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Utility of impulse oscillometry in patients with moderate to severe persistent asthma

Outcomes measured with impulse oscillometry are more closely related to asthma control than spirometry in moderate to severe asthma.

Inhaled corticosteroid dose-response on blood eosinophils in asthma

We read with interest the article by David Price and colleagues (Oct 19, p 849) showing a clear association between asthma control and a spot measurement of blood eosinophils. The mean beclomethasone-equivalent inhaled corticosteroid (ICS) dose in their cohort was 219 μg/day. The doseresponse relationship between ICS and blood eosinophils is important to consider. Evidence exists of a dose-response effect of ICS on the reduction of blood eosinophils and eosinophilic cationic protein (ECP) for beclomethasone-equivalent ICS doses of up to 800 μg/day. In terms of mechanism, dose-related reduction in blood eosinophils and ECP by ICS seems to be disconnected from commensurate adrenal suppression, suggesting that systemic bioavailability of ICS might not be the principal cause of suppressing blood eosinophils. The data from Price and colleagues were somewhat contradictory, showing that patients on step 4 treatment with high dose ICS had a 13% increased likelihood of having a blood eosinophil count of more than 400 cells/μL, which was not reported for patients on step 3 treatment who were also taking 800 μg/day or more of beclomethasone-equivalent ICS dose, although step 2 patients on low dose ICS were 8% less likely to have a raised blood eosinophil counts. However, we appreciate that diff erentiation would be difficult between the suppressive effects of ICS on eosinophils per se and the ICS dose being a proxy for associated asthma severity. Titration of ICS dose over 1 year against mannitol airway hyperresponsiveness results in reduced exacerbations, improved symptom control, and reduced reliever use, accompanied by a 34% fall in ECP. The relative suppression in response to 400 μg/day beclomethasoneequivalent ICS dose of blood is 23% in eosinophils and 17% in ECP and of sputum is 76% in eosinophils and 55% in ECP. These fi ndings suggest that sputum is a more sensitive measure, although it is less practical than blood. In this regard, titration of ICS against sputum eosinophils results in reduced exacerbations and associated airway hyper-responsiveness. Therefore, use of serial blood eosinophils to adjust ICS dose might result in reduced exacerbations, especially in patients who already have an Asthma Control Questionnaire score of less than 0·75, indicative of optimum asthma control, at the time when the eosinophil count is measured.

Real-life effect of long-acting β2-agonist withdrawal in patients with controlled step 3 asthma

Approximately 45% of patients with asthma in the United Kingdom are receiving step 3 or higher therapy,1 most commonly inhaled corticosteroids (ICSs) and long-acting b2-agonists (LABAs). The 2016 Global Initiative for Asthma (GINA) guidelines propose a cycle of assessment, stepwise adjustment of treatment, and review of response to ascertain the lowest treatment to achieve control.2 In addition, the US Food and Drug Administration advocates stopping use of LABAs once asthma control is achieved and maintained and switching to ICS monotherapy.3 In clinical practice, it is more commonly observed that patients with asthma are stepped up to ICSs or LABAs (GINA step 3) than stepped down to ICSs alone (step 2). We hypothesize that LABA withdrawal may be safely performed in patients with controlled asthma. We therefore assessed the effect of stopping LABA treatment in patients referred from primary care for inclusion in clinical trials. The East of Scotland Research Ethics Service granted ethical approval for studies included in this analysis, and all patients provided written informed consent. We evaluated a series of 58 patients with stable, GINA step 3 asthma. At the baseline visit, current asthma therapy was recorded. Spirometry (Micromedical, Chatham, United Kingdom) and Impulse oscillometry (IOS, Jaeger Masterscreen, Hochberg, Germany) were performed according to European Respiratory Society guidelines, and exhaled nitric oxide (NIOX, Aerocrine, Morrisville, North Carolina) was recorded. IOS is an effort-independent technique performed during quiet tidal breathing to measure frequency-dependent resistance and reactance. Resistance at 5 Hz (R5) and 20 Hz (R20) is regarded as reflecting total and central airway resistance, respectively. The difference between R5 and R20 (R5 R20) is a surrogate for the resistance of peripheral airways. IOS relates more closely to asthma control than the effortdependent spirometry.4 After the screening visit, patients had their LABA treatment stopped. If they were using combination inhalers (comprising fluticasone-salmeterol, fluticasone-formoterol, budesonideformoterol, or beclomethasone-formoterol), the patient was issued an ICS alone at a beclomethasone equivalent dose. In accordance with GINA guidelines, their ICS dose was also reduced by approximately 25%. The patients then attended a 3-weeks follow-up to have tests performed again. They were issued a diary card to record their global rated symptom scores (0to 3-point scale: none, mild, moderate, severe) and reliever

Un-diagnosing persistent adult asthma

The diagnosis of asthma is usually based on typical symptoms, family history, audible wheeze, peak flow, spirometry, possibly in conjunction with atopy and blood eosinophilia, as well as response to treatment. In cases for which the diagnosis is less clear-cut, other tests may be required, including impulse oscillometry (IOS), exhaled nitric oxide fraction (FeNO) and bronchial challenge testing (figure 1). A pragmatic process should be considered in patients with a questionable asthma diagnosis http://ow.ly/VRNr30fwzgs

What can we learn about COPD from impulse oscillometry

Impulse oscillometry (IOS) is the most commonly used type of forced oscillation technique in clinical practice, although relatively little is known about its application in COPD. Resistance at 20 Hz (R20) is unrelated to COPD severity and does not improve with bronchodilatation or bronchoconstriction, inferring a lack of large airway involvement in COPD. Peripheral airway resistance expressed as frequency dependent heterogeneity between 5 Hz and 20 Hz (R5-R20), and peripheral airway compliance as area under the reactance curve (AX), are both closely related to COPD severity and exacerbations. Both R5-R20 and AX markedly improve in response to long acting bronchodilators, while AX appears to be more sensitive than R5-R20 in response to bronchoconstriction. Future studies may be directed to assess if IOS in combination with spirometry is more sensitive at predicting future exacerbations. Perhaps AX might also be useful as a screening tool in early stage disease or to monitor long term decline in COPD.

Current appraisal of single inhaler triple therapy in COPD

A single inhaler containing inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA)/long-acting muscarinic antagonist (LAMA) is a more convenient way of delivering triple therapy in patients with COPD. Single triple therapy has been shown to be superior at reducing exacerbations and improving quality of life compared to LABA/LAMA, especially in patients with a prior history of frequent exacerbations and blood eosinophilia, who have ICS responsive disease. The corollary is that patients with infrequent exacerbations who are noneosinophilic may be safely de-escalated from triple therapy to LABA/LAMA without loss of control. Pointedly, there is a substantially increased risk of pneumonia associated with the triple therapy containing fluticasone furoate but not beclometasone dipropionate or budesonide. Since triple therapy is also better than ICS/LABA at reducing exacerbations and improving lung function, symptoms, and quality of life, this brings into question the rationale for using ICS/LABA. Hence, we propose a simplified pragmatic decision process based on symptoms, prior to exacerbation history, and blood eosinophils to select which patients should be given a single triple inhaler or LABA/LAMA. Differences in patient preference of inhaler device, formulations and drugs will also determine which triple inhaler prescribers elect to use.

Blood eosinophils: The forgotten man of inhaled steroid dose titration

Blood eosinophil counts that were once regarded as normal, have become of increasing interest in the era of Interleukin-5 (IL-5) asthma treatment. Blood eosinophils as low as 150 cells/lL have been suggested as treatment cut-offs for eosinophil-depleting therapies such as mepolizumab, whilst a value of 300 cells/lL has been deemed a more pragmatic cut-off by the National Institute for Health and Care Excellence (United Kingdom). In this era of eosinophil post-truths, inhaled corticosteroids (ICS), the eosinophil’s oldest adversary, are very much the forgotten man. Corticosteroids reduce the numbers of eosinophils in blood and sputum by inhibiting the expression of pro-eosinophilic cytokines such as IL-5 and increase the rate of apoptosis and associated phagocytosis. It is known that titrating ICS against sputum eosinophils results in improved asthma control. Whilst it is also known that sputum eosinophils correlate well with blood eosinophils, the effects of increasing ICS dose on blood eosinophils are less well documented. We therefore wanted to know whether ICS dose titration suppresses blood eosinophil counts in patients with persistent asthma. In addition, we investigated whether leukotriene receptor antagonists (LTRA) have a similar effect when used as add-on therapy. Another surrogate marker of Th2-mediated inflammation is exhaled breath nitric oxide (FeNO), where it has already been demonstrated that there is a dose-response effect of ICS. We, therefore, performed a pooled analysis of our own studies performed by the Scottish Centre for Respiratory Research, where we measured blood eosinophils and FeNO from a baseline of none or low-dose ICS to medium-dose ICS with or without LTRA. Fourteen studies were included in this analysis and are listed in Table 1. All were approved by the East of Scotland Regional Ethics Committee and registered at clinicaltrials.gov. A total of 217 non-smoking patients with mild-moderate persistent asthma were included in the ICS dose titration analysis, of these 144 also received additive LTRA. Patients had a mean age of 38 years and a mean FEV1 of 85% predicted. In all studies analysed, patients must have been free from an asthma exacerbation requiring systemic corticosteroids in the 3 months prior to trial enrolment. In the nine of fourteen studies included, patients had at least one positive skin prick test to a common aeroallergen, with a mean number of positive tests of two. Baseline median low-dose inhaled corticosteroid (ICS) dose was 200 lg/day as beclometasone dipropionate (BDP) equivalent dose. Baseline mean eosinophils were 356 cells/lL, mean eosinophilic cationic protein (ECP) was 24.9 lg/L and mean exhaled nitric oxide (FeNO) was 41.4 ppb. Participants were stepped up to medium-dose ICS as median 800 lg/day BDP equivalent, with a median treatment duration of 2 weeks. Median treatment duration of additive LTRA was also 2 weeks. Changes in blood eosinophils and FeNO are presented in Figure 1. We observed a significant mean fall in eosinophils of 71 cells/lL (95% CI 38-105) P = .001 comparing lowversus medium-dose ICS and a further non-significant fall with LTRA amounting to 20 cells/lL. FeNO also significantly fell by 14.5 ppb (95% CI 7.921.1), P = .001 comparing lowand medium-dose ICS but did not decrease further with addition of LTRA. Mean ECP levels for lowand medium-dose ICS were 24.9 and 18.8 lg/L, respectively, representing a significant (P = .005) decrease of 6.1 lg/L (95% CI 2.49.6), although there were insufficient data to assess effects of LTRA. FEV1% predicted did not significantly change between low-dose ICS and medium-dose ICS: 1.6% (95% CI 0.5 to 3.2). We demonstrated that ICS even at a medium dose of 800 lg BDP results in a significant fall in blood eosinophils over a period of 2 weeks. Our data showed a non-significant further fall in blood eosinophils amounting to 20 cells/lL when adding LTRA, whilst Laviolette et al found a significant additive effect of LTRA amounting to a mean change of 40 cells. In contrast, Greene et al found no significant additive fall with LTRA on top of ICS, albeit measuring sputum rather than blood eosinophils. Their study also found no significant additive effect on FeNO in keeping with our data. In terms of ICS dose response, Kips et al reported significantly lower sputum DOI: 10.1111/cea.13057

P230 Does the global asthma visual analogue scale relate to the asthma control questionnaire

Control based asthma management results in improved asthma outcomes. The Asthma Control Questionnaire (ACQ-6), is a widely used and well validated metric which strongly predicts future exacerbations.1 It demarcates between controlled (C), partially controlled (P), and uncontrolled (U), based on cut point scores of <0.75, 0.75<1.5, and ≥1.5 respectively. The global asthma visual analogue scale (VAS) is a 10 cm continuum indicating the overall symptom burden.2 It discriminates GINA categories of C, P and U as <1.5, 1.5<7.19, and ≥7.19 respectively. We evaluated how VAS relates to ACQ in terms of predefined GINA cut points. We analysed n=87 patients who attended for asthma screening into clinical trials. 90% of patients were receiving ICS(mean BDP equiv 675 µg/day), of whom 80% received ICS/LABA, 42% with LTRA, mean FeNO 45 ppb, mean FEV1 89%, and mean number +ve skin prick tests were 2. Overall Spearman’s correlation was 0.62, p<0.001.Mean VAS levels for ACQ were: C: 2.2 cm (95% CI 1.35–3.06), P: 2.56 cm (95% CI 2.61–4.50), U: 5.27 cm (95% CI 4.46–6.08), i.e.,<7.19 cm GINA defined cut off (figure 1). There was no significant difference between patients with ACQ≥1.5 vs<1.5 for FeNO (51 ppb vs 41 ppb), or BDP equiv dose (674 µg vs 543 µg). Chi-square test demonstrated a weak relationship between ACQ≥1.5 and GINA defined VAS cut off ≥7.19 cm. A VAS≥7.19 had a sensitivity of 29% and specificity of 92% for detecting an ACQ≥1.5. ROC analysis, using ACQ to compare C vs U/P revealed an optimal cut point for VAS of 1.95 (AUC 0.8, sensitivity 88%, specificity 68%). Comparing U vs P/C revealed VAS cut point of 3.2 cm (AUC 0.7, sensitivity 71%, specificity 57%). We conclude that the GINA defined VAS cut off (≥7.19) is a poor predictor of control in relation to an ACQ≥1.5. Hence, further evaluation is required to define the VAS threshold in relation to control defined by ACQ rather than GINA. Figure Legend Distribution of ACQ control categories relative to VAS levels. References Meltzeret al. JACI2011;127:167–172. Ohtaet al. J Asthma2013;50:514–521.

Impact of Spacers on Therapeutic Ratio with Inhaled Corticosteroids

To the Editor: We read with interest the article of Guilbert et al, which showed, using retrospective observational data, that using a spacer with either extra-fine particle hydrofluoroalkane (HFA) beclomethasone pressurized metered dose inhaler (pMDI) or fine particle fluticasone pMDI did not significantly affect severe exacerbations or risk domain asthma control. Pointedly, this study did not look at the impact of using spacers on systemic adverse effects, and hence the relative therapeutic ratio cannot be deduced. In vitro studies with extra-fine particle HFA beclomethasone (100 mg ex-valve dose) using an Andersen cascade impactor showed that the overall fine particle dose (particles <4.7 mm) was higher when using an Aerochamber plus than pMDI alone (39.0 mg vs 22.4 mg) along with a lower mass median aerodynamic diameter (0.8 mm vs 1.4 mm). This drug-device interaction will of course depend on the patient using an optimal inhaler technique with pMDI alone or in conjunction with a spacer. An important but often overlooked consequence of a higher fine particle dose when using a spacer device will be increased lung deposition and hence enhanced lung bioavailability, in turn resulting in the potential for greater dose-related systemic adverse effects such as adrenal suppression. For example, in asthmatic patients, using fine particle HFA fluticasone propionate pMDI where there is almost complete hepatic first pass inactivation for the swallowed dose, the addition of an Aerochamber plus, in conjunction with optimal spacer priming and inhaler technique, has been shown to increase the degree of adrenal suppression by 65%, whereas an Aerochamber max results in a 71% increase, presumably due to a higher degree of lung bioavailability. For extra-fine HFA beclomethasone, a reduction in oral bioavailability might be expected to counterbalance increased lung bioavailability when using a spacer, due to the incomplete first pass inactivation for the swallowed dose. Hence in asthmatic patients, chronic dosing with HFA beclomethasone 400 mg/day (ex-valve dose) pMDI with Aerochamber plus produced no significant suppression of overnight urinary cortisol/creatinine compared with inhaled corticosteroid (ICS) na€ıve baseline values, despite significant improvements in both methacholine hyperresponsiveness and exhaled breath nitric oxide. Further prospective randomized trials are required to examine both antiasthmatic efficacy and systemic adverse effects to properly define the therapeutic ratio of currently available ICS pMDI formulations used alone and with spacers.

P239 Effects of tiotropium on asthma exacerbations are not explained by airway hyperresponsiveness, exhaled breath nitric oxide or airway geometry

Background Long acting muscarinic antagonists (LAMA) such as tiotropium (TIO) reduce asthma exacerbations in patients receiving inhaled corticosteroids and long-acting beta-agonists (ICS/LABA). However the mechanism for this protective action of LAMA remains unclear. Objectives To evaluate the response to indacaterol (IND) either alone in combination with tiotropium (IND/TIO) in addition to ICS on airway hyperresponsiveness (AHR), FeNO and impulse oscillometry (IOS). Methods n = 14 ICS treated asthmatic patients (Mean age 46 years, FEV1 86% predicted, R5 160% predicted, ICS 693ug/day),were randomised in cross-over fashion to receive either IND 150ug alone (ICS/LABA) or in combination with TIO 18ug once daily (ICS/LABA/LAMA) for 4 weeks with 2 week run-in and washout periods. Mannitol sensitivity (PD15) and reactivity (RDR), airway resistance (R5,R5-R20), reactance (AXE) and FeNO were measured at 24 hours after the first and last doses. Results There were significant improvements in mannitol PD15 and RDR with IND or IND/TIO vs baseline after single but not chronic dosing (Figure) . There was also a significant difference in RDR between single and chronic dosing for both treatments. R5,R5-R20 and AXE were significantly improved with both treatments compared to baseline after single and chronic dosing . There were no significant differences between treatments after chronic dosing for either mannitol or IOS . In contrast FeNO was unchanged with either treatment compared to baseline. Conclusions There were significant improvements in mannitol sensitivity and reactivity with either IND or IND/TIO after single but not chronic dosing, while FeNO remained unchanged . Airway resistance and reactance were significantly decreased to the same degree with both treatments after chronic dosing . This in turn suggests that the mechanism by which LAMA reduces exacerbations is unlikely to be related to AHR, FeNO or airway geometry. Abstract P239 Figure 1 Effects of randamised treatment compared to baseline on mannitol sensitivity and reactivuity. Values presented as geometric mean and 95% confidence interval. P value denotes significant difference for randamised treatment compatred to baseline. There was also a significant difference between single and chronic dosing for RDR with both treatments.