James J.P. Goldring

Temporal Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease

RATIONALE Exacerbations are important events in chronic obstructive pulmonary disease. Preventing exacerbations is a key treatment goal. Observational data suggest that after a first exacerbation, patients may be at increased risk of a second exacerbation, but this has not been specifically studied. We hypothesized that exacerbations may cluster together in time, a finding that would have important implications for targeting preventative interventions and the analysis of clinical trial data. OBJECTIVES To assess whether exacerbations are random events, or cluster in time. METHODS A total of 297 patients in the London chronic obstructive pulmonary disease cohort recorded daily symptoms and were assessed for a total of 904 patient-years. The observed timing of second exacerbations after an initial exacerbation was compared with that expected should exacerbations occur randomly. MEASUREMENTS AND MAIN RESULTS The observed timing distribution of second exacerbations differed significantly (P < 0.001) from the expected exponential function (shape parameter of the fitted Weibull function, 0.966 [95% confidence interval, 0.948-0.985]), suggesting that more second exacerbations occurred sooner than later and that exacerbations cluster together in time. Twenty-seven percent of first exacerbations were followed by a second recurrent event within 8 weeks. Approximately one third of exacerbations were recurrent exacerbations. Although initial exacerbations were milder than isolated events, they were not less likely to receive treatment, and under-treatment of initial events is not a plausible explanation for exacerbation recurrence. Recurrent exacerbations contribute significantly to overall exacerbation frequency (rho = 0.81; P < 0.0001). CONCLUSIONS Exacerbations are not random events but cluster together in time such that there is a high-risk period for recurrent exacerbation in the 8-week period after an initial excerbation.

Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD

Background Prevalence and load of airway bacteria in stable and exacerbated chronic obstructive pulmonary disease (COPD) has been previously studied using microbiological culture. Molecular techniques, such as quantitative PCR (qPCR), may be more informative. Methods In this study, 373 sputum samples from 134 COPD outpatients were assessed for prevalence and load of typical airway bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis) by multiplex qPCR, with 176 samples analysed for atypical bacteria. Paired stable and exacerbation typical bacteria data were compared in 52 patients. We compared routine culture with qPCR in 177/373 samples. Results Typical bacteria were more prevalent in exacerbation than stable-state paired samples: 30/52 (57.7%) vs. 14/52 (26.9%); p=0.001. In patients who were bacteria-positive at both time points, mean (±1 SEM) load was significantly higher at exacerbation than stable state (108.5(±0.3) vs. 107.2(±0.5) cfu/ml), constituting a 20-fold increase (p=0.011). qPCR was more discriminatory at detecting typical bacteria than microbiological culture (prevalence 59.3% vs. 24.3%; p<0.001). At stable state, higher airway bacterial load correlated with more severe airflow limitation (FEV1%predicted) (r=−0.299; p=0.033) and higher inhaled corticosteroid dosage (r=0.382; p=0.008). Mean C-reactive protein was higher in bacterial-associated exacerbations (35.0 Vs 25.1 mg/L; p=0.032). Conclusions Airway bacterial prevalence and load increase at COPD exacerbations and are an aetiological factor. qPCR is more discriminatory than culture, identifying higher airway bacterial prevalence. Exacerbations associated with bacterial detection showed a higher mean C-reactive protein level. In the stable state, airway bacterial load is related to more severe airflow limitation and higher inhaled corticosteroid dosage used.

IL-1α/IL-1R1 Expression in Chronic Obstructive Pulmonary Disease and Mechanistic Relevance to Smoke-Induced Neutrophilia in Mice

Background Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood. Methodology and Principal Findings The objective of this study was to assess IL-1 α and β expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation. Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1α and β. Here, we demonstrate an underappreciated role for IL-1α expression in COPD. While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1α was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1α/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation. Conclusions and Significance This study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.

Serum IP-10 as a Biomarker of Human Rhinovirus Infection at Exacerbation of COPD

BACKGROUND Human rhinovirus (HRV) is the most frequent virus associated with COPD exacerbations. Viral infections increase exacerbation severity and likelihood of hospitalization. As ease of sampling blood makes serum a more practical marker than sputum, we investigated whether changes in serum interferon-gamma-inducible protein 10 (IP-10) from baseline to exacerbation were higher in airway HRV-positive exacerbations and whether IP-10 levels related to HRV load. METHODS One hundred thirty-six patients with COPD and 70 controls were included over 2 years and 72 exacerbations sampled. HRV positivity and load were determined by reverse transcriptase-polymerase chain reaction in nasopharyngeal swabs and/or sputum at baseline and exacerbation. IP-10 was measured by enzyme-linked immunosorbent assay in serum and compared with HRV load. RESULTS At baseline, serum IP-10 was higher in patients with COPD than controls; medians were 149.4 pg/mL (103-215) and 111.7 pg/mL (82-178), P = .02. The presence of HRV at baseline did not increase IP-10: patients with COPD, 166.9 pg/mL (110-240) and 149.4 pg/mL (103-215), P = .30; controls, 136.4 pg/mL (77-204) and 111.7 pg/mL (82-178), P = .53. IP-10 increased significantly from baseline to exacerbation in HRV-positive exacerbations: 154.9 pg/mL (114.0-195.1) to 207.5 pg/mL (142.1-333.5), P = .009. There was no change in IP-10 between baseline and exacerbation in HRV-negative exacerbations: 168.3 pg/mL (94.3-249.8) and 175.6 pg/mL (107.2-290.4), P = .49. At exacerbation, IP-10 correlated with sputum viral load: rho = 0.48; P = .02. In receiver operating characteristics analysis, the combination of IP-10 and coryzal symptoms gave an area under the curve of 0.82 (95% CI, 0.74-0.90). CONCLUSIONS 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.

Determinants and impact of fatigue in patients with chronic obstructive pulmonary disease.

RATIONALE The perception of fatigue in COPD has been associated with reduced health status. We have shown that exacerbations are associated with reduced activity and health status. However, the relationship between fatigue and exacerbation is unknown. OBJECTIVES To investigate the hypothesis that increased fatigue is related to physical inactivity and COPD exacerbations. METHODS Fatigue was studied in COPD and age-matched control subjects. The relationship between fatigue and stable patient characteristics in COPD, and the effect of exacerbation on fatigue were evaluated. MEASUREMENTS 107 COPD patients mean age 69 years (range 43-86), FEV(1) 53% (SD 21), and 30 aged-matched control subjects; Functional Assessment of Chronic Illness Therapy-Fatigue Scale, Centre for Epidemiological Studies Depression Scale. MAIN RESULTS Fatigue in COPD patients was significantly increased compared to control subjects (mean 35.3 units (SD 11.0) versus 43.2 (10.5), p=0.001). Increase in fatigue in COPD was related to reduced time spent outdoors (r=-0.43, p<0.001), increase in depression (r=-0.59, p<0.001) and annual exacerbation frequency (r=-0.27, p=0.005). Fatigue increased at exacerbation in 31/32 patients. Overall, fatigue increased by 8.3 units (5.9), p<0.001. Change in fatigue at exacerbation was related to increase in depression (r=-0.46, p=0.008). Fatigue recovered at 6 weeks following exacerbation. CONCLUSIONS The perception of fatigue increased in patients with COPD compared to age-matched control subjects, and associated with morbidity when patients were stable and at exacerbation.

Influence of Season on Exacerbation Characteristics in Patients With COPD

BACKGROUND Patients with COPD experience more frequent exacerbations in the winter. However, little is known about the impact of the seasons on exacerbation characteristics. METHODS Between November 1, 1995, and November 1, 2009, 307 patients in the London COPD cohort (196 men; age, mean, 68.1 years [SD, 8.4]; FEV(1), mean, 1.12 L [SD, 0.46]; FEV(1), mean, % predicted, 44.4% [SD, 16.1]) recorded their increase in daily symptoms and time outdoors for a median of 1,021 days (interquartile range [IQR], 631-1,576). Exacerbation was identified as ≥ 2 consecutive days with an increase in two different symptoms. RESULTS There were 1,052 exacerbations in the cold seasons (November to February), of which 42.5% and 50.6% were patients who had coryzal and cough symptoms, respectively, compared with 676 exacerbations in the warm seasons (May to August), of which 31.4% and 45.4% were in patients who had coryzal and cough symptoms, respectively (P < .05). The exacerbation recovery period was longer in the cold seasons (10 days; IQR, 6-19) compared with the warm seasons (9 days; IQR, 5-16; P < .005). The decrease in outdoor activity during exacerbation, relative to a pre-exacerbation period (-14 to -8 days), was greater in the cold seasons (-0.50 h/d; IQR, -1.1 to 0) than in the warm seasons (-0.26 h/d; IQR, -0.88 to 0.18; P = .048). In the cold seasons, 8.4% of exacerbations resulted in patients who were hospitalized, compared with 4.6% of exacerbations in the warm seasons (P = .005). CONCLUSIONS Exacerbations are more severe between November and February. This contributes to the increased morbidity during the winter seasons.

Domiciliary pulse-oximetry at exacerbation of chronic obstructive pulmonary disease: prospective pilot study

BackgroundThe ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD) from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this.Methods40 patients with moderate-severe COPD collected daily data on changes in symptoms, heart-rate (HR), oxygen saturation (SpO2) and peak-expiratory flow (PEF) over a total of 2705 days. 31 patients had data suitable for baseline analysis, and 13 patients experienced an exacerbation. Data were expressed as multiples of the standard deviation (SD) observed from each patient when stable.ResultsIn stable COPD, the SD for HR, SpO2 and PEF were approximately 5 min-1, 1% and 10l min-1. There were detectable changes in all three variables just prior to exacerbation onset, greatest 2-3 days following symptom onset. A composite Oximetry Score (mean magnitude of SpO2 fall and HR rise) distinguished exacerbation onset from symptom variation (area under receiver-operating characteristic curve, AUC = 0.832, 95%CI 0.735-0.929, p = 0.003). In the presence of symptoms, a change in Score of ≥1 (average of ≥1SD change in both HR and SpO2) was 71% sensitive and 74% specific for exacerbation onset.ConclusionWe have defined normal variation of pulse oximetry variables in a small sample of patients with COPD. A composite HR and SpO2 score distinguished exacerbation onset from symptom variation, potentially facilitating prompt therapy and providing validation of such events in clinical trials.

Celebrating 25 years of the BTS: the Silver Jubilee Meeting

The BTS took over the entire Queen Elizabeth II Conference Centre in London again this year to host its Silver Jubilee year Winter Meeting. This, the biggest and most comprehensive meeting so far, was also the first to accommodate an additional day for allied health professionals, held in conjunction with the Association of Chartered Physiotherapists in Respiratory Care (ACPRC). In his Presidential address, “Beyond the prescription”, Professor Martyn Partridge focused on the way health care delivery might change in the future with more consultations being delivered in community-based clinics at times which would be more convenient to our patients. The BTS medal was jointly presented to Professor Peter Barnes and Dr Alistair Brewis for their outstanding contributions to respiratory medicine and, at the lively reception, Professor Sue Hill, Chief Scientific Officer at the Department of Health, presented the BTS Silver Jubilee Awards. These covered seven categories celebrating innovation and excellence in respiratory medicine care and service delivery and were a showcase of achievement through teamwork. Also at the reception, the BTS Young Investigator Prize was awarded to Dr David Simcock for his work on airway neovascularisation by airway smooth muscle in asthma.1 The BALR prize went to Dr Yang for his studies on altered gene regulation in familial pulmonary hypertension2 and the BLF prize winner was Dr Kewin for his work on a novel cytokine found to induce eosinophilic airway inflammation.3 Other abstracts submitted for prizes covered a wide range of topics such as statin treatment in hypoxic pulmonary hypertension,4 the search for molecules to block polymerisation of Z α1-antitrypsin5 and the role of vascular endothelial growth factor on the cell cycle of alveolar cells.6 In recognition of the increasing interest and research in COPD, a large proportion of the programme was …

Assessment of nodal involvement in non-small-cell lung cancer with 18F-FDG-PET/CT: mediastinal blood pool cut-off has the highest sensitivity and tumour SUVmax/2 has the highest specificity

Objectives Lymph node involvement in non-small-cell lung cancer (NSCLC) is a major factor in determining management and prognosis. We aimed to evaluate the accuracy of fluorine-18-fluorodeoxyglucose-PET/computed tomography (CT) for the assessment of nodal involvement in patients with NSCLC. Patients and methods In this retrospective study, we included 61 patients with suspected or confirmed resectable NSCLC over a 2-year period from April 2013 to April 2015. 221 nodes with pathological staging from surgery or endobronchial ultrasound-guided transbronchial needle aspiration were assessed using a nodal station-based analysis with original clinical reports and three different cut-offs: mediastinal blood pool (MBP), liver background and tumour standardized uptake value maximal (SUVmax)/2. Results Using nodal station-based analysis for activity more than tumour SUVmax/2, the sensitivity was 45%, the specificity was 89% and the negative predictive value (NPV) was 87%. For activity more than MBP, the sensitivity was 93%, the specificity was 72% and NPV was 98%. For activity more than liver background, the sensitivity was 83%, the specificity was 84% and NPV was 96%. Using a nodal staging-based analysis for accuracy at detecting N2/3 disease, for activity more than tumour SUVmax/2, the sensitivity was 59%, the specificity was 85% and NPV was 80%. For activity more than MBP, the sensitivity was 95%, the specificity was 61% and NPV was 96%. For activity more than liver background, the sensitivity was 86%, the specificity was 81% and NPV was 92%. Receiver-operating characteristic analysis showed the optimal nodal SUVmax to be more than 6.4 with a sensitivity of 45% and a specificity of 95%, with an area under the curve of 0.85. Conclusion Activity more than MBP was the most sensitive cut-off with the highest sensitivity and NPV. Activity more than primary tumour SUVmax/2 was the most specific cut-off. Nodal SUVmax more than 6.4 has a high specificity of 95%.

S18 A comparison of prevalence and load of airway bacteria in COPD patients with paired stable and exacerbation state samples

Introduction Airway bacterial infections are associated with COPD exacerbations. The most frequently identified bacteria in COPD are Haemophilus influenzae (HI), Moraxella catarrhalis (MC) and Streptococcus pneumoniae (SP) (Wilkinson et al, 2006), though studies have used culture techniques, with little data available on PCR methodology in airway infection. Using the London COPD cohort, we aimed to assess and quantify bacterial prevalence and load via quantitative PCR, in paired baseline and exacerbation sputum samples. Methods Quantitative PCR was utilised, measuring prevalence and load on paired baseline and exacerbation samples, with baseline samples obtained within 1 year prior to its paired exacerbation. SP, HI and MC gene targets were Spn9082; Haemophilus influenzae P4 lipoprotein gene; copB outer-membrane-protein gene, respectively. The baseline state was defined as being at least 6 weeks after, and 2 weeks before, an exacerbation. Exacerbation was defined as two consecutive days of at least two increased symptoms (Anthonisen criteria), at least one of which is a major symptom (dyspnoea; sputum purulence; sputum volume). Results Sixty-nine paired baseline and exacerbation sputum samples were obtained from 56 patients: mean (±SD) age 71.0 years (±8.4); predicted FEV1 46.4% (±17.0); male gender 60.4%; current smoker 30.2%. Bacteria were detected at significantly higher rate at exacerbation, being seen in 36/69 (52.2%) exacerbations, and 19/69 (27.5%) baseline samples (χ2-test; p=0.003). Mean bacterial load was significantly higher at exacerbation, with mean load of 8.3 (±1.1) log10 cfu/ml, compared with mean of 7.3 (±1.8) log10 cfu/ml at baseline (paired-samples t test; p<0.001), indicating a 10-fold overall-load increase at exacerbation. MC frequency increased significantly from 4.3% (3/69) at baseline to 17.4% (12/69) at exacerbation (p=0.014). Prevalence of HI (17.4% vs 26.1%) and SP (8.7% vs 20.3%) showed non-significant increases. Mean loads of SP and MC increased significantly from baseline to exacerbation (p=0.048; p=0.008, respectively). Conclusion Prevalence and load of airway bacteria in COPD increases from baseline to exacerbation. This confirms that bacteria play an important role in exacerbation aetiology, implicating increasing bacterial load as a key underlying mechanism, and emphasises the importance of prompt antibiotic therapy at COPD exacerbation.Abstract S18 Figure 1 Bacterial load at baseline and exacerbation of COPD as determined by quantitative PCR.