2141 Diagnostic Procedures in Respiratory Disease CHAPTER 286

Brushing and Endobronchial Biopsy Bronchoscopic brushing is a minimally invasive sampling technique that can be used to

sample the mucosal biofilm for microbiologic analyses as well as the

bronchial epithelial layer for cytologic analyses. Endobronchial biopsy

allows sampling of abnormal bronchial mucosa and submucosa for

histopathologic analysis (as may be indicated in cases of endobronchial

amyloidosis or sarcoidosis, for example). Among cigarette smokers

with one or more lung nodules and a nondiagnostic bronchoscopy,

bronchial brushings can be used with a commercially available classifier

that estimates lung cancer probability based on a gene expression signature. Patients with intermediate pretest probability who end up with

low posttest probability can more confidently opt for imaging surveillance, thus avoiding further invasive testing and related complications.

Transbronchial Biopsy Including Cryobiopsy Transbronchial

biopsy involves removing a piece of alveolated lung tissue by passing a

sampling tool into the alveolar space. The most commonly employed

biopsy tool is flexible forceps, typically 2.0 mm or 2.8 mm in caliber.

When a specific pulmonary lesion such as a lung nodule is being biopsied, various imaging and navigation tools (described below) may be

used to help guide the site of forceps biopsy. When random sampling

of the lung parenchyma is desired, e.g., to assess for posttransplant lung

rejection, either fluoroscopic guidance or tactile feedback is commonly

used to position the forceps in the subpleural lung parenchyma. Limited data point to three biopsy samples being adequate for optimizing

sensitivity in case of malignant lung nodules. On the other hand, at

least five distinct pieces of alveolated lung tissue are needed for formal

diagnosis of acute cellular rejection among lung transplant recipients

per current recommendations. An increasingly popular biopsy tool is

the cryoprobe, a flexible catheter with a blunt tip that delivers liquid

nitrogen or carbon dioxide over a few seconds to freeze a portion of

lung parenchyma and make it adhere to the probe itself. Before the tissue can thaw and detach, the probe is pulled back (typically along with

the bronchoscope itself), and a frozen piece of lung tissue is removed

alongside. Cryobiopsy has a higher diagnostic yield than forceps biopsy

for diffuse parenchymal illnesses such as idiopathic pulmonary fibrosis

but comes with a higher risk of major bleeding and pneumothorax.

Transbronchial Needle Aspiration Transbronchial needle aspiration (TBNA) involves using a hollow-bore needle for obtaining

aspirated specimens. This may be accompanied by suction or simply

rely on capillary action, with data not pointing to suction impacting

diagnostic sensitivity. TBNA has diagnostic sensitivity superior to

that of transbronchial biopsy for malignant peripheral nodules. This

makes intuitive sense given that the lesion may lie extraluminally and

require traversing the airway wall, which only the needle may be able

to accomplish. Furthermore, combining TBNA with conventional

transbronchial biopsy appears to increase pooled diagnostic sensitivity.

Endobronchial Ultrasound-Guided Transbronchial Needle

Aspiration Endobronchial ultrasound (EBUS) and EBUS-guided

transbronchial needle aspiration (EBUS-TBNA) represent a major

advance in diagnostic bronchoscopy over the turn of the twentieth

century, largely replacing surgical methods for lymph node sampling.

EBUS-TBNA involves using a specialized flexible bronchoscope that

simultaneously operates a video camera and a convex ultrasound probe

(which is installed at its distal end). Under real-time ultrasonographic

visualization, the aspiration needle is inserted through the airway wall

into the mediastinal target and the aspirate is sent for microbiologic

or cytologic analyses as indicated (Fig. 286-2). Newer variants of this

technique involve the use of core needles or mini-forceps, providing

tissue specimens rather than aspirates that can be sent for histopathologic analysis. EBUS-TBNA has a sensitivity of approximately 90% for

epithelial malignancies and approximately 70% for lymphoma (higher

for detecting cases of lymphoma recurrence than for de novo lymphoma). For sarcoidosis, estimates point to a sensitivity of at least 80%

A B

FIGURE 286-2 A. Endobronchial ultrasound-guided transbronchial needle aspiration of a mediastinal lymph node. B. Rapid on-site evaluation (ROSE) using Diff-Quik stain

indicative of noncaseating granuloma. (Source: Majid Shafiq, MD, MPH)

2142 PART 7 Disorders of the Respiratory System

(higher if combined with endobronchial and transbronchial biopsies).

EBUS-TBNA has been shown to provide adequate amounts of material

to provide ancillary testing in cases of malignancy, such as immunostaining or genetic testing. A related needle-based technique, also using

ultrasound guidance, involves sampling mediastinal structures through

the esophagus, which can be a useful adjunct to EBUS-TBNA as it may

provide better access to certain mediastinal lymph node stations. The

combined sensitivity of these two techniques is slightly higher compared to either one alone. Esophageal sampling can be accomplished

either by inserting the same EBUS bronchoscope through the esophagus or by using the standard endoscope used by gastroenterologists for

endoscopic ultrasound (EUS).

At many centers, EBUS-TBNA is accompanied by rapid on-site

cytologic evaluation (ROSE), wherein a portion of the aspirated specimen is immediately examined by a cytotechnologist or pathologist

using rapid staining. This rapid assessment, while often inadequate for

a definitive final diagnosis, can be helpful in establishing adequacy of

sampled material by providing the bronchoscopist with real-time feedback on whether additional sampling is advisable.

The optimal way to process samples obtained via EBUS-TBNA is

unknown. Some centers practice the tissue coagulum clot method, in

which multiple aspirates are emptied onto a single piece of filter paper

to form a clot that can help with preparation of a cell block. Other

centers simply use the residue from spun specimens for this purpose.

There is no conclusive evidence that one technique is superior to the

other, but this question has not been well studied to date.

Guided Peripheral Bronchoscopy Guided peripheral bronchoscopy involves the use of advanced tools to aid with one or more of three

tasks involved in successful bronchoscopic sampling of peripherally

located lesions, such as lung nodules (see below). Various tools are

available to help the bronchoscopist accomplish these tasks (Fig. 286-3).

(A) Navigating to the appropriate lobe/segment/subsegment: Electromagnetic navigational bronchoscopy (which involves GPS-like

feedback as the bronchoscope is advanced toward the target) and

virtual bronchoscopy (which overlays live endoscopic images onto

a CT-derived virtual bronchoscopic map) can help with successful

navigation through the airways. Shape-sensing technology, used

as part of one robotic bronchoscopy platform (see below), also

aims to achieve the same purpose.

(B) The aforementioned technologies can also help localize a lesion,

although they are limited by relying on previously acquired CT

images that may or may not accurately represent precisely where

the lesion is currently located in a three-dimensional space.

Radial EBUS uses a thin ultrasound-tipped catheter that can be

passed through the bronchoscope’s working channel all the way

to the lung periphery. This provides real-time images of structures

beyond airway walls. A concentric image of the target, indicating

a lesion with the airway going through its center, is associated with

a high diagnostic yield. Alternatively, fluoroscopic imaging can

be used to recalibrate the precise target location on navigational

bronchoscopic platforms, potentially improving localization as

well. Cone-beam CT, which is a distilled version of CT imaging

that has been used intra-procedurally in multiple other fields

such as interventional radiology, can be used for confirmation of

optimal tool-in-lesion (with the patient undergoing a breath hold)

prior to sampling.

(C) The tools available for peripheral sampling include biopsy forceps,

brushes, and aspiration needles as described above, with TBNA

having the highest diagnostic sensitivity for discrete malignant

lesions. Evidence for use of cryobiopsy for sampling discrete

lesions in the lung periphery is currently limited. Recent innovations also include steerable sampling tools, which hold promise for

more optimal sampling of the target lesion.

Robotic Bronchoscopy In 2018, the US Food and Drug Administration (FDA) approved two robotic bronchoscopy platforms for commercial use. These platforms offer improved bronchoscope stability

and reach, but whether navigation, target localization, and adequacy

of sampling are superior to other techniques is less certain. Early data

on diagnostic yields are encouraging, but multicenter prospective data

are not yet available.

MEDICAL IMAGING

Imaging has revolutionized the practice of medicine. Technologies

such as x-ray, CT, MRI, and positron emission tomography (PET) can

provide noninvasive assessments of alveolar perfusion, the metabolic

FIGURE 286-3 Example of an electromagnetic navigational bronchoscopic platform. The target lesion turns green when successfully reached by bronchoscopy. (Source:

Majid Shafiq, MD, MPH)

2143 Diagnostic Procedures in Respiratory Disease CHAPTER 286

activity of a lung nodule, the bronchovascular source of hemoptysis,

or the earliest disease-related changes in parenchymal structure. Given

the breadth of advances in respiratory system imaging and increasingly specialized applications across diseases, the following section is

organized by technology. The final part of this section is dedicated to

deep learning and the role it is increasingly playing in medical image

interpretation.

■ CHEST X-RAY

The field of medical imaging can be traced back to work done by

Wilhelm Roentgen in the 1890s. Roentgen noted that after connecting

a cathode ray tube to a power supply, material in his lab would fluoresce even if the emission of visible light from the tube was blocked.

He quickly deduced the presence of additional invisible “x-rays” and

subsequently observed that their passage through solid material was

attenuated in proportion to the material’s density. Within weeks of

its discovery, x-ray technology was being widely leveraged to guide

surgical exploration and the extraction of foreign objects such as

shrapnel from the battlefield. Chest x-ray (CXR) has since become the

foundation of clinical practice for respiratory medicine and is a widely

available technology even in resource-limited settings.

The most commonly used CXR images for respiratory medicine are

the posteroanterior (PA) and lateral films in the outpatient setting and

anteroposterior (AP) films for those studies obtained at the bedside.

These are 2-dimensional representations of 3-dimensional structures

and the differing views can be used to examine superimposed structures (for example, a parenchymal opacity in the retrocardiac space).

The contours of the chest wall, the silhouette of the heart, great vessels,

and mediastinum, as well as the appearance of the parenchyma and

bronchovascular bundle are all used to detect and classify disease as

well as monitor its progression or response to therapeutic intervention.

An example of a normal PA and lateral CXR is provided in Fig. 286-4.

In this image of the normal lung, many of the smaller structures

such as the lymphatics and distal airways are beyond the ability of

conventional x-ray technology to resolve. Larger structures such as the

pulmonary vasculature may also be indistinct because of body position

and the redistribution of blood flow to more gravitationally dependent

regions. Diseases involving these structures may enhance or obscure

their appearance. An example of these diseases is congestive heart failure where the lymphatics become engorged (Kerley B lines), the nondependent vasculature more prominent (cephalization), and the outer

boundaries of the bronchial walls blurred (bronchial cuffing). Each of

these findings must be clinically contextualized and while a thickened

interstitium may be due to hydrostatic pulmonary edema, it may also

be indicative of interstitial lung disease or carcinomatosis. CXR can

also be used to discriminate pulmonary and extra-pulmonary disease

and because of that it is an excellent initial diagnostic for nonspecific

symptoms. An elevated hemidiaphragm, fibrosis of the mediastinum,

or hyperlucency of the lung parenchyma all reflect processes that cause

dyspnea, but their treatment and prognosis differ markedly.

■ COMPUTED TOMOGRAPHY

CT was introduced to clinical care in the 1980s and quickly became one

of the most heavily leveraged modalities for medical imaging. While

CXR provides one or two views of the thorax from which an experienced clinician must disambiguate overlying structures, CT provides

spatially resolved reconstructions of all structures in the thorax. The

acquisition of a CT scan involves the same basic process as an x-ray

with a patient placed between a source of photons and a detector, but

the image reconstruction and advanced analytics that can be applied to

those images differ markedly. The passage of photons through the body

is impeded in proportion to tissue density. This absorption or attenuation of photon passage is measured in Hounsfield units (HU) and

clinical CT scanners are regularly calibrated to a standard scale with

water having an HU of 0 and air –1000 HU. The broad range of tissue

densities (reflected as attenuation values) in the thorax and the limited

human ability to visually discriminate between two structures of similar densities are addressed by modifying the image display. A window

width and level (the range and center of the range of HU values to display) is selected to optimize viewing structures of interest. For example,

lung windows are optimized for visual inspection of the low-density

lung parenchyma and all of the surrounding higher-density structures

appear white, whereas the mediastinal windows are optimized to view

the higher-density structures and anything of lower tissue density such

as the lung parenchyma appears black. This does not change the HU

values of the voxels (3-dimensional pixels) in the image, just their presentation for visual inspection.

The visual interpretation of thoracic CT is based upon the appearance of the secondary pulmonary lobule. This structure is a fundamental subunit of the lung consisting of a central airway and pulmonary

artery, parenchyma, and then surrounding interstitium with the lymphatics and pulmonary veins (Fig. 286-5).

A B

FIGURE 286-4 Posteroanterior (A) and lateral (B) CXR of a normal healthy subject. (Source: George Washko)

2144 PART 7 Disorders of the Respiratory System

FIGURE 286-5 A. Illustration of the anatomy of the secondary pulmonary lobule. B. CT image showing the visible anatomy of the secondary pulmonary lobule. (Panel A

adapted from WR Webb: Thin-section CT of the secondary pulmonary lobule: Anatomy and the Image–The 2004 Fleischner Lecture. Radiology 2006;239:322, 2004; Panel B

source from Samuel Yoffe Ash MD)

Acinus

0.6-1 cm

Respiratory

bronchiole

Terminal

bronchiole

Lobular bronchiole

diameter 1 mm

wall thickness 1.05 mm

Lobular artery

diameter 1 mm

Pulmonary vein

diameter 0.5 mm

Interlobar septa

thickness 0.1 mm Visceral pleura

thickness 0.1 mm

Bronchiole wall thickness 0.05-0.1 mm

Acinar artery and bronchioles diamter 0.5 mm

A

Pulmonary vein

Lobular artery

Lobular

bronchiole

B

Processes affecting the small airways such as respiratory bronchiolitis may appear as centrilobular nodules. Parenchymal diseases such

as emphysema may begin by effacing the centroid of the lobule (CLE:

centrilobular emphysema), the periphery of the lobule (PSE: paraseptal

emphysema), or diffusely across the lobule (PLE: panlobular emphysema). Pathology of the lymphatics or interstitium (interstitial lung

disease, ILD) results in beading and/or thickening of the interlobular

septa. Examples of many of these processes are provided in Chaps.

292 and 293.

The diagnostic information provided by the appearance of the

secondary pulmonary lobule is further augmented by the distribution

of these patterns of injury across the lung. Whereas CLE tends to first

appear in the upper lung zones, PLE has a predilection to be basilar

predominant. Interstitial thickening in the apices is more likely to be

nonspecific interstitial pneumonitis (NSIP) while a basal and dependent predominant distribution of that same process is more consistent

with idiopathic pulmonary fibrosis (IPF).

Finally, morphology of the central airways and vessels can be used to

diagnose disease and estimate its severity. Bronchiectatic dilation of the

airways may be cylindrical and predominantly in the lower lobes as is

seen in chronic obstructive pulmonary disease (COPD), cystic dilation

in the upper lobes (cystic fibrosis), or there may be a focal nonspecific

dilation of an airway due to prior infection. Pathologic dilation of the

airways may also be due to disease of the surrounding parenchyma.

Because of the mechanical interdependence of the bronchial tree and

parenchyma, conditions that reduce lung compliance may result in

traction bronchiectasis. This may be a local process or more diffuse

depending on the distribution of the underlying parenchymal disease,

and likely provides further insight into disease severity.

The caliber of the central pulmonary arterial (PA) trunk proximal to

its first bifurcation is directly related to pulmonary arterial pressure. A

measure of >3 cm is suggestive of the presence of elevated pulmonary

vascular pressures and more recent studies have demonstrated that an

increased ratio of the PA diameter to the diameter of the adjacent aorta

(PA/A) provides a metric of disease severity and in the case of chronic

respiratory diseases such as COPD is prognostic for both acute respiratory exacerbations and death. Assessment of the intraparenchymal

pulmonary vasculature is typically augmented through the intravenous

2145 Diagnostic Procedures in Respiratory Disease CHAPTER 286

infusion or bolus of iodinated contrast. This bolus and subsequent

image acquisition may be timed to visualize passage of contrast

through the pulmonary arteries to enable detection of thromboembolic

disease, which appears as dark filling voids in otherwise bright white

vessels.

It must be noted that the acquisition of CXRs and thoracic CT scans

involves exposing the patient to ionizing radiation. Several studies have

estimated the excess numbers of cancer due to CT scanning and extensive efforts have been made by both CT manufacturers and clinicians to

reduce the radiation dose to the lowest possible amount that does not

jeopardize image quality and interpretability.

■ MAGNETIC RESONANCE IMAGING

MRI is based upon the behavior of protons in a magnetic field. A

strong magnetic field is applied to align the protons and then a pulse of

radiofrequency current is then applied to the subject. This perturbs the

protons and the speed at which they subsequently realign differs based

upon the properties of the tissues within the region of interest. While

this technique provides exquisite imaging data for the chest wall or

solid organs such as the brain or heart, the abundance of air in the lung

creates an artifact that impairs direct assessment of the parenchyma.

For this reason, MRI of the lung leverages intravenous contrast agents

such as gadolinium and is increasingly exploring the use of inhaled

agents such as hyperpolarized noble gas. These respective agents enable

in vivo assessments of organ perfusion and detailed measures of the

morphology of the distal airspaces. An example of noble gas–enhanced

MRI is shown in Fig. 286-6. The inhaled agent is 3

He and because it

is proton rich, it can be used to examine lung ventilation visually and

objectively. Regions of the lung that are poorly ventilated due to disease

of the airways or distal airspaces have low concentrations of 3

He and

appear as dark regions in an otherwise bright blue organ.

While an MRI may have a longer acquisition time than CT, and the

geometry of the equipment often leads to a sense of claustrophobia, it

does not involve the administration of ionizing radiation. This makes

it a modality of choice in the pediatric population or clinical situations

where repeated assessments are required.

■ POSITRON EMISSION TOMOGRAPHY

PET generates an image based upon the aggregation of radiolabeled tracers. The most common agent used for these purposes is

[18F]-fluoro-2-deoxyglucose (FDG). This radiolabeled glucose analogue is administered intravenously and is taken up by cells in direct

proportion to their metabolic activity. In the clinical setting, it is most

commonly used for the discrimination of benign and malignant lung

nodules, as well as lung cancer staging. Given the relatively low resolution of PET, co-registration with CT is common and the aligned

imaging modalities allow the reader to determine the structural source

of heightened metabolic activity.

There is increasing interest in the use of PET imaging in the biomedical community. These applications are largely still confined to research

but advances in areas such as in vivo assessments of vascular biology in

acute and chronic disease have been impressive.

Healthy Asthma

FIGURE 286-6 Noble gas MR. Healthy control on left and asthma on right. (Images

courtesy of Grace Parraga, PhD, Department of Medical Biophysics, Department of

Medicine, School of Biomedical Engineering, Robarts Research Institute, Western

University, London, Ontario, Canada.)

FIGURE 286-7 Arterial/venous segmentation of the pulmonary vasculature (blue:

arteries; red: veins) and epicardial surface of the right (blue) and left ventricles (red).

(Image courtesy of Raul San Jose Estepar, PhD, Applied Chest Imaging Laboratory,

Department of Radiology, Brigham and Women’s Hospital, Boston, MA.)

■ ARTIFICIAL INTELLIGENCE/DEEP LEARNING

The final aspect to thoracic imaging that must be discussed is the

growing field of artificial intelligence and deep learning applied to

image analysis. Classic machine learning approaches to medical

image interpretation involve the development of advanced algorithms

to detect structures of interest, segment their boundaries, and then

extract metrics related to size, shape, texture, etc. The massive increase

in processing capacity afforded by graphical processing units (GPUs),

the increasing availability of large amounts of data, and the wide

dissemination of open-source software libraries allowing developers

to create powerful work environments has led to explosive growth in

the utilization of deep learning for image analytics. Some of the first

medical applications of deep learning were in the field of dermatology

and, more recently, this advanced form of pattern recognition has been

reported to excel at the discrimination of benign and malignant lung

nodules in thoracic CT scan. The breadth of application of these tools

continues to expand to include image navigation and feature detection,

biomarker development, and direct prediction of clinical outcomes.

An example of deep learning–enabled segmentation of the heart and

pulmonary vasculature from noncontrast enhanced noncardiac gated

CT scan is shown in Fig. 286-7.

TRANSTHORACIC NEEDLE ASPIRATION

Radiologically guided needle biopsy has served as a long-standing

mechanism for evaluation of parenchymal lung lesions, both malignant

and infectious. In the setting of published guidelines recommending low-dose screening CT scan for lung malignancy in high-risk

patients and with evolving guidelines for monitoring and assessment

of incidental lung lesions arising in this setting, radiologically guided

sampling of lung lesions has become an increasingly important mechanism to address parenchymal lung abnormalities concerning for

cancer. Moreover, as novel immune modulators and biologic agents

are increasingly utilized for the management of systemic disease and

transplantation, effective interventions are becoming progressively

more important in assessing for potential pulmonary infections arising

as complications of immune suppression. Transthoracic needle aspiration (TTNA) remains one important arm in the assessment of these

pulmonary complications.

TTNA can be accomplished with a variety of complementary imaging mechanisms, including under fluoroscopic, CT, ultrasound, or

MRI guidance. CT is currently the most common imaging modality

2146 PART 7 Disorders of the Respiratory System

used to assess parenchymal lung lesions, with sensitivity and specificity

reported to be >90%. Sensitivity of CT-guided TTNA is increased in

more peripheral lesions. Transthoracic ultrasound has the advantages

of a low complication rate in the setting of fine needle aspiration (FNA)

and portability, allowing for more logistical simplicity in the setting of

lung lesion assessment. In a prospective study of ultrasound-guided

percutaneous FNA compared with CT-guided FNA, diagnostic rates

were comparable between the two groups, with shorter procedure

time associated with ultrasound guidance, numerical suggestion of

decreased complication rate using ultrasound guidance, and lower

costs associated with ultrasound guidance. Use of elastography to better characterize lung lesions has also been proposed in the context of

ultrasound, though additional diagnostic yield has not yet been proven.

Color Doppler ultrasonographic imaging has been demonstrated to

have a high sensitivity and specificity and a low complication rate in

another study. Electromagnetic guidance, unlike CT imaging, can be

used in combination with endobronchial ultrasound and or navigational bronchoscopy in the operative setting, theoretically allowing for

a multimodal approach that could increase diagnostic yield and allow

for a combined staging procedure. Electromagnetic TTNA alone has

demonstrated an 83% diagnostic yield in a pilot study, with an increase

to 87% when combined with navigational bronchoscopy. Conflicting data are available regarding the diagnostic superiority of TTNA

compared with alternative biopsy modalities such as endobronchial

ultrasound for diagnosis of lung lesions, and results may depend on

center experience.

Transthoracic sampling can be obtained using FNA or core needle

biopsy. In one retrospective study, FNA was found to have an inferior

diagnostic rate, compared with core needle sampling, as well as lower

specificity. In this study, a method involving two FNA passes was compared to core needle sampling with six cores obtained from a single

pass. No significant differences in complication rates were noted. In

another retrospective study, in which procedure was determined by

operator preferences, core needle aspirate samples were more likely to

provide sufficient material for molecular testing than FNA. A systematic review of these techniques concluded that insufficient evidence was

available to support a difference between FNA and core needle biopsy in

diagnostic efficiency, though core needle biopsy may be more specific

in diagnosing benign lung lesions. Given the negative predictive value

estimate of 70%, negative results from TTNA are less reliable than

positive results and should not be considered definitive to eliminate the

concern for malignancy. Further assessment is needed to directly compare imaging modalities for TTNA guidance and to compare TTNA

with other diagnostic modalities to determine the optimal choice of

procedure in particular settings. Choice of procedure should be considered in the context of the size and location of the lesion, the experience

of the center and operator, and patient-specific factors.

In regards to the safety of TTNA, in a retrospective study from

2015, the presence of mild to moderate pulmonary hypertension in

patients did not increase complication rates in the setting of TTNA.

The complication rates noted in this report were substantial, however,

with hemorrhage occurring in one-third to one-quarter of patients,

and pneumothorax in 17–28%. The majority of pneumothoraces

did not require chest tube placement. Other complications included

hemoptysis and hemothorax, though these were uncommon. These

complication rates are consistent with those reported in other studies.

In a meta-analysis of complication rates of CT-guided TTNA, complication rates were higher with core needle aspirates than FNA (38.8%

[95% CI 34.3–43.5%] vs 24% [95% CI 18.2–30.8%]). The majority of

these complications were minor. Risk factors for complications with

FNA included smaller nodule diameter, larger needle diameter, and

increased traversed lung parenchyma. No clear risk factors were noted

for complications after core needle biopsies in this publication. More

generally, the risks of TTNA increase for more centrally located lesions

and those residing in close proximity to intrathoracic vasculature.

Despite the outstanding questions regarding the optimal approach

for TTNA, this modality has been shown to be effective in cancer diagnosis in the thorax. Adenocarcinoma has become the most prevalent

parenchymal lung malignancy in reported studies, and also the most

common malignant diagnosis found on TTNA of the lung. TTNA can

also be effective in diagnosing less common tumors of the lung, both

malignant and benign, including squamous and small cell carcinomas,

lymphomas, and others, as well as in assessing tumors of the mediastinum. The diagnostic utility of TTNA is consistent across solid,

subsolid, and partially calcified lung nodules. Immunocytochemistry

markers can be utilized in TTNA samples to assist with diagnosis,

prognosis, and prediction of response to therapy, and samples should

be preserved whenever possible to allow for these studies, if needed.

RNA extraction has also proven feasible in the setting of a single FNA

sample, which could be instrumental in gene expression profiling,

though this has thus far only been successfully accomplished in a

research context.

The utility of TTNA in diagnosing pulmonary infections is variable

in published literature. Some publications have reported that TTNA

establishes a diagnosis of infection in 60–70% of cases, with a particularly high yield in the setting of Aspergillus infections. TTNA has also

been shown to be particularly effective in the diagnosis of pulmonary

tuberculosis, though a wide variety of infections have been diagnosed

using this method. The presence of necrosis in lung lesions makes

establishing an infectious diagnosis more likely using TTNA. Numerous staining techniques are available to assist with infectious diagnoses,

and immunohistochemistry can also aid in the diagnosis of infection.

Cytology should be correlated with histopathology and culture results,

when available. Metagenomics using next-generation sequencing for

detection of infection is evolving but requires further study. TTNA has

also been useful in identifying granulomatous inflammation, which

can provide supportive evidence of a granulomatous parenchymal lung

disease in the appropriate clinical setting.

In summary, TTNA is an important element of diagnostic algorithms in the setting of lung nodules and masses, particularly when

concern for malignancy is not high enough to warrant immediate

excision, when the patient is not a surgical candidate, or the lesion or

disease is not amenable to surgical resection. Further study is needed,

however, to better understand the role of TTNA and other diagnostic

modalities in the evaluation of parenchymal lung lesions.

MISCELLANEOUS TESTING

■ SPUTUM TESTING

Sputum microscopy and culture are commonly utilized to diagnose

respiratory tract infections and identify the causative organisms. In

patients with productive cough the sampling is simple and noninvasive, however, subject to patient technique and the potential for

oropharyngeal and/or upper respiratory tract contamination. In those

who are not expectorating, sputum induction can be considered using

provocative nebulization with saline. Numerous studies have attempted

to define criteria for reliability and reproducibility of sputum samples.

The majority include quantification of number of epithelial cells and

white blood cells per low power field, and many assess the ratio of the

two for adequacy of sampling. None has been confirmed as superior

in establishing the reliability of sampling to reflect lower respiratory

tract growth. The quality of the sputum sample directly impacts the

diagnostic reliability in the setting of bacterial pneumonia. Growth of

Mycobaterium tuberculosis, Legionella, or pneumocystis should raise

concern for infection, even in the setting of a poor sample. Endotracheal aspirates have not been demonstrated to be clearly superior to

expectorated sputum in terms of diagnostic reliability, but such sampling may be required if spontaneous coughing is nonproductive and

induced sputum is not feasible or successful.

As in the context of infection, sputum cytologic analysis has been

utilized to assist in the diagnosis of malignancy, mainly because it

can be obtained noninvasively. While sputum cytology demonstrating

malignant cells is highly specific for a diagnosis of lung malignancy, its

sensitivity has been reported at <40%. A systematic review of screening

methods demonstrated no added benefit from sputum cytology when

combined with CXR to screen for lung cancer. Advanced molecular

techniques such as polymerase chain reaction, DNA methylation markers, micro-RNA assessment, and tumor-related protein analysis have

2147Asthma CHAPTER 287

been proposed in sputum assessment for diagnostic purposes and risk

stratification. At present, however, sputum cytology is recommended

only when more invasive techniques cannot be pursued, such as in

patients with prohibitive comorbidities or in resource-limited settings.

■ EXHALED BREATH CONDENSATE

Exhaled breath condensate includes gaseous, liquid, and water-soluble

components, with numerous biomarker types and collection system

varieties developed over time. Validation standards for many components are still being determined. Exhaled nitric oxide is the most highly

validated of the biomarkers identified in exhaled breath condensate.

The fraction of exhaled nitric oxide (FeNO) has been demonstrated

in higher concentrations in exhaled breath condensate of patients

with asthma than in healthy individuals, and has been shown in some

studies to correlate with the presence of eosinophils in the sputum and

blood and with response to inhaled corticosteroids, though data are

conflicting. For example, in a systematic review and meta-analysis,

FeNO elevation increased the odds of having asthma in both children

above the age of 5 years and adults. In another systematic review

of FeNO utilization in the management of adults with asthma, the

assessment was helpful in the management of severe exacerbations

but had no significant impact on overall exacerbations or inhaled corticosteroid use. Moreover, evidence suggests that tailoring of asthma

therapy based on sputum eosinophil levels was effective in decreasing

asthma exacerbations, but tailoring of therapy based on FeNO was

not beneficial in improving outcomes, and insufficient evidence was

observed to advocate the use of either sputum analysis or FeNO in clinical practice. FeNO has also been shown to be influenced by ethnicity,

and appropriate reference standards for different ethnic groups have

yet to be established. While FeNO has been proposed as a potential

clinical guide to management, its use has not been incorporated into

all guideline recommendations, and it has not been formally approved

for clinical use.

■ SWEAT TESTING

Assessment of chloride concentration in sweat using pilocarpine iontopheresis, or sweat testing, remains a key element in the diagnostic

framework of cystic fibrosis (CF). This method utilizes pilocarpine to

stimulate sweat production. As patients with CF suffer from alterations

to the sodium chloride ion channel, measurement of electrolytes in

their secretions such as sweat reveals elevated chloride concentrations,

amongst other abnormalities. This testing has been considered the

gold standard in the diagnosis of CF due to its functional nature, its

relative noninvasiveness, the establishment of validated standards for

its performance, and its ability to discriminate between healthy individuals and those with CF at a chloride concentration of ≥60 mmol/L.

The likelihood of a diagnosis of CF at a concentration of <40 mmol/L

has been observed to be low, and an indeterminate range was defined

as 40–59 mmol/L, which could be consistent with the disease if genetic

and clinical manifestations were supportive.

While functional testing such as sweat chloride testing remains an

essential component of diagnostic algorithms in CF, the evolution of

genetic analysis has led to identification of an extensive array of genetic

mutations associated with varied phenotypic impacts in this disease.

In this context, the indeterminate range of chloride concentrations

of 40–59 mmol/L on sweat test analysis was found to inadequately

identify milder or more heterogenous forms of the disease associated

with newly identified genetic mutations. As a result, the Cystic Fibrosis

Foundation provided updated guidance for the interpretation of sweat

test results, with a decreased lower threshold to define an intermediate range of chloride concentration (changed from 40–50 mmol/L to

30–50 mmol/L), which could be consistent with the diagnosis of CF in

the appropriate genetic and clinical context. In a subsequent analysis,

utilization of the new guidance was found to enhance the probability

of identifying patients with CF without increasing the false-positive

diagnosis rate in the population. Sweat testing is a critical component

of the CF diagnostic algorithm but should be interpreted in the context

of clinical manifestations of disease and correlated with genetic testing

in those suspected of the diagnosis.

■ ALLERGY TESTING

Allergy testing is often considered in the assessment of environmental

exposures, including seasonal allergens, food allergens, and drug allergens. In the case of drug allergens in particular, drug reactions are often

reported based on remote history and are often unconfirmed. The

hesitancy to re-expose patients with an unconfirmed drug allergy can

lead to limited options for treatment, to delay in treatment, and to utilization of treatments with more extended spectrum, potentially influencing the resistance patterns of these agents. Drug reactions can be

mediated by IgE (immediate type reactions, type I), IgG or IgM (type

II), immune complex reactions (type III), and delayed-type hypersensitivity reactions mediated by cellular immune mechanisms (type IV).

Skin testing, including patch testing and/or delayed intradermal testing, is available to test exposure to particular allergens and determine

reactivity. These tests have been shown to aid in clinical phenotyping

of type I reactions and potentially in type IV reactions, though their

role in type IV assessment remains more controversial. In the context

of suspected type I reactions, patch testing is more cost effective and

may be as effective as intradermal testing in identifying potential causative agents. The negative predictive value of intradermal skin testing

in assessing for IgE-mediated drug allergies is high; however, the high

sensitivity of this testing limits its specificity, and results must be interpreted in the context of the pretest probability and the clinical experience of the patient. Skin tests have also been demonstrated to assist

in identifying the causative agent in type IV reactions and to assess

cross-reactivity between structurally related drugs. Intradermal testing

may be more sensitive than patch testing to assess for type IV drug

reactions. Though some debate continues regarding a mandatory role

for skin testing in the assessment of potential drug allergies, drug provocation testing or rechallenge is generally regarded as safe in low-risk

individuals with history of urticaria or immediate rash, whereas skin

testing has been proposed as a preliminary assessment in higher-risk

individuals with a history of two or more reactions, angioedema, or

anaphylaxis, prior to consideration of drug provocation testing.

■ FURTHER READING

Callister ME et al: British Thoracic Society guidelines for the investigation

and management of pulmonary nodules. Thorax 70(Suppl 2):ii1, 2015.

Deng CJ et al: Clinical updates of approaches for biopsy of pulmonary

lesions based on systematic review. BMC Pulm Med 18:146, 2018.

Shepherd W: Image-guided bronchoscopy for biopsy of peripheral pulmonary lesions. In: UpToDate. Post TW (ed). UpToDate,

Waltham, MA, 2020.

Silvestri G et al: Methods for staging non-small cell lung cancer:

Diagnosis and management of lung cancer, 3rd ed: American College

of Chest Physicians evidence based clinical practice guidelines. Chest

143(5Suppl):e211s, 2013.

Webb WR: Thin-section CT of the secondary pulmonary lobule:

Anatomy and the image. The 2004 Fleischner Lecture. Radiology

239:322, 2006.

Section 2 Diseases of the Respiratory

System

287 Asthma

Elliot Israel

Asthma is a disease characterized by episodic airway obstruction and

airway hyperresponsiveness usually accompanied by airway inflammation. In most cases, the airway obstruction is reversible, but in a

subset of asthmatics, a component of the obstruction may become

irreversible. In a large proportion of patients, the airway inflammation

2148 PART 7 Disorders of the Respiratory System

is eosinophilic, but some patients may present with differing types of

airway inflammation, and in some cases, there is no obvious evidence

of airway inflammation.

MANIFESTATIONS

Asthma most frequently presents as episodic shortness of breath,

wheezing, and cough, which can occur in relation to triggers but may

also occur spontaneously. These symptoms can occur in combination

or separately. Other symptoms can include chest tightness and/or

mucus production. These symptoms can resolve spontaneously or with

therapy. In some patients, wheezing and/or dyspnea can be persistent.

Episodes of acute bronchospasm, known as exacerbations, may be

severe enough to require emergency medical care or hospitalization

and may result in death.

EPIDEMIOLOGY

Asthma is the most common chronic disease associated with significant morbidity and mortality, with ~241 million people affected

globally. Cross-sectional studies suggest that 7.9% of the population

in the United States suffers from asthma as compared to ~4.3% prevalence worldwide. Prevalence continues to increase (starting at 7.3%

in 2001 in the United States) and is associated with transition from

rural to urban living. Asthma is more prevalent among children (8.4%)

than adults (7.7%). In children, the prevalence is greatest among boys

(2:1 male-to-female ratio), with a trend toward greater prevalence in

women in adulthood. In some patients, asthma resolves as they enter

adulthood only to “recur” later in life.

In the United States in 2016, 1.8 million people visited an emergency

department for asthma, and 189,000 were hospitalized. The total economic cost in the United States in 2007 was estimated at $56 billion. In

the United States, asthma is more prevalent in blacks than Caucasians,

and black race is associated with greater case morbidity. The ethnicity

with the greatest prevalence in the United States is the Puerto Rican

population.

Asthma mortality increased worldwide in the 1960s, apparently

related to overuse of inhaled β2

-agonists. Reduction in mortality since

then has been attributed to increased use of inhaled corticosteroids.

Asthma mortality declined globally from 0.44 per 100,000 people

in 1993 to 0.19 in 2006, but further reduction in mortality has not

occurred since that time.

Recurrent exacerbations

Triggers

(See Table 287-2)

Unknown factors

Genetic susceptibility

Risk genes and atopy

Exposures and risk factors

(See Table 287-1)

• Prenatal

• Childhood

• Adult

Symptomatic or asymptomatic asthma

• AHR

 +/–

• Inflammation

• Structural changes

Increased symptoms or

exacerbations

 +/–

• Increased AHR

• Increased inflammation

• Structural changes

FIGURE 287-1 Asthma development pathway. Illustration of how genetic susceptibility and development and exposure during the life span interact to produce a disease that

can vary in intensity and chronicity. Disease expression is characterized by airway hyperresponsiveness with varying degrees of airway inflammation and airway structural

changes accompanied by varying degrees of symptoms that can be influenced by exposure to triggers that can cause acute deterioration as well as chronic symptoms.

AHR, airway hyperresponsiveness.

TABLE 287-1 Exposures and Risk Factors Related to the Development

of Asthma

1. Allergen exposure in those with a predisposition to atopy

2. Occupational exposure

3. Air pollution

4. Infections (viral and Mycoplasma)

5. Tobacco

6. Obesity

7. Diet

8. Fungi in allergic airway mycoses

9. Acute irritants and reactive airway dysfunction syndrome (RADS)

10. High-intensity exercise in elite athletes

THE PATHWAY TO THE DEVELOPMENT

OF ASTHMA

The pathway to development of asthma can be varied. As illustrated

in Fig. 287-1, there is an interplay between genetic susceptibility (see

below) and environmental exposure and endogenous developmental

factors (e.g., aging and menopause [see “Etiologic Mechanisms and

Risk Factors” and Table 287-1]) that can lead to the development of

asthma. Continued or additional exposures and triggers (Table 287-2)

can affect the progression of disease and the degree of impairment.

PATHOPHYSIOLOGY

■ MECHANISMS LEADING TO ACUTE AND

CHRONIC AIRWAY OBSTRUCTION

The pathobiologic processes in the airways that lead to episodic and

chronic airway obstruction of asthma are discussed below. Their pathologic correlates are highlighted in Fig. 287-2, illustrating the pathologic

changes that can occur in asthmatic airways. These processes can occur

individually or simultaneously. There can be temporal variation of

these processes in an individual based on exogenous factors, discussed

later in this chapter, as well as the aging process itself. These processes

can involve the entire airway (but not the parenchyma), but there can

be significant spatial heterogeneity, as has now been demonstrated

using hyperpolarized gas ventilation studies and high-resolution computed tomography (CT) of the thorax.

2149Asthma CHAPTER 287

TABLE 287-2 Triggers of Airway Narrowing

1. Allergens

2. Irritants

3. Viral infections

4. Exercise and cold, dry air

5. Air pollution

6. Drugs

7. Occupational exposures

8. Hormonal changes

9. Pregnancy

Lumen

Invagination of airway

mucosa due to smoothmuscle constriction

Normal airway

Mucus

production Cellular

infiltration

Vascular

proliferation

Neuronal

proliferation

Epithelial

denudation

and shedding

Airway

edema

FIGURE 287-2 Pathologic changes that can be seen in asthmatic airways. Illustrated is a cross-sectional lumen of a bronchus. The left-hand side represents the normal

airway, the right represents an asthmatic airway highlighting the pathologic changes that can be seen in asthma. The asthmatic airway lumen is reduced by smooth-muscle

constriction, mucus in the airway lumen, and thickening of the submucosa due to edema and cellular infiltration. In addition, the ability of the lumen to increase in size with

smooth-muscle relaxation may be impaired by deposition of collagen. The epithelium is disrupted, and there is evidence of vascular and neuronal proliferation. All these

changes may not be present in one individual, and certain patients may have normal-appearing airways.

Airway Hyperresponsiveness Airway hyperresponsiveness is a

hallmark of asthma. It is defined as an acute narrowing response of the

airways in reaction to agents that do not elicit airway responses in nonaffected individuals or an excess narrowing response to inhaled agents

as compared to that which would occur in nonaffected individuals. A

component of the hyperresponsiveness occurs at the level of the airway

smooth muscle itself as demonstrated by hyperresponsiveness to direct

smooth-muscle–acting agents such as histamine or methacholine. In

many patients, the apparent hyperresponsiveness is due to indirect

activation of airway narrowing mechanisms as a result of stimulation

of inflammatory cells (which release direct bronchoconstrictors and

mediators that cause airway edema and/or mucus secretion) and/

or stimulation of sensory nerves that can act on the smooth muscle

or inflammatory cells. Agents and physical stimuli that elicit such

responses are discussed later.

The apparent increased responsiveness of the airways in asthma

may also have a structural etiology. In asthma, airway wall thickness

is associated with disease severity and duration. This thickening,

which may result from a combination of smooth-muscle hypertrophy

and hyperplasia, subepithelial collagen deposition, airway edema,

and mucosal inflammation, can result in a tendency for the airway to

narrow disproportionately in response to stimuli that elicit increased

airway muscle tension. A major therapeutic objective in asthma is to

decrease the degree of airway hyperresponsiveness.

2150 PART 7 Disorders of the Respiratory System

Inflammatory Cells While airway inflammation can be precipitated by acute exposure to inhalants, most asthmatics have evidence of

chronic inflammation in the airways. Most commonly, this inflammation is eosinophilic in nature. In some patients, neutrophilic inflammation may be predominant, especially in those with more severe asthma.

Mast cells are also more frequent. Many inflammatory cells are present

in an activated state, as will be discussed in the section on inflammation.

Airway Smooth Muscle Airway smooth muscle can contribute

to asthma in three ways. First, it can be hyperresponsive to stimuli, as

noted above. Second, hypertrophy and hyperplasia can lead to airway

wall thickening with consequences for hyperresponsiveness, as noted

above. Lastly, airway smooth-muscle cells can produce chemokines

and cytokines that promote airway inflammation and promote the

survival of inflammatory cells, particularly mast cells.

Subepithelial Collagen Deposition and Matrix Deposition

Thickening of the subepithelial basement membrane occurs as a result

of deposition of repair-type collagens and tenascin, periostin, fibronectin, and osteopontin primarily from myofibroblasts under the epithelium. The deposition of collagen and matrix stiffens the airway and can

result in exaggerated responses to increased circumferential tension

exerted by the smooth muscle. Such deposition can also narrow the

airway lumen and decrease its ability to relax and thus can contribute

to chronic airway obstruction.

Airway Epithelium Airway epithelium disruption takes the form

of separation of columnar cells from the basal cells. The damaged

epithelium is hypothesized to form a trophic unit with the underlying

mesenchyme. This unit elaborates multiple growth factors thought

to contribute to airway remodeling as well as multiple cytokines and

mediators that promote asthmatic airway inflammation.

Vascular Proliferation In a subset of asthmatics, there is a significant degree of angiogenesis thought to be secondary to elaboration of

angiogenic factors in the context of airway inflammation. Inflammatory mediators can result in leakage from postcapillary venules, which

can contribute to the acute and chronic edema of the airways.

Airway Edema Submucosal edema can be present as an acute

response in asthma and as a chronic contributor to airway wall thickening.

Epithelial Goblet Cell Metaplasia and Mucus Hypersecretion

Chronic inflammation can result in the appearance and proliferation

of mucus cells. Increased mucus production can reduce the effective

airway luminal area. Mucus plugs can obstruct medium-size airways

and can extend into the small airways.

Neuronal Proliferation Neurotrophins, which can lead to

neuronal proliferation, are elaborated by smooth-muscle cells, epithelial cells, and inflammatory cells. Neuronal inputs can regulate

smooth-muscle tone and mucus production, which may mediate acute

bronchospasm and potentially chronically increased airway tone.

■ AIRWAY INFLAMMATION (TYPE 2 AND NON–TYPE 2 INFLAMMATION)

Most asthma is accompanied by airway inflammation. In the past,

asthma had been divided into atopic and nonatopic (or intrinsic)

asthma. The former was identified as relating to allergen sensitivity

and exposure, with production of IgE, and occurring more commonly

in children. The latter was identified as occurring in individuals with

later onset asthma, with or without allergies, but frequently with eosinophilia. This paradigm is being superseded by a nosology that favors

consideration of whether asthma is associated with type 2 or non–type

2 inflammation. This approach to immunologic classification is driven

by a developing understanding of the underlying immune processes

and by the development of therapeutic approaches that target type 2

inflammation (see later sections on asthma therapy).

Type 2 Inflammation Type 2 inflammation is an immune

response involving the innate and adaptive arms of the immune system to promote barrier immunity on mucosal surfaces. It is called type

2 because it is associated with the type 2 subset of CD4+ T-helper cells,

which produce the cytokines interleukin (IL) 4, IL-5, and IL-13. As

shown in Fig. 287-3, these cytokines can have pleiotropic effects. IL-4

induces B-cell isotype switching to production of IgE. IgE, through

its binding to basophils and mast cells, results in environmental sensitivity to allergens as a result of cross-linking of IgE on the surface of

these mast cells and basophils. The products released from these cells

include type 2 cytokines as well as direct activators of smooth-muscle

constriction and edema. IL-5 has a critical role in regulating eosinophils. It controls formation, recruitment, and survival of these cells.

IL-13 induces airway hyperresponsiveness, mucus hypersecretion, and

goblet cell metaplasia. While allergen exposure in allergic individuals

can elicit a cascade of activation of type 2 inflammation, it is now

understood (see Fig. 287-3) that nonallergic stimuli can elicit production of type 2 cytokines, particularly due to stimulation of type 2

innate lymphoid cells (ILC2). These cells can produce IL-5 and IL-13.

ILC2s can be activated by epithelial cytokines known as alarmins,

which are produced in response to “nonallergic” epithelial exposures

such as irritants, pollutants, oxidative agents, fungi, or viruses. Thus,

these “nonallergic” stimuli can be associated with eosinophilia.

The development of anti–IL-5 drugs that dramatically reduce eosinophils has allowed us to determine that, in many asthmatics, eosinophils play a major role in asthma pathobiology. They may induce

hyperresponsiveness through release of oxidative radicals and major

basic protein, which can disrupt the epithelium. In addition, recent CT

imaging has suggested that mucus plugs, which may contain significant

amounts of eosinophil aggregates, may accumulate in the airways and

contribute to asthma severity.

Non–Type 2 Processes As shown in Fig. 287-2, multiple processes

can contribute to airway narrowing and apparent airway hyperresponsiveness. While type 2 inflammatory processes are most common,

non–type 2 processes can exist either in combination with type 2 inflammation or without type 2 inflammation. Neutrophilic inflammation, as

shown in Fig. 287-3, can also occur. This type of inflammation is more

commonly seen in severe asthma that has not responded to the common

anti-inflammatory therapies, such as corticosteroids, that usually suppress type 2 inflammation. In some cases, it may also be associated with

chronic infection, occasionally with atypical pathogens such as Mycoplasma, perhaps accounting for the response of some of these patients

to macrolide antibiotics. It is also commonly seen in reactive airway

dysfunction syndrome (see “Etiologic Mechanisms and Risk Factors”).

In a small subset of asthmatics, the pathologic changes seen in

Fig. 287-2 may occur without any evidence of tissue infiltration by

inflammatory cells. The etiology of such pauci-granulocytic asthma

is unclear.

■ MEDIATORS

Many chemical substances or signaling factors can contribute to the

pathobiologic picture of asthma. Some of them have been successfully

targeted in developing asthma therapies.

Cytokines As illustrated in Fig. 287-3, and as discussed above, IL-4,

IL-5, and IL-13 are the major cytokines associated with type 2 inflammation. They have all been targeted successfully in asthma therapies.

Thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 also play a

role in the signaling cascade and are being actively studied as targets

for treatment of asthma. IL-9 has been implicated as well. IL-6, IL-17,

tumor necrosis factor α (TNF-α), IL-1β, and IL-8 have been implicated

in non–type 2 inflammation.

Fatty Acid Mediators Proinflammatory mediators derived from

arachidonic acid include leukotrienes and prostaglandins. The cysteinyl leukotrienes (leukotrienes C4

, D4

, and E4

) are produced by eosinophils and mast cells. They are potent smooth-muscle constrictors.

They also stimulate mucus secretion, recruit allergic inflammatory

cells, cause microvascular leakage, modulate cytokine production, and

influence neural transmission. Cysteinyl leukotriene modifiers have

shown clinical benefit in asthma. The non-cysteinyl leukotriene, LTB4

,

is produced primarily from neutrophils but can also be synthesized

2151Asthma CHAPTER 287

by macrophages and epithelial cells. It is a potent neutrophil chemoattractant. Prostaglandins are for the most part proinflammatory.

Prostaglandin D2

 (PGD2

) is produced by mast cells. Receptors for PGD2

(CRTH2

 receptors) are present on TH2 cells, ILC2 cells, mast cells, eosinophils, macrophages, and epithelial cells, and the activation of these

receptors upregulates type 2 inflammation. Initial studies with drugs

blocking CRTH2

 have shown mild to moderate effectiveness in asthma.

There are several classes of fatty acid–derived mediators that are

responsible for the resolution of inflammation. These include the

resolvins and lipoxins. Several studies suggest that deficiencies in these

moieties may be responsible for the ongoing inflammation in asthma,

especially in severe asthma.

Nitric Oxide Nitric oxide is a potent vasodilator, and in vitro studies suggest that it can increase mucus production and smooth-muscle

proliferation. It is produced by epithelial cells, especially in response

to IL-13, and by stimulated inflammatory cells including eosinophils,

mast cells, and neutrophils. Its precise role in the asthmatic diathesis

is unclear. However, its production is increased in the airways in

the presence of asthmatic eosinophilic inflammation, and it can be

detected in exhaled breath.

Reactive Oxygen Species When allergens, pollutants, bacteria,

and viruses activate inflammatory cells in the airway, they induce respiratory bursts that release reactive oxygen species that result in oxidative

stress in the surrounding tissue. Increases in oxidative stress have been

shown to affect smooth-muscle contraction, increase mucus secretion,

produce airway hyperresponsiveness, and result in epithelial shedding.

Chemokines A variety of chemokines are secreted by the epithelium (as well as other inflammatory cells) and attract inflammatory

cells into the airways. Those of particular interest include eotaxin (an

eosinophil chemoattractant), TARC and MDC (which attract TH2

cells), and RANTES (which has pluripotent pro-phlogistic effects).

ETIOLOGIC MECHANISMS, RISK FACTORS,

TRIGGERS, AND COMPLICATING

COMORBIDITIES

As illustrated in Fig. 287-1, the development of asthma involves an

interplay between risk factors and exposures (see Table 287-1) and

genetic predisposition.

■ HERITABLE PREDISPOSITION

Asthma has a strong genetic predisposition. Family and twin studies

suggest a 25–80% degree of heritability. Genetic studies suggest complex

polygenic inheritance complicated by interaction with environmental

exposures. Further, epigenetic modifications related to environmental

exposures may also produce heritable patterns of asthma. Many of

the genes related to asthma have been associated with risk for atopy.

However, there appear to be genetic modifications that predispose to

asthma and its severity. Association studies have identified multiple

candidate genes. In many cases, these genes vary from population

Type 2

inflammation

Non-type 2

inflammation

CRTH2

CRTH2

CRTH2

GATA3

GATA3

IL-13

IL-4

KIT

IgE

SCF

IL-5

IL-6

IL-17

IL-8

IL-13

Antigens Irritants, pollutants, microbes, and viruses

IL-4, 5, and 13

IL-3, 4, 5, and 9

Histamine

PGD2

PGD2

PGD2

Leukotrienes

GM-CSF

IL-4

IgE

SCF

B cell

KIT

F

IL-3

KIT L

SCF CRTH2

IL-13

 9

s

CRTH2

GATA3

3

Mast cell Eosinophil

IL-8

Neutrophil

ILC2

IL-6

IL-17

CRTH2

GATA3

IL-4

PGD2

GATA3

Th17 cell

Th1 cell

Th2 cell

TSLP

IL-6

IFN-γ

TNF-α

BLT2

LTB4

Leukotriene B4

CXCL8

TGF-β

TGF-β IL-23

NO

IL-25

Contraction, hyperresponsiveness, smooth-muscle proliferation Smooth-muscle constriction, airway hyperresponsivneness

Mucus secretion

Epithelial shedding

ROS, MPO, Elastase

Mucus secretion

GM-CSF

CXCR2

IL-33

FIGURE 287-3 Inflammatory cells and mediators involved in type 2 and non–type 2 inflammation. Allergens and nonallergic stimuli can trigger activation of multiple

inflammatory cells and release of mediators that are responsible for recruiting and activating these cells. The mediators can affect airway smooth-muscle proliferation and

hyperresponsiveness and fibroblast proliferation and matrix deposition. BLT2, leukotriene B4

 receptor 2; CRTH2, chemoattractant receptor-homologous molecule (PGD2

receptor); CXCL8, CXC motif chemokine ligand 8; CXCR2, CXC chemokine receptor 2; GATA3, GATA Binding Protein 3; GM-CSF, granulocyte-macrophage colony-stimulating

factor; IFN-γ, interferon gamma; ILC2, innate lymphoid type 2 cells; KIT, mast/stem cell growth factor receptor; LTB4, leukotriene B4; MPO, myeloperoxidase; NO, nitric oxide;

IL, interleukin; PGD2, prostaglandin D2; ROS, reactive oxygen species; SCF, stem cell factor; Th, T helper; TNF-α, tumor necrosis factor α; TGF-β, transforming growth factor

β; Th, T helper; TSLP, thymic stromal lymphopoietin.

2152 PART 7 Disorders of the Respiratory System

to population. The most consistently identified include ORMDL3/

GSDMB (in the 17q21 chromosomal region), ADAM33, DPP-10, TSLP,

IL-12, IL-33, ST2, HLA-DQB1, HLA-DQB2, TLR1, and IL6R. In many

cases, association studies have identified polymorphisms in noncoding

regions of the genome, suggesting that the majority of the currently

identified traits act as “enhancers” of biologic processes.

Genetic polymorphisms have also been associated with differential

responses to asthma therapies. Variants in the β-receptor (Arg16Gly in

ADRB2

), the glucocorticoid-induced transcript 1 gene, and genes in the

leukotriene synthesis and receptor pathways have been associated with

altered response to the pharmacologic agents acting at those receptors

or through those pathways.

While genetic variation plays a key role in asthma susceptibility,

it is important to understand that unraveling the complexities of the

genetic contribution to asthma remains elusive. To wit, only 2.5% of

asthma risk can be explained by the 31 single nucleotide polymorphisms that have been associated with asthma.

A significant proportion of the heritability of asthma relates to the

heritability of atopy. Atopy is the genetic tendency toward specific

IgE production in response to allergen exposure. Serum levels of

IgE correlate closely with the development of asthma. The National

Health and Nutrition Examination Survey (NHANES) III found that

half of asthma in patients aged 6–59 could be attributed to atopy with

evidence of allergic sensitization. The allergens most associated with

risk include house dust mites, indoor fungi, cockroaches, and indoor

animals.

■ EXPOSURES AND RISK FACTORS

Allergic Sensitization and Allergen Exposure Like asthma,

the development of allergic sensitization involves an interplay between

heritable susceptibility and allergen exposure. Allergen exposure during vulnerable developmental periods is believed to increase the risk of

development of allergic sensitization in those with a tendency toward

atopy. Allergic sensitization is increased in industrialized nations.

Recent research has suggested that varied microbiome exposure (exposure to bacteria and bacterial products) may influence the development

of atopy with decreased risk for atopy in those in rural environments.

Studies of the role of early allergen avoidance in reducing the risk

of developing asthma have produced contradictory results, possibly

related to the inability to eliminate all allergen exposure.

Tobacco Maternal smoking and secondhand smoke exposure are

associated with increased childhood asthma. Childhood secondhand

smoke exposure increased asthma risk twofold. Active smoking is

estimated to increase the incidence of asthma by up to fourfold in adolescents and young adults.

Air Pollution Early life exposure to pollution increases the risk of

development of asthma. Proximity to major roadways increases the risk

of early childhood asthma, thought to be attributed to levels of nitrogen dioxide exposure. Decreasing nitrogen dioxide exposure has been

found to decrease asthma incidence in children. Studies of exposure

to mixed pollutants suggest that most risk lies with carbon monoxide

and nitric dioxide, with marginal effects of sulfur dioxide. Indoor air

pollution from open fires and use of gas stoves has been associated

with increased risk of children developing asthma symptoms. Mechanistically, pollutants are thought to cause oxidative injury to the airways, producing airway inflammation and leading to remodeling and

increased risk of airway sensitization.

Infections Respiratory infections clearly can precipitate asthma

deteriorations. However, the degree to which respiratory infections indicate susceptibility to asthma, represent a causal factor, or in some cases

provide protection from asthma is unclear. Incidence and frequency of

human rhinovirus and respiratory syncytial virus infections in children

are associated with development of asthma, but whether they play a

causal role is unclear. Evidence of prior Mycoplasma pneumoniae infection has been associated with the development of asthma in Taiwanese

adults.

Occupational Exposures Occupational asthma is estimated to

account for 10–25% of adult-onset asthma. The occupations associated with the most cases in European Community Health Surveys

were nursing and cleaning. Two types of exposures are recognized: (1)

an immunologic stimulus (further subdivided into high-molecularweight [e.g., proteins, flour] and low-molecular-weight [e.g., formaldehyde, diisocyanate] stimuli based on whether they act as haptens or

can directly stimulate a response), and (2) an irritative stimulus. The

immunologic form is associated with a latency period between time of

exposure and development of symptoms. The irritative form, known

as reactive airway dysfunction syndrome (RADS), will be discussed

below. A combination of genetic predisposition (including atopy), timing, intensity of exposure, and co-exposure (e.g., smoking) influences

whether an individual will develop occupational asthma.

Diet There are suggestions that prenatal diet or vitamin deficiency may alter the risk of developing asthma. The evidence is not

yet definitive, but vitamin D insufficiency may increase asthma risk

in the progeny and supplementation may decrease such risk. Similarly, preliminary studies suggest that maternal supplementation with

vitamins C and E and zinc may decrease asthma in children. One study

suggested that maternal polyunsaturated fatty acid supplementation

may decrease childhood asthma risk. Observational studies have suggested that increased maternal sugar intake may increase childhood

asthma risk.

Obesity Multiple studies suggest that obesity may be a risk factor

for development of childhood and adult asthma. Adipokines and IL-6

have been thought to play a pathobiologic role. Some have argued that

the risk is overestimated, and a study from NHANES II found an association with dyspnea but not with airway obstruction.

Medications There are conflicting data regarding prenatal and

early childhood risk for asthma posed by certain classes of medications.

Use of H2

 blockers and proton pump inhibitors in pregnancy has been

associated with an increased risk of asthma in children (relative risk,

1.36–1.45); however, another study found a small risk for H2

 blockers

only. Conflicting data have been presented on the risk of perinatal acetaminophen and early childhood acetaminophen use. In a prospective

study, the use of acetaminophen was not associated with an increased

risk of exacerbations in young children with asthma, when compared

to ibuprofen.

Prenatal and Perinatal Risk Factors Preeclampsia and prematurity have been associated with increased risk of asthma in the

progeny. Babies born by cesarean section are at higher risk for asthma.

Those with neonatal jaundice are also at increased risk. Breast-feeding

reduced early wheezing but has a less clear effect on later incidence of

asthma.

Endogenous Developmental Risk Factors Asthma is more

prevalent among boys than girls, with the difference receding by age 20

and reversing (more prevalent among women) by age 40. Atopy is more

prevalent among boys in childhood, and they have reduced airway size

compared with girls. Both factors are thought to contribute to the sex

discrepancy. A subset of women develop asthma around menopause.

Such asthma tends to involve non–type 2 mechanisms. Pregnancy may

precipitate or aggravate asthma as well.

High-Concentration Irritant Exposure and RADS A solitary exposure to a high concentration of irritant agents that rapidly

(usually within hours) produces bronchospasm and bronchial hyperactivity is known as RADS. Causative agents include oxidizing and

reducing agents in an aerosol or high levels of particulates. The acute

pathology usually involves epithelial injury with neutrophilia. There

is little evidence of type 2 inflammation. This syndrome differs from

occupational asthma in that these patients have not become sensitized

to the provocative agent and can return to work in that environment

once they have recovered. However, the course of the disease may be

variable, with some series showing documented abnormalities and

persistent symptoms 10 years after exposure.