Part 1: Principles of Pulmonology

INTRODUCTION

The lung is composed of numerous cell types and structures, all of which develop and grow at different rates. Understanding lung growth and development is critical for understanding normal pulmonary physiology as well as the developmental basis for the pathogenesis of pediatric respiratory disease. The primary function of lungs is gas exchange. Gas exchange occurs through development of lung parenchyma into millions of alveoli in close coordination with capillaries. Disruption of this developmental pathway can result in congenital lung lesions or impaired lung function.

STAGES OF LUNG DEVELOPMENT

OVERVIEW

Lung development traditionally has been divided into 5 stages (Fig. 495-1). Phases of lung development may overlap to some extent, and the gestational age ranges associated with each stage are rough estimates. The primitive endoderm is the initial site of lung development. Primitive endoderm is formed during gastrulation, at 3 weeks after conception in humans. This process is accomplished with the help of many nuclear transcription factors that regulate gene expression in the embryo. Some of the identified factors include forkhead box A2 (FOXA2), GATA binding protein 6 (GATA6), sex-determining region Y related HMG box (SOX17), and SOX2. Aberrations in these transcription factors will result in disruption of lung formation.

EMBRYONIC STAGE (0–6 WEEKS OF GESTATION)

Foregut Patterning

The embryonic stage is the first stage of lung development and begins with the formation of 2 primary lung buds, small saccular outgrowths of the ventral wall of foregut endoderm. The endodermal cells of the ventral wall of the foregut express the transcription factor NK2-homeobox 1 (Nkx2-1), which marks the site of formation of the primary lung buds. Just anterior to the lung buds, the foregut tube begins to separate into 2 structures: a dorsal esophagus and a ventral trachea. Regulators of gene expression such as retinoic acid and signaling peptides such as fibroblast growth factor (FGF) 10 facilitate this process. Disruption of this process can result in agenesis or hypoplasia of the larynx, trachea, or lungs. Several pathways have been described that play roles in dorsoventral axis patterning of the foregut endoderm. SOX2 expression is increased dorsally in the future esophagus, whereas Nkx2-1 expression is increased ventrally in the future trachea. This patterning depends on bone morphogenic proteins, FGF and Wnt, signaling peptides secreted from surrounding mesenchyme. Defects in this process may also lead to disruption of development of the foregut.

Development of the Central Tracheobronchial Tree

Epithelial cells of the lung bud invade the mesoderm to form tubules. Repetitive lateral and terminal dichotomous branching forms the proximal structures of the tracheobronchial tree. The region proximal to the bifurcation of the primary lung buds becomes the trachea and larynx. Disruption of branching morphogenesis during the early weeks can result in tracheal or bronchial stenosis. By the fourth week of gestation, the trachea and esophagus separate into 2 distinct entities. A tracheoesophageal fistula can occur if this process is disrupted. Separation of the tracheal tube from the esophagus and branching morphogenesis are distinct developmental processes.

During the fifth week of gestation, a second round of branching occurs. This yields 3 secondary bronchial buds on the right and 2 on the left, which become the primary lobes of the right and left lungs. A third round of branching occurs by the sixth week of gestation and results in formation of the bronchopulmonary segments.

Role of Mesenchyme

During the embryonic stage, the mesenchyme is comprised of loosely arranged primitive cells that will eventually differentiate into future blood vessels, lymphatics, smooth muscles, cartilage, and connective tissue component. Mesenchymal cells interact with epithelial cells through autocrine and paracrine signaling pathways. This interaction is critical for lung morphogenesis and dependent on transcription factors associated with these pathways, such as the HOX family, and embryos lacking Hoxa5 have defects in tracheal cartilage.

PSEUDOGLANDULAR STAGE (6–16 WEEKS)

Branching Morphogenesis

The main developmental process that occurs during the pseudoglandular stage is the development of the conducting airways, which is accomplished through branching morphogenesis. Branching morphogenesis is characterized by an increased rate of cell proliferation leading to sequential branching of airway and vascular structures. This process is remarkably stereotyped and consists of 3 geometrically simply modes of branching in 3 different orders throughout the lung. Branching morphogenesis during the pseudoglandular stage leads to formation of terminal bronchioles with acinar buds arising at its distal branches. The pleuroperitoneal cavity closes early in the pseudoglandular period. Failure to close the pleural cavity, often accompanied by herniation of the abdominal contents into the chest (congenital diaphragmatic hernia [CDH]), leads to pulmonary hypoplasia. By the end of the pseudoglandular stage, development of the conducting airways is complete, and normally branching morphogenesis does not continue postnatally.

Several FGFs, including FGF10 and FGF7, are required for branching morphogenesis to occur. FGF signaling is regulated by transforming growth factor-β (TGF-β). TGF-β accumulates at branching points and prevents further branching. TGF-β also plays a role in left-right differentiation of lung and proximal-distal patterning.

Cell Differentiation

During branching morphogenesis, the endoderm begins to develop distinct cell lineages along its proximal-distal axis. The proximal progenitors give rise to airway neuroendocrine cells, secretory cells, and ciliated and mucosal cells, whereas the distal progenitors give rise to type 1 and type 2 alveolar epithelial cells. The bronchial tubules are lined by a pseudostratified columnar epithelium. Cytodifferentiation occurs with formation of tall columnar epithelium in proximal airways and cuboidal epithelium in distal acinar tubules and buds. The basement membrane, myofibroblasts, and cartilage also develop during this stage. Cartilage appears centrifugally, starting in the trachea and extending into segmental bronchi. Production of surfactant proteins (SP) B and C can be detected as early as 12 to 14 weeks of gestation, although functional levels of SPs are not achieved until later in gestation. β1 integrins and other cell adhesion molecules, including E-cadherin (cadherin 1), may be aberrantly expressed during this stage.

CANALICULAR STAGE (16–26 WEEKS)

The principal feature of the canalicular stage is formation of acinar structures in distal tubules with luminal expansion of the tubules. This stage also is characterized by formation of capillaries multiplying in the interstitial compartment formed by mesenchyme. Mesenchyme becomes thinner as the capillaries rapidly expand, forming the alveolar-capillary membrane, which is critical for gas exchange. During the canalicular stage, the nature of branching morphogenesis changes. The terminal bronchioles become narrower. The structures undergo further differentiation to form the pulmonary acinus or the respiratory unit, comprising respiratory bronchioles, the alveolar duct, and alveoli. Epithelial and endothelial cells lining the terminal bronchioles divide more rapidly, while there is a decline in proliferation of dividing interstitial cells (fibroblasts). Interstitial cells undergo apoptosis, contributing to mesenchymal involution. Basal lamina of mesenchyme and epithelium fuse and align adjacent to the endothelial layer of developing capillaries, forming the alveolar-capillary membrane.

SACCULAR STAGE (26–36 WEEKS)

During the saccular stage, true alveolar units are formed. The terminal clusters of acinar tubules dilate and expand into thin smooth-walled terminal alveolar saccules that can participate in gas exchange. There is a reduction in epithelial cell proliferation with an increase in cytodifferentiation. Differentiation of alveolar type 1 cells leads to enlargement of potential gas exchange surface. Elastin is deposited in areas where future interalveolar septa will form, subdividing the terminal alveolar saccules into true alveoli. During this stage, the lung contains relatively less elastin and collagen fibers and has little elastic recoil. This makes the immature lung susceptible to pneumothorax. The saccular stage represents the earliest time in lung development when true gas exchange can occur, and, therefore, it is the current limit of viability following preterm birth.

Mucus and ciliated cells have already appeared by the beginning of the saccular stage. Cartilage and submucosal glands extend as far down the airway as they do in the adult lung. The epithelial cells are capable of producing fetal lung fluid. The fluid is associated with active transport of chloride ions. Experimentally increasing fluid pressure has been shown to enhance the rate of branching, thus emphasizing its morphogenetic role.

Maturation of type 2 alveolar cells continues with an increase in number and size of lamellar bodies. There is an increase in the amount of tubular myelin in terminal air spaces, the secretory form of pulmonary surfactant. The concentration of surfactant is still low, and the phospholipid composition differs from that at term. For this reason, preterm infants born during this stage of development will often develop respiratory distress of the newborn.

ALVEOLAR STAGE (36 WEEKS TO ADULTHOOD)

The formation of functional units of gas exchange occurs during the alveolar stage. This is accomplished by the secondary formation of septae, which partitions saccules into alveolar ducts and alveoli and facilitates formation of the alveolar-capillary membrane. The alveolar stage begins at 36 weeks after conception and continues postnatally. The bulk of alveolar formation occurs in the first 2 years of life, with the remainder being completed at approximately 8 to 10 years. However, recent data indicate that alveoli can continue to be formed even in adulthood.

At the end of the saccular stage, the walls of the saccules (primary septae) are tightly associated with the vascular plexus. The extracellular matrix is rich in elastin and other mesenchymal cell types including precursors of myofibroblasts. During alveolarization, the primary septae are subdivided by ingrowths of ridges or crests, forming secondary septae. Myofibroblast precursors and endothelial cells migrate into these crests. A scaffold of matrix protein is deposited in secondary septae with increased elastin at its tip. Several signaling factors have been described that facilitate secondary septation. The differentiation of myofibroblasts and production of elastin are regulated by platelet-derived growth factor-α (PDGF-α); ephrin B2, fibrillin-1, FGF, and retinoic acid also play critical roles. In the absence of PDGF-α, myofibroblasts fail to multiply and migrate into primary septae, causing emphysema. Several transcription factors necessary for early lung development are also important for cytodifferentiation and maturation of lung. For instance, heterozygous loss of FOXF1 has been associated with impaired formation of lung buds from foregut endoderm as well as defective pulmonary vascular development (alveolar capillary dysplasia).

PULMONARY VASCULAR DEVELOPMENT

Pulmonary vascular development occurs in a parallel process with development of the airways, interstitium, and alveoli. Both vasculogenesis (in situ differentiation and growth of blood vessels from mesodermal-derived hemangioblasts) and angiogenesis (new blood vessels sprout from existing blood vessels) contribute to formation of the pulmonary vascular system. By the end of the embryonic stage, the primitive pulmonary vascular bed is created through vascular connections with the right and left atria. Pulmonary arteries arise from the sixth pair of aortic arches and grow into the surrounding mesoderm. They accompany the developing airways, segmenting with each bronchial subdivision, and connect to the vascular plexus forming in the pulmonary mesenchyme. The pulmonary veins develop as an outgrowth of the left atrium, which divides several times before connecting to the pulmonary vascular bed. Lymphatic vessels originate from the cardinal veins.

Vascular growth is regulated primarily by vascular endothelial growth factor (VEGF), which is synthesized in the epithelium and secreted into the mesenchyme, Vascular development is also dependent on interactions with surrounding extracellular matrix components. During the saccular stage, a distinctive array of vascular supply forms the capillary network surrounding each terminal saccule, providing an ever-expanding gas exchange area that is completed in adolescence. Signaling via sonic hedgehog, VEGF-A, FOXF1, notch, ephrins, and PDGF plays an important role in pulmonary vascular development. VEGF-A secreted by respiratory epithelium stimulates pulmonary vasculogenesis via paracrine signaling to receptors that are expressed by progenitor cells in the mesenchyme. PDGF-α, another growth factor secreted by the respiratory epithelium, influences proliferation and differentiation of myofibroblasts in the developing lung.

DISRUPTION OF LUNG GROWTH AND REPAIR

As discussed earlier, numerous growth factors and signaling molecules play key roles in the development of different parts of the lung, and disruption or dysregulation of these molecular pathways can result in congenital lung abnormalities (Table 495-1). Preterm birth and postnatal exposures can also affect subsequent lung development.

Extremely premature infants are born between 24 and 28 weeks of gestation, which corresponds to the beginning of the saccular stage. Disruption of lung development at this stage results in impaired alveolar formation and alveolar simplification. These impairments are reflected in a lower diffusion capacity to carbon monoxide. The consequences of prematurity and bronchopulmonary dysplasia on lung development and lung function are discussed further in Chapter 62.

A major prenatal factor that affects lung development is maternal smoking during pregnancy. In utero nicotine impairs alveolar formation, resulting in a permanent reduction in number of alveoli. Maternal smoking during pregnancy also is associated with decreased airway caliber and increased bronchial hyperresponsiveness.

As discussed earlier, lung growth and development continue postnatally, and this process can be disrupted by events in early life. Children who have had lobectomies due to congenital lung abnormalities (eg, congenital lobar emphysema) have normal lung volumes, suggesting that compensatory growth can occur postnatally. However, forced expiratory flows are reduced, indicating that alveolar and airway growth are disproportionate. These findings are in contrast to those in adults who have undergone lobectomy, where both lung volumes and function are permanently reduced. In CDH, abdominal contents can occupy the thoracic space through the hernia, resulting in pulmonary hypoplasia. Studies of children with repaired CDH have found decreased expiratory flows, gas trapping, and decreased diffusing capacity of the lungs for carbon monoxide. The results from studies of CDH and infants who have undergone lobectomies suggest that compensatory lung growth can occur in response to early disruption of normal lung development, but whereas lobectomy, which occurs postnatally, can be associated with “catch-up” alveolar growth, the in utero effects of CDH result in increased volume due to overdistension, rather than through increased alveolar growth.

LUNG DEVELOPMENT IN CHILDHOOD

As somatic growth occurs throughout childhood and adolescence, the lungs also grow to keep up with increased demands on gas exchange. Data from the Global Lung Initiative (GLI), a project that collected spirometry data from subjects age 3 to 95 years, show that forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) increase throughout childhood and achieve a plateau at 20 to 25 years. Thereafter, there is a decline in FEV₁ and FVC. The GLI has also provided insight into the relationship between airway growth and alveolar growth. As noted earlier, formation of the conducting airways occurs well before alveolar development, and new airway branching does not occur, only an increase in size of existing branches. In contrast, the bulk of alveolar growth occurs postnatally. These differences in lung growth are reflected in the change in FEV₁/FVC with age, since FEV₁ is a measure of airway function, whereas FVC is related to lung volume. In infancy and young childhood, the FEV₁/FVC ratio is high, reflecting a relatively higher proportion of total cross-sectional airway area compared to lung volume. As alveolar growth increases, the FEV₁/FVC ratio falls with age. However, the ratio increases during adolescence due to the fact that lung volume growth no longer outpaces airway caliber growth. In adulthood and older age, loss of alveolar attachments can lead to a reduced FEV₁/FVC ratio. Airway and lung parenchymal growth can also progress unequally, a phenomenon known as dysanapsis. Dysanapsis has been invoked to explain the variation in expiratory flows in older children and adults and between male and female subjects.

SUGGESTED READINGS

BASIC RESPIRATORY PHYSIOLOGY

The principles of respiratory physiology underlie the understanding of pulmonary function testing. Assumptions about the respiratory system being measured are implicit in all measurements of lung function but are often poorly understood by the clinicians charged with interpreting the tests and using the results for patient care. This chapter will review simple principles of respiratory physiology with an emphasis on providing a basic understanding of how the respiratory system works and what physiologic principles and assumptions underlie common measurements of lung function used in children. This chapter will not provide a comprehensive explanation of the intricacies of respiratory physiology, nor will it provide a “how to” of lung function testing. The interested reader is directed to the references listed under Suggested Readings.

SUBDIVISIONS OF LUNG VOLUMES

An understanding of the terminology for the different volumes and capacities of the respiratory system associated with different phases of respiration is fundamental to understanding pulmonary function. Volumes are measured and capacities are inferred from volumes. Figure 496-1 shows a schematic representation of the basic subdivision of lung volume. Tidal volume is the volume breathed in and out with each breath. By definition, the amount of air left in the lungs at the end of a tidal breath is the functional residual capacity (FRC). When an adult or older child is breathing quietly at rest, FRC may equal the elastic equilibrium volume (EEV) of the respiratory system (see the following section on static mechanical properties). However, in infants or children breathing actively, FRC may be above or below EEV. The basic principle is that the amount of air left in the lung at the end of a tidal breath is FRC, and that this volume may vary from moment to moment and from breath to breath in infants and young children, introducing instability and variability into measurements of lung function. Total lung capacity is the total amount of air that the lung can contain at the end of a maximal inspiration, and vital capacity is the total amount that can be breathed out, either slowly or with a maximal forced expiration; in that latter case, the term forced vital capacity (FVC) is used. The volume of air left over is the residual volume (RV) that cannot be expelled from the lungs.

STATIC MECHANICAL PROPERTIES OF THE RESPIRATORY SYSTEM

The respiratory system consists of a number of components including, from the outside moving inward, the chest wall consisting of skin and subcutaneous tissue; the rib cage, diaphragm, and intercostal muscles; the pleural membranes and virtual pleural space; the pulmonary parenchyma, with pulmonary capillaries and interstitial tissue; airspaces and airways (ie, alveoli, alveolar ducts, bronchioles, bronchi, and trachea); and the upper (supraglottic) airway. The fundamental static mechanical property of the respiratory system is elastic recoil. When the respiratory system is stretched (inflated), elastic energy is stored in the tissues, and provides the elastic recoil pressure. The chest wall and the lungs are the main components to consider. As shown in Figure 496-2, the combination of the recoil properties of both combined, coupled via the pleura, determines the recoil properties of the respiratory system. The elastic recoil pressure of the lung will always be positive and will try to collapse the lung. The chest wall has a volume at which the elastic recoil pressure is zero; deviations from this volume will exert a recoil pressure to return the chest wall to its neutral position. The volume at which the inward recoil pressure of the lungs is balanced by an outward recoil pressure of the chest wall is the EEV, and total recoil pressure is zero. Given the tendency for the lungs to collapse, a volume may be reached below which the recoil pressure of the respiratory system is unable to keep airways open. This is known as the closing volume (CV). As can be seen from Figure 496-2, there is not a linear relationship between elastic recoil pressure (Pel) and lung volume (V). Elastance or stiffness of the respiratory system (Ers) is calculated by dividing Pel by V:

Compliance or the dispensability of the respiratory system (Crs) is the reciprocal or Ers:

As these variables are calculated in the absence of gas movement, they are known as static elastance and static compliance. However, in real life, true static conditions are physiologically unrealizable, and the correct term is quasi-static Ers or Crs.

The functional implication of the static elastic properties of the respiratory system is that in situations in which the chest wall is less stiff, as is commonly seen in infants, or the lungs are stiffer, also seen in infants, EEV will occur at a lower volume and may occur lower than CV. The “softer” chest wall seen in infants, especially in those born prematurely, is manifest clinically in sternal retractions. If EEV falls below CV, the infant can compensate by increasing lung volume by expiratory braking using vocal cord adduction or activating inspiratory muscles during expiration. More extreme examples are manifested as “grunting” in infants with respiratory distress.

DYNAMIC MECHANICAL PROPERTIES OF THE RESPIRATORY SYSTEM

During breathing, lung volume increases and decreases and air moves in and out of the respiratory system, altering the mechanical properties of the respiratory system.

Airway Dynamics During Breathing

To breathe in, inspiratory muscles contract, the diaphragm descends, and the rib cage is expanded. This lowers the pressure in the pleural space to subatmospheric. The negative pressure is transmitted to the interstitial tissues and alveolar airspaces, and air flows into the lungs down the negative pressure gradient from the mouth and nose (atmospheric) to alveoli. As the pressure inside the airway tree is greater (less negative) than that in the surrounding interstitium, the airways are pulled open during inspiration (Fig. 496-3). At the end of inspiration, the inspiratory muscles are relaxed, and when breathing quietly, elastic recoil transmits a positive pressure to the pleural space and the interstitial tissue and alveolar airspaces, and air flows from the lungs down the pressure gradient to the airway opening (atmospheric pressure). As the pressure surrounding the airways is greater (more positive) than the pressure in the airway lumen, intrathoracic airways narrow during expiration (see Fig. 496-3).

During breathing, the respiratory system is less stiff or more compliant than under quasi-static conditions, due to pressure loss, which moves the tissues of the lungs (viscoelastic pressure) and by moving air through the airways (Newtonian or resistive pressure). The volume-pressure relationship of the respiratory system is different during inspiration and expiration, with more pressure being required per unit of volume change during inspiration than is recovered during expiration. The difference between the inspiratory and expiratory curves is known as hysteresis (Fig. 496-4), which is contributed to by viscoelastic pressure losses as well as by uneven gas distribution between lung units (ventilation inhomogeneity).

Singe-Compartment Equation of Motion

The simplest representation of the pressure required to move air in and out of the lungs can be described by a single compartment of motion, where pressure as a function of time (Pt) is described as a combination of elastic pressure (E.V), resistive pressure (R.V′), and inertive pressure (I.V″), where V′ is the first time derivative of volume or flow and V″ is the second time derivative of volume or acceleration:

A constant (k) is added to allow for pressure in the airspaces not being zero at the end of inspiration or expiration. This equation of motion is a linear, second-order differential equation, and while the respiratory system is not a linear system, it does provide a useful approximation that allows understanding of the forces that need to be overcome during breathing. During quiet breathing at low frequency, this is negligible and often ignored.

Time Constants

In physics, the ability of a system to respond to change is known as the time constant (τ) of the system, and it describes the time the system requires for a specified parameter to change by 1 – 1/e or approximately 63%. In the respiratory system, τ describes the time the lung (or part of it) takes to change volume by 63%. Figure 496-5 shows a schematic representation of the time constant of empting. During quiet breathing, τ is determined by R and E as follows:

Thus, an increase in R or decrease in E results in a longer time constant.

The main physiologic relevance of τ in the respiratory system is that it can also be applied to individual lung units and underlies the concept of ventilation inhomogeneity. Lung units with narrowed airway and increased resistance will fill and empty more slowly than will units with normal airways and, as shown schematically in Figure 496-6, resulting in an uneven distribution of air at the end of normal breathing cycles. This is referred to “ventilation inhomogeneity.”

Flow Limitation

Flow limitation is an extremely important physiologic principle that underpins all assessments of forced expiration. While it is a complex concept, it simply refers to the situation whereby more air is trying to be forced through the airways than can be accommodated. A simple analogy is a cold water tap. When turned on a little, a smooth stream of water flows from the tap. However, if turned on flat out (assuming there is adequate water pressure), the water stream will not be smooth but contain swirls and bubbles as the water pressure tries to push more water through the pipe than it can carry.

The maximal velocity that air can travel through the airway tree is proportional to the airway caliber (bigger airways can carry more flow), is inversely proportional to the compliance of the airway wall (stiffer, less compliant airways can carry more flow), and proportional to the gas density (less dense gases can travel faster). Airway caliber and airway wall compliance are dependent on lung volume and change with airway generation. The anatomic site where flow becomes limited is known as the choke point, and at high lung volumes in healthy lungs, it usually is located in large central airways and, as volume falls moves progressively to more peripheral airways. In diseased lungs, the choke point can literally be located in any airway generation where gas moves by bulk flow. If one peripheral segment becomes flow limited, adjacent segments can increase their contribution to expiratory flow and maintain the shape of the expiratory flow-volume curve unchanged. For this reason, forced expiratory volume in 1 second (FEV₁) does not only reflect large airways and forced expiratory flow (FEF_25-75) does not only reflect small airways. There is no reliable anatomically localizing information in the shape of an expiratory flow-volume curve. Every conceivable pattern can come about by abnormalities or combinations of abnormalities in numerous airway generations.

The other consequence of expiratory flow limitation is that the excess driving pressure, above what is required for the amount of flow that can be carried, must be dissipated. In the airways, it occurs as vibrations or fluttering of the airway wall on the mouth side (proximal) to the choke point. When loud enough, it can be heard as wheezing. Thus, the presence of wheeze, by definition, indicates the presence of expiratory flow limitation. However, the absence of wheeze does not exclude flow limitation, as any clinician who has dealt with a severe asthmatic with a “silent chest” knows, where so little air is being moved that no sounds are made.

PHYSIOLOGIC ASSUMPTIONS UNDERLYING PULMONARY FUNCTION TESTING

All measurements of lung function rely on underlying assumptions about the basic physiology involved; however, these assumptions are frequently overlooked or unknown by those using the results of the tests in the clinical management of patients. In this section, these assumptions will be discussed. This section is primarily written for pediatricians and pediatric trainees and will be too simple for physiologists, who can look elsewhere!

SPIROMETRY AND MEASUREMENTS OF FORCED EXPIRATION

The major assumption that underpins all measurements of forced expiration is that flow limitation has been reached and maintained during the forced expiration. Under such conditions, the expiratory flow achieved is determined by the mechanical properties of the airway, as discussed earlier, and is independent of the effort made by the patient. One of the main reasons why spirometry has been so useful clinically is that, under many circumstances, expiratory flow limitation is easier to achieve and maintain in the presence of lung disease. There are, of course, exceptions, and these will be discussed below.

Forced Expiration in Infants

Measurements of forced expiration can be made in sedated infants, lying supine and with the pressure driving expiration provided externally by rapidly inflating a jacket wrapped around the infant’s chest and abdominal wall. Forced expirations can be induced from the end of a normal tidal inspiration (the rapid thoracoabdominal compression test) or from a raised volume after the infant’s lungs have been inflated by an external gas source (the raised-volume rapid thoracoabdominal compression test). The outcome variables from the tests can be forced flows at a given volume (eg, the flow at the previous FRC level [V_max FRC]) or volumes exhaled in a given time (eg, FEV_0.5). However, critical to the validity of the test and of the outcome measure is achieving and maintaining flow limitation at the volume (or time) the outcome is measured. All measurements of forced expiration in infants should include a demonstration that flow limitation has been achieved; otherwise, the data remain suspect.

Reporting measures of forced expiration in a given time has become increasingly popular and is sometimes referred to as infant spirometry. One justification is that the outcome variables more closely resemble those from standard spirometry in older children and adults. Measurements that are based on FVC rely on fully inflating and then fully emptying the lung. Full inflation usually is standardized by inflating to an airway opening pressure (assumed to be the same as alveolar pressure, which it will not be unless a shutter is closed at full inflation and time is allowed for pressures to equilibrate) of 30 cm H₂O. However, ensuring full deflation is more challenging. The original protocols included holding the “squeeze” until a definite zero flow plateau was achieved. This is one detail that may not always be included in current measurement protocols, especially in automated commercially available equipment.

Despite potential limitations with deflating the lungs to RV, measurements of forced expiration in a given time, most commonly 0.5 or 0.75 seconds can still be valid, provided that flow limitation has been maintained for that long and that the lungs have not been emptied to RV by that time. This matter is more relevant to preschool-aged children and will be discussed in more detail in the following section.

Forced Expiration in Preschool-Aged Children

Young children have difficulty with forced expiration. In general, they can be induced to either breathe “long” or to breathe “fast,” but doing both together represents a challenge. Many “video incentives” included in modern spirometers do help with getting the child to produce an adequate forced expiration but do not help that much with ensuring a full inspiration. It is not possible to calculate an accurate FVC from forced expirations that follow an inadequate inspiration or that are terminated early. If FVC is unreliable, then other spirometry outcomes that rely on it are also invalid. Such variables include FEV₁/FVC, FEF_25-75, and flows at a fived proportion of FVC. However, provided that an adequate inspiration has been achieved and that flow limitation has been maintained long enough, volumes exhaled in a given time (eg, FEV_0.75) may be valid.

Young children empty their lungs more rapidly than do older children or adults. The FEV₁/FVC in healthy children age 5 to 7 years has been reported as being 0.94, meaning that the lungs have been essentially emptied (maybe down to RV) within 1 second. Thus FEV₁ has a systematically different physiologic meaning at different ages. It has been postulated, but not systematically studied or proved, that the equivalent of an adult FEV₁ is FEV_0.5 in infants and FEV_0.75 in preschool-aged children. The best indication that flow limitation has been achieved comes from overlying successive forced flow-volume curves, for which identical expiratory limbs indicate where expiratory flow limitation is likely to have been achieved (Fig. 496-7).

MEASUREMENTS OF RESISTANCE

Strictly speaking, measuring the resistance of the airways, lungs, or respiratory system is a misinformed concept. There is no single resistance, but commonly used measurements return a single number to represent resistance. Conceptually, measuring resistance means measuring the pressure required to move air at a given rate (flow) through an airway of given mechanical properties. This resistance is Newtonian resistance but, as discussed earlier, does not account for non-Newtonian (ie, where flow does not occur) resistive pressure losses. Most Newtonian resistance resides in the larger central airways (generations 3–6), with airways beyond generation 7 to 10 in healthy adults thought to contribute little to the overall resistance. This is despite resistance of a Newtonian fluid passing down a rigid tube, with fully developed laminar flow being inversely proportional to the fourth power of the airway radius (ie, Rα 1/r⁴) where smaller airways have higher resistance. However, in the lungs during breathing, 2 factors interfere with this relationship. First, fully developed laminar flow is probably never established, especially in children. Second, with each airway division, the cross-sectional area of the 2 daughter branches is greater than that of the parent airway. The cross-sectional area of the airway tree increases exponentially with increasing airway generations. The airway tree consists of airways in series (ie, following a single airway path through successive divisions and resistors in series sum by simple addition [Rt = R1 + R2 + Rn]) and airways in parallel (ie, airways of a given generation [eg, generation 15] and resistors in parallel sum by summing their inverses [1/Rt = 1/R1 + 1/R2 + 1/Rn]).

In a diseased lung, it is not possible to tell with certainty which part of the respiratory system is contributing to an increased resistance, and exactly the same increase can occur from abnormalities in large central airways, medium-sized airways, or small peripheral airways. Increases in non-Newtonian resistive losses (eg, from increased energy dissipation by lung parenchyma in interstitial lung disease) may also contribute to an increased overall resistance.

Plethysmography

When a whole-body plethysmograph is used to measure airway resistance (Raw), it is done by having the subject breathe in and out with a normal tidal volume at approximately 30 to 60 breaths per minute, initially through an open shutter and then with the shutter closed. Pressure is measured at the airway opening and in the plethysmograph (box pressure), and flow is measured at the airway opening when the shutter is open. To measure Raw, the pressure drop from the airway opening to the alveolus is divided by flow at the airway opening. However, alveolar pressure cannot be measured and needs to be inferred. When breathing against a closed shutter, no flow is assumed to occur and airway opening pressure is assumed to reflect alveolar pressure. When breathing through the open shutter, the flow is measured and Raw is calculated by relating data obtained in both closed and open shutter breathing. What is actually measured during standard plethysmography is specific resistance (sRaw) or the lung volume-corrected resistance and thoracic gas volume (TGV; ie, the total volume of gas inside the thorax during the closed shutter breathing). sRaw is calculated from the slope obtained by plotting flow at the airway opening (y-axis) against box pressure, representing the change in lung volume occurring during tidal breathing (x-axis). Raw is then calculated from sRaw and TGV (Raw = sRaw/TGV).

Physiologic assumptions that underlie the measurement of Raw include the following:

1. Airway opening pressure equals alveolar pressure when breathing against a closed shutter. This may be a reasonable assumption for healthy adults but becomes increasingly questionable in the presence of high airway resistance as seen with airway obstruction and in younger children. The cheeks and upper airway represent a proximal compliant compartment that can dissipate pressure. Cheek support during the maneuver can help decrease the effect of a cheek shunt but is unlikely to remove it entirely. Similarly, in airways that are more compliant than usual, as seen with tracheomalacia and in survivors of chronic neonatal lung disease, flow can occur along the airways, known as serial pendelluft. In these circumstances, the airway opening pressure will be systematically different from alveolar pressure, and the estimate of Raw will be incorrect.

2. No change in the respiratory system has occurred between the closed shutter and open shutter breathing maneuvers. While this assumption may be reasonable in adults and older children, younger children may not tolerate the closed shutter, at least not without a change in breathing pattern. For this reason, sRaw often is measured alone in young children, without actually measuring resistance or lung volume!

Forced Oscillations

The various applications of the forced oscillation technique measure respiratory mechanics by applying a forcing function to measure the impedance of the respiratory system (Zrs). Most commonly, this procedure is done by applying the forcing function at the airway opening (flow or pressure), and input impedance is calculated from the resultant output (pressure of flow) also measured at the airway opening. It is possible to apply the forcing function on the chest (pressure; eg, in a plethysmograph) and measure the resultant flow at the airway opening. Zrs measured in this way is known as transfer impedance. An advantage of measuring Zrs using forced oscillations is that it usually is done by imposing the forcing function on top of normal tidal breathing and does not require any special breathing maneuver from the subject.

Numerous different forcing functions have been used. Usually, 1 or more sinusoidal waves, generated by a loudspeaker or piston, are applied at the airway opening. However, square waves, which actually contain many sinusoids added together, are used in a variation of the technique known as impulse oscillometry. When using sinusoids, they vary in amplitude and phase to produce an optimized signal with a peak-to-peak pressure amplitude that is small compared to the pressure amplitudes involved in tidal breathing. With sinusoids, it is possible to construct a forcing function with more power directed to a particular frequency or frequencies and to vary them with the respiratory system being measured; most notably, different signals usually are used for children and adults. This optimization is not possible when using a square wave as a forcing function. The relationship between the applied pressure wave and the resulting flow is used to calculate Zrs. Pressure and flow as functions of time are converted to functions of frequency to allow Zrs to be calculated at each frequency included in the forcing function by Fourier transformation. Zrs is a complex function of pressure and flow that has components as “real” and “imaginary” parts or “magnitude” and “phase” relationships. More simply, Zrs consists of components representing the resistance (Rrs) and reactance (Xrs) of the respiratory system. Rrs represents the component of the applied pressure that is in phase with the resulting flow and contains both Newtonian and non-Newtonian pressure losses. Xrs represents the component of applied pressure that is in phase with volume change and consists of elastic and inertive pressure losses. These pressure changes are 180 degrees out of phase with each other; elastic pressure is negative, and inertive pressure is positive. At lower frequencies, elastance dominates and Xrs is negative. As frequency increases, the contribution from inertance increases and the frequency at which elastic and inertive pressure are equal and opposite and Xrs is equal to zero is known as the resonant frequency (Fig. 496-8). At frequencies around the resonant frequency, Rrs is dominated by Raw, whereas at lower frequencies, the contribution of non-Newtonian pressure dissipation in the pulmonary tissues increases. Thus, the physiologic meaning of Rrs varies with frequency. In addition, resonant frequency varies with age, being systematically higher in children, young children, and infants. For this reason, the optimal frequencies used to measure Zrs need to vary with age. Again, this is not possible with a square wave forcing function.

Numerous physiologic assumptions underlie measurement of Zrs using forced oscillations, the most important of which is that the respiratory system is linear and behaves as a linear system. Fourier transformation is also a linear process that relies on the linearity of the system under investigation. Unfortunately, the respiratory system is far from linear and does not behave in a linear fashion. To minimize the effects of violating the linear assumption, it is important to keep the amplitude of the oscillations small in comparison with the amplitudes during tidal breathing, which is considerably easier with sinusoidal oscillations than with a square wave forcing function. The major problem with low-amplitude driving signals is signal-to-noise ratio, so the successful implementation of forced oscillatory techniques requires balancing the signal-to-noise ratio against violation of the linear system requirement. Again, this procedure is considerably easier with sinusoidal oscillations.

Rint

Interrupter resistance (Rint) is measured by closing a shutter at the airway opening during tidal breathing and relating the pressure change occurring after the shutter has closed to the flow occurring immediately before the closure (Fig. 496-9). When the shutter closes, flow is stopped and the pressure that was driving flow builds up behind the shutter and can be measured. In theory, this pressure, in the absence of flow, equals alveolar pressure and represents the pressure drop across the airways. However, in practice, this interrupter pressure includes both Newtonian and non-Newtonian pressures and, as such, is more a measure of Rrs than of Raw. Rint is a simple technique that has been used in children as it is quick to perform, does not require complicated expensive equipment, and does not require complicated breathing maneuvers. The major assumptions underlying Rint include the following:

1. The shutter closes instantaneously allowing the pressure change to be related to the flow occurring immediately prior to closure. An instantaneous shutter closure is physically unrealizable, and time is required for the shutter to close. During the time it takes the shutter to close, flow continues, resulting in an underestimation of the true flow. The software extrapolates both flow and pressure to the time of theoretical shutter closure, usually the midpoint of true closure. A closure time of longer that 10 milliseconds is considered to be too long and to introduce too much inaccuracy into the data.

2. Occlusion pressure instantly equals alveolar pressure. This assumption is physiologically unrealizable for several reasons. As flow continues during shutter closure, occlusion pressure will underestimate alveolar pressure. In addition, even when flow stops, the respiratory tissues will not stop moving immediately, resulting in a slower change in pressure (see Fig. 496-9) and an increase in pressure for occlusions made during expiratory or a decrease in pressure for occlusions made during inspiration, related to dissipation on non-Newtonian (viscoelastic) pressures. Finally, in the presence of uneven ventilation, gas will redistribute between lung units (pendelluft) following occlusion until gas distribution is even. This will also result in a slow pressure change that is indistinguishable from the viscoelastic pressure changes. Commercial software generally ignores these pressure changes and measures pressure at a given time after shutter closure is initiated.

MEASUREMENTS OF COMPLIANCE

Although methods for measuring compliance in infants and young children exist and have been used in the past, they have essentially fallen out of favor and will not be described here. Quasi-static compliance can be measured using single or multiple occlusion techniques, and dynamic compliance can be measured by using multiple linear regression fit to the single compartment of motion described earlier.

MEASUREMENTS OF LUNG VOLUME

Measurement of lung volume can be useful clinically and can help interpret other measurements of lung function. Respiratory mechanics are volume-dependent, which means that the volume at which they are measured will influence the results. In addition, as can be seen from Figure 496-2, there may be a number of circumstances in which increasing lung volume renders breathing easier. However, with severe obstructive disease, the lungs may be hyperinflated to such a degree to make the respiratory system so stiff that breathing becomes difficult. Understanding what the lung volumes are can influence treatment. There are 2 main ways to measure lung volumes: in a whole-body plethysmograph or using a gas dilution technique. The major difference between the 2 techniques is that plethysmograph will measure all gas in the thoracic whereas gas dilution will measure only gas in relatively free communication with the airway opening. In health, the 2 measurements are likely to be similar, but in the presence of airway obstruction and ventilation inhomogeneity, gas dilution volumes are likely to be less than those measured plethysmographically. Lung volumes can also be estimated radiologically, but as this is rarely used in children, it will not be discussed further here.

Plethysmography

As has been outlined earlier, absolute lung volume can be measured in a whole-body plethysmograph and is known as thoracic gas volume (TGV). This technique relates the change in airway pressure estimated from airway opening pressure (which is assumed to equal alveolar pressure in the absence of flow), to changes in lung volume, estimated from changes in box pressure (which is assumed to equal changes in box volume), when the subject makes breathing efforts against the closed shutter. As the shutter is closed at the end of a normal tidal expiration, the volume measured is FRC and is variably known as TGV at FRC or FRC measured in a plethysmograph (FRCpleth).

As discussed earlier, plethysmography can be difficult for young children, and plethysmographic lung volumes are rarely attempted in preschool-aged children. The same assumptions that underlie plethysmographic measurements of resistance underlie the measurements of lung volume. Plethysmographic lung volumes include all gas in the thorax whether it is in communication with the airway opening or not. However, gas in the stomach and bowel does not influence the lung volume measured in a plethysmograph.

Gas Dilution

The principle underlying measurement of lung volume by gas dilution is that if an inert gas that does not exist in the lung (eg, helium) of known concentration from a container of known volume is breathed until a new equilibrium concentration has been reached, the unknown volume that has been added to the system (ie, lung volume) can be calculated from the change in gas concentration. The inert gas is traditionally switched into the circuit at the end of a normal tidal expiration, and the volume measured is FRC.

MEASUREMENTS OF GAS MIXING

Measurement of the evenness of ventilation distribution, annoyingly called ventilation inhomogeneity, was initially popular in the middle of the last century but fell out of favor. In adults, both multiple-breath and single-breath protocols were used but were limited by the speed and accuracy of gas analyzers and the frustrations inherent with mass spectrometers. Recent advances have seen a resurgence of gas-mixing techniques especially in children with cystic fibrosis. The single-breath technique is difficult in young children and thus will not be discussed here.

Multiple Breath Gas Washout

The most popular and commonly used technique in children is the multiple breath washout (MBW), and the primary outcome is the lung clearance index (LCI), which measures the number of times the lung volume must be changed (lung volume turnovers) to wash an inert gas such as sulfur hexafluoride (SF₆) from the lungs. Two incarnations of the technique have been in recent use, the SF₆MBW and the nitrogen washout. The principles of the 2 are exactly the same, but the application is different. With the SF₆MBW, the inert gas SF₆ is switched into the breathing circuit and the subject breathes a gas mixture containing 4% to 5% SF₆ in air until the end expiratory concentration is stable (ie, SF₆ has equilibrated throughout the lung). This is known as the wash-in phase. Once this equilibrium has been reached, the SF₆ is switched off during expiration. The subject now breathes SF₆-free gas until the end-expiratory concentration has reached 1/40th of the wash-in concentration (an arbitrary concentration, the wash-out phase). Cumulative expired gas volume is measured, and FRC is calculated by gas dilution. The number of FRCs (lung volume turnovers) required to reduce the end-expiratory SF₆ concentration to 1/40th is the LCI. This process is repeated until 3 consistent values of FRC and LCI have been obtained.

With the nitrogen washout, 100% oxygen is used to wash the nitrogen from lung. No wash-in phase is required for the first maneuver as nitrogen is already in equilibrium within the lung. The wash-out phase is terminated when the end-expiratory nitrogen falls to 1/40th of the starting concentration. For the second and third repeats, nitrogen has to be washed back into the lung by breathing room air.

It is also possible to attempt to locate the site of inhomogeneity by measuring the so-called “phase 3 slope” and using it to calculate an index of inhomogeneity related to conducting airways (Scond) or to the acinar zone of the lung (Sacin). However, these indices are difficult to calculate and have not been validated in young children and will not be discussed here.

The major physiologic assumptions underlying these multiple breath wash out techniques are that: (1) the inert gas does not “interact” with the lung (ie, is not absorbed, metabolized, or derived from the lung); (2) breathing the gas mixture does not alter the respiratory system that is being measured; and (3) the dilution in gas concentration accurately measures the lung volume turnovers. For the SF₆MBW, these assumptions are fairly well satisfied. SF₆ is indeed inert in the lungs and does not alter the breathing pattern. However, it is an extremely dense gas and, in theory, could be difficult to clear and could displace oxygen from areas of the lung that are in poor communication with the airway opening. Also SF₆ is a greenhouse gas that is not registered for human use in many countries. It is also very expensive, and large volumes are required for MBW beyond infancy. These limitations are likely to impose practical imitations to the use of SF₆MBW in the future.

Using 100% oxygen for nitrogen washout has more theoretical and practical problems. Breathing 100% oxygen does alter the breathing pattern of infants and is not suitable for use in this age range. There are no data on whether 100% oxygen also alters the breathing pattern of preschool-aged children. Nitrogen, the gas being washed out, is not inert in the lungs, and tissue production of nitrogen does add to the exhaled nitrogen concentration. How much error this could introduce into nitrogen washout estimates of ventilation distribution or FRC is unknown.

SUMMARY

An understanding of the basic physiologic principles governing how the respiratory system works is necessary for understanding measurements of lung function. Importantly, a knowledge of the assumptions underlying each test and when these are likely to be violated, are critical to the intelligent and accurate interpretation of lung function in children. The most important principles to grasp are: how the quasi-static mechanical properties of the respiratory system are altered during breathing and during lung function testing; under what circumstances the inherently nonlinear system can be measured by techniques that assume (and require) linearity; the concept of expiratory flow limitation and how failure to achieve and maintain this can invalidate spirometry; and lastly the limitations of nitrogen washout for measuring FRC and LCI.

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THE GLOBAL BURDEN OF LOWER RESPIRATORY TRACT INFECTION IN CHILDREN

Lower respiratory tract infection (LRTI), predominantly pneumonia, remains a major cause of morbidity and mortality in children globally despite a substantial decline in the incidence in the last decade. Advances in immunization, improvements in socioeconomic status, and effective human immunodeficiency virus (HIV) preventative and treatment strategies have been effective in reducing the burden of childhood LRTI and severe disease. However, recent estimates are that globally pneumonia still causes approximately 15% (or just under 1 million) of an estimated 6.3 million deaths annually in children younger than 5 years of age. Pneumonia is the main single cause of death in children outside the neonatal period. This burden is disproportionately high in Africa and Southeast Asia, where almost 90% of all global childhood deaths occur. Five high-burden countries, either in Africa (Nigeria and the Democratic Republic of Congo) or Southeast Asia (Pakistan, India, and China), account for more than 50% of childhood deaths globally. Respiratory syncytial virus (RSV) causes a high incidence of LRTI in children, approximately 34 million LRTI episodes or 22% of all LRTIs. Of these, 10% of episodes result in severe illness and hospitalization, and 99% of deaths occurr in low- and middle-income countries (LMICs). This proportion can be expected to increase as immunization against bacterial pathogens is strengthened as shown by recent case-control studies in children well vaccinated with 13-valent pneumococcal conjugate vaccine (PCV13), which reported RSV to be a predominant pathogen in children with LRTI. The incidence and severity of pneumonia are highest in the first year of life, especially in the first 6 months.

Several risk factors or exposures that may render a child vulnerable to LRTI or to severe disease may be especially prevalent in LMICs. They include smoke exposure, lack of breastfeeding, chronic underlying disease, prematurity or low birth weight, low socioeconomic status, crowded living conditions, malnutrition, or HIV. Pediatric HIV is largely confined to sub-Saharan Africa, where 90% of HIV-infected children reside; HIV infection is an important risk factor for pneumonia, severe disease, and mortality, with HIV-infected children having a 6-fold higher risk of developing severe pneumonia compared to uninfected children and a 6-fold higher risk of death. Furthermore, HIV-exposed but uninfected children, an increasingly important population as mother-to-child HIV transmission programs are strengthened, are emerging as another important vulnerable group who have a higher risk of developing pneumonia than do HIV-unexposed infants.

Lack of access to care and unavailability of effective management strategies are further factors that place children in LMICs more at risk of developing severe disease and of mortality from LRTI. Use of case management guidelines, with effective use of antibiotics, has been shown to substantially reduce pneumonia and all-cause mortality in children younger than 5 years. Community-based interventions including use of case management guidelines by community workers can reduce the mortality associated with pneumonia. Use of oxygen for hypoxic disease is an effective intervention and is lifesaving. However, globally, almost 40% of children with pneumonia are not taken to a healthcare facility. Furthermore, the availability and affordability of some essential drugs, including oxygen, in many LMICs are suboptimal.

Prevention of LRTI in children in LMIC settings may be hampered by limited coverage and affordability of effective preventive interventions. Vaccination is one of the most effective strategies for reducing the burden of childhood pneumonia, but coverage for childhood immunizations, especially the newer conjugate vaccines, is also suboptimal in several LMICs. Conjugate vaccines against Streptococcus pneumoniae (PCV) and Haemophilus influenzae type b (Hib) have substantially reduced the burden of childhood pneumonia in vaccinated children. Data from studies of the effectiveness of Hib conjugate vaccine in LMICs indicate a reduction of 18% in radiologic pneumonia, of 6% in severe pneumonia, and of 7% in pneumonia-associated mortality. Although PCV reduces the incidence of severe invasive pneumococcal disease and bacteremia, prevention of nonbacteremic pneumococcal pneumonia is almost 20-fold greater compared to that of bacteremic pneumonia. PCV has also led to a decline in hospitalization and death for adult pneumonia due to indirect protection through reduction in circulating pneumonia causing pneumococci serotypes. However, a South African study found that even with high coverage for the 13-valent PCV, the incidence of pneumonia remained high, especially in the first 6 months of life. PCV also may have considerable impact on mortality, reducing childhood mortality by approximately 15%. Early use of antiretroviral therapy and cotrimoxazole prophylaxis in HIV-infected infants also is effective for reducing the incidence and severity of pneumonia in children, but coverage is still suboptimal in areas of sub-Saharan Africa.

Importantly, the impact of childhood LRTI extends beyond acute disease in childhood, which is especially relevant as health systems are challenged to address the Sustainable Development Goals for 2030. Chronic sequelae from early childhood LRTI such as bronchiectasis are increasingly recognized as occurring in approximately 15% of children. In addition, early childhood LRTI has been associated with the development of chronic noncommunicable respiratory diseases, such as asthma or chronic obstructive pulmonary disease (COPD), into childhood and adulthood. Early RSV or rhinovirus-associated LRTI has been associated with the development of childhood asthma in high-income populations. Accumulating evidence from several cohort studies has shown that lung health is established early in life and that lung function follows a set trajectory into adulthood, implying that the roots of adult lung disease, such as COPD, lie in early exposures including childhood LRTI.

Effective strategies to prevent and manage LRTI in children must be urgently strengthened given the substantial burden of disease, impact on mortality, and accumulating evidence of the association with development of chronic lung disease and respiratory noncommunicable diseases. The strengthening and implementation of available effective interventions, such as making immunizations widely available and use of case management, have the potential to substantially reduce pneumonia burden and under-age-5 mortality. Further strategies to reduce risk factors, such as optimizing nutrition, promoting breastfeeding, preventing HIV transmission through mother-to-child prevention programs, and reducing exposure to biomass or cigarette smoke, must be strengthened. In addition, new strategies are needed to address the residual burden of LRTI once available vaccines have been well implemented and to develop effective interventions for pathogens for which current strategies are limited. Among these, RSV is the most prominent pathogen for which there is no effective specific treatment and for which current prevention strategies are limited to an expensive monoclonal antibody given monthly via intramuscular injection (when affordable) to specific groups of high-risk infants. The development of several new RSV vaccine candidates is promising. Immunization of women in late pregnancy may enable transplacental transfer of antibody and protection against RSV disease in infants in the first months of life; an alternate promising strategy is the development of an affordable long-acting monoclonal antibody against RSV in which a single dose will protect the infant throughout the RSV season. Greater understanding of innate and adaptive immunity to organisms causing LRTI is essential for development of better strategies for prevention and management.

MUCOSAL IMMUNOLOGY OF THE LOWER RESPIRATORY TRACT IN CHILDREN

A broad swath of microbes that include many diverse viruses and bacteria, can lead to pneumonia in children. All are pathobionts, microbes to which the respiratory tract is inevitably exposed but which usually do not cause severe disease. Such a panoply of microbes can likely never be fully covered by any armament of vaccines and antimicrobial agents, no matter how large or sophisticated. Furthermore, microbe-targeting approaches inevitably alter the dynamics of host-microbe interactions, so that drug-resistant organisms and nonvaccine strains (with sometimes troubling pathogenicity profiles such as a propensity to cause empyema) can sometimes emerge and predominate. What determines whether and when ubiquitous respiratory pathobionts cause severe infection depends as much or more on host susceptibility as on microbial virulence. A greater understanding is needed of the mucosal immune responses to respiratory pathobionts that are essential to preventing pneumonia, to reveal the failures in mucosal immunity that lead to severe infection and to guide the development of new strategies for fighting childhood pneumonia.

Innate immune protection of the lower respiratory tract is critical throughout the lifetime, and perhaps especially so in the youngest children who have little or no immunologic memory against respiratory pathobionts. The lower respiratory tract is lined by a heterogeneous population of epithelial cells. They coordinate to provide continuous innate immune defenses including the mechanical actions of the mucociliary escalator and the molecular actions of the surfactant proteins and mucus proteins with collecting and immunomodulating activities. Alveolar macrophages within the air spaces ingest and dispose of microbes that land in the lungs, if these microbes are not too numerous and do not have effective means of countering phagocytes. When such resident innate immunity is overcome, additional innate immune responses are initiated. Dendritic cells and alveolar macrophages are especially well situated and endowed with pattern-recognition receptors to recognize infection. Dendritic cells initiate adaptive immune responses, whereas alveolar macrophages have pivotal innate immunity roles that include acting as sentinel cells that alert other lung cells and immune cells of danger. A critical and rapid response to microbial recognition is the recruitment of neutrophils. These cells are exceptionally capable of innate immunity effector functions, with combined activities of phagocytosis to sequester microbes, degranulation to deliver antimicrobial proteins, a respiratory burst generating antimicrobial reactive oxygen species, and the elaboration of neutrophil extracellular traps consisting of chromatin and granule proteins that serve to ensnare and kill extracellular pathogens. Epithelial cells lining the respiratory surface can be stimulated by microbes or by macrophage cytokines to express their own distinct set of cytokines, a subset of which functions to further amplify local neutrophil recruitment and activation. Severe respiratory infections are frequently encountered in children with deleterious mutations in genes for innate immunity mediators such as primary ciliary dyskinesia (from mutations in any of > 30 different genes related to ciliary function), chronic granulomatous disease (from mutations in NADPH oxidase proteins), cystic fibrosis (from CFTR mutation), hyper–immunoglobulin E (IgE) syndrome (from mutations in STAT3), anhidrotic ectodermal dysplasia with immunodeficiency (from mutations in the NF-κB signaling proteins NEMO and IκBα), and more (such as from mutations in the NF-κB signaling proteins MyD88 or IRAK4), highlighting the importance of innate immune defense of the lung. These innate immune activities are compromised by prematurity, malnourishment, cigarette smoke exposures, and other risk factors for pneumonia. In animal models, purposefully stimulating these innate immunity pathways in the lung, such as by providing ligands that mimic infection in the air spaces, can provide profound but limited duration protection against a wide breadth of organisms capable of infecting the lower respiratory tract. Better ways to distinguish children with defects in innate immunity and new ways to amplify and direct innate immunity in the lungs are needed.

Because the microbes that cause pneumonia are ubiquitous, children develop immunologic memory against most or all respiratory pathobionts before reaching adolescence, resulting from repeated exposures and infections. Although microbes have important variation in key antigens such as capsular polysaccharides or surface glycoproteins as a means to subvert the most effective arms of adaptive immunity, some epitopes must be conserved across types or strains of that microbe. For influenza viruses, immune responses to such conserved epitopes, sometimes referred to as heterotypic immunity, in healthy young adults correlate inversely with the severity of naturally acquired or experimentally administered infections with viral strains to which the subjects had not previously been exposed. It is likely that the development of heterotypic immunity against each of the common respiratory pathobionts contributes substantially to the declining pneumonia susceptibility through childhood years. Such heterotypic immunity includes antibodies, CD4+ T cells, and CD8+ T cells, all of which can confer protection, with roles and efficacies of each varying across different types of respiratory microbes.

A more recently recognized component of immunologic memory resides within the mucosal tissue itself, resident memory T (T_RM) cells. In contrast with naïve T cells and other memory T cells (eg, central memory T cells and effector memory T cells), that recirculate among the blood, lymphatics, and secondary lymphoid organs, the T_RM cells are restricted to the organs where they differentiate. Lung T_RM cells cannot be collected by venipuncture or bronchoalveolar lavage, but must be retrieved after digestion of lung tissue to single-cell suspensions. T_RM cells are generated in animal lungs after primary influenza virus infection, and upon transfer to naïve hosts, the protection they provide against subsequent influenza infections is superior to that from other memory T cells. The relative contribution of T_RM cells to lung defense in the presence of integrated systemic immune responses is not yet well established. Human lungs contain abundant T_RM cells, both CD4+ T_RM cells and CD8+ T_RM cells. More T cells from the lung recognize influenza virus than do T cells from the blood, skin, or other tissues; little else is known about their antigen specificity, but it seems likely that lung T_RM cells may be generated by infections with many or all of the respiratory pathobionts causing childhood pneumonias. Infant lungs contain T cells with different characteristics from those in adult lungs, but they are not yet well understood; the dynamics of T cells in the lung is an area needing more attention. Even less is currently known about B cells in the lung tissue, but they also appear in the lungs and persist for extended periods of time after influenza infection of animals. Lung B cells are more likely than are systemic B cells to produce heterotypic antibodies, suggesting that this mucosal tissue may be especially empowered for heterotypic protection. While the fundamental biology and physiologic significance of lung resident memory has only begun to be elucidated, this is likely a major mediator of the protection against pneumonia that develops in childhood.

Physicians and scientists know so much yet so little about the underlying biology of childhood pneumonia. It is tragically common, yet it is actually an exceptional event and unusual outcome, because all children are frequently exposed to the microbes that cause pneumonia, but most such interactions do not result in disease. New insights into the mechanisms defending the lungs against respiratory pathobionts will provide insights into which children are susceptible and why and new opportunities to intervene in order to prevent or cure childhood pneumonia. Mucosal immunology is a pivotal determinant of the global burden of LRTI in children.

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INTRODUCTION

The primary function of the respiratory system is to provide adequate and adaptive gas exchange with a supply of oxygen to the body and removal of carbon dioxide. Illness can disturb this function by affecting 1 or more of the following: the central control of breathing, the respiratory pump comprising the chest cage and respiratory muscles, the small and large airways, and the pulmonary parenchyma. Nonrespiratory functions of the lung include production and regulation of surfactant, defense against infections, effective mucociliary clearance, participation in water and fluid balances, filtering of blood cells and emboli, and elimination of volatile substances.

Respiratory illness in children usually presents with clinical symptoms and signs that offer important diagnostic information. A clinical examination of the respiratory system should including inspection, palpation/percussion, and auscultation.

CHEST WALL CHANGES

The thoracic cage is vital for the efficient bellows action of the respiratory pump. Congenital or acquired malformations of the chest wall can, therefore, impact considerably on lung volume and function. Congenital anomalies involve the sternum with concavity (pectus excavatum, see Fig. 498-1) or protrusion (pectus carinatum), the spine (eg, scoliosis, kyphosis), or the ribs themselves, sometimes in combination with an overall small thoracic cage (eg, Jeune syndrome or cerebrocostomandibular syndrome).

Acquired deformations of the chest wall can be secondary to neuromuscular weakness (eg, flattening of the chest in children with spinal muscular atrophy) or reflect underlying chronic respiratory diseases. The Harrison sulcus, for example, is a groove along the lower ribs corresponding to the attachment of the diaphragm that develops after prolonged increase in the work of breathing. A secondary pectus excavatum might develop after longstanding upper airway obstruction. Chronic hyperinflation (eg, in asthma or cystic fibrosis) can lead to a barrel chest with increase of the anterior-posterior diameter of the thorax.

RESPIRATORY RATE

The respiratory rate (breaths per minute) is essential for assessing the respiratory function of children. Normal ranges are dependent on age, weight, body temperature, wakefulness, and the activity level of the child. The respiratory rate is counted by observing chest and abdominal movements or by listening to breaths with a stethoscope. The respiratory rate can be calculated by counting breaths for 15 or 30 seconds and multiplying the resulting number by 4 or 2, respectively. Table 498-1 shows reference values for afebrile children from birth to 18 years of age.

In young febrile children, tachypnea, that is, a respiratory rate faster than normal, is an important predictive sign for pneumonia when the respiratory rate per minute exceeds 59 in those younger than 6 months of age, 52 in those between 6 and 11 months, and 42 in those between 1 and 2 years.

Abnormal breathing rates are not seen only in respiratory conditions. Cardiac disorders, metabolic acidosis, and psychogenic conditions also lead to tachypnea, whereas bradypnea (abnormally low rate) can indicate raised intracranial pressure.

Apart from the respiratory rate, it is important to recognize pathologic breathing patterns. The most relevant in pediatrics include the following:

• Apnea (complete cessation of breathing due to central or obstructive causes)

• Hypopnea (shallow breathing)

• Hypo- and hyperventilation (decreased or increased alveolar ventilation leading to hypercapnea or hypocapnea, respectively)

• Kussmaul breathing (deep, regular sighing respiration due to metabolic acidosis)

• Cheyne-Stokes breathing (repetitive pattern of increasing then decreasing tidal volumes followed by an apnea, indicative for brain injury)

• Periodic breathing (clusters of breaths interrupted by apneas lasting as long as 10 seconds, a common finding in neonates and preterm babies)

DYSPNEA AND WORK OF BREATHING

Dyspnea is the subjective feeling of breathlessness and can be accompanied by increased work of breathing. Reasons for increased work of breathing in respiratory illness include not only increased resistance to air flow (eg, in airway obstruction) or decreased pulmonary compliance (eg, in atelectasis and restrictive lung diseases, or marked air trapping), but also restrictive chest wall conditions (eg, in severe thoracic scoliosis).

Objective signs of increased respiratory effort are a tracheal tug (an indrawing seen at the sternal notch) and intercostal or subcostal recessions; the latter is readily seen in young children, as the chest wall is more compliant.

Children in respiratory distress also use the accessory respiratory muscles (sternocleidomastoid and scalene muscle, the pectoralis major, trapezius, and abdominal muscles). This effort can lead to “head bobbing” in infants, whereas older children tend to adopt a tripod position (resting of the arms or hands on the knees while bending forward). Nasal flaring also may be observed, especially in infants, and helps to decrease the resistance in the upper airways during inspiration.

Severe respiratory distress is characterized by seesaw-type movements of the thorax and abdomen; whereas normal inspiration causes the abdominal content to be pushed outward, seesaw breathing is characterized by an inward movement of the abdomen during inspiration.

Increased work of breathing with asymmetric chest excursion (with possible tracheal deviation from the midline) may occur in a pneumothorax, lung aplasia/hypoplasia, and paralysis of 1 hemidiaphragm.

DIGITAL CLUBBING

Digital clubbing is thickening of the connective tissue of the distal phalanges of toes and fingers with a flattening of the nail bed. While typically found in suppurative lung disorders such as cystic fibrosis, bronchiectasis, chronic empyema, and lung abscesses, digital clubbing also is associated with cardiac diseases, endocarditis, liver diseases, or inflammatory bowel disease. Rarely, clubbing can be idiopathic or familial.

Clubbing can be demonstrated by Schamroth’s sign: opposing the thumbs or index fingers nail-to-nail creates a diamond-shaped gap in healthy individuals that is obliterated in the presence of digital clubbing. Additionally, the hyponychial angle (angle between the skin fold from which the nail originates and the nail surface) is > 180° in digital clubbing, whereas healthy individuals have an angle of < 180° (Fig. 498-2).

Several hypotheses are discussed for the development of clubbing, and most involve vascular endothelial growth factor (VEGF). Local overproduction of VEGF and also systemically raised levels of VEGF are thought to lead to increased mesenchymal proliferation of the distal phalanges of fingers and toes. Activated megakaryocytes and thrombocytes may be local sources of VEGF. Megakaryocytes normally are filtered in the pulmonary capillary bed; however, in conditions with intrapulmonary shunts, they can end up in the capillary bed of the phalanges, where they are thought to release VEGF. Generalized hypoxemia also leads to increased levels of VEGF.

Occasionally, clubbing can be associated with increased periosteal inflammation called hypertrophic osteoarthropathy; typical signs are painful swelling of the wrists, knees, ankles, or elbows.

CYANOSIS

Cyanosis refers to bluish or purplish discoloration of skin and mucous membranes caused by an increased proportion of deoxygenated hemoglobin in the circulation. Deoxygenated hemoglobin has a blue hue, whereas oxyhemoglobin has a bright red color. Cyanosis becomes clinically detectable only after considerable hypoxemia: deoxygenated hemoglobin needs to exceed 3 g/dL in arterial blood and 4 to 6 g/dL in venous blood for cyanosis to become apparent. Additionally, the detection of cyanosis also is influenced by skin pigmentation, intensity of light, and the patient’s hemoglobin concentration. Clinical detection of cyanosis is quite unreliable. In polycythemia, for example, cyanosis will easily become apparent at arterial oxygen saturations below 85%, whereas in anemia, the saturation has to fall below 65%.

Central cyanosis indicates arterial hypoxemia and is always a serious sign. It is best seen by examining the mucous membranes, lips, and tongue. Peripheral cyanosis of fingers and toes can be present without arterial hypoxemia when oxygen extraction in the capillary bed is increased due to sluggish circulation, for example, with cold-induced vasoconstriction or decreased perfusion pressures.

A reliable method to detect hypoxemia in clinical practice is pulse oximetry, which is sometimes called the fifth vital sign in addition to the 4 classical vital signs of temperature, heart rate, respiratory rate, and blood pressure. Pulse oximetry, however, does have some clinical limitations. Measurements of oxygen saturation (SpO₂) rely on the absorption characteristics of oxyhemoglobin and deoxyhemoglobin and the systolic pulsatile wave. During hemodynamic shock and in situations with severely compromised circulation, pulse oximetry may yield inaccurate or failed readings. Pulse oximetry also is unreliable in carbon monoxide intoxication and sickle cell vaso-occlusive crises (false normal or high SpO₂), methemoglobinemia (both false low or high SpO₂), inherited dyshemoglobinemias, excessive movement, severe anemia, and ambient light interference (false low SpO₂ readings).

Fetal and adult hemoglobin do not differ in regard to their absorption characteristics, which renders pulse oximetry a reliable test in neonates.

PALPATION AND PERCUSSION

Palpation of the chest is used to feel for transmitted vibrations and to examine chest excursions during respiration. The air-filled lungs normally dampen all vibrations caused by phonation. In diseases with increased tissue density (eg, caused by pneumonic consolidation), vibrations originating from the vocal cords might become palpable, a phenomenon called vocal fremitus.

Palpation of the chest wall can also be used to detect loose secretions while the patient coughs or “huffs”—a forced expiration with maximal flow. Palpable secretions are found in patients with cystic fibrosis and can indicate a pulmonary exacerbation.

To assess chest excursion, the examiner’s hands are positioned on the lateral thorax with the thumbs meeting over the sternum. Normal expansion of the ribcage leads to a “bucket handle movement,” which causes the examiner’s thumbs to move away from the midline.

Palpation of the chest also includes assessment of the position of the trachea above the suprasternal notch, which should normally adopt a central position.

Percussion of the lungs plays an important role in detecting pneumothoraces (hyperresonant percussion) or consolidation and pleural effusion (dullness to percussion).

RESPIRATORY SOUNDS

Chest auscultation and assessment of respiratory sounds are central components of the chest examination. Still, the subjective nature of perceiving and describing respiratory sounds and the confusing nomenclature often limit the value of auscultation. New methods using recording of respiratory sounds and computerized sound analysis might help in the future in standardizing the nomenclature and training.

Respiratory sounds fall into the broad categories of normal or basic breath sounds and abnormal or adventitious breath sounds. Table 498-2 gives an overview of the types of respiratory sounds, their acoustic characteristics, and their clinical relevance.

Normal Respiratory Sounds

Normal (basic) lung sounds can be heard over the chest wall in healthy individuals. The term vesicular has been used previously as a descriptive term but is inaccurate because normal lung sounds do not originate from airflow in the alveolar (vesicular) space. Rather, they are generated in the central to segmental airways, while at the level of the alveolar space, gas movement is facilitated by silent diffusion.

Lung sounds should always be compared between corresponding lung areas to detect overall or localized change in breath sounds. Reduced breath sounds are caused by either diminished sound generation or decreased sound transmission. Diminished generation of breath sounds typically occurs in conditions with reduced respiratory drive (in uncooperative or sedated patients) or weakness of the respiratory muscles (either due to neuromuscular diseases or tiring during a severe asthma attack) and also in obesity or air trapping. During an acute asthma attack, sound production and transmission both are affected as the airway obstruction leads to reduced flow intensity (ie, sound production) as well as reduced sound transmission due to hyperinflation of the lungs.

Localized reduction of breath sounds is typical for atelectasis and consolidations in the lung parenchyma or for abnormalities of the pleural space (pneumothorax, empyema, or pleural effusion or fibrotic thickening of the pleura).

Tracheal sounds are best heard over the suprasternal notch and originate from the turbulent air flow in the central airways. In healthy individuals, they cannot be heard over the lateral chest wall due to dampening by the air-filled lungs. Consolidation of lung tissue surrounding a ventilated bronchus (eg, in pneumonia) facilitates better acoustic conductance, and typical sounds from the central airways (tracheal sounds) can be heard over the chest wall. This phenomenon is then called bronchial breathing and is the acoustic equivalent to an air bronchogram seen on a chest x-ray film.

Additionally, voice transmission also may be enhanced over areas with consolidated lung tissue. While in healthy individuals speech is perceived only as an incomprehensible mumbling when auscultating the chest wall, compressed and consolidated lung tissue improves transmission. This phenomenon is called bronchophony for normal speech or, in case of whispered sounds, pectoriloquy.

Abnormal Respiratory Sounds

Abnormal breath sounds, also known as adventitious sounds, comprise stridor, wheeze, crackles, squeaks, and pleural rub. They are classically divided into musical (continuous; ie, longer) and nonmusical (discontinuous; ie, shorter) sounds.

Stridor is a musical, high-pitched sound that is in most cases audible without a stethoscope. Inspiratory stridor indicates narrowing of the extrathoracic airways (larynx and proximal trachea) due to croup, laryngomalacia, or vocal cord lesions, whereas expiratory stridor is caused by intrathoracic pathologies such as tracheobronchomalacia or extrinsic compression of the trachea or main bronchi.

Biphasic stridor indicates fixed lesions and severe obstruction (eg, croup, paralysis of both vocal cords, laryngeal mass or web).

Wheeze and rhonchi are breath sounds indicating partial airway obstruction. The musical aspect is caused by the periodic sinusoidal waveform, which is less prominent in rhonchi, which have a harsher and more “snoring” character.

Wheeze is one of the most commonly reported symptoms; however, it can be difficult to recognize, especially for parents but also for health professionals. It is often confused with noisy breathing such as rattles or noisy whistling noises from the upper airways. This confusion can lead to considerable overdiagnosis of asthma, especially in preschool children, and consequent overtreatment.

Wheezes are mainly expiratory and signify partial airway obstruction in the second to seventh generations of airway branches. To overcome the increased resistance in the obstructed airways, maximal driving pressures are generated, which at one point fail to translate into higher air flow. Consequently, the resulting excess energy causes vibrations of the airway walls, which create the characteristic expiratory wheeze.

The absence of wheeze does not rule out airway obstruction. For example, wheeze may not be heard in shallow breathing, as the airflow intensity is not strong enough to cause the airways to oscillate. With deep breaths, the wheeze becomes audible. However, it is important to note that very forceful expirations can cause wheeze even in healthy individuals. On the other hand, airway obstruction may be so severe that the resulting decreased flow is insufficient to cause any sounds. This phenomenon is called a silent chest and is characteristic of severe, life-threatening asthma attacks or upper airway obstruction.

Wheeze caused by airway obstruction can be disseminated throughout the lung, as in asthma, or localized, for example due to mucous plugs, bronchomalacia, or a foreign body. Failure to recognize a localized wheeze can lead to an erroneous diagnosis of asthma. Consequently, this might result in unnecessary and especially ineffective treatment, and some patients might even be misdiagnosed with difficult-to-treat asthma.

Rhonchi are “snore-like” musical sounds of lower frequency than wheeze, and they disappear or change with coughing. They are generated by secretions in the airways and increased airway instability and are typical for asthma or bronchitis.

Crackles are nonmusical (discontinuous), mostly inspiratory sounds that are subcategorized into fine and course crackles. Fine crackles are most likely due to sudden opening of small airways during inspiration and are heard predominately late during inspiration. They are typical for pediatric interstitial lung diseases in which small airways collapse due to increased elastic recoil forces, edema, or inflammation, as, for example, in acute bronchiolitis.

Course crackles are louder with a lower frequency and occur during early to mid-inspiration but also in expiration. Course crackles are attributed to the movement of secretions in bronchi and bronchioles. Another mechanism is intermittent opening of airways as pockets of air pass through. Crackles can be present in bronchiectasis, cystic fibrosis, and the early stages of pneumonia (changing to more end-inspiratory fine crackles with further progression of the disease). Course crackles with long duration during inspiration can be a sign of congestive cardiac failure. Transmitted sounds from the pharynx in patients with swallowing difficulties and constant pooling of oral secretions can resemble course crackles. They are loud, have a snoring character, and disappear after suctioning or swallowing.

Some respiratory sounds are detectable without a stethoscope and are often referred to as noisy breathing. These sounds include snoring, rattling, snuffling, and grunting.

Snoring is predominately inspiratory and caused by obstruction in the oropharynx due to adenotonsillar hypertrophy, increased instability of the upper airways (neuromuscular diseases, obesity), or craniofacial disorders. Rattles, which can be confused with wheeze when taking a history, are lower and harsher than a wheeze, present in inspiration and expiration, and often associated with palpable chest wall vibrations. They most likely are caused by increased secretions in the central and extrathoracic airways moving alongside with the normal airflow and will clear with coughing. Snuffling refers to nasal sounds only.

Grunting is an important sign of respiratory distress in neonates and small infants. In older children, grunting is mainly associated with pneumonia. It is generated by short closure of the glottis during expiration, which creates the characteristic grunt. It is thought to generate a positive end-expiratory pressure preventing alveolar collapse.

COUGH

Cough is the most common symptom of respiratory disease and a frequent cause for seeking medical attention. In most cases, cough is harmless and self-limiting and a normal physiologic airway defense mechanism.

Coughing is a complex process; subepithelial mechanoreceptors in the airways are triggered by a multitude of stimuli (dust, chemicals, inflammation, cold temperature, or airway distortion), initiating the cough reflex. After a deep inspiration, the initial forceful expiration is briefly halted by glottic closure, and explosive exhalation follows opening of the vocal cords and closing of the nasopharynx with the soft palate.

Cerebral venous blood flow may be reduced by the high intrathoracic pressures generated by coughing, causing conjunctival hemorrhage, sparse petechial lesions on the face, and headaches. Paroxysmal coughing (bouts of coughing that cannot be stopped) is typical for pertussis infection or cystic fibrosis and sometimes causes vomiting. Additional complications such as air-leak or rib fractures are rare.

Cough, especially when chronic, poses a considerable health burden for patients and families as it affects quality of life and causes considerable parental concern. The definition of chronic cough still differs among national guidelines and varies between 4 and 8 weeks; however, recent data suggest that using a 4-week cut off for seeking advice improves the outcome of children with chronic cough. A structured diagnostic approach is shown in Figure 498-3.

Not all children with chronic cough need further investigations or therapy. Dry cough in otherwise healthy children is harmless in most cases, even if persisting for weeks, and “watchful waiting” might be appropriate. However, it is important to exclude any alarm signs or “pointers” in clinical history and examination. Additionally, it is often helpful to actually listen to the patient coughing either during the consultation or on a recording provided by the caregivers. Symptoms such as productive, wet cough, chest pain, hemoptysis, cyanosis, dyspnea at rest, and reduced activity levels equally point toward an underlying pathology. Cough associated with systemic signs such as failure to thrive or recurrent fever as well as a history of neurodevelopmental abnormalities, cardiac diseases, or immunodeficiency should also be investigated further. Respiratory diseases associated with chronic cough are summarized in Table 498-3.

HEMOPTYSIS

Hemoptysis is a rare symptom in children. Young children are more likely to swallow blood emanating from the lungs, and subsequent vomiting can be mistaken for gastrointestinal bleeding. Additionally, pulmonary hemorrhage does not always manifest with hemoptysis and may present with nonspecific symptoms such as cough, dyspnea, or wheeze or extrapulmonary symptoms of anemia.

The causes of pulmonary hemorrhage can be divided into focal (localized) bleeding and diffuse bleeding. Focal hemorrhage usually originates from hypertrophied bronchial arteries and can be due to cystic fibrosis or other causes of bronchiectasis, or tuberculosis. Rarer causes include hemangiomas, arteriovenous fistulas, or tumors.

Causes of diffuse hemorrhage are coagulation disorders or cardiac diseases that lead to pulmonary congestion (cardiac failure, left-sided obstruction, or left-to-right shunt), isolated pulmonary and systemic vasculitis (granulomatosis with polyangiitis, previously known as Wegener disease, Henoch-Schönlein purpura, Churg-Strauss syndrome, or microscopic polyangiitis), and diseases affecting the alveoli (in isolation [eg, idiopathic pulmonary hemosiderosis] or as part of a systemic disease [eg, Goodpasture syndrome]). Factitious and induced origins of hemoptysis also need consideration.

SUGGESTED READINGS

INTRODUCTION

Viewing the pediatric chest and lungs, whether by radiographic or bronchoscopic means, is often central in the clinical evaluation of children. Although the chest x-ray has a venerable place in history, radiologic technologies now available include computed tomography (CT), chest ultrasound, magnetic resonance imaging (MRI), and nuclear medicine. These technologies allow for better evaluation of the respiratory tract both anatomically and physiologically. The rigid bronchoscope has been available since the early part of the 20th century, but advances in fiberoptics now allow for safer bronchoscopic studies in pediatric patients. This section will deal with the various imaging techniques as well as with bronchoscopic evaluation of the airways.

RADIOLOGIC IMAGING

Children are often unwilling or unable to cooperate with the maneuvers required to produce high-quality imaging. Optimal studies are most often the product of experienced personnel who work with children in friendly surroundings with appropriate distraction, immobilization, analgesic, and sedation techniques.

Although plain film radiography remains the mainstay for chest imaging, cross-sectional techniques provide remarkably detailed images with versatile multiplanar and 3-dimensional reconstruction capabilities, sophisticated angiographic and Doppler techniques, and functional imaging even at the molecular level. It has become increasingly important to tailor the imaging studies to the specific clinical questions and concerns or limitations of individual patients. Imaging is no longer “one size fits all,” and close collaboration between radiology and clinical colleagues is not just desirable but essential in making the most appropriate choices and providing the best patient care.

CHEST RADIOGRAPHS AND CHEST FLUOROSCOPY

Plain radiographs with frontal and lateral views of the chest remain the mainstay of screening imaging of a child with a suspected chest abnormality. Digital imaging systems are now widely available. These radiographs usually include portions of the upper airway, larynx, trachea, and central bronchi as well as the mediastinal structures, heart, lungs, and bony and soft tissue chest wall. Evaluation of a chest radiograph should include an overview of the following:

1. Patient history and specific reason for the current radiograph

2. Quality of the study: patient name and positioning, inspiratory effort, motion, or presence of artifacts (eg, jewelry)

3. Overall pulmonary aeration and symmetry, position, and patency of the airway

4. Presence and location of any tubes, lines, catheters, and foreign bodies

5. Mediastinum: contour and position; location of the aortic arch; presence of any mass, displacement, or compression of the mediastinum and/or airways

6. Heart size and configuration

7. Central and peripheral pulmonary vessels and symmetry

8. Lung parenchyma: symmetry, vascularity, lucency, density, mass, volume loss, or air trapping

9. Pleura, diaphragm, and bony and soft tissues of the chest wall

10. Comparison with prior related imaging studies

When appropriate, 2 views of the chest increase diagnostic confidence, determining the location of a lesion more precisely and assessing its impact on adjacent structures such as the diaphragm or airway. Some lesions may look quite different on the frontal and lateral views, and others may be appreciated on only one view or the other. It is important to be aware that the normal thymus is very prominent in infancy (Fig. 499-1).

Radiographs of the neck, with both frontal and lateral projections, may be helpful in evaluating the upper airway for an intrinsic or extrinsic lesion.

Inspiratory and expiratory radiographs may be useful when evaluating for air trapping, as is seen with an aspirated foreign body or pneumothorax; they are limited to children who are able to hold their breath. Lateral decubitus views of the chest do not require cooperation for inspiratory and expiratory breath-holding and are more useful for infants and young children. In this circumstance, the dependent lung normally deflates while the opposite lung inflates; the expected deflation of the dependent lung is not seen when a foreign body is present. Decubitus views are also useful for evaluating suspected nonloculated pleural effusion, which layers dependently, or pneumothorax, which rises superiorly. However, decubitus views are of no value in assessing for pleural effusion if the lung in question is completely opacified, as any fluid present cannot be distinguished from the adjacent, completely opacified hemithorax (Fig. 499-2).

Fluoroscopy of the chest and airways is useful for dynamic evaluation of airway caliber and demonstration of expiratory airway collapse in tracheo- or bronchomalacia. Fluoroscopy is also helpful in evaluating for the presence of an airway foreign body when plain films are not definitive and for assessing motion of the diaphragm. Note that normal airway fluoroscopy does not definitively exclude the presence of an airway foreign body, and bronchoscopy may still be indicated depending on the clinical scenario.

A fluoroscopic contrast esophagram still has significant value, including evaluating swallowing function, aspiration of liquids or solid materials, the presence of a tracheoesophageal fistula, esophageal foreign body (Fig. 499-3) and other masses, and esophageal stricture or dysfunction. An experienced pediatric fluoroscopist and a well-distended esophagus (may require placement of a nasogastric tube for contrast injection) are important as subtle lesions are easily missed. An esophagram/upper gastrointestinal study has only an adjunctive role in evaluating gastroesophageal reflux, and it is not the preferred test to establish this diagnosis. With regard to extrinsic masses, especially vascular lesions, the esophagram has a limited role.

When a vascular ring is suspected as the cause for clinical symptoms, the best approach usually is to first obtain frontal and lateral chest radiographs. The presence of a right-sided aortic arch along with anterior bowing of the trachea on the lateral view is highly suggestive of the presence of a vascular ring. CT or MRI provides exquisite detail of the precise anatomy of these lesions. Although an esophagram may confirm the likelihood of a vascular ring, it usually does not sufficiently define the exact anatomy and is probably an unnecessary additional study.

ULTRASOUND

Ultrasound is especially useful to image the pleural space and thoracic wall, as the air-filled lungs reflect and distort the ultrasound beam (see Fig. 499-2C). Sonography can evaluate diaphragmatic motion, especially in children who cannot easily be transported. It is also useful in evaluating the amount and nature of pleural fluid collections. The septations and loculations of exudative effusions usually are better appreciated on ultrasound than on other cross-sectional imaging modalities such as CT (see Fig. 499-2). Ultrasound can also be used to guide percutaneous drainage of pleural fluid. Parenchymal consolidation and masses may also be visualized on ultrasound when there is not intervening aerated lung between the lesion and the chest wall. Because ultrasound is an inexpensive, portable, and versatile technology, its use has expanded, especially in cost- and equipment-constrained environments. Ultrasound imaging is of some use in evaluating chest masses, particularly lesions that abut the mediastinum or diaphragm. Ultrasound is particularly useful in differentiating normal thymus from a mediastinal mass or fluid collection and has the advantage of ready availability, lack of ionizing radiation, or need for sedation. Although the nature and anatomic extent of a mass may be better defined on CT or MRI, ultrasound and Doppler screening will often be helpful in determining whether a lesion is cystic, solid, or vascular, and direct further appropriate imaging. Pericardial effusion and complex cardiovascular anatomy and function are regularly imaged and thoroughly evaluated by ultrasound. Depending on local preference, ultrasound, CT, and/or MRI are used for image guidance of interventional procedures such as pericardial drainage and biopsies.

COMPUTED TOMOGRAPHY IMAGING

CT of the chest provides far more anatomic detail than plain radiographs. The use of chest CT has expanded to include the evaluation of trauma, unusual air collections or densities, nodules, masses and metastases, suspected pulmonary emboli, vascular and airway abnormalities, congenital lung anomalies, complicated or unusual infection, and suspected interstitial lung disease or bronchiectasis (Figs. 499-2, and 499-4,499-5,499-6,499-7). The image acquisition algorithm may vary depending on the clinical question; however, the images usually are reconstructed so that they can be optimally viewed for soft tissue (high-contrast resolution algorithm), lung parenchyma, or bone (higher spatial resolution algorithms).

Modern scanners and computer software now permit image reconstructions in planes other than the axial plane to which early scanners were limited. Coronal reconstructions are particularly helpful for lesions especially in the paramediastinal and paradiaphragmatic regions. Curved planar reconstructions, maximum- and minimum-intensity projections, 3-dimensional (3D) volume and surface reconstructions, and “virtual bronchoscopy” programs are available to display complex anatomy. These reconstruction options require thin section contiguous slices and usually are performed on an independent workstation. Subcentimeter volumetric imaging of the entire chest provides exquisite anatomic detail.

Modern ultrafast multidetector CT scanners can image the entire chest in 1 second or less such that sedation or a breath-hold is infrequently required and imaging is achieved via wrapping or other immobilization techniques. However, in some instances, such as cardiac gated CT angiography or high-resolution CT (HRCT), breath-hold imaging may be needed and can be obtained only in a cooperative patient or in an infant who is sedated or anesthetized. Techniques such as controlled ventilation or spirometry-controlled CT imaging provide excellent motion-free images of the chest at specific levels of inspiration and/or expiration (see Fig. 499-5). A controlled ventilation study relies on imaging during the brief period of apnea that can be induced in infants following a period of hyperventilation.

With the many options available for CT imaging, it is increasingly critical that there is clear communication among clinical and radiologic colleagues to provide an optimal study. Options include contiguous thicker slices (typically 3–5 mm, depending on patient size) or very thin or overlapping volumetric slices (as small as 0.6 mm with a 50% overlap) when detailed 2-dimensional or 3D anatomic reconstructions are needed. HRCT usually results in thin (1 mm) slices with gap intervals (5–10 mm) and might include both inspiratory and expiratory imaging to evaluate for lung parenchymal or interstitial disease, bronchiectasis, and expiratory air trapping (see Figs. 499-4 and 499-5).

Intravenous dynamic contrast enhancement may be necessary in children, particularly when evaluation of mediastinal or paramediastinal structures is required (see Fig. 499-6). Contrast enhancement is usually needed when evaluating vascular lesions, mediastinal masses, adenopathy, and selected infectious and neoplastic lesions that involve the chest. HRCT and most evaluations for pulmonary metastases are often obtained without intravenous (IV) contrast. CT angiography (CTA) is an important technology for detailed visualization of vascular structures.

The contrast used for most studies is a low osmolar nonionic agent with an iodine concentration of 300 mg/mL, administered as a dynamic volume bolus of 2 mL/kg. For vascular studies, the concentration can be increased to 350 mg/mL, and if needed, in infants, the bolus can be increased to 3 to 4 mL/kg and/or diluted with saline to provide a longer bolus profile. Children receiving iodinated contrast intravenously should be well hydrated before and after the study to protect their renal function. Special techniques and drug pretreatment may be needed in the face of decreased renal function and contrast allergy, the details of which are beyond the scope of this overview.

CTA consists of contiguous thin cuts (0.6–1 mm) obtained during administration of a large rapid bolus of contrast (1–5 mL/s), optimally administered via a large-bore peripheral IV (18–22 gauge) using a mechanical injector. However, one can produce high-quality CTA studies in tiny newborn infants using IV contrast administered by hand bolus technique (< 1 mL/s). Regardless of the technique used for administration, specific timing or real-time monitoring of the contrast bolus and triggering of the CT scan is often used for optimal visualization of the desired vascular structures. Central lines may be incompatible with the use of an injector or rapid IV bolus and may therefore not be appropriate for CTA or even other chest applications for which vascular opacification is desirable.

Electrocardiogram (ECG)-gated CTA is available to assess very small vascular structures that move with the heart, such as the coronary arteries, and to evaluate cardiac function in patients who are not able to undergo MRI, for example, in the presence of a pacemaker. Newer techniques such as prospective ECG triggering and modulated dose retrospective gating have allowed for significant dose reductions for cardiac gated studies.

The dose of ionizing radiation is a major consideration in using chest CT imaging in children. As techniques become more sophisticated and slices ever thinner, radiation doses have tended to increase significantly. CT is responsible for the largest percentage of medical radiation dose to the general population. Children are particularly vulnerable; not only are their tissues intrinsically more sensitive to radiation, especially certain organs such as the thyroid gland and breast, but they also have less surrounding soft tissue to attenuate the radiation so that their organ dose is higher than a similar study in an adult. Also, they have a longer time to manifest the possible cancer induction effect of ionizing radiation. The risk of cancer from a single CT examination is controversial but quite small (estimated at about 1 in 1–2000) relative to the overall lifetime risk of cancer (1 in 5). However, the risk appears to be dependent on dose and is thought to be cumulative with multiple studies. It is imperative, therefore, that prospective CT imaging be carefully assessed for risk versus benefit. When appropriate, other modalities such as ultrasound or MRI could be substituted. The “As Low As Reasonably Achievable” (ALARA) principle should be followed in regard to decreasing the radiation dose in children. ALARA emphasizes the importance of balancing the lowering of radiation dose along with maintaining diagnostic image quality. Imaging sites should have specific pediatric protocols that adjust imaging parameters such as kVp, mAs, slice collimation, gantry rotation, and pitch based on the size and weight of the child and the requirements of the study. For example, on follow-up imaging, using a lower dose technique and limited anatomic coverage may be appropriate. Whenever possible, CT imaging should be limited to a single series; it is usually unnecessary to obtain both noncontrast and contrasted images. Although it has been standard to image at 120 kVp for CT in the past, 80 kVp or 100 kVp are suitable for most pediatric uses and produce significantly decreased radiation exposure. Iterative reconstruction noise reduction techniques have also been useful in facilitating imaging at lower dose.

MAGNETIC RESONANCE IMAGING

Although MRI avoids the use of ionizing radiation, image acquisition is much slower than with CT scanning. As a result, MRI often requires sedation or anesthesia in young children. MRI is inferior to CT in evaluating the lung parenchyma, and its spatial resolution is also less than CT spatial resolution. However, tissue differentiation such as fluid and fat is often clearly depicted by MRI, and as a result, it is most useful in evaluating mediastinal and spinal or paraspinal lesions, vascular lesions of the chest, and lesions involving the chest wall. MRI is also well established in evaluating cardiac anatomy and function. In the heart, MRI is used to demonstrate anatomy and cardiac function and vascular flow using ECG-gated techniques. Contrast MRI or magnetic resonance angiography (MRA) most often uses gadolinium as the contrast agent. Good-quality, non–breath-hold MRA techniques are available that can include ECG-gating and respiratory triggering. The lack of ionizing radiation exposure gives MRA an advantage over CTA in that multiple passes can be obtained encompassing arterial, venous, and delayed phases of imaging. Four-dimensional flow imaging combines anatomy, physiology, function, and flow. Ferumoxytol can be used as an IV contrast agent in patients with renal dysfunction or when very small vessel detail is needed (Fig. 499-8). Ferumoxytol, however, carries an increased risk of allergic reactions as compared to gadolinium-based agents. The physics of the multiple imaging modes in MRI are beyond the scope of this discussion.

The major contraindication to the use of MRI is the presence of a pacemaker and intracranial aneurysm clips. In general, other metallic items such as sutures, clips, staples, and coils may not be a definite contraindication to MRI; the specific device compatibility can be checked with the manufacturer. Often MRI can be successfully performed in such cases, although metallic artifact can sometimes be quite marked and obscure the anatomy.

NUCLEAR MEDICINE IMAGING

Nuclear medicine scanning still has considerable value, although many of its prior common uses have been supplanted by other technologies. For example, CTA to evaluate pulmonary embolism is faster and more sensitive than is nuclear medicine ventilation/perfusion (V/Q) scanning. V/Q scanning, however, can be used to evaluate a wide variety of pulmonary and vascular abnormalities, particularly when differentiating vascular from airway abnormalities. Perfusion scanning and evaluating differential flow to the lungs (see Fig. 499-6C) are often done by nuclear medicine, although phase contrast MRI can also provide similar information. Scintigraphic imaging of bone lesions, occult infections, and cardiac function may also be performed, although such studies are not done frequently in children.

Positron emission tomography (PET) and PET/CT scanning are used less frequently in children than in adults. The most common use for PET and/or PET/CT is in evaluating and following select pediatric tumors, lymphoma in particular (see Fig. 499-7). Combined PET/MRI is also becoming available.

CONTRAST ANGIOGRAPHY

The development of sophisticated, less invasive CTA and MRA techniques including gated coronary angiography has replaced conventional catheter angiography in many instances. There are, however, limitations to CTA and MRA, mainly in the lack of detailed visualization of more distal smaller vascular branches that can be seen with conventional angiography. Also, additional data such as vascular dynamics, vascular pressure, and blood gas measurements are more easily done with conventional catheter angiography. Catheterization angiography is most often obtained in cases of complex congenital heart disease, vascular malformations, and catheter-based interventions. In addition to the invasive nature of the catheterization procedure and frequent need for sedation or anesthesia, the ionizing radiation dose and the IV contrast load are additional concerns.

AIRWAY ENDOSCOPY

The airway begins in the nose and mouth and ends in the alveoli. Equipment to allow endoscopic airway visualization and tissue sampling in adults has been available for approximately a century, and newer technologies allow for safer visualization and sampling of the airways of infants and children. Current bronchoscopes permit the visual inspection of the pediatric airway from the nares to bronchi distal to the lobar orifices. Sampling of the airway surface liquid and its constituents down to the alveoli also can be performed, as can biopsy of tissue from the mucosa of proximal airways to the periphery of the lung parenchyma. Emerging technologies that may allow for bronchoscopic visualization of the airway parenchyma at the cellular level are under development.

INDICATIONS AND CONTRAINDICATIONS

The major indications for nasopharyngoscopy and nasolaryngoscopy as well as bronchoscopy are included in Tables 499-1 and 499-2. Often, several of the indications are present in a single patient. The main clinical indication for bronchoscopy can be summed up as the need to visually inspect the airways or to obtain material (eg, biopsies, airway secretions, or bronchoalveolar lavage fluid) from the lower respiratory tract in a situation for which bronchoscopy provides the most accurate and safest way to obtain it. The decision as to whether rigid or flexible bronchoscopy is the procedure of choice depends on several factors including the availability of equipment and staff with suitable expertise in bronchoscopy, the clinical question being raised, and the patient’s underlying diagnosis and clinical status. Table 499-1 outlines the relative advantages and disadvantages of each procedure and instrument, and it should be apparent that they are complementary and that the availability of both types of bronchoscopes with staff trained in their use is necessary for the care of pediatric patients.

Contraindications to bronchoscopy depend chiefly on the type of procedure planned. Major contraindications include patient instability, cardiac arrhythmias, or risk of a sudden increase in pulmonary vascular resistance in a patient with pulmonary hypertension. In some circumstances, the underlying cause of these contraindications may in fact be the indication for bronchoscopy (eg, massive atelectasis and hypoxemia). Thrombocytopenia is a relative contraindication to bronchoalveolar lavage and transbronchial biopsy, but replacement of clotting factors and platelets usually can permit performing these procedures. Even very small patients receiving extracorporeal membrane oxygenation (ECMO) can safely undergo bronchoscopy, usually with the flexible instrument; in these cases, the nasal approach is not advised because of the risk of uncontrolled nasal bleeding, and instead, the patient is bronchoscoped via an endotracheal tube or “intubated” orally with the flexible fiberoptic bronchoscope (FFB).

INSTRUMENTS

There are 2 types of instruments for airway visualization: rigid and flexible. Each has distinct advantages and disadvantages (Table 499-3). Flexible nasopharyngoscopes and bronchoscopes allow for the evaluation of the upper airway to the glottic opening. They are useful in determining anatomic causes of upper airway obstruction and stridor or to identify sites of bleeding, but there are several other important indications for the procedure (see Table 499-1). When possible, the flexible instrument should be used first with the patient breathing spontaneously in order to assess airway dynamics and vocal cord movement. If further study or invasive instrumentation is required, the rigid instrument can be used with the patient anesthetized.

The open tube rigid bronchoscope (OTRB) has for years been one of the most important tools in the diagnosis of lung disease. Modern ventilating rigid bronchoscopes allow for control of the airway during an examination, improving safety of patients undergoing bronchoscopy. The Stortz-Hopkins glass rod telescope, which was first produced in 1967, can be passed through the OTRB or, in some circumstances, used alone to provide an unparalleled magnified view of the airway. This technology set the ORTB apart from older fiberoptic instruments, which produced images that were not as clear as those seen with the telescope. The OTRB allows the passage of a variety of instruments, in addition to the telescope. It permits the safe removal of foreign bodies from the airway, the biopsy of airway lesions, and the passage of laser fibers for ablation of lesions or tumors. Further, the ability to ventilate the patient, coupled with the large bore of the rigid bronchoscope, allows for safer suctioning of brisk bleeding in the distal respiratory tract.

There are certain disadvantages of the rigid bronchoscope (see Table 499-3). It is passed through the mouth of the patient, requiring that the patient, especially the pediatric patient, must be anesthetized. If there are orthodontic or jaw abnormalities that do not permit adequate jaw opening, it is difficult to pass the OTRB. Patients already intubated and supported by mechanical ventilation must first be extubated before the OTRB can be passed. Those with existing tracheostomy tubes must have the tube removed and the stoma covered while undergoing rigid bronchoscopy. The OTRB, especially when used as a ventilating bronchoscope, may distort the architecture and dynamic properties of the airway wall, making it difficult to appreciate changes in airway caliber during respiration, as may be seen with tracheo- or bronchomalacia. Finally, the relative size and inherent rigidity of the OTRB, which is an advantage in some ways, prevent the instrument from reaching more distal airways or those that are at an acute angle to the direction of the instrument, such as the airways to the apices of the lung.

The older FFB and nasopharyngoscope rely on 1 fiberoptic bundle to transmit light to their distal tip and a second bundle to serve as a lens; most, but not all, have an internal channel, through which liquids can be instilled, materials in the airway suctioned, and small instruments such as brushes or forceps passed. Newer flexible bronchoscopes have a charge coupled device (CCD) chip serving as a camera at the distal end of the insertion tube; this technology produces markedly improved images that are close in quality to those seen with the Stortz-Hopkins rod telescope.

Flexible instruments have certain advantages compared with rigid instruments (see Table 499-3). Because they are flexible, they can be passed transnasally, allowing inspection of the upper and lower respiratory tract with a single procedure. Because they can fit within an endotracheal tube, they can be used as an aid to intubation, particularly in patients with orthodontic abnormalities or limited jaw opening. They can be passed through an endotracheal tube without discontinuing mechanical ventilation when used with a swivel connector. They are smaller and this, combined with their flexibility, allows them to reach more distal sites in the lung as well as areas requiring angulation such as the apices of the lungs. Because of its small size, the FFB can be “wedged” or seated in a distal bronchus, where multiple aliquots of fluid (usually sterile, nonbacteriostatic saline) can be instilled through the infusion/suction channel and sequentially aspirated into sterile containers. This technique samples the conducting airways as well as the alveoli subtending the “wedged” bronchus; the aspirated fluid, containing lining fluid, cells, and pathogens from the washed area, is called a bronchoalveolar lavage (BAL). The use of BAL to detect infectious pathogens and to evaluate cytopathologic changes in the returned cells is one of the most important clinical and research uses of the FFB.

For many pediatric patients, flexible bronchoscopy can be accomplished with light sedation, but this will depend on the age and medical condition of the patient, the planned procedure, and the bronchoscopist. It is not uncommon to perform flexible bronchoscopy in the operating room with deep sedation provided by an anesthesiologist. The transnasal approach or the use of a laryngeal mask will still allow for spontaneous respiration by the patient.

Instrumentation through the FFB is relatively limited. Brushes for obtaining mucosal cells or airway secretions may be useful for pathologic study. Protected brushes, in which the brush is contained within a catheter, which is in turn within a larger catheter, can sample distal airway secretions without causing risk of contamination while passing through the suction channel. The available protected brush, however, requires a 2-mm suction channel for passage through a bronchoscope, and the current (2016) standard pediatric bronchoscope channel is only 1.2 mm in diameter. Biopsy forceps can be used to obtain mucosal and/or transbronchial biopsy samples; the latter are central to the evaluation of recipients of lung or heart-lung transplants and for some selected patients with interstitial lung disease. Bronchial biopsies to study chronic inflammation in poorly controlled asthmatics are increasingly being used at research centers. Laser fibers can also be passed through the suction channel, permitting laser ablation of endobronchial lesions, although at most centers, laser procedures are preferably done through the OTRB.

There are several disadvantages of the FFB when compared with the OTRB. Ventilation cannot be done through the FFB, and the patient must breathe around it. However, instillation of large aliquots of air (or oxygen) into atelectatic lobes via a “wedged” bronchoscope can reinflate atelectatic lobes. Although the image is fairly good with a fiberoptic instrument and improved with the newer CCD chip camera systems, the image quality remains below that achievable with the Storz-Hopkins rod telescope used with the OTRB. The suction channel of the FFB will accommodate brushes, biopsy forceps, and laser fibers, but larger instruments, including those designed for foreign body removal, are more appropriately used with the OTRB.

COMPLICATIONS OF BRONCHOSCOPY

Although bronchoscopy is a relatively safe procedure, it is not without risk. Generally, the overall risk of flexible bronchoscopy is less than with rigid bronchoscopy, but complications can be seen when using either instrument. Minor complications of flexible and rigid bronchoscopy include a low risk of infection and minor airway trauma leading to localized and limited bleeding secondary to the procedure. More important major complications include pneumothorax or pneumomediastinum, which are more likely to occur when transbronchial biopsies or other airway instrumentation such as removal of a foreign body is carried out. Subglottic edema and airway obstruction more commonly follow rigid bronchoscopy because of the size of the insertion tube.

During flexible bronchoscopy without an artificial airway, the patient must ventilate around the instrument; physiologic complications including hypoxemia, hypercapnia, and (rarely) cardiac arrhythmias such as bradycardia or tachycardia can be seen. For this reason, all patients should be carefully monitored with pulse oximetry, continuous ECG, and visualization of chest wall movement during the procedure; if the procedure is done via an endotracheal tube or laryngeal mask, end-tidal carbon dioxide monitoring is recommended. The utility of transcutaneous carbon dioxide measurements during flexible bronchoscopy has been studied, but currently (2016), there are no specific recommendations for its use.

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