Cenicriviroc, a dual CCR2 and CCR5 antagonist leads to a reduction in plasma fibrotic biomarkers in persons living with HIV on antiretroviral therapy.

Background: Chronic HIV is associated with increased inflammation and tissue fibrosis despite suppressive antiretroviral therapy (ART). Monocytes and macrophages have been implicated in the pathogenesis of fibrosis, facilitated by chemokine receptor interactions.Methods: We assessed systemic fibrotic biomarkers (transforming growth factor beta-1 [TGF-ß1], thrombospondin-1 [TSP-1], C-terminal pro-peptide of collagen type I [CICP], and IL-11) in banked plasma from a previously published 24-week open-label trial of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, among persons living with HIV (PLWH) on stable ART with undetectable plasma HIV RNA (<50 copies/mL). Fibrotic markers were assessed by ELISA and Luminex. Untreated HIV-seronegative individuals (n = 6) of similar age and demographics served as a comparator group.Results: Median age of PLWH was 55 years. At baseline, PLWH had higher median TGF-ß1 (2.11 vs 1.62 ng/mL, p = 0.01), TSP-1 (236.74 vs 83.29 ng/mL, p < 0.0001), and CICP (200.46 vs 111.28 ng/mL, p = 0.01), but lower IL-11 (36.00 vs 53.74 pg/mL, p = 0.01) compared to HIV-uninfected individuals. Over 24 weeks, median TGF-ß1 (-0.74 ng/mL, p = 0.006), TSP-1 (-52.12 ng/mL, p < 0.0001), and CICP (-28.12 ng/mL, p < 0.0001) decreased and IL-11 (28.98 pg/mL, p < 0.0001) increased in PLWH. At week 24, TGF-ß1, CICP, and IL-11 were similar between the two groups (p > 0.05), while TSP-1 remained elevated in PLWH (p = 0.009) compared to controls.Conclusions: PLWH had higher levels of the plasma fibrotic markers TGF-ß1, TSP-1, and CICP. After 24 weeks of CVC, fibrotic markers generally returned to levels comparable to HIV-uninfected controls. Dual CCR2 and CCR5 blockade may ameliorate the detrimental fibrotic events that persist in treated HIV.

Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria.

BACKGROUND: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30-1500 IU/mL) and bodyweight (30-150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). OBJECTIVES: To determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. METHODS: Data were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). RESULTS: Data for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria; other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV1 ) improved among above-range participants. There was no difference in response between above-range and within-range participants. Above-range participants due to either IgE alone or IgE and weight had similar improvements in ACQ-5, AQLQ and FEV1 . CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.

Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry.

BACKGROUND: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbidities are limited. AIMS: To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. METHODS: A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. RESULTS: Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 ≥ 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). CONCLUSION: Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.

The health behaviour and clinical characteristics of ambulance users with acute asthma.

OBJECTIVE: This study sought to determine if ambulance service users differ in their health behaviours to "walk-in" patients attending an emergency department (ED) with acute asthma. METHOD: Retrospective cross-sectional study of people with acute asthma stratified by ambulance use attending two ED. The health-promoting lifestyle profile and health risk appraisal tools assessed health and risk-taking behaviours, and the clinical variables assessed include: forced expiratory volume in 1 s, admission rates, severity, asthma medications, anxiety and depression. RESULTS: Of the 142 patients, 26% used the ambulance service as transport to the ED. Ambulance users were significantly older than walk-in patients (40 vs 32 years, p < or = 0.05) and were less likely to return to follow-up appointments (odds ratio (OR) 2.93, 95% CI 1.16 to 7.37). Walk-in patients were more likely to report higher levels of education (OR 4.36, 95% CI 1.11 to 17.09). There was no difference between the groups for health-promoting behaviours. In reducing risks to their health and after adjusting for age and gender, there was a trend towards ambulance users undertaking preventive health measures more often than walk-in patients. CONCLUSIONS: Ambulance users with acute asthma are more likely to be older, married and less educated. There is no evidence that this group is less responsible in managing their health; however, fewer ambulance users attended their follow-up appointment and the implication for ongoing care requires further investigation.

Standard versus patient-centred asthma education in the emergency department: a randomised study.

High re-attendance rates are common after asthma emergency department (ED) care. Inadequate patient education has been cited as a potential cause of re-attendance and the optimal format of education is uncertain. The present study aimed to compare the effectiveness of patient-centred education (PCE) and standard asthma patient education on ED re-attendance. A randomised controlled trial was conducted at two inner-city Australian teaching hospitals' EDs, where patients received either standard patient education (SPE) or PCE. Both groups received a six-topic curriculum. However, PCE patients reordered the topics according to their own priority and thus controlled the order of education. In total, 146 adult patients presenting to EDs with acute asthma were enrolled. After 4 months, ED re-attendance decreased from 22 to 12% in the PCE group and remained unchanged in the SPE group (between group odds ratio 0.4, 95% confidence interval (0.2-1.1)). In 78 patients discharged after ED care, the PCE group had fewer re-attendances after 4 and 12 months (0.3 (0.1-0.9) and 0.3 (0.1-0.8), respectively ). PCE patients with no general practitioner care in the preceding 7 days had fewer re-attendances after 4 and 12 months (0.1 (0.0-0.7) and 0.2 (0.0-0.6), respectively). A trend of better asthma control was evident, with a reduction in activity limitation. In conclusion, patient-centred education offers promise as a brief education process in the emergency department. However, a large multicentre trial of patient-centred education is required.

Daily versus weekly azithromycin in cystic fibrosis patients.

Four randomised, placebo-controlled trials have previously documented the clinical benefits of azithromycin (AZM) in cystic fibrosis (CF) patients. The present study examined whether the beneficial effect of AZM is equivalent when administered daily or weekly. A double-blind, randomised study was carried out in 208 CF patients aged 6-58 yrs who were assigned to AZM either 250 mg daily (n = 103) or 1,200 mg weekly (n = 105) for 6 months, with assessments at baseline and at 1, 3, 6 and 7 months. Patients were taken from five adult and children CF centres in South-east Queensland, Australia. Equivalence was demonstrated between the two groups (daily versus weekly) with respect to improvements in lung function (forced expiratory volume in one second and forced vital capacity), C-reactive protein, days spent in hospital, admission rates and nutrition (body mass index, z-scores) using 95% confidence intervals with a tolerance interval of +/-10%. In patients aged <18 yrs the daily group had significantly better improvements in z-scores for height and weight after 6 months. In children, a nutritional advantage for daily administration was found. Gastro-intestinal adverse effects were more common with weekly therapy. Apart from these findings, daily and weekly administered azithromycin demonstrated similar outcomes for cystic fibrosis patients.

Abstracts from the Society for Acute Medicine: Spring meeting.

We have successfully been running with a Consultant presence in day-time (0900-1700) in the admissions area for a number of years. The recent NCEPOD report - an Acute Problem, criticised the lack of Consultant input into care of patients being transferred to Critical care areas out of hours. The DoH Hospital at Night project has suggested extending the normal working day into the twilight shift.

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 (FEV(1)) 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 microg (three of 11, 73%) compared to 2000 microg 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.

Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.

BACKGROUND: Relentless chronic pulmonary inflammation is the major contributor to morbidity and mortality in patients with cystic fibrosis (CF). While immunomodulating therapies such as prednisolone and ibuprofen may be beneficial, their use is limited by side effects. Macrolides have immunomodulatory properties and long term use dramatically improves prognosis in diffuse panbronchiolitis, a condition with features in common with the lung disease of CF. METHODS: To determine if azithromycin (AZM) improves clinical parameters and reduces inflammation in patients with CF, a 3 month prospective randomised double blind, placebo controlled study of AZM (250 mg/day) was undertaken in adults with CF. Monthly assessment included lung function, weight, and quality of life (QOL). Blood and sputum collection assessed systemic inflammation and changes in bacterial flora. Respiratory exacerbations were treated according to the policy of the CF Unit. RESULTS: Sixty patients were recruited (29 men) of mean (SD) age 27.9 (6.5) years and initial forced expiratory volume in 1 second (FEV1) 56.6 (22.3)% predicted. FEV1% and forced vital capacity (FVC)% predicted were maintained in the AZM group while in the placebo group there was a mean (SE) decline of -3.62 (1.78)% (p=0.047) and -5.73 (1.66)% (p=0.001), respectively. Fewer courses of intravenous antibiotics were used in patients on AZM (0.37 v 1.13, p=0.016). Median C reactive protein (CRP) levels declined in the AZM group from 10 to 5.4 mg/ml but remained constant in the placebo group (p<0.001). QOL improved over time in patients on AZM and remained unchanged in those on placebo (p=0.035). CONCLUSION: AZM in adults with CF significantly improved QOL, reduced CRP levels and the number of respiratory exacerbations, and reduced the rate of decline in lung function. Long term AZM may have a significant impact on morbidity and mortality in patients with CF. Further studies are required to define frequency of dosing and duration of benefit.

Cost comparison of hospital- and home-based treatment models for acute chronic obstructive pulmonary disease.

This trial compared the cost of an integrated home-based care model with traditional inpatient care for acute chronic obstructive pulmonary disease (COPD). 25 patients with acute COPD were randomised to either home or hospital management following request for hospital admission. The acute care at home group costs per separation ($745, CI95% $595-$895, n = 13) were significantly lower (p < 0.01) than the hospital group ($2543, CI95% $1766-$3321, n = 12). There was an improvement in lung function in the hospital-managed group at the Outpatient Department review, decreased anxiety in the Emergency Department in the home-managed group and equal patient satisfaction with care delivery. Acute care at home schemes can substitute for usual hospital care for some patients without adverse effects, and potentially release resources. A funding model that allows adequate resource delivery to the community will be needed if there is a move to devolve acute care to community providers.

The effects of salbutamol, beclomethasone, and dexamethasone on fibronectin expression by cultured airway smooth muscle cells.

Possible mechanisms of adverse drug effects in asthma include worsening of cellular hyperplasia and stimulation of extracellular matrix deposition. In this study, salbutamol, dexamethasone and beclomethasone were investigated to ascertain their ability to induce mitogenesis and stimulate fibronectin expression in cultured canine airway smooth muscle cells. In cells maintained in serum-free media for 72 h, salbutamol (1 nM-10 microM) caused mitogenesis. The control cells had 2.57 +/- 0.34 x 10(5) cells per ml (mean +/- SEM, N = 13), while salbutamol (1 microM) caused a maximal increase in cell number to 3.57 +/- 0.23 x 10(5) cells/ml (P < 0.01). In cells stimulated to replicate by addition of either fetal bovine serum or canine serum, no additional mitogenic effect of salbutamol was seen. Salbutamol did not have a detectable quantitative effect on fibronectin matrix expression. The glucocorticoids, beclomethasone and dexamethasone, significantly altered fibronectin expression by cultured airway smooth muscle cells. Beclomethasone increased fibronectin expression, while dexamethasone decreased expression.

Are antipseudomonal antibiotics really beneficial in acute respiratory exacerbations of cystic fibrosis?

BACKGROUND: Although anti-pseudomonal antibiotics are routinely used in the treatment of acute respiratory exacerbations of adult cystic fibrosis (CF), the specific efficacy of such treatment remains uncertain, the mechanism of action of these agents is not fully understood, and the role of sputum susceptibility testing in clinical decision making is controversial. AIMS: We investigated the relationship between susceptibility testing and clinical outcome in adult CF patients colonised with Pseudomonas aeruginosa. METHODS: Sputum samples were collected before, during and after respiratory exacerbations from 31 admissions (17 patients). Sputum colony counts and MIC of P. aeruginosa were performed. RESULTS: Sputum colony counts did not change significantly during or after intravenous (IV) antibiotic therapy. Clinical outcome parameters (lung function, 12-minute walking distance, sputum weight and quality of life) were compared with susceptibility of P. aeruginosa colonies isolated at admission to the antibiotics used, and no correlation was evident. There was no evidence for the development of cross-resistance and there was no change in the proportion of mucoid colonies with therapy. CONCLUSIONS: While this study has a small patient sample size, it highlights the inconsistency of the role of antipseudomonal drugs also shown in other similar studies. The presence of P. aeruginosa in sputum of acutely ill CF patients prompts us to prescribe i.v. antipseudomonal drugs. If this approach was valid, we would expect to find a reduction in sputum colony counts and improvement in clinical parameters with the use of antibiotics to which the organisms were sensitive. The fact that such a relationship cannot be consistently demonstrated in this and other studies suggests that the use of antipseudomonal therapy in these patients requires more critical bacteriological and clinical evaluation.

Cytokines and inflammatory mediators do not indicate acute infection in cystic fibrosis.

Various treatment regimens and difficulties with research design are encountered with cystic fibrosis (CF) because no standard diagnostic criteria exist for defining acute respiratory exacerbations. This study evaluated the role of serial monitoring of concentrations of selected cytokines and inflammatory mediators in serum and sputum as predictors of respiratory exacerbation, as useful outcome measures for CF, and to guide therapy. Interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha), neutrophil elastase-alpha-1-protease inhibitor complex (NE complex), protein, and alpha-1-protease inhibitor (alpha-1-PI) were measured in serum and sputum collected from CF patients during respiratory exacerbations and periods of well-being. Levels of NE complex, protein, and alpha-1-PI in sputum rose during respiratory exacerbations and fell after institution of antibiotic therapy (P = 0.078, 0.001, and 0.002, respectively). Mean (+/- standard error of the mean) levels of IL-8 and TNF-alpha were extremely high in sputum (13,780 +/- 916 and 249.4 +/- 23.5 ng/liter, respectively) but did not change significantly with clinical deterioration of the patient (P > 0.23). IL-8 and TNF-alpha were generally undetectable in serum, and therefore these measures were unhelpful. Drop in forced expiratory volume in 1 s was the only clinical or laboratory parameter that was close to being a determinant of respiratory exacerbation (P = 0.055). This study provides evidence of intense immunological activity occurring continually within the lungs of adult CF patients. Measurement of cytokines and inflammatory mediators in CF sputum is not helpful for identifying acute respiratory exacerbations.

Role extension or expansion: a qualitative investigation of the perceptions of senior medical and nursing staff in an adult intensive care unit.

The Scope of Professional Practice (UKCC 1992) has significantly altered the interpretation of nurses' roles, emphasizing individual professional accountability and clinical decision-making. However, 5 years after the issue of the document, uncertainties remain regarding interprofessional legal accountability between medicine and nursing. To investigate issues surrounding role extension or expansion in intensive care nursing, a small qualitative study was conducted centred on one intensive care unit (ICU) within a large teaching hospital. Data were collected by semi-structured interviews from a purposive sample of five senior intensive care nurses and three consultant anaesthetists. Four major categories emerged, identified as: interpretation confusion; education for change; struggles for power and task versus autonomy. The findings revealed that the senior critical care nurses identified themselves as independent, autonomous practitioners involved in clinical decision-making. However, there was evidence of a reluctance to empower more junior staff to perform extended or expanded roles. Medical respondents viewed extended or expanded roles as taking on mechanical tasks for which anyone could be trained to perform. In conclusion, it is argued that although nursing is maturing in its growth towards professionalization, broader issues such as the legal quagmire, failure to adopt the philosophy of role expansion and the existence of sacred boundaries intra- and inter-professionally need to be addressed.

Buteyko breathing techniques in asthma: a blinded randomised controlled trial.

OBJECTIVE: To evaluate the effect of Buteyko breathing techniques (BBT) in the management of asthma. DESIGN: Prospective, blinded, randomised study comparing the effect of BBT with control classes in 39 subjects with asthma. The study was conducted from January 1995 to April 1995. PARTICIPANTS AND SETTING: Subjects recruited from the community, aged 12 to 70 years, with asthma and substantial medication use. MAIN OUTCOME MEASURES: Medication use; morning peak expiratory flow (PEF); forced expiratory volume in one second (FEV1); end-tidal (ET) CO2; resting minute volume (MV); and quality of life (QOL) score, measured at three months. RESULTS: No change in daily PEF or FEV1 was noted in either group. At three months, the BBT group had a median reduction in daily beta 2-agonist dose of 904 micrograms (range, 29 micrograms to 3129 micrograms), whereas the control group had a median reduction of 57 micrograms (range, -2343 micrograms to 1143 micrograms) (P = 0.002). Daily inhaled steroid dose fell 49% (range, -100% to 150%) for the BBT group and 0 (range, -82% to +100%) for the control group (P = 0.06). A trend towards greater improvement in QOL score was noted for BBT subjects (P = 0.09). Initial MV was high and similar in both groups; by three months, MV was lower in the BBT group than in the control group (P = 0.004). ET CO2 was low in both groups and did not change with treatment. CONCLUSION: Those practising BBT reduced hyperventilation and their use of beta 2-agonists. A trend toward reduced inhaled steroid use and better quality of life was observed in these patients without objective changes in measures of airway calibre.