S100A8 chemotactic protein is abundantly increased, but only a minor contributor to LPS-induced, steroid resistant neutrophilic lung inflammation in vivo

Neutrophilic lung inflammation is an essential component of host defense against diverse eukaryotic and prokaryotic pathogens, but in chronic inflammatory lung diseases, such as chronic obstructive lung disease (COPD), severe asthma, cystic fibrosis, and bronchiolitis, it may damage the host. Glucocorticosteroids are widely used in these conditions and in their infectious exacerbations; however, the clinical efficacy of steroids is disputed. In this study, we used a proteomic approach to identify molecules contributing to neutrophilic inflammation induced by transnasal administration of lipopolysaccharide (LPS) that were also resistant to the potent glucocorticosteroid dexamethasone (Dex). We confirmed that Dex was biologically active at both the transcript (suppression of GM-CSF and TNFalpha transcripts) and protein levels (induction of lipocortin) and used 2D-PAGE/MALDI-TOF to generate global expression profiles, identifying six LPS-induced proteins that were Dex resistant. Of these, S100A8, a candidate neutrophil chemotactic factor, was profiled in detail. Steroid refractory S100A8 expression was highly abundant, transcriptionally regulated, secreted into lung lavage fluid and immunohistochemically localized to tissue infiltrating neutrophils. However, in marked contrast to other vascular beds, neutralizing antibodies to S100A8 had only a weak anti-neutrophil recruitment effect and antibodies against the related S100A9 were ineffective. These data highlight the need for extensive in vivo profiling of proteomically identified candidate molecules and demonstrates that S100A8, despite its abundance, resistance to steroids and known chemotactic activity, is unlikely to be an important determinant of LPS-induced neutrophilic lung inflammation in vivo.

Doubling daily inhaled corticosteroid dose is ineffective in mild to moderately severe attacks of asthma in adults

Background: Asthma guidelines recommend increasing or doubling inhaled corticosteroid (ICS) dose to treat mild and moderate exacerbations of asthma in adults. Aim: To: (i) compare the effectiveness of doubling existing daily ICS dose (fluticasone) with maintaining usual ICS dose and usual daily ICS dose accompanied by oral steroids (OS) (dexamethasone) during mild and moderately severe exacerbations of asthma in adults; (ii) examine determinants of success and failure; and (iii) compare side-effect profiles. Methods: A randomized, double-blind, placebo-controlled (double-dummy), triple crossover trial. Participants acted as their own control. Outcome measures included treatment success/failure, peak expiratory flow (PEF) after 7 days therapy or at treatment failure, and side-effects. Results: From 22 participants (nine males and 13 females), 18 pairs of data were available for maintaining usual ICS versus doubling ICS and doubling ICS versus OS, and 19 for maintaining usual ICS versus OS. Median (fifth-95th percentile) age was 46.5 (32-64) years and forced expiratory volume in one second (FEV1) 73% (29-97%) predicted. The outcome after doubling ICS was not superior to maintaining usual ICS, with 11 (61%) failures in both arms (P = 0.66). OS, with only 5 (26%) failures, was superior to maintaining usual ICS with 12 (63%) failures (P = 0.04), and to doubling ICS with 5 (28%) versus 11 (61%) failures (P = 0.07). Median PEF (as percentage of run-in best) at end-points were 90.5% (57.1-177.1) for OS, 78.3% (39.5-103.1) for maintaining usual ICS and 77.9 (27.7-110.3) for doubling ICS. Neither gender nor PEF at exacerbation were predictive of failure. Although doubling ICS was not an effective therapy overall, ICS dose at exacerbation were predictive of success in the doubling ICS arm (P = 0.04). Treatment failures when doubling daily ICS dose were more common if achieved fluticasone dose was less than 2000 mu g (three of 11, 73%) compared to 2000 mu g or greater (eight of eight, 37.5%). Increasing age and the presence of an upper respiratory tract infection (URTI) were predictive of failure with OS. Side-effects were more commonly reported with OS (52.6%) than doubling ICS (42.1%) or maintaining usual ICS (19.1%) with the most common being mood changes (36.8%), sleep disturbance (31.6%) and changes in appetite (26.3%). Conclusions: Doubling daily ICS dose per se is not effective for the treatment of mild to moderately severe exacerbations of asthma in adults. Success may depend on achieved ICS dose. Oral steroids are effective, but side-effects are common. A review of current guidelines may be warranted.

Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, P-corrected = 0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

A review of telemedicine and asthma

The literature contains a number of reports of early work involving telemedicine and chronic disease; however, there are comparatively few studies in asthma. Most of the telemedicine studies in asthma have investigated the use of remote monitoring of patients in the home, e.g. transmitting spirometry data via a telephone modem to a central server. The primary objective of these studies was to improve management. A secondary benefit was that patient adherence to prescribed treatment is also likely to be improved. Early results are encouraging; home monitoring in a randomized controlled trial in Japan significantly reduced the number of emergency room visits by patients with poorly controlled asthma. Other studies have described the cost-benefits of a specialist asthma nurse who can manage patients by telephone contact, as well as deliver asthma education. Many web-based systems are available for the general public or healthcare professionals to improve education in asthma, although their quality is highly variable. The work on telemedicine in asthma clearly shows that the technique holds promise in a number of areas. Unfortunately - as in telemedicine generally - most of the literature in patients with asthma refers to pilot trials and feasibility studies, with short-term outcomes. Large-scale, formal research trials are required to establish the cost effectiveness of telemedicine in asthma.

Asthma management by New Zealand pharmacists: a pharmaceutical care demonstration project

Background: Pharmaceutical care services became recognized in New Zealand in the mid-1990s, albeit with limited evidence of the acceptability and effectiveness of the model. An asthma-specific pharmaceutical care service was trialled in southern New Zealand, based on a 'problem-action-outcome' method, with pharmacists adopting a patient-centred, outcome-focused approach with multidisciplinary consultation. Objective: To report on the implementation and outcomes of a specialist asthma service offered by community pharmacists. Design: Pharmacists in five pharmacies, servicing predominantly rural, established clientele, received training in the asthma service and research documentation. Ten patients per pharmacy were recruited in each year (years 1 and 2) of the study. The patients were entered into the study in cohorts of five per pharmacy twice yearly, with year 2 mirroring year 1. The phase-in design minimized the impact on the pharmacists. The patients acted as their own controls. All patients received individualized care and had approximately monthly consultations with the pharmacist, with clinical and quality of life (QoL) monitoring. Results: A total of 100 patients were recruited. On average, 4.3 medication-related problems were identified per patient; two-thirds of them were compliance-related. The most common interventions were revision of patients' asthma action plans, referral and medication counselling. Clinical outcomes included reduced bronchodilator use and improved symptom control in around two-thirds of patients. Asthma-specific QoL changes were more positive and correlated well with clinical indicators. Conclusion: Further research is warranted to integrate this service into daily practice. Clinical outcomes were generally positive and supported by QoL indicators. Characteristics of New Zealand practice and this sample of pharmacies may limit the generalizability of these findings.

Snoring and its association with asthma in Indigenous children living in the Torres Strait and Northern Peninsula Area

Objective: Respiratory health of Indigenous and minority ethnic groups in affluent countries is poorer than their non-minority counterparts and sleep disorders are no exception. In children, obstructive sleep apnoea has the potential to result in serious long-term consequences. In 1999, we studied 1650 children and adolescents living in the Torres Strait and the Northern Peninsula Area, Australia. Here we report prevalence of snoring in these communities and relate its association with asthma symptoms. Methods: A population-based cross-sectional study was conducted in the Torres Strait region. Five indigenous communities were randomly selected and information was collected using a structured face-to-face interview based on a standardized questionnaire. There was a 98% response rate, and 1650 children, 0-17 years of age, were included in the study. Results: Overall, the prevalence of snoring was 14.2% (95% CI 12.5-15.9); 3.6% (95% CI 2.7-4.6) reported snorting, and 6% (95% CI 4.9-7.2) reported restless sleep. The prevalence of snoring was significantly higher among males (17.1% for males and 10.8 for females, P = 0.005). Children were five times more likely to have experienced snoring and snorting if they reported wheezing in the last 12 months. Conclusion: We conclude that the prevalence of symptoms suggestive of obstructive sleep problems is relatively high in children of this region. This highlights the need for awareness among the community patients and physicians about the problem of obstructive sleep-disordered breathing, especially in children with asthma, and for the need for further studies to measure prevalence of sleep breathing disorders among Indigenous Australians.

Clinical presentation of metabolic alkalosis in an adult patient with cystic fibrosis

In subtropical and tropical climates, dehydration is common in cystic fibrosis patients with respiratory exacerbations. This may lead to a clinical presentation of metabolic alkalosis with associated hyponatraemia and hypochloraemia. An adult cystic fibrosis patient who presented with a severe respiratory exacerbation accompanied by metabolic alkalosis is presented and the effects of volume correction are reported.

Asthma and internalizing behavior problems in adolescence: A longitudinal study

Objective: Clinical studies of asthmatic children have found an association between lung disease and internalizing behavior problems. The causal direction of this association is, however, unclear. This article examines the nature of the relationship between behavior and asthma problems in childhood and adolescence. Methods: Data were analyzed on 5135 children from the Mater University Study of Pregnancy and its outcomes (MUSP), a large birth cohort of mothers and children started in Brisbane, Australia, in 1981. Lung disease was measured from maternal reports of asthma/bronchitis when the children were aged 5 and maternal reports of asthma symptoms when the children were aged 14. Symptoms of internalizing behaviors were obtained by maternal reports (Child Behavior Checklist) at 5 years and by maternal and children's reports at 14 years (Child Behavior Checklist and Youth Self Report). Results: Although there was no association between prevalence of asthma and externalizing symptoms, asthma and internalizing symptoms were significantly associated in cross-sectional analyses at 5 and 14 years. In prospective analyses, after excluding children with asthma at 5 years, internalizing symptoms at age 5 were not associated with the development of asthma symptoms at age 14. After excluding children with internalizing symptoms at 5 years, those who had asthma at 5 years had greater odds of developing internalizing symptoms at age 14. Conclusion: Children who have asthma/bronchitis by the age of 5 are at greater risk of having internalizing behavior problems in adolescence.