Case. Fungal infections for the community provider. Case. Case. April 25, 2014 Peter V. Chin-Hong M.D. Infectious Diseases UCSF UCSF

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1 Case Fungal infections for the community provider April 25, 2014 Peter V. Chin-Hong M.D. Infectious Diseases UCSF UCSF A 38-year-old African-American female financial analyst is referred to you for asthma exacerbation. She reports shortness of breath with frequent expectoration of brownish plugs. Albuterol inhalers are only minimally helpful. She has had hemoptysis in the past. Temperature is 38.3 C. Chest with minimal wheezing. Her serum total IgE > 1000 ng/ml, she has a twofold elevation in specific anti- Aspergillus fumigatus IgE and IgG. Case Which of the following should you recommend? A. Albuterol nebulizers every six hours B. Prednisone taper over 3-6 months C. Voriconazole D. Itraconazole Case Which of the following should you recommend? A. Albuterol nebulizers every six hours B. Prednisone taper over 3-6 months C. Voriconazole D. Itraconazole 1

2 Allergic bronchopulmonary Aspergillosis (ABPA) Hypersensitivity reaction to noninvasive Aspergillus in the airways Repeated inflammation and mucoid impaction in airways can lead to bronchiectasis May affect up to 5% of asthma patients Mild bronchiectasis Allergic Bronchopulmonary Aspergillosis (ABPA). Rx: Steroids ± itraconazole Pulmonary Aspergilloma. Rx: Surgery ± itraconazole Invasive Aspergillosis. Rx: Voriconazole or posaconazole or caspofungin or amphotericin Case A You see a 32 year old woman with AML in your office with low grade fevers to 101, hemoptysis and increasing subcutaneous nodules 2

3 Case What would you do at this time? A. Admit B. Fine needle aspiration C. FNA and admit D. Voriconazole and return to clinic if worse She becomes acutely short of breath after receiving some blood products CXR HD#2 3

4 Aspergillus fumigatus SFGH mycology 10/00 Epidemiology Aspergillus: Risk Factors Diagnosis % Bone marrow transplant Autologous 7 Allogenic 25 Hematologic disease Leukemia/Lymphoma 29 Solid organ transplant 9 AIDS 8 Solid organ tumor 4 Chronic granulomatous disease 2 Other pulmonary disease 9 Epidemiology Aspergillus: Outcomes: Mortality Risk group Fatality rate (%) Bone marrow transplant (BMT) 87 Leukemia/Lymphoma 49 AIDS 86 Neutropenia (<500/mm 3 ) 51 CNS/disseminated 88 Pulmonary 59 Overall 58 Lin S, et al. Clin Infect Dis. 2001; 32: (Review of 1941 pts from 50 studies) 4

5 Medical Mycology: The Last 50 Years # of drugs L-AmB ABCD ABLC Terbinafine 5-FC Itraconazole Fluconazole Miconazole Ketoconazole Halo sign Treatment Voriconazole: Global Comparative Aspergillosis Study Voriconazole +/- OLAT Amphotericin B +/- OLAT Probability of Survival Survival at wk 12 VORI OLAT 70.8% AmB OLAT 57.9% Hazard ratio = 0.59 ( 95% CI ) Number of Days of Treatment Dismukes WE, Clin Infect Dis 2006; 42: Herbrecht et al. NEJM 2002: 347 OLAT: Other Licenced Antifungal Therapy 5

6 Question Which of the following is voriconazole not associated with? Voriconazole Cancer A. Seeing white flashes B. Seeing Star Wars characters C. Skin cancer D. Renal toxicity Arch Dermatol. 2010;146(3): J Am Acad Dermatol Jan;62(1):31-7 Voriconazole available Aspergillus Allergic Bronchopulmonary Aspergillosis (ABPA). Rx: Steroids ± itraconazole Pulmonary Aspergilloma. Rx: Surgery ± itraconazole Invasive Aspergillosis. Rx: Voriconazole or posaconazole or caspofungin or amphotericin Kontoyiannis et al, JID,

7 B Midwest, SE USA; Central and South America, Africa Lung (most common), dissemination to skin (like basal cell CA), bones Blastomycosis Itraconazole is drug of choice for blastomycosis Amphotericin B Prior to 1980s, amphotericin B was drug of choice. Cure rates up to 97% with 2g total dose. Significant toxicity. Azoles have replaced amphotericin B as therapy of choice Itraconazole cure rates 90-95%. Less toxic than ketoconazole and amphotericin. Few relapses. Dismukes WE et al, Am J Med 1992; 93: Ohio and Mississippi River Valleys; Central and South America; Bird and bat droppings Lung (most common), dissemination, hepatosplenomegaly, oral ulcers Histoplasmosis 7

8 Itraconazole is drug of choice for most with histoplasmosis Amphotericin B Prior to 1980s, amphotericin B was drug of choice. Cure rates up to % depending on disease. Significant toxicity. Azoles have replaced amphotericin B as therapy of choice Itraconazole cure rates 90-95%. Less toxic than ketoconazole and amphotericin. Few relapses. Dismukes WE et al, Am J Med 1992; 93: Mexico, south to Argentina Lungs, painful mouth ulcers, skin, can mimic TB Males >>> females Paracoccidiodomycosis 49 year-old gardener comes to see you in clinic with a progressive rash 1 week ago noticed a papule on the 4 th finger which ulcerated Now more nodular lesions have developed proximally Case Case After no help with multiple courses of antibiotics, what is your next step? A. More antibiotics B. Empiric antifungals C. Referral for biopsy D. Reassurance 8

9 Worldwide Contact with soil or decaying wood; gardening Begins as a hard nontender subcutaneous nodule then more nodules along lymphatics; can disseminate Sporotrichosis C Case 25 year-old Filipino- American runner comes to see you in clinic with fevers, cough, malaise for 4 weeks No help with azithromycin for a 5 day course, followed by levofloxacin Family lives in the Central Valley, California, and the patient visits often Southwest USA, Mexico, Central and South America Flu-like illness, lung, dissemination to CNS (meningitis), bone, skin Erythema nodosum in some Coccidioidomycosis 9

10 Dramatic increase in Valley Fever CDC looked at incidence of coccidioidomycosis from Incidence increased from 5 cases per 100,000 in 1998 in endemic area to 43 cases per 100,000 <1% have disseminated disease but >40% require hospitalization Fresno dust storm Coccidioidomycosis MMWR 2013 Cocci for 7 years with severe exacerbation in January Rx: amphotericin B 2.4 g orally per day. Fiese MJ. Proc Symp Cocci, Phoenix, Feb 11-13, 1957 & Cal Med 1957; 86: Pre-Rx post 3 mos RX 10

11 Itraconazole and Fluconazole are both effective for cocci Amphotericin B was drug of choice for 50 years with cure rates up to 70%. No clinical trials Use as initial treatment for severely ill C Itraconazole cure rates 63-75%. Preferred azole for skeletal disease. Galgiani JN et al, Ann Intern Med 2000; 133: Fluconazole cure rates 50-67%. Preferred azole for meningitis. Treat for life. Galgiani JN et al, Ann Intern Med 2000; 133: Worldwide Soil and dried pigeon dung Lung, dissemination in immunocompromised hosts (skin, CNS); most common cause of fungal meningitis Can be first AIDS-defining illness Cryptococcosis Use amphotericin plus flucytosine in AIDS patients with crypto Earlier studies showed lower dose of amphotericin (0.4mg/kg/day) plus 5-FC (150mg/kg/day) for 6 weeks cured 67% non-hiv Bennett JE et al, N Engl J Med 1979; 301: First AIDS studies (RCT) showed amphotericin (same dose) vs fluconazole monotherapy for 10 weeks only successful in 40% vs 34% (P=NS) Saag MS et al, N Engl J Med 1992; 326:

12 Use amphotericin plus flucytosine in AIDS patients with crypto Amphotericin (0.7mg/kg/day) plus 5-FC (100mg/kg/day) vs amphotericin X 2 weeks. CSF neg in 60% vs 51% (P=0.06). No difference in mortality (overall 5.5%). then Fluconazole (400mg/day) vs. itraconazole (400mg/day) X 8 weeks. Overall mortality 3.9%. No difference in CSF sterilization. Van der Horst et al, N Engl J Med 1997; 337:15-21 Other key crypto studies Maintain AIDS patients on fluconazole 200mg PO daily Relapse 4% (FLU) vs 23% (ITRA) Saag MS et al, Clin Infect Dis 1999; 28:291-6 Mortality associated with opening pressure >250mmHg 21% <250, 27% , 38% >350mmHg Graybill JR et al, Clin Infect Dis 2000; 30:47-54 Stop maintenance if CD4>100 on HAART (6 mo) Vibhagool A et al, Clin Infect Dis 2003; 36: Case 31 year old with AIDS CD4 157, VL<40 with headaches 12

13 Cryptococcus immune reconstitution inflammatory syndrome (IRIS) Can occur in up to 30% of patients with a history of cryptococcus after starting HAART Usually within 30 days after initiating HAART Can have higher CSF cryptococcal antigen titers and opening pressures Usually treated with amphotericin followed by fluconazole Treatment outcomes better in IRIS Shelburne SA et al, Clin Infect Dis 2005; 40:1049 Haddow LJ et al, Lancet ID 2010; 10:791 Cryptococcus gattii Clinical Infectious Diseases 2009;49: Compared to C. neoformans, C. gattii occurs in immunocompetent and has more brain lesions Case C A 43 year-old previously healthy woman sees you in clinic s/p discharge from the hospital for bowel perforation repair She was treated with broad-spectrum antibiotics for two weeks then discharged You note that the patient is febrile with T39, HR 130, BP 120/80 13

14 Question Which of the following organisms would you most be worried about as you prepare the ED accepting physician with the sign out? A. Candida albicans B. Candida non-albicans spp C. Citrobacter D. Coagulase negative Staphylococcus Epidemiology Candidemia Candida now the 4 th most common isolate recovered from blood cultures in the US Half of all Candida infections occur in surgical ICUs Transmission can occur from patient to patient and from health care worker to patient Significant shift in infection caused by nonalbicans spp of Candida Nosocomial Bloodstream Infections in 49 US Hospitals UCSF The SCOPE* Program ( ) No. of Crude Rank Pathogen Isolates % Mortality (%) 1 Coagulase-negative staphylococci Staphylococcus aureus Enterococci Candida species * Surveillance and Control of Pathogens of Epidemiologic Importance. Adapted with permission from Edmond et al. Clin Infect Dis. 1999;29: Azarbal F et al,

15 Epidemiology Candidemia: Risk Factors Use of antibiotics Indwelling catheters Hyperalimentation Cancer chemotherapy Immunosuppressive rx post-transplant ICU hospitalization Candiduria Colonization with Candidal spp Candida spectrum Oral Esophageal Vaginal, Balanitis Candidemia Other: Eye, Spleen, Liver, Endocarditis Not usually: Lungs, Urine Macular abscess with string of pearls inferiorly. Vose M et al. Postgrad Med J 2001;77: Copyright The Fellowship of Postgraduate Medicine. All rights reserved. 15

16 Candida Infection (non bloodstream) Treatment pearls Don t routinely prophylax (resistance may develop) For treatment, fluconazole 100mg po qd If no response, can use up to 800mg/day Alternatives: itraconazole po 200mg/day, voriconazole po 200mg/day, amphotericin IV 0.3 mg/kg/day, caspofungin 70mg IV X 1 then 50mg IV qd. D Bartlett J and Gallant JE. Medical Management of HIV Infection, 2006 ed. 16

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18 Dermatophyte pearls Scrape your patient s skin and add KOH to the slide Most dematophytes can be treated by topical antifungals or oral agents (terbinafine, fluconazole, itraconazole) except oral medication will be needed for tinea capitis and tinea versicolor Treatment is generally for 2-4 weeks (1 dose usually enough for tinea versicolor) 18

19 Patient with meningitis 19 days following epidural steroid injection at an ambulatory surgery center Lab calls you about this weird fungus What is this? Bonus case Question Which of the following has been in the news as the main organism associated with injection of epidural steroids? A. Aspergillus B. Exserohilum C. Rhizopus D. Candida Exserohilum meningitis, United States Multistate outbreak of fungal meningitis associated with three lots of preservativefree methylprednisolone acetate (80mg/ml) from the New England Compounding Center (NECC) that were recalled on September 26, The potentially contaminated injections were given starting May 21, CDC 10/23/13. Dermatiaceous (pigmented) mould Lives on grass and in soil Can cause disease in immunocompetent In vitro susceptibility to Amphotericin B, voriconazole, itraconazole, caspofungin CDC recommends voriconazole +/ lipsosomal Amphotericin B Exserohilum what? 19

20 Case Z Patient with DKA, renal failure, immunosuppressed Black necrotic lesions of nose with invasion Broad, branching, nonseptate hyphae Almost 100% mortality in immunosuppressed Rx: Surgery and Ampho Zygomycosis Fungus Mortality Risk group Fatality rate (%) Aspergillosis Non-Aspergillus hyalohyphomycetes 80 (Scedosporium spp, Fusarium spp) Zygomycosis 100 (Rhizopus, Mucor) Phaeohyphomycosis 20 Candida 29 Zygomycosis Hussain et al, CID 2003:37 Pappas, ICAAC

21 Voriconazole available ABCD and Z Kontoyiannis et al, JID, 2005 Take home points - Aspergillus Aspergillus can cause a spectrum of disease Think of ABPA in patient with wheezing and refractory disease Treatment of choice for ABPA is steroids Invasive Aspergillosis is a rare disease but is important to recognize patients at risk Voriconazole is the most effective agent for invasive disease Important complications seen with voriconazole Amphotericin will also work but limited by toxicity Key challenge in the future remains better diagnostic strategies Take home points Blasto and others Think of geography and epidemiology in your patients with strange pulmonary and skin findings: Blastomycosis: Histoplasmosis: Penicillium marneffei: Sporotrichosis: 21

22 Take home points - Cocci Take home points - Crypto Increasing in incidence so coming soon to a clinic near you Think of coccidioidomycosis in a person from an endemic area with a pneumonia that is not improving with antibiotics Disseminated disease to bones and CNS can occur Latinos, Asians particularly at risk for disseminated disease Low threshold to call your favorite ID consultant for help May be the most common AIDS defining illness in some parts of the world Use Amphotericin and 5- FC as first line therapy in patients with AIDS Watch out for cryptococcal IRIS, especially in patients with a history of cryptococcal meningitis put on ART Most cases of cryptococcal IRIS occur within 4 weeks after starting ART Take home points - Candida Infections due to Candida species are the most common fungal infections There is a broad range of infections possible from oral thrush to invasive candidiasis that may involve any organ Candidal spp are the 4 th most frequent cause of nosocomial bloodstream infections but comprise a disproportionate mortality (40%) Early recognition is key think of the risk factors of candidiasis There has been a recent trend of non-albicans spp Take home points Dermatophytes Scrape your patient s skin and add KOH to the slide Most dematophytes can be treated by topical antifungals or oral agents (terbinafine, fluconazole, itraconazole) except oral medication will be needed for tinea capitis and tinea versicolor Treatment is generally for 2-4 weeks (1 dose usually enough for tinea versicolor) 22

23 Take home points - Zygomycosis Invasive Zygomycosis is a rare but fatal disease and is increasing Voriconazole is not effective. Only amphotericin as backbone Traditional risk group: DKA, now BMT and other transplant patients Diagnosis is tough like all the invasive mycoses. Get a biopsy Key challenge in the future remains better diagnostic strategies 23