The life expectancy for subjects with progressive neuromuscular disorders has increased over the last 40 years. Whether this is the result of more aggressive use of mechanical ventilation and airway clearance devices, better detection of sleep-related breathing disorders, identifying and treating cardiac complications, creation of centres of excellence, or combinations of these factors remains a matter of discussion. Nevertheless, the early 21st century ushers in a time of great excitement and hope for patients with neuromuscular disease (NMD), as investigators not only gain a better understanding of the cellular and biochemical mechanisms that cause many of the disorders, but also potentially develop ways to circumvent production of faulty proteins so as perhaps to curtail the loss of muscle function. At the same time, clinicians have recognized the role and benefits of prompt recognition of cardiopulmonary dysfunction in patients with NMD, and when possible, of supportive intervention. more >>
Summary: Subjects with progressive neuromuscular diseases undergo a typical sequence of respiratory compromise, leading from normal unassisted gas exchange to nocturnal hypoventilation with normal daytime gas exchange, and eventually to respiratory failure requiring continuous ventilatory support. Several different abnormalities in respiratory pump function have been described to explain the development of respiratory failure in subjects with neuromuscular weakness. Early in the progression of respiratory failure, the use of nocturnal assisted ventilation can reverse both night- and day-time hypercapnia. Eventually, however, diurnal hypercapnia will persist despite correction of nocturnal hypoventilation. The likely beneficial effects of mechanical ventilatory support include resting fatigue-prone respiratory muscles and resetting of the central chemoreceptors to PaCO2. Recent experience shows that select patients who require daytime ventilation can be supported with non-invasive ventilation continuously to correct gas exchange abnormalities while avoiding detrimental aspects of tracheostomy placement. more >>
Summary: Pulmonary compromise is common in neuromuscular disease. Respiratory failure may be a presenting feature of neuromuscular disease and remains a major cause of morbidity and mortality. This article will review the current understanding of the more commonly encountered neuromuscular disorders in childhood and emphasize related pulmonary issues. more >>
Summary: Paediatric neuromuscular disease compromises both the gas exchange and pump functions of the respiratory system. This can have profound implications for both growth and development of the respiratory system, as well as morbidity and mortality. Aspiration lung disease is common, and leads to increasingly restrictive pulmonary physiology over time. Abnormal lung and chest wall mechanics, and weak respiratory muscles, can combine to cause respiratory failure. Improving the balance between the work of breathing (by decreasing the respiratory load) and the respiratory pump (by improving respiratory muscle strength and decreasing respiratory muscle fatigue) can help prevent the onset of respiratory failure. Airway clearance techniques and non-invasive ventilation are two important tools in this effort. Better ways of assessing the respiratory pump, mechanical function, control and fatigue are needed especially in children. more >>
Summary: Sleep disordered breathing (SDB) is now well recognized in children with neuromuscular diseases (NMD) and may lead to significant morbidity and increased mortality. Predisposing factors to SDB in children with NMD include reduced ventilatory responses, reduced activity of respiratory muscles during sleep and poor lung mechanics due to the underlying neuro-muscular disorder. SDB may present long before signs of respiratory failure emerge. When untreated, SDB may contribute to significant cardiovascular morbidities, neuro-cognitive deficits and premature death. One of the problems in detecting SDB in patients with NMD is the lack of correlation between lung function testing and daytime gas exchange. Polysomnography is the preferred method to evaluate for SDB in children with NMD. When the diagnosis of SDB is confirmed, treatment by non-invasive ventilation (NIV) is usually recommended. However, other modalities of mechanical ventilation do exist and may be indicated in combination with or without other supportive measures. more >>
Summary: Airway clearance consists of two linked processes: mucociliary clearance and cough clearance. Patients with neuromuscular weakness are at risk for impaired cough clearance and therefore the development of pneumonia and atelectasis. Aiding airway clearance in the patient with neuromuscular weakness is critical to the maintenance of health and the prevention of significant respiratory morbidity. This can be achieved using both manual and mechanical techniques. This review will discuss the physiology of cough and the mechanics of aiding cough clearance in the patient with neuromuscular weakness. In addition, technologies and techniques used to improve mucociliary clearance will also be discussed. Newer technologies such as mechanical insufflation-exsufflation have gained widespread acceptance in the management of airway clearance in the patient with neuromuscular weakness. more >>
Summary: Cardiac abnormalities occur in association with many of the neuromuscular disorders that present in childhood. Genetic defects involving the cytoskeleton, nuclear membrane, and mitochondrial function have all been described in patients with skeletal myopathy and cardiac involvement. The most common classes of neuromuscular disorders with cardiac manifestations are the muscular dystrophies- Duchenne, Becker, limb-girdle and Emery Dreifuss. Friedreich Ataxia and myotonic dystrophy also have important cardiac involvement. The type and extent of cardiac manifestations are specific to the type of neuromuscular disorder. The most common cardiac findings include dilated or hypertrophic cardiomyopathy, atrioventricular conduction defects, atrial fibrillation and ventricular arrhythmias. Screening for cardiac involvement should be performed in all children with neuromuscular disorders that have the potential for cardiac involvement. This review discusses the cardiac findings associated with specific neuromuscular disorders and outlines the indications for evaluation and treatment. more >>
Summary: Acute viral bronchiolitis remains a cause of substantial morbidity and health care costs in young infants. It is the most common lower respiratory tract condition and most common reason for admission to hospital in infants. Many respiratory viruses have been associated with acute viral bronchiolitis although respiratory syncytial virus (RSV) remains the most frequently identified virus. Most infants have a mild self limiting illness while others have more severe illness and require hospital admission and some will need ventilatory support. Differences in innate immune function in response to the respiratory viral insult as well as differences in the geometry of the airways may explain some of the variability in clinical pattern. Young age and history of prematurity remain the most important risk factors although male gender, indigenous status, exposure to tobacco smoke, poor socioeconomic factors and associated co-morbidities such as chronic lung disease and congenital heart disease increase the risks of more severe illness. Supportive therapy remains the major treatment option as no specific treatments to date have been shown to provide clinically important benefits except for inhaled hypertonic saline. Prophylaxis of high risk infants with palivizumab should be considered although the cost effectiveness is still unclear. Many questions remain regarding optimal management approaches for infants requiring hospitalisation with bronchiolitis including use of nasogastric feeding, the optimal role of supplemental oxygen, optimal use of hypertonic saline and the role of combinations of therapies, the use of heliox or modern physiotherapy approaches. more >>
Summary: Helium-oxygen (heliox) gas mixtures have been studied for over 70 years as an adjunctive therapy for airway obstruction in a variety of respiratory diseases. The medical use of heliox is based on the physical properties of helium as its low density makes it advantageous in promoting more efficient flow through narrowed passages. Clinical evidence of the efficacy of heliox in treating paediatric respiratory diseases is increasing in the medical literature. This article consists of a comprehensive review of the literature investigating the utility of heliox in the treatment of paediatric respiratory disorders, including upper and lower airway obstruction, mechanical ventilation, and aerosol delivery. more >>
Summary: Lung transplantation is well-established in the treatment of end-stage lung disease in children. Our understanding of the problems associated with transplantation has increased rapidly over the past 25 years. Recent figures suggest this knowledge is starting to translate into improvements in management and survival. The common indications for lung transplantation in children, the process of assessment and the outcomes and complications of transplantation are reviewed. We discuss briefly some of the ethical issues relevant to lung transplantation and review strategies for the future. This information may help the respiratory paediatrician prepare potential candidates and their families for the process of assessment and help him or her anticipate common problems that may occur. more >>
Probably most senior people can recall the teaching (or lack of it) when they were students. Most will recall being presented with opportunities to learn, but largely being left to their own devices and resources in exploiting them. Teachers varied from the charismatic to the bored (and boring), and it was really up to the students to find their own paths from entrance to the medical school to exit with the final diploma. Parts of the system worked very well – most if not all can remember time spent with brilliant bedside teachers, sharing years of priceless wisdom and experience – but many teachers fell far short of this standard. more >>
The European Union (EU) is an economic and political union of 27 member states with approximately 500 million citizens. The EU has developed a single market, including free access for European medical specialists to the European job market via two relevant directives (issued in 1995 and 2005) with an automatic recognition of the diplomas and certificates of qualification in medicine in all member countries. However, within Europe, countries are in different stages of development of medical training and some countries even do not formally recognise Paediatric Respiratory Medicine (PRM) as a subspecialty. This has at least two important implications: 1) a strategy has to be developed to further strengthen PRM in Europe and 2) harmonised training standards across the entire European Union have to be ensured to make an open job market within the EU acceptable. more >>
Pediatric pulmonology is a recognized pediatric subspecialty in the United States. Individuals are certified as Pediatric Pulmonologists by the American Board of Pediatrics, and Fellowship Training Programs are accredited by the Accreditation Council on Graduate Medical Education (ACGME). Guidelines exist for Fellowship curricula, and a body of knowledge has been assembled which the American Board of Pediatrics uses to test candidates for recognition as competent subspecialists. Fellowship training has advanced to the point where subspecialists must not only demonstrate clinical competence by the end of fellowship training, but they must also demonstrate competence in the scholarship skills of research and proficiency in teaching. The successful completion of a research project is required before a candidate can sit for the Pediatric Pulmonology Subboard Examination. Medical knowledge advances at a rapid rate, especially within subspecialties, so maintenance of certification in the subspecialty is also required. The above represent a long road to reach the current point. No doubt further improvements and advances in medical education will continue to improve the training of Pediatric Pulmonologists in the future. more >>
The assessment of knowledge is important in the evaluation of competence in any professional activity, especially medicine. Paediatric Pulmonology has been one of the most rapidly advancing sub-specialties of children's care, particularly in the developed world and has now reached the stage where formal examinations of competency at a tertiary level are appropriate. As in other specialties in Europe, the level of knowledge and experience to be tested has now been comprehensively set out according to a detailed syllabus relevant to clinical practice. This is delivered through a clearly defined curriculum of training. more >>
Paediatric Respiratory Medicine has evolved as a distinct discipline in Australia and New Zealand from the early 1970s. It now focuses on providing expertise to professional colleagues and the community in addressing the new paediatric pulmonary morbidity including asthma, cystic fibrosis, congenital abnormalities, sleep related disorders, management of the acute and long term respiratory illnesses in the extremely preterm baby and management of pulmonary complications of the immuno-compromised child. The discipline must adopt useful new technologies related to endoscopy, ventilation, lung function measurements particularly in the younger child and sleep physiology. Guidelines have been developed for the management of common paediatric pulmonary conditions such as asthma, cough, cystic fibrosis, home oxygen and bronchiolitis. more >>
Summary: Objectives: The aims were to evaluate the profile of newly diagnosed adult asthma cases and the approach adopted to the secondary care management at the launch of the Finnish asthma programme in 1994 and seven years later, in 2001.Methods: A retrospective medical record audit was made of non-acutely referred patients with asthma in 1994 (n=165) and in 2001 (n=133). Clinical profile data, numbers of out-patient visits and periods of in-patient care before and after asthma diagnosis were gathered from referral letters and secondary care records.Results: The newly diagnosed asthma patients in 2001 were older, more obese and had more co-morbidities. The main asthma symptoms, such as dyspnoea, wheezing and cough, occurred equally in both years but were more often periodic than daily in 2001. Wheezing during auscultation was significantly less common in 2001. The diagnostic process was associated to a history of asthma in first-degree relatives (OR 5.34, 95% CI 1.12–24.49) in 1994 and a visit to a nurse prior to that to a physician (OR 3.13, 95% CI 1.17–8.37) in 2001. Secondary care visits per new case of asthma (7.3 in 1994 vs. 5.4 in 2001) and days in hospital (3.6 in 1994 vs. 0.95 in 2001) decreased significantly.Conclusions: The profile of asthma diagnosed in secondary care indicates milder disease with more co-morbidities in 2001 than in 1994.Trends towards assigning a more active role on the part of primary care physicians and more rational use of secondary care resources in the management of asthma were found. more >>
Summary: Background: Exacerbations are a major risk and a cause of asthma morbidity and healthcare utilization. Viral-induced upper respiratory tract infections are the most frequent trigger of asthma-related exacerbations. Studies have traditionally assessed exacerbations without documentation regarding exacerbation etiology. Therefore, it remains unknown whether asthma medications can alter exacerbation susceptibility based on a specific etiology.Objective: To examine whether treatment with inhaled corticosteroids plus long-acting beta2-agonists reduced the number of exacerbations associated with upper respiratory tract infections versus inhaled corticosteroids alone.Methods: Two large datasets comparing treatment with fluticasone propionate and fluticasone propionate plus salmeterol were analyzed, including the number of clinically reported upper respiratory tract infections, asthma-related exacerbations, and the presence of an exacerbation and concurrent report of an upper respiratory tract infection.Results: Both treatment groups had similar incidences of upper respiratory tract infections. Of those reporting an upper respiratory tract infection, statistically significantly fewer reported an asthma-related exacerbation comparing fluticasone propionate plus salmeterol with fluticasone propionate (p=0.0057).Discussion: This retrospective analysis suggests that therapy with fluticasone propionate plus salmeterol provides protection against asthma exacerbations temporally associated with upper respiratory tract infections. This retrospective analysis supports the hypothesis that specific therapeutic approaches to mitigate virus-associated exacerbations may benefit asthma care. Well-controlled prospective studies are warranted. more >>
Summary: Background: Among older persons, we previously endorsed a two-step spirometric definition of chronic obstructive pulmonary disease (COPD) that requires a ratio of forced expiratory volume in 1sec to forced vital capacity (FEV1/FVC) below .70, and an FEV1 below the 5th or 10th standardized residual percentile (“SR-tile strategy”).Objective: To evaluate the clinical validity of an SR-tile strategy, compared to a current definition of COPD, as published by the Global Initiative for Obstructive Lung Disease (GOLD-COPD), in older persons.Methods: We assessed national data from 2480 persons aged 65–80 years. In separate analyses, we evaluated the association of an SR-tile strategy with mortality and respiratory symptoms, relative to GOLD-COPD. As per convention, GOLD-COPD was defined solely by an FEV1/FVC<.70, with severity staged according to FEV1 cut-points at 80 and 50 percent predicted (%Pred).Results: Among 831 participants with GOLD-COPD, the risk of death was elevated only in 179 (21.5%) of those who also had an FEV1<5th SR-tile; and the odds of having respiratory symptoms were elevated only in 310 (37.4%) of those who also had an FEV1<10th SR-tile. In contrast, GOLD-COPD staged at an FEV1 50–79%Pred led to misclassification (overestimation) in terms of 209 (66.4%) and 77 (24.6%) participants, respectively, not having an increased risk of death or likelihood of respiratory symptoms.Conclusion: Relative to an SR-tile strategy, the majority of older persons with GOLD-COPD had neither an increased risk of death nor an increased likelihood of respiratory symptoms. These results raise concerns about the clinical validity of GOLD guidelines in older persons. more >>
Summary: We evaluated the accuracy of a point-of-care test designed to measure adherence to isoniazid (INH) preventive therapy in a hospital setting in Rio de Janeiro, Brazil. Patients on treatment with daily INH and patients not receiving INH were included. Sensitivity and specificity of the test were 84%/98% at the first minute, and 95%/98% at the fifth minute, respectively. Among smokers, sensitivity and specificity was reduced (80%/89% at the fifth minute, respectively), but only 17% smoked. This test accurately detected INH metabolites 24h following directly observed INH intake, though sensitivity and specificity may be compromised by tobacco smoke exposure. more >>
Summary: Background: The aim of this study was to determine the prognostic significance of right ventricular dilation on CT pulmonary angiogram in acute pulmonary embolism and to distinguish if this feature predicts mortality independently of the Pulmonary Embolism Severity Index, an established admission severity score.Methods: A retrospective study of patients admitted with pulmonary embolism confirmed by CT pulmonary angiogram to three teaching hospitals in East Scotland between January 2005 and July 2007. Two radiologists judged presence of right ventricular dilation on CT pulmonary angiogram independently. The outcome of interest was 30 day mortality. Multivariable logistic regression was used to compare this outcome in patients with right ventricular dilation compared to those without right ventricular dilation, adjusting for Pulmonary Embolism Severity Index score.Results: There were 585 patients included and 30.4% had right ventricular dilation on CT pulmonary angiogram. Patients with right ventricular dilation had increased 30 day mortality rates compared to patients without right ventricular dilation (12.4% vs. 5.4%; p=0.006). Survival analysis showed that a significantly greater proportion of deaths in the right ventricular dilation group occurred within the first 48h after admission compared to the group without right ventricular dilation (45.5% deaths vs. 9.1%; p=0.016). On multivariable analysis, adjusting for Pulmonary Embolism Severity Index score, right ventricular dilation was independently associated with increased 30 day mortality (OR 2.98; 95% CI 1.54–5.75; p=0.001).Conclusion: Right ventricular dilation on CT pulmonary angiogram is an independent predictor of 30 day mortality in acute pulmonary embolism. more >>
Summary: Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease with a poor prognosis for which there is no effective medical therapy. An awareness of comorbidities that are treatable and might impact outcomes in these patients is therefore very important. We sought to determine the prevalence of coronary artery disease (CAD) in IPF patients in comparison to a control group of patients with chronic obstructive pulmonary disease (COPD). We also sought to assess the impact of CAD on IPF patient outcomes.Patients and methods: IPF and COPD transplant candidates whose work-up included left heart catheterization were categorized as having significant CAD, non-significant CAD or no disease. The risk factor profile and prevalence of CAD in both groups was compared.Results: There were 73 IPF and 56 COPD patients. The prevalence of CAD was 65.8% in the IPF group compared to 46.1% in the COPD patients (p<0.028). Significant disease was present in 28.8% of IPF patients vs.16.1% of the COPD patients (p<0.081). Unsuspected significant CAD was found in 18% of IPF patients versus 10.9% of COPD patients (p<0.004). Outcomes of IPF patients with significant CAD was worse than those with no or non-significant disease (p<0.003) with a median survival of 572 days from the time of left heart catheterization.Conclusion: There is a higher prevalence of CAD in IPF patients compared to a similarly matched COPD group. This increased association appeared to be independent of common coronary artery risk factors. IPF patients with significant CAD appear to have worse outcomes. more >>
Summary: Few studies on the concomitant effects of beclomethasone dipropionate and asthma-related factors on the growth of prepubertal asthmatic children have been published to date. In this prospective long-term ‘real-life’ cohort study we recruited 82 prepubertal steroid-naïve asthmatic patients aged 3 + years, excluding those with birth weight lower than 2500 g, malnutrition, and other concurrent chronic diseases. Height/age and weight/age Z scores were calculated every three months. Random effects multivariate longitudinal data analysis was used to adjust height/age and weight/age Z scores with independent variables. Among the studied patients, 63.4% were male, aged 4.7 ± 1.5 years, 68.3% suffered from severe persistent asthma and had normal values for height/age and weight/age Z scores at enrolment. They were followed for 5.2 years (range 2.3–6.1) and used a mean daily beclomethasone dipropionate dose of 351.8 mcg (range 137.3–1140.0). Height/age and weight/age Z scores were not affected by either duration of treatment or doses of beclomethasone dipropionate up to 500 mcg, 750 mcg and higher than 750 mcg (p-values > 0.17). The multivariate analysis final model showed that severe persistent asthma was associated to lower height for age Z score (p = 0.04), whereas hospitalizations because of acute asthma (before and during follow-up) were associated (p = 0.02) to lower weight for age Z score. Growth parameters were not affected by the use of beclomethasone dipropionate. more >>
Summary: Background: Exhaled NO (FENO) is a steroid dose dependent eosinophilic inflammometer, but also a mediator of bronchomotor tone, but statistically significant relationships have infrequently been obtained with pulmonary function tests (PFT). The aim was to test the hypothesis that the relationships between FENO and PFT could be uncovered by inhaled corticosteroid (ICS) treatment, namely that a link between FENO and bronchodilator response (an index of bronchomotor tone) would appear under ICS.Methods: Exhaled NO, forced expiratory flows and lung volumes were measured in atopic asthmatic children without recent (one month) respiratory symptoms.Results: Two hundred and thirty children (mean±SD, age: 11.2±2.5 years, 69 girls) were included (% predicted, FEV1: 100±14; FEF50%: 76±23; RV: 107±29). The relationship between ICS dose (GINA classification) and FENO plateaued in children with an ICS dose higher than 200μg beclomethasone equipotent daily dose: FENO (median [25th–75th percentiles]), 43ppb [15–105] (no treatment, n=65), 33ppb [15–77] (low dose, n=70), 23ppb [12–57] (medium dose, n=57) and 26ppb [9–49] (high dose, n=38). Statistically significant relationships between FENO and PFT were only observed in children receiving more than 200μg/day ICS: with FEV1 (medium ICS dose: ρ=0.43, p=0.001; high dose: ρ=0.32, p=0.052) and bronchodilator (400μg salbutamol) response (medium dose: ρ=0.54, p=0.001; high dose: ρ=0.65, p=0.002).Conclusions: A positive correlation between FENO and bronchomotor tone appears with increasing ICS doses in atopic children with clinically controlled asthma, which further suggests that children depicting the highest FENO values may have lesser steroid sensitivity. more >>
This was one of the results from a survey of 265 patients with COPD in Colorado. I agree with the 40% of patients who “vary their inhaler use from what is prescribed”. The only proven value of any of these medications is either to relieve dyspnea (for the duration of the bronchodilation) or slightly lower the risk of an exacerbation, but not to suppress the rapid loss of lung function. (Post hoc and subgroup analyses don't count.) Only smoking cessation halts progression of COPD, but it is much easier to write a prescription for an inhaler than to help a patient through the process of smoking cessation. more >>
Summary: Background: Cardiovascular manifestations in COPD include increased arterial stiffness, ischaemic heart disease, chronic heart failure and cor pulmonale. We hypothesised that sub-clinical right (RV) and left ventricular (LV) dysfunction occurs in patients with COPD, related to the severity of airflow obstruction, arterial stiffness and systemic inflammation.Methods: Thirty six patients and 14 controls, all free of overt cardiovascular disease underwent tissue Doppler echocardiography, spirometry, measurement of aortic pulse wave velocity (PWV) and venous sampling for inflammatory markers.Results: Mean LV myocardial strain and strain rate were less in patients than controls, p<0.05. LV isovolumic relaxation time (IVRT) was prolonged in patients (125±15.2ms) compared with controls (98.2±21.1ms), p<0.01, indicating LV diastolic dysfunction. The RV free wall strain and strain rate were less in patients than controls, both p<0.05, indicating RV systolic dysfunction. Patients had sub-clinical pulmonary arterial hypertension with a greater RV myocardial relaxation time and Tei index, both p<0.01. Patients with mild airways obstruction had LV and RV dysfunction and evidence of increased RV afterload compared with controls. In multivariate analyses aortic PWV predicted LV IVRT, p<0.01, while FEV1 predicted RV Tei index and myocardial relaxation time, both p<0.01.Conclusions: Patients with COPD have sub-clinical left ventricular dysfunction related to arterial stiffness, and right ventricular dysfunction related to airways obstruction. Both right and left ventricular dysfunction are present in patients with mild airways obstruction suggesting that cardiac co-morbidities commence early in the development of COPD. more >>
Summary: Background: Immunocompromised patients with influenza are at higher risk of pneumonia and death. However, risk factors for progression to pneumonia still need evaluation.Methods: Retrospective study in immunocompromised patients with influenza-related respiratory infections. Risk factors for pneumonia were identified by multivariable logistic regression.Results: We identified 100 immunocompromised patients infected with influenza (68 hematological malignancies, 11 HIV, 21 iatrogenic immunosuppression). Immunofluorescence was positive in 95% of patients, mainly on nasopharyngeal aspirates (84%). Influenza A virus was involved in 80% of patients. Associated infection was documented in 34 patients. All patients presented with upper respiratory tract infection and 53 progressed to pneumonia. Thirty-two patients were critically ill, 11 received mechanical ventilation, and 10 died. All the patients who died had pneumonia. Patients with pneumonia were older (46y (36–63) vs. 33y (13–51), P=0.003) and more often had influenza A (89% vs. 70%, P=0.04) and associated infection (56% vs. 9%, P<0.0001). Factors independently associated with progression to pneumonia were influenza A (OR 5.54, 95% CI [1.16–26.47]) and hematological malignancies (OR 3.85, 95% CI [1.1–14.5]).Conclusions: In our cohort of hospitalized immunocompromised patients, influenza progresses to pneumonia in more than half the patients. Patients with hematological malignancies and influenza A infection are at higher risk for pneumonia and should be included in preemptive antiviral therapy trials. more >>
Summary: We compared the efficacy and safety of ipratropium bromide/albuterol delivered via Respimat® inhaler, a novel propellant-free inhaler, versus chlorofluorocarbon (CFC)-metered dose inhaler (MDI) and ipratropium Respimat® inhaler in patients with COPD.This was a multinational, randomized, double-blind, double-dummy, 12-week, parallel-group, active-controlled study. Patients with moderate to severe COPD were randomized to ipratropium bromide/albuterol (20/100mcg) Respimat® inhaler, ipratropium bromide/albuterol MDI [36mcg/206mcg (Combivent® Inhalation Aerosol MDI)], or ipratropium bromide (20mcg) Respimat® inhaler. Each medication was administered four times daily. Serial spirometry was performed over 6h (0.15min, then hourly) on 4 test days. The primary efficacy variable was forced expiratory volume in 1s (FEV1) change from test day baseline at 12 weeks.A total of 1209 of 1480 randomized, treated patients completed the study; the majority were male (65%) with a mean age of 64 yrs and a mean screening pre-bronchodilator FEV1 (percent predicted) of 41%. Ipratropium bromide/albuterol Respimat® inhaler had comparable efficacy to ipratropium bromide/albuterol MDI for FEV1 area under the curve at 0–6h (AUC0–6), superior efficacy to ipratropium Respimat® inhaler for FEV1 AUC0–4 and comparable efficacy to ipratropium Respimat® inhaler for FEV1 AUC4–6. All active treatments were well tolerated.This study demonstrates that ipratropium bromide/albuterol 20/100mcg inhaler® administered four times daily for 12 weeks had equivalent bronchodilator efficacy and comparable safety to ipratropium bromide/albuterol 36mcg/206mcg MDI, and significantly improved lung function compared with the mono-component ipratropium bromide 20 mcg Respimat® inhaler. [Clinical Trial Identifier Number: NCT00400153] more >>
Summary: The causes of the worldwide increase in asthma seen during the last decades remain largely unexplained, but lifestyle and diet are suggested to play important roles. In this follow up of a large-scale population sample in Sweden, we wanted to identify modifiable risk factors for the cumulative incidence over a 13-year follow-up period.In 1990, a self-administered questionnaire was completed by 12,560 individuals from three age groups (16, 30–39 and 60–69 years of age) in two counties of Sweden. In 2003, the eligible subjects (n = 11,282) were sent a new postal questionnaire.In total 8150 (response rate 73%) answered the questionnaire. The prevalence of asthma in 2003 had increased in all ages. In the young adults, the asthma prevalence rose from 11.3% in 1990 to 25.0% in 2003. Adult asthma onset was identified in 791 of the participants. Smoking [RR (95% CI) = 1.37 (1.12–1.68)], BMI [1.49 (1.25–1.77 per inter quartile range)], and nocturnal gastro-oesophageal reflux (GOR) [2.16 (1.72–2.72)] were significant independent risk factors for the cumulative incidence of asthma. The impact of risk factors differed between the age groups where BMI and GOR had a significantly higher impact in the middle aged and the elderly (p < 0.05). High consumption of fruit and fish was protective especially in the elderly [0.52 (0.35–0.77)]. No significant difference was found in the impact of risk factors between men and women.Weight loss, smoking cessation and a diet rich in fruit and fish may be of importance in preventing onset of adult asthma. more >>
Summary: Background: Physical activity (PA) has been reported to be reduced in severe chronic obstructive pulmonary disease (COPD). Studies in moderate COPD are currently scarce. The aim of the present study was to investigate physical activity in daily life in patients with COPD (n=70) and controls (n=30).Methods: A multi-center controlled study was conducted. PA was assessed using a multisensor armband device (SenseWear, BodyMedia, Pittsburgh, PA) and is reported as the average number of steps per day, and the time spent in mild and moderate physical activity.Results: Patients suffered from mild (n=9), moderate (n=28), severe (n=23) and very severe (n=10) COPD. The time spent in activities with mild (80±69min vs 160±89min, p<0.0001) and moderate intensity (24±29min vs 65±70min; p<0.0036) was reduced in patients compared to controls. The number of steps reached 87±34%, 71±32%, 49±34% and 29±20% of control values in GOLD-stages I to IV respectively. The time spent in activities at moderate intensity was 53±47%, 41±45%, 31±47% and 22±34% of the values obtained in controls respectively with increasing GOLD-stage. These differences reached statistical significance as of GOLD stage II (p<0.05). No differences were observed among centers.Conclusions: Physical activity is reduced early in the disease progression (as of GOLD-stage II). Reductions in physical activities at moderate intensity seem to precede the reduction in the amount of physical activities at lower intensity. more >>
Summary: Many asbestos-exposed subjects have minor parenchymal changes on high resolution computed tomography (HRCT) that do not fulfil the diagnostic criteria for pulmonary fibrosis and asbestosis. We investigated if these borderline parenchymal changes in asbestos-exposed subjects are related to pulmonary inflammatory activity.Exhaled nitric oxide was measured, exhaled breath condensate collected and HRCT scanned in 104 subjects with moderate to high occupational asbestos exposure. Forty-one healthy unexposed subjects served as a comparison group.After excluding other pulmonary diseases, 35 asbestos-exposed subjects had normal parenchymal findings and 31 subjects had borderline parenchymal changes on HRCT. Lung function was poorer in the latter group, but there was no difference in the degree of asbestos exposure between these groups. As compared with the unexposed comparison group, asbestos-exposed subjects with borderline parenchymal changes had increased alveolar NO concentration (3.0 ± 0.2 vs. 2.3 ± 0.1 ppb, p = 0.008) and increased levels of leukotriene B4 (12.2 ± 1.1 vs. 3.3 ± 0.8 pg/ml, p < 0.001) and 8-isoprostane (9.4 ± 0.7 vs. 7.3 ± 0.6 pg/ml, p = 0.021) in breath condensate. Asbestos-exposed subjects with normal parenchymal findings had only increased breath condensate levels of leukotriene B4 (11.4 ± 0.9, p < 0.001).Borderline parenchymal changes on HRCT in asbestos-exposed subjects are associated with increased markers of pulmonary inflammation. Such borderline parenchymal changes are likely a mild or early form of the same pathological process that leads to asbestosis. more >>
Summary: This review aims to compare continuous with on-demand pharmacotherapy of allergic rhinitis by focusing on pharmacodynamic, pharmacokinetic, safety, effectiveness, cost and cost-effectiveness considerations. A working party of experts reviewed and discussed the literature and guidelines, and conducted a qualitative analysis of the Summary of Product Characteristics of specific medicines. With respect to medicines, the working party limited itself to antihistamines, nasal corticosteroids and leukotriene antagonists. Based on a review of the evidence from a multidisciplinary perspective, this article makes pharmacotherapeutic recommendations that are easy, functional and applicable to daily practice in primary care.The pharmacotherapeutic evidence for continuous versus on-demand treatment of allergic rhinitis was limited. Clearly, for corticosteroids, their mechanism of action in allergic rhinitis of reducing allergic inflammation requires continuous therapy at least for the duration of symptoms. For H1-antihistamines, some trials suggest that continuous treatment is preferable but more studies are needed to confirm this conclusion. For both H1-antihistamines and nasal corticosteroids safety data indicate that continuous treatment may be given without fears of adverse consequences, although a distinction can be made between the first and the second generation antihistamines. With regard to the cost and cost-effectiveness implications of continuous therapy versus on-demand therapy, more studies are necessary before definitive conclusions may be made. more >>
Summary: Hypersensitivity Pneumonitis (HP) is a lung inflammatory disorder caused by inhalation of organic particles by a susceptible host. However, only a small proportion of individuals exposed to HP-associated antigens develop the disease, suggesting that additional host/environmental factors may play a role. We have previously found that genetic susceptibility associated to the major histocompatibility complex (MHC) plays an important role in this disease. The low molecular weight proteosome (LMP, currently named PSMB) genes code for subunits of the proteosome, a multimeric enzymatic complex that degrades proteins into peptides in order to be presented in the MHC class I pathway. We hypothesized that polymorphisms in PSMB8 or PSMB9 genes could be involved in the susceptibility to HP. Thus, in this study we analyzed the polymorphic site at amino acid position 60 (Arg/His) of the fourth exon in the PSMB9 gene and the amino acid position 49 (Gln/Lys) in the second exon of PSMB8 gene in 50 Mexican patients with HP and 50 healthy ethnically matched controls. PSMB typing was performed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Our results demonstrated that HP patients had a significant increase of the PSMB8 KQ genotype frequency (OR = 7.25, CI = 2.61–21.3; p = 0.000034). No differences were found in the distribution of PSMB9 alleles/genotypes. However, PSMB9-RH/PSMB8 KQ haplotype was significantly increased in HP patients (OR = 6.77, CI = 1.34–65.31, p < 0.02). These findings suggest that PSMB8 KQ genotype could increase the risk to develop hypersensitivity pneumonitis. more >>
Summary: Aims: To investigate the long-term safety of inhaled iloprost in patients with pulmonary hypertension (pH), including idiopathic PAH (IPAH group) and other forms of pulmonary hypertension (PHother).Methods and results: Sixty-three patients (IPAH group, n=40, PHother n=23) were enrolled to receive inhaled iloprost either from baseline or after 3 months in a prospective, open-label 2-year study. Iloprost was inhaled 6–9 times daily with a night pause employing a jet nebulizer delivering an inhaled single dose of 4μg at the mouthpiece. In the case of side effects the single dose was reduced to 2μg. Sixty patients received at least 1 dose of inhaled iloprost. Thirty-six patients completed at least 630 days of therapy (25 IPAH, 11 PHother), 19 patients dropped out prematurely and 8 patients died (3 IPAH, 5 PHother). There were no drug-induced toxicities and only mild to moderate side effects. The most common side effects were coughing and flushing. Two-year survival was estimated at 85% (IPAH group 91%, PHother 78%). A modified analysis was performed to correct for differential drop-out. It included follow-up data from the premature discontinuations and revealed a 2-year survival of 87% [95% CI, 76%–98%] in the IPAH group while the predicted survival was 63%. The iloprost dose increased by 16% over 2 years.Conclusion: Inhaled iloprost is well tolerated as long-term therapy and no substantial dose increase is required. Although uncontrolled, the data suggest a long-term clinical benefit from continued therapy with inhaled iloprost. more >>
Summary: Background: While lung hyperinflation is frequent in asthma, measurement of lung volumes is not recommended in current guidelines. The aim of this descriptive functional study was to assess whether systematic measurement of volumes by plethysmography may detect isolated hyperinflation with normal expiratory flows.Methods and patients: One hundred sixty asthmatic children (mean age±SD: 10.8±2.7 years; 50 girls) receiving inhaled corticosteroid underwent lung function tests before and after bronchodilation (BD). To avoid the problem of dysanaptic lung growth on predicted values in childhood, airflow limitation and hyperinflation were defined by ratios (FEV1,%pred/FVC%pred for the former, RV/TLC for the latter) and values below and above the 5th or 95th percentiles of reference values, were chosen as cut-off values.Results: Different functional phenotypes were evidenced, mainly normal lung function (142/160 [89%] after BD), but also isolated airflow limitation (35/160 [22%] before and 7/160 [4%] after BD) and isolated hyperinflation (17/160 [11%] before and 11/160 [7%] after BD), while the combination of both impairments before BD (13/160 [8%]) was never observed after BD. There was no statistical relationship between airflow limitation and hyperinflation, either before or after BD. Indices of spirometry (FEV1, FEF50%) were unable to predict isolated hyperinflation that corresponds to small airway obstructive syndrome.Conclusion: Isolated hyperinflation is not infrequent in asthmatic children (7–11%) and small airway obstruction is not detected by forced expiratory flows. more >>
Summary: This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany.Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments.A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, €47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired.This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany. more >>
Abstract: Background: The Burden of Obstructive Lung Disease study showed that in Germany, to confirm the diagnosis of chronic obstructive lung disease (COPD) in one subject, eight people ≥40 years of age have to be screened. The number-needed-to-screen (NNS) increased to 18 for identifying a patient with COPD≥GOLD stage II. These high numbers limit the cost-effectiveness of COPD screening by population spirometry. We investigated in a primary care setting whether using two simple questions regarding smoking status and presence of cough and/or dyspnea may help to preselect patients for proper diagnosis of COPD.Methods: A total of 1088 patients aged ≥40 yrs without a history of chronic lung disease, who were either current or ex-smokers and complained of cough and/or dyspnea, were examined by respiratory physicians. Spirometry was carried out to confirm COPD diagnosis and severity.Results: A total of 61.6% of patients were male. Mean smoking history was 31.8 pack-yrs. In 516 patients (47.4%), a diagnosis of COPD was confirmed. Among these, 379 (34.8% of total) had at least GOLD stage II COPD, while 89 (8.2% of total) had advanced disease (GOLD stages III/IV). COPD prevalence was significantly associated with age and the extent of cigarette smoke exposure.Conclusions: Two questions regarding smoking status and presence of cough and/or dyspnea enabled general practitioners to select patients at risk for COPD for subsequent spirometry. This preselection reduced the NNS to 2.1 for identifying a COPD patient, and to 2.9 for identifying a patient of at least GOLD stage II. more >>
Summary: Objective: Increased arterial stiffness and sympathovagal imbalance are noted in patients with obstructive sleep apnea (OSA). It has been thought that continuous positive airway pressure (CPAP) therapy can have beneficial effects on the vascular function in such cases. However, it is not yet clear whether the improvement of sympathovagal balance by CPAP might be related to reduction of the arterial stiffness, independent of changes in the blood pressure.Methods: In 50 consecutive eligible patients with OSA (apnea–hypopnea index≥20/hour) receiving CPAP therapy, the brachial-ankle pulse wave velocity (baPWV), heart rate variability (LF, HF and LF/HF ratio), baroreceptor sensitivity (BRS), plasma levels of C-reactive protein (CRP), and endothelial function as assessed by changes in the forearm blood flow before and after reactive hyperemia (END) were measured before and after 3-months' CPAP therapy.Results: Significant decrease of the LF/HF ratio, plasma levels of CRP, baPWV and heart rate were observed after 3 months' CPAP therapy. The change in the baPWV following 3-months' CPAP therapy was significantly correlated with the change in the LF/HF ratio and mean blood pressure (MBP), but not with that of the BRS, CRP or END after the therapy. Multivariate linear regression analysis demonstrated a significant correlation between the change in the LF/HF ratio and that in the baPWV (beta=0.305, p=0.041), independent of the changes in the MBP, plasma CRP levels and heart rate.Conclusions: Improvement of the sympathovagal balance by CPAP therapy may be significantly related to decreased stiffness of the central to middle-sized arteries, independent of the changes in the blood pressure and vascular endothelial status. more >>
Summary: Introduction: Measurement of biomarkers in exhaled breath condensate (EBC) may be useful for monitoring lung inflammation and injury in mechanically ventilated patients. The aim of this study was to analyze changes in biomarkers of inflammation in EBC associated with prolonged mechanical ventilation.Methods: EBC samples were collected from critically ill patients weaning from mechanical ventilation without lung disease and from healthy nonsmokers. The following parameters were measured: pH after helium deaeration, nitrogen oxide and 8-isoprostane concentrations.Results: EBC was obtained from 10 patients and 20 controls. Ventilation time before the start of sample collection was 250 (85–714)h. The post-deaeration pH of EBC samples was significantly lower in ventilated patients than controls (7.50 [7.28–7.70] vs 8.07 [7.60–8.40]; P=0.008). Ventilation time before sample collection inversely correlated with pH (r=−0.636; P=0.048). A significantly higher concentration of nitrogen oxide (μM) was seen in ventilated patients vs controls (66.22 [22.26–83.13] vs 15.06 [10.73–23.30]; P=0.002), whereas levels of 8-isoprostane (pg/mL) were not significantly different between both groups (5.73 [4.0–11.4] vs 9.09 [6.63–11.43]; P=0.169). The nitrogen oxide concentration correlated negatively with dynamic compliance (r=−0.952; P<0.001) and positively with respiratory rate (r=0.683; P=0.029).Conclusions: EBC analysis is a non-invasive technique that can be used to monitor ventilated patients. Mechanically ventilated patients had higher EBC acidity and nitrogen oxide concentrations. Duration of ventilation correlated with breath condensate pH. more >>
Summary: Background: Our aim was to explore the association between respiratory health and proximity air quality in elderly.Methods: The prevalence of respiratory conditions was linked in 2104 individuals aged ≥65 years recruited in Bordeaux (3C Study) to home address concentrations of NO2, CO, SO2, fine particles (PM10), VOCs and benzene, estimated through a dispersion model combining data on background air pollution, traffic characteristics, and conditions of topographical and meteorological dispersion of air pollutants.Results: Mean [minimum; maximum] values of the annual concentrations (μg/m3) of proximity air pollutants were respectively: 28 [18; 72.2] for NO2, 420 [350; 1337] for CO, 7.5[5; 13.7] for SO2, 23.1 [19; 51] for PM10, 8.1 [0.01; 116.6] for VOCs and 1.8 [1.5; 6.9] for benzene. Using a binary logistic regression model, PM10 were significantly associated with usual cough (Odds-Ratio=1.33 (95% confidence interval: 1.00–1.77) for exposed compared to non-exposed) and SO2 with usual cough (1.55 (1.16–2.08)) and phlegm (1.45 (1.04–2.01)). We found a 10% and a 23% increase in usual cough for a 10μg/m3 increment in PM10 and a 1μg/m3 increment in SO2 respectively, and a 23% increase in usual phlegm for a 1μg/m3 increase in SO2. A sensitivity analysis showed similar results when considering 3-year proximity pollution. A more pronounced effect of SO2 and PM10 on usual cough and phlegm was observed in woman.Conclusions: Our assessment of exposure to proximity air pollution has shown an increased prevalence of bronchitis-like symptoms in elderly living in areas polluted by SO2 and PM10. more >>
Summary: Exhaled nitric oxide (FENO) has been used as a marker of asthmatic inflammation in non-occupational asthma, but some asthmatics have a normal FENO. In this study we investigated whether, normal FENO variants have less reactivity in methacholine challenge and smaller peak expiratory flow (PEF) responses than high FENO variants in a group of occupational asthmatics.Methods: We measured FENO and PD20 in methacholine challenge in 60 workers currently exposed to occupational agents, who were referred consecutively to a specialist occupational lung disease clinic and whose serial PEF records confirmed occupational asthma. Bronchial responsiveness (PD20 in methacholine challenge) and the degree of PEF change to occupational exposures, (measured by calculating diurnal variation and the area between curves score of the serial PEF record in Oasys), were compared between those with normal and raised FENO. Potential confounding factors such as smoking, atopy and inhaled corticosteroid use were adjusted for.Results: There was a significant correlation between FENO and bronchial hyper-responsiveness in methacholine challenge (p = 0.011), after controlling for confounders. Reactivity to methacholine was significantly lower in the normal FENO group compared to the raised FENO group (p = 0.035). The two FENO variants did not differ significantly according to the causal agent, the magnitude of the response in PEF to the asthmagen at work, or diurnal variation.Conclusions: Occupational asthma patients present as two different variants based on FENO. The group with normal FENO have less reactivity in methacholine challenge, while the PEF changes in relation to work are similar. more >>
Summary: Background: The histopathologic pattern is currently the most important prognostic marker for idiopathic interstitial pneumonia (IIP). However, more highly sensitive markers are now required. Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagens, and it has been demonstrated that HSP47 expression is significantly higher in the lung specimens of idiopathic UIP than in UIP associated with collagen vascular diseases (CVD). However, its expression in nonspecific interstitial pneumonia (NSIP), the other common pathological pattern of IIP, has not been well investigated. Therefore, the association between lung fibroblast HSP47 expression and prognosis in fibrotic NSIP was evaluated.Methods: Surgical lung biopsy specimens of 63 patients [idiopathic fibrotic NSIP=19, fibrotic NSIP associated with CVD=9, idiopathic UIP=26, and UIP associated with CVD=9] were reviewed, and a score for lung fibroblast HSP47 expression was assigned. These patients' clinical features and survival were also analyzed.Results: There was no significant difference in HSP47 expression between idiopathic fibrotic NSIP and fibrotic NSIP associated with CVD. The idiopathic fibrotic NSIP patients with higher HSP47 expression levels in their lung specimens had a poorer prognosis than patients with lower HSP47 expression levels.Conclusions: The present results suggest that lung fibroblast HSP47 expression may be a useful new prognostic marker for idiopathic fibrotic nonspecific interstitial pneumonia. more >>
Summary: Background: Tracheostomy is increasingly performed in intensive care units (ICU), with many patients transferred to respiratory ICU (RICU). Indications/timing for closing tracheostomy are discussed.Aim and Method: We report results of a one-year survey evaluating: 1) clinical characteristics, types of tracheostomy, complications in patients admitted to Italian RICU in 2006; 2) clinical criteria and systems for performing decannulation, and outcome of patients undergoing tracheostomy (number decannulated; number non-decannulated/non-ventilated; number non-decannulated/ventilated; dead/lost patients).Results: 22/32 RICUs replied. There were 846 admissions of 719 patients (Mean age 64,3 (±14.2) years, 489 (68%) males). Causes of admission were: acute respiratory failure with underlying chronic co-morbidities 176 (24.4%); exacerbation of Chronic Obstructive Pulmonary Disease 222 (34.4%); neuromuscular diseases 200 (27.8%); surgical patients 77 (10.7%); thoracic dysmorphism 28 (3.8%); obstructive sleep apnea syndrome 16 (2.2%). Percutaneous tracheostomies were 65.9%. Major complications after tracheostomy were 2%. 427 tracheostomies were evaluated for decannulation: 96 (22.5%) were closed; 175 patients (41%) were discharged with home mechanical ventilation; 114 patients (26.5%) maintained the tracheostomy despite weaning from mechanical ventilation and 42 patients (10%) died or lost.The clinical criteria chosen for decannulation were: stability of respiratory conditions, effective cough, underlying diseases and ability to swallow. The systems for evaluating feasibility of decannulation were: closure of tracheostomy tube; laryngo-tracheoscopy; use of tracheal button and down-sizing.Conclusions: There were few major complications of tracheostomy. A substantial proportion of patients maintain the tracheostomy despite not requiring mechanical ventilation. There was no agreement on indications and systems for closing tracheostomy. more >>
Summary: Dyspnoea is the most common symptom associated with poor quality of life in patients affected by Chronic Obstructive Pulmonary Disease (COPD). While COPD severity is commonly staged by lung function, the Medical Research Council (MRC) dyspnoea scale has been proposed as a more clinically meaningful method of quantifying disease severity in COPD. We wished to assess whether this scale might also be useful during telephone surveys as a simple surrogate marker of perceived health status in elderly patients with COPD.We conducted a comprehensive health status assessment by telephone survey of 200 elderly patients who had a physician diagnosis of COPD. The telephone survey contained 71 items and explored such domains as educational level, financial status, living arrangements and social contacts, co-morbid illness, and the severity and the impact of COPD on health status. Patients were categorized according to the reported MRC score: mild dyspnoea (MRC scale of 1), moderate dyspnoea (MRC scale of 2 and 3), or severe dyspnoea (MRC of 4 and 5). Deterioration in most of the recorded indicators of health status correlated with an increasingly severe MRC score. This was most evident for instrumental activities of daily living (IADL), perceived health and emotional status, pain-related limitations, limitations in social life, hospital admissions in preceding year and prevalence of most co-morbidities.The MRC dyspnoea scale is a reliable index of disease severity and health status in elderly COPD patients which should prove useful for remote monitoring of COPD and for rating health status for epidemiological purposes. more >>
Summary: Rationale: A subgroup of patients with chronic obstructive pulmonary disease require frequent hospitalization because of exacerbations of the disease. We hypothesized that airway infection by non-usual pathogens is a major factor driving hospitalization needs in these patients.Objectives: 1) To describe the clinical and functional characteristics of a cohort of COPD patients requiring ≥2 hospitalizations per year; 2) to determine prospectively their microbiological pattern during exacerbations; and, 3) to analyze the prognostic value of several clinical, functional and microbiological variables with respect to hospitalizations and mortality.Methods: Open cohort study of 116 COPD patients who had been hospitalized at least twice during the last 12 months. Patients were followed for an average of 21 months.Measurements and main results: Clinical data, forced spirometry and 6min walking distance were determined, and the BODE index was calculated, at the time of inclusion in the study. During follow-up, sputum culture was obtained during exacerbations, and hospitalization and mortality were collected every two months. Mean age was 71 yrs, and 94% of patients were male. Main findings show that: 1) not all patients had severe disease according to either the degree of airflow limitation or the BODE index; 2) non-usual pathogens, mainly Pseudomonas aeruginosa, other gram-negative non-fermentative rods and Enterobacteriaceae, were isolated among 71.1% of the sputum obtained during exacerbations; and, 3) these pathogens were associated with poor prognosis and frequent hospitalization.Conclusions: Airway infection by non-usual pathogens appears to be a key driver of frequent hospitalizations and mortality in COPD. more >>
Summary: Background: Fractional exhaled NO (Fe,NO) has yielded inconsistent results in COPD. Measuring exhaled NO at multiple flow rates however, allows to dissect exhaled NO in an alveolar (CAlv,NO) and bronchial (J'aw,NO) fraction, which are claimed to better reflect the bronchial and alveolar inflammation in COPD. We examined whether the use of Fe,NO, CAlv,NO and J'aw,NO may contribute to the clinical diagnosis of COPD.Methods: One hundred and fifty one patients were included in this case–control design: 28 healthy nonsmokers, 39 healthy smokers, 55 COPD nonsmokers and 29 COPD smokers. Prior to spirometry, exhaled NO was measured at three different flow rates (50, 100 and 200ml/s; NIOX-FLEX) from which Fe,NO, CAlv,NO and J'aw,NO were calculated.Results: Mean Fe,NO, mean CAlv,NO and mean J'aw,NO of healthy individuals were not significantly different from COPD patients and none of these variables correlated with FEV1. In both healthy and COPD patients, current smoking significantly reduced Fe,NO, J'aw,NO and CAlv,NO. Multivariate analysis demonstrated that in contrast to gender, age, BMI, GOLD stage and the use of inhaled corticosteroids, current smoking was the only variable affecting CAlv,NO. (p=0.0115)Conclusion: We conclude that similar to single breath exhaled NO, exhaled NO at different flow rates does not contribute to the diagnosis of COPD in standard respiratory practice. more >>
Summary: Introduction: Pulmonary hypertension can be associated with decreased functional capacity and poor prognosis in patients with parenchymal lung diseases (PLD). Yet, little attention has been given to current beliefs and practice patterns.Methods: An 18-question survey was submitted electronically to members of four Networks of the American College of Chest Physicians.Results: Analyzable responses were received from 453 physicians. Most (95%) respondents reported testing for PH in patients with PLD using transthoracic echocardiography (TTE) or right-heart catheterization (RHC) and believed that PH could occur in the absence of severe compromise in pulmonary function (70%) and hypoxemia (50%). Approximately 30% of physicians reported not performing RHC to confirm a diagnosis of PH before initiating therapy. Most respondents (92%) felt that medical therapy was effective and the medication of first choice was either bosentan or sildenafil. Most respondents believed that treating PH in these patients improves quality of life (63%) and dyspnea (67%), but were less sure about the impact on functional capacity and survival.Conclusions: Approximately 30% of physicians do not perform RHC to confirm this diagnosis prior to initiating therapy. Despite relatively little supportive evidence, most physicians treat with vasoactive medications and believe that medical therapy confers benefit. more >>
Summary: Background: Most issues concerning pharmacotherapy of pulmonary sarcoidosis have not been resolved in clinical trials. The objective was to survey sarcoidosis experts concerning the treatment of pulmonary sarcoidosis and attempt to reach a consensus by these experts using a Delphi method.Methods: A 6-item questionnaire was developed. Experts were identified at the Diffuse Lung Disease Network at the annual CHEST meeting in October 2008. Three rounds of questionnaires were presented to the experts. Respondent feedback and supporting literature was incorporated into the questionnaires of subsequent rounds.Results: Experts reached a consensus concerning the following issues: (a) corticosteroids are the initial therapy of choice; (b) initial use of inhaled corticosteroids are not recommended; (c) methotrexate was the preferred second-line drug; (d) 40mg of daily prednisone equivalent was the maximum dose recommended for the treatment of acute pulmonary sarcoidosis; (e) tapering to 10mg of daily prednisone equivalent for chronic pulmonary sarcoidosis was considered a successful taper. The experts could not resolve the following issues: (a) the initial corticosteroid dose for the treatment of acute pulmonary sarcoidosis; (b) the decision and timing of corticosteroid therapy in a patient with mild, Stage 2 pulmonary sarcoidosis.Conclusions: This Delphi study revealed that sarcoidosis experts reached a consensus concerning several aspects of the treatment of pulmonary sarcoidosis; these could be considered as appropriate approaches to therapy. Other issues concerning the therapy of pulmonary sarcoidosis remain unresolved by experts, and are areas where further clinical research could be directed. more >>
Summary: Background: The aim of this analysis was to examine associations between lung health in childhood and mortality between ages 18 and 44 years in the Tasmanian Longitudinal Health Study (TAHS).Methods: The 1961 Tasmanian birth cohort who attended school in 1968 (n=8583) were linked to the Australian National Death Index (NDI) to identify deaths. Additional deaths were notified by families through a 37 year follow-up postal questionnaire. Information on lung health at age 7 years and on potential confounders was obtained from the original 1968 TAHS survey and school medical records. Cox proportional hazards modelling was used to assess determinants of mortality.Results: A total of 264 (3%) deaths were identified. The principal causes of death were external injury (56.1%, n=97) and cancer (17.9%, n=31). Males were more likely than females to have died (p=<0.1). Only two (1.1%) participants had died from respiratory conditions. Having an FEV1<80% predicted at 7 years of age was associated with a 2-fold increased incidence of death. Tonsillectomy before age 7 years was associated with a 1.5-fold increase in mortality (p=0.05); being male with a 3.6-fold increase in mortality (p=0.0001); and repeated chest illnesses at age 7 years causing >30 days confinement in the last year, was associated with a 2.2-fold increase in mortality (p=0.03).Conclusions: Childhood lung health appears to be associated with increased mortality in adulthood, perhaps by affecting the ability to survive trauma, major illnesses and other physical stresses. more >>
Summary: Monitoring of asthma control can be performed with different means including measurement of the concentration of nitric oxide (NO) in exhaled air. Due to its action on the NO-metabolism; we hypothesized that the intake of Sildenafil might augment and falsify the NO-values in exhaled air of subjects taking the drug to treat erectile dysfunction.This randomised, placebo-controlled cross-over study including 10 male non-asthmatic volunteers taking a single dose of 50 mg Sildenafil did not confirm this assumption in non-asthmatic subjects. We cannot think of any reason why asthmatics should behave differently.On the basis of these results, it does not seem necessary to ask asthma patients with elevated NO-values if they had taken any selective inhibitor of the cGMP-specific phosphodiesterase Type 5 as Sildenafil prior to the test. more >>
Summary: Background: Current asthma patient-reported outcome (PRO) measures focus on symptoms and functioning and may not capture the holistic impact of asthma on the quality of life of the patient.Objective: To develop a PRO measure capturing the overall impact of asthma on patient's quality of life.Methods: Items for the Asthma Life Impact Scale (ALIS) were generated from patients with asthma during interviews in the UK and focus groups in the US. The ALIS was tested with UK and US asthma patients during cognitive debriefing interviews and included in large, two-administration, validation studies in the UK and US.Results: Issues raised by asthma patients during interviews (n = 39 patients) and focus groups (n = 16 patients) were included in the draft ALIS. Cognitive debriefing interviews with 29 UK and US asthma patients showed that the scale was relevant and comprehensive. 140 UK and 185 US asthma patients participated in the validation study. The analysis showed that the ALIS measures a single construct, namely the overall impact of asthma on patients' quality of life. Internal consistency (Cronbach's Alpha) was high (UK = 0.94; US = 0.92) as was test-retest reliability (UK = 0.93; US = 0.83). Patients reporting worse general health or more severe asthma had significantly higher ALIS scores (p < 0.001) (indicating greater negative impact of asthma). Correlations with the Asthma Quality of Life Questionnaire were moderate to high.Conclusions: The final 22-item ALIS is unidimensional, reliable and valid, and a valuable tool for comprehensively assessing the holistic impact of asthma from the patient's perspective. more >>
Summary: Background: Asthma is characterized by variable airflow obstruction and airway wall thickening. Multidetector-row computed tomography (MDCT) is useful for the evaluation of airway wall structural changes in asthma. The objective of the study is to assess the relationship between airflow limitation and airway dimensions from the third to fifth generation bronchi in asthma using MDCT.Methods: Thirty-eight subjects with asthma underwent MDCT to measure the airway wall area (WA) and luminal area (Ai), WA and Ai corrected by body surface area (BSA), up to the fifth generation of the apical bronchus (B1) and the posterior basal bronchus (B10) of the right lung.Results: WA/BSA, WA percentage (WA%) and Ai/BSA in the fifth generation were significantly correlated with forced expiratory volume in 1 s (FEV1)% predicted. The correlation coefficients between WA% and FEV1% predicted increased when tracking the airways from the third to the fifth generation (r=−0.25, p>0.05; r=−0.40, p<0.01; r=−0.63, p<0.001 for B1; r=−0.23, p>0.05; r=−0.47, p<0.01; r=−0.69, p<0.001 for B10). At the generation 5, WA% was greater and Ai/BSA was smaller in severe asthma than mild-to-moderate asthma.Conclusion: These results suggest that airway flow limitation in asthma is closely related to the more distal airways (third to fifth generation). more >>
Summary: Rationale: End of test criteria can influence spirometry results. Epidemiology studies initiated before adoption of the 1987 American Thoracic Society (ATS) guidelines typically used a 1 or 2 s plateau on the volume-time curve, not a minimum test duration of 6 s, to terminate a test.Objectives: To determine the effect of changing guidelines on FEV1, FVC and FEV1/FVC during a longitudinal study of young adults.Methods: Spirometry was performed on participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Values obtained at entry and 2, 5 and 10 years later using accepted procedures were re-evaluated using the 2005 ATS–ERS guidelines, which were in effect for the year 20 exam. Generalized estimating equations were used to adjust tests with short exhalations that were acceptable by then current end of test criteria.Results: The percentage of participants at years 0, 2, 5, and 10 with exhalations less than 6 s but with an acceptable plateau was 33%, 29%, 9%, and 2%, respectively. Exhalations less than 6 s occurred more frequently in younger and female participants, and were associated with lower FVC and higher FEV1/FVC. For short exhalations the adjusted FVC was 47 ml and 110 ml higher than the measured FVC when 6 and 8 s exhalation times were used.Conclusions: In longitudinal studies of young adults, changing end of test criteria may affect lung function, especially among younger and female participants. Determining adjusted values for tests with short exhalations may better represent the lung health of participants. more >>
Abstract: Background: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist bronchodilator currently in Phase III clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacodynamics, pharmacokinetics, safety and tolerability of ascending doses of aclidinium bromide in patients with COPD.Methods: This double-blind, randomised, placebo-controlled, crossover study was conducted in patients with moderate to severe COPD (forced expiratory volume in 1s [FEV1] <65% predicted). Patients were randomly assigned to one of four treatment sequences of aclidinium bromide 100, 300, 900μg and placebo with a washout period between doses. The primary outcome was area under the FEV1 curve over the 0–24h time interval.Results: Seventeen patients with COPD were studied. Mean FEV1 over 24h was 1.583L for placebo, and 1.727L, 1.793L and 1.815L for aclidinium bromide 100, 300 and 900μg, respectively (p<0.001 vs. placebo, all doses). Significant changes from baseline in FEV1 were detected 15min post-dose for aclidinium bromide 300 and 900μg, with a peak effect 2h post-dose (all doses). Aclidinium bromide was undetected in plasma. The majority of adverse events was unrelated to study medication and did not result in discontinuation.Conclusion: Aclidinium bromide 100–900μg produced sustained bronchodilation over 24h in patients with COPD. more >>
Summary: The mainstay of the diagnosis of asthma is the presence of reversible airway obstruction. Exhaled NO levels are increased in asthma, in close relationship with the amount of airway inflammation, and may be used for monitoring the disease and adjusting therapy. In this study we investigated the role of eNO as a diagnostic for asthma, compared with the FEV1-reversibility and the PC20 (20% decrease of the FEV1 in the bronchial histamine provocation test), in two independent centers, on an unselected population. ENO measurements were performed with chemoluminesence technique in one center and with an electrochemical device in the other. Only after correction for so-called nuisance factors (allergy, use of inhaled steroids, recent infection, smoking, sex and the use of nitrate food) the eNO appeared as a diagnostic with equal power as the FEV1-reversibility and the PC20.Therefore, screening for asthma in our study population, with the eNO measurement, is a simple, fast and safe strategy. more >>
Summary: Background: HRQL in IPF patients is impaired. Data from other respiratory diseases led us to hypothesize that significant gender differences in HRQL in IPF also exist.Methods: Data were drawn from the NIH-sponsored Lung Tissue Research Consortium (LTRC). Demographic and pulmonary physiology data along with MMRC, SF-12, and SGRQ scores from women vs. men were compared with two-sample t-tests. Multivariate linear regression was used to examine the association between SF-12 component scores and gender while adjusting for other relevant variables.Results: The study sample consisted of 147 men and 74 women. Among several baseline variables, only DLCO% predicted differed between women and men, (43.7 vs. 38.0, p=0.03). In general, men exhibited lower (better) MMRC scores (1.7 vs. 2.4, p=0.02), particularly those with milder disease as measured by DLCO% predicted. In an adjusted analysis, SF-12 PCS scores in men were lower (worse) than women (p=0.01), an effect that was more pronounced in men with greater dyspnea scores. In a similar analysis, SF-12 MCS scores in women were lower than men (worse) (48.3 vs. 54.4, p=0.0004), an effect that was more pronounced in women with greater dyspnea scores.Conclusions: Significant gender differences in HRQL exist in IPF. As compared to women, men reported less severe dyspnea, had worse SF-12 PCS scores, but better SF-12 MCS scores. Dyspnea appears to have a greater impact on the physical HRQL of men and the emotional HRQL of women. An improved understanding of the mechanism behind these differences is needed to better target interventions. more >>
Summary: Bronchial asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) or both, necessitating additional treatment. Patients ≥18years (n=1681) with mild-to-moderate asthma received oral montelukast 10mg added to ICS or ICS+LABAs, and were followed for 6months in a prospective, open-label observational study. The primary endpoint was change in Asthma Control Test (ACT) score. Secondary endpoints included mini-Asthma Quality-of-Life Questionnaire (mini-AQLQ) and FEV1/PEF. Mean ACT scores improved from 14.6±4.6 (baseline) to 19.4±4.4 (month 6; p<0.0001). Using ACT score categories, the percentage of patients with uncontrolled (57.5%) or poorly controlled (25.0%) asthma at baseline decreased at month 6 (17.6 and 21.7%, respectively); the percentage of patients with well controlled (13.9%) or completely controlled (1.2%) asthma at baseline increased at month 6 (47.5 and 11.4%, respectively). The mini-AQLQ score (mean±SD) improved from 4.0±1.1 to 5.3±1.1 (p<0.0001); FEV1 increased from 2.46±0.89 to 2.60±0.92L (p<0.0001). Treatment with montelukast was generally well tolerated. In patients insufficiently controlled with ICS or ICS+LABAs, daily add-on montelukast improved both asthma control and asthma-related quality of life. Clinicaltrials.gov registry number NCT00802789. more >>
Summary: Introduction: Aspirin hypersensitivity represents two distinct clinical syndromes, such as aspirin exacerbated respiratory disease (AERD) and aspirin-intolerant chronic urticaria/angioedema (AICU) which have different clinical phenotypes resulting from different genetic backgrounds in a Korean population. Persistent eosinophilic inflammation in airway is a characteristic feature of AERD and chemokine CC motif receptor 3 (CCR3) plays an important role in eosinophilic infiltration into the asthmatic airway.Objectives: The main objective of this study is to investigate the association between CCR3 gene polymorphisms and aspirin hypersensitivity, including AERD and AICU.Methods: CCR3 mRNA expression was measured after an aspirin provocation test by real-time PCR. In total, 330 patients with aspirin hypersensitivity (191 AERD and 139 AICU) and 217 normal healthy controls (NC) were genotyped for two CCR3 promoter polymorphisms (-520T/G and -174C/T), and the functional effects of the polymorphisms were analyzed applying a luciferase reporter assay and an electrophoretic mobility shift assay.Results: CCR3 mRNA expression was significantly increased after aspirin provocation in AERD patients (P=0.002) but not in AICU patients. An in vitro functional study showed that the reporter construct having a -520G allele exhibited significantly higher promoter activity compared with the construct having a -520T allele in human myeloid (U937), lymphoid (Jurkat), and mast (HMC-1) cell lines (P<0.001). We found -520G and -174T specific bands on EMSA.Conclusion: This result suggests that the CCR3 genetic polymorphisms may contribute to the development of the AERD phenotype and may be used as a genetic marker for differentiating between the two major aspirin hypersensitivity phenotypes. more >>
Summary: Background: The co-existence between chronic obstructive pulmonary disease (COPD) and heart failure has been previously described. However, the co-existence between COPD and subclinical left ventricular (LV) dysfunction, without the presence of heart failure symptoms, is less well understood. This study determined the relationship and clinical relevance of COPD and subclinical LV dysfunction in vascular surgery patients.Methods: 1005 consecutive vascular surgery patients were included in which COPD was determined using spirometry and LV function using echocardiography. Mild COPD was defined as FEV1≥80% of predicted+FEV1/FVC-ratio<0.70. Moderate/severe COPD was defined as FEV1<80% of predicted+FEV1/FVC-ratio<0.70. Systolic LV dysfunction was defined as LV ejection fraction <50% and diastolic LV dysfunction was diagnosed based on E/A-ratio, pulmonary vein flow and deceleration time. Multivariate regression analyses were used to evaluate the impact of COPD and LV dysfunction on all-cause mortality. The mean follow-up time was 2.2±1.8 years.Results: Both, mild and moderate/severe COPD were associated with increased risk for subclinical LV dysfunction with odds ratio of 1.6 (95%-CI=1.1–2.3) and 1.7 (95%-CI=1.2–2.4), respectively. mild- or moderate/severe COPD in combination with LV dysfunction was associated with increased risk for all-cause mortality (mild: hazard ratio 1.7; 95%-CI=1.1–3.6, moderate/severe: hazard ratio 2.5; 95%-CI=1.5–4.7).Conclusions: COPD was associated with increased risk for subclinical LV dysfunction. COPD+subclinical LV dysfunction was associated with increased risk for all-cause mortality compared to patients with COPD+normal LV function. Echocardiography may be useful to detect subclinical cardiovascular disease and risk-stratify COPD patients undergoing vascular surgery. more >>
Summary: Background: The epidemiological, pathophysiological and clinical links between upper and lower airways are nowadays clearly demonstrated. Most of asthmatics are suffering from rhinitis while up to 40% of rhinitic patients have asthma. Asthmatics and COPD patients are also prone to develop concomitant chronic rhinosinusitis (CRS).This study aimed to determine the predictive value of cough for concomitant asthma in patients suffering from upper airway diseases.Methods: This cross-sectional study described a group of 143 consecutive patients suffering simultaneously from common upper and lower airway disorders. Both ENT-specialists and respiratory physicians consecutively examined the patients in Ghent University Hospital from October 2004 till October 2006. This study was based on the demographic characteristics, upper and lower airway conditions.Results: Forty-seven percent of the patients included in the study were males and the mean age of studied population was 43.6years. The major complaint was chronic cough. When present, patients with chronic cough have an increased risk of suffering from a concomitant asthma in both allergic rhinitis (OR=5.8) and CRS with nasal polyps (OR=10.4), but not in CRS without polyps.Conclusions: Chronic cough was found to be a key symptom of associated asthma in allergic rhinitis and CRS with nasal polyps. Interestingly, chronic cough in CRS without nasal polyps did not show the same predictive value: this suggests different pathophysiological mechanisms. more >>
Summary: Objective: It is well documented that plasma ammonia accumulates during exercise under conditions of metabolic stress. Metabolic stress (when skeletal muscle ATP supply fails to meet demand) occurs at low work rates during cycling in patients with COPD, but not been described during walking. Walking is an important activity for many patients with COPD and is commonly prescribed in pragmatic outpatient pulmonary rehabilitation programmes. In this study we explored whether metabolic stress occurs during incremental walking at the low work rates these patients achieve.Methods: Twenty-nine subjects with stable COPD [mean(SD) age 68(7)years, FEV1 50(19)% predicted] performed maximal cardiopulmonary exercise tests on a cycle ergometer and treadmill. Plasma ammonia concentration was measured at rest, 1 and 2min of exercise, peak exercise and 2min recovery.Results: Subjects achieved mean(SD) cycle work rate of 57(20)W with VO2max 15.5(4.6)ml/min per kg, and treadmill distance 284(175)m with VO2peak 16.8(4.2)ml/min per kg. Plasma ammonia concentration rose significantly (p<0.001) with walking [mean(SEM) change 24.7(3.8)μmol/l] and cycling [mean(SEM) change 35.2(4.3)μmol/l], but peak exercise ammonia was lower in walking (p<0.01). In a subgroup of subjects (n=7) plasma ammonia did not rise during either cycling or walking despite similar lactate rise and peak exercise indices.Conclusion: Our data indicate that failure of muscle ATP re-synthesis to meet demand and development of metabolic stress can occur during walking in COPD patients at the low work rates these patients achieve. This may therefore be a factor contributing to exercise limitation independent of ventilatory limitation. more >>
Summary: Turbuhaler has a very high resistance hence patient inhalation flow when using it would be low.The total emitted dose (TED) of 500μg terbutaline sulphate from a Bricanyl Turbuhaler was determined using a range of inhalation flows (10–60L min−1) with inhalation volume of 2 and 4L using a DPI sampling apparatus after one and two inhalations.The relative lung and systemic bioavailability of terbutaline from Bricanyl Turbuhaler when used by healthy subjects and COPD patients were determined after one and two inhalations at slow and fast inhalation flows using a novel urinary terbutaline pharmacokinetic method.The TED resulted from the one and two inhalations increased significantly (p<0.05) with the increase of the inhalation flow at both 2 and 4L inhalation volumes. The relative lung and systemic bioavailability after one inhalation at fast inhalation flow were significantly higher (p<0.01) than at slow inhalation flow in both healthy subjects and patients. Also the healthy subjects results were significantly higher (p<0.05) than the COPD patients after one inhalation.However after two inhalations there was no significant difference between slow and fast inhalation flow or healthy subjects and COPD patients.Hence it is essential to inhale twice and as deep and hard as possible from each dose of Turbuhaler for patients with low inspiratory flow and limited inhalation volume as they may not receive much benefit from one inhalation. more >>
Summary: Objectives: To characterize a comprehensive comorbidity profile and to explore the economic implications of comorbidity among patients with chronic obstructive pulmonary disease (COPD).Methods: This retrospective cohort study analyzed medical claims from the Maryland Medicaid database. We employed a 1:2 case–control design to select COPD patients (n=1388) and demographically matched controls (n=2776) aged 40 to 64 years with 24 months of continuous enrollment. Odds ratios were employed to compare comorbidity differences, including 17 conditions defined by the Charlson Comorbidity Index (CCI) and 6 additional conditions commonly observed in COPD patients. We estimated the incremental medical utilization and medical cost by specific condition.Results: Compared with the controls, Medicaid COPD patients had higher comorbidity burden and were more likely to have myocardial infarction, congestive heart failure, cerebrovascular disease, peptic ulcer, mild liver disease, hypertension, sleep apnea, tobacco use, and edema. COPD patients on average had 24% more medical claims (81.4 vs. 65.4, p<0.001) and were 33% more expensive than controls ($7603 vs. $5732, p<0.001). Ten conditions defined by the CCI as well as hypertension, tobacco use, and edema were associated with incremental medical utilization and cost in COPD patients; depression was associated with incremental medical utilization but not cost.Conclusions: The high burden of comorbidity in COPD patients translates into additional medical utilization and cost. Effective disease management and treatment protocols are needed to reduce comorbidity burden. The development of a COPD-specific comorbidity measure may be used to identify high-risk subgroups and to predict utilization and cost. more >>
Summary: Introduction: There is increasing evidence that non-invasive imaging modalities such as ultrasonography may be able to detect subclinical atherosclerotic lesions, and as such may be useful tools for risk-stratification. However, the clinical relevance of these observations remains unknown in patients with COPD. Therefore we investigated the association between COPD and carotid wall intima-media thickness (IMT) in patients undergoing vascular surgery and its relationship with mortality in these patients.Methods: Carotid wall IMT was measured in 585 patients who underwent lower extremity, aortic aneurysm or stenosis repair. Primary study endpoint was increased carotid wall IMT which was defined as IMT≥1.25mm. Secondary study endpoints included total and cardiovascular mortality over a mean follow-up of 1.5 years.Results: Thirty-two percent of patients with mild COPD and 36% of the patients with moderate/severe COPD had increased carotid wall IMT, while only 23% had an increased carotid wall IMT in patients without COPD (p<0.01). COPD was independently associated with an increased carotid wall IMT (OR 1.60; 95% CI 1.08–2.36). Among patients with COPD, increased carotid wall IMT was associated with an increased risk of total (HR, 3.18 95% CI 1.93–5.24) and cardiovascular mortality (HR 7.28, 95% CI 3.76–14.07).Conclusions: COPD is associated with increased carotid wall IMT independent of age and smoking status. Increased carotid wall IMT is associated with increased total and cardiovascular mortality in patients with COPD suggesting that carotid wall measurements may be a good biomarker for morbidity and mortality in these patients. more >>
Summary: Purpose: A considerable body of non clinical evidence has accumulated to support peroxisomal proliferator-activated receptor gamma agonists as candidate anti-inflammatory drugs in asthma. We utilized rosiglitazone as a tool compound in the inhaled allergen challenge model of asthma.Methods: A single centre, double-blind, randomised, placebo controlled, two period cross-over study. Subjects received rosiglitazone 4mg and placebo twice daily for 28 days in random order. On day 28, inhaled allergen challenge was performed 1hour post-dose. A methacholine challenge was performed on day 29 and an adenosine monophosphate challenge on day 14. Exhaled nitric oxide was measured on days 1, 14, 28, 29. Blood was collected pre dose on days 1, 14 and 28 and analysed for markers associated with PPAR activity and systemic markers of inflammation.Results: The late asthmatic reaction (LAR) change from post saline FEV1 from 4–10 hrs post allergen on day 28 was statistically significant for the weighted mean LAR. The difference in weighted mean was 0.06 L (95% CI 0.01 to 0.11) which equates to a 15% attenuation of the response during placebo treatment. This was accompanied by trends in other markers of efficacy and anti-inflammatory activity but none were considered major effects.Discussion: Treatment with a PPARγ agonist (rosiglitazone) was associated with a modest (15%) reduction in the late asthmatic reaction in the allergen challenge model of asthma. Based on the results of this study, PPARγ agonist monotherapy is unlikely to represent a clinically useful intervention in human asthma.Registered with www.clinicaltrials.gov (NCT00318630). more >>
Summary: Diagnosing lung function abnormalities requires application of the appropriate reference equation for a given patient population. Current guidelines recommend the National Health and Examination Study III data set for evaluating patients in the United States. In Caucasian patients, relying on older reference equations, as opposed to those derived from the NHANES III data set, will often result in a different interpretation of a patient's spirometry. The present study assessed whether similar discordance would occur in African–American patients.A cross-sectional analysis of African–American patients undergoing spirometry testing at our hospital was performed. Patients were classified as normal, restricted, obstructed or mixed based upon the ATS/ERS guidelines, using Crapo, Knudson, Morris, Glindmeyer, and NHANES III prediction equations. Differences in classification were evaluated.4463 subjects were identified, with a mean age of 49.6. Discordance in interpretation was most common when results from prediction equations by Morris, Knudson, and Glindmeyer were compared to NHANES III (24.6%, 26.4%, and 20.1%, respectively). Discordance was less common when comparing Crapo to NHANES III (12.8%). There was a tendency for Knudson, Morris and Glindmeyer to under classify restriction, and for Crapo, Morris, and Glindmeyer to over classify obstruction.There is significant discordance in interpretation when spirometry for African–American patients is referenced to equations published by Crapo, Morris, Knudson, and Glindmeyer, compared to NHANES III. more >>
Increased ventilation during upper limb exercises (ULE) in COPD patients is associated with dynamic hyperinflation (DH) and a decrease in inspiratory capacity (IC). The best level of ULE loads training is still unknown. Our objective was to evaluate the dynamic hyperinflation development during ULE using three constant workloads.
Methods:
A prospective, randomized protocol involving 24 severe COPD patients (FEV1 < 50%) performing an endurance symptom-limited arm exercise of up to 20 minutes in an arm cyclergometer with different workloads (50%, 65% and 80% of the maximal load). Ventilation, metabolic and lung function variables (static IC pre and post exercise) were measured.
Results:
DH was observed during exercises with 65% (- 0.23 L) and 80% (- 0.29 L) workloads (p < 0.0001). Total time of exercise with 80% workload (7.6 min) was shorter than with 50% (12.5 min) (p < 0.0005) and with 65% (10.1 min-NS). Oxygen consumption predicted (VO2 %) (p < 0.01), was lower with 50% workload than with 80%. Eighty percent workload showed lower work efficiency (VO2 (ml/Kg)/exercise time) than the other two workloads (p < 0.0001).
Conclusion:
Different workloads during upper limb exercises showed a direct influence over dynamic hyperinflation and the endurance exercise duration.
Previous studies of the qualitative sensation of breathlessness have suggested that greater sensory discomfort is reported as airflow obstruction increases. This study investigated relationships between the language of breathlessness and severity of impairment in Australians with chronic obstructive pulmonary disease (COPD).
Methods:
Using a prospective, observational approach, subjects completed a structured interview in which they volunteered words to describe their sensation of breathlessness and endorsed statements from a pre-existing descriptor list. Global impairment was assessed by the body-mass index, airflow obstruction, dyspnoea and exercise capacity (BODE) index. Independent t-tests and logistic regression analyses (odds ratios) were used to assess relationships between language categories and severity of impairment.
Results:
In this group of 91 people (47 males, 70 ± 10 years, percent predicted FEV1 54 ± 23), subjects volunteering extreme affective descriptors (Frightening, Awful, Worried) had greater impairment (BODE index, perceived respiratory disability, functional exercise capacity and airways obstruction) and this language category was significantly associated with increasing BODE index scores (OR is 1.49, 95% CI 1.18 to 1.86, p = 0.001). Descriptors denoting heavy, rapid, more, shallow or does not go in or out all the way were significantly less likely to be selected as BODE index scored increased (OR 0.75, 95% CI 0.16 to 0.93).
Conclusions:
Affective descriptors or the emotional response to the sensation of breathlessness have a significant relationship with severity of COPD impairments. Affective descriptors may reflect the degree of threat imposed by the sensation and predict the likelihood of long term behavioural changes.
Little is known about the role of abnormal lung function for heart size and heart dysfunction in patients with chronic obstructive pulmonary disease (COPD). Here we studied the relationship of lung function with heart size and heart dysfunction and associated consequences for 6-minute walk distance (6MWD) in patients with COPD of different severity.
Methods:
In 138 patients with COPD (GOLD I-IV) we measured by echocardiography the size of all cardiac chambers, left ventricular diastolic dysfunction (relaxation and filling), and global right ventricular dysfunction (Tei-index). We measured lung function (spirometry, bodyplethysmography, diffusion capacity) and 6MWD.
Results:
Size of all cardiac chambers decreased with GOLD stages. Overall, moderate relationships existed between variables of lung function and cardiac chamber sizes. Static hyperinflation (inspiratory-to-total lung capacity ratio [IC/TLC], functional residual capacity, and residual volume) showed stronger associations with cardiac chamber sizes than airway obstruction or diffusion capacity. IC/TLC ratio correlated best with cardiac chamber sizes and was an independent predictor of cardiac chamber sizes after adjustment for body surface area. Patients with an IC/TLC ratio ≤ 0.25 had a significantly impaired left ventricular diastolic filling pattern and a significantly impaired Tei-index compared to patients with an IC/TLC ratio > 0.25. An impaired left ventricular diastolic filling pattern was independently associated with a reduced 6MWD.
Conclusions:
An increasing severity of COPD is associated with a decreasing heart size. Hyperinflation might have an important role for heart size and heart dysfunction in patients with COPD.
Sarcoidosis (SA) is a systemic granulomatous inflammatory disorder with complex etiology and strong clustering in families. Genome-wide association studies have been successful in the identification of common risk variants for the disease. To reveal susceptibility variants with low frequencies but strong effects, we performed a genome-wide linkage scan in a large sample of SA families.
Methods:
We genotyped 528 members of 181 German SA families for 3882 single nucleotide polymorphism (SNP) assays from the SNPlexTM System Human Linkage Mapping Set 4K (Applied Biosystems).
Results:
Non-parametric linkage analysis revealed one region of suggestive linkage on chromosome 12p13.31 at 20 cM (LOD = 2.53; local P value (pL) = 0.0003) and another linkage peak of nearly suggestive linkage on 9q33.1 at 134 cM (LOD = 2.12; pL = 0.0009). The latter has been reported to show suggestive evidence for linkage in a sample of 229 African-American SA families before. Analysis of acute and chronically affected families revealed a subphenotype-specific linkage pattern and an additional, nearly suggestive linkage peak on chromosome 16p13.11 at 38 cM (LOD = 2.09; pL = 0.001), which was confined to acute SA.
Conclusions:
Our results propose that the respective regions might harbor r yet unidentified, possibly subphenotype-specific risk factors for the disease, e.g. with immune-related functions like the tumor necrosis factor receptor 1. They should be proved to be important for SA pathogenesis and investigated in detail with an emphasis on rare variants. Subphenotype-specific risk factors might serve for prognosis of the clinical course of the disease.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has been documented to cause community acquired pneumonias (CAP), notable for necrotizing features. The frequency of occurrence, risk factors, and optimal treatment of CA-MRSA CAP are unclear.
Methods:
Retrospective analysis of patients admitted to Northwestern Memorial Hospital (NMH) from January 2005 to April 2007 with initial clinical presentation of pneumonia and respiratory or blood culture positive for CA-MRSA. Definition of CA-MRSA was based on sensitivity to trimethoprim/sulfamethoxazole and clindamycin.
Results:
15 patients with CA-MRSA CAP were identified over the 28 month period. Only one of the 14 patients tested had evidence of preceding influenza and no seasonal pattern was seen. Seven patients were never admitted to the ICU. 8/14 with chest CT scans had evidence of lung necrosis. 9/15 had evidence of pleural effusions early in their hospital course and 5/9 required at least one pleural drainage procedure. 7/15 were immunocompromised (3 HIV, 1 acute lymphocytic leukemia [ALL], 1 high dose steroids, and 2 immunoglobulin deficiency) with an additional 3 patients with diabetes. Mortality was only 13% (2/15); both deaths occurred in patients with severe immunocompromise (ALL post-chemotherapy and AIDS). 14/15 patients were treated with antimicrobials which inhibit exotoxin production (clindamycin or linezolid).
Conclusion:
CA-MRSA pneumonia is also not necessarily a post influenza infection. Despite necrotizing features in many, the mortality of CA-MRSA pneumonia in our series is lower than previously reported and patients do not routinely require ICU care. Treatment with antibiotics which inhibit exotoxin production and/or nontoxigenic strains may explain this improved outcome.
Distinct inflammatory cellular phenotypes of severe refractory asthma (SRA) have been reported. Fractional exhaled nitric oxide (FeNO) is primarily related to eosinophilic inflammation. Exhaled Breath Condensate (EBC) pH has been suggested to be a non-invasive tool in the assessment of patients with asthma. We sought to determine whether FeNO and EBC pH could identify the presence and the type of the underlying cellular inflammation in SRA patients.
Methods:
29 patients with SRA, 27 patients with moderate asthma and 17 healthy subjects underwent FeNO measurement, EBC collection for pH measurement and sputum induction for cell count identification.
Results:
FeNO was significantly higher whereas pH was significantly lower in patients with SRA compared to the other groups. In SRA, FeNO levels > 19 ppb were associated with a sensitivity of 0.78 and a specificity of 0.73 for sputum eosinophilia whereas FeNO levels < 19ppb were associated with a sensitivity of 0.63 and a specificity of 0.9 for sputum neutrophilia irrespective of the presence of eosinophils. pH failed to predict the cellular profile in SRA but a cut-off value < 7.37 could predict sputum eosinophilia in moderate asthma.
Conclusions:
In patients with SRA different FeNO threshold values can identify those with predominant eosinophilia as well as those with neutrophilia. FeNO levels were found to be reduced in patients with predominant neutrophilia regardless of the concomitant presence of eosinophilia. Although pH could not identify the cellular profile in SRA, it seemed to be a better index for predicting eosinophilia in moderate asthma.
Home diagnosis and therapy of OSA may improve access to testing and CPAP treatment. We compared subjective sleepiness, sleep quality, quality of life, blood pressure and CPAP adherence after four weeks of CPAP therapy in subjects diagnosed and treated at home and in those evaluated in the sleep laboratory.
Methods:
A randomised trial of: 1. Home-based level III testing followed by one week of autoCPAP and fixed-pressure CPAP based on P95; 2. In-lab PSG (using mostly split-night protocol) with CPAP titration was performed; 102 subjects were randomised (age: 47.4 ± 11.4 yrs; 63 males, BMI: 32.3 ± 6.3 kg/m2; ESS: 12.5 ± 4.3). The outcome measures were daytime sleepiness (ESS), sleep quality (PSQI), quality of life (SAQLI, SF-36), blood pressure and CPAP adherence after 4 weeks.
Results:
After 4 weeks of CPAP therapy there was no significant difference in ESS (PSG: 6.4 ± 3.8 vs. HM 6.5 ± 3.8, p= 0.71), PSQI (PSG: 5.4 ± 3.1 vs. HM: 6.2 ± 3.4, p= 0.30), SAQLI (PSG: 4.5 ± 1.1 vs. HM: 4.6 ± 1.1, p= 0.85), SF-36 Vitality (PSG: 62.2 ± 23.3 vs. HM 64.1 ± 18.4, p= 0.79), SF-36 MH (PSG: 84.0 ± 10.4 vs. HM 81.3 ± 14.9 p = 0.39) and blood pressure (PSG: 129/84 ± 11/0 vs. HM 125/81 ± 13/9, p 0.121). There was no difference in CPAP adherence (PSG: 5.6 ± 1.7 hr/night vs. HM: 5.4 ± 1.0hr/night, p = 0.49).
Conclusions:
Compared with the home-based protocol, diagnosis and treatment of OSA in the sleep laboratory does not lead to superior four-week outcomes in sleepiness scores, sleep quality, quality of life, blood pressure, and CPAP adherence.
Protocol-driven early goal-directed therapy (EGDT) has been shown to reduce mortality in patients with severe sepsis and septic shock in the Emergency Department (ED). EGDT appears to be underutilized, even in centers with formalized protocols. The aim of our study was to identify factors associated with not initiating EGDT in the ED.
Methods:
Cohort study of 340 EGDT-eligible patients presenting to a single center ED from 2005-2007. EGDT eligibility was defined as a serum lactate ≥4 mmol/L or systolic blood pressure <90 mm Hg after volume resuscitation. EGDT initiation was defined as the measurement of central venous oxygen saturation via central venous catheter. Multivariable logistic regression was employed to adjust for potential confounding.
Results:
EGDT was not initiated in 142 eligible patients (42%). EGDT was not completed in 43% of patients in whom EGDT was initiated. Compliance with the protocol varied significantly at the physician level, ranging from 0-100%. Four risk factors were found to be associated independently with decreased odds of initiating EGDT: female gender of the patient (p=0.001), female gender of the clinician (p=0.041), serum lactate, rather than hemodynamic, criterion for EGDT (p=0.018), and non-consultation to the Severe Sepsis Service (p<0.001).
Conclusions:
Despite a formalized protocol, we found that EGDT was underutilized. We identified potential barriers to the effective implementation of EGDT at the patient, clinician and organizational level. The use of a consultation service to facilitate the implementation of EGDT may be an effective strategy to improve protocol adherence.
Sepsis is a major public health problem. Social factors may impact health behaviors, economic resources, and immune response, leading to hospitalization for infection. This study examines the association between marital status and sepsis incidence and outcomes in a population-based cohort.
Methods:
We analyzed 1,113,581 hospitalizations in New Jersey in 2006. We estimated risk-adjusted incidence rate ratios for sepsis among divorced, widowed, legally separated (LS), single, and married subjects using population data from the American Community Survey. We used multivariable logistic regression to estimate marital status-specific hospital mortality.
Results:
We identified 37,524 hospitalizations for sepsis, of which 40% were among married (14,924), 7% were among divorced (2,548), 26% were among widowed (9,934), 2% (763) were among LS, and 26% (9355) among single subjects. The incidence of hospitalization for sepsis was 5.8 per 1,000 population. The age, gender, and race-adjusted incidence rate ratio for hospitalization with sepsis was greatest for single (IRR=3.47, 95%CI:3.1,3.9), widowed (IRR=1.38, 95%CI:1.2,1.6), and LS (IRR=1.46, 95%CI:1.2,1.8) subjects compared to married (ref). We observed that single men and women and divorced men had greater odds of in-hospital mortality compared to married men; widowed and LS men and all ever-married women had no excess mortality during hospitalization for sepsis.
Conclusions:
Hospitalization for sepsis is more common among single, widowed, and LS individuals, independent of other demographic factors. Among patients hospitalized for sepsis, single and divorced males and single women experience greater hospital mortality, highlighting the need to characterize the potentially modifiable mechanisms linking marital status to its greater burden of critical illness.
Longitudinal FEV1 data in children with non-cystic fibrosis (non-CF) bronchiectasis are contradictory and there are no multi-factor data on the evolution of lung function and growth in this group. We longitudinally reviewed lung function and growth in children with non-CF bronchiectasis and explored biologically plausible factors associated with changes in these parameters over time.
Methods:
Fifty-two children with ≥3-years of lung function data were retrospectively reviewed. Changes in annual anthropometry and spirometry at year-3 and year-5 from baseline were analyzed. The impact of gender, age, aetiology, baseline FEV1, exacerbation frequency, radiological extent, socio-economic status, environmental tobacco smoke exposure and period of diagnosis was evaluated.
Results:
Over 3-years, the group mean FEF25-75%predicted and BMI z-score improved by 3.01 (p=0.04, 95%CI 0.14-5.86) and 0.089 (p=0.01, 95%CI 0.02-0.15) per annum, respectively. FEV1%predicted, FVC%predicted and height z-score all showed non-significant improvement. Over 5-years, there was improvement in FVC%predicted (slope 1.74, p=0.001) annually but only minor improvement in other parameters. Children with immunodeficiency and those with low baseline FEV1 had significantly lower BMI at diagnosis. Frequency of hospitalized exacerbation and low baseline FEV1 were the only significant predictors of change in FEV1 over 3-years. Decline in FEV1%predicted was large (but non-significant) for each additional year in age of diagnosis.
Conclusions:
Spirometric and anthropometric parameters in children with non-CF bronchiectasis remain stable over a 3-5 year follow-up period once appropriate therapy is instituted. Severe exacerbations result in accelerated lung function decline. Increased medical cognizance of children with chronic moist cough is needed for early diagnosis, better management and improving overall outcome in bronchiectasis.
There are no data on the association between acute inflammation during critical illness and long-term mortality in intensive care unit (ICU) patients.
Methods:
Non-surgical patients with an ICU length of stay >24 hours surviving until ICU discharge were included into this prospective, observational, follow-up study. Demographics, chronic diseases, admission diagnosis, the Simplified Acute Physiology Score II, length of ICU stay, maximum CRP levels during the ICU stay (CRPmax) and CRP levels at ICU discharge (CRPdis) were documented. After a follow-up time of 1.88±1.16 (range, 0.5-4) years, the survival status was determined.
Results:
Seven-hundred-five patients were enrolled into the study protocol. Hundred-fifty-eight patients (20.7%) died within 0.62±0.88 years after ICU discharge. Cumulative survival rates differed between patients grouped into CRPmax and CRPdis quartiles. Patients in the first and second CRPmax quartile had better cumulative survival rates than those in higher CRPmax quartiles (all p<0.001). Patients in the first CRPdis quartile had better cumulative survival rates than those in higher CRPdis quartiles (all p<0.001). Using adjusted Cox proportional hazards models, both CRPmax and CRPdis were independently associated with post-ICU mortality (both p<0.001). Furthermore, the number of chronic diseases (p<0.001), age (p<0.001) and the Simplified Acute Physiology Score II (p=0.03) were associated with post-ICU mortality in both Cox models.
Conclusions:
CRP levels during critical illness seem independently associated with post-ICU survival in non-surgical ICU patients. Future research focusing on the association between acute systemic inflammation and post-ICU outcome is warranted in order to improve long-term survival of critically ill patients.
Our study aimed to determine the prevalence of habitual snoring (HS) in primary school children, and to evaluate the diurnal symptoms and conditions that may be associated with it.
Methods:
A validated questionnaire completed by parents was used to assess the sleep and daytime behaviors of Chinese children aged 5-14 years. Thirteen primary schools in two representative districts were randomly selected.
Results:
A total of 6,349 out of 9,172 questionnaires (response rate 69.2%) with complete answers were returned. The prevalence rate of HS was 7.2%. Male gender [OR(95%CI): 2.5(1.7-3.6)]; BMI z score [OR(95%CI): 1.4(1.1-1.6)]; maternal HS [OR(95%CI): 3.4(2.0-5.7)]; paternal HS [OR(95%CI): 3.8(2.7-5.5)]; allergic rhinitis [OR(95%CI): 2.9(2.0-4.2)]; asthma [OR(95%CI): 2.4(1.2-5.2)]; nasosinusitis [OR(95%CI): 4.0(1.5-10.6)] and tonsillitis [OR(95%CI): 3.1(1.9-5.1)] in the past 12 months were identified to be independent risk factors associated with HS. HS was also associated with daytime, nocturnal, parasomnaic and sleep-related breathing symptoms. HS was demonstrated to be an independent risk factor for parent-reported poor temper [OR(95%CI): 1.9(1.4-2.5)]; hyperactivity [OR(95%CI): 1.7(1.2-2.5)] and poor school performance [OR(95%CI): 1.7(1.2-2.5)].
Conclusions:
HS was a significant and prevalent problem in primary school children. Male gender, obesity, parental HS, atopic symptoms and history of upper respiratory infections were significant risk factors. HS was also associated with sleep-disordered breathing symptoms and adverse neurobehavioral outcomes.
Hypertrophic cardiomyopathy (HCM) is associated with arrhythmias and cardiovascular death. Left atrial enlargement and atrial fibrillation (AF) are considered markers for death due to heart failure in patients with HCM. Obstructive sleep apnea (OSA) is independently associated with heart remodeling and arrhythmias in other populations. We hypothesized that OSA is common and is associated with heart remodeling and AF in patients with HCM.
Methods and Results
We evaluated 80 consecutive stable patients with a confirmed diagnosis of HCM by sleep questionnaire, blood tests, echocardiography and sleep study (overnight respiratory monitoring). OSA (apnea-hypopnea index >15 events/hour) was present in 32 patients (40%). Patients with OSA were significantly older [56 (41-64) vs. 38.5 (30-53) years, p<0.001], presented higher body mass index (BMI: 28.2±3.5 vs. 25.2±5.2 Kg/m2, p<0.01), increased left atrial diameter [45 (42-52.8) vs. 41 (39-47) mm, P=0.01] and aorta diameter [34 (30-37) vs. 29 (28-32) mm, p<0.001] compared with patients without OSA. Stepwise multiple linear regression showed that apnea-hypopnea index (p=0.05) and BMI (p=0.06) were associated with left atrial diameter. Apnea-hypopnea index was the only variable associated with aorta diameter (p=0.01). AF was present in 31% vs. 6% in patients with and without OSA, respectively (P<0.01). OSA (P=0.03) and left atrial diameter (P=0.03) were the only factors independently associated with AF.
Conclusions:
OSA is highly prevalent in patients with HCM and it is associated with left atrial and aortic enlargement. OSA is independently associated with AF, a risk factor for cardiovascular death in this population.
transthoracic contrast echocardiography (TTCE) can detect pulmonary right-to-left shunting (RLS) and is used to screen for pulmonary arteriovenous malformations (PAVMs) in patients with hereditary hemorrhagic telangiectasia (HHT). We studied the prevalence and size of pulmonary RLS in HHT type 1, HHT type 2, and HHT negative controls, and its positive (PPV) and negative (NPV) predictive value for PAVMs that can be treated by embolotherapy.
Methods:
In 343 consecutive persons, referred for possible HHT as first degree family members of index patients, a TTCE and chest CT were performed. All persons were offered genetic analysis.
Results:
An HHT causing mutation was confirmed in 92 (mean age 41±15 yr; 59% female) HHT1, and in 95 (mean age 47±14 yr; 52% female) HHT2 relatives. TTCE showed a pulmonary RLS in 78 (85%) HHT1, and in 34 (35%) HHT2 related mutation carriers, respectively (p<0.0001). In HHT1 relatives 29 of 53 (55%) PAVMs, and in HHT2 relatives 3 of 17 (18%) PAVMS were treated, resulting in a PPV of TTCE for treatable PAVMs of 36.3% and 8.3%, respectively. The accompanying NPV was 100%. A minimal, moderate and large shunt was present in 12 (13%), 24 (26%) and 42 (46%) HHT1, and in 20 (21%), 6 (6%) and 8 (8%) HHT2 related mutation carriers, respectively (p for trend < 0,0001). A large shunt predicted treatable PAVMs in 55.8% of HHT1, and 37.5% of HHT2 relatives. TTCE was positive in 4 (6%) of 63 persons without HHT.
Conclusion:
A pulmonary shunt on TTCE is more prevalent and larger inHHT1, as compared with HHT2 related mutation carriers. Shunt grading is helpful to predict treatable PAVMs, particularly in the HHT2 group. TTCE is also positive in a small fraction of persons without HHT.
The objectives of our study were to compare patient characteristics and severity of disease in obese and normal-weight confirmed asthmatics, and to explore reasons for misdiagnosis of asthma including potential interactions with obesity.
Method:
We randomly selected patients with physician-diagnosed asthma from 8 Canadian cities. Asthma diagnosis was confirmed via a sequential lung function testing algorithm. Logistic analysis was conducted to compare obese and normal-weight confirmed asthmatics and to assess characteristics associated with misdiagnosis of asthma. Interaction with obesity was investigated.
Results:
Complete assessments were obtained on 496 subjects who reported physician-diagnosed asthma (242 obese and 254 normal-weight subjects); 346 had asthma confirmed with sequential lung testing, however in 150 subjects a diagnosis of asthma was ruled out. Obese asthmatics were significantly more likely to be male, have a history of hypertension and GERD, and have a lower FEV1 compared to normal-weight asthmatics. Older subjects, males, and subjects with higher FEV1 were more likely to have been misdiagnosed with asthma. Obesity was not an independent predictor of misdiagnosis, however there was an interaction between obesity and urgent visits for respiratory symptoms. The odds ratio for being misdiagnosed as asthma, for obese individuals as compared to normal-weight individuals was 4.08 (95% CI 1.23 – 13.5) for those with urgent visits in the past 12 months.
Conclusion:
Obese asthmatics have lower lung function and more co-morbidities compared to normal weight asthmatics. Obese individuals who make urgent visits for respiratory symptoms are more likely to be misdiagnosed with asthma.
In cases of pleural effusion, tissue samples can be obtained through Abrams’ needle pleural biopsy (ANPB), thoracoscopy, or cutting-needle pleural biopsy under the guidance of computerized tomography (CT-CNPB) for histopathological analysis. This study aimed to compare the diagnostic efficiency and reliability of ANPB under CT guidance (CT-ANPB) with that of medical thoracoscopy in patients with pleural effusion.
Methods:
Between January 2006 and January 2008, 124 patients with exudative pleural effusion who could not be diagnosed by cytological analysis were included in the study. All patients were randomized after the CT was performed. Patients either underwent CT-ANPB or thoracoscopy. The two groups were compared in terms of diagnostic sensitivity and complications associated with the methods used.
Results:
Of the 124 patients, 33 were diagnosed with malignant mesothelioma, 47 with metastatic pleural disease, 42 with benign pleural disease, and 2 were of indeterminate origin. In the CT-ANPB group, the diagnostic sensitivity was 87.5%, as compared to 94.1% in the thoracoscopy group; the difference was not statistically significant (p=0.252). No difference was identified between the sensitivities of the two methods based on the etiology, the CT findings, and the degree of pleural thickening. Complication rates were low and acceptable.
Conclusion:
We recommend the use of CT-ANPB as the primary method of diagnosis in patients with pleural thickening or lesions observed by CT. In patients with only pleural fluid appearance on CT and in those who may have benign pleural pathologies other than tuberculosis, the primary method of diagnosis should be medical thoracoscopy.
We suspected based on clinical experience that the prevalence of both intracardiac and pulmonary arteriovenous malformations (PAVM) are higher than previously reported in a healthy population when using modern ultrasound technology combined with a rigorous saline contrast echo (SCE) protocol. We hypothesized the prevalence of right-to-left shunts (RLS) would be so high when employing this sensitive technique, there would be no significant association of RLS with migraine headache.
Methods:
We recruited 104 healthy volunteers to undergo a SCE followed by completion of a migraine questionnaire. The SCE were meticulously graded for shunt size and location based on left heart contrast quantity and timing. The migraine headache questionnaire was graded by a neurologist blinded to SCE results.
Results:
104 volunteers underwent the study protocol. We found 71% of volunteers exhibited evidence of RLS. PFO was identified in 40(38%), PAVM in 29 (28%), and 5 subjects had evidence of both (5%). Based on questionnaires, 42 (40%) of the volunteers had migraine headache (29% with aura). There was no significant association of migraine headache with PFO (OR 0.59, 95% CI 0.16-2.12, p=0.54) or PAVM (OR 0.8, 95% CI .34-1.9, p=0.67), although only 13 (13%) of volunteers had evidence of large RLS.
Conclusions:
When using modern ultrasound technology combined with a rigorous SCE technique, the majority of healthy volunteers demonstrate some degree of RLS. PAVM in an otherwise healthy population is common. Small and moderate size RLS do not appear to be significantly associated with migraine headache.
To evaluate the efficacy of non-invasive CPAP delivered by helmet in improving oxygenation in comparison to oxygen therapy in community-acquired pneumonia (CAP).
Methods:
a multicentre, randomized, controlled trial enrolling CAP patients admitted to an Emergency Department with moderate hypoxemic acute respiratory failure (ARF) (PaO2/FiO2 ratio ≥210 and ≤285). Patients were randomized to helmet CPAP or standard oxygen therapy (control group). The primary endpoint was the time to reach a PaO2/FiO2 ratio >315. After reaching this value, patients randomized to CPAP were switched to oxygen and the proportion of subjects who could maintain a PaO2/FiO2 ratio >315 at 1 hour was recorded.
Results:
Forty-seven patients were recruited: 20 randomized to CPAP and 27 to controls. Patients randomized to CPAP reached the endpoint in a median of 1.5 hour, while controls in 48 hours, (p<0.001). The proportion of patients who reached the primary endpoint was 95% (19/20) among CPAP group, and 30% (8/27) among controls (p<0.001). One hour after reaching the primary endpoint, 2/14 patients in CPAP group maintained a PaO2/FiO2 value >315.
Conclusions:
CPAP delivered by helmet rapidly improves oxygenation in patients with CAP suffering from a moderate hypoxemic ARF. This trial represents a "proof of concept" evaluation of the potential utility of CPAP in CAP patients.
Cigarette smoking is causally related to several cancers, in particular lung cancer, yet for some cancers there are inconsistent associations. This study investigates the association of smoking with other cancers by correlating them with the regional incidence rates for lung cancer, which was used as a proxy for cigarette smoking. This ecologic approach relating cigarette smoking to cancer utilizing a large database avoids the limitations and bias present in case-control and cohort studies.
Methods:
Based on the assumption that regions with a high rate of lung cancer also have a high rate of cigarette smoking, our original hypothesis is that these high intensity regions will also have high rates of other cancers if they are associated with cigarette smoking. Linear regression and correlation analysis of regional incidence rates for lung cancer, obtained from the SEER Program, were plotted with incidence rates of other cancers to determine the association between lung cancer and the other cancers.
Results:
Cancers that have shown a strong correlation with cigarette smoking in the literature also demonstrate a strong correlation with lung cancer. These cancers included urinary bladder, laryngeal, esophageal, colorectal, and kidney cancer. A number of cancers showed a weak association with cigarette smoking, such as pancreatic and liver cancer. Other cancers showed no correlation, such as ovarian and prostate cancer.
Conclusions:
Cancers that respectively showed a strong or absent correlation with lung cancer in the SEER Program were similarly strongly or weakly correlated with cigarette smoking in the literature. Cancers with borderline correlations show ambiguous results or confounding variables in the literature.
Mediastinal lymph nodes must often be biopsied to accurately stage lung cancer. Endobronchial ultrasound-guided, transbronchial needle aspiration (EBUS-TBNA) allows real-time guidance in sampling paratracheal, subcarinal, and hilar lymph nodes, and esophageal, ultrasound-guided-guided fine-needle aspiration (EUS-FNA) can sample mediastinal lymph nodes located adjacent to the esophagus.
Nodes can be sampled and staged more completely by combining these procedures, but to date, use of two different endoscopes has been required. We examined whether both procedures could be performed with a single EBUS bronchoscope.
Patients and Methods:
Consecutive patients with a presumptive diagnosis of non-small cell lung cancer (NSCLC) underwent endoscopic staging by EBUS-TBNA and EUS-FNA through a single linear ultrasound- bronchoscope. Surgical confirmation and clinical follow-up was used as the reference standard.
Results:
Among 150 evaluated patients, 139 (91%; 83 male; 56 female; mean age 57.6 y) were diagnosed with NSCLC. In these 139 patients, 619 nodes were endoscopically biopsied: 229 by EUS-FNA and 390 by EBUS-TBNA. Sensitivity was 89% for EUS-FNA and 92% for EBUS-TBNA. The combined approach had a sensitivity of 96% and negative predictive value of 95%, values higher than either approach alone. No complications occurred.
Conclusions:
The two procedures can easily be performed with a dedicated linear EBUS bronchoscope in one setting and by one operator. They are complementary and provide better diagnostic accuracy than either one alone. The combination may be able to replace more invasive methods as a primary staging method for lung cancer patients.
It has been demonstrated that there is an increased risk of venous thromboembolism (VTE) during air travel on flights of long duration. Patients with COPD are also at increased risk of VTE, particularly during exacerbations, possibly due to a hypercoagulable state secondary to hypoxia and/or heightened systemic inflammation. We investigated the effects of hypoxia on indices of coagulation and systemic inflammation in patients with COPD.
Methods:
Twenty clinically stable patients with mild COPD were recruited. Patients were randomised to receive either medical air or 100% nitrogen through a 40% venturi mask at a flow rate of 10 L/min for two hours. Blood was sampled for thrombin anti-thrombin complex (TAT), prothrombin activation fragments 1+2 (F1+2), von Willebrand factor antigen (VWF:Ag), D-dimer and interleukin-6 (IL-6) at baseline and after two hours.
Results:
Patients in the hypoxia and control groups were similar in terms of age, gender, pack years smoked and severity of airflow obstruction. There was no difference in baseline TAT, F1+2, VWF:Ag, D-dimer or IL-6 levels between groups. In the control group, there was no change in markers of coagulation or systemic inflammation over the 2 hour study. In patients who underwent hypoxic challenge, there was an increase in TAT (p<0.001), F 1+2 (p<0.01) and IL-6 (p<0.01), while D-dimer and VWF:Ag levels were unchanged.
Conclusions:
This study demonstrates that a two hour hypoxic challenge in patients with COPD results in coagulation activation in conjunction with a rise in systemic inflammation.
The concept healthcare-associated pneumonia (HCAP) exists to identify patients infected with highly resistant pathogens. It is unclear how precise this concept is and how well it performs as a screening tool for resistance.
Methods:
We retrospectively identified patients presenting to the hospital with pneumonia complicated by respiratory failure. We examined the microbiology of these infections based on pneumonia type and determined the sensitivity and specificity of HCAP as a screen for resistance. Through logistic regression and modeling we created a scoring tool for determining who may be infected with resistant pathogens.
Results:
The cohort included 190 subjects (37% with Acute Respiratory Distress Syndrome) and we noted resistant pathogens in 33%. Resistance was more common in HCAP (78% vs. 44%, p=0.001). HCAP alone performed poorly as a screening test (sensitivity and specificity 78.3% and 56.2%, respectively). Variables independently associated with a resistant organism included: immunosuppression (adjusted odds ratio (AOR) 4.85, p<0.001), long term care (LTC) admission (AOR 2.36 p=0.029), and prior antibiotics (AOR 2.12, p=0.099). A decision rule based only on these factors performed moderately well at identifying resistant infections. The presence of HCAP itself, based on meeting defined criteria for this, was not independently associated with resistance using logistic regression to control for co-variates..
Conclusions:
HCAP is common in patients presenting to the hospital with pneumonia leading to respiratory failure. The HCAP concept does not correlate well with the presence of infection due to a resistant pathogen. A simpler clinical decision rule based on select HCAP criteria performs as well as the HCAP concept for potentially guiding antibiotic decision making.
Historical influenza A epidemics have carried elevated rates of cardiovascular disease, including transient cardiac dysfunction. Whether such an association holds for the novel influenza A strain, pandemic-2009-H1N1, remains unknown. We report an index case of transient cardiac dysfunction associated with H1N1 infection. Next, we reviewed 123 sequential cases of patients hospitalized with pandemic-2009-H1N1 influenza A at a single academic medical center in the United States from April 1-October 31, 2009. We identified that 4.9% (6/123) of patients had either new or worsened left ventricular dysfunction. These cases ranged in age from 23 to 51 years and all had pre-existing medical conditions. ICU level care was required in 83% (5/6) of the cases. Sixty-seven percent (4/6) of the cases had follow-up echocardiograms, and in all four, left ventricular function improved. Therefore, potentially reversible cardiac dysfunction is a relatively common complication associated with hospitalized pandemic-2009-H1N1 influenza.
The co-stimulatory molecules OX40 and OX40 ligand (L) mediate key aspects of allergic airway inflammation in animal models of asthma including eosinophilic airway inflammation, airway hyperresponsiveness and Th2 polarization. We sought to examine OX40/OX40L and IL-4 expression in asthma across severities.
Methods:
Bronchial biopsies were obtained from 27 subjects with asthma (mild GINA 1 [n=10], moderate GINA 2-3 [n=7] and severe GINA 4-5 [n=10]) and 13 healthy controls. The number of OX40+, OX40L+, IL-4+, and IL-4R+ cells in the lamina propria and airway smooth muscle (ASM) bundle and the intensity of IL-4R+ expression by the ASM was assessed.
Results:
The number of OX40+, OX40L+, and IL-4+ cells in the lamina propria and OX40+ and IL-4+ cells in the ASM-bundle was significantly increased in subjects with mild asthma, but not in those with moderate or severe asthma, compared to healthy controls. In the subjects with asthma OX40/OX40L expression was positively correlated with the number of eosinophils and IL-4+ cells in the lamina propria. The number of IL-4R+ cells in the lamina propria was significantly increased in moderate to severe disease, but not mild asthma, compared to controls. IL-4R expression by the ASM-bundle was not different between groups.
Conclusion:
OX40/OX40L expression is increased in the bronchial submucosa in mild asthma, but not in moderate to severe disease and is related to the degree of tissue eosinophilia and IL-4 expression. Whether these co-stimulatory molecules have a role as targets for asthma requires further investigation.
The association of obesity with sleep-associated respiratory disturbances that have traditionally been described as a problem of adults actually originates in childhood. We aimed to seek for an association between sleep-disordered breathing (SDB) and overweight and/or obesity in a large cohort of school and pre-school aged children of Southern Italy.
Methods:
One thousand-two-hundred-seven children (612 females and 595 males; mean age 7.3 years) were screened by a self-administered questionnaire. According to answers, children were divided in three groups: "non snorers (NS)", "occasional snorers (OS)", and "habitual snorers (HS)". All HS, who also failed an oximetry study at home, underwent a polysomnographic monitoring for the definition of SDB. Body mass index (BMI) was calculated according to Italian growth charts.
Results:
A total of 809 (67.0%) children were eligible for the study. Of them, 44 children (5.4%) were classified as HS, 138 (17.0%) as OS, and 627 (77.5%) as NS. Fourteen children (1.7%) were diagnosed with obstructive sleep apnea syndrome (OSAS). Sixty-four subjects (7.9%) were defined obese, 121 (14.9%) overweight and 624 (77.2%) normal weight. The frequency of HS was significantly higher in obese children than in overweight and normal weight subjects (12.5% vs 5.8% vs 4.6%; p=0.02), while the frequency of OSAS was 1.6% in normal weight, 1.6% in overweight, and 3.1% in obese children (p=ns).
Conclusion:
Our findings in a large sample of Italian children suggest that obesity is associated with snoring.
Critical pressure (Pcrit) is considered a reliable parameter to evaluate the mechanical properties of passive upper airway (UA) and is significantly increased in OSAH patients compared to normals. The volume exhaled in the first 0.5 sec. after application at the mouth of 5 cmH2O negative pressure at the onset of expiration (V,NEP0.5) during wakefulness has been used as a marker of UA collapsibility. The aim of this study was to investigate if there is a significant relationship between V,NEP0.5 and Pcrit in normals, snorers and OSAH patients.
Methods:
30 males: 10 OSAH (age 64±9.1 yrs, BMI 32±4.9 Kg/m2, AHI 43.8±24, neck circumference 46.6±3.7 cm), 10 snorers, (age 68±11 yrs, BMI 26.6±4.6 Kg/m2, AHI 3.5±0.8, snoring time ≥ 30% of sleep time, neck circumference 42.2±3.9 cm), 10 controls (age 67±12 yrs, BMI 25.4±2.2 Kg/m2, AHI 1.9±1.2, neck circumference 41.2±2.2 cm) underwent V,NEP0.5 measurement in supine position while awake and Pcrit measurement during sleep. Correlation between V,NEP0.5 and Pcrit was performed in all subjects.
Results:
Controls had V,NEP0.5 of 456±82 mL and Pcrit of -1.38±0.6 cmH2O, snorers had V,NEP0.5 of 321±33 mL and Pcrit -0.55±0.3 cmH2O while OSAH patients showed V,NEP0.5 of 295±67 mL and Pcrit of 0.99±1 cmH2O (p < 0.001 vs. normals). A strong correlation was found between V,NEP0.5 and Pcrit (r2=0.61, p < 0.0001).
Conclusions:
In males with neck circumference > 37 cm, V,NEP0.5 during wakefulness strongly reflects Pcrit in a wide range of values. Our findings suggest that V,NEP0.5 can be used as valuable substitute of Pcrit to assess UA collapsibility for clinical and research purposes in these subjects.
Distinction of malignant mesothelioma (MM) from reactive mesothelial cells (RM) in effusions is notoriously difficult. The aim of our study was to test chromosomal aberrations detected by fluorescence in situ hybridization (FISH) in the diagnosis of MM in effusion cytology and to explore the potential role of p16, p14 and p15 gene methylation as an alternative mechanism of tumour suppressor gene inactivation.
Methods:
52 effusions of biopsy proven MM and 28 benign effusions were retrospectively analyzed by multi-target FISH assay for aberrations of chromosomes 3, 7, 17 and 9p21. In case of a negative result the corresponding MM biopsy was analyzed. Methylation specific polymerase chain reaction (MSP) for p16, p14 and p15 was performed on FISH negative MM biopsies.
Results:
79% of effusions with biopsy proven MM had chromosomal aberrations with loss of 9p21 as the most common finding. All benign effusions were FISH negative. Sensitivity, specificity, positive and negative predictive values for detection of MM by FISH was 79%, 100%, 100%, and 72%, respectively. Six of nine FISH negative effusions with biopsy proven MM were also FISH negative in the MM biopsies. Four of five FISH negative biopsies showed promoter methylation in p16 and p14 as compared to one of 12 benign controls.
Conclusions:
FISH is a sensitive and highly specific method for the definitive diagnosis of MM in effusion cytology. In the subset of FISH negative MM, tumour suppressor genes on the chromosomal region 9p21 are often inactivated by promoter methylation.
Current evidence indicates that measurement of pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) levels can aid in distinguishing pleural effusions of cardiac origin from those of noncardiac origin. To date only one study has described simultaneous measurement of pleural fluid brain natriuretic-32 peptide (BNP) and NT-proBNP. The purpose of the present study was to determine pleural fluid BNP and NT-proBNP levels and analyze the relationship between these two measurements. We hypothesized that there would be a positive correlation between pleural fluid NT-proBNP and BNP while NT-proBNP levels would be higher than BNP levels.
Methods:
Levels of pleural fluid NT-proBNP and BNP were measured by enzyme immunoassay (EIA) in a total of 80 patients: 20 with congestive heart failure (CHF), 20 status post coronary artery bypass graft (CABG), 20 with carcinoma, and 20 with pneumonia.
Results:
Comparison of NT-proBNP and BNP concentrations using Spearman s method of statistical analysis revealed a correlation coefficient of 0.572, p < 0.001. Evaluation of the diagnostic accuracy of BNP and NT-proBNP in patients with pleural effusions of cardiac origin demonstrated an area under the receiver operating characteristic curve (AUC) of 0.700 (95% confidence interval [CI], 0.569 to 0.831) and 0.835 (95% CI, 0.721 to 0.949), respectively.
Conclusions:
Though levels of pleural fluid BNP have a statistically significant correlation with those of NT-proBNP, this relationship only explains 32% of the variancein NT-proBNP levels. Furthermore, when compared to BNP, NT-proBNP is a more accurate diagnostic aid in the evaluation of pleural effusions of cardiac origin.
Although many studies suggested that biomass smoke is a risk factor for chronic obstructive pulmonary disease (COPD), the relationship between biomass smoke and COPD has not been firmly established. Especially, the extent of the association of the exposure of biomass smoke with COPD in different populations as well as the relationship between biomass smoke and cigarette smoke is not clear. To ascertain the relationship between biomass smoke and COPD, we performed a meta-analysis.
Methods:
We searched the Medline, Embase, LILACS and analyzed 15 epidemiologic (sectional and 4 case-control) studies that met our criteria. Data were extracted and analyzed independently by two investigators using a standardized protocol.
Results:
Overall, people exposed to biomass smoke have an odds ratio (OR) of 2.44 (95 percent confidence interval (95% CI) 1.9 -3.33) for developing COPD, relative to those not exposed to biomass smoke. Biomass smoke exposure was clearly identified as a risk factor for developing COPD in both women (OR: 2.73, 95% CI: 2.28-3.28) and men (OR: 4.30, 95% CI: 1.85-10.01), as well as in both Asian population (OR: 2.31, 95% CI: 1.41-3.78) and non-Asian population (OR: 2.56, 95% CI: 1.71-3.83). This risk factor has also be revealed in patients with chronic bronchitis (OR: 2.56, 95% CI: 1.77-3.70) and COPD (OR: 2.65, 95% CI: 1.75-4.03), and in cigarette smokers (OR=4.39, 95%CI: 1.40-4.66) and non cigarette smokers (OR=2.55, 95%CI: 2.06-3.15).
Conclusions:
Exposure to biomass smoke is a risk factor for COPD.
Allergic rhinitis and asthma frequently coexist. However, the nature of this association is poorly understood. Therefore, we examined whether upper and lower airway patencies are associated.
Methods:
We investigated 221 six-year-old children from the Copenhagen Prospective Study on Asthma in Childhood birth cohort assessing upper airway patency by acoustic rhinometry before and after -agonist and lower airway patency by spirometry before and after β2-agonist. Furthermore, we measured blood eosinophil count, nasal eosinophila, total immunoglobulin E, and fraction of exhaled nitric oxide. Associations were investigated by generalized linear models.
Results:
Decongested nasal airway patency and post-β2 FEV1 were significantly associated, p=0.007. The association remained significant after adjustments for sex, body size, forced vital capacity, and atopic diseases (β-coefficient, 2.85cm3; 95% CI, 0.42 to 5.29; p=0.02). Baseline values of upper and lower airway patency were also significantly associated (β-coefficient, 0.89cm3; 95% CI, 0.26 to 1.51; p=0.01). In addition, blood eosinophil count and nasal eosinophila were inversely associated with decongested nasal airway patency, β-coefficient -0.42cm3 (95% CI, -0.77 to -0.07; p=0.02) and β-coefficient -0.47cm3 (95% CI, -0.89 to -0.05; p=0.03), respectively.
Conclusion:
We found a strong and consistent association between upper and lower airway patency. This may be due to a common pathology as suggested from the inverse association between decongested nasal airway patency, blood eosinophil count, and nasal eosinophilia. Alternatively, the association between upper and lower airway patency reflects a physiologic background for the common co-morbidity.
At diagnosis of pulmonary arterial hypertension (PAH), some patients are considered to have a "near-normal" 6-min walk distance (6MWD), i.e. >450 m. As they are generally excluded from randomized controlled trials, little is known about these patients.
Methods:
We analyzed baseline characteristics and treatment responses of 49 consecutive patients with a 6MWD >450 m at the time of newly diagnosed PAH. Data from this cohort was then compared with data from hemodynamically-matched patients with a 6MWD ≤450 m.
Results:
Patients with a 6MWD >450 m were either in World Health Organization (WHO) functional class (FC) II (n=23) or III (n=26) at baseline. Compared to patients in FC II, those in FC III had more severe hemodynamic impairment – that is, a lower cardiac index and higher pulmonary vascular pressures and resistance – but similar 6MWD. At first evaluation after initiation of PAH-specific treatment (3-6 months), FC improved (FC I-II: n=38; FC III: n=11, p<0.005) and cardiac index increased. However, 6MWD remained unchanged. Compared to matched patients with a 6MWD ≤450 m (n=98), individuals with a 6MWD >450 m were approximately 9 years younger (p=0.0006) and had a lower body mass index (BMI) (p=0.0009).
Conclusions:
Anthropometric characteristics such as younger age and lower BMI may explain higher 6MWD in some PAH patients. In the cohort of patients with a 6MWD >450m, hemodynamic indices and WHO FC were more sensitive than 6MWD to detect changes secondary to PAH-specific treatments.
Investigate whether there is a difference in pulmonary function between healthy adult US-born Asian Indians and immigrant Asian Indians attributable to country of birth, environmental and socioeconomic factors.
Design:
Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and forced mid-expiratory flow (FEF25-75) were measured in India-born and US-born subjects residing in the Chicago metropolitan area. Hollingshead Index of Social Position was used to evaluate socioeconomic factors.
Results:
There were 262 India-born (61.8% male), and 200 US-born (50% male) subjects who were healthy lifelong nonsmokers; their age range was 16-36 years. US-born Asian Indian men and women were taller and had higher pulmonary function values for height and age compared to immigrant Asian Indian men and women. The differences were most pronounced in women: about 7% for FVC, 9% for FEV1, and 17% for FEF25-75. Immigrant and US born subjects did not differ in socioeconomic position.
Conclusion:
We conclude that US-born Asian Indian men and women have higher pulmonary function values for age and height compared to immigrant Asian Indian men and women. This probably reflects the effect of differing environmental conditions, which cause year of birth trends in lung volumes.
Thoracoscopic talc insufflation (TTI) has been used to obliterate the pleural space, and prevent recurrent pleural effusions or pneumothorax. Reports of acute pneumonitis and ARDS following the use of talc raised concern about its safety. Differences in particle size of various talc preparations may explain the variable occurrence of pneumonitis. We sought to determine the incidence of lung injury following TTI over a 13-year period at our institution.
Methods:
Patients who underwent TTI between January 1994 and July 2007 were identified from a prospectively maintained logbook. The talc used was commercially available sterile talc (Sclerosol®). The hospital course was reviewed in detail, and all cases of respiratory insufficiency were examined with regards to onset, suspected etiology and outcome. Talc-related lung injury was defined as the presence of new infiltrates on chest radiograph and increased oxygen requirements, with no other identifiable trigger than talc exposure.
Results:
A total of 138 patients underwent 142 TTI for recurrent pleural effusions or spontaneous pneumothorax. TTI was performed most frequently for malignant pleural effusions (75.5% of effusions). The median dose of talc was 6 g (range 2-8 g). Twelve patients developed dyspnea with increased O2 requirements within 72 hours post-procedure. Talc-related lung injury occurred in 4 patients (2.8%) and talc exposure may have contributed to the respiratory deterioration in 4 additional patients.
Conclusion:
We report the occurrence of lung injury following TTI using the only talc approved by the FDA. These results reinforce previous concerns regarding the talc used for pleurodesis in North America.
Though several biological factors have been suggested to play a role in the development and persistence of severe asthma, those associated with psychological factors remain poorly understood. This study assessed levels of psychological distress and a range of disease-relevant emotional and behavioural coping styles in patients with severe versus moderate asthma.
Methods:
84 patients (50% female, M age 46 yrs) with severe (n=42) and moderate (n=42) asthma were recruited. Severe asthma was defined according to ATS criteria. Patients underwent demographic and medical history interviews, pulmonary function and allergy testing. Patients also completed questionnaires measuring asthma symptoms and the Millon Behavioural Medicine Diagnostic Inventory (MBMDI), which assesses psychological distress and emotional/behavioural coping factors that influence disease progression and treatment.
Results:
After adjustment for covariates and applying a correction factor that reduced the significant p-level to <.01, patients with severe vs. moderate asthma reported experiencing more psychological distress including worse cognitive dysfunction [F=6.72, p<.01]) and marginally worse anxiety-tension [F=4.02, p<.05]. They also reported worse emotional coping (higher illness apprehension [F=9.57, p<.01], pain sensitivity [F=10.65, p<.01], future pessimism [F=8.53, P<.01], and interventional fragility [F=7.18, p<.01]), and marginally worse behavioral coping (more functional deficits [F=5.48, p<.05] and problematic compliance [F=4.32, p<.05]).
Conclusion:
Patients with severe asthma have more psychological distress and difficulty coping with their disease both emotionally and behaviorally relative to moderate asthmatics. Future treatment studies should focus on helping severe asthma patients manage distress and cope more effectively with their illness, which may improve outcomes in these high-risk patients.
Removing the artificial airway is the last step in the mechanical ventilation withdrawal process. In order to assess cough effectiveness, a critical component of this process, we evaluated the involuntary peak flow (CPFi), to predict the extubation outcome for patients weaned from mechanical ventilation in intensive care units (ICUs).
Methods:
150 patients were weaned from ventilators, passed a spontaneous breathing trial (SBT), and were judged by their physician to be ready for extubation in the Tri-Service General Hospital ICUs from February to July 2003. Involuntary CPF was induced by 2 mL of normal saline solution at the end of inspiration and measured using a hand-held respiratory mechanics monitor. All patients were then extubated.
Results:
Of 150 enrolled patients for this study, 118 (78.7%) had successful extubation and 32 (21.3%) patients failed. In the univariate analysis, there were higher APACHE II scores (16.0 vs. 18.5, p=0.018), less negative maximum inspiratory pressure (Pimax) (-45.0 vs. –39.0, p = 0.010), lower cough peak flows (CPF’s) (74.0 vs. 42.0 L/min, p < 0.001), longer post-extubation hospital stays (15.0 vs. 31.5 days, p < 0.001) and longer post-extubation ICU stays (1.0 vs. 9.5 days, p < 0.001) in the extubation failures compared to the extubation successes. In the multivariate analysis, we found that a higher APACHE II score and a lower CPF were related to increasing risk of extubation failure [OR = 1.13, 95% confidence interval: (1.03, 1.25) and OR = 0.95, 95% confidence interval: (0.93, 0.98), respectively]. The receiver operator characteristic (ROC) curve cut-off point for CPF was 58.5 L/min, with a sensitivity of 78.8 % and specificity of 78.1 %.
Conclusions:
CPFi as an indication of the cough reflex has the potential to predict successful extubation in patients who pass an SBT.
Analysis of exhaled breath by biosensors discriminates between patients with asthma and healthy subjects. An electronic nose consists of a chemical sensor array for the detection of volatile organic compounds (VOCs) and an algorithm for pattern recognition. We compared the diagnostic performance of a prototype of an electronic nose with lung function tests and fractional exhaled nitric oxide (FENO) in patients with atopic asthma.
Methods:
A cross-sectional study was undertaken in 27 patients with intermittent and persistent mild asthma and in 24 healthy subjects. Two procedures for collecting exhaled breath were followed to study the differences between total and alveolar air. Seven patients with asthma and 7 healthy subjects participated in a study with mass spectrometry (MS) fingerprinting as an independent technique for assessing between group discrimination. Classification was based on principal component analysis and a feed forward neural network.
Results:
The best results were obtained when the electronic nose analysis was performed on alveolar air. Diagnostic performance for electronic nose, FENO, and lung function testing was 87.5%, 79.2%, and 70.8%, respectively. The combination of electronic nose and FENO had the highest diagnostic performance for asthma (95.8%). MS fingerprints of VOCs could discriminate between patients with asthma and healthy subjects.
Conclusions:
The electronic nose has a high diagnostic performance that can be increased when combined with FENO. Large studies are now required to definitively establish the diagnostic performance of the electronic nose. Whether this integrated non-invasive approach will translate into an early diagnosis of asthma has to be clarified.
We investigated illness perceptions among critically ill patients or their surrogates in a university medical intensive care unit using a prospective survey. We hypothesized that these would vary by demographic, personal, and clinical measures.
Methods:
Patients (n=23) or their surrogates (n=77) were recruited. The Illness Perception Questionnaire-Revised (IPQ-R) measured six domains of illness perception: timeline-acute/chronic, consequences, emotional impact, personal control, treatment efficacy, and illness comprehension. Multiple variable linear regression models were developed with IPQ-R scores as the outcomes.
Results:
African Americans tended to perceive the illness as less enduring and reported more confidence in treatment efficacy (p<0.01 for each). They also tended to report the illness as less serious, having less emotional impact, and having greater personal control (p=.0002 for each). Conversely, African Americans reported lower illness comprehension (p=.002).
Faith/religion was associated with positive illness perceptions including less concern regarding consequences (p=0.02); less emotional impact (p=0.03); and more confidence in treatment efficacy (p<0.01).
Lower patient pre-critical illness quality-of-life (QOL) was associated with negative perceptions including greater concern about illness duration and consequences as well as perception of less personal control and less confidence in treatment efficacy (p<0.01 for each).
These variables were independently associated with illness perceptions after controlling for race, faith/religion, and survival to hospital discharge whereas clinical measures were not.
Conclusions:
Illness perceptions among critically ill patients and surrogates are influenced by patient/surrogate factors including race, faith, and pre-critical illness quality of life rather than clinical measures. Clinicians should recognize the variability in illness perceptions and the possible implications for patient/surrogate communication.
Mucus hypersecretion is an important pathophysiologic index of airway disease. Measurement of secreted mucin in sputum has been reported in asthma, but not in chronic cough with or without increased sputum production.
Methods:
We studied 49 patients with classical asthma, 39 with cough variant asthma, 9 and 5 with chronic cough associated with sinobronchial syndrome and gastroesophageal reflux disease, respectively, and 11 healthy controls. Seventeen patients with classical asthma but none from the other groups were taking anti-inflammatory medications. Mucin levels in induced sputum supernatants were measured by ELISA, which detects airway mucin, probably including MUC5AC and MUC5B.
Results:
Mucin levels were higher in classical asthma (674.2±548.8 µg/ml) and sinobronchial syndrome (638.4±650.7 µg/ml) than in controls (212.0±167.1 µg/ml) (p=0.0037 and 0.044). They were also higher in classical asthma than in cough variant asthma (350.4±374.0 µg/ml) and gastroesophageal reflux disease (134.3±93.1 µg/ml) (p=0.0016 and 0.015), but results did not differ between the latter groups and controls. When the four disease groups were combined, patients with frequent sputum production had greater mucin levels than those with occasional (p=0.0023) or no sputum production (p<0.0001). Patients with classical asthma showed negative correlations of mucin levels with respiratory resistance indices on impulse oscillation and with airway sensitivity to methacholine.
Conclusions:
Sputum mucin levels differ in various respiratory conditions when compared with controls, primarily reflecting the degree of sputum production. Airway mucin might possibly exert protective effects in asthma, at least between exacerbations, but this issue needs to be further clarified by future studies.
Although there is now compelling evidence for cross-infection by strains of Pseudomonas aeruginosa at some specialist (cystic fibrosis) CF centres, the clinical impact of infection by transmissible strains is unclear.
Methods:
In an 8-year prospective study, we compared the clinical outcome for two groups of patients with CF infected by transmissible (n=28) and sporadic strains (n=52) of P. aeruginosa.
Results:
There were no differences between the two groups in survival, or annual changes in spirometry or body mass index. There were differences in requirements for intravenous antibiotic treatment (mean [SD] 29.3 [21.9] days v. 53.1 [32.5] days) and hospitalisation (median [range] 11.6 [1.1, 49.3] days v. 23.3 [5.5, 103.6] days) between patients infected with sporadic and transmissible strains of P. aeruginosa, respectively.
Conclusions:
We conclude that infection by transmissible P. aeruginosa does not increase mortality but is associated with an increased healthcare utilisation and antibiotic usage for patients with CF.
Architectural design of healthcare facilities can influence patient safety, however, it is unknown whether patient outcomes are significantly affected by intensive care unit (ICU) design.
Methods:
664 patients admitted to the medical intensive care unit (MICU) of Columbia University Medical Center during 2008 were included in this retrospective study. Patient outcome measures, which included hospital mortality, ICU mortality, ICU length of stay, and ventilator-free days, were compared based on random room assignment. Patients assigned to rooms which were not visible from the MICU central nursing station were designated as low visible rooms (LVRs), while the remaining rooms were designated as high visible rooms (HVRs).
Results:
Overall hospital mortality did not differ among patients assigned to LVRs versus HVRs, however, severely ill patients (those with APACHE II scores greater than 30) had significantly higher hospital mortality when admitted to a LVR than similarly ill patients admitted to a HVR (82.1 and 64.0%, N=39 and 75, respectively; p=0.046). ICU mortality showed a similar pattern. ICU length of stay and ventilator-free days did not differ significantly between groups.
Conclusions:
Severely ill patients may experience higher mortality rates when assigned to ICU rooms that are poorly visualized by nursing staff and physicians.
Acute pulmonary embolism (PE) may be rapidly fatal if not diagnosed and treated. Intravenous (IV) heparin reduces mortality and recurrence of PE, but the relationship between survival and timing of anticoagulation has not been extensively studied.
Methods:
We studied 400 consecutive emergency department (ED) patients diagnosed with acute PE by CT angiography and treated in the hospital with IV unfractionated heparin from 2002 to 2005. Patients received heparin either in the ED or after admission. Time from ED arrival to therapeutic activated partial thromboplastin time (aPTT) was calculated. Outcomes included in-hospital and 30-day mortality, hospital and intensive care unit (ICU) lengths-of-stay, hemorrhagic events on heparin, and recurrent venous thromboembolism (VTE) within 90 days.
Results:
In-hospital and 30-day mortality rates were 3.0% and 7.7%, respectively. Patients who received heparin in the ED had lower in-hospital (1.4% versus 6.7%, p=0.009) and 30-day (4.4% versus 15.3%, p<0.001) mortality rates as compared to patients given heparin after admission. Patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital (1.5% versus 5.6%, p=0.093) and 30-day (5.6% versus 14.8%, p=0.037) mortality rates as compared to patients who achieved a therapeutic aPTT after 24 hours. In multiple logistic regression models, receiving heparin in the ED remained predictive of reduced mortality, and ICU admission remained predictive of increased mortality.
Conclusions:
We report an association between early anticoagulation and reduced mortality for patients with acute PE. We advocate further study with regard to comorbidities in order to assess the utility of modifications to hospital protocols.
Macrophages have an important role in COPD. We genotyped at risk smokers to evaluate the role of polymorphisms in the MSR1 gene in COPD susceptibility and related measures of lung function. Then in macrophages from donors with specific MSR1 genotypes, we determined the effect of MSR1 SNPs on macrophage function by examining in vitro adhesion, receptor expression and cell number in culture as an index of increased survival/reduced apoptosis.
Methods:
Smokers (≥ 20 pack-years), > 40 years (n =714) were genotyped for 7 SNPs; 1 nonsense change (ex6R293X_C/T) 4 missense changes (ex4V113A_T/C, ex4P174Y_G/T, ex11H441R_A/G and in the ligand binding site ex6P275A_C/G), -176511_A/G in the promoter region, IVS5-59_C/A in the intron. Non-smoking healthy volunteers (n=85) were genotyped and peripheral blood monocytes were isolated from 7 P275A_CG/GG and 8 P275A_CC controls; and cultured to generate monocytes-derived macrophages (MDM). The effectiveness of trypsin and scraping to dislodge MDM was scored on a 4-point subjective scale. MDM were counted on a Z1 particle counter and surface expression of MSR1 determined by FACS analysis using secondary staining of antibodies against human MSR1.
Results:
The MSR1 coding SNP P275A, was associated with susceptibility to COPD in smokers (p < 0.005) and a lower ppFEV1, FEV1/FVC, and ppFEF25-75 (p=0.03). P275A_CG/GG was also associated with increases in maintenance of cell number in culture (increased survival/reduced apoptosis), MSR1 expression and adhesion of macrophages to plastic in vitro (p<0.05).
Conclusions:
The MSR1 association with COPD susceptibility, COPD related measures of lung function and abnormalities of macrophage function may account for significant COPD morbidity.
Although several serum markers have shown their ability to reflect lymphocytic alveolitis and disease progression in pulmonary sarcoidosis, no prior study has made comparative evaluations of these markers.
Methods:
Forty-three patients with pulmonary sarcoidosis were enrolled. Bronchoalveolar lavage fluid (BALF) cells were analyzed, and serum levels of serum amyloid A (SAA), soluble interleukin 2 receptor (sIL-2R), lysozyme, angiotensin converting enzyme (ACE) and KL-6 were measured at disease presentation. Clinical data, including chest radiographs, were collected at presentation and during follow-ups. Univariate and multivariate analyses were used to identify markers best predictive of increased parenchymal infiltration.
Results:
Significantly higher serum levels of sIL-2R, lysozyme and KL-6 were found in patients with parenchymal infiltration compared to those without parenchymal infiltration. The numbers of total cells and lymphocytes in BALF were significantly higher in patients with parenchymal infiltration. Serum levels of sIL-2R, lysozyme and KL-6 were significantly correlated with the numbers of total cells, lymphocytes and CD4+ T lymphocytes in BALF. At the cut-off levels determined by receiver operating characteristic curves, sIL-2R, lysozyme, KL-6 serum levels and the number of BAL-lymphocytes showed significant correlations with increased parenchymal infiltrations by univariate analysis. However, multivariate analysis revealed that only KL-6 was a predictor of increased parenchymal infiltration.
Conclusion:
Our results suggest that initial serum sIL-2R, lysozyme and KL-6 levels may reflect lymphocytic alveolitis in pulmonary sarcoidosis. Furthermore, initial serum KL-6 tends to associate with increased parenchymal infiltration in pulmonary sarcoidosis.
Central venous catheterization (CVC) is associated with patient risks, known to be inversely related to experience. We developed and evaluated a performance assessment tool for use in a simulation-based central line workshop. We hypothesized that instrument scores would discriminate less experienced and more experienced clinicians.
Methods:
Participants included trainees enrolled in an institutionally-mandated CVC workshop and a convenience sample of faculty attendings. The workshop integrated several experiential learning techniques including practice on cadavers and part-task trainers. A group of clinical and education experts developed a 15-point CVC Proficiency Scale using national and institutional guidelines. After the workshop participants completed a certification exercise in which they independently performed a CVC in a part-task trainer. Two authors reviewed videotapes of the certification exercise to rate performance using the CVC Proficiency Scale. Participants were grouped by self-reported CVC experience.
Results:
105 participants (92 trainees and 13 attendings) participated. Interrater reliability on a subset of 40 videos was 0.71, and Cronbach's alpha was 0.81. The CVC Proficiency Scale Composite score varied significantly by experience: (median [range]) 87% [47-100%] for low experience (0-1 CVC's in the last 2 years, N=27), 87% [60-100%] for moderate experience (2-49 CVC's, N=62), and 93% [73-100%] for high experience (>49 CVC's, N=16) (p=0.02, comparing low and high experience).
Conclusions:
Evidence from multiple sources, including appropriate content, high interrater and internal consistency reliability, and confirmation of hypothesized relations to other variables, supports the validity of using scores from this 15-item scale for assessing trainee proficiency following a central line workshop.
The natural history of viral shedding from the upper respiratory tract of this new pandemic influenza A H1N1 2009 (pH1N1) and the effect of oseltamivir treatment were uncertain.
Methods:
A retrospective cohort study involving 145 consecutive patients with specimens positive by RT-PCR for the matrix and new H1 genes was conducted.
Results:
The non-treated and oseltamivir-treated patients were comparable in their viral load at presentation, demography and the presenting symptoms. No correlation was observed between viral load with their age and number of symptoms. Viral load of NPA was significantly lower in treated than in non-treated patients at day 5 post-symptom onset. When oseltamivir was initiated ≤ 2 days post-symptom onset, a greater rate of viral load reduction in NPA than that of non-treated patients was observed [-0.638 (95% C.I -0.809 to -0.466) versus -0.409 (95% C.I. -0.663 to -0.185) log10 copies/mL/day post-symptom onset], and the viral load was undetectable at day 6 post-oseltamivir initiation, which was 1 day earlier than that of those whose treatment were initiated > 2 days of symptom onset. The viral load was inversely correlated with concomitant absolute lymphocyte count in non-treated patients [Pearson’s correlation coefficient (r) = -0.687, p=0.001], and treated patients (Pearson’s r = -0.365, p <0.001). Resolution of fever was 1.4 days later in non-treated than treated patients (p = 0.012)
Conclusions:
The natural viral load profile was described. Oral oseltamivir suppresses viral load more effectively when given early in mild cases of pH1N1 infections.
Successful extubation conventionally necessitates the passing of "spontaneous breathing trials" (SBTs)/ventilator weaning parameters. We report successful extubation of neuromuscular disease/weakness (NMD) patients who could not.
Methods:
NMD-specific extubation criteria and a new extubation protocol were developed. Data were collected on 157 consecutive "unweanable" patients including 83 transferred from other hospitals who refused tracheostomies. They could not pass SBTs before or after extubation. Once SpO2 was maintained ≥95% in ambient air patients were extubated to full noninvasive ventilation (NIV) support and aggressive mechanically assisted coughing (MAC). Rather than oxygen, NIV and MAC were used to maintain or return SpO2 to ≥95%. Extubation success was defined as not requiring re-intubation during the hospitalization and was considered as a function of diagnosis, pre-intubation NIV experience, and vital capacity (VC) and assisted cough peak flows (CPF) at extubation.
Results:
Before hospitalization 96 (61%) patients had no experience with NIV, 41 (26%) used it less than 24 hrs. per day, and 20 (13%) were continuously NIV dependent. First attempt protocol extubation success rate was 95% (149 patients). All 98 extubation attempts on patients with assisted CPF ≥ 160 L/m were successful. Dependence on continuous NIV and duration of dependence prior to intubation correlated with extubation success (p<0.005). Six of 8 patients who initially failed extubation succeeded on subsequent attempts, so only two with no measurable assisted CPF underwent tracheotomy.
Conclusion:
Continuous volume-cycled NIV via oral interfaces and masks and MAC with oximetry feedback in ambient air can permit safe extubation of unweanable NMD patients.
It is uncertain whether pathologically prolonged International Normalized Ratio INR seen in Chronic Liver Disease CLD protects against venous thromboembolism VTE. Previous studies reported VTE incidence of 0.5-1.9% in CLD patients .We sought to evaluate VTE incidence among hospitalized CLD patients according to INR levels.
Methods:
This is a retrospective cohort study performed at a tertiary university hospital. We included all adult patients admitted with a primary diagnosis of CLD over a seven year period. The primary outcome was the development of VTE during hospital stay. Patients were divided into quartiles according to their highest admission INR.VTE events and prophylaxis rates were compared among INR quartiles.
Results:
Over the allotted 7 year period, we included 190 patients. Of these 12 developed VTE events yielding a VTE incidence of 6.3% .There was no significant difference in the incidence of VTE between INR quartiles. Hospital mortality rates were higher in the higher INR quartiles than in the lower ones (p<0.001), but hospital length of stay was not significantly different. Of the patients with documented VTE, one (4.2%) was Child-Pugh stage A, three (4.6%) were stage B, and eight (8.0%) were stage C (p=0.602).VTE prophylaxis was not utilized in 75% of patients.
Conclusions:
An elevated INR in the setting of CLD does not appear to protect against the development of hospital-acquired VTE. The notion that "auto-anticoagulation" protects against VTE is unfounded. Utilization of DVT prophylaxis was extremely low in this population.
Walking is a familiar daily activity that is generally limited by breathlessness, whereas cycling is an uncommon physical effort typically limited by leg discomfort. The hypothesis was that patients with chronic obstructive pulmonary disease (COPD) would exhibit greater improvements in exercise endurance and relief of breathlessness with bronchodilator therapy during treadmill walking compared with cycling.
Methods:
In this randomized, 2 x 2, double-blind, placebo-controlled, crossover trial, 20 patients with COPD (age, 64 ± 7 years; forced expiratory volume in one second, 56 ± 14 percent predicted) performed constant-load endurance exercise on the treadmill and cycle ergometer at 85% of capacity after inhaling normal saline (NS) or aformoterol (ARF) (15 µg).
Results:
Increases in endurance times and consistency of responses were greater with treadmill walking (: 157 ± 286 s; p = 0.024; 80% improved) than with cycle exercise (: 110 ± 219 s;
p = 0.038; 65% improved) with ARF compared with NS. However, these changes were not significantly different. The slope of breathlessness-time (mean = - 29 %; p = 0.007) and the magnitude of oxygen desaturation were significantly lower with ARF compared with NS during treadmill, but not cycle exercise. Inspiratory capacity values were similar between modes of exercise when comparing the same study medication.
Conclusions:
Improved endurance times support both constant-load treadmill and cycle exercise to assess the efficacy of bronchodilator therapy in patients with COPD. Unique differences in physiological and perceptual responses with bronchodilation demonstrate advantages of treadmill walking as an exercise stimulus.
A comprehensive survey-based COPD severity score has utility for epidemiologic and health outcomes research. We previously developed and validated the survey-based COPD Severity Score without using lung function or other physiologic measurements. In this study, we aimed to further validate the severity score in a different COPD cohort and using a combination of patient reported and objective physiologic measurements.
Methods.
Using data from the FLOW Cohort Study of COPD, we evaluated the concurrent and predictive validity of the COPD Severity Score among 1,202 subjects. The survey instrument is a 35-point score based on symptoms, medication and oxygen use, and prior hospitalization or intubation for COPD. Subjects were systemically assessed using structured telephone survey, spirometry, and six minute walk testing.
Results.
We found evidence to support concurrent validity of the score. Higher COPD Severity Score values were associated with poorer FEV1 (r=-0.38), FEV1% predicted (r=-0.40), BODE Index (r=0.57), and distance walked in 6 minutes (r=-0.43) (p<0.0001 in all cases). Greater COPD severity was also related to poorer generic physical health status (r=-0.49) and disease-specific health-related quality of life (r=0.57) (p<0.0001). The score also demonstrated predictive validity. It was also associated with a greater prospective risk of acute exacerbation of COPD defined as ED visits (HR 1.31; 95% CI 1.24-1.39), hospitalizations (1.59; 95% CI 1.44-1.75), and either measure of hospital-based care for COPD (HR 1.34; 95% CI 1.26-1.41) (p<0.0001 in all cases).
Conclusion.
The COPD Severity Score is a valid survey-based measure of disease-specific severity, both in terms of concurrent and predictive validity. The score is a psychometrically sound instrument for use in epidemiologic and outcomes research in COPD.
While many studies have compared in-vitro tuberculosis diagnostic tests with the venerable tuberculin skin test (TST), there is little understanding of the quantitative relationship between critical measures of anti-mycobacterial immunity used to detect tuberculosis infection. We therefore decided to determine the degree of redundancy between quantitative read-outs of in-vivo and in-vitro assays of anti-mycobacterial immunity.
Methods:
We enrolled 475 healthy HIV-negative children and young adults living in a hyper-endemic area of tuberculosis. We measured in-vivo TST responses and a 1:10 diluted 3 or 7-day whole blood assay was used to determine the in-vitro antigen-specific IFN cytokine release. The frequency of antigen-specific IFN+CD4+ and IFN+CD8+ cells was tested using intracellular cytokine staining after 1 day incubation.
Results:
In-vivo TST responses segregated into two well separated groups with either no measurable response (TST induration < 5mm; n=164) or a normally distributed group with TST indurations ≥5mm with peak at 15mm (n=260). In-vitro assays provided a less pronounced separation of responders and non-responders. Correlation analysis of responses among persons with TST ≥5mm demonstrated that extent of TST response was poorly correlated with IFN release (coefficients of correlation =0.17-0.22) and frequency of IFN+CD4+/CD8+ cells (=0.05-0.17) across three stimulating antigens (BCG, PPD, ESAT-6).
Conclusion:
We conclude that in-vivo and in-vitro assays are non-redundant, complementary measures of anti-mycobacterial immunity. Both TST and in-vitro assays provided valuable information about anti-mycobacterial immunity and by interference latent tuberculosis in the studied high incidence tuberculosis settings.
Complications of blind feeding tube (FT) placement include pneumothorax, pneumonia, empyema, and death. A safe and effective method of FT placement is desired. The Davis FT is a novel device that detachably couples to an ultrathin transnasal gastroscope. The objective of this study was to evaluate the safety and efficacy of Davis FT placement.
Methodology:
Fifty consecutive patients requiring transpyloric enteral tube feeding underwent placement of the Davis FT. Placement efficacy was evaluated with post-placement radiographs. Patient demographics, route of tube placement, use of sedation, and complications were abstracted.
Results:
The Davis FT was placed successfully in 50 patients. The mean age of the cohort was 52 (+/-18) years. Sixty-two percent (31/50) was male. The success rate of non-pulmonary placement was 100% (50/50) and the post-pyloric success rate was 96% (48/50). Intravenous sedation was used in 72% (36/50) of placements. Eighty-six percent (43/50) of tubes were placed transnasally. The majority (62%) of esophagogastroduodenoscopy and Davis FT placements were performed by a pulmonologist. Forty-four percent (22/50) of patients had an endotracheal tube, 20% (10/50) had a tracheotomy, and 36% (18/50) had no breathing tube at the time of Davis FT placement. There were no complications.
Conclusions:
Transpyloric placement of the Davis FT is safe (100%) and effective (96%). The tube can be placed transorally or transnasally with or without sedation. The data suggest that post-placement radiographs are not necessary to confirm placement. Pulmonologists were successful in performing esophagogastroduodenoscopy and Davis FT placement.
A silver-coated endotracheal tube (ETT) reduced the incidence of ventilator-associated pneumonia (VAP), compared with an uncoated ETT in the North American Silver-Coated Endotracheal Tube (NASCENT) study.
Methods:
To evaluate effect of ETT and risk factors on mortality, we performed a retrospective cohort analysis in patients who developed VAP in the NASCENT study. We determined causes of death and VAP due to potentially multidrug-resistant bacteria (eg, Pseudomonas, Acinetobacter), and performed stepwise multivariate logistic regression with the following predefined variables: treatment group, APACHE II, continuous sedation, coma, COPD, emergency surgery/trauma, immunodeficiency, potentially multidrug-resistant bacteria, and inappropriate initial antibiotics.
Results:
The silver-coated ETT was associated with reduced mortality in patients with VAP (silver vs control, 5/37 [14%] vs 20/56 [36%]; p=0.03), but not in those without VAP (228/729 [31%] vs 178/687 [26%]; p=0.03). The only between-group difference in leading causes of death was respiratory failure (silver vs control, 45/233 [19%] vs 22/198 [11%]; p=0.02). Of the VAP-related deaths, 1 in the silver group was caused by Acinetobacter sepsis. In the control group, 6 deaths were caused by sepsis and 3 by pneumonia; 6 of 9 pathogens were potentially multidrug-resistant. In multivariate analysis, treatment group was a predictor of mortality (odds ratio, silver vs control, 0.28; 95% confidence interval, 0.09–0.89; p=0.03). APACHE II ≥20 and inappropriate antibiotics also remained in the model (p<0.1).
Conclusions:
These findings suggest that silver-coated ETT was associated with reduced mortality in patients who developed VAP in the NASCENT study. Studies are needed to confirm these exploratory findings.
To examine the association between 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) and prognosis in patients with surgically treated, clinical stage Ia non-small cell lung cancer (NSCLC)
Methods:
We reviewed data collection forms and VA administrative records of 75 patients with surgically treated, stage Ia NSCLC who were enrolled in a prospective study of PET imaging from 1999 to 2001. We used Cox proportional hazards analysis to examine the association between FDG uptake and survival 4 years following enrollment.
Results:
Most patients were men (97%) and the mean age was 67 ± 9 years. Almost half of the patients (44%) had adenocarcinoma and 35% underwent a sub-lobar resection. The mean maximum standardized uptake value (SUVmax) was 4.9 ± 2.5 in survivors and 7.1 ± 3.9 in non-survivors (p=0.045). Before and after adjustment for age, tumor size, histology and type of resection, the hazard of death was significantly higher in patients with squamous cell histology (adjusted HR 4.6, 95% CI 1.09 to 18.9) and those with higher degrees of FDG uptake (adjusted HR 1.21 per 1 unit increment, 95% CI 1.01 to 1.45). At a threshold value of 5 for SUVmax, 34 of 39 patients (87%) with low FDG uptake survived, compared to only 24 of 36 patients (67%) with high FDG uptake (p=0.04). Visual assessment of FDG uptake was not associated with an increased hazard of death (HR 0.66, 95% CI 0.19 to 2.29)
Conclusions:
High FDG uptake as measured by SUVmax identifies individuals with clinical stage Ia NSCLC who are at increased risk of death following surgery. Such high-risk patients may be good candidates for participation in future trials of adjuvant therapy.
Few data are available regarding the benefits of one mode over another for ventilatory support. We set out to compare clinical outcomes of patients receiving synchronized intermittent mandatory ventilation with pressure support (SIMV-PS) compared to assist-control (A/C) ventilation as their primary mode of ventilatory support.
Methods:
Secondary analysis of an observational study conducted in 349 intensive care units from 23 countries. A propensity score stratified analysis was used to compare 367 patients ventilated with SIMV-PS with 1228 patients ventilated with A/C ventilation. The primary outcome was in-hospital mortality.
Results:
In a logistic regression model, patients were more likely to receive SIMV-PS if they were from North-America, had lower severity of illness, or were ventilated postoperatively or for trauma. SIMV-PS was less likely to be selected if patients were ventilated due to asthma or coma, or if they developed complications such as sepsis or cardiovascular failure during mechanical ventilation. In the stratified analysis according to propensity score, we did not find significant differences in the in-hospital mortality. After adjustment for propensity score, overall effect of SIMV-PS on in-hospital mortality was not significant (odds ratio 1.04; confidence interval for 95%: 0.77 to 1.42; P = 0.78).
Conclusions:
In our cohort of ventilated patients, ventilation with SIMV-PS compared with A/C did not offer any advantage in terms of clinical outcomes, despite treatment-allocation bias that would have favored SIMV-PS.
Test accuracy of interferon-gamma release assays (IGRAs) for diagnosing tuberculosis (TB) differs when utilizing older or pre-commercial tools and inconsistent diagnostic criteria. This meta-analysis critically appraises studies investigating sensitivity and specificity of the commercial T-Spot. TB and the in tube version of QuantiFERON-TB Gold (QFT-IT) among definitely confirmed TB cases.
Methods:
We searched Medline, EMBASE and Cochrane bibliographies of relevant articles. Sensitivities, specificities and indeterminate rates were pooled using a fixed effect model. Sensitivity of the tuberculin skin test (TST) was evaluated in the context of IGRA studies. In addition, the rates of indeterminates of both IGRAs were assessed.
Results:
The pooled sensitivity of TST was 70% [95% CI 0.67 to 0.72] compared with 81% [95% CI 0.78 to 0.83] for the QFT-IT and 88% [95% CI 0.86 to 0.90] for the T-SPOT.TB. Sensitivity increased to 84% [95%CI 0.81 to 0.87] and 90% [0.87 to 0.92] for the QFT-IT and T-Spot.TB, respectively, when restricted to performance in developed countries. In contrast, specificity of the QFT-IT was 99% [95% CI 0.98 to 1.00] versus 88% for the T-Spot. TB [0.84 to 0.91].
The pooled rate of indeterminate results was low, 2.1% [95% CI 0.02-0.023] for the QFT-IT and 3.8% [95% CI 0.035-0.042] for the T-Spot.TB, increasing to 4.4% [95% CI 0.039 to 0.05]) and 6.1% [95% CI 0.052 to 0.071], respectively, among immunosuppressed hosts.
Conclusions:
Newest commercial IGRAs are superior, in comparison to the TST, for detecting confirmed active TB disease, especially when performed in developed countries.
Antiviral therapy and vaccination are important strategies for controlling pandemic (H1N1) 2009 influenza but efficacy depends on the timing of administration and is often limited by shortage of supply. Patients with dyspnea, tachypnea, evidence of hypoxemia and pulmonary infiltrates on chest radiograph should be hospitalized. Patients with severe illness or underlying medical conditions that increase the risk of more severe disease should be treated with oseltamivir or zanamivir as soon as possible, without waiting for the results of laboratory tests. Lung protective ventilation strategy with a low tidal volume and adequate pressure, in addition to a conservative fluid management approach, is recommended when treating adult patients with acute respiratory distress syndrome. Extracorporeal membrane oxygenation has emerged as an important rescue therapy for critically ill patients. Use of systemic steroids was associated with delayed viral clearance in SARS and H3N2 infection. Low dose corticosteroids may be considered in the treatment of refractory septic shock. Passive immunotherapy in the form of convalescent plasma or hyper-immune globulin may be explored as rescue therapy. More data are needed to explore the potential role of intravenous gammaglobulin and other drugs with immuno-modulating properties such as statins, gemfibrozil, and N-acetyl-cysteine. Healthcare workers must apply strict standard and droplet precautions when dealing with suspected and confirmed cases, and upgrade to airborne precautions when performing aerosol-generating procedures. Non-pharmacological measures such as early case isolation, household quarantine, school/workplace closure, good community hygiene, and restrictions on travel are useful measures in controlling an influenza pandemic at its early phase.
Patients with chronic obstructive pulmonary disease (COPD) are at risk of cardiovascular events. This has been attributed to increased systemic inflammation. The course of COPD is punctuated by exacerbations, which further increase systemic inflammation, but the risk of vascular events in the post-exacerbation period has never been defined.
Design:
We analysed data from 25,857 COPD patients entered in The Health Improvement Network (THIN) database over a two year period. Exacerbations were defined using a health care utilization definition of prescription of oral corticosteroids >20mg/day and/or selected oral antibiotics. The risk of myocardial infarction (MI) and stroke in the post-exacerbation period was calculated relative to the patient's baseline risk using the self-controlled case series approach.
Results:
We identified 524 MI in 426 patients and 633 ischaemic strokes in 482 patients. The incidence rates of MI and stroke were 1.1 and 1.4 per 100 patient years respectively. There was a 2.27 fold (95% CI 1.1-4.7; P=0.03) increased risk of MI 1-5 days after exacerbation (defined by prescription of both steroids and antibiotics). This relative risk diminished progressively over time and was not significantly different from the baseline MI risk at any other post-exacerbation time interval. One in 2,513 exacerbations was associated with MI within 1-5 days. There was a 1.26 fold (95% CI 1.0-1.6; P=0.05) increased risk of stroke 1-49 days after exacerbation.
Conclusion:
The results suggest that exacerbations of COPD increase the risk of myocardial infarction and stroke. This may have implications for therapy in both stable and exacerbated COPD.
Theoretical considerations and limited scientific evidence suggest that whole body plethysmography overestimates lung volume in patients with severe airflow obstruction. We sought to compare plethysmographic-, helium dilution- and CT-derived lung volume measurements in a sample containing many patients with severe airflow obstruction.
Methods:
We measured total lung capacity (TLC) in 132 patients at 3 hospitals, with monitored application of recommended techniques for plethysmographic and helium dilution (He) measurements of lung volume and by thoracic CT scans obtained during breath hold at full inspiration.
Results:
Average TLC among 132 subjects was 6.18L (± 1.69L) by plethysmography, 5.55L (± 1.39L) by helium dilution, and 5.31L (±1.47) by CT. Plethysmographic TLC was significantly greater than either He- or CT-TLC (p≤0.001) while there was no significant difference between He and CT values. When examined separately, there were significant within subject differences in TLC by measurement technique among subjects with airflow obstruction, but not among those without airflow obstruction. Plethysmographic overestimation of TLC was greatest among subjects with FEV1 less than 30% of predicted.
Conclusions:
In the setting of airflow obstruction, plethysmography systematically overestimates lung volume relative to helium dilution or thoracic imaging despite adherence to current recommendations for proper measurement technique.
While cystic fibrosis (CF) is the most common inherited respiratory disease, the burden of influenza among individuals with CF is not well characterized.
Methods:
We used the CF Foundation Patient Registry to determine the relationship between pulmonary exacerbation incidence rate and influenza virus season from July 2003 through June 2007. The outcome of interest, pulmonary exacerbation, was defined as treatment of a respiratory illness with intravenous antibiotics. Each influenza season was defined as all months during which ≥15% of laboratory tests for influenza virus were positive in the US Influenza Virologic Surveillance System. We calculated incidence rates of pulmonary exacerbation during the influenza and summertime seasons as well as relative rates with 95% confidence intervals. A multivariate regression model adjusted for demographic and clinical predictors.
Results:
In 2003, the patient cohort size was 21,506 patients, and 7,727 patients experienced at least one pulmonary exacerbation. The overall pulmonary exacerbation incidence rate in the influenza season was 595.0 per 10,000 person-months compared to a summertime baseline of 549.6 per 10,000 person-months. The incidence rate ratio was 1.08 (95% CI 1.06, 1.10). Multivariate analysis did not change our estimate of risk (adjusted OR 1.07; 95% CI 1.05, 1.10). An estimated annual excess of 147.6 per 10,000 person-months or an excess 2.1% of total exacerbations occur during the influenza season.
Conclusion:
Our data demonstrate a substantial contribution of the influenza season to CF morbidity. Further studies to determine any causal link between influenza infection and CF pulmonary exacerbations are necessary.
To describe the initial antibiotic treatment regimens, severity of illness, and in-hospital mortality among culture-negative (CN) and culture-positive (CP) patients with healthcare-associated pneumonia (HCAP).
Design:
Retrospective cohort study.
Setting:
Barnes-Jewish Hospital, a 1,200-bed urban teaching hospital.
Patients:
Hospitalized adults with HCAP.
Interventions:
Retrospective data collection.
Measurements and Main Results:
Eight hundred seventy patients with HCAP were identified over a three-year period (January 2003 through December 2005) of whom 431 (49.5%) were CP. Among the non-CP patients, 290 (66.1%) had no respiratory cultures obtained and 149 (33.9%) had no growth or nonpathogenic oral flora identified and were classified as CN. CN patients were more likely to have received an initial antibiotic regimen (ceftriaxone ± azithromycin or moxifloxacin) targeting community-acquired pneumonia (CAP) pathogens compared to CP patients (71.8% v. 25.5%, p < 0.001). Severity of illness as assessed by intensive care unit (ICU) admission and mechanical ventilation (MV) were statistically lower in CN compared to CP patients (ICU admit: 12.1% v. 48.7%, p< 0.001; MV: 6.7% v. 44.5%, p< 0.001). In-hospital mortality and hospital length of stay were also statistically lower for CN patients (Mortality: 7.4% v. 24.6%, p< 0.001; Hospital length of stay: 6.7±7.4 days v. 12.1±11.7 days; p< 0.001).
Conclusion:
In this analysis, CN HCAP patients had lower severity of illness, hospital mortality, and hospital length of stay compared to CP patients. These data suggest that CN HCAP patients differ substantially from HCAP patients with positive microbiologic cultures.
Isolation of Mycobacterium tuberculosis (MTB) from the clinical specimens of patients with suspected tuberculosis (TB) remains the gold standard for diagnosis of TB. However, false-positive MTB cultures can occur, as a result of laboratory contamination.
Setting:
A university-affiliated hospital in Taipei, Taiwan
Patients and Methods:
After review the medical record of 400 TB cases identified during January 2008 to January 2009 by the infection control unit of the hospital, five patients were considered as clinically suspected false-positive cases and were referred to a mycobacteriology laboratory for confirmation. Spoligotyping and mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) analysis were performed for all the suspected isolates and all other isolates cultured on the same day as the five suspected isolates.
Results:
Three cases were confirmed as false-positive culture cases based on the laboratory investigation. The culture from one of these cases (index case 1) grew multidrug-resistant TB. Another patient (index case 2) received an extended course of anti-TB treatment after he was considered to have failed treatment because of the false-positive MTB culture result. No anti-TB medication was given for index case 3. All three cases with false-positive cultures had only one positive culture specimen among multiple consecutive specimens submitted for cultures. In addition, specimens of the false-positive cultures were all negative for acid-fast smears.
Conclusions:
False-positive MTB cultures should be suspected in the following situations: when growth is observed on only one specimen among multiple specimens submitted, when it is positive in only one culture media, especially in broth or when there is only one specimen submitted. False-positive MTB cultures can be further confirmed with modern molecular typing techniques.
The majority of new cases of cystic fibrosis (CF) are diagnosed before age two. Diagnoses in older individuals have increased because of improved genetic testing and increased awareness of the disease. A comprehensive description of clinical, genetic and microbiologic characteristics of adult-age presentation of CF does not exist. We compare newly diagnosed CF in adults with newly diagnosed CF in children and adolescents in the United States.
Methods:
This is a cross-sectional study of new CF diagnoses from the Cystic Fibrosis Foundation Patient Registry between 1995 and 2005. Diagnostic, microbiologic and clinical features during year of diagnoses were analyzed for subjects by age group. Descriptive statistics were calculated for variables on characteristics by age group.
Results:
9766 new diagnoses of CF were reported to the Registry between 1995 and 2005. Proportion of adult diagnoses increased significantly in the years 2001-2005 as compared to 1995-2000 (9.0% vs. 7.7%, p=0.012). FEV1% predicted decreased with increasing age at diagnosis (p<0.001). Infection with Pseudomonas aeruginosa was most common in adults (p<0.001). Both the number of positive sweat chloride tests and prevalence of F508 mutation, the most common mutation in the U.S., decreased significantly with older age at diagnosis (p<0.001).
Conclusions:
Between 1995 and 2005, the proportion of new diagnoses of CF in adults in the U.S. increased significantly. Adults present with commonly described CF respiratory disease (Pseudomonas aeruginosa infection and reduced lung function), but have lower sweat chloride values and lower frequency of F508 mutation. Knowledge of clinical characteristics and diagnostic limitations of adult patients presenting with CF will hopefully lead to earlier recognition and intervention.
A cohort of patients with bacteremic Streptococcus pneumoniae pneumonia was reviewed to assess why mortality is higher in healthcare-associated pneumonia(HCAP) than in community-acquired pneumonia(CAP).
Methods:
Prospective cohort of all adult patients with bacteremic pneumococcal pneumonia attended at the emergency department.
Results:
One hundred and eighty-four cases were classified as CAP and 44 (19%) as HCAP. Fifty-two(23%) were admitted to the ICU. Three (1.5%) isolates were resistant to beta-lactams and only two patients received inappropriate therapy. The CAP cohort was significantly younger (median age 68 years old –IQR 42-78- vs 77 -67-82, p<0.001). The HCAP cohort presented higher Charlson's index (2.81 ± 1.9 vs 1.23 ±1.42, p<0.001) and had higher severity-of-illness at admission (altered mental status, RR>30/min, PaO2/FiO2<250 and multilobar involvement). HCAP patients had a lower rate of ICU admission (11.3% vs 25.5 % p<0.05) and a trend towards lower mechanical ventilation (9% vs 19% p=0.17) and vasopressor use (9% vs 18.4% p=0.17) were documented. More patients in the HCAP cohort presented with PSI score > 90 (class IV-V, 95% vs 65%, p<0.001), and 30-day mortality was significantly higher (29.5% vs 7.6%, p<0.001). A multivariable regression logistic analysis adjusting for underlying conditions and variables related to severity-of-illness confirmed that HCAP is an independent variable associated with increased mortality (OR= 5.56 95%, CI 1.86 to 16.5).
Conclusions:
Pneumococcal HCAP presents excess mortality which is independent of bacterial susceptibility. Differences in outcomes were probably due to differences in age, comorbidities, and criteria for ICU admission rather than to therapeutic decisions.
One of the contributors to exercise limitation in COPD is dynamic hyperinflation. Although dynamic hyperinflation appears to occur during several exercise protocols in COPD and seems to increase with increasing disease severity, it is unknown whether dynamic hyperinflation occurs at different severity stages according to GOLD in daily life. The present study, therefore, aimed to compare dynamic hyperinflation between COPD GOLD stages II-IV during daily activities.
Methods:
Thirty-two clinically stable COPD patients GOLD II (N=10), III (N=12) and IV (N=10) participated in this study. Respiratory physiology during a daily activity was measured at patients’ home with Oxycon Mobile. Inspiratory capacity maneuvers were performed at rest, at 2-minutes intervals during the activity and at the end of the activity. Change in inspiratory capacity is commonly used to reflect change in end expiratory lung volume ( EELV) and therefore dynamic hyperinflation. The combination of static and dynamic hyperinflation was reflected by inspiratory reserve volume (IRV) during the activity.
Results:
Overall, increase in EELV occurred in GOLD II-IV without significant difference between the groups. There was a tendency for a smaller EELV in GOLD IV. EELV was inversely related to static hyperinflation. IRV during the daily activity was related to the level of airflow obstruction.
Conclusions:
Dynamic hyperinflation occurs independent of GOLD stage during real life daily activities. The combination of static and dynamic hyperinflation, however, increases with increasing airflow obstruction.
in many primary tumors, parathyroid hormone related peptide (PTHrP) and PTHrP type I receptor (PTH1R) are co-expressed supporting the possibility that PTHrP/PTH1R system can mediate important signals for tumor progression through paracrine/autocrine mechanisms. In non-small cell lung carcinoma the clinical relevance of the expression of PTH1R remains to be investigated.
Methods:
fifty-four lung adenocarcinomas of mixed histologic type from stage I and II patients were assayed by quantitative immunohistochemistry for the expression of PTHrP and PTH1R.
Results:
PTHrP and PTH1R were expressed in a wide range of intensity in the cytoplasm of tumor cells and their values showed a positive correlation. PTH1R, but not PTHrP, was expressed by plasma cells infiltrating the tumor stroma. PTHrP and PTH1R were not associated with age, tumor diameter and histopathological grading, whereas they were directly associated with lymph node involvement at presentation. Cox regression analysis, using PTHrP and PTH1R as continuous covariates, showed that the covariate levels were directly associated with the risk of death and metastasis. Patients, whose tumors co-expressed high levels of PTHrP and PTH1R, showed the highest risk of metastasis (relative risk: 5.89; C.I.95%: 2.1-16.6; p= 0.0003) and death (relative risk: 6.24; C.I.95%: 1.6-23.9; p= 0.0033). The presence of PTH1R positive plasma cells in the tumor stroma was associated with a more favorable survival rate independently from the PTHrP status of the tumor.
Conclusion:
the paracrine/autocrine signaling through PTHrP/PTH1R could be important in early stage lung adenocarcinoma progression.
Acute exacerbations of chronic obstructive pulmonary disease (COPD) reflect in part an inappropriate host response to abnormal bacterial colonisation. Orally administered inactivated non-typeable Haemophilus influenzae (NTHi) can drive a specific T cell response that by promoting intrabronchial phagocytosis downregulates bronchus inflammation.
Methods:
Subjects with recurrent exacerbations of COPD were studied in a randomised, multicentre, double blind, placebo controlled trial, to test efficacy of an NTHi oral immunotherapeutic (HI-164OV). This report describes the outcome in 38 subjects with severe COPD defined as having an FEV1 ≤ 50% of predicted normal.
Results:
Exacerbations defined as an increase in volume and purulence of sputum were reduced by 16% (not significant (NS)) in the active group. However, moderate-severe exacerbations (defined as requiring corticosteroid therapy) were reduced by 63% (p=0.05). The proportion with any acute exacerbation was little changed with treatment, but the proportion with episodes requiring corticosteroid therapy was reduced by 56% (p=0.07). The mean duration of episodes was reduced by 37% (p=0.01) and prescribed courses of antibiotics were reduced by 56% (p=0.03) following therapy. Exacerbations requiring admission into hospital were reduced by 90% (p=0.04) in the active group. No specific adverse effect was detected.
Conclusions:
Treatment of severe COPD with frequent exacerbations with HI-164OV was safe and effective, especially with respect to reduction in parameters of severity.
Novel influenza A H1N1 2009 (novel H1N1) infection has significantly affected intensive care units (ICU). We sought to characterize our region's clinical findings and demographic associations with ICU admission due to novel H1N1.
Methods:
Observational study from May 19, 2009 to June 30, 2009 of descriptive clinical course, inpatient mortality, financial data, and demographic characteristics of an ICU cohort. Case-control study comparing the ICU cohort to Salt Lake County residents.
Results:
The ICU cohort of 47 influenza patients had a median age of 34, APACHE II score of 21, and body mass index (BMI) of 35. Mortality was 17% (8/47). All 8 deaths occurred among the 64% of patients (n=30) with acute respiratory distress syndrome, twenty-six (87%) of whom also developed multiorgan failure. Compared to the Salt Lake County population, novel H1N1 patients were more likely to be obese (22% versus 74%; p<0.001), medically uninsured (14% versus 45%; p<0.001), and Hispanic (13% versus 23%; p<0.01) or Pacific Islander (1% versus 26%; p<0.001). Observed ICU admissions were 15-fold greater than expected for those with BMI ≥40 (SMR 15.8, 95% CI 8.3, 23.4) and 1.5-fold greater among those with BMI 30-39 than expected for age- and sex-adjusted rates for Salt Lake County.
Conclusion:
Severe ARDS with multiorgan dysfunction in the absence of bacterial infection was a common clinical presentation. In this cohort, young non-whites without medical insurance were disproportionately likely to require ICU care. Obese patients were particularly susceptible to critical illness due to novel H1N1 infection.
Both disability and depression are common in COPD, but limited information is available on the time-ordered relationship between increases in disability and depression onset.
Methods:
Subjects were members of a longitudinal cohort with self-reported physician-diagnosed COPD, emphysema, or chronic bronchitis. Data were collected through 3 annual structured telephone interviews (T1, T2, and T3). Depression was defined as a score ≥4 on the Geriatric Depression Scale Short Form (GDS). Disability was measured with the Valued Life Activities (VLA) scale; 3 disability scores were calculated: % of VLAs unable to perform, % of VLAs affected (unable to perform or with some degree of difficulty), and mean VLA difficulty rating. Disability increases were defined as a 0.5 SD increase in disability score between T1 and T2. Multiple logistic regression analyses estimated the risk of T3 depression following a T1-T2 disability increase for the total cohort and then excluding individuals who met the depression criterion at T1 or T2.
Results:
Approximately 30% met the depression criterion each year. 8%-19% experienced a T1-T2 disability increase, depending on the disability measure. Including all cohort members and controlling for baseline GDS scores, T1-T2 increases in disability yielded a significantly elevated risk of T3 depression (% affected OR=3.6 [1.7, 7.7]; % unable OR=6.1 [17, 21.8]; mean difficulty OR=3.6 [1.7, 8.0]). Omitting individuals depressed at T1 or T2 yielded even stronger risk estimates for % unable (OR=13.4 [2.0, 9.14]) and mean difficulty (OR=3.9 [1.3, 11.8]).
Conclusions:
Increases in VLA disability are strongly predictive of the onset of depression.
Gastroesophageal reflux (GER) is thought to be induced by decreasing intraesophageal pressure during obstructive sleep apnea (OSA). However, pressure changes in the upper esophageal sphincter (UES) and gastroesophageal junction (GEJ) pressure during OSA events have not been measured. The aim of this study was to determine UES and GEJ pressure change during OSA and characterize the GER and esophago-pharyngeal reflux (EPR) events during sleep.
Methods:
We studied 15 controls, 9 gastroesophageal reflux disease (GERD) patients without OSA, 6 OSA patients without GERD and 11 OSA patients with GERD for 6-8 hours post-prandially during sleep. We concurrently recorded: a) UES, GEJ esophageal body (ESO) and gastric pressures by high-resolution manometry, b) pharyngeal and esophageal reflux events by impedance and pH recordings, c) sleep stages and respiratory events using polysomnogram. End inspiration UES, GEJ, ESO and gastric pressures over intervals of OSA were averaged in OSA patients and compared to average values for randomly selected ten-second intervals during sleep in controls and GERD patients.
Results:
ESO pressures decreased during OSA events. However, end-inspiratory UES and GEJ pressures progressively increased during OSA, and at the end of OSA events were significantly higher than at the beginning (p<0.01). The incidence of GER and EPR events during sleep in OSA patients with GERD did not differ from those in controls, GERD patients without OSA, and OSA patients without GERD.
Conclusions:
Despite a decrease in ESO pressure during OSA events, compensatory changes in UES and GEJ pressures prevent reflux.
Warfarin is the primary therapy to prevent stroke and venous thromboembolism. Significant periods of nonadherence frequently go unreported by patients and undetected by providers. Currently, no comprehensive screening tool exists to help providers assess the risk of nonadherence at the time of initiation of warfarin therapy.
Methods:
Prospective cohort study of adults initiating warfarin therapy at two anticoagulation clinics (University and VA-affiliated). Nonadherence, defined by failure to record a correct daily pill bottle opening, was measured daily by electronic pill cap monitoring. A multivariable logistic regression model was used to develop a point system to predict daily nonadherence to warfarin.
Results:
We followed 114 subjects for a median of 141 days. Median nonadherence of the participants was 14.4% [interquartile range (IQR) 5.8-33.8]. A point system, based on nine demographic, clinical and psychosocial factors distinguished those demonstrating low versus high levels of nonadherence: 4 points or less, median nonadherence 5.8% (IQR 2.3-14.1); 5 points, 9.1% (IQR 5.9-28.6); 6 points, 14.5% (IQR 7.1-24.1); 7 points, 14.7% (IQR 7.0-34.7); 8 points or more, 29.3% (IQR 15.5-41.9). The model produces a c-statistic of 0.66 (95% CI 0.61-0.71) suggesting modest discriminating ability to predict day-level warfarin nonadherence.
Conclusions:
Poor adherence to warfarin is common. A screening tool based on nine demographic, clinical and psychosocial factors may, if further validated in other patient populations, may help to identify groups of patients at lower risk for nonadherence so that intensified efforts at increased monitoring and intervention can be focused on higher risk patients.
The association between Chronic Obstructive Pulmonary Disease (COPD) and chronic renal failure (CRF) has never been assessed. Lean mass is frequently reduced in COPD, and glomerular filtration rate (GFR) might be depressed in spite of normal serum creatinine (concealed CRF). We aimed at investigating the prevalence and correlates of both concealed and overt CRF in elderly COPD patients.
Methods:
We evaluated 356 consecutive elderly COPD outpatients enrolled in the Extrapulmonary Consequences of COPD in the Elderly (ECCE) Study, and 290 age-matched outpatients free from COPD. GFR was estimated using the Modification of Diet in Renal Disease (MDRD) study equation. Patients were categorized as having normal renal function (GFR≥60 ml/min/1.73 m2), concealed (normal serum creatinine and reduced GFR) or overt (increased serum creatinine and reduced GFR) CRF. Independent correlates of CRF were investigated by logistic regression analysis.
Results:
The prevalence of concealed and overt CRF in COPD patients was 20.8% and 22.2%, respectively. Corresponding figures in controls were 10.0% and 13.4%, respectively. COPD and age were significantly associated with both concealed (COPD: OR=2.19, 95%CI=1.17-4.12; age: OR=1.06, 95%CI=1.04-1.09) and overt CRF (COPD: OR=1.94, 95%CI=1.01-4.66; age: OR=1.06, 95%CI=1.04-1.10). Diabetes (OR=1.96, 95%CI=1.02-3.76), hypoalbuminemia (OR=2.83, 95%CI=1.70-4.73), and muscle-skeletal diseases (OR=1.78, 95%CI=1.01-3.16) were significant correlates of concealed CRF. BMI (OR=1.05, 95%CI=1.01-1.10) and diabetes (OR=2.25, 95%CI=1.26-4.03) were significantly associated with overt CRF.
Conclusions:
CRF is highly prevalent in COPD patients, even with normal serum creatinine, and might contribute to explain selected conditions such as anemia frequently complicating COPD.
In tuberculosis (TB) outbreaks, detecting active cases is the key step in stopping transmission of the disease. The aim of this study was to evaluate the role of high-resolution computed tomography of the chest (HRCT) in the investigation of an outbreak of TB that developed in a cohort of 92 soldiers in the South Korean army.
Methods:
Outbreak investigation, including tuberculin skin test (TST), QuantiFERON® TB Gold In-Tube (QFT), and simple chest radiography (CXR), was performed. For participants with any abnormal findings in these tests, HRCT was carried out. Active pulmonary TB was diagnosed based on sputum studies or HRCT findings. In addition, participants with positive results in both TST and QFT were treated as having a latent TB infection (LTBI). TST and QFT were repeated in participants with a positive result in one of these tests. CXR was repeated in all participants at 3 and 6 months of follow-up.
Results:
87 participants completed the study protocol. Among them, 18 active TB cases were diagnosed. Nine of these had normal CXR but had lesions that were suggestive of active TB upon HRCT. 22 participants with normal HRCT and positive results with TST and QFT at initial investigation were treated as LTBI. Among 13 participants with normal CXR and positive results in either TST or QFT, nine completed a 3-month investigation. All but one of nine participants revealed positive results in both tests.
Conclusion:
Inclusion of HRCT in outbreak investigation of TB may be helpful in differentiating active TB from LTBI more reliably.
Inferior vena cava (IVC) filter placement may be life-saving, but after contraindications to anticoagulation remit, patient management is uncertain.
Methods:
We followed patients who had venous thromboembolism, followed by treatment with permanent IVC filter placement, and were anticoagulated long-term as soon as safety allowed. We conducted annual physical examinations and ultrasound surveillance of the lower extremity deep veins and of the IVC filter site. Clot detected at the filter site was treated with graded intensities of anticoagulation, depending upon the clot burden.
Results:
Symptomatic deep vein thrombosis occurred in 24 of 121 patients (20%; 95% CI 14 - 28%) ; symptomatic pulmonary embolism (1 fatal) was diagnosed in 6 (5%; 95% CI 2 - 10%). There were 45 episodes of filter clot in 36 patients (30%; 95% CI 22-38%). The rate of major bleeding (6.6%) was similar to that of a concurrent persistently anticoagulated cohort without IVC filters (5.8%).
Conclusions:
If therapeutic anticoagulation can be safely begun in patients with IVC filters inserted after venous thromboembolism, further management with clinical surveillance, including ultrasound examination of the IVC filter and graded degrees of anticoagulation therapy if filter clot is detected, has a favorable prognosis. This approach appears valid for current IVC filter patients and can serve as a comparison standard in subsequent clinical trials to optimize clinical management of these patients.
The airway mucus in patients with cystic fibrosis (CF) is dehydrated and adhesive, and accumulates in the airways resulting in chronic inflammation, infection and progressive loss of lung function. Inhaled mannitol improves mucus clearance and, when administered over 2-weeks, it improves lung function in CF (Jaques A et al. CHEST 2008;133:1388-1396). The changes in the physical properties of sputum after a 2-week treatment with mannitol were investigated in the same CF subjects.
Methods:
Sputum was collected before and at the end of the 2-week treatment period from 28 CF subjects who participated in the double blind crossover study. Mannitol or placebo 420 mg was inhaled twice daily over 2–weeks. The solids content, surface tension, contact angle and viscoelasticity was measured.
Results:
Two-week treatment with mannitol reduced the solids from 7.3±3.0 to 5.7±3.0% (p=0.012), surface tension from 83.1±7.2 to 78.6±8.0 mN/m (p<0.039) and contact angle from 52.4±7.7 to 47.9±7.3 degrees. There was no significant change in the viscoelastic properties of sputum (p>0.1). Placebo treatment had no significant effect on the sputum properties. The change in solids content correlated with the change in both FEV1 (rs=-0.78, p=0.004) and FEF25-75 (rs=-0.80, p=0.003) and the % change in surface tension and contact angle correlated with the % change in the FEV1 (rs=-0.73, p=0.012 and rs=-0.63, p=0.03 respectively) in these subjects.
Conclusion:
Treatment with inhaled mannitol over 2 weeks improved the hydration and surface properties of sputum in patients with CF. This effect was sustained and correlated with airway function changes.
Atrial Fibrillation (AF) is associated with a high risk of stroke. The contribution of arrhythmia to events is clear in sustained forms of AF, but in paroxysmal AF, presently available data have yet to identify what proportion of time spent in AF (i.e. arrhythmia burden, AFB) is of clinical relevance. We aimed to assess this relationship using surrogate blood markers for the hypercoagulable state associated with AF.
Methods:
121 consecutive outpatients [mean age 74.7 ± 7.8 years; 73 (60.3%) male] with pacemakers capable of arrhythmia detection were recruited. AFB was assessed over a 1-month period and classified as AFB=0%, 0.1-10%, 10.1-50%, >50%.
Results:
Baseline characteristics and co-morbidities were comparable between groups. There were no significant differences in levels of sE-selectin, vonWillebrand factor (vWf), high sensitivity C-reactive protein (hsCRP), Interleukin-6 (IL-6), sP-selectin, or Tissue Factor (TF) across the 4 patient groups. Levels of plasma Brain Natriuretic Peptide (BNP) were approximately two-fold greater in the group with the highest AFB (p<0.001). Following a step-wise multiple linear regression analysis, age was a significant predictor of vWf (P=0.010), sP-selectin (P=0.042) and BNP (P=0.012). Left ventricular fractional shortening was predictive of BNP (P=0.001) and sE-selectin (P=0.012). Anticoagulation was a predictor of vWf levels (P=0.005), whilst hypertension was predictive of TF (P<0.001).
Conclusion:
Given no appreciable difference in levels of prothrombotic markers in relation to AFB in this study, it is plausible that these abnormalities do in fact relate to underlying risk factors, and that such patients should be anticoagulated if risk factors dictate. Thus, AFB per se should probably not influence the decision to anticoagulate, but rather the presence of AF combined with clinical risk scoring should remain the predominant tool for stroke risk assessment.
We previously reported that bronchoscopy-guided, internally cooled radiofrequency ablation (RFA) in normal sheep lung was a safe, effective, and feasible procedure without major complications.
Purpose:
The aim of this study was to evaluate the safety, effectiveness, and feasible conditions of bronchoscopy-guided, internally cooled RFA as a clinical application for non-small cell lung cancer (NSCLC).
Methods:
Ten patients pathologically diagnosed with NSCLC, and the clinical stage of T1N0M0 were enrolled in the study. Three types of internally cooled electrode catheter tips were prepared using different procedure conditions involving ablation time: an internally cooled electrode with a 5 mm cylindrical active tip at a power output of 20 W, flow rate of 50 mL/min, and an ablation time of 30 s (n=3), an electrode with an 8 mm active tip with 4 beads at 20W, 50 mL/min, and 40 s (n=3), and an electrode with a 10 mm active tip with 5 beads at 20 W, 50 mL/min, and 50 s (n=4). CT-guided bronchoscopy-guided, internally cooled RFA was performed, and the patients underwent standard lung resection therapy. The resected lung tissue was examined histopathologically to assess the ablated areas.
Results:
Ablated areas pathologically evaluated with the 10 mm active tip were significantly larger than those with the 5 mm tip. Thus, the ablated areas were enlarged depending on the tip length and prolonged ablation time. There were no complications during RFA, such as bronchial bleeding or pneumothorax.
Conclusions:
Bronchoscopy-guided, internally cooled RFA in humans with CT imaging guidance is a safe and feasible procedure that could become a potential therapeutic tool for local control in medically inoperable patients with stage I NSCLC.
Learning medical procedures relies predominantly on the apprenticeship model and competency is established based on number of performed procedures. Our study aimed to establish bronchoscopy competency metrics based on performance and enhance learning with educational interventions.
Methods:
We conducted a prospective study of the acquisition of bronchoscopy skills and cognitive knowledge in two successive cohorts of starting pulmonary fellows between July 5, 2006 and June 30, 2008. At pre-specified milestones, validated tools were used for testing: the Bronchoscopy Skills and Tasks Assessment Tool (BSTAT), an objective evaluation of bronchoscopy skills with scores ranging from 0-24, and written multiple-choice questions examinations. The first cohort received training in bronchoscopy as per the standards set by each institution, while the second cohort received educational interventions including training in simulation bronchoscopy and an on-line bronchoscopy curriculum.
Results:
There was significant variation among study participants in bronchoscopy skills at their 50th bronchoscopy, the minimum number previously set to achieve competency in bronchoscopy. An educational intervention of incorporating simulation bronchoscopy enhanced the speed of acquisition of bronchoscopy skills, as shown by the statistically significant improvement in mean BSTAT scores for 7 of the 8 milestone bronchoscopies (p<0.05). The online-curriculum did not improve the performance on the written tests; however, compliance of the learners with the curriculum was low.
Conclusions:
Performance-based competency metrics can be used to evaluate bronchoscopy skills. Educational interventions such as simulation-based training accelerated the acquisition of bronchoscopy skills among first year pulmonary fellows as assessed by a validated objective assessment tool.
Human rhinovirus (HRV) is the most frequent virus associated with COPD exacerbations. Viral infections increase exacerbation severity and likelihood of hospitalisation. As ease of sampling blood makes serum a more practical marker than sputum, we investigated whether changes in serum IP-10 from baseline to exacerbation were higher in airway HRV positive exacerbations, and whether IP-10 levels related to HRV load.
136 COPD patients and 70 controls were included over 2 years and 72 exacerbations sampled. HRV positivity and load was determined by RT-PCR in NPS and/or sputum at baseline and exacerbation. IP-10 was measured by ELISA in serum and compared to HRV load.
At baseline, serum IP-10 was higher in COPD patients than controls; medians 149.4pg/ml (103–215) and 111.7pg/ml (82–178); p=0.02. The presence of HRV at baseline did not increase IP-10; COPD patients 166.9pg/ml (110–240) and 149.4pg/ml (103–215); p=0.30, controls 136.4pg/ml (77–204) and 111.7pg/ml (82–178); p=0.53. IP-10 increased significantly from baseline to exacerbation in HRV positive exacerbations; 154.9pg/ml (114.0–195.1) to 207.5pg/ml (142.1–333.5); p=0.009. There was no change in IP-10 between baseline and exacerbation in HRV negative exacerbations; 168.3pg/ml (94.3–249.8) and 175.6pg/ml (107.2–290.4); p=0.49. At exacerbation, IP-10 correlated with sputum viral load: rho=0.48; p=0.02. In ROC analysis, the combination of IP-10 and coryzal symptoms gave an AUC of 0.82 (95% CI 0.74–0.90).
IP-10 increases from baseline to exacerbation in HRV positive exacerbations and correlates with sputum HRV load. Serum IP-10 may be useful as a novel marker for these events.
Psychological factors affect how patients with chronic obstructive pulmonary disease (COPD) respond to attempts to improve their self-management skills. Learned helplessness may be one such factor, but there is no validated measure of helplessness in COPD.
Methods:
We administered a new COPD Helplessness Index (CHI) to 1202 COPD patients. Concurrent validity was assessed through the CHI's association with established psychosocial measures and COPD severity. The association of helplessness with incident COPD exacerbations was then examined by following subjects over a median 2.1 years, defining COPD exacerbations as COPD-related hospitalizations or emergency department visits.
Results:
The CHI demonstrated internal consistency (Cronbach's = 0.75); factor analysis was consistent with the CHI representing a single construct. Greater CHI-measured helplessness correlated with greater COPD severity assessed by the BODE Index (r=0.34; p< 0.001). Higher CHI scores were associated with worse generic (Short Form-12, Physical Component Summary Score) and respiratory-specific (Airways Questionnaire 20) health-related quality of life, greater depressive symptoms, and higher anxiety (all p<0.001). Controlling for sociodemographics and smoking status, helplessness was prospectively associated with incident COPD exacerbations (hazard ratio=1.31; p<0.001). After also controlling for the BODE Index, helplessness remained predictive of COPD exacerbations among subjects with BODE Index ≤median (hazard ratio=1.35; p=0.01), but not among subjects with higher BODE Index values (hazard ratio=0.93; p=0.34).
Conclusions:
The CHI is an internally consistent and valid measure, concurrently associated with health status and predictively associated with COPD exacerbations. The CHI may prove a useful tool in analyzing differential clinical responses mediated by patient-centered attributes.
Transfusion related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO) commonly complicate transfusion in critically ill patients. Prior outcome studies of TACO and TRALI have focused on short term morbidity and mortality while the long term survival and quality of life (QOL) of these patients remain unknown.
Methods:
In a nested case-control study we compared survival and QOL between critically ill medical patients who developed pulmonary edema after transfusion (TRALI or TACO) and medical critically ill transfused controls, matched by age, gender, and admission diagnostic group. QOL in survivors was assessed with a 36-Item Short Form Health Survey one year after initial hospitalization.
Results:
Hospital, one and two year mortality among the 74 TRALI cases and 74 matched controls were 43.2% vs. 24.3% (p=0.020), 63.8% vs. 46.4% (p=0.037) and 74.3% vs. 54.3% (p=0.031), while among the 51 TACO cases and 51 matched controls were 7.8% vs. 11.8% (p=0.727), 38.0% vs. 28.0% (p=0.371), 44.9% vs. 38.8% (p=0.512).
When adjusted for age and baseline severity of illness in a Cox proportional hazard analysis, the development of TRALI remained associated with decreased survival (hazard ratio 1.86; 95% CI 1.19 to 2.93, p=0.006). Both TRALI (p=0.006, p=0.03) and TACO (p=0.03, p=0.049) were associated with prolonged ICU and hospital lengths of stay.
Conclusions:
In critically ill medical patients, development of TRALI, but not TACO, is independently associated with decreased long-term survival.
Lower respiratory tract infection (LRTI) is common in the community, and may result in hospitalization or death. This observational study aimed to investigate the role of antibiotics in the management of LRTI in UK primary care.
Methods
Patients receiving a first diagnosis of LRTI during 2004 and satisfying inclusion and data quality criteria were identified in the General Practice Research Database. Factors associated with respiratory infection-related admissions and death in the 3 months following initial diagnosis were identified using Cox proportional hazards regression.
Results
Antibiotic prescribing on the day of diagnosis was associated with a decreased rate of respiratory infection-related admission (hazard ratio: 0.73; 95% confidence interval: 0.58–0.92), while antibiotic prescribing in the previous 7 days (1.92; 1.24–2.96) and prior referral or hospitalization (1.48; 1.20–1.83) were associated with an increased risk of admission. Female sex (0.73; 0.64–0.84), allergic rhinitis (0.48; 0.27–0.83), influenza vaccination (0.75; 0.65–0.87), prior inhaled corticosteroid use (0.63; 0.52–0.76) and antibiotic prescription on the day of diagnosis (0.31; 0.26–0.37) were associated with decreased respiratory infection-related mortality, while a Charlson comorbidity index of > 2 (2.24; 1.72–2.92), antibiotic prescription in the previous 7 days (1.56; 1.20–2.03) and frequent consultation (1.62; 1.09–2.40) were associated with increased mortality.
Conclusions
Antibiotic prescribing on the day of LRTI diagnosis was associated with reductions in admissions and mortality related to respiratory infection. Antibiotics may help to prevent adverse outcomes for some patients with LRTI.
Congenital central hypoventilation syndrome (CCHS) is characterized by compromised chemo-reflexes resulting in sleep hypoventilation. We report a Chinese family with PHOX2B mutation-confirmed CCHS, with a clinical spectrum from newborn to adulthood, to increase awareness on its various manifestations.
Methods
After identifying central hypoventilation in an adult male (index case), clinical evaluation was performed on the complete family, which consisted of the parents, five siblings, and five offsprings. Pulmonary function tests, overnight polysomnography, arterial blood gases, hypercapnia ventilatory response, and PHOX2B gene mutation screening were performed on living family members. Brain MRI, 24-h Holter, and echocardiography were done on members with clinically diagnosed central hypoventilation.
Results
The index patient and four offsprings manifested with clinical features of central hypoventilation. The index patients had hypoxia and hypercapnia while awake, polycythemia, and hematocrit of 70%. The first and fourth children had frequent cyanotic spells and both died of respiratory failure. The second and third children remained asymptomatic until adulthood, when they experienced impaired hypercapnic ventilatory response. The third child had nocturnal hypoventilation with nadir SpO2 of 59%. Adult-onset CCHS with PHOX2B gene mutation of the + 5 alanine expansions were confirmed in the index patient and the second and third children. The index patient and the third child received BiPAP treatment, which improved the hypoxemia, hypercapnia, and polycythemia without altering their chemo-sensitivity.
Conclusions
Transmission of late-onset CCHS is autosomal-dominant. Genetic screening of family members of CCHS probands allows for early diagnosis and treatment.
Epidemiological studies have suggested that female hormones might play a role in asthma and that menopausal hormone therapy (MHT or hormone replacement therapy (HRT)) might increase the risk of asthma in postmenopausal women. The only prospective study addressing this issue reports an increase in the risk of developing asthma which was similar for oestrogen alone and oestrogen/progestagen treatment.
Methods
The association between the use of different types of MHT and the risk of asthma onset in postmenopausal women was investigated prospectively from 1990 to 2002 by biennial questionnaires as part of the French E3N cohort study. Asthma onset was considered to be the time of medical diagnosis of asthma cases occurring during the follow-up of women who were asthma free at baseline. Cox proportional hazards models were used, adjusting for potential confounding factors.
Results
Among 57 664 women free of asthma at menopause, 569 incident cases of asthma were identified during 495 448 years of follow-up. MHT was related to an increased risk of asthma onset (HR=1.20, 95% CI 0.98 to 1.46) among recent users. The increase in risk of asthma onset was only significant among women reporting the use of oestrogen alone (HR=1.54, 95% CI 1.13 to 2.09) particularly in never smokers (HR=1.80, 95% CI 1.15 to 2.80) and women reporting allergic disease prior to asthma onset (HR=1.86, 95% CI 1.18 to 2.93). A small increase in the risk of asthma onset associated with the use of oestrogen/progestagen was also observed in these subgroups.
Conclusion
Postmenopausal use of oestrogen alone was associated with an increased rate of newly diagnosed asthma in menopausal women.
Rationale: Antibiotic therapy for early Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) is effective, but the optimal therapeutic regimen and duration for early treatment remains unclear. The EarLy Inhaled Tobramycin for Eradication (ELITE) study was designed to assess the efficacy and safety of two regimens (28 and 56 days) of tobramycin inhalation solution (TIS) 300 mg/5 mL (TOBI®) twice daily for the treatment of early onset P. aeruginosa infection in CF patients.
Methods: In this open-label, randomised, multicentre study, CF patients (aged ≥6 months) with early P. aeruginosa infection were treated for 28 days with TIS twice daily administered by the PARI LC PLUSTM jet nebuliser. After 28 days, patients were randomised 1:1 to either stop TIS (n=45) or to receive a further 28 days of TIS (n=43).
Measurements: The primary endpoint was the median time to recurrence of P. aeruginosa (any strain). Secondary endpoints included the proportion of patients free of P. aeruginosa infection one month after cessation of therapy and safety assessments.
Main results: The median time to recurrence of P. aeruginosa (any strain) was similar between the two groups. In total, 93% and 92% of the patients were free of P. aeruginosa infection one month after the end of treatment and 66% and 69% remained free after 27 months in the 28-day and 56-day groups, respectively. TIS was well tolerated.
Conclusions: Treatment with TIS for 28 days is an effective and well tolerated therapy for early P. aeruginosa infection in CF patients.
Introduction: Vitamin D deficiency has been associated with many chronic illnesses, but little is known about its relation with chronic obstructive pulmonary disease (COPD).
Objectives: We measured serum 25-hydroxyvitamin D levels (25-OHD) in 414 (ex)-smokers older than 50 years and assessed the link between vitamin D status and presence of COPD. The rs7041 and rs4588 variants in the vitamin D binding gene (GC) were genotyped and their effects on 25-OHD levels were tested.
Results: In COPD patients 25-OHD levels correlated significantly with FEV1 (r = 0.28, p<0.0001). Compared to 31% of the smokers with normal lung function, as much as 60% and 77% of GOLD stage 3 and 4 patients exhibited deficient 25-OHD levels lower than 20ng/ml (p<0.0001). Additionally, 25-OHD levels were reduced by 25% in homozygous carriers of the rs7041 at-risk T-allele (p<0.0001). This correlation was found to be independent of COPD severity, smoking history, age, gender, body mass index, corticosteroid intake, seasonal variation and rs4588 (p<0.0001). Notably, 76% and 100% of GOLD stage 3 and 4 patients homozygous for the rs7041 T-allele, exhibited 25-OHD levels lower than 20ng/ml. Logistic regression corrected for age, gender and smoking history, further revealed that homozygous carriers of the rs7041 T-allele exhibited an increased risk for COPD (OR=2.11; 95% CI: 1.20-3.71; p=0.009).
Conclusion: Vitamin D deficiency occurs frequently in COPD and correlates with severity of COPD. Our data warrant vitamin D supplementation in patients with severe COPD, especially in those carrying at-risk rs7041 variants.
Background: Tuberculous pleuritis remains the commonest cause of exudative effusions in areas with a high prevalence of tuberculosis and histological and/or microbiological confirmation on pleural tissue is the gold standard for its diagnosis. Uncertainty remains regarding the choice of closed pleural biopsy needles.
Objectives: This prospective study compared ultrasound-assisted Abrams and Tru-cut needle biopsies with regards to their diagnostic yield for pleural tuberculosis.
Methods: We enrolled 89 patients (38.7+/-16.7 years; 54 males) with pleural effusions and a clinical suspicion of tuberculosis. Transthoracic ultrasound was performed on all, whereafter patients were randomly assigned to undergo either four or more Abrams needle biopsies followed by four or more Tru-cut needle biopsies or vice versa. Medical thoracoscopy was performed on cases with nondiagnostic closed biopsies. Histological and/or microbiological proof of tuberculosis on any pleural specimen was considered the gold standard for pleural tuberculosis.
Results: Pleural tuberculosis was diagnosed in 66 patients, alternative diagnoses established in 20 patients and 3 remained undiagnosed. Pleural biopsy specimens obtained with Abrams needles contained pleural tissue in 81 patients (91.0%) and were diagnostic for TB in 54 patients (sensitivity=81.8%), whereas Tru-cut needle biopsy specimens only contained pleural tissue in 70 patients (78.7%, p=0.015) and were diagnostic in 43 patients (sensitivity=65.2%, p=0.022).
Conclusions: US-assisted pleural biopsies performed with an Abrams needle are more likely to contain pleura and have a significantly higher diagnostic sensitivity for pleural tuberculosis.
Rationale: Airway inflammation in asthma is heterogeneous, with different phenotypes. The inflammatory phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in eosinophilic asthma (EA), but evidence is conflicting regarding non-eosinophilic asthma (NEA).
Objectives: To assess inflammatory phenotypes in asthma after eliminating potentially confounding effects; to compare steroid response in EA versus NEA; to investigate changes in sputum cells with inhaled corticosteroid (ICS). Methods: Subjects undertook ICS withdrawal until loss of control or 28 days. Those with airway hyper-responsiveness (AHR) took inhaled fluticasone 1000µg daily for 28+ days. Cut-points were ≥/<2% for sputum eosinophils and ≥/<61% for neutrophils. Results: After steroid withdrawal (n=94), 67% were eosinophilic, 31% paucigranulocytic, and 2% mixed; there were no neutrophilic subjects. With ICS (n=88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased (19.3% to 27.7%, p=0.024). Treatment response was greater in EA for symptoms (p<0.001), quality of life (p=0.012), AHR (p=0.036) and exhaled nitric oxide (FENO) (p=0.007). Lesser but significant changes occurred in NEA (i.e. paucigranulocytic asthma). FENO was the best predictor of steroid response in NEA for AHR (AUC 0.810), with an optimum cut-point of 33ppb.
Conclusions: After eliminating the effects of ICS and smoking, we were unable to identify a neutrophilic phenotype in our patients with moderate stable asthma. ICS use led to phenotype misclassification. Steroid responsiveness was greater in EA, but the absence of eosinophilia did not indicate absence of steroid response. In NEA this was best predicted by baseline FENO.
Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. We tested the hypothesis that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP.
Methods:
A prospective, observational cohort study in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age- and sex-matched volunteers.
Growth of pathogens at >104 colony forming units/ml bronchoalveolar lavage fluid (BALF) distinguished VAP from ‘non-VAP’. Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves.
Results:
Seventy-two patients had recoverable lavage - 24% had VAP. BALF interleukin (IL)-1β, IL-8, granulocyte-colony stimulating factor and macrophage inflammatory protein 1 were significantly higher in the VAP group (all P<0·005). Using a cut off of 10 pg/ml, BALF IL-1β generated negative likelihood ratios for VAP of 0·09. In patients with BALF IL-1β <10 pg/ml the post-test probability of VAP was 2·8%. Using a cut off value for IL-8 of 2 ng/ml, positive likelihood ratio was 5.03. There was no difference in cytokine levels between patients with sterile BALF and those with growth of <104 CFU/ml.
Conclusions:
BALF IL-1β and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations.
High frequency chest wall oscillation (HFCWO) is standard treatment for airway clearance in the United States of America, and has recently been introduced to the United Kingdom (UK) and Europe. There is little published research comparing HFCWO with airway clearance techniques (ACTs) frequently used in the UK and Europe. The aim of this study was to compare the short-term effects of HFCWO with usual ACTs in people with cystic fibrosis hospitalised with an infective pulmonary exacerbation.
A four-day randomised cross-over design was used. Patients received either HFCWO on Days 1 & 3 and usual ACTs on Days 2 & 4 or vice versa. Wet weight of sputum, spirometry and oxygen saturation were measured. Perceived efficacy, comfort, incidence of urinary leakage and preference were assessed. Data were analysed by mixed model analysis.
Twenty-nine patients, (72% male) mean age in years (sd) 29.4 (8.4) and mean FEV1 as percent predicted (FEV1%) (sd) 38 (16.7) completed the study. Statistically significantly more sputum was expectorated during a single treatment session and over a 24 hour period (mean difference 4.4g and 6.9g respectively; p < 0.001), with usual ACTs than HFCWO. No statistically significant change in FEV1% or oxygen saturation was observed after either HFCWO or usual ACTs, compared with baseline. Seventeen (55%) patients expressed a preference for their usual ACT.
During both a finite treatment period and over 24 hours less sputum was cleared using HFCWO than usual ACT. HFCWO does not appear to cause any adverse physiological affects and may influence adherence.
Background: Current guidelines recommend the use of
a combination of inhaled beta2-agonists and
anticholinergics, particularly for patients with acute
severe or life threatening asthma in the emergency
setting. However, this statement is based on a relatively
small number of randomised controlled trials and related
systematic reviews. This review was undertaken to
incorporate the more recent evidence available about the
effectiveness of treatment with beta2-agonists and
anticholinergics compared with beta2-agonists in acute
asthma treatment.
Methods: A search was conducted of all randomised
controlled trials published prior to April 2005.
Results: Data from 32 randomised controlled trials
(n = 3611 subjects) showed significant reductions in
hospital admissions in both children (RR = 0.73; 95% CI:
0.63 to 0.85, p = 0.0001) and adults (RR = 0.68; 95% CI:
0.53 to 0.86, p = 0.002) that received inhaled
anticholinergics. Combined treatment also produced a
significant increase on spirometric tests at 60-120 min
after the last treatment in children (SMD = -0.54; 95% CI:
-0.28 to -0.81, p = 0.0001) and adults (SMD = -0.36; 95%
CI: -0.23 to -0.49, p = 0.00001).
Conclusions: This review strongly suggests that the
addition of multiple doses of inhaled ipratropium bromide
to beta2-agonists seems indicated as the standard
treatment in children, adolescent and adult patients with
moderate to severe exacerbations of asthma in the
emergency setting.
