What can we expect novel therapies to do for patients with cystic fibrosis (CF)? Everyone wants a cure, but how will we know if we have achieved it? Mortality is only applicable if Methuselah was the principle investigator, because survival curves are so flat. Horsley et al (see
It is by no means straightforward to analyse the change in the rate of chronic obstructive pulmonary disease (COPD) exacerbations in clinical trials. Exacerbation rates do not follow a normal distribution, nor do they occur at random. High exacerbation rates in a few patients can make average rates difficult to calculate and interpret. So, surely, transforming exacerbation rates into numbers needed to treat (NNT) should help. Not necessarily so—this is the message from Professor Suissa's paper.
I have used the exponential model suggested by Suissa, with the data from two of the arms of...]]>
The paper by Wang is somewhat unusual because it essentially reports a negative conclusion. Judging by the number of internet blogs on the topic, it seems there is genuine concern about the inability to publish negative results, and there is now quantitative evidence to suggest that there is a growing trend for journals to publish studies with positive outcomes.
The EINSTEIN-PE study was designed to compare efficacy and safety of fixed-dose oral rivaroxaban therapy against standard heparin plus warfarin in the treatment of symptomatic pulmonary emboli.
When one is presented with a blinded report of survival rates for lung cancer across developed countries, how can one identify the result for the UK? Exactly, choose the one with the poorest outcome. You would be correct more often than not (unless Denmark was included).
In 2007 and 2009, the EUROCARE Group published results of cancer survival identifying the UK among the countries with the lowest survival rates for lung cancer in Europe.
Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data.
To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma.
ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine.
ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086.
These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma.
The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β2 agonist vilanterol (VI) is in development for asthma and chronic obstructive pulmonary disease.
To assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma.
Patients (aged ≥12 years; on inhaled corticosteroid) were randomised (2:2:1) to FF/VI 100/25 µg or FF/VI 200/25 µg once daily in the evening, or fluticasone propionate (FP) 500 µg twice daily. Safety evaluations included adverse events (AEs), non-fasting glucose, potassium, 24-h urinary cortisol excretion, ophthalmic assessments, heart rate and pulse rate.
On-treatment AEs were similar across groups (FF/VI 66–69%; 73% FP). Oral candidiasis/oropharyngeal candidiasis was more common with FF/VI (6–7%) than FP (3%). Twelve serious AEs were reported; one (worsening hepatitis B on FP) was considered drug related. Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 (ratios [95% CI] to FP ranged from 1.43 [1.11 to 1.84] to 1.67 [1.34 to 2.08]; p≤0.006), but not at Week 52 (ratios to FP were 1.05 [0.83 to 1.33] for FF/VI 100/25 µg and 1.09 [0.87 to 1.38] for FF/VI 200/25 µg). No clinically important changes in non-fasting glucose, potassium, QT interval corrected using Fridericia's formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [Tmax], Week 52) was significantly increased with FF/VI versus FP (3.4 bpm, 95% CI 1.3 to 5.6; p=0.002 [FF/VI 100/25 µg]; 3.4 bpm, 95% CI 1.2 to 5.6; p=0.003 [FF/VI 200/25 µg]). Mean heart rate (24-h Holter monitoring) decreased from screening values in all groups (0.2–1.1 bpm FF/VI vs 5 bpm FP; Week 52).
FF/VI (100/25 µg or 200/25 µg) administered once daily over 52 weeks was well tolerated by patients aged ≥12 years with asthma. The overall safety profile of FF/VI did not reveal any findings of significant clinical concern.
NCT01018186
The alveolar pathology in chronic obstructive pulmonary disease (COPD) involves antigen-driven immune events. However, the induction sites of alveolar adaptive immune responses have remained poorly investigated.
To explore the hypothesis that interfaces between the alveolar lumen and lymphoid aggregates (LAs) provide a structural basis for increased alveolar antigen uptake in COPD lungs.
Lung samples from patients with mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), moderate–severe (GOLD II–III), and very severe (GOLD IV) COPD were subjected to detailed histological assessments of adaptive immune system components. Never smokers and smokers without COPD served as controls.
Quantitative histology, involving computerised three-dimensional reconstructions, confirmed a rich occurrence of alveolar-restricted LAs and revealed, for the first time, that the vast majority of vascular or bronchiolar associated LAs had alveolar interfaces but also an intricate network of lymphatic vessels. Uniquely to COPD lungs, the interface epithelium had transformed into a columnar phenotype. Accumulation of langerin (CD207)+ dendritic cells occurred in the interface epithelium in patients with COPD but not controls. The antigen-capturing capacity of langerin+ dendritic cells was confirmed by increased alveolar protrusions and physical T cell contact. Several of these immune remodelling parameters correlated with lung function parameters.
Severe stages of COPD are associated with an emergence of remodelled and dendritic cell-rich alveolar–lymphoid interfaces. This novel type of immune remodelling, which predicts an increased capacity to respond to alveolar antigens, is suggested to contribute to aggravated inflammation in COPD.
Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures.
To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy.
A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers.
Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31).
We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.
Several recent trials in chronic obstructive pulmonary disease (COPD) have assessed the effectiveness of the fluticasone–salmeterol combination inhaler in preventing COPD exacerbations, while finding an increased risk of pneumonia. The number needed to treat (NNT) is a simple measure to perform the comparative benefit–risk impact, but its calculation involving repeated outcome events such as COPD exacerbations has been incorrect. We describe the proper methods to calculate the NNT and, using data from published trials, apply them to evaluate the relative impact of fluticasone–salmeterol treatment on exacerbations and pneumonias in patients with COPD.
We review the fundamental definition of NNT and quantify it for situations with varying follow-up times. We review the ‘event-based’ NNT, proposed and used for repeated event outcomes, show its inaccuracy, describe its proper use and provide an approximate formula for its application.
We show that a 1-year trial of the fluticasone–salmeterol combination versus salmeterol used the incorrect event-based approach to calculate the NNT as two patients that need to be treated for 1 year to prevent one COPD exacerbation, when the proper calculation results in a NNT of 14. In contrast, 20 patients need to be treated to induce one pneumonia case. For the TORCH trial, the NNT is 44 patients treated for 3 years with fluticasone–salmeterol versus salmeterol to prevent one exacerbation compared with 16 patients to induce one pneumonia case.
The NNT is a useful measure of the effect of drugs, but its proper calculation is essential to prevent misleading clinical practice guidelines.
On 11 March 2011, the Tohoku earthquake and tsunami struck off the coast of northeastern Japan. Within 3 weeks, an increased number of pneumonia admissions and deaths occurred in local hospitals.
A multicentre survey was conducted at three hospitals in Kesennuma City (population 74 000), northern Miyagi Prefecture. All adults aged ≥18 years hospitalised between March 2010 and June 2011 with community-acquired pneumonia were identified using hospital databases and medical records. Segmented regression analyses were used to quantify changes in the incidence of pneumonia.
A total of 550 pneumonia hospitalisations were identified, including 325 during the pre-disaster period and 225 cases during the post-disaster period. The majority (90%) of the post-disaster pneumonia patients were aged ≥65 years, and only eight cases (3.6%) were associated with near-drowning in the tsunami waters. The clinical pattern and causative pathogens were almost identical among the pre-disaster and post-disaster pneumonia patients. A marked increase in the incidence of pneumonia was observed during the 3-month period following the disaster; the weekly incidence rates of pneumonia hospitalisations and pneumonia-associated deaths increased by 5.7 times (95% CI 3.9 to 8.4) and 8.9 times (95% CI 4.4 to 17.8), respectively. The increases were largest among residents in nursing homes followed by those in evacuation shelters.
A substantial increase in the pneumonia burden was observed among adults after the Tohoku earthquake and tsunami. Although the exact cause remains unresolved, multiple factors including population aging and stressful living conditions likely contributed to this pneumonia outbreak.
The authors consider whether differences in stage at diagnosis could explain the variation in lung cancer survival between six developed countries in 2004–2007.
Routinely collected population-based data were obtained on all adults (15–99 years) diagnosed with lung cancer in 2004–2007 and registered in regional and national cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Stage data for 57 352 patients were consolidated from various classification systems. Flexible parametric hazard models on the log cumulative scale were used to estimate net survival at 1 year and the excess hazard up to 18 months after diagnosis.
Age-standardised 1-year net survival from non-small cell lung cancer ranged from 30% (UK) to 46% (Sweden). Patients in the UK and Denmark had lower survival than elsewhere, partly because of a more adverse stage distribution. However, there were also wide international differences in stage-specific survival. Net survival from TNM stage I non-small cell lung cancer was 16% lower in the UK than in Sweden, and for TNM stage IV disease survival was 10% lower. Similar patterns were found for small cell lung cancer.
There are comparability issues when using population-based data but, even given these constraints, this study shows that, while differences in stage at diagnosis explain some of the international variation in overall lung cancer survival, wide disparities in stage-specific survival exist, suggesting that other factors are also important such as differences in treatment. Stage should be included in international cancer survival studies and the comparability of population-based data should be improved.
Protein kinase G-1- knockout (Prkg1–/–) mice had decreased PKG-1 and increased pulmonary artery systolic pressure compared to wild type mice. Prkg1–/– mice had marked microvascular remodelling and precapillary occlusion in the lung, suggesting the two mechanisms cause PH in Prkg1–/– mice. The increased pulmonary artery pressure was independent of left-sided heart disease and systemic hypertension at day 45 in Prkg1–/– mice. Furthermore, the western blot of Prkg1–/– mice showed decreased phosphorylation of Rho A Ser188 and increased activation of Rho A. After fasudil (a Rho kinase inhibitor) treatment, a significant decrease in pulmonary artery pressure was noted in Prkg1–/– mice.
In this study, the authors showed that PKG-1 deficiency results in activation of Rho A-Rho kinase signalling, which causes vascular...]]>
Cadmium (Cd) is an important metal with both common occupational and environmental sources of exposure. Although it is likely to cause adverse respiratory effects, relevant human data are relatively sparse.
A cross-sectional study of 133 workers in jewellery workshops using Cd under poor hygienic conditions and 54 referent jewellery sales staffs was performed. We assessed symptoms, performed spirometry, measured urinary Cd levels in all study subjects and quantified airborne total oxidant contents for 35 job areas in which the studied workforce was employed. We tested the association of symptoms with exposure relative to the unexposed referents using logistic regression analysis, and tested the association between urinary Cd levels and lung function using multiple regression analysis, adjusting for demographics, smoking and area-level airborne oxidants.
Exposed workers had 10 times higher urinary Cd values than referents (geometric mean 5.8 vs 0.41 µg/dl; p<0.01). Of the exposed subjects, 75% reported respiratory tract symptoms compared with 33% of the referents (OR=3.1, 95% CI 1.4 to 7.3). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were also lower among the exposed workers than the referents (>600 ml decrement for each, p<0.001). For every 1 µg increase in urinary Cd there was a 34 ml decrement in FVC and a 39 ml decrement in FEV1 (p<0.01), taking into account other covariates including workplace airborne oxidant concentrations.
This cohort of heavily exposed jewellery workers experienced frequent respiratory symptoms and manifested a marked deficit in lung function, demonstrating a strong response to Cd exposure.
In vitro oestradiol induced more alginate production, defining mucoid conversion, at 3 days and 4 weeks compared with ethanol and testosterone, and more mucoid colonies were seen at 4 weeks following oestradiol culture. In 80% of oestradiol-exposed colonies, a frameshift mutation in the mucA gene was identified causing loss of gene function and development of pseudomonas mucoidy.
Exacerbations closely followed oestradiol levels with increased numbers seen during the high oestradiol follicular phase. However, the sample size was small, 44 patients and 139 exacerbations, with only 23 patients and 72 exacerbations analysed. The percentage of mucoid sputum isolates was also higher during the follicular phase, compared with the luteal phase when no mucoid strains were isolated, although again the sample size was small. Oestradiol was higher during exacerbations in women than...]]>
Host and bacterial factors as well as different treatment regimens are likely to influence the outcome in patients with bacteraemic pneumococcal pneumonia.
To estimate the relative contribution of host factors as well as bacterial factors and antibiotic treatment to mortality in bacteraemic pneumococcal pneumonia.
A cohort study of 1580 adult patients with community-acquired bacteraemic pneumococcal pneumonia was conducted between 2007 and 2009 in Sweden. Data on host factors and initial antibiotic treatment were collected from patient records. Antibiotic resistance and serotype were determined for bacterial isolates. Logistic regression analyses were performed to assess risk factors for 30-day mortality.
Smoking, alcohol abuse, solid tumour, liver disease and renal disease attributed to 14.9%, 13.1%, 13.1%, 8.0% and 7.4% of the mortality, respectively. Age was the strongest predictor, and mortality increased exponentially from 1.3% in patients <45 years of age to 26.1% in patients aged ≥85 years. There was considerable confounding by host factors on the association between serotype and mortality. Increasing age, liver disease and serotype were associated with mortality in patients admitted to the ICU. Combined treatment with β-lactam antibiotics and macrolide/quinolone was associated with reduced mortality in patients in the ICU, although confounding could not be ruled out.
Host factors appear to be more important than the specific serotype as determinants of mortality in patients with bacteraemic pneumococcal pneumonia. Several host factors were identified that contribute to mortality, which is important for prognosis and to guide targeted prevention strategies.
Following thoracotomy, patients frequently receive routine respiratory physiotherapy which may include incentive spirometry, a breathing technique characterised by deep breathing performed through a device offering visual feedback. This type of physiotherapy is recommended and considered important in the care of thoracic surgery patients, but high quality evidence for specific interventions such as incentive spirometry remains lacking.
180 patients undergoing thoracotomy and lung resection participated in a prospective single-blind randomised controlled trial. All patients received postoperative breathing exercises, airway clearance and early mobilisation; the control group performed thoracic expansion exercises and the intervention group performed incentive spirometry.
No difference was observed between the intervention and control groups in the mean drop in forced expiratory volume in 1 s on postoperative day 4 (40% vs 41%, 95% CI –5.3% to 4.2%, p=0.817), the frequency of postoperative pulmonary complications (PPC) (12.5% vs 15%, 95% CI –7.9% to 12.9%, p=0.803) or in any other secondary outcome measure. A high-risk subgroup (defined by ≥2 independent risk factors; age ≥75 years, American Society of Anaesthesiologists score ≥3, chronic obstructive pulmonary disease (COPD), smoking status, body mass index ≥30) also demonstrated no difference in outcomes, although a larger difference in the frequency of PPC was observed (14% vs 23%) with 95% CIs indicating possible benefit of intervention (–7.4% to 2.6%).
Incentive spirometry did not improve overall recovery of lung function, frequency of PPC or length of stay. For patients at higher risk for the development of PPC, in particular those with COPD or current/recent ex-smokers, there were larger observed actual differences in the frequency of PPC in favour of the intervention, indicating that investigations regarding the physiotherapy management of these patients need to be developed further.
In 68 school-aged children (44 with mild CF lung disease) three standard nitrogen (N2) MBWs were applied. We assessed repeatability and diagnostic performance of (1) LCI measured earlier from three MBW runs and (2) LCI measured at complete MBW (1/40th of starting N2 concentration) from two runs only.
Compared with the standard LCI from three complete MBW runs, the new LCI based on three N2MBW runs until 1/20th, or two complete runs until 1/40th, provided similar or better repeatability as well as sensitivity and specificity for CF lung disease. Alternative ways to measure LCI reduced test duration in children with CF by 30% and 41%, respectively.
LCI measurements can be reliably shortened in children. These new MBW protocols may advance the transition of LCI from research into clinical settings.
]]>The study design and baseline characteristics have...]]>
The editorial by Jenkins and Beasley
Individuals at an advanced age, with diseases such...]]>
We read with interest the recent study done by Obiora et al
However, we...]]>
Hlaing TM, Wang J-S. A molecular assay to predict survival in resected non-squamous non-small-cell lung cancer. Thorax 2013;68:47 doi:10.1136/thoraxjnl-2012-202055.
The correspondence address for Jeng-Shing Wang should read: Dr Jeng-Shing Wang, Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Department of Thoracic Medicine, Pingtung, and Department of Internal Medicine, Taipei Medical University, Taipei, Pingtung 928, Taiwan; wangjs6@hotmail.com.
]]>A 32-year-old man worked as a subsistence farmer raising pigs and tending his small garden; he also kept cats and dogs. He reported fever, night sweats, weight loss of 10 kg over 3 months, haemoptysis and skin ulcers (
Sporotrichosis is a chronic pyogranulomatous infection caused by a dimorphic fungus that contaminates skin or subcutaneous tissue after trauma with plant materials such as thorns or splinters, or through cat scratches or bites.