Evaluation of Acute Bronchodilator Reversibility in Symptomatic GOLD Stage I COPD D. E. O'Donnell, P. Laveneziana, J. Ora, K. A. Webb, Y. M. Lam, D. Ofir. (Thorax 2008; Dec 3. Epub ahead of print)
Background
Symptomatic patients with GOLD stage I COPD can have significant abnormalities of ventilatory mechanics with greater exertional symptoms and exercise limitation than age-matched healthy subjects. In such patients, the impact of bronchodilator therapy remains unknown and is difficult to evaluate.
Methods
We measured the acute effects of nebulized ipratropium bromide 500 microg (IB) on resting pulmonary function and on dyspnoea and ventilatory parameters during symptom-limited constant work-rate cycle exercise. In a randomized, double-blind, crossover study, 16 patients with COPD [post-bronchodilator forced expiratory volume in one second (FEV1) = 90 ± 7% predicted, FEV1/forced vital capacity (FVC) = 59 ± 7%; mean ± SD] with a significant smoking history (44 ± 16 pack-years) inhaled either IB or placebo (PL) on each of two separate visits. Pulmonary function tests and cycle exercise at 80–85% of each subject's maximal work capacity were performed 2-hours after dosing.
Results
After IB compared with PL: FEV1 increased 5 ± 9% predicted; residual volume decreased 12 ± 20% predicted; and specific airway resistance decreased 81 ± 93% predicted (all p < 0.05). At a standardized time during exercise: dynamic inspiratory capacity and tidal volume significantly increased in tandem by 0.12 and 0.16 L, respectively (each p < 0.05); dyspnoea fell by 0.9 ± 1.8 Borg units (p = 0.07) and dyspnoea/ventilation ratios fell significantly (p < 0.05). The fall in dyspnoea at higher submaximal ventilations correlated with the concurrent decrease in end-expiratory lung volume (p < 0.05).
Conclusion
In symptomatic GOLD stage I COPD, IB treatment was associated with modest but consistent improvements in airway function, operating lung volumes and dyspnoea intensity during exercise. Our results provide a physiological rationale for a trial of bronchodilator therapy in selected patients with milder but symptomatic COPD.
Comments
In this study O'Donnell and colleagues show that use of the short acting anticholinergic, ipratropium bromide, provided improvements in FEV1, RV and specific airway resistance in patients with Stage I COPD. Interestingly, the more impressive changes in airways resistance may reflect the importance of small airways as an early primary target in COPD. It will be important to similarly study beta agonists in this early disease population. Presumably patients with Stage I disease have less airway remodeling and hence may be more likely to demonstrate a significant beta agonist response. They may also be the group more likely to have up regulation of their beta receptors after use of an inhaled corticosteroid and demonstrate increased beta agonist responses compared to a cohort who does not get an inhaled steroid.
Perhaps the most important question is whether these noted changes translate into improvements in quality of life and possibly impact long-term complications or comorbidities. O'Donnell and his colleagues have demonstrated the need for further studies to look at the difference in using MDI versus nebulized formulations, use of concomitant inhaled steroids, beta agonist versus anticholinergic in this under-studied under diagnosed COPD population.
Reduced Risk of Next Exacerbation and Mortality Associated with Use of Antibiotics in COPD. B. M. Roede, P. Bresser, J. M. Prins, F. Schellevis, T. J. Verheij, P. J. Bindels. (Eur Respir J 2008; Dec 1. Epub ahead of print).
The long-term risk of a subsequent exacerbation of COPD after treatment with oral corticosteroids without (OS) or with antibiotics (OSA) was compared in a historical general practice-based cohort. Eligible were patients ≥50 years with a registered diagnosis of COPD on maintenance respiratory drugs, who experienced at least one exacerbation defined as a prescription OS or OSA. Times to second and third exacerbations were assessed using Kaplan-Meier survival analysis, the risk of a subsequent exacerbation in a Cox proportional hazards analysis, and all cause mortality. Then, 842 patients had one or more exacerbations. The median time from first to second exacerbation was comparable for the OS group and the OSA group, but the time from second to third exacerbation differed: 189 versus 258 days. The protective effect of OSA was most pronounced during the first three months following treatment (HR 0.72; 95%CI 0.62–0.83). Exposure to antibiotics unrelated to a course of oral corticosteroids almost halved the risk of a new exacerbation. Mortality during follow-up was considerably lower in the OSA group. Adding antibiotics to oral corticosteroids was associated with a reduced risk of a subsequent exacerbation, especially in patients with recurrent exacerbations, and a reduced risk of all cause mortality.
Comments
We hear from our infectious disease colleagues the plea for prudent and rational use of antibiotics for fear of generating widespread multidrug resistant microbes, yet this study certainly suggests there are clinically relevant benefits to combining antibiotics with oral steroids for treatment of acute exacerbations. This is not a prospective double-blind randomized controlled trial and hence common concerns regarding incomplete data such as for lung function, variation in treatment regimens as far as length of antibiotic and or steroid dose and selection bias for the different treatment regimens is a major issue. It is interesting to note that a group who apparently only had antibiotics did better than the group who had steroids and antibiotics but it was not possible to include this group because it could not be ascertained if all antibiotic courses were given for COPD exacerbations. Presumably the patients who had been treated with antibiotics and oral steroids were more severely affected and despite this had a longer time to next exacerbation compared to the group treated with steroids alone.
One would assume that if there is a signal of benefit in the antibiotic plus oral steroid treated group despite likely being the more severely affected population that this signal would be even more prominent if the patients were randomized to the two treatment groups. The study does not access whether the differences in treatment were the result of physicians treating more severe patients more aggressively or if it reflects differences in practice habits of clinicians in their general approach to the treatment of acute exacerbations of COPD. It would have been useful to have a breakdown of the frequency of use of different antibiotics presuming that these were started empirically. Currently there are large multicenter studies that are looking at the benefit of prophylactic antibiotics used every few months to reduce exacerbations. It would be equally valuable to have a prospective study with a broad cross-section of COPD patients to determine which subgroups are the best candidates for routine empiric treatment with antibiotics plus steroids versus steroids alone or antibiotics alone. Clearly not all patients routinely require both for good outcomes
Circulating fibronectin to C-reactive protein ratio and mortality: a biomarker in COPD? S. F. Man, L. Xing, J. E. Connett, N. R. Anthonisen, R. A. Wise, D. P. Tashkin, X. Zhang, R. Vessey, T. G. Walker, B. R. Celli, D. D. Sin. (Eur Respir J 2008 Dec; 32(6):1451–7).
The balance between inflammatory and repair processes is important in maintaining lung homeostasis in chronic obstructive pulmonary disease (COPD). The aim of the present study was to determine whether or not an integrated index of a biomarker involved in inflammation, C-reactive protein (CRP), and another involved in wound repair, fibronectin, may be a good measure to predict clinical outcomes in COPD. Circulating blood levels of CRP and fibronectin were measured in 4,787 individuals with mild-to-moderate COPD who were prospectively followed for > 7 yrs after blood collection as part of the Lung Health Study.
To assess the balance between repair and inflammation, a simple ratio was calculated by dividing fibronectin levels by CRP levels and a Cox proportional hazards model was used to determine the relationship between this ratio and all-cause and disease-specific causes of mortality. The relationship between the fibronectin to CRP ratio and all-cause mortality was L-shaped. There was an exponential decay in the adjusted hazard function (i.e., the risk of mortality) as the ratio decreased until a value of 148 was reached, beyond which point the hazard function did not change significantly. Similar results were observed for the risk of coronary and cardiovascular mortality. Circulating fibronectin to CRP ratio is significantly associated with all-cause mortality of COPD patients.
However, in contrast to other biomarkers, the relationship appears to be L-shaped (and not linear), suggesting a threshold at approximately 150. While promising, future studies are needed to validate this simple index as a biomarker in COPD.
Comments
This study the cohort from the well-characterized Lung Health Study. Patients started out with moderate airflow obstruction and have been followed for up to 14.5 years. Patients with severe comorbidities were excluded to maximize follow up of this cohort. They were able to complete evaluation of 89% of the initial cohort. Patients were grouped into quintiles according to their CRP and fibronectin levels. The findings suggest that indeed patients who have the lowest fibrinogen to CRP ratio are at the greatest risk for cardiovascular related and all cause mortality, implying that their repair mechanisms are overwhelmed by the inflammatory response.
Questions remain about the exact relationship between the imbalances of these biomarkers and morbidity and mortality in COPD. CRP is an acute phase protein synthesized in the liver. Fibronectin mediates cellular repair, promoting hemostasis and wound healing. Interestingly CRP binds to fibronectin and initiates the repair process creating in essence a negative feedback loop. Fibronectin levels are lower in the systemic circulation and higher in lung tissue with more severe levels of COPD, suggesting a possible migration of fibronectin to sites of local injury. At this point it is unclear whether the reduced fibronectin/CRP ratio reflects a cause or an effect of increased morbidity/mortality in COPD patients. Further this relationship was significant for cardiovascular and all cause mortality but not for respiratory-related mortality.
Man and colleagues have demonstrated that the underlying pathogenesis of COPD is complex and multifactorial, and that it is unlikely that we will find any one set of biomarkers that are applicable to all COPD patients. It is more likely that we will find, like in asthma, that there are subphenotypes of COPD for which certain biomarkers are more likely to be important. While this may provide information regarding prognosis and risk stratification, longitudinal serial follow-up of this cohort with repeat measures is important to assess if this ratio is responsive to changes in health status or progression of disease over time and how specific this may be to COPD versus the many co-morbidities of this patient population.