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Highlights from this issue

2017-09-13T07:50:05-07:00

Seasonal COPD

Season of mists and mellow fruitfulness ...’ was John Keats’ description of the current autumn season. However, autumn does more than just ‘... fill all fruit with ripeness to the core ....’ It heralds the beginning of the peak season for COPD exacerbations. On page 919 of this issue, Wilkinson and colleagues describe the seasonal changes in airway pathogens in COPD exacerbations. They found that non-typeable Haemophilus influenzae increased the risk of COPD exacerbations from October to March. Moraxella catarrhalis, on the other hand, exerted its malign influence year-round. All this will leave respiratory physicians very little time for seasonal leisure activities such as sitting by the ‘... cyder-press, with patient look ...’ watching ‘... the last oozings, hours by hours ...’ Time please gentlemen!

Biomarkers: poetic and prophetic ...

In 1821, John Keats died of what is believed to have been tuberculosis, though the tubercle bacillus was not described until 1882 (by Robert Koch)....




Divide and conquer: identifying acute respiratory distress syndrome subphenotypes

2017-09-13T07:50:05-07:00

The acute respiratory distress syndrome (ARDS) definition identifies patients with acute onset hypoxaemia and respiratory failure, who have bilateral opacities on chest radiograph that are not fully explained by cardiac failure or fluid overload.1 ARDS is a common illness that accounts for approximately 10% of critical care admissions and 20% of patients requiring mechanical ventilation.2 The hospital mortality in patients with ARDS remains high, increasing from approximately 35% for those with mild disease to 46% for those with severe ARDS.2 This high mortality has remained relatively unchanged in the last 20 years.3 To date, despite decades of research, there is no pharmacological treatment that can modify the underlying biological mechanisms implicated in ARDS and improve patient outcomes.4 Within ARDS populations, there is substantial biological and outcome heterogeneity, with observed differences in dominant pathogenic mechanisms, treatment responses and outcomes.5–7




Does a lung cancer screening programme promote smoking cessation?

2017-09-13T07:50:05-07:00

Lung cancer is a preventable form of cancer with approximately 90% of cases attributable to cumulative tobacco exposure.1 Smoking cessation and early detection of lung cancer remain critical goals for lung cancer prevention and control. Indeed, the health benefits of smoking cessation reach well beyond reducing the risk of lung cancer,2 resulting in an overall reduction of tobacco-related mortality. Unfortunately, smoking cessation delivery and patient adherence is still a major challenge.

While there is a body of evidence supporting smoking cessation (primary prevention) and early detection of lung cancer (secondary prevention) to decrease lung cancer mortality, data on the effectiveness and interaction between smoking cessation and lung cancer screening are still sparse and inconsistent.3–6 The administration of a rigorous smoking cessation intervention (based on the combination of counselling and drug treatment) to a lung cancer screening population...




Interplay of physiology, social, familial and behavioural adaptation in the long-term outcome of ARDS

2017-09-13T07:50:05-07:00

Discharge from a hospital after the intensive care unit (ICU) is challenging. Please do not mistake us—we agree many patients are happy to go home. In fact, most critical care survivors are desperate to leave the hospital, typically after a prolonged frightening hospital stay lasting weeks or longer. Unfortunately, most patients have not returned to their preillness physical status when they go home, and many face new cognitive or psychological disabilities that may just be emerging. Yet, constrained budgets, limited acute hospital beds and wide variation in formal rehabilitation mean many patients enter posthospital survivorship without coordinated support. No matter which health system cares for them, many survivors experience an unplanned rehospitalisation within a few months.1–4

Hospital discharge prior to full recovery may be inevitable, as recovery after many illnesses simply takes a really long time (or might never be complete). Data...




GDF11: a fountain of youth for the ageing COPD lung?

2017-09-13T07:50:05-07:00

Smoking is the single most important causal risk factor for COPD. The public health campaigns and policies have worked to reduce smoking rates by over 50% since those of the 1970s and are now at an all-time low in the UK,1 Canada and throughout most of the western world. Yet, curiously and paradoxically, the burden of COPD (as measured by its prevalence, hospitalisation and mortality rate) is at an all-time high in these countries, and over the next 20 years, the burden of COPD is expected to more than double.2 Why? 

The answer is a simple math issue related to ageing. Most industrialised countries of the world are getting older and, unquestionably, COPD is an age-related disorder. Whereas COPD is almost unheard of in individuals less than 40 years of age (even among heavy smokers), 1 in 10 lifetime never-smokers and 1 in 3 develop COPD...




Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis

2017-09-13T07:50:05-07:00

Rationale

We hypothesised that patients with acute respiratory distress syndrome (ARDS) can be clustered based on concentrations of plasma biomarkers and that the thereby identified biological phenotypes are associated with mortality.

Methods

Consecutive patients with ARDS were included in this prospective observational cohort study. Cluster analysis of 20 biomarkers of inflammation, coagulation and endothelial activation provided the phenotypes in a training cohort, not taking any outcome data into account. Logistic regression with backward selection was used to select the most predictive biomarkers, and these predicted phenotypes were validated in a separate cohort. Multivariable logistic regression was used to quantify the independent association with mortality.

Results

Two phenotypes were identified in 454 patients, which we named ‘uninflamed’ (N=218) and ‘reactive’ (N=236). A selection of four biomarkers (interleukin-6, interferon gamma, angiopoietin 1/2 and plasminogen activator inhibitor-1) could be used to accurately predict the phenotype in the training cohort (area under the receiver operating characteristics curve: 0.98, 95% CI 0.97 to 0.99). Mortality rates were 15.6% and 36.4% (p<0.001) in the training cohort and 13.6% and 37.5% (p<0.001) in the validation cohort (N=207). The ‘reactive phenotype’ was independent from confounders associated with intensive care unit mortality (training cohort: OR 1.13, 95% CI 1.04 to 1.23; validation cohort: OR 1.18, 95% CI 1.06 to 1.31).

Conclusions

Patients with ARDS can be clustered into two biological phenotypes, with different mortality rates. Four biomarkers can be used to predict the phenotype with high accuracy. The phenotypes were very similar to those found in cohorts derived from randomised controlled trials, and these results may improve patient selection for future clinical trials targeting host response in patients with ARDS.




Are physical measures related to patient-centred outcomes in ARDS survivors?

2017-09-13T07:50:05-07:00

Objective

To inform selection of physical measures for studies of acute respiratory distress syndrome (ARDS) survivors within 12 months of ARDS.

Methods

Secondary analysis of data from 6-month survivors participating in a US multicentre prospective study (ARDSNet Long-Term Outcome Study, N=134) or a multisite prospective study in Baltimore, Maryland, USA (Improving Care of Acute Lung Injury Patients, N=99). Physical measures, assessed at 6-month follow-up, were categorised according to the WHO's International Classification of Disability and Health: body functions and structures, activity and participation. Patient-centred outcomes were evaluated at 6 and 12 months: survival, hospitalisation, alive at home status and health-related quality of life. Pearson correlation, linear and logistic regression models were used to quantify associations of physical measures with patient-centred outcomes.

Main results

No 6-month body functions and structures measure demonstrated consistent association with 6-month or 12-month outcomes in multivariable regression. The 6 min walk test, an activity measure, was associated with 6-month Short-Form 36 (SF-36) physical component scores (PCS, β range: 0.99 to 1.52, p<0.05). Participation measures (Functional Performance Inventory, FPI; Instrumental Activities of Daily Living, IADLs) were associated with SF-36 PCS (β range: FPI, 1.51–1.52; IADL, –1.88 to –1.32; all p<0.05) and Euro-QOL-5D utility score (β range: FPI, 2.00–3.67; IADL, –2.89 to –2.50; all p<0.01) at 6 and 12 months.

Conclusions

Participation measures better reflect patient's quality of life than measures of body functions and structures within 12 months of ARDS among 6-month survivors, and are recommended for inclusion as a core measure in future studies.




Decrease in an anti-ageing factor, growth differentiation factor 11, in chronic obstructive pulmonary disease

2017-09-13T07:50:05-07:00

Rationale

Cellular senescence is observed in the lungs of patients with COPD and may contribute to the disease pathogenesis. Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor β superfamily and was recently reported to be a circulating protein that may have rejuvenating effects in mice. We aimed to investigate the amounts of GDF11 in the plasma and the lungs of patients with COPD and elucidate the possible roles of GDF11 in cellular senescence.

Methods

The plasma levels of GDF11 were investigated in two separate cohorts by western blotting. The localisation and expression of GDF11 in the lungs were investigated by immunohistochemistry and quantitative reverse transcription PCR, respectively. The effects of GDF11 on both cigarette smoke extract (CSE)-induced cellular senescence in vitro and on elastase-induced cellular senescence in vivo were investigated.

Results

The levels of plasma GDF11 in the COPD group were decreased compared with the control groups in the two independent cohorts. The levels of plasma GDF11 were significantly positively correlated with pulmonary function data. The mRNA expression of GDF11 in mesenchymal cells from the COPD group was decreased. Chronic exposure to CSE decreased the production of GDF11. Treatment with GDF11 significantly inhibited CSE-induced cellular senescence and upregulation of inflammatory mediators, partly through Smad2/3 signalling in vitro. Daily GDF11 treatment attenuated cellular senescence and airspace enlargement in an elastase-induced mouse model of emphysema.

Conclusions

The decrease in GDF11 may be involved in the cellular senescence observed in COPD.




Cardiovascular and neuropsychiatric risks of varenicline and bupropion in smokers with chronic obstructive pulmonary disease

2017-09-13T07:50:05-07:00

Background

Varenicline and bupropion are effective smoking cessation treatments, but there are concerns about their safety in smokers with COPD.

Objective

To investigate whether varenicline and bupropion are associated with serious adverse cardiovascular and neuropsychiatric events in smokers with COPD.

Methods

In a retrospective cohort study, we used data from 14 350 patients with COPD included in the QResearch database, which holds data from 753 National Health Service general practices across England. We identified patients with COPD who received a prescription of nicotine replacement therapy (NRT; N=10 426; reference group), bupropion (N=350) or varenicline (N=3574) in the period between January 2007 and June 2012. Patients were followed up for 6 months to compare incident cardiovascular (ie, ischaemic heart disease, stroke, heart failure, peripheral vascular disease and cardiac arrhythmias) and neuropsychiatric (ie, depression and self-harm) events using Cox proportional hazards models, adjusted for potential confounders. Propensity score analysis was used as an additional approach to account for potential confounding by indication. We also modelled the effects of possible unmeasured confounders.

Results

Neither bupropion nor varenicline showed an increased risk of adverse events compared with NRT. Varenicline was associated with a significantly reduced risk of heart failure (HR=0.56, 95% CI 0.34 to 0.92) and depression (HR=0.73, 95% CI 0.61 to 0.86). Similar results were obtained from the propensity score analysis. Modelling of unmeasured confounding provided additional evidence that an increased risk of these adverse events was very unlikely.

Conclusion

In smokers with COPD, varenicline and bupropion do not appear to be associated with an increased risk of cardiovascular events, depression or self-harm in comparison with NRT.




Impact of low-dose CT screening on smoking cessation among high-risk participants in the UK Lung Cancer Screening Trial

2017-09-13T07:50:05-07:00

Background

Smoking cessation was examined among high-risk participants in the UK Lung Cancer Screening (UKLS) Pilot Trial of low-dose CT screening.

Methods

High-risk individuals aged 50–75 years who completed baseline questionnaires were randomised to CT screening (intervention) or usual care (no screening control). Smoking habit was determined at baseline using self-report. Smokers were asked whether they had quit smoking since joining UKLS at T1 (2 weeks after baseline scan results or control assignment) and T2 (up to 2 years after recruitment). Intention-to-treat (ITT) regression analyses were undertaken, adjusting for baseline lung cancer distress, trial site and sociodemographic variables.

Results

Of a total 4055 individuals randomised to CT screening or control, 1546 were baseline smokers (759 intervention, 787 control). Smoking cessation rates were 8% (control n=36/479) versus 14% (intervention n=75/527) at T1 and 21% (control n=79/377) versus 24% (intervention n=115/488) at T2. ITT analyses indicated that the odds of quitting among screened participants were significantly higher at T1 (adjusted OR (aOR) 2.38, 95% CI 1.56 to 3.64, p<0.001) and T2 (aOR 1.60, 95% CI 1.17 to 2.18, p=0.003) compared with control. Intervention participants who needed additional clinical investigation were more likely to quit in the longer term compared with the control group (aOR 2.29, 95% CI 1.62 to 3.22, p=0.007) and those receiving a negative result (aOR 2.43, 95% CI 1.54 to 3.84, p<0.001).

Conclusions

CT lung cancer screening for high-risk participants presents a teachable moment for smoking cessation, especially among those who receive a positive scan result. Further behavioural research is needed to evaluate optimal strategies for integrating smoking cessation intervention with stratified lung cancer screening.

Trial registration number

Results, ISRCTN 78513845




A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD

2017-09-13T07:50:05-07:00

Background

The aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood. Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the incidence and seasonality of these events.

Methods

In this prospective, observational cohort study (NCT01360398), patients with COPD aged 40–85 years underwent sputum sampling monthly and at exacerbation for detection of bacteria and viruses. Results are presented for subjects in the full cohort, followed for 1 year. Interactions between exacerbation occurrence and pathogens were investigated by generalised estimating equation and stratified conditional logistic regression analyses.

Findings

The mean exacerbation rate per patient-year was 3.04 (95% CI 2.63 to 3.50). At AECOPD, the most common bacterial species were non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, and the most common virus was rhinovirus. Logistic regression analyses (culture bacterial detection) showed significant OR for AECOPD occurrence when M. catarrhalis was detected regardless of season (5.09 (95% CI 2.76 to 9.41)). When NTHi was detected, the increased risk of exacerbation was greater in high season (October–March, OR 3.04 (1.80 to 5.13)) than low season (OR 1.22 (0.68 to 2.22)). Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than stable state (8.6%). A significant interaction was detected between NTHi and rhinovirus presence and AECOPD risk (OR 5.18 (1.92 to 13.99); p=0.031).

Conclusions

AECOPD aetiology varies with season. Rises in incidence in winter may be driven by increased pathogen presence as well as an interaction between NTHi airway infection and effects of viral infection.

Trial registration number

Results, NCT01360398.




Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome

2017-09-13T07:50:05-07:00

Background

Acute respiratory distress syndrome (ARDS) is an often fatal neutrophil-dominant lung disease. Although influenced by multiple proinflammatory mediators, identification of suitable therapeutic candidates remains elusive. We aimed to delineate the presence of mitochondrial formylated peptides in ARDS and characterise the functional importance of formyl peptide receptor 1 (FPR1) signalling in sterile lung inflammation.

Methods

Mitochondrial formylated peptides were identified in bronchoalveolar lavage fluid (BALF) and serum of patients with ARDS by liquid chromatography–tandem mass spectrometry. In vitro, human neutrophils were stimulated with mitochondrial formylated peptides and their effects assessed by flow cytometry and chemotaxis assay. Mouse lung injury was induced by mitochondrial formylated peptides or hydrochloric acid. Bone marrow chimeras determined the contribution of myeloid and parenchymal FPR1 to sterile lung inflammation.

Results

Mitochondrial formylated peptides were elevated in BALF and serum from patients with ARDS. These peptides drove neutrophil activation and chemotaxis through FPR1-dependent mechanisms in vitro and in vivo. In mouse lung injury, inflammation was attenuated in Fpr1–/– mice, effects recapitulated by a pharmacological FPR1 antagonist even when administered after the onset of injury. FPR1 expression was present in alveolar epithelium and chimeric mice demonstrated that both myeloid and parenchymal FPR1 contributed to lung inflammation.

Conclusions

We provide the first definitive evidence of mitochondrial formylated peptides in human disease and demonstrate them to be elevated in ARDS and important in a mouse model of lung injury. This work reveals mitochondrial formylated peptide FPR1 signalling as a key driver of sterile acute lung injury and a potential therapeutic target in ARDS.




Current understanding and management of pulmonary Langerhans cell histiocytosis

2017-09-13T07:50:05-07:00

Pulmonary Langerhans cell histiocytosis (PLCH) is a diffuse lung disease that usually affects young adult smokers. PLCH affects different lung compartments; bronchiolar, interstitial and pulmonary vascular dysfunction may coexist to varying extents, resulting in diverse phenotypes. Analyses of PLCH tissues have identified activating mutations of specific mitogen-activated protein kinases (BRAFV600E and others). The current consensus is that PLCH represents a myeloid neoplasm with inflammatory properties: the myeloid tumour cells exhibit surface CD1a expression and up to 50% of the cells harbour activating BRAF or other MAPK mutations. PLCH may be associated with multisystem disease. The detection of disease outside of the thorax is facilitated by whole body positron emission tomography. The natural history of PLCH is unpredictable. In some patients, disease may remit or stabilise following smoking cessation. Others develop progressive lung disease, often associated with evidence of airflow limitation and pulmonary vascular dysfunction. Due to the inability to accurately predict the natural history, it is important that all patients undergo longitudinal follow-up at least twice a year for the first few years following diagnosis. The treatment of PLCH is challenging and should be individualised. While there is no general consensus regarding the role of immunosuppression or chemotherapy in management, selected patients may experience improvement in lung function with therapy. Determination of BRAFV600E or other mutations may assist with the development of an individualised approach to therapy. Patients with progressive disease should be referred to specialised centres and considered for a trial of pharmacotherapy or evaluated for transplantation.




Corticosteroids and infliximab impair the performance of interferon-{gamma} release assays used for diagnosis of latent tuberculosis

2017-09-13T07:50:05-07:00

The impact of immunosuppression on interferon- release assays and novel cytokine biomarkers of TB infection, mycobacteria-specific IL-2, IP-10 and TNF-α responses was investigated in an ex vivo model. Cytokine responses in standard QuantiFERON-TB Gold in-Tube (QFT-GIT) assays were compared with duplicate assays containing dexamethasone or infliximab. Dexamethasone converted QFT-GIT results from positive to negative in 30% of participants. Antigen-stimulated interferon-, IL-2 and TNF-α responses were markedly reduced, but IP-10 responses were preserved. Infliximab caused QFT-GIT result conversion in up to 30% of participants and substantial reductions in all cytokine responses. Therefore, corticosteroids and anti-TNF-α agents significantly impair interferon- release assay performance. IP-10 may be a more robust TB biomarker than interferon- in patients receiving corticosteroids.




Secondary-care costs associated with lung cancer diagnosed at emergency hospitalisation in the United Kingdom

2017-09-13T07:50:05-07:00

Lung cancer diagnosis during emergency hospital admission has been associated with higher early secondary-care costs and lower longer-term costs than outpatient diagnoses. This retrospective cohort study analyses the secondary-care costs of 3274 consecutive patients with lung cancer. Patients diagnosed during emergency admissions incurred greater costs during the first month and had a worse prognosis compared with outpatient diagnoses. In patients who remained alive, costs after the first month were comparable between diagnostic routes. In addition to improving patient experience and outcome, strategies to increase earlier diagnosis may reduce the additional healthcare costs associated with this route to diagnosis.




A toddler with a cough and wheeze refractory to treatment

2017-09-13T07:50:05-07:00

Tommy Lwin (Medical Student)

A 20-month-old girl weighing 12 kg presented with 2 weeks of worsening dry cough and wheeze. Aside from respiratory symptoms she was otherwise well, without fever or weight loss. There was no history of foreign body inhalation or choking. She had no significant personal or family medical history, and her immunisations were up to date. Prior to admission she had been treated for 1 week for a community-acquired pneumonia with oral amoxicillin and roxithromycin, as well as for a first presentation asthma exacerbation with oral prednisolone (2 mg/kg) and inhaled salbutamol, three hourly. Despite these interventions no clinical improvement had been noted. On examination, her respiratory rate and oxygen saturations were normal. She had mild respiratory distress, a loud biphasic wheeze and a prolonged expiratory phase. A chest X-ray (CXR) demonstrated hyperinflation of the right lung (figure 1A). Given the suspicion of a foreign body obstructing...




A central venous catheter that revealed a vascular paradox

2017-09-13T07:50:05-07:00

Clinical presentation

A 60-year-old man with insignificant past medical history, was admitted to the intensive care unit with acute respiratory failure following community-acquired pneumonia. On admission, he was haemodynamically stable in sinus rhythm, febrile and neurologically intact with no focal neurological findings. Under mechanical ventilation, the ratio of arterial oxygen (PaO2) to fractional inspired oxygen concentration (FiO2) was 100. An antibiotic regime of ceftriaxone plus moxifloxacin was administered.

On day 6, a 3-lumen central venous catheter (CVC) (Arrow, 7 Fr x 20 cm, polyurethane radiopaque) was easily inserted into his left internal jugular vein using anatomical landmarks. Aspiration of blood from the distal tip of the catheter confirmed its intravascular placement; however, the sample’s bright red appearance strongly suggested it was ‘arterial’ in origin. Bedside B-mode ultrasonography excluded false cannulation of the carotid artery. Furthermore, connection of the CVC with a pressure transducer produced a venous waveform with low pressure....




Visual identification of pulmonary ventilation and perfusion: a new application of lung ultrasound

2017-09-13T07:50:05-07:00

A 32-year-old lady with a history of haemochromatosis with iron infiltration of the myocardium and aplastic anaemia was admitted with H1N1-related severe adult respiratory distress syndrome with dense bilateral consolidations in all lobes at chest X-ray and CT scan (figure 1A, B). The severe hypoxaemia requiring mechanical ventilation and refractory to inhaled nitric oxide and pronation led ultimately to venovenous extracorporeal membrane oxygenation placement. Transthoracic echocardiography (TTE) demonstrated a mildly biventricular systolic impairment alike the last TTE done during the follow-up for the haemochromatosis, without any intracardiac shunt as demonstrated by agitated-saline bubble study. Lung ultrasound (LUS) showed bilateral complete consolidation of the lung (tissue-like pattern) in the mid-lower lobes, which was present from admission. On the day 3, the decline in minute volume, worsening gas exchange and decrease of VCO2 from the native lung corresponded to the presence of arterial systolic and venous diastolic flow...




Primary racemose haemangioma of the right bronchial artery with thrombus and slow meandering blood flow

2017-09-13T07:50:05-07:00

A 48-year-old man was admitted to our hospital because of an abnormal lung shadow detected on health check-up. He had no history of lung disease. Chest X-ray showed a nodule overlapping the pulmonary artery at the right hilar area; there was no other abnormality (figure 1A). Contrast-enhanced CT of the chest showed hyperplasia of a right racemose haemangioma of a bronchial artery (RHBA), with an area of low density that was suspected as thrombus or malignant tumour (figures 1B, C). Bronchial arteriography showed a pattern that was similar to the beans of a pagoda tree (an herbal medicine) and revealed a blood flow that was disproportionally slow to the artery branch and was meandering in the right RHBA. In addition, there was a relatively small shunt to the pulmonary artery at the right lower lobe (figure 2A). CT scan during bronchial arteriography...




Whats hot that the other lot got

2017-09-13T07:50:05-07:00

Azithromycin in asthma treatment

Azithromycin is being used in a variety of respiratory diseases for its anti-inflammatory effects as well as its antimicrobial properties. The AMAZES study (Gibson PG, et al. Lancet 2017;390:659–668) investigated whether azithromycin had any beneficial effects on asthma exacerbations and quality of life when added to standard therapy of inhaled corticosteroid and long-acting bronchodilators in patients with persistent symptomatic asthma. The randomised, double-blind placebo-controlled study allocated patients to receive azithromycin 500 mg (217 patients) or placebo (207 patients) three times a week for 48 weeks. Primary endpoints were the number of severe or moderate exacerbations (measured by need for increased corticosteroids, hospital visit, antibiotics or a reduction in asthma control questionnaire score) and asthma quality of life. Secondary endpoints were asthma control, nasal symptoms, cough, respiratory infections and sputum production. Azithromycin significantly reduced overall asthma exacerbations (1.07 per patient-year (95% CI 0.85 to 1.29) compared with...