Sebastian Majewski

Heart Rate-Lowering Efficacy and Respiratory Safety of Ivabradine in Patients with Obstructive Airway Disease

BackgroundThere is substantial evidence that heart rate (HR) is a powerful predictor of mortality in both normal individuals and in patients with cardiovascular disease. The use of b-adrenoceptor antagonists (β-blockers) has confirmed the importance of lowering elevated HR in a patient’s prognosis. However, these agents can have undesirable adverse effects (AEs) and due to the risk of bronchoconstriction are contraindicated in patients with obstructive airway disease. A selective bradycardic agent, without such undesirable effects, could be of therapeutic interest. Ivabradine, a new Ifinhibitor that acts specifically on the sino-atrial node, is a pure HR-lowering agent.ObjectiveThe objective of this study was to assess HR-lowering efficacy and respiratory safety of ivabradine in patients with asthma and chronic obstructive pulmonary disease (COPD).MethodsThis was a randomized, single-center, double-blind, placebo-controlled, crossover trial. Enrolment began in May 2009, and the last patient completed the study in January 2011. The study was conducted in an ambulatory setting. A total of 40 patients completed the study (20 asthmatic patients and 20 COPD patients). Inclusion criteria were: documented diagnosis of asthma or COPD according to international guidelines, age 18–75 years, and mean HR on Holter ECG recording of ≥60 beats/min. Exclusion criteria included disease exacerbation in a previous month or inability to understand instructions on the study procedures. All patients received ivabradine 7.5 mg twice daily for 5 days and placebo twice daily for 5 days in a crossover manner, in one of the two arms of the study, with at least 2 days of washout between treatments. The main outcome measures included the difference in HR between ivabradine and placebo treatment and change in HR in comparison with baseline. Other evaluated outcomes were differences in the peak expiratory flow rate (PEFR), the daily symptom score, rescue medication consumption, and AEs. Results: Ivabradine produced significantly lower mean HR than placebo in both groups of patients: asthma 67.4 ± 8.38 versus 82.85±11.19 beats/min (p<0.001) and COPD 69.75 ± 8.9 versus 81.05 ± 9.75 beats/min (p<0.001). Similar results were observed for the minimal HR as well as for the maximal noted HR. In comparision with baseline, ivabradine significantly reduced HR in both groups of studied patients (all p < 0.05), whereas placebo did not have such an effect. No significant difference, in either the asthma or the COPD group, was found between ivabradine and placebo in morning and evening peak expiratory flow rate, peak expiratory flow diurnal variability, daily symptom scores, and rescue medication usage (all p > 0.05). Both treatments were well tolerated. The incidence of AEs was low and generally similar in both periods of treatment, except for visual symptoms during treatment with ivabradine, which was reported by 5% of the patients.ConclusionOur study demonstrated that selective HR reduction with ivabradine is effective in patients with asthma and COPD, with no alteration in respiratory function or symptoms over the duration of the study. Ivabradine offers an interesting alternative, as an HR-lowering agent, in patients with respiratory disease and contraindications to β-blockers.Clinical Trial RegistrationRegistered at www.clinicaltrials.gov (NCT01365286).

Exhaled breath 8-isoprostane as a marker of asthma severity.

Introduction Oxidative stress is a non-specific feature of airway inflammation in asthmatics. 8-Isoprostane (8-IP), a prostaglandin-F2α isomer, is a relatively new marker of oxidative stress and may be measured in exhaled breath condensate (EBC) of patients with asthma. This research study aimed to evaluate the usefulness of EBC 8-IP as a marker of severity and control of severe adult asthma. Material and methods Twenty-seven severe, never-smoking asthmatics were studied. According to positive or negative reversibility testing, this group was subdivided into reversible and irreversible asthma groups. All participants were observed for 8 weeks during which they completed daily diary observations including day and night symptoms, number of awakenings, peak expiratory flow (PEF) variability, daily rescue medication usage and oral steroids consumption. They attended the clinic 3 times and on these occasions spirometry assessments, EBC collection and asthma control tests (ACT) were done. Two control groups were included: 11 healthy never-smokers and 16 newly diagnosed and never-treated, non-smoking mild asthmatics. Results There were no statistically significant differences between severe asthma and healthy control or never-treated asthma groups in concentrations of EBC 8-IP (median and interquartile range: 4.67; 2.50-27.92 vs. 6.93; 2.5-12.98 vs. 3.80; 2.50-10.73, respectively). No correlations were found between EBC 8-IP and asthma control parameters, such as ACT results, night and day symptoms, consumption of rescue medication, percentage of days free of oral steroids, PEF diurnal variation, lung function test results, forced expiratory volume in the 1 s reversibility, and markers of systemic inflammation. Conclusions Our study results suggest that EBC 8-IP measurements are not useful for asthma monitoring.

Pulmonary manifestations of inflammatory bowel disease

Bronchopulmonary signs and symptoms are examples of variable extraintestinal manifestations of the inflammatory bowel diseases (IBD). These complications of Crohns disease (CD) and ulcerative colitis (UC) seem to be underrecognized by both pulmonary physicians and gastroenterologists. The objective of the present review was to gather and summarize information on this particular matter, on the basis of available up-to-date literature. Tracheobronchial involvement is the most prevalent respiratory presentation, whereas IBD-related interstitial lung disease is less frequent. Latent and asymptomatic pulmonary involvement is not unusual. Differential diagnosis should always consider infections (mainly tuberculosis) and drug-induced lung pathology. The common link between intestinal disease and lung pathology is unknown, but many hypotheses have been proposed. It is speculated that environmental pollution, common immunological mechanisms and predisposing genetic factors may play a role.

Orally exhaled nitric oxide in patients with seasonal allergic rhinitis during natural pollen season.

Background Nitric oxide (NO) is the endogenous molecule involved in regulatory, protective, and defensive mechanisms. Although exhaled NO (ENO) has been used to monitor patients with asthma, possible usage of ENO in allergic rhinitis (AR) still needs to be evaluated. The authors wanted to determine the levels of NO exhaled orally both out of the pollen season and during the natural pollen exposure in patients with AR without asthma. Methods Forty-six patients without asthma, with seasonal AR (SAR) and 15 healthy, nonreactive, nonatopic subjects as a control group were investigated. ENO, congestion score, and peak nasal inspiratory flows (PNIFs) were measured in all subjects 6 weeks before the pollen season, at the height of the pollen season, and 6 weeks after the end of the pollen season. Results Patients with SAR had significantly higher basal ENO values compared with healthy control. The number of parts of NO increased in both groups during the pollen season but only in AR patients was the increase significant compared with the levels before the pollen season. Those with SAR and high levels of NO in exhaled air at the height of the pollen season had significantly lower PNIF rates and higher obstruction scores than out of the pollen season and in the healthy group. Conclusion Natural exposure may lead to an elevation of ENO in the patients with SAR without asthma. We estimate that the increased ENO may result from subclinical allergic inflammation present within the lower airways of nonasthmatic patients with SAR.

Pulmonary arterial hypertension: a current review of pharmacological management

Pulmonary hypertension (PHTN) is a rare and devastating disease characterized by progressive increases in pulmonary arterial pressure and pulmonary vascular resistance, which eventually leads to right ventricular failure and death. At present there is no cure for pulmonary arterial hypertension (PAH); however over the past decade targeted pharmaceutical options have become available for the treatment of PAH. Prior to evaluation for therapeutic options a definitive diagnosis of pulmonary arterial hypertension must be made via comprehensive physical exam and definitive diagnostic testing. Screening test of choice remains echocardiography and gold standard for definitive diagnosis is right heart catheterization. Once the establishment of a diagnosis of PAH is made therapeutic options may be a possibility based on a diagnostic algorithm and disease severity of the PAH patient. There are different classes of medications available with different mechanisms of actions which net a vasodilatory effect and improve exercise tolerance, quality of life as well and survival.

Asthma control, quality of life and successful sputum induction.

Introduction Induced sputum is widely used in clinical practice and scientific studies. This technique has become enormously useful in assessment of airway inflammation. However, some asthmatics are unable to expectorate sputum of sufficient quality and quantity necessary for further processing, therefore not providing reliable results. This research study aimed to examine whether asthma control and asthma quality of life influence the results of sputum induction. Material and methods Fourty-seven adult subjects, current non-smokers with symptomatic asthma, were studied. All participants underwent clinical assessment, skin prick testing, spirometry and sputum induction. Before sputum induction, subjects were asked to fill in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and Asthma Control Questionnaire (ACQ). Results Twenty-nine (62%) subjects produced sputum eligible for processing. This group had a significantly lower ACQ score (0.83 ±0.65 vs. 1.37 ±0.77; p = 0.02), higher MiniAQLQ total score (5.67 ±0.99 vs. 4.86 ±1.07; p = 0.011), higher MiniAQLQ symptoms domain score (5.54 ±1.13 vs. 4.63 ±1.24; p = 0.013) and higher MiniAQLQ activity limitations domain score (6.08 ±0.92 vs. 5.07 ±1.37; p= 0.014). The noted differences between groups of patients were not only statistically but were clinically important. Conclusions The study results suggest that successful sputum induction may be expected in patients with better asthma control and better quality of life.

Short-Term Reproducibility of the Inflammatory Phenotype in Different Subgroups of Adult Asthma Cohort

Inflammatory phenotype classification using induced sputum appears attractive as it can be applied to inflammation-based management of the patients with asthma. The aim of the study was to determine the reproducibility of inflammatory phenotype over time in patients with asthma. In 66 adults asthma was categorized as steroid-naïve (SN, n = 17), mild to moderate (MMA, n = 33), and refractory treated with oral corticosteroids (RA, n = 16). Clinical assessment, skin prick testing, spirometry, and two sputum inductions in 4–6-week interval were done. Inflammatory phenotypes were classified as eosinophilic (EA), consisting of eosinophilic and mixed granulocytic phenotypes, and noneosinophilic (NEA) consisting of paucigranulocytic and neutrophilic phenotypes. During study asthma treatment remained constant. In SN group 25% of patients changed phenotype from EA to NEA and 44% changed phenotype from NEA to EA. In MMA group 26% of patients changed phenotype from EA to NEA and 50% changed phenotype from NEA to EA. In 29% of RA patients inflammatory phenotype changed from EA to NEA and in 22% it changed from NEA to EA. Inflammatory classification, using induced sputum, is not fully reproducible in adults with asthma in short-term evaluation. EA seems to be more stable phenotype across all subgroups whereas NEA remained stable only in RA group.

The association between airway eosinophilic inflammation and IL-33 in stable non-atopic COPD

BackgroundInterleukin(IL)-33 is an epithelial alarmin important for eosinophil maturation, activation and survival. The aim of this study was to examine the association between IL-33, its receptor expression and airway eosinophilic inflammation in non-atopic COPD.MethodsIL-33 concentrations were measured in exhaled breath condensate (EBC) collected from healthy non-smokers, asthmatics and non-atopic COPD subjects using ELISA. Serum and sputum samples were collected from healthy non-smokers, healthy smokers and non-atopic COPD patients. Based on sputum eosinophil count, COPD subjects were divided into subgroups with airway eosinophilic inflammation (sputum eosinophils > 3%) or without (sputum eosinophils ≤3%). IL-33 and soluble form of IL-33 receptor (sST2) protein concentrations were measured in serum and sputum supernatants using ELISA. ST2 mRNA expression was measured in peripheral mononuclear cells and sputum cells by qPCR. Hemopoietic progenitor cells (HPC) expressing ST2 and intracellular IL-5 were enumerated in blood and induced sputum by means of flow cytometry.ResultsIL-33 levels in EBC were increased in COPD patients to a similar extent as in asthma and correlated with blood eosinophil count. Furthermore, serum and sputum IL-33 levels were higher in COPD subjects with sputum eosinophilia than in those with a sputum eosinophil count ≤3% (p < 0.001 for both). ST2 mRNA was overexpressed in sputum cells obtained from COPD patients with airway eosinophilic inflammation compared to those without sputum eosinophilia (p < 0.01). Similarly, ST2 + IL-5+ HPC numbers were increased in the sputum of COPD patients with airway eosinophilia (p < 0.001).ConclusionsOur results indicate that IL-33 is involved in the development of eosinophilic airway inflammation in non-atopic COPD patients.

Skin condition and its relationship to systemic inflammation in chronic obstructive pulmonary disease

Background The systemic (extrapulmonary) effects and comorbidities of chronic obstructive pulmonary disease (COPD) contribute substantially to its burden. The supposed link between COPD and its systemic effects on distal organs could be due to the low-grade systemic inflammation. The aim of this study was to investigate whether the systemic inflammation may influence the skin condition in COPD patients. Materials and methods Forty patients with confirmed diagnosis of COPD and a control group consisting of 30 healthy smokers and 20 healthy never-smokers were studied. Transepidermal water loss, stratum corneum hydration, skin sebum content, melanin index, erythema index, and skin temperature were measured with worldwide-acknowledged biophysical measuring methods at the volar forearm of all participants using a multifunctional skin physiology monitor. Biomarkers of systemic inflammation, including high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α), were measured in serum using commercially available enzyme-linked immunosorbent assays. Results There were significant differences between COPD patients and healthy never-smokers in skin temperature, melanin index, sebum content, and hydration level (P<0.05), but not for transepidermal water loss and erythema index. No significant difference was noted between COPD patients and smokers in any of the biophysical properties of the skin measured. The mean levels of hsCRP and IL-6 in serum were significantly higher in COPD patients and healthy smokers in comparison with healthy never-smokers. There were significant correlations between skin temperature and serum hsCRP (R=0.40; P=0.02) as well as skin temperature and serum IL-6 (R=0.49; P=0.005) in smokers. Stratum corneum hydration correlated significantly with serum TNF-α (R=0.37; P=0.01) in COPD patients. Conclusion Differences noted in several skin biophysical properties and biomarkers of systemic inflammation between COPD patients, smokers, and healthy never-smokers may suggest a possible link between smoking-driven, low-grade systemic inflammation, and the overall skin condition.