Ishlt GuidelinesThe 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary
Section snippets
Evidence summary
All information on fungal colonization in lung transplant (LT) candidates has been obtained from observational studies, most of them from single centers. Therefore, confidence about the exact prevalence of fungal colonization in LT candidates is limited. The data are more robust in the cystic fibrosis (CF) population due to these patients’ ability to produce sputum. Studies have included colonization at any time pre-transplant, and there is a distinct lack of data regarding colonization rates
Pediatrics epidemiology
Pediatric LT is now an accepted therapy that offers carefully selected children a survival benefit.35, 36 FIs are burdensome for pediatric LT patients; however, epidemiologic data on the effect of FIs in pediatric LT have been sparse.
Most children undergo LT for end-stage CF lung disease, and many of these patients are chronically colonized with fungal pathogens. In a retrospective, single-center study from Texas Children’s Hospital, 29 children (70%) were colonized before transplantation.37
Evidence summary
One of the main limitations of the enzyme-linked immunosorbent assay galactomannan (GM) test is its reduced sensitivity in non-neutropenic individuals. One meta-analysis49 showed the sensitivity of serum GM testing was 82% in a hematology population and 22% in SOT patients.
Most studies conducted in SOT recipients have shown that serum GM testing is associated with an unacceptably low sensitivity for the diagnosis of IA.50, 51 Husain et al52 demonstrated that the test had a sensitivity of only
Evidence summary
The lateral flow device (LFD) test is a rapid single-sample point-of-care test that is based on the detection of an Aspergillus extracellular glycoprotein antigen by monoclonal antibody JF5. Recently, comparative data started emerging in SOT recipients in a semi-prospective study including 26 LTRs and 2 heart transplant recipients. The reported sensitivity and specificity was 91% and 83%, respectively.71
Evidence summary
IA in SOT recipients occurs more commonly as an airway disease than as an angioinvasive
Pediatrics diagnosis
Data regarding diagnostic strategies have not been reported in the pediatric CT literature. Extrapolation with caution from adult recommendations is possible, but further investigations of accurate diagnostic biomarkers of IFD in pediatric CT are suggested.
Evidence summary
Pre-transplant isolation of molds from the lower respiratory tract has been documented, raising questions about transplant candidacy and the need for pre-transplant treatment. The spectrum of infection has included colonization and allergic bronchopulmonary aspergillosis (up to 50%),76 aspergilloma/mycetoma (3%),77 chronic necrotizing/cavitary pulmonary aspergillosis or semi-invasive disease (2.3%),7 and IPA (1.1%).8 Patients in whom pre-transplant mycetomas were detected only in explanted
Pediatric prophylaxis
Very limited data exist to respond to any of the questions related to anti-fungal prophylaxis for pediatric LTRs, and a recent multicenter survey showed the wide range of anti-fungal prophylaxis strategies as current international practice in pediatric LTRs.111
Evidence summary
Given the poor prognosis of IFD in many previous studies, some investigators have sought to improve outcomes with the administration of combination anti-fungal therapy. To date, no randomized trials of combination therapy for IA in CT recipients have been performed. However, in addition to case reports, 2 studies have suggested a possible benefit of such therapy in certain patient sub-sets. Singh et al112 performed a retrospective, multicenter comparison of 40 SOT recipients with IA treated
Pediatrics therapy
Combination anti-fungal therapy has been addressed in only 1 single-center study that evaluated results in 11 patients37 (azole and AmB or an echinocandin; some subjects received aerosolized amphotericin as part of the therapy).
Evidence summary
Much of the data on the use of TDM for azoles have come from other patient groups (e.g., the hematopoietic stem cell transplantation population). One retrospective audit of heart and lung transplant recipients demonstrated considerable inter- and intrapatient variability in itraconazole concentrations and sub-therapeutic concentrations (see Table 7 for the therapeutic range).121 IFD developed in 6 of 57 patients (10.5%), but itraconazole concentrations were sub-therapeutic in 3 (50%) of those
Pediatrics TDM
Data regarding TDM strategies have not been reported in the pediatric CT literature.
Background
The field of MCSD has made tremendous progress in recent decades, with more than 30,000 patients receiving durable MCSDs worldwide.134 The initial device design consisted of a pulsatile-flow pump, which could be intracorporeal or extracorporeal. During the past decade, continuous-flow devices have superseded the pulsatile-flow design. These devices have superior outcomes with better adverse event profiles, significantly lower rates of infection, smaller pump sizes, smaller-width drivelines, and
Pediatrics MCSD
MCSD have been increasing in use as the preferred intermediate and long-term means for MCSD in pediatric heart failure patients, predominantly as a bridge to transplant but also as bridge to recovery or destination therapy. Most of the pediatric literature focused on VADs has reported substantial complications related to infections after implantation. Single-center and multicenter case series have both consistently reported infectious episodes, including sepsis and non–device-related
Future directions
The landscape of IFD in CT organ transplant recipients continues to evolve. Although more resistant fungal infections are on the horizon, the availability of novel preparations of azoles (e.g., posaconazole tablets or isavuconazole) provide better opportunities in prophylaxis and treatments of IFD. The development of novel point-of-care fungal diagnostic tests coupled with refinements in TDM may shape the future of fungal infection management.
Disclosure statement
S.H. has received research grants from Pfizer, Merck, and Astellas. B.D.A. has received research grants from Synexis, Viamet, Astellas, and Charles River Laboratories and is a site investigator for Synexis, Astellas, Optimer, ViroPharma, and Gilead. R.A. has received research grants from Viropharma/Shire, Astellas, Chimerix. and Merck. D.C. has received a research grant and honorarium from MSD and consulting fees and is on the advisory board of Pfizer. P.G. has received honorariums from MSD,
References (177)
- et al.
A survey of anti-fungal management in lung transplantation
J Heart Lung Transplant
(2004) - et al.
Antifungal prophylaxis in lung transplantation—a world-wide survey
Am J Transplant
(2011) - et al.
A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients
J Heart Lung Transplant
(2011) - et al.
Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients
Chest
(2003) - et al.
Pulmonary aspergillosis in cystic fibrosis lung transplant recipients
Chest
(1998) - et al.
Infections in patients with cystic fibrosis following lung transplantation
Chest
(1997) - et al.
Voriconazole prophylaxis in lung transplant recipients
Am J Transplant
(2006) - et al.
Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients
Am J Transplant
(2012) - et al.
Aspergillus airway colonization and invasive disease after lung transplantation
Chest
(1997) - et al.
Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness
Am J Transplant
(2009)