Assessing the Individual Risk

for Fungal infection

Dimitrios P. Kontoyiannis, MD, ScD, FACP, FIDSA

Frances King Black Endowed Professor

Deputy Head, Division of Internal Medicine

The University of Texas M.D. Anderson Cancer Center

Houston, TXESCMID eLibrary

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Disclosures

Research support and/or honoraria from:Merck, Inc

Astellas, Inc

Pfizer, Inc

Gilead, Inc

T2 Biosystems

Cidara, Inc

MSG/Matinas, Inc

F2G, IncESCMID eLibrary

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Patient level clinical risk factors

Risk factors for IFIs in the context of prior antifungal exposure

Some promising future directions with immunogenetics

Outline

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Risk stratification

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Risk for Invasive Aspergillosis Based on Primary Host Factor

Chronic granulomatous disease

Allogeneic HSCT with graft versus host disease

AML/MDS treated with remission-induction chemotherapy

Lung or heart transplantation

Small-bowel transplantation

Liver transplantation

Herbrecht et al. Ann NY Acad Sci 2012;1272:23-30.

Allogeneic HSCT without graft versus host disease

Acute myeloblastic leukemia during consolidation phase

Acute lymphoblastic leukemia

Heart transplantation

Chronic lymphocytic leukemia

Myelodysplastic syndrome

Multiple myeloma

COPD with acute exacerbation

AIDS

Non-Hodgkin’s lymphoma

Autologous HSCT

Kidney transplantation

Solid tumor

Autoimmune disorder

HIGH RISK

INTERMEDIATE

RISK

LOW

RISK

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Risk Factors Influencing Host Condition

ENVIRONMENTAL FACTORS

UNDERLYING CONDITION

OTHER FACTORS

INNATE IMMUNE STATUS

Toll-like receptor polymorphism

C-type lectin receptor polymorphism

Mannose binding lectin polymorphism

Plasminogen polymorphism

Other polymorphisms?

Herbrecht et al. Ann NY Acad Sci 2012;1272:23-30.

Neutropenia

Progressive cancer

Graft versus host disease

Anticancer chemotherapy

Corticosteroids

Anti-T-cell antibodies

Diabetes

Iron overload

Trauma, burns

Renal impairment

Metabolic acidosis

Prior respiratory disease

Climate

Construction work

Place of residence

Tobacco or cannabis use

Contaminated food or spices

Pets, plotted plants and gardening

No HEPA filtration during hospitalizations

PRIMARY HOST FACTOR

Hematological Malignancy

Allogeneic HSCT

SOT

Solid tumor

Other immune disorder

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BoSCORE: A clinical risk model for invasive mold disease in hematology pts that separates them at low versus high probability for IMD: 1% 90d probability if BoScore<6 vs >5% if BoScore≥ 6%

0-2 3-5 6-8 9-130

10

20

30

2005-2008 686 535 345 143

Risk Score

0.6 0.8

7.3

16.8

% P

roven o

r P

robable

IM

D

2009-2012 669 629 350 98

0.9

5.1

26.5

0.9

=1,746 admissions

=1,709 admissions

BoSCORE PointsNeutropenia > 10 days 4Previous mold infection 4Uncontrolled malig. 3Lymphopenia or 2lymph. dysfunct.

Stanzani M et al. PloS One 2013

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Reduced GI toxicity, less severe neutropenia =fewer fungal infections?

Antifungal prophylaxis needed?

Fenaux et al. J Clin Oncol 2010;28:562-569.

Nor all patients with MDS need antifungal prophylaxis: Impact of epigenetic therapeutics on the management of AML/MDS

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Epidemiology of invasive fungal disease

Invasive Fungal Infections in Patients with High-Risk MDS and AML Treated with Azacitidine.

Helena Pomares, Montserrat Arnan, Isabel Sánchez-Ortega, Anna Sureda,Rafael F. Duarte-ASH 2015

N=121 patients(n=86 MDS, 35 AML)Median age, 70 years

948 total cycles ofazacitabine

(median 5, range 1-43)

91% of courses frontline9% refractory or relapse

No antifungal prophylaxis administered

75 mg/m2/day for 7 days, every 28 day cycle

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Invasive fungal infections in patients with high-risk MDS and AML treated with azacitidine.

274/948 courses (28%) associated with grade 4 neutropenia (< 0.5x109/L for >10 days) 12% associated with febrile neutropenic

episode

Only 4 invasive fungal infection documented Incidence: 0.42% per treatment cycle, 3.3% among

patients with grade 4 neutropenia

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Sorrer et al. Blood;2005;106:2992.

HSCT-CI: A modification of the Charlson Comorbidity Index (CCI)

Co-morbidities are important for assessing IFI risk Busca A et al. ASH 2015

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HSCT CI risk score for prognosis of invasive fungal disease

301 patients with HSCT-CI risk score assessment undergoing first allogeneic HSCT 62% acute leukemia, 58% alternative donor

source

58% low of intermediate risk score (0-2)

42% high HSCT-CI risk score (≥ 3)

Cumulative incidence of IFI HCT-CI 0-2 (11%)

HSCT-CI ≥ 3 (17%)

P=0.052ESCMID eLibrary

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HSCT CI risk score for prognosis of invasive fungal disease

Risk for infection-related mortalityHR 3.37 (P=0.01)

More intensivediagnostic workup,antifungal prophylaxisESCMID eLibrary

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Most IFIS occurred during RIC or during relapse: Epidemiology of fungemia in hematological malignancies: preliminary report of SEIFEM-2015 survey

39% of episodes at first induction of malignancy diagnosis32% of episodes during treatment of refractory/relapsed disease14% of episodes while in remission17% of episodes were associated with allogeneic transplant

42%

27%

9%

6%

5%4%

3% 2% 1% 1%

Study population

LMA

LNH

LLA

MM

SMD

ALTRO

LLC

LH

Aplasia

LMC

Slides courtesy of Livio Pagano

N=118 patients20 centers

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Climate Incidence of IA associated with climate/season

Environmental exposures Soil contact, food safety, water safety

Construction increases risk IFIs, especially IA

Increased in-hospital transfers out of hematology ward-> increased risk for filamentous

IFIs

Metabolic factors

Increased bone marrow and peripheral markers of iron stores associated with an

increased risk of fungal infections, including mucormycosis

Hyperglycemia

Viral and bacterial coinfections

CMV and respiratory virus coinfections increase risk of IA

Bacteremia increases risk of IFIs

Mycobiome

Baseline colonization important risk for invasive candidiasis and predictive of infection

>1 site of colonization/heavy colonization at single site increases risk

Nasal/sputum cultures for Aspergillus spp predict increased risk of IA

Halpern AB…, Kontoyiannis DP, Walter RB. BLOOD 2015

Other factors

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Risk for a specific IFI in the era of mold-active prophylaxis: Importance of epidemiology, spectrum and PK of drugs

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Mucormycosis at MDACC

Still a problem in POSA prophylaxis era

Kontoyiannis & Lewis. Blood 2011

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AMB FLU ITRA VORI POSA ANID CAS MICA 5FC

Ye

as

tsM

old

sD

imo

rph

ic

Aspergillus fumigatus

Aspergillus terreus

Mucorales

Fusarium spp.

Histoplasma capsulatum

Blastomyces dermatitidis

Coccidioides immitis

Candida albicans

C. tropicalis

C. parapsilosis

C. krusei

C. glabrata

Cryptococcus neoformans

TriazolesPolyene Echinocandins Other

Spectrum of Systemic Antifungal Agents: No antifungal is perfect

Lewis RE. Mayo Clinic Reviews 2011;86:805-17.

Good activitySome activity

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77%

6%

2%

3% 1%7%

1%1% 1% 1%

Candida spp

Geotrichum spp

Trichosporon spp

Rhodotorula spp

Blastoschizomyces c.

Fusarium spp

Mucor

Scedosporium

Trichodema v

Fusarium+Rhodotorula

Breakthrough fungemias in hematological malignancies: preliminary report of SEIFEM-2015 survey-ASH 2015

2

53

68

1011

13

19

8

0

5

10

15

20

2011 2012 2013 2014 2015

C. albicans Non albicans

55% of patientsreceiving antifungalprophylaxis

23% of isolatesbloodstream isolatesnot treatablewith echinocandins

Slides courtesy of Livio Pagano

Key risk factors:• CVC, bladder catheters• Lack of PMN recovery• corticosteroids

Farmakiotis D.. .Kontoyiannis DP. EID 2015, Jung L...Kontoyiannis EID 2015, Chitasombat M…Kontoyiannis DP. J Infect 2012

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Spectrum of Activity

Differences in conformation of 14α-demethylasebinding pocket and azole structure define binding potential

Differences in spectrum of activity

Fungal Species Fluconazole Voriconazole Posaconazole Isavuconazole

Candida &

Cryptococcus spp.

✔

(+/-)

✔ ✔ ✔

Aspergillus spp. ✖ ✔ ✔ ✔

Fusarium spp. ✖ ✔

(+/-)

✔

(+/-)

✔

(+/-)

Scedosporium spp. ✖ ✔

(+/-)

✔

(+/-)

✔

(+/-)

Mucorales spp.(Mucormycosis)

✖ ✖ ✔ ✔

Dodds-Ashley et al. Clin Infect Dis 2006; 43(suppl 1): S28-S39.

Thompson et al. Mycopathologia 2010; 170: 281-313.

Lewis. Mayo Clin Proc 2011; 86: 805-817.

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Specificity & Drug-Drug Interactions

Selectivity for fungal CYP enzymes notexclusive IC50 against Candida CYP = 10-9M

IC50 against human CYP450 = 10-6MMechanism Fluconazole Voriconazole Posaconazole Isavuconazole

Inhibitor

CYP 2C19 ✚ ✚✚✚ − −

CYP 2C9 ✚✚ ✚✚ − −

CYP 3A4 ✚✚ ✚✚ ✚✚✚ ✚✚✚

Substrate

CYP 2C19 − ✚✚✚ − −

CYP 2C9 − ✚ − −

CYP 3A4 ✚ ✚ − ✚✚✚

Dodds-Ashley et al. Clin Infect Dis 2006; 43(suppl 1): S28-S39.Chau et al. Intern Med J 2014; 44: 1364-1388.

Isavuconazole US Prescribing Information 2015.

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Factors Affecting PK/PD of Antifungal Agents

Age/gender

Severity of illness

Renal function

Hepatic function

States that affect oral absorption (GVHD, high gastric pH)

Limited IV access

Genetic component (voriconazole)

Drug interactions

PolypharmacyESCMID eLibrary

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Triiazole-resistance in Aspergillus:? another element of complexity

Verweij, Chowdhary, Melchers & Meis. Clin Infect Dis 2016;62:362-368.

Shaded areas showing countries that have reported TR34/L98H and TR46/Y121F/T289A resistance mechanism

White- no data

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Clinical Clues to differentiate breakthrough infections

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Presentation and syndrome-oriented approach lacks sensitivity and specificity

Cerebritis

ScedosporiumSino-orbital

disease due to

Aspergillus flavus

Cutaneous infection

FusariumESCMID eLibrary

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Pulmonary mucormycosis vs. aspergillosis: difficult to differentiate by chest CT

Clues for mucormycosis

Concomitant sinusitis

Develops on voriconazole prophylaxis

Multiple (≥ 10) nodules

Pleural effusion

Reverse halo sign

Chamilos et al. Clin Infect Dis 2005;41:60-66, Wahba H, Kontoyiannis DP, Marom E. CID 2008, Georgiadou S et al. CID 2011; Jung et al. Clin Microbil Infect 2015;684:e11-8

.

Reverse Halo SignESCMID eLibrary

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CT pulmonary angiography (CTPA) can differentiate mold versus bacterial pneumonia

CTPA positive,

proven mold

disease

CTPA negative,

bacterial PNA

Stanzani M et al. Clin Infect Dis 2012;54(5):610-6.

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Lymphoma relapse in lung of extensively-treated patient presenting with fever

CT pulmonary angiography (CTPA)

can differentiate mold vs. malignancy

negativetest

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Integration of Genetic Risk Factors into Risk Score Models: An example

Suitable donors

Screened for TLR or

Dectin-1 haplotypes

Allogeneic

HSCT

Intensive monitoring/

prevention approach (i.e. prophylaxis)

Less intensive monitoring /

prevention approach (i.e. premptive)

High risk

Low riskESCMID eLibrary

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SNPs in Toll-like receptor genes

• SNPs in plasminogen genes

• IL-1 gene polymorphisms and haplotype

• Polymorphisms in the chemotactic cytokine

CXC10

• Dectin-1 deficiency

• Mannose-binding lectin deficiency

Immunogenetics and IA risk

Halpern AB…, Kontoyiannis DP, Walter RB. BLOOD 2015

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What is unique about this case?

Pathogen genome sequenced

Host whole exome sequencing

Biweekly microbiome and mycobiomesequencing (buccal and stool sample)

Holobiome=sum total of genomes

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Identification and characterization of a virulent strain of Mucor velutinosus

POSA MIC: 4000 ng/mLShelburne S…Kontoyiannis DP. PLOS ONE, 2015

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Oral mycobiome in weeks leading up to disease onset

Shelburne S… Kontoyiannis DP. PLOS ONE, 2015

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Whole exome sequencing of a patient with early onset disseminated mucormycosis

Shelburne S… Kontoyiannis DP. PLOS ONE 2015

Gene Allele frequency (depth)

dbSNP ID Amino Acid change Comments

PTX3 1.0 (45) rs2305619 None (intronic) G-A/G-A have increased invasive aspergillosis vs. A-C/A-C and A-C/G-A genotypes

PTX3 1.0 (53) rs3816527 p.A48D

TLR6 0.48 (102) rs5743810 p.S249P Associated with invasive aspergillosis in HSCT recipients when TLR1 743A>G is also present

NOD2 0.47 (64) rs2066844 p.R702W Associated with Crohn’sdisease

DDX58/RIG-I 0.45 (29) rs10813831 p.R7C Associated with decreased receptor function

CCR5 0.29 (165) None p.184_194del Resistance to HIV infection

FUT2 0.99 (225) rs6013338 p.W154X Leads to non-secretor phenotype

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The revolution in patient-opportunistic fungus interface is arriving…

Slide courtesy of Sam Shelburne

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Putting everything together: Individualized Risk for IFIs

Hepatic & renal

function?

Sanctuary site

involvement?

Immunosuppression &

reconstitution?Diagnostic

certainty? Concomitant

Infections?

Prior therapies?

Drug interactions?

Infected hardware

or catheters?

GI function?

Dose, timing, intensity of

Immunosuppressive therapy?

Resistance?

PK/PD & Drug dosing?

Pathogen virulence?

Leventakos K… Kontoyiannis DP. CID 2010

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Thank you!

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