10/2/2018

Endemic Mycoses: Update on Diagnostics and Treatment

George R. Thompson III, MD Associate Professor Division of Infectious Diseases Department of Internal Medicine Department of Medical Microbiology and Immunology University of California-Davis Medical Center

Key Questions

▪ Expanding geographic range New locations or simply newly recognized? 10% diagnosed outside of normal range ▪ Taxonomy updates and new species ▪ New diagnostic methods Development of rapid diagnostics, kinetics of serology ▪ Prolonged treatment – unique toxicities? New azoles and new formulations

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Endemic Mycoses

Dimorphic fungal Location

• Scattered worldwide • Scattered worldwide • US/Latin America • Latin America • Talaromycosis Northern Thailand/China • Worldwide • Emergomycosis/Emmonsia Scattered

Case 1: 45 y/o with recurrent pneumonia presents for second opinion • 45 y/o African American male with no prior history • Presents with severe cough and chest pain. • Works as long-haul truck driver. Recent project in Bakersfield, CA. • No headache or MSK complaints • Exam reveals: tired appearing, course breath sounds, no skin lesions.

What is likely diagnosis? Appropriate workup?

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Origin of spp?

▪ 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 Most recent ▪ Arizona-N. Mexico origin common ancestor for C. posadasii ~ 5 million years ago AZ Kangaroo pocket Rat mouse

Engelthaler DM, et al. Mbio. 2016 Apr 26;7(2):e00550-16.

Epidemiology

Affects approximately 150,000 yearly Continual increase ▪ ½ to 1/3 are subclinical ▪ Almost universal protection from reinfection

Cause of CAP in 17-29% of patients in endemic areas!

Definite seasonal increase in early fall

Cooksey GS. MMWR Morb Mortal Wkly Rep. 2017 Aug 11;66(31):833-34. Brown J, et al. Clin Epidemiol. 2013 Jun 25;5:185-97.

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Diagnostics

Culture/Histology ▪ Culture: definitive, laboratory hazard

▪ Histopath dx: characteristic forms in tissue ID50 ~1 arthroconidia! Serological diagnosis ▪ ID/CF: used to establish diagnosis ▪ May be negative early or immunocompromised ▪ Dissem. : 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 Arthroconidia ▪ Lateral Flow assay Rupturing spherule and empty spherule Alternative methods: investigational ▪ Antigen testing: varies widely -timing and host/site ▪ PCR (limited sensitivity) – no different than Cx ▪ Skin test: new test (Spherusol) decreased sensitivity compared to prior (Spherulin)

Thompson GR et al. Clin Infect Dis. 2011;53:e20-4; Thompson GR, et al. J Clin Micro. 2012; 50(9):3060-2 Thompson GR, et al. Chest. 2012; 143(3):776-81.

Diagnostics

Antigen and Later IgG spike PCR in minority of or patients: culture 1) reinfection? 2) ruptured granuloma 3) Kinetics not consistent with false (+)

Mchardy I, Thompson GR. J Clin Micro. 2018 In press

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Diagnostics

▪ Significant differences in serology kinetics

▪ Closely correlate with symptomatic improvement – (symptom scores not shown) Serofast *

▪ Minority of patients are serofast even Cohort of 500+ patients with 4 distinct forms of years later disease followed over 5 years

Mchardy I, Thompson GR. J Clin Micro. In press

Sequalae: Peripheral nodules

Low-dose CT screening for current and former smokers (ages 55-80) No guidance for those in endemic regions

Peripheral pulmonary infiltrates and lesions ▪ Coccidioides ▪ Blastomyces ▪ Histoplasma ▪ Cryptococcus

✓ PET scan not always reliable ✓ Bronchoscopy 65-88% sens ✓ Peripheral<2cm lesions ~34% ✓ Transthoracic biopsy for <6mm nodules: Electromagnetic ✓ Non-diagnostic ~15% Navigational Bronchscopy

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Electromagnetic Navigational Bronchoscopy

Case 2: 65 y/o male with hand lesions after fall

• 65 y/o male painter fell off ladder while painting state capital building. • Fell onto bush and had puncture to dorsum of hand. • Exam with purulent drainage, no warmth, and no . • Cultures return after ~10 days.

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Sporotrichosis

• S. brasiliensis (cat), S. schenckii (plant), S. globosa, S. luriei, S. mexicana • Prevalence ~0.1-0.5% • Cutaneous disease, spread via lymphatics. • Pulmonary or disseminated in immunosuppressed

• Shift of environmental to zoonotic disease – Outbreak in South America – Human = feline cases (claws+ in 29%!) • Human cases – Adults: extremity – Children: face/neck • Facial lesions secondary to high-inoculum occupational factors

Rodrigues AM, et al. PLoS Pathog. 2016 Jul:12(7):e1005638 Lyon GM, et al. Clin Infect Dis. 2003;36:34-9. Zhang Y, et al. Persoonia 2015;35:1-20

▪ S. brasiliensis exhibits increased virulence ▪ Outbreak and expansion over last 2 decades ▪ Preliminary evidence AMB (>1 µg/mL) and ITZ (>2) MICs are increasing (shift of MIC90 from 2 → 4); TBF MICs remains low (0.1)

Gremiao ID, et al. PLoS Pathog. 2017;13:e1006077 Borba-Santos et al. Med Mycol 2015; 53(2):178-188. Rodrigues AM, BMC Infect Dis. 2014;14:219

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What almost was….

▪ Sporothrix spp vs Ophiostoma proposed taxonomic changes

▪ Cause of Dutch Elm disease

Bark Beetle

De Beer ZW, et al. Stud Mycol. 2016;83:165-191. Lopes-Bezerra LM, et al. Med Mycol. 2018;56:S126-143

Diagnostics

Culture/Histology ▪ Culture: definitive (4-20 days), rosettes ▪ Histopath dx: “asteroid” bodies (5-13 µm)

Serological diagnosis ▪ Immunodiffusion and western blot ▪ Latex agglutination – useful in Sporothrix “Asteroid” body in tissue meningitis? not specific ▪ ELISA (cell wall antigen) ▪ ScCBF-ELISA – Sens: 90%, useful as response to therapy with decreasing titers over time ▪ AUC ROC= 0.9154

Alternative methods: ▪ PCR in tissue (none commercially available) ▪ Skin test: sporotrichin (not commercially available) Rosettes at tips of conidiophores

Kusuhara M, et al. Mycopathologia. 1988 102(2):129-33. Barros MB, et al. Clin Micro Rev 2011; 23(4):633-54. Bernardes-Engemann AR et al. Med Mycol 2005;43(6):487 Bernardes-Engemann, et al. Med Mycol 2015;53(1):28

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Sporotrichosis: Treatment

• Severe disease/dissemination: Ampho B • Cutaneous: SSKI, , new azoles? • Long durations of therapy common despite debridement/drainage

Itraconazole 200mg orally twice daily

Day 0 Day 62 Day 152 Day 247 Day 467

Case 3: South American man with chronic cough, weight loss.

• 65 y/o man from Peru • 3 month history of 20 pound weight loss, fatigue, cough • Examination: chronically ill man with wasting • Chest radiograph: bilateral granulomatous disease

Evaluation at this point? Likely diagnosis?

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Paracoccidioidomycosis

Paracoccidioides brasiliensis (dimorphic ) • Most common systemic in Latin America • Tissue phase: “pilot wheel” • New spp proposals: • P. lutzii, P. americana, P. restrepiensis, • P. venezuelensis • Clinical Presentation & Diagnosis – Granulomatous disease: pulm and disseminated infection

• Diagnosis – Double immunodiffusion (gold standard) – ELISA: More sens, less spec – CF: More spec, less sens – Antigen detection: useful in highly immunocompromised

Marques da Silva SH, et al. J Clin Micro 2004 42(6):2419-24. de Camargo ZP. Mycopathologia. 2008 165(4-5):289-302. Perenha-Viana MCZ, et al. Clin Vaccine Immunol. 2012 19(4):616-619.

Case 4: Forester returning home from Thailand

• A 52 yo man, with no prior medical history, returned home with extensive pedunculated skin lesion over his face and trunk, some of which had become ulcerated

• His history was significant for extensive world-wide travel in course of his work as a forester

• During the last trip he tripped and fell, injuring forehead in a bamboo thicket.

Case Courtesy of Dr. Tom Patterson. Thanks! Likely diagnoses?

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Talaromycosis (formerly Penicilliosis)

Talaromyces marneffei • Produces red pigment in culture media; may be a laboratory hazard • Associated with bamboo rats • Patients with AIDS: Thailand/Southern China, Vietnam, NE India, Hong Kong

Clinical Presentation & Diagnosis • Chronic granulomatous infection: fever, weight loss

Diagnosis • Cultures (~14 days): red diffusible pigment • Blood culture (+): ~76% • (+): ~100% • Non-invasive: • GM cross reactivity (73-80%) • Antigen testing: Sens-75-100%; Spec 83-100% Characteristic transverse septum Le T, et al. NEJM 2017;376:2329-2340. Prakit, et al. Euro J Clin Micro 2016

Treatment

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Treatment: Toxicity (Fluconazole)

▪ Fluconazole toxicity? ▪ Alopecia, cheilitis, dry skin ▪ Generally well tolerated, even at doses > 800 mg/day; for many life-long therapy ▪ Eval of >300 patients on fluconazole for > 30 days: 50% discontinued secondary to toxicity ▪ Change to itra/posa/or stop – ~14-21 days to resolution of skin toxicity, ~90 days to resolution of alopecia

P=0.007 P<0.001

Thompson GR 3rd, et al. Antimicrob Agents Chemother. Pending revisions Davis M, Nguyen V…Thompson GR, et al. Pending submission

Treatment: Toxicity (Posaconazole and Itraconazole)

Recognition of 7 patients: ▪ Tablet formulation has improved Hypertension, hypokalemia, alkalosis serum [conc] (median of 0.74 → All had posa level >4 μg/mL 1.92 μg/mL) Undetectable renin and aldo Elevated 11-deoxycortisol, and cortisol/cortisone ratio

Mean posa 5.62 (range 3-9.5 µg/mL)

11β-OH? ▪ 10% with levels > 3.5 μg/mL

▪ Ceiling for toxicity? Proven Inhibition

11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1 and type 2

Jung DS, et al. Antimicrob Agents Chemother. 2014 58(11): 6993–6995. Thompson et al. Antimicrob Agents Chemother. 2017 25;61(8) Odermatt, Thompson. Pending submission

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Treatment: Toxicity (Posaconazole and Itraconazole)

Human CYP11B1 (29 March 2018)

Fluconazole 100 80 Hydroxy-Itraconazole 60 Posaconazole 40 Itraconazole Isavuconazole 20

0

-20 -9 -8 -7 -6 -5 -4 log M

Treatment: Toxicity (Voriconazole)

▪ CNS and peripheral neuropathy ▪ Hepatotoxicity ▪ Photopsia ▪ Bipolar On-Cells ▪ Photosensitivity ▪ N-oxide metabolite

Long term use: ▪ Cutaneous malignancy ▪ Fluoride toxicity

Lat A, Thompson GR 3rd. Infect Drug Resist. 2011;4:43-53. Thompson GR 3rd, et al. Antimicrob Agents Chemother. 2012 Jan;56(1):563-4.

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Conclusions

Update in Endemic Mycoses:

✓ Evolutionary biology ✓ Epidemiology and endemicity ✓ Taxonomic changes!! ✓ New Diagnostics are under active evaluation ✓ Toxicity of current agents – new agents are on the way!

▪ Unanswered questions Genomics, new diagnostic modalities, performance characteristics, best agent(s)? Combination therapy, drug repurposing, New Toxicities?

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