High body mass index and pre-existing autoimmune disease are associated with an increased risk of immune-related adverse events in cancer patients treated with PD-(L)1 inhibitors across different solid tumors.

BACKGROUND: Treatment with anti-PD-(L)1 antibodies, approved for several oncology indications, can lead to immune-related adverse events (irAEs). We aimed to investigate risk factors associated with an increased reporting of irAEs in patients treated with PD-(L)1 inhibitors approved for solid tumor indications. PATIENTS AND METHODS: A retrospective review was performed of individual data from patients in phase II/III registrational studies for PD-(L)1 inhibitors in solid tumors. Data on baseline characteristics and adverse events were extracted. Univariate and multivariable logistic regression models were used to identify risk factors. RESULTS: In total, 5123 patients were included from 15 studies reporting on the use of four PD-(L)1 inhibitors for five solid tumor indications. Univariate analysis suggested that type of study drug (P < 0.001), indication (P = 0.003), body mass index (BMI) (P = 0.001), and baseline autoimmune disease (P < 0.001) were associated with an increased occurrence of any irAE. Using logistic regression analyses, three factors were identified as increasing the risk of irAE: BMI ≥ 30 kg/m2 [odds ratio (OR) 1.5, 95% confidence interval (CI) 1.2-1.8] in comparison to normal BMI, having an autoimmune disease at baseline (OR 1.8, 95% CI 1.1-2.7), and use of a PD-L1 inhibitor (OR 1.6, 95% CI 1.2-2.0). The latter finding is probably biased due to the selection of the studies in the dataset with complete information on baseline characteristics. CONCLUSION: This study was conducted using a large dataset of individual patient data from clinical trials comprising multiple solid tumor indications. We demonstrated that patients with obesity and concurrent autoimmune disease were at increased risk of developing irAEs.

Whole-grain intake and its inverse relationships with fatty acids intake among multiethnic Malaysian schoolchildren.

INTRODUCTION: Little is known about the relationship of whole-grain intake with dietary fatty acids intake. The present study aimed to assess the whole-grain intake and its relationships with dietary fatty acids intake among multiethnic schoolchildren in Kuala Lumpur, Malaysia. METHODS: This cross-sectional study was conducted among 392 schoolchildren aged 9-11 years, cluster sampled from five randomly selected schools in Kuala Lumpur. Whole-grain and fatty acids intakes were assessed by 3-day, 24-h diet recalls. All whole-grain foods were considered irrespective of the amount of whole grain they contained. RESULTS: In total, 55.6% (n = 218) were whole-grain consumers. Mean (SD) daily intake of whole grain in the total sample was 5.13 (9.75) g day-1 . In the whole-grain consumer's only sample, mean (SD) intakes reached 9.23 (11.55) g day-1 . Significant inverse associations were found between whole-grain intake and saturated fatty acid (SAFA) intake (r = -0.357; P < 0.001), monosaturated fatty acid (MUFA) (r = -0.373; P < 0.001) and polyunsaturated fatty acid (PUFA) (r = -0.307; P < 0.001) intake. Furthermore, whole-grain intake was a significant predictor of SAFA (ß = -0.077; P = 0.004), MUFA (ß = -0.112; P = <0.001) and PUFA (ß = -0.202; P = <0.001) intakes, after controlling for sex, age and ethnicity. CONCLUSIONS: Whole-grain intake in Malaysia was well below recommendations. Schoolchildren who consumed higher whole grain tend to reduce fat intake; however, it would also reduce the SAFA, MUFA and PUFA intakes. Future collaboration may be conducted between industry, government and universities to promote unsaturated fatty acids-rich foods and whole-grain food, although not to promote processed whole-grain foods with a high sugar and salt content.

Working while unwell: Workplace impairment in people with severe asthma.

BACKGROUND: Severe asthma affects quality of life; however, its impact on workplace productivity is poorly understood. OBJECTIVE: To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma. METHODS: The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years; 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated. RESULTS: At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P < .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P < .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P < .01). CONCLUSION AND CLINICAL RELEVANCE: Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age.

Comorbid "treatable traits" in difficult asthma: Current evidence and clinical evaluation.

The care of patients with difficult-to-control asthma ("difficult asthma") is challenging and costly. Despite high-intensity asthma treatment, these patients experience poor asthma control and face the greatest risk of asthma morbidity and mortality. Poor asthma control is often driven by severe asthma biology, which has appropriately been the focus of intense research and phenotype-driven therapies. However, it is increasingly apparent that extra-pulmonary comorbidities also contribute substantially to poor asthma control and a heightened disease burden. These comorbidities have been proposed as "treatable traits" in chronic airways disease, adding impetus to their evaluation and management in difficult asthma. In this review, eight major asthma-related comorbidities are discussed: rhinitis, chronic rhinosinusitis, gastroesophageal reflux, obstructive sleep apnoea, vocal cord dysfunction, obesity, dysfunctional breathing and anxiety/depression. We describe the prevalence, impact and treatment effects of these comorbidities in the difficult asthma population, emphasizing gaps in the current literature. We examine the associations between individual comorbidities and highlight the potential for comorbidity clusters to exert combined effects on asthma outcomes. We conclude by outlining a pragmatic clinical approach to assess comorbidities in difficult asthma.

Vimentin over-expression and carbonic anhydrase IX under-expression are independent predictors of recurrence, specific and overall survival in non-metastatic clear-cell renal carcinoma: a validation study.

PURPOSE: Clinical outcomes prognostic markers are awaited in clear-cell renal carcinoma (ccRCC) to improve patient-tailored management and to assess six different markers' influence on clinical outcomes from ccRCC specimen and their incremental value combined with TNM staging. MATERIALS AND METHODS: This is a retrospective, multicenter study. One hundred and forty-three patients with pT1b-pT3N0M0 ccRCC were included. Pathology specimens from surgeries were centrally reviewed, mounted on a tissue micro-array and stained with six markers: CAIX, c-MYC, Ki67, p53, vimentin and PTEN. Images were captured through an Ultra Fast Scanner. Tumor expression was measured with Image Pro Plus. Cytoplasmic markers (PTEN, CAIX, vimentin, c-MYC) were expressed as surface percentage of expression. Nuclear markers (Ki67, p53) were expressed as number of cells/mm2. Clinical data and markers expression were compared with clinical outcomes. Each variable was included in the Cox proportional multivariate analyses if p < 0.10 on univariate analyses. Discrimination of the new marker was calculated with Harrell's concordance index. RESULTS: At median follow-up of 63 months (IQR 35.0-91.8), on multivariate analysis, CAIX under-expression and vimentin over-expression were associated with worse survival (recurrence, specific and overall survival). A categorical marker CAIX-/Vimentin+ with cutoff points for CAIX and vimentin of 30 and 50 %, respectively, was designed. The new CAIX-/Vimentin+ marker presented a good concordance and comparable calibration to the reference model. Limitations are the retrospective design, the need for external validation and the large study period. CONCLUSION: Using an automated technique of measurement, CAIX and vimentin are independent predictors of clinical outcomes in ccRCC.

Profile of difficult to treat asthma patients referred for systematic assessment.

AIM: We determined the proportion of asthma patients under specialist care who remain difficult-to-treat and might benefit from systematic assessment. We additionally report the characteristics and indications for referral in 90 patients who received systematic assessment for difficult asthma. METHODS: We conducted a three-month prospective audit of our hospital's general asthma clinic. We then analyzed consecutive patients over 18 months referred on for systematic assessment of difficult asthma. RESULTS: Over 3 months, 22/166 patients (13.3%) in the general asthma clinic were considered likely to benefit from systematic assessment of difficult asthma. These patients had higher inhaled steroid requirements (890 ± 604 mg), lower lung function (FEV1: 65 ± 18%), and more often received GINA step 5 treatment (22.7%). However, 7/22 (32%) of suitable patients were not referred for assessment, mainly due to patient factors. Over 18 months, 90 patients received systematic assessment for difficult asthma, on account of poor symptom control (62%), frequent exacerbations (44%), poor lung function (42%), patient factors (29%), and diagnostic uncertainty (26%). There was a high disease burden with a mean (±SD) asthma control test score and asthma quality of life questionnaire score of 14 ± 5 and 4.26 ± 1.45 respectively. 80% fulfilled criteria for severe asthma. The majority were either atopic (66.7%) or eosinophilic (54.4%); only 15.6% were neither. Patients had a median of three extra-pulmonary comorbidities, of which most were previously unrecognised. CONCLUSION: One-in-eight asthma patients already under specialist care were suitable for systematic assessment of difficult asthma, but a third of these were not referred due to patient factors. Diagnostic uncertainty and patient factors were important indications for systematic assessment. Most patients who underwent systematic assessment exhibited severe asthma phenotypes potentially responsive to targeted treatment, but also had multiple comorbidities. Our results highlight the importance of management strategies to address patient factors, severe asthma biology, and concurrent contributory conditions.

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.

Elevated total serum immunoglobulin E (>1000 IU/mL): implications?

Atopic eczema, allergic broncho-pulmonary aspergillosis, helminthic infections and rare primary immunodeficiencies are known to elevate total serum immunoglobulin E (IgE) above 1000 IU/mL. However, of 352 patients with IgE >1000 IU/mL seen in our hospital over a 5-year period, less than 50% had these conditions. Markedly elevated IgE levels in the rest of the patients were associated with asthma, allergic rhinitis and food allergy, instances where the test is of limited diagnostic utility.

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.

CD11b immunophenotyping identifies inflammatory profiles in the mouse and human lungs.

The development of easily accessible tools for human immunophenotyping to classify patients into discrete disease endotypes is advancing personalized therapy. However, no systematic approach has been developed for the study of inflammatory lung diseases with often complex and highly heterogeneous disease etiologies. We have devised an internally standardized flow cytometry approach that can identify parallel inflammatory alveolar macrophage phenotypes in both the mouse and human lungs. In mice, lung innate immune cell alterations during endotoxin challenge, influenza virus infection, and in two genetic models of chronic obstructive lung disease could be segregated based on the presence or absence of CD11b alveolar macrophage upregulation and lung eosinophilia. Additionally, heightened alveolar macrophage CD11b expression was a novel feature of acute lung exacerbations in the SHIP-1(-/-) model of chronic obstructive lung disease, and anti-CD11b antibody administration selectively blocked inflammatory CD11b(pos) but not homeostatic CD11b(neg) alveolar macrophages in vivo. The identification of analogous profiles in respiratory disease patients highlights this approach as a translational avenue for lung disease endotyping and suggests that heterogeneous innate immune cell phenotypes are an underappreciated component of the human lung disease microenvironment.

Direct ultrasound localisation for pleural aspiration: translating evidence into action.

BACKGROUND: There is strong evidence that direct ultrasound localisation for pleural aspiration reduces complications, but this practice is not universal in Australia and New Zealand. AIMS: To describe the current utilisation and logistical barriers to the use of direct ultrasound localisation for pleural aspiration by respiratory physicians from Australia and New Zealand, and to determine the cost benefits of procuring equipment and training resources in chest ultrasound. METHODS: We surveyed all adult respiratory physician members of the Thoracic Society of Australia and New Zealand regarding their use of direct ultrasound localisation for pleural aspiration. We performed a cost-benefit analysis for acquiring bedside ultrasound equipment and estimated the capacity of available ultrasound training. RESULTS: One hundred and forty-six of 275 respiratory physicians responded (53% response). One-third (33.6%) of respondents do not undertake direct ultrasound localisation. Lack of training/expertise (44.6%) and lack of access to ultrasound equipment (41%) were the most frequently reported barriers to performing direct ultrasound localisation. An average delay of 2 or more days to obtain an ultrasound performed in radiology was reported in 42.7% of respondents. Decision-tree analysis demonstrated that clinician-performed direct ultrasound localisation for pleural aspiration is cost-beneficial, with recovery of initial capital expenditure within 6 months. Ultrasound training infrastructure is already available to up-skill all respiratory physicians within 2 years and is cost-neutral. CONCLUSION: Many respiratory physicians have not adopted direct ultrasound localisation for pleural aspiration because they lack equipment and expertise. However, purchase of ultrasound equipment is cost-beneficial, and there is already sufficient capacity to deliver accredited ultrasound training through existing services.

Chest ultrasound in practice: a review of utility in the clinical setting.

Clinician-performed chest ultrasound is rapidly entering clinical practice in the fields of intensive care, respiratory medicine and acute medicine. Ultrasound is clearly useful in the diagnosis and characterisation of pleural diseases. It is also critical in improving the safety of pleural interventions. More recently, attention has also focused on the use of lung ultrasound. While the normal aerated lung is not well imaged by ultrasound, lung pathology reaching the pleura often provides an 'acoustic window' for a number of lung conditions. Lung ultrasound is useful to diagnose pneumothorax, interstitial and alveolar lung abnormalities, and pleurally based lung masses. There is some evidence that integrating routine chest ultrasound into clinical practice has benefit in the emergency and intensive care settings. In the future, chest ultrasound is likely to become an essential physician skill, and training requirements are evolving in light of current developments.

Mediastinal staging of non-small-cell lung cancer among Australasian thoracic physicians: clinical practice and constraints on minimally invasive techniques.

BACKGROUND/AIM: We determined current practice among Australasian thoracic physicians in the mediastinal staging of non-small-cell lung cancer (NSCLC). We focused on the availability of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) and constraints to its use, as there has been no systematic analysis regarding the availability and uptake of this new technology among thoracic physicians. METHODS: Physician members of the Thoracic Society of Australia and New Zealand were emailed a survey seeking their current approach to three scenarios requiring mediastinal staging of NSCLC. Respondents were also asked for their preferred investigation for each scenario if any current constraints were removed. Relevant demographic information was sought. RESULTS: We received 164 responses from 512 Australasian physicians (34%). Without constraints, EBUS-TBNA was the preferred investigation for all three clinical scenarios, but only 33% of respondents had access to EBUS-TBNA. Constraints included lack of availability and lack of expertise. Reduced EBUS-TBNA access was associated with a number of clinician factors. CONCLUSIONS: Australasian thoracic physicians prefer EBUS-TBNA for the mediastinal staging of NSCLC, but access to EBUS-TBNA services is limited. We recommend targeted measures to improve access to EBUS-TBNA use and optimise mediastinal staging of NSCLC.

Critical appraisal of the PADUA classification and assessment of the R.E.N.A.L. nephrometry score in patients undergoing partial nephrectomy.

PURPOSE: We validated the PADUA classification and assessed the R.E.N.A.L. nephrometry score to predict perioperative complications of partial nephrectomy. In addition, we assessed their interobserver variability, and the ability to predict the use of ischemia and ischemia time. MATERIALS AND METHODS: Data from consecutive cases of partial nephrectomy with or without ischemia from 3 centers were retrospectively collected. Associations between preoperative variables and complications were evaluated in univariate and multivariate analyses. Reproducibility was assessed by determining Fleiss' generalized kappa and intraclass correlation coefficients in a subcohort scored by 3 physicians with different degrees of urological expertise. RESULTS: A total of 134 partial nephrectomies were included in the study and 31 cases (23%) presented with complications. On univariate analyses complications were associated with age (p = 0.02), tumor size on computerized tomography (p = 0.01), pT stage (p = 0.001), and PADUA (p = 0.001) and R.E.N.A.L. scores (p = 0.02). In 3 multivariate models PADUA score 10 or greater (OR 3.98, p = 0.01), R.E.N.A.L. score 9 or greater (OR 4.21, p = 0.02), tumor size in cm (OR 1.35, p = 0.02) and age (OR 1.04, p = 0.04) were independent predictors of complications. The R.E.N.A.L. nephrometry score predicted the use of ischemia (p = 0.03) and both scores predicted ischemia time (both p <0.001). Kappa was 0.37 to 0.80 for PADUA components and 0.23 to 0.73 for R.E.N.A.L. components. The intraclass correlation coefficient was 0.73 for PADUA and 0.70 for R.E.N.A.L. score. CONCLUSIONS: The highest categories of PADUA and R.E.N.A.L. scores as well as clinical tumor size predict the risk of perioperative complications of partial nephrectomy. Both scores can indicate ischemia time. Their reproducibility is substantial but the implementation of these systems in clinical practice needs further refinement.

Bronchoscopic evaluation of the mediastinum using endobronchial ultrasound: a description of the first 216 cases carried out at an Australian tertiary hospital.

BACKGROUND: Performance of linear probe endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for staging non-small-cell lung cancer has been extensively studied. Alternate indications for its use are less well characterised, and performance in other clinical settings may differ. METHODS: We examined a prospectively collected cohort comprising the first 215 patients undergoing EBUS-TBNA at our institution. Patients were analysed according to the clinical and radiological indication for referral. We also examined the effect of the procedural learning curve on diagnostic sensitivity. RESULTS: A total of 215 patients underwent 216 EBUS-TBNA procedures. EBUS-TBNA returned adequate tissue for cytopathological analysis in 202 of 216 procedures (94%). Overall sensitivity for detection of malignancy was 0.92 (95% confidence interval 0.86-0.96); however, this varied according to the primary indication for EBUS-TBNA. Diagnostic sensitivity was high among all sub-groups, but the negative predictive value varied depending on the clinical indication for the procedure. We estimate 104 invasive surgical procedures and 32 inpatient admissions were avoided by use of EBUS-TBNA. Significant improvement in diagnostic performance was seen after 20 procedures were completed, and diagnostic accuracy did not peak until after 50 procedures. CONCLUSIONS: EBUS-TBNA is able to confirm accurately histologically a large number of disease processes, both malignant and benign, in all clinical indications studied. The procedure is safe even when carried out by proceduralists with minimal prior experience. Diagnostic performance continues to improve beyond 50 cases carried out.

Corticosteroid insensitivity in severe asthma: significance, mechanisms and aetiology.

Chronic severe asthma remains a challenging clinical problem despite the availability of modern treatments. Relative corticosteroid insensitivity is present in severe asthma and may contribute to continuing disease severity. Advances in the understanding of molecular mechanisms underlying corticosteroid insensitivity may yield new therapeutic targets. Furthermore, aetiological factors for corticosteroid insensitivity have been identified and these may be amenable to modification.

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma.

Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone. We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentration-dependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method. SD282 (10(-7) M), with dexamethasone (10( -6) M), caused a greater inhibition of release of IL-1beta, IL-6, macrophage inflammatory protein-1alpha and IL-10, than with dexamethasone alone in AMs from severe and non-severe asthma. At 10(-9) and 10(-10) M, GW-A, that had no direct effects, increased the inhibitory activity of dexamethasone (10(-8) and 10( -6) M) on LPS-induced IL-8 release in PBMCs from severe asthma. Corticosteroid insensitivity in severe asthma patients may be improved by inhibitors of p38 MAPK.

Inflammatory biomarkers in airways of patients with severe asthma compared with non-severe asthma.

BACKGROUND: About 5-10% of patients with asthma suffer from poorly-controlled disease despite corticosteroid (CS) therapy. OBJECTIVE: We determined whether there were any differences in inflammatory biomarkers between severe and non-severe asthma patients. METHODS: Nineteen severe and 20 non-severe asthma patients were recruited and underwent collection of induced sputum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies. RESULTS: Biopsy results showed no differences in eosinophils (major basic protein positive), neutrophils, macrophages, T cells and mast cells in the bronchial submucosa. However, subbasement membrane (SBM) thickness and smooth muscle area were increased in the biopsies. No significant differences were observed in the induced sputum inflammatory cells. In BAL fluid, there was a significant increase in neutrophils but a significant decrease in macrophages. Eosinophil counts were non-significantly increased threefold in both sputum and BAL in severe asthma. Levels of IL-8 and IL-13 in sputum supernatants were similar in both groups of asthma patients. There was a significant inverse correlation between post-bronchodilator forced expiratory volume in 1 s and provocative concentration of methacholine causing a 20% fall in FEV(1) with SBM thickness. CONCLUSION: Differences in inflammatory cells were observed mainly in terms of increased neutrophils and reduction in macrophage numbers in BAL fluid with a trend towards increased eosinophils in severe asthma compared with non-severe asthma. However, the most notable features are the increase in features of airway wall remodelling of SBM thickness and smooth muscle area.

Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma.

BACKGROUND: About 5-10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1). METHODS: Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 mug/ml) and dexamethasone (10(-8) and 10(-6) M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts. RESULTS: The inhibition of LPS-induced interleukin (IL)1beta, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha release by dexamethasone (10(-6) M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma. CONCLUSION: Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.