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.

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.

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.

Corticotropin deficiency: a rare cause of hyponatremia mimicking SIADH.

We describe 2 patients presenting with severe chronic hyponatremia in whom clinical and biochemical features strongly suggested the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Both, however, were proven to have a primary pituitary deficiency of corticotropin. Their short synacthen tests were only mildly abnormal but associated with low basal ACTH levels. The diagnosis of ACTH deficiency was made more convincingly by their dramatic response to glucocorticoid replacement therapy. In patients in whom no cause for SIADH can be found, a trial of maintenance cortisol therapy is warranted to exclude this eminently treatable condition.

Homologous serum increases fibronectin expression and cell adhesion in airway smooth muscle cells.

This study describes altered patterns of growth and upregulation of fibronectin expression of cultured canine airway smooth muscle cells grown in homologous serum, which provides a model of the vascular leakage occurring in asthma, compared to fetal bovine serum (FBS). Cells were incubated in increasing concentrations of serum (2.5-40%) for 72 hours. Both homologous serum and FBS caused cellular proliferation which reached a maximum increase at 2.5-5% serum concentration. Differences in the cellular responses to the two types of sera were noted at higher concentrations of sera. At a concentration of 40% FBS, airway smooth muscle cells increased in number by 307 +/- 16% (n = 5) compared to serum-free control cells, whereas in canine serum the increase in growth was significantly smaller, 239 +/- 25% (n = 7) (P < 0.05). Airway fibrocytes similarity treated increased in number by 256 +/- 43% (n = 3) in 40% FBS, but exhibited a reduction in cell number to 80 +/- 10% (n = 3) of controls in 40% homologous serum (P < 0.05). Smooth muscle cells demonstrated a dose-dependent increase in fibronectin expression when grown in homologous serum but not in FBS, suggesting phenotypic change occurred in these cells when exposed to homologous serum. These data suggest that the leakage of plasma in the asthmatic airway may trigger phenotypic change in both airway smooth muscle cells and airway fibrocytes leading to cellular proliferation and expression of extracellular matrix molecules. These in vitro changes are consistent with the histological findings in clinical asthma.

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.

Airway smooth muscle proliferation in asthma: the potential of vascular leakage to contribute to pathogenesis.

Proliferation of the non-vascular smooth muscle in the walls of the bronchi and bronchioles is a prominent histopathological feature of asthma and is thought to contribute to airway hyperreactivity and narrowing. Increased vascular permeability with plasma leakage is also a feature of asthma pathology and causes submucosal oedema. We hypothesize that, in asthmatics, the accumulation of enriched plasma in the environment surrounding airway smooth muscle promotes respiratory smooth muscle mitogenesis and hyperplasia. This situation represents the in vivo correlate of the increase in airway smooth muscle cell growth seen in vitro with increasing concentrations of serum in the culture medium. Thus, we hypothesize that vascular leakage in the airways in asthma is a primary pathogenic event leading to airway smooth muscle hyperplasia and hypertrophy, and consequently airway narrowing, promoting the characteristic bronchial hyperreactivity associated with narrowing of the airway lumen.

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.

Long acting beta agonists.

Long acting beta agonists (LABAs) such as salmeterol and eformoterol provide 12 hour bronchodilatation, giving continuous control of asthma symptoms particularly at night. More recent evidence also suggests a role as 'steroid-sparing' agents, allowing control of asthma at lower doses of inhaled corticosteroids (ICS). Providing a sufficient dose of inhaled steroid (in adults around 800 micrograms of belcomethasone or budesonide or 400 micrograms of fluticasone) is used in conjunction with LABAs, there is no evidence of any increase in asthma exacerbation. Cost is the major impediment to the widespread application of these useful agents.

Management of the acute asthma attack at home.

Asthma is a disease of remission and exacerbation but the combination of optimal interval therapy with early aggressive self initiated medication during deterioration (particularly oral corticosteroids) should prevent the crises which require emergency intervention. The first and last words in acute asthma management must be prevention and prevention.

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.

Meningococcal disease.

This article discusses meningococcal disease and outlines the role of the nurse in treating patients who may suffer from meningitis, one of the illnesses caused by meningococcal disease. It goes on to discuss how nurses can support the relatives of these patients.

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.