Sarah Elkin

British Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICE

### The role of pulmonary rehabilitation ### Referral and assessment of patients for pulmonary rehabilitation #### Specific situations at assessment ##### Smoking

Outgrowth of the Bacterial Airway Microbiome after Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease

RATIONALE Rhinovirus infection is followed by significantly increased frequencies of positive, potentially pathogenic sputum cultures in chronic obstructive pulmonary disease (COPD). However, it remains unclear whether these represent de novo infections or an increased load of organisms from the complex microbial communities (microbiome) in the lower airways. OBJECTIVES To investigate the effect of rhinovirus infection on the airway bacterial microbiome. METHODS Subjects with COPD (n = 14) and healthy control subjects with normal lung function (n = 17) were infected with rhinovirus. Induced sputum was collected at baseline before rhinovirus inoculation and again on Days 5, 15, and 42 after rhinovirus infection and DNA was extracted. The V3-V5 region of the bacterial 16S ribosomal RNA gene was amplified and pyrosequenced, resulting in 370,849 high-quality reads from 112 of the possible 124 time points. MEASUREMENTS AND MAIN RESULTS At 15 days after rhinovirus infection, there was a sixfold increase in 16S copy number (P = 0.007) and a 16% rise in numbers of proteobacterial sequences, most notably in potentially pathogenic Haemophilus influenzae (P = 2.7 × 10(-20)), from a preexisting community. These changes occurred only in the sputum microbiome of subjects with COPD and were still evident 42 days after infection. This was in contrast to the temporal stability demonstrated in the microbiome of healthy smokers and nonsmokers. CONCLUSIONS After rhinovirus infection, there is a rise in bacterial burden and a significant outgrowth of Haemophilus influenzae from the existing microbiota of subjects with COPD. This is not observed in healthy individuals. Our findings suggest that rhinovirus infection in COPD alters the respiratory microbiome and may precipitate secondary bacterial infections.

Rhinovirus Infection Induces Degradation of Antimicrobial Peptides and Secondary Bacterial Infection in Chronic Obstructive Pulmonary Disease

RATIONALE Chronic obstructive pulmonary disease (COPD) exacerbations are associated with virus (mostly rhinovirus) and bacterial infections, but it is not known whether rhinovirus infections precipitate secondary bacterial infections. OBJECTIVES To investigate relationships between rhinovirus infection and bacterial infection and the role of antimicrobial peptides in COPD exacerbations. METHODS We infected subjects with moderate COPD and smokers and nonsmokers with normal lung function with rhinovirus. Induced sputum was collected before and repeatedly after rhinovirus infection and virus and bacterial loads measured with quantitative polymerase chain reaction and culture. The antimicrobial peptides secretory leukoprotease inhibitor (SLPI), elafin, pentraxin, LL-37, α-defensins and β-defensin-2, and the protease neutrophil elastase were measured in sputum supernatants. MEASUREMENTS AND MAIN RESULTS After rhinovirus infection, secondary bacterial infection was detected in 60% of subjects with COPD, 9.5% of smokers, and 10% of nonsmokers (P < 0.001). Sputum virus load peaked on Days 5-9 and bacterial load on Day 15. Sputum neutrophil elastase was significantly increased and SLPI and elafin significantly reduced after rhinovirus infection exclusively in subjects with COPD with secondary bacterial infections, and SLPI and elafin levels correlated inversely with bacterial load. CONCLUSIONS Rhinovirus infections are frequently followed by secondary bacterial infections in COPD and cleavage of the antimicrobial peptides SLPI and elafin by virus-induced neutrophil elastase may precipitate these secondary bacterial infections. Therapy targeting neutrophil elastase or enhancing innate immunity may be useful novel therapies for prevention of secondary bacterial infections in virus-induced COPD exacerbations.

European cystic fibrosis bone mineralisation guidelines

Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF-related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology.

Designing and implementing a COPD discharge care bundle

National surveys have revealed significant differences in patient outcomes following admission to hospital with acute exacerbation of COPD which are likely to be due to variations in care. We developed a care bundle, comprising a short list of evidence-based practices to be implemented prior to discharge for all patients admitted with this condition, based on a review of national guidelines and other relevant literature, expert opinion and patient consultation. Implementation was then piloted using action research methodologies with patient input. Actively involving staff was vital to ensure that the changes introduced were understood and the process followed. Implementation of a care bundle has the potential to produce a dramatic improvement in compliance with optimum health care practice.

Relationship of skeletal muscle mass, muscle strength and bone mineral density in adults with cystic fibrosis.

Few studies have investigated peripheral muscle strength and quality in patients with cystic fibrosis (CF). The present study tested the isometric and isokinetic strength of the quadriceps and hamstrings using an isokinetic dynamometer and a strength-testing chair in 25 CF adults and 25 controls. Total body and leg muscle mass were determined by dual-energy X-ray absorptiometry, and bone mineral density (BMD) was also measured. Both muscle strength and muscle mass (total body and leg) were decreased in the CF group. In both groups there was a highly significant relationship between quadriceps strength and leg muscle mass (CF, r=0.7, P=0.0002; controls, r=0.6, P=0.0013). When strength was normalized for muscle size, there was no significant difference between the two groups. Total body and leg BMD were significantly reduced in CF subjects compared with controls. However, when corrected for height, the differences disappeared. There was a significant relationship found between leg muscle mass and leg BMD. We conclude that CF adults are significantly weaker than controls. This is due to lower muscle mass, and not to a reduced force-generating capacity of the muscle, implying that there is no decrease in the quality of CF muscle. BMD is also reduced in CF subjects, and this appears to be related to shorter stature in this group.

Inhaled corticosteroids and pneumonia in chronic obstructive pulmonary disease

Inhaled corticosteroids are widely used in chronic obstructive pulmonary disease (COPD) and, in combination with long-acting β2 agonists, reduce exacerbations and improve lung function and quality of life. However, inhaled corticosteroids have been linked with an increased risk of pneumonia in individuals with COPD, but the magnitude of this risk, the effects of different preparations and doses, and the mechanisms of this effect remain unclear. Therefore, making informed clinical decisions--balancing the beneficial and adverse effects of inhaled corticosteroids in individuals with COPD--is difficult. Understanding of the mechanisms of increased pneumonia risk with inhaled corticosteroids is urgently needed to clarify their role in the management of COPD and to aid the development of new, safer therapies.

Breathlessness and Skeletal Muscle Weakness in Patients Undergoing Lung Health Screening in Primary Care

Abstract Earlier diagnosis of COPD is a major public health challenge as symptoms may be attributed to the normal consequences of aging. The optimum strategy for identifying patients with COPD remains to be determined. People aged 35 and over (n = 1896) on a GP practice register were randomised to either invitation or an opportunistic lung health check which included spirometry, quadriceps strength and MRC dyspnoea score. Then, 101 participants subsequently completed the General Practice Physical Activity Questionnaire. A total of 335 attended over a 15-week period; 156 were in the invitation group and 179 from the opportunist group. In 25 persons, spirometry was unsatisfactory or contraindicated. Spirometry was normal in 204(65.8%) and restrictive in 36(11.6%). 70(22.6%) had airflow obstruction, corresponding to Global Initiative for Chronic Lung Disease (GOLD) stages I-IV in 18(5.8%), 35(11.3%), 14(4.5%) and 3(1.0%), respectively. The opportunist group were significantly more likely to have airflow obstruction 30.1% vs 14.3% (p = 0.001). Breathlessness was reported commonly (40.5%) and quadriceps strength correlated significantly with MRC dyspnoea score independent of age, sex, pack-years smoked, fat-free mass and FEV1 percent predicted. This relationship was also present in the subgroup of healthy participants (n = 143). 51.5% of participants screened were classified as “inactive” and this group were weaker and more breathless than those who were more active. Airflow obstruction was more common in those screened opportunistically. Breathlessness and inactivity are common in patients taking part in spirometry screening. Breathlessness is significantly associated with leg strength independent of spirometry and should be amenable to interventions to increase physical activity.

Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD

Background Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection. Methods Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured. Results Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines. Conclusions O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.

Oxygen Uptake Efficiency Slope and Breathing Reserve, Not Anaerobic Threshold, Discriminate Between Patients With Cardiovascular Disease Over Chronic Obstructive Pulmonary Disease.

Objectives The study sought to compare the relative discrimination of various cardiopulmonary exercise testing (CPX) variables between cardiac and respiratory disease. Background CPX testing is used in many cardiorespiratory diseases. However, discrimination of cardiac and respiratory dysfunction can be problematic. Anaerobic threshold (AT) and oxygen-uptake to work-rate relationship (VO2/WR slope) have been proposed as diagnostic of cardiac dysfunction, but multiple variables have not been compared. Methods A total of 73 patients with chronic obstructive pulmonary disease (COPD) (n = 25), heart failure with reduced ejection fraction (HFrEF) (n = 40), or combined COPD and HFrEF (n = 8) were recruited and underwent CPX testing on a bicycle ergometer. Following a familiarization test, each patient underwent a personalized second test aiming for maximal exercise after ∼10 min. Measurements from this test were used to calculate area under the receiver-operator characteristic curve (AUC). Results Peak VO2 was similar between the 2 principal groups (COPD 17.1 ± 4.6 ml/min/kg; HFrEF 16.4 ± 3.6 ml/min/kg). Breathing reserve (AUC: 0.91) and percent predicted oxygen uptake efficiency slope (OUES) (AUC: 0.87) had the greatest ability to discriminate between COPD and HFrEF. VO2/WR slope performed significantly worse (AUC: 0.68). VO2 at the AT did not discriminate (AUC for AT as percent predicted peak VO2: 0.56). OUES and breathing reserve remained strong discriminators when compared with an external cohort of healthy matched controls, and were comparable to B-type natriuretic peptide. Conclusions Breathing reserve and OUES discriminate heart failure from COPD. Despite it being considered an important determinant of cardiac dysfunction, the AT could not discriminate these typical clinical populations while the VO2/WR slope showed poor to moderate discriminant ability. (Identifying an Ideal Cardiopulmonary Exercise Test Parameter [PVA]; NCT01162083)