Visual quantitation and observer variation of signs of small airways disease at inspiratory and expiratory CT.

Areas of decreased pulmonary attenuation representing small airways disease can be identified on computed tomography (CT). The objective was to quantify differences between inspiratory and expiratory CT for the detection of signs of small airways disease by four observers. Observer variation and the superiority of a fine versus a coarse grading system were also evaluated. Inspiratory and expiratory CT scans of 106 patients with conditions characterized by small airways disease and 19 healthy individuals were assessed by four observers. The extent of decreased attenuation was scored on a fine scale to the nearest 5% and also semiquantitatively on a coarser 5-point scale. Decreased attenuation was more extensive on expiratory CT (median. 6.7%; 0-76.7%) than on inspiratory CT (median, 3.8%; 0-81.7%). The fine scoring system had unacceptable interobserver variation (coefficient of variation, 80% for inspiratory CT, 70% for expiratory CT). The semiquantitative system had acceptable interobserver agreement (inspiratory CT k(w) = 0.64; expiratory CT, k(w) = 0.69) and good intra-observer agreement (inspiratory CT, k(w) = 0.80; expiratory CT, k(w) = 0.64). The major CT sign of small airways disease is more confidently quantified on expiratory CT. A fine scoring system is associated with unacceptable observer variation, and a coarse semiquantitative system is more suitable for quantitative studies of small airways disease.     

Small airways diseases: detection and insights with computed tomography.

Diseases affecting the small airways are difficult to detect by traditional diagnostic tests. Widespread involvement is needed before symptoms and abnormalities on pulmonary function testing or chest radiography become apparent. Obstruction of the bronchioles may be detected indirectly by computed tomography (CT) because regional under-ventilation results in reduced perfusion which in turn is shown as a mosaic attenuation pattern of the lung parenchyma. When there is inflammation of the bronchioles with accompanying exudate, the airways may become directly visible on CT, for example in cases of diffuse panbronchiolitis. Quantification of the various morphological features of small airways disease is possible from CT images and this increased precision has aided investigations of structure/function relationships. An understanding of the pathology and microscopic distribution of disease in relation to the airways allows some prediction of the likely computed tomography appearances in this wide spectrum of conditions, and thus helps to refine the differential diagnosis.     

Small airways disease in asthma

A mounting body of physiologic and pathologic evidence indicates that asthma involves the central and the more distal airways. In patients with asthma, the peripheral lung accounts for a significant portion of airway resistance and, similar to the large airways, the small airways have been shown to be hyperresponsive to nonspecific stimuli, such as methacholine. Cellular inflammation, consisting of an infiltrate rich with lymphocytes and eosinophils, is present in the small airways of patients with asthma and may be more intense than that observed in the large airways. Clinical assessment of the peripheral airways continues to be a challenge, and new techniques, such as quantitative analysis of chest CT images, have proven to be useful research tools. The recognition of small airways involvement in asthma has clinical relevance, as new formulations of inhaled corticosteroids with smaller particle aerosols may be more effective in addressing this component of asthma.     

Imaging of the small airways

Small airways disease (SAD) is defined as a pathologic condition in which the small conducting airways are affected either primarily or as part of other pulmonary changes. Diagnosis is often difficult because the many histopathologic subtypes that have been described often lack obvious clinical or imaging correlates and because widespread involvement is needed before clinical symptoms and abnormalities on pulmonary function testing occur. High-resolution computed tomography (HRCT) can be helpful to detect, characterize, and quantify small airways involvement. These airways may become visible directly when inflammation of the bronchiolar wall and accompanying exudates develop. Obstruction of the small airways may be detected indirectly by HRCT when it causes regional underventilation resulting in reduced perfusion. This article discusses the direct and indirect HRCT signs of small airways involvement and, based on the fundamental differences between these signs, gives a short review of the HRCT features of the most important diseases that can affect the small airways.     

Pathophysiology of the small airways

This review describes, in some detail, the normal structure of the small airways, how this structure is achieved during the development of the bronchial tree from embryogenesis to adulthood, and how the structure determines the function of the airways at different ages and in disease. We then describe the structural abnormalities in small airways in chronic obstructive pulmonary disease (COPD) and their relationship with the disordered pulmonary function found in this disease, as an example of the mechanisms leading to airflow limitation in diseased airways. We address the pathology of small airways in different stages of COPD, summarizing the structural abnormalities associated with the progressive deterioration of pulmonary function from smokers with normal lung function to smokers with severe COPD. The importance of the elastic recoil in the normal and abnormal function of the airways is also highlighted.     

Computed tomographic imaging of the airways in COPD and asthma

Computed tomography (CT) is the modality of choice for imaging the airways. Volumetric data sets with isotropic spatial resolution based on multidetector thin-section CT with overlapping reconstruction should be used. Chronic obstructive pulmonary disease and asthma are the 2 most common disease entities that are defined by airflow obstruction. The morphologic correlates of airway changes are dilation of the lumen, thickening of the wall, visibility of small airways due to mucus or edema, air trapping, hypoxic vasoconstriction, and collapsibility. To assess air trapping, additional expiratory low-dose scans are recommended. In clinical routine, these findings are visually assessed and should be routinely reported. However, the interobserver variability is high, and there is a clear need for objective software-based measurements. The development of such tools is challenging, and they are just becoming available on a broader scale. Novel techniques based on dual-energy CT aim to measure iodine distribution maps to assess pulmonary perfusion as well as the distribution of inhaled xenon gas to assess the distribution and time course of pulmonary ventilation. However, these techniques are still being investigated in clinical studies. This review will provide an overview of CT for the diagnosis of chronic obstructive pulmonary disease and asthma, its role in phenotyping these diseases, and the measurement of disease severity and functional compromise.     

Grading airway stenosis down to the segmental level using virtual bronchoscopy

OBJECTIVE: To assess the sensitivity of noninvasive virtual bronchoscopy based on multirow detector CT scanning in detecting and grading central and segmental airway stenosis using flexible bronchoscopic findings as the reference standard. MATERIALS AND METHODS: In a blinded controlled trial, multirow detector CT virtual bronchoscopy and flexible bronchoscopy were used to search for and grade airway stenosis in 20 patients. CT scan data were obtained with a multirow detector CT scanner using 4 x 1 mm collimation. Flexible bronchoscopy findings were graded by a pulmonologist and served as the reference standard for 176 central airway regions (ie, trachea, main bronchi, and lobar bronchi) and 302 segmental airway regions. The extent of airway narrowing was categorized as grade 0 (no narrowing), grade 1 (< 50%), or grade 2 (> or =50%). RESULTS: Flexible bronchoscopy revealed 30 stenoses in the central airways and 10 in the segmental airways. Virtual bronchoscopy detected 32 stenoses in the central airways (sensitivity, 90.0%; specificity, 96.6%; accuracy, 95.5%) and 22 in the segmental airways (sensitivity, 90.0%; specificity, 95.6%; accuracy, 95.5%). The number of false-positive findings was higher in the segmental airways (13 false-positive findings) than in the central airways (5 false-positive findings), which caused a lower positive predictive value for the segmental airways (40.9%) than for the central airways (84.4%). Flexible and virtual bronchoscopic gradings correlated better for central airway stenosis (r = 0.87) than for segmental airway stenosis (r = 0.61). CONCLUSION: Although a high sensitivity was found for the detection of both central and segmental airway stenosis, the number of false-positive findings was higher for segmental airways. However, noninvasive multirow detector CT virtual bronchoscopy enables high-resolution endoluminal imaging of the airways down to the segmental bronchi.     

Imaging of small airways disease and chronic obstructive pulmonary disease

CT is a useful tool for identification of small airways diseases, and it can be used to classify these entities into inflammatory and constrictive bronchiolitis. Inflammatory forms of bronchiolitis include cellular bronchiolitis (usually caused by infection or aspiration), respiratory bronchiolitis, panbronchiolitis, and follicular bronchiolitis. Constrictive bronchiolitis may be caused by previous infection, toxic inhalation, collagen vascular disease, or transplantation. CT also helps categorize chronic obstructive pulmonary disease into emphysema predominant and airway predominant forms.     

Radiology of the airways with emphasis on the small airways

The anatomy and pathophysiology of obstructive airways diseases are reviewed, with emphasis on the pivotal functional roles of the respiratory and terminal bronchioles. The array of radiologic findings associated with abnormal airways, large or small, is correlated with gross pathologic changes, using surgical and autopsy cases. Examples of inflammatory changes of smaller airways are also drawn from pathologically unproven clinical material. Peripheral linear and nodular densities, which can be distinguished from vascular shadows or septal lines, are seen in association with small bronchial and bronchiolar inflammation. In many cases it is possible to distinguish airways disease patterns from those of "alveolar" or "interstitial" disease.     

The role of small airways in lung disease

The small airways constitute one of the least understood areas of the lungs. They play a role in many lung diseases, and small airway pathology results in significant morbidity New approaches to their evaluation may provide insights into this major area of lung disease. Asthma is well recognized as a disease of both large and small airways. Physiological and pathological evidence, from techniques such as post-mortem tissue histological analysis, induced sputum and transbronchial biopsies, has reinforced the concept of the involvement of the entire bronchial tree n the inflammatory process in asthma, In addition to describing the airway pathology in asthma, th s review focuses on the pathogenesis and role of small airway obstruction n other diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), sarcoidosis and obliterative bronchiolitis (OB). COPD is characterized by the presence of airflow obstruction resulting from lesions in the small airways. In addition, features compatible with small airways disease are common in IPF, sarcoidosis and OB. Recent advances in pulmonary imaging, such as high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) with hyperpolarized 3He, have allowed non-invasive reproducible measurements of structure-function relationships to be made for the small airways.These techniques have great potential for diagnosing changes in small airway function and for assessing responses to treatment. New insights into the contribution of small airways to a range of lung diseases may lead to the development of therapies targeted at this part of the bronchial anatomy.     

Absence of bacterial colonization of the airways after therapeutic rigid bronchoscopy without stenting.

Following airway stenting, bacterial colonization of the airways with potentially pathogenic micro-organisms occurs within 4 weeks after treatment in the majority of patients. The objective of this study was to prospectively investigate whether nonstenting therapeutic rigid bronchoscopy (using laser, cryotherapy, mechanical dilatation or debridement) is followed by airway colonization or infection. Protected specimen brush sampling of the central airways and quantitative culture were performed immediately prior to, and 4 weeks after nonstenting therapeutic rigid bronchoscopy in 20 consecutive patients with central airway lesions. Prior to therapeutic bronchoscopy, airway colonization/infection was present in nine of 20 (45%) patients. In these nine patients, 10 different potential pathogens were identified: Streptococcus pneumoniae (four cases), Pseudomonas aeruginosa (three), Haemophilus influenzae (two), and Serratia marcescens (one). Eight of these nine patients had a history of postobstructive infections, of which three were currently being treated with antibiotics. Four weeks following therapeutic bronchoscopy, airway colonization/infection was present in five of 20 (25%) patients, each of whom had airway colonization/infection prior to bronchoscopy. In three of these five patients, the same organisms were found 4 weeks after bronchoscopy as at baseline bronchoscopy. In two of five patients new organisms were identified: one case of Streptococcus viridans and one case of Haemophilus parainfluenzae, both considered to be nonpathogens. In four of nine patients with airway colonization/infection prior to bronchoscopy, the airways were clear of micro-organisms after the procedure. The authors conclude that: 1) nonstenting therapeutic rigid bronchoscopy is not complicated by airway colonization or infection by new potential pathogens; and 2) therapeutic rigid bronchoscopy led to clearing of airway colonization/infection in almost half of the patients studied.     

Pathogenesis of small airways in asthma

Asthma is a lung disease characterized by inflammation and remodeling of the airways. It is now widely accepted that airway inflammation and remodeling occur not only in the central airways but also in the small airways and even in the lung parenchyma. Inflammation of the distal lung can be observed even in mild asthmatics with normal or noncompromised lung function. Moreover, the small airways and the lung parenchyma can produce many Th2 cytokines and chemokines involved in initiation and perpetuation of the inflammatory process. In addition, the distal parts of the bronchial tree have been recognized as a predominant site of airflow obstruction in many asthmatics. In fact, the inflammation at this distal site has been described as more severe when compared to the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance, highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease.     

Montelukast improves regional air-trapping due to small airways obstruction in asthma.

Quantitative image analysis of high-resolution computed tomography (HRCT) performed at residual volume, before and after methacholine, is a sensitive method of detecting small airways involvement in asthma and response to therapy targeted to the small airways. Since an oral anti-leukotriene reaches the small airways via the circulation, the present authors hypothesised that treatment with montelukast would lead to improved small airway patency. A double-blind crossover study compared the effect of montelukast versus placebo for 4 weeks in 16 mild-to-moderate steroid-na?ve asthmatics. Small airways function was evaluated by HRCT at residual volume before and after methacholine to assess regional air-trapping and airways hyperresponsiveness, as well as by physiological studies of small airways. Montelukast treatment resulted in significantly less regional air-trapping on HRCT on the pre-methacholine images when compared with placebo, as well as improvement in total quality of life scores and symptom sub-scores. However, montelukast treatment had no effect on increases in regional air-trapping on HRCT in response to methacholine. No differences were noted in global measures of small airways physiology between placebo and montelukast. In conclusion, distal airways disease improves in asthmatic subjects treated with montelukast. This improvement can be detected with high-resolution computed tomography, but not with conventional physiological studies.     

Light chain deposition disease involving the airways: diagnosis by fibreoptic bronchoscopy.

Light chain deposition disease (LCDD) infrequently affects the lungs and usually causes damage to the parenchyma, while bronchial involvement appears to be very rare. The present authors report the case of a 64-yr-old female with LCDD characterised by asymptomatic airway involvement. Ten months after excision of a poorly differentiated vaginal carcinoma, a routine chest computed tomography (CT) scan revealed two lung cysts, several bilateral nodules and diffuse bronchial thickening. Pulmonary function tests were normal. Fibreoptic bronchoscopy showed marked diffuse mucosal thickening with highly conspicuous vascular plexuses. Nonamyloidal deposits were found in the bronchial wall, but no definite diagnosis could be proposed. On follow-up, the patient was still asymptomatic and the CT scan and endoscopic appearance remained unchanged. The final diagnosis of kappa LCDD was established 18 months later by another series of bronchial biopsies with frozen samples. Interestingly, electron microscopy showed dense granular deposits associated with nonamyloidal fibrils. An increased number of lung cysts were observed 32 months after identification of bronchial abnormalities, confirming the progressive nature of the disease. No extrapulmonary deposits or immunoproliferative disorder were found. In conclusion, light chain deposition disease, which may remain latent for several years, can entirely involve large airways and may be diagnosed by bronchial biopsy.     

Assessment of airways inflammation utilizing bronchoalveolar lavage

Pathologic correlations and examination of expectorated sputum have suggested that chronic bronchitis is an inflammatory disorder of the airways. Bronchoscopy and bronchoalveolar lavage provide a means for sampling airway epithelial lining fluid. Application of bronchoscopy and bronchoalveolar lavage to a group of patients with chronic bronchitis confirms the association of airways inflammation and chronic bronchitis.     

State-of-the-art imaging of the central airways

Recent technological advances in CT imaging have revolutionized non-invasive imaging of the central airways. It is now possible to image the entire central airways in a few seconds and to create elegant three-dimensional reconstructions of the airways in a few minutes. The fast speed of CT scanning now allows for a dynamic assessment of the central airways, expanding the ability to non-invasively detect functional abnormalities such as tracheobronchomalacia. The purpose of this article is to familiarize clinicians with recent advances in airway imaging. A special emphasis is placed upon advanced CT reconstruction methods and their potential contributions to the evaluation of a variety of airway disorders.     

Small airways function in nonsmokers with rheumatoid arthritis

To evaluate the possible relationship between rheumatoid arthritis (RA) and airways dysfunction independent of cigarette smoking, we studied 19 lifetime nonsmokers with RA and 47 healthy nonsmokers. Ten tests of small airways function were administered to the subjects. In addition, diffusing capacity and static lung compliance were measured, and upstream airway conductance at mid-to-low lung volumes was calculated. Mean values were not significantly lower in the RA group than in the control group in any of the tests of small airways function. Three of the 19 (16%) patients with RA versus 15 of the 47 (32%) control subjects had abnormal findings on greater than 2 tests of small airways function (P greater than 0.1). Although mean diffusing capacity and static lung compliance were both within normal limits in each group, the former tended to be lower, while the latter was significantly lower, in the RA subjects. We conclude that airways dysfunction in RA, if present, is probably related to factors other than the underlying disease; if an association between RA and small airways abnormality is present in some patients, its prevalence is too small to have been detected in our sample.     

Computer-aided diagnosis of the airways: beyond nodule detection

Although to date, the major impetus for the development of computer-assisted diagnosis (CAD) has been the detection of pulmonary nodules, CAD should properly be viewed as a potential tool for assisting radiologic interpretation of the entire gamut of chest diseases, including not just enhanced detection of disease but also characterization and quantification, ideally leading to improved patient management. The use of CAD to improve visualization of the airways using advanced computer techniques, including sophisticated methods for obtaining 3-dimensional segmentation of the central airways and, in particular, the development of virtual bronchoscopy has been recently studied. In this paper, the authors review the development of a specific series of CAD applications enabling automated identification and characterization of chronically inflamed airways. The advantages to the use of computer methodologies to quantify peripheral airway disease include reproducible visualization methods to display the location, severity, and extent of airway dilatation, bronchial wall thickening, and the presence of mucoid impacted airways. Currently, a number of semiquantitative global scoring systems have been proposed to assess disease extent and severity in patients with bronchiectasis. Unfortunately, with the exception of patients with cystic fibrosis, these are rarely if ever employed, largely owing to the considerable inconvenience of measuring individual airway dimensions and computing a global score. It is apparent that for this specific purpose, CAD may be ideally suited. Automated staging allows for more complete assessment of the entire bronchial tree while providing improved standardization and eliminating an otherwise tedious and time-consuming task.     

Cystic fibrosis lung disease starts in the small airways: Can we treat it more effectively?

The aims of this article are to summarize existing knowledge regarding the pathophysiology of small airways disease in cystic fibrosis (CF), to speculate about additional mechanisms that might play a role, and to consider the available or potential options to treat it. In the first section, we review the evidence provided by pathologic, physiologic, and imaging studies suggesting that obstruction of small airways begins early in life and is progressive. In the second section we discuss how the relationships between CF transmembrane conductance regulator (CFTR), ion transport, the volume of the periciliary liquid layer and airway mucus might lead to defective mucociliary clearance in small airways. In addition, we discuss how chronic endobronchial bacterial infection and a chronic neutrophilic inflammatory response increase the viscosity of CF secretions and exacerbate the clearance problem. Next, we discuss how the mechanical properties of small airways could be altered early in the disease process and how remodeling can contribute to small airways disease. In the final section, we discuss how established therapies impact small airways disease and new directions that may lead to improvement in the treatment of small airways disease. We conclude that there are many reasons to believe that small airways play an important role in the pathophysiology of (early) CF lung disease. Therapy should be aimed to target the small airways more efficiently, especially with drugs that can correct the basic defect at an early stage of disease. Pediatr Pulmonol. 2010; 45:107–117. © 2010 Wiley‐Liss, Inc.     

Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999

Tracheobronchial amyloidosis (TBA), an idiopathic disorder characterized by deposition of fibrillar proteins in the tracheobronchial tree, occurred in 10 patients referred to the Amyloid Program at Boston University over the past 15 years. Fewer than 100 cases of TBA have been described; only 1 series encompassed more than 3 patients. We analyzed our experience with biopsy-proven TBA to define better its natural history. Follow-up averaged approximately 8 years and was obtained in all cases, making this outcome reporting the largest and most complete to date. Three of these patients were prospectively studied for up to 24 months to examine the utility of bronchoscopy, computerized tomography (CT) imaging, and pulmonary function tests (PFTs) in monitoring disease progression. No patient with TBA developed signs or symptoms of systemic amyloidosis during the period reviewed. Conversely, tracheobronchial disease was not diagnosed in 685 patients with primary systemic (AL) amyloidosis during the 15-year study period at Boston University. Bronchoscopy proved most useful in establishing the diagnosis by biopsy. Narrowing of major airways limited its inspection of the tracheobronchial tree, however. In contrast, CT imaging provided quantitative assessment of airway narrowing and mural thickening--2 major consequences of amyloid infiltration. These CT features, in the presence of mural calcifications sparing the posterior tracheal membrane, have been reported in few disorders other than TBA. The ability of CT to map airway involvement and identify extraluminal manifestations of TBA made it the study of choice for establishing disease extent. Three patterns of disease were evident by CT imaging and bronchoscopic examination: proximal, mid, and distal airways involvement. Those with severe proximal disease had significantly decreased air flows, air trapping, and fixed upper airway obstruction on PFTs. Patients with distal disease had normal airflows. PFTs could not clearly distinguish proximal from severe mid airways disease. Thirty percent of patients died within 7-12 years after diagnosis, all having proximal or severe mid airways disease. Repeated rigid bronchoscopic debridement and laser treatments did not prevent progressive airways narrowing in patients dying from TBA. Most patients with mid airways involvement, and all distal airway cases, had either stagnant disease or slowly increasing amyloid deposits when followed for up to 14 years. In a small subset of patients followed prospectively, serial PFTs were most sensitive to disease progression. CT-derived measures of airway lumen diameter and wall thickness did not change significantly despite marked improvements in airflow after rigid bronchoscopy. Our experience suggests that serial PFTs and CT imaging together offer the best assessment of airway involvement and disease progression in patients with TBA. In the future, radiation therapy may provide more definitive treatment of TBA than debulking procedure have to date.