1Division of Infectious Diseases and 2Organ Transplantation, 3Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA4Division of Infectious Diseases, Cleveland Clinic Florida, Weston, FL, USA

Abstract

Background

Objectives

Results

Invasive Fungal Infections (IFI) After Heart Transplantation (HT)An 11-Year, Single-Center Experience

Michael Lin, Ignacio Echenique4, Michael Angarone1, Allen Anderson3, Valentina Stosor1,2

Methods

Background:

Invasive fungal infections disproportionately affect organ transplant recipients, causing significant

morbidity and mortality. The cumulative incidence of IFIs following HT varies by era, center, and

immunosuppression practices, ranging from 4% to >25%.

Methods:

We conducted a prospective observational cohort study of HT recipients from 6/2005-6/2016 to define

the contemporary incidence, epidemiology and outcomes of IFI after HT. Probable and proven IFIs were

defined by EORTC/MSG criteria.

Results:

256 HT recipients were followed for mean 1184 d (0-3076 d). 140 (55%) and 61 (24%) received

basiliximab and thymoglobulin (ATG) induction, respectively, followed by tacrolimus, mycophenolate, and

prednisone. 238 (93%) received ≥ 3 mo of prophylaxis with clotrimazole and 24 (9%) received antifungal

prophylaxis with voriconazole.

23 IFIs occurred in 23 pts (9%) at mean of 283 d post HT (range 2–1579 d), with 1 pulmonary

Cryptococcus, 7 invasive Candida (5 with candidemia), 7 pulmonary Aspergillus, 3 pulmonary Rhizopus,

2 Histoplasma, 2 Blastomyces, and 1 multifocal cutaneous Alternaria.

Univariate predictors of IFI were Hispanic ethnicity (17.4% v. 5.6%, p=.05), ATG induction (43.5% v.

21.9%, p=.02), diabetes mellitus (DM) (52.2% v. 27.0%, p=.01), re-operation (39.1% v. 20.6%, p=.04),

and heart-kidney transplant (17.4% v. 5.2%, p=.04), but not age (57 v. 56.6, p=.92), male gender (69.6%

v. 68.7%, p=.93), Caucasian race (69.6% v. 67.8%, p=.86), chronic kidney disease (30.4% v. 40.8%,

p=.33), lower nadir absolute neutrophil count (1909 cells/uL v. 2280 cells/uL, p=.33), re-transplantation

(4.3% v. 3.4%, p=.58), any rejection (43.5% v. 36.5%, p=.51), or CMV infection (8.7% v. 14.2%, p=.75).

Recipients with IFI had higher overall (43.5% v. 18.5%, p=.01) and 1-YR (30.4% v. 7.3%, p=0.002)

mortality, with attributable mortality 4.3%.

Conclusion:

IFI occurred in 9% of HT recipients at our center and were associated with high mortality. Important

potential predictors of IFI were ATG induction, DM, re-operation and heart-kidney transplant. These

factors represent potential identifiers for targeted antifungal prophylaxis and risk reduction strategies.

Ethnic disparities in development of IFI require further investigation and validation.

• Invasive fungal infections disproportionally affect organ transplant

recipients, causing significant morbidity and mortality1.

• The cumulative incidence of IFIs following heart transplantation

varies by era, center, and immunosuppression practices, ranging

from 4% to >25%2.

IFI

N=23

No IFI

N=233

CharacteristicN or

Median% or IQR

N or

Median% or IQR

P-

value

Median age in years 57 (54 – 63) 56.6 (48 – 68) -

Gender (male) 16 69.6 160 68.7 0.93

Race/ethnicity

Caucasian 16 69.6 158 67.8 0.86

African-American 2 8.7 53 22.7 0.18

Hispanic 4 17.4 13 5.6 0.05

Asian 1 4.3 7 3.1 0.06

Re-Transplant 1 4.3 8 3.4 0.58

Heart-Kidney

Transplant

4 17.4 12 5.2 0.04

Co-morbid condition

DM 12 52.2 63 27.00 0.01

CKD 7 30.4 95 40.80 0.33

Renal replacement therapy 2 8.7 49 2.1 0.12

Desensitization therapy 2 8.7 26 11.2 1

Transplant re-operation 9 39.1 48 20.6 0.04

Induction

immunosuppressive agent

Basiliximab 12 52.2 128 54.9 0.80

Anti-thymocyte globulin 10 43.5 51 21.90 0.02

Rejection

2R or 3R 7 30.4 72 30.9 0.96

AMR 6 26.1 47 20.2 0.59

Any rejection 10 43.5 85 36.5 0.51

RRT post-HT 2 8.7 13 5.6 0.63

Post-HT CMV Infection 2 8.7 13 5.6 0.63

Nadir ANC 1908.7 (950 – 2400) 2279.66 (1000 – 3100) 0.33

OutcomeN or

Median% or IQR

N or

Median% or IQR

P-

value

Invasive fungal infections 23 9 - - -

Post-transplant day 283 (2 – 1579) - - -

Death 10 43.5 43 18.5 0.01

1-year mortality 7 30.4 17 7.3 0.002

IFI-related mortality 1 4.3 - - -

• To define the contemporary incidence and epidemiology of invasive

fungal infections after heart transplantation in an academic center

• To determine the characteristics associated with invasive fungal

infections

• To examine the outcomes of patients with invasive fungal infections

Table 1. Demographics, Characteristics, or Outcomes

of 256 Heart Transplant Recipients Table 2. Spectrum of Invasive Fungal Infections after Heart Transplantation

PTD, post-transplant day; CAS, caspofungin; FLC, fluconazole; AFG, anidulafungin; CNS, central nervous system; ITC, itraconazole; VRC, voriconazole; L-AmB, liposomal amphotericin B; POS, posaconazole; SXT,

sulfamethoxazole-trimethoprim; ISA, isavuconazole, MSOF, multisystem organ failure

• A prospective observational cohort study of HT recipients from

6/2005-6/2016 at Northwestern Memorial Hospital

• Probable and proven IFIs were defined by EORTC/MSG criteria.

• Standard immunosuppression protocol in place during the study

period included:

o Use and choice of induction immunosuppression agent

(basiliximab v. thymoglobulin (ATG)) at the discretion of the

clinical team.

o Methylprednisolone 500 mg on day 0, 125 mg every 8 h X 3

doses, then 20 mg daily until replaced by prednisone 20 mg daily

for 1st 3 months post-HT and followed by prednisone taper.

o Mycophenolate mofetil 2 g daily.

o Tacrolimus dose adjusted to achieve target serum trough

concentration 10-15 ng/mL for the 1st 6 months post-HT.

• Prophylaxis: Standard anti-infective prophylaxis included

valganciclovir (valacyclovir if CMV D-/R-), trimethoprim-

sulfamethoxazole, and clotrimazole troches. After 2013, select HT

recipients who received ATG also received voriconazole 200 mg BID

for 3 months post-HT.

• Statistical analysis: Continuous variable analyzed by student’s T-

test, and categorical variables by chi-square or Fisher’s exact test

(SPSS, version 24).

DM, diabetes mellitus, CKD, chronic kidney disease, RRT, renal replace therapy, Any Rejection includes 2R, 3R, AMR

Case Type of Fungal Infection Onset, PTD Treatment(s) Infection Status and Outcome

Invasive Candidiasis

1 C. albicans fungemia 7 CAS; FLC (until death) Resolution of infection; death PTD19, unrelated

2 C. glabrata and C.albicans fungemia 118 AFG Death PTD 150, CNS mycotic aneurysm

3 Disseminated C. tropicalis 16 CAS; FLC Resolution of infection; alive PTD 1598

4 C. glabrata esophagitis 99 CAS (until death) Partial resolution of infection; death PTD 146, sepsis, unrelated

5 Candida sp. esophagitis 20 FLC Resolution of infection; alive PTD 1368

6 C. parapsilosis fungemia 50 FLC Resolution of infection; alive PTD 963

7 C. glabrata fungemia 23 L-AmB (until death) Resolution of infection; death PTD 43, MSOF, unrelated

Cryptococcosis

8 Pulmonary C. neoformans 2 FLC Resolution of infection; alive PTD 2349

Endemic Mycoses

9 Pulmonary H. capsulatum 491 ITC (until death) Resolution of infection; death PTD 1606, cardiac arrest, unrelated

10 Pulmonary B. dermatidis 1043 VRC; L-AmB; ITC; FLC Resolution of infection; alive PTD 1508

11 Disseminated B. dermatidis 704 L-AmB; ITC Resolution of infection; alive PTD 747

12 Pulmonary H. capsulatum 472 L-AmB; ITC; VRC Resolution of infection; alive PTD 524

Aspergillosis

13 Pulmonary Aspergillus non-fumigatus sp. 128 VRC; CAS; POS Resolution of infection; alive PTD 1978

14 Pulmonary A. fumigatus 77 VRC; CAS Partial resolution of infection; death PTD 265, acute rejection, unrelated

15 Pulmonary A. fumigatus 43 VRC Resolution of infection; alive PTD 1250

16 Pulmonary A. fumigatus 479 POS, VRC Resolution of infection; alive PTD 732

17 Pulmonary A. fumigatus 151 VRC Partial resolution of infection; alive PTD 717

18 Pulmonary A. fumigatus 20 VRC (until death) Partial resolution of infection; death PTD 45, acute rejection, unrelated

19 Pulmonary A. fumigatus 293 CAS; VRC Resolution of infection; alive, PTD 732

Mucormycosis

20 Pulmonary Rhizopus sp. 79 L-AmB; CAS; POS (until death) Partial resolution of infection, death PTD 743, cardiac arrest, unrelated

21 Pulmonary Rhizopus sp. 308 L-AmB; POS Partial resolution of infection; alive PTD 918

22 Pulmonary Cunninghamella sp. 94 Lobectomy; POS; ISA (until death) Resolution of infection; death on PTD 449, MSOF, unrelated

Dematiaceous Mold Infections

23Multifocal cutaneous Alternaria alternata 342 VRC (until death)

Partial resolution of infection; death PTD 362, Pneumocystis-related

ARDS, unrelated

Figure 1. Pathogens in Invasive Fungal Infections Conclusions

• Invasive fungal infections occurred in 9% of heart

transplant recipients at our center and were associated

with high attributable and 1 year mortality.

• Important potential predictors of invasive fungal were

thymoglobulin induction, diabetes mellitus, re-operation

and simultaneous heart-kidney transplantation.

• The role of targeted voriconazole for antifungal prophylaxis

after heart transplant is unknown and deserves further

study.

References

1. De Pauw B, et al. Clin Infect Dis 2008, 46: 1813-21

2. Pappas PG, et al. Clin Infect Dis 2010, 50: 1101-11

Pulmonary Cryptococcus4% (1)

Invasive Candida30.5% (7)

Pulmonary Aspergillus30.5% (7)

Pulmonary Rhizopus13% (3)

Histoplasma 9% (2)

Blastomyces9% (2)

Cutaneous Alternaria4% (1)