10/2/2018

1

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

10/2/2018

2

Endemic Mycoses

Dimorphic fungal infections Location

• Histoplasmosis Scattered worldwide

• Blastomycosis Scattered worldwide

• Coccidioidomycosis US/Latin America

• Paracoccidioidomycosis Latin America

• Talaromycosis Northern Thailand/China

• Sporotrichosis 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?

10/2/2018

3

Origin of Coccidioides 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

▪ Arizona-N. Mexico origin

for C. posadasii

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

Most recent

common ancestor

~ 5 million years

agoAZ

pocket

mouse

Kangaroo

Rat

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!

Definite seasonal increase in early fall

Epidemiology

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.

Continual

increase

10/2/2018

4

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▪ Lateral Flow assay

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.

Arthroconidia

Rupturing spherule and

empty spherule

ID50 ~1

arthroconidia!

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

Diagnostics

Antigen

and

PCR

or

culture

Later IgG spike

in minority of

patients:

1) reinfection?

2) ruptured

granuloma

3) Kinetics not

consistent

with false (+)

10/2/2018

5

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

Diagnostics

Serofast*

▪ Significant differences

in serology kinetics

▪ Closely correlate with

symptomatic

improvement –

(symptom scores not

shown)

▪ Minority of patients

are serofast even

years laterCohort of 500+ patients with 4 distinct forms of

disease followed over 5 years

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: ✓ Non-diagnostic ~15%

Sequalae: Peripheral nodules

Electromagnetic

Navigational

Bronchscopy

10/2/2018

6

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

lymphadenopathy.

• Cultures return after ~10 days.

10/2/2018

7

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

10/2/2018

8

What almost was….

▪ Sporothrix spp vs

Ophiostoma proposed

taxonomic changes

▪ Cause of Dutch Elm

disease

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

Bark Beetle

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

meningitis?▪ 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)

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

“Asteroid” body in tissue

not specific

Rosettes at tips of

conidiophores

10/2/2018

9

Sporotrichosis: Treatment

• Severe disease/dissemination: Ampho B

• Cutaneous: SSKI, itraconazole, new azoles?

• Long durations of therapy common despite debridement/drainage

Day 0 Day 62 Day 152 Day 247

Itraconazole 200mg orally twice daily

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?

10/2/2018

10

Paracoccidioidomycosis

Paracoccidioides brasiliensis (dimorphic fungus)

• Most common systemic mycosis 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.

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

10/2/2018

11

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%

• Bone Marrow (+): ~100%

• Non-invasive: • GM cross reactivity (73-80%)

• Antigen testing: Sens-75-100%; Spec 83-100%

Le T, et al. NEJM 2017;376:2329-2340. Prakit, et al. Euro J Clin Micro 2016

Characteristic

transverse septum

Treatment

10/2/2018

12

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)

▪ Tablet formulation has improved

serum [conc] (median of 0.74 →

1.92 μg/mL)

▪ 10% with levels > 3.5 μg/mL

▪ Ceiling for toxicity?

11β-HSD1, 11β-hydroxysteroid dehydrogenase

type 1 and type 2

Recognition of 7 patients:

Hypertension, hypokalemia, alkalosis

All had posa level >4 μg/mLUndetectable renin and aldo

Elevated 11-deoxycortisol, and cortisol/cortisone ratio

Mean posa 5.62 (range 3-9.5 µg/mL)

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

11β-OH?

Proven Inhibition

10/2/2018

13

Treatment: Toxicity (Posaconazole and

Itraconazole)

Human CYP11B1(29 March 2018)

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

0

20

40

60

80

100Fluconazole

Voriconazole

Hydroxy-Itraconazole

Posaconazole

Itraconazole

Isavuconazole

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.

10/2/2018

14

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 questionsGenomics, new diagnostic modalities, performance characteristics,

best agent(s)? Combination therapy, drug repurposing, New

Toxicities?