Can inhaled corticosteroids influence the natural history of asthma?

PURPOSE OF REVIEW: Asthma is characterised by variable airflow obstruction, airway inflammation and hyper-responsiveness. Persistent inflammation is thought to lead to 'remodelling' of the airway, which in turn leads to the progressive loss of lung function seen in asthmatics. It would appear logical that anti-inflammatory drugs such as inhaled corticosteroids (ICS) would influence the natural history of asthma by reducing inflammation, subsequent remodelling, and thus preventing the decline in lung function. This review will summarise the effects of ICS on the secondary prevention of asthma, lung function and remodelling. RECENT FINDINGS: Many published studies show a reduction in airway inflammation, improvement in clinical symptoms and prebronchodilator lung function whilst taking ICS. Few studies, however, examine their effect on the natural history of asthma. Several recent studies have targeted very young children with asthma using ICS, and despite their differing target populations and treatment strategies, have failed to show any difference in lung function. Studies in adults with mild persistent asthma show similar findings. ICS appear to reverse some of the processes involved in airway remodelling, but not all. SUMMARY: Although ICS are effective in controlling symptoms they do not appear to alter the natural history of asthma.     

Inflammatory markers and Acid-base equilibrium in exhaled breath condensate of stable and unstable asthma patients

Background: Nitrosative and acid stress play an important role in the pathogenesis of asthma. The aim of this study was to evaluate whether, in asthmatics, a link exists between the concentrations of nitrite/nitrate, ammonia and pH values in exhaled breath condensate (EBC) and asthma severity, lung function, exhaled nitric oxide (F(ENO)), total IgE, eosinophil cationic protein (ECP) and blood eosinophilia. Methods: The above-mentioned parameters were measured in 19 healthy volunteers and 91 allergic asthmatics divided into three groups, i.e. 22 subjects with steroid-na?ve stable asthma, 35 with inhaled corticosteroid (ICS)-treated stable asthma and 34 with ICS-treated unstable asthma. Results: Compared with healthy subjects, EBC from asthmatics had significantly lower pH values and ammonia concentrations and significantly higher levels of nitrite/nitrate. The extent of these changes was higher in patients with unstable than in patients with steroid-na?ve and stable ICS-treated asthma. The EBC pH was positively correlated with ammonia and negatively correlated with nitrite/nitrate, F(ENO) or blood eosinophilia in all three groups of asthmatics. Significant positive correlations between EBC nitrite/nitrate and blood eosinophilia, ECP levels or F(ENO) were observed in all groups of asthmatics. Significant negative correlations between EBC ammonia and nitrite/nitrate, F(ENO), ECP concentrations or blood eosinophilia were demonstrated in the groups of ICS-na?ve and ICS-treated stable asthmatics. Conclusions: In asthmatic patients there is a relationship between EBC pH, ammonia and nitrite/nitrate concentrations and other recognized markers of airway inflammation. EBC pH values, ammonia and nitrite/nitrate levels measured together may help to assess airway inflammatory status and asthma severity.     

A comparison of exhaled nitric oxide and induced sputum as markers of airway inflammation

BACKGROUND: Exhaled nitric oxide (ENO) has been proposed as a noninvasive marker of airway inflammation in asthma. OBJECTIVE: We investigated the relationships among ENO, eosinophilic airway inflammation as measured by induced sputum, and physiologic parameters of disease severity (spirometry and methacholine PC(20)). We also examined the effect of corticosteroid treatment and atopy on ENO levels and eosinophil counts in induced sputum. METHODS: Measurements were taken on one day in 22 healthy nonatopic subjects, 28 healthy atopic subjects, 38 asthmatic subjects not taking inhaled steroids, 35 asthmatic subjects taking inhaled steroids, and 8 subjects with eosinophilic bronchitis without asthma. RESULTS: ENO levels showed significant but weak correlations with eosinophil differential counts in the steroid-naive asthmatic and healthy atopic groups (r (s) < 0.05). ENO levels were significantly lower in the asthmatic subjects taking steroids compared with the asthmatic subjects not taking steroids, despite there being no difference in the sputum cell counts, and a tendency to increased airflow limitation. ENO levels and sputum eosinophil counts were equally good at differentiating from steroid-naive asthmatic subjects. ENO levels were consistently raised in subjects with eosinophilic bronchitis without asthma. Atopy had no effect on ENO levels in the healthy subjects. CONCLUSION: We conclude that ENO is likely to have limited utility as a surrogate clinical measurement for either the presence or severity of eosinophilic airway inflammation, except in steroid-naive subjects.     

Urine leukotriene E4 levels are associated with decreased pulmonary function in children with persistent airway obstruction

BACKGROUND: Use of leukotriene receptor antagonists improves disease control in children and adults with asthma. However, the relationship between cysteinyl leukotriene levels and indices of daily asthma control has not been studied directly. OBJECTIVES: We sought to assess the relationship between daily variability in urinary leukotriene E(4) (LTE(4)) levels and daily lung function in children primarily taking inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs). METHODS: Fifty children primarily with moderate-to-severe asthma were followed with measurements of urinary LTE(4), monitoring of FEV(1), and albuterol use. RESULTS: Increasing urinary LTE(4) levels were associated with significant (P = .006) decreases in percent predicted FEV(1) (ppFEV(1)) averaging 4.7% per interquartile range increase in LTE(4) and accompanied by increased albuterol use (P = .03). Children with lower FEV(1)/forced vital capacity ratios demonstrated larger LTE(4)-related FEV(1) decreases (6.4%) compared to those with higher ratios (4.2%, P = .009). This association was blunted in children taking montelukast (1.4% ppFEV(1) decrease) compared with that in children not taking this medication (5.4% ppFEV(1) decrease, P = .05). Children with lower lung function ratios demonstrated greater blunting of the LTE(4) effect with montelukast (0.9% ppFEV(1) decrease) compared to those with higher ratios (3.6% ppFEV(1), P = .0002). CONCLUSIONS: Daily variability in LTE(4) levels is associated with clinically significant decreases in pulmonary function. In children who demonstrate a response associated with an increase in urinary LTE(4) levels, leukotriene receptor antagonists protect against daily FEV(1) decreases. This protection might be greatest in those with persistent airway obstruction despite use of ICS and LABA therapy. CLINICAL IMPLICATIONS: Therapies designed to block cysteinyl leukotriene production or function might benefit children receiving ICS and LABA therapy who continue to experience persistent disease.     

Concentrations of exhaled nitric oxide in asthmatics and subjects with allergic rhinitis sensitized to the same pollen allergen.

BACKGROUND: Some studies have reported that the levels of exhaled nitric oxide (ENO) in asthmatics are similar to those in subjects with allergic rhinitis, and it has been postulated that atopic status might be the determinant of enhanced nitric oxide production in asthma. OBJECTIVES: The aim of this study was to determine differences in ENO levels between asthmatics and subjects with allergic rhinitis sensitized to the same allergen, and to correlate these levels with airway responsiveness. METHODS: Nineteen patients with asthma and 18 subjects with allergic rhinitis monosensitized to Parietaria pollen were enrolled in the study. ENO values and airway responsiveness to methacholine and adenosine 5'-monophosphate (AMP) were measured during the pollen season. The response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall in FEV1 (PC20). ENO was measured with the single-exhalation method. RESULTS: The geometric mean (95% confidence interval) ENO values were significantly higher in asthmatics than in subjects with allergic rhinitis: 72.4p.p.b. (54.9-93.3p.p.b) vs. 44.7p.p.b. (30.9-64.6p.p.b., P = 0.03). In asthmatics, a significant correlation was found between ENO and PC20 AMP values (p = -0.57, P=0.02), whereas no correlation was detected between ENO and PC20 methacholine (p = -0.35, P = 0.14). CONCLUSIONS: Our results suggest that atopy is not the only determinant of increased ENO levels detected in subjects with asthma, and that responsiveness to AMP may be a more sensitive marker for assessing airway inflammation in asthma compared to methacholine.     

Buffering airway acid decreases exhaled nitric oxide in asthma

BACKGROUND: The human airway is believed to be acidified in asthma. In an acidic environment nitrite is converted to nitric oxide (NO). OBJECTIVE: We hypothesized that buffering airway lining fluid acid would decrease the fraction of exhaled NO (F(ENO)). METHODS: We treated 28 adult nonsmoking subjects (9 healthy control subjects, 11 subjects with mild intermittent asthma, and 8 subjects with persistent asthma) with 3 mL of 10 mmol/L phosphate buffered saline (PBS) through a nebulizer and then serially measured F(ENO) levels. Six subjects also received PBS mouthwash alone. RESULTS: F(ENO) levels decreased after buffer inhalation. The maximal decrease occurred between 15 and 30 minutes after treatment; F(ENO) levels returned to pretreatment levels by 60 minutes. The decrease was greatest in subjects with persistent asthma (-7.1 +/- 1.0 ppb); this was more than in those with either mild asthma (-2.9 +/- 0.3 ppb) or healthy control subjects (-1.7 +/- 0.3 ppb, P < .001). Levels did not decrease in subjects who used PBS mouthwash. CONCLUSION: Neutralizing airway acid decreases F(ENO) levels. The magnitude of this change is greatest in persistent asthma. These data suggest that airway pH is a determinant of F(ENO) levels downstream from NO synthase activation. CLINICAL IMPLICATIONS: Airway biochemistry modulates F(ENO) levels. For example, nitrite is converted to NO in the airway, particularly the inflamed airway, by means of acid-based chemistry. Thus airway pH should be considered in interpreting clinical F(ENO) values. In fact, PBS challenge testing integrates airway pH and F(ENO) analysis, potentially improving the utility of F(ENO) as a noninvasive test for the type and severity of asthmatic airway inflammation.     

Airway cell and cytokine changes in early asthma deterioration after inhaled corticosteroid reduction

BACKGROUND: Back-titration of inhaled corticosteroid (ICS) dose in well-controlled asthma patients is emphasized in clinical guidelines, but there are few published data on the airway cell and cytokine changes in relation to ICS reduction. In our study, 20 mild-to-moderate persistent (inspite of low-moderate dose ICS treatment) asthmatic subjects prospectively rendered largely asymptomatic by high-dose ICS were assessed again by clinical, physiological, and airway inflammatory indices after 4-8 weeks of reduced ICS treatment. We aimed at assessing the underlying pathological changes in relation to clinical deterioration. METHODS: Patients recorded daily symptom scores and peak expiratory flows (PEF). Spirometry and airways hyperreactivity (AHR) were measured and bronchoscopy was performed with assessment of airway biopsies (mast cells, eosinophils, neutrophils, and T lymphocytes), bronchoalveolar lavage (BAL) IL-5 and eotaxin levels and cellular profiles at the end of high-dose ICS therapy and again after ICS dose reduction. Baseline data were compared with symptomatic steroid-free asthmatics (n=42) and non-asthmatic controls (n=28). RESULTS: After ICS reduction, subjects experienced a variable but overall significant increase in symptoms and reductions in PEF and forced expiratory volume in 1 s. There were no corresponding changes in AHR or airways eosinophilia. The most relevant pathogenic changes were increased CD4(+)/CD8(+) T cell ratio, and decreased sICAM-1 and CD18 macrophage staining (potentially indicating ligand binding). However, there was no relationship between the spectrum of clinical deterioration and the changes in cellular profiles or BAL cytokines. CONCLUSIONS: These data suggest that clinical markers remain the most sensitive measures of early deterioration in asthma during back-titration of ICS, occurring at a time when AHR and conventional indices of asthmatic airway inflammation appear unchanged. These findings have major relevance to management and to how back-titration of ICS therapy is monitored.     

Effect of fluticasone propionate-salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma.

BACKGROUND: There has been concern that in allergic asthmatic patients there might be an interactive effect on inflammation between regular salmeterol use and exposure to allergens, resulting in increased airway responsiveness. OBJECTIVE: To determine the effects of salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide (ENO) levels in allergic asthmatic patients concomitantly taking inhaled corticosteroids. METHODS: Forty-two asthmatic patients sensitized to pollen allergens were randomly allocated to treatment with fluticasone propionate-salmeterol (n=21) or fluticasone propionate alone (n=21). Spirometry, the methacholine provocation concentration causing a 20% decline in forced expiratory volume in 1 second (PC20), the adenosine 5'-monophosphate (AMP) PC20, and ENO levels were measured before and at the height of the pollen season after 6 weeks of treatment. RESULTS: Changes in the methacholine PC20, the AMP PC20, and ENO levels were not significantly different between treatment groups. No significant changes in the AMP PC20 were observed among the fluticasone propionate-salmeterol and fluticasone propionate groups during natural pollen exposure. However, a significant increase in the methacholine PC20 was observed in the fluticasone propionate-salmeterol group (P = .03) and in the fluticasone propionate group (P = .04); ENO concentrations decreased significantly in both groups during natural allergen exposure (P = .009 and .005). CONCLUSIONS: In patients with pollen-induced asthma, treatment with either fluticasone propionate or fluticasone propionate-salmeterol is associated with significant reductions in methacholine responsiveness and ENO concentrations, even during natural pollen exposure. Furthermore, at least in patients with mild asthma, natural allergen exposure and the regular use of fluticasone propionate-salmeterol are not associated with a greater increase in ENO levels and airway responsiveness than natural allergen exposure and fluticasone propionate use alone.     

Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids

BACKGROUND: Although inhaled corticosteroids (ICSs) are effective in preventing deterioration in asthma control, at least half of subjects with mild-to-moderate asthma will remain stable when these agents are discontinued. OBJECTIVE: We sought to determine whether noninvasive markers of inflammation predict which individuals maintain asthma control after discontinuation of ICSs. METHODS: We analyzed data obtained from 164 subjects with mild-to-moderate asthma who participated in a 16-week trial comparing the effects of continued ICS use with the effects of a switch to salmeterol or placebo. RESULTS: In comparison with continued ICS use, a switch to salmeterol or placebo was associated with increased rates of asthma deterioration over 16 weeks (9.3% vs 24.1% and 37.5%, respectively; P = .04 and P < .001, respectively). We found that neither exhaled nitric oxide nor methacholine PC 20 , when measured at randomization or 2 weeks after randomization, were significant predictors of subsequent asthma control in subjects who discontinued ICSs. However, both induced sputum eosinophil counts measured 2 weeks after a switch from ICS to placebo and changes in sputum eosinophil counts from before cessation of ICSs to after a switch to placebo predicted subsequent asthma deterioration (area under the receiver-operating characteristic curve, 0.771 [ P < .001] and 0.825 [ P < .001], respectively). CONCLUSION: On the basis of a model treatment strategy, we estimate that allocating subjects to ICS therapy on the basis of changes in sputum eosinophil counts after a trial discontinuation could allow 48% of subjects with mild-to-moderate asthma to discontinue ICS therapy without an increased risk of asthma deterioration over a period of at least 14 weeks.     

Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE

BACKGROUND: Patients with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy are a challenging population with significant unmet medical need. We determined the effect of omalizumab on clinically significant asthma exacerbations (requiring systemic corticosteroids) in the first omalizumab study to exclusively enrol patients from this difficult-to-treat patient population. METHODS: Following a run-in phase, patients (12-75 years) inadequately controlled despite therapy with high-dose inhaled corticosteroids (ICS) and long-acting beta(2)-agonists (LABA) with reduced lung function and a recent history of clinically significant exacerbations were randomized to receive omalizumab or placebo for 28 weeks in a double-blind, parallel-group, multicentre study. RESULTS: A total of 419 patients were included in the efficacy analyses. The clinically significant asthma exacerbation rate (primary efficacy variable), adjusted for an observed relevant imbalance in history of clinically significant asthma exacerbations, was 0.68 with omalizumab and 0.91 with placebo (26% reduction) during the 28-week treatment phase (P = 0.042). Without adjustment, a similar magnitude of effect was seen (19% reduction), but this did not reach statistical significance. Omalizumab significantly reduced severe asthma exacerbation rate (0.24 vs 0.48, P = 0.002) and emergency visit rate (0.24 vs 0.43, P = 0.038). Omalizumab significantly improved asthma-related quality of life, morning peak expiratory flow and asthma symptom scores. The incidence of adverse events was similar between treatment groups. CONCLUSIONS: In patients with inadequately controlled severe persistent asthma, despite high-dose ICS and LABA therapy, and often additional therapy, omalizumab significantly reduced the rate of clinically significant asthma exacerbations, severe exacerbations and emergency visits. Omalizumab is effective and should be considered as add-on therapy for patients with inadequately controlled severe persistent asthma who have a significant unmet need despite best available therapy.     

Relationship between recurrent croup and airway hyperreactivity

The relationship between recurrent croup and bronchial asthma was evaluated by measuring bronchial hyperreactivity (methacholine challenge), physiologic parameters of upper airway obstruction, and skin response to environmental allergens. Patients with recurrent croup (n = 10) had a significantly higher degree of airway hyperreactivity and atopy than healthy children (n = 15), but significantly less than the patients with bronchial asthma (n = 30). No physiologic signs of upper airway obstruction could be detected at rest or following methacholine. It is suggested that bronchial asthma and recurrent croup share a few characteristics.     

Sequential development of airway hyperresponsiveness and acute airway obstruction in a mouse model of allergic inflammation

BACKGROUND: Mouse models have been established mirroring key features of human bronchial asthma including airway hyperresponsiveness (AHR). Acute airway obstruction in response to an allergen challenge, however, remains to be demonstrated in these models. OBJECTIVE: A mouse model of allergic lung inflammation was employed to analyze the development of specific (allergen-induced) and nonspecific (methacholine-induced) airway obstruction. METHODS: Mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol twice each week during four weeks. Changes in lung functions were determined by noninvasive head-out body plethysmography. The development of acute airway obstruction after OVA challenge and AHR after methacholine aerosol application were assessed by a decrease in the mid-expiratory flow rate (EF(50)). Results: Two airway challenges were sufficient to induce AHR (5.7 vs. 15 mg/ml methacholine). Further OVA challenges reduced the baseline EF(50) from 1.85 to 1.20 ml/s (4th week) and induced acute airway obstruction. The OVA-induced obstruction was maximal in the 4th week (EF(50) = 0.91 ml/s). CONCLUSION: The development of acute airway obstruction in allergen-sensitized mice was demonstrated by means of head-out body plethysmography. In our model, AHR was observed before the development of airway obstruction.     

Characterization of within-subject responses to fluticasone and montelukast in childhood asthma

BACKGROUND: Responses to inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs) vary among asthmatic patients. OBJECTIVE: We sought to determine whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other. METHODS: Children 6 to 17 years of age with mild-to-moderate persistent asthma were randomized to one of 2 crossover sequences, including 8 weeks of an ICS, fluticasone propionate (100 microg twice daily), and 8 weeks of an LTRA, montelukast (5-10 mg nightly depending on age), in a multicenter, double-masked, 18-week trial. Response was assessed on the basis of improvement in FEV 1 and assessed for relationships to baseline asthma phenotype-associated biomarkers. RESULTS: Defining response as improvement in FEV 1 of 7.5% or greater, 17% of 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication. Compared with those who responded to neither medication, favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil counts, levels of serum IgE, and levels of serum eosinophil cationic protein and lower levels of methacholine PC(20) and pulmonary function; favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use, bronchodilator response, exhaled nitric oxide levels, and eosinophil cationic protein levels and lower methacholine PC(20) and pulmonary function values. CONCLUSIONS: Response to fluticasone and montelukast vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation should receive ICS therapy. Other children could receive either ICSs or LTRAs.     

Role of small airways in asthma: investigation using high-resolution computed tomography

BACKGROUND: Small airways may have an important role in asthma but are more difficult to assess pathologically than central airways. Computed tomographic indices of lung density are assumed to reflect air trapping and may be a useful noninvasive measure of small airways disease, but their pathophysiological relevance remains undetermined. OBJECTIVE: To evaluate lung density on high-resolution computed tomography and examine its correlations with clinical and physiologic variables in 29 patients with stable asthma. METHODS: Both lungs were scanned at full-inspiratory and full-expiratory phases to quantify percentage of lung field occupied by low attenuation area (LAA%; < -960 Hounsfield units) and mean lung density. Asthma severity, pulmonary function, methacholine airway sensitivity and reactivity, and sputum eosinophil counts were evaluated. RESULTS: The mean lung density increased and LAA% decreased in all patients at expiratory phase compared with inspiratory phase. The inspiratory density indices and expiratory mean lung density correlated only with FEV(1)/forced vital capacity (FVC). Expiratory LAA% correlated more strongly than other variables with FEV(1)/FVC and with indices of peripheral airflow obstruction. Expiratory/inspiratory ratios of LAA% and mean lung density correlated, the former more strongly, with disease severity, residual volume/total lung capacity, and airway sensitivity, as well as with indices of global (FEV(1) and FEV(1)/FVC) and peripheral airflow obstruction. CONCLUSION: Expiratory/inspiratory high-resolution computed tomography is useful for assessing small airways disease in asthma. Small airways involvement is associated with airflow obstruction, airway hypersensitivity, and more severe disease. CLINICAL IMPLICATIONS: Small airways are an important therapeutic target in asthma.     

Exhaled nitric oxide levels and airway responsiveness to adenosine 5'-monophosphate in subjects with nasal polyposis

BACKGROUND:It is widely appreciated that asthma is an inflammatory disease of the airways associated with airway hyperresponsiveness, and that nasal polyposis and asthma are related diseases. The objective of this study was to determine differences in exhaled nitric oxide (ENO) levels and airway responsiveness to adenosine 5'-monophosphate (AMP) between nonasthmatic patients with nasal polyposis and healthy controls. METHODS: Twenty patients without asthma with nasal polyposis and 16 healthy control subjects were enrolled in the study. Participants were challenged with increasing concentrations of AMP and methacholine. ENO was measured with the single-exhalation method. RESULTS: Bronchoconstriction in response to AMP was detected in 7 (35%) subjects with nasal polyposis. The geometric mean (95% CI) of ENO for subjects with nasal polyposis was 33.1 parts per billion (ppb) (24.0-45.7 ppb) compared with 12.3 ppb (8.5-18.2 ppb) for the healthy controls (p = 0.0002). ENO values were significantly higher in atopic than in nonatopic subjects with nasal polyposis [51.3 ppb (32.3-83.2 ppb) vs. 24.5 ppb (16.2-37.1 ppb), p = 0.02]. Nonatopic subjects with nasal polyposis also had higher concentrations of ENO than healthy control subjects (p = 0.016). CONCLUSIONS: Inhaled AMP causes airway narrowing in a significantly higher proportion of nonasthmatic subjects with nasal polyposis than in healthy controls. Furthermore, increased concentrations of ENO are detected in atopic and nonatopic subjects with nasal polyposis. These results suggest that bronchial inflammation is present in nonasthmatic subjects with nasal polyposis.     

Rhinosinusitis in severe asthma

BACKGROUND: Chronic rhinosinusitis is a common comorbidity of asthma. However, sinonasal involvement in severe steroid-dependent asthma is still undefined. OBJECTIVE: The aim of the study was to evaluate chronic rhinosinusitis in 35 patients with severe steroid-dependent asthma by using a clinical score and coronal computed tomography (CT) scanning. METHODS: Thirty-five subjects (16 female subjects) with severe asthma requiring daily doses of oral corticosteroids were compared with 34 patients (19 female patients) with mild-to-moderate asthma. Sinonasal involvement was studied by using clinical and CT scores. Airflow obstruction, therapy requirement, and asthma triggering factors were carefully assessed. RESULTS: The proportion of patients with symptoms of rhinosinusitis was similar in both groups of asthmatic subjects (74% in patients with severe steroid-dependent asthma and 70% in patients with mild-to-moderate asthma). All subjects with steroid-dependent asthma versus 88% of subjects with mild-to-moderate asthma had abnormal CT scan results. The clinical (P <.05) and CT scan (P <.0005) severity scores were higher in the subjects with severe steroid-dependent asthma. In both groups the CT scan scores were correlated to the clinical scores (P <.0001 and P <.006), but only in the mild-to-moderate group were both scores correlated with high significance (P <.002 and P <.0005) to the absolute number of blood eosinophils. CONCLUSION: Frequency of rhinosinusitis in patients with mild-to-moderate or severe steroid-dependent asthma is similar; however, sinonasal involvement, as evaluated by clinical symptoms and CT scan imaging, is significantly greater in the patients with severe steroid-dependent asthma than in those with mild-to-moderate asthma.     

Basement membrane thickening and clinical features of children with asthma

BACKGROUND: Asthma is a chronic inflammatory disease, characterized by airway inflammation, bronchial hyper-responsiveness, and airway obstruction. Although asthma induces partially reversible airway obstruction, obstruction can sometimes become irreversible. This may be a consequence of airway remodeling, which includes a number of structural changes, such as epithelial detachment, basement membrane (BM) thickening, smooth muscle hypertrophy, and new vessel formation. This study evaluated children with asthma for the presence of BM thickening. METHODS: Eighteen children with asthma and 24 control subjects underwent flexible bronchoscopy with endobronchial biopsy. Light microscopy was used to measure BM thickness in paraffin-embedded biopsy sections. The association between BM thickening and age, sex, duration of asthma, asthma severity, FEV(1), FEV(1)/FVC, FEF(25-75%), methacholine PC(20), eosinophil count, and presence of atopy was examined. RESULTS: Basement membrane thickness was greater in subjects with asthma (8.3 +/- 1.4 microM) than in control subjects (6.8 +/- 1.3 microM, P = 0.0008). Multiple regression analysis revealed that sex, FEV(1)/FVC, total IgE, and atopy (IgE for Dermatophagoides pteronyssinus >0.34 kUA/l) were significant predictive factors for BM thickness. There was no significant association between BM thickness and age, duration of asthma, FEV(1), FEF(25-75%), methacholine PC(20), eosinophil count, or asthma severity. CONCLUSIONS: Basement membrane thickening has been known to be present in children with asthma. In addition, we report an association between BM thickness and sex, FEV(1)/FVC, total IgE, and the presence of IgE specific to D. pteronyssinus.     

Add‐on montelukast to inhaled corticosteroids protects against excessive airway narrowing

Rationale Excessive airway narrowing in response to broncho‐active stimuli is a predictor for severe exacerbations in asthma. Leukotriene receptor antagonists (LTRAs) have complementary properties to inhaled corticosteroids (ICS) on asthma control. Objectives The LTRA montelukast may provide an additional protection against excessive airway narrowing. We tested the add‐on effects of montelukast on the maximal response plateau and PD₂₀ to inhaled methacholine in asthmatics on a stable dose of ICS. Methods Thirty‐one patients with allergic asthma [14M/17F, 19–50 years, forced expiratory volume in 1 s (FEV₁) >70% pred., PD₂₀ <3.9 μmol methacholine], with a twice documented response plateau to methacholine, were randomized in a double‐blind (montelukast 10 mg or matching placebo once daily), 12‐week parallel study. Bronchoprovocation tests with methacholine (0.03–256 μmol or 40% decline in FEV₁) were repeated every 4 weeks and after wash‐out. The main study objectives were changes from baseline in maximal FEV₁ decline at the response plateau (i.e. >2 post‐dose FEV₁ values within 5%) and PD₂₀ to methacholine after 12 weeks' treatment. Results Neither treatment affected baseline FEV₁ (P=0.62). Compared with placebo, montelukast significantly decreased the maximal response plateau to methacholine (mean difference 9.4%; 95% confidence interval 3.9–15.7; P<0.005), improved the FEV₁ decline (mean change in FEV₁ decline was 2.1% [montelukast] and ?0.8% [placebo], respectively, P<0.05), and increased PD₂₀ methacholine (mean change in PD₂₀ of 5.3 [montelukast] and 1.4 [placebo] doubling doses, respectively, P<0.001). Conclusion Add‐on montelukast to ICS has disease‐modifying effects in adults with persistent asthma, and hence reduces the risk of excessive airway narrowing (NCT 00913328). Cite this as: C. S. Ulrik and Z. Diamant, Clinical & Experimental Allergy, 2010 (40) 576–581.     

Sputum eosinophil counts and eosinophil cationic protein levels in cough-variant asthma and in classic asthma, and their relationships to airway hypersensitivity or maximal airway response to methacholine

Background:  The aims of this study were to compare the degree of airway inflammation in cough-variant asthma (CVA) with that in classic asthma (CA), and to examine the relationship between airway inflammation and airway hypersensitivity or maximal airway response to methacholine in both conditions.
Methods:  Sputum was induced in 41 CVA patients, in 41 methacholine PC₂₀-matched CA patients, and in 20 healthy children. The sputum samples were analyzed for total and differential cell counts, and for eosinophilic cationic protein (ECP). A high-dose methacholine challenge test was performed in CVA and CA patients to determine PC₂₀ and maximal airway response.
Results:  Sputum eosinophil percentages and ECP levels were significantly elevated in CVA and CA vs the control, but no significant differences were found between the two asthma groups. In the two asthma groups, neither sputum parameters correlated significantly with methacholine PC₂₀. However, the absence of a maximal response plateau or its higher level, when present, was associated with increased eosinophil percentages and ECP levels in the CVA group.
Conclusions:  The degree of eosinophilic inflammation may not be causally related to differences in presented asthma manifestations. The identification of a maximal response plateau and the level of this plateau in patients with CVA may provide information pertinent to airway eosinophilic inflammation.     

An evaluation of the cost-effectiveness of omalizumab for the treatment of severe allergic asthma

Omalizumab is the first licensed anti-immunoglobulin (Ig) E antibody shown to be effective for treatment of allergic (IgE-mediated) asthma. Recent international guidelines recommend omalizumab as add-on treatment to fixed dose inhaled corticosteroid (ICS) and long-acting β₂-agonist (LABA) combination therapy. However, omalizumab is more expensive than other current asthma treatments and health and reimbursement authorities are increasingly demanding evidence of economic benefit to support pricing and formulary listing. The aims of this article are to (i) summarize data on the human and economic burden of severe asthma, (ii) summarize the efficacy data obtained for omalizumab in clinical trials in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA, and (iii) discuss the cost-effectiveness evidence published for omalizumab in this patient population. A wealth of evidence exists highlighting that the health, economic and societal burden of asthma is considerable and is highly skewed towards patients with severe asthma, particularly when asthma is inadequately controlled. Omalizumab is clinically beneficial in patients with severe persistent allergic asthma despite high-dose ICS plus a LABA, particularly in a subgroup of patients who respond to therapy. In patients who respond to therapy, the cost-effectiveness of omalizumab compares well with other biologic treatments for chronic illness.