Case

A 38-year-old African-American female financial analyst is referred to you for asthma Fungal infections for the exacerbation. community provider She reports shortness of breath with frequent expectoration of brownish plugs. Albuterol inhalers are only minimally helpful. She has April 25, 2014 had hemoptysis in the past. Peter V. Chin-Hong M.D. Temperature is 38.3°C. Chest with minimal wheezing. Her serum total IgE > 1000 ng/ml, Infectious Diseases UCSF she has a twofold elevation in specific anti- [email protected] fumigatus IgE and IgG. UCSF

Case Case

Which of the following should you recommend? Which of the following should you recommend?

A. Albuterol nebulizers every six hours A. Albuterol nebulizers every six hours B. Prednisone taper over 3-6 months B. Prednisone taper over 3-6 months C. Voriconazole C. Voriconazole D. Itraconazole D. Itraconazole

1 Allergic bronchopulmonary (ABPA) Hypersensitivity reaction Allergic Bronchopulmonary to noninvasive Aspergillus Aspergillosis (ABPA). • Rx: Steroids ± in the airways itraconazole Repeated inflammation Pulmonary . and mucoid impaction in • Rx: Surgery ± airways can lead to itraconazole bronchiectasis Invasive Aspergillosis. May affect up to 5% of • Rx: Voriconazole or asthma patients posaconazole or Mild bronchiectasis caspofungin or amphotericin

Case

You see a 32 year old woman with AML in your office with low A grade fevers to 101, hemoptysis and increasing subcutaneous nodules

2 Case CXR HD#2

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

3 Aspergillus SFGHfumigatus mycology 10/00

Epidemiology Epidemiology Aspergillus: Risk Factors Aspergillus: Outcomes: Mortality Diagnosis % Risk group Fatality rate (%) Bone marrow transplant Autologous 7 Bone marrow transplant (BMT) 87 Allogenic 25 Leukemia/Lymphoma 49 Hematologic disease AIDS 86 Leukemia/Lymphoma 29 Neutropenia (<500/mm3)51 Solid organ transplant 9 CNS/disseminated 88 AIDS 8 Pulmonary 59 Solid organ tumor 4 Overall 58 Chronic granulomatous disease 2 Other pulmonary disease 9 Lin S, et al. Clin Infect Dis. 2001; 32:358-366. (Review of 1941 pts from 50 studies)

4 Medical Mycology: The Last 50 Years

# of drugs L-AmB ABCD ABLC Terbinafine Itraconazole Fluconazole Ketoconazole Miconazole 5-FC

“Halo sign”

Treatment Voriconazole: Global Comparative Aspergillosis Study Voriconazole +/- OLAT Amphotericin B +/- OLAT

Survival at wk 12 VORI  OLAT 70.8% AmB  OLAT 57.9%

Hazard ratio = 0.59 ( 95% CI 0.42-0.88) Probability of Survival Probability of

Number of Days of Treatment

Dismukes WE, Clin Infect Dis 2006; 42:1289-96 Herbrecht et al. NEJM 2002: 347 OLAT: Other Licenced Antifungal Therapy

5 Question Voriconazole Cancer Which of the following is voriconazole not associated with?

A. Seeing white flashes B. Seeing Star Wars characters C. Skin cancer D. Renal toxicity

Arch Dermatol. 2010;146(3):300-304 J Am Acad Dermatol. 2010 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, 2005

6 Midwest, SE USA; Central and South B America, Africa Lung (most common), dissemination to skin (like basal cell CA), bones

Itraconazole is drug of choice for blastomycosis • Amphotericin B Ohio and Mississippi • Prior to 1980s, amphotericin B was drug of River Valleys; Central choice. Cure rates up to 97% with 2g total and South America; dose. Significant toxicity. Bird and bat droppings • Azoles have replaced amphotericin B as Lung (most common), therapy of choice dissemination, • Itraconazole cure rates 90-95%. Less toxic hepatosplenomegaly, than ketoconazole and amphotericin. Few oral ulcers… relapses. Dismukes WE et al, Am J Med 1992; 93:489-97

7 Itraconazole is drug of choice for most with histoplasmosis • Amphotericin B Mexico, south to • Prior to 1980s, amphotericin B was drug of Argentina choice. Cure rates up to 57-100% depending on disease. Significant toxicity. Lungs, painful mouth ulcers, skin, can mimic • Azoles have replaced amphotericin B as TB therapy of choice Males >>> females • Itraconazole cure rates 90-95%. Less toxic Paracoccidiodomycosis than ketoconazole and amphotericin. Few relapses. Dismukes WE et al, Am J Med 1992; 93:489-97

Case Case

49 year-old gardener After no help with multiple courses of antibiotics, comes to see you in clinic what is your next step? with a progressive rash 1 week ago noticed a A. More antibiotics papule on the 4th finger B. Empiric antifungals which ulcerated C. Referral for biopsy Now more nodular lesions D. Reassurance have developed proximally

8 Worldwide Contact with soil or decaying wood; C gardening Begins as a hard nontender subcutaneous nodule then more nodules along lymphatics; can disseminate

Case

25 year-old Filipino- Southwest USA, American runner comes to Mexico, Central and see you in clinic with South America fevers, cough, malaise for 4 weeks Flu-like illness, lung, No help with azithromycin dissemination to CNS for a 5 day course, (), bone, followed by levofloxacin skin Family lives in the Central Erythema nodosum in Valley, California, and the some patient visits often

9 Dramatic increase in Valley Coccidioidomycosis Fever 1998-2011 CDC looked at incidence of coccidioidomycosis from 1998-2011 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 Fresno dust storm hospitalization

MMWR 2013

Cocci for 7 years with severe exacerbation in January 1956.

Rx: amphotericin B 2.4 g orally per day.

Fiese MJ. Proc Symp Cocci, Phoenix, Feb 11-13, 1957 & Cal Med 1957; 86:119-20. Pre-Rx post 3 mos RX

10 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 C • Use as initial treatment for severely ill

• Itraconazole cure rates 63-75%. Preferred azole for skeletal disease. Galgiani JN et al, Ann Intern Med 2000; 133:676-86 • Fluconazole cure rates 50-67%. Preferred azole for meningitis. Treat for life. Galgiani JN et al, Ann Intern Med 2000; 133:676-86

Use amphotericin plus flucytosine in AIDS patients with crypto Worldwide • Earlier studies showed lower dose of Soil and dried pigeon amphotericin (0.4mg/kg/day) plus 5-FC dung Lung, dissemination in (150mg/kg/day) for 6 weeks cured 67% immunocompromised non-HIV hosts (skin, CNS); most Bennett JE et al, N Engl J Med 1979; 301:126-31 common cause of fungal meningitis… • First AIDS studies (RCT) showed Can be first AIDS-defining amphotericin (same dose) vs illness fluconazole monotherapy for 10 weeks only successful in 40% vs 34% (P=NS) Saag MS et al, N Engl J Med 1992; 326:83-9

11 Use amphotericin plus flucytosine Other key crypto studies in AIDS patients with crypto • Maintain AIDS patients on fluconazole • Amphotericin (0.7mg/kg/day) plus 5-FC 200mg PO daily (100mg/kg/day) vs amphotericin X 2 • Relapse 4% (FLU) vs 23% (ITRA) weeks. CSF neg in 60% vs 51% (P=0.06). Saag MS et al, Clin Infect Dis 1999; 28:291-6 No difference in mortality (overall 5.5%). then • Mortality associated with opening pressure >250mmHg • Fluconazole (400mg/day) vs. itraconazole • 21% <250, 27% 250-349, 38% >350mmHg (400mg/day) X 8 weeks. Overall mortality Graybill JR et al, Clin Infect Dis 2000; 30:47-54 3.9%. No difference in CSF sterilization. Van der Horst et al, N Engl J Med 1997; 337:15-21 • Stop maintenance if CD4>100 on HAART (6 mo) Vibhagool A et al, Clin Infect Dis 2003; 36:1329-31

Case 31 year old with AIDS CD4 157, VL<40 with headaches

12 Cryptococcus immune reconstitution Cryptococcus gattii

inflammatory syndrome (IRIS) Compared to C. neoformans, C. gattii • Can occur in up to 30% of patients with a occurs in history of cryptococcus after starting HAART immunocompetent and • Usually within 30 days after initiating HAART has more brain lesions • 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 Clinical Infectious Diseases 2009;49:591–595

Case

A 43 year-old previously healthy woman sees you in clinic s/p discharge from the hospital for C 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 Question Epidemiology Candidemia Which of the following organisms would you most • Candida now the 4th most common isolate be worried about as you prepare the ED accepting physician with the sign out? recovered from blood cultures in the US • Half of all Candida infections occur in surgical A. ICUs B. Candida non-albicans spp • Transmission can occur from patient to C. Citrobacter patient and from health care worker to patient D. Coagulase negative Staphylococcus • Significant shift in infection caused by non- albicans spp of Candida

Nosocomial Bloodstream UCSF Infections in 49 US Hospitals

The SCOPE* Program (1995-1998) No. of Crude Rank Pathogen Isolates % Mortality (%)

1 Coagulase-negative staphylococci 3908 31.9 21 2 Staphylococcus aureus 1928 15.7 25 3 Enterococci 1354 11.1 32 4 Candida species 934 7.6 40

* Surveillance and Control of Pathogens of Epidemiologic Importance. Adapted with permission from Edmond et al. Clin Infect Dis. 1999;29:239-244. Azarbal F et al, 2011

14 Epidemiology Candida spectrum Candidemia: Risk Factors Use of antibiotics •Oral Indwelling catheters • Esophageal Hyperalimentation • Vaginal, Balanitis Cancer chemotherapy Immunosuppressive rx post-transplant • Candidemia ICU hospitalization • Other: Eye, Spleen, Liver, Endocarditis Candiduria • Not usually: Lungs, Urine Colonization with Candidal spp

Macular abscess with “string of pearls” inferiorly.

Vose M et al. Postgrad Med J 2001;77:119-120

Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

15 Candida Infection (non bloodstream) Treatment pearls

•Don’t routinely prophylax (resistance may develop) D • 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.

Bartlett J and Gallant JE. Medical Management of HIV Infection, 2006 ed.

16 17 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 and • Treatment is generally for 2-4 weeks (1 dose usually enough for tinea versicolor)

18 Bonus case Question

Patient with meningitis Which of the following has been in the news as the main organism associated with injection of 19 days following epidural steroids? epidural steroid injection at an A. Aspergillus ambulatory surgery B. Exserohilum center C. Rhizopus Lab calls you about D. Candida this weird fungus What is this?

Exserohilum meningitis, United States Exserohilum what?

• 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 Multistate outbreak of fungal meningitis associated with three lots of preservative‐ Amphotericin B free methylprednisolone acetate (80mg/ml) from the New England Compounding Center (NECC) that were recalled on September 26, 2012. The potentially contaminated injections were given starting May 21, 2012. CDC 10/23/13.

19 Case

•Patient with DKA, renal failure, immunosuppressed Z •Black necrotic lesions of nose with invasion •Broad, branching, non- septate hyphae •Almost 100% mortality in immunosuppressed •Rx: Surgery and Ampho •

Fungus Mortality

Risk group Fatality rate (%) Aspergillosis 45-54 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 2003

20 Voriconazole available

ABCD and Z

Kontoyiannis et al, JID, 2005

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

21 Take home points - Cocci Take home points - Crypto

•Increasing in incidence – •Latinos, Asians •May be the most common •Watch out for so coming soon to a clinic particularly at risk for AIDS defining illness in cryptococcal IRIS, near you disseminated disease some parts of the world especially in patients with a history of cryptococcal •Think of •Low threshold to call your •Use Amphotericin and 5- meningitis put on ART coccidioidomycosis in a favorite ID consultant for FC as first line therapy in person from an endemic help patients with AIDS •Most cases of area with a pneumonia cryptococcal IRIS occur that is not improving with within 4 weeks after antibiotics starting ART •Disseminated disease to bones and CNS can occur

Take home points – Take home points - Candida •Infections due to Candida •Candidal spp are the 4th • Scrape your patient’s skin and add KOH to species are the most most frequent cause of the slide common fungal infections nosocomial bloodstream infections but comprise a • Most dematophytes can be treated by topical •There is a broad range of disproportionate mortality antifungals or oral agents (terbinafine, infections possible from (40%) oral thrush to invasive fluconazole, itraconazole) that may •Early recognition is key – • except oral medication will be needed for involve any organ think of the risk factors of candidiasis tinea capitis and tinea versicolor • Treatment is generally for 2-4 weeks (1 dose •There has been a recent trend of non-albicans spp usually enough for tinea versicolor)

22 Take home points - Zygomycosis •Invasive Zygomycosis is •Voriconazole is not a rare but fatal disease effective. Only and is increasing amphotericin as backbone

•Traditional risk group: DKA, now BMT and other •Key challenge in the transplant patients future remains better diagnostic strategies •Diagnosis is tough like all the invasive mycoses. Get a biopsy

23