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.     

Effectiveness of mepolizumab therapy on symptoms,asthma exacerbations,steroid dependence,and small airways in patients with severe eosinophilic asthma

Background/aim The efficacy of mepolizumab has been largely demonstrated in clinical trials in patients with severe eosinophilic asthma (SEA). However, reports on experience with mepolizumab in a real-life cohort are limited. Moreover, data about the effectiveness of mepolizumab on small airways is scarce. This study evaluated the effectiveness of mepolizumab therapy on symptoms, asthma exacerbations, blood eosinophils, steroid dependence, and small airways in a real-life cohort of patients with SEA.Materials and methodsWe retrospectively analyzed patients with SEA who were receiving fixed-dose mepolizumab. The effects of mepolizumab on clinical, laboratory, functional parameters were evaluated at 12th, 24th, and 52nd weeks. Small airways were assessed with the FEF 25-75.Results A total of 41 patients were enrolled in the study. Mepolizumab significantly reduced asthma exacerbation rates, reduced mOCS dose, and improved asthma control test (ACT) scores at 12th, 24th, and 52nd weeks. However, we found no significant changes in FEV₁ and FEF25-75 values at baseline, 12th, 24th, and 52nd weeks (78.9 ± 23.3%, 82.9 ± 23.4%, 81.9 ± 23.9%, and 78.9 ± 23.5% for FEV1; 45.1 ± 23.1%, 48.8 ± 23.5%, 48.7 ± 23.1%, and 41.0 ± 20.1% for FEF25-75, respectively)Conclusion In this study, mepolizumab significantly improved all outcomes (symptom scores, asthma exacerbations, OCS sparing, and blood eosinophils) except functional parameters. Still, despite the dose reduction in mOCS dosage, no significant deterioration was observed in FEV₁ and FEF25-75 values.     

Effects of 24-week add-on treatment with ciclesonide and montelukast on small airways inflammation in asthma

BackgroundEosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients. The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown.ObjectiveTo examine the effects of add-on therapy with either ciclesonide, an inhaled corticosteroid with extrafine particles, or montelukast on small airway inflammation.MethodsSixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a randomized, open-label, parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast. Patients were randomly assigned to 3 groups: ciclesonide (n = 19), montelukast (n = 22), or no add-on as controls (n = 19). At baseline and at weeks 4, 12, and 24, extended nitric oxide analysis; pulmonary function tests, including impulse oscillometry; blood eosinophil counts; and asthma control tests (ACTs) were performed.ResultsA total of 18 patients in the ciclesonide group, 19 in the montelukast group, and 15 in the control group completed the study and were analyzed. With repeated-measures analysis of variance, ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time. Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores, whereas no such changes were observed in the control group. Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control.ConclusionCiclesonide add-on therapy and montelukast add-on therapy may act differently, but both separately can improve small airway abnormalities and provide better asthma control.Trial Registrationumin.ac.jp/ctr Identifier: UMIN000001083     

Rhinovirus infections: induction and modulation of airways inflammation in asthma

There is renewed interest in the role of respiratory virus infections in the pathogenesis of asthma and in the development of exacerbations in pre-existing disease. This is due to the availability of new molecular and experimental tools. Circumstantial evidence points towards a potentially causative role as well as to possibly protective effects of certain respiratory viruses in the cause of allergic asthma during early childhood. In addition, it now has become clear that exacerbations of asthma, in children as well as adults, are mostly associated with respiratory virus infections, with a predominant role of the common cold virus: rhinovirus. Careful human in vitro and in vivo experiments have shown that rhinovirus can potentially stimulate bronchial epithelial cells to produce pro-inflammatory chemokines and cytokines, may activate cholinergic- or noncholinergic nerves, increase epithelial-derived nitric oxide synthesis, upregulate local ICAM-1 expression, and can lead to nonspecific T-cell responses and/or virus-specific T-cell proliferation. Experimental rhinovirus infections in patients with asthma demonstrate features of exacerbation, such as lower airway symptoms, variable airways obstruction, and bronchial hyperresponsiveness, the latter being associated with eosinophil counts and eosinophilic cationic protein levels in induced sputum. This suggests that multiple cellular pathways can be involved in rhinovirus-induced asthma exacerbations. It is still unknown whether these mechanisms are a distinguishing characteristic of asthma. Because of the limited effects of inhaled steroids during asthma exacerbations, new therapeutic interventions need to be developed based on the increasing pathophysiological knowledge about the role of viruses in asthma.     

The nose-lung interaction in allergic rhinitis and asthma: united airways disease

The link between upper and lower respiratory tracts has been repeatedly observed in the past 50 years but only carefully investigated during the past decade. Several clinical and experimental observations suggested the hypothesis of the unity of upper and lower airways (allergic rhinobronchitis or united airways disease). The relationships between rhinitis (and sinusitis) and asthma also include non-epidemiological aspects such as viral infections and bronchial hyperreactivity. The hypotheses have been confirmed by means of epidemiological observations, functional and immunological evidence and, indirectly, by observing the effects of drugs used mainly for rhinitis on asthma symptoms. In this article, therefore, we collected and reviewed the most relevant experimental results available to support the hypothesis for united airways disease and the studies conducted on the possible mechanisms of nose-lung interaction.     

High‐affinity immunoglobulin E receptor expression is increased in large and small airways in fatal asthma

Background IgE and its high‐affinity receptor Fc?RI play an important role in allergy and asthma. The distribution of Fc?RI expression in the airways and within the airway wall, however, is largely unknown. Objective In this study, we aimed to map the distribution of Fc?RI in different layers of large airways (LA) and small airways (SA) in lung tissue from non‐smoking and smoking patients who died of asthma [fatal asthma (FA)] and non‐smoking controls (CTR). Methods Postmortem lung tissue from 24 cases of non‐smoking FA, 13 smoking FA patients and from 19 subjects who died of non‐pulmonary causes (CTR) was immunohistochemically stained for Fc?RI and AA1 (mast cell tryptase marker). The expression of these markers was analysed in inner, muscle, and outer layers of both LA and SA by image analysis. Results Fc?RI expression was higher in non‐smoking and smoking FA compared with CTR in the inner and outer layer of SA. In the outer layer of LA, Fc?RI expression was higher in non‐smoking FA compared with CTR. AA1 was higher in non‐smoking FA compared with smoking FA and CTR in the outer layer of the SA, which was correlated with Fc?RI in this layer. Conclusion Our results show that the expression of Fc?RI is higher in both LA and SA in FA compared with CTR. These differences are predominantly found in the outer layer where they can be attributed in part to the increased mast cell numbers. These results indicate an increased capacity to mount IgE‐mediated reactions in FA, both in LA and SA. Cite this as: I. den Otter, L. F. F. Silva, A. L. N. Carvalho, R. C. Pires‐Neto, R. Annoni, D. S. Ferreira, I. Bajema, A. van Schadewijk, K. F. Rabe, M. Dolhnikoff, P. J. Sterk, P. S. Hiemstra and T. Mauad, Clinical & Experimental Allergy, 2010 (40) 1473–1481.     

The link between allergic rhinitis and asthma: the united airways disease

Rhinitis and asthma are often associated and the two disorders interact at various levels. Rhinitis typically precedes the development of asthma and can contribute to unsatisfactory asthma control. The presence and type of asthma is influenced by sensitization, and the duration and severity of allergic rhinitis. Nasal symptoms, airflow and markers of inflammation directly correlate with lower airway involvement. Local tissue factors, such as microbial stimuli and systemic inflammatory mechanisms, play a role in the clinical expression of the allergic airway syndrome. There is increasing evidence that suggests a major involvement of airway epithelial cells in the pathogenesis of both asthma and allergic rhinitis. Even in patients with rhinitis who do not have asthma, subclinical changes in the lower airways and inflammatory mediators can be detected. The pathogenic role of paranasal sinus infections in respiratory allergy has been better elucidated but there remains a need for further research. Treatment of established rhinitis may affect asthma control and could have some impact on airway obstruction, but a direct effect of rhinitis therapy on lower airway inflammation remains to be clearly established.     

Cyclosporin A treatment and airways inflammation in corticosteroid-dependent asthma

Cyclosporin A is a potent immunosuppressive agent which inhibits activation of T cells and other inflammatory ceils. It has been shown to be of clinical benefit in patients with corticosteroid dependent asthma, but there are no data on its in vivo effects on airways inflammation. In this report, we describe the case of a 47-year-old man with chronic severe corticosteroid-dependent asthma who made a dramatic clinical response to therapy with cyclosporin
A. Fibreoptic bronchoscopy with bronchoalveolar lavage and endobronchial biopsy were performed before and after a 12-month period of treatment with cyclosporin A and demonstrated a concomitant reduction in airway inflammatory indices.     

Prizes to solve problems in and beyond medicine, big and small: it can work

This article complements Dr. Charlton's follow-up of David Horrobin's suggestion in Nature two decades ago to offer sizeable prizes for practical approaches to either eliminate a problem in medicine or reduce the cost of its solution. Examples from the 20th and 21st centuries illustrate that prizes--small and big--have generated sustained and successful attacks on defined problems in biology, physics and, lately, mathematics. Provided that glittering prizes are offered and awarded with care, they can lead to effective problem-solving in medicine and related biomedical sciences as well.     

Chronic transmural bronchiolitis: a non-specific lesion of small airways.

AIMS: To investigate nine patients with histological changes at open lung biopsy compatible with so-called "small airways disease"; to define these changes and distinguish them from other types of bronchiolitis; and to correlate them with clinical features, respiratory physiology, and other laboratory investigations. METHODS: The open biopsy sections and the clinical records were reviewed. RESULTS: There was chronic inflammation of the walls of centri-acinar respiratory bronchioles and peribronchiolar alveoli. Peripheral alveoli of affected acini were spared. Although lumens were narrowed and distorted, obstruction by granulation tissue plugs was not a feature. Clinical backgrounds included Hodgkin's disease, yellow nail syndrome, sicca syndrome, asthma and psoriasis. The main presenting symptoms were cough, dyspnoea and wheeze, often associated with basal crackles and basal shadowing. There was no consistent immunological or haematological abnormality. Sputum culture was negative in six patients, and a variety of organisms were cultured from three others. In most cases respiratory function tests revealed an irreversible obstructive defect (combined in some cases with a restrictive defect), gas trapping, and well preserved gas transfer. Lung volumes were normal. Bronchodilators, with steroids and azathioprine in more seriously affected patients, stabilised the disease process. CONCLUSIONS: The histological changes may be distinguished from bronchiolitis obliterans and bronchiolitis obliterans organising pneumonia by the absence of intraluminal granulation tissue plugs, and from the obliterative bronchiolitis of rheumatoid disease and diffuse peribronchiolitis on clinical grounds. Although often striking, this lesion does not represent a clinico-pathological entity, and may occur in the distal lung in association with a number of different diseases. "Small airways disease" is often used by clinicians in a functional context, and may lead to confusion. It is suggested that "chronic transmural bronchiolitis" is a more appropriate term.     

T lymphocyte responses against human parvovirus B19: small virus,big response

Parvovirus B19 elicits both humoral and cellular immune responses. Recently some advances have been made in determining the frequencies, peptide targets and function of virus-specific CD8+ T lymphocyte responses. A single HLA B35-restricted epitope derived from the NS1 protein has been studied so far, but others clearly exist. Surprisingly large, persistent responses have been detected in healthy seropositive individuals, using interferon-gamma ELISpot assays and HLA class I peptide tetramers. Similar techniques are available for exploration of the CD4+ T cell epitopes, although less detail is currently available. Mapping of cellular immune responses against the entire B19 genome (the parvovirus "immunome") is now possible and if similarly large populations are found consistently, this could yield important insight into normal immunological control and abnormalities in B19-related disease.