A proportion of patients with asthma develops a refractory period, during which the bronchoconstrictor response to a second indirect challenge is reduced. A better understanding of factors associated with the development of refractoriness is potentially important as the refractory period may be the vestigial expression of a bronchoprotective pathway that may be pathogenically important and could be manipulated for therapeutic effect. We investigated factors associated with refractoriness in 10 subjects with mild to moderate asthma.
Methods
Subjects were recruited from primary care, had mild to moderate (Step 1 or 2 BTS guideline) asthma and were aged 18–50 years. Subjects underwent a standardised laboratory exercise challenge test breathing cold dry air. Those who had a positive test (>15% fall in FEV1) were observed until lung function returned to within 5% of baseline and then underwent a further standardised exercise challenge test. The refractory index was calculated on the % reduction in the maximum percent fall in FEV1 between the first and second challenge. On a separate occasion the subjects undertook a sodium metabisulphite challenge test (a known, indirectly acting bronchoconstrictor) and a PD20 (MBS PD20) was calculated for this from interpolation of the log-dose response curve.
Results
22 individuals were screened to find 10 (1F; 9M) with a positive exercise test; these then went on to have a second challenge test. The mean (SEM) fall in FEV1 was 24.9% (2.4) and 13.7% (2.5) with first and second challenge respectively. The mean (SEM) refractory index was 50.1% (6.5). There was no correlation between the refractory index and age, sex, FEV1 % predicted, FVC, FEV1/FVC ratio, MBS PD20, or % fall in FEV1 on first challenge.
Conclusions
Our findings suggest that refractoriness is independent of baseline lung function and the magnitude of the response to the initial challenge. Further studies are required to determine whether other demographic factors are associated with this phenomenon.
The relationship between immediate symptom control, reliever medication use and exacerbation risk on treatment response and factors that modify it have not been assessed in an integrated manner. Here we apply simulation scenarios to evaluate the effect of individual baseline characteristics on treatment response in patients with moderate–severe asthma on regular maintenance dosing monotherapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR). Reduction in reliever medication use (puffs/24 h), change in symptom control scores (ACQ-5), and annualised exacerbation rate over 12 months were simulated in a cohort of patients with different baseline characteristics (e.g. time since diagnosis, asthma control questionnaire (ACQ-5) symptom score, smoking status, body mass index (BMI) and sex) using drug–disease models derived from large phase III/IV clinical studies. Simulation scenarios show that being a smoker, having higher baseline ACQ-5 and BMI, and long asthma history is associated with increased reliever medication use (p < 0.01). This increase correlates with a higher exacerbation risk and higher ACQ-5 scores over the course of treatment, irrespective of the underlying maintenance therapy. Switching non-responders to ICS monotherapy to combination therapy after 3 months resulted in immediate reduction in reliever medication use (i.e. 1.3 vs. 1.0 puffs/24 h for FP/SAL and BUD/FOR, respectively). In addition, switching patients with ACQ-5 > 1.5 at baseline to FP/SAL resulted in 34% less exacerbations than those receiving regular dosing BUD/FOR (p < 0.01). We have identified baseline characteristics of patients with moderate to severe asthma that are associated with greater reliever medication use, poor symptom control and higher exacerbation risk. Moreover, the effects of different inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) combinations vary significantly when considering long-term treatment performance. These factors should be considered in clinical practice as a basis for personalised management of patients with moderate–severe asthma symptoms. In this study we looked at how different factors affect the response to asthma treatment in people with moderate to severe asthma who are taking regular medication. Specifically, we wanted to quantify how much asthma duration, differences in the degree of symptom control and lung function, as well as smoking habit, body weight, and sex influence how well someone responds to regular maintenance therapy. Using computer simulations based on models obtained from data in a large patient population with moderate–severe asthma, we explored scenarios that reflect real-life management of patients undergoing treatment with inhaled corticosteroids alone or in combination with long-acting beta agonists over a 12-month period. We looked at how much reliever inhaler they use, how well they rate their asthma control, and how often they have asthma attacks. By considering these results together, we evaluated how well the treatments work on ongoing symptoms and/or reduce the risk of future asthma attacks. Our simulations showed that smokers, people with higher asthma symptom scores, who are obese, and have a longer history of asthma tend to use their reliever inhalers more often. This was linked to a higher risk of having asthma attacks and worse symptom control. Switching those patients who do not respond well to their initial treatment with corticosteroid to combination therapy reduced how much reliever inhaler they need. Also, the effects of fluticasone propionate/salmeterol combination therapy were greater than budesonide/formoterol. In conclusion, our study found that certain patient characteristics can predict how well someone responds to asthma treatment.
BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used to assess the role of prostaglandins in asthma but their effects on bronchoconstrictor challenges have been inconsistent. The effects of three nebulised nonsteroidal anti-inflammatory drugs on the airway response to inhaled sodium metabisulphite (MBS) and adenosine 59-monophosphate (AMP) were compared in the same asthmatic subjects to see whether contractile prostaglandins were involved in MBS or AMP induced bronchoconstriction. A possible protective effect of the osmolarity or pH of the inhaled solutions was also assessed. METHODS: Two double blind placebo controlled studies were carried out. In study 1, 15 non-aspirin sensitive patients with mild asthma attended on four occasions and inhaled 5 ml of lysine aspirin (L-aspirin) 900 mg, indomethacin 50 mg, sodium salicylate 800 mg, or saline 20 minutes before an inhaled MBS challenge. On four further occasions 14 of the patients inhaled the same solutions followed by an inhaled AMP challenge. In study 2, 10 of the patients attended on four additional occasions and inhaled 5 ml of 0.9%, 3%, 10%, or 9.5% saline with indomethacin 50 mg 20 minutes before an inhaled MBS challenge. RESULTS: In study 1 inhaled lysine aspirin had a similar effect on MBS and AMP induced bronchoconstriction, increasing the provocative dose causing a 20% fall in FEV1 (PD20) by 1.29 (95% CI 0.54 to 2.03) and 1.23 (95% CI 0.53 to 1.93) doubling doses, respectively. Indomethacin increased the MBS PD20 and AMP PD20 by 0.64 (95% CI -0.1 to 1.38) and 0.99 (95% CI 0.29 to 1.69) doubling doses, respectively. Sodium salicylate had no significant effect on either challenge. The two solutions causing most inhibition were the most acidic and the most alkaline. In study 2 inhaled 9.5% saline with indomethacin (osmolarity 3005 mOsm/kg) increased the MBS PD20 by 1.1 doubling doses (95% CI 0.2 to 2.0) compared with only 0.09 (95% CI -0.83 to 1.0) and 0.04 (95% CI -0.88 to 0.95) doubling doses with 3% saline (918 mOsm/kg) and 10% saline (2994 mOsm/ kg), respectively. CONCLUSIONS: Inhaled L-aspirin and indomethacin have broadly similar protective effects against MBS and AMP induced bronchoconstriction in the doses given, although the effect of indomethacin on MBS was not quite statistically significant. The osmolarity and pH of the solutions did not appear to be important determinants of the response. The effect of L-aspirin and indomethacin is likely to be the result of cyclooxygenase inhibition reducing the production of contractile prostaglandins during MBS and AMP challenge.
The field of asthma has undergone a dramatic change in recent years. Advances in our understanding of type 2 airway inflammation have driven the discovery of monoclonal antibodies targeting specific aspects of the immune pathway. In landmark trials, these drugs have shown efficacy in reducing asthma attacks and exposure to oral corticosteroids, important causes of morbidity in people with asthma. Our review explores the key features of type 2 inflammation in asthma and summarizes the clinical trial evidence of the novel monoclonal antibody treatments and future avenues for treatment.
The identification of inflammatory asthma phenotypes, using sputum analysis, has proven its value in diagnosis and disease monitoring. However due to technical limitations of sputum analysis, there is a strong need for fast and noninvasive diagnostics. This study included the activation state of eosinophils and neutrophils in peripheral blood to phenotype and monitor asthma.To (i) construct a multivariable model using the activation state of blood granulocytes, (ii) compare its diagnostic value with sputum eosinophilia as gold standard and (iii) validate the model in an independent patient cohort.Clinical parameters, activation of blood granulocytes and sputum characteristics were assessed in 115 adult patients with asthma (training cohort/Utrecht) and 34 patients (validation cohort/Oxford).The combination of blood eosinophil count, fractional exhaled nitric oxide, Asthma Control Questionnaire, medication use, nasal polyposis, aspirin sensitivity and neutrophil/eosinophil responsiveness upon stimulation with formyl-methionyl-leucyl phenylalanine was found to identify sputum eosinophilia with 90.5% sensitivity and 91.5% specificity in the training cohort and with 77% sensitivity and 71% specificity in the validation cohort (relatively high percentage on oral corticosteroids [OCS]).The proposed prediction model identifies eosinophilic asthma without the need for sputum induction. The model forms a noninvasive and externally validated test to assess eosinophilic asthma in patients not on OCS.
The Shorter Oxford Dictionary defines ‘exacerbation’ as ‘an increase in the severity of a disease’—which does not imply reversibility or otherwise. However, we wonder how many chest physicians define exacerbation as ‘an acute and temporary deterioration in either symptoms or signs (and for the sophisticated, biomarkers)’ of asthma, chronic obstructive pulmonary disease (COPD) or whatever. We know that many of our patients do not understand the term; some confuse it with exasperations. The editorial by Mark FitzGerald1 proposes to discard this term in favour of the phrase ‘lung attack’. Is this mere sensationalism or trendy fiddling with what actually works well (as with the Church of England discarding the Book of Common Prayer in favour of series 17.2)? …
For asthma patients, achieving asthma control and improving health-related quality of life (HRQoL) are important long-term management goals. Dupilumab is a monoclonal antibody targeting interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases. Here, we report effects of long-term dupilumab treatment on asthma control and HRQoL outcomes from the TRAVERSE open-label extension (OLE) study (NCT02134028) in patients with moderate-to-severe asthma who had previously completed a dupilumab asthma study (phase 2b (P2b) or phase 3 QUEST).
Methods
During TRAVERSE, patients received add on dupilumab 300 mg every 2 weeks. Asthma control (5-item Asthma Control Questionnaire, ACQ-5; range 0–6, lower scores indicate better control) and HRQoL (Asthma Quality of Life Questionnaire - standardized, AQLQ(S); range 1–7, higher scores indicate improved asthma-specific quality of life) were assessed at TRAVERSE Week 0, 24, and 48. The overall intention-to-treat population and the type 2 asthma population, defined as patients with blood eosinophils ≥150 cells/µL or FeNO ≥25 ppb at parent study baseline (PSBL), were evaluated.
Results
2,062 patients from QUEST (n=1,530; 517 PBO/DPL and 1,013 DPL/DPL patients) and P2b (n=532; 111 PBO/DPL and 421 DPL/DPL patients) rolled over into TRAVERSE. Mean (SD) ACQ-5 scores improved from PSBL at OLE Week 0, Week 24, and Week 48 in dupilumab/dupilumab and placebo/dupilumab groups from both QUEST and P2b studies. ACQ-5 scores exceeded the clinically meaningful response threshold (≥ 0.5 reduction) in 79–87% of patients (table 1). Mean (SD) AQLQ(S) scores improved from PSBL at OLE Week 0, Week 24, and Week 48; 65–78% of all patients showed clinically meaningful improvements (≥ 0.5 increase) (Table). In general, the largest mean improvements and percentage of patients with a clinically meaningful response was seen in the patient group who had received dupilumab in the parent study. Improvements were comparable in patients with a type 2 phenotype. The dupilumab safety profile during TRAVERSE was similar to that observed in the parent study populations.
Conclusions
In line with patient-reported outcomes observed in P2b and QUEST, dupilumab-treated patients with moderate-to-severe asthma demonstrated clinically meaningful and sustained improvements in asthma control and HRQoL during the TRAVERSE OLE study. Please refer to page A191 for declarations of interest related to this abstract.
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