INVASIVE FUNGAL INFECTIONS

IN SOLID ORGAN TRANSPLANTATION

Jordi CarratalàDepartment of Infectious Diseases

Bellvitge Hospital-IDIBELL

University of Barcelona BellvitgeHospital

Invasive Fungal Infections in TransplantRecipients in Spain (1-09-03 / 01-03-05)

KIDNEY1330

LIVER979

HEART283

LUNG167

PANCREAS53

BMT944

TOTAL

Candida spp 41 (3%) 30 (3.1%) 11 (3.8%) 6 (3.6%) 2 (3.7%) 34 (3.6%) 124

Aspergillus spp 2 (0.2%) 5 (0.5%) 3 (1%) 10 (6%) 2 (3.7%) 56 (6%) 78

RESITRA

C. albicans 37%, C. glabrata 34%, C. krusei 13%, C. parapsilosis 11%, C. tropicalis 5%

Pappas PG. CID 2010

16.459 SOT recipients (Mar. 2001-Sep. 2005)

One-year cummulative incidence: 3.1%

Small bowel 11.6%

Lung 8.6%

Liver 4.7%

Heart 4.0%

Pancreas 3.4%

Kidney 1.3%

Pappas PG. CID 20101208 proven (42%) and probable (58%) IFI among

1063 SOT recipients

Pappas PG. CID 2010

575

343

312

184

103

467

Median time to onset of IFI

Pappas PG. CID 2010

TRANSNET. One-Year Mortality

Candidiasis 34%

Aspergillosis 41%

Non-Aspergillus molds 39%

Cryptococcosis 27%

Neofytos D. Transpl Infect Dis 2010

PATH (Prospective Antifungal Therapy Alliance)

Prospective observational study. USA/Canada (2004-2007)414 adult SOT recipients with 515 IFI episodes

Neofytos D. Transpl Infect Dis 2010

PATH (Prospective Antifungal Therapy Alliance)

3-month mortality 38% - Aspergillosis 52% - Candidiasis 24%

Risk Factors for Invasive Candidiasis

in Liver Transplant Recipients

Patient functional status

Age >65 yrs

High APACHE II score

Posttranspantation dialysis

Hyperglycemia and insulin therapy

Surgery

High requirements for transfusion

Retrasplantation

Choledochojejunostomy

Microbiology

Bacterial infection

Quinolone prophylaxis

Prolonged broad-spectrum ATB use

Immunodepression

Allograft rejection and

Corticosteroid therapy

CMV

Albano L. CID 2009

Contamination of graft or preservation fluid

18,617 kidney grafts

18 cases (12 donors) of graft-site candidiasis

Incidence, 1 case per 1000 grafts

13 Candida albicans

14 cases of renal arteritis (13 aneurysm)

2 graft site abscesses, 1 urinoma, 1 SSI

3 deaths, 9 nephrectomy

Pappas PG. CID 2010

n= 1208 n= 729

Lockhart SR. J Clin Microbiol 2011

Invasive Aspergillosis in SOT Recipients

Gavaldà J. CID 2005

Incidence: 1.4% (156/11014)

Mortality: 76.3% (119/156)

0

0,5

1

1,5

2

2,5

3

Lung Heart Liver Pancreas/Kidney Kidney

3%

2.4%

0.9% 0.9%

0.2%

80/3981

17/566

47/1920

2/230

10/4317

Risk Factor for Invasive Aspergillosis in SOT Recipients:

A Case-Control Study

Gavaldà J. CID 2005

Invasive Aspergillosis (n= 156)

Early-onset (3 months) 57%

Use of vascular amines >24h

Additional ICU stay

Posttransplantation renal failure

Posttransplantation dialysis

>1 episode of bacterial infection

CMV disease

Late-onset (>3 months) 43%

SOT at age >50 years

Posttransplantation renal failure

Chronic agraft rejection

Overimmunosuppressed state

>1 episode of bacterial infection

POPULATION SENSITIVITY (%) SPECIFICITY (%)

Hematologic malignancy 70 92

BMT 82 86

Pediatric BMT + malignancy 89 85

Solid organ transplant 22 84

Pfeiffer CD. Clin Infect Dis 2006

Clancy CJ. J Clin Microbiol 2007

Pasqualotto AC. Transplantation 2010

Singh N. Transplantation 2006

Survival at 90 days

Vorico + Caspo 68% (27/40)

Control group 51% (24/47) (P= .117)

Combination Therapy

Improved 90-day survival

Renal failure HR 0.32 (P= .022)

A. fumigatus HR 0.37 (P= .019)

2003-2005

1999-2002

The role of combination therapy in the treatment

of invasive aspergillosis as primary or salvage

therapy is uncertain and warrants a prospective,

controlled trial

Clin Infect Dis 2008

IDSA GUIDELINES

Primary Endpoint

277 SCT pts withproven/probable IA

Courtesy of KA Marr

Cryptococcosis in Solid Organ Transplant Recipients

Third IFI in frequency

Incidence ≈ 2.8% (0.3 – 5%)

- Alemtuzumab > risk

- Calcineurin inh. < disseminated

Late IFI (16 – 21 months)

Clinical Presentation

- 53 – 72% CNS or disseminated

- 54% lung, 8% bone or SST

- fungemia 30 – 40%

Cryptococcal Collaborative Transplant Study Group

Sun HY. CID 2010

Singh N. Transplantation 2005

83 recipients followed for a median of 2.1 and up to 5.2 years

Induction: L-AmB + 5FC (14 d) or L-AmB (4 w)

Consolidation: Fluconazole 400 – 800 mg/d (8 w)

Maintenance: Fluconazole 200 – 400 mg/d (6 -12 m)

Relapse: 1.3% (1/79 pts)

Less severe forms (lung): Fluconazole 400 mg/d (6 -12 m)

Calcineurin and mTOR Inhibitors as Antifungal Agents

Singh N. Transplantation 2004

Shoham S. Future Medicine 2012

Immune Reconstitution Syndrome (IRS) and Cryptococcosis

IRS occurs in 5-10% of pts (4-6 w after antifungal therapy).

Manifestations: aseptic meningitis, cerebral mass lesions,

arachnoiditis, hydrocephalus, lymphadenitis, lung nodules.

Cultures are usually negative.

IRS may be associated with higher rates of allograft loss.

Reduction as opposed to abrupt cessation of calcineurin

inhibitors, with tapering of corticosteroids.

The optimal treatment of IRS is unclear. Corticosteroids

may be considered in life-threatening situations.

Park BJ. Emerg Infect Dis 20111-year mortality: 39%

Zygomycosis in SOT Recipients

Cases typically develop within 3-6 months of Tx

Pulmonary disease predominates

Risk Factors:

- Receipt of corticosteroids

- Neutropenia

- Diabetes mellitus

- Renal failure at baseline

- Prior voriconazole and/or caspofungin use

- Liver transplantation

Singh N. J Infect Dis 2009

Overall the treatment success rate was 60%.

Renal failure (OR, 11.3; P= .023) and disseminated

disease (OR, 14.6; P= .027) were independently

predictive of treatment failure.

Surgical resection was associated with treatment

success (OR, 33.3; P= .003).

The success rate with liposomal AmB was 4-fold

higher, even when controlling for other variables.

San Juan R. Transplantation 2011

Fortún J. Transplantation 2009

Guidelines for the Treatment of IFI issued by the SEIMC

(2011 Update)

Fortún J. Enferm Infecc Microbiol Clin 2011

Thank you for your attention!

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