Imaging Procedures and Bronchial Thermoplasty for Asthma Assessment and Intervention

CHAPTER 18

Imaging Procedures and Bronchial Thermoplasty for Asthma Assessment and Intervention SHWETA SOOD, MD, MS  •  CHASE HALL, MD  •  MARIO CASTRO, MD, MPH

ABBREVIATIONS ADC  Apparent diffusion coefficient ATS  American Thoracic Society AWA  Airway wall area AWT  Airway wall thickness BT  Bronchial thermoplasty COPD  Chronic obstructive pulmonary disease CT  Computed tomography EBUS  Endobronchial ultrasound ED  Emergency department ERS  European Respiratory Society FDA  U.S. Food and Drug Administration FEV1  Forced expiratory volume in 1 s HP MRI  Hyperpolarized MRI HRCT  High-resolution computed tomography HU  Hounsfield units ICS  Inhaled corticosteroids LA  Lumen area LABA  Long-acting β-agonists MDCT  Multidetector CT OCT  Optical coherence tomography PEF  Peak expiratory flow PET  Positron emission tomography PFT  Pulmonary function testing qCT  Quantitative CT QOL  Quality of life RF  Radiofrequency TLC  Total lung capacity X-ray  Radiation

INTRODUCTION Asthma is characterized by airway epithelial injury, subepithelial fibrosis, excess mucus secretion, airway inflammation, increased airway smooth muscle (ASM) mass, and dysregulated angiogenesis collectively referred to as airway remodeling.1–3

Remodeling causes variable airflow obstruction. Airflow obstruction results in reduced lung ventilation, which in turn leads to decreased lung perfusion.4 Abnormal ventilation and perfusion can lead to air trapping and worsen asthma symptoms. The diagnosis of asthma is based on history, physical examination, pulmonary function tests (PFTs), and bronchoprovocation testing.5 In the clinical setting, imaging techniques are rapidly evolving to detect remodeling changes and assess response to approved and emerging asthma therapies, such as bronchial thermoplasty (BT). Historically, asthma severity and the efficacy of asthma treatments have been grossly assessed with subjective assessments and spirometry. However, asthma is a heterogeneous disease because some airways have marked remodeling whereas others have minimal remodeling. Current modalities of assessment cannot detect this heterogeneity or isolate specific lung regions with remodeling or abnormal ventilation. For example, often spirometry can be normal and yet there is known airflow resistance in the small airways.4 With the development of advanced imaging techniques, distal airway remodeling, air trapping, and alveolar gas exchange can now be evaluated before and after therapeutic interventions. In addition, novel imaging techniques can identify different asthma phenotypes or clusters. By utilizing advanced imaging techniques, asthma diagnosis and therapy can be personalized for each patient.4 In this chapter, we highlight the strengths and weaknesses of current imaging modalities used to evaluate airway and lung structural and functional defects in asthma patients (Table 18.1). Furthermore, we discuss the role of BT in asthma management and illustrate how imaging modalities may serve to guide BT and serve as biomarkers to predict response to BT.6  191

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TABLE 18.1

Summary of Asthma Imaging Techniques Modality

Structural Assessment

Functional Assessment

Clinical Utility

Disadvantages

CT

Detailed assessment • Airway tree • Vascular tree • Lung parenchyma

• Regional ventilation • Parenchymal perfusion

• Noninvasive measure of airway remodeling • Biomarker to assess response to therapy

• Radiation exposure prohibits serial examinations

MRI

• Lung microstructure using ADC • Combined with CT for detailed structural evaluation

• High spatial resolution evaluation of regional ventilation • Gas exchange

• Biomarker to assess response to therapy • Assessment of ventilation/perfusion ratio

• Less structural detail than CT • Limited to specialized MRI centers

EBUS

• Access airways as small as 4 mm with visualization of multiple layers of airway wall

• None

• Monitor serial airways changes

• Requires bronchoscopy • No functional assessment • Standards not yet established

OCT

• Two-dimensional images of airway wall with spatial resolution of 1–15 μm and penetration of 2–4 mm

• None

• Microscopic view of WT and subepithelial matrix • Monitor serial airway changes

• Requires bronchoscopy • Subject to respiratory cycle movement • Standards not yet established

PET

• Combine with CT for detailed structural evaluation

• Pulmonary inflammation • Ventilation/perfusion

• Response to antiinflammatory therapies • Evaluate inhaled drug delivery

• Limited spatial resolution • Radiation exposure

ADC, apparent diffusion coefficient; CT, computed tomography; EBUS, endobronchial ultrasound; MRI, magnetic resonance imaging; OCT, optical coherence tomography; PET, positron emission tomography; WT, airway wall thickness. From Trivedi A, Hall C, Hoffman EA, Woods JC, Gierada DS, Castro M. Using imaging as a biomarker for asthma. J Allergy Clin Immunol. 2017;139(1):1–10; with permission.

CHEST RADIOGRAPHY Most asthmatics have normal chest radiographs even during exacerbations.7,8 Clinically, chest radiographs are not needed routinely but if available can corroborate asthma diagnosis by excluding other pathologies. The most common structural abnormalities seen on asthmatics’ chest radiographs include hyperinflation and bronchial wall thickening.9 Findings such as consolidation, pulmonary edema, pneumothorax, and cardiomegaly can be identified in asthmatics unresponsive to asthma therapy and suggest alternate causes for dyspnea.10 In general, the decision to obtain a chest radiograph in an asthmatic patient should be guided by the history and physical examination. One study recommended patients with complicated asthma (defined as presenting with fever greater than 100.0°F, heart disease, intravenous drug use, seizures,

immunosuppression, other pulmonary comorbidities, or prior thoracic surgery) may benefit the most from chest radiographs in the emergency department (ED).11 Chest radiographs have several advantages including portability, relatively low cost, fast examination times, and minimal radiation exposure. However, the major disadvantage is that a simple two-dimensional (2-D) image is captured. Minimal structural data and no functional data can be obtained from chest X-ray. Therefore, more advanced imaging techniques are needed to analyze the focal structural and functional defects that often occur in asthmatic airways. 

COMPUTED TOMOGRAPHY SCANS Throughout the years, there has been a gradual evolution in computed tomography (CT) scan capabilities. Older

CHAPTER 18  Imaging Procedures and Bronchial Thermoplasty CT scans initially employed a single radiation (X-ray) beam that rotated around the patient who sat in the gantry, or the cylindrical tube-shaped CT machine.12,13 Over time, spiral or helical CT scanners began moving patients through the gantry so that multiple slices could be obtained in a single breath, thus shortening CT scan times and improving spatial resolution. High-resolution computed tomography (HRCT) used multiple detectors and multiple X-ray beam sources and acquired thinner (1–2 mm) slice images in noncontiguous axial planes ∼10 mm apart in the lung parenchyma.1 Pulmonary anatomy up to the secondary pulmonary lobule could be appreciated on HRCT. HRCT can visualize subtle abnormalities such as interlobular thickening, submillimeter nodules, ground-glass opacities, and bronchiectasis better.14 In recent years, the multidetector row CT (MDCT), also referred to as volumetric, obtain contiguous and overlapping axial slices.15 Most MDCT scans today use 64 or 128 detectors with one or several X-ray beam sources. The use of multiple detectors allows for multiple cross-sectional slices as thin as 0.60–0.75 mm with no interslice gaps to be obtained.1,15 The key difference between older CT scans and the latest MDCT is the ability to extract quantitative data from MDCT images. MDCT obtains images of the lung parenchyma continuously with no gaps. Therefore, images can be reconstructed in x, y, and z planes more accurately and depicted as voxels or three-dimensional (3-D) volume elements.1,2,16,17 Special imaging processing software packages, such as Apollo Workstation (VIDA Diagnostics, Inc.) or Airway Inspector for SLICER (Harvard University), use this data to generate 3-D models.18 From these models, computer algorithms can acquire quantitative data on airway remodeling and lung density. Similar to chest radiographs, chest CT scans in asthmatics aid in ruling out other etiologies of dyspnea. This is especially true for difficult-to-treat asthmatics who are unresponsive to traditional therapy and may have comorbidities contributing to their respiratory symptoms. Common CT findings in asthmatics include bronchial wall thickening, air trapping, and bronchiectasis.2 CT scans can help diagnose diseases that mimic asthma such as intrathoracic or extrathoracic airway obstruction, obliterative bronchiolitis, chronic obstructive pulmonary disease (COPD), congestive heart failure, hypersensitivity pneumonitis, hypereosinophilic syndromes, allergic bronchopulmonary aspergillosis, pulmonary embolism, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).2,19 The ATS/ERS guidelines recommend limiting HRCT imaging to severe asthmatics who have an atypical presentation.5

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The advantages of all CT scans include improved structural evaluation of all airways compared with chest radiographs. Furthermore, when combined with other imaging techniques such as hyperpolarized gas magnetic resonance imaging (MRI) or xenon enhanced duel energy CT,20 ventilation abnormalities can be evaluated. However, in contrast to chest radiographs, CT scans expose patients to more radiation, are more timeconsuming, are more expensive, and are not portable. As technology evolves, very low-dose CT scan protocols using third-generation CT scanners and iterative reconstruction algorithms are being developed with radiation levels approaching that of a two-view chest radiograph.21 In recent years, MDCT images have been used with quantitative software in asthma. It is important for clinicians to be aware of the role of MDCT as a noninvasive biomarker. MDCT and its 3-D reconstructions calculate remodeling changes and lung density alterations via computer algorithms. Remodeling is assessed via airway metrics such as airway wall thickness (WT), airway wall area (WA), airway lumen area (LA), and branch angles. Lung density measurements can be used to evaluate the degree of air trapping and emphysemalike lung. Asthma clusters have also been recently identified by using quantitative CT (qCT) metrics.22

Role of Computed Tomography in Assessing Remodeling Airway remodeling due to inflammation and fibrosis increases WT and WA while simultaneously decreasing airway LA in asthmatics. Previously, remodeling could only be detected on autopsy analysis or bronchial biopsies. WT was noted to be increased 50%–300% of fatal asthma cases and 10%–100% of nonfatal asthmatics.23 Bronchial biopsies revealed increased airway epithelial layer thickness and lamina reticularis thickness in severe asthma patients compared with normal individuals and patients with chronic bronchitis and mild asthma.24 However, because asthma is a heterogeneous disease with normal airways interspersed among severely remodeled airways, bronchial biopsies may miss detecting remodeling when samples are inadvertently obtained from nonremodeled lung regions. MDCT is a noninvasive technique to measure remodeling across all airways and assess the effect of asthma therapies on remodeling. Aysola et al. showed a correlation between increased epithelial and lamina reticularis thickness on biopsy samples and WT% and WA% measurements obtained via qCT.25 Severe asthmatics had thicker epithelial and lamina reticularis on biopsy and higher WT% and WA% on MDCT compared with

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normal patients and mild asthmatics (Fig. 18.1). This suggested that remodeling changes found on biopsy could be assessed noninvasively with MDCT by measuring WT% and WA%. LA was decreased in patients with severe asthma compared with controls indicating as the airway WT increases it narrows the airway LA and potentially contributes to airflow obstruction.26 In asthmatics, WA% correlates with duration of asthma and inversely with lower FEV1 values in a few trials.22,27,28 The increases in WT and decreases in LA also seem to be diminished in asthmatics more than COPD patients.29 

Assessing Air Trapping by Measuring Lung Density with Multidetector Computed Tomography Remodeling causes airflow obstruction that can result in air trapping. Air trapping has been shown to be increased in asthmatic patients compared with healthy subjects and can worsen airway symptoms.22 It has traditionally been measured with PFT that reveal an

elevated residual volume. Now with the emergence of MDCT and quantitative software, small airways and air trapping can be evaluated. CT images are obtained at maximal inhalation (at total lung capacity, TLC) and maximal exhalation (at residual volume). Some institutions obtain images at maximal inhalation and at rest (at functional residual capacity) On CT scans, air trapping due to distal obstruction can result in zones of decreased attenuation called mosaic attenuation.30 Air trapping is defined by voxels that fall below −856 HU at end expiration.2,17 Alternatively, expiratory to inspiratory mean lung density ratios can also identify regions of air trapping.31 Patients with asthma have been shown to have increased percentage of lower attenuation areas on MDCT compared with control subjects32,33 (Fig. 18.2). Furthermore, Busacker et al. showed that asthmatics with air trapping (defined as more than 9.66% of their total lung volume at functional residual capacity below −850 HU) were significantly more likely to have a history of asthma related hospitalizations, ICU visits, and/

Epi

A

Avg Wall Thickness: 1.2mm Area: 19.3mm2 Minor Diameter: 4.2mm Major Diameter: 6.0mm

LR

C

Epi

B

Avg Wall Thickness: 1.7mm Area: 7.7mm2 Minor Diameter: 2.6mm Major Diameter: 3.7mm

LR

D

FIG. 18.1  (A) Multidetector computed tomography (MDCT) image from a healthy subject. (B) MDCT im-

age from a severe asthmatic. (C) Corresponding biopsy sample from a healthy subject. (D) Corresponding biopsy sample from a severe asthmatic. Note that there is significant narrowing of the airway lumen and increase airway wall thickness and airway wall area in the severe asthmatic (Image B), which is also seen on corresponding biopsy sample (Image D) compared with healthy subjects (Image A and C). Epi, epithelial layer; LR, lamina reticularis; dashed line indicates basement membrane. (From Aysola R, et al. Airway remodeling measured by multidetector computed tomography is increased in severe asthma and correlates with pathology. Chest. 2008;134(6):1183–1191; with permission.)

CHAPTER 18  Imaging Procedures and Bronchial Thermoplasty or mechanical ventilation.34 Drug therapies, such as oral and inhaled corticosteroids (ICS) and montelukast, have been shown to improve air trapping in select asthmatics.4 This suggests that lung density assessment can identify patients at increased risk for complications. 

standardized protocols are being established.36,37 Although CT scanners have evolved to visualize small distal airways, it is still difficult to measure airways smaller than 1 mm.38 Lastly, the radiation dose of CT scanners continues to decrease in newer models but is still significantly higher than digital chest radiography and therefore its application in longitudinal assessments may be limited. 

Novel Asthma Phenotypes and Measuring Therapeutic Response via Multidetector Computed Tomography Several studies have attempted to identify novel asthma phenotypes by utilizing MDCT measurements. For example, Gupta et al. described three distinct asthma phenotypes based on clinical and radiologic features.26 This was one of the first studies to base asthma phenotypes on MDCT measurements. Several studies are currently in progress to evaluate the role of MDCT to characterize phenotypes. Haldar et al. found that WT was reduced in subjects treated with mepolizumab compared with patients who were given placebo.35 Each phenotype may respond to individual asthma therapies in its own unique way and further studies are needed using qCT to assess their impact on airway remodeling. 

HYPERPOLARIZED MAGNETIC RESONANCE IMAGING The primary purpose of hyperpolarized MRI (HP MRI) imaging is to evaluate for distal airway abnormalities and ventilation defects. Hyperpolarized gases, such as Helium-3 and Xenon-129, are polarized beyond thermal equilibrium to effectively serve as contrast material filling the airways, terminal bronchioles, and alveoli.1,39 Helium-3 is confined to the alveolar region. Xenon-129 is mostly confined to the alveoli but about 1/5th of xenon has the capability to cross the alveolarcapillary barrier.40 This allows Xenon-129 scans to assess both gas exchange and ventilation simultaneously. There has been an increase in xenon-based MRI studies as the demand for Helium-3 (for airport security neutron detectors) exceeded supply (decaying nuclear warheads), causing stricter government allocation regulations for Helium-3.41 In contrast to Helium-3, Xenon-129 produces lower signal because of its smaller magnetic moment and is more challenging to polarize. Xenon is also routinely inhaled during ventilation-perfusion scans commonly used in clinical

Limitations of Multidetector Computed Tomography qCT is currently limited by lack of standardization in obtaining scans using different types of MDCT (4 to 128 detector scanners), dissimilar imaging protocols, and various ways to measure remodeling and lung density. There are no established normal values for airway and lung density measurements, but new

Expiratory scan

A

195

B

FIG. 18.2  Chest computed tomography (CT) for lung density. (A) Three-dimensional volume rendition of

the lung, lobes, and bronchial tree detected from a CT image of the fully inflated (total lung capacity) lung of a healthy subject. (B) CT scan of the chest showing a similar volume rendition using the expiratory image (in this case functional residual capacity) of a patient with severe asthma. Note the areas of air trapping and pruning of the airways. Image processing was derived by using Apollo software (VIDA Diagnostics, Coralville, Iowa). (From Trivedi A, Hall C, Hoffman EA, Woods JC, Gierada DS, Castro M. Using imaging as a biomarker for asthma. J Allergy Clin Immunol. 2017;139(1):1–10; with permission.)

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practice; however, Xenon-129 HP MRI images have markedly improved resolution.41 During an HP MRI scan, a patient inhales a hyperpolarized gas mixture, a breath hold is performed, and MRI images are obtained. The hyperpolarized gas can be mixed with another inert gas, such as nitrogen, to obtain a prespecified volume for inhalation. Prolonged inhalation of hyperpolarized gas for 10–20 s can lead to transient oxygen desaturations. Once inhaled, a 6- to 15-s breath hold allows the hyperpolarized gas to distribute equally through ventilated airspaces and generate high signal to noise images. Whole lung images are obtained and used to identify ventilation defects. Several methods for quantifying ventilation defects have been described, including manual scoring, pre-determined intensity threshold cutoffs and clustering methods such as K-means or Otsu’s method (Fig. 18.3).2,41a–41e Several studies have found that HP MRI identifies regional ventilation defects in asthmatics.42–44 Asthmatics can have both larger ventilation defects and an increased number of ventilation defects compared with healthy volunteers.40 Severe asthmatics have larger ventilation defects than mild or moderate asthmatics.45 The number of ventilation defects is inversely correlated with FEV1 values in some studies.42,45 Forced expiratory flow (FEF25–75%) values are also decreased in asthmatics with higher amount of ventilation defects.45 Ventilation defects increase after methacholine challenge testing or exercise in both healthy volunteers and asthmatics.43,45,46 However, these ventilation defects persist longer in asthmatics compared with controls after methacholine challenge.47 Furthermore, bronchodilator therapy can result in improvement in ventilation defects in asthmatics.48 Finally, the integration of MDCT and HP MRI testing in individual patients reveals

A

that regions with impaired ventilation on HP MRI correlate to regions with remodeling on MDCT.42,48,49 The major benefit of MRI over other imaging modalities discussed thus far is that there is no radiation risk. Lack of radiation allows for serial imaging to be done to assess disease progression and response to therapy. This is especially vital for monitoring pediatric asthma patients who should not be exposed to excess radiation in childhood. HP MRI elegantly illustrates the heterogeneity of asthma by delineating focal ventilation defects. It may be a useful tool in the future to establish asthma phenotypes based on ventilation defect patterns. However, the main limitations continue to be the need for experienced staff and expensive equipment (MRI with multinuclear package, polarizer, and a special radiofrequency [RF] coil). Hyperpolarization of gases is a lengthy process and can take up to 12 hours. However, other modalities are being discovered including oxygen-enhanced MR and fluorinated gas MR that do not require special polarization equipment.50,51 In general, most HP MRI scans are expensive.39 In addition, MRI alone is not as useful for structural analysis unless coupled to another imaging modality. For example, when combined with MDCT, hyperpolarized MR can provide data on structure (remodeling), function (ventilation defects), and gas exchange defects (Xenon129 HP MRI).1 This can be used to isolate distal airways that are most affected by airway remodeling and focus therapies such as BT (discussed below) to these regions.

Hyperpolarized Magnetic Resonance Imaging and Apparent Diffusion Coefficient All gases diffuse through the tracheobronchial tree at their own rates based on each individual gas’ intrinsic physiochemical properties.52 The walls of the

B

FIG. 18.3  (A) Hyperpolarized gas magnetic resonance imaging (HP MRI) images from mild asthmatics

showing small ventilation defects (arrows). (B) HP MRI images from severe asthmatic showing larger ventilation defects (arrowheads). (From Castro M, Fain SB, Hoffman EA, et al. Lung imaging in asthmatic patients: the picture is clearer. J Allergy Clin Immunol. 2011;128(3):467–478; with permission.)

CHAPTER 18  Imaging Procedures and Bronchial Thermoplasty tracheobronchial tree serve as obstacles to diffusion of these gases. ADC, or apparent diffusion coefficient, is a measure of diffusion of a gas. By using MRI diffusion weighted images, the extent of diffusion can be calculated via computer algorithms and visualized on an ADC map. Diffusion MRI can measure short time scale diffusions over milliseconds, which represent diffusion at the alveoli level, with normal ADC values of ∼0.2 cm2/s for healthy lung using Helium-3.52 Diffusion MRI can also measure long time scale diffusion of gases up to 1 s, which represents diffusion at the distal small airways, with normal ADC values ∼0.03 cm2/s in healthy lung.53 In diseases that destroy airway walls, such as emphysema, ADC increases because gases have fewer barriers and diffuse more easily. This is best appreciated in emphysema as destruction of the alveolar walls results in higher short time scale ADC values averaging 0.55 cm2/s.52 In asthma, there is no destruction of the alveolar walls. However, small airway remodeling changes cause air trapping, which can potentially raise ADC values. Wang et al. found that normal subjects had low ADC values, asthmatics had specific parenchymal regions with increased ADC values, and COPD patients had diffuse areas of increased ADC values. Furthermore, long time ADC values (which measure diffusion of gases through the distal airways rather than alveoli) were significantly higher in asthmatics compared with healthy volunteers.53 Regional elevations in ADC values occur after methacholine challenge testing in asthmatics.43 However, there is no correlation between ADC and spirometry testing.53 It is still unclear if elevations in ADC represent focal areas of air trapping in asthmatics, but this is currently the leading hypothesis.53 

ENDOBRONCHIAL ULTRASOUND In endobronchial ultrasound (EBUS), an ultrasonographic probe is advanced through the working channel of a fiberoptic bronchoscope. The probe contains a saline-filled balloon, which when inflated contacts the airway wall and facilitates production of real-time 2-D image using sound waves.54 EBUS can visualize the three layers of the bronchial wall in distal, noncartilaginous airways.55 In a small study, the mucosal, submucosal, and smooth muscle layers were significantly thicker in asthmatics compared with controls similar to results from MDCT.55 Other studies have confirmed airway wall thickness (AWT) is localized to submucosal zones and correlated hypertrophy of these zones to airway hyperresponsiveness.56 EBUS has several advantages

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including its ability to produce real-time images and lack of ionizing radiation, which allows for serial imaging over a short period of time. Limitations of EBUS are that it is still a novel technique that requires expert bronchoscopy skills, larger caliber endoscopes capable of housing an ultrasonographic catheter, and sedation as it is a minimally invasive procedure. In asthma, its role is being investigated and validated. 

OPTICAL COHERENCE TOMOGRAPHY As EBUS employs sound wave reverberations to capture images, optical coherence tomography (OCT) uses long-wavelength (near-infrared) light backscatter to provide detail on cellular elements within the airway. An OCT catheter is advanced through bronchoscope and infrared light penetrates the local tissues. Each tissue absorbs and reflects infrared light in a unique pattern based on its intrinsic optical refractive properties.2,4,57 Two-dimensional in situ and in real-time images are generated of structures that are 2–3 mm in depth and with resolutions of 1–15 μm.58 In the airway, the thickness of the epithelial layer, basement membrane, and smooth muscle can be measured. Measurements of wall area and lumen area in COPD patients show a strong correlation between MDCT measurements and OCT values.17 In one study, OCT wall thickness measurements have been shown to improve after BT.59 OCT has several advantages including its ability to produce real-time images. Unlike sound waves emitted from EBUS, light waves from OCT do not require a liquid interface and create higher resolution pictures than EBUS. Lastly, OCT lacks ionizing radiation and can be used to assess disease progression or response to therapy. Limitations of OCT are similar to EBUS in that it is still a novel technique that requires expert bronchoscopy skills, large caliber endoscopes capable of housing the OCT catheter, sedation, and lacks standardization. 

POSITRON EMISSION TOMOGRAPHY During a positron emission tomography (PET) scan, a radiotracer, such as fluorine-18-fluorodeoxyglucose, is preferentially taken up by metabolically active tissues. Radiotracers emit positrons that are annihilated on interaction with an electron.4 This annihilation releases photons that can be detected and show preferential uptake of glucose into highly active tissues.3 These images can be superimposed on CT scans to generate PET-CT images. Nitrogen-13 diffuses from the blood to alveoli in a single breath hold allowing for rapid assessment of perfusion. The volume of nitrogen-13 in

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the lung is directly proportional to lung perfusion (as long as the patient holds their breath) and ventilation is then measured on exhalation.4 In asthma, PET may be helpful in identifying lung inflammation. In a small study with six asthma patients, allergen challenge to the right middle lobe resulted in a localized inflammatory response measured by increased eosinophils in bronchoalveolar lavage and increased thickening of airway walls on MDCT.60 Furthermore, the right middle lobe showed reduced perfusion and ventilation on PET imaging. This study is interesting and could potentially indicate a role for PET imaging in monitoring patients with eosinophilic asthma who are treated with monoclonal anti-IL-5 antibody.1 N-13 PET scan provides low-resolution ventilation images compared with other imaging modalities discussed previously.2 

BRONCHIAL THERMOPLASTY BT is an intervention for severe asthma patients with uncontrolled symptoms despite combined high-dose ICS and long-acting β-adrenergic agonist bronchodilator (LABA) therapy. ASM hypertrophy and hyperplasia are both increased in fatal asthmatic biopsy specimens and are thought to contribute to remodeling changes and airflow obstruction.61 BT reduces smooth muscle area, thus minimizing asthma exacerbation rates.62 BT is performed using the Alair Bronchial Thermoplasty System comprising the Alair RF Controller and the Alair Catheter.63 The specialized radiofrequency catheter is advanced through the endoscope into the distal airways. Radiofrequency energy converts into thermal energy with resistance and treats the local bronchial smooth muscle tissue. Airways as small as 3–10 mm can be targeted, but a single session only focuses on treatments to one to two lobes. Usually three sessions are done over 3–6 weeks. Typically, the right lower lobe is treated first, then the left lower lobe, and finally bilateral upper lobes. Historically, the right middle lobe was not treated; however, we (and others) are now treating the right middle lobe at the same session as the right lower lobe.64 A methodic approach is vital and the physician must move systematically from distal to proximal in each segment to ensure adequate treatment to all accessible lobar segments.

Evidence for Bronchial Thermoplasty Several clinical studies have evaluated the safety and efficacy of BT in adults (Table 18.2). In 2010, BT was approved by the U.S. Food and Drug Administration (FDA) for adults with severe asthma with uncontrolled

symptoms despite high-dose ICS and LABA. Currently BT has not been studied in children. From a histopathologic standpoint, several studies began to describe reductions in ASM in BT patients. Three months after BT, patients not only reported improved quality of life (QOL) and asthma control but also were found to have decreased ASM area and reductions in subepithelial basement membrane thickening on biopsy.65 Other studies revealed reductions in ASM mass, airway basement membrane collagen deposition, and inflammatory cytokine production in BT recipients.66,67 The largest study of BT was a multicenter, doubleblinded, sham-controlled study with 288 adult asthmatics (AIR2). While the BT group received actual BT treatments, the sham group patients underwent bronchoscopy with sham catheters that were indistinguishable from real BT catheters except that no energy was delivered. Nearly 1 year after the treatment sessions were completed, the BT group had a greater improvement in QOL scores compared with the sham group. In addition, the BT group had decreased number of emergency room (ER) visits and less work/school absenteeism compared with the control group. In the first 6 weeks, more patients in the BT group reported increased respiratory-related adverse events, as expected. Patients typically experience increased coughing, wheezing, chest tightness, and dyspnea for 24–48 h after BT but most improve within 1 week.64 However, up to 1 year later, the BT group had less adverse pulmonary symptoms compared with the sham group.68 At their 5-year follow-up, the proportion of BT patients with severe exacerbations and ER visits continued to be less than those observed in the 12 months before BT treatment.69 A recent study demonstrated peribronchial consolidations or ground-glass opacities within the first 24 hours following BT on CT.70 These abnormalities sometimes affect an untreated adjacent lobe and resolve or decrease in all patients on follow-up CT 1 month later. These changes may be due to alveolar inflammation and edema secondary to BT thermal therapy. Only 8% of patients had lobar atelectasis on CT scans at 24 h and this resolves by 1 month without bronchoscopic intervention. No patients had evidence of pulmonary infection on CT at 1 month. These studies indicate that a short course of systemic steroids following BT can often help patients recover faster. Finally, both the AIR2 and RISA studies showed that there were no new structural changes on CT scans obtained 5 years after therapy.62 Thus although BT recipients may have increased pulmonary symptoms and new radiographic findings for several weeks after their BT sessions, these symptoms and imaging abnormalities resolve in a few weeks.

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TABLE 18.2

Summary of Bronchial Thermoplasty (BT) Results From Randomized Controlled Trials and Extension Studies Approximate FEV1 values

Study

Subjects

Results

Conclusions

AIR

• 112 moderate to severe asthmatics • Randomized BT or usual care • Follow-up to 1  year • Age: 39.36 ± 11.18 years

• 72%–76%

• At 12 months, mean rate of mild exacerbation, compared with baseline, reduced in BT group • At 12 months, improved PEF, QOL scores, and less rescue medication use in BT patients (significantly greater than controls) • At 12 months, airway responsiveness and FEV1 similar in both groups • At 6 weeks, increased AE in BT group • At 12 months, AE similar in both groups

• BT causes transient increase in AE at 6 weeks • BT does not cause increased AE or pulmonary decline at 1 year • BT is safe at least at 1 year after therapy

AIR: 5-year follow-up

• 69 asthmatics from AIR • 45/52 BT groups • 24/49 control group • Follow-up to 5  years • Age: 40.0 ± 11.2 years

• 72%–75% • Stable FEV1 values at 5 years

• At 5 years, stable rate of AE in BT group • At 5 years, no increase in hospitalizations or ER visits for BT patients compared with first year after BT • Stable FVC and FEV1 for BT patients over 5 years

• BT is safe and effective at least 5 years after therapy

AIR2

• 288 severe asthmatics • Randomized to BT versus sham-BT therapy • Follow-up to 1  year • Age: 40.7 ± 11.89 years

• 77%–80%

• 6% higher hospitalization rates in BT group in first 6 weeks Between 6 weeks and 52 weeks post-BT • 84% reduction in ER visits for respiratory symptoms in BT group (BT = 0.07 BT vs. sham = 0.43 visits/subject/ year) • 73% reduction in hospitalizations for respiratory symptoms in BT group (BT = 2.6% vs. sham = 4.1%) • 66% reduction in absenteeism in BT group (BT = 1.3 vs. sham = 3.9 days/year) • 79% improvement in baseline QOL in BT groups (vs. 64% in sham group) • 32% reduction in severe exacerbations in BT groups (BT = 26.3% vs. sham = 39.8%)

• BT causes transient increase in hospitalizations at 6 weeks • From 6 to 52 weeks, fewer severe exacerbations, ER visits, hospitalizations, and absenteeism for respiratory issues in BT group • BT is safe and effective at least 1 year after therapy

Continued

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TABLE 18.2

Summary of Bronchial Thermoplasty (BT) Results From Randomized Controlled Trials and Extension Studies—cont’d Study

Subjects

Approximate FEV1 values

Results

Conclusions

AIR2: 2-year follow-up

• 166 BT recipients in AIR2 • Follow-up at 2  years • Age: 41.1 ± 11.8 years

• 74.5% • Clinical stability of FEV1 at 2 years

• At 2 years, BT patients had a 23% severe exacerbation rate (2 years earlier, prior to any BT sessions, this same group had a 51% severe exacerbation rate)

• BT is safe and effective at least 2 years after therapy

AIR2: 5-year follow-up

• 162 BT recipients in AIR2 • Follow-up at 5  years • Age: 41.5 ± 11.8 years

• 77%–78% • Clinical stability of FEV1 at 5 years

• At 5 years, 44% average decrease in severe exacerbations • At 5 years, BT patients had no deterioration in FEV1 • At 5 years, BT patients did not have increase in hospitalizations from baseline • At 5 years, HRCT scans did not show any significant structural changes

• A single BT treatment comprising three procedures is safe and provides long-term benefit to at least 5 years

RISA

• 32 severe asthmatics • Randomized to BT or usual care • Age: 39.1 ± 13.0 years

• 63%–66%

• Before 22  weeks, increased hospitalizations in BT groups • At 22 weeks, 14% improvement in FEV1 in BT group. No improvement in FEV1 in control group • At 22  weeks, significant improvement in QOL scores in BT group versus controls • At 22 weeks, significantly less rescue medication use in BT group versus controls

• Transient increase in hospitalizations before 22 weeks • After 22  weeks, marked improvement in FEV1 and QOL scores in BT group • BT may preferentially benefit severe asthmatics with lower FEV1 values than moderate asthmatics

RISA: 5-year follow-up

• 14/15 BT recipients from RISA • Age: 38.6 ± 13.3 years

• 63.5% • Clinical stability in FEV1 at 5 years

• At 5 years, BT patients had stable FEV1 values • At 5 years, BT patients had no increase in hospitalizations compared with the year before BT therapy

• BT is safe and effective for at least 5 years after therapy in severe asthmatics

ER, emergency room; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HRCT, high-resolution computed tomography; PEF, peak expiratory flow; QOL, quality of life; AE, Adverse event.

For the clinician: is bronchial thermoplasty safe and effective for my patient? The decision to pursue BT for a patient begins with a thorough history, examination, and objective testing. Clinicians should consider BT as a treatment that reduces ASM that complements antiinflammatory

therapy with ICS and biologic modifiers. BT should be considered in severe asthma patients that are receiving GINA Step 4 or 5 therapy yet are not achieving asthma control. BT should be avoided in patients who are noncompliant, current tobacco users, during active asthma exacerbations or in patients with prior serious

CHAPTER 18  Imaging Procedures and Bronchial Thermoplasty RB2

RB3

RB4

RB5

RB6

RB7

RB8

RB9

RB10

After Therapy

Before Therapy

RB1

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FIG. 18.4  Top row: Hyperpolarized gas magnetic resonance imaging (HP MRI) showing defects of

the right lung in a severe asthma patient prior to bronchial thermoplasty (BT). Darker regions correspond to regions with focal ventilation defects. Bottom row: Ventilation defects with color coded segment labels. Defects are most notable in RB2 (Blue), RB5 (orange), RB6 (green), RB7 (brown), RB10 (purple) for this patient. Bottom Images: HP MRI showing defects of the right lung in a severe asthma patient 12 weeks after BT. Note in corresponding regions there is improved ventilation after BT. (From Thomen RP, Sheshadri A, Quirk JD, et al. Regional ventilation changes in severe asthma after bronchial thermoplasty with (3)He MR imaging and CT. Radiology. 2015;274(1):250–259; with permission.)

reactions to moderate sedation or anesthesia. Randomized controlled trials have established the safety of BT in individuals with FEV1 values above 50% and less than four exacerbations 1 year before enrollment.62 However, experienced BT centers have now successfully treated patients with a postbronchodilator FEV1 40% or greater and with more frequent exacerbations (Hogarth K, et al. Castro M. Personal Communication). For clinicians, novel imaging techniques have proven useful in evaluating the mechanism of action of BT. Case series utilizing MDCT, HP MRI, and OCT have

noted improvements with select BT recipients. MDCT has found decreased %WA and air trapping in individuals after BT sessions.71,72 HP MRI also detected regional ventilation changes in patients after BT73 (Fig. 18.4). Kirby et al. used OCT to show reduced AWT in a patient post-BT that persisted for 2 years.59 A Cochrane review evaluated three trials with over 400 patients who underwent BT. The authors concluded that BT provides a modest clinical benefit in QOL and decreased asthma exacerbation rates. An increase in adverse events was noted immediately posttreatment,

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but overall the authors concluded that BT has a reasonable safety profile.74 A large metaanalysis of 200 moderate to severe asthma patients undergoing BT found there was no significant decline in FEV1 values after 5 years follow-up, suggesting that BT might prevent deterioration of lung function. Furthermore, about 10% patients completely weaned off LABA treatments after BT. These results indicated that not only is BT safe for most patients long term, but it can also stabilize their asthma control and decrease medication use in select patients.75 Finally, a study analyzing the cost of BT revealed overall benefits as well. Assessing quality-adjusted life-years (QALY), the study discovered that BT treatment resulted in 6.4 QALY and $7512 in cost compared with 6.2 QALY and $2054 for usual care cost. In addition, there was an expected decrease in ER and hospital costs by about $4600. There was also an expected $3000 savings from reduction in medications. For BT to be cost-effective, a higher probability of asthma exacerbation is required. This highlights the need for BT referral for select patients with severe asthma and uncontrolled symptoms with a history of two or more prior exacerbations requiring systemic corticosteroids.76 In conclusion, BT may benefit a specific asthma phenotype with chronic airflow obstruction, bronchial wall thickening, and remodeling on imaging. Patients with severe and uncontrolled symptoms despite medication compliance seem to benefit the most from BT. When the procedure is performed by a physician experienced in bronchoscopy in consultation with an asthma expert, BT is a safe and effective therapy that improves asthma control and QOL while reducing exacerbations. In the future, more studies will evaluate its long-term beneficial effects, and novel imaging techniques may play a role in selecting patients and in guiding therapy. 

SUMMARY Novel lung imaging techniques using qCT, HP MRI, PET, EBUS, and OCT have been developed to assess structural changes, such as airway remodeling, and functional changes, such as air trapping and ventilation defects, in asthma. qCT can generate 3-D models of the tracheobronchial tree and clearly evaluate airway structural changes such as airway remodeling and air trapping. HP MRI can evaluate functional changes in the lung by detecting regional ventilation abnormalities. EBUS and OCT allow for real-time assessment of local

airway structure while PET scans may detect increased regional airway inflammation. A clinician can appreciate the true heterogeneity of airway remodeling in each individual patient, which is not possible with current clinical tests for asthma (such as spirometry or chest X-ray). In the future, these newer imaging techniques should be considered in patients with severe uncontrolled asthma and chronic airflow obstruction or in those with progressive loss of lung function despite therapy with ICS and LABA. Standardization of these techniques in specialized asthma centers will facilitate their application in the future. Furthermore, these imaging modalities can help better identify asthma phenotypes and response to new therapeutic interventions such as BT. BT is a safe and effective therapeutic intervention to reduce smooth muscle mass in severe uncontrolled asthma when performed by an experienced bronchoscopist in consultation with an asthma expert. HP MRI studies have demonstrated similar ventilation defects in children with asthma; therefore future studies are needed to evaluate the appropriate utilization of BT in children. Ongoing studies are evaluating the predictive value of imaging studies in selecting appropriate patients for BT and in guiding therapy.

FUNDING The study is supported by the National Heart, Lung, and Blood Institute/National Institutes of Health NIH/ NHLBI U10 HL109257 (MC) and NIH/NCATS UL1 TR000448.

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