Colm T. Leonard

Management of Cytomegalovirus Infection in Lung Transplant Recipients: Evidence-based Recommendations

Cytomegalovirus (CMV) continues to cause significant morbidity and mortality in lung transplant recipients. This article presents recommendations based on available evidence for the optimal management of CMV in lung transplant recipients, which have been developed by an expert committee of transplant physicians-surgeons and infectious disease specialists.

Natural Killer Cells in Peripheral Blood and Lung Tissue Are Associated With Chronic Rejection After Lung Transplantation

BACKGROUND Natural killer (NK) cells have the capacity to recognize and respond to alloantigen, yet their role in lung transplant rejection is not well defined. The aim of this study was to correlate NK cell numbers and immunophenotype in peripheral blood and tissue with graft function after lung transplantation. METHODS NK cell subsets were immunophenotyped in peripheral blood (n = 41). Lung tissue was stained for NK cells via CD16 and morphologic assessment (n = 30). RESULTS Peripheral blood NK cells were activated in patients with chronic rejection, but the overall number of cells was lower in these patients when compared with stable patients. Furthermore, there was significantly more CD16(+) NK cells in the lung compartment of patients with bronchiolitis obliterans syndrome compared with stable patients (p = 0.001). CONCLUSIONS In patients with chronic rejection, peripheral blood NK cells are activated but their numbers decrease, while the number of NK cells in the lungs increases. This suggests NK cells systemically activate and migrate to the lung during the progression of chronic rejection after lung transplantation.

PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model

The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

The MDR1/ABCB1 gene, a high-impact risk factor for cardiac transplant rejection.

Background. Variations in the expression and activity levels of the multidrug-resistance MDR1/ABCB1 encoded P- glycoprotein (P-gp) have an impact on the therapeutic efficacy of many drugs. C3435T and G2677 polymorphisms of the MDR1/ABCB1 gene correlate with cellular expression levels of P-gp, a membrane-bound efflux pump which removes a multitude of drugs, including chemotherapy drugs and immunosuppressants, from cells. We aimed to investigate whether the phenomenon of drug resistance, mediated by the MDR1/ABCB1 gene and seen in tumor cells to chemotherapeutic agents, is important in the field of transplantation, predisposing some patients to resistance to immunosuppressants. Methods. G2677 and C3435T polymorphisms of the ABCB1 gene were determined by PCR in 170 heart transplant recipients. We examined the relationship between MDR1/ABCB1 polymorphisms and endomyocardial biopsy-proven rejection (EBPR) determined by biopsy performed at set intervals according to a standard protocol. Results. A significant relationship was found between a patients C3435T genotype and freedom from first grade ≥3A rejection episode. 3435-CC recipients were 1.8 times (1.05–3.09; P=0.03) more likely to undergo a ≥3A rejection episode in the first 12 months. Haplotypes derived from the G2677 and C3435T polymorphisms (GG/CC, GT/CT and TT/TT) amplified this phenomenon further (log rank, P=0.03; HR 2.18; 1.21–4.26; P=0.02). Conclusions. ABCB1 polymorphisms correlate with freedom from grade ≥3A EBPR and we believe that this may be attributed to MDR1/ABCB1 encoded P-gp mediating the efflux of immunosuppressants out of leukocytes, with depleted immunosuppressant levels in leukocytes manifesting as increased cellular rejection.

Smoking cessation. Techniques and benefits.

Tobacco dependency syndrome is an organic disease caused by chronic use of inhaled tobacco smoke. It is occasionally controlled by willpower alone, but often requires pharmacotherapy in conjunction with various techniques to manage the psychological manifestations. The two effective drugs are bupropion, which is an oral antidepressant, and nicotine, which can be administered by several modalities, including a skin patch, an oral inhalant, a nasal spray, and a chewable oral preparation. Successful therapy may require both drugs, and multiple simultaneous nicotine modalities. High-dose nicotine therapy may achieve an abstinence rate of 80% during therapy, but maintaining drug-free abstinence at such high levels over long periods is less successful, possibly because the tobacco smoke-induced changes in brain structure and function are not easily reversed.

Extracorporeal membrane oxygenator as a bridge to successful surgical repair of bronchopleural fistula following bilateral sequential lung transplantation: a case report and review of literature

BackgroundLung transplantation (LTx) is widely accepted as a therapeutic option for end-stage respiratory failure in cystic fibrosis. However, airway complications remain a major cause of morbidity and mortality in these patients, serious airway complications like bronchopleural fistula (BPF) are rare, and their management is very difficult.Case presentationA 47-year-old man with end-stage respiratory failure due to cystic fibrosis underwent bilateral sequential lung transplantation. Severe post-operative bleeding occurred due to dense intrapleural adhesions of the native lungs. He was re-explored and packed leading to satisfactory haemostasis. He developed a bronchopleural fistula on the 14th post-operative day. The fistula was successfully repaired using pericardial and intercostal vascular flaps with veno-venous extracorporeal membrane oxygenator (VV-ECMO) support. Subsequently his recovery was uneventful.ConclusionThe combination of pedicled intercostal and pericardial flaps provide adequate vascular tissue for sealing a large BPF following LTx. Veno-venous ECMO allows a feasible bridge to recovery.

Inducible nitric oxide synthase transcription in human lung transplantation

BACKGROUND Recent animal data suggest that inducible nitric oxide synthase (iNOS) mRNA expression in the bronchoalveolar lavage (BAL) may be useful for the diagnosis of lung rejection. The aim of this study was to evaluate iNOS mRNA transcription in the BAL fluid of human lung allografts. METHODS iNOS mRNA transcription was quantified by competitive reverse transcription-polymerase chain reaction in 51 BAL cell pellets of lung transplant patients. According to bacteriological and histological results, BAL samples were divided into three groups: normal (n=21), acute rejection (AR, n=15), and infection (INF, n=15). RESULTS Compared with the control group, iNOS transcription increased significantly with INF (P=0.0005) but only slightly with AR (P>0.05). INF values were significantly higher than AR values (P=0.0029). CONCLUSION BAL iNOS mRNA transcript determination by competitive reverse transcription-polymerase chain reaction may be useful in differentiating infected from normal and/or acutely rejecting allografts.

Environmental tobacco smoke and lung cancer incidence.

Tobacco smoking has been irrefutably linked to lung cancer risk. Exposure to environmental tobacco smoke and lung cancer risk has been more controversial. Various sources have claimed confounding factors such as diet and classification bias could account for the reported link. We review the available evidence and some recent papers on this topic and conclude that the evidence linking environmental tobacco smoke and lung cancer is unequivocal and cannot be explained by confounding factors.

CD4-veCD8-ve CD30+ve T cells are Detectable in Human Lung Transplant Patients and Their Proportion of the T Cell Population After In vitro Stimulation With Donor Spleen Cells Correlates With Preservation of Lung Physiolog

INTRODUCTION Survival following lung transplantation is less than 50% at 5 years, mainly due to immune-mediated chronic rejection. Recently a novel subset of T cells, CD4-veCD8-ve CD30+ve, so-called double negative (DN) CD30+ve T cells, has been described and shown to be responsible for tolerance in an animal model of skin transplantation. METHODS We investigated 18 lung transplant recipients for the presence of DN CD30+ve T cells in resting peripheral blood and also following in vitro stimulation of recipient peripheral blood mononuclear cells (PBMCs) with donor spleen cells. RESULTS Small percentages (0.2% to 6%) of DN T cells are detectable in resting PBMCs of human transplant patients (n = 18), but these did not correlate with allograft function, acute rejection episodes, HLA mismatch, or CMV status. On repeated stimulation of recipient PBMCs (two exposures) in vitro by donor spleen cells (2:1 ratio stimulators to responders) the percentage of DN CD30+ve T cells within the lymphocyte pool correlated with preservation of allograft lung function (both for FEV(1), P = .009, and FEF(25-75), P = .036) and was inversely correlated with grade of chronic rejection. On repeated exposure of recipient PBMCs to donor spleen cells with a 1:1 ratio the percentage of DN CD30+ve T cells correlated with the number of acute rejection episodes of grade 2 or greater. The total number of HLA mismatches correlated with the percentage DN CD30+ve T cells present after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio). The number of mismatches at the B locus inversely correlated with the percentage of DN CD30+ve T cells after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio; P = .031, n = 18). CONCLUSION Percentages of DN CD30+ve T cells present following repeated stimulation of recipient PBMCs by donor spleen cells correlated with preservation of graft function following lung transplantation.