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ABSTRACT: Rationale: The barrier to long-term success following lung transplantation is the development of chronic lung allograft dysfunction. As the experience with lung transplantation accrues, it has become increasingly apparent that not all chronic allograft dysfunction is consistent with the traditionally recognized small-airway histological process of obliterative bronchiolitis. Objective: To identify and describe chronic allograft dysfunction that is not consistent with the well described Bronchiolitis Obliterans Syndrome and to further characterize a novel histopathological process, acute fibrinoid organizing pneumonia that has led invariably to respiratory decline and death following lung transplantation. Methods: We evaluated 194 bilateral lung transplant recipients identifying 87 individuals who developed chronic allograft dysfunction. They were then classified according to features on spirometry, chest imaging and histopathological specimens. Measurements and Main Results: Two main phenotypes of chronic allograft dysfunction were identified, 39 (45%) recipients were categorized as having developed obliterative bronchiolitis and 22 (25%) with acute fibrinoid organizing pneumonia. Survival in those that developed acute fibrinoid organizing pneumonia was significantly worse than in those that developed obliterative bronchiolitis (median time to death 101 vs. 294 days (p = 0.02)) with all exhibiting a rapid decline in respiratory function leading to death. Conclusion: Acute fibrinoid organizing pneumonia is a novel form of chronic allograft dysfunction exhibiting spirometric, radiological and histopathological characteristics that differentiate it from obliterative bronchiolitis. The further characterization of chronic allograft dysfunction and its heterogeneous manifestations will allow the targeting of clinical and experimental efforts to prevent and treat chronic allograft dysfunction.
American Journal of Respiratory and Critical Care Medicine 04/2013; · 11.08 Impact Factor
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ABSTRACT: The success of pediatric lung transplantation continues to be limited by long-term graft dysfunction. Historically this has been characterized as an obstructive spirometric defect in the form of the bronchiolitis obliterans syndrome (BOS). It is recognized, however, that this does not reflect many of the other acknowledged etiologies of chronic lung dysfunction-noting it is the sum of the parts that contribute to respiratory morbidity and mortality after transplant. The term chronic lung allograft dysfunction (CLAD) has been coined to reflect these other entities and, in particular, a group of relatively recently described lung disorders called the restrictive allograft syndrome (RAS). RAS is characterized by a restrictive spirometric defect. Although these entities have not yet been studied in a pediatric setting their association with poor compliance, antibody-mediated rejection (AMR), and post-infectious lung damage (particularly viral) warrants attention by pediatric lung transplant teams. Current therapy for the BOS subset of CLAD is otherwise limited to changing immunosuppressants and avoiding excessive infectious risk by avoiding over-immunosuppression. Long-term macrolide therapy in lung transplantation is not of proven efficacy. Reviewing previous BOS studies to explore restrictive spirometric cases and joint projects via groups like the International Pediatric Lung Transplant Collaborative will be the way forward to solve this pressing problem.
Paediatric Drugs 04/2013; · 1.79 Impact Factor
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ABSTRACT: Lung transplantation is a recognised treatment for patients with end stage pulmonary disease. Transplant recipients receive life-long administration of immunosuppressive drugs that target T cell mediated graft rejection. However little is known of the impact on NK cells, which have the potential to be alloreactive in response to HLA-mismatched ligands on the lung allograft and in doing so, may impact negatively on allograft survival. NK cells from 20 healthy controls were assessed in response to Cyclosporine A, Mycophenolic acid (MPA; active form of Mycophenolate mofetil) and Prednisolone at a range of concentrations. The impact of these clinically used immunosuppressive drugs on cytotoxicity (measured by CD107a expression), IFN-γ production and CFSE proliferation was assessed in response to various stimuli including MHC class-I negative cell lines, IL-2/IL-12 cytokines and PMA/Ionomycin. Treatment with MPA and Prednisolone revealed significantly reduced CD107a expression in response to cell line stimulation. In comparison, addition of MPA and Cyclosporine A displayed reduced CD107a expression and IFN-γ production following PMA/Ionomycin stimulation. Diminished proliferation was observed in response to treatment with each drug. Additional functional inhibitors (LY294002, PD98059, Rottlerin, Rapamycin) were used to elucidate intracellular pathways of NK cell activation in response to stimulation with K562 or PMA-I. CD107a expression was significantly decreased with the addition of PD98059 following K562 stimulation. Similarly, CD107a expression significantly decreased following PMA-I stimulation with the addition of LY294002, PD98059 and Rottlerin. Ten lung transplant patients, not receiving immunosuppressive drugs pre-transplant, were assessed for longitudinal changes post-transplant in relation to the administration of immunosuppressive drugs. Individual patient dynamics revealed different longitudinal patterns of NK cell function post-transplantation. These results provide mechanistic insights into pathways of NK cell activation and show commonly administered transplant immunosuppression agents and clinical rejection/infection events have differential effects on NK cell function that may impact the immune response following lung transplantation.
PLoS ONE 01/2013; 8(3):e60144. · 4.09 Impact Factor
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ABSTRACT: Human Cytomegalovirus (CMV) reactivation continues to influence lung transplant outcomes. Cross-reactivity of anti-viral memory T cells against donor human leukocyte antigens (HLA) may be a contributing factor. We identified cross-reactive HLA-A*02:01-restricted CMV-specific cytotoxic T lymphocytes (CTL) co-recognizing the NLVPMVATV (NLV) epitope and HLA-B27. NLV-specific CD8+ T cells were expanded for 13 days from 14 HLA-A*02:01/CMV seropositive healthy donors and 11 lung transplant recipients (LTR) then assessed for the production of IFN-γ and CD107a expression in response to 19 cell lines expressing either single HLA-A or -B class I molecules. In one healthy individual, we observed functional and proliferative cross-reactivity in response to B*27:05 alloantigen, representing approximately 5% of the NLV-specific CTL population. Similar patterns were also observed in one LTR receiving a B27 allograft, revealing that the cross-reactive NLV-specific CTL gradually increased (days 13-193 post-transplant) before a CMV reactivation event (day 270) and reduced to basal levels following viral clearance (day 909). Lung function remained stable with no acute rejection episodes being reported up to 3 years post-transplant. Individualized immunological monitoring of cross-reactive anti-viral T cells will provide further insights into their effects on the allograft and an opportunity to predict sub-clinical CMV reactivation events and immunopathological complications.
PLoS ONE 01/2013; 8(2):e56042. · 4.09 Impact Factor
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ABSTRACT: This case details the decline in lung function due to bronchial webs in a lung transplant recipient. The decline occurred 2 years after transplantation and, despite therapy, the webs, which had an inflammatory component, became treatment resistant. We outline the pathological findings and management strategies used, discuss the evidence in the literature, and offer possible causes for these unusual clinical findings.
The Annals of thoracic surgery 11/2011; 92(5):1893-6. · 3.74 Impact Factor
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ABSTRACT: During the Northern Hemisphere spring of 2009, a novel H1N1 influenza A virus emerged in Mexico, causing widespread human infection and acute critical respiratory illness. The 2009 H1N1 virus spread initially to the United States and Canada, with subsequent rapid global dissemination, leading the World Health Organization (WHO) to declare "a public health emergency of international concern" in April 2009, and upgrading the viral threat to pandemic status in June 2009. Despite initial fears, the severity of the 2009 H1N1 pandemic overall did not differ significantly from that of seasonal influenza. However, the demographics of those at risk of severe illness did differ (affecting children and young adults, rather than the very young and the very old). The 2009 H1N1 pandemic led to rapid implementation of health care initiatives, including the provision of critical care services, to limit the effect of the influenza outbreak on the community. This review focuses on the critical care response to the H1N1 pandemic and examines whether the implementation of critical care services as planned a priori matched the reality of the clinical workload and the patient burden that transpired during the 2009 H1N1 influenza pandemic.
Seminars in Respiratory and Critical Care Medicine 08/2011; 32(4):400-8. · 2.43 Impact Factor
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ABSTRACT: This article reviews recent developments in the selection, assessment, and management of the potential lung donor that aim to increase donor organ use. The scarcity of suitable donor organs results in long waiting times and significant mortality for those patients awaiting transplant. Strategies to expand the donor pool can substantially improve donor lung use rates. Although further long-term studies are required to confirm that long-term outcomes are not being compromised, the available evidence suggests that the traditional factors defining a lung as marginal or extended do not actually compromise outcomes within the framework of current donor management strategies.
Clinics in chest medicine 06/2011; 32(2):223-32. · 2.51 Impact Factor
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ABSTRACT: 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.
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.
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<0.05). LTR who developed BOS or died during the study period had higher plasma MBL levels at 6 and 12 months posttransplant (P ≤ 0.05) compared with LTR with stable graft function. MBL was not routinely detected in the lung allograft; however if present in the BAL at 3 and 6 months posttransplant, it was associated with the later development of BOS (P<0.05).
Plasma MBL levels increase after lung transplantation and persistently increased MBL levels are associated with poor long-term outcomes.
Transplantation 03/2011; 91(9):1044-9. · 4.00 Impact Factor
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ABSTRACT: We evaluated long-term safety and lung function outcomes in a cohort of patients with severe upper-zone heterogeneous emphysema who underwent bronchoscopic lung volume reduction (BLVR) performed with the Emphasys one-way valve.
A retrospective cohort study was undertaken to assess long-term outcomes in 23 consecutive patients who underwent upper lobe BLVR between July 2001 and November 2003 as part of a first-in-humans study. Long-term follow up (>12 months) was available in 16/23 patients (median duration of follow up 64 months (range 15-90 months)). Both unilateral (n=4) and bilateral (n=12) BLVR procedures were performed with a mean of 6 (range 3-11) valves being inserted. Changes in pulmonary function tests were assessed longitudinally following the procedure.
13/16 and 11/16 patients showed post-procedure improvements in FEV1 and DL(CO) , respectively. However, early improvements in pulmonary function were not sustained with only 6/16 patients still showing improved lung function at the end of follow up. There were no significant improvements in other indices of pulmonary function. Three patients, in the absence of clinical benefit, proceeded to lung transplantation at 15, 16 and 44 months post BLVR. Four patients died during the course of the study at 27, 29, 39 and 50 months post procedure.
BLVR with the Emphasys one-way valve has an acceptable safety profile and in select patients may achieve long-term sustained improvements in pulmonary function.
Respirology 11/2010; 16(1):167-73. · 2.42 Impact Factor
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ABSTRACT: Chronic allograft dysfunction continues to limit the enduring success of lung transplantation. Increasingly it is recognized that events very early post-transplant such as primary graft dysfunction can be linked to poor clinical outcomes at much later time points. In this article we review a number of the different processes that predispose the allograft to ischemia early post-transplant and explore how these events may contribute to obliterative bronchiolitis, the histological correlate of chronic lung allograft dysfunction.
Allograft ischemia may arise during explantation (warm ischemia), at implantation (in the absence of bronchial arterial reanastomosis) or at later time points (small airway microvascular damage). We describe how allograft ischemia may result in a hypoxic inflammatory milieu within the lung allograft that is conducive to vascular remodelling and angiogenesis.
Whilst the published literature for vascular remodelling in post-transplant obliterative bronchiolitis is not as extensive as that for asthma, a disease also characterized by airway pathology, there are clear parallels and shared pathophysiological pathways between the two diseases. An understanding of the complex interaction between ischemia, vascular remodelling and chronic lung allograft dysfunction may lead to the future development of therapeutic strategies that can unravel this association.
Current opinion in organ transplantation 10/2010; 15(5):558-62. · 1.22 Impact Factor
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ABSTRACT: A recent history of malignancy is considered by most transplant units as an absolute contraindication to transplantation. This particularly applies to the adult population, where the higher incidence of malignancy is related to age and exposure to relevant risk factors (e.g. smoking). In contrast, paediatric recipients are not extensively screened. Increasingly, children who develop chronic pulmonary graft-versus-host disease (GVHD) having survived treatment for haematological malignancies are being referred for lung transplantation. These patients do have a significant risk of secondary malignancy as a result of their underlying disease and/or prior treatments that need to be considered when being assessed for lung transplantation. We describe a 15- year-old patient who underwent cut-down lobar lung transplant for end-stage obliterative bronchiolitis secondary to GVHD that had developed as a result of haematopoietic stem cell transplantation for childhood acute lymphoblastic leukaemia. Unexpectedly, histopathological examination of the explant revealed extensive metastatic papillary thyroid cancer.
Transplant International 09/2010; 23(9):e45-8. · 2.92 Impact Factor
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ABSTRACT: 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.
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).
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.
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.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 04/2010; 29(4):439-44. · 3.54 Impact Factor
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ABSTRACT: In addition to their known antiviral and host defense functions, emerging evidence suggests that natural killer (NK) cells may influence allograft outcomes after solid organ transplantation. Although it is accepted that NK cells are activated in the absence of self-major histocompatibility complex (MHC) class I molecules, little is known of how NK cell dynamics change after transplantation of a MHC disparate lung allograft.
To assess this, we characterized longitudinal changes in NK cell frequency and phenotype, using flow cytometry, both in the peripheral blood and lung allograft in 34 patients undergoing lung transplantation.
NK cell frequency decreased with time from transplant with mature NK cells being replaced by a population of less differentiated NK cells expressing lower levels of killer cell immunoglobulin-like receptors. In contrast to peripheral blood, NK cells within the allograft consisted of a greater proportion of CD56 cells, expressed less killer cell immunoglobulin-like receptors, and demonstrated an activated phenotype. In clinically stable recipients, peripheral blood NK cells were not activated, however, this contrasted markedly with a small subset of patients experiencing acute allograft rejection or cytomegalovirus reactivation, whose NK cells demonstrated a more activated profile.
Our studies suggest that NK cells become activated after MHC-mismatched lung transplantation.
Transplantation 12/2009; 89(6):756-63. · 4.00 Impact Factor
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ABSTRACT: The clinical limits and most relevant definition of warm ischemic time (WIT) for donation after cardiac death (DCD) donor lungs are unclear.
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.
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.
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.
Transplantation 01/2009; 86(12):1702-6. · 4.00 Impact Factor
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ABSTRACT: Two children with advanced lung disease underwent successful cadaveric bilateral lobar lung transplantation, using lungs "cut down" from deceased adult donors - the first reported use of the technique in Australia. This approach, while it cannot address the lack of donor organs, may enable us to redress any size bias limiting paediatric lung transplantation.
The Medical journal of Australia 09/2008; 189(3):173-5. · 2.81 Impact Factor
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ABSTRACT: Complement staining as a predictor of antibody-mediated rejection (AMR) after lung transplantation continues to be debated.
In a cohort of 33 lung transplant recipients (LTRs) we assessed early post-transplant (<or=3 months) graft deposition of the complement factors C3d and C4d and correlated staining with clinical outcome. A retrospective analysis of allograft C3d and C4d deposition was performed by an experienced histopathologist blinded to clinical outcomes. Biopsies were graded 0 to 3 based on extent of septal capillary complement staining.
Significant C3d and C4d staining (i.e., Grade >or=2 on more than one occasion) was observed in 20 and 11 LTRs, respectively. Complement staining was increased in LTRs with severe primary graft dysfunction or airway infection, but was not associated with acute cellular or chronic rejection, or with morphologic features of AMR. In a sub-group analysis we identified 9 LTRs who developed early bronchiolitis obliterans syndrome (BOS) in the absence of acute cellular rejection or cytomegalovirus reactivation, but they had significant lung allograft C3d/C4d deposition along with corroborative light-microscopic features suggestive of AMR.
Complement activation, as judged by lung allograft deposition of C3d/C4d, is common early post-lung transplant and may be triggered by primary graft dysfunction and/or airway infection, and may play a role in the development of early BOS.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 07/2008; 27(7):722-8. · 3.54 Impact Factor
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Respirology 10/2007; 12(5):631-3. · 2.42 Impact Factor
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ABSTRACT: Significant similarities between the challenges of lung transplantation in patients of all ages should lead to better access to this life-saving surgery for children and adolescents.
The Medical journal of Australia 10/2007; 187(5):260-1. · 2.81 Impact Factor
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ABSTRACT: Leiomyosarcoma is a rare Epstein-Barr virus (EBV)-related complication of solid-organ transplantation. We report the case of a 19-year-old woman with cystic fibrosis who presented with protracted headaches 15 months after an EBV-mismatched bilateral sequential lung transplant. A parasagittal lesion was found on cranial magnetic resonance imaging; surgical resection revealed a leiomyosarcoma. We discuss treatment options of what is, to our knowledge, the first described case of a cranial leiomyosarcoma in a lung transplant recipient.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2007; 26(7):753-5. · 3.54 Impact Factor
