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Biomedical subjects

K McNeil

Publications and source records attributed to K McNeil.

At least 19 recordsLinked to original sources
PubMed2005

Extended ganciclovir prophylaxis in lung transplantation.

BACKGROUND: Positive cytomegaloviral status of the donor or of the recipient adversely affects survival and enhances the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. The role of ganciclovir prophylaxis in cytomegalovirus infection in respect to obliterative bronchiolitis or to BOS development is not known. METHODS: From the Papworth transplant database, we identified 146 patients who received organs from cytomegalovirus-positive donors. We classified patients into 3 groups as follows: Group 1 consisted of 42 patients who underwent transplantation between 1990 and 1992 when no prophylaxis was given; Group 2 consisted of 49 patients who underwent transplantation between 1992 and 1995 when 4 weeks of IV ganciclovir was given as prophylaxis; and Group 3 consisted of 55 patients who underwent transplantation between 1995 and 1998 when cytomegalovirus prophylaxis consisted of IV (1 week) followed by oral ganciclovir for a total of 3 months. Donor management, recipient management during and after surgery, and pharmacotherapy were uniform during the study period. We used survival and regression methods to compare these groups, adjusting for the transplantation type (single lung, double lung, or heart-lung) and for HLA typing. RESULTS: We found a significant difference among all 3 groups in numbers of cytomegaloviral disease episodes in the 1st year after transplantation. The number of rejection episodes in the 3 groups during the 1st post-transplant year gradually decreased from Group 1 to Group 3. We identified no statistically significant benefit in the time to BOS occurrence or in actuarial survival. CONCLUSION: Extended prophylaxis with IV and oral ganciclovir practically abolishes cytomegaloviral disease and is related to a decreased incidence of rejection episodes. However, ganciclovir prophylaxis is not related to a decreased incidence or progression of BOS or survival.

Adult↗
PubMed2004

Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness.

The success of lung transplantation has improved over time as evidenced by better long-term survival and functional outcomes. Despite the success of this procedure, there are numerous problems and complications that may develop over the life of a lung transplant recipient. With proper monitoring and treatment, the frequency and severity of these problems can be decreased. However, significant improvement for the overall outcomes of lung transplantation will only occur when better methods exist to prevent or effectively treat chronic rejection.

Cost-Benefit Analysis↗
PubMed2003

Atrial septostomy in the treatment of severe pulmonary arterial hypertension.

BACKGROUND: Atrial septostomy (AS) may improve symptoms and haemodynamics in patients with severe pulmonary arterial hypertension (PAH). METHODS: Twenty AS performed in 17 patients with severe progressive PAH (13 primary pulmonary hypertension, two collagen vascular disease, one thromboembolic disease, one vaso-occlusive disease) were analysed. Seven patients were in NYHA class III and 10 in NYHA IV. Fifteen patients were on long term prostanoid treatment. AS was performed under fluoroscopy using graded balloon technique. RESULTS: AS improved clinical symptoms and increased the cardiac index from 1.8 to 2.2 l/min/m(2) and systemic oxygen transport from 263.2 to 329.6 ml/min/m(2) (p<0.001). Procedure related complications included one non-fatal atrial puncture and one unsuccessful septal puncture. Four patients died within 1 week of surgery from uncontrolled tachyarrhythmia (n=1), severe hypoxaemia (n=1), and multiorgan failure (n=2). One further patient died after voluntarily discontinuing renal dialysis. Twelve patients are alive 5-17 months after the operation with five patients undergoing heart-lung transplantation. There were no differences in haemodynamic and functional parameters between the non-survivors and the mid term survivors. However, the non-survivors were significantly older (52 v 36 years, p<0.01) and had a significantly lower creatinine clearance rate (70 ml/min v 48 ml/min, p<0.05). CONCLUSION: Atrial septostomy improves clinical symptoms, cardiac index, and systemic oxygen transport and has the potential to influence the prognosis in selected cases of severe PAH.

Adolescent↗
PubMed2002

Molecular evidence of Helicobacter cinaedi organisms in human gastric biopsy specimens.

One hundred twenty-six urease-negative gastric biopsy specimens were evaluated for the presence of Helicobacter genus-specific 16S ribosomal DNA (rDNA) and H. pylori-specific glmM DNA sequences by PCR. The species specificity of the glmM PCR assay was demonstrated, as H. pylori was the only Helicobacter species that yielded the expected glmM amplicon. Most urease-negative specimens (118 of 126 specimens) lacked Helicobacter DNA. However, 8 of 126 urease-negative specimens contained Helicobacter 16S rDNA. In order to identify the Helicobacter species present in urease-negative gastric biopsy specimens, 16S rDNA amplicons were cloned and sequenced. Sequence comparisons were performed by analyses of the sequences in public sequence databases. Two samples contained 16S rDNA that was identified as H. cinaedi with 100% identity and that spanned approximately 400 bp (398 and 398 bp, respectively). In contrast, multiple differences (97% identity; 390 of 398 bp) were observed with H. pylori 16S rDNA in this region. This finding was verified by sequencing an overlapping 537-bp fragment within the 5' portion of 16S rDNA. Although the clinical findings were consistent with H. pylori infection (e.g., duodenal ulcer disease), rapid urease testing and DNA sequence analyses suggested the presence of H. cinaedi organisms and the absence of H. pylori in two human antral biopsy specimens. This study represents the first report of an enteric urease-negative helicobacter in the human stomach. Although these organisms were previously associated with extragastric infections, the roles of these organisms in the pathogenesis of chronic gastritis or peptic ulcer disease remain unclear.

Base Sequence↗
PubMed2001

A model for analyzing the cost of the main clinical events after lung transplantation.

BACKGROUND: The aim of this project was to model clinically important events experienced by lung transplant patients (from the day after transplant to 5 years or death) and costs associated with these events, and to assess the economic impact of different immunosuppression therapies. METHODS: The population comprised 356 lung transplant patients (223 heart-lung, 102 single lung and 31 double lung) transplanted between April 1984 and December 1997. All patients received a cyclosporine-based triple-immunosuppression protocol. We designed a Markov model that included 3 time periods (0 to 6, 7 to 12, and 13 to 60 months), 5 clinical states (well, acute rejection, cytomegalovirus infection, non-cytomegalovirus infection and bronchiolitis obliterans syndrome), and death. For the well state, cost elements were immunosuppression, prophylaxis, and routine clinic visits. For all other states, cost elements were diagnosis, treatment, and bed days/visits. We excluded costs of the procedure. RESULTS: The monthly costs associated with the well state decreased over time, from pound sterlings 1,778 ($2,658) in the first 6 months to pound sterlings 503 ($752) in months 7 to 12 and pound sterlings 350 ($523) after the first 12 months. The cost per event of the acute states remained reasonably constant over the 3 periods: pound sterlings 1,850 ($2,766) for rejection, pound sterlings 3,380 ($5,053) for cytomegalovirus, and pound sterlings 2,790 ($4,171) for other infections. The average cost per patient, discounted at 6%, over 5 years was pound sterlings 35,429 ($52,966) (95% range, pound1,435 [$2,145] to pound67,079 [$100,283]). This estimate is most sensitive to changes in immunosuppression. Substituting tacrolimus for cyclosporine increased 5-year costs by 5%; substituting mycophenolate mofetil for azathioprine increased 5-year costs by 26%. CONCLUSIONS: This model is valuable in estimating the effect of new immunosuppression agents on the costs of follow-up care.

Adult↗
PubMed2000

BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

Adolescent↗
PubMed1999

Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients.

Cytomegalovirus (CMV) disease has had a significant clinical impact on the heart, heart-lung and lung transplant recipients in our centre. CMV disease has been so severe with CMV antibody-negative heart-lung transplant patients receiving organs from CMV antibody-positive donors (CMV-mismatched patients) that in 1986 we adopted the policy of not transplanting CMV-positive organs into CMV-negative heart-lung or lung recipients. In December 1992, we instituted a policy of providing intravenous ganciclovir (5 mg/kg twice a day for 28 days) during the immediate postoperative period for CMV-mismatched heart recipients and CMV antibody-positive heart-lung and lung patients, who have been the patients at greatest risk of severe CMV disease in our centre. A placebo group was not employed because of ethical considerations, ganciclovir having been shown to be effective for the treatment of CMV infections among transplant patients. Compared with a historical control group of patients receiving no prophylaxis, prophylactic ganciclovir reduced the incidence of CMV infection (39 % vs 91 %, P = 0.0006) and CMV disease (17 % vs 74 %, P = 0.0004) among CMV antibody-positive heart-lung recipients. Prophylactic ganciclovir did not significantly reduce the incidence of CMV infection or disease among heart or isolated lung recipients. Ganciclovir was well tolerated, with few adverse reactions. In the case of heart-lung transplant patients, one month of intravenous prophylactic ganciclovir significantly reduced the incidence of both CMV infection and disease when compared with patients who received no prophylaxis. With the lung transplant and heart transplant patients, there were no significant differences between the prophylaxis and nonprophylaxis groups, although there was a consistent trend towards less infection and disease in the prophylaxis groups.

Adolescent↗
PubMed1999

[Lung transplantation at the Papworth Hospital: 9-year experience].

OBJECTIVE: To review and compare our results for single lung transplantation (SLT) and double lung transplantation (DLT). METHODS: One hundred twenty-three patients transplanted between September 1988 and July 1997 (99 SLT and 24 DLT) were reviewed. Mean follow-up was 749 days. RESULTS: The following variables were significantly different for the two recipient populations: the most common indication was restriction for SLT and sepsis for DLT; mean ages were 50.3 +/- 9.2 and 40.6 +/- 14.3 for SLT and DLT, respectively; and nutritional status measured as body mass index was 21.5 +/- 4 for SLT and 18.6 +/- 2.7 for DLT. DLT patients experienced longer periods of ischemia during surgery (287 +/- 75 min versus 242 +/- 65 min for SLT, p = 0.01) and more of them required extracorporeal circulation (67% versus 37%, p = 0.005). Early postoperative morbidity after DLT was greater because of bleeding (1,046 +/- 848 ml versus 690 +/- 503 ml; p = 0.01) and time of intubation (9 hours, interquartile range 7 to 13 for DLT patients versus 5 hours, interquartile range 1 to 10 for SLT; p = 0.001). DLT recipients also suffered more respiratory infections during the first 3 months after surgery. Long term, DLT patients had greater pulmonary function capacity than did SLT patients, a difference that was maintained over the three years of follow-up. Readmission was more frequent among DLT patients because of infection (0.40 versus 0.26 readmissions per patient per 100 days; p < 0.02). CONCLUSIONS: Both unilateral and bilateral lung transplants are valid therapeutic options for patients with terminal phase lung disease. DLT offers more hope of long term functional recovery without negatively affecting survival.

Adolescent↗
PubMed1999

Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients.

The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6 were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p < 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0 measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0 as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0 but not C2 or C6 were associated with the risk of acute lung allograft rejection.

Adult↗
PubMed1998

Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors.

BACKGROUND: In lung transplantation, obliterative bronchiolitis is the major factor limiting long-term survival. Bronchiolitis obliterans syndrome (BOS), defined as staged decline in pulmonary function has proved a reproducible and sensitive marker of obliterative bronchiolitis. METHODS: The incidence of, and risk factors for, BOS were investigated in 230 lung transplant recipients who underwent transplantation from April 1984 to December 1995 and who survived at least 3 months after operation. Progression and prognosis was investigated in the 109 cases with development of BOS. RESULTS: Actuarial BOS-free probability at 5 years was 36%. Post-BOS onset survival was 51% at 3 years. BOS onset conferred increased risk of death (hazard ratio [HR], 5.96; 95% confidence interval [CI], 3.61, 9.83). Donor and recipient characteristics such as sex, age, underlying disease, type of transplant, and graft ischemic time did not affect BOS onset, progression, or prognosis. Cytomegalovirus serologic status and early acute rejection were risk factors for BOS onset in multivariate modeling. In univariate analysis, other risk factors were lung infection, cytomegalovirus episodes, organizing pneumonia, and human leukocyte antigen mismatch. Later transplantation era (1991 to 1995) was associated with decreased risk of BOS (HR, 0.64; 95% CI, 0.44, 0.92). Acute rejection affected post-BOS progression (HR, 1.28/episode; 95% CI, 1.12, 1.45) and survival (HR, 1.20/episode; 95% CI, 1.05, 1.37). Post-BOS lung infection was an independent prognostic factor (HR, 1.12/episode; 95% CI, 1.01, 1.24). BOS onset in the later half of the series (1992 to 1997) was associated with decreased risk of progression (HR, 0.52; 95% CI, 0.33, 0.82). CONCLUSIONS: This study confirms that BOS is a major problem in lung transplantation, with a high incidence, rapid progression, and poor survival. It affects all modes of lung transplantation, regardless of sex, age, or underlying diagnosis. Acute rejection is a major prognostic factor. Lung infections after BOS onset worsen survival rates.

Actuarial Analysis↗