Coccidioidomycosis: DISCLOSURES. Key Questions. Coccidioides: Life Cycle. Epidemiology. Origin of Coccidioides spp? 3/25/2018

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1 Coccidioidomycosis: Recent Advances and Remaining Problems DISCLOSURES Name of Organization Relationship George R. Thompson III, MD, FIDSA Associate Professor Division of Infectious Diseases Department of Internal Medicine Department of Medical Micro and Immunology University of California-Davis Pfizer, Merck, Astellas, Wako, Scynexis, Cidara, Vical, T2, F2G Astellas, Vical Research Support Consulting Key Questions Coccidioides: Life Cycle Discuss controversies/uncertainties in key areas: Expanding geographic range/changing epidemiology New locations or simply newly recognized? Diagnostic methods? Development of new tests Treatment options and trials? New azoles, new formulations, combination Unanswered questions? Genomics, other diagnostic modalities and advances Dimorphic = mould phase and a yeast-like phase Brown J, et al. Clin Epidemiol Jun 25;5: Origin of Coccidioides spp? Epidemiology Geographic expansion requires further analysis of population structure and evolutionary history Phylogenetics and population genomics (86 isolates) Additional ~200 added C. posadasii is the more ancient of the two spp Arizona-N. Mexico origin for C. posadasii AZ pocket mouse Engelthaler DM, et al. Mbio Apr 26;7(2):e Kangaroo Rat Most recent common ancestor ~ 5 million years ago Affects approximately 150,000 yearly ½ to 1/3 are subclinical Almost universal protection from reinfection Cause of CAP in 17-29% of patients in endemic areas! No definitive recommendations for Coccidioidomycosis testing in IDSA or IDSA/ATS CAP guidelines Vugia DJ,et al. MMWR Morb Mortal Wkly Rep. 2009;58:105 9 Brown J and Thompson GR. Clin Epidemiol Jun 25;5:

2 Host Susceptibility Pregnancy Men > Women (6:1) Anthropogenic disruption of soil Immunosuppressed HIV/AIDS Chemotherapy/malignancy Transplant TNF-α blockers, etc Pregnancy Ethnicity suggests genetic predisposition Filipino (175X risk) African-Americans (10X risk) Asian and Hispanics? Targeted analysis of TLR2/4, MR, Dectin-1, STAT1, etc = negative Large scale, whole exome sequencing project in collaboration with Broad Institute and NIH. Thompson GR et al. Med Mycol Apr:51(3): Crum et al. Medicine. 2004;83: β-estradiol, progesterone, and testosterone are highly stimulatory for the parasitic phase Estrogen receptor Decreases in total lymphocyte T-helper T-suppressor Presumably secondary to an increase in plasma volume. Barbee RA et al. Chest Sep;100(3):709-15; Drutz DJ et al. Infect Immun May;32(2): Powell BL et al. Infect Immun Sep;45(3): * * * * * * Virulence of organism Primary Coccidioidal Pneumonia Endospores and human neutrophil Spherule and human neutrophil Presentation: Fever Cough Chills Pleuritic chest pain Erythema nodosum/rash Eosinophilia Subpopulation (~15%) of endospores that do NOT induce chemotaxis or undergo phagocytosis Size likely to be major virulence factor for Coccidioides spp Indistinguishable from CAP!! Lee CY, Thompson GR, et al. PLoS One (6):e Vugia DJ,et al. MMWR Morb Mortal Wkly Rep. 2009;58:105 9 Sunenshine RH et al. Ann N Y Acad Sci. 2007;1111: Primary Coccidioidal Pneumonia 2.5 (1996) 8.4 (2006) cases/100,000 in CA 21 (1997) 91 (2006) cases/100,000 in AZ Cause of CAP in 17-29% of patients in endemic areas How to diagnosis? RASH or Eosinophilia Good news: >95% of patients resolve infection even without antifungal therapy Bad news: Remaining 3-5% often difficult to treat Vugia DJ,et al. MMWR Morb Mortal Wkly Rep. 2009;58:105 9 Sunenshine RH et al. Ann N Y Acad Sci. 2007;1111: Decision to Treat? Unsettled debated issue!!! TO TREAT? Not treating is historical rec based on AMB as only option May decrease intensity, duration of symptoms NOT TO TREAT? Meds patient may not need Observational data shows worse outcomes Always Treat: Immunosuppressed (HIV, transplant, TNF-α inh, etc.) Ampel NM. Clin Infect Dis ;48(2): Thompson GR et al. Clin Infect Dis ;48(2):

3 A Randomized, Double-Blinded, Placebo-Controlled Study in Adults with Community Acquired Pneumonia to Assess the Effect of Empiric Antifungal Treatment of Coccidioidomycosis Pneumonia (Valley Fever Pneumonia) in Endemic Areas Follow Primary Infection to Resolution 2012 Clinical Trial Proposal submitted to CDC under Mycoses Study Group Joint discussions with CDC/NIH 2013 U.S. House Majority Leader Kevin McCarthy (R) advocacy for trial Panel convened for trial design, site selection Trial to begin enrollment this fall Initial : Day 0 Day 32 Day 71 Day 299 Following to resolution potentially avoids later work-up/resection of nodules Complications of Primary Infection Complications of Cavities Residual nodule Cavity Ruptured cavity Chronic fibrocavitary disease Infrequently maintain positive CF serologic response Diagnosis difficult without history and prior films No treatment needed for most, even if resected. Infrequently maintain positive CF serologic response More common in DM Treat if abuts pleura to prevent fistula formation Overlapping endemic regions of TB and Cocci in U.S. May produce bronchopleural fistula Initial manifestation for some Typically requires resection of ruptured cavity or lobectomy with decortication (minority with antifungals and chest drainage alone) Symptoms of chronic pneumonia (i.e. fever, chest pain, night sweats, etc) May be bilateral More common in DM Complications of Primary Infection Cutaneous Disease ARDS Miliary Disease Papules Pustules Plaques Nodules Ulcers Abscesses Verrucous lesions Infrequent complication Typically follows massive inhalational exposure (lab, archeology, etc) Utility of corticosteroids in fungal associated ARDS debated Seen in immunosuppressed Requires more aggressive treatment (Amphotericin B formulation) May require life-long antifungals as most with this form have immunologic derangement Locus Minoris Resistentiae Erythema nodosum (favorable sign) NOT dissemination 3

4 MIC (µg/ml) 3/25/2018 Osteoarticular Disease Monoarticular joint disease most common Knee joint most frequently affected. Antifungal therapy without surgical intervention may be effective Vertebral osteomyelitis is notoriously difficult to manage Nuclear imaging or magnetic resonance imaging (MRI) are more sensitive than X-ray or computed tomographic (CT) scans. Prospective studies have shown itraconazole > fluconazole. Meningitis Half of all individuals with disseminated disease (racial predisposition) Filipino (175X risk) negative skin testing African-American (10X risk) Asian and Hispanics? Death nearly universal without antifungal therapy Occur weeks-months following primary infection Clinically presents as headache >>> altered mental status, fever, nausea, vomiting, focal neurologic deficits Any + serologic result from CSF is significant* Cultures positive 30-50%; eosinophilia uncommon. Thompson GR, et al. Plos One May 22;8(5):e Johnson, R. Clin Infect Dis 2006;42:103-7 Diagnostics Emerging Diagnostics Culture/Histology Culture: definitive, laboratory hazard Histopath dx: characteristic forms in tissue Serological diagnosis ID/CF: used to establish diagnosis May be negative early or immunocompromised Dissem. infection: IDCF titers 1:16 + CSF ab: meningeal infection Impact of early fluconazole in reducing development of CF ab EIA: sensitivity, potential false +; cross react w/ other endemic fungi good for rapid screen Alternative methods: investigational Antigen testing: varies widely -timing and host/site useful in HEAVILY immunocompromised patients PCR (limited sensitivity) no different than Cx (1 3)-β-D-glucan Adenosine deaminase (ADA) Rupturing spherule releasing endospores Empty spherule Lateral Flow Assay Developed specifically to improve turn around time Simplicity of use Yes or no answer while patient in urgent care/clinic/er Example patient serum positive for IgM and IgG antibodies Thompson GR et al. Clin Infect Dis. 2011;53:e20-4; Thompson GR, et al. J Clin Micro. 2012; 50(9): Thompson GR, et al. Chest. 2012; 143(3): Unpublished data Emerging Diagnostics Immunosignature Pattern of antibodies, allows for pathogen specific signature Advantages: not hypothesis driven Able to detect multiple different pathogens Questions: Over time? Sequential samples? Acute vs Immune? Those at risk for chronic infection? Immunosuppressed? Coinfections? Immunosignature profile of different Coccidioides spp. Unpublished data Collaborations with Phillip Stafford and Stephen Johnston; ASU and Dept Homeland Security under review Large scale susceptibility testing >400 isolates >1/3 of isolates with FLC MICs > 16 µg/ml 22 isolates with FLC MICs > 64 Susceptibility Coccidioides spp. MIC AMB FLU ITR POS VOR AFG CFG MFG In vitro susceptibility of Coccidioides isolates to AMB, triazoles and echinocandins ITC > 2, 1.0% VOR >2, 1.2%; POS >1, 1.1% AMB > 2, 2.8% Biased? isolates sent to reference lab Prior literature animal models and one clinical trial suggest mould active azoles more favorable response has this played a role in prior studies of 1 o disease? Thompson GR et al. Antimicrob Agents Chemother ahead of print 4

5 Antifungal agents Treatment: Toxicity (Fluconazole) Fluconazole: Itraconazole: Posaconazole: Voriconazole: Amphotericin B: Echinocandins: Other (IFN-γ, etc): cheap, high doses needed diss. disease, TDM absorption?, TDM drug interactions, TDM toxicity, IV only ONLY as combination cases/in vitro Fluconazole toxicity? Generally well tolerated, even at doses > 800 mg/day; for many life-long therapy Alopecia, cheilitis, dry skin Thompson GR et al. Clin Chest Med Jun;30(2): Levy ER, et al. Clin Infect Dis Jun;56(11): P=0.007 P<0.001 ** Significant differences at day 14 and 21 Treatment: Toxicity (Posaconazole) Treatment: Toxicity (Voriconazole) Tablet formulation has improved serum [conc] (median of μg/ml) ~10% still with levels < 0.7 Recognition of 3 patients in last 6 weeks Hypertension, hypokalemia, alkalosis All had posa level >4 μg/ml Undetectable renin and aldo Elevated 11-deoxycortisol, and cortisol/cortisone ratio Multiple drug-drug interactions Hepatotoxicity Photosensitivity Long term use: Cutaneous malignancy Fluoride toxicity 10% with levels > 3.5 μg/ml Ceiling for toxicity? Thompson et al. Antimicrob Agents Chemother β-HSD1, 11β-hydroxysteroid dehydrogenase type 1 and type 2 Lat A, Thompson GR 3rd. Infect Drug Resist. 2011;4: Thompson GR 3rd, et al. Antimicrob Agents Chemother Jan;56(1): Conclusions Thank You! Through collaborative efforts - substantial progress!! Advanced our understanding of: Evolutionary biology of Coccidioides spp. Epidemiology and endemicity New Diagnostics Question current treatment approach based on MIC values Proven the benefit of adjunctive therapy (not shown today) Toxicity of current agents new agents are on the way! Unanswered questions Genomics, new diagnostic modalities, best agent? New Toxicities? Prevention: Vaccines? UC-Davis Angie Gelli PhD Kiem Vu PhD Jane Sykes DVM Ian McHardy PhD Tgen Dave Engelthaler PhD Chandler Roe PhD Elizabeth Driebe MS Bridget Barker PhD CDC Tom Chiller MD Kaitlin Benedict MS Immy Sean Baumann PhD NIH and Broad Institute Funding for genetics work Christina Cuomo PhD 5

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