Publications by authors named "Tom C Kotsimbos"

30 Publications

  • Page 1 of 1

CD8 T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph.

Nat Commun 2021 05 18;12(1):2931. Epub 2021 May 18.

Department of Biochemistry and Molecular Biology & Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. Here, we define CD8 T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8 T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2-specific CD8 T cells being cross-reactive between IAV and IBV. Memory CD8 T cells towards these specificities are present in blood (CD27CD45RA phenotype) and tissues (CD103CD69 phenotype) of healthy individuals, and effector CD27CD45RAPD-1CD38CD8 T cells in IAV/IBV patients. Our data show influenza-specific CD8 T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8 T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.
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http://dx.doi.org/10.1038/s41467-021-23212-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132304PMC
May 2021

Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients.

Nat Commun 2021 05 11;12(1):2691. Epub 2021 May 11.

Department of Biochemistry and Genetics, La Trobe Institute For Molecular Science, La Trobe University, Bundoora, VIC, Australia.

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8 or CD4 T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
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http://dx.doi.org/10.1038/s41467-021-23018-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113517PMC
May 2021

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

Cell Rep Med 2021 Mar 5;2(3):100208. Epub 2021 Feb 5.

Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3cT1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.
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http://dx.doi.org/10.1016/j.xcrm.2021.100208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862905PMC
March 2021

A Shared TCR Bias toward an Immunogenic EBV Epitope Dominates in HLA-B*07:02-Expressing Individuals.

J Immunol 2020 09 19;205(6):1524-1534. Epub 2020 Aug 19.

Department of Medicine, Monash University, Central Clinical School, The Alfred Hospital, Melbourne, Victoria 3004, Australia;

EBV is one of the most common viruses found in humans and is prototypic of a persistent viral infection characterized by periods of latency. Across many HLA class I molecules, the latent-specific CD8 T cell response is focused on epitopes derived from the EBNA-3 protein family. In the case of HLA-B*07:02 restriction, a highly frequent class I allele, the T cell response is dominated by an epitope spanning residues 379-387 of EBNA-3 (RPPIFIRRL [EBV]). However, little is known about either the TCR repertoire specific for this epitope or the molecular basis for this observed immunodominance. The EBV CD8 T cell response was common among both EBV-seropositive HLA-B*07:02 healthy and immunocompromised individuals. Similar TCRs were identified in EBV-specific CD8 T cell repertoires across multiple HLA-B7 individuals, indicating a shared Ag-driven bias in TCR usage. In particular, TRBV4-1 and TRAV38 usage was observed in five out of six individuals studied. In this study, we report the crystal structure of a TRBV4-1 TCR-HLA-B*07:02/EBV complex, which provides a molecular basis for the observed TRBV4-1 bias. These findings enhance our understanding of the CD8 T cell response toward a common EBV determinant in HLA-B*07:02 individuals.
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http://dx.doi.org/10.4049/jimmunol.2000249DOI Listing
September 2020

Preferential HLA-B27 Allorecognition Displayed by Multiple Cross-Reactive Antiviral CD8 T Cell Receptors.

Front Immunol 2020 19;11:248. Epub 2020 Feb 19.

Respiratory Medicine Laboratory, Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.

T cells provide essential immunosurveillance to combat and eliminate infection from pathogens, yet these cells can also induce unwanted immune responses via T cell receptor (TCR) cross-reactivity, also known as heterologous immunity. Indeed, pathogen-induced TCR cross-reactivity has shown to be a common, robust, and functionally potent mechanism that can trigger a spectrum of human immunopathologies associated with either transplant rejection, drug allergy, and autoimmunity. Here, we report that several virus-specific CD8 T cells directed against peptides derived from chronic viruses (EBV, CMV, and HIV-1) presented by high frequency HLA-A and -B allomorphs differentially cross-react toward HLA-B27 allotypes in a highly focused and hierarchical manner. Given the commonality of cross-reactive T cells and their potential contribution to adverse outcomes in allogeneic transplants, our study demonstrates that multiple antiviral T cells recognizing the same HLA allomorph could pose an extra layer of complexity for organ matching.
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http://dx.doi.org/10.3389/fimmu.2020.00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042382PMC
March 2021

Human γδ T-cell receptor repertoire is shaped by influenza viruses, age and tissue compartmentalisation.

Clin Transl Immunology 2019 23;8(9):e1079. Epub 2019 Sep 23.

Department of Microbiology and Immunology University of Melbourne at The Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia.

Background: Although γδ T cells comprise up to 10% of human peripheral blood T cells, questions remain regarding their role in disease states and T-cell receptor (TCR) clonal expansions. We dissected anti-viral functions of human γδ T cells towards influenza viruses and defined influenza-reactive γδ TCRs in the context of γδ-TCRs across the human lifespan.

Methods: We performed Cr-killing assay and single-cell time-lapse live video microscopy to define mechanisms underlying γδ T-cell-mediated killing of influenza-infected targets. We assessed cytotoxic profiles of γδ T cells in influenza-infected patients and IFN-γ production towards influenza-infected lung epithelial cells. Using single-cell RT-PCR, we characterised paired TCRγδ clonotypes for influenza-reactive γδ T cells in comparison with TCRs from healthy neonates, adults, elderly donors and tissues.

Results: We provide the first visual evidence of γδ T-cell-mediated killing of influenza-infected targets and show distinct features to those reported for CD8 T cells. γδ T cells displayed poly-cytotoxic profiles in influenza-infected patients and produced IFN-γ towards influenza-infected cells. These IFN-γ-producing γδ T cells were skewed towards the γ9δ2 TCRs, particularly expressing the public GV9-TCRγ, capable of pairing with numerous TCR-δ chains, suggesting their significant role in γδ T-cell immunity. Neonatal γδ T cells displayed extensive non-overlapping TCRγδ repertoires, while adults had enriched γ9δ2-pairings with diverse CDR3γδ regions. Conversely, the elderly showed distinct γδ-pairings characterised by large clonal expansions, a profile also prominent in adult tissues.

Conclusion: Human TCRγδ repertoire is shaped by age, tissue compartmentalisation and the individual's history of infection, suggesting that these somewhat enigmatic γδ T cells indeed respond to antigen challenge.
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http://dx.doi.org/10.1002/cti2.1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756999PMC
September 2019

Human CD8 T cell cross-reactivity across influenza A, B and C viruses.

Nat Immunol 2019 05 18;20(5):613-625. Epub 2019 Feb 18.

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8 T cells confer cross-protection against IAV strains, however the responses of CD8 T cells to IBV and ICV are understudied. We investigated the breadth of CD8 T cell cross-recognition and provide evidence of CD8 T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8 T cell epitopes from IBVs that were protective in mice and found memory CD8 T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8 T cells displayed tissue-resident memory phenotypes. Notably, CD38Ki67CD8 effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8 T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines.
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http://dx.doi.org/10.1038/s41590-019-0320-6DOI Listing
May 2019

Inability To Detect Cross-Reactive Memory T Cells Challenges the Frequency of Heterologous Immunity among Common Viruses.

J Immunol 2018 06 7;200(12):3993-4003. Epub 2018 May 7.

Department of Medicine, Monash University, Central Clinical School, The Alfred Hospital, Melbourne, Victoria 3004, Australia;

Human memory T cells that cross-react with epitopes from unrelated viruses can potentially modulate immune responses to subsequent infections by a phenomenon termed heterologous immunity. However, it is unclear whether similarities in structure rather than sequence underpin heterologous T cell cross-reactivity. In this study, we aimed to explore the mechanism of heterologous immunity involving immunodominant epitopes derived from common viruses restricted to high-frequency HLA allotypes (HLA-A*02:01, -B*07:02, and -B*08:01). We examined EBV-specific memory T cells for their ability to cross-react with CMV or influenza A virus-derived epitopes. Following T cell immunoassays to determine phenotype and function, complemented with biophysical and structural investigations of peptide/HLA complexes, we did not detect cross-reactivity of EBV-specific memory T cells toward either CMV or influenza A virus epitopes presented by any of the selected HLA allomorphs. Thus, despite the ubiquitous nature of these human viruses and the dominant immune response directed toward the selected epitopes, heterologous virus-specific T cell cross-reactivity was not detected. This suggests that either heterologous immunity is not as common as previously reported, or that it requires a very specific biological context to develop and be clinically relevant.
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http://dx.doi.org/10.4049/jimmunol.1800010DOI Listing
June 2018

Maintenance of the EBV-specific CD8 TCRαβ repertoire in immunosuppressed lung transplant recipients.

Immunol Cell Biol 2017 01 4;95(1):77-86. Epub 2016 Oct 4.

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.

Epstein-Barr virus (EBV) is one of the most common viruses in humans, capable of causing life-threatening infections and cancers in immunocompromised individuals. Although CD8 T cells provide key protection against EBV, the persistence and dynamics of specific T-cell receptor (TCR) clones during immunosuppression in transplant patients is largely unknown. For the first time, we used a novel single-cell TCRαβ multiplex-nested reverse transcriptase PCR to dissect TCRαβ clonal diversity within GLCTLVAML (GLC)-specific CD8 T cells in healthy individuals and immunocompromised lung transplant recipients. The GLC peptide presented by HLA-A*02:01 is one of the most immunogenic T-cell targets from the EBV proteome. We found that the GLC-specific TCRαβ repertoire was heavily biased toward TRAV5 and encompassed five classes of public TCRαβs, suggesting that these clonotypes are preferentially utilized following infection. We identified that a common TRAV5 was diversely paired with different TRAJ and TRBV/TRBJ genes, in both immunocompetent and immunocompromised individuals, with an average of 12 different TCRαβ clonotypes/donor. Moreover, pre-transplant GLC-specific TCRαβ repertoires were relatively stable over 1 year post transplant under immunosuppression in the absence or presence of EBV reactivation. In addition, we provide the first evidence of early GLC-specific CD8 T cells at 87 days post transplant, which preceded clinical EBV detection at 242 days in an EBV-seronegative patient receiving a lung allograft from an EBV-seropositive donor. This was associated with a relatively stable TCRαβ repertoire after CD8 T-cell expansion. Our findings provide insights into the composition and temporal dynamics of the EBV-specific TCRαβ repertoire in immunocompromised transplant patients and suggest that the early detection of EBV-specific T cells might be a predictor of ensuing EBV blood viremia.
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http://dx.doi.org/10.1038/icb.2016.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214975PMC
January 2017

Deciphering the clinical relevance of allo-human leukocyte antigen cross-reactivity in mediating alloimmunity following transplantation.

Curr Opin Organ Transplant 2016 Feb;21(1):29-39

aDepartment of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Commercial Road, Melbourne bInfection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton cDepartment of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville dAustralian Research Council Centre of Excellence for Advanced Molecular Imaging eDepartment of Medicine, Central Clinical School, Monash University, Clayton, VIC, Australia.

Purpose Of Review: Despite a growing awareness regarding the potential of cross-reactive virus-specific memory T cells to mediate alloimmunity, there has been limited clinical evaluation on allograft immunopathology. This review will explore published models of human T-cell cross-reactivity and discuss criteria required to drive this mechanism as a contributing cause of allograft dysfunction in transplantation.

Recent Findings: Published models of human allogeneic (allo)-human leukocyte antigen (HLA) cross-reactivity have enabled dissection of the cross-reactive T cell receptor/peptide/major histocompatibility complex (TCR/peptide/MHC) interaction. In many of the models, the cross-reactive T cells express a unique TCR, although the relevance of a public cross-reactive TCR repertoire has yet to be determined. Equally, allopeptide identity, a vital component driving cross-recognition, remains unknown in the majority of models thereby prompting further characterization utilizing novel technologies. Although clinical studies examining the presence and impact of specific cross-reactive virus-specific T cells have been minimally explored, the existing data suggest that there may be a marginal set of requirements that need to be satisfied before the potentially damaging effects of allo-HLA cross-reactivity can be realized.

Summary: Our understanding of allo-HLA cross-reactivity continues to evolve as improved technology and novel strategies allow us to better question the contribution of allo-HLA cross-reactivity in clinically relevant allograft dysfunction.
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http://dx.doi.org/10.1097/MOT.0000000000000264DOI Listing
February 2016

The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection.

PLoS One 2015 24;10(8):e0135972. Epub 2015 Aug 24.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia.

The human cytomegalovirus (CMV) immune evasion protein, UL40, shares an identical peptide sequence with that found in the leader sequence of many human leukocyte antigen (HLA)-C alleles and when complexed with HLA-E, can modulate NK cell functions via interactions with the CD94-NKG2 receptors. However the UL40-derived sequence can also be immunogenic, eliciting robust CD8+ T cell responses. In the setting of solid organ transplantation these T cells may not only be involved in antiviral immunity but also can potentially contribute to allograft rejection when the UL40 epitope is also present in allograft-encoded HLA. Here we assessed 15 bilateral lung transplant recipients for the presence of HLA-E-restricted UL40 specific T cells by tetramer staining of peripheral blood mononuclear cells (PBMC). UL40-specific T cells were observed in 7 patients post-transplant however the magnitude of the response varied significantly between patients. Moreover, unlike healthy CMV seropositive individuals, longitudinal analyses revealed that proportions of such T cells fluctuated markedly. Nine patients experienced low-grade acute cellular rejection, of which 6 also demonstrated UL40-specific T cells. Furthermore, the presence of UL40-specific CD8+ T cells in the blood was significantly associated with allograft dysfunction, which manifested as Bronchiolitis Obliterans Syndrome (BOS). Therefore, this study suggests that minor histocompatibility antigens presented by HLA-E can represent an additional risk factor following lung transplantation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135972PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547726PMC
May 2016

Influenza epidemiology, vaccine coverage and vaccine effectiveness in sentinel Australian hospitals in 2013: the Influenza Complications Alert Network.

Commun Dis Intell Q Rep 2014 Jun 30;38(2):E143-9. Epub 2014 Jun 30.

ACT Health Directorate, Canberra, Australian Capital Territory.

The National Influenza Program aims to reduce serious morbidity and mortality from influenza by providing public funding for vaccination to at-risk groups. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at 14 sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with confirmed influenza, estimates vaccine coverage and influenza vaccine protection against hospitalisation with influenza during the 2013 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals, with influenza confirmed by nucleic acid testing. Controls were patients who had acute respiratory illnesses who were test-negative for influenza. Vaccine effectiveness was estimated as 1 minus the odds ratio of vaccination in case patients compared with control patients, after adjusting for known confounders. During the period 5 April to 31 October 2012, 631 patients were admitted with confirmed influenza at the 14 FluCAN sentinel hospitals. Of these, 31% were more than 65 years of age, 9.5% were Indigenous Australians, 4.3% were pregnant and 77% had chronic co-morbidities. Influenza B was detected in 30% of patients. Vaccination coverage was estimated at 81% in patients more than 65 years of age but only 49% in patients aged less than 65 years with chronic comorbidities. Vaccination effectiveness against hospitalisation with influenza was estimated at 50% (95% confidence interval: 33%, 63%, P<0.001). We detected a significant number of hospital admissions with confirmed influenza in a national observational study. Vaccine coverage was incomplete in at-risk groups, particularly non-elderly patients with medical comorbidities. Our results suggest that the seasonal influenza vaccine was moderately protective against hospitalisation with influenza in the 2013 season.
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June 2014

Recognition of distinct cross-reactive virus-specific CD8+ T cells reveals a unique TCR signature in a clinical setting.

J Immunol 2014 Jun 28;192(11):5039-49. Epub 2014 Apr 28.

Department of Medicine, Monash University, Central Clinical School, The Alfred Centre, Melbourne, Victoria 3004, Australia; Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria 3004, Australia;

Human CMV still remains problematic in immunocompromised patients, particularly after solid organ transplantation. CMV primary disease and reactivation greatly increase the risks associated with incidences of chronic allograft rejection and decreased survival in transplant recipients. But whether this is due to direct viral effects, indirect viral effects including cross-reactive antiviral T cell immunopathology, or a combination of both remains undetermined. In this article, we report the novel TCR signature of cross-reactive HLA-A*02:01 (A2) CMV (NLVPMVATV [NLV])-specific CD8(+) T cells recognizing a specific array of HLA-B27 alleles using technical advancements that combine both IFN-γ secretion and multiplex nested RT-PCR for determining paired CDR3α/β sequences from a single cell. This study represents the first evidence, to our knowledge, of the same A2-restricted cross-reactive NLV-specific TCR-α/β signature (TRAV3TRAJ31_TRBV12-4TRBJ1-1) in two genetically distinct individuals. Longitudinal posttransplant monitoring of a lung transplant recipient (A2, CMV seropositive) who received a HLA-B27 bilateral lung allograft showed a dynamic expansion of the cross-reactive NLV-specific TCR repertoire before CMV reactivation. After resolution of the active viral infection, the frequency of cross-reactive NLV-specific CD8(+) T cells reduced to previremia levels, thereby demonstrating immune modulation of the T cell repertoire due to antigenic pressure. The dynamic changes in TCR repertoire, at a time when CMV reactivation was subclinical, illustrates that prospective monitoring in susceptible patients can reveal nuances in immune profiles that may be clinically relevant.
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http://dx.doi.org/10.4049/jimmunol.1303147DOI Listing
June 2014

Hospital-acquired influenza in an Australian sentinel surveillance system.

Med J Aust 2013 Apr;198(7):370-2

Infectious Diseases Unit, Alfred Health, Melbourne, VIC, Australia.

Objective: To review cases of nosocomial influenza and compare the epidemiology, clinical characteristics and outcomes with community-acquired cases.

Design, Setting And Participants: Prospective case series of adults hospitalised with influenza during April - November of 2010 and 2011 using a hospital-based sentinel surveillance system. A nosocomial case was defined as polymerase chain reaction-confirmed influenza where symptom onset was more than 2 15s after admission or, if this was not known, where the date of the positive test was more than 7 15s after admission.

Main Outcome Measures: Demographic, clinical and outcome measures for patients with nosocomial influenza compared with patients admitted with community-acquired influenza.

Results: In 2010-2011, 598 cases of influenza were detected, of which 26 (4.3%) were nosocomial. All patients with nosocomial influenza had chronic comorbidities, compared with 71.7% of patients (410/572) with community-acquired influenza (P = 0.001). Similar proportions of community-acquired (32.5%) and nosocomial (36.4%) cases occurred in patients vaccinated in the current season. Clinical findings at time of enrollment did not differ between the two groups, with similar rates of fever, cough, chest pain and dyspnoea. Compared with community-acquired cases, a higher proportion of patients with nosocomial influenza received neuraminidase inhibitors within 2 15s of symptom onset (38.5% v 15.9%; P = 0.003). Admission to intensive care took place in 21.3% and 23.1% of community-acquired and nosocomial cases, respectively. One death from nosocomial influenza occurred in a patient with end-stage respiratory disease.

Conclusions: Nosocomial influenza is uncommon but may be associated with severe disease. It may be partially preventable as patients frequently have comorbidities for which influenza vaccination is recommended. Patients, particularly those at high risk of complications, and their contacts (including health care workers) should be vaccinated to prevent severe disease.
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http://dx.doi.org/10.5694/mja12.11687DOI Listing
April 2013

Impact of commonly used transplant immunosuppressive drugs on human NK cell function is dependent upon stimulation condition.

PLoS One 2013 21;8(3):e60144. Epub 2013 Mar 21.

Department of Medicine, Monash University, Melbourne, Victoria, Australia.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060144PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605368PMC
September 2013

Cross-reactive anti-viral T cells increase prior to an episode of viral reactivation post human lung transplantation.

PLoS One 2013 6;8(2):e56042. Epub 2013 Feb 6.

Department of Medicine, Monash University, Central Clinical School, The Alfred Centre, Melbourne, Victoria, Australia.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056042PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566045PMC
August 2013

Donor clara cell secretory protein polymorphism is a risk factor for bronchiolitis obliterans syndrome after lung transplantation.

Transplantation 2012 Sep;94(6):652-8

Heart and Lung Transplant Unit, Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.

Background: We hypothesized that a reduced potential for bronchiolar stem-cell (Clara cell)-related repair in the setting of an ever-present risk of small airway injury would increase the risk of bronchiolitis obliterans syndrome (BOS).

Method: CCSP A38G gene polymorphism was assessed in both lung donors and recipients in a longitudinal study cohort of 63 consecutive lung transplant recipients (LTR) with a median follow-up of 493 days (range, 26-894). Clara cell secretory protein (CCSP) and interleukin 8 levels were assessed in the bronchoalveolar lavage and plasma at 1, 3, 6, and 12 months after transplantation. CCSP-positive cells were assessed in transbronchial biopsies at 1 and 3 months.

Results: Of the 63 LTR, there were 5 early deaths (≤90 days, 8% [95% confidence interval, 4%-21%]), and 20 developed BOS (32%, [95% confidence interval, 21%-45%]). Donor but not recipient CCSP A38G polymorphism was associated with more risk of BOS (relative risk, 8.6 [2.2-33.5], P<0.0001) and decreased overall survival (log-rank test, P=0.011). Bronchoalveolar lavage CCSP and CCSP/interleukin 8 levels were low and decreasing early after transplantation in LTR who developed BOS (P=0.015). CCSP+ve cells in transbronchial biopsies increased at 3 months only in LTR who remained free of BOS (P=0.003).

Conclusion: Donor CCSP A38G polymorphism is associated with decreased CCSP levels early after lung transplantation and poor long-term outcomes.
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http://dx.doi.org/10.1097/TP.0b013e31825ffca6DOI Listing
September 2012

High levels of mannose-binding lectin are associated with poor outcomes after lung transplantation.

Transplantation 2011 May;91(9):1044-9

Department of Respiratory Medicine St Vincent's Hospital, Victoria, Australia.

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<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).

Conclusions: Plasma MBL levels increase after lung transplantation and persistently increased MBL levels are associated with poor long-term outcomes.
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http://dx.doi.org/10.1097/TP.0b013e318212c7d6DOI Listing
May 2011

The impact of nocturnal oxygen desaturation on quality of life in cystic fibrosis.

J Cyst Fibros 2011 Mar 30;10(2):100-6. Epub 2010 Dec 30.

Department of Allergy Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, 3004, Australia.

Background: Nocturnal oxyhaemoglobin desaturation is common in cystic fibrosis (CF) but the effect on quality of life (QoL) remains unknown.

Methods: Sixty stable CF outpatients with mean age 31±8 years (mean±1 SD), BMI 20.8±3.2 kg/m(2) and FEV(1) 42±13% predicted had arterial blood gas sampling, lung function testing, overnight pulse oximetry and completed the CF QoL questionnaire, Epworth Sleepiness Scale and Medical Research Council dyspnoea scale.

Results: 11 (18%) of the CF patients were 'desaturators,' (SpO(2)<90% for ≥30% recording time on overnight oximetry). Desaturators had greater difficulty performing their treatments (39±22 vs 61±26, p<0.01) and more exertional dyspnoea (3.2±0.8 vs 2.0±0.9, p<0.001) than non-desaturators after controlling for the effects of FEV(1), awake PaO(2) and PaCO(2) (adjusted p-values <0.01 and 0.04 respectively).

Conclusions: Nocturnal oxyhaemoglobin desaturation is associated with impaired QoL, independent of the effects of lung function and awake gas exchange, in stable CF outpatients with moderate to severe lung disease.
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http://dx.doi.org/10.1016/j.jcf.2010.11.001DOI Listing
March 2011

Quantitative and functional diversity of cross-reactive EBV-specific CD8+ T cells in a longitudinal study cohort of lung transplant recipients.

Transplantation 2010 Dec;90(12):1439-49

Department of Medicine, Monash University, Central Clinical School, The Alfred Hospital, Melbourne, Victoria, Australia.

Background: Cross-reactive antiviral memory T cells constitute a significant proportion of the alloresponse, potentially playing a pivotal role in adverse posttransplant outcomes in human leukocyte antigen (HLA)-mismatched allografts. We explored the longitudinal dynamics of cross-reactive HLA-B8-restricted Epstein-Barr virus-specific CD8+ T cells directed toward the EBNA3A epitope FLRGRAYGL (FLR) in lung transplant recipients (LTRs) to determine whether their corecognition of HLA-B*4402 expressed on the allograft contributed to poorer posttransplant outcomes.

Methods: Cross-reactive FLR-specific CD8+ T cells were measured in the peripheral blood mononuclear cells and bronchoalveolar lavage fluid in 11 HLA-B8+ LTR, who had received HLA-B44+ lung allograft, after in vitro autologous (FLR pulsed) or allogeneic stimulation by multiparameter flow cytometry.

Results: FLR-specific CD8+ T cells were detectable ex vivo and after 13 days following in vitro peptide stimulation of peripheral blood mononuclear cells. Individual LTR and demonstrated diverse functional profiles of either cytokine production and/or cytotoxic potential (interferon-g+, interferon-g+CD107a+ and CD107a+ subsets). However, cells isolated from bronchoalveolar lavage exhibited a skewed functional phenotype toward CD107a expression alone, indicating cytotoxic-producing but not cytokine-producing capabilities. In addition, our findings suggested that the presence of cross-reactive FLR-specific CD8+ T cells may influence the alloreactive hierarchy directed against the allograft, although they were not associated with poorer short- or long-term clinical outcomes in the absence of Epstein-Barr virus reactivation and in the setting of current immunosuppression and antiviral prophylaxis protocols.

Conclusion: We report, for the first time, the longitudinal measurement of cross-reactive FLR-specific CD8 T cells within a clinical transplantation framework.
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http://dx.doi.org/10.1097/TP.0b013e3181ff4ff3DOI Listing
December 2010

Cross-presentation of HCMV chimeric protein enables generation and measurement of polyclonal T cells.

Immunol Cell Biol 2010 Aug 2;88(6):676-84. Epub 2010 Mar 2.

Malignant Haematology and Stem Cell Transplantation Service, The Alfred Hospital, Victoria, Australia.

CD8(+) T cell immunity has a critical function in controlling human cytomegalovirus (HCMV) infection. In immunocompromized individuals, HCMV reactivation or disease can lead to increased morbidity and mortality, particularly in transplant recipients. In this setting, adoptive transfer of HCMV-specific CD8(+) T cells is a promising vaccine strategy to restore viral immunity, with most clinical approaches focussing on the use of peptides for the generation of single epitope-specific CD8(+) T cells. We show that using an IE1-pp65 chimeric protein as the antigen source promotes effective cross-presentation, by monocyte-derived dendritic cells (MoDCs), to generate polyclonal CD8(+) T cell epitopes. By exploring human leukocyte antigen (HLA)-restricted immunodominance hierarchies both within and across two immunodominant proteins, we show that HLA-B7 epitopes elicit higher CD8(+) T cell responses compared with HLA-A1, -A2 or -B8. This study provides important evidence highlighting both the efficacy of the IE1-pp65 chimeric protein and the importance of immunodominance in designing future therapeutic vaccines.
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http://dx.doi.org/10.1038/icb.2010.20DOI Listing
August 2010

Natural killer cell activation in the lung allograft early posttransplantation.

Transplantation 2010 Mar;89(6):756-63

Department of Medicine, Monash University, Melbourne, Victoria, Australia.

Background: 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.

Materials And Methods: 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.

Results: 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.

Conclusions: Our studies suggest that NK cells become activated after MHC-mismatched lung transplantation.
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http://dx.doi.org/10.1097/TP.0b013e3181cab17fDOI Listing
March 2010

Differential dynamics of donor DC and non-DC peripheral blood mononuclear cell microchimerism in lung transplantation.

Clin Immunol 2009 Nov 19;133(2):179-83. Epub 2009 Aug 19.

Department of Medicine, Monash University, Melbourne, Australia.

Donor cell microchimerism induces tolerance in animal models and may increase graft survival in man. Since dendritic cells (DC) are critical for induction of both tolerance and alloreactivity we developed a method to quantitate microchimerism in donor DC and non-DC in peripheral blood mononuclear cells (PBMC) after lung transplantation. Longitudinal analysis of donor cell microchimerism in eleven sex mismatched lung transplant recipients (LTR) up to 12 months post-transplant used Y chromosome based real-time PCR on sorted cells. Total DC or a proportion of DC subsets in PBMC did not change but there were heterogeneous and dynamic changes in microchimerism in DC and non-DC. Analysis of changes in DC using a mixed model analysis showed significantly less reduction in DC compared to non-DC over time (0.49, p=0.001). Preferential DC persistence compared to non-DC may indicate tolerance induction but future studies are required to determine if DC microchimerism after transplantation affects clinical outcomes.
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http://dx.doi.org/10.1016/j.clim.2009.07.012DOI Listing
November 2009

Cranial leiomyosarcoma in an Epstein-Barr virus (EBV)-mismatched lung transplant recipient.

J Heart Lung Transplant 2007 Jul;26(7):753-5

Heart and Lung Transplant Unit, Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1016/j.healun.2007.05.007DOI Listing
July 2007

Interleukin-17 and airway inflammation: a longitudinal airway biopsy study after lung transplantation.

J Heart Lung Transplant 2007 Jul;26(7):669-74

Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.

Background: Interleukin-17 (IL-17) is a pro-inflammatory cytokine produced from CD4+ T cells and is associated with neutrophilia in infection, ischemia-reperfusion injury, and possibly acute and chronic rejection (bronchiolitis obliterans syndrome, or BOS) after lung transplantation (LTx). Everolimus (ERL) decreases acute rejection, possibly via decreasing airway CD4+ cells and neutrophils. This prospective study aims to assess: (1) the possible role of IL-17 as a link between LTx clinical outcomes (such as infection, acute rejection and BOS) and airway immunopathologic measures from endobronchial biopsy (EBB) and bronchoalveolar lavage (BAL); and (2) any differences in IL-17 production between ERL and azathioprine (AZA)-based immunosuppression.

Methods: This sub-study, from a larger, prospective clinical ERL vs AZA randomized, controlled trial, examines EBB IL-17 expression, relating this to clinical outcomes, BAL and EBB cell counts. EBB IL-17 staining was measured by immunohistologic techniques and expressed as cells per square millimeter of lamina propria.

Results: Thirty-four LTx patients were randomized in a double-blind study (ERL = 19, AZA = 15) and underwent a total of 113 bronchoscopies over a 3-year follow-up period. Twenty-six EBBs were taken from LTx recipients with BOS of at least Grade 0p (10 patients). Univariate associations correlated IL-17 positively with EBB CD8+ cells (R2 = 0.010, p = 0.001) and negatively with days post-LTx (R2 = 0.07, p = 0.002). In a multivariate model, IL-17 variability was explained by: days post-LTx (6.2%, p = 0.02); EBB CD8+ (5.9%, p = 0.02); cytomegalovirus mismatch (6.1%, p = 0.02); BAL lymphocyte percentage (4.2%, p = 0.05); and clinical infection (3.7%, p = 0.06).

Conclusions: IL-17 is associated with the early post-LTx time period and airway CD8+ cells. Unexpectedly, rejection grade, BOS, BAL IL-8 and neutrophil counts are not associated. ERL appears not to directly affect IL-17, despite its effects on CD4 cells.
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http://dx.doi.org/10.1016/j.healun.2007.05.004DOI Listing
July 2007

Gastroesophageal reflux (symptomatic and silent): a potentially significant problem in patients with cystic fibrosis before and after lung transplantation.

J Heart Lung Transplant 2005 Oct;24(10):1522-9

Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Melbourne, Australia.

Background: The significance of gastroesophageal reflux (GER) and aspiration are unclear in cystic fibrosis (CF) and may contribute to declining lung function before and after lung transplantation (LTx).

Methods: We sought to establish whether GER occurs in patients with CF on the LTx waiting list and after LTx. We then investigated whether GER correlates with patients' symptoms. Adults with CF on the waiting list and after LTx were prospectively recruited. Completion of a valid, structured symptom questionnaire was followed by ambulatory, dual-probe, 24-hour esophageal pH monitoring.

Results: Twenty-four patients were studied, including 11 (6 males) in the pre-LTx group and 13 (9 males) in the post-LTx group. The pre-LTx group was 29.3 +/- 8.2 years of age, and the post-LTx group was 32.7 +/- 8.2 years of age. DeMeester score (normal value <14.7) was 36.6 +/- 22.3 for the pre-LTx group and 40.0 +/- 37.3 for the post-LTx group. Proximal esophageal acid exposure was significantly higher in both CF groups compared with normal. Symptom scores (normal <4, range -2 to 18) were: pre-LTx group, 5.8 +/- 6.5; post-LTx group, 7.7 +/- 5.4. Percent forced expiratory volume in 1 second (FEV1%) predicted was: pre-LTx group, 31.3 +/- 7.8; post-LTx group, 65.2 +/- 29.3. In the pre-LTx group, 10 of 11 (90.9%) patients had significant GER on monitoring, including 4 (40%) with symptomatic GER and 6 (60%) with silent GER. In the post-LTx group, 11 of 13 (84.6%) had significant GER on monitoring, including 9 (82%) with symptomatic GER and 2 (18%) with silent GER.

Conclusions: GER, symptomatic and silent, is a significant problem in CF. This condition should be aggressively treated and surgery should be considered if GER persists on re-testing.
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http://dx.doi.org/10.1016/j.healun.2004.11.312DOI Listing
October 2005

Everolimus alters the bronchoalveolar lavage and endobronchial biopsy immunologic profile post-human lung transplantation.

Am J Transplant 2005 Jun;5(6):1446-51

Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital and Monash University, Melbourne, Australia.

Everolimus has recently shown promise in terms of short- and long-term clinical lung transplant outcomes. This study aims to determine the altered lung allograft cellular and cytokine mileau when everolimus is substituted for azathioprine (AZA). Twenty-three stable lung transplantation (LTx) recipients were randomized in a double-blinded study to receive everolimus (13) or AZA (10) plus standard cyclosporine/prednisolone. Bronchoalveolar lavage (BAL) and endobronchial biopsies (EBB) were performed on three occasions (T(0)-T(2)) to elucidate cellular and cytokine profiles via immunocytochemistry, immunohistology and enzyme-linked immunosorbent assay (ELISA) techniques. There were no group differences for demographics or clinical events throughout the study nor baseline cellular/cytokine differences. BAL lymphocyte percentage fell in the AZA group by T(2) (p = 0.05). BAL and EBB CD4 measures significantly declined in the everolimus group by T(2) (p < 0.05). EBB neutrophils rose significantly in the AZA group, with a fall in the everolimus group resulting in a significant difference at T(2) (p = 0.01). In conclusion, everolimus has contributed to potentially important differences in BAL and EBB cellular profiles.
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http://dx.doi.org/10.1111/j.1600-6143.2005.00863.xDOI Listing
June 2005

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

Transplantation 2004 Aug;78(4):599-606

Heart and Lung Transplant Unit, Alfred Hospital, Monash University Medical School, Commercial Road, Melbourne, Victoria 3004, Australia.

Background: 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.
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http://dx.doi.org/10.1097/01.tp.0000131975.98323.13DOI Listing
August 2004

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

Transplantation 2004 Jul;78(2):205-10

Heart and Lung Transplant Service, The Alfred Hospital, Prahran, Melbourne, Victoria 3181, Australia.

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.
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http://dx.doi.org/10.1097/01.tp.0000128611.71038.0cDOI Listing
July 2004
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