G. Snell

A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.

The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation

BACKGROUND The bronchiolitis obliterans syndrome (BOS) remains the major constraint on the long term success of lung transplantation. Neutrophils have been associated with fibrosing lung conditions and have been noted to be increased in the bronchoalveolar lavage (BAL) fluid of patients with BOS. METHODS This study was undertaken to examine neutrophil accumulation in the BAL fluid, airway wall and lung parenchyma, as well as levels of interleukin (IL)-8 in the BAL fluid, in normal controls and lung transplant recipients with and without BOS. Bronchoscopic examination included endobronchial biopsy (EBB), BAL fluid, and transbronchial biopsy (TBB) sampling. Tissue neutrophils were identified by neutrophil elastase staining on 3 μm paraffin biopsy sections and quantified by computerised image analyser. IL-8 levels were measured in unconcentrated BAL fluid by ELISA. RESULTS Compared with controls, airway wall neutrophilia was increased in both stable lung transplant recipients and those with BOS (p<0.05). BAL neutrophils and IL-8 levels were also increased in both groups of transplant recipients compared with controls (p<0.01), the levels being significantly higher in the BOS group (p<0.01). Neutrophil numbers in the lung parenchyma were not significantly different between the two groups of lung transplant recipients. CONCLUSION Increased levels of neutrophils are present in the airway wall and BAL fluid of lung transplant recipients with and without BOS. BAL fluid levels of IL-8 are also increased, raising the possibility that neutrophils and/or IL-8 may play a part in the pathogenesis of BOS following lung transplantation.

Early Lung Transplantation Success Utilizing Controlled Donation After Cardiac Death Donors

Donation‐after cardiac death (DCD) donor organs have potential to significantly alleviate the shortage of transplantable lungs. However, only limited data so far describes DCD lung transplantation (LTx) techniques and results. This study aims to describe the Alfred Hospitals early and intermediate outcomes following DCD donor LTx. Following careful experimentation and consultation DCD guidelines were created to utilize Maastricht category III lung donors from either the ICU or operating room(OR), with a warm ischemic time(WIT) of <60 min. Between May 2006 and December 2007, 22 referred DCD donors led to 11 attempted retrievals after withdrawal, resulting in 8 actual bilateral LTx (2 donors did not arrest in prescribed period and 1 donor had nonacceptable lungs). ICU WIT = 38.4 min (range 20–54, OR WIT = 12.7 min (11–15), p < 0.05. Post‐LTx, 1 pulmonary hypertensive patient required ECMO for PGD3. The mean group pO2/FiO2 ratio at 24 hours was 307.7 (240–507) with an ICU stay of 9.5 days (2–21) and ward stay of 21.5 days (11–76). All 8 survive at a mean of 311 days (10–573) with good performance status and lung function. In conclusion, the use of Maastricht category III lungs for human LTx is associated with acceptable early clinical outcomes.

Everolimus versus azathioprine in maintenance lung transplant recipients: An international, randomized, double-blind clinical trial

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double‐blind clinical trial, 213 BOS‐free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1–3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV1 >15%[ΔFEV1 >15%], graft loss, death or loss to follow‐up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of ΔFEV1 >15%, ΔFEV1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.

Excellent Clinical Outcomes From a National Donation-After-Determination-of-Cardiac-Death Lung Transplant Collaborative

Donation‐after‐Determination‐of‐Cardiac‐Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5‐year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an “extra” 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 ± 4.0 min (range 18–89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO2/FiO2 ratio 315 (range 50–507)]. Overall the incidence of grade 3 chronic rejections was 5%. One‐ and 5‐year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain‐dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs.

Antifungal Prophylaxis in Lung Transplantation— A World-wide Survey

While variations in antifungal prophylaxis have been previously reported in lung transplant (LTx) recipients, recent clinical practice is unknown. Our aim was to determine current antifungal prophylactic practice in LTx centers world‐wide. One nominated LTx clinician from each active center was invited by e‐mail to participate in a web‐based survey between September 2009 and January 2010. Fifty‐seven percent (58/102) responded. The majority of responses were from medical directors of LTx centers (72.4%), and from the United States (44.8%). Within the first 6 months post‐LTx, most centers (58.6%) employed universal prophylaxis, with 97.1% targeting Aspergillus species. Voriconazole alone, and in combination with inhaled amphotericin B (AmB), were the preferred first‐line agents. Intolerance to side effects of voriconazole (69.2%) was the main reason for switching to alternatives. Beyond 6 months post‐LTx, most (51.8%) did not employ antifungal prophylaxis. Fifteen centers (26.0%) conducted routine antifungal therapeutic drug monitoring during prophylactic period. There are differences in strategies employed between U.S. and European centers. Most respondents indicated a need for antifungal prophylactic guidelines. In comparison to earlier findings, there was a major shift toward prophylaxis with voriconazole and an increased use of echinocandins, posaconazole and inhaled lipid formulation AmB.

Human Cytomegalovirus Load in Plasma and Bronchoalveolar Lavage Fluid: A Longitudinal Study of Lung Transplant Recipients

BACKGROUND In lung transplant recipients (LTRs), the measurement of human cytomegalovirus (HCMV) load dynamics in the local environment of the lung allograft may offer distinct advantages over their assessment in the peripheral blood compartment. METHODS We compared HCMV load in paired bronchoalveolar lavage (BAL) and plasma samples in a prospective cohort of LTRs. RESULTS In all, 182 paired samples were collected from 41 LTRs. Qualitative findings were concordant for 79.7% of the paired samples (virus load detected or absent in 8.1% and 71.5% of paired samples, respectively). In 35 paired samples (20.3%), HCMV was detected in the BAL but not the plasma sample; the converse was not found for any of the paired samples. HCMV inclusions were histologically detected in the lungs of 8 patients on 9 occasions. HCMV was detected in both BAL and plasma samples on 7 of the 9 occasions and in only the BAL sample on 2 occasions. Application of a threshold virus load in BAL samples, to predict histologically proven HCMV infection, was associated with improved diagnostic sensitivity and specificity. CONCLUSIONS Quantification of HCMV in the lung allograft correlates with histological detection and, in addition, offers the potential to monitor subclinical viral replication in the lung allograft.

Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation

Rapamycin/sirolimus (SR), trade named Rapammune (Wyeth-Ayerst, Sydney, Australia), is a potent immunosuppressive drug associated with myelosuppression, hypertension, hyperlipidemia, and infection. Rapamycin/sirolimus-induced pneumonitis has been described previously in renal transplant recipients, and this report describes a stable heart-lung transplant recipient who developed a pulmonary infiltrate that reversed after ceasing SR therapy. We believe that immunosuppression-induced pneumonitis in a lung allograft is a serious dilemma for lung transplant physicians

Bronchiolitis obliterans syndrome and early human cytomegalovirus Dnaaemia dynamics after lung transplantation

Background. Bronchiolitis obliterans syndrome (BOS) remains a major cause of morbidity and mortality after lung transplantation. The major identified risk factors for BOS are acute rejection and human cytomegalovirus (HCMV) infection, the latter despite the use of relatively insensitive and nonspecific measures such as HCMV pneumonitis and HCMV serostatus, respectively. We hypothesized that a more accurate prospective analysis of HCMV reactivation in lung transplant recipients (LTRs) would improve our understanding of the association between HCMV and BOS development. Methods. In 26 LTRs, HCMV DNAaemia was measured using quantitative polymerase chain reaction at monthly intervals during the initial 6 months posttransplantation. BOS was defined as a sustained irreversible 20% decrease in FEV1 compared with the best baseline FEV1 posttransplantation in the absence of any other cause. Results. Of the 26 LTRs, 23 were assessable with regard to the BOS outcome variable. At a median follow-up of 37 months, 10 patients had developed BOS. During the first 6-month monitoring period, HCMV DNAaemia was detected in 15 of the 23 patients on at least one occasion, and there were 12 episodes of HCMV pneumonitis in eight patients. Episodes of grade A3 or greater acute rejection occurred in eight LTRs, six of whom had been HCMV DNAaemia positive at least once and four of whom also demonstrated HCMV pneumonitis. Our results revealed a strong association between BOS and early HCMV DNAaemia detection (univariate analysis [P =0.002] and freedom from BOS analysis [P =0.006]). Conclusion. Early HCMV DNAaemia in LTRs is associated with the development of BOS despite routine ganciclovir prophylaxis.