE Immune stimulation Control fungal burden Immune stimulation Interferon- Antibody therapies Vaccines Immune suppression Inhibitors of Th1 & Th17 Antibody therapies Steroids DECREASE Immune stimulation Fungal burden controlled WEAK RESPONSE Candidemia Cryptococcosis (non-iris) Aspergillosis (non-allergic) Histoplasmosis (disseminated) Pneumocystis Moulds STRONG RESPONSE Candida vaginitis IRIS-associated cryptococcosis Allergic aspergillosis Histoplasmosis Pneumocystis (after treatment) Cutaneous mycoses