E.H. Bel

Risk factors of frequent exacerbations in difficult-to-treat asthma

Recurrent exacerbations are a major cause of morbidity and medical expenditure in patients with asthma. Various exogenous and endogenous factors are thought to influence the level of asthma control, but systematical data on the involvement of these factors in the recurrence of asthma exacerbations are scarce. In this study, 13 clinical and environmental factors potentially associated with recurrent exacerbations were investigated in 136 patients with difficult-to-treat asthma. Patients with more than three severe exacerbations (nu200a=u200a39) in the previous year were compared with those with only one exacerbation per year (nu200a=u200a24). A systematic diagnostic protocol was used to assess 13 potential risk factors. Factors significantly associated with frequent exacerbations included: severe nasal sinus disease (adjusted odds ratio (OR) 3.7); gastro-oesophageal reflux (OR 4.9); recurrent respiratory infections (OR 6.9); psychological dysfunctioning (OR 10.8); and obstructive sleep apnoea (OR 3.4). Severe chronic sinus disease and psychological dysfunctioning were the only independently associated factors (adjusted OR 5.5 and 11.7, respectively). All patients with frequent exacerbations exhibited at least one of these five factors, whilst 52% showed three or more factors. In conclusion, the results show that recurrent exacerbations in asthma are associated with specific co-morbid factors that are easy to detect and that are treatable. Therapeutic interventions aimed at correcting these factors are likely to reduce morbidity and medical expenditure in these patients.

Recurrent Exacerbations in Severe Asthma Are Associated with Enhanced Airway Closure During Stable Episodes

Excessive airway narrowing is a cardinal feature of asthma, and results in closure of airways. Therefore, asthmatic patients in whom airway closure occurs relatively early during expiration might be prone to severe asthma attacks. To test this hypothesis, we compared closing volume (CV) and closing capacity (CC) in a group of asthmatic patients with recurrent exacerbations (more than two exacerbations in the previous year; difficult-to-control asthma), consisting of 11 males and two females, aged 20 to 51 yr, with those in a group of equally severely asthmatic controls without recurrent exacerbations (stable asthma) consisting of 13 males and two females aged 18 to 52 yr. Both groups used equivalent doses of inhaled corticosteroids and were matched for sex, age, atopy, postbronchodilator FEV(1), and provocative concentration of methacholine causing a 20% decrease in FEV(1). They were studied during a clinically stable period of their disease. The patients inhaled 400 microg salbutamol via a spacer device, after which TLC and RV were measured by multibreath helium equilibration, together with the slope of Phase 3 (dN(2)), CV, and CC, by single-breath nitrogen washout. CV and CC were expressed as ratios of VC and TLC, respectively, and all data are presented as % predicted (mean +/- SEM). There was no difference in TLC in patients with difficult-to-control asthma and those with stable asthma (106.7 +/- 4.0% predicted versus 101.7 +/- 4.3% predicted, p = 0.40), RV (113.1 +/- 7.8% predicted versus 100.9 +/- 7.1% predicted, p = 0.26), or dN(2) (142.7 +/- 16.3% predicted versus 116.0 +/- 20.2% predicted, p = 0.23). In contrast, CV and CC were increased in the patients with difficult-to-control asthma as compared with the group with stable asthma (CV: 159.5 +/- 26.8% predicted versus 98.8 +/- 12.5% predicted, p = 0.024; CC: 114.0 +/- 6.4% predicted versus 99.9 +/- 3. 6% predicted, p = 0.030). These findings show that asthmatic individuals with recurrent exacerbations have increased CV and CC as compared with equally severely asthmatic but stable controls, even after bronchodilation during well-controlled episodes. The findings imply that airway closure at relatively high lung volumes under clinically stable conditions might be a risk factor for severe exacerbations in asthmatic patients.

Repeatability of cellular and soluble markers of inflammation in induced sputum from patients with asthma

Sputum induced by inhalation of nebulized hypertonic saline is increasingly used to monitor airways inflammation in asthma. The aim of this study was to assess the repeatability of measuring cellular and soluble markers of inflammation in whole sputum samples as obtained by sputum induction in patients both with mild and moderate-to-severe asthma. Twelve patients with mild, atopic asthma without inhaled steroid treatment and nine patients with moderate-to-severe, atopic asthma treated with inhaled steroids were studied on two separate days at least 2 days apart. Whole sputum samples, induced by inhalation of hypertonic (4.5%) saline, were homogenized, and analysed for differential cell counts and for concentrations of albumin, fibrinogen, interleukin-8 (IL-8), and eosinophil cationic protein (ECP). Repeatability was expressed as intraclass correlation coefficient (Ri), and as coefficient of repeatability (CR) in percentage cells or in doubling concentration. Samples from two patients with mild asthma contained more than 80% squamous cells and were excluded from analysis. The repeatability for cell differential counts in both groups combined was: for neutrophils, Ri = 0.57 and CR = 31.0; for eosinophils, Ri = 0.85 and CR = 12.4; and for lymphocytes, Ri = 0.76 and CR = 6.9. The repeatability of the fluid phase measurements was: for albumin, Ri = 0.71 and CR = 3.2; for fibrinogen, Ri = 0.88 and CR = 2.8; for IL-8, Ri = 0.66 and CR = 2.2; and for ECP, Ri = 0.82 and CR = 1.1. We conclude that the repeatability of cellular and soluble markers of inflammation in induced sputum from patients with mild and moderate-to-severe asthma is satisfactory. Hence, induced sputum, processed by using the whole expectorated sample, seems to be a valuable method to monitor airway inflammation in asthma.

Airway inflammation in obese and nonobese patients with difficult-to-treat asthma.

Background:u2002 Asthma and obesity are associated disorders, but the contribution of obesity to difficult‐to‐treat asthma as well as the mechanisms responsible for this relationship are unclear. The aim of this study was to investigate the relationship between obesity (body mass indexu2003≥u200330) and factors related with asthma severity in patients with difficult‐to‐treat asthma.

Alveolar nitric oxide versus measures of peripheral airway dysfunction in severe asthma

Alveolar nitric oxide (NO) is a measure of peripheral airway inflammation in asthma, potentially associated with disease severity. The relationship between alveolar NO and physiological tests of peripheral airway (dys)function has not been investigated. The present authors hypothesised that peripheral airway inflammation and dysfunction are inter-related and associated with asthma severity. Alveolar NO was compared between 17 patients with mild-to-moderate asthma and 14 patients with severe asthma and related to total lung capacity (TLC), residual volume (RV)/TLC, thoracic gas volume (FRC), slope of the single breath nitrogen washout curve (dN2), closing capacity (CC)/TLC and fall in forced vital capacity at the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second. In patients with severe asthma, strong correlations were found between alveolar NO and RV/TLC % pred, FRC % pred, dN2, and CC/TLC. Patients with oral steroid-dependent asthma had higher alveolar NO levels (2.7u2005ppb) compared with the other patients with severe (0.6u2005ppb) and mild-to-moderate asthma (0.3u2005ppb). The present authors conclude that alveolar nitric oxide is closely related to parameters of peripheral airway dysfunction in patients with severe asthma, and that oral steroid-dependent asthmatics have more peripheral airway disease than nonsteroid-dependent asthmatics. This suggests that patients on chronic oral steroid treatment have more extensive disease and require additional anti-inflammatory treatment to better target the peripheral airways.

Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma.

A subset of patients with asthma is known to have progressive loss of lung function despite treatment with corticosteroids. The aim of the present study was to identify risk factors of decline in forced expiratory volume in one second (FEV1) in patients with difficult-to-treat asthma. In total, 136 nonsmoking patients with difficult-to-treat asthma were recruited between 1998 and 1999. Follow-up assessment was performed 5–6u2005yrs later in 98 patients. The predictive effect of clinical characteristics and inflammatory markers were analysed at baseline (asthma onset and duration, atopy, airway hyperresponsiveness, blood and sputum eosinophils, and the fraction of nitric oxide in exhaled air (FeNO)) on subsequent decline in post-bronchodilator FEV1. Patients with high FeNO (≥20u2005ppb) had an excess decline of 40.3 (95% confidence interval (CI) 7.3–73.2)u2005mL·yr−1 compared to patients with low FeNO. FeNO ≥20u2005ppb was associated with a relative risk of 1.9 (95% CI, 1.1–2.6) of having an accelerated (≥25u2005mL·yr−1) decline in FEV1. In patients with baseline FEV1 ≥80% of predicted, this relationship was even stronger: 90 versus 29% had accelerated decline in FEV1 (FeNO ≥20u2005ppb versus FeNO <20u2005ppb respectively; relative risk 3.1 (95% CI, 1.7–3.4). Exhaled nitric oxide is a predictor of accelerated decline in lung function in patients with difficult-to-treat asthma, particularly if forced expiratory volume in one second is still normal.

Illness Perceptions and Quality of Life in Patients with Chronic Obstructive Pulmonary Disease

This study aimed at identifying cognitive and emotional representations relevant for improving health care communication and quality of life (QoL) in patients with chronic obstructive pulmonary disease (COPD). One-hundred-seventy-one COPD outpatients completed questionnaires on illness perceptions and QoL. After controlling for the effects of age, pulmonary function, and dyspnea, patients with decreased attention to symptoms, with more positive beliefs about the effects and outcomes of their illness, and with less strong emotional reactions to the illness, had higher QoL scores. The results of this study are discussed in relation to the associations found in other illnesses.

Similar psychological characteristics in mild and severe asthma.

OBJECTIVEnPsychological factors have been implicated as potentially contributing to asthma severity. In the present study, we investigated whether patients with mild and severe asthma differ with regard to several psychological characteristics.nnnMETHODSnNinety outpatients with severe asthma (74% female, mean [S.D.] age: 46.5 [13.7] years) and 37 outpatients with mild asthma (73% female, age: 39.4 [13.9] years) were compared with respect to general psychological health, anxiety sensitivity, hyperventilation symptoms, personality, and locus-of-control orientation, all measured by well-validated self-report questionnaires. Analysis of (co)variance (ANCOVA) was used to assess between-groups differences.nnnRESULTSnNo significant differences in psychological characteristics were found between patients with mild and severe asthma. Only on the subscale for external locus-of-control orientation, severe asthmatic patients differed from those with mild disease (P=.005) in showing less trust in physicians and medication with regard to influencing their asthma.nnnCONCLUSIONnThe results suggest that mild and severe asthmatic patients cannot be differentiated on the basis of psychopathology or personality. Whether or not the observed lack of confidence in the influence of physicians or medication on asthma course is cause or consequence of disease severity, remains to be established.

A rational approach to the management of severe refractory asthma.

Severe refractory asthma is a heterogeneous condition with different patterns of severity and different reasons for loss of asthma control. The three main patterns include asthma with frequent exacerbations, asthma with irreversible airway obstruction, and asthma with reduced sensitivity or resistance to corticosteroids. Each of these patterns has distinct risk factors. The assessment of patients with severe asthma requires a systematic, diagnostic and management protocol. The majority of patients will benefit from thorough analysis and treatment of aggravating factors. In some patients with severe refractory asthma, in particular those with concomitant chronic rhinosinusitis, long-term administration of systemic corticosteroids may be necessary. In these patients all efforts should be directed towards reducing the dose of corticosteroids as much as possible. Although several corticosteroid-sparing agents and immunosuppressants have been proposed in the literature, none of these has gained complete acceptance in clinical practice, either because of limited efficacy or unacceptable adverse effects. Novel potent anti-inflammatory therapies aimed at reducing the need for systemic corticosteroids in patients with severe, refractory asthma are urgently needed.

Quantification of Theophylline-Induced Eosinopenia and Hypokalaemia in Healthy Volunteers

SummaryThe relationship between theophylline pharmacokinetics and its eosinopenic and hypokalaemic effects were studied in 6 healthy volunteers after an oral dose of theophylline 250mg. The mean peak theophylline concentration (Cmax) of 8.33 ±2.16 mg/L occurred 1.02 ± 0.26h after ingestion. The delay between the Cmax and the subsequent eosinopenic or hypokalemic nadirs was 4.52 ± 1.73 and 3.65 ± 1.32h, respectively. The time courses of theophylline and its effects were linked by a sigmoid Emax effect model. The maximal eosinopenic and hypokalaemic effects (Emax) of the drug were 83 ± 25.8% and 16 ± 9.7% of the possible, respectively. The theophylline concentrations causing 50% of the Emax (EC50) were 5.06 ± 1.84 and 5.04 ± 2.09 mg/L, respectively. The data obtained with our methodology indicate that, in humans, theophylline induced eosinopenia could be mediated through a receptor and/or postreceptor mechanism unrelated to the mechanism of theophylline induced bronchodilation. We conclude that therapeutic theophylline plasma concentrations have a profound effect on the redistribution of blood eosinophils.