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Role of infection in exacerbations of chronic obstructive pulmonary disease.

In this review, we present the latest findings on the cause, pathogenesis and management of patients with chronic obstructive pulmonary disease (COPD) and an infective phenotype.

RECENT FINDINGS: More than half of COPD exacerbations are infective. Bacteria are isolated in 70% of them, but viruses also play an important role, both alone and in combination with bacteria. Furthermore, in many cases, viral infection can be followed by bacterial infection in patients with COPD but not in individuals with normal lung function. Viral infection may produce changes in the lung microbiome that may precipitate subsequent bacterial infection. Research on the lung microbiome is providing new insight into the pathogenesis of infection in healthy and diseased lungs.

SUMMARY: COPD patients have alterations in their lung microbiome that may result in chronic infection with potentially pathogenic microorganisms (PPMs) even in periods of clinical stability and associated with a higher frequency of bacterial exacerbations. Patients with this infective phenotype may require a personalized approach to therapy with the use of short-term or long-term antibiotic treatment in addition to the usual treatment for COPD.

The COPD assessment test (CAT) assists prediction of COPD exacerbations in high-risk patients

We evaluated the predictive value of the COPD assessment test (CAT™) for exacerbation in the following six months or time to first exacerbation among COPD patients with previous exacerbations.

COPD outpatients with a history of exacerbation from 19 hospitals completed the CAT questionnaire and spirometry over six months. Exacerbation events were prospectively collected using a structured questionnaire.

The baseline CAT score categorised into four groups (0–9, 10–19, 20–29, and 30–40) showed strong prediction for time to first exacerbation and modest prediction for any exacerbation or moderate-severe exacerbation (AUC 0.83, 0.64, and 0.63 respectively). In multivariate analyses, the categorised CAT score independently predicted all three outcomes (p = 0.001 or p < 0.001). Compared with the lowest CAT score category, the higher categories were associated with significantly shorter time to first exacerbation and higher exacerbation risks. The corresponding adjusted median time was >24, 14, 9, and 5 weeks and the adjusted RR was 1.00, 1.30, 1.37, and 1.50 in the category of 0–9, 10–19, 20–29, and 30–40 respectively. Exacerbation history (≥2 vs. 1 event in the past year) was related to time to first exacerbation (adjusted HR 1.35; p = 0.023) and any exacerbation during the study period (adjusted RR 1.15; p = 0.016).

The results of this study support the use of the CAT as a simple tool to assist in the identification of patients at increased risk of exacerbations. This could facilitate timely and cost-effective implementation of preventive interventions, and improve health resource allocation. Trial registration Clinicaltrials.gov: NCT01254032.

Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations

The FORWARD study is a randomised, double-blind trial that compares the efficacy and safety of 48 weeks treatment with extrafine beclomethasone dipropionate/formoterol fumarate (BDP/FOR), 100/6 μg pMDI, 2 inhalations BID, vs. FOR 12 μg pMDI, 1 inhalation BID, in severe COPD patients with a history of exacerbations. Co-primary endpoints were exacerbation rate over 48 weeks and pre-dose morning FEV1 at 12 weeks. The ITT population included 1186 patients (69% males, mean age 64 years) with severe airflow limitation (mean post-bronchodilator FEV1 42% predicted). Salbutamol as rescue therapy, theophylline and tiotropium (if stable regimen prior to screening) were allowed.

Compared to FOR, BDP/FOR: (1) reduced the exacerbation rate (rate ratio: 0.72 [95% confidence interval 0.62–0.84], p < 0.001); (2) improved pre-dose morning FEV1 (mean difference: 0.069 L [0.043–0.095] p < 0.001); (3) prolonged the time to first exacerbation; (4) improved the SGRQ total score. The percentage of patients with adverse events was similar (52.1% with BDP/FOR and 49.2% with FOR). Pneumonia incidence was low, slightly higher with BDP/FOR (3.8%) than with FOR (1.8%). No difference for laboratory values, ECG or vital signs.

Extrafine BDP/FOR significantly reduces the exacerbation rate and improves lung function of patients with severe COPD and history of exacerbations as compared to FOR alone.

Improvement in COPD management by access to asthma/COPD clinics in primary care: Data from the observational PATHOS study

Chronic obstructive pulmonary disease (COPD) guidelines emphasize the importance of patient education to improve quality of life and avoid exacerbations. Longitudinal evaluations of structured management of COPD in primary care are lacking.

Aim To evaluate the impact of primary care asthma/COPD clinics on exacerbations, hospitalizations, and associated costs in COPD.

Methods This population-based, retrospective, observational study, linking primary care medical records data to mandatory Swedish national registries, included patients with COPD from 76 primary healthcare centers (1999–2009). A questionnaire on access to an asthma/COPD clinic was retrospectively answered. Propensity score matching was performed at index (COPD diagnosis) by center type (with and without an asthma/COPD clinic). Poisson regression was used to compare the yearly rate of exacerbations (hospitalization, emergency visits, or prescription for oral steroids or antibiotics) and COPD-related prescriptions at the centers. An economic analysis was performed from the Swedish healthcare perspective using 2011 unit costs and the incremental cost-effectiveness ratio was calculated.

Results The study included 21,361 patients (mean age, 68.0 years; 53% female). Access to asthma/COPD clinics increased from 34% to 85% during the study period. Patients at primary healthcare centers with asthma/COPD clinics had 27% fewer exacerbations (0.71 vs. 0.98) and 37% fewer hospitalizations annually (0.36 vs. 0.58) (p < 0.0001). Asthma/COPD clinics reduced the annual cost of medication and healthcare contacts by 37% (SEK 52,892 [€5858] to SEK 33,410 [€3700] per patient).

Conclusions Patients at primary healthcare centers with asthma/COPD clinics experienced fewer COPD exacerbations and hospitalizations, and overall treatment costs were substantially reduced. ClinicalTrials.gov identifier: NCT01146392.

Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study

Introduction Tiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat® SoftMist™ inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment.

Methods This randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5 μg, 2.5 μg and 1.25 μg versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1 s within 3 h post-dose from baseline (peak FEV1(0–3h)).

Results From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0–3h) response for tiotropium 5 μg was significantly greater versus placebo (p = 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 μg (p < 0.00001) and 1.25 μg (p = 0.0134) versus placebo, but not for 2.5 μg (p = 0.0975), while FEV1 area under the curve(0–3h) responses were significant for all doses (p = 0.00001–0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose-dependent observations. The majority of adverse events were mild to moderate in intensity.

Conclusion This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS. ClinicalTrials.gov identifier; NCT01122680.

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