Mitesh Pancholi

Blood Eosinophils to Direct Corticosteroid Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease A Randomized Placebo-Controlled Trial

RATIONALE Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. OBJECTIVES Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. METHODS Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. MEASUREMENTS AND MAIN RESULTS There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). CONCLUSIONS The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

Aspergillus fumigatus during stable state and exacerbations of COPD

Bacteria are often isolated in stable chronic obstructive pulmonary disease (COPD). Whether fungi are also commonly present and associated with clinical and pathological features of disease is uncertain. We investigated the frequency of filamentous fungal culture and IgE sensitisation to Aspergillus fumigatus and the relationship to clinical outcomes in COPD subjects. COPD subjects were recruited to enter a 1-year observational study. Assessments of lung function, allergen testing and sputum analysis for inflammation, bacteria and fungus were undertaken in COPD subjects and healthy smoking and nonsmoking controls. Filamentous fungi were cultured at baseline in 49% (63 out of 128) of COPD subjects, of which 75% (47 out of 63) were A. fumigatus. Fungus was cultured in three out of 22 controls (two were A. fumigatus). The total sputum cell count and inhaled corticosteroid dosage were significantly increased in COPD patients with a positive filamentous fungal culture at baseline (p<0.05). Sensitisation to A. fumigatus was present in 13% of COPD subjects and was associated with worse lung function (forced expiratory volume in 1 s 39% predicted versus 51% predicted; p=0.01), but not related to filamentous fungal culture. A. fumigatus sensitisation is related to poor lung function. Positive filamentous fungal culture is a common feature of COPD. The clinical significance of this remains uncertain. A. fumigatus sensitisation links to poor COPD lung function; clinical significance of positive fungal culture is unclear http://ow.ly/qfr5q

Blood Eosinophils to Direct Corticosteroid Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease

RATIONALE Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. OBJECTIVES Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. METHODS Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. MEASUREMENTS AND MAIN RESULTS There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). CONCLUSIONS The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

Systemic and pulmonary inflammation is independent of skeletal muscle changes in patients with chronic obstructive pulmonary disease

Background Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. Objectives To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. Methods Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m2 and/or fat-free mass index (FFMI) less than 15 or 17 kg/m2 in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. Results Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P<0.01). There were no differences in airway inflammation and bacterial colonization in patients with and without nutritional depletion. At baseline, BMI correlated positively with serum CRP (rs=0.14, P=0.04). Change in weight and change in FFM over time could not be predicted from baseline patient characteristics. Conclusion Nutritional depletion and progressive muscle atrophy are not related to airway inflammation or bacterial colonization. Overspill of pulmonary inflammation is not a key driver of muscle atrophy in COPD.

Nociceptin/orphanin FQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma

There is evidence supporting a role for the nociceptin/orphanin FQ (N/OFQ; NOP) receptor and its endogenous ligand N/OFQ in the modulation of neurogenic inflammation, airway tone and calibre. We hypothesized that NOP receptor activation has beneficial effects upon asthma immunopathology and airway hyperresponsiveness. Therefore, the expression and function of N/OFQ and the NOP receptor were examined in healthy and asthmatic human airway tissues. The concept was further addressed in an animal model of allergic asthma.

P212 Assessing the Repeatability of Bacterial Detection in Stable COPD Using Several Methods

Background Stable COPD patients are colonised if potentially pathogenic organisms are identified on sputum culture. Associations between colonisation and clinical features such as exacerbation frequency and airway inflammation have been suggested. There is however limited data describing the reproducibility of sputum microbiology results in clinically stable COPD patients. Aims Examine repeatability of sputum microbiology in subjects with stable COPD over time. Methods Subjects with COPD were enrolled into an observational study and seen at baseline and at stable visits after 3 and 6 months. Sputum was obtained and samples were divided and analysed over time using standard culture, semi-quantitative bacterial count (colony forming units, CFU), PCR for potentially pathogenic organisms [(Haemophilus influenzae (HI), Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Moraxella catarrhalis (MC)] and quantitative bacterial 16S analysis. Results 63 subjects provided paired sputum samples; 52 were male with a mean (SD) FEV1 (L) and FEV1/FVC ratio (%) of 1.48(0.54) and 53% (12.8) respectively. 40% were current smokers with an exacerbation frequency of 3 in the preceding year. Results for standard culture were divided into two groups (culture positive or negative). Results are expressed as Kappa values (95% CI). There was moderate agreement after 3 months, Kappa = 0.48 (0.24 to 0.71); and after 6 months, Kappa = 0.50 (0.25 to 0.76). Individual PCR revealed fair agreement after both time intervals. After 3 months, HI=0.17(–0.08 to 0.43), SA=0.27(–0.03 to 0.56), SP=0.30(0.06 to 0.53), MC=0.19(–0.04 to 0.43). After 6 months, HI=0.09(–0.18 to 0.35), SA=0.10(–0.22 to 0.43), SP=0.37(0.13 to 0.62) and MC= –0.14(–0.4 to 0.11). Quantitative bacterial analysis demonstrated no differences (mean difference; 95% CI) at 3 or 6 months in bacterial load measured by CFU (–0.18; –0.41 to 0.04, p=0.11 and –0.06; –0.32 to 0.2, p=0.65 respectively) or 16S (–0.03; –0.28 to 0.33, p=0.86 and –0.1; –0.42 to 0.22, p=0.54 respectively). Discussions These results demonstrate that sputum microbiological assessment in stable COPD is complex. Further longitudinal assessments of sputum microbiology and associations with clinical features are needed.

Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial.

RATIONALE Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. OBJECTIVES Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. METHODS Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. MEASUREMENTS AND MAIN RESULTS There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). CONCLUSIONS The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

S91 Aspergillus fumigatus sensitisation in patients with chronic obstructive pulmonary disease

Background Bacteria and viruses have been implicated in exacerbations of chronic obstructive pulmonary disease (COPD) and bacteria are often isolated in stable state. Whether fungi are also commonly present and associated with clinical and pathological features of disease is uncertain. Objectives To determine the frequency of filamentous fungal culture and sensitisation to Aspergillus fumigatus in COPD and its relationship to clinical outcomes. Methods Subjects with COPD were recruited from a single centre into a 1-year observational study. Assessments of lung function, allergen testing, and sputum analysis for inflammation, bacterial and fungal cultures were undertaken in COPD subjects and in smoking healthy controls. Results Fungi were cultured at baseline in 63/128 subjects of which 47/63 were A fumigatus. A fungus was cultured in 2/11 controls (both were A fumigatus). The total sputum cell count, sputum neutrophil % and inhaled corticosteroid dosage were significantly increased in COPD patients with a positive fungal culture compared to those without a fungal culture (p<0.05), but the within subject repeatability of fungal culture between stable visits was low (K=−0.04). Sensitisation to A fumigatus was present in 13% of COPD subjects and was associated with worse lung function (FEV1 % predicted 39% vs 51%; p=0.01), but not related to fungal culture. Positive fungal cultures were present in 42/110 exacerbations and were not associated with bacterial culture or severity of exacerbation. Conclusions A fumigatus sensitisation is related to poor lung function. Positive fungal culture is a common feature of COPD. The clinical significance of this remains uncertain.