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Aim: Single (SLTx) and double lung transplantation (DLTx) are therapeutic options for end-stage interstitial lung disease (ILD). The aim of this study is to describe oscillometry indices in stable SLTx compared to DLTx recipients. Methods: Oscillometry & spirometry were performed on all stable LTx recipients at 2 Australian centres from 2020-2021 using TremoFlo C-100 to obtain resistance (R5, R5-19), reactance (X5) and reactance area (Ax). Subjects with baseline, acute or chronic lung allograft dysfunction were excluded. SLTx for ILD (SLTx-ILD) recipients were compared with DLTx for ILD (DLTx-ILD) and were matched by age and gender. Results: 17 SLTx-ILD were included and compared with 10 matched stable DLTx-ILD. Baseline demographics of SLTx-ILD [88% males; mean age 64 (SD 5)] and DLTx-ILD [90% males; mean age 63 (SD 6)] were similar. Median X5 (-1.86 vs -1.14, p=0.02) and Ax (12.60 vs 5.57, p=0.04) differed significantly between SLTx-ILD and DLTx-ILD recipients, but resistance (R5, R5-19) measurements did not. Conclusion: SLTx for ILD is characterised by significantly worse X5 and Ax (increased elastance) as compared to DLTx for ILD. The abnormal reactance, in addition to insignificant differences in resistance measurements between SLTx and DLTx, may be due to the fibrotic contralateral native lung. However, contribution from other factors such as differences in lung size matching needs to be assessed. Longitudinal oscillometry studies are required to ascertain whether abnormal reactance – when assessed against patients9 baseline measurements – can be indicative of earlier progressive lung graft dysfunction and a worse prognosis in SLTx, as compared to using traditional methods.

We provide the results of the first interventional study of cytomegalovirus (CMV)-specific immune monitoring to direct the length of antiviral prophylaxis in lung transplantation (LTx).Patients (n = 118) at risk of CMV infection were randomized 1:2 to either 5 months or variable length valganciclovir prophylaxis (5-11 mo post-LTx), as determined by the QuantiFERON (QFN)-CMV assay. Patients with a negative QFN-CMV assay ( 0.2 IU/mL) received prolonged valganciclovir prophylaxis.The primary endpoint that was the incidence of CMV infection in the lung allograft within 18 months of LTx was significantly reduced in the QFN-CMV directed arm (37% versus 58%, P = 0.03). Secondary endpoints that included blood viremia, acute rejection, and chronic lung allograft dysfunction did not differ between the 2 arms. Of the 80/118 patients who ceased antiviral prophylaxis at 5 months, the incidence of viremia ( 600 copies/mL) within the blood was significantly reduced in patients with a positive QFN-CMV assay compared with those without protective immunity (13% versus 67%, P = 0.0003), as was the incidence of severe viremia ( 10 000 copies/mL) (3% versus 50%, P 0.001). Ceasing antiviral prophylaxis at 11 months in patients with a negative assay was associated with a 25% incidence of late CMV viremia.Cytomegalovirus immune monitoring allows an individualized approach to CMV prophylaxis and reduces late CMV infection within the lung allograft.

Background Severe pulmonary chronic graft versus host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Few treatments influence outcome, with 5-year overall survival as low as 13%. Lung transplantation (LTx) has been reported in small numbers of patients worldwide. Methods We investigated the outcomes of LTx performed for this indication at 2 large Australian LTx centers. Results Eighteen patients (aged 10-64 y; median, 29.6 y) received bilateral deceased lung transplants for pulmonary chronic GVHD between 2002 and 2017. LTx was performed at a median of 8.6 years after allogeneic stem cell transplantation (range, 2-23 y) with a median interval of 16 months from the time of transplant unit review to LTx. There were 2 early infective deaths and 3 further deaths from pulmonary infection and lung allograft rejection. There were no primary disease relapses. At a median follow-up of 5 years, the 5-year overall survival post-LTx is 80% and comparable to the Australia and New Zealand registry data of 64% for LTx performed for all indications. Conclusions From one of the largest series of deceased LTx for this indication, we conclude that it is a feasible option for selected patients with severe pulmonary GVHD. The outcomes appear superior to that of non-LTx-based therapies and similar to the survival of the general LTx population. Establishing guidance on referral triggers, patient eligibility, organ selection, prophylaxis of allograft rejection, and supportive care would assist hematopoietic and lung transplant units in optimizing resource allocation and patient outcomes.

Diabetes mellitus (DM) is associated with increased mortality after transplantation, but the effect of glycemic control on survival is unknown.We sought to determine the relationship between glycemic control (random blood glucose [RBG], fasting blood glucose [FBG], and glycated hemoglobin [HbA1c]) and survival in all lung transplant (LTx) recipients and those with either persistent or no DM.All 210 LTx recipients from August 1, 2010 to November 1, 2013, were included (median observation 3.0 years). All underwent oral glucose tolerance tests pre-LTx and serially post-LTx. All glucose and HbA1c results from LTx until study end were included, and hazard ratios were calculated.Of 210 patients, 90 had persistent DM, and 84 had no DM. Overall mortality/repeat LTx was 31%. In the whole cohort, each 1 mM (18 mg/dL) increase in mean FBG and RBG and each 1% increase in mean HbA1c were associated with mortality increases of 18% (95% confidence interval [CI], 5-32%, P = 0.006), 38% (95% CI, 15-65%; P0.001), and 46% (95% CI, 15-85%; P = 0.002), respectively. RBG correlated with mortality in the persistent DM and no DM groups, 37% (95% CI, 7-75%; P = 0.012) and 109% (95% CI, 3-323%; P = 0.041) increases/1 mM, respectively).Glycemic control strongly correlates with survival after LTx. RBG predicted mortality overall and in patients with and without DM. We propose hyperglycemia be managed promptly after LTx.

Background. The clinical limits and most relevant definition of warm ischemic time (WIT) for donation after cardiac death (DCD) donor lungs are unclear. Methods. Prospectively collected postwithdrawal and postmortem DCD donor hemodynamics and oximetry were temporally studied to determine the range, pattern, and potential clinical relevance to DCD clinical lung transplant outcomes. Different definitions of WIT were examined including the timing of withdrawal, systolic blood pressure less than 50 mm Hg, initiation of ventilation or the onset of pulmonary arterial flush. Intensive care unit donor management was strictly according to local practice guidelines. Results. Between May 2006 and August 2008, 24 DCD donor referrals led to 13 attempted lung retrievals, resulting in nine bilateral lung transplantions (three donors did not arrest within prescribed 90 min window and one donor had unacceptable lungs). The mean WIT for the 10 retrieved DCD lungs varied according to the different potential definitions and ranged from 10 to 42 min (absolute range, 3-65 min). Donor blood pressure, heart rate, and oximetry fell linearly from the time of withdrawal, leading to cardiac arrest on average 13.8 min later. Conclusions. From a practical perspective, a WIT definition starting when systolic blood pressure is less than 50 mm Hg and finishing with cold arterial flush, provides the simplest, most universal definition that encompasses all important elements of warm ischemia. There is a need to prospectively collect data on all potential DCD lung donors and correlate these with clinical outcomes.

Background. T lymphocytes are crucial in lung allorejection. The contribution of lymphocyte subtypes to the pathogenesis of chronic rejection (bronchiolitis obliterans syndrome [BOS]) remains unclear. Methods. Twenty-nine initially healthy lung transplant recipients underwent 136 bronchoscopic assessments, including bronchoalveolar lavage (BAL) (with flow cytometry) and endobronchial biopsies (EBB) (with immunohistochemistry) over 3 years of follow-up. Results. Of the 29 patients studied over 3 years, 23 developed BOS category 0p and 17 went on to BOS 1. Compared with controls, the BAL percentage of CD4 + cells was lower and the percentage of CD8 + cells was increased significantly early posttransplant. Subsequent BAL lymphocyte subtype changes with time, or with the development of BOS, were minimal. By contrast, the early posttransplant EBB lymphocyte numbers were normal (P>0.05 vs. controls); subsequently, CD3 + and CD8 + (but not CD4 +) cells were increased with time in patients who did not develop BOS (P

Background. Bronchiolitis obliterans syndrome (BOS) is a common late complication in lung transplant recipients (LTR). Chlamydia pneumoniae (C. pneumoniae) is a common but difficult to diagnose respiratory pathogen with a propensity to latency. Methods. We studied the impact of C. pneumoniae on BOS development using donor-recipient serology obtained before transplantation in a cohort of 76 LTR. Results. BOS was present in 29.9% patients (mean follow-up 866 days). High donor C. pneumoniae immunoglobulin (Ig)G titers were associated with BOS in the recipient (area under the curve [AUC] 0.71, 95% confidence interval [CI] 0.52-0.91, P=0.027), whereas high recipient titers were inversely associated with BOS (AUC 0.27, 95% CI 0.11-0.44, P=0.018). The risk of developing BOS was 75.0% in the case of a primary seromismatch for C. pneumoniae (D+/R-), whereas a reverse mismatch had a risk of 4.6% (likelihood ratio 9.8, P=0.02). In a multivariate model that included human leukocyte antigen matching, acute rejection and cytomegalovirus pneumonitis, C. pneumoniae IgG donor 32 or greater and C. pneumoniae IgG recipient 32 or greater remained positive and negative independent risk factors, respectively, for BOS in LTR. In the freedom from BOS analysis, BOS occurred more frequently and earlier in C. pneumoniae seropositive donors, and the reverse was true in seronegative recipients. Conclusion. C. pneumoniae serology in donor and recipient is associated with the development of BOS in LTR.

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

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.

Background. It is postulated that bronchiolitis obliterans syndrome (BOS) is preceded by airway inflammation that has been described even in stable lung transplant recipients. Airway inflammation is known to be suppressed by inhaled steroids in other chronic inflammatory lung diseases, e.g., asthma and chronic obstructive pulmonary disease. BOS is the major cause of morbidity and mortality after lung transplantation. Objective. To examine the effect of inhaled corticosteroids on the development of BOS in lung transplant recipients. Methods. Thirty patients were recruited and randomized in a double-blind fashion to receive either 750 μg of fluticasone propionate (FP) or an identical-appearing placebo twice daily for 3 months; 20 of this group continued until 2 years posttransplantation. Detailed spirometry was performed regularly throughout the study. Results. In the short-term study no differences were found in any examined parameters. In the long-term component of the study no differences were found in the development of neither BOS nor survival. There were minor differences in bronchoalveolar lavage (BAL) lymphocyte percentages. Conclusions. FP is ineffective for the prevention of BOS after lung transplantation despite the airway inflammation that characterizes this condition. Inadequate local delivery, timing of the therapy relative to transplantation and inherent steroid resistance of this condition may explain the negative finding of this study.

Background. Human cytomegalovirus (HCMV) reactivation and disease remain relatively common in lung transplant recipients (LTR) despite the use of ganciclovir prophylaxis protocols for all HCMV at-risk patients. The specific aims of this study were to (1) describe the HCMV DNA viral load in the peripheral blood leukocytes (PBL) of a cohort of LTR during the first 6 months after lung transplantation; (2) prospectively determine whether HCMV DNA viral load predicts episodes of HCMV pneumonitis in LTR; and (3) study the effect of ganciclovir on HCMV viral load. Methods. Competitive polymerase chain reaction using an internal standard and fluorometric detection were used to quantitate HCMV DNA in the PBL of a cohort of 26 LTR monthly for the first 6 months after transplantation (145 samples). All patients were treated with standard triple immunosuppression, and ganciclovir prophylaxis was given to all at-risk LTR (donor or recipient HCMV seropositive) for at least 8 weeks after transplantation. Results. Thirteen episodes of histopathologically proven HCMV pneumonitis in nine subjects occurred during follow-up with a wide intra- and intersubject variation in the HCMV DNA PBL levels. HCMV detection had a sensitivity of 92% and specificity of 76% for HCMV pneumonitis (negative likelihood ratio, 9.5), whereas greater than 10-fold increases in HCMV DNA load had a specificity of 93% and sensitivity of 67% (positive likelihood ratio, 11). HCMV DNA detection had an adjusted odds ratio for HCMV pneumonitis of 107 (95% confidence interval, 14-821; P

Background. Mannose-binding lectin (MBL) is a key molecule of the innate immune system and, in addition to the classical and alternative pathways, a principle driver of complement activation. Genetic mutations of MBL are common, result in low serum levels of MBL, and are associated with increased infection risk in solid-organ transplant recipients. Methods. We performed a retrospective study of MBL2 genotype and plasma and bronchoalveolar lavage (BAL) MBL levels in 37 lung transplant recipients (LTR). Plasma MBL levels were measured pretransplant and both plasma and BAL MBL levels were measured at 3, 6, and 12 months after lung transplantation. MBL2 genotyping was performed on recipient and donor peripheral blood mononuclear cells. Clinical variables analyzed included primary graft dysfunction, intensive care unit stay, acute allograft rejection, infection, bronchiolitis obliterans syndrome (BOS), and mortality. Results. Plasma MBL levels posttransplant were predicted by recipient, and not donor MBL2 genotype. Compared with pretransplant levels, plasma MBL was significantly increased at 3, 6, and 12 months posttransplant (P

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 PaO 2 /FiO 2 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.

Human lung and heart transplantation using donation-after-cardiac-death donors has recently been shown to be feasible and associated with excellent clinical results. Considering this, if we are to avoid confusing the lay and medical public, perhaps the better term is donation-after-cardiocirculatory death.

It is common to assign an upper age limit for potential lung transplant recipients. The influence of age on LTX outcome is, however not, documented. A review of our first 103 LTXs, 51 single LTXs and 52 double LTXs, includes 31 recipients aged 50-63 years (mean 55.3 +/- 3.9); 19 received single LTX, and 12 received double LTX. Indications for LTX in those aged greater than 50 included proportionately more patients with emphysema and interstitial lung disease. Actuarial survivals in those aged less than 50 at 12, 36, and 60 months were 68%, 60%, and 55%, and in those aged greater than 50 was 70%, 61%, and 61%, respectively. The causes of death reflect a tendency of younger patients to die from graft rejection and older patients to die from sepsis. Acute rejection more than 6 weeks posttransplant and chronic rejection were less frequent in older patients (P < 0.05). The 6-minute walk and modified Bruce protocol tests, the incidence of CMV pneumonitis, and the late post-LTX renal function were not related to age. In conclusion, in carefully selected candidates in their sixth and seventh decades, LTX is an acceptable operation for end-stage lung disease. The tendency of older patients to a lower incidence of late allograft rejection (acute or chronic) may reflect decreased immunological responsiveness with age.