Impact of Mucolytic Agents on COPD Exacerbations: A Pair-wise and Network Meta-analysis

Mucolytics are potentially useful for the management of chronic obstructive pulmonary disease (COPD), although there is conflicting advice on their use in different guideline documents. Furthermore, there is paucity of data comparing the efficacy of the different mucolytic agents in reducing the odds of COPD exacerbations. We performed pair-wise and network meta-analyses to evaluate the impact of mucoly-tics in COPD. Randomized clinical trials lasting at least 3 months and investigating the effects of mucolytics on COPD exacerbations were identified from published studies and repository databases. Mucolytics significantly reduced the odds of exacerbation vs. placebo (11 studies analyzed: odds ratio (OR) 0.51, 95% confidence interval (CI) 0.39–0.67; p < 0.001). The most effective drugs were carbocysteine, erdosteine, and N-acetylcysteine 1,200 mg/day (SUCRA 68.0–79.0%), whereas the OR was similar to placebo for ambroxol and N-acetylcysteine 600 mg/day. Only N-acetylcysteine 1,200 mg/day significantly protected against exacerbations vs. placebo (2 studies analyzed: OR 0.56, 95% CI 0.35–0.92; p < 0.05; high quality of evidence). A signal of effectiveness was detected for carbocysteine (2 studies analyzed: OR 0.45, 95% CI 0.20–1.01; p ≥ 0.05; moderate quality of evidence). Specific differences in study designs and patient-related characteristics, such as history of exacerbations and ethnicity, were potential effect modifiers for our statistical models, whereas neither respiratory function nor the use of corticosteroids influenced the analysis. This meta-analysis demonstrates that mucolytics are useful in preventing COPD exacerbations as maintenance add-on therapy to patients with frequent exacerbations. The effectiveness of mucolytics is independent of the severity of airway obstruction and the use of inhaled corticosteroids.     

Inflammatory Biomarkers in Sputum Predict COPD Exacerbations

Introduction

Exacerbations in chronic obstructive pulmonary disease (COPD) reduce quality of life and are associated with a more rapid deterioration of the disease. It is desirable to predict an oncoming exacerbation before it occurs. The aim of the present study was to identify biomarkers that may predict a forthcoming exacerbation.

Materials and Methods

Forty-three patients with COPD in their stable state were included and followed up monthly until exacerbation, or for a maximum of 6 months. The patients come for an extra visit (prior to a scheduled visit) when exacerbated. The patients completed the questionnaires CCQ and MRC. Exhaled breath condensate (EBC) was collected followed by spirometry, impulse oscillometry, and sputum induction.

Results

Twenty-five patients had an exacerbation within the 6-month period. Leukotriene B₄ in sputum was the only biomarker that was increased at the visit prior to exacerbation compared to at the stable phase (p = 0.05). There also was a tendency for a similar but not significant increase in the sputum levels of 8-isoprostane, myeloperoxidase activity, and interleukin-8, as well as additional increases during exacerbation. Sputum purulence was not increased until exacerbation (p = 0.02). In contrast, none of the inflammatory biomarkers in EBC, the quality-of-life questionnaire score, CRP, spirometric parameters, or impulse oscillometry parameters were increased at the visit prior to exacerbation compared to the values at the stable phase.

Conclusion

Sputum biomarkers, especially leukotriene B₄, could be used as predictors of a forthcoming exacerbation and worsening of COPD. This would be of great value for the patient, who may be a subject for early treatment and thereby avoid a progression of the disease.     

Chitotriosidase Activity in Plasma and COPD Exacerbations

Introduction

This study aimed to determine the association between plasma chitotriosidase activity and the clinical characteristics and exacerbation rate of COPD patients.

Methods

The study comprised 97 patients with COPD. Their clinical characteristics and a history of exacerbations in the last 12 months were noted. Plasma chitotriosidase activity was determined. Patients were followed up for 12 months, and the number of moderate and severe exacerbations during this period was recorded.

Results

Chitotriosidase activity positively correlated with patient age (rho = 0.217, p = 0.036) and inversely with CAT (rho = − 0.240, p = 0.020). There was no correlation with lung function. Chitotriosidase activity was significantly lower in patients with a history of ≥ 2 exacerbations compared to patients without a history of exacerbations (93 [38–312] vs. 264 [168–408] nmol/h/mL, p = 0.033). Overall, there was no difference in chitotriosidase activity between patients with or without observed exacerbations. Patients with a history of ≥ 1 exacerbation and ≥ 1 observed exacerbation had higher chitotriosidase activity compared to patients without further exacerbations (240 [144–456] vs. 52 [39–240] nmol/h/mL, p = 0.035). Multivariate analysis identified FEV₁ (HR 0.976, 95% CI 0.956–0.996, p = 0.016) and blood eosinophil percentage (HR 1.222, 95% CI 1.048–1.424, p = 0.011) as independent predictors of future exacerbations in the total patient population, while in patients with a history of ≥ 1 exacerbation ,the only independent predictor was chitotriosidase activity (HR per 10 nmol/h/mL 1.028, 95% CI 1.002–1.055, p = 0.037).

Conclusion

While mixed associations between chitotriosidase activity and clinical outcomes were seen, chitotriosidase activity could be a predictor of future exacerbations in patients with a history of ≥ 1 exacerbation in the past  12 months.

     

Inflammatory Response in Acute Viral Exacerbations of COPD

Background  Respiratory viruses are important triggers of acute exacerbations of COPD (AE-COPD). However, the inflammatory response in virus-positive exacerbations is still not fully understood. Methods  We investigated CRP, IL-6, IL-8, IL-10, IFN-γ, blood and sputum cells in patients with acute exacerbation (n = 36) and in stable disease (n = 20) and correlated these parameters to virus detection in respiratory secretions. Results  Similar to other studies we found a significant increase in systemic CRP and absolute numbers of blood leukocytes in AE-COPD patients. Sputum IL-6 levels and sputum eosinophils tended to be higher during exacerbation. In patients with detection of respiratory viruses in nasal lavage, local IL-6 production in sputum was significantly increased; FEV₁ was significantly decreased and both parameters were inversely correlated to each other. Conclusion  This study supports previous findings of both, increased local and systemic inflammation in acute exacerbation of COPD. In virus-associated exacerbations, IL-6 is significantly increased and negatively correlated to FEV₁ indicating a relation between virus-induced inflammation and airway obstruction. However, regarding our finding and previous data, it is becoming increasingly clear that the mediators investigated so far do not permit identifying the etiology of AE-COPD. Hence, further studies are needed to better define the inflammatory response in AE-COPD in general and in viral exacerbations in particular. Supported by Bundesministerium für Bildung und Forschung (BMBF) grant #01GC0101.     

Preventing Exacerbations of Chronic Bronchitis and COPD

It is important to find interventions that will reduce the frequency and severity of exacerbations of COPD, because of their effect on morbidity and healthcare expenditure. A Cochrane systematic review included 23 studies that had evaluated the effects of treatment with mucolytic agents in patients with chronic bronchitis or COPD. Mucolytic treatment was associated with a significant reduction of 0.79 exacerbations per patient per year compared with placebo, a 29% decrease. Patients who received treatment with mucolytic agents were twice as likely to remain exacerbation-free in the study period than if they had received placebo, with six patients needing regular treatment with mucolytic agents for 3–6 months to achieve one less exacerbation over that time. Treatment with mucolytic agents resulted in nearly 7 days less illness per patient per year.How mucolytic agents work is unknown, although they may reduce exacerbations by altering mucus production, antioxidation, or antibacterial or immunostimulatory effects. They do not appear to affect the decline in lung function that occurs in COPD. The treatment appears to be without any adverse effects, apart from the need to take oral medication daily. Cost-effectiveness analysis suggests that the point at which the costs of treatment and non-treatment were equal was 1.2 less exacerbations per year. This is higher than the effect observed in the Cochrane review, suggesting that treating everyone with COPD with mucolytic agents would not be cost effective. Those with more frequent and severe exacerbations appear to have the most to gain.     

Post-traumatic Stress Symptoms and Exacerbations in COPD Patients

Background: Post-Traumatic Stress Disorder (PTSD) is a common psychological consequence of exposure to traumatic stressful life events. During COPD exacerbations dyspnea can be considered a near-death experience that may induce post-traumatic stress symptoms. The aim of this study was to evaluate the relationship between COPD exacerbations and PTSD- related symptoms. Method: Thirty-three in-patients with COPD exacerbations were screened for the following: PTSS (Screen for Posttraumatic Stress Symptoms), anxiety (Beck Anxiety Inventory) and depression (Beck Depression Inventory). Patients had a median age of 72 years and 72.7% were female. Results: Mean FEV1 and FVC were 0.8±0.3 (37.7 ± 14.9% of predicted) and 1.7 ± 0.6 (60 ± 18.8% of predicted), respectively with a mean exacerbation of 2.9 episodes over the past year. Post-traumatic stress symptoms related to PTSD were found in 11 (33.3%) patients (SPTSS mean score 4.13 ± 2.54); moderate to severe depression in 16 (48.5%) (BDI mean score 21.2 ± 12.1) and moderate to severe anxiety in 23 (69.7%) (BAI mean score 23.5 ± 12.4). In a linear regression model, exacerbations significantly predicted post-traumatic stress symptoms scores: SPTSS scores increased 0.9 points with each exacerbation (p = 0.001). Significant correlations were detected between PTSD-related symptoms and anxiety (rs = 0.57; p = 0.001) and PTSD symptoms and depression (rs = 0.62; p = 0.0001). In a multivariable analysis model, two or more exacerbation episodes led to a near twofold increase in the prevalence ratio of post-traumatic stress symptoms related to PTSD(PR1.71; p = 0.015) specially those requiring hospitalization (PR 1.13; p = 0.030) Conclusion: PTSD symptoms increase as the patient's exacerbations increase. Two or more exacerbation episodes lead to a near twofold increase in the prevalence ratio of post-traumatic symptomatology. Overall, these findings suggest that psychological domains should be addressed along with respiratory function and exacerbations in COPD patients.     

Domiciliary Cough Monitoring for the Prediction of COPD Exacerbations

Introduction

Acute exacerbations of COPD (AE-COPD) are a leading cause of health service utilisation and are associated with morbidity and mortality. Identifying the prodrome of AE-COPD by monitoring symptoms and physiological parameters (telemonitoring) has proven disappointing and false alerts limit clinical utility. We report objective monitoring of cough counts around AE-COPD and the performance of a novel alert system identifying meaningful change in cough frequency.

Methods

This prospective longitudinal study of cough monitoring included chronic obstructive pulmonary disease (COPD) patients experienced in telemonitoring that had two or more AE-COPD in the past year. Participants underwent cough monitoring and completed a daily questionnaire for 90 days. The automated system identified deteriorating trends in cough and this was compared with alerts generated by an established telemonitoring questionnaire.

Results

28 patients [median age 66 (range 46–86), mean FEV-1% predicted 36% (SD 18%)] completed the study and had a total of 58 exacerbations (43 moderate and 15 severe). Alerts based on cough monitoring were generated mean 3.4 days before 45% of AE-COPD with one false alert every 100 days. In contrast, questionnaire-based alerts occurred in the prodrome of 88% of AE-COPD with one false alert every 10 days.

Conclusion

An alert system based on cough frequency alone predicted 45% AE-COPD; the low false alert rate with cough monitoring suggests it is a practical and clinically relevant tool. In contrast, the utility of questionnaire-based symptom monitoring is limited by frequent false alerts.

     

Co-morbidities and 90-day Outcomes in Hospitalized COPD Exacerbations

COPD exacerbations resulting in hospitalization are accompanied by high mortality and morbidity. The contribution of specific co-morbidities to acute outcomes is not known in detail: existing studies have used either administrative data or small clinical cohorts and have provided conflicting results. Identification of co-existent diseases that affect outcomes provides opportunities to address these conditions proactively and improve overall COPD care. Cases were identified prospectively on admission then underwent retrospective case note audit to collect data including co-morbidities on up to 60 unselected consecutive acute COPD admissions between March and May in each hospital participating in the 2008 UK National COPD audit. Outcomes recorded were death in hospital, length of stay, and death and readmission at 90 days after index admission. 232 hospitals collected data on 9716 patients, mean age 73, 50% male, mean FEV₁ 42% predicted. Prevalence of co-morbidities were associated with increased age but better FEV₁ and ex-smoker status and with worse outcomes for all four measures. Hospital mortality risk was increased with cor pulmonale, left ventricular failure, neurological conditions and non-respiratory malignancies whilst 90 day death was also increased by lung cancer and arrhythmias. Ischaemic and other heart diseases were important factors in readmission. This study demonstrates that co-morbidities adversely affect a range of short-term patient outcomes related to acute admission to hospital with exacerbations of COPD. Recognition of relevant accompanying diseases at admission provides an opportunity for specific interventions that may improve short-term prognosis.     

Missing Potential Opportunities to Reduce Repeat COPD Exacerbations

Introduction

Long-acting beta-agonists (LABA) and/or inhaled corticosteroids (ICS) have been shown to reduce COPD exacerbation risk. Using data from a large integrated health-care system, we sought to examine whether these medication classes were initiated after an exacerbation of COPD.

Methods

We identified patients who experienced an inpatient or outpatient COPD exacerbation within the Veterans Affairs Integrated Service Network (VISN)-20. We assessed the addition of a new inhaled therapy (an ICS, LABA or both) within 180 days after the exacerbation. We assessed independent predictors of adding treatment using logistic regression.

Results

We identified 45,780 patients with COPD, of whom 2,760 patients experienced an exacerbation of COPD. Of these individuals, 2,570 (93.1 %) were on either none or only one long-acting medication studied (LABA or ICS). In the subsequent 180-day period after their exacerbation, only 875 (34.1 %) patients had at least one of these additional therapies dispensed from a VA pharmacy. Among patients who were treated in the outpatient setting, older age [OR 0.98/year, 95 % CI (0.97–0.99)], current tobacco use [OR 0.74, 95 % CI (0.60–0.90)], greater use of ipratropium bromide [OR 0.97/canister, 95 % CI (0.96–0.98)], prior COPD exacerbation [OR 0.55, 95 % CI (0.46–0.67)], depression [OR 0.77, 95 % CI (0.61–0.98)], CHF [OR 0.74, 95 % CI (0.57–0.97)], and diabetes (OR 0.77 (0.60–0.99)] were associated with lower odds of additional therapy. Patients who were treated in the hospital had similar associated predictors.

Conclusion

Among patients treated for an exacerbation of COPD, we found relatively few were subsequently prescribed inhaled therapies known to reduce exacerbations.     

Predictors of Change in Dyspnea Level in Acute Exacerbations of COPD

The aim of this study was to identify factors related to changes in dyspnoea level in the acute and short-term periods after acute exacerbation of chronic obstructive pulmonary disease. This was a prospective cohort study of patients with symptoms of acute chronic obstructive pulmonary disease exacerbation who attended one of 17 hospitals in Spain between June 2008 and September 2010. Clinical data and patient reported measures (dyspnoea level, health-related quality of life, anxiety and depression levels, capacity to perform physical activity) were collected from arrival to the emergency department up to a week after the visit in discharged patients and to discharge in admitted patients (short term). Main outcomes were time course of dyspnoea over the acute (first 24 hours) and short-term periods, mortality and readmission within 2 months of the index episode. Changes in dyspnoea in both periods were related capacity to perform physical activity as well as clinical variables. Short-term changes in dyspnoea were also related to dyspnoea at 24 hours after the ED visit, and anxiety and depression levels. Dyspnoea worsening or failing to improve over the studied periods was associated with poor clinical outcomes. Patient-reported measures are predictive of changes in dyspnoea level.