Disease progression in idiopathic pulmonary fibrosis with mild physiological impairment: analysis from the Australian IPF registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrosing lung disease of unknown cause. The advent of anti-fibrotic medications known to slow disease progression has revolutionised IPF management in recent years. However, little is known about the natural history of IPF patients with mild physiological impairment. We aimed to assess the natural history of these patients using data from the Australian IPF Registry (AIPFR). METHODS: Using our cohort of real-world IPF patients, we compared FVC criteria for mild physiological impairment (FVC ≥ 80%) against other proposed criteria: DLco ≥ 55%; CPI ≤40 and GAP stage 1 with regards agreement in classification and relationship with disease outcomes. Within the mild cohort (FVC ≥ 80%), we also explored markers associated with poorer prognosis at 12 months. RESULTS: Of the 416 AIPFR patients (mean age 70.4 years, 70% male), 216 (52%) were classified as 'mild' using FVC ≥ 80%. There was only modest agreement between FVC and DLco (k = 0.30), with better agreement with GAP (k = 0.50) and CPI (k = 0.48). Patients who were mild had longer survival, regardless of how mild physiologic impairment was defined. There was, however, no difference in the annual decline in FVC% predicted between mild and moderate-severe groups (for all proposed criteria). For patients with mild impairment (n = 216, FVC ≥ 80%), the strongest predictor of outcomes at 12 months was oxygen desaturation on a 6 min walk test. CONCLUSION: IPF patients with mild physiological impairment have better survival than patients with moderate-severe disease. Their overall rate of disease progression however, is comparable, suggesting that they are simply at different points in the natural history of IPF disease.

Atopy in people aged 40 years and over: Relation to airflow limitation.

BACKGROUND: Previous studies have reached conflicting conclusions about the role of atopy as a risk factor for COPD. In part, this is attributable to variation in the definitions of airflow limitation and the treatment of people with asthma. OBJECTIVE: To establish whether there is any independent association between atopy and post-bronchodilator airflow limitation in the general population aged 40 years and over. METHODS: A cross-sectional survey was conducted in a general population sample of 2415 people aged 40 years and over in Australia. A history of ever being diagnosed with asthma was elicited by questionnaire. Atopy was defined as any skin prick test weal to common aeroallergens ≥4 mm. Airflow limitation was defined as post-bronchodilator spirometric (FEV1 /FVC) ratio

Bronchopulmonary pharmacokinetics of (R)-salbutamol and (S)-salbutamol enantiomers in pulmonary epithelial lining fluid and lung tissue of horses.

AIMS: Salbutamol is usually administered as a racemic mixture but little is known about the enantioselectivity of salbutamol pharmacokinetics in the lung. This study was designed to investigate enantiomer concentrations in lung tissue after inhaled dosing. METHODS: Horses (n = 12) received racemic salbutamol 1000 µg via inhalation. Enantioselective ultra performance liquid chromatography-tandem mass spectrometry was used to determine salbutamol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15 min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25 min respectively), and in plasma samples. RESULTS: Mean ± 95% confidence interval (CI) yield of PELF was 57 ± 10 mg. Initial mean ± 95%CI (R)- and (S)-salbutamol PELF concentrations were 389 ± 189 ng g-1 and 378 ± 177 ng g-1 respectively, and both reduced approximately 50% by 15 min. Mean ± 95%CI central lung levels of drug were higher than peripheral lung tissue for both (R)-salbutamol (875 ± 945 vs. 49.5 ± 12 ng g-1 ) and (S)-salbutamol (877 ± 955 vs. 50.9 ± 12 ng g-1 ) respectively. There was no evidence of enantioselectivity in PELF or central lung but minor (~2%) enantioselectivity was observed in the peripheral lung. Enantioselectivity was clearly evident in plasma with (S):(R) ratio of 1.25 and 1.14 for both area under the concentration-time curve (0-25 min) and Cmax respectively. CONCLUSIONS: PELF sampling in horses offers sufficient yield allowing direct detection of drug and, combined with tissue sampling, is a valuable model to investigate bronchopulmonary pharmacokinetics. Salbutamol did not demonstrate enantioselectivity in PELF or central lung tissue uptake following acute dosing, however, enantioselective plasma concentrations were demonstrated, with minor enantioselectivity in the peripheral lung.

Unravelling the health and economic burden of interstitial lung diseases in adults in Australia.

BACKGROUND: Interstitial lung diseases (ILD) are a heterogenous group of over 200 disorders affecting the pulmonary interstitium. Although there have been advances in knowledge on ILDs in Australia, the characterisation of the health and economic burden of disease remained largely undetermined until recently. OBJECTIVE: The main objective of this review is to provide a synopsis of health and economic burden of ILDs in Australia, based on recently completed research. DISCUSSION: Recent research has demonstrated that idiopathic pulmonary fibrosis (IPF) is the most frequent ILD in Australia. Incidence and prevalence of IPF have demonstrated an increasing trend over the past decades. Mortality has also increased over the past decades, but has shown a slight decreasing trend recently, since the introduction of antifibrotic medication. Health-related quality of life is poor in patients with IPF, and care is estimated to cost approximately AU$299 million per year in Australia. Early diagnosis and referral to tertiary care is crucial for favourable outcomes, and general practitioners are considerably important to this as the first interface to identify patients at risk and detect early symptoms of ILDs.

Perceived feasibility of a community pharmacy-based asthma intervention: a qualitative follow-up study.

WHAT IS KNOWN AND OBJECTIVE: Asthma is a National Health Priority Area in Australia; however, recent evidence suggests that its management remains suboptimal. Community pharmacists are in a unique position to help patients manage asthma, and a number of community pharmacy-based asthma interventions have demonstrated effectiveness with improved patient outcomes. This study aimed to explore the views of general practitioners (GPs), community pharmacists and patients towards a pharmacy-based intervention that saw patients with poorly managed asthma supplied with educational material and referred to their GP for an asthma management review. METHODS: A qualitative follow-up study of participants who had been involved in the intervention was conducted. A sample of six GPs, 10 community pharmacists and 10 patients participated in semi-structured face-to-face interviews. Data were analysed using interpretive phenomenology. RESULTS AND DISCUSSION: General practitioners accepted the intervention process if they had positive relationships with pharmacists. There was also some hesitance of GPs towards the intervention, related to a perceived encroachment on their area of responsibility and a perceived conflict of interest of pharmacists in providing health care. GPs indicated the need to be more involved with the intervention process, and expressed that patients were rarely forthcoming about problems with their asthma. Community pharmacists felt that patients can be apathetic about asthma and often fail to seek medical advice. The intervention was implemented very easily, with minimal disruptions to the pharmacists' workflow, and pharmacists suggested that it would be better if GPs were more involved with the intervention process. Patients' general satisfaction with pharmacy services was high, but their expectations were quite low. Although there was an appreciation by patients of community pharmacists' interest in their health, this did not necessarily translate into appointments with GPs for an asthma management review. The reason for this related primarily to patients' under-estimation of their asthma severity. WHAT IS NEW AND CONCLUSION: A wider rollout of the asthma intervention, with an improved process for involving GPs, would be feasible and well accepted. Further research should determine the best approach in influencing patients' perceptions of asthma control and whether these perceptions are amenable to a more intensive educational intervention. This could result in more efficient asthma interventions, translating to improved patient outcomes.

Childhood immunization and atopic disease into middle-age--a prospective cohort study.

The association between childhood immunizations and risk of atopic diseases is unclear. No study has examined possible associations between childhood immunizations and such diseases in middle age. The Tasmanian Longitudinal Health Study (TAHS) is a population based cohort study of respiratory disease. The TAHS participants were followed from 7 to 44 yrs of age. Immunizations during childhood were examined for any association with asthma and atopic disease at age 44 yrs. Multivariable regression models were used to estimate relative risks while adjusting for confounders. Cox regression was used to estimate the association between childhood immunizations and asthma developing after the age of 7 yrs. We found no association between any childhood immunization (Diphtheria, Tetanus, Pertussis, Polio, Smallpox) and asthma (ORs ranged from 0.87 to 1.17 p > 0.05), eczema (ORs ranged from 0.99 to 1.07 p > 0.05), food allergy (ORs ranged from 0.97 to 1.11 p > 0.05), or hay fever (ORs ranged from 1.02 to 1.05 p > 0.05) at age 44. Nor did we find any association between childhood immunizations and an increased risk of incident asthma after the age of 7 yrs (Diphtheria HR = 1.06, 95% CI 0.82, 1.36; Tetanus HR = 1.13, 95% CI 0.88, 1.44; Pertussis HR = 1.03, 95% CI 0.81, 1.30; Polio HR = 1.15, 95% CI 0.86, 1.54; Smallpox HR = 1.21, 95% CI 0.99, 1.48; DTP HR = 1.05, 95% CI 0.85, 1.30). Our analysis does not support any association between common childhood immunizations and risk of asthma and atopic disease in middle-age. Our findings should provide reassurance that in terms of life time risk of asthma and atopic disease, childhood immunization is safe.

Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control.

Salmeterol (USAN, INN, BAN) is a long-acting beta2-adrenoceptor agonist (LABA) widely used in the treatment of airways disease. Although salmeterol is permitted via inhalation by athletes and supratherapeutic dosing may enhance performance, no urine threshold has been established by the World Anti-Doping Agency (WADA). Salmeterol is a chiral compound consisting of (R)- and (S)-enantiomers, normally administered as racemic (rac-) mixture via inhalation. Levels of rac-salmeterol in urine are often below detectable levels and there is surprisingly little information regarding the enantioselectivity of salmeterol pharmacokinetics. In this study, subjects inhaled either 50 (n = 6) or 200 µg (n = 4; generally regarded as maximum therapeutic dose) of salmeterol and urine was then collected for 24 h and analyzed by enantioselective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Maximum rac-salmeterol urine concentrations were obtained at 2 h for both doses with medians of 0.084 ng/mL after the 50 µg dose and 2.1 ng/mL after the 200 µg dose, with an individual maximum of 5.7 ng/mL. Levels were detectable at 24 h for both doses. Salmeterol displayed enantioselective pharmacokinetics, with a mean ± SD log (S):(R) = 0.055 ± 0.025 (P < 0.0001) equivalent to (S):(R) of 1.13. In conclusion, rac-salmeterol by inhalation exhibits modest enantioselectivity in urine following single dose administration and can be detected following a single 50 µg dose for up to 24 h after inhalation. The present findings are of relevance if a urine threshold limit is to be introduced for salmeterol on the list of prohibited substances. The application of an enantiomer ratio analysis may offer improved discriminatory detection capability for doping control analysis applications. Copyright © 2016 John Wiley & Sons, Ltd.

Is childhood immunisation associated with atopic disease from age 7 to 32 years?

BACKGROUND: There is ongoing conjecture over whether childhood immunisation leads to an increased risk of developing atopic diseases. OBJECTIVE: To examine associations between childhood immunisation and the risk of atopic disease. METHOD: Immunisation histories of 8443 Tasmanian children born in 1961 obtained from school medical records were linked to the Tasmanian Asthma Study. Associations between immunisation status and atopic diseases were examined while adjusting for possible confounders using multiple logistic regression. RESULTS: Diphtheria immunisation was weakly associated with an increased risk of asthma by age 7 years (odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1 to 1.7), but there was no evidence of any association for four other vaccinations studied. An increased risk of eczema by age 7 years was associated with immunisation against diphtheria (OR 1.5, 95% CI 1.1 to 2.1), tetanus (OR 1.5, 95% CI, 1.1 to 2.0), pertussis (OR 1.5, 95% CI 1.1 to 1.9) and polio (OR 1.4, 95% CI 1.0 to 1.9) but not small pox. Similar but slightly weaker patterns of association were observed between the risk of food allergies and immunisation against diphtheria (OR 1.5, 95% CI 1.0 to 2.1), pertussis (OR 1.4, 95% CI 1.1 to 1.9), polio (OR 1.4, 95% CI 1.00 to 2.1) and tetanus (OR 1.30 95% CI 0.99 to 1.70), but not with small pox. There was no evidence of associations between immunisation history and hay fever, or incidence of later-onset atopic outcomes. CONCLUSIONS: The few effects seen in this study are small and age-dependent, and nearly all our findings support numerous previous studies of no effect of vaccines on asthma. Based on these findings, the fear of their child developing atopic disease should not deter parents from immunising their children, especially when weighed against the benefits.

Are asthma medications and management related to deaths from asthma?

There is controversy about the role of beta-agonists in asthma mortality, and the impact of asthma management plans remains unclear. We compared blood beta-agonist levels in patients dying from asthma with those in controls, and estimated the risks associated with specific classes of medication and patterns of management. We identified 89 asthma deaths and recruited 322 patients presenting to hospitals with acute asthma. A questionnaire was administered to the next of kin in 51 cases, and to 202 controls. Blood drawn from 35 cases and 229 controls was assayed for salbutamol. Smoking, drinking, and family problems were significantly more likely among the cases of asthma death than among the controls. The two groups were reasonably well matched with regard to markers of chronic asthma severity. Cases of asthma death were significantly less likely than controls to use a peak flow meter. Written action plans were associated with a 70% reduction in the risk of death. Use of nebulized bronchodilators or oral steroids was significantly more likely in cases of asthma death. Mean blood salbutamol concentrations were 2.5 times higher in cases of asthma. The use of oral steroids for an attack of asthma reduced the risk of death by 90%. More widespread adoption of written asthma management plans, with less reliance on beta-agonists and closer medical supervision, should reduce asthma mortality.

An antiinflammatory effect of salmeterol, a long-acting beta(2) agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma.

The addition of long-acting beta(2) agonists to inhaled corticosteroid (ICS) therapy in symptomatic patients with asthma improves clinical status more than increasing the dose of ICS. It has been suggested that these benefits could be at the cost of an increase in airway inflammation, but few histopathological studies have been performed in the relevant group. In a double-blind, parallel-group, placebo-controlled study, we randomly assigned 50 symptomatic patients with asthma who were receiving ICS (range, 100 -500 microgram/d) to 12 wk of supplementary treatment with salmeterol (50 microgram twice daily) or fluticasone (100 microgram twice daily) or placebo. Bronchial biopsies and BAL were obtained from 45 patients before and after treatment and analyzed. After treatment with salmeterol there was no deterioration of airway inflammation as assessed by mast cells, lymphocytes, or macrophages in BAL or biopsies, but rather a significant fall in EG1-positive eosinophils in the lamina propria (from a median 18.3 to 7.6 cells/mm, p = 0.01), which was not seen after treatment with fluticasone. The only cellular effect of added fluticasone was a decrease in BAL lymphocyte activation. There was a concurrent improvement in clinical status, more marked with salmeterol than with increased ICS. Thus, adding salmeterol to ICS is not associated with increased "allergic" airway inflammation, but conversely with a complementary antieosinophil effect.

In stable lung transplant recipients, exhaled nitric oxide levels positively correlate with airway neutrophilia and bronchial epithelial iNOS.

In conditions characterized by airway inflammation, exhaled nitric oxide (eNO) levels are increased. Variable degrees of airway inflammation are present in stable lung transplant recipients (LTR), and may lead to airway remodeling and chronic graft dysfunction. The hypothesis tested is that in stable LTR, eNO concentrations would reflect the expression of inducible (iNOS) (but not constitutive [cNOS] nitric oxide synthase) in the bronchial epithelium as well as the degree of airway inflammation. We determined eNO concentrations in 20 stable LTR, free of infection, rejection, or obliterative bronchiolitis (OB). At routine bronchoscopy, we measured the differential cell count on bronchoalveolar lavage (BAL) and a quantitative assessment of iNOS and cNOS expression in endobronchial biopsies by immunohistochemistry. Mean +/- SEM eNO concentrations in stable LTR were not significantly different from control subjects (13 +/- 0.7 ppb versus 14.2 +/- 0.49; p = 0.42). Percent BAL neutrophils was 11.5 +/- 3.2 which was significantly higher than in a group of local control subjects (1.7 +/- 0.6; p < 0.001). The bronchial epithelium and lamina propria contained abundant iNOS but cNOS was present only in the lamina propria. Using regression analysis, percent BAL neutrophils (r(2) = 0.82; p < 0.0001) and iNOS expression in the bronchial epithelium (r(2) = 0.75; p < 0.0001), but not in the lamina propria (r(2) = 0.16; p = 0.08), were positively predictive of eNO. There was an inverse relationship between cNOS and eNO. We conclude that eNO concentrations although normal for the group, still reflect the degree of airway inflammation in stable LTR. Epithelial iNOS appears to be the major source of eNO and expression of cNOS may be downregulated with increasing iNOS expression.

Residential characteristics predict changes in Der p 1, Fel d 1 and ergosterol but not fungi over time.

BACKGROUND: Allergen and fungal exposures are important risk factors for asthma. We conducted a longitudinal analysis of allergen levels in Melbourne homes between 1996 and 1998 to examine the effects of changing residential characteristics on allergen and fungal levels. We also examined the changes in levels of indoor allergens. METHODS: The subjects were participants in the European Community Respiratory Health Survey (ECRHS) in Melbourne. In 1996, 485 subjects participated in a follow-up study, which involved both home and laboratory visits. Dust and air samples were collected from participants' bedrooms and a validated residential questionnaire was administered. In 1998, 360 participants underwent further follow-up. House dust mite (Der p 1) and cat allergens (Fel d 1) and ergosterol were measured in dust. RESULTS: We observed moderate within home correlations between 1996 and 1998 in floor Der p 1 (intraclass correlation ICC=0.48), bed Der p 1 (ICC=0.61), Fel d 1 (kappa=0.53) and ergosterol (ICC=0.28) levels. We found that the floor Der p 1 levels decreased from 1996 to 1998 in the homes of participants who moved to an attached home, moved their bedrooms to the first floor, removed fitted carpet or central heating. Replacing or vacuuming the mattress more than twice per year reduced levels of Der p 1 in the bed. Ergosterol levels were reduced by removing visible mould and fitted carpet. CONCLUSIONS: These findings provide evidence to support current advice with regard to allergen avoidance in patients with dust mite and fungal allergies.