Trials of endovascular thrombectomy of basilar-artery occlusion compared to real-life data.

BACKGROUND: Two recent clinical trials showed mechanical thrombectomy (MT) of basilar-artery occlusions (BAO) in stroke to be safe and effective: Endovascular Treatment for Acute BAO (ATTENTION) and BAO Chinese Endovascular (BAOCHE). The trials restricted patient inclusion on both age and pre-stroke mRS, and with both trials conducted in China, population differences may affect generalisability of the trial results. METHODS: Consecutive patients with BAO undergoing MT were registered from 2017 to 2021 with retrospective data collection at a single centre with a predominantly Caucasian catchment population of 2.7 million. Age and pre-stroke modified Rankin Scale (mRS) were not absolute contraindications for MT. We present functional outcome as mRS at 90 days, patient characteristics and procedural safety compared to the trial intervention groups. RESULTS: Of the 108 included patients, 50 % achieved mRS 0-3 at 90 days and mortality was 32 %, which was no different from ATTENTION (46 %, p = 0.40, 37 %, p = 0.31, respectively) and BAOCHE (46 %, p = 0.50, 31 %, p = 0.93). Pre-stroke mRS 0 was seen in 62 %, 89 %, and 77 % of the study patients, ATTENTION, and BAOCHE, respectively. Proximal segment BAO was less common (22 % vs. 31 %, p = 0.04, and 65 %, p < 0.01) and intracranial stenting less frequently used (9 % vs. 40 % and 55 %, p < 0.01) in study patients compared to ATTENTION and BAOCHE, respectively. CONCLUSION: Outcome of MT in BAO stroke in a clinical patient cohort was similar to recent trials, despite broader patient inclusion and differences in both occluded BAO segment and use of stenting. Our study suggest that MT is safe and effective in a Caucasian population.

Confirmatory digital subtraction angiography after clinical brain death/death by neurological criteria: impact on number of donors and organ transplants.

Background: Demand for organs exceeds the number of transplants available, underscoring the need to optimize organ donation procedures. However, protocols for determining brain death (BD)/death by neurological criteria (DNC) vary considerably worldwide. In Denmark, digital subtraction angiography (DSA) is the only legally approved confirmatory test for diagnosing BD/DNC. We investigated the effect of the time delay caused by (repeat) confirmatory DSA on the number of organs donated by patients meeting clinical criteria for BD/DNC. We hypothesized that, first, patients investigated with ≥2 DSAs donate fewer organs than those investigated with a single DSA; second, radiological interpretation of DSA is subject to interrater variability; and third, residual intracranial circulation is inversely correlated with inotropic blood pressure support. Methods: All DSAs performed over a 7-year period as part of BD/DNC protocols at Rigshospitalet, Copenhagen University Hospital, Denmark, were included. Clinical data were extracted from electronic health records. DSAs were reinterpreted by an independent neurinterventionist blinded to the original radiological reports. Results: We identified 130 DSAs in 100 eligible patients. Patients with ≥2 DSAs (n = 20) donated fewer organs (1.7 +/- 1.6 SD) than patients undergoing a single DSA (n = 80, 2.6 +/- 1.7 organs, p = 0.03), and they became less often donors (n = 12, 60%) than patients with just 1 DSA (n = 65, 81.3%; p = 0.04). Interrater agreement of radiological DSA interpretation was 88.5% (Cohen's kappa = 0.76). Patients with self-maintained blood pressure had more often residual intracranial circulation (n = 13/26, 50%) than patients requiring inotropic support (n = 14/74, 18.9%; OR = 0.23, 95% CI [0.09-0.61]; p = 0.002). Discussion: In potential donors who fulfill clinical BD/DNC criteria, delays caused by repetition of confirmatory DSA result in lost donors and organ transplants. Self-maintained blood pressure at the time of clinical BD/DNC increases the odds for residual intracranial circulation, creating diagnostic uncertainty because radiological DSA interpretation is not uniform. We suggest that avoiding unnecessary repetition of confirmatory investigations like DSA may result in more organs donated.

Mechanical thrombectomy in stroke patients of advanced age with score-based prediction of outcome.

BACKGROUND: Stroke patients ≥80 years constituted only 15% in randomised trials on mechanical thrombectomy (MT), but is a considerable higher proportion in clinical practice. Association of clinical variables collected before MT with functional outcome has not been independently described in these patients, while being important in the decision of patient eligibility for MT. METHODS: We included patients consecutively at a single centre (2017-2021) categorised as octogenarians (age: 80-89 years) or nonagenarians (age: 90-99 years). Functional outcome at 90 days was defined as fair (modified Rankin Scale (mRS) 0-3) or poor (mRS 4-6). Clinical variables collected before MT were analysed for association with shift of mRS in a poor direction. Significant predictors were used to produce a risk score of fair outcome. Significance was set at the p < 0.05 level. RESULTS: Nonagenarians (n = 43, 15.5%) compared to octogenarians (n = 235, 84.5%) less likely achieved fair outcome (20.9% vs. 46.0%, p < 0.01) with higher mortality (65.1% vs. 31.9%, p < 0.01). Significant predictors of outcome were: age, adjusted odds ratio (aOR) = 0.91 (95% confidence interval (CI): 0.86-0.97); pre-stroke mRS, aOR = 0.57 (95% CI: 0.44-0.73); National Institute of Health Stroke Scale at admission, aOR = 0.91 (95% CI: 0.87-0.95); Alberta Stroke Program Early Computed Tomography, aOR = 1.23 (95% CI: 1.05-1.45). After bootstrap validation, the area under the curve of the risk score was 0.74 and the optimal cut-off for fair outcome was a score of >7 points. CONCLUSIONS: One in two octogenarians achieved fair outcome, however, only one in five nonagenarians had fair outcome. The clinical risk score could be considered as guidance when deciding patient eligibility for MT.

Mortality among patients treated for aneurysmal subarachnoid hemorrhage in Eastern Denmark 2017-2019.

OBJECTIVE: The aim of the study was to investigate (1) the 30-day, 3-month, and 12-month cumulative mortalities for patients who underwent aneurysm occlusion, and (2) the causes of death, and (3) the potential risk factors for death. METHODS: All patients who underwent surgical clipping or endovascular treatment of a ruptured aneurysm at Copenhagen University Hospital, during the period of January 1, 2017-December 31, 2019, were included and followed up for 12 months. Data regarding vital status, causes of death, comorbidities, treatment, and clinical presentations on admission was collected. The absolute mortality risk was estimated as a function of time with a 95% confidence interval. The associations between potential risk factors and death were estimated as odds ratios with 95% confidence intervals using logistic regression models. RESULTS: A total of 317 patients were included. The overall cumulative mortalities after 30 days, 3 months, and 12 months were 10.7%, 12.9%, and 16.1%, respectively. The most common cause of death was severe primary hemorrhage (52.9%), followed by infections (15.7%) and rebleeding (11.8%). WFNS score > 3 and Fisher score > 3 on admission, preprocedural hydrocephalus, and preprocedural rebleeding were found significantly associated with higher risk of death. CONCLUSIONS: Considerable mortality was seen. Possible preventable causes accounted for approximately 22% of the deaths. The occurrence of both pre- and postprocedural rebleeding's indicates an opportunity of further improvement of the mortality by (1) further reduction of time from aSAH to aneurysm occlusion and (2) continuous efforts in improving methods of aneurysm occlusion.

[Challenges and advances in paediatric arterial ischaemic stroke].

Neurological sequelae occur in more than 50% of children with arterial ischemic stroke. Early recognition and treatment are essential in improving outcome. However, diagnostic delay in paediatric stroke often extends beyond 24 hours, and children rarely access hyperacute recanalisation therapies. This review describes clinical presentations, risk factors and treatment of paediatric ischaemic stroke. Additionally, we share our experience from a systematic paediatric stroke pathway implemented in Eastern Denmark since 2017.

Endovascular treatment for cerebral venous sinus thrombosis - a single center study.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare cerebrovascular disorder. The majority of these patients respond favorably to systemic anticoagulation. However, a subset of patients will deteriorate clinically, despite optimal medical therapy. METHODS: Retrospective single center study of 28 consecutive CVST patients treated with systemic anticoagulation and additional endovascular therapy. RESULTS: Median age was 37.5 years (range 15-76 years), there were 21 (75%) women, and 20 (71%) had thrombosis involving ≥2 venous sinuses. Intracranial hemorrhage (ICH) was present at admission in 18 patients (64%). Endovascular therapy consisted of local thrombolysis in 26 (93%) patients; 9 patients (32%) had additional mechanical thrombectomy, and in 2 (7%) patients thrombectomy alone was performed. Complete recanalization at end of the final intervention was achieved in 15 patients (54%), partial recanalization in 11 patients (39%), whereas there was no recanalization in 2 patients (7%). On follow-up imaging, conducted between 3 and 6 months, recanalization further improved to 76%, 19% and 5%, respectively. A favorable outcome (mRS ≤ 2) was achieved in 63% of patients at 3 months, which improved to 79% at 6 months. Post-procedural ICH or volume expansion of preexisting ICH was seen in 9 patients (32%). In total 5 patients died (18%). CONCLUSIONS: Systemic anticoagulation with the addition of endovascular therapy with local thrombolysis and/or mechanical thrombectomy is a potential strategy to obtain recanalization in patients with CVST who deteriorate clinically despite medical therapy or are comatose. Endovascular therapy may increase the risk of ICH.

Acute Tentorial Subdural Hematoma Caused by Rupture of the Posterior Cerebral Artery after Minor Trauma-A Case Report.

Acute subdural hematoma (aSDH) is a common pathology encountered after head trauma. Only a minority of aSDHs have an arterial source. In this article, we report a case of aSDH originating from a traumatic pseudoaneurysm of the distal segment of posterior cerebral artery (PCA), diagnosed several days after the initial minor trauma and successfully treated with endovascular coiling. This case emphasizes the importance of searching for vascular pathology when the localization, severity or relapsing course of the intracranial hemorrhage does not fully correspond to the severity of initial trauma and when the bleeding has a delayed onset. Characteristics, diagnostics and treatment possibilities of traumatic cerebral aneurysms, an important cause of arterial aSDH, are described in the article.

Plasma Levels of IL-6, IL-8, IL-10, ICAM-1, VCAM-1, IFNγ, and TNFα are not Associated with Delayed Cerebral Ischemia, Cerebral Vasospasm, or Clinical Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage (SAH). The pathophysiology behind DCI remains poorly understood, but inflammation has been proposed to play a significant role. This study investigated the relationship between plasma levels of some of the most important inflammatory markers and DCI, cerebral vasospasm, and functional outcome in patients with SAH. METHODS: In 90 patients with SAH, interleukin-6, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, high sensitivity C-reactive protein (HsCRP), interleukin-8, interleukin-10, interferon gamma, and tumor necrosis factor alpha were measured in peripheral blood day 3 and day 8 after SAH. Any occurrence of DCI or infection was recorded, and computed tomography angiography was performed on day 8. Clinical outcome was assessed after 3 months. RESULTS: HsCRP on day 3 was higher in patients with angiographic vasospasm (P = 0.003), and HsCRP on day 8 was higher in patients with poor outcome (P = 0.014). No association with DCI, vasospasm, or outcome was found for any of the remaining analyzed substances. CONCLUSIONS: High plasma levels of HsCRP were significantly associated with angiographic vasospasm and clinical outcome. Plasma levels of interleukin-6, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interleukin-8, interleukin-10, interferon gamma, and tumor necrosis factor alpha were not associated with DCI, angiographic vasospasm, or clinical outcome at 3 months.

[Endovascular thrombectomy in ischaemic apoplexy treatment].

The goal when treating ischaemic apoplexy is a rapid, safe and effective recanalization. For some years, the main treatment has been the administration of IV thrombolysis, but due to several restrictions, lack of efficacy and a limited window of opportunity for treatment, an alternative method was needed. This formed the foundation for the develop-ment of endovascular thrombectomy. This review describes the development and the mechanisms involved as well as the results and treatment gains.

High Plasma Levels of Neuropeptide Y Correlate With Good Clinical Outcome But are not Correlated to Cerebral Blood Flow or Vasospasm After Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage. Treatments with convincing effect are lacking and the pathophysiology behind DCI remains poorly understood. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor and a role of NPY in the development of DCI has been proposed. This study investigated the relationship between plasma-NPY and cerebral blood flow (CBF), cerebral vasospasm, DCI, and clinical outcome. METHODS: In 90 patients with subarachnoid hemorrhage, NPY was measured in peripheral blood days 2 to 11. Any occurrence of DCI was recorded and CBF was quantified day 3 and day 8 using computed tomography (CT) perfusion. CT angiography was performed day 8. Clinical outcome was assessed after 3 months. RESULTS: No correlation was found between plasma-NPY and CBF or angiographic vasospasm. The correlation between reduced plasma-NPY and DCI reached borderline statistical significance (P=0.05). Increased levels of NPY measured on days 2 to 4 were correlated to good outcome (P=0.006). CONCLUSIONS: Our findings in peripheral blood were not supportive of a causal relationship between NPY secretion and DCI. Although high levels of plasma-NPY were correlated with good clinical outcome, NPY did not show promise as a clinically useful biomarker.

Thrombectomy assisted by carotid stenting in acute ischemic stroke management: benefits and harms.

Extracranial carotid artery occlusion or high-grade stenosis with concomitant intracranial embolism causes severe ischemic stroke and shows poor response rates to intravenous thrombolysis (IVT). Endovascular therapy (EVT) utilizing thrombectomy assisted by carotid stenting was long considered risky because of procedural complexities and necessity of potent platelet inhibition-in particular following IVT. This study assesses the benefits and harms of thrombectomy assisted by carotid stenting and identifies factors associated with clinical outcome and procedural complications. Retrospective single-center analysis of 47 consecutive stroke patients with carotid occlusion or high-grade stenosis and concomitant intracranial embolus treated between September 2011 and December 2014. Benefits included early improvement of stroke severity (NIHSS ≥ 10) or complete remission within 72 h and favorable long-term outcome (mRS ≤ 2). Harms included complications during and following EVT. Mean age was 64.3 years (standard deviation ±12.5), 40 (85%) patients received IVT initially. Median NIHSS was 16 (inter-quartile range 14-19). Mean time from stroke onset to recanalization was 311 min (standard deviation ±78.0). Early clinical improvement was detected in 22 (46%) patients. Favorable outcome at 3 months occurred in 32 (68%) patients. Expedited patient management was associated with favorable clinical outcome. Two (4%) patients experienced symptomatic hemorrhage. Eight (17%) patients experienced stent thrombosis. Four (9%) patients died. Thrombectomy assisted by carotid stenting seems beneficial and reasonably safe with a promising rate of favorable outcome. Nevertheless, adverse events and complications call for additional clinical investigations prior to recommendation as clinical standard. Expeditious patient management is central to achieve good clinical outcome.

Real-time changes in brain tissue oxygen during endovascular treatment of cerebral vasospasm.

The use of endovascular intervention to treat cerebral vasospasm after subarachnoid hemorrhage has increased. Although the effect on angiographic vasospasm can be easily demonstrated, the effect on cerebral blood flow and clinical outcome is still controversial. In this report, we investigate minute-by-minute changes in brain tissue oxygen during balloon angioplasty and intraarterial administration of vasodilators in three patients.Our results confirm that endovascular intervention is capable of not only resolving angiographic vasospasm, but also of normalizing values of brain tissue oxygen pressure (PtiO2) in target parenchyma. However, during the intervention, dangerously low levels of brain tissue oxygen, leading to cerebral infarction, may occur. Thus, no clinical improvement was seen in two of the patients and a dramatic worsening was observed in the third patient. Because the decrease in brain tissue oxygen was seen after administration of vasopressor agents, this may be a contributing factor.

Effects of prostacyclin on cerebral blood flow and vasospasm after subarachnoid hemorrhage: randomized, pilot trial.

BACKGROUND AND PURPOSE: Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome in patients with subarachnoid hemorrhage. In this trial, we investigated the therapeutic potential of prostacyclin, an endogen substance with known effect on vascular tone and blood flow regulation, on factors related to DIND. METHODS: This trial is a single-center, randomized, blinded, clinical, pilot trial with 3 arms. Ninety patients were randomized to continuous infusion of prostacyclin 1 ng/kg per minute, prostacyclin 2 ng/kg per minute, or placebo. The intervention was initiated day 5 after subarachnoid hemorrhage and discontinued day 10. Primary outcome was the difference in change from baseline in global cerebral blood flow. Secondary outcome measures were occurrence of DIND, angiographic vasospasm, and clinical outcome at 3 months. RESULTS: No statistically significant difference in change of global cerebral blood flow was found between the intervention groups. The observed incidence of DIND and angiographic vasospasm was markedly higher in the placebo group, although this difference was not statistically significant. No statistically significant differences in safety parameters or clinical outcome were found between the 3 groups. CONCLUSIONS: Administration of prostacyclin to patients with subarachnoid hemorrhage may be safe and feasible. Global cerebral blood flow after subarachnoid hemorrhage is not markedly affected by administration of prostacyclin in the tested dose range. It may be possible that the observed reduction in the point estimates of DIND and vasospasm in the prostacyclin groups represents an effect of prostacyclin as this trial was not powered to investigate the effect of prostacyclin on these outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01447095.

The effects of continuous prostacyclin infusion on regional blood flow and cerebral vasospasm following subarachnoid haemorrhage: study protocol for a randomised controlled trial.

BACKGROUND: One of the main causes of mortality and morbidity following subarachnoid haemorrhage (SAH) is the development of cerebral vasospasm, a frequent complication arising in the weeks after the initial bleeding. Despite extensive research, to date no effective treatment of vasospasm exists. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. In vitro models have shown a relaxing effect of prostacyclin after induced contraction in cerebral arteries, and a recent pilot trial showed a positive effect on cerebral vasospasm in a clinical setting. No randomised, clinical trials have been conducted, investigating the possible pharmacodynamic effects of prostacyclin on the human brain following SAH. METHODS: This trial is a single-centre, randomised, placebo-controlled, parallel group, blinded, clinical, pilot trial. A total of 90 patients with SAH will be randomised to one of three intervention arms: epoprostenol 1 ng/kg/min, epoprostenol 2 ng/kg/min or placebo in addition to standard treatment. Trial medication will start day 5 after SAH and continue to day 10. The primary outcome measure is changes in regional cerebral blood flow from baseline in the arterial territories of the anterior cerebral artery, medial cerebral artery and the posterior cerebral artery, measured by CT perfusion scan. The secondary outcomes will be vasospasm measured by CT angiography, ischaemic parameters measured by brain microdialysis, flow velocities in the medial cerebral artery, clinical parameters and outcome (Glasgow Outcome Scale) at 3 months. TRIAL REGISTRATION: Clinicaltrials.gov NCT01447095.

[Computer tomography angiography of the cerebral and cervical vessels]. / Computertomografiangiografi af hjernens og halsens kar.

Due to the high temporal and spatial resolution in multislice computed tomography it is possible to perform high-quality computer tomography angiography (CTA) of the cerebral and cervical vessels. Compared to digital subtraction angiography (DSA), a method that is still considered to be the golden standard, CTA is faster and can be performed using a minimal invasive technique. In this paper we outline the clinical indications for performing CTA (aneurysms, stroke, vasospasms, arterio-venous malformations, dissection). Examples of scan protocols are given both for angiography of the cerebral vessels alone and for angiography of the cervical and cerebral vessels in combination. Postprocessing methods for evaluating the images in 2D and 3D are described. Finally CTA is compared to other modalities (DSA, magnetic resonance angiography and Doppler ultrasound).

Rapid fall in lung density following smoking cessation in COPD.

INTRODUCTION: Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate. We used computed tomography (CT) to evaluate the effect of smoking cessation on lung density in patients with COPD. MATERIAL AND METHODS: Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests (LFT) for 2?4 years as part of a randomised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density. Lung density was expressed as the 15th percentile density (PD15) and relative area of emphysema below -910 HU (RA-910). From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities. RESULTS: Following smoking cessation RA-910 increased by 2.6% (p = 0.003) and PD15 decreased by -4.9 HU (p = 0.0002). Furthermore, changes were larger in the budesonide group than the placebo group (PD15: -7.1 vs -2.8 HU. RA-910 3.7% vs 1.7%). These differences were, however, not statistically significant. The LFT parameters (FEV(1) and diffusion capacity) were not significantly influenced by smoking cessation. CONCLUSION: Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density, which resembles rapid progression of emphysema. This fall in density is probably due to an anti-inflammatory effect of smoking cessation.

The effect of inhaled corticosteroids on the development of emphysema in smokers assessed by annual computed tomography.

The objective was to evaluate the effect of inhaled corticosteroids on disease progression in smokers with moderate to severe chronic obstructive pulmonary disease (COPD), as assessed by annual computed tomography (CT) using lung density (LD) measurements. Two hundred and fifty-four current smokers with COPD were randomised to treatment with either an inhaled corticosteroids (ICS), budesonide 400 microg bid, or placebo. COPD was defined as FEV(1) < or = 70% pred, FEV(1)/FVC < or = 60% and no reversibility to beta(2)-agonists and oral corticosteroids. The patients were followed for 2-4 years with biannual spirometry and annual CT and comprehensive lung function tests (LFT). CT images were analysed using Pulmo-CMS software. LD was derived from a pixel-density histogram of the whole lung as the 15th percentile density (PD15) and the relative area of emphysema at a threshold of -910 Hounsfield units (RA-910), and both were volume-adjusted to predicted total lung capacity. At baseline, mean age was 64 years and 64 years; mean number of pack-years was 56 and 56; mean FEV(1) was 1.53 L (51% pred) and 1.53 L (53% pred); mean PD15 was 103 g/L and 104 g/L; and mean RA-910 was 14% and 13%, respectively, for the budesonide and placebo groups. The annual fall in PD15 was -1.12 g/L in the budesonide group and -1.81 g/L in the placebo group (p = 0.09); the annual increase in RA-910 was 0.4% in the budesonide group and 1.1% in the placebo group (p = 0.02). There was no difference in annual decline in FEV(1) between ICS (-54 mL) and placebo (-56 mL) (p = 0.89). Long-term budesonide inhalation shows a non-significant trend towards reducing the progression of emphysema as determined by the CT-derived 15th percentile lung density from annual CT scans in current smokers with moderate to severe COPD.

The extent of emphysema in patients with COPD.

BACKGROUND AND AIMS: The global initiative for COPD (GOLD) adopted the degree of airway obstruction as a measure of the severity of the disease. The objective of this study was to apply CT to assess the extent of emphysema in patients with chronic obstructive pulmonary disease (COPD) and relate this extent to the GOLD stage of airway obstruction. MATERIALS AND METHODS: We included 209 patients with COPD. COPD was defined as FEV(1)/FVC < 0.70 and no reversibility to beta(2)-agonists. All patients were current smokers with a smoking history of >or=20 pack-years. Patients were assessed by lung function measurement and visual and quantitative assessment of CT, from which the relative area of emphysema below -910 Hounsfield units (RA-910) was extracted. RESULTS: Mean RA-910 was 7.4% (n = 5) in patients with GOLD stage I, 17.0% (n = 119) in stage II, 24.2% (n = 79) in stage III and 33.9% (n = 6) in stage IV. Regression analysis showed a change in RA-910 of 7.8% with increasing severity according to GOLD stage (P < 0.001). Combined visual and quantitative assessment of CT showed that 184 patients had radiological evidence of emphysema, whereas 25 patients had no emphysema. CONCLUSION: The extent of emphysema increases with increasing severity of COPD and most patients with COPD have emphysema. Tissue destruction by emphysema is therefore an important determinant of disease severity in COPD.