Introduction of spirometry into clinical practice in Georgetown, Guyana: quality and diagnostic outcomes.

SETTING: Georgetown Public Hospital Corporation (GPHC), a 600-bed publicly funded referral hospital in Georgetown, Guyana. OBJECTIVE: To assess spirometry quality and diagnostic outcomes 2 years after the introduction of spirometry into routine clinical practice at GPHC. DESIGN: We performed a retrospective review of 476 consecutive spirometry assessments performed from November 2013 to November 2015. We assessed the proportion and trend of spirometry tests meeting acceptability criteria, along with diagnostic interpretations and spirometry laboratory referral patterns. RESULTS: Overall, 80.4% of the 454 initial spirometry measurements on unique patients met the acceptability criteria, with no significant change in the proportion of acceptable spirometry over the study period (P = 0.450). Of the 369 (81.3%) first tests considered interpretable, 139 (30.6%) were normal, 151 (33.3%) were obstructive, 54 (11.9%) were suggestive of a restrictive pattern, 25 (5.5%) were suggestive of a mixed disorder and 119 (26.2%) tests met the definition of reversibility. CONCLUSION: Over a 2-year period, high-quality spirometry was performed in GPHC, a publicly funded hospital in a middle-income country with no pre-existing specialised respiratory service.

Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past.

BACKGROUND: Solid organ transplant (SOT) recipients are at risk for Pneumocystis pneumonia (PCP), especially in the first year post transplant. Although trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis substantially decreases this risk, there is little data or consensus on optimal duration of prophylaxis. Consequently, there is lack of standardization of prophylaxis duration (3 months to lifelong, depending on organ group) in SOT programs. METHODS: We performed a retrospective chart review of all cases of confirmed PCP, in adult kidney, pancreas, liver, and lung transplant recipients from 2001 to 2011 in our SOT program. RESULTS: Of 1241 patients followed in our clinic (657 kidney, 44 kidney/pancreas, 436 liver, and 104 lung or heart/lung), a total of 14 PCP cases were identified in 2 kidney, 1 kidney/pancreas, 5 liver, 5 single lung, and 1 heart/lung transplant recipient. At the time of PCP diagnosis, immunosuppression in most cases consisted of prednisone, tacrolimus, and mycophenolate mofetil (79% of patients), and 53% had previously received TMP-SMX for prophylaxis. None were on PCP prophylaxis at the time of illness onset. PCP occurred early in all 5 liver transplant recipients and in 1 kidney transplant recipient, none of whom had ever received prophylaxis (17-204 days post transplant). Of those who had received 6 months of prophylaxis (1 kidney, 1 kidney/pancreas), PCP occurred at 846 and 4778 days, respectively. Late onset PCP occurred in lung recipients who had received 12 months of prophylaxis (lung 645-1414 days, heart/lung 1583 days post transplant). Five patients had experienced acute rejection and 6 patients had cytomegalovirus (CMV) viremia on average 59 and 204 days preceding PCP, respectively. Three deaths (1 liver, 2 lung) were thought to be directly related to complications of PCP. CONCLUSION: Our experience with late PCP cases in lung transplant recipients receiving only 1 year of prophylaxis lends support to prolonged PCP prophylaxis in this group. Given the number of patients who had experienced an acute rejection episode or CMV disease preceding PCP in non-lung SOT recipients, consideration should be given to re-institution of PCP prophylaxis for a period of time after these events in kidney, kidney/pancreas, and liver transplant recipients.

Permanent pacemaker insertion after CoreValve transcatheter aortic valve implantation: incidence and contributing factors (the UK CoreValve Collaborative).

BACKGROUND: Permanent pacemaker (PPM) requirement is a recognized complication of transcatheter aortic valve implantation. We assessed the UK incidence of permanent pacing within 30 days of CoreValve implantation and formulated an anatomic and electrophysiological model. METHODS AND RESULTS: Data from 270 patients at 10 centers in the United Kingdom were examined. Twenty-five patients (8%) had preexisting PPMs; 2 patients had incomplete data. The remaining 243 were 81.3±6.7 years of age; 50.6% were male. QRS duration increased from 105±23 to 135±29 milliseconds (P<0.01). Left bundle-branch block incidence was 13% at baseline and 61% after the procedure (P<0.001). Eighty-one patients (33.3%) required a PPM within 30 days. Rates of pacing according to preexisting ECG abnormalities were as follows: right bundle-branch block, 65.2%; left bundle-branch block, 43.75%; normal QRS, 27.6%. Among patients who required PPM implantation, the median time to insertion was 4.0 days (interquartile range, 2.0 to 7.75 days). Multivariable analysis revealed that periprocedural atrioventricular block (odds ratio, 6.29; 95% confidence interval, 3.55 to 11.15), balloon predilatation (odds ratio, 2.68; 95% confidence interval, 2.00 to 3.47), use of the larger (29 mm) CoreValve prosthesis (odds ratio, 2.50; 95% confidence interval, 1.22 to 5.11), interventricular septum diameter (odds ratio, 1.18; 95% confidence interval, 1.10 to 3.06), and prolonged QRS duration (odds ratio, 3.45; 95% confidence interval, 1.61 to 7.40) were independently associated with the need for PPM. CONCLUSION: One third of patients undergoing a CoreValve transcatheter aortic valve implantation procedure require a PPM within 30 days. Periprocedural atrioventricular block, balloon predilatation, use of the larger CoreValve prosthesis, increased interventricular septum diameter and prolonged QRS duration were associated with the need for PPM.

Candidate genes for COPD in two large data sets.

Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV1 % predicted and FEV1/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.

What is the impact of providing a transcatheter aortic valve implantation service on conventional aortic valve surgical activity: patient risk factors and outcomes in the first 2 years.

OBJECTIVES: To assess the impact of introducing a transcatheter aortic valve implantation (TAVI) service on aortic valve surgical activity and outcomes. DESIGN: A retrospective analysis of prospectively collected data. SETTING: University hospital of south Manchester. PATIENTS: 815 consecutive patients undergoing isolated aortic valve replacement (AVR) or coronary artery bypass grafting plus AVR from January 2006 to December 2009. Fifty consecutive patients who underwent TAVI from January 2008 to December 2009. MAIN OUTCOME MEASURES: Aortic valve surgical activity in the 2years before the introduction of a TAVI service and in the 2years following. Outcomes following conventional aortic valve surgery and TAVI. RESULTS: In the 2years following the introduction of TAVI at this centre, conventional AVR activity has increased by 37% compared with an 8% increase nationally (p<0.001). Compared with the 2years before TAVI there was no change in the mean logistic EuroSCORE (7.4 vs 7.9 p=0.16) or crude mortality rate (2.9% vs 2.1% p=0.48). Fifty high-risk patients underwent TAVI with a 30-day mortality rate of 0%. The mean logistic EuroSCORE of the TAVI patients was 25.3. CONCLUSIONS: TAVI is an emerging alternative to AVR in high-risk patients. Since the introduction of a TAVI service at this centre, conventional AVR activity has increased. Despite a trend of increasing mean logistic EuroSCORE indicating that more complex cases are being undertaken, there has been a non-significant reduction in the crude mortality rate. Offering a TAVI service has a positive impact on the volume of conventional AVR surgical activity.

Misplaced pulmonary arteries in an adult patient with pulmonary hypertension.

Misalignment of pulmonary vessels, with or without alveolar capillary dysplasia, is a rare cause of persistent pulmonary hypertension in the newborn. The prognosis is poor, with virtually all patients succumbing to unremitting hypoxaemic respiratory failure and death during the newborn period. We report the CT and histological findings of misplaced pulmonary arteries in a previously healthy young adult patient who presented with pulmonary arterial hypertension. Contiguous high-resolution spiral CT angiography showed small pulmonary arteries coursing within the interlobular septa and enlarged central pulmonary arteries. Surgical lung biopsy demonstrated anomalous muscularised pulmonary arteries in the interlobular septa. This is, to our knowledge, the first report of misplaced pulmonary arteries presenting in an adult patient and may represent a forme fruste of the neonatal vascular anomaly. A possible association with pulmonary arterial hypertension is also suggested in this case.

Outcome in the real-world of coronary high-risk intervention with drug-eluting stents (ORCHID) -- a single-center study comparing Cypher sirolimus-eluting with Taxus paclitaxel-eluting stents.

OBJECTIVE: We present real world experience from a single center registry comparing the 6-month outcome of percutaneous coronary intervention (PCI) in unselected high-risk individuals using either sirolimus-eluting (SES) or paclitaxel-eluting stents (PES). METHODS/RESULTS: We compared clinical outcome at 6 months follow-up in two cohorts of 156 consecutive patients (total n = 312) who underwent SES (June 2002-February 2003) and PES (march 2003-July 2003) implantation. The primary endpoint was a composite of major adverse cardiac events (MACE). Baseline clinical characteristics were well matched. The 6-month target vessel revascularization (TVR) rates were 1.9% (SES) and 2.6% (PES) and MACE rates were similar in the two groups (SES 4.5% vs. PES 3.2%, P = NS). In the PES group, intervention for multivessel disease, bifurcation lesions and in small vessels was more common, and for in-stent restenosis less common, reflecting the impact of drug eluting stents on indications for PCI. The incidence of sub-acute stent thrombosis, related to inadequate antiplatelet therapy in 3 of the 6 cases, was 0.95% with no difference between the two groups. CONCLUSION: This study confirms the safety and efficacy of SES and PES in unselected high risk patients undergoing PCI. Clinical outcomes of both stents are equivalent at 6 months with low rates of MACE and TVR. These data provide important complementary information to forthcoming randomized studies.

Bronchiolitis obliterans following lung transplantation: early detection using computed tomographic scanning.

BACKGROUND: Computed tomographic (CT) scanning may enable earlier diagnosis of chronic lung allograft dysfunction than forced expiratory volume in 1 second (FEV1). A study was undertaken to determine intra-observer and inter-observer agreement of composite and air trapping CT scores, to examine the association of FEV1 with the composite and air trapping CT score, and to relate the baseline composite CT score to changes in FEV1 and changes in the composite CT score over 1 year. METHODS: Lung function and baseline CT scans following transplantation and at subsequent annual follow ups were analysed in 38 lung transplant recipients. Scans were randomly scored by two observers for bronchiectasis, mucus plugging, airway wall thickening, consolidation, mosaic pattern, and air trapping, and re-scored after 1 month. CT scores were expressed on a scale of 0-100 and correlated with FEV1 as a percentage of the post-transplant baseline value. RESULTS: The mean (SD) interval between baseline and follow up CT scans was 11.2 (4.7) months. Inter-observer and intra-observer agreement was good for both the composite and air trapping CT scores. There was a significant association between FEV1 and the composite CT score, with each unit of worsening in the baseline composite CT score predicting a 1.55% and 1.37% worsening in FEV1 over the following year (p<0.0001) and a 1.25 and 1.12 unit worsening in the composite CT score (p<0.0001) for observers 1 and 2, respectively. CONCLUSION: These findings indicate a potential role for a composite CT scoring system in the early detection of bronchiolitis obliterans.

Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment.

The development of pulmonary hypertension is a poor prognostic sign in patients with chronic obstructive pulmonary disease (COPD), affecting both mortality and quality of life. Although pulmonary hypertension in COPD is traditionally viewed as a result of emphysematous destruction of the vascular bed and/or hypoxia, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressures. New human and animal experimental data are beginning to show that pulmonary hypertension in this setting is probably a result of the direct effect of tobacco smoke on the intrapulmonary vessels with abnormal production of mediators that control vasoconstriction, vasodilatation, and vascular cell proliferation, ultimately leading to aberrant vascular remodelling and aberrant vascular physiology. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest that the treatments used for primary pulmonary hypertension may be beneficial in patients with COPD.

Interpretation of transbronchial lung biopsies from lung transplant recipients: inter- and intraobserver agreement.

BACKGROUND: Transbronchial lung biopsy results are crucial for the management of lung transplant recipients. Little information is available regarding the reliability and reproducibility of the interpretation of transbronchial lung biopsies. OBJECTIVE: To examine the inter-reader variability between two lung pathologists with expertise in lung transplantation. METHODS: Fifty-nine transbronchial lung biopsy specimens were randomly selected. Active infection had been excluded in all cases. The original interpretations (as per the Lung Rejection Study Group) for acute rejection grade included 19 biopsies scored as A0 (none), 14 scored as A1 (minimal), 12 as A2 (mild), 11 as A3 (moderate) and three as A4 (severe). The pathologists worked independently without clinical information or knowledge of the original interpretation. The specimens were graded using the Lung Rejection Study Group criteria for acute rejection (grades A0 to A4), airway inflammation (grades B0 to B4) and bronchiolitis obliterans (C0 absent and C1 present). Between-reader agreement for each category was analyzed using a Kappa statistic. RESULTS: Because many transplant specialists initiate augmented immunosuppression with biopsy grades of A2 or higher, results for each reader were dichotomized as A0/A1 versus A2/A3/A4. Using this dichotomy, there was only moderate agreement (kappa 0.470, P < 0.001) between readers. For categories B and C, the results were dichotomized for the absence or presence of airway inflammation and bronchiolitis obliterans, respectively. The level of agreement between readers was fair for category B (kappa 0.333, P = 0.014) and poor for category C (kappa 0.166, P = 0.108). The intrareader agreement for acute rejection was substantial (kappa 0.795, P = 0.0001; kappa 0.676, P = 0.0001). CONCLUSIONS: Because the agreement between expert pathologists is only modest, optimum clinical decision-making requires that transbronchial lung biopsy results be used in an integrated clinical context.

Plasma concentrations of tumour dimeric pyruvate kinase are increased in patients with chronic cardiac failure.

BACKGROUND: The aim of the study was to assess the effect of chronic cardiac failure (CCF) on circulating plasma concentrations of tumour metabolic marker dimeric pyruvate kinase type M2 (M2-PK). METHODS: Fifty patients with clinically stable CCF were studied. Patients with a history of past or ongoing malignancy were excluded. Dimeric M2-PK was measured by enzyme-linked immunosorbent assay in EDTA plasma. RESULTS: Dimeric M2-PK concentration increased significantly (P = 0.005) with increasing clinical severity of CCF as assessed by the New York Heart Association classification grade. CONCLUSIONS: Chronic cardiac failure results in an increased circulating plasma concentration of M2-PK, probably related to increased glycolytic flux. The physiological significance of the results is at present unclear but may relate to maintaining a balance between energy production and the supply of glycolytic intermediates to maintain synthetic processes. The results of this investigation will also have significance in the clinical interpretation of M2-PK concentrations.

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.

Impaired exercise performance after successful liver transplantation.

BACKGROUND: Recipients of heart, lung, and kidney transplants have impaired peak exercise performance (peak Vo2 40% to 60% predicted, reduced anaerobic threshold [AT]) without evidence of ventilatory or cardiac limitations. The aim of this study was to determine whether similar exercise impairment occurs in liver transplant recipients. METHODS: We studied eight healthy liver transplant recipients (age 42+/-9 [SD] years, 6 male, 31+/-13 months posttransplant). Immunosuppression included FK506 or cyclosporine, azathioprine or mycophenolate mofetil, and prednisone. Subjects underwent lung function testing and cardiopulmonary exercise testing on a cycle ergometer. RESULTS: Peak exercise oxygen consumption (Vo2) was 22+/-8 ml/min/kg (66+/-20% predicted maximum). No subject demonstrated exercise desaturation or ventilatory limitation (peak minute ventilation 55+/-8% predicted maximum voluntary ventilation). Peak heart rate was 87+/-8% of predicted maximum. Early AT was evident (1.2+/-0.34 L/min, 48+/-11% predicted Vo2max). CONCLUSIONS: Liver transplant recipients exhibit impaired peak exercise performance similar to that observed after other solid organ transplants, possibly as a result of chronic deconditioning or myopathy related to immunosuppressive medications.

A limited sampling strategy for cyclosporine area under the curve monitoring in lung transplant recipients.

We developed a limited sampling strategy (LSS) for predicting cyclosporine (Neoral) area under the curve from concentration-time data obtained specifically from lung transplant recipients. The optimal and most clinically convenient LSS for lung transplant recipients, based on patient wait time, number of blood samples required, percent prediction error, and assessment of predictive performance is one that requires 2 blood samples collected at 1 and 3 hours post-dose: AUC = 1.75 x C(1) + 4.91 x C(3) + 185.62.

Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years.

PURPOSE: To (1) identify greatest 6-minute walk distance (6MWD) from among several repetitions (best 6MWD) in a wide age range of healthy volunteers to develop reference values for the multiple repetition 6MWD, and (2) investigate the influence of demographics, anthropometrics, and habitual exercise activity on best 6MWD. METHODS: Four 6MWD were performed on the same day in a 20-meter corridor by 41 male and 38 female healthy volunteers ranging in age from 20 to 80 years. The greatest 6MWD by each subject from among four 6MWDs was the primary outcome measure. RESULTS: Eighty-six percent had their best 6MWD after the first walk; an average increase of 43 meters was observed from first to best 6MWD (P < 0.003). Best 6MWD averaged 698 +/- 96 meters and was inversely related to age (P < 0.001), directly to height (P < 0.001), and was greater in men than women (P < 0.0002). A regression model accounted for 41% of between-subject variability in best 6MWD (P < 0.00000001). In a subset of older subjects, predicted 6MWD significantly underestimated measured best 6MWD when reference values were used from another study where test familiarization was not provided, but this difference disappeared when value were used from the present and a third study where test familiarization was provided. CONCLUSIONS: The present study is the first to provide predicted 6MWD values performed with multiple repetitions and for subjects in the 20-40-year-old age range. Selection of appropriate predicted 6MWD values for interpretation of performance should be guided by subject age and degree of test familiarization provided.

Myositis associated graft-versus-host-disease presenting as respiratory muscle weakness.

Myositis associated with graft-versus-host-disease (GVHD) typically presents with proximal muscle weakness, myalgias, and a raised creatinine phosphokinase (CPK) level. We report a case of a 51 year old man who developed respiratory muscle weakness five years after an allogeneic bone marrow transplant for multiple myeloma. His symptoms included tachypnoea, abdominal paradox, and orthopnoea. Pulmonary function tests revealed diminished vital capacity and maximal inspiratory and expiratory pressures. Serum CPK levels were raised and a peripheral muscle biopsy specimen was consistent with GVHD. He improved with immunosuppressive therapy.

The real cost of aspirin.

Aspirin is a widely used drug and perceived by most physicians to be inexpensive. High rates of concurrent gastroprotective agents are reported from a study of cardiology outpatients. Aspirin takers are more likely to also be taking a proton pump inhibitor, H(2) antagonist, or antacid than non-aspirin takers. They are more than 10 times as likely to be experiencing upper gastrointestinal symptoms. Although aspirin is inexpensive, it is emphasised that the overall cost implications for therapy can be significant and it is suggested that it may be more appropriate to consider the use of alternative antiplatelet agents in patients who tolerate aspirin poorly.

Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation.

Three patients with diffuse large B-cell type of post-transplant lymphoproliferative disease after lung transplantation were treated with rituximab, an anti-CD20 monoclonal antibody. Treatment resulted in two complete remissions and one non-response.

Glutathione-linked enzymes in benign and malignant oesophageal tissue.

Oxyradicals are involved in multiple mutational events and can contribute to the conversion of healthy cells to cancer cells. Glutathione (GSH) and the GSH-replenishing enzymes keep the antioxidant status of normal cells at a level where they can avert oxyradical derived mutations. The aim of this study was to determine whether in cancer cells the GSH-replenishing, GSH antioxidant and GSH-depleting enzymes were not at appropriate levels and therefore not able to protect cancer cells adequately against oxyradical-induced mutations. Cancer of the oesophagus was chosen since it is the most common gastrointestinal malignancy in South African Blacks. Biopsies and blood from 31 patients with cancer of the oesophagus and 29 non-cancer patients were assessed for these enzymes. The mean activity of the antioxidant and depleting enzyme GSH-peroxidase was elevated significantly by twofold in the cancer tissue compared to normal tissue. However, the activity of the replenishing enzyme GSSG-reductase and the level of the depleting enzyme GSH-s-transferase P1-isoenzyme were significantly reduced by 23% and 33% respectively. As in a previous paper we found that GSH was depleted and gamma-glutamine transpeptidase was diminished in oesophageal cancer. There can be two reasons for GSH depletion. Firstly, elevated GSH-peroxidase will use more GSH in an attempt to cope with the excessive production of oxyradicals as revealed by elevated lipid peroxidation; this was, as shown by us before, elevated sixfold in oesophageal cancer. Secondly, if little replenishment of GSH occurred the level of GSH would become lower. This was confirmed by our findings that the activities of the replenishing enzymes were significantly diminished in oesophageal cancer tissue. Contrary to what was expected, the other depleting enzyme GSH-s-transferase P1 was not elevated in cancer tissue but was significantly lower. However, in the blood of the same patients it was significantly elevated. An explanation for this phenomenon is that, although the production of GST-P1 was enhanced in cancer, it did not show because it was rapidly extruded into the blood by an unknown mechanism operational only in cancer cells.