Anne P. Griffiths

Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome

Early studies reported cytomegalovirus (CMV) pneumonitis as a risk factor for development of bronchiolitis obliterans syndrome (BOS) following lung transplantation. While improvements in antiviral prophylaxis have resulted in a decreased incidence of CMV pneumonitis, molecular diagnostic techniques allow diagnosis of subclinical CMV replication in the allograft. We hypothesized that this subclinical CMV replication was associated with development of BOS. We retrospectively evaluated 192 lung transplant recipients (LTR) from a single center between 2001 and 2009. Quantitative (PCR) analysis of CMV viral load and histological evidence of CMV pneumonitis and acute cellular rejection was determined on 1749 bronchoalveolar lavage (BAL) specimens and 1536 transbronchial biopsies. CMV was detected in the BAL of 41% of LTR and was significantly associated with the development of BOS (HR 1.8 [1.1–2.8], p = 0.02). This association persisted when CMV was considered more accurately as a time‐dependent variable (HR 2.1 [1.3–3.3], p = 0.003) and after adjustment for significant covariates in a multivariate model. CMV replication in the lung allograft is common following lung transplantation and is associated with increased risk of BOS. As antiviral prophylaxis adequately suppresses CMV longer prophylactic strategies may improve long‐term outcome in lung transplantation.

A donor history of smoking affects early but not late outcome in lung transplantation.

Backgrounds. Liberalization of tobacco exposure history as an exclusion to lung donation has recently occurred to increase donor organ availability. This study investigated the effect of donor smoking status and current and cumulative cigarette dose on early and late outcomes in lung transplantation. Methods. From 1995 to 2002, 173 heart-lung and bilateral single-lung transplant recipients were retrospectively reviewed. Seventy-seven (45%) of 173 donors were ever-smokers and 64 of those 77 were current smokers. These were divided into subgroups by current number of cigarettes smoked to investigate acute dose effects and by pack-year to investigate cumulative dose effects. Risks of smoking were assessed by univariate and multivariate hazard regression models. Results. Univariate analysis revealed that there were significant differences between current and cumulative dose subgroups in early postoperative variables, including Pao2/Fio2 ratio, ventilation time, and intensive care unit stay. Additionally, these variables were dose dependent. There was no significant difference in 3-year survival between never-smokers and ever-smokers (73% versus 64%, P=0.27), and a rate of decline of survival was similar. There was a trend for the percentage of patients dying of bronchiolitis obliterans syndrome to be lower in the ever-smokers group compared with the never-smokers group (6% versus 11%, respectively). Multivariate analysis revealed current and cumulative smoking as a risk factor for early but not late outcomes. Conclusions. Donor smoking history had a significant effect on early outcomes in lung transplantation in a current and cumulative dose-dependent fashion. However, no significant effect on late outcomes, including bronchiolitis obliterans syndrome, was seen.

Availability of lungs for transplantation: exploring the real potential of the donor pool.

BACKGROUND It is important to utilize all lung donor offers to maximize lung transplant (LTx) opportunities. METHODS This report describes the results of strategies that have evolved to evaluate and optimize cadaveric donor lung function and intra- and post-operative ICU management. Ongoing interactions between the intensive care unit (ICU) staff, donor coordinators and the LTx team all contribute to this process. Data are compared with the annual reports of the 2005 USA Organ and Transplant Procurement Network and UK Transplant. RESULTS In 2001, 41% of all local (State of Victoria) multiple-organ donors referred for LTx were transplanted at the Alfred Hospital, with 36% considered functionally unusable. In 2006, 66% of Victorian donors contributed lungs for LTx (18% functionally unusable, 16% logistically unusable). Of the interstate (rest of Australia) lung donor offers, 50% (no local LTx unit present) and 32% (local LTx unit with first offer) were utilized, with 33% and 48% functionally unusable, respectively. Of the 47 resultant Alfred Hospital LTxs in 2006, survival rates were 100% at 180 days and 96% at 365 days, with no mortality directly attributable to donor quality. Overall, 54% (91 of 163) of Australian organ donor offers were used for LTx (i.e., 4.5 per million population [PMP]), compared with 17% in the USA (3.8 PMP) and 13% in the UK (2.0 LTx donors PMP) in 2005. CONCLUSIONS A strategy of peri-operative lung donor evaluation and intervention suggests the number of truly unusable donor lungs is only a small fraction of the overall donor pool. In Australia, this strategy makes a significant difference in lung retrieval and transplantation rates, despite an intrinsically low (10 PMP) national donor rate.

Maximizing thoracic organ transplant opportunities: the importance of efficient coordination

BACKGROUND In Australia, despite large distances and one of the worlds lowest multiorgan donor rates (11.4/million population/year), the thoracic organ transplant (TOTx) rate of 9.6/million population/year is one of the worlds highest. METHODS As an example of the Australian approach, a system of transplant coordination and organ allocation has evolved at the Alfred Hospital. Donor organs are assigned locally, or between the 4 major TOTx units on rotation. The recipient team then selects appropriate recipients, matching by blood group, size, cytomegalovirus (CMV) status, prospective cross matching and clinical status. An experienced recipient coordinator takes responsibility for organization of the retrieval and transplant process, including all operating room staff, all medical personnel, and transport for the donor team and the potential TOTx recipients. RESULTS Between February 1989 and February 1999, 307 hearts, 48 heart/ lung, 124 single and 116 bilateral lung transplants were performed from 452 donor offers (52% beyond 500 miles). This represents 1.74 organs transplanted/thoracic donor and compares favourably to American United Network for Organ Sharing (1.43) and European (1.3) figures. CONCLUSIONS The Australia TOTx model has enabled high transplant rates by efficiently using the available donor organs. This has been achieved through an enlarged, experience TOTx team, the optimizing of donor acceptance criteria and improving coordination logistics to allow multiple thoracic procedures simultaneously.

Association between Primary Graft Dysfunction among Lung, Kidney and Heart Recipients from the Same Multiorgan Donor

Even organs from an ideal donor will occasionally develop primary graft dysfunction (PGD) causing a significant morbidity and mortality after transplantation. It is likely that this situation represents subtle undetectable levels of ongoing donor organ dysfunction. The aim of this study is to investigate the association of PGD between lung, kidney and heart recipients from the one donor.

Epstein-Barr virus primary mismatching and HLA matching: key risk factors for post lung transplant lymphoproliferative disease.

Background: Posttransplant lymphoproliferative disease (PTLD) in lung transplant recipients (LTRs) is potentially lethal with considerable morbidity. The role of donor (D)/recipient (R) HLA matching is unknown. Method: We reviewed our LTRs from January 1994, when routine D/R Epstein-Barr virus (EBV) serologic screening was begun, through to January 2000. We examined whether D/R HLA match status influenced the risk of PTLD in EBV D+/R− mismatched LTRs. Results: There were 16 D+/R− EBV-mismatched LTRs, 5 (31%) of whom developed PTLD (from a total of 237 LTRs; 218 survived >30 days). There were only two other cases of PTLD among the non-EBV primary mismatched patients. All patients received baseline immunosuppression of cyclosporine, azathioprine, and prednisolone without cytolytics and ganciclovir prophylaxis if “at risk” from cytomegalovirus. The five PTLD cases were diagnosed 81 to 734 (median 116) days from transplantation; three involved the lung allograft and two others involved lymph nodes. All PTLD patients seroconverted for EBV, whereas 7 of the 11 remaining EBV-mismatched patients who did not develop PTLD did not seroconvert. In the 16 EBV primary mismatched patients, there were 4 of 66 HLA allele matches in the 11 PTLD-free patients versus 15 of 30 matches in the 5 PTLD patients (P<0.001). This resulted in 2 or more HLA (A/B/DR) matches in 4 of 5 patients with PTLD versus 0 of 11 in the PTLD-free group (P=0.003). All PTLD patients were treated with reduced immunosuppression and antiviral therapy. Only two of the five LTRs who developed PTLD died, one with progressive disease despite chemotherapy and the other from chronic allograft rejection. Conclusion: A high degree of HLA matching in D/R EBV-mismatched LTRs significantly increases the risk of PTLD.

Long-term outcomes of cadaveric lobar lung transplantation: Helping to maximize resources

BACKGROUND Cadaveric lobar lung transplantation (CLLTx) represents a potential opportunity to address the bias against smaller recipients, especially children, on transplant waiting lists. The widespread use of CLLTx is hindered by the paucity of outcome data with respect to early complications and long-term lung function and survival. METHODS We looked at the long-term outcomes in 9 patients undergoing CLLTx since May 2003, including early surgical complications, pulmonary function tests, and survival. Patients were analyzed by whether the decision to perform CLLTx was elective (made at the time of listing) or emergent (surgical decision). RESULTS The incidence of early complications in the entire group was low, with the most common being atrial arrhythmias and prolonged thoracostomy tube. Lung function at 1 and 2 years (mean forced expiratory volume in 1 second % predicted +/- standard deviation of 73 +/- 18 and 60.5 +/- 27, respectively) was equivalent to living lobar transplant results. Overall survival was similar to 199 patients who received conventional cadaveric LTx during the same period. CONCLUSION This study suggests that CLLTx has a low complication rate with acceptable lung function and long-term survival, especially in cases where consideration has been given to CLLTx at the time of listing. CLLTx warrants consideration more often for patients of smaller physique to improve their chance of receiving LTx.

Donor history of asthma is not a contraindication to lung transplantation: 12-year single-center experience

BACKGROUND Donor asthma has been regarded as a contraindication to lung transplantation (LTx) because of concerns that pre-existing airway inflammation will predispose to early and late graft dysfunction. The aim of this study was to describe LTx outcomes in which lungs had been transplanted from donors with a history of asthma. METHODS A retrospective chart review was undertaken of 743 consecutive donor lung referrals to the Alfred Hospital between 1990 and September 2002. Seventy-four were noted to have a history of asthma, including 18 in whom asthma was the cause of death. Twenty-seven patients became lung donors, of whom 16 were on asthma treatment (on-treatment group) and 11 were not (no-treatment group). RESULTS From 27 lung donors, 35 LTx procedures were performed (16 double LTx [DLTx], 19 single LTx [SLTx]). Five recipients died at <30 days (including 3 of early graft failure in the no-treatment group), and 7 died at >30 days (only 1 due to BOS). The 30-day, 1-year and 5-year survival rates in the on- and no-treatment donor groups were 90% vs 76%, 74% vs 69% and 74% vs 60%, respectively, and were not significantly different from our overall LTx survival rates. There were no significant differences in percent predicted forced expiratory volume in 1 second, ICU stay or hospital stay overall, or when analyzed according to on treatment vs no treatment and SLTx vs DLTx. Only 2 procedures LTx were performed from fatal asthma donors, both of whom had subsequent graft dysfunction and died on Days 73 and 484, respectively. CONCLUSIONS The use of lungs from carefully selected lung donors with a history of asthma may increase the donor pool with acceptable long-term outcomes. The use of fatal asthma donors remains problematic.

The Implications of Pulmonary Embolism in a Multiorgan Donor for Subsequent Pulmonary, Renal, and Cardiac Transplantation

BACKGROUND Unexpected donor pulmonary embolism is suggested to be associated with primary graft dysfunction (PGD) after lung transplantation. In multiorgan donors with pulmonary embolism, multiple organs could potentially be at high risk for the development of post-transplant PGD. This study investigated (1) the association of donor pulmonary embolism with different organ transplant outcomes where a recipient received an organ (heart or kidney) from a lung donor, (2) the effect of different composition of pulmonary embolism (fat or thromboemboli) on multiorgan post-transplant PGD, and (3) the effect of removal of pulmonary embolism (therapeutic flush) on lung transplant outcomes. METHODS The study included 130 multiorgan donors and 135 lung, 38 heart, and 172 kidney transplant recipients. RESULTS Pulmonary embolism was detected in 40 of 130 (31%) multiorgan donors (10 fat emboli, 30 thromboemboli). A significant association between donor pulmonary embolism and PGD was seen in lung, but not in heart and kidney transplant recipients. A multivariate analysis showed that lung transplant recipients receiving lungs with fat emboli and thromboemboli were 20.6-fold (p = 0.0002) and 4.8-fold (p = 0.02) more likely to develop severe PGD, respectively, compared with those who received lungs without pulmonary embolism. Removal of pulmonary embolism reduced the incidence of PGD (p = 0.01) in lung transplantation. CONCLUSIONS The deleterious effect of donor pulmonary embolism seems to be a local phenomenon, limited to the lung; therefore, the heart and kidneys can be safely used even from a donor with pulmonary embolism. When pulmonary embolism (especially fat emboli) is diagnosed, the likely effect on lung transplant clinical outcomes and the impact of further interventional strategies (therapeutic flush) must be considered.

Aprotinin in lung transplantation is associated with an increased incidence of primary graft dysfunction

OBJECTIVE Aprotinin has been widely used to reduce bleeding and transfusion requirements in cardiac surgery and in lung transplantation. A recent study found a significant reduction in severe (grade III) primary graft dysfunction (PGD) in lung transplantation where aprotinin had been used. However, recently, concerns regarding the safety of aprotinin have been raised, and the future use of aprotinin is uncertain. In our institution, aprotinin has been widely used in cardiac surgery and transplantation. We decided to review our lung transplant caseload to investigate the impact of aprotinin on PGD and mortality and to guide our future clinical use of this antifibrinolytic. METHODS A retrospective review of prospectively collected data on 213 consecutive patients who underwent single- or double-lung transplantation was performed. Ninety-nine patients, who received aprotinin, were compared with 114 patients who did not. The main outcome variables analysed were development of primary graft dysfunction, renal impairment and mortality. RESULTS Aprotinin was associated with a significantly increased risk of PGD in the first 48 h postoperatively (p=0.01). CONCLUSIONS In conclusion, although the benefits of aprotinin on blood loss are well established, this study does not provide support for the use of aprotinin to reduce PGD in lung transplantation and indicates that aprotinin may in fact have a detrimental effect.