Avis Williamson

Effects of steroid therapy on inflammatory cell subtypes in asthma

Rationale Airway inflammation in asthma is heterogeneous with different phenotypes. The inflammatory cell phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in eosinophilic asthma (EA), but evidence is conflicting regarding non-eosinophilic asthma (NEA). Objectives To assess the inflammatory cell phenotypes in asthma after eliminating potentially confounding effects; to compare steroid response in EA versus NEA; and to investigate changes in sputum cells with inhaled corticosteroid (ICS). Methods Subjects undertook ICS withdrawal until loss of control or 28 days. Those with airway hyper-responsiveness (AHR) took inhaled fluticasone 1000 μg daily for 28+ days. Cut-off points were ≥/<2% for sputum eosinophils and ≥/<61% for neutrophils. Results After steroid withdrawal (n=94), 67% of subjects were eosinophilic, 31% paucigranulocytic and 2% mixed; there were no neutrophilic subjects. With ICS (n=88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased from 19.3% to 27.7% (p=0.024). The treatment response was greater in EA for symptoms (p<0.001), quality of life (p=0.012), AHR (p=0.036) and exhaled nitric oxide (p=0.007). Lesser but significant changes occurred in NEA (ie, paucigranulocytic asthma). Exhaled nitric oxide was the best predictor of steroid response in NEA for AHR (area under the curve 0.810), with an optimum cut-off point of 33 ppb. Conclusions After eliminating the effects of ICS and smoking, a neutrophilic phenotype could be identified in patients with moderate stable asthma. ICS use led to phenotype misclassification. Steroid responsiveness was greater in EA, but the absence of eosinophilia did not indicate the absence of a steroid response. In NEA this was best predicted by baseline exhaled nitric oxide.

The effect of adiposity measured by dual-energy X-ray absorptiometry on lung function

Respiratory function is impaired in obesity but there are limitations with body mass index and skin-fold thickness in assessing this effect. The present authors hypothesised that the regional distribution of body fat and lean mass, as measured by dual-energy X-ray absorptiometry (DXA), might be more informative than conventional measurements of total body fat. In total, 107 subjects (55 female, 51.4%) aged 20–50 yrs with no respiratory disease were recruited. Respiratory function tests, anthropometric measurements and a DXA scan were performed. Partial correlation and linear regression analyses were used to explore the effect of adiposity and lean body mass on respiratory function. The majority of respiratory function parameters were significantly correlated with DXA and non-DXA measurements of body fat. Neither thoracic nor abdominal fat had a greater effect. There were some differences in the effect of adiposity between the sexes. Respiratory function was negatively associated with lean body mass in females but positively associated in males. This disappeared after adjustment in females but remained in males. The effects of thoracic and abdominal body fat on respiratory function are comparable but cannot be separated from one another.

Systemic inflammation and lung function in young adults

Background: Impaired lung function is associated with systemic inflammation and is a risk factor for cardiovascular disease in older adults. It is unknown when these associations emerge and to what extent they are mediated by smoking, chronic airways disease, and/or established atherosclerosis. We explored the association between the forced expiratory volume in one second (FEV1) and the systemic inflammatory marker C-reactive protein (CRP) in young adults. Methods: Associations between spirometric lung function and blood CRP were assessed in a population based birth cohort of approximately 1000 New Zealanders at ages 26 and 32 years. Analyses adjusted for height and sex to account for differences in predicted lung function and excluded pregnant women. Results: There were significant inverse associations between FEV1 and CRP at both ages. Similar results were found for the forced vital capacity. These associations were similar in men and women and were independent of smoking, asthma, and body mass index. Conclusions: Reduced lung function is associated with systemic inflammation in young adults. This association is not related to smoking, asthma, or obesity. The reasons for the association are unexplained, but the findings indicate that the association between lower lung function and increased inflammation predates the development of either chronic lung disease or clinically significant atherosclerosis. The association between poor lung function and cardiovascular disease may be mediated by an inflammatory mechanism.

Factors affecting exhaled nitric oxide measurements: the effect of sex

BackgroundExhaled nitric oxide (FENO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect FENO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting FENO in a well characterised adult population.MethodsData were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on FENO were explored by unadjusted and adjusted linear regression analyses.ResultsThe effect of sex on FENO was both statistically and clinically significant, with FENO levels approximately 25% less in females. Overall, current smoking reduced FENO up to 50%, but this effect occurred predominantly in those who smoked on the day of the FENO measurement. Atopy increased FENO by 60%. The sex-related differences in FENO remained significant (p < 0.001) after controlling for all other significant factors affecting FENO.ConclusionEven after adjustment, FENO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.

Simvastatin in the treatment of asthma: lack of steroid-sparing effect.

Background Statins have anti-inflammatory actions which in theory are potentially beneficial in asthma. Small trials have failed to show a significant benefit, but a systematic study to evaluate the steroid-sparing effect of statin treatment has not been carried out. Methods A randomised, placebo-controlled, crossover trial was conducted of simvastatin 40 mg at night with simultaneous stepwise reduction of fluticasone propionate dose until loss of control occurred, followed by an increase until regain of control (‘minimum’ dose required) in 51 patients with asthma and sputum eosinophils (steroid-free) ≥2%. Results 43 patients completed the study. There was no significant difference in ‘minimum’ inhaled corticosteroid (ICS) dose requirement between simvastatin and placebo: (median (IQR) 50 μg daily (0–250) vs 100 μg daily (0–250), p=0.931). ‘Minimum’ dose distribution was similar (p=0.269). The fluticasone dose at which loss of control occurred did not differ significantly between simvastatin and placebo (p=0.404). In patients with loss of control in both treatment arms, fluticasone dose at loss of control was similar with simvastatin and placebo (median (IQR) 50 μg daily (0–100) for both, p=0.620). In those patients who reached 0 μg/day (n=18), Astma Control Questionnaire (ACQ) was lower (p=0.037), forced expiratory volume in 1 s (FEV1) higher (p<0.01) and sputum eosinophils lower with simvastatin compared with placebo (9.5% compared with 25.4%, p=0.033). Conclusions Simvastatin does not have clinically important steroid-sparing effects in patients with eosinophilic asthma. In the absence of steroid, simvastatin is associated with minor improvements in symptoms and lung function, and a reduction in sputum eosinophils. Clinical trial number ACTRN12606000531516.

Asthma phenotypes: consistency of classification using induced sputum.

Background and objective:  Asthma can be classified as eosinophilic or non‐eosinophilic based on the cell profile of induced sputum. This classification can help determine whether corticosteroid treatment is indicated. We assessed the stability of these phenotypes over time and with different treatment regimens.

Exercise-induced wheeze: Fraction of exhaled nitric oxide-directed management

Background and objective:  Exercise‐induced wheeze (EIW) is common. Several treatment options exist. Patients with low fraction of exhaled nitric oxide (FENO) are unlikely to be steroid‐responsive and might benefit from non‐steroidal therapies. We assessed: the efficacy of cromoglycate, formoterol and montelukast in patients with EIW and low FENO (<35 ppb) in a randomized cross‐over trial, and the efficacy of inhaled corticosteroid in a high FENO (>35 ppb) group.

Association between exhaled nitric oxide and systemic inflammatory markers

BACKGROUND Asthma is an inflammatory condition of the airways, and there is some evidence to suggest that it is associated with a systemic inflammatory response, as measured by C-reactive protein (CRP) and fibrinogen. Exhaled nitric oxide is a noninvasive measure of asthmatic airway inflammation. OBJECTIVE To determine if there is an association between exhaled nitric oxide and these systemic inflammatory markers. METHODS The Dunedin Multidisciplinary Health and Development Study is a birth cohort of approximately 1,000 individuals born between April 1, 1972, and March 31, 1973. At the age of 32 years, study members were assessed for diagnosis of asthma, atopy by skin prick testing, smoking, body mass index, exhaled nitric oxide, high-sensitivity serum CRP, and plasma fibrinogen level. RESULTS There was no significant association between exhaled nitric oxide and CRP (P = .99). There was a trend to an inverse association between exhaled nitric oxide and fibrinogen (P = .049), but this was not significant after adjusting for smoking and use of corticosteroids or after further adjustment for body mass index and atopy (P = .71). CONCLUSION In this population-based sample of young adults, there was no association between airway inflammation, as measured by exhaled nitric oxide, and systemic inflammation, as measured by either CRP or fibrinogen.