Severe Asthma Group Research Articles

Airway remodeling assessed by high-resolution computed tomography in patients with asthma: relationship to biological markers in induced sputum

To explore the significance of assessing asthma control by high-resolution computed tomography (HRCT) and biological markers in induced sputum. Forty-eight patients with asthma (asthma group) and 10 healthy subjects (control group) were retrospectively analyzed. The asthma patients were divided into 4 groups based on severity: 6 with near-fatal attacks, 12 with severe, 14 with moderate and 16 with mild asthma. These patients received step therapy for 6 months based on the guidelines for the prevention and treatment of asthma. After achieving asthma control or partial control, HRCT, lung function and cytokine levels in induced sputum were measured. The ratio of wall area to total airway area (WA%), the ratio of 2 airway wall thickness to outer diameter (2T/D) and lung densities in both the inspiratory and expiratory phases were measured. Matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), and transformation growth factor-β(1) (TGF-β(1)) levels in the sputum were assessed by enzyme-linked immunosorbent assay. There were significant differences in forced vital capacity and forced expiratory volume in 1 second as the percentage of predicted value (FVC% and FEV(1)%, respectively), the ratio of FEV(1)/FVC, and diffusing capacity of the lung for carbon monoxide (D(LCO)) among groups (F = 5.526, 15.064, 16.326, 2.945, respectively, P < 0.05). Sputum levels of MMP-9, TIMP-1 and TGF-β(1) were significantly increased in the near-fatal asthma, severe asthma, moderate asthma and mild asthma groups [MMP-9: (80 ± 16), (70 ± 9), (59 ± 6), and (52 ± 7) µg/L, respectively; TIMP-1: (212 ± 95), (258 ± 167), (28 ± 51), and 98 ± 60 µg/L, respectively; TGF-β(1): (586 ± 81), (513 ± 54), (401 ± 45) and (351 ± 57) µg/L, respectively]compared with the control group [MMP9: (46 ± 5) µg/L; TIMP: (19 ± 13) µg/L; and TGF-β(1): (258 ± 29) µg/L]. These parameters were progressively increased in the asthma groups with the severity of disease (F = 11.179, 49.914, 9.286, respectively, P < 0.05). The ratio of MMP-9/TIMP-1 in sputum was decreased in the near-fatal attack, severe, moderate and mild asthma groups (0.50 ± 0.28, 0.34 ± 0.13, 0.53 ± 0.22, and 0.87 ± 0.75, respectively) compared with the control group (2.93 ± 1.13). The MMP-9/TIMP-1 ratio in the severe asthma group was lowest among the asthma groups (F = 43.335, P < 0.05). 2T/D and WA% were higher in both the near-fatal asthma group (0.51 ± 0.01 and 0.75 ± 0.01, respectively) and the severe asthma group (0.53 ± 0.03 and 0.77 ± 0.03, respectively) as compared to the moderate asthma group (0.43 ± 0.04 and 0.67 ± 0.04, respectively) or the mild group (0.42 ± 0.04 and 0.66 ± 0.04, respectively). 2T/D and WA% were higher in the asthma groups than in the control group (0.35 ± 0.03 and 0.57 ± 0.04, respectively), (F = 40.224, 41.294, respectively, P < 0.05). Lung densities in both the inspiratory and expiratory phases were lower in the near-fatal attack group as compared to those in the other asthma groups or the control group; and the lung density differences between the two phases in the near-fatal attack group were smaller than those in the other asthma groups or the control group (F = 5.048, 13.247, 11.541, respectively, P < 0.05). 2T/D and WA% were correlated positively with MMP-9, TIMP-1 and TGF-β(1) levels, but negatively with the MMP-9/TIMP-1 ratio, respectively. HRCT and biological markers in induced sputum could be used to accurately evaluate asthma control. These findings suggest that the severity of asthma, especially, near-fatal attack of asthma, is correlated not only with the degree of airway remodeling, but also with the degree of air trapping.

P12 Fluticasone propionate/formoterol fumarate combination therapy: treatment effects in patients by baseline asthma severity across the dose range

BackgroundA new asthma therapy containing a combination of the inhaled steroid fluticasone propionate (FLUT) and the long-acting β2 agonist (LABA) formoterol fumarate (FORM) in a metered-dose inhaler has been developed...

P1 Omalizumab in Paediatric Asthma: Importance of Multi-Disciplinary Assessment to Identify Eligible Patients

Omalizumab is effective treatment for patients with severe asthma. It is reserved for patients with truly severe disease as it is expensive and associated with significant treatment burden. Identifying this...

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Associations between fluctuations in lung function and asthma control in two populations with differing asthma severity

BackgroundLung function is a major criterion used to assess asthma control. Fluctuation analyses can account for lung function history over time, and may provide an additional dimension to characterise control....

Expiratory flows and airway inflammation in elderly asthmatic patients

Asthma in the elderly is often underrecognized and suboptimally treated, resulting in an increased morbidity and mortality. The characteristics of asthma-related bronchitis and its optimal treatment remain to be determined in this population. We aimed to compare lung function and airway inflammation in elderly and younger asthmatic subjects. Data from two induced sputum databases were analyzed in three groups of asthmatic subjects (18-30 y, n = 136; 31-59 y, n = 385; 60-72 y, n = 172) and one group of healthy elderly subjects (60-89 y, n = 16). Expiratory flows and induced sputum cell counts were analyzed. Airway obstruction was more marked in elderly asthmatics compared with healthy elderly or younger asthmatic subjects (p < 0.01). An increase in sputum neutrophils and a decrease in macrophages and lymphocytes were observed in elderly asthmatics (p < 0.0001). Neutrophil percentages significantly increased with asthma severity in the young and the middle-aged groups, while they remained similar in elderly asthmatics regardless of asthma severity (p < 0.05). Neutrophil percentages weakly correlated with the dose of ICS in all asthmatics (r = 0.17, p < 0.0001). Age and dose of ICS were independent predictors of neutrophil percentage in asthmatic subjects in a regression model (R(2) = 0.12). Asthma in the elderly is associated with a more marked airway obstruction and sputum neutrophilia. Both age and the dose of corticosteroids need to be considered in the interpretation of the clinical relevance of sputum neutrophil count.

Safety of investigative bronchoscopy in the Severe Asthma Research Program

Investigative bronchoscopy was performed in a subset of participants in the Severe Asthma Research Program to gain insights into the pathobiology of severe disease. We evaluated the safety aspects of this procedure in this cohort with specific focus on patients with severe asthma. To evaluate prospectively changes in lung function and the frequency of adverse events related to investigative bronchoscopy. Bronchoscopy was performed by using a common manual of procedures. A subset of very severe asthma was defined by severe airflow obstruction, chronic oral corticosteroid use, and recent asthma exacerbations. Subjects were monitored for changes in lung function and contacted by telephone for 3 days after the procedure. A total of 436 subjects underwent bronchoscopy (97 normal, 196 not severe, 102 severe, and 41 very severe asthma). Nine subjects were evaluated in hospital settings after bronchoscopy; 7 of these were respiratory-related events. Recent emergency department visits, chronic oral corticosteroid use, and a history of pneumonia were more frequent in subjects who had asthma exacerbations after bronchoscopy. The fall in FEV₁ after bronchoscopy was similar in the severe and milder asthma groups. Prebronchodilator FEV₁ was the strongest predictor of change in FEV₁ after bronchoscopy with larger decreases observed in subjects with better lung function. Bronchoscopy in subjects with severe asthma was well tolerated. Asthma exacerbations were rare, and reduction in pulmonary function after the procedure was similar to that in subjects with less severe asthma. With proper precautions, investigative bronchoscopy can be performed safely in severe asthma.

Reduced work ability in middle-aged men with asthma from youth- a 20-year follow-up

We studied, whether asthma diagnosed in childhood or early adulthood affects work ability 20 years later. We used Finnish Defence Force registers, 1986-1990, to select: (1) conscripts with asthma to represent a mild/moderate asthma group (n=485), (2) asthmatics who were exempted from military service to represent a relatively severe asthma group (n=393) and (3) a control group (n 1500) without asthma. A questionnaire consisting of validated questions on asthma and work ability was sent out in 2009. A total of 54% of the men in the first study group, 44% of those in the second study group and 44% of the controls answered. The mean age of the participants was 41 (range 37-51). Self-assessed current work ability compared with lifetime best had decreased in 28.9% of the first asthma group, in 31.1% of the second asthma group, and in 19.7% of the controls (p = 0.0007). Current smoking (OR 2.5), only basic education (OR 2.6), being a manual worker (OR 2.7) and current severe asthma (OR 3.8) associated most strongly with decreased work ability among the asthmatics. Both mild and more severe asthma at the age of around 20 seems to be associated with reduced work ability in 40-year-old males.

Sex dependence of airflow limitation and air trapping in children with severe asthma

In this cross-sectional evaluation of 77 severe and 71 non-severe asthmatics ages 6–17, boys, unlike girls with severe asthma, exhibited adult-like patterns of air-trapping and post-bronchodilator airflow limitation, apparently coincident with the onset of the severe asthma phenotype.

Multicenter Study of Chronic Asthma Severity Among Emergency Department Patients With Acute Asthma

Objective. The initiation of controller therapy for asthma depends on chronic asthma severity. To facilitate initiation of inhaled corticosteroids (ICSs), the preferred controller therapy, in the emergency department (ED), the objective of the study was to describe chronic asthma severity, as defined by the national asthma guidelines, among children presenting to the ED with acute asthma. Methods. Investigators at 14 U.S. sites prospectively enrolled consecutive children 2–17 years presenting to the ED with acute asthma. Three factors (daytime symptoms, nighttime symptoms, and medication usage) were used to categorize children into four chronic asthma severity groups: intermittent, mild persistent, moderate persistent or severe persistent. Results. This multistate cohort of 311 children had a mean age of 7.7 years, was 51% Black, and 89% had a primary care provider (PCP). Regarding chronic severity, 18% were intermittent and 82% persistent: 37% mild persistent, 24% moderate persistent, and 20% severe persistent. Chronic severity groups did not differ by demographics or PCP status. Patients with persistent asthma were more likely to report moderate-severe asthma symptoms (58% versus 19%; p < .001), poor asthma control (2% versus 18%; p = .002), and more ED visits (median, 2 versus 1; p < .001) in the past year. The groups did not differ in acute asthma severity, ED treatment, or admission rate. Rate of discharge prescription for ICSs was low, albeit higher among children with persistent asthma (24% versus 4%; p = .003). Conclusions. The high prevalence of persistent asthma among ED patients exceeds the prevalence reported previously, and supports ED initiation of ICS, as recommended by national guidelines.

Prosurvival activity for airway neutrophils in severe asthma

BackgroundAirway neutrophilia is a recognised feature of chronic severe asthma, but the mechanisms that underlie this phenomenon are unknown. Evidence for factors present in airway secretions that prolong neutrophil survival...

Influence of Maternal Asthma and Asthma Severity on Newborn Morphometry

Objective. To determine if maternal asthma or asthma severity affects newborn morphometry. Study Design. A secondary analysis was performed on data collected in a multicenter prospective observational cohort study of asthma in pregnancy. Patients enrolled included women with asthma stratified by severity of disease and controls. Asthma severity was defined according to the classification proposed by the National Asthma Education Program (NAEP) Report of the Working Group on Asthma and Pregnancy, modified to include medication requirements. Newborn morphometry measurements included birth weight (BW) and multiples of the median birth weight (BW-MOM), head circumference (HC), length (L), HC:BW ratio, and ponderal index (PI). Results. Of 2480 patients there were 828 nonasthmatic controls, 828 with mild, 775 with moderate, and 49 with severe disease. Comparing all groups, there were statistically significant differences in maternal age (p < .001), race (p = .005), parity (p = .006), prepregnancy weight (p = .028), and medical care source (p = .001), with the severe asthma group having the highest mean maternal age (25.7 years), and proportion of African Americans (71.4%), proportion of multiparous patients (63.3%), and proportion of patients receiving government assistance (85.7%). When the control group was excluded from the comparisons, differences in prepregnancy weight and medical care source were no longer significant. BW-MOM and L did not differ between groups. The HC:BW ratio increased with asthma severity (p = .029) and was increased compared to controls (p = .010). This remained significant after controlling for confounding variables (both p <.001). HC was statistically significantly different between all groups (p = .032), as well as among women with varying degrees of asthma severity (p = .013), which was not clinically significant. After covariates adjustment, HC was not significantly different among all groups (p = .228), nor the asthma groups (p = .144). Conclusion. Asthma severity is associated with an increased HC:BW ratio. Severity was not found to impact HC, BW-MOM, L, or PI independently. However, the magnitudes of the effects were too small to suggest a clinically significant effect of asthma on neonatal morphometry in this large prospectively studied sample.

Change and significance of peripheral blood Th17 cells in patients with acute asthma

To observe the change of peripheral blood Th17 cells and relationship between the severity and Th17 cells in patients with acute asthma. We recruited patients with mild acute asthma(n=10) and severe acute asthma(n=10), and healthy volunteers(n=10). T-lymphocytes were collected from the peripheral blood mononuclear cells (PBMC). Flow cytometer (FCM) was used to detect the expression of peripheral blood Th17 cells. IL-17 levels in the peripheral blood were measured by enzyme-linked immunosorbentassay (ELISA). The rate of positive Th17 cells of peripheral blood in the severe acute asthma group was higher than that in the mild acute asthma group(P<0.05) and the rate of positive Th17 cells of peripheral blood in healthy volunteer group were the lowest among all groups (P<0.05, respectively). The level of IL-17 in the peripheral blood of patients with severe acute asthma increased significantly compared with that in patients with mild acute asthma and healthy volunteers (P<0.05). The positive Th17 cells of peripheral blood in patients with acute asthma were positively correlated with the severity of acute asthma(r=0.869, P<0.05). The positive rate of Th17 cells in the peripheral blood increases in patients with acute asthma and has positive correlation with the severity of acute asthma.

Different inflammatory mechanisms in lungs of severe and mild asthma: crosstalk of NF‐kappa‐B, TGFβ1, Bax, Bcl‐2, IL‐4 and IgE

Objective: To examine differences in the apoptotic, inflammatory, allergic and immunological features in the lungs of adults with asthma. Material and methods: Thirty‐six patients with mild asthma (MA), 16 with severe asthma (SA) and 20 healthy volunteers (HVs) were enrolled. Bronchoalveolar lavage fluid (BALF) was processed into cell‐free fluid for enzyme‐linked immunosorbent assay detecting soluble TGFβ1, IL‐4 and IgE and BALF lymphocytes for immunocytochemical staining of cellular Bax, Bcl‐2 and nuclear factor‐Kappa‐B (NFκB). Results: Cellular NFκB expression was higher in SA than in MA and HVs, while extracellular TGFβ1 was high in both the SA and MA groups but low in the HVs. Bcl‐2/Bax ratio was higher in SA than in MA and in MA than in HV groups and correlated significantly with NFκB level. Interestingly, the levels of IgE and, to a lesser extent, IL‐4 were higher in MA than in SA and both were much higher than in HVs, and were inversely correlated with NFκB level in the SA group and with TGFβ1 level in the MA group. Conclusions: NFκB has a central role in the perpetuation of persistent inflammation in SA and might induce apoptosis via Bcl‐2. The SA group appears not associated much with allergen‐based IgE and IL‐4 reactions as efficiently as in MA. This was supported by the lower levels of IgE and IL‐4 in SA compared to MA. TGFβ1 appears to be associated with asthma pathogenesis, especially allergen‐based MA.

Reply to Macklem and Irvin

to the editor: We thank Drs. Macklem and Irvin ([3][1]) for their comments, and for their insights regarding the 1996 paper coauthored by Dr. Macklem ([2][2]). As noted in our paper ([4][3]), the study by Gibbons et al. ([2][2]) was the first to introduce the concept of partitioning the forced

Increased sputum and bronchial biopsy IL-13 expression in severe asthma

The importance of IL-13 in the asthma paradigm is supported by increased expression in human subjects, particularly in patients with mild-to-moderate asthma. However, the role of IL-13 in severe asthma needs to be further defined. We sought to assess IL-13 expression in sputum and bronchial biopsy specimens from subjects with mild-to-severe asthma. Sputum IL-13 concentrations were measured in 32 control subjects, 34 subjects with mild asthma, 21 subjects with moderate asthma, and 26 subjects with severe asthma. Enumeration of mast cells, eosinophils, and IL-13+ cells in the bronchial submucosa and airway smooth muscle (ASM) bundle was performed in 7 control subjects, 14 subjects with mild asthma, 7 subjects with moderate asthma, and 7 subjects with severe asthma. The proportion of subjects with measurable IL-13 in the sputum was increased in the mild asthma group (15/34) and severe asthma group (10/26) compared with that seen in the control group (4/32; P = .004). IL-13+ cells were increased within the submucosa in all asthma severity groups compared with control subjects (P = .006). The number of IL-13+ cells were increased within the ASM bundle in the severe asthma group compared with that seen in the other groups (P < .05). Asthma control questionnaire scores positively correlated with sputum IL-13 concentrations (R(s) = 0.35, P = .04) and mast cells in the ASM bundle (R(s) = 0.7, P = .007). IL-13+ cells within the submucosa and ASM correlated with sputum eosinophilia (R(s) = 0.4, P < or = .05). IL-13 overexpression in sputum and bronchial biopsy specimens is a feature of severe asthma.

Cysteinyl‐leukotrienes in nasal lavage fluid in children with asthma

The aim of this study was to investigate repeatability of cysteinyl-leukotrienes (cys-LT) measurements in nasal lavage fluid (NLF) and to determine if cys-LT levels in NLF are related to asthma severity in children. As a second outcome, we investigated if cys-LT in NLF reflect lower airway inflammation as assessed by exhaled NO measurement. To assess the repeatability of cys-LT measurements, two NLF samples were obtained from eight healthy controls 24 h apart. Sixty-nine asthmatic children (mean age; range: 12.8; 7.3-17.7 yr), which were grouped according to asthma severity were studied cross-sectionally on one occasion. Cys-LT in NLF were analyzed using a specific enzyme immunoassay, exhaled NO, and pulmonary function parameters were measured. The coefficient of repeatability for the repeated cys-LT measurements was 1.45 pg/ml. Cys-LT levels in NLF differed significantly between asthma severity groups (p < 0.001): mild intermittent: [median (IQR)] 6.88 pg/ml (2.00-27.87); mild persistent: 21.09 pg/ml (4.50-84.67); and moderate persistent asthmatics: 36.41 pg/ml (11.03-118.40). Concentration of cys-LT in NLF and exhaled NO was positively correlated (r = 0.85; p < 0.001). In conclusion, concentration of cys-LT in NLF correlates with asthma severity in children and is related to lower airway inflammation.

Aspirin sensitivity and eicosanoids

Aspirin sensitive respiratory disease (ASRD) was first described in 1922 by the French physician Widal.1 It is characterised by asthma, chronic rhinosinusitis and nasal polyps on a background of aspirin...

Control of asthma and its correlation to non-specific bronchial hyperreactivity in young patients

One of the most important purposes of treatment of asthma is achievement and maintenance of control of the disease. The present study investigated relationship between a level of asthma control and bronchial hyperreactivity (BHR). This study involved 145 outpatients aged 18 to 34 yrs. The control of asthma was evaluated using the Asthma Control Test (ACT). The ACT score of 25 indicated the full control of asthma, the scores between 20 and 24 indicated the good control and the scores < 20 suggested the poor control. BHR was assessed in the methacholine challenge test; PD20 was the dose of methacholine causing 20 % fall in FEV 1 . PD 20 ≤ 0.046 mg suggested high BHR, PD 20 ranged 0.047 mg to 0.228 mg indicated moderate BHR, and PD 20 of 0.229–0.471 mg corresponded to low BHR. Asthma was fully controlled in 17 mild asthma patients (22 %) and was poorly controlled in 13 of them (17 %). No-one of moderate and severe asthma patients had the full control of the disease. Good control of moderate and severe asthma was found in 22 (50 %) and 2 (8 %) respectively, poor control was estimated in 22 (50 %) and 23 (92 %) patients respectively. The mean methacholine concentrations in mild, moderate and severe asthma groups were 0.304 ± 0.011 mg, 0.211 ± 0.019 mg and 0.101 ± 0.015 mg respectively (p = 0.03). BHR was low in all patients with fully controlled asthma with no regards to its severity. The patients with well controlled asthma had predominantly low and moderate BHR, and 9 % of them had high BHR. BHR was also high in 57 % of the patients with poorly controlled asthma. There was a close correlation between the ACT score and PD20 of methacholine (r = 0.78; р < 0.001). In conclusion, the results revealed insufficient quality of outpatient treatment of asthma, particularly of moderate and severe asthma. ACT is reasonable to be used in wide clinical practice, especially in primary care settings.

Profiles of proinflammatory cytokines in sputum from different groups of severe asthmatic patients

Severe asthma represents a heterogeneous group of patients whose characteristics of airway inflammation are poorly known. To evaluate the sputum cytokine profiles of different phenotypes of severe asthma. Severe asthmatic patients (n = 45) were divided into 3 groups: frequent exacerbations, persistent bronchoconstriction, and both features. Two other groups (9 patients with untreated mild asthma and 10 control subjects) were also studied. Selected sputum portions were assayed for differential cell count, supernatant interleukin 5 (IL-5), granulocyte-macrophage colony-stimulating factor, IL-8, and eosinophil cationic protein. There were no statistically significant differences among the 3 severe asthma groups in terms of sputum inflammatory cell percentages, IL-8 levels, and eosinophil cationic protein levels, although IL-8 levels tended to be higher in patients with persistent bronchoconstriction. Sputum concentrations of granulocyte-macrophage colony-stimulating factor and IL-5 were significantly higher in patients with frequent exacerbations compared with the other 2 groups. Levels of IL-5 and IL-8 were higher in severe asthmatic patients compared with mild asthmatic patients and controls, whereas sputum eosinophil percentages were intermediate between those of mild asthmatic patients and controls. Proeosinophilic cytokine levels are increased in severe asthmatic patients with frequent exacerbations but not in severe asthmatic patients with persistent bronchoconstriction, suggesting that different cytokine profiles could be associated with different phenotypes of severe asthma.