Serum prednisolone levels as a marker of oral corticosteroid adherence in severe asthma.

BACKGROUND: Severe asthma is a complex heterogeneous disease typically requiring advanced therapies. Underlying the treatment of all asthma, however, is the consistent recommendation across international guidelines to ensure that adherence to therapy is adequate. Currently, there is no consensus on an objective marker of adherence. METHODS: We performed a prospective observational study of 17 participants taking oral prednisolone using serum prednisolone levels as a marker of adherence, and sputum eosinophilia as a marker of control of type 2 airway inflammation. Based on these biomarkers, we classified participants into a non-adherent and an adherent cohort, and further stratified by the presence of ongoing sputum eosinophilia. RESULTS: We identified 3 non-adherent participants and 14 who were adherent, based on their serum prednisolone levels. Stratification using sputum eosinophil counts identified one participant as having ongoing sputum eosinophilia in the setting of non-adherence, while six were identified as steroid resistant with ongoing sputum eosinophilia despite adherence to oral prednisolone therapy. CONCLUSION: Serum prednisolone can be used an objective marker of adherence in those patients with severe asthma taking daily oral prednisolone. In combination with sputum eosinophil counts, a steroid resistant cohort can be distinguished from one with ongoing inflammation in the setting of non-adherence. This information can then be used by clinicians to differentiate the optimal next steps for treatment in these specific populations. TRIAL REGISTRATION: Participants were recruited as part of the Markers of Inflammation in the Management of Severe Asthma (MIMOSA) study, trial registration ACTRN12616001015437 , 02 August 2016.

An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness.

It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A4 hydrolase (LTA4H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B4 (LTB4) and degradation of proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB4 signaling ameliorated inflammation and airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss of LTA4H exacerbated AHR, despite the absence of LTB4 This exacerbated AHR was attributable to a neutrophil-independent capacity of PGP to promote pathological airway epithelial remodeling. Thus, we demonstrate a disconnect between airway inflammation and AHR and the ability of a matrikine to promote an epithelial remodeling phenotype that negatively affects lung function. Subsequently, we show that substantial quantities of PGP are detectable in the sputum of moderate-severe asthmatics in two distinct cohorts of patients. These studies have implications for our understanding of remodeling phenotypes in asthma and may rationalize the failure of LTA4H inhibitors in the clinic.

Exposure to dust and endotoxin in textile processing workers.

BACKGROUND: Inhalation of cotton-based particulate has been associated with respiratory symptoms and overt lung disease related to endotoxin exposure in some studies. This cross-sectional study measures personal exposure to inhalable dust and endotoxin in the textile industry of Nepal. METHODS: This study was conducted in four sectors (garment making, carpet making, weaving, and recycling) of the textile industry in Kathmandu, Nepal. Personal exposure to inhalable dust and airborne endotoxin was measured during a full-shift for 114 workers. RESULTS: Personal exposure to cotton dust was generally low [geometric mean (GM) 0.81 mg m(-3)) compared to the UK workplace exposure limit (WEL) (2.5 mg m(-3)) but with nearly 18% (n = 20) of the workers sampled exceeding the limit. Exposures were lowest in the weaving and the garment sector (GM = 0.30 mg m(-3)), higher in the carpet sector (GM = 1.16 mg m(-3)), and highest in the recycling sector (GM = 3.36 mg m(-3)). Endotoxin exposures were high with the overall data (GM = 2160 EU m(-3)) being more than 20-fold higher than the Dutch health-based guidance value of 90 EU m(-3). The highest exposures were in the recycling sector (GM = 5110 EU m(-3)) and the weaving sector (GM = 2440 EU m(-3)) with lower levels in the garment sector (GM = 157 EU m(-3)). The highest endotoxin concentrations expressed as endotoxin units per milligram inhalable dust were found in the weaving sector (GM = 165 EU mg(-1)). There was a statistically significant correlation between inhalable dust concentrations and endotoxin concentrations (r = 0.37; P < 0.001) and this was particularly strong in the garment (r = 0.82; P = 0.004) and the carpet sector (r = 0.81; P < 0.001). CONCLUSIONS: Inhalable dust exposures measured in the weaving, carpet, and garment sectors were all below the UK WEL for cotton dust. A significant proportion of the measurements from the cotton recycling sector were above the UK WEL suggesting that better hygiene control measures are required. Airborne endotoxin concentrations in all sectors were found to exceed the Dutch health-based guidance limit of 90 EU m(-3) and may be associated with respiratory health effects.

IPEADAM study: indoor endotoxin exposure, family status, and some housing characteristics in English children.

BACKGROUND: Many environmental factors have been investigated to determine their involvement in the asthma epidemic. OBJECTIVE: We sought to investigate the indoor environment of English children. METHOD: The Indoor Pollutants, Endotoxin, Allergens, Damp and Asthma in Manchester (IPEADAM) study recruited 200 asthmatic and age-, sex-, and sibship size-matched nonasthmatic children after a questionnaire-based community screening epidemiology survey. Their homes were sampled for several indoor air factors, and reservoir dust samples were obtained. Endotoxin, Der p 1, and dampness levels were assayed. Questionnaires were administered to record housing characteristics. Indoor pollutants, including environmental tobacco smoke, volatile organic compounds, nitrogen dioxide, formaldehyde, temperature, and relative humidity, were investigated. STATA univariate and multivariate analyses were used to compare the indoor environments of the children. RESULTS: The levels of endotoxin (adjusted odds ratio, 1.88; 95% CI, 1.11-3.18; P=.018), living in a single-parent family (adjusted odds ratio, 3.89; 95% CI, 1.25-12.1; P=.019), redecoration in the living room (adjusted odds ratio, 3.15; 95% CI, 1.36-7.33; P=.008), and self-reported absence of dampness (adjusted odds ratio, 0.36; 95% CI, 0.14-0.91; P=.030) were all independent predictive factors of asthma. There was no difference between asthmatic and healthy children in their exposure to Der p 1, objective measurements of dampness, guardian's smoking habits, pet ownership, house type or age, time in residence, central heating systems, insulation types, glazing systems, floor types, and age and measurements of several indoor pollutants. CONCLUSION: The IPEADAM study has shown that there were very few differences in the indoor environments of English asthmatic and nonasthmatic children. However, once asthma has been established, the presence of endotoxin is positively associated with an asthmatic child's living room carpet reservoir dust. CLINICAL IMPLICATIONS: There are no direct clinical implications of this research, although it needs interpreting with other clinical data on endotoxin exposure in epidemiologic settings.