Jan O. Cowan

Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study

BACKGROUND Breastfeeding is widely advocated to reduce risk of atopy and asthma, but the evidence for such an effect is conflicting. We aimed to assess long-term outcomes of asthma and atopy related to breastfeeding in a New Zealand birth cohort. METHODS Our cohort consisted of 1037 of 1139 children born in Dunedin, New Zealand, between April, 1972, and March, 1973, and residing in Otago province at age 3 years. Children were assessed every 2-5 years from ages 9 to 26 years with respiratory questionnaires, pulmonary function, bronchial challenge, and allergy skin tests. History of breastfeeding had been independently recorded in early childhood. FINDINGS 504 (49%) of 1037 eligible children were breastfed (4 weeks or longer) and 533 (51%) were not. More children who were breastfed were atopic at all ages from 13 to 21 years to cats (p=0.0001), house dust mites (p=0.0010), and grass pollen (p<0.0001) than those who were not. More children who were breastfed reported current asthma at each assessment between age 9 (p=0.0008) and 26 years (p=0.0008) than those who were not. Breastfeeding effects were not affected by parental history of hayfever or asthma. Multifactor analysis controlling for socioeconomic status, parental smoking, birth order, and use of sheepskin bedding in infancy, showed odds ratios of 1.94 (95% CI 1.42-2.65, p<0.0001) for any allergen positive at age 13 years, 2.40 (1.36-4.26, p=0.0003) for current asthma at 9 years, and 1.83 (1.35-2.47, p<0.0001) for current asthma at 9-26 years by repeated-measures analysis. INTERPRETATION Breastfeeding does not protect children against atopy and asthma and may even increase the risk.

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.

Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship

Exhaled nitric oxide (eNO) is an easily measured marker of airway inflammation. This study was undertaken to evaluate the usefulness of serial eNO in investigating the dose-response relationship for inhaled beclomethasone (BDP), and to compare eNO with other markers of airway inflammation. Following withdrawal of inhaled corticosteroid (ICS) therapy, 65 patients entered a double-blind, parallel-group, placebo-controlled trial of 50, 100, 200 or 500 µg·BDP·day−1 for eight weeks. eNO and spirometry were performed weekly and a hypertonic saline challenge with sputum induction was performed at the beginning and end of treatment. The relationship between the dose of ICS and changes in eNO and forced expiratory volume in one second (FEV1) was linear at 1 week and at the end of treatment. A linear dose-response relationship was also seen for sputum eosinophils. Changes in eNO correlated significantly with changes in sputum eosinophils. Changes in the provocative dose of saline causing a 15% fall in FEV1 saline did not differ across the treatment groups nor did they correlate with changes in other measurements. Exhaled nitric oxide may be used to assess the dose-response relationship for the anti-inflammatory effects of inhaled beclomethasone. The relationship found in this study was linear over the dose range 0–500 µg·day−1 soon after commencing therapy and continued over time.

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.

Relationship between socioeconomic status and asthma: a longitudinal cohort study

Background: There is conflicting information about the relationship between asthma and socioeconomic status, with different studies reporting no, positive, or inverse associations. Most of these studies have been cross sectional in design and have relied on subjective markers of asthma such as symptoms of wheeze. Many have been unable to control adequately for potential confounding factors. Methods: We report a prospective cohort study of approximately 1000 individuals born in Dunedin, New Zealand in 1972–3. This sample has been assessed regularly throughout childhood and into adulthood, with detailed information collected on asthma symptoms, lung function, airway responsiveness, and atopy. The prevalence of these in relation to measures of socioeconomic status were analysed with and without controls for potential confounding influences including parental history of asthma, smoking, breast feeding, and birth order using cross sectional time series models. Results: No consistent association was found between childhood or adult socioeconomic status and asthma prevalence, lung function, or airway responsiveness at any age. Having asthma made no difference to educational attainment or socioeconomic status by age 26. There were trends to increased atopy in children from higher socioeconomic status families consistent with previous reports. Conclusions: Socioeconomic status in childhood had no significant impact on the prevalence of asthma in this New Zealand born cohort. Generalisation of these results to other societies should be done with caution, but our results suggest that the previously reported associations may be due to confounding.

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.

Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes

BACKGROUND Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. OBJECTIVE This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. METHODS An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. RESULTS From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1β (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. CONCLUSIONS A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.

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.

Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide.

RATIONALE Predicting corticosteroid response in COPD is important but difficult. Response is more likely to occur in association with eosinophilic airway inflammation, for which the fraction of exhaled nitric oxide (Fe(NO)) is a good surrogate marker. OBJECTIVES We aimed to establish whether Fe(NO) levels would predict the clinical response to oral corticosteroid in COPD. METHODS We performed a double-blind, crossover trial of steroid in patients with COPD. After a 4-week washout of inhaled steroids, patients received prednisone 30 mg/d or matching placebo, in random order, with an intervening 4-week washout. The predictive values of Fe(NO) for clinically significant changes in 6-minute-walk distance (6MWD), spirometry (FEV(1)), and St. Georges Respiratory Questionnaire (SGRQ) were calculated. MEASUREMENTS AND MAIN RESULTS A total of 65 patients (mean FEV(1) = 57% predicted) were randomized. With prednisone, there was a net increase of 13 m in 6MWD (P = 0.02) and 0.06 L in postbronchodilator FEV(1) (P = 0.02) compared with placebo. The change in SGRQ was not significant. Using receiver operator characteristic analysis, the area under the curve for an increase of 0.2 L in FEV(1) was 0.69 (P = 0.04) with an optimum Fe(NO) cut-point of 50 ppb. The positive and negative predictive values were 67 and 82%, respectively. FE(NO) was not a significant predictor for changes in 6MWD or SGRQ. CONCLUSIONS Fe(NO) is a weak predictor of short-term response to oral corticosteroid in COPD, its usefulness being limited to predicting increase in FEV(1). Clinical trial registered with www.anzctr.org.au (ACTRN12605000683639).

Reversing acute bronchoconstriction in asthma : the effect of bronchodilator tolerance after treatment with formoterol

Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction. This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist, formoterol. The modifying effect of intravenous corticosteroid was also studied. Ten asthmatic subjects (using inhaled steroids) participated in a randomised, double-blind, placebo-controlled, cross-over study. Formoterol 12 microg b.i.d. or matching placebo was given for 10-14 days with >2 weeks washout. Following each treatment, patients underwent a methacholine challenge to induce a fall in forced expired volume in one second (FEV1) of at least 20%, then salbutamol 100 microg, 100 microg, and 200 microg was inhaled via a spacer at 5 min intervals, with a further 400 microg at 45 min. After a third single-blind formoterol treatment period, hydrocortisone 200 mg was given intravenously prior to salbutamol. Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry. Regular formoterol resulted in a significantly lower FEV1 after salbutamol at each time point compared to placebo (p<0.01). The area under the curves (AUCs) for 15 (AUC0-15) and 45 (AUC0-45) min were 28.8% and 29.5% lower following formoterol treatment (p<0.001). Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration. It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol. This bronchodilator tolerance is evident in circumstances of acute bronchconstriction.