Arvind Manoharan

Small airway dysfunction is associated with poorer asthma control

To the Editor: The clinical relevance of the small airways in persistent asthma has been gaining greater recognition in recent years [1]. Studies have shown that a significant proportion of asthmatics on standard treatment fail to achieve satisfactory asthma control. For example, in one study of 3421 asthmatic subjects who underwent guideline-driven dose titration with standard inhaled corticosteroids (ICS)/long-acting β-agonist (LABA) combination therapy over 1 year, only 41% achieved total control of their asthma while 71% were well controlled [2]. Anderson et al. [3] found a high prevalence of adult patients with persistent small airway dysfunction determined by impulse oscillometry (IOS) (assessed as the difference between the resistance at 5 Hz ( R 5) and that at 20 Hz oscillation ( R 20)) and spirometry (assessed as the forced expiratory flow at 25–75% of forced vital capacity (FEF25–75%)) across British Thoracic Society (BTS) treatment steps for asthma, many of whom had a preserved forced expiratory volume in 1 s (FEV1). This, in turn, suggests an unmet clinical need in terms of patients who may have a small airway asthma phenotype. We therefore evaluated whether small airway dysfunction was associated with worse control in adult asthmatics with a preserved FEV1 (>80% predicted). Spirometry and IOS measurements from unselected asthmatics referred from primary care who attended screening for clinical trials were linked to prescription data. The prescription data were obtained from the Tayside Health Informatics Centre (Dundee, UK), which links all community-dispensed prescriptions using a person’s unique identifier, the Community Health Index. Spirometry and IOS measurements from asthmatics were …

The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma

The murine asthma model shows that switching off airway β2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 μg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 μg/day compared with placebo plus HFA-BDP at 400 μg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 μg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.

Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma.

BACKGROUND Impulse oscillometry (IOS) is a novel method of assessing airway resistance. IOS is rarely used in assessing airway resistance after bronchoprovocation in adult asthma. OBJECTIVE To ascertain the degree of change in IOS measurements seen in patients with asthma undergoing bronchial challenge testing. METHODS Patients 18 to 65 years old with mild to moderate asthma, forced expiratory volume in 1 second (FEV1) greater than 80% predicted, and diurnal FEV1 variation less than 30% and taking inhaled corticosteroid (≤1,000 μg/day of beclomethasone dipropionate equivalent dose) were recruited. Sequential spirometry and IOS results were measured during bronchial challenge testing to inhaled methacholine and histamine. RESULTS The magnitude of percentage of change demonstrated in total airway resistance at 5 Hz was greater than that observed for FEV1 in the 2 bronchial challenge tests. For example, at a methacholine provocation concentration that caused a decrease in FEV1 of 20%, a 43.5% change (95% confidence interval 29.4-57.5) was seen in total airway resistance at 5 Hz as measured by IOS compared with a 23.3% change (95% confidence interval 18.7-27.9) in FEV1. The magnitude of change seen with other IOS outcomes, including peripheral airway resistance, area under the curve, and resonant frequency, also was greater compared with spirometry. CONCLUSION The potential application of IOS in the assessment of airway hyperresponsiveness in adult asthma has been demonstrated. Further population studies are required. TRIAL REGISTRATION www.clinicaltrials.gov (NCT01074853).

The potential role of direct and indirect bronchial challenge testing to identify overtreatment of community managed asthma

Although airway hyperresponsiveness (AHR) is a defining feature of asthma pathophysiology, bronchial challenge testing is not routinely used in primary care asthma management.

Effects of formoterol or salmeterol on impulse oscillometry in patients with persistent asthma

BACKGROUND Effects of small-particle long-acting β-agonists on the small airways have been poorly documented. OBJECTIVE We used impulse oscillometry (IOS) to compare single and repeated dosing effects of small- and large-particle long-acting β-agonists. METHODS After a 1- to 2-week run-in period, patients received either 12 μg of small-particle hydrofluoroalkane 134a-formoterol solution or 50 μg of large-particle salmeterol dry powder twice daily plus inhaled corticosteroid for 1 to 2 weeks with a 1- to 2-week washout period in between. Measurements were made over 60 minutes after the first and last doses. RESULTS Sixteen patients completed the study as follows: mean age, 43 years; FEV1, 80%; forced midexpiratory flow between 25% and 75% of forced vital capacity (FEF(25-75)), 48%; total airway resistance at 5 Hz, 177%; peripheral airway resistance as the difference between 5 and 20 Hz, 0.18 kPa·L(-1)·s; Asthma Control Questionnaire score, 0.76; and inhaled corticosteroid dosage, 550 μg/d. There were significantly greater improvements with formoterol versus salmeterol in all IOS outcomes and FEF25-75, but not FEV1, at 5 minutes after the first dose, which were not sustained over 60 minutes. After the last dose, all IOS outcomes, but not FEV1 or FEF(25-75), were significantly better with formoterol over the entire 60 minutes: mean difference at 60 minutes between formoterol and salmeterol in total airway resistance at 5 Hz, 7.50% (95% CI, 1.56% to 13.43%, P = .02); central airway resistance at 20 Hz, 5.37% (95% CI, 0.13% to 10.62%, P = .045); peripheral airway resistance as the difference between 5 and 20 Hz, 12.76% (95% CI, 1.28% to 24.24%, P = .03); reactance area under the curve, 19.46% (95% CI, 7.56% to 31.36%, P = .003); reactance at 5 Hz, 11.19% (95% CI, 4.62% to 17.76%, P = .002); and resonant frequency, 9.34% (95% CI, 3.21% to 15.47%, P = .005). Peak expiratory flow significantly improved to a similar degree with both drugs. CONCLUSION Significant improvements in IOS outcomes but not spirometry results occurred after chronic dosing with formoterol compared with salmeterol. This might reflect better deposition to the entire lung, including the small airways.

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.

Influence of β2-adrenoceptor 16 genotype on propranolol-induced bronchoconstriction in patients with persistent asthma.

response to gum arabic after experiencingwork-related rhinitis and dyspnea.6 One case report involved 4 separate allergic reactions after a man drank coffee made from gum arabicecoated coffee beans.7 Two of the reactions were anaphylactic in nature, leading to cardiac arrest; however, these were noted to have occurred after the patient had been prescribed timolol eye drops. Although the patient was found to have dual sensitivity to coffee and gum arabicecoated coffee beans via skin prick testing and human basophil degranulation testing, the case also highlighted the potential risk of b-blockers in potentiating anaphylaxis to these allergens. An extensive search on cases of anaphylaxis to gum arabic alone yielded no results. We report a case of a 21-year-old college student with no prior exposure to the pharmaceutical or confectionery industry who experienced anaphylaxis after drinking soda that contained gum arabic. The patient reported having symptoms of anaphylaxis 1 hour after imbibing approximately 4 oz of Mountain Dew Code Red (contains gum arabic). She noted urticaria on the central upper part of her chest, dyspnea, and inability to complete full sentences. The patient was then immediately taken to her university’s health services clinic for further evaluation, at which time she was noted to have facial swelling and wheezing on examination. Because of the anaphylactic reaction, the patient was initially unclear of all the events that occurred before treatment; however, further investigation revealed that the patient’s clinical presentation immediately improved after epinephrine administration in the health clinic. She reported that since the incident, she has avoided drinking

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.

Effects of the inverse alpha-agonist doxazosin in allergic rhinitis.

We examined the paradoxical hypothesis that the alpha‐receptor inverse agonist doxazosin might produce beneficial effects in allergic rhinitis.

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