ATS Core Curriculum 2016: Part III. Pediatric Pulmonary Medicine

The American Thoracic Society CORE Curriculum updates clinicians annually in adult and pediatric pulmonary diseases, medical critical care, and sleep medicine in a 3- to 4-year recurring cycle of topics. The 2016 course is presented in May during the annual International Conference and is published monthly in four parts. Part III covers advances in pediatric pulmonary medicine. An American Board of Pediatrics Maintenance of Certification module (MOC) and a Continuing Medical Education (CME) exercise covering the contents of the CORE Curriculum can be accessed online at www.thoracic.org until November 2019.

The Pulmonary Complications of Sickle Cell Lung Disease

Robyn Cohen and Devika Rao

Sickle cell disease affects 100,000 people in the United States and is associated with early mortality. Sickle cell disease is caused by a mutation in the β-globin chain of heme, resulting in HbS. In the deoxygenated form, HbS forms polymers leading to red cell rigidity, acute vasoocclusion of the microvasculature, chronic hemolysis, vessel injury, and a chronic progressive vasculopathy with end-organ complications.

Acute Chest Syndrome

Acute chest syndrome is a poorly understood clinical syndrome defined as a new radiographic pulmonary infiltrate accompanied by fever, oxygen desaturation, and respiratory signs and symptoms including cough, tachypnea, retractions, dyspnea, and/or chest pain. It is the second most common cause of hospitalization in sickle cell disease after painful vasoocclusive crises.

Acute chest syndrome results in long hospitalizations; often requires blood transfusions; can progress to respiratory failure, stroke, and heart failure; and accounts for 15 to 25% of sickle cell disease deaths (1). Fifty percent of children with the most severe form of sickle cell disease—sickle cell anemia (HbSS or HbSβ⁰)—have their first episode of acute chest syndrome before age 6 years and are at a high risk of recurrence (2).

The 2014 NHLBI guidelines recommend treatment with antibiotics, incentive spirometry, supplemental oxygen as needed, and transfusion when indicated (3). There are almost no data on preventing acute chest syndrome, with the exception of using hydroxyurea therapy as primary prevention (3). Although one randomized trial of 38 patients showed a beneficial effect of intravenous dexamethasone in reducing the severity of acute chest syndrome episodes (4), a number of small observational studies—and even the randomized trial—demonstrate a possible but not definitive association between systemic corticosteroid use for acute chest syndrome and subsequent readmission for vasoocclusive crises, making this an important area for future study (5).

More longitudinal data are needed to determine whether recurrent acute chest syndrome episodes are associated with an increased risk of long-term pulmonary function abnormalities or the development of pulmonary hypertension.

Asthma and Sickle Cell Disease

Asthma is a common comorbidity in sickle cell disease and is associated with increased risk of pain episodes, acute chest syndrome events, and mortality (6). The relationship between sickle cell disease and asthma is not well understood, given that both airway hyperreactivity and wheezing are common findings in isolation among patients with sickle cell disease, including among those who do not have asthma (Table 1). Further research is needed to understand which children with sickle cell disease actually have asthma versus sickle cell disease–specific wheezing and if treatment of either condition ameliorates pulmonary complications and overall progression of sickle cell disease (7).

Table 1.

Features of asthma and their significance for children with sickle cell disease

Feature Associated with Asthma	Key Points for Patients with Sickle Cell Disease
Wheezing	Noted in patients with sickle cell disease and no prior asthma diagnosis, family history of asthma, or signs of atopy
	Some children with sickle cell disease have intermittent wheezing that occurs with vasoocclusive episodes
	Wheezing associated with increased future risk of acute chest syndrome and vasoocclusive pain episodes
Airway obstruction	Present in 10–20% of children with sickle cell disease (15)
	May be associated with increased rates of vasoocclusive crisis and acute chest syndrome
	Associated with echocardiographic and CT indicators of increased pulmonary capillary blood volume
Airway hyperresponsiveness	High prevalence of airway hyperresponsiveness to methacholine in children with sickle cell disease
	Not associated with baseline airway obstruction
	Associated with biomarker of hemolysis

Definition of abbreviation: CT = computed tomography.

Sleep-disordered Breathing

Clinical observations and small cohort studies have demonstrated that patients with sickle cell disease are prone to sleep-disordered breathing, including obstructive sleep apnea and nocturnal oxygen desaturation without obstruction (8). The largest published study in children with sickle cell disease demonstrates an increased prevalence of sleep apnea compared with the general population (9). Features associated with sleep-disordered breathing in sickle cell disease include snoring, low daytime oxygen saturations, nocturnal enuresis, and recurrent priapism. The long-term consequences of sleep-disordered breathing in sickle cell disease need further investigation.

Lung Function in Sickle Cell Disease

Children with sickle cell disease have reduced lung function compared with those without sickle cell disease. Individual studies have demonstrated hyperinflation and lower airway obstruction in infants (10), decreased lung growth velocity compared with healthy control subjects (11), and a longitudinal decline in lung function at a rate similar to that of patients with cystic fibrosis (12).

Current NHLBI sickle cell disease guidelines do not recommend universal pulmonary function testing as a screening tool, as there has not been evidence to suggest it is associated with reduced morbidity or mortality (3); however, abnormal pulmonary function may be a valuable marker of sickle cell disease severity, especially regarding cardiopulmonary status (13).

Pulmonary Hypertension

Hemolysis-associated pulmonary hypertension (PH) is a well-described clinical syndrome that affects patients with sickle cell disease and is associated with a high risk of mortality among adults (14). Sickle cell disease with PH was originally defined as having a tricuspid regurgitant jet velocity greater than or equal to 2.5 m/s on echocardiogram, but there is a high false-positive rate with this definition. PH can only truly be diagnosed via cardiac catheterization, which is rarely performed in children with sickle cell disease; therefore, the true prevalence is unknown. The significance and natural history of elevated tricuspid regurgitant jet velocity in children with sickle cell disease are still being investigated.

Vasculitic Pulmonary Disease

Jonathan Rayment and Sharon Dell

Pulmonary vasculitis is a rare disorder that is usually a serious manifestation of a recognized systemic inflammatory disease but may also occur as a primary isolated lung disease. The systemic vasculitides are classified into subtypes according to vessel size affected (1). Pulmonary involvement is most commonly observed in predominantly small vessel disease (2, 3), particularly the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides: granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Isolated pulmonary capillaritis is an idiopathic disease that is sometimes ANCA positive but not classically considered an ANCA-associated vasculitis (4). This review focuses on ANCA-associated vasculitides and isolated pulmonary capillaritis.

Features suspicious for pulmonary vasculitis include diffuse alveolar hemorrhage, pulmonary nodules or cavities and tracheobronchial stenosis in association with constitutional symptoms (fever, weight loss, fatigue), glomerulonephritis, rash, and ANCA positivity. Granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and isolated pulmonary capillaritis each have distinctive features (Table 2) (5–7). Diffuse alveolar hemorrhage is a life-threatening syndrome characterized by diffuse alveolar infiltrates, hypoxia, and anemia and frequently presents without hemoptysis. When diffuse alveolar hemorrhage occurs without extrapulmonary manifestations, isolated pulmonary capillaritis needs to be considered (4).

Table 2.

Small vessel vasculitides with frequent pulmonary involvement

	GPA	MPA	EGPA	IPC
Common presenting features	Epistaxis, saddle nose deformity, dyspnea, cough, pulmonary nodules, constitutional symptoms	Necrotizing crescentic glomerulonephritis (pauciimmune), marked constitutional symptoms	Severe asthma, chronic rhinosinusitis, peripheral blood eosinophilia, migrating chest infiltrates, constitutional symptoms	Anemia, diffuse alveolar infiltrates with or without hemoptysis
Frequency of pulmonary involvement	>80%	∼30%–60%	70–90%	100%
Typical pulmonary manifestations	Nodules with or without cavities, tracheobronchial stenosis, DAH	DAH	Asthma, patchy pulmonary infiltrates, rarely DAH	DAH
Autoantibody status (3, 4)	85–90% PR3-ANCA+	50–75% MPO-ANCA+	0–25% MPO-ANCA+ in children; 35–50% MPO-ANCA+ in adults	0–?*
Other organ involvement	Kidney, skin, ocular, MSK, nervous system, heart	Kidney, skin, MSK, bowel, cardiac, ocular	Kidney, skin, cardiac, GI, CNS, mononeuritis multiplex, skin	None at initial presentation; may evolve into MPA with kidney disease

Definition of abbreviations: CNS = central nervous system; DAH = diffuse alveolar hemorrhage; EGPA = eosinophilic granulomatosis with polyangiitis; GI = gastrointestinal; GPA = granulomatosis with polyangiitis; IPC = isolated pulmonary capillaritis; MPA = microscopic polyangiitis; MPO-ANCA+ = myeloperoxidase-antineutrophil cytoplasmic antibody positive; MSK = musculoskeletal; PR3-ANCA+ = proteinase 3-antineutrophil cytoplasmic antibody positive.

Data from References 3 and 4.

^*IPC cases (n = 12) reported in literature to date all ANCA negative, but ANCA+ cases may have been classified as MPA, and MPO-ANCA+ idiopathic pulmonary hemosiderosis cases are reported.

Diagnostic Evaluation

Initial workup for pulmonary vasculitis includes a complete blood count, coagulation profile, inflammatory biomarkers, renal studies (urinalysis, creatinine), autoantibody panel, high resolution chest (with or without sinus) computed tomography scan, and an echocardiogram. Bronchoscopy will identify alveolar hemorrhage, infection, and large airway lesions. Transthoracic lung biopsy can aid in diagnosis; however, small vessel vasculitis may be underappreciated on lung histology, particularly if treatment with steroids is initiated before biopsy. Even in patients with known small vessel vasculitis, lung biopsy often shows only bland pulmonary hemorrhage and not the pathognomonic change of necrotizing neutrophilic capillaritis (4).

When the pediatric pulmonologist encounters the rare child with isolated diffuse alveolar hemorrhage, ANCA-negative status, and bland pulmonary hemorrhage on lung histology, the diagnosis of “idiopathic pulmonary hemosiderosis” is commonly given. The clinical course of this condition can be similar to isolated pulmonary capillaritis, calling into question whether this diagnostic distinction is helpful (4).

Treatment

Treatment and surveillance of pulmonary vasculitis can best be achieved in close collaboration with a pediatric rheumatologist. There are no clinical trials in the treatment of children with vasculitis, and pediatric treatment regimens are extrapolated from adult studies.

Treatment of vasculitis involves induction and maintenance phases. Induction of remission is typically achieved with corticosteroids and cyclophosphamide, although recent evidence shows that rituximab and corticosteroids may be more effective (8). Maintenance therapy has classically consisted of methotrexate or azathioprine, although recent studies have shown that rituximab may be more effective in select cases (9). Areas of active research include the role of plasmapheresis in induction therapy, optimal maintenance dosing of rituximab, and duration of maintenance therapy required to prevent disease relapse.

Medical surveillance for signs of active inflammatory disease, low-level pulmonary hemorrhage, and new extrapulmonary organ involvement is important, because recurrence and progression of disease is common. Complications include infection, thrombosis, medication toxicity, and end-organ damage (including pulmonary fibrosis) (10).

Pulmonary Defense Mechanisms

Ruobing Wang and Fei J. Dy

The airways represent the largest epithelial surface area exposed to the external environment. Therefore, a broad range of host defense mechanisms are necessary to protect the respiratory system from the myriad of microorganisms, toxins, and particulates it encounters. Although many of these mechanisms are interconnected, they can be largely divided into (1) physical/anatomic barriers, (2) innate cellular immunity, and (3) adaptive immunity. Dysregulation of these mechanisms can lead to many disease states.

Anatomic Barriers

The first line of protection is the anatomic barrier formed by the nose, upper airway, and lower conducting airways, which reduces particulate penetration into the lung. Almost all particles larger than 10 µm are filtered out as air is forced through the curved path of the nasopharynx, whereas particles 5 to 10 µm in size are deposited in the oropharynx and early generations of bronchi, and those smaller than 2 µm may reach the terminal bronchioles and alveoli (1). The conducting airways are also lined by ciliated epithelium, which, along with goblet cells and submucosal glands, helps to produce mucus. The viscous and elastic mucus traps foreign particles and disrupts microbe aggregation and binding to the respiratory epithelium. The expulsion of trapped particles and pathogens is then driven by coordinated ciliary beating, also known as mucociliary transport. When this primary barrier and filtering are overwhelmed, our cough and sneezing reflexes become activated by irritant receptors in the nasopharynx and tracheobronchial tree and enhance clearance by forcefully expelling foreign materials (2).

Respiratory epithelial cells harbor desmosomes and junctional complexes, anchoring structures between cells that are organized to form a mucosal barrier. They also secrete IgA and an array of antimicrobial peptides, such as lysozyme and lactoferrin, which neutralize invading microbes (3).

Innate Immunity

If microbes evade physical barriers, innate immunity defense mechanisms exist to provide nonspecific responses, which can be activated within hours to several days. Most pathogens express molecular structures, known as pathogen-associated molecular patterns, which are recognized by pattern-recognition receptors. These interactions lead to an amplified inflammatory response (4). Alveolar macrophages play a key role in phagocytic and antimicrobial functions. They secrete oxygen metabolites, lysozyme, antimicrobial peptides, and proteases and are able to clear most of the invading foreign particles aspirated daily. If the particle burden is particularly high, macrophages are able to release proinflammatory cytokines and chemokines, recruit other inflammatory cells, and function as antigen-presenting cells as a bridge to adaptive immunity (5).

Neutrophils are one of the first recruited cells; they engage in phagocytosis on activation, releasing reactive oxygen species and hydrolytic enzymes. Neutrophils are also capable of degranulation and neutrophil-extracellular trap formation. Dendritic cells form a sentinel network around respiratory epithelium for antigen capture, and they are additionally able to engulf apoptosed material from viral-infected cells. γδ T cells and natural killer cells represent a subset of specialized T lymphocytes whose functions lie at the intersection of innate and adaptive immunity (6).

Adaptive Immunity

After several days, antigen-specific adaptive immune responses are activated. Antigen-presenting cells that carry specific pathogens are transported to lymphatic organs, where they are recognized by naive B and T cells. CD8⁺ and CD4⁺ T cells engage with major histocompatibility complex class I and II on the surfaces of antigen-presenting cells, respectively. Cytokine release by activated CD4⁺ T lymphocytes drives B-cell maturation to antibody-secreting plasma cells and similarly causes CD8⁺ T lymphocytes to acquire cytolytic properties. Naive B cells, with signals from helper T cells, undergo clonal expansion and differentiate into antibody-secreting plasma cells that target the specific pathogens (7, 8).

The importance of these pulmonary defenses is highlighted by the pathophysiology of various diseases (Table 3).

Table 3.

Examples of compromised immune defenses in pulmonary disease

Disease	Presentation	Pathophysiology
Chronic granulomatous disease	Severe bacterial and fungal infections	Inherited mutations affecting the NADPH oxidase complex
	Most common sites: lung, skin, lymph nodes, and liver	NADPH oxidase activity necessary to form neutrophil extracellular traps that bind bacteria and fungi
	Most infections caused by Aspergillus species, Staphylococcus aureus, Serratia marcescens, and Burkholderia cepacia complex
Common variable immunodeficiency	Recurrent infection due to impaired antibody responses, with high incidence of inflammatory, autoimmune, and malignant comorbidities	Defective B-cell differentiation leads to impaired secretion of immunoglobulins
	Major pulmonary features are bronchiectasis from recurrent infections and granulomatous interstitial lung disease	Other abnormalities include blunted T-lymphocyte proliferation, reduced numbers of T-regulatory cells, defective T-cell receptor signal transduction, and loss of plasma cells
Cystic fibrosis	Persistent productive cough	Impaired mucociliary clearance secondary to reduced periciliary fluid layer and increased mucous viscosity
	Chronic airway inflammation and infection	Dysregulated signaling related to pathogen recognition and proinflammatory activity in innate immunity
	Progressive bronchiectasis with repeated exacerbations	Neutrophil recruitment is excessive and ineffectual, particularly those entrapped in biofilms
	Colonization of the airway with pathogenic bacteria
	Progressive respiratory failure
Hyper-IgE syndrome	Elevated IgE, recurrent pneumonia, and eczema	Autosomal dominant mutations in STAT3 pathway
	Chronic upper airway infections such as sinusitis, suppurative otitis media, and mastoiditis	Impaired Th17 differentiation and function; necessary for neutrophil chemotaxis and proliferation, as well as inflammatory cytokine production
	Pneumonia may be complicated by pneumatoceles, bronchiectasis, and bronchopleural fistulae
	Skeletal and vascular abnormalities may also occur
Primary ciliary dyskinesia	Neonatal respiratory distress without apparent cause	Inherited mutations result in defective outer or inner dynein arms, radial spoke, central apparatus, or cytoplasmic assembly proteins
	Persistent rhinitis from early age	Leads to abnormal ciliary function and poor mucociliary function
	Recurrent middle ear infections leading to hearing loss
	Chronic airway infections, which may lead to bronchiectasis
	Situs inversus totalis in 40–50% of cases

Definition of abbreviation: NADPH = nicotinamide adenine dinucleotide phosphate.

Lung Growth and Development

Jennifer Wambach and Jade Tam-Williams

Successful transition from intrauterine to extrauterine life depends on the lung’s ability to provide adequate gas exchange. Therefore, lung organogenesis is critical for survival of the neonate and sets the stage for future health of the child.

Stages of Lung Development

Human lung development is divided into five overlapping stages: embryonic (4–7 wk gestation), pseudoglandular (5–17 wk), canalicular (16–26 wk), saccular (24–36 wk), and alveolar (36 wk to term). During the embryonic stage, the lung bud forms from a ventral outpouching of the primitive foregut and gives rise to the trachea and major lobar bronchi. Anomalies such as pulmonary agenesis or tracheoesophageal fistula can arise during this stage. During the pseudoglandular stage, the conducting airways form to the level of the terminal bronchioles (1), mesenchymal cells give rise to cartilage and smooth muscle of the proximal airways, and the proximal airway epithelium differentiates into basal cells, goblet cells, pulmonary neuroendocrine cells, ciliated cells, and club cells. Anomalies such as bronchopulmonary sequestration and congenital pulmonary airway malformations can arise during the pseudoglandular stage.

During the canalicular stage, the terminal bronchioles continue branching to complete the conducting airways and give rise to the respiratory bronchioles and alveolar ducts (2). The increasingly developed capillary network surrounds the airspace and comes into close apposition with the epithelium, forming the early air–blood barrier (3). Alveolar epithelial type II cells begin to synthesize surfactant proteins. With adequate support, an infant born toward the end of the canalicular stage may be able to perform sufficient gas exchange for survival. Maldevelopment during the canalicular stage is observed among infants with alveolar capillary dysplasia who develop severe, refractory pulmonary hypertension and progressive respiratory failure after birth.

During the saccular stage, clusters of thin-walled saccules appear in the distal lung, and there is marked thinning of the interstitium (3). A bilayer capillary network forms within the intersaccular primary septae, and the lymphatic network becomes increasingly developed (2, 3). Mesenchymal ridges arise on the saccule walls and initiate early secondary septation (3). Alveolar epithelial type II cells mature in their ability to produce surfactant, and a subset of these cells differentiate into type I cells that line the airspace. In addition, there is continued thinning of the alveolar capillary membrane allowing for gas exchange. The alveolar stage is defined by secondary septation and generation of alveoli, thinning of the primary septae, and maturation of the capillary network (3, 4).

New Developments in Lung Growth and Development

Transcription factors and growth factors are critical to lung morphogenesis and alveolar growth (Table 4). Currently, there are a number of exciting new developments in this area that should be mentioned. The contributions of microRNAs to normal lung branching, proliferation, and differentiation as well as to disease processes such as bronchopulmonary dysplasia are increasingly being recognized and may yield potential therapeutic targets (5). Fetal sex has been recently shown to influence gene transcription in the developing lung during the pseudoglandular and early canalicular stages (6). The Lung MAP initiative aims to characterize cell-specific gene expression for human and mouse lung development from the late canalicular-saccular stage through alveolar development (7). The development of three-dimensional models of alveologenesis permits more specific characterization of spatiotemporal regulation and the specialized cellular composition and interactions involved in alveolar formation (8).

Table 4.

Select transcription and growth factors in fetal lung development

Factor	Mechanism of Action
Thyroid transcription factor-1 (TTF-1 or NKX2-1)	Expressed in endodermal cells of anterior foregut in region of future lung/trachea, regulated by Wnt β-catenin
Sonic hedgehog (Shh)	Expressed in ventral foregut endoderm and mediates endodermal/mesodermal signaling, involved in branching morphogenesis
Fibroblast growth factor family member-10 (FGF-10)	Binds to FGFR2 receptor, initiates lung bud formation, essential for branching and alveolarization
Bone morphogenetic protein-4 (BMP4)	Expressed in high levels in distal epithelium buds, affects lung branching
Transforming growth factor-β family	Expressed in subepithelial mesenchyme, signaling inhibits branching
Platelet-derived growth factor (PDGF)	Regulates myofibroblast differentiation and elastin synthesis
Vascular endothelial growth factor (VEGF)	Regulates vascular development of lung
Retinoic acid	Involved in early lung morphogenesis and alveolar development
N-myc	Expressed in epithelial cells, regulates cellular proliferation and differentiation

Congenital Abnormalities of the Upper Airway

Dawn Simon and Eric Price

The upper airway extends from the nasal aperture to the subglottis and can be the site of numerous congenital malformations causing anatomical or functional obstruction. As newborns are obligate nose breathers, congenital upper airway abnormalities typically present in infancy, most commonly with stridor, respiratory distress, and failure to thrive (1).

Choanal Atresia/Pyriform Aperture Stenosis

Choanal atresia involves the posterior nasal aperture, where there is membranous (10%) or osseous (90%) obstruction. It occurs in 1 in 7,000 live births, with one-third being bilateral. Bilateral choanal atresia typically presents with signs of upper airway obstruction that worsens during feeding and improves with crying. Immediate management of symptomatic infants includes establishment of an oral airway and, if this fails, endotracheal intubation. Definitive repair includes transnasal puncture and stenting, where the atretic bone is punctured and widened by curettage. Transnasal stents are placed for several months (2).

Pyriform aperture stenosis has a similar presentation to choanal atresia, although the lesion is at the anterior bony inlet and is secondary to overgrowth of the maxillary’s medial nasal process. Computed tomography is required to differentiate pyriform aperture stenosis from choanal atresia. Treatment initially is conservative, with topical nasal decongestants, humidification, and gavage feeding (3); however, in more severe cases, intubation may be required. Surgical correction is performed if there is no improvement with conservative therapy.

Laryngomalacia and Laryngeal Webs

Laryngomalacia, the most common congenital laryngeal anomaly (4), refers to the collapse of the supraglottic structures during inspiration. Mechanisms include delayed maturation of supporting structures and redundant supraglottic soft tissue. Typical presentation includes intermittent low-pitched inspiratory stridor worse in supine and improved in prone position. Reassurance is appropriate with mild laryngomalacia, as stridor typically resolves by 12 to 18 months. As laryngomalacia is largely a clinical diagnosis, the need for ancillary evaluation is controversial, but general agreement is that imaging and laryngoscopy should be reserved for infants with feeding difficulty, hoarseness, dyspnea, cyanosis, atypical stridor, and/or apnea.

Laryngeal webs are a rare anomaly, occurring in 1 in 10,000 births (5), caused by failure of epithelial resorption of the laryngeal opening during normal development. Laryngeal atresia, the most severe form of web, is incompatible with life and requires immediate tracheostomy after birth. Patients are aphonic, with complete airway obstruction. Rigid bronchoscopy is required to assess the location, quality, and extent of the web. These findings contribute to classification and determination of treatment. Simple anterior commissure webs can be lysed with a CO₂ laser or scalpel. Laryngeal atresia requires reconstruction and stent placement to establish an adequate airway. Laryngeal webs may occur in conjunction with velocardiofacial syndromes. Therefore, it is recommended that these patients have fluorescence in situ hybridization for 22q11 deletion.

Congenital Subglottic Stenosis and Laryngeal Clefts

Congenital subglottic stenosis presents with recurrent croup and biphasic stridor typically between 6 and 12 weeks of age. This commonly requires serial endoscopic dilation and/or surgical intervention to widen the airway. Subglottic hemangiomas, a rare cause of subglottic narrowing, undergo rapid growth until 12 to 18 months of age and then slowly involute (6). By 5 years of age, 50% have complete resolution. Treatment may include propranolol, systemic corticosteroids, laser ablation, and/or tracheostomy.

Laryngeal clefts occur in 1 in 10,000 live births and can lead to dysphagia and aspiration. Children may present with increased secretions, feeding difficulty, aspiration, failure to thrive, and chronic respiratory symptoms and infections (7). Definitive diagnosis requires palpation of the interarytenoid area with direct rigid laryngoscopy.

Vocal Cord Paralysis

Vocal cord paralysis is the second most common congenital laryngeal anomaly. In bilateral paralysis, the cords are commonly fixed midline, so clinical presentation includes respiratory distress with nasal flaring, retractions, and cyanosis (8). In severe cases, obstruction can lead to respiratory failure and emergency tracheostomy.

Aspiration is common, especially in unilateral paralysis, often resulting in recurrent pulmonary infections. Treatment varies based on severity and if paralysis is unilateral or bilateral. For mild unilateral paralysis, injection of hyaluronic acid or methylcellulose into the vocal fold provides temporary medialization to reduce aspiration risks. In severe unilateral vocal cord paralysis, medialization thyroplasty can be performed, where the thyroid cartilage is incised at the level of the vocal folds and Gor-Tex or silastic inserted to medialize the vocal fold. Surgical correction of bilateral paralysis, including cordotomy, arytenoidectomy, and vocal fold lateralization, may be considered to establish an adequate airway.

Congenital Abnormalities of the Lower Airway

Christopher M. Oermann and Alvin Singh

Congenital abnormalities of the lower airways are rare but potentially life-threatening malformations. The epidemiology, pathophysiology, and clinical characteristics of the most common abnormalities are displayed in Table 5. This review focuses on current areas of investigation as well as controversies in management.

Table 5.

Summary of the epidemiology, pathophysiology, and clinical characteristics of congenital abnormalities of the lower airways

	Epidemiology: Incidence, Sex Distribution, Age at Identification	Pathophysiology: Histology, Connection to Airways, Location	Clinical Characteristics: Age at Symptom Onset, Typical Symptoms, Associated Anomalies
CPAM	1:10,000 M:F, 1:1 Prenatal	Various-sized cysts composed of tracheal, bronchial, bronchiolar, or alveolar tissue	1/4 in neonatal period, 3/4 later in childhood
		Connection to airways	Respiratory distress and hypoxemia at birth, recurrent infection later in childhood
		Equal distribution in all lobes	Associated anomalies with some types
BPS
ELS (10–25%)	1:800,000 M:F, 3:1 Prenatal	Abnormal microcystic lung tissue, separate pleura, systemic arterial connection	Variable (birth to adulthood)
		No connection to airways	Respiratory distress and hypoxemia at birth, recurrent infection later in childhood
		Predominantly lower lobes	Associated anomalies in up to 40%
ILS (75–90%)	1:200,000 M:F, 1:1 Postnatal	Abnormal microcystic lung tissue, contained within pleura of normal lobe, systemic arterial connection	Late childhood to adulthood
		No connection to airways	Recurrent infection
		Predominantly lower lobes	No associated anomalies
BC	1:20,000 M:F, 1:1 Prenatal	Fluid-filled cysts lined with respiratory epithelium, cartilage plates	Variable (birth to adulthood)
		No connection to airways	Respiratory distress, cough, wheeze, recurrent infection
		2/3 mediastinal; 1/3 parenchymal	No associated anomalies
CLE	1:20,000–30,000M:F, 3:1 Postnatal	Histologically normal enlarged airways and alveoli	1/3 at birth, 1/2 by 6 mo, most by 1 yr
		Connected to airways (stenotic or obstructed)	Respiratory distress, tachypnea, decreased air movement, chest wall asymmetry
		Predominantly upper lobes	May be associated with other anomalies, particularly congenital heart disease

Definition of abbreviations: BC = bronchogenic cysts; BPS = bronchopulmonary sequestration; CLE = congenital lobar emphysema; CPAM = congenital pulmonary airway malformation; ELS = extralobar sequestration; ILS = intralobar sequestration.

Lower Airway Malformations

Most congenital abnormalities of the lower airways (congenital pulmonary airway malformation, bronchopulmonary sequestration, bronchogenic cyst, and congenital lobar emphysema) are identified on prenatal ultrasound. Although many demonstrate regression before birth, the natural history of these lesions is highly variable, and complete resolution is rare. Therefore, advanced postpartum imaging is required in all cases (1, 2). Most authorities recommend elective computed tomography within the first 6 months of life, as characterization of lesions is crucial in developing long-term management plans, as discussed below.

The embryogenesis and resulting histopathology of congenital abnormalities of the lower airways are poorly understood. For this reason, pathologic and clinical correlation has been inconsistent, and the resulting classification systems have been controversial (3). Normal lung development depends on the organized temporal and spatial interaction of a large array of specific mesenchymal and epithelial regulatory signals (4).

Alterations in either timing or location of these signals during any stage of lung development can result in the diverse histopathology presented in Table 5. As an example, the bronchiolar pattern seen in Stocker type I, II, and III congenital pulmonary airway malformations suggests that aberrations in signaling occur during the pseudoglandular period of development. A more acinar/alveolar pattern is seen in Stocker type IV lesions, which suggests development during the saccular stage of lung development. However, specific malformations cannot be traced to specific signaling abnormalities, and there is often histopathologic overlap among lesions such as congenital pulmonary airway malformation, bronchopulmonary sequestration, and congenital lobar emphysema.

Recent publications suggest intrauterine airway obstruction as a possible common pathway leading to the variable pathology observed (3, 5). Additional investigation into the underlying mechanisms of development of congenital abnormalities of the lower airways and our resulting understanding and classification of lesions is needed.

Surgical Resection

Another area of significant controversy is the management of asymptomatic infants and children with lesions identified on prenatal ultrasound or as an incidental finding on a chest radiograph. The arguments for and against surgical resection of these lesions are eloquently presented elsewhere and are summarized here (2, 6–8). The preponderance of evidence suggests that congenital pulmonary airway malformations are at increased risk for the development of significant complications (pneumonia, malignancies, pneumothorax, hemoptysis, and hemothorax), which may be life threatening. Therefore, it is common to suggest resection for those children with congenital pulmonary airway malformations (2, 6, 7).

Similarly, resection is often recommended for intralobar bronchopulmonary sequestrations and bronchogenic cysts, as the bulk of evidence suggests that they eventually become infected or develop other complications, as above. Most children with congenital lobar emphysema become symptomatic by 1 year of age and require surgical intervention (2). Although many surgeons recommend resection of these specific lesions, as noted below, not all congenital abnormalities of the lower airway require resection.

Congenital Pulmonary Airway Malformations and Pleuropulmonary Blastoma

Of particular significance in the long-term management of congenital pulmonary airway malformations is the association between Stocker types I and IV congenital pulmonary airway malformation and pleuropulmonary blastoma (9, 10). These lesions are difficult to differentiate based on clinical characteristics, although the presence of multifocal or bilateral lesions and DICER1 mutations are more strongly associated with pleuropulmonary blastoma (10). Additional arguments in favor of early resection include better compensatory lung growth and decreased radiation exposure from repeated computed tomography studies (6).

Controversies

The issue of whether all congenital abnormalities of the lower airways must be resected remains somewhat controversial. A body of literature supports that not all lesions require surgical removal (2, 8). Most authors agree that infants and children with a small extralobar bronchopulmonary sequestration may be observed, as may the small percentage of children with completely asymptomatic congenital lobar emphysema. Others will extend this conservative approach to all asymptomatic lesions, citing lack of symptoms, surgical risk, relatively low risk of complications, and lack of long-term outcome data as reasons to avoid surgical resection. Clearly, more research is needed in this area to best determine optimal management in this patient population. Treatment recommendations must take into account symptoms, comorbidities, and potential future complications.

Pediatric Acute Respiratory Failure

Jordan S. Rettig and Elizabeth D. Duncan

More than 50,000 children are admitted to pediatric intensive care units (PICUs) each year and placed on mechanical ventilators (1–3). In the average PICU, approximately 30% of patients receive mechanical ventilation (4, 5). Among patients requiring mechanical ventilation, those with acute respiratory distress syndrome (ARDS) are some of the most challenging to manage.

Pediatric Acute Respiratory Distress Syndrome

ARDS was first defined in 1994 by the American-European Consensus Conference (6). In 2011 the Berlin Definition of ARDS created three subgroups of ARDS on the basis of severity (7). In 2015, the Pediatric Acute Lung Injury Consensus Conference Group recommended a definition for pediatric ARDS. Among other changes, the oxygenation index (OI) is used to determine level of severity for patients receiving invasive mechanical ventilation, with mild being OI less than 8, moderate being 8 or greater but less than 16, and severe being OI 16 or greater. The term acute lung injury is no longer used (8).

Mechanical ventilation can be a life-saving maneuver in acute respiratory failure, but ventilator-induced lung injury is a potential consequence (9). Barotrauma results from end-inspiratory overdistension, which leads to air leak and pneumothorax (10, 11). Volutrauma is caused by cycling of the lung, independent of pressure required, resulting in both epithelial and microvascular injury (10, 11). Atelectrauma is caused by the shearing injury created by the repeated opening and closing of under-recruited alveoli (9, 10).

The ARDSnet trial demonstrated that in adult patients with ARDS, mechanical ventilation with a lower tidal volume (6 ml/kg) resulted in a 22% decreased mortality and increased the number of days without ventilator use as compared with a more “traditional” 12 ml/kg tidal volume strategy (12). This study has not been reproduced in the pediatric population, but despite clear evidence a low tidal volume approach with permissive hypercapnia is used in the PICU setting. The open lung approach is another strategy to reduce dynamic strain. This approach involves opening atelectatic lung, followed by a low tidal volume strategy (avoiding barotrauma and volutrauma) and positive end-expiratory pressure titration to maintain recruitment and avoid atelectrauma (13, 14). Although both concepts are commonly applied in patients on conventional mechanical ventilation, there is still more research required to better understand optimizing lung protection in pediatric patients.

High-Frequency Oscillatory Ventilation and Inhaled Nitric Oxide

High-frequency oscillatory ventilation is an alternative to conventional mechanical ventilation. This technique uses a constant distending pressure to pursue alveolar recruitment, coupled with a sinusoidal flow oscillation to achieve ventilation using smaller tidal volumes than conventional mechanical ventilation. High-frequency oscillatory ventilation facilitates alveolar recruitment (avoidance of atelectrauma) and reduces the need for high peak airway pressures in the poorly compliant lung. In 2013, the OSCAR (High Frequency OSCillation in ARDS) study group reported the use of high-frequency oscillatory ventilation in adults with ARDS had no significant effect on 30-day mortality (15). Simultaneously, the OSCILLATE (Oscillation for Acute Respiratory Distress Syndrome [ARDS] Treated Early Trial) study group reported the early application of high-frequency oscillatory ventilation in adults increases mortality (16).

It is unclear how relevant adult studies looking at early (nonrescue) application of high frequency are to pediatric practice, where this form of ventilation remains commonly used as a rescue modality (17). It was recently reported that early high frequency use in children was associated with a longer duration of mechanical ventilation than conventional ventilation or late use of high frequency but not associated with improved mortality (18).

Inhaled nitric oxide has been studied as an adjunct in acute hypoxemic respiratory failure. Inhaled nitric oxide transiently improves arterial oxygenation but rarely demonstrates a sustained benefit and, therefore, is not routinely recommended (8, 19, 20). There is some evidence indicating that it may be useful in cardiac patients with pulmonary hypertension (21, 22).

Not all respiratory failure is pulmonary in origin. The need for mechanical ventilation may be secondary to neurologic dysfunction, postoperative/procedural, or required due to airway pathology. When patients are intubated for nonpulmonary reasons, principles of lung protection are perhaps even more important. Avoidance of hyperoxia and ventilator-induced lung injury is essential.

Chronic Respiratory Failure in Children

Christopher D. Baker and Deborah R. Liptzin

Respiratory failure occurs when the respiratory system cannot adequately support oxygenation or ventilation (1). Chronic respiratory failure can result from a wide variety of congenital and acquired conditions in children and may occur at any age (2). Although the duration of respiratory failure is not defined, a child is diagnosed with chronic respiratory failure when the need for ventilatory support extends beyond the expected duration of an acute illness. Various conditions can be associated with chronic respiratory failure, including severe congenital airway abnormalities, parenchymal lung disease (including lung developmental arrest and interstitial disease), and neuromuscular disorders (2, 3). Some children have minimal respiratory reserve and develop chronic respiratory failure as a sequela of an acute respiratory infection.

Long-term Mechanical Ventilation

In the setting of chronic respiratory failure, long-term mechanical ventilation may be indicated. The decision to pursue long-term mechanical ventilation via either invasive or noninvasive methods can be controversial and involves consideration of medical, social, and ethical factors as well as the services available in a given community (4, 5). Treating children with long-term mechanical ventilation is associated with risks such as airway obstruction and equipment malfunction, warranting close observation by trained caregivers. Therefore, a discussion of how life will change for the child and family is essential before proceeding. Achieving medical stability on a home ventilator, educating caregivers, and obtaining durable medical equipment and nursing support can result in an expensive and lengthy inpatient stay (6).

Long-term mechanical ventilation can be provided noninvasively with a nasal interface. However, continuous use can result in skin breakdown and may interfere with activities of daily living. In these cases, ventilation may be administered effectively and safely via a surgically placed tracheostomy tube. The tracheostomy tube diameter should be sufficiently large to minimize airflow resistance yet small enough to avoid airway injury.

Regardless of whether ventilation is provided invasively or noninvasively, a mode of ventilation should be appropriate for the child’s underlying respiratory condition. When the child’s central control of breathing is intact, assist modes of ventilation may be effective. Without adequate control of breathing, volume or pressure control ventilation is appropriate. In severe chronic lung disease, larger tidal volumes (10 ml/kg) delivered with a longer inspiratory time may optimize oxygenation and ventilation; lower rates may prevent air trapping (7). Many of these children benefit from higher peak end expiratory pressures to help minimize dynamic airway collapse.

Weaning from Mechanical Ventilation

In progressive diseases such as neuromuscular disorders, long-term ventilation may be required indefinitely. Children with other disease processes, such as severe bronchopulmonary dysplasia, may improve over time to permit weaning of chronic ventilation (8). Weaning long-term mechanical ventilation may involve slowly lowering the ventilator settings or initiating trials without mechanical ventilation. Weaning requires close observation of the work of breathing, the child’s oxygenation and ventilation status, and, especially, the child’s energy level and growth, as these may suffer if weaning occurs prematurely or too rapidly. Innovative protocols using polysomnography or inpatient observation can help determine readiness for weaning nighttime ventilation (9).

Once long-term ventilation is no longer required, tracheostomy decannulation can be considered. The tracheostomy tube may be downsized and occluded to determine readiness for decannulation. Flexible or rigid bronchoscopy can be performed to ensure there are no anatomic concerns before decannulation. As with weaning, polysomnography or brief inpatient observation can help ensure the child’s safety (9).

An interdisciplinary ventilator care program can help address the myriad needs of this high-risk technology-dependent population (10).