Joanne Milot

How Should We Quantify Asthma Control?: A Proposal

BACKGROUND Current asthma guidelines suggest a series of criteria to assess if asthma is controlled. However, there is a need to develop a simple and practical method to quantify the degree of such control, both in clinical practice and research. STUDY OBJECTIVES This report describes a new method to quantify asthma control based on a percentage score. It also aims at comparing the percentage scores obtained with patients self-evaluation of asthma control and a current validated Mini Asthma Quality of Life (MAQOL) questionnaire. SETTING AND SUBJECTS Forty-two subjects (25 female and 17 male patients) with asthma of different severity recruited from a tertiary center asthma clinic. METHODS The asthma scoring method provided a percentage control for symptoms, baseline expiratory flows and, an optional parameter, for airway inflammation assessed from induced-sputum eosinophil count. These control parameters were compared to an overall assessment of asthma control by the patient (also on a 100% scale) and the score obtained from a validated MAQOL questionnaire. RESULTS Mean +/- SEM scores for symptoms, expiratory flows, and airway eosinophilia (last 2 weeks) were 87.8 +/- 1.4%, 88.6 +/- 1.8%, and 66.2 +/- 3.9%, respectively. No significant correlation was found between these three parameters (p > 0.05). The mean global asthma control score and the score estimated by the patient were 80.9 +/- 1.5% and 91.7 +/- 1.5%, respectively (not significantly different). There was a significant correlation between asthma control score (percentage) and percentage symptom score (p < 0.001), while it almost achieved significance for FEV(1) (p = 0.05). Only symptom scores correlated with the MAQOL questionnaire. CONCLUSIONS We developed a simple easy-to-use asthma control scoring system based on a percentage of optimal control. The percentage symptom score but not the global control score of this new method correlated with patients global assessment of asthma control. This could be a simple tool that is potentially useful both for the clinician and for research purposes, to quantify global or specific aspects of asthma control.

Effects of long-term use of high-dose inhaled steroids on bone density and calcium metabolism

BACKGROUND Inhaled steroids are the mainstay in the antiinflammatory treatment of asthma. In the last few years, these agents have been used in increasing doses. Because high doses of inhaled steroids can reduce serum osteocalcin levels, there are concerns regarding their long-term effects on bone metabolism. METHODS We examined the effects of doses of 800 micrograms/day or greater of beclomethasone or budesonide for more than 18 months in 37 asthmatic subjects (group A), matched to a control group of 37 asthmatic subjects using little or no inhaled steroids (< 500 micrograms, group B). All had a clinical evaluation, measurements of expiratory flows, and determination of serum creatinine, calcium, phosphate, gamma-glutamyl transpeptidase, alkaline phosphatase, cortisol, and osteocalcin levels. A 2-hour urinary sample was obtained for creatinine, calcium, phosphate, hydroxyproline, and cortisol measurements. Bone density was assessed at the lumbar spine level and at the hip with a Hologic-QDR-2000 osteodensitometer (Hologic, Boston, Mass.). RESULTS The mean (+/- SD) daily dose of inhaled steroids over the last 2 years was 1140 +/- 353 micrograms in group A (mean duration of use of > 800 micrograms/day, 34.2 +/- 13.0 months) and 89 +/- 98 micrograms for group B (mean duration of use of < 500 micrograms/day, 15.7 +/- 18.8 months). The number of oral steroid treatments (< 15 days) during the last 2 years was small in the two groups, 0.92 +/- 1.27 in group A and 0.05 +/- 0.23 in group B (p > 0.05). The only differences between our two groups in terms of serum or urinary parameters were for mean osteocalcin level, which was lower in group A (2.16 +/- 1.09 ng/ml) than in group B (2.70 +/- 0.98 ng/ml) (p = 0.029), and in mean urinary phosphorous level, which was higher in group A (1.44 +/- 0.76 mmol/2 hr) than in group B (1.26 +/- 0.89 mmol/2 hr (p = 0.034). Mean urinary hydroxyproline levels were 15.51 +/- 6.98 mumol/2 hr in group A and 13.53 +/- 7.13 mumol/2 hr in group B (p > 0.05). Mean mineral bone densities of the lumbar spine and hip were similar in the two groups with values of 0.923 +/- 0.136 gm/cm2 and 0.719 +/- 0.147 gm/cm2 in group A and 0.933 +/- 0.154 gm/cm2 and 0.694 +/- 0.095 gm/cm2 in group B (p > 0.05). The T and Z scores for lumbar spine were -1.32 +/- 1.22 and -0.85 +/- 1.02 in group A and -1.19 +/- 1.33 and -0.72 +/- 1.08 in group B (p > 0.05). There was no correlation between the duration or dose of steroid use and bone density or osteocalcin. Although the serum osteocalcin level was lower in the group of subjects using high-dose inhaled steroids, suggesting an osteoblastic depression, bone density was not significantly different compared with the control group. CONCLUSIONS This study shows that although the serum osteocalcin level was lower and the urinary phosphorus level was higher in subjects using high-dose inhaled steroids for a mean of 34 months, compared with a control group, no significant difference in bone density or other markers of bone metabolism was found between the two groups.

Preliminary ReportsHow Should We Quantify Asthma Control?: A Proposal

BACKGROUND Current asthma guidelines suggest a series of criteria to assess if asthma is controlled. However, there is a need to develop a simple and practical method to quantify the degree of such control, both in clinical practice and research. STUDY OBJECTIVES This report describes a new method to quantify asthma control based on a percentage score. It also aims at comparing the percentage scores obtained with patients self-evaluation of asthma control and a current validated Mini Asthma Quality of Life (MAQOL) questionnaire. SETTING AND SUBJECTS Forty-two subjects (25 female and 17 male patients) with asthma of different severity recruited from a tertiary center asthma clinic. METHODS The asthma scoring method provided a percentage control for symptoms, baseline expiratory flows and, an optional parameter, for airway inflammation assessed from induced-sputum eosinophil count. These control parameters were compared to an overall assessment of asthma control by the patient (also on a 100% scale) and the score obtained from a validated MAQOL questionnaire. RESULTS Mean +/- SEM scores for symptoms, expiratory flows, and airway eosinophilia (last 2 weeks) were 87.8 +/- 1.4%, 88.6 +/- 1.8%, and 66.2 +/- 3.9%, respectively. No significant correlation was found between these three parameters (p > 0.05). The mean global asthma control score and the score estimated by the patient were 80.9 +/- 1.5% and 91.7 +/- 1.5%, respectively (not significantly different). There was a significant correlation between asthma control score (percentage) and percentage symptom score (p < 0.001), while it almost achieved significance for FEV(1) (p = 0.05). Only symptom scores correlated with the MAQOL questionnaire. CONCLUSIONS We developed a simple easy-to-use asthma control scoring system based on a percentage of optimal control. The percentage symptom score but not the global control score of this new method correlated with patients global assessment of asthma control. This could be a simple tool that is potentially useful both for the clinician and for research purposes, to quantify global or specific aspects of asthma control.

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

BackgroundPhosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.Methods25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.ResultsRoflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.ConclusionsThis study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.Trial RegistrationClinicalTrials.gov: NCT01365533

Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids

Long-acting beta2-adrenoceptor agonists such as salmeterol reduce airway responsiveness for at least 12 h, but this effect seems to decrease with regular use. We evaluated the time-course of the protective effects of salmeterol on methacholine-induced bronchoconstriction, its modulation by inhaled corticosteroids (ICS) and its influence on asthma control. Thirty two subjects (13 males and 19 females) with mild to moderate stable asthma were divided into two groups according to their medication needs: bronchodilators (BD) alone (n=16) or with ICS (n=16). After a 2 week run-in period, a double-blind crossover study was conducted. Subjects from both groups received salmeterol 50 microg b.i.d. or a placebo for 4 weeks each in random order, separated by a 2 week washout period. The provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) was measured before and after each treatment period, 1 h prior to inhalation of salmeterol or placebo and 1 and 12 h after. Baseline forced expiratory volume in one second (FEV1) increased significantly after salmeterol, both after the first dose and at 4 weeks (BD group: 19 and 17%; ICS: 22 and 13%). On the first day of administration, salmeterol provided significant protection in both groups up to 12 h with a PC20 before and 1 and 12 h postdose of 2.2, 21.7 and 12.4, mg x mL(-1), respectively, in the BD group and 2.1, 11.6 and 55 mg x mL(-1), respectively, in the ICS group. After 4 weeks, this effect was significantly attenuated in both groups with a PC20 before, 1 and 12 h postdose of 3.3, 10.9 and 7.1 mg x mL(-1), respectively, in the BD group and 2.1, 5.0 and 2.3 mg x mL(-1), respectively, in the ICS group. This loss of protective effect was of similar magnitude in both groups. Respiratory symptoms, rescue beta2-agonist use and baseline FEV1 did not change significantly throughout the study in both groups. In conclusion, the bronchoprotective effect of salmeterol decreased with regular use both 1 and 12 h postdose; inhaled corticosteroids did not prevent this reduction. However, the development of tolerance was not associated with loss of asthma control.

Airway inflammation after removal from the causal agent in occupational asthma due to high and low molecular weight agents

In order to determine 1) the features of airway inflammation after removal from exposure to high (HMW) and low (LMW) molecular weight agents 2) if there are any differences in the pattern of inflammation induced by these two types of agents, we studied 18 subjects with a recently confirmed diagnosis of occupational asthma (OA) due to HMW (n = 11) and LMW (n = 7) agents. The duration of asthma symptoms varied from 2 to 108 months (mean 33 months), and withdrawal from exposure to the sensitizing agent from 3 to 24 weeks (mean 10 weeks). All subjects underwent measurements of expiratory flow rates, methacholine inhalation tests, and a flexible bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsies. Endoscopic findings were compared with a group of 10 normal subjects. At the time of the bronchoscopy, asthma symptoms were minimal in most subjects. Although 15/18 subjects had normal forced expiratory volume in one second (FEV1 > 80% pred), all subjects had increased airway responsiveness to methacholine (provocation concentration producing a 20% fall in FEV1 = 0.2-10.0 mg.ml-1). BAL analysis showed similar median percentages of the total number of cells and differentials in control subjects and those exposed to HMW and LMW agents. Bronchial biopsies showed that mean inflammatory cell count, both epithelial and sub-epithelial, was similarly raised in OA subjects exposed to either HMW or LMW agents, compared to controls, except for epithelial lymphocyte count. In contrast to the controls, bronchial biopsy of both groups with OA also showed other changes such as extensive epithelial desquamation, ciliary abnormalities of the epithelial cells, smooth muscle hyperplasia and subepithelial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged bronchoprotection against inhaled methacholine by inhaled BI 1744, a long-acting β2-agonist, in patients with mild asthma

BACKGROUND Long-acting ss(2)-agonists are an established controller medication in asthma. BI 1744 is a novel L\long-acting ss(2)-agonist with a preclinical profile that suggests 24-hour bronchodilation and bronchoprotection may be achieved. OBJECTIVE To examine the bronchoprotective effects of single doses of BI 1744 against methacholine provocation in subjects with mild asthma. METHODS Thirty-one subjects with mild asthma were randomized to receive single doses of BI 1744 (2, 5, 10, 20 microg) or placebo on separate days according to a double-blind, 5-way crossover design. Methacholine challenges were performed at 30 minutes and at 4, 8, 24, and 32 hours after each single dose of medication, and the results were expressed as PC(20) FEV(1). RESULTS All doses of BI 1744 produced statistically significant increases in the methacholine PC(20) compared with placebo as long as 32 hours. The mean (geometric SEM) methacholine PC(20) 24 hours after dosing with placebo was 1.73 (1.13) mg/mL, which increased after 2 microg to 3.86 (1.14) mg/mL, after 5 microg to 5.67 (1.14) mg/mL, after 10 microg to 9.42 (1.13) mg/mL, and after 20 microg to 13.71 (1.14) mg/mL (all P < .0001). After 32 hours, the methacholine PC(20) value remained significantly increased for all doses. No safety or tolerability concerns were identified. CONCLUSION BI 1744 provides significant bronchoprotection against inhaled methacholine for up to 32 hours after single-dose administration.

Effect of salmeterol on allergen‐induced airway inflammation in mild allergic asthma

A previous study suggested that the long‐acting β2‐adrenergic agonist salmeterol (SM) had inhibitory effects on bronchial mucosal inflammation 6 hours after allergen exposure.

Asthma-COPD Overlap Phenotypes and Smoking :Comparative features of asthma in smoking or non-smoking patients with an incomplete reversibility of airway obstruction

ABSTRACT The development of COPD features, such as an incomplete reversibility of airway obstruction (IRAO), in smoking or non-smoking asthmatic patients, a condition often named Asthma-COPD Overlap (ACO), has been recognized for decades. However, there is a need to know more about the sub-phenotypes of this condition according to smoking. This study aimed at comparing the clinical, physiological and inflammatory features of smoking and non-smoking asthmatic patients exhibiting IRAO. In this cross-sectional study, patients with an IRAO with (ACO, ≥20 pack-years) or without (NS-IRAO, <5 pack-years) significant smoking history completed questionnaires about asthma control (ACQ, score 0–6, 6 = better score) and quality of life (AQLQ, score 1–7, 1 = better score) and performed expiratory flows, lung volume and carbon monoxide diffusion capacity measurements. Blood sampling and induced sputum were obtained for systemic and lower airway inflammation assessment. A total of 115 asthmatic patients were included (75 ACO: age 61 ± 10 years, 60% women and 40 NS-IRAO: age 64 ± 9 years, 38% women). ACO patients had worse asthma control scores (1.8 ± 0.9 vs 1.4 ± 0.9, P = 0.02) and poorer asthma quality of life (5.3 ± 1.0 vs 5.9 ± 1.0, P = 0.003). In addition, ACO had higher residual volume (145 ± 45 vs 121 ± 29% predicted, P = 0.008) and a lower carbon monoxide diffusing capacity corrected for alveolar volume (90 ± 22 vs 108 ± 20% predicted, P = 0.0008). No significant differences were observed in systemic or lower airway inflammation. In conclusion, in smokers and non-smokers, the presence of IRAO in asthmatics is associated with different phenotypes that reflect the addition of smoking-induced changes to asthma physiopathology.

The asthma-COPD overlap syndrome: A comparison of asthma outcomes in smoking vs non-smoking patients with incompletely reversible airway obstruction (IRAO)

Background: Asthma may be associated with IRAO, either due to an acquired smoking-related component of COPD or to asthma-related airway structural changes. This so called asthma-COPD overlap syndrome has been poorly studied. Aim: To evaluate the comparative clinical, physiologic and inflammatory features of smoking and non-smoking patients with an IRAO. Methods: This was an observational study comparing clinical characteristics, pulmonary function, and systemic or lower airway inflammation between the two groups of patients studied. Results: Sixty-five smoking IRAO (S-IRAO) and 37 non-smoking IRAO (NS-IRAO) were included. There were significantly more women in the S-IRAO group ( P =0.02) than in the NS-IRAO group. S-IRAO patients had lower scores on the asthma control questionnaire ( P =0.02) and asthma quality of life questionnaire ( P =0.01) than NS-IRAO. In addition, S-IRAO showed a higher residual volume ( P =0.009) and a lower diffusing capacity for carbon monoxide corrected for alveolar volume ( P =0.0003) as compared to NS-IRAO. No differences were observed in systemic or lower airway inflammation. Conclusions: S-IRAO patients have a different phenotype as compared to patients with NS-IRAO, characterized poorer asthma control and quality of life, increased gas trapping and lower CO diffusion capacity.