Progressive Pulmonary Disease Research Articles

CORRELATION OF C-REACTIVE PROTEIN AND COPD SEVERITY

Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease characterized by systemic inflammation. The aim of this study was to correlate the parameters of systemic inflammation, C-reactive protein (CPR) and total leukocyte count, with clinical indicators of the disease. Our study included 157 COPD patients, both outpatients and those hospitalized at the Knez Selo Department of Pulmonology of the Niš Clinical Centre during a six-month period, while in the phase of disease exacerbation. The symptoms of COPD in each patient were estimated by the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. The parameters of pulmonary function (FEV1 and FVC), acid-base status, body mass index, history of exacerbation and comorbidities were also evaluated. The level of CRP, but not leukocytes, showed significant correlation with the severity of clinical presentation according to GOLD classification. The higher the CRP concentration, the higher was the disease severity determined according to GOLD classification (p < 0.001). There was no statistically significant difference in CRP level and leukocyte count according to comorbidities (p = 0.29). The level of CRP was higher in patients with a high CAT score and mMRC scale (p < 0.001). The same trend was observed for leukocyte count when compared with CAT results, but not when correlated to mMRC scale. The level of CRP during COPD exacerbation can be an independent predictor of the disease severity and paraclinical findings.

Iron Homeostasis and Inflammatory Status in Mice Deficient for the Cystic Fibrosis Transmembrane Regulator.

BackgroundCystic Fibrosis (CF) is a frequent and lethal autosomal recessive disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Patients with CF suffer from chronic infections and severe inflammation, which lead to progressive pulmonary and gut diseases. Recently, an expanding body of evidence has suggested that iron homeostasis was abnormal in CF with, in particular, systemic iron deficiency and iron sequestration in the epithelium airway. The molecular mechanisms responsible for iron dysregulation and the relationship with inflammation in CF are unknown.Methods and ResultsWe assessed the impact of CFTR deficiency on systemic and tissue iron homeostasis as well as inflammation in wildtype and CFTR knockout (KO) mice. First, in contrast to the systemic and intestinal inflammation we observed in the CFTR KO mice, we reported the absence of lung phenotype with regards to both inflammation and iron status. Second, we showed a significant decrease of plasma ferritin levels in the KO mice, as in CF patients, likely caused by a decrease in spleen ferritin levels. However, we measured unchanged plasma iron levels in the KO mice that may be explained by increased intestinal iron absorption.ConclusionThese results indicate that in CF, the lung do not predominantly contributes to the systemic ferritin deficiency and we propose the spleen as the major organ responsible for hypoferritinemia in the KO mouse. These results should provide a better understanding of iron dysregulation in CF patients where treating or not iron deficiency remains a challenging question.

Toward Precision Medicine in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) remains a progressive and fatal pulmonary vascular disease despite advances in care during the last two decades (1–3). Detrimental pulmonary vascular remodeling, in concert with persistent vasoconstriction and additional perivascular changes, occurs as a result of a variety of identified and unidentified local and systemic factors, including enhanced endothelin-1 expression and levels (4–6). Pharmacologic antagonism of the endothelin receptor (via endothelin receptor antagonists [ERAs]) has been an important cornerstone of the therapeutic options available to combat PAH, with improvements in survival, time to clinical worsening, hemodynamics, and functional performance (7). However, unexplained variability remains with regard to individual clinical response to ERAs and other PAH-specific therapies (8, 9). In this issue of the Journal, Benza and colleagues (pp. 1345–1354) advance our understanding of ERA response via the discovery that certain common genetic variations in the endothelin pathway may identify subgroups of patients more or less likely to favorably respond to ERAs (10). This approach may ultimately provide a step toward the application of pharmacogenetics to individualize each patient’s PAH treatment.

Multiparametric Magnetic Resonance Imaging in Pulmonary Hypertension

Quantitative magnetic resonance imaging provides a comprehensive and non-invasive assessment of the heart and lungs in patients with suspected pulmonary hypertension with the potential for accurate assessment of disease severity and response to treatment. Magnetic resonance imaging (MRI) can provide detailed reliable information of heart structure and function as the heart responds to elevated right ventricle afterload in patients with progressive pulmonary vascular disease; notably, progressive changes in right ventricle volume and function are of prognostic value independent of established biomarkers. This article reviews the current literature on MRI in pulmonary hypertension and also describes new and exciting developments in imaging of the heart, pulmonary vasculature and lungs, including assessment of myocardial changes with late gadolinium-enhanced imaging and T1 mapping, evaluating changes in the proximal pulmonary vasculature using image-based computational modelling and quantitative assessment of the capillary bed using MRI perfusion analysis.

Histoplasmosis: Up-to-Date Evidence-Based Approach to Diagnosis and Management.

Histoplasmosis is the most common endemic mycosis in the North America, Central America, and many countries of South America and also occurs in China, India, Southeast Asia, Africa, Australia, and Europe. Clinical syndromes are not specific and histoplasmosis often is overlooked in the evaluation of patients with community-acquired pneumonia, chronic cavitary pneumonia resembling tuberculosis or anaerobic infection, granulomatous inflammatory diseases such as sarcoidosis or Crohn disease, and malignancy. The diagnosis depends on understanding the geographic distribution, common clinical presentations, and tests used for diagnosis of histoplasmosis. While histoplasmosis resolves without treatment in most patients, treatment is indicated in all immunocompromised patients and those with progressive disseminated disease or chronic pulmonary disease. Treatment is appropriate in most patients with acute pulmonary disease but rarely in those with other pulmonary or mediastinal manifestations. The preferred agents include liposomal amphotericin B for more severe cases and itraconazole for milder cases and "step-down" therapy following response to amphotericin B.

Pulmonary hypertension related to congenital heart disease: A comprehensive review

Pulmonary arterial hypertension (PAH) is a serious complication of congenital heart disease, causing an increase in morbidity and mortality. The progressive and irreversible pulmonary vascular disease is more often the consequence of a significant, uncorrected, left-to-right shunt. The rise in pulmonary vascular resistance may lead to the reversal of the shunt and cyanosis, condition known as Eisenmenger syndrome. The management of this population is challenging and requires specific expertise both for diagnosis and follow-up. The progress in the understanding of the underlying pathophysiology of this condition has promoted recent pharmacological trials. New therapeutic options are now available that could improve the long-term prognosis and the quality of life of these patients, but several controversial points still remain and need to be addressed.

Peripheral Adaptation to Vigorous Aerobic Exercise in Women with Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease of unknown etiology which causes a worsening ventilation-perfusion mismatch leading to activity-limiting dyspnea and physical inactivity. Recent studies indicate that aerobic exercise training (AET) improves physical function and health-related quality of life in populations with PAH, yet little is known about the mechanisms responsible for adaptations to AET. PURPOSE: To examine changes in peripheral muscle oxygen use after 10 weeks of vigorous AET in a population with PAH. METHODS: Twenty-four women with WHO Group I PAH were randomly assigned to receive either 10 weeks of AET or 10 weeks of education lectures (EDU). The AET consisted of treadmill walking thrice weekly for 30-45 minutes each session, with treadmill speed and inclination continuously adjusted to maintain subjects’ heart rates between 70 and 80% of heart rate reserve. Graded treadmill exercise tests (GXT) were performed on all subjects before and after the 10-week intervention period. Metabolic gases were collected and cardiac output (CO) was measured via impedance electrocardiography. Muscle tissue oxygen use was measured during both GXTs using near-infrared spectroscopy with the optodes placed over the right lateral belly of the gastrocnemius. RESULTS: Eleven women were assigned to the AET group (54±11 yrs, BMI=30±7 kg/m2; mean±SD) and 13 to the EDU group (56±9 yrs, BMI=32±7 kg/m2). The AET group improved GXT duration by 121±75 sec (p=0.001) with no significant change in the EDU group. Significant differences were observed between the groups for amplitude changes during GXT for oxyhemoglobin (O2Hb) (AET: -1.61±2.82 vs. EDU: 1.1±3.41 a.u., p=0.048) and hemoglobin difference (HbDiff) levels (-3.18±4.93 vs. 0.82±4.45 a.u., p=0.048). No significant changes were observed between groups for deoxyhemoglobin, total hemoglobin, or cardiac output. CONCLUSIONS: Ten weeks of AET improved physical performance without improving CO. Improvements in O2Hb suggest more oxygen availability within the muscle, and decreased HbDiff indicates more oxygen reserve was used after AET. These results suggest that peripheral rather than central adaptations may play a larger role in cardiorespiratory fitness improvements observed with AET in patients with PAH. Funding NIH/IRP 1 Z01 CL06006802.

Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in developed countries of the world, while the main cause of mortality and morbidity in COPD patients are acute exacerbations and cardiovascular diseases. With regard to the frequency of exacerbations the phenotype «frequent exacerbators» has been defined, which, besides a more severe clinical course and a significantly higher total mortality, is also characterised by an elevated risk of cardiovascular mortality, as some indicators show us.It is notable that during the exacerbation of COPD, next to other changes, a significant aggravation of endothelial function occurs while the ED and COPD relationship seems very complex and is still in greater part unknown. Making the pathophysiological link between the frequency of exacerbations of COPD and ED could change our understanding of the character of this type of pulmonary disease. We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with ancillary systemic effects.Our opinion is that differences in COPD phenotype do not only determine the clinical picture but could also be of key importance in defining the progressivity of the disease. ED, which in these patients persists between frequent exacerbations, could be the main cause of the progression of pulmonary disease, and not only of the high cardiovascular risk of these patients.Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms, could contemporaneously induce new exacerbations of COPD, the progression of pulmonary changes and the development of systemic atherosclerosis as a main extrapulmonary manifestation in these patients. Such a model defines endothelium as a common soil of progressive pulmonary and cardiovascular changes in FE COPD. It can fully explain all the elements of the clinical course and co-morbidity in FE COPD, for which we still do not have adequate explanation.

Optimal management of pulmonary arterial hypertension: prognostic indicators to determine treatment course.

Pulmonary arterial hypertension (PAH) is a rapidly progressive pulmonary vascular disease with a multifactorial etiopathogenesis that can result in right-sided heart failure and death. A number of studies indicate that an early therapeutic intervention yields better results on disease progression as compared to delayed treatment. In this review, we will analyze treatment strategies that may be used for monitoring disease progression and for guiding treatment decisions. Several factors (ie, symptoms, functional class, exercise capacity as assessed by a walking test and cardiopulmonary stress testing, hemodynamic parameters, cardiac magnetic resonance imaging, and plasma levels of biochemical markers) have been prognostic of survival. These indicators may be used both at the time of diagnosis and during treatment follow-up. No resolutive therapy is currently available for PAH; however, in the last decade, the advent of specific pharmacological treatments has given new hope to patients suffering from this debilitating disease with a poor prognosis. Combination drug therapies offer increased benefits over monotherapy, and current guidelines recommend a sequential “add on” design approach for patients in functional class II–IV. The goal-oriented “treat to target” therapy sets the timing for treatment escalation in case of inadequate response to currently known prognostic indicators. To date, further longitudinal studies should be urgently conducted to identify new goals that may improve therapeutic strategies in order to optimize personalized treatment in PAH patients.

Relationships between ventilatory impairment, sleep hypoventilation and type 2 respiratory failure.

Conditions that increase load on respiratory muscles and/or reduce their capacity to cope with this load predispose to type 2 (hypercapnic) respiratory failure. In its milder forms, this imbalance between load and capacity may primarily manifest as sleep hypoventilation which, if untreated, can increase the likelihood of wakeful respiratory failure. Such problems are commonly seen in progressive respiratory neuromuscular disorders, morbid obesity and chronic obstructive pulmonary disease, either separately or together. Identifying patients at risk can be important in determining whether and when to intervene with treatments such as non-invasive ventilatory assistance. Measurements of wakeful respiratory function are fundamental to this risk assessment. These issues are reviewed in this paper.

Pulmonary Tuberculosis in Children

: Tuberculosis (TB) is the most common cause of infection-related death worldwide. Children represent 5 to 15% of all TB cases around the world and are more frequently infected and more easily affected by the most severe forms of the disease such as meningitis and disseminated form .Here, we reviewed TB in children with impact on the routes of transmission, clinical manifestations, treatment, control, and prophylaxis. Electronic databases (PubMed, Scopus) were searched from June1995 to May 2014 by using key words (pulmonaryTB,epidemiology,transmission,clinical manifestations,treatment,control, and prophylaxis) . Pulmonary tuberculosis may manifest in several forms, including endobronchial TB with focal lymphadenopathy, progressive pulmonary disease, pleural involvement, and reactivated pulmonary disease . Symptoms of primary pulmonary disease in the pediatric population are often insignificant. Gastric aspirates are used instead of sputum in children younger than 6 years. BCG vaccination is used in many parts of the world and the major role of vaccination is the prevention of life-threatening illness such as disseminated TB and meningitis in children.Treatment is the same as for adults. Most people infected with M .tuberculosis do not develop active disease. In healthy individuals, the lifetime risk of developing infection to disease is 5-10%. Reactivation of TB often occurs in older children and adolescent and is more common in patients who acquire TB at age 7 years and older.

Cystic fibrosis: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.

Cystic fibrosis (CF) is a life-limiting, monogenic disorder characterized by chronic sinopulmonary and gastrointestinal involvement. Progressive pulmonary disease leads to death in the majority of patients. Despite its well-defined molecular basis related to defects in the cystic fibrosis transmembrane conductance regulator anion transport channel, there are large gaps in our understanding of the origin of CF lung disease. Disease has been shown to be present in infancy, and there is mounting evidence that abnormalities begin in utero. Heterogeneity of clinical presentations and severity suggest that many factors involved in lung disease have yet to be fully elucidated. Although new advances in therapeutic treatments have shown promise in delaying disease progression, the prevention of pulmonary disease at its origin (primary prevention) should be a key goal of CF care. The objective of this workshop was to (1) review our understanding of the origins of CF lung disease, (2) determine gaps in the knowledge base that are most significant and most likely to enable prevention of CF lung disease, and (3) prioritize new research questions that will promote pulmonary health in both CF and other childhood lung diseases. The goal of this report is to provide recommendations for future research that will improve our understanding of pulmonary development in health and disease, improve outcome measures and biomarkers for early lung disease, and determine therapeutic targets and strategies to prevent the development of lung disease in children with CF.

Cystic fibrosis: NHLBI workshop on the primary prevention of chronic lung diseases

Cystic fibrosis (CF) is a life-limiting, monogenic disorder characterized by chronic sinopulmonary and gastrointestinal involvement. Progressive pulmonary disease leads to death in the majority of patients. Despite its well-defined molecular basis related to defects in the cystic fibrosis transmembrane conductance regulator anion transport channel, there are large gaps in our understanding of the origin of CF lung disease. Disease has been shown to be present in infancy, and there is mounting evidence that abnormalities begin in utero. Heterogeneity of clinical presentations and severity suggest that many factors involved in lung disease have yet to be fully elucidated. Although new advances in therapeutic treatments have shown promise in delaying disease progression, the prevention of pulmonary disease at its origin (primary prevention) should be a key goal of CF care. The objective of this workshop was to (1) review our understanding of the origins of CF lung disease, (2) determine gaps in the knowledge base that are most significant and most likely to enable prevention of CF lung disease, and (3) prioritize new research questions that will promote pulmonary health in both CF and other childhood lung diseases. The goal of this report is to provide recommendations for future research that will improve our understanding of pulmonary development in health and disease, improve outcome measures and biomarkers for early lung disease, and determine therapeutic targets and strategies to prevent the development of lung disease in children with CF.

Plasmapheresis rescue therapy in progressive systemic ANCA-associated vasculitis: Single-center results of stepwise escalation of immunosuppression

We evaluated 26 patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) with progressive disease despite treatment with cyclophosphamide and steroids treated with additional plasmapheresis and compared outcome with 50 matched-disease controls. Patients diagnosed with AAV and treated with cyclophosphamide from January 1990 to December 2009 (n = 272) were included when plasmapheresis was not started at diagnosis but added for progressive disease during initial standard therapy (n = 26). We selected controls equal for age, Birmingham vasculitis activity score, and creatinine at diagnosis. Primary endpoint was estimated glomerular filtration rate (eGFR) or death. Plasmapheresis was added 18 days (range 5-41) after start of therapy. In 11 patients, a rise in serum creatinine >30% led to plasmapheresis; insufficient response to induction (n = 11), progressive pulmonary disease (n = 3), or progressive necrotic lesions (n = 1) were other indications.In the plasmapheresis group, six patients were in need of renal replacement therapy (RRT), and three controls. Five years after diagnosis, four patients had died in the plasmapheresis against eight controls (P = 0.94). At baseline, mean eGFR was 44 ml/min/1.73 m(2) in plasmapheresis group versus 43 ml/min/1.73 m(2) in controls. At start of plasmapheresis, eGFR was 26 ml/min/1.73 m(2) (P = 0.003), at 6 months mean eGFR had significantly improved to 44 ml/min/1.73 m(2) (P = 0.0003), comparable to eGFR in controls, 48 ml/min/1.73 m(2). During long-term follow-up, there was no difference in renal function between the groups. AAV patients with progressive disease despite standard induction therapy in whom plasmapheresis was added had significant improvement in renal function and similar long-term outcome in both renal and patient survival as matched disease controls.

Nutritional Indicators are Correlated with the Radiological Severity Score in Patients with &lt;i&gt;Mycobacterium avium&lt;/i&gt; Complex Pulmonary Disease: A Cross-sectional Study

Body weight loss in patients with Mycobacterium avium complex (MAC) pulmonary disease can be fatal. The administration of nutritional supplements should be an important component in the treatment of this disease. Objective data regarding the association between the nutritional status and disease severity have not been reported. This cross-sectional study aimed to compare the nutritional status and radiological severity scores in MAC pulmonary disease patients. We retrospectively reviewed the records of 40 patients who were admitted to our institution for the treatment of MAC pulmonary disease between July 2008 and July 2010. Nutritional indices, including the ideal body weight ratio, triceps skinfold, mid-upper arm muscle circumference, and percentage of predicted resting energy expenditure, were compared with the radiological severity scores. Quantitative values of the extent of nodules, infiltration shadows, cavities, and bronchiectasis on the computed tomography scans were used to evaluate the radiological severity scores. The patients suffered from a significantly decreased percentage of ideal body weight, body fat and muscle mass. The average radiological score was 17.6±8.4 points. The percentage of ideal body weight (p<0.001), percentage of triceps skinfold (p<0.001) and percentage of mid-upper arm muscle circumference (p<0.002) were negatively correlated with the radiological scores, while the percentage of the predicted resting energy expenditure (p<0.001) was positively correlated with the scores. A poor nutritional status is common in patients with progressive MAC pulmonary disease, which supports the hypothesis that aggressive nutritional interventions are indicated in the treatment of this disease.

CXCL6 antibody neutralization prevents lung inflammation and fibrosis in mice in the bleomycin model

IPF is a chronic, progressive pulmonary disease, leading to respiratory failure. In search of mechanisms of IPF, we used the bleomycin-induced lung-injury model in mice, which causes acute inflammation that may progress to chronic lung inflammation and fibrosis. Here, we asked whether CXCL6/GCP-2, a member of the CXC chemokine superfamily, may be involved in IPF development. First, we reported an increase of CXCL6 levels in BALF from patients with IPF, as well as in the lung of mice, 24 h after bleomycin administration. To investigate whether CXCL6 played a role in experimental bleomycin-induced pulmonary fibrosis, we treated mice with an anti-mCXCL6 mAb that has been shown to inhibit neutrophil chemotaxis in vitro. CXCL6 antibody blockade attenuated acute inflammation with a reduced pulmonary neutrophil influx, IL-1β, CXCL1, and TIMP-1 production. In the later phase (14 days after bleomycin exposure), lymphocyte recruitment and fibrosis markers, such as collagen and TIMP-1, were diminished, as well as collagen deposition and fibrotic lesion the lung. Therefore, the data suggest that CXCL6 contributes to experimental pulmonary fibrosis, and CXCL6 inhibition might be used to reduce lung toxicity associated with bleomycin treatment.

Specific targeting of Egr-1 reduces neointimal lesions and improves RV remodeling in PAH

Purpose: Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease with a high mortality and to date no curable treatment. Increased pulmonary blood flow, as in congenital heart disease, is an essential trigger for the development of neointimal lesions that are characteristic for PAH. We recently identified a flow-specific signal, Egr-1, which was activated in both experimental and human PAH. The aim of the present study was to identify the role of Egr-1 in the development of neointimal lesions in experimental PAH. Methods: In wistar rats (n=76), flow-associated PAH was created by combining monocrotaline with an aortocaval (av) shunt. Egr-1 was inhibited via chronic intravenous delivery (every 48h) of catalytic oligodeoxynucleotides (called DNAzymes) specifically targeting Egr-1 in vivo via RNA degradation. Starting at av-shunt, rats were randomized for either DNAzyme therapy (PAH\_DZ), scrambled DNAzymes (PAH\_SCR; scrambled oligonucleotides that do not recognize Egr-1 RNA) or vehicle (PAH_VEH). Sham operated rats served as control (Con). Increased flow was confirmed by echocardiography. At both 1 week and 3 weeks after increased flow animals underwent hemodynamic evaluation and were sacrificed for further histopathological analysis. Results: At 3 weeks PAH rats had increased vascular occlusion (33%±3, vs. 2±0%, p<0.001) and wall thickness (5.6μm±0.7 vs. 0.3±0.0 p<0.001), presence of neointimal lesions (36% vs. 0% of all arterioles), and subsequently increased right ventricular (RV) peak pressure (60mmHg±2 vs. 24±1, p<0.001) and hypertrophy (RV/BW ratio 1.5mg/g±0.1 vs. 0.6±0.1, p<0.001). Treatment with DNAzymes targeting Egr-1 attenuated vascular remodeling as early as 1 week after flow. At 3 weeks DNAzyme treatment significantly reduced vascular occlusion (-47%, p<0.001), wall thickness (-48%, p<0.001) and the development of neointimal lesions (-69%, p<0.001) compared to PAH\_VEH. PAH\_SCR showed no change compared to PAH\_VEH. Moreover, DNAzyme treatment significantly attenuated pulmonary vascular resistance (-27%, p<0.05), RV peak pressure (-12%, p<0.05) and RV hypertrophy (RV/body weight -27%, p<0.05) compared to PAH\_VEH and PAH_SCR. Conclusion: Here we show that RNA specific targeting of Egr-1 attenuates pulmonary vascular remodeling and disease development in a neointimal model of PAH. These data suggest that Egr-1 is an important regulator of PAH development and may possibly form a therapeutic target for future PAH treatment.

Infections of the respiratory system in patients with ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive multiorgan disease characterized by progressive neurologic deterioration in which the most common causes of death are diseases of the respiratory system and cancer. This retrospective case-series characterizes the pulmonary disease seen in 101 cancer-free A-T patients who were living with chronic respiratory symptoms or who had pulmonary disease listed as the cause of their death. All of the 101 patients developed chronic progressive pulmonary disease with intermittent acute exacerbations and irreversible radiographic changes. Seventy-nine patients had microbiologic analysis of their respiratory secretions and of the patients less than 15 years of age, 25/27 cultured Staphylococcus aureus, Hemophilus influenzae, or Streptococcus pneumoniae and 35/47 older patients cultured Pseudomonas aeruginosa. Opportunistic infections of the lungs were not observed. Thirty-two patients had histologic examination of their lungs and 21 of the specimens had both acute and chronic inflammatory changes. The results of this study describe the natural history of the suppurative lung disease in patients with A-T that often progresses to bronchiectasis and pneumonias and ultimately respiratory failure. The etiology of the progressive deterioration is unknown but the pulmonary disease of A-T described in this study shows similarities to the lung disease seen in cystic fibrosis. Treatment of the lung disease in patients with A-T may benefit from many of the same therapies that have improved the quality of life for patients with cystic fibrosis.

Mycobacterium abscessus isolated from municipal water - a potential source of human infection

BackgroundMycobacterium abscessus is a rapidly growing mycobacterium responsible for progressive pulmonary disease, soft tissue and wound infections. The incidence of disease due to M. abscessus has been increasing in Queensland. In a study of Brisbane drinking water, M. abscessus was isolated from ten different locations.The aim of this study was to compare genotypically the M. abscessus isolates obtained from water to those obtained from human clinical specimens.MethodsBetween 2007 and 2009, eleven isolates confirmed as M. abscessus were recovered from potable water, one strain was isolated from a rainwater tank and another from a swimming pool and two from domestic taps. Seventy-four clinical isolates referred during the same time period were available for comparison using rep-PCR strain typing (Diversilab).ResultsThe drinking water isolates formed two clusters with ≥97% genetic similarity (Water patterns 1 and 2). The tankwater isolate (WP4), one municipal water isolate (WP3) and the pool isolate (WP5) were distinctly different. Patient isolates formed clusters with all of the water isolates except for WP3. Further patient isolates were unrelated to the water isolates.ConclusionThe high degree of similarity between strains of M. abscessus from potable water and strains causing infection in humans from the same geographical area, strengthens the possibility that drinking water may be the source of infection in these patients.

Older children at time of norwood operation have ongoing mortality vulnerability that continues after the cavopulmonary connection

Background Delayed 1st stage palliation of children with hypoplastic left heart syndrome (HLHS) and related pathologies can be associated with poor outcomes due to development of progressive pulmonary vascular disease) and volume load effects on systemic ventricle and atrioventricular valve (AVV). We examine current era survival of this patients’ subgroup. Methods Fifty-five infants >2 weeks old underwent Norwood surgery (2003-07). Separate competing risks analyses were performed to model outcomes (death, transition to next stage) after Norwood and after bidirectional cavo-pulmonary connection (BCPC). Results Median age was 32 days (range:15-118). 47% had HLHS, 53% had other complex univentricular variants. Mean ascending aorta was 4.4 ± 1.9 mm, 10% had impaired ventricle function, 11% moderate AVV regurgitation, 32% restrictive pulmonary venous return. Pulmonary blood flow was established via aortopulmonary shunt (30) or Sano shunt (25) Following Norwood, patients required longer ventilation, more oxygen & nitric oxide and had higher inotropic scores compared to traditional management protocol. Competing risks analysis showed that 2-years after Norwood 39% had died and 57% underwent BCPC. 4-years after BCPC, 15% had died and 85% underwent Fontan operation. Overall 3 years survival post-Norwood was 53%. Factors associated with mortality were age, lower weight at Norwood, impaired ventricular function, longer circulatory arrest and lower pre-BCPC saturation. Conclusions Children >2 weeks old undergoing Norwood operation frequently require postoperative pulmonary vasodilatation and high inotropic support. A significant hazard of death persists through all steps of multi-stage palliation. Elevated pulmonary vascular resistance, volume load effects such as systemic ventricle impairment and AVV regurgitation are commonly evident in patients who fail or don’t qualify to proceed to next stage palliation. Those patients should be closely monitored for timely referral for heart transplantation when indicated.