1 Fungal infections for the community provider April 25, 2014 Peter V. Chin-Hong M.D. Infectious Diseases UCSF [email protected]UC SF Case 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
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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 hoursB. Prednisone taper over 3-6 monthsC. Voriconazole D. Itraconazole
Case
Which of the following should you recommend?
A. Albuterol nebulizers every six hoursB. Prednisone taper over 3-6 monthsC. Voriconazole D. Itraconazole
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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
A
CaseYou see a 32 year
old woman with AML in your office with low grade fevers to 101, hemoptysis and increasing subcutaneous nodules
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Case
What would you do at this time?
A. AdmitB. Fine needle aspirationC. FNA and admitD. Voriconazole and return to clinic if worse
CXR HD#2
She becomes acutely short of breath after receiving some blood products
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SFGH mycology 10/00Aspergillus fumigatus
EpidemiologyAspergillus: Risk Factors
Diagnosis %Bone marrow transplant
Autologous 7Allogenic 25
Hematologic diseaseLeukemia/Lymphoma 29
Solid organ transplant 9AIDS 8Solid organ tumor 4Chronic granulomatous disease 2Other pulmonary disease 9
EpidemiologyAspergillus: Outcomes: Mortality
Risk group Fatality rate (%)
Bone marrow transplant (BMT) 87
Leukemia/Lymphoma 49
AIDS 86
Neutropenia (<500/mm3) 51
CNS/disseminated 88
Pulmonary 59
Overall 58
Lin S, et al. Clin Infect Dis. 2001; 32:358-366. (Review of 1941 pts from 50 studies)
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“Halo sign”
Medical Mycology:The Last 50 Years
5-FCMiconazole
KetoconazoleFluconazole
Itraconazole
L-AmBABCDABLC
Terbinafine
# of drugs
Dismukes WE, Clin Infect Dis 2006; 42:1289-96
Amphotericin B +/- OLAT
Voriconazole +/- OLAT
TreatmentVoriconazole: Global Comparative Aspergillosis Study
Number of Days of Treatment
Pro
ba
bili
ty o
f S
urv
iva
l
Hazard ratio = 0.59 ( 95% CI 0.42-0.88)
Survival at wk 12VORI OLAT 70.8%AmB OLAT 57.9%
Herbrecht et al. NEJM 2002: 347OLAT: Other Licenced Antifungal Therapy
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Question
Which of the following is voriconazole not associated with?
A. Seeing white flashesB. Seeing Star Wars charactersC. Skin cancerD. Renal toxicity
VoriconazoleCancer
Arch Dermatol. 2010;146(3):300-304 J Am Acad Dermatol. 2010 Jan;62(1):31-7
Itraconazole is drug of choice for most with histoplasmosis
• Amphotericin B• Prior to 1980s, amphotericin B was drug of
choice. Cure rates up to 57-100% 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; 93:489-97
Mexico, south to Argentina
Lungs, painful mouth ulcers, skin, can mimic TB
Males >>> females
Paracoccidiodomycosis
Case49 year-old gardener comes to see you in clinic with a progressive rash
1 week ago noticed a papule on the 4th finger which ulcerated
Now more nodular lesions have developed proximally
Case
After no help with multiple courses of antibiotics, what is your next step?
A. More antibioticsB. Empiric antifungalsC. Referral for biopsyD. Reassurance
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Worldwide
Contact with soil or decaying wood; gardening
Begins as a hard nontender subcutaneous nodule then more nodules along lymphatics; can disseminate
Sporotrichosis
C
Case25 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
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Dramatic increase in Valley 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 hospitalization
MMWR 2013
Fresno dust storm
Coccidioidomycosis
Fiese MJ. Proc Symp Cocci, Phoenix, Feb 11-13, 1957 & Cal Med 1957; 86:119-20.
Pre-Rx post 3 mos RX
Cocci for 7 years with severe exacerbation in January 1956.
Rx: amphotericin B 2.4 g orally per day.
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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
• Itraconazole cure rates 63-75%. Preferred azole for skeletal disease.
• Fluconazole cure rates 50-67%. Preferred azole for meningitis. Treat for life.
Galgiani JN et al, Ann Intern Med 2000; 133:676-86
Galgiani JN et al, Ann Intern Med 2000; 133:676-86
C
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
• First AIDS studies (RCT) showed amphotericin (same dose) vs fluconazole monotherapy for 10 weeks only successful in 40% vs 34% (P=NS)
Bennett JE et al, N Engl J Med 1979; 301:126-31
Saag MS et al, N Engl J Med 1992; 326:83-9
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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
• 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.
Bartlett J and Gallant JE. Medical Management of HIV Infection, 2006 ed.
D
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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)
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Bonus case
Patient with meningitis 19 days following epidural steroid injection at an ambulatory surgery center
Lab calls you about this weird fungus
What is this?
Question
Which of the following has been in the news as the main organism associated with injection of epidural steroids?
A. AspergillusB. ExserohilumC. RhizopusD. Candida
Exserohilummeningitis, United States
Multistate outbreak of fungal meningitis associated with three lots of preservative‐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.
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 +/‐ lipsosomalAmphotericin B
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Z
Case
•Patient with DKA, renal failure, immunosuppressed•Black necrotic lesions of nose with invasion•Broad, branching, non-septate hyphae•Almost 100% mortality in immunosuppressed•Rx: Surgery and Ampho•Zygomycosis
Zygomycosis
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
Hussain et al, CID 2003:37 Pappas, ICAAC 2003
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Kontoyiannis et al, JID, 2005
Voriconazole available
ABCD and Z
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:
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Take home points - Cocci•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
Take home points - Crypto•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 4th
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)
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Take home points -Zygomycosis
•Invasive Zygomycosis is a rare but fatal disease and is increasing
•Traditional risk group: DKA, now BMT and other transplant patients
•Diagnosis is tough like all the invasive mycoses. Get a biopsy
•Voriconazole is not effective. Only amphotericin as backbone
•Key challenge in the future remains better diagnostic strategies