Part 2: Disorders of the Respiratory System

INTRODUCTION

Antenatal ultrasound and, increasingly, fetal magnetic resonance imaging (MRI) diagnose many congenital lung malformations, but we now have to decide what to do for a baby affected by an abnormality that may previously have escaped detection. Many lung lesions disappear or regress from the second trimester to term, and the outcome for such fetuses generally is good. Postnatal regression of lung malformations also has been described. The dilemma in the postnatal period is whether to opt for observation or surgery.

DESCRIPTION OF DISORDERS

The nomenclature of congenital lung disease may be confusing. For example, sequestration and cystic adenomatoid malformation (CCAM) are sometimes assumed to be separate identities, but histologic features of both may be found within the same lesion. There is inconsistent use of nomenclature before and after birth. It is necessary to think in new ways about congenital lung disease. The following principles should be followed:

1. What is actually seen should be described, without embryologic or pathologic speculation, which may later be proved wrong. The same clinical appearance (eg, a multicystic mass) may have 1 of several different histologic appearances when excised. A simple “catch-all” term, congenital thoracic malformation (CTM), is useful for clinical discussions, prior to any pathologic examination.

2. The description should be in everyday language, avoiding ambiguity. For example, hypoplastic lung could mean a lung that is small but otherwise normal, or small and structurally abnormal; congenital small lung (CSL) is clearer and avoids assumptions about structure. Congenital lobar “emphysema” is another source of confusion because in adults it implies lung destruction. What is actually seen is a congenital large hyperlucent lobe (CLHL). Throughout this chapter, established terms will be given in parentheses after the proposed new term. A summary comparison of old and new nomenclature is given in Table 500-1, and relevant investigations are summarized in Table 500-2.

3. The respiratory system should be described systematically. The lung is formed from 6 “trees”: bronchial, systemic and pulmonary arterial, systemic and pulmonary venous, and lymphatic. There are no known abnormalities of bronchial venous drainage, so in practice, only 5 trees need to be considered.

4. Important associated organs (in particular, the heart, great vessels, chest wall, and abdominal contents) should be considered in a systematic manner. Congenital multisystem diseases may affect the lung.

Pathologic descriptions should also describe what is actually seen (eg, epithelial and mesenchymal components of the mass). Finally, a specific diagnosis may be given, but even after pathologic examination, embryologic speculation is best avoided.

AGE-RELATED PRESENTATIONS

Age-related presentations of congenital lung disease are summarized in Table 500-3. Antenatal presentation is usually with either a focal abnormality or abnormal amniotic fluid volume detected by antenatal ultrasound. Absence or reduced fetal breathing movements may be noted, for example, in antenatal onset of severe spinal muscular atrophy. Anything interrupting neural traffic from centrally to the peripheral myocyte that prevents normal respiratory movements will lead to bilateral CSLs. Other conditions relevant to the lungs, which may be diagnosed antenatally, include the skeletal dysplasias associated with bilateral CSL secondary to a small thoracic cavity; many of these are manifestations of ciliopathy.

Postnatal presentation of a lesion missed antenatally is very uncommon. Primary large airway obstruction presents as stridor, failure to pass an endotracheal tube (ETT), or successful passage of the ETT but inability to establish ventilation immediately after birth. Typically, tracheoesophageal fistula presents as a child choking on feeding, not swallowing saliva, and in whom a nasogastric tube cannot be passed. Respiratory distress in the absence of major airway disease may be due to disorders of the lung parenchyma, including a large cystic or solid CTM; unilateral or bilateral CSL; and unilateral or bilateral congenital pleural effusion or lymphatic disorder. Congenital vascular abnormalities may present at this time and include alveolar-capillary dysplasia, congenital alveolar dysplasia spectrum, and pulmonary arteriovenous malformation (PAVM, see below). PAVMs usually present as cyanosis in a well baby (not with heart failure, unless there is an associated systemic, particularly cerebral, arteriovenous malformation). Chest wall disease may present as respiratory distress with difficulty in establishing ventilation. Neuromuscular disease usually is characterized by inadequate respiratory effort with ease of establishing ventilation, unless there are associated severe unilateral or bilateral CSLs.

Congenital lung disease may present later in childhood and in adults. Presentation with respiratory distress is a rare occurrence after infancy and usually indicates an acute increase in size of the malformation due to bleeding, for example, or rupture causing pneumothorax. CTMs can present as an asymptomatic radiologic abnormality. Unilateral CSL also may be a chance finding. A cystic CTM enters the differential diagnosis of recurrent pneumonia in the same location, atelectasis due to large airway compression, dysphagia, lung abscess, focal bronchiectasis, pneumothorax, hemoptysis or hemothorax, or rarely malignant transformation (see below). Complications are unusual in the first 2 years of life. Abnormalities characterized by abnormal systemic arterial supply, unilateral obstruction to pulmonary venous drainage, and PAVM may present with hemoptysis. PAVM may also present with progressive cyanosis in a well person, which may lead to polycythemia, or with systemic abscess or embolism, including acute cerebral disease, due to bypass of the pulmonary vascular filter. Large airway narrowing such as tracheomalacia, vascular rings and slings, or complete cartilage rings may present as “steroid-resistant asthma.” H-type tracheoesophageal fistula may present late, with recurrent bouts of coughing after drinking or hemoptysis.

ANTENATAL DIAGNOSIS AND MANAGEMENT

A fetal lung lesion is suspected either when a thoracic mass is identified or because of mediastinal shift. Investigation may result in fetal therapy being offered or identification of fetuses that should be delivered in a center offering high-level neonatal intensive care and early postnatal surgery. Most abnormalities are detected after approximately 20 weeks of gestation, but some, including diaphragmatic hernias and pleural effusions, may not be detected unless a third trimester scan is performed or until after birth. Imaging cannot provide a definitive diagnosis for many anomalies. The ultrasonographer should describe the lesion as either macro- or microcystic, not using the term cystic adenomatoid malformation (CCAM); cystic lesions may be confused with a diaphragmatic hernia. They usually occur alone, although other associated abnormalities have been described. The prognosis for a fetus with a CTM usually is good; the lesion tends to peak in size at 25 weeks and then regresses. Hydrops is a bad prognostic sign, and a high congenital pulmonary airway malformation volume ratio (CVR; the volume of the mass normalized for gestational age) has also been proposed as an indicator of a poor prognosis, as have the ratio of mass-to-thorax size, cystic predominance, and diaphragmatic eversion; these fetuses need careful follow-up. Accurate prediction of outcome for prenatally diagnosed lesions can be difficult following a single scan, and serial scans should be performed. MRI also has been deployed antenatally, but there is no evidence that this expensive technique improves outcomes. Early consultation with neonatal and pediatric surgical staff is helpful for parents. When there are single or multiple large cysts with associated hydrops or polyhydramnios, improvement has been reported with in utero decompression by thoracocentesis, the insertion of a shunt, or even surgical resection. However, because many lesions spontaneously regress, fetal intervention should be seen as a last resort. A so-called fetal sequestrated lobe is most often identified as an echogenic mass of uncertain origin in the chest or subdiaphragmatic area. Prenatally, it is not possible to make a definitive diagnosis even if an independent blood supply is demonstrated, because a CCAM may also have a blood supply from the aorta, which underscores the value of the generic term CTM. Where any lesion has persisted or increased in size and mediastinal shift persists in the third trimester, delivery in a center with neonatal intensive care and surgical facilities is advisable. All infants in whom any suggestion of a lung malformation has been made antenatally will require a chest radiograph (CXR) prior to discharge, but it is only 61% sensitive for the presence of a CTM, compared with computed tomography (CT).

POSTNATAL FEATURES

Airway and Lung Parenchyma

Congenital Abnormalities of the Trachea

Tracheomalacia leads to tracheal collapse due to localized or generalized weakness of the tracheal wall and respiratory obstruction. The differential diagnosis includes extrinsic compression of the trachea; intrinsic tracheal wall disease, such as complete cartilage rings; and luminal problems, such as tracheal web. Congenital tracheomalacia may be associated with bronchomalacia and other abnormalities such as tracheoesophageal fistula or laryngeal cleft. There is usually early-onset expiratory stridor. The child may become profoundly cyanosed during crying. Diagnosis is by bronchoscopy, bronchography using small volumes of water-soluble contrast, or MRI. First treatment is of the underlying cause if feasible. Mild tracheomalacia needs no active treatment, but the family should be taught cardiopulmonary resuscitation. Proposed surgical treatments include aortopexy, tracheopexy, and stenting, but as yet, the evidence of benefit is limited. Short malacic segments may be amenable to excision. If surgery is not thought feasible or is refused by the family, then ventilatory support should be considered. Providing continuous positive airway pressure (CPAP) while the child is asleep may be sufficient, but if ventilatory support is required during wakefulness as well, then tracheostomy must be considered. CPAP is very effective for short-segment tracheomalacia but is problematic when the distal trachea is involved. Tracheal atresia is rare; isolated atresia may be amenable to surgical reconstruction, but most cases are fatal. Minor tracheal hypoplasia and other airway abnormalities, including complete cartilage rings, may be seen in Down syndrome.

Stenosis usually occurs as a result of a web in the subglottic area or just above the carina, although diffuse involvement has also been recorded. An abnormally long and funnel-shaped trachea may also occur with complete cartilage rings, which may be associated with pulmonary artery sling. This diagnosis may be confirmed by bronchoscopy, endobronchial ultrasound, MRI, or low-contrast-volume bronchography. If the tracheal lumen is small, it may be incompatible with survival. In milder cases, there may be respiratory distress in the delivery room unrelieved by intubation or even tracheostomy. Milder cases may require no treatment, and often tracheal growth keeps pace with the child. Surgery may become necessary as the child grows, if exercise tolerance is severely limited. Options include resection or reconstruction of the stenotic segment or even tracheal transplant for really severe and complex cases. The multiplicity of surgical techniques reflects the relatively poor outcome in the severely symptomatic.

Congenital Abnormalities of the Bronchial Tree

Congenital bronchial stricture occurs predominantly in a main stem or middle lobe bronchus and can lead to acute and/or chronic pulmonary infection. Inflammatory scarring of the congenitally stenosed bronchus leads to distal suppuration, atelectasis, and bronchiectasis. Atresia usually is asymptomatic and detected incidentally on x-ray. The airway may be blocked by a simple membrane, or there may be a discontinuity. Atresia often results in cystic degeneration of the lobe distal to the obstruction before birth, as fetal lung liquid continues to be secreted and cannot drain. Absent bronchus and bronchogenic cyst may be more common than was once thought (see below).

Abnormal Bronchial Origin and Bronchial Branching

Bronchi can arise from the gastrointestinal tract. The right upper lobe bronchus can arise from the trachea (“pig bronchus”). It usually is of no clinical significance but may be a cause of recurrent right upper lobe collapse in an intubated patient if the ETT is low. The right lower lobe bronchus may also arise from the left bronchial tree, a so-called bridging bronchus. Rarely, whole lung segments may cross over.

Disorders of Bronchial Laterality

The 2 most useful determinants of right lung morphology are the presence of 3, not 2, lobes and a very short main bronchus prior to the takeoff of the upper lobe. Mirror-image arrangement must be distinguished from congenitally small (hypoplastic) right lung with right-sided heart (dextroposition). Mirror-image arrangement and other forms of heterotaxy are a feature of primary ciliary dyskinesia, whereas a CSL needs to have its vascular supply delineated (see below). The word isomerism is so entrenched that it is probably not feasible to replace it with the term bilateral right lung, which might be simpler to understand. Nearly 80% of children with right isomerism (bilateral right lung) have asplenia and are thus at risk of developing overwhelming pneumococcal sepsis. Ivemark syndrome consists of right isomerism, asplenia, a midline liver, malrotation of the gut, and a variety of cardiac abnormalities. Left isomerism (bilateral left lung) is associated with polysplenia in approximately 80% of patients. These patients may also have a midline liver, malrotation of the gut, partially anomalous pulmonary venous drainage, and cardiac septal defects.

Disorders of the Bronchial Walls

All or part of the bronchial wall caliber may be too large or too small. These patients may present with recurrent infections, steroid-unresponsive wheeze, or stridor. Congenital tracheobronchomegaly (Mounier-Kuhn syndrome) is characterized by tracheomalacia and greatly dilated major airways. True congenital bronchiectasis is much rarer than previously thought. The bronchial lumen may be narrowed by complete cartilage rings. There may be an associated pulmonary artery sling. A short segment may require no treatment. If ventilation is critically compromised, surgical excision or a Z-plasty may be indicated. Congenital bronchomalacia may be isolated, often with a good prognosis, or associated with other congenital abnormalities.

Pulmonary Agenesis, Aplasia (Absent Lung), and Hypoplasia (Small Lung)

Bilateral absent lungs is a rare malformation that may occur in anencephaly. Unilateral absent lung is slightly more common. Lobar agenesis and aplasia are rarer than complete absence of 1 lung and usually affect the right upper and middle lobes together. Pulmonary hypoplasia (CSL) consists of incompletely developed lung parenchyma connected to bronchi that may also be underdeveloped dependent on when the presumed casual insult took effect in embryogenesis. There are a large number of causes of CSLs (Tables 500-4, 500-5, 500-6). Children with complex malformations, for example, unilateral CSL with abnormal vasculature, may be asymptomatic for long periods despite a formidable list of abnormalities. Any aortopulmonary collaterals should be occluded. Long survival, even with an absent lung, is quite possible.

Congenital Cystic Lesions

Numerous pathologic conditions present with cystic changes in the lung, with acquired lesions outnumbering those that are developmental in origin. It has been recognized pathologically that bronchial atresia is a common accompaniment of CTMs. Presentation of these lesions has been discussed earlier. This section discusses the pathology. It is usually only after surgical excision that sensible pathologic diagnoses can be made.

Foregut (Bronchogenic) Cysts (Clinically, Cystic CTM)

Foregut cysts are epithelial-lined sacs in the thorax. Bronchogenic cysts, distinguished by the presence of cartilage in the wall, are the most common cysts reported in infancy, although many do not present until adulthood. Approximately 50% are situated in the mediastinum close to the carina, and less frequently adjacent to the esophagus and alongside the tracheobronchial tree. More rarely, they are found within the lung parenchyma and exceptionally they are extrathoracic. Foregut cysts are usually single, unilocular, and are usually right-sided. They may have a systemic blood supply. Fistulous connections between cysts and the bronchial tree have been reported. Malignant transformation is exceptionally rare but is reported.

Cystic Adenomatoid Malformation

CCAMs encompass a spectrum of variably sized cysts with differing histology. The incidence is approximately 1:10,000 pregnancies. Type 0 CCAMs, also termed acinar dysplasia, are rare, incompatible with life, and typically associated with other abnormalities. Type 1 is the most common type of CCAM and has the best prognosis; cysts are more than 2 cm in diameter by definition. The cystic spaces are lined by pseudostratified ciliated columnar epithelium, and mucous cell hyperplasia is seen in 35% to 50% of cases. Type 2 CCAMs are the second most frequent type. They generally cause respiratory distress in the first month of life and may be associated with renal agenesis, cardiovascular defects, diaphragmatic hernia, and syringomyelia. Macroscopically, the lesions are multiple small cysts. Microscopically, the cystic airspaces relate to a relative overgrowth of dilated bronchiolar structures that are separated by alveolar tissue, which appears comparatively underdeveloped. Type 3 CCAMs are uncommon and occur almost exclusively in males. They typically involve and expand a whole lobe, with the others being compressed. Macroscopically, lesions appear solid and not cystic. Microscopically, there is an excess of bronchiolar structures separated by air spaces that resemble late fetal lung. Type 4 CCAMs are also very rare and comprise peripheral thin-walled cysts that are often multiloculated. The cystic spaces typically are lined by alveolar type I or type II cells, with the intervening stroma being thin and comprising loose mesenchymal tissue. There is overlap with type 1 pleuropulmonary blastomas.

Treatment of Congenital Cystic Lesions

If a cystic lesion is causing significant symptoms, usually during the newborn period, despite medical therapy, then the baby needs surgery. For all but the smallest, sickest infants, lobectomy (usually thoracoscopic) is a safe and well-tolerated procedure, with few if any significant sequelae. Pneumonectomy carries a significant mortality in infancy and long-term morbidity, in particular scoliosis, which may worsen during the pubertal growth spurt.

If a previously asymptomatic cystic lesion has become infected, the lesion should be excised. Other unequivocal indications for treatment, usually surgery or coil embolization of a feeding vessel, are respiratory distress and failure to thrive, usually in the newborn period; high-output heart failure due to aortopulmonary collateral flow; pneumothorax nonresponsive to conventional therapy; infection of the malformation or chronic distal infection due to airway compression; and uncontrolled hemorrhage from the malformation (hemothorax or hemoptysis). The management of the small, asymptomatic CTM is controversial. A meta-analysis suggested a complication rate of approximately 3% in the first decade of life in CTMs that have not become symptomatic in the newborn period. The risk of pleuropulmonary blastoma in a CTM is 4%, and concerningly, there are no radiologic features that reliably distinguish benign from malignant lesions; the presence or otherwise of DICER1 mutations may be helpful. There are also reports of coexistence of other malignancies with CTM. However, excision of a CTM cannot prevent the development of malignant disease elsewhere in the lung, implying that the malformation is merely a marker of generalized increased malignant potential. Air embolism during flights is a rare but potentially devastating complication. Although many units would disagree, my preference is for elective excision of all but the most trivial CTMs to prevent complications.

Pretreatment Investigations in Congenital Cystic Lung Disease

If surgery is contemplated, it is essential to delineate the anatomy of the CTM, including the blood supply. Contrast high-resolution chest CT (HRCT) gives the best images of parenchymal abnormalities and is currently probably the investigation of choice in suspected CTM.

Pulmonary Sequestration

The classic definition of pulmonary sequestration is tissue that is isolated from normal functioning lung and is nourished by systemic arteries, although the separation may be purely vascular. The intrapulmonary variant is contained within otherwise normal lung parenchyma. The less common extralobar sequestration is accessory to the lung. Sequestrations also may connect to the esophagus or stomach, as well as contain pancreatic tissue, and also may show histologic features of CCAM. The etiology is not understood. Intralobar sequestrations are usually found in the posterior basal segment of the left lower lobe and extralobar sequestrations beneath the left lower lobe. Approximately 15% of extralobar sequestrations are abdominal. The intralobar sequestration is encircled by visceral pleura and has no pleural separation from the rest of the lobe. The remainder of the affected lobe and lung is normal, unless secondary changes such as infection have supervened. More than half the cases of intralobar sequestration are diagnosed after adolescence, and symptoms in neonates and infants are uncommon. Extralobar sequestration usually is detected in infancy because of associated malformations and affects males 4 times more frequently than females. Although much rarer, intralobar sequestrations may also be associated with other malformations. Treatment of sequestration is surgical excision. The vascular supply should be carefully delineated by preoperative investigations, and embolization of aortopulmonary collaterals may be considered.

Congenital Large Hyperlucent Lobe (Congenital Lobar Emphysema)

Congenital large hyperlucent lobe (CLHL) is a rare condition that affects the left upper (42%), right middle (35%), right upper (21%), and lower (2%) lobes. The affected lobe overdistends and displaces adjacent lobes and subsequently the mediastinum and may herniate into the contralateral hemithorax. The condition may be diagnosed antenatally; present as respiratory distress, often with consequent failure to thrive in infancy; or be a chance finding on a CXR taken later in life. Clinical features of infantile lobar emphysema are suggestive of a tension pneumothorax. Usually, a CXR will demonstrate a hyperlucent lobe with features of compression and collapse of the adjacent lung, ipsilateral depression of the diaphragm, and mediastinal shift. Bronchoscopy may reveal causes of intrinsic obstruction and permit the removal of a foreign body or inspissated secretions, or even provide temporary relief of symptoms to facilitate surgery. The differential diagnosis is any intrinsic or extrinsic airway cause of failure of airspace emptying and any cause of loss of lung volume on the contralateral side including absent lung and lobar or lung collapse due to bronchial obstruction. Children who are thriving and asymptomatic require no treatment; otherwise, treatment is lobectomy.

Abnormal Connections Between the Bronchial Tree and Other Structures

Tracheoesophageal Fistula and Esophageal Atresia

The genetics, associated disorders, diagnosis, and treatment of tracheoesophageal fistula are discussed in Chapter 387.

Other Abnormal Connections

Rare direct communications between the bronchial tree and CTM, the biliary tract, and the stomach have been described.

Congenital Abnormalities of the Pulmonary Arterial Tree

Systemic arterial abnormalities can be separated into those of the bronchial circulation; other pathologic collaterals; and airway compression by abnormal great vessels, for example, a double aortic arch. The pulmonary capillary bed may be bypassed by direct arteriovenous communication or absent, resulting in minimal pulmonary arteriovenous connections.

Disorders of Pulmonary Artery Arrangement

In general, pulmonary arterial and venous arrangement mirrors bronchial arrangement. Exceptions include congenital origin of the left pulmonary artery from the right (pulmonary artery sling), where the left pulmonary artery traverses the mediastinum compressing the trachea. There may also be a crossover arterial segment, with the right upper lobe supplied from the left pulmonary artery, or complete cartilage rings. Isolated crossover pulmonary artery branches in the absence of bronchial crossover are seen occasionally (see Chapter 479).

Absent or Small Pulmonary Artery

Absent or small pulmonary artery may be isolated or associated with other cardiovascular anomalies. Symptoms may not arise until adult life and include pulmonary infection or hemorrhage. Congenitally small unilateral pulmonary artery is usually associated with an ipsilateral CSL. Pulmonary arterial stenosis may affect lobar and segmental vessels as well as the main pulmonary arteries. Isolated unilateral absence of a pulmonary artery may be asymptomatic, or there may be infection or bleeding from bronchopulmonary anastomoses. Anomalous systemic arteries supplying the lung may be associated with any CTM or even be an isolated finding. They are also found if the pulmonary artery is absent and may also be part of complex arteriovenous malformations. One or both pulmonary arteries may take origin from the aorta. Bilateral origin from the aorta is part of the spectrum of common arterial trunk, or truncus arteriosus, and usually will present to the pediatric or fetal cardiologist. Unilateral origin of a pulmonary artery from the aorta may be an isolated abnormality, sometimes presenting with persistent tachypnea.

Relevant Congenital Abnormalities of the Systemic Arterial Tree

Vascular ring causes compression of the tracheoesophageal complex. Presentation is typically with stridor, cough, or steroid resistant asthma, though in some cases dysphagia may be the predominant symptom. Diagnostic workup may include a barium swallow, with indentation of the esophagus, but full evaluation requires referral to a cardiologist with subsequent ECHO and CT angiogram.

Congenital Abnormalities of the Pulmonary Venous Tree

Abnormal Pulmonary Venous Drainage

Anomalous pulmonary veins may join the systemic venous circuit at many sites and may be obstructed or unobstructed. The anomaly may be total or partial, unilateral or bilateral, and isolated or associated with other cardiopulmonary developmental defects. Anomalous pulmonary venous connections often are narrow and may cause relatively mild pulmonary hypertension. Unilateral anomalous venous drainage may be part of complex lung malformations; it may also be seen in association with what appears to be a simple lung cyst. The “scimitar” syndrome is characterized by a small right lung cardiac dextroposition and an abnormal band shadow representing abnormal venous drainage to the systemic veins. Infants presenting with heart failure have a worse prognosis, often because of associated abnormalities, among which may be left heart malformations. Aortopulmonary collaterals should be sought and occluded. More invasive treatment options include reimplantation of the vein or pneumonectomy. Severe pulmonary hypertension is an adverse prognostic feature.

Congenital Absence of the Pulmonary Veins

Absence or narrowing of the pulmonary veins results in pulmonary venous obstruction and pulmonary hypertension. Atresia may be unilateral or bilateral. Prognosis is poor.

Abnormalities of the Connections Between the Pulmonary Arterial and Venous Trees

Disorders of Alveolar Capillary Development

Part of the alveolar capillary dysplasia–congenital alveolar dysplasia spectrum encompasses misalignment of lung vessels, representing a failure of capillaries to grow in appropriate number and location within the alveolar tissue of the lung. It was once thought to be sometimes associated with abnormally sited pulmonary veins; in fact, they are hypertrophied bronchial veins.

Pulmonary Arteriovenous Malformation

Pulmonary arteriovenous malformations (PAVMs) are abnormal direct connections between the pulmonary arterial and venous trees. PAVMs occur most commonly in the lower lobes; approximately 75% of patients have unilateral lesions, and approximately 36% of patients have multiple lesions, of which around half are bilateral. Many are associated with hereditary hemorrhagic telangiectasia (HHT). Mutations in the endoglin and ALK1 genes, respectively, cause HHT1 and HHT2; mutations in other genes have been described. The fistula is fed by at least 1 afferent artery, usually pulmonary, and may be drained by several veins, almost always pulmonary. In 80% of patients, there is a single feeding pulmonary artery and a single draining pulmonary vein. Abnormal direct connections between the pulmonary arterial and venous trees (PAVMs) may also be diffuse and microscopic. Presentation is with dyspnea, cyanosis, hemoptysis, or neurologic complications, such as cerebral abscess. There may be clubbing, cyanosis, and a chest wall bruit. The circulation is hyperdynamic only if there is a substantial systemic arterial component. The CXR may be normal, but more usually, well-defined single or multiple opacities are seen, with vessels connecting them to the hilar, which are strongly suggestive of the diagnosis. HRCT will show all but diffuse microscopic malformations. Diagnosis is suspected on imaging and confirmed by documenting an abnormal intrapulmonary right-to-left shunt by contrast echocardiography. Treatment is by coil occlusion, which reduces the risk of complications. Some of the fistulae are closed permanently by this procedure; however, recurrences may occur in the same lung or may manifest in the other lung. Systemic complications are related primarily to the bypassing of the filtration function of the pulmonary circulation and hyperviscosity secondary to systemic arterial hypoxemia. Pulmonary hypertension does not develop because there is no alveolar hypoxia. The patient may develop systemic abscess or thrombosis. Patients with diffuse PAVM are a high-risk group. Local complications include hemothorax and massive hemoptysis.

Congenital Abnormalities of the Lymphatic Tree

Congenital pulmonary lymphangiectasia may be primary to obstruction of pulmonary lymphatic or venous drainage or secondary, either limited to the lung or generalized. It causes severe respiratory distress and often is fatal in the neonatal period, but milder cases with prolonged survival have been described.

Congenital Cardiac Disorders

Congenital cardiac malformations may be coincidental to, or a fundamental part of, a pulmonary malformation (see Chapter 479). Echocardiography should be performed routinely in most suspected congenital lung abnormalities. Vascular compression of the airways in the setting of congenital heart disease is not uncommon.

Multisystem Congenital Disorders That Affect the Lung

A few congenital lung abnormalities are part of a generalized disorder, such as tuberous sclerosis, and metabolic diseases, such as Niemann-Pick. Presentation may be suggestive of interstitial lung disease.

LONG-TERM FOLLOW-UP

Lobectomy is well tolerated, and it is extent, not age at resection, that is important. It is unlikely that a large malformation would interfere with the growth of surrounding normal lung. Follow-up of children with a residual CTM is not evidence based.

SUMMARY AND CONCLUSIONS

Congenital lung disease can present at any time and is part of the differential diagnosis in many situations. Lesions may regress to virtually nothing, require relatively straightforward surgery, or be a complex therapeutic challenge. We need better information so that more precise counseling can be given. Children with congenital lung disease should be enrolled in international registries.

SUGGESTED READINGS

INTRODUCTION

The neuronal and musculoskeletal components of the respiratory system mature postnatally, whereas the systems governing respiratory control in general, and more specifically rhythmogenesis, must be mature and functional by birth to enable the successful transition from fetus to infant. In newborn infants, whose chest wall is highly compliant, rhythmical respiration must be coordinated with other behaviors including sucking, swallowing, crying, and other vocalizations. Premature infants display deficiencies of central respiratory rhythmogenesis or of activation of respiratory musculature. However, such problems are not restricted to this particular stage of life, and alterations in the control of breathing may play a role in many conditions that become apparent throughout childhood and adolescence, particularly during sleep. During sleep, the clinical manifestations of many diseases of respiratory control as well as other conditions affecting the respiratory system in general are more likely to emerge. Thus, understanding the pathogenesis of breathing problems is an important component of the clinical evaluation of any child with respiratory symptoms.

DEVELOPMENT OF RESPIRATORY CONTROL AND NORMAL FUNCTION

Current understanding of the mechanisms governing the control of respiration has evolved significantly over the last century. Breathing is an important and vital function, and as such should be prioritized during evolution, it has become apparent that at least in mammals, and more particularly in humans, the control of respiration undergoes substantial maturation during the first few years of life. There is, however, substantial uncertainty regarding the exact anatomic locations and functions of specific neural respiratory pathways. Furthermore, the complexities of neuronal firing activities, the multitude of neurotransmitters within each brainstem nucleus, and the frequently nucleus-dependent opposing roles played by these neurotransmitters on respiratory function make integration of all these elements a difficult and sometimes confusing task. The progress in our understanding of the intricate neural networks of respiration has been tremendous, and the identity of several of the genes that control the development and maturation of multiple neurally controlled respiratory functions is now emerging.

THE RESPIRATORY RHYTHM GENERATOR

The presumed neural region underlying the generation of respiratory rhythmic activity has now been identified, and specific markers such as neurokinin and opioid receptors in these neurons have revealed that this uniquely important neural center consists of a small cluster of only 150 to 200 neurons in the brainstem region designated as pre-Bötzinger complex. These relatively few rhythmically firing neurons appear both necessary and sufficient to generate most of the complex normal respiratory behaviors that we currently recognize, such as eupnea, sigh, and gasping. The development of several elegant models, ranging from highly reductionistic (brainstem slice) to less reductionistic approaches (whole brainstem-heart-lung preparation), has now permitted extensive characterization of the network connectivity and responses and the functional neurotransmitters involved in generation of respiratory rhythm, thus enabling a comprehensive understanding of the electrophysiologic properties of these unique cells during development, sleep, or exercise, as well as in the context of specific diseases. Several genes, such as Phox2a, Hox paralogs, and Hox-regulating genes kreisler/mafB and Krox20, have now been identified as important players in the embryonic generation of respiratory centers and their intrinsic connectivities. These and probably other yet unknown genes govern the regulation of brainstem functional ontogeny and will undoubtedly provide in the upcoming years important insights into the regulation of the initial phases involved in the normal and abnormal formation of the respiratory network.

SLEEP AND BREATHING DURING DEVELOPMENT

In addition to the pre-Bötzinger complex, suprapontine sites, including important efferent projections to areas mediating the sleep-wake cycle, thermoregulation, and circadian rhythm rhythmicity, also modulate respiratory rhythm. Respiratory controllers also receive afferent inputs from both central and peripheral chemoreceptors and from other receptors within the respiratory pump (upper airways, chest wall, and lungs). During fetal life, breathing is discontinuous, and bursts of respiratory-like activity coincide with a fetal electroencephalographic state that closely resembles rapid eye movement (REM) sleep. Following birth, respiratory rhythm is established as a continuous and dynamically adjustable process that allows for the maintenance of cellular oxygen and carbon dioxide homeostasis.

Respiratory activity is, nonetheless, chaotic in nature, with nonrandom, nonlinear properties governing its moment-to-moment variability. For example, short apneic episodes lasting less than 5 seconds are extremely common in preterm infants, and their frequency is reduced progressively with maturation. These episodes occur predominantly during REM sleep, although they may emerge during any transitional state. To understand the high probability for sleep-associated disruption of normal gas exchange in early postnatal life, it is useful to identify some of the developmental differences between the infant and the adult respiratory systems that contribute to the occurrence of infantile apnea:

• The majority of young infants can be considered as obligatory or near-obligatory nasal breathers, such that any increased resistance to airflow in the nasal passages or congenital size reduction in the nasal orifices (eg, choanal atresia) may translate into major disruption of breathing and inability to sustain adequate gas exchange.

• In early postnatal life, the reflexes that originate in the upper airway (ie, laryngeal chemoreflex) are stronger and may provoke the onset of profound apnea and bradycardia. This respiratory depressant component of the laryngeal chemoreflex slowly declines with maturation such that prolonged apnea and bradycardia induced by stimulation of the laryngeal chemoreflex are more prominent in premature infants. Thus, frequent events such as gastroesophageal reflux (GER) or even swallowing can trigger this reflex and manifest as apnea and bradycardia events in the nursery.

• Chest wall compliance is higher in infants and, therefore, requires dynamically active maintenance of the functional residual capacity (FRC) of the lungs. Furthermore, younger infants have barrel-shaped ribcages, which makes the ribcage contribution to tidal breathing less effective when compared to older children and adults. As a corollary of this developmental issue, situations that reduce or compromise the ability to maintain FRC (eg, REM sleep) may promote the occurrence of oxyhemoglobin desaturations, even in the absence of apnea.

• Asynchronous breathing is very common in sleeping newborns because of the discoordinated interactions between chest and abdominal respiratory muscles. It usually improves as postnatal age increases such that it is rarely present beyond 3 years of age.

• The basal respiratory rate is much higher in the neonatal period and decreases during infancy and early childhood, reflecting changes in metabolic rate as well as the integrated outcome of many of the factors discussed herein. Respiratory rate decreases exponentially with increasing body weight and is faster during REM sleep.

• Short apneic episodes (less than 5–10 seconds) are extremely common in neonates, occur more frequently during REM sleep, and are mostly central (ie, absence of respiratory effort during cessation of airflow). The frequency of these events decreases with age. Obstructive and mixed apneas are also more frequently seen in preterm infants, most likely as the result of the ongoing developmental changes in pharyngeal, laryngeal, and central airway collapsibility.

• Periodic breathing, defined as 3 episodes of apnea lasting longer than 3 seconds and separated by continued respiratory activity over a period of 20 seconds or less, is extremely common in preterm infants and in some full-term infants. Generally, the frequency and duration of periodic breathing decrease over time during the first year of life. Despite initial concerns about the implications of periodic breathing, this breathing pattern is currently not considered to bear any pathologic significance. However, environmental factors such as sleep state transitions, arousals, hypoxia, high altitude, and hypothermia or hyperthermia can all enhance the probability and severity of periodic breathing in infants and can ultimately lead to significant hypoxemia and bradycardia.

• Apneas during sleep in infants are associated with a fall in heart rate, particularly during non–rapid eye movement (NREM) sleep, and the presence of hypoxemia enhances the reflex bradycardic response during apnea.

• The ability to arouse from sleep is considered one of the most important components leading to the termination of an apneic episode. Not surprisingly, arousal deficits have been implicated in the pathophysiology of the sudden infant death syndrome. However, fewer than 10% of apneic events are terminated by an electroencephalographic arousal in infants. Autonomic arousals (ie, changes in heart rate and blood pressure) are nonetheless, frequent during the period surrounding the termination of an apneic event but are associated with vastly different autonomic responses. Moreover, whereas hypercapnia is a very potent stimulus for arousal, hypoxia, and particularly rapidly developing hypoxia, is much less effective. Finally, prone position, sleep deprivation, and prenatal/postnatal exposure to cigarette smoking are accompanied by decreased arousability in infants, thereby providing the putative link between arousal deficits and sudden infant death syndrome.

• It is important to emphasize that a decrease in oxyhemoglobin saturation below 92% during sleep in the first 4 weeks of life is an extremely rare occurrence among full-term infants. Normative blood oxygen levels reach lowest levels during the first week of life and subsequently increase during the next 1 to 3 months, at which time values of 97% to 100% are the rule. Baseline values for arterial carbon dioxide tension during sleep are generally between 36 and 42 mm Hg in newborns and infants.

The implications of REM sleep on breathing are substantial; the loss of muscle tone during REM is particularly influential to the upper airway muscles and airway patency. A frequently overlooked aspect of breathing control is the close interaction of breathing and the cardiovascular system. The continuous interactions between the 2 systems can be readily recognized (eg, respiratory sinus arrhythmia), with inspiratory efforts being associated with accelerated heart rate and expiratory efforts with cardiac frequency decelerations, all of which are the result of reflex activity from pulmonary afferents and vagal outflow, with coupling between breathing and heart rate being particularly prominent during NREM sleep. Therefore, assessment of heart rate variability can provide important information about state (REM, NREM sleep, or awake) and also about the respiratory status. As a corollary of these interactions, particular conditions associated with altered respiratory control will manifest unique patterns of respiratory- and cardiac-related variations; for example, children with congenital central hypoventilation syndrome (CCHS) show a relative absence of variation of respiratory modulation of heart rate, and infants who later succumb to sudden infant death syndrome also show reduced variation in breathing, particularly during REM sleep.

CENTRAL CHEMORECEPTORS AND THEIR DEVELOPMENT

The physiologic underpinnings of chemoreflexes are extremely complex, and the exact molecular mechanisms that regulate these important functions are still being actively sought. The classic concepts formulated during the late 1950s proposed that the central chemoreceptors were located in the ventrolateral medullary surface of the brainstem and responded to hypercapnia and pH changes, whereas the peripheral chemoreceptors were located in the carotid bodies and primarily responded to changes in the arterial blood oxygen tension. Although this concept has now been revised and reformulated, it is noteworthy that hypercapnia (particularly transient changes in carbon dioxide tension above the apneic threshold) will also activate the peripheral chemoreceptors and accounts for up to one-third of peripheral chemoreceptor activity. Activation of either central or peripheral chemoreflexes exerts powerful effects on sympathetic activity in both health and disease and may be an important contributor to pathophysiology of sleep apnea.

In marked contradistinction with classic theory, neurons exhibiting intrinsic chemosensitive properties (ie, the ability to sense changes in extracellular pH and to contribute to the ventilatory response) are diffusely located in the central nervous system and appear to be serotoninergic neurons. Indeed, brain regions such as the posterior hypothalamus, cerebellum, locus ceruleus, raphe, and multiple nuclei within the brainstem all contribute to the hypercapnic ventilatory response. The immediate clinical relevance and importance of these discoveries reside in the fact that the severity of a condition such as central alveolar hypoventilation, particularly when occurring secondarily to other disorders (eg, myelomeningocele, tumors, stroke), cannot be adequately explained by either the location or the magnitude of the brain lesions in these patients. Second, the diffuse distribution of central chemosensitive neurons points to the importance of these sensing elements in preserving respiratory stability during respiratory transients, particularly during sleep. As such, conditions such as apparent life-threatening events or even sudden infant death syndrome may develop as a consequence of dysfunctional development of the respiratory rhythm controllers, the neural networks that mediate hypoxic and hypercapnic chemosensitivities, or those pathways mediating arousal from sleep.

The complete array of neurotransmitters involved in central chemoreception has yet to be fully delineated. The presence of cholinergic muscarinic and serotoninergic receptors in those brain stem areas traditionally associated with carbon dioxide (CO₂) chemosensitivity appears to play a major role in the neuronal excitation associated with the enhanced ventilatory response to hypercapnia. As with other respiratory control functions, central CO₂ chemosensory mechanisms are not fully functional or mature at birth. For example, exogenous hypercapnic challenges will elicit a relatively sustained ventilatory increase in term infants that is almost entirely due to an increase in tidal volume without consistent change in respiratory frequency. In contrast, the ventilatory response to hypercapnia in premature infants is attenuated and can even become inhibitory at higher concentrations of inhaled CO₂, with the ventilatory increase being characterized by progressive increases in expiratory duration and consequent reductions in frequency over time, both of which appear to be associated with diaphragmatic recruitment during expiration (respiratory braking or grunting). This unique response aims to preserve a high end-expiratory lung volume, such as to optimize gas exchange and promote respiratory stability. Of note, prepubertal children also exhibit enhanced ventilatory responses to hypercapnia when compared to adults, perhaps due to differences in weight-adjusted metabolic rates. Similarly, significant developmental differences in CO₂ responses are present when the CO₂ stimulus is presented in either a step (sudden increase) or ramp (slow progressive increase) fashion. These findings in older children indicate that during transition from infancy to childhood and on to adulthood, major changes occur in the relative contributions and integration of peripheral and central chemoreceptor inputs.

PERIPHERAL CHEMOREFLEXES

The ventilatory responses related to changes in blood oxygen levels represent complex interactions between peripheral and central components. However, peripheral chemoreceptors are uniquely positioned to sense rapid changes in blood oxygenation changes, and activation of these peripherally located chemosensory cells (ie, glomus cells within the carotid bodies) leads to a fast, transient increase in minute ventilation after inhalation of gases containing low concentrations of oxygen. Several strategies to measure peripheral chemoreceptor function have been developed and include progressive isocapnic hypoxic responses (over a period of 2–3 minutes), sudden 5 tidal breaths of pure nitrogen, or assessment of the ventilatory decline following inhalation of 100% oxygen (Dejours test). However, these tests may be quite variable over time, such that more sophisticated procedures consisting of random alternations of nitrogen and oxygen in a computerized setting have demonstrated reproducible and consistent findings in infants and children who are thought to be at risk for chemoreceptor dysfunction. As would be expected, substantial attention given to the sleep state in which respiratory chemoreceptor responses are being assessed is necessary for accurate interpretation of such tests.

THE UPPER AIRWAY

UPPER AIRWAY CONTROL

Snoring and obstructive sleep apnea (OSA) represent opposite ends of a severity spectrum associated with increased upper airway resistance. Although a thorough review of the complex anatomic and physiologic mechanisms underlying the maintenance of upper airway patency during sleep is beyond the scope of this text, some basic principles are enumerated and should provide the conceptual framework of this important function. The upper airway consists of the nose, pharynx, larynx, and extrathoracic trachea and is designed for the numerous functions of vocalization, ingestion, airway protection, and respiration. Maintenance of a relatively rigid and patent upper airway is, therefore, mandatory for achieving adequate respiration and represents the balance between forces promoting airway closure and dilatation. Thus, inherent collapsibility of the pharynx predisposes to the occurrence of impaired respiration, particularly when the regulation of the pharyngeal muscles is impaired (eg, during sleep).

The smaller the cross-sectional area of the upper airway, the less the ability to maintain upper airway patency will be. Because the upper airway behaves as a collapsible tube, increased inspiratory effort may only result in more collapse of the airway rather than increased flow. Hence, snoring and obstructive apnea can become worse during a common cold (increased nasal upstream resistance), which provokes more inspiratory effort. In addition, the longer the airway, the more collapsible it will be.

Although the overall hypoxia and hypercapnic ventilatory drive appear to be normal in children with OSA, even if occasional studies may suggest otherwise, it is possible that centrally mediated augmentation of upper airway neuromotor function is abnormal. During sleep, upper airway tone is consistently reduced. It is unknown whether children with OSA obstruct because of a relatively larger decrease in airway tone during sleep, in comparison to controls, or whether the decrease in tone is similar but those with OSA have an increased structural load. The upper airway muscles are accessory muscles of respiration and, as such, are activated by stimuli such as hypoxemia, hypercapnia, and upper airway subatmospheric pressure. When upper airway muscle function is decreased or absent (eg, during anesthesia), the airway is prone to collapse. Conversely, stimulation of the upper airway muscles with hypercapnia or electrical stimulation results in decreased collapsibility. These studies confirm that the tendency of the upper airway to collapse is inversely related to the level of activity of the upper airway dilator muscles. Therefore, increased upper airway neuromotor tone may be one way that patients can compensate for a narrow upper airway, and this assumption has been confirmed in children and adults with OSA. Pharyngeal airway neuromotor responses are prominently present in normal children but are lacking in children with OSA, even during wakefulness, most likely because of habituation to chronic respiratory abnormalities during sleep, mechanical damage to the upper airway, or genetically determined differences in these upper airway protective reflexes.

In addition, children with OSA demonstrate impaired arousal responses to inspiratory loads during REM and NREM sleep compared to healthy children. This arousal threshold was particularly high during REM sleep, a time when most obstructive apneic events occur, and suggests that neuromotor factors play a key role in upper-airway obstruction. The absence or delayed arousal in children during the occurrence of an obstructive respiratory event and the presumed lack of ventilatory compensation to upper airway loading may contribute to the development of the prolonged periods of obstructive alveolar hypoventilation that uniquely characterize OSA in children.

Whereas dynamic functional factors such as those discussed previously have been implicated in the pathophysiology of upper airway obstruction during sleep in children, the important contributions of either anatomic elements or genetic factors must be emphasized as well. Whereas micrognathia and severe retrognathia are clearly associated with an increased risk for upper airway obstruction, the mandibular dimensions of otherwise healthy children with OSA appear to be within the normal range. However, a detailed analysis of the upper airway using magnetic resonance imaging (MRI) techniques suggested that the upper airway in children with OSA is narrowest where adenoids and tonsils overlap and that such narrowing spans over the upper two-thirds of its length rather than being restricted to a discrete region adjacent to either the adenoids or tonsils. Moreover, it is imperative to dispel previous beliefs that proposed a higher prevalence of OSA in children 2 to 8 years old because of increased growth rate of lymphadenoid tissue within the upper airway compared to other upper airway structures. More recent imaging studies clearly show that all tissues within the upper airway, including adenoids and tonsils, grow proportionally to each other and that exogenous (eg, respiratory viruses, pollution, and inflammation) rather than endogenous processes promote enhanced proliferation and hypertrophy of lymphadenoid tissues within the airway and are mechanistically implicated in the pathophysiology of pediatric OSA. Recent imaging approaches coupled with computational fluid dynamics analyses may provide accurate estimates of upper airway collapsibility in individual patients as well as predict the effect of treatment.

UPPER AIRWAY DYSFUNCTION

During infancy, the upper airway has decreased muscle tone and high nasal resistance, and the chest wall is highly compliant. The exact prevalence of OSA in infants is not well documented because most epidemiologic studies have concentrated on older children. However, OSA may occur in up to 10% of infants, occurs more frequently in premature infants, and is associated with hypoxemia. OSA is seen more frequently in male infants than in females, which may be attributable to gender-related differences in the anatomy of the upper airway or to a protective role of female hormones. The main risk factors for OSA in the first year of life include (1) craniofacial abnormalities (eg, micrognathia, cleft palate, Pierre Robin syndrome, Treacher-Collins syndrome, choanal atresia, mucopolysaccharidoses, Down syndrome); (2) soft tissue infiltration, which may result from infection, inflammation, laryngomalacia, subglottic stenosis, and also, as in older children, adenotonsillar hypertrophy; and (3) neurologic disorders accompanied by pharyngeal hypotonia, such as Arnold-Chiari malformation, cerebral palsy, and poliomyelitis. Although the anatomic site of obstruction in infants is widely thought to be the retroglossal region, recent evidence using MRI and airway manometry suggests that upper airway obstruction with clinically significant OSA occurs in the retropalatal region 80% of the time and only 20% of the time in the retroglossal region. As noted earlier, upper airway reflexes that are greatly enhanced during early life, such as the laryngeal chemoreflex, will predispose infants to develop obstructive apneic events. Although the laryngeal chemoreflex aims to prevent aspiration of food, it is enhanced by viral infections, particularly respiratory syncytial virus (RSV) infection, which may explain the inordinately high prevalence of apnea among young babies with RSV infection. Similarly, prenatal exposure to maternal smoking, which potentiates the laryngeal chemoreflex, also increases the frequency of OSA in infants.

In summary, several potential mechanisms have been identified in the maintenance of upper airway patency during sleep and wakefulness. Each of these mechanisms, or a combination thereof, likely plays a role in the causation of respiratory compromise in the normal child during sleep or in children with clinical problems that predispose to OSA during infancy and childhood.

GENETIC AND NONGENETIC DISORDERS AFFECTING CONTROL OF BREATHING

The following sections will discuss disorders affecting the control of breathing.

CENTRAL APNEA AND HYPOVENTILATION SYNDROMES

Insufficient central respiratory drive is a primary cause of alveolar hypoventilation. The presence of a hypoventilation syndrome is suggested by the medical history as well as examination of the patient during wake and sleep. When evaluating alveolar hypoventilation in a child, all disorders that could explain this condition must be evaluated and progressively excluded to narrow the scope of the diagnosis; at the same time, a polysomnographic evaluation that includes measurements of tidal volume and carbon dioxide should be conducted. The measurement of spontaneous resting tidal volumes and noninvasive assessments of gas exchange across all sleep states should be sufficient to establish the presence and severity of alveolar hypoventilation. In the subsequent subsections, several prominent conditions leading to alveolar hypoventilation in children are reviewed.

CONGENITAL CENTRAL HYPOVENTILATION SYNDROME

Central hypoventilation syndromes can be primary (CCHS and late-onset central hypoventilation syndrome) or secondary (Table 501-1). Primary CCHS is a relatively rare entity that is being reported more frequently in the medical literature worldwide. It was originally described in 1970 and is traditionally defined as the idiopathic failure of automatic control of breathing. CCHS is a life-threatening disorder primarily manifesting as sleep-associated respiratory insufficiency and markedly impaired ventilatory responses to hypercapnia and hypoxemia. Ventilation is most severely affected during quiet or NREM sleep, a state during which automatic neural control is predominant. Abnormal respiratory patterns also occur during active sleep and even during wakefulness, although to a milder degree. The spectrum of disease in cases of CCHS is far reaching, ranging from relatively mild and often asymptomatic hypoventilation during quiet sleep with fairly good alveolar ventilation during wakefulness to recurrent and severe apneic episodes during sleep also accompanied by severe alveolar hypoventilation during waking. Likely, the wide range of clinical phenotypes may be accounted for the variance in residual chemosensitivity in these patients in addition to their genotypic characteristics. The increased awareness leading to recognition and earlier clinical management of patients with CCHS has also revealed the presence of wide-ranging structural and functional impairments of the autonomic nervous system. In particular, Hirschsprung disease and tumors of autonomic neural crest derivatives such as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma are noted in 20% and in 5% to 10% of patients with CCHS, respectively. In addition, abnormal regulation of body-temperature responses or even moment-to-moment heart rate variability is consistently documented in these patients. In recent years, 3 major advances in our understanding of the pathophysiology and treatment of CCHS have occurred: (1) paired-like homeobox 2B (PHOX2b) identification as the putative gene underlying CCHS; (2) functional imaging of neural structures in patients with CCHS, enabling major insights into the respiratory and autonomic disturbances of this syndrome; and (3) implementation of noninvasive mechanical ventilatory support among many patients, leading to improved quality of life without detriment to survival and other medical outcomes.

Many years before the discovery of the gene associated with CCHS, substantial suspicions already supported a genetic cause for this condition. Early onset during the newborn period in the vast majority of cases, along with familial recurrence of CCHS as well as parental autosomal dominant transmission patterns and the strong coassociation with Hirschsprung disease, an autosomal recessive disorder of neural crest origin, strongly supported this assumption. This association of CCHS and Hirschsprung disease further pointed to the possibility of abnormal development and/or migration of the neural crest. Finally, in 2003, a group of investigators from Paris, France, conclusively identified PHOX2B as the causative gene. Not only were mutations in PHOX2B, mostly consisting of additional polyalanine expansions, identified, but also the autosomal dominant mode of inheritance was confirmed, along with evidence of de novo mutation occurrence in the first generation. The PHOX2B gene plays essential roles in the embryogenesis of the autonomic nervous system. Furthermore, the same team subsequently showed that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous system development, namely, late-onset central hypoventilation syndrome, Hirschsprung disease, and tumors of the sympathetic nervous system such as neuroblastoma. The identification of PHOX2B mutations in the vast majority of patients with CCHS (> 95% of afflicted patients) has enabled genetic counseling and prenatal diagnosis for this condition. At the same time, the prevalence of sudden infant death syndrome is high in families with cases of CCHS, which suggests that the 2 disorders may share common abnormalities in the embryogenesis of respiratory control.

Functional and advanced structural MRI studies have further revealed disruptions in the connectivity of brain regions underlying autonomic functions. As a corollary to these anatomic findings, decreased heart rate beat-to-beat variability is consistently found in Holter recordings, and the circadian patterning of such variability further suggests major imbalances in sympathetic/parasympathetic regulation in patients with CCHS. Furthermore, alterations in regulation of blood pressure during simple daily activities or during sleep further provide evidence for autonomic nervous system abnormalities. Neuro-ocular findings are also frequently identified in children with CCHS, and marked reduction in the size of arterial chemoreceptors, carotid bodies, and intrapulmonary neuroepithelial bodies with decreased staining for tyrosine hydroxylase and serotonin support the extensive and diffuse nature of autonomic nervous system involvement.

DIAGNOSIS AND CLINICAL MANAGEMENT

The clinical presentation of CCHS is extremely variable and requires a high index of suspicion. For example, some infants will not breathe at birth and will require assisted ventilation in the newborn nursery. Such infants may or may not develop adequate breathing during wakefulness over time, but they will almost universally manifest either apnea or severe alveolar hypoventilation during sleep that will persist and become a lifelong problem. The apparent improvement that may occur during the first few months of life is most likely accounted for by the normal maturation of the respiratory system and, as such, does not represent a true change in the severity of the disorder. Other infants may present at a later age with cyanosis, edema, and signs of right heart failure and may be mistaken for patients with cyanotic congenital heart disease. However, cardiac catheterization reveals only pulmonary hypertension. Infants with even less severe CCHS may present with tachycardia, diaphoresis, and/or cyanosis during sleep, and others may present with unexplained apnea or an apparent life-threatening event. Finally, other a priori asymptomatic children will manifest sleep-associated alveolar hypoventilation following a respiratory infection or an intercurrent illness at a much later age, and, therefore, will be assigned to the diagnostic entity of late-onset CCHS. The wide spectrum of severity in clinical manifestations determines the age at which recognition of CCHS takes place. Increased awareness of this unusual clinical entity and a comprehensive evaluation of every patient are critical for early diagnosis and appropriate intervention.

Although other symptoms indicative of brain stem or autonomic nervous system dysfunction may be present, the criteria for diagnosis of CCHS usually include (1) persistent evidence of sleep hypoventilation (partial pressure of carbon dioxide [PaCO₂] > 60 mm Hg), particularly during quiet sleep (best measured by overnight polysomnography); (2) usually, albeit not exclusively, presentation of symptoms occurring during the first year of life; and (3) absence of cardiac, pulmonary, or neuromuscular dysfunction that could explain the alveolar hypoventilation. Furthermore, hypercapnic ventilatory challenges are an important component for establishing the diagnosis of CCHS. Steady-state or rebreathing incremental carbon dioxide challenges are similarly valid and will usually reveal absent or near-absent responses. Confounding variables, including asphyxia, infection, trauma, tumor, and infarction, must be discarded from CCHS by appropriate assessments. Currently, there are no specific guidelines regarding the use of genetic testing for CCHS. However, identification of mutations in genes such as RET, HASH, BDNF, GDNF, the endothelin gene family, and more particularly the PHOX2B gene, in the context of clinical manifestations supporting central alveolar hypoventilation, is highly supportive of the diagnosis of CCHS.

CCHS is a lifelong condition, and, depending on the severity of clinical manifestations, patients may require ventilatory support while asleep or as much as 24 hours a day. As such, a multidisciplinary approach to provide for comprehensive care and support of every child is needed. The treatment of CCHS should aim to ensure adequate ventilation when the patient is unable to achieve adequate gas exchange while breathing spontaneously. Because CCHS does not resolve spontaneously, chronic ventilatory support, such as positive-pressure ventilation (either via a tracheotomy or mask bilevel positive airway pressure) or negative-pressure ventilation, is required. The majority of children with CCHS initially require positive-pressure ventilation through a permanent tracheotomy, although successful transition to noninvasive ventilation has been now extensively reported, with a trend toward earlier transition to noninvasive ventilation. However, families may opt for negative-pressure ventilation as well. Daytime diaphragm pacing usually is reserved for children with CCHS who exhibit 24-hour mechanical ventilation dependency, as this approach provides greater ability to ambulate during the daytime. Issues related to the successful implementation of domiciliary mechanical ventilatory support have been reviewed recently, along with consensus recommendations. In recent years, improved pacer technology has prompted many adolescent and young adult patients to transition to this modality as well. As a rule, the diaphragm pacer settings should provide adequate alveolar ventilation and oxygenation during rest as well as during daily activities such as exercise, whereas major disadvantages of diaphragm pacing include cost, discomfort associated with surgical implantation, and potential need for repeated surgical revisions due to pacer malfunction.

LATE-ONSET ALVEOLAR HYPOVENTILATION WITH HYPOTHALAMIC DYSFUNCTION

In recent years, a series of cases presenting with alveolar hypoventilation during sleep that developed later during childhood and was associated with clinical manifestations of hypothalamic dysfunction were reported. Although underlying congenital brain stem abnormalities have not been extensively confirmed or excluded, the most characteristic manifestations in these patients consist of rapid-onset obesity in the first 10 years of life, followed by hypothalamic dysfunction, and then by the onset of symptoms of autonomic dysregulation with later onset of alveolar hypoventilation around the age of 6 years. Intriguingly, this distinct entity does not show evidence of abnormalities in candidate genes such as PHOX2B, HCRT, or necdin.

SECONDARY CENTRAL HYPOVENTILATION SYNDROMES

Patients with myelomeningocele and/or Arnold-Chiari type II malformation frequently exhibit sleep-disordered breathing (SDB), and such respiratory control disturbances are frequently suspected as causative mechanisms in the sudden unexpected deaths that occur in this population. Moderate or severe breathing disturbances occur in approximately 20% of cases. The largest proportion of cases exhibit central apnea, whereas others show obstructed breathing; obstructed cases are seldom resolved with surgical intervention for tonsillectomy, suggesting that the primary dysfunction is due to damage to central neural structures. The possible damage to vermis cerebelli structures from foramen magnum herniation in Arnold-Chiari type II malformation has the potential to interfere with both blood pressure and breathing regulation, particularly under extreme challenges of hypotension or prolonged apnea. Compression of ventral neural surfaces also is a major concern. The presence of thoracic or thoracolumbar myelomeningocele or the addition of severe brainstem malformations has been shown to enhance the potential for manifesting SDB. Support for affected patients with Arnold-Chiari II syndrome must consider the needs for recovery from pronounced hypotension during sleep, the overall respiratory disturbances that are present, and the surgical interventions required for decompression of neural structures. As such, a multidisciplinary approach is necessary and yields optimal outcomes. Of note, alveolar hypoventilation can also be acquired in a child with previously normal control of breathing, following an event resulting in brain stem injury, such as severe asphyxia, stroke, brain stem tumors, encephalitis, and infectious encephalopathies. Other important causes of secondary hypoventilation are discussed below.

PRADER-WILLI SYNDROME

Prader-Willi syndrome (PWS) was first described in 1956 by endocrinologists Prader, Labhart, and Willi. They reported on several patients with poor feeding in infancy, underdeveloped sexual characteristics, short stature, hypotonia, small hands and feet, cognitive impairment, and the onset of gross obesity after infancy. It was not until 1981 that PWS became the first recognized microdeletion syndrome identified by high-resolution chromosome analysis. PWS is now known to be one of the most common microdeletion syndromes. It is the first known human genomic imprinting disorder and is the leading known genetic cause of obesity. PWS is also associated with growth deficiency, abnormal body composition, hyperghrelinemia, hypogonadism, and specific behavioral and learning issues. PWS syndrome results when there is an absence of the normally active, paternally inherited genes on the proximal long arm of chromosome 15 and, consequently, no active copy of this genetic information. In approximately 75% of cases, the absence is due to a de novo deletion of the paternally contributed chromosome 15 between bands 15q11 and 15q13.2. Most of these cases involve the same breakpoints on the chromosome, resulting in the same 4-megabyte deletion. The remaining patients with PWS (approximately 20% of the cases) have 2 maternal copies of chromosomes 15 but no paternal chromosome 15, a phenomenon known as maternal uniparental disomy. Among the genes located in the PWS deletion region is the human necdin gene, a maternally imprinted gene thought to be involved in cell cycle control and apoptosis. The necdin gene is completely absent in the brain and in fibroblasts of patients with PWS. In the homologous mouse necdin gene, messenger RNA expression is highest in the hypothalamus, which is where the main pathology of PWS is thought to occur. Consensus diagnostic criteria for PWS were developed in 1993 to aid in early recognition and diagnosis and have since been confirmed using molecular and cytogenetic techniques. Many of the clinical features of PWS are believed to be secondary to hypothalamic insufficiency.

Patients with PWS have a unique combination of sleep- and breathing-related manifestations. Excessive daytime sleepiness and increased frequency of REM sleep periods occur in a subset of patients with PWS, while others show disturbances in circadian rhythmicity with a tendency for multiple microsleep periods. In addition, the combination of obesity and hypotonia favors the occurrence of OSA. Patients with PWS also display significant alterations in central and peripheral elements of respiratory control that, although not immediately related to the obesity, can be severely modified and exacerbated by the mechanical consequences of increased adiposity, ultimately leading to ventilatory failure. A unique and almost universal feature of these patients is the absence of ventilatory responses to peripheral chemoreceptor stimulation; this deficiency leads to abnormal arousal patterns during sleep. When untreated, obesity progressively reduces central chemosensitivity as well, with the latter being ameliorated by growth hormone therapy and increased muscle mass. However, growth hormone therapy has also been associated with reports of sudden unexpected death, the mechanisms of which remain to be elucidated.

RETT SYNDROME

Rett syndrome is a severe neurodevelopmental disorder affecting primarily females and has an incidence of 1:10,000 female births by the age of 12 years, rendering it one of the most common genetic causes of severe mental retardation in females. Rett syndrome is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a transcriptional repressor involved in chromatin remodeling and the modulation of RNA splicing. Table 501-2 depicts the diagnostic criteria for Rett syndrome as proposed in 2002.

The autonomic features of Rett syndrome include abnormalities in cardiorespiratory patterns and the presence of abnormal blood pressure responses. Some of the more prominent features of respiratory pattern abnormalities have been replicated in the murine model of this disease and should permit a better understanding on the role of MeCP2 in this respiratory phenotype. The typical respiratory abnormalities include hyperventilation, apnea, breath-holding, and rapid shallow breathing during wakefulness and occasionally during sleep. During wakefulness, breathing abnormalities are associated with behavioral agitation as well as with other stereotypic motor functions. During sleep, an increased frequency of desaturation events and periodic breathing has been reported. Girls with Rett syndrome who demonstrate hypoxemia without hypercarbia, awake or asleep, need to be treated with supplemental oxygen, whereas patients who demonstrate evidence for OSA, usually without a treatable cause, need to be treated with mask bilevel positive airway pressure during sleep, such as to prevent some of the morbidities associated with repeated desaturation episodes. Of note, recent reports using desipramine in mice suggest a potentially promising role for this pharmacologic approach in patients with Rett syndrome. In addition, a recent trial with glatiramer acetate, a compound that increases release of brain-derived neurotrophic factor (BDNF) in the brain, showed significant improvements in breathing abnormalities.

JOUBERT SYNDROME

Joubert syndrome is an autosomal recessive condition characterized by hypotonia, ataxia, psychomotor delay, and variable occurrence of oculomotor apraxia and neonatal breathing abnormalities. It is part of a cluster of conditions consisting of ciliary trafficking defects, including Joubert syndrome, Bardet-Biedl syndrome, and some forms of retinitis pigmentosa. Exome sequencing in patients with Joubert syndrome has identified a complex array of mutations in several genes underlying ciliary transport with phenotypes comprising a variety of overlapping conditions. The neuroradiologic hallmark of this unusual and rare condition is a complex midbrain-hindbrain malformation known as the molar tooth sign, which is related to the association of cerebellar vermis hypoplasia or aplasia, horizontally oriented and thickened superior cerebellar peduncles, and a deepened interpeduncular fossa. The most typical respiratory manifestations of Joubert syndrome consist of the occurrence of episodes of marked hyperpnea occasionally followed by severe alveolar hypoventilation and respiratory failure, potentially necessitating mechanical ventilation.

FAMILIAL DYSAUTONOMIA (RILEY-DAY SYNDROME)

Familial dysautonomia (FD) is one of the many hereditary diseases associated with insensitivity to pain. It is an autosomal recessive disorder with extensive central and peripheral autonomic abnormalities associated with abnormal development and survival of unmyelinated sensory and autonomic neurons, with the sympathetic system being more extensively affected. Patients with FD display inappropriate cardiovascular or catecholamine responses to physical stress, changes in position, or exercise. The gene encoding for this disorder has been identified as IKBKAP (IκB kinase–associated protein gene), and more than 99% of individuals with FD are homozygous for a mutation in intron 20, which leads to marked reductions in the correctly spliced messenger RNA in neuronal tissues and, consequently, to absent expression of the normal protein. However, other genes have been identified among variants of FD. It should be noted that although central autonomic symptoms are present, no consistent central neuropathology has been described. Many of the respiratory disturbances have been attributed to dysfunction of both chemoreceptors and baroreceptors. Typically, patients develop severe and prolonged breath-holding episodes, usually following emotional outbursts, that can result in decerebrate posturing. In addition, periodic breathing and central apnea during sleep, lack of appropriate reflexive tachypnea with respiratory infections, and inability to adapt to low-oxygen environments all are frequently reported. When sustained hyperventilation occurs, it is usually followed by prolonged apnea or even respiratory arrest, further emphasizing the abnormal chemoreceptor functions in these patients. Therefore, sleep studies and more extended cardiorespiratory recordings appear to be necessary in the evaluation and potential treatment of the respiratory disturbances frequently encountered in patients with FD.

APNEA OF PREMATURITY

Apnea in infants has been traditionally defined as a pause in breathing of greater than 20 seconds or an apneic event of less than 20 seconds associated with bradycardia and/or cyanosis. Recurrent episodes of apnea are common in preterm infants, and the incidence and severity increase as gestational age decreases. Reduced respiratory drive and impaired pulmonary function due to lung immaturity as well as a variety of mechanical factors adversely affecting respiratory mechanics will predispose the premature infant to development of apnea and hypoventilation, which, in turn, may precipitate oxyhemoglobin desaturations and/or bradycardia. Alternatively, excessive peripheral chemoreceptor sensitivity can lead to destabilization of the respiratory system by creating exaggerated ventilatory responses to small fluctuations in oxyhemoglobin saturation, which then may lead to hypocapnia below the apneic threshold and reduced respiratory drive, thereby promoting apnea. Although apneic episodes can occur spontaneously and be attributable to the interactions of prematurity and sleep state alone, such apneic events can also be provoked or worsened if there is some additional insult, such as infection, underlying hypoxemia, hypothermia or hyperthermia, or any evolving intracranial pathology. Although most of the apneic events are self-resolving and seldom prompt medical recognition or intervention, apneic events associated with hypoxemia and reflex bradycardia may require active resuscitative efforts to reverse this condition.

Idiopathic apnea of prematurity (AOP) is a common, albeit often unsuspected, problem in the clinical setting and seems to be related primarily to the immaturity of the infants’ neurologic and respiratory systems. Premature infants breathe irregularly during sleep, with markedly greater breath-to-breath variability during all sleep and waking states, and this enhanced irregularity in their pattern of breathing renders them susceptible to developing apnea. Both central and obstructive apneas are frequently reported in preterm infants, although the most common form of apnea is mixed apnea (ie, the occurrence of an initial central apnea that then develops an obstructive pattern as respiratory effort begins in the context of a collapsed airway). Mixed apnea typically accounts for more than half of all clinically relevant apneic episodes, followed in decreasing frequency by central and obstructive apnea. By definition, there is no airway obstruction in central apnea, although some studies suggest that the central airways frequently will progressively reduce their cross-sectional area and even collapse during the course of a central apnea, with a rule of thumb proposing that such airway occlusion will be more likely as the duration of the event is prolonged. Such apneic events have also been termed silent obstruction due to the lack of respiratory effort. AOP generally resolves by approximately 36 to 40 weeks of postconceptional age. However, in the most premature infants (born at 24–28 weeks of gestation), apnea may frequently persist beyond 40 weeks of postconceptional age, finally resolving by 43 to 44 weeks of postconceptional age. Beyond this developmental stage, the incidence and severity of cardiorespiratory events do not appear to differ between babies born at term and those born prematurely.

PATHOPHYSIOLOGY

Immaturity of central respiratory control and of the various ventilatory muscles and ribcage is the key element in the pathogenesis of AOP. Because breathing patterns are more disorganized during REM sleep, the predominant mode of sleep in preterm infants, it is not surprising that apneic events will be more common, longer, and more frequently associated with profound bradycardia during active or REM sleep than during quiet or NREM sleep. Premature infants have altered responses to increased CO₂ and decreased oxygen (O₂) and will, for example, reduce rather than mount an increased respiratory effort response when exposed to elevated CO₂. This remarkably different response of respiratory timing during hypercapnia is associated with prolongation of expiratory duration, which appears to be centrally mediated within the brain stem, especially via the inhibitory neurotransmitter γ-aminobutyric acid (GABA). It is also well established that premature infants exhibit a biphasic ventilatory response to decreases in inspired oxygen concentration: a rapid increase in minute ventilation associated with peripheral chemoreceptor stimulation is subsequently followed by a decline in ventilation to levels that fall below those in normoxia. The decrease in ventilation, also termed hypoxic ventilatory depression, may persist for several weeks and even months postnatally and is probably the result of interactions between the decrease in PaCO₂ in arterial blood secondary to the initial hyperventilation, the accompanying decrease in cerebral blood flow, a decrease in metabolic rate with hypoxia, the direct inhibitory effect of hypoxia on central respiratory centers and neural transmission, and the activation of inhibitory receptors such as GABAergic, adenosinergic, and/or platelet-derived growth factor β receptors. In this context, administration of adenosine receptor antagonists such as theophylline or caffeine is used routinely for the treatment of AOP.

There has been speculation that when hypoxic ventilatory depression develops, additional episodes of apnea are more likely to develop. In other words, infants experiencing more apneic episodes would have reduced initial increases in ventilation and subsequent greater depression of ventilation in response to hypoxia. However, Nock and colleagues have challenged this concept and documented increased initial ventilation but attenuated ventilatory depression during the hypoxic challenge in premature infants who developed more frequent and severe apnea. As indicated earlier, infants with more severe and/or prolonged apnea may have greater peripheral chemoreceptor sensitivity and possibly increased central respiratory drive due to the repetitive periods of intermittent hypoxia, which are known to induce a condition called long-term facilitation of ventilation, and, therefore, these changes may promote respiratory instability and thus facilitate the occurrence of further apneic episodes.

The site of obstruction during either mixed or obstructive apneic events in the upper airways of premature infants suffering from AOP is mostly within the pharynx; however, it may also occur at the level of the larynx and possibly at both locations. Integrated pharyngeal muscle dilator functions are reduced during sleep and will result in airway collapse and subsequent apnea in susceptible infants. In addition, the airway may be compromised by postural changes, such as flexing of the neck, such that spontaneous obstructive apnea in the absence of a positional issue is uncommon. Reflexes originating in the upper airway may alter the pattern of respiration and play a role in the initiation and termination of apneas. Stimulation of the laryngeal mucosa, either by chemical (ie, milk, water, saliva) or mechanical (eg, swallowing) stimuli, may induce reflex inhibition of breathing and apnea. There appears to be a maturational change in this type of reflex-induced apnea, as chemical stimulation of the larynx in newborn piglets will elicit respiratory arrest, which does not develop in older piglets. Preterm infants have an exaggerated laryngeal inhibitory reflex, which may elicit prolonged apnea in response to instilling saline in the oropharynx, GER, or during the course of RSV infection.

DIAGNOSIS

Although AOP typically results from immaturity of the respiratory control system, it also may be the presenting sign of other unrelated diseases or pathophysiologic states frequently affecting preterm infants. AOP can be diagnosed only after a thorough evaluation has been completed and all other potential causes of apnea have been ruled out (Table 501-3). They include prematurity; infection; impaired oxygenation; central nervous system problems such as intracranial hemorrhage or brain malformation; metabolic disorders such as hypoglycemia, electrolyte imbalance, fatty acid disorders, and metabolic acidosis; temperature instability; and drugs such as narcotics or anticonvulsants. Often, apnea is attributed to the occurrence of coexisting GER, but studies assessing the timing of reflux in relation to apneic events do not support this association. Furthermore, there is no clear evidence that treatment of GER will affect the frequency or severity of apnea in most preterm infants. Thus, even the presence of GER, as shown by esophageal pH monitoring in an infant with proven apnea in a sleep study, should not necessarily assign the cause of the respiratory disturbance during sleep to GER. When a high level of suspicion is present, simultaneous assessment of sleep measures and of esophageal pH and, if possible, impedance esophageal recordings are necessary to establish that GER and apnea are present and enable formulation of a more effective management plan in these infants.

As a reminder, alveolar hypoventilation, oxygen desaturation, and even frank apnea and bradycardia may occur in premature infants during nutritive sucking as the result of immaturity. In the normal healthy infant, as fluid enters the pharynx or larynx, breathing will be discontinued to protect the airway and prevent aspiration. However, this protective reflex is excessive in some premature or even full-term infants and may promote prolonged apnea. With advancing maturation, feeding-associated apneic events become less frequent and eventually disappear.

TREATMENT

Treatment usually is with either pharmacologic therapy or continuous positive airway pressure (CPAP) ventilation, although other supportive measures, such as placing the infant with the head in the midline and the neck in the neutral position to minimize upper airway obstruction, are clearly recommended. Methylxanthines have been the mainstay of pharmacologic treatment of AOP. Both theophylline and caffeine citrate can be used and are effective possibly through multiple physiologic and pharmacologic mechanisms of action. A likely major mechanism of action for xanthine therapy is through competitive antagonism of adenosine receptors, because adenosine acts as an inhibitory neuroregulator in the central nervous system.

It is important to rule out systemic conditions (sepsis), seizure disorders, and severe GER before initiation of methylxanthine therapy because these compounds will lower the seizure threshold and decrease muscle tone of the esophageal sphincter. Methylxanthines stimulate the central nervous system and rapidly decrease the frequency of all types of apnea. Xanthine therapy has been shown to increase minute ventilation, improve carbon dioxide sensitivity, decrease hypoxic depression of breathing, enhance diaphragmatic activity, and decrease periodic breathing. REM sleep may also be acutely decreased, although this effect will slowly fade over time with ongoing treatment. Caffeine has clear advantages over other methylxanthines because it more effectively stimulates the central nervous and respiratory systems and has a higher therapeutic index; as such, central nervous system toxicity is less of a concern. A recent meta-analysis on the use of methylxanthines in AOP concluded that both theophylline and caffeine are effective in reducing the frequency and severity of apneic episodes and are also of value in reducing the need for mechanical ventilation. Elimination of methylxanthines is prolonged in infants when compared to children and adults and is especially prolonged in preterm infants, and pharmacodynamics considerations should be incorporated into decisions regarding appropriate dosage. Thus, serum measurement of theophylline should be monitored whenever aminophylline or theophylline is used. Caffeine levels are less critical but should also be followed at least during the initial phases of treatment.

The decision to discontinue xanthine therapy is largely empirical, although it is to be encouraged at least 1 to 2 weeks prior to discharge from the nursery. Toxic levels of xanthines may cause tachycardia, cardiac dysrhythmias, feeding intolerance, diuresis, and seizures, although these side effects are seen less frequently with caffeine at commonly prescribed therapeutic doses. Although recent concerns about potential long-term side effects of methylxanthines on the neurodevelopmental outcomes of low-birth-weight infants have been dispelled, discontinuation of treatment as soon as possible should be pursued. Novel approaches consisting of ampakine therapy or limb-focused proprioceptive stimulation may be adopted in the future once appropriate randomized trials are conducted.

ROLE OF CONTINUOUS POSITIVE AIRWAY PRESSURE

Among the nonpharmacologic strategies widely used in the treatment of AOP, CPAP is relatively safe and effective and usually requires relatively low pressures to achieve the desired effect (3–6 cm H₂O). CPAP appears to be effective by splinting the upper airway with positive pressure and decreasing the risk of pharyngeal or laryngeal obstruction, and also by increasing FRC and improving oxygenation. Studies have also compared nasal CPAP to nasal intermittent positive-pressure ventilation (NIPPV) in the treatment of AOP and found that NIPPV reduces the frequency of apneas more effectively than does nasal CPAP, particularly when apnea is frequent or severe. In addition, high-flow nasal cannula therapy seems to be equivalently efficacious to nasal CPAP but allows for greater mobility of the infant by parents and caretakers. Of course, endotracheal intubation and artificial ventilation may be needed as a last resort when extremely severe or refractory episodes are present.

The effect of supplemental oxygen on cardiorespiratory events and sleep architecture in premature infants has also been examined, and low-flow supplemental oxygen via a nasal cannula will lead to resolution of AOP and periodic breathing. The modest increase in the concentration of inspired oxygen required to reduce AOP is probably best explained by a decrease in breath-to-breath variability. Of particular note, unsuspected cardiorespiratory events, such as apnea and bradycardia, occur very frequently in otherwise healthy premature infants, and supplemental oxygen will not only prevent these events but also improve sleep architecture. As mentioned earlier, AOP generally resolves by 36 to 40 weeks of postconceptional age, and beyond 43 to 44 weeks, the risk appears to be similar to that of term infants, such that the majority of premature infants should be AOP-free by the time they are discharged home. In this context, the safe minimum apnea-free observation period before discharge has been suggested as 8 apnea-free days. However, accurate and thorough monitoring in the neonatal intensive care unit is critical because clinically significant apneas with either bradycardia and/or desaturation will likely go unnoticed.

The clinical significance and long-term consequences of persistent apnea, bradycardia, or desaturation are still under considerable debate, particularly because idiopathic apnea is most often seen in high-risk preterm infants, such that separation of the consequences of premature birth from the specific effects of AOP is difficult. Premature infants who were followed until early school age showed that AOP was one of the predictors of poor neurodevelopmental outcomes, but this issue requires more extensive and comprehensive studies before a definitive conclusion can be reached.

OBSTRUCTIVE SLEEP APNEA

The spectrum of SDB, which includes OSA, upper airway resistance syndrome, and primary snoring, occurs in children across the complete age spectrum (Fig. 501-1). OSA is characterized by repeated events of either partial or complete upper airway obstruction during sleep, resulting in disruption of normal gas exchange and sleep patterns. OSA was initially described more than a century ago and was rediscovered in children by Guilleminault in 1976; the clinical characterization of this syndrome is, therefore, still evolving, particularly since this complex and prevalent disorder has become recognized as a major public health problem.

Common nighttime symptoms and signs of SDB include snoring, paradoxical chest and abdomen motion, retractions, witnessed apnea, snorting episodes, enuresis, frequent nightmares and night terrors, difficulty breathing, cyanosis, sweating, and restless sleep. Daytime symptoms can include morning headaches, mouth breathing, difficulty in waking up, moodiness, nasal obstruction, daytime sleepiness and tiredness, hyperactivity, and cognitive problems, with severe cases of OSA associated with cor pulmonale, failure to thrive, developmental delay, or even death.

It is clear that the classic clinical syndrome of OSA in children is a disorder that is distinct from the condition that occurs in adults, particularly with respect to gender distribution, clinical manifestations, polysomnographic findings, and treatment approaches. OSA in children is frequently diagnosed in association with adenotonsillar hypertrophy and is also a common finding in children with obesity, craniofacial abnormalities, and neurologic and muscular disorders affecting upper-airway patency.

EPIDEMIOLOGY

OSA occurs in all pediatric age groups. Although accurate data regarding prevalence in infants is missing, OSA is particularly common in young children (preschool and early school years) with a peak prevalence around 2 to 8 years of age and subsequent declines in frequency, with the latter probably related to age-related reductions in viral loads that contribute to adenotonsillar lymphoid tissue proliferation. Habitual snoring, the hallmark indicator of increased upper airway resistance during sleep, is an extremely frequent occurrence and affects as many as 27% of children, with median frequencies revolving around 10% to 12%. Although specific clinical and sleep study–based criteria that link polysomnographically defined thresholds with OSA-associated morbidity are only now being developed, the current diagnosis of OSA relies on several consensus guidelines and is currently estimated to affect approximately 1% to 4% of children. Thus, the odds for identifying OSA vary from 1 of every 4 to 6 habitually snoring children. Unfortunately, reliable identification of habitually snoring children who have OSA, on the basis of medical history and physical examination, is particularly arduous and error prone. Therefore, at this time, overnight sleep studies remain the only objective and validated diagnostic approach for establishing the diagnosis of OSA in children.

PATHOPHYSIOLOGY

OSA occurs when the upper airway collapses during inspiration, a dynamic process that involves interactions between sleep state, pressure-flow airway mechanics, and respiratory drive. When resistance to inspiratory flow increases or when activation of the pharyngeal dilator muscle decreases, negative inspiratory pressure may collapse the airway. Both functional and anatomic factors may tilt the balance toward airway collapse. For example, the site of upper airway closure in children with OSA is at the site where the tonsils and adenoids overlap in the upper airway, whereas in children with OSA in the absence of hypertrophied adenoids and tonsils, collapse is more likely to occur at the level of the soft palate. The size of the tonsils and adenoids increases from birth to approximately 12 years of age, with the greatest increase occurring in the first few years of life, albeit proportionately to the growth of other upper airway structures. However, the mass of upper airway lymphadenoid tissue will particularly proliferate in children exposed to cigarette smoking, children with allergic rhinitis, asthmatic children, and obviously, children exposed to a variety of upper airway respiratory infections, particularly viruses.

It is important to remember that although childhood OSA is associated with adenotonsillar hypertrophy, the presence of the latter does not mandatorily imply that OSA will be present. OSA is clearly the combined result of structural, anatomic, and neuromuscular factors within the upper airway, since patients with OSA do not obstruct their upper airway during wakefulness, and the correlation between upper airway adenotonsillar size and OSA is only modest at best. In addition, a small percentage of children with adenotonsillar hypertrophy but no other known risk factors for OSA will not be cured by surgical removal of tonsils and adenoids, whereas in others, postsurgical improvements may be only temporary. Therefore, childhood OSA is a dynamic process resulting from the combination of structural and neuromotor abnormalities rather than from structural abnormalities alone. These predisposing factors occur as part of a spectrum: In some children (eg, those with craniofacial anomalies), structural abnormalities predominate, whereas in others (eg, those with cerebral palsy), neuromuscular factors predominate. In otherwise healthy children with adenotonsillar hypertrophy and OSA, neuromuscular abnormalities are subtle.

ASSOCIATED CONDITIONS

OSA also occurs in children with narrowing of the upper airway due to craniofacial anomalies and in those with neuromuscular abnormalities such as hypotonia (eg, muscular dystrophy) or muscular discoordination (eg, myelomeningocele). In addition to craniofacial anomalies and abnormalities of the central nervous system, altered soft tissue size may result from obesity, infection of the airways, allergy, supraglottic edema, adenotonsillar hypertrophy, mucopolysaccharide storage disease, laryngomalacia, subglottic stenosis, neck tumors, or an enlarged thyroid gland in the context of hypothyroidism. Of particular emphasis, the global epidemic of obesity is leading to marked increases in the proportion of obese symptomatic children referred for evaluation of habitual snoring. Genetic factors clearly also play roles in the pathophysiology of OSA, as demonstrated by studies of family cohorts, but it remains unclear whether this is due to the modulating influence of genetic factors on ventilatory drive, anatomic features, or both. Ethnicity is also important, with OSA occurring more commonly in African American and Hispanic children. Table 501-4 lists the major conditions associated with OSA in children.

CLINICAL EVALUATION AND DIAGNOSIS

The clinical presentation of a child with suspected OSA syndrome is usually very nonspecific and, therefore, requires not only increased awareness but also consistent and periodic assessments using specific questions on sleep during physician visits. If symptoms are present, a thorough history should be obtained and should include detailed information pertaining to the sleep environment (Table 501-5). In the otherwise normal child, the principal parental complaint will be snoring during sleep, such that even when the clinical consultation is conducted by a sleep specialist, the predictive accuracy of OSA based on history alone is poor, and an overnight polysomnographic assessment is required. The routine physical examination of a snoring child is usually not likely to demonstrate significant and obvious findings. However, considering the very high prevalence of OSA among obese children, special attention to otherwise asymptomatic children with body mass index z-scores of greater than 1.64 is justified. Attention to the size of the tonsils with careful documentation of their position and relative intrusion into the retropalatal space should be conducted. In addition, the presence of allergic rhinitis, nasal polyps (in which case one should also screen for cystic fibrosis), nasal septum deviation, or any other factor likely to increase nasal airflow resistance should be sought. The relative size (ie, micrognathia) and positioning of the mandible (ie, retrognathia) should also be documented. Finally, attention should be paid to systemic blood pressure values and to the presence of auscultatory findings suggestive of increased pulmonary artery pressures.

Polysomnography

An overnight sleep study remains the only definitive diagnostic approach for OSA. The American Academy of Pediatrics has published a consensus statement outlining the requirements for pediatric polysomnography. Table 501-6 shows the currently recommended channels usually used in the laboratory evaluation of snoring children. Normative reference values in children are now available, and specific guidelines for definitions of events have also been recently defined. Of note, one of the differences between children and adults consists in the relative resistance of the pediatric upper airway to collapse, and as such, complete obstructive events are less likely to develop and are replaced instead by prolonged periods of increased upper-airway resistance leading to alveolar hypoventilation (also termed obstructive hypoventilation). Also worthy of mention, children with OSA may not manifest electroencephalographic arousals following obstructive apneas, and, therefore, sleep architecture is usually relatively preserved even in children with relatively severe OSA. Notwithstanding, although initial parental surveys suggested that excessive sleepiness is present among only 7% of children with OSA, more recent studies that included more specific questions on behaviors associated with excessive daytime sleepiness indicated 40% to 50% have such symptoms. When sleepiness was measured objectively using the multiple sleep latency test, approximately 13% to 20% of children with OSA displayed increased sleepiness, with obese children being much more severely affected. Esophageal catheters are used in some laboratories instead of nasal pressure catheters to assess respiratory effort.

Of note, the use of ambulatory sleep studies using restricted number of channels or assessing only specific issues during sleep (home video or sound recordings or nocturnal oximetry) is now being intensively evaluated. Generally speaking, the feasibility studies that have been performed to date have been overall successful, with several reporting > 90% of their home recordings as meeting desired quality criteria regarding signal artifact and minimum recording times. However, although type 2 studies with in-laboratory polysomnography have shown no significant differences in respiratory parameters, the accuracy results pertaining to type 3 home sleep apnea testing devices remain inconclusive, as they tend to underestimate the severity and, as such, may lead to diagnostic inaccuracies among the milder cases of OSA. In addition, the potential value of nocturnal oximetry should not be ignored, particularly in resource-limited environments.

SHORT-TERM AND LONG-TERM MORBIDITY

The consequences of untreated OSA in young children can be serious. Early reports of children with severe OSA were often associated with the presence of failure to thrive, although currently only a minority of children with OSA will present with this problem. A combination of increased energy expenditure during sleep and disruption of the growth hormone and insulin growth factor and binding proteins most likely accounts for the reductions in growth velocity. Adenotonsillectomy and complete resolution of OSA in children will result in catch-up growth and will also increase the height and weight velocities even in obese children.

Frequent oxygen desaturations during sleep are common in children with OSA. Elevation of pulmonary artery pressure due to hypoxia-induced pulmonary vasoconstriction is a serious consequence of OSA in children and can lead to cor pulmonale. Although pulmonary hypertension probably occurs more frequently than predicted from clinical assessment, the exact prevalence of this complication is unknown. In addition, whereas treatment of OSA will result in normalization of pulmonary artery pressures, some remodeling of the pulmonary circulation may have occurred. Furthermore, intermittent hypoxia may also affect left ventricular function through both direct and indirect effects on myocardial contractility, such as induced by interventricular septal hypertrophy and deviation, and will lead to increased sympathetic neural activity, and the latter will be sustained and induce changes in baroreceptor function, leading to systemic hypertension. Increased tonic and reactive sympathetic activity is present in children with OSA, and elevation of arterial blood pressure will occur. Furthermore, preliminary evidence suggests that OSA-induced disruption of baroreceptor function may not resolve after treatment and, in fact, may be lifelong in susceptible individuals. This concept in which childhood perturbations may lead to lifelong consequences deserves further exploration, particularly when considering the endothelial functional abnormalities and alterations in lipid profiles among both obese and nonobese children with OSA. The long-term implications of the cardiovascular morbidity identified in pediatric OSA patients has yet to be evaluated.

Another potentially very sobering consequence of OSA in children involves its short-term and long-term deleterious effects on neuronal and intellectual functions. Although reports of decreased intellectual function in children with tonsillar and adenoidal hypertrophy date back to 1889, when Hill reported on “some causes of backwardness and stupidity in children,” only more recently has this topic been investigated in a more systematic fashion. Schooling problems have been repeatedly reported in case series of children with OSA, and OSA may in fact underlie more extensive behavioral disturbances such as restlessness, aggressive behavior, excessive daytime sleepiness and poor test performances. Moreover, habitual snoring even in the absence of OSA has also been demonstrated to be associated with neurocognitive deficits.

There is increasing evidence to support an association between OSA and attention-deficit/hyperactivity disorder (ADHD) in children, particularly with the hyperactive/impulsive subtype. Several subjective studies have documented that children with habitual snoring and OSA often have problems with attention and behavior similar to those observed in children with ADHD. In addition, survey studies encompassing large cohorts of children have documented daytime sleepiness, hyperactivity, and aggressive behavior in children who snored.

The mechanism(s) by which OSA may contribute to hyperactivity remain unknown. It is possible that both the sleep fragmentation (ie, recurrent arousals) and episodic hypoxia that characterize OSA will lead to alterations within the neurochemical substrate of the prefrontal cortex with resultant executive dysfunction.

Inverse relationships between memory, learning, and OSA have also been documented. In addition, improvements in learning and behavior have been reported following treatment for OSA in children, suggesting the neurocognitive deficits are at least partially reversible. However, children who snored frequently and loudly during their early childhood were at greater risk for having poor academic performance in later years, well after snoring had resolved, suggesting that long-term sequelae may occur.

In rodent models, intermittent hypoxia during sleep is associated with significant increases in neuronal cell loss and adverse effects on spatial memory tasks in the absence of significant sleep fragmentation or deprivation, and these consequences are magnified during development.

Incremental evidence suggestive of adverse effects of SDB on quality of life, depressive mood, enuresis, fatty liver disease in obese children, and increased health-related costs and morbidity further reinforce the extensive and multifactorial implications of this condition.

TREATMENT

Tonsillectomy and adenoidectomy are usually the first line of treatment for pediatric OSA, and both meta-analysis and a randomized controlled trial on the efficacy of tonsillectomy and adenoidectomy suggested a relatively high immediate efficacy for this surgical procedure. Because OSA is the conglomerate result of the relative size and structure of the upper airway components rather than the absolute size of the adenotonsillar tissue, both tonsils and adenoids should be removed, even when one or the other appears to be the primary culprit. It should be emphasized that children with OSA are at risk for developing respiratory compromise postoperatively due to upper airway edema, increased secretions, respiratory depression secondary to analgesic and anesthetic agents, and postobstructive pulmonary edema. A high risk for such complications is particularly encountered among children younger than 3 years old, those with severe OSA, and those with additional medical conditions such as craniofacial syndromes; these patients should not undergo outpatient surgery, and cardiorespiratory monitoring should be performed for at least 24 hours postoperatively to ensure their stability. Supplemental oxygen results in improved arterial oxygen saturation in children with OSA without worsening of the degree of obstruction. However, because oxygen does not address many of the pathophysiologic features associated with the symptoms of OSA, it should be reserved as a temporary palliative measure prior to surgery and clearly should not be used as the first-line treatment. Furthermore, supplemental oxygen should never be used without monitoring the potential resultant changes in PCO₂ because some patients with OSA can develop unpredictable and potentially life-threatening hypercapnia when breathing supplemental oxygen. It has also recently become apparent that in a proportion of children with OSA, usually those with less severe disease or nonobese children, the condition may resolve without treatment.

There is growing evidence that the outcomes of tonsillectomy and adenoidectomy may not be as favorable as previously anticipated, particularly when OSA is severe preoperatively or when obesity is present. The frequency of residual mild OSA after surgical removal of adenoids and tonsils is estimated at 45% to 50%, with 20% to 25% displaying moderate to severe OSA after surgery. These findings have prompted a heated debate as to whether overnight sleep studies should routinely be conducted after tonsillectomy and adenoidectomy. Additional unresolved issues include the choice of the surgical technique (eg, tonsillotomy vs tonsillectomy; cold surgery vs coblation vs harmonic laser), the need for tonsillectomy and adenoidectomy versus nonsurgical approaches, and whether to use 1 of these 2 surgical procedures in isolation or to use corticosteroids.

Additional treatment options are available for the management of OSA in children before they undergo tonsillectomy and adenoidectomy, for those children who do not respond to tonsillectomy and adenoidectomy, or for the small minority in whom tonsillectomy and adenoidectomy are contraindicated. When residual OSA after tonsillectomy and adenoidectomy is moderate to severe, administration of nasal CPAP is usually preferred and is overall effective and associated with minimal complications. However, the cost-benefit ratio of CPAP in milder cases of residual OSA probably does not justify its use; other approaches are now being advocated. For example, anti-inflammatory therapy is increasingly being recognized as a potential alternative to surgery or as an effective intervention in residual mild OSA after adenotonsillectomy. In addition, favorable initial experience with oral appliances and orthodontic approaches for treatment of OSA in children are now being reported.

Selected surgical procedures have been used for complicated cases of OSA in children. Uvulopharyngopalatoplasty has been found to be useful in patients with upper-airway hypotonia (ie, those with Down syndrome or cerebral palsy). Craniofacial reconstructive procedures are usually reserved for some children with craniofacial anomalies. Other procedures, such as tongue wedge resection, epiglottoplasty, and mandibular advancement or distraction, may occasionally be indicated. With the advent of CPAP, tracheostomy is now rarely if ever required.

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INTRODUCTION

A survey from the National Sleep Foundation (NSF) has shown that 69% of children younger than 10 years of age experience some type of sleep disturbance. Significant sleep problems affect 25% to 40% of children and adolescents. These sleep problems tend to persist into adulthood if left untreated. Despite the high prevalence of sleep problems, most pediatricians do not ask questions about their patients’ sleep. A survey of community practices has shown that pediatricians acknowledge the importance of sleep problems, but they fail to adequately screen for them, especially in older children and adolescents. Untreated sleep disorders can lead to long-term consequences. Several studies have demonstrated the association between sleep disorders and cardiovascular and neurocognitive complications. Therefore, it is crucial that pediatricians recognize signs and symptoms of sleep disorders and integrate sleep issues into routine health maintenance visits. In this chapter, normal sleep development and common sleep problems encountered in general pediatric practices are discussed. Obstructive sleep apnea is reviewed in Chapter 501.

NORMAL SLEEP AND SLEEP MATURATION

Knowledge of sleep regulation, normal sleep, and its change during development is essential to understanding and recognizing sleep disorders in children and adolescents. Certain characteristics of sleep will also help in the diagnosis of sleep disorders. For example, night terrors, phenomena that occur in non-rapid eye movement (NREM) sleep, are more likely to occur during the first part of the night, whereas nightmares, rapid eye movement (REM) sleep phenomena, are common during the latter part of the night when REM sleep is predominate. Sleep is the result of a complex interaction between sleep- and wake-promoting neurons. The sleep-promoting neurons are located in the ventrolateral preoptic nucleus, which contains GABAergic and galaninergic neurons. The wake-promoting neurons are located in several areas of the brain including the lateral hypothalamus (orexin/hypocretin neurons), the posterior hypothalamus (histaminergic neurons), the pons and midbrain (cholinergic neurons), the raphe nuclei (serotonergic neurons), and the locus coeruleus (adrenergic neurons). A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep. Sleep and alertness are regulated by 2 important factors: the homeostatic factor, which depends on prior sleep duration and sleep quality and awakening time, and the circadian rhythm or intrinsic biological clock. These 2 forces interact and allow humans to have a diurnal pattern of sleep with consolidated sleep at night and wakefulness during the day. Two “sleepiness” periods occur in human. The first occurs at night between midnight and 6:00 AM, and the second occurs in the early afternoon. The circadian rhythm is affected by several environmental cues (zeitgebers) such as social interaction and timing of meals. However, the most important environmental cue is light exposure, which has different effects on the biological clock depending on the time of exposure.

Normal human sleep comprises 2 major stages, NREM and REM sleep, based on characteristic appearances of the electroencephalogram (EEG), electromyogram (EMG), and electro-occulogram (EOG). NREM sleep is subdivided into 3 stages, namely NREM 1, NREM 2, and NREM 3. NREM 1 is defined by an attenuation of high-frequency alpha wave (8–13 Hz), the presence of low-amplitude mixed frequency EEG (theta wave 4–7 Hz), the vertex shape wave, slow rolling eye movements, and a slight decrease in chin EMG compared to awake (Fig. 502-1). NREM 1 accounts for 3% to 8% of total sleep time. NREM 2 is characterized by the presence of sleep spindles (distinct waves with frequency of 12–14 Hz) and K-complex (negative sharp wave followed by a positive component) (Fig. 502-2). Humans spend 45% to 55% of total sleep time in NREM 2, rendering it the most prevalent stage of sleep. NREM 3 is typified by increased slow wave sleep (SWS) (>20% of total sleep time) (Fig. 502-3). NREM 3 accounts for 15% to 20% of total sleep time. REM sleep is characterized by a significant decrease in chin EMG; the presence of low-amplitude, mixed-frequency EEG pattern; and the occurrence of rapid eye movements (Fig. 502-4). REM sleep accounts for 20% to 25% of total sleep time.

Sleep patterns and sleep architecture undergo developmental changes from infancy to adolescence. Sleep in infants has several features that are distinct from sleep in children and adults (Table 502-1). Active or REM sleep makes up approximately 50% of the sleep time and is the dominant state of sleep in infants. Quiet or NREM sleep accounts for only 35% to 45% of total sleep time. REM sleep in premature infants can be as high as 80% of total sleep time. The percentage of REM sleep decreases with increasing age and reaches an adult proportion of 20% to 25% by 5 to 6 years of age. The sleep cycle (the total duration of NREM and REM in 1 cycle) of infants is 50 to 60 minutes, whereas that of adults is 90 to 100 minutes. In infants, NREM and REM sleep are distributed equally throughout the night. In contrast, in older children and adults, NREM sleep predominates in the first part of the night, whereas REM sleep predominates in the later part of the night. Another distinct feature of infant sleep is that the entry of sleep is through REM sleep, whereas that of children and adults is through NREM sleep. Normal full-term neonates spend most of their time sleeping (16–18 hours per day). The sleep pattern in infants is polymorphic, with several naps during the day. Infants begin to consolidate their sleep by about 3 months. By 12 months of age, infants will have a long nighttime sleep and 2 daytime naps. At 18 months of age, the naps are decreased from 2 to 1. At 5 years of age, 75% of children give up their naps; however, social and cultural difference may influence this pattern. By 6 years of age, children sleep approximately 10 to 11 hours a day, and the need for sleep does not change until adolescence.

Sleep in adolescents has unique features as a result of physiologic changes during puberty. The major change is a shift in melatonin secretion and circadian sleep phase leading to phase delay with a propensity to later sleep onset and wake-up time. In addition, social and academic demands during this period can predispose adolescents to sleep deprivation. Some adolescents cope with this problem by sleeping longer during the weekend, which can make the phase delay worse. Studies have shown that adolescents need 9 hours of sleep, which does not change across the adolescent span (10–17 years old). However, most adolescents sleep only 7 to 7.5 hours each night, which results in significant sleep debt over time. Only 15% of adolescents sleep 8.5 or more hours on school nights, and 26% of high school students sleep 6.5 hours or less each school night. Adolescents also have irregular sleep patterns that may contribute to a shift in sleep phase. The average increase of weekend over weekday sleep is almost 2 hours per night. The sleep debt in adolescents can lead to significant long-term consequences including daytime sleepiness and changes in mood, attention, memory, behavior, and academic performance.

COMMON SLEEP DISORDERS IN CHILDREN AND ADOLESCENTS

Restless Legs Syndrome and Periodic Limb Movement Disorder

Periodic limb movements during sleep (PLMS) are characterized by periodic episodes of repetitive and highly stereotypic limb movements during sleep. Periodic limb movement disorder (PLMD) is defined by the presence of periodic limb movement during sleep associated with symptoms of insomnia or excessive daytime sleepiness. Restless legs syndrome (RLS) is a clinical diagnosis characterized by the urge to move or disagreeable leg sensations that usually occur prior to sleep onset. RLS and PLMD are common in adults, with a prevalence of 4% to 10%. Recent epidemiologic studies have shown that RLS is common in children and adolescents, with an estimated prevalence of 2% to 4%. The prevalence of RLS in boys and girls is similar, whereas the female-to-male ratio is 2:1 in adult RLS. Several studies have shown the strong association between attention-deficit/hyperactivity disorder (ADHD) and RLS and PLMD, although this relationship is somewhat complex. An estimated 10% to 30% of children with ADHD may have RLS or PLMD. In addition, 44% of RLS children have been found to have ADHD or ADHD symptoms. This association has many possible explanations. First, sleep disruption associated with RLS might lead to ADHD symptoms. Second, RLS and PLMD may be a comorbidity of ADHD. Third, RLS and a subset of ADHD may share a common dopaminergic pathway abnormality. Finally, diurnal manifestation of RLS and PLMD might mimic ADHD.

Several etiologies have been proposed to play a role in the pathophysiology of RLS and PLMD and include genetics, dopamine dysfunction, and low iron stores. Recent studies have shown the roles of both genetic predisposition and genetic susceptibility in the pathogenesis of RLS and PLMD. A large population study in adults demonstrated the association between RLS and PLMD and a common variant in an intron of the protein called BTBD9 on chromosome 6p21.2. Other genetic variants such as the homeobox gene MEIS1 on chromosome 2p and the gene encoding MAP2K5 and the transcription factor LBXCOR1 on chromosome 15q have been reported in adult patients with RLS. Interestingly, one study on childhood-onset RLS has shown the association with MEIS1 and LBXCOR1, but not with BTBD9 as seen in adults. There is emerging evidence of the role of iron in the pathophysiology of RLS and PLMD. Many children with RLS and PLMD have low iron storage as evidenced by low serum ferritin and/or iron. Iron is a cofactor of tyrosine hydroxylase, a rate-limiting enzyme of dopamine synthesis. Therefore, low concentrations of iron in brain tissue may lead to RLS and PLMD through alteration of the dopaminergic system.

Children with RLS and PLMD may present with nonspecific symptoms such as restless sleep, growing pains, sleep onset and sleep maintenance insomnia, and daytime sleepiness. These symptoms often go unnoticed by parents, although a family history of RLS and PLMD is common. Young children may describe RLS symptoms with nonspecific but age-appropriate terms such as “oowies,” “tickles,” “ants crawling,” “aching feeling,” “spiders in the legs,” and “energy in the legs.” One study showed that the time between onset of clinical sleep disturbances and diagnosis of RLS is more than 10 years. RLS and PLMD are underrecognized and underdiagnosed in children.

The diagnosis of RLS is challenging, particularly because young children may not be able to describe typical RLS symptoms or because these symptoms may not manifest at very young ages. The diagnosis of RLS and PLMD in children requires specific diagnostic criteria, which have been developed by the International RLS Study Group. As in adult RLS, 5 essential RLS criteria must be met in children. They are (1) the urge to move the legs and any accompanying sensations; (2) worsening of the urge to move during rest and inactivity; (3) partial or total relief by movement; (4) worsening during the evening or at night; and (5) the urge to move not solely accounted for as symptoms primary to another medical or behavioral condition such as venous stasis, arthritis, leg cramps, or positional discomfort. In addition, specific features should be considered in making a diagnosis of RLS in children (Table 502-2). First, children must describe the RLS symptoms in their own words. Therefore, language and cognitive development determine the applicability of the RLS diagnostic criteria, rather than age. It is very important that pediatricians are aware of the typical words children and adolescents use to describe RLS. Second, as in adults, a significant impact on sleep, mood, cognition, and function is found. However, impairment is often manifest in behavioral and educational domains in children. Third, PLMD may precede the diagnosis of RLS in some cases. Finally, certain clinical features are closely associated with pediatric RLS and can be used to support the diagnosis of RLS in children. These features include PLMS more than 5 per hour, family history of RLS, or PLMD among first-degree relatives.

For PLMD, the diagnosis requires a polysomnographic study to establish a minimum PLM index of more than 5 per hour. The PLMS are characterized by a sequence of 4 or more limb movements with duration of 0.5 to 10 seconds that are separated by an interval of more than 5 seconds and less than 90 seconds (Fig. 502-5). In addition, clinicians should demonstrate that PLMS cause clinically significant sleep disturbances or impairment in daytime function, especially in educational and behavioral domains in children. Because sleep-related respiratory abnormalities such as obstructive sleep apnea and upper airway resistance syndrome can lead to arousals associated with limb movements, the movements following respiratory events should be excluded. Therefore, respiratory monitoring including nasal airflow and respiratory efforts is essential in making a diagnosis of PLMD. Finally, the PLMS are not better explained by another current sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder (Table 502-3).

Treatment of RLS and PLMD includes nonpharmacologic and pharmacologic therapy. It is important to identify precipitating factors that could worsen RLS and PLMD, including sleep deprivation, caffeine, nicotine, and alcohol. Caffeinated beverages, smoking, and drinking alcohol should be avoided in all children and adolescents with RLS. Certain medications such as selective serotonin reuptake inhibitors (SSRIs), metoclopramide, diphenhydramine, and dopamine antagonists have been shown to aggravate RLS and PLMD. Because iron deficiency and low iron stores play important roles in the pathogenesis of RLS and PLMD, iron therapy is indicated in children with serum ferritin less than 50 μg/L. Iron treatment should be avoided in children with hemolytic anemia and hemochromatosis. The dose of iron therapy is 3 mg/kg of elemental iron per day until serum ferritin is raised above 50 μg/L. It is important to periodically check serum iron and ferritin levels, and adjust the iron dose accordingly. The duration of treatment is 3 months followed by slow tapering for 1 to 2 years. Iron therapy leads to long-lasting improvement in clinical symptoms and should be considered as the initial option in children with low iron stores.

Currently, there is no US Food and Drug Administration (FDA)-approved medication available to treat RLS and PLMD in children. There is increasing literature on the use of dopaminergic medications in children. Published case reports have shown the benefit of levodopa, ropinirole, pramipexole, and pergolide in improving RLS and PLMD in children. In children with ADHD who have associated RLS and PLMD, dopaminergic medication may improve ADHD symptoms. Benzodiazepines such as clonazepam can be useful when given in combination with other medications; however, they may aggravate hyperactivity in children with ADHD. Other medications including alpha-2 ligands and opioids have not been adequately studied in children.

Rhythmic Movement Disorders

Rhythmic movement disorders are characterized by stereotypic body movements such as head banging, body rocking, and head rolling. These movements usually occur during the transition from wakefulness to sleep or following arousals to awake periods, but they may arise from any stage of sleep including REM sleep. The movements last 5 to 15 minutes but may persist for several hours. They are quite common in infants and young children. It is estimated that 59% of all infants at 9 months of age exhibit sleep-related rhythmic movements. The prevalence decreases to 33% by 18 months and to 5% by 5 years of age. This condition is, therefore, benign and typically resolves spontaneously. However, significant injury may occur from repetitive movements. Diagnosis is based on obtaining a characteristic clinical history and excluding other medical and psychiatric disorders. Rarely, rhythmic movements may be a manifestation of seizure disorders. A sleep study is not usually needed. Treatment consists of supportive care and reassurance. It is important to ensure that children are protected from injury during these episodes. In severe cases associated with injury and family disruption, medical therapy with tricyclic antidepressants or benzodiazepines such as clonazepam may be effective.

Parasomnias

Parasomnias are defined as undesirable physical events or experiences that occur predominately during entry into sleep, within sleep, or during arousals from sleep. Parasomnias can be subclassified into disorders of arousal from NREM sleep and parasomnias associated with REM sleep. Arousal disorders from NREM sleep consist of several common disorders in children such as confusional arousals, sleep terror, and sleep walking. Parasomnias associated with REM sleep include nightmares, commonly seen in children, and REM sleep behavior disorder, a rare condition in children.

Disorders of Arousal from NREM Sleep: Confusional Arousals, Sleep Terrors, and Sleep Walking

NREM parasomnias are characterized by mental confusion or confused behavior that occurs while children are in bed resulting from impaired or partial arousal from SWS. These disorders are common in preschoolers and school-aged children, and they usually resolve spontaneously. In confusional arousals, children wake up suddenly, cry, speak unintelligible words, and may appear frightened. Sleep drunkenness is probably a variation of confusional arousals. The prevalence rate of confusional arousals in children 3 to 13 years of age is 17%. Sleep terrors are characterized by episodes of abrupt frightening screams and extreme panic associated with significant autonomic arousal signs including dilated pupils, diaphoresis, piloerection, tachypnea, and tachycardia. The prevalence rate of sleep terrors is 1% to 6.5% in children. Sleep walking is characterized by repeated episodes of rising from bed during sleep and walking about. The events range from simple sitting up in bed to walking and even frantic attempts to “escape.” These episodes generally last a few minutes but may last much longer. The prevalence of sleep walking in childhood is as high as 17%. Confusional arousals, sleep terrors, and sleepwalking usually occur in the first part of the night, corresponding to prominent SWS during this period. The child typically fails to respond to comforting measures, may not recognize parents, and has no recollection of the events upon awakening. Any attempt made to awaken the child can prolong the event. These episodes can be precipitated by stress, sleep deprivation, anxiety, and environmental noises. Some studies suggest that coexisting sleep disorders such as sleep-disordered breathing and RLS can precipitate these events, resulting in persistent parasomnia.

Diagnosis of NREM arousal disorders is done by obtaining a clinical history with an emphasis on eliciting a detailed description of the event, including timing, and response to intervention. Differential diagnosis includes nocturnal partial complex seizure, frontal lobe seizure, nocturnal panic attack, nightmares, and posttraumatic stress disorder. There is no need for a sleep study for children with simple arousal disorders. A referral to a sleep center is indicated in children with an unusual presentation, persistent parasomnias, violent behaviors, or symptoms of other sleep disorders. There is no definite polysomnographic characteristic of disorders of arousals from NREM sleep. Polysomnography can support a clinical diagnosis by demon­strating precipitous arousals from SWS (Figs. 502-6 and 502-7), especially if preceding the typical features of confusional arousals, sleep terrors, or sleepwalking. In addition, a sleep study can help identify coexisting sleep disorders that could potentially precipitate arousals, such as obstructive sleep apnea, and can exclude conditions that may mimic partial arousal disorders, such as sleep-related epilepsy. Treatment consists of reassurance and good sleep hygiene in mild cases. Prevention of accident or injury during the episode should be discussed. Parents should be instructed not to intervene because such action may prolong the events. Behavioral therapy may benefit some children. Coexisting and precipitating factors such as obstructive sleep apnea should be treated. In severe cases, pharmacologic therapy with benzodiazepines (eg, clonazepam) may be indicated.

Nightmares

Nightmares are more common than are confusional arousals and sleep terrors. The prevalence is approximately 10% to 50% in preschool children. They equally affect boys and girls. In adolescents and young adults, nightmares are reported more frequently by females. Nightmares are characterized by frightening and coherent dreams that seem real and disturbing, resulting in anxiety and fear upon awakening. In contrast to confusional arousals and sleep terrors, nightmares usually occur during the latter part of the night when REM sleep predominates. The episode is usually not intense, with less autonomic agitation. Upon awakening, children are fully oriented, easily comforted, and have a clear recollection of dream content. Return to sleep after the nightmare event often is delayed. The episode can be triggered by many factors including traumatic events, stress, anxiety, and sleep deprivation. Certain medications (eg, β-blockers, amphetamines, dopamine agonists, hypnotic medications, leukotriene receptor antagonists, and certain antibiotics [erythromycin]) can precipitate nightmares. Withdrawal from REM-suppressant medications such as tricyclic antidepressants and SSRIs can lead to REM rebound, which predisposes children to nightmares. Diagnosis is based on obtaining a typical clinical history. Polysomnographic evaluation usually is not required. It may be indicated in children with unusual presentations, violent behavior, or injury during the episode to exclude other parasomnias or nocturnal seizures. Treatment includes reassurance, education, and good sleep hygiene. Eliminating or minimizing precipitating factors is important in the management of nightmares. Only children with severe persistent nightmares require further medical and psychological evaluation.

Narcolepsy

Narcolepsy is a primary sleep disorder characterized by the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. The prevalence is approximately 1:2000 to 1:3000 in the United States and 1:600 in Japan. The prevalence is equal among boys and girls. Onset of narcolepsy usually occurs during the teenage years or young adulthood. Approximately 34% of patients with narcolepsy report onset of symptoms before reaching 15 years of age, 16% before 10 years, and 4.5% before 5 years. However, the diagnosis of narcolepsy is made in only 4% of patients younger than 15 years of age. A family history of narcolepsy is present in 25% of cases. There are 2 types of narcolepsy: type I (narcolepsy with cataplexy) and type II (narcolepsy without cataplexy).

The etiology of narcolepsy is unknown; however, several factors, including genetic, environments, and infections, have been shown to play roles in the pathogenesis of narcolepsy. Certain human leukocyte antigen (HLA) genetic markers, including HLA-DR2 (DR 15) and HLA-DQ6 (HLA-DQB1*0602), are common in patients with narcolepsy. Hypocretin/orexin deficiency has been shown to play a major role in the pathophysiology of narcolepsy. Hypocretin is a neuropeptide in the hypothalamus that plays a significant role in sleep regulation, energy homeostasis, and neuroendocrine function. Human narcoleptics have 85% to 95% reduction in the number of hypocretin neurons. In addition, hypocretin deficiency is closely related to the presence of cataplexy and HLA-DQ1*0602. Decreased hypocretin activation of cholinergic neurons in the brainstem and basal forebrain may result in daytime sleepiness in narcoleptic patients. Several recent studies have shown that early onset of narcolepsy is linked to streptococcal and H1N1 infections. It is speculated that infection may trigger an autoimmune-mediated mechanism, leading to loss of hypocretin neurons.

The most common presenting symptom in children with narcolepsy is excessive daytime sleepiness despite long hours of sleep. Children with narcolepsy may present with reappearance of daytime napping after naps had previously been eliminated. Sleep episodes often are irresistible and usually occur with passive activity. Some children may describe the sleepiness as “tiredness” or “lack of energy.” In addition, narcolepsy in children has certain features that are different from those in adults. Naps in children are longer and not as refreshing compared to those in adults. Cataplexy or sudden loss of muscle tone triggered by emotional events is present in only 25% of children with narcolepsy and may develop 5 to 10 years after the onset of hypersomnia. Cataplexy usually involves striated muscle with preservation of respiratory muscles and ocular movements. The duration typically is brief with rapid recovery and without postictal confusion, but it may last a few minutes. Frequency of cataplexy varies from several episodes a day to once every few months. Cataplexy can manifest as a variety of features including buckling of the knees, head nodding, drooping of the eyelids, or an internal sensation of weakness. Cataplectic facies have recently been described in children during the onset of disease. They are characterized by facial muscle weakness, ptosis, repetitive mouth opening, tongue protrusion, and a “droopy” look. Hypnagogic hallucinations are visual, auditory, or tactile hallucinations that are vivid and often frightening. They typically occur at sleep onset, often with realistic awareness of the presence of someone or something. Patients may report unusual experiences such as being caught in a fire, impending attack by a stranger, or flying through the air. Young children are often terrified by these episodes, which may be misdiagnosed as sleep terrors or nightmares. Sleep paralysis is a transient, generalized inability to move or to speak during the transition between sleep and wakefulness. It is a frightening experience and often occurs in conjunction with hypnagogic hallucinations. Because of these unusual experiences, some children with narcolepsy may be misdiagnosed with psychiatric disorders or behavior problems.

Other associated clinical features include automatic behaviors, obesity, and disrupted nocturnal sleep. Automatic behaviors can manifest as a sloppy handwriting or performing household work without recollection in children. Obesity is common in patients with narcolepsy and is thought to be due to the interaction between hypocretin and leptin, leading to impairment of energy metabolism. Children with narcolepsy often have nocturnal sleep disruptions. Furthermore, children often present with nonspecific symptoms such as learning disabilities, poor concentration, emotional lability, and social isolation.

Evaluation for narcolepsy should start with obtaining a detailed history with emphasis on the narcolepsy tetrad and other associated features. It is important to perform a general and neurologic examination to exclude other causes of hypersomnia. The differential diagnosis includes delayed sleep-wake phase disorder (DSWPD); chronic sleep deprivation; psychiatric disorders, especially depression and substance abuse; idiopathic hypersomnia; and recurrent hypersomnia (Kleine-Levin syndrome and menstrual-related hypersomnia). Secondary narcolepsy or narcolepsy due to other medical or neurologic conditions such as hypothalamic tumor, Neiman-Pick type C disease, head trauma, multiple sclerosis, myotonic dystrophy, Prader-Willi syndrome, Parkinson disease, and multiple system atrophy should be excluded.

In addition to clinical history, a sleep study and other diagnostic tests are essential in making a diagnosis of narcolepsy. The specific sleep test for narcolepsy is overnight polysomnography with a multiple sleep latency test (MSLT). The overnight polysomnography is required before an MSLT to evaluate overall sleep quality and to exclude other causes of hypersomnia such as obstructive sleep apnea. The MSLT is performed by allowing children to take several naps in a dark room during the day. Children with narcolepsy demonstrate pathologic sleepiness with a short sleep latency and several early REM onsets during brief naps (Fig. 502-8). The typical characteristic MSLT in narcoleptic patients includes a mean sleep latency of less than 8 minutes and the presence of 2 or more REM onsets in 5 naps. However, there are diagnostic challenges for interpretation of MSLT in children. Sleep propensity in children changes with maturation and Tanner staging. There is limited normative data for sleep latency during MSLT in young children (<8 years old). In addition, the MSLT in narcoleptic children during the early stage may not show typical early REM onsets. Therefore, serial polysomnograms and MSLT may be needed to establish a diagnosis in children who are sleepy with no obvious explanation. The other diagnostic tool is measurement of levels of hypocretin-1 in the cerebrospinal fluid (CSF), which is highly specific and sensitive for narcolepsy with cataplexy. Hypocretin-1 in the CSF less than or equal to 110 pg/mL, or one-third of the mean normal control value, is used in the diagnosis of narcolepsy. This test may be useful when the subject is too young to undergo an MSLT. Diagnosis of narcolepsy requires specific criteria. In addition to excessive daytime sleepiness for at least 3 months, a positive MSLT test is needed to make the diagnosis of narcolepsy. For narcolepsy type I, the presence of cataplexy or low CSF hypocretin is essential in making a diagnosis.

Treatment for narcolepsy consists of pharmacologic and nonpharmacologic therapy. Pharmacologic therapy in children involves the use of stimulant medications and REM-suppressant medications. Stimulant medications are the mainstay of therapy for excessive daytime sleepiness. The common stimulant medications include schedule II controlled substances such as methylphenidate and dextroamphetamine. Pemoline is currently off the market due to significant liver side effects. Modafinil (schedule IV) is a new generation of stimulant medication with relatively fewer problems of drug tolerance and addiction. REM-suppressant medications are effective in managing children with REM-related symptoms such as cataplexy, hypnagogic hallucinations, and sleep paralysis. The common REM-suppressant medications used in children include tricyclic antidepressants and SSRIs such as fluoxetine and paroxetine. Venlafaxine is a serotonin and norepinephrine reuptake inhibitor and has been used in adults with benefit of less sedation, but data on children are limited. Nonpharmacologic therapy is important in children with narcolepsy. Patients and their families should be educated about the chronic nature of their condition. Parents, teachers, and employers should be aware of the symptoms of narcolepsy to avoid confusing the behaviors with laziness, hostility, rejection, or lack of interest and motivation. Children with narcolepsy can lead productive lives if they are provided with proper medical care. If possible, patients with narcolepsy should avoid jobs that require driving long distances, handling hazardous materials, or being alert for lengthy periods. Children with narcolepsy should practice good sleep hygiene, including instituting a regular sleep routine. Some children may benefit from scheduled short naps. It is essential to discuss safety issues with patients and their families. Adolescents with narcolepsy should be assessed to determine that their sleepiness is well controlled on the medication regimen prior to beginning to drive.

Behavioral Insomnia of Childhood

Behavioral insomnia of childhood is the most common sleep disorder in children. It results from the interaction between normal developmental changes in circadian rhythm and parental reaction to those changes. There are three main types: sleep-onset association type, limit-setting type, and combined type. Sleep-onset association type is characterized by the child’s dependency on specific objects or settings for initiating sleep or returning to sleep following an awakening. Limit-setting type is characterized by bedtime stalling or bedtime refusal that is the result of inadequate limit setting by a caregiver. The prevalence is estimated to be 10% to 30% of children. There is a slightly increased incidence in boys.

In sleep-onset association type, children associate their sleep with specific soothing procedures (eg, rocking, car rides, watching television), objects (eg, bottles, parents’ bed), or settings (eg, lighted condition). These children experience difficulty falling asleep at bedtime and upon nighttime awakening in the absence of particular conditions associated with falling asleep, such as the presence of parents. When those expected conditions are established, the children resume sleep relatively quickly. In limit-setting type, children stall or refuse to go to sleep, leading to sleep-onset delay. Some children may present with nighttime fears, which are the manifestation of bedtime stalling. The problems often result from parental difficulties in setting limits and enforcing a regular bedtime. For some parents, inconsistent or lack of bedtime rules can lead to prolonged bedtime struggles or bedtime refusal behavior. When parents enforce limits, sleep often occurs quickly.

The diagnosis is based on a typical clinical description from parents or other caregivers. Behavioral insomnia of childhood is quite common even in normal children; therefore, the parents or caregivers must perceive this sleep issue as highly problematic or demanding to make a diagnosis. Because infants do not develop regular sleep patterns until 3 to 6 months of age, the diagnosis cannot be entertained before 6 months of age. The American Academy of Sleep Medicine has developed the guidelines for making the diagnosis of behavioral insomnia of childhood. In sleep-onset association type, the following features are present: (1) falling asleep is an extended process that requires special conditions; (2) sleep-onset associations are highly problematic or demanding; (3) in the absence of the associated conditions, sleep onset is significantly delayed or sleep is otherwise disrupted; and (4) nighttime awakenings require caregiver intervention for the child to return to sleep. Limit-setting type includes the following features: (1) the child has difficulty initiating or maintaining sleep; (2) the child stalls or refuses to go to bed at an appropriate time or refuses to return to bed following a nighttime awakening; and (3) the caregiver demonstrates insufficient or inappropriate limit setting to establish appropriate sleeping behavior in the child. In both types, the sleep problem is not explained by another sleep disorder, medical or mental disorder, or medication use. A sleep study usually is not required unless patients have symptoms of other sleep disorders.

Treatment for sleep-onset association type includes good sleep hygiene and behavioral interventions. The extinction process involves steps to reduce parental assistance and allows children to relearn the sleep association with their own bed environment. This intervention is labor intensive and can be difficult for some children. Therefore, it is important that pediatricians are sensitive to both the parents’ and child’s needs. In limit-setting type, children may benefit from good sleep hygiene, established bedtime routines, and positive reinforcement. Several studies have shown that behavioral interventions are effective and recommended in the treatment of bedtime problems and night waking in young children.

Delayed Sleep-Wake Phase Disorder

Delayed sleep-wake phase disorder (DSWPD) is a common sleep disorder in teenagers and young adults with an estimated prevalence of 7% to 16%. It is also the major cause of sleep deprivation in this age. The onset usually starts during adolescence but may begin in early childhood. DSWPD is classified within the circadian rhythm disorders. It is characterized by sleep onset delay in relation to desired sleep time, resulting in sleep-onset insomnia and/or difficulty awakening at the desired time. The precise mechanisms underlying DSWPD are currently unknown. An abnormal interaction between the endogenous circadian rhythm and the sleep homeostatic process may play an important role in the pathophysiology of DSWPD. Certain genetic markers such as polymorphism in the circadian clock gene called hPer3 (a length polymorphism in human Per3 gene) are associated with DSWPD. In fact, a positive family history is present in approximately 40% of patients with DSWPD. Certain pediatric populations, such as those with ADHD and autism spectrum disorder, have an increased susceptibility to DSWPD.

Clinical manifestations include habitual sleep and wake times that are delayed relative to socially acceptable times. The delay usually is longer than 2 hours. Children and adolescents with DSWPD have difficulty falling asleep but have no problem maintaining sleep. They are sleepy when they have to conform to conventional sleep-wake schedules; however, when they are allowed to choose their preferred sleep schedule, they exhibit normal sleep quality and duration. The sleep deprivation in patients with DSWPD can result in daytime sleepiness, decreased school performance, behavior problems, and mood disturbances. Diagnosis can be made by obtaining a typical clinical history. A sleep diary or actigraphy is beneficial in documenting the delayed sleep phase pattern. There is no need for polysomnography to make a diagnosis. The differential diagnosis includes a normal sleep pattern with delayed schedule, chronic insomnia, inadequate sleep hygiene with insufficient sleep syndrome, depression, and substance abuse. Some adolescents and young adults maintain a delayed sleep schedule without impaired function. In addition, DSWPD should be differentiated from school avoidance and antisocial behavior in adolescents.

The management involves specific interventions to shift the sleep phase back to a socially acceptable time. These interventions include light therapy, chronotherapy, and pharmacotherapy. The light exposure affects circadian rhythm in a phase-dependent manner, which means that light has different effects on the human biological clock (circadian rhythm) depending on the time of administration. Bright light exposure in the early morning hours advances the circadian rhythm, while light in the afternoon delays the rhythm. In fact, 2 hours of bright light exposure in the morning along with light restriction in the evening has been shown to be effective in shifting the phase back to a desirable time in patients with DSWPD. For patients living in areas with limited sunlight, commercially available light boxes can provide an alternative light source. The minimum effective light intensity is 2500 lux. Chronotherapy is done by having patients intentionally delay or advance sleep onset by a few hours every day until sleep occurs at the desired time. The process is time consuming and needs close parental involvement in children and adolescents. The sleep environment during chronotherapy should be optimal, with a dark and quiet room during the sleep portion of this process. Pharmacotherapy with melatonin can be used as an adjunct therapy for patients with DSWPD. The effect of melatonin on circadian rhythm is also phase-dependent, but the phase-response curve is in the opposite direction of light exposure. Melatonin administration in the evening and early night will advance the circadian phase, and its administration in the morning will delay the phase. In patients with DSWPD, administration of melatonin in the evening is shown to be effective in advancing the circadian phase, shortening sleep-onset time, and improving quality of life. A low dose of melatonin (0.5 mg) is as effective as a higher dose (3 mg). Timing of administration is crucial such that the maximal effect occurs when melatonin is given 6.5 hours prior to dim light melatonin onset. In clinical practices, it is recommended to give a low dose of melatonin 4 to 6 hours before the scheduled bedtime. Patients with DSWPD should have a regular sleep routine by attempting to minimize variation in the sleep and wake-up times from weekdays to weekends.

AN APPROACH TO CHILDREN AND ADOLESCENTS WITH SLEEP DISORDERS

Because of the high prevalence of pediatric sleep disorders, it is crucial that pediatricians know how to recognize and screen for them. An understanding of normal sleep and its maturation is essential. The screening process for sleep problems should be integrated into routine health visits. Many screening tools for pediatric sleep problems have been developed for use in a variety of settings and for different age groups, emphasizing specific areas of pediatric sleep. One such tool, the BEARS, was developed by Owens and Mindell with the intent of addressing the most common sleep problems in children age 2 to 18 years in a primary pediatric office setting. Five basic sleep domains are incorporated and thought to represent the most common presenting sleep complaints in children. They are: bedtime problems, excessive daytime sleepiness, awakenings during the night, regularity and duration of sleep, and snoring. Because parents may not be aware of sleep problems in their children, it is important to ask both children and their parents about these issues. Developmentally appropriate trigger questions are made from each domain, with the intent of promoting further discussion after any affirmative responses.

In children and adolescents whose screening process reveals suspected sleep problems, it is important to obtain a more in-depth sleep history. Sleep habits that should be assessed include the bedtime and wake-up times on school days and nonschool days, time it takes to fall asleep, bedtime routine, night awakenings, and daytime naps. In children who snore at night, inquiries of other associated symptoms of sleep-disordered breathing, such as respiratory pauses, gasping or choking during sleep, mouth breathing, and morning headaches, should be made. For children with suspected sleep-related movement disorders, providers should ask about leg discomfort prior to sleep onset and abnormal movements of arms and legs during sleep. The presence of other parasomnias, especially nightmares, sleep terrors, sleepwalking, and violent behavior during sleep, should be reviewed. Children with hypersomnia should be assessed for other accessory symptoms of narcolepsy, including cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis. The degree of daytime sleepiness can be assessed by asking about children’s propensity to fall asleep during various daytime activities, such as in the classroom, while watching television, and while taking a shower. It is important to evaluate the effects of sleep disturbances on neurocognitive function, particularly inquiring about school performance, attention problems, and hyperactivity. Details of the sleep environment, such as use of night light level of noise, room temperature, and access to television or other screens in the bedroom, should be sought. Other sleep issues, such as cosleeping, bedtime refusal, and bedtime stalling, should be addressed. Because a variety of medications can affect sleep, a detailed history of medication use including current medications, caffeine and alcohol consumption, and cigarette smoking or environmental tobacco smoke exposure, should be obtained. In the past medical history, attention should be directed to risk factors for sleep-disordered breathing (eg, history of Down syndrome, craniofacial abnormalities, neuromuscular disease, frequent pharyngitis or tonsillitis, allergic rhinitis, or sinusitis). Certain medical conditions, such as RLS and PLMD (iron deficiency anemia and renal disease) and secondary narcolepsy (brain tumor, Prader-Willi syndrome, and myotonic dystrophy), can be associated with specific sleep disorders. Psychiatric history, such as depression, bipolar disorder, and anxiety disorder, should be obtained. It is essential to inquire about family history of sleep disorders, including sleep apnea, RLS, PLMD, narcolepsy, and parasomnias.

During physical examination, attention should be directed to physical features that are vulnerable to sleep apnea, such as obesity, nasal area (boggy nasal turbinate and reduced nasal airflow), oropharynx (tonsillar hypertrophy, macroglossia, elongated uvula, and crowded oropharynx), and craniofacial anomalies (adenoid facies, steep and retroposition of mandibular plane, maxillary hypoplasia, and elongated face). Children with suspected RLS, PLMD, or narcolepsy should have a complete neurologic examination. It is important to keep in mind that children with a sleep disorder may have a normal physical examination.

Children with suspected sleep disorders should be referred to a pediatric sleep center for further evaluation. Several studies have shown that the clinical history and examination may not reliably discriminate between primary snoring and obstructive sleep apnea syndrome. Further evaluation in the sleep center includes subjective evaluation with sleep diary and objective evaluation, including actigraphy, polysomnography, and other specialized tests such as MSLT. Sleep diary and actigraphy can provide a longitudinal assessment of the patient’s sleep schedule. They are useful in evaluation of patients with insomnia and circadian rhythm disorders such as DSWPD. The polysomnogram, or sleep study, is the diagnostic tool of choice for most sleep disorders. In addition to identifying sleep-related abnormalities, polysomnography provides information on the effect of sleep disorders on sleep quantity and quality.

SUMMARY

Despite frequently being underdiagnosed, sleep disorders are common in children and adolescents. Untreated sleep disorders can lead to significant long-term cardiovascular and neurocognitive complications, notably poor school performance and behavior problems. Therefore, it is critical for pediatricians and general practitioners to recognize signs and symptoms of sleep disorders and to integrate a process for screening sleep problems in their routine health maintenance visits. Once a sleep problem is identified, the primary care provider should have the ability to proceed with an initial assessment and know when to refer the patient to a pediatric sleep center. Referrals to a subspecialty center should be initiated, particularly for those in whom sleep-disordered breathing, excessive daytime sleepiness, sleep-related movement disorders, or an unusual parasomnia is suspected.

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INTRODUCTION

It is important to recognize the differences between the pediatric and adult upper airways to fully understand why even a relatively minor obstruction can cause significant airway compromise in children. The pediatric airway is shorter and narrower, and the larynx is placed more anterior than in adults. Young children, and infants especially, have a large tongue in relation to the small oropharynx. They also have a larger epiglottis. Signs of partial inspiratory obstruction include stridor (a high-pitched sound heard on inhalation), hoarseness, and increased work of breathing (suprasternal and intercostal retractions). Stridor can be inspiratory or expiratory, depending on whether the obstruction is supraglottic or subglottic, respectively. If the obstruction is severe or near-complete, worsening agitation, cyanosis, and respiratory failure likely will occur. Although acute stridor usually is infectious in etiology, other disorders may be present, especially when symptoms are severe or persistent. This chapter discusses inspiratory airway obstruction of infectious and noninfectious origin.

NONINFECTIOUS CAUSES OF UPPER AIRWAY OBSTRUCTION

Laryngeal Anomalies

Laryngomalacia is the most common cause of noninfectious, persistent stridor in infants. It is characterized by an omega-shaped epiglottis that is tightly curled, with varying degrees of prolapse of the arytenoid mucosa and cartilage during inspiration. The supraglottic structures prolapse into the airway, leading to obstruction during inspiration. The inspiratory stridor can begin in the first 2 weeks after birth, and it commonly worsens with crying and feeding. Choking, cough, and regurgitation frequently occur during feeding. Diagnosis can be based on the history and physical examination; however, a flexible fiberoptic laryngoscopy performed at bedside or in the clinic confirms the diagnosis. The condition usually resolves by 12 to 18 months. In more severe cases, surgery (supraglottoplasty) may be necessary. Gastroesophageal reflux disease (GERD) has been linked to laryngomalacia, and the possibility of concurrent reflux should be considered and treated. GERD may worsen the symptoms of laryngomalacia by contributing to further inflammation and edema of the larynx.

Laryngeal cysts and webs are much less common conditions that can cause airway obstruction. Depending on the degree of obstruction, they can present soon after birth. Laryngeal cysts can present with dysphagia, hoarseness, and stridor. Diagnosis is made via airway endoscopy, and treatment requires resection. Laryngeal webs are rare congenital anomalies that can present in the newborn period, causing respiratory distress and stridor. Severity of symptoms depends on the thickness of the web and whether they are incomplete or complete. The most severe condition along the spectrum of laryngeal webs is laryngeal atresia, which presents at birth and requires immediate intervention with tracheotomy. Treatment includes surgical approaches such as laryngotracheal reconstruction. Infants with congenital laryngeal anomalies should have a genetic and cardiovascular evaluation to screen for other syndromes that may occur in conjunction.

Thyroglossal duct cysts (originating from the thyroglossal duct) can present early in infancy in addition to later in childhood and even in adulthood. They can be found in the neck but can also be seen at the base of the tongue in the vallecula. Stridor, cough, and swallowing problems can occur. Laryngoscopy confirms the diagnosis, and treatment is surgical.

Subglottic Lesions

Congenital subglottic stenosis consists of narrowing of the airway lumen at the cricoid region not thought to be secondary to intubation, trauma, or other acquired causes. Common presentations include biphasic stridor (stridor that is both inspiratory and expiratory) and recurrent croup. If the stenosis is mild, it may cause symptoms only during times of upper respiratory tract infection. Differential diagnosis includes hemangiomas or cysts in the subglottic region. Airway endoscopy is necessary to evaluate the severity of the stenosis and confirm the diagnosis. Endoscopic intervention or other surgical procedures may be necessary for extremely severe cases. Milder cases, however, are managed conservatively with observation and follow-up.

Subglottic hemangiomas (congenital vascular lesions) are rare but can be life threatening because of their location and size. Symptoms can include recurrent croup, biphasic stridor, hoarseness, and cough. More than half of children with subglottic hemangiomas will also have cutaneous hemangiomas. Infants often present prior to 6 months of age. Diagnosis is confirmed by airway endoscopy. Characteristically, hemangiomas enlarge (initial proliferative phase) until 6 to 10 months of age and involute starting at about 18 months of age. There have been many reports of successful treatment with propranolol.

Laryngopharyngeal Reflux Disease

Laryngopharyngeal reflux disease (LPRD) is reflux into the larynx, oropharynx, and/or nasopharynx leading to extraesophageal symptoms. It can present with a variety of symptoms depending on the age of the patient. Infants can present with apnea, chronic cough, stridor, dysphagia, and croup. Children may present with cough, vomiting, hoarseness, or sore throat. Reflux of gastric contents into the laryngopharyngeal region can lead to chronic inflammation and edema of those tissues, increasing risk for microaspiration. Diagnosis of LPRD starts with a thorough history focusing on airway symptoms and feeding. Laryngoscopy can reveal findings such as postglottic edema, arytenoid edema, and vocal fold nodules, which are associated with reflux. Management includes lifestyle changes and medical therapy. Diagnostic testing for reflux disease and management are discussed in Chapter 389.

Vocal Cord Abnormalities

Vocal Cord Dysfunction

Vocal cord dysfunction (VCD), also known as paradoxical vocal fold motion (PVFM), is a cause of upper airway obstruction as a result of paradoxical closure of the true vocal folds during inspiration. It was described initially as being associated with underlying psychological disorders leading to emotional stress. VCD can occur across a wide range of ages from childhood to adulthood. A wide spectrum of symptoms, including throat tightness, chest tightness and pain, hoarseness, difficulty getting air “in,” cough, inspiratory stridor, dysphonia, and dyspnea, can occur. Patients may experience anxiety and panic during these acute episodes. GERD exists as a comorbid condition with VCD and should be considered and treated if necessary. VCD may be mismanaged, with a false diagnosis of asthma, and patients may be placed on unnecessary medications such as corticosteroids. Exposure to irritants, such as cleaning solutions, perfumes, or chlorine in swimming pools, has also been associated with VCD. Evaluation includes careful history and physical examination, spirometry with inspiratory loops, and laryngoscopic confirmation of vocal cord adduction during episodes. Spirometry may reveal attenuation of inspiratory flow, indicating extrathoracic airway obstruction, whereas asthma causes intrathoracic airway obstruction. Laryngoscopy after exercise challenge can also document paradoxical vocal cord motion in patients whose symptoms are related to exertion. Treatment of VCD is best carried out via a multidisciplinary approach. It involves the patient’s physician as well as a speech therapist who can focus on breathing exercises. Patient education and understanding of the condition also are extremely important.

Vocal Cord Paralysis

Neonates commonly present with inspiratory stridor caused by unilateral (often with a hoarse cry) or bilateral (often with a normal but weak voice) vocal cord paralysis. It can be caused by cardiac or thoracic surgery (eg, patent ductus arteriosus surgery) or be secondary to neurologic disease, birth trauma, or idiopathic. The possibility of other congenital airway disease (such as tracheomalacia or subglottic stenosis) should be investigated. Airway obstruction, apnea, and cyanosis are more severe with bilateral paralysis, and many infants with these conditions need intubation and tracheotomy. Diagnosis is confirmed with airway endoscopy to observe the motion and position of the vocal cords. Over time, paralysis may resolve spontaneously, but until then, the infant is at risk for aspiration with feeding. A modified barium swallow with a feeding evaluation is helpful in assessing aspiration and swallowing problems in these patients.

Recurrent Respiratory Papillomatosis

Recurrent respiratory papillomatosis (RRP), caused by human papillomavirus (HPV), commonly affects the vocal folds. HPV types 6 and 11 may cause these lesions. Patients can present with hoarseness, dysphagia, a weak or hoarse cry, and advanced lesions, stridor, and shortness of breath. The virus can be transmitted to the infant from the mother with genital HPV infection during vaginal delivery. Evaluation includes history and physical examination, followed by nasopharyngolaryngoscopy or direct laryngoscopy for visualization. The diagnosis is made on gross appearance of the lesions as well as pathology. Treatment includes surgical therapies, such as carbon dioxide laser ablation, as well as adjuvant treatments such as cidofovir injections. Unfortunately, papillomas commonly recur, and some patients require multiple procedures during their lifetimes. There is a very low risk of malignant transformation, but progression to squamous cell carcinoma has been reported. Lower airway manifestations are described below.

Foreign Bodies in the Throat

Foreign body aspiration is discussed in detail in Chapter 118. Foreign bodies may lodge just below the vocal cords or in the upper esophagus and produce symptoms similar to those of croup or asthma. There is often not a witnessed choking episode or clear history of foreign body aspiration. Physicians should have a high suspicion (of foreign body) in a toddler, for example, who presents with sudden onset of stridor, cough, and hoarseness without other signs of an upper respiratory tract infection (such as fever, rhinorrhea, or other viral prodrome). Common foreign bodies include seeds, nuts, coins, and pieces of plastic.

Upper airway and chest radiography is recommended when an abrupt onset of symptoms of upper airway obstruction occurs. Radiography of the neck/upper airway can be helpful if the inhaled object is radiopaque (coins, batteries) but not if the object is radiolucent. Endoscopic inspection and removal of the foreign body in the upper airway are performed by otolaryngology.

Hereditary Angioedema

Angioedema and hereditary angioedema are discussed further in Chapter 190. Angioedema consists of localized swelling that is distinct from urticaria, which can occur in response to several triggers, and most commonly is seen in vascular areas of the body such as the face, eyes, mouth, and oropharynx.

Hereditary angioneurotic edema is a disorder secondary to low levels of, or defective, C1 inhibitor, a protein that inactivates targets (such as C1 esterase) specifically in the complement system as well as in the clotting and kinin pathways. Unchecked activation of these mediators leads to formation of edema (via vascular permeability). The clinical manifestations are subcutaneous edema, abdominal/intestinal edema, and laryngeal edema. Episodes of laryngeal edema are rare but extremely concerning because of its serious consequences. Symptoms include stridor, hoarseness, a feeling that something is stuck in the throat (globus sensation), and respiratory distress. Acute management includes control of the airway with intubation if necessary and replacement with intravenous C1 inhibitor concentrate.

INFECTIOUS CAUSES OF UPPER AIRWAY OBSTRUCTION

Croup (Laryngotracheobronchitis)

Croup is the most common infectious cause of acute stridor and upper airway obstruction seen in children (see also Chapter 118). It is seen in the early fall and winter months, when viral upper respiratory tract infections reach their peak. The age group most frequently affected is between 6 months and 3 years of age. Several viruses can cause croup and include parainfluenza types I to III, respiratory syncytial virus, and adenovirus. Mycoplasma pneumoniae also has been implicated in croup. Many children have a 1- to 3-day history of viral prodrome consisting of nasal symptoms such as congestion or rhinorrhea and possibly fever. Subsequently, they develop a harsh, barky cough that often is described to be similar to “a barking seal or dog.” They may also have inspiratory stridor as well as respiratory distress indicated by nasal flaring and suprasternal and subcostal retractions. Stridor often is worsened with activity, crying, and increased anxiety or agitation. Typically, the course of illness lasts for no more than 1 week. The viral infection causes inflammation and edema of the airway, especially in the subglottic region. Croup is diagnosed clinically by history and physical examination. Obtaining a thorough and careful history greatly helps to differentiate croup from these other conditions. Children who have recurrent croup should be investigated for other problems beyond simply recurring viral infections, such as anatomic abnormalities or GERD.

Most children with croup do not require hospitalization; however, many will need to be evaluated in an acute care setting if they are having worsening stridor and respiratory distress. Reduction of fever and avoidance of agitation are useful, both at home and in the hospital setting. Obtaining blood work such as blood gas measurements rarely is necessary and can lead to further agitation, increasing a child’s stridor and dyspnea.

Corticosteroids continue to be one mainstay of therapy, even for more mild cases of croup. Dexamethasone, either oral or intramuscular, is effective in decreasing the severity of symptoms and hospitalization rates, and increasing resolution of symptoms. Prednisolone has also been shown to be efficacious compared with placebo for treatment of croup. Nebulized racemic epinephrine often is used to acutely relieve upper airway obstruction by decreasing edema via vasoconstriction and possibly preventing further progression and need for intubation. It will not alter the course of the illness as corticosteroids do. It is classically used in patients with more moderate to severe croup.

Acute Epiglottitis

Acute epiglottitis (also known as supraglottitis) is an infection leading to inflammation and swelling of the epiglottis, which can progress quickly to becoming a life-threatening emergency (see also Chapter 118). Prior to the standard use of Haemophilus influenzae b (Hib) vaccine, this organism was the most common cause of epiglottitis. Currently, Streptococcus pneumoniae, Staphylococcus aureus, and group A β-hemolytic streptococci are among the most common pathogens that cause this infection. It is now rarely seen in children but must be considered when an ill-appearing child presents with acute onset of stridor. Children affected are usually between 2 and 8 years old, although most recently, the age appears to be increasing. It presents quite suddenly (over 6–24 hours) with high fever, irritability, throat pain, stridor, and what is known as a “hot potato” or muffled voice. Unlike croup, the child usually has no preceding viral prodrome or cough and has an extremely ill appearance. The child will prefer to sit in the “tripod” position, leaning forward and extending the neck to open the airway and increase air entry. Eventually, it becomes hard for the patient to handle secretions and saliva, and, therefore, drooling will occur. Cyanosis, stridor, and drooling all point to advanced, severe airway swelling and impending respiratory failure due to airway obstruction.

Airway management is the first priority if epiglottitis is suspected. Therefore, obtaining blood work and aggressive attempts at visualization of the oropharynx should be avoided. Only in a child who appears stable should a cautious examination of the posterior pharynx (without the use of a tongue depressor) be attempted. Manipulating or touching the oropharynx with a tongue depressor can cause complete obstruction. The examination may reveal a grossly swollen, erythematous epiglottis, projecting beyond the base of the tongue. A definitive diagnosis of epiglottitis should occur in a controlled situation (such as the operating room) with appropriate personnel (anesthesiologist and otolaryngologist) who are trained to manage difficult airways and are able to secure the airway surgically if necessary. A lateral neck radiograph can be helpful but should not delay treatment. A “thumbprint sign,” which describes a round and thickened epiglottis, can be seen on the x-ray. Once the child has a secured airway and is out of danger of progressing to total airway obstruction, a complete blood count (CBC) and blood culture can be done and intravenous antibiotics can be started. High-dose, broad-spectrum antibiotics should be used.

Bacterial Tracheitis (Pseudomembranous Croup or Bacterial Croup)

Bacterial tracheitis is an uncommon entity but an important cause of severe upper airway obstruction. It is commonly caused by S aureus; however, Moraxella catarrhalis, S pneumoniae, and H influenzae also are seen (see also Chapter 118). Children present with symptoms similar to epiglottitis and croup. After this initial presentation, they can progress to having respiratory distress with high fever and become very ill-appearing. Lateral neck radiographs can show subglottic narrowing (steeple sign, as can be seen in viral croup) and irregularity of the tracheal air column (indicating sloughing of pseudomembranous material from the tracheal wall). Airway endoscopy reveals large amounts of mucopurulent secretions and subglottic edema. These secretions are thick and can occlude the airway. Treatment includes appropriate intravenous antibiotics as well as airway management such as endotracheal intubation if necessary.

Retropharyngeal and Peritonsillar Abscess

The retropharyngeal space refers to the area between the anterior cervical vertebrae and the posterior pharyngeal region. A retropharyngeal abscess occurs in this space either by spread of an upper respiratory tract infection (such as pharyngitis) to the retropharyngeal lymph nodes or by a penetrating oropharyngeal injury. Group A Streptococcus, anaerobic organisms, and S aureus commonly cause this disease. This infection is not common, but it needs to be diagnosed correctly and treated without delay. It is seen mostly in children younger than 4 years of age, especially toddlers, because the lymphatics that drain the retropharyngeal space atrophy by this age. Clinical presentation includes fever, dysphagia, drooling, neck stiffness, and pain. As the infection progresses and pus collects, forming the abscess, stridor and respiratory distress can develop from compression of the pharynx. The differential diagnosis includes meningitis, epiglottitis, and croup. Physical examination can reveal bulging of the posterior wall of the pharynx. Computed tomography (CT) scan of the neck is necessary to distinguish between a true abscess and cellulitis and often is used in evaluation of this deep neck infection. Treatment requires the use of appropriate intravenous antibiotics; however, surgical drainage is performed in those cases for which medical management fails. Complications can include respiratory failure, aspiration pneumonia (from abscess rupture), and spread of infection to other areas in the deep neck.

Peritonsillar infections and abscesses occur as a result of spread from an infection in the tonsils. They occur most frequently in adolescents who have recurrent tonsillitis. Fever, throat pain, decreased oral intake, and drooling are some of the symptoms seen. Both anaerobic and aerobic organisms cause this infection. Physical examination can reveal displacement of the uvula. CT scan often is used to aid in the diagnosis of abscess. Treatment includes intravenous antibiotics and may include surgical drainage. Airway obstruction is a potential complication of peritonsillar abscess.

EXPIRATORY AIRWAY OBSTRUCTION

Obstruction of the intrathoracic airways while exhaling generally results in wheezing. Other symptoms that may be associated with obstruction of airways while exhaling are cough and shortness of breath. A vast majority of children who have expiratory obstruction and wheeze have asthma, discussed in Chapter 505. However, wheezing is not related only to asthma, as discussed in this chapter.

Obstruction of lower airways is important to recognize and treat because the consequences can lead to significant complications. Obstruction of an airway may lead to atelectasis as gas is absorbed into the lung and that portion of the lung collapses. This area may fill with mucus, and the likelihood of secondary infection developing increases. With time, chronic infection can lead to formation of an abscess and/or bronchiectasis. If the obstruction is not complete, air trapping may occur, leading to hyperinflation of lung tissue that can develop emphysematous or cystic formations. These areas of hyperinflated lung can compromise adjacent healthy lung tissue.

This section focuses on entities that have signs and symptoms consistent with expiratory obstruction but are not due to asthma. Expiratory obstruction may be intraluminal (something within the airway), extraluminal (something outside the airway causing compression), or intrinsic (the airway itself is injured or unable to maintain its shape during exhalation).

Intraluminal Obstruction

Perhaps the most common cause of expiratory obstruction (other than asthma) is something within the airway either completely or partially impeding airflow. This obstruction may result from foreign bodies, aspirated particulate matter or food, gastroesophageal reflux, tumors, vascular malformations, edema, and infection. Intraluminal obstruction in intrathoracic airways can cause expiratory obstruction.

Foreign Body Aspiration

Children, more so than adults, can aspirate foreign material into the lungs. A majority of children who aspirate foreign bodies have a history of a choking or acute coughing episode, but the history may not be volunteered and should actively be sought. If the foreign body is not discovered early, there may be an asymptomatic period, and complications such as pneumonia, chronic cough, and/or dyspnea eventually occur. On physical examination, findings of a unilateral, monophonic wheeze or diminished breath sounds should suggest the possibility of foreign body aspiration. Negative radiographic studies (chest x-rays and CT scans) should not exclude the possibility of a foreign body, especially if the history and physical examination are consistent with foreign body aspiration. Most commonly, the aspirated object is food, which often does not appear on plain radiographs. Toys and other household objects are also common findings because children in their toddler years are exploring and often place objects in their mouths.

The treatment for foreign body aspiration is removal of the object as soon as possible to prevent complications. In most cases, the foreign body can be removed via rigid bronchoscopy. Rarely, thoracotomy is necessary to remove the foreign body. The most severe long-term complication of foreign body aspiration is bronchiectasis. It is a consequence of delayed removal of the object, which can obstruct mucus clearance and cause chronic infection and inflammation. Delay in treatment usually results from incorrect diagnosis of symptoms, usually ascribed to asthma.

Chronic Aspiration and Gastroesophageal Reflux

Expiratory obstruction from aspiration also can occur on a less acute basis, as with chronic aspiration of food particles, oral secretions, or stomach contents (GERD). Foreign material in the airway not only obstructs airflow but can irritate the airways, causing inflammation and mucus secretion that can further obstruct airflow. In an infant with small airways, it does not take much to cause obstruction and significant symptoms. This subject is discussed in more detail in Chapter 389.

Other Intraluminal Obstructions

Intraluminal tumors are rare occurrences in children. Bronchial adenomas, which arise from mucous glands and ducts of the airways, occur in 2 histologic types. The carcinoid type is the most common; it resembles carcinoid tumor of the gastrointestinal tract but does lead to symptoms of carcinoid syndrome. The other, the cylindromatous type, is much less common and resembles mixed tumors of the salivary gland with cuboidal or flattened epithelial cells. The carcinoid adenomas are less likely than are the cylindromatous type to become malignant.

Papillomas of the airway may occur in children exposed to HPV. They often are pedunculated, and numerous papillomas may occur throughout the airway, leading to obstruction. Although nonmalignant, they have the potential to give rise to squamous carcinoma. Furthermore, these papillomas may occur in abundance and return after surgical removal, leading to numerous procedures throughout the child’s lifetime. Upper airway manifestations are described earlier. Other benign tumors that may occur in the airways and cause obstruction include hamartomas and hemangiomas. Malignant airway tumors that occur in adults are rare findings in children, probably because most of the adult malignancies are secondary to significant and prolonged exposure to tobacco smoke; however, late diagnosis is common.

Extraluminal Obstruction

Obstruction may occur from a compressing lesion outside the lumen of the airway. Most often, these lesions are in the mediastinum and include enlarged lymph nodes, thymus (although airway compression by a large but normal thymus is rare and should suggest another diagnosis), cysts, tumors, or vascular structures. Congenital causes, such as cysts that may compress the airways, are discussed in Chapter 368.

Tumors of the mediastinum include thymic tumors, teratomas, lymphomas, thyroid tumors, and neurogenic tumors. Englargement of lymph nodes may occur secondary to hematologic malignancies, sarcoidosis, and chronic inflammatory or infectious diseases, particularly tuberculosis. Vascular and lymphatic malformations such as hemangiomas and lymphangiomas also may occur outside the airway lumen and cause compression of tracheal or bronchial airways. Characterizing the lesion by chest CT and determining the compartment of the mediastinum in which it originates (anterior, superior, middle, or posterior) will help to diagnose the lesion. Treatment of compressing lesions usually is surgical and often is necessary to prevent future complications of atelectasis, pneumonia, emphysematous changes, and the possibility of malignant conversion.

Intrinsic Airway Wall Abnormalities

Airway obstruction may be due to a defect in the airway itself. The airway may become deformed or narrowed during exhalation because intrathoracic pressures placed upon the airways exceed the ability of the airways to maintain patency.

Tracheomalacia and Bronchomalacia

Malacia, or “softening” of the airway, is a condition in which the intrathoracic airways narrow pathologically during exhalation, resulting in airflow obstruction. Tracheomalacia and bronchomalacia are the results of compromised elastic fibers in the airway walls. These elastic fibers are responsible for providing shape and structure. For the purposes of discussion, tracheomalacia and bronchomalacia are referred to as tracheobronchomalacia (TBM) unless specifically noted.

Many infants and children with TBM have an underlying or associated problem. Cardiovascular anomalies may occur in as many as 60% of the cases, and half of infants with TBM have bronchopulmonary dysplasia and/or GERD. Malacia of the airways can be primary (congenital) or secondary (acquired). Primary TBM is the result of inadequate maturation of cartilage in the trachea or bronchi. A common cause of primary TBM is prematurity, but it may also occur in term infants. Disorders associated with TBM include polychondritis, chondromalacia, Ehlers-Danlos syndrome, mucopolysaccharidoses, CHARGE and VATER anomalies, trisomy 21, DiGeorge syndrome, and 22q11 deletions. Tracheoesophageal fistula also is a cause of primary tracheomalacia that persists long after repair of the fistula. The area of the fistula can cause widening of the membranous (or posterior) portion of the trachea, leading to flattening of the trachea and a focal collapse.

More frequently, TBM occurs secondarily. It usually results from injury to the airway, as after prolonged intubation of the premature infant. Tracheostomy also can compromise airway structure and strength, leading to tracheomalacia. External compression caused by vasculature, tumors, or vascular malformations may inhibit maturation of the airway structure. Infection also may disrupt maturation of the airway, leading to TBM.

Signs and symptoms of TBM typically are wheeze or stridor. Many infants and children exhibit a harsh, barking cough reminiscent of croup. Recurrent episodes of croup should alert the clinician to the possible presence of TBM. These symptoms of wheeze, stridor, or harsh cough are due to the close approximation of the anterior and posterior walls on exhalation. Other signs and symptoms of TBM include cyanotic spells, failure to thrive, chest wall retractions, and recurrent pneumonia. Children with TBM have been shown to have more respiratory illnesses that are more severe and prolonged. An increased incidence of TBM also has been noted in patients with protracted bacterial bronchitis. Protracted bacterial bronchitis is a diagnosis of exclusion, characterized by a chronic wet cough and bronchoalveolar lavage findings of neutrophilia and positive bacterial cultures; specific diagnoses such as cystic fibrosis must be excluded.

Plain radiographs of the neck and chest are not helpful for evaluating TBM. Flexible bronchoscopy allows direct visualization of the airway. Although invasive, bronchoscopy can and should be performed with minimal sedation in order to observe the airway with the child breathing spontaneously to allow for visualization of dynamic collapse. Flexible bronchoscopy is a better alternative to rigid bronchoscopy when evaluating TBM. Bronchoscopy not only identifies the area of TBM but can determine the etiology. In some cases, the area of TBM appears pulsatile due to vascular compression. If there is external compression of the airway, CT or magnetic resonance angiography may help distinguish the cause of the compression.

The best treatment for TBM is supportive care and allowing the child to outgrow the condition. Most children with primary TBM will improve by 2 to 3 years of age, although those with tracheoesophageal fistulas may have significant problems into their adult years. Chest physiotherapy can be helpful to clear retained secretions trapped by collapsible airways. Devices that produce positive expiratory pressure can stent open collapsible airways during exhalation. Such airway clearance devices can be used to facilitate removal of retained secretions.

In extreme cases of TBM, tracheostomy or other surgical treatment may be needed. Patients who have severe TBM may have poor growth, frequent and recurrent respiratory exacerbations, or even death spells. Such patients will need an intervention to decrease their burden of breathing. A tracheostomy can stent open collapsible airways either by bypassing the level of malacia or providing a conduit for positive airway pressure. Other surgical procedures include aortopexy, external splinting, and airway stent placement. Aortopexy is a procedure in which the anterior portion of the aorta is fixed to the posterior portion of the sternum, allowing the anterior wall of the trachea to move forward. Silicone or metallic airway stents can be placed endoscopically, but their use is fraught with complications due to erosion, obstruction, infection, and, specifically in children, the need for replacement. Because of the invasiveness of aortopexies and external splinting and the complication of stents, surgical treatments for TBM are reserved for infants and children with severe, life-threatening TBM.

Bronchopulmonary Dysplasia

Infants born prematurely may have airway obstruction for reasons other than TBM. Bronchopulmonary dysplasia (BPD) is a common cause of obstruction during exhalation; this is discussed in more detail in Chapter 62.

Bronchiectasis

Bronchiectasis describes the abnormal dilation of bronchi and bronchioles that has resulted from airway damage. This damage may be the result of a congenital disease, such as cystic fibrosis, or an acquired insult, such as infection, foreign body aspiration, or systemic inflammatory disease that affects the lungs (Table 503-1). Persistent infiltrate or atelectasis of the right middle lobe may occur in individuals with bronchial stenosis, foreign body aspiration, or difficult-to-control asthma or cystic fibrosis. This so-called right middle lobe syndrome can lead to focal bronchiectasis.

Whatever the cause, the pathophysiology of airway damage is consistent. An insult occurs that incites an inflammatory reaction in the airways. Neutrophil influx damages airway walls by releasing elastases and collagenases. Since the lung parenchyma is spared, the elastic forces of the lung tissue pull these damaged airways open and ectasis (Greek for stretching) of the bronchi (Greek for windpipe) occurs. In these stretched and damaged airways, squamous metaplasia and mucous cell hyperplasia occur in conjunction with impairment of mucus clearance. As a consequence, secretions are retained in distal airways and serve as a nidus for infection. Infection further intensifies the inflammatory response, and a vicious cycle is set up for more airway damage.

Clinically, bronchiectasis presents as chronic cough with purulent sputum production. Examination may include weight loss; lung crackles, wheezes, or rhonchi; and digital clubbing. Examination of the sputum may reveal typical pathogens, with Pseudomonas aeruginosa being a bacterium that frequently causes chronic infection. Figure 503-1 demonstrates the radiographic findings encountered with bronchiectasis. Pulmonary function testing often shows findings consistent with airways obstruction.

Cystic fibrosis (see Chapter 507) is the most common congenital cause of bronchiectasis in the developed world. In low- and middle-income settings, posttuberculous and other postinfective causes should be considered

Primary Ciliary Dyskinesia

Bronchiectasis is also the end result of primary ciliary dyskinesia (PCD). Also autosomal recessive, PCD has a prevalence of 1 in 15,000 to 30,000, although this prevalence likely is underestimated because individuals with this disease are undiagnosed. Kartagener syndrome is the triad of bronchiectasis, sinusitis, and situs inversus. The underlying defect in PCD is an abnormal ciliary ultrastructure and function. Normally, the cilia that line the upper and lower airways have a synchronous beat that sweeps mucus from distal to proximal airways where the mucus that has foreign material can be expectorated or swallowed. In PCD, the cilia demonstrate an abnormal beating pattern or no motility at all, leading to stasis of mucus secretions. Retained mucus leads to upper and lower respiratory tract infections, and left unchecked, these infections can cause significant damage. In the lower airways, recurrent and chronic infections can lead to bronchiectasis. The diagnosis of PCD can be difficult to establish. The diagnosis seldom is considered in children who have frequent, recurrent respiratory tract infections because such infections are common in this age group. Certainly, nasal congestion is a symptom of PCD that can occur in all individuals, but in the child who has nasal congestion from birth, PCD should be considered. Most notably, patients with PCD will have a year-round, wet cough starting in infancy. Other factors that would alert the clinician to the diagnosis of PCD are neonatal respiratory distress, wheeze, bronchiectasis, and recurrent sinusitis and otitis media. Nonrespiratory issues that would raise suspicion of PCD include situs inversus or other heterotaxic syndromes, complex congenital heart disease, ectopic pregnancies, and male infertility.

The most important factor in diagnosing PCD is considering the diagnosis, after which screening and diagnostic tests help establish a diagnosis. Diagnosis requires phenotypic features of disease and a combination of variables depending on age because not all ciliary defects result in abnormal findings on all tests. In children older than 5 years of age who are capable of performing lung function testing, nasal nitric oxide can be measured and is concerning if significantly low. Electron microscopy of biopsied airway tissue can be evaluated for ultrastructural defects in dynein arms, central apparatus, and/or radial spokes of cilia, which identifies approximately 70% of PCD cases. High-speed video microscopy of biopsied tissue can be used to assess for abnormal beat frequency and waveform. This technique, similar to nasal nitric oxide measurement and electron microscopy assessments, is frequently available only at specialty centers and requires expertise in interpretation to avoid false-positive or false-negative results. Recently, there have been significant advancements in our understanding of the genetic etiologies of PCD. Bialleleic mutations in 1 of more than 30 known PCD-associated genes can also provide definitive diagnosis of PCD in an estimated 70% of patients by using a commercially available panel.

Much of the treatment of PCD has been adopted from experience with cystic fibrosis. Enhancing mucociliary clearance with chest physiotherapy and monitoring and treating acute exacerbations with antibiotics remain the mainstay of treatment. As with cystic fibrosis, individuals with PCD can become infected with organisms such as S aureus, H influenzae, and P aeruginosa. Intense monitoring and treatment such as identifying and treating infections are important to stabilizing lung function. Inhaled medications such as bronchodilators, hypertonic saline, and mucolytics have been used to aid in mucus clearance and are recommended on a case-by-case basis. Genetic counseling should also be offered to parents of an affected child or those who are carriers of known disease-causing mutations.

Bronchiolitis Obliterans

Bronchiolitis obliterans affects small and medium-sized airways, causing expiratory obstruction and wheeze, but unlike asthma, the expiratory obstruction is not reversible with bronchodilators. Bronchiolitis obliterans is seen primarily in individuals with chronic rejection after lung transplantation and in those with graft-versus-host disease secondary to allogeneic bone marrow transplantation. It can occur in previously healthy individuals as well, although this occurrence is unusual.

Chronic rejection is quite common in the transplanted lung and manifests as bronchiolitis obliterans. This condition is present in greater than 50% of transplant recipients who survive to 5 years. Bronchiolitis obliterans is a heterogeneous disease that may have an insidious or rapid onset. It rarely occurs in the first 6 months after transplantation. Its median time to diagnosis after transplant is 16 to 20 months. Certain factors appear to place a lung transplant recipient at considerable risk. Acute rejection is thought to have significant effects on the development of later chronic rejection. Other risk factors responsible include human leukocyte antigen mismatching, cytomegalovirus pneumonitis, other respiratory viruses (influenza, respiratory syncytial virus, parainfluenza virus, adenovirus), donor factors (underlying asthma, smoking, head injury as a cause of death), and gastroesophageal reflux. In addition, nonadherence to the medical regimen should be considered. In patients with allogeneic bone marrow transplantation, it is estimated that up to 10% of those with active graft-versus-host disease develop bronchiolitis obliterans.

One of the first clues to the presence of bronchiolitis obliterans is a decrease in small airways function with forced expiratory flow (FEF) of 25% to 75%, and symptoms of cough, mucus production, and dyspnea. The patient’s symptoms may be difficult to distinguish from acute infection. Some have no symptoms and are identified only by screening lung function tests, which display airways obstruction and even air trapping. High-resolution CT scanning with inspiratory and expiratory views can demonstrate air trapping in bronchiolitis obliterans.

In the nontransplant patient, bronchiolitis obliterans may occur as a result of several different insults, with the most frequent being infection, often adenovirus. Clinical entities associated with bronchiolitis obliterans are listed in Table 503-2. Bronchiolitis obliterans occurs as infection or other insult leads to acute and chronic inflammation that causes fibrosis of the airway and subsequent obliteration of the airway lumen.

In some instances, the process occurs early in life and thus may lead to arrest of maturation in the lung, resulting in Swyer-James-MacLeod syndrome. This syndrome occurs as a manifestation of a postinfectious obliterative bronchiolitis. The involved lung does not grow normally because the bronchiolitis leads to diminished blood supply and diminished alveolarization, resulting in hyperlucency noted radiographically. It is usually the result of an infectious process, and adenovirus, Mycoplasma, Staphylococcus, pertussis, Streptococcus, influenza, and respiratory syncytial virus have been implicated. Noninfectious causes of Swyer-James-MacLeod syndrome include inhalation injuries, foreign body aspiration, radiation therapy, and lung transplantation.

Patients with Swyer-James-MacLeod syndrome often are asymptomatic, and it may be discovered serendipitously on chest radiography. Others develop cough, hemoptysis, dyspnea, and chest pain. Physical examination may reveal unilateral wheezing, diminished airflow in the affected lung, hyperresonance during percussion, and unilateral small chest. In most cases, oxyhemoglobin saturations are normal but may decrease when the patient exercises. Radiographic findings, aside from hyperlucency, include mediastinal shift toward the normal lung on exhalation or decreased diaphragmatic excursion on the affected side. CT scan demonstrates the hyperlucency and is also helpful in excluding most focal causes of obstruction to airflow. Ventilation-perfusion scanning of the chest can identify air-trapped areas of the lung and will display a matched ventilation and perfusion defect of the affected areas.

Treatment for bronchiolitis obliterans in the nontransplant patient and Swyer-James-MacLeod syndrome consists of monitoring for infection and avoidance of any further injury such as aspiration, reflux, or inhalation injury. Occasionally, the affected lung may develop a chronic infection or bronchiectasis. In this situation, lobectomy or pneumonectomy should be considered. However, in most cases, the prognosis for Swyer-James-MacLeod syndrome is excellent and minimal, if any, morbidity occurs. Treatment for bronchiolitis obliterans secondary to transplantation involves enhancing immunosuppression and aggressive treatment of infection. Unfortunately, bronchiolitis obliterans secondary to transplantation is unrelenting and very difficult to treat. The morbidity and mortality rates attributed to bronchiolitis obliterans in the transplanted individual are quite significant. In the individual who has bronchiolitis obliterans due to chronic rejection after lung transplantation, the 3-year survival approximates 50%. Because of its devastating effects, monitoring for bronchiolitis obliterans and its risk factors are of paramount importance in the transplanted individual.

SUGGESTED READINGS

INTRODUCTION

Pulmonary aspiration is defined as the passage of foreign material or fluid into the lungs during inspiration. Although food or gastric contents are considered the main culprits, anything from saliva to plastic toys can be aspirated. Aspiration of saliva and gastric contents can occur in normal individuals silently, especially at night. The degree of pathology seen in aspiration syndromes relates to the volume, the type and causticity, and the chronicity of material aspirated. Pathologic aspiration events can be divided into 2 main categories: acute and chronic. The acute events include large-volume aspiration of gastric contents or other fluid, hydrocarbon aspiration, near drowning, and foreign body aspiration. The chronic events include recurrent, small-volume aspiration of saliva, food, upper airway secretions, or gastroesophageal reflux disease (GERD). Large-volume aspiration events (with the exception of many cases of foreign body aspiration, discussed in more detail in Chapter 118) are usually witnessed and can be addressed directly. Recurrent small-volume aspirations often are silent and more difficult to diagnose and manage. It is important to recognize the risk factors to properly diagnose aspiration (Table 504-1).

PATHOGENESIS AND EPIDEMIOLOGY

The true hazards of aspiration were not reported in the medical literature until 1946, when Mendelson described the clinical and pathologic findings in obstetric patients who aspirated large-volume gastric contents. He described the “asthma-like” symptoms of these patients and then showed in animal models that acidic material, with pH less than 2.5, caused inflammation, damage, and desquamation of the mucosa in the lungs. Small amounts of aspirated material are usually cleared without consequence. Large-volume aspiration of gastric contents causes a pneumonitis that is the same as that seen with near drowning and consists of desquamation of the epithelium of the bronchi, bronchioles, and alveoli; edema; and hemorrhage. There is a secondary infiltrate of neutrophils and fibrin around the alveoli with resulting atelectasis. Within 48 to 72 hours, hyaline membranes begin to form, and fibroblasts start to proliferate in an effort to repair. Repair of the epithelium may require 2 to 3 weeks, but scarring, chronic inflammation with lymphocytes, and even bronchiolitis obliterans may occur. The pathophysiology of lung damage from smaller volume, recurrent aspiration arises from the inflammatory cascade triggered by the aspiration. Levels of interleukin-8 and tumor necrosis factor-α are increased, and a significant neutrophilic migration to the site of aspiration occurs, with subsequent activation and sequestration of the neutrophils. This process leads to epithelial damage, increased permeability, decreased compliance, and, over time, scarring. Acid is irritating and induces inflammation in the airway. Even aspiration of materials with a pH higher than 2.5 induces pneumonitis in an animal model. This finding would indicate that when aspiration of gastric contents occurs regularly, pulmonary disease ensues. There is no difference in the extent of neutrophilic infiltration between acidic (from stomach acid) and neutral (direct aspiration) aspirated food. Animal models support dysregulation of surfactant proteins when infant formulas are transiently aspirated, confirming the damage food alone can induce. When it is saliva being aspirated, the aspirate contains bacteria and yeast that are potentially pathological to the lungs if aspirated in large enough quantities or frequently. Recurrent pneumonia or even pulmonary abscesses may occur. In these cases, aspiration of oral secretions, not inflammation due to food or gastric acid, is the main source of lung damage.

The epidemiology of aspiration syndromes is age-dependent, occurring most frequently in children and the elderly. Large-volume aspiration often occurs at times of suppressed consciousness, such as during general anesthesia. Small-volume aspiration occurs at any time but is more common at times of stress and illness. There are several clinical states and syndromes that predispose someone to aspiration (see Table 504-1).

CLINICAL MANIFESTATIONS

Large-volume aspiration is usually apparent, with a witnessed aspiration event. Without a witnessed event, the clinical symptoms on presentation vary depending on the quantity of aspirate and the nature of the aspirate (Table 504-2). Mendelson’s classic description of aspiration pneumonitis can occur and consists of respiratory distress and cyanosis within 2 hours of the event. The symptoms that should raise concern are acute-onset dyspnea, fever, cyanosis, hypoxemia, diffuse crackles on lung exam, and chest radiograph with infiltrates in dependent lung fields.

Typical symptoms of aspiration due to swallowing dysfunction include coughing, wheezing, choking, and gagging that is temporally related to the intake of food. It may be intermittent, occurring only at times of stress such as during upper respiratory tract infections; it may be positional; and it often changes over time with growth and development. Unfortunately, direct aspiration of food can also be silent, especially in neurologically compromised children, so it is important to have a high index of suspicion. Repeated bouts of direct aspiration can lead to significant morbidity from recurrent bronchitis or pneumonia and bronchiectasis as well as chronic hypoxia and dyspnea. Left untreated, children can die from respiratory failure.

There is evidence that GERD, with or without aspiration, is associated with respiratory symptoms such as cough, wheeze, pneumonia, and apnea. There is also evidence of an association of GERD with lung disease, documented by improvement in pulmonary symptoms with treatment of GERD. A causal relation between GERD and respiratory symptoms due to aspiration is much more difficult to prove. We know that stimulation of esophageal receptors by GERD can cause reflex bronchospasm, cough, and wheeze without actual aspiration of GERD. Laryngeal exposure to acid decreases the sensation of the larynx, diminishing its ability to defend against aspiration, so chronic GERD without aspiration may eventually lead to GERD with aspiration.

The clinical symptoms of aspiration of oral secretions include choking and gagging as well as chronic or intermittent cough and wheeze and recurrent pneumonia. Additionally, children with these symptoms often have sialorrhea with drooling and pooling of saliva in the mouth. They often have overt choking on their saliva and may improve when positioned so saliva runs out of the mouth. Many of these children are developmentally delayed, although cranial nerve palsies, vocal cord paralysis, laryngoesophageal cleft, and craniofacial abnormalities also lead to inability to handle saliva appropriately. In these children, swallowing is severely dysfunctional, not allowing them to swallow saliva appropriately, and their laryngeal sensation is abnormal, not allowing them to protect their airway adequately. Recurrent pneumonia or even pulmonary abscesses are possible.

DIAGNOSIS

Many tools are available to evaluate possible aspiration. Given the overlapping nature of processes that lead to aspiration, more than one tool often is employed.

As mentioned earlier, large-volume aspiration often is a witnessed event and needs no additional inquiry. Diagnosis of the complications of large-volume aspiration, such as pneumonia and lung damage, may, however, require additional tools.

Discovering aspiration starts with understanding what material is being aspirated: food or liquid from the mouth, gastric contents, or saliva. Table 504-3 summarizes the diagnostic approach.

Video Fluoroscopic Swallowing Study

The video fluoroscopic swallowing study (VFSS) is the gold standard for evaluating swallowing function. Barium-marked liquids and foods are given to a child by a speech therapist while a radiologist obtains fluoroscopic images. It allows the evaluation of all stages of swallowing including oral, pharyngeal, and esophageal and detects issues with bolus formation, timing, pooling, penetration, aspiration with or without cough clearance, impaired passage, and regurgitation. It distinguishes issues with different consistencies of food and liquid and allows for a feeding plan be developed by the speech therapist.

Fiberoptic Endoscopic Evaluation of Swallowing/Sensory Testing

Fiberoptic endoscopic evaluation of swallowing (FEES) is a newer procedure done by a physician with a speech therapist. The physician places a flexible laryngoscope through the nasal passage of the child while awake, and the speech therapist feeds the child dyed food or dyes the saliva. This technique allows direct visualization of the larynx with observation of the swallowing mechanism with or without feeding. Pooling of secretions and penetration or aspiration of oral secretions can be seen with a small amount of dye added to the secretions. Sensory testing involves graduated puffs of air delivered to the larynx to determine the threshold necessary to induce protective laryngeal reflexes and can help distinguish those at risk for aspiration. There is good evidence that this testing can predict the tendency toward aspiration without giving the child a feeding. This study can be useful to detect aspiration of either saliva or feedings.

Flexible Bronchoscopy with Bronchoalveolar Lavage

Flexible bronchoscopy performed under anesthesia is used to evaluate the airway for anatomic lesions predisposing a child to aspiration as well as a way to obtain material from the lower airway. The use of a lipid-laden macrophage index (LLMI) obtained during bronchoscopy is used most often as evidence of aspiration of food. Washings from the bronchoalveolar lavage (BAL) are stained for lipid (from food) in the macrophages. However, finding lipid in the lower airways does not help determine whether the lipid came from GERD or from direct aspiration due to swallowing dysfunction. Not finding lipid, however, is a strong indicator against aspiration of GERD or food. Using alternative markers of GERD aspiration is a topic of significant research. In recent years, pepsin has been studied and found to have good correlation with respiratory symptoms when found in the airways. Milk proteins have been evaluated without much success. Having a marker specific to GERD versus food would help distinguish between direct aspiration and aspiration of GERD. Currently, bronchoscopy results must be used together with other evidence of GERD, absence of swallowing issues, and clinical findings to formally diagnose aspiration of GERD. Use of flexible bronchoscopy with BAL to detect aspiration of saliva is also problematic. Whereas the presence of significant oral secretions visually in the lower airway during flexible bronchoscopy may be indicative of aspiration, there is no proven marker of saliva in the BAL. Salivary amylase is an obvious target, but studies have failed to confirm its utility. Like the diagnosis of GERD on bronchoscopy, the diagnosis of salivary aspiration must be made conjunctively with clinical findings and the results of other testing.

Upper Gastrointestinal Series/Barium Esophagram

This simple test detects the presence of reflux of swallowed barium. Its advantages are that it is simple, inexpensive, and quick. It also detects certain anatomic lesions such as vascular rings and malrotation. Unfortunately, it captures GERD only if GERD happens to occur during the study, and it cannot quantify GERD. Unlike the VFSS, it can detect GERD, not aspiration, and must be used in conjunction with direct evidence of aspiration.

Esophageal pH or Impedance Monitoring

Esophageal pH monitoring is considered the gold standard for detecting GERD. Most studies are done with 2 pH channels, one just above the lower esophageal sphincter and the other in the posterior pharynx. It detects drops in pH, indicating the presence of acid from the stomach at those 2 levels. Done over 24 hours, it is a reasonable test of GERD of acid. It cannot, however, detect nonacid reflux or acid reflux events that occur after a pH drop but before pH normalization. Because of its limitations, it must be performed in individuals who are not on acid-suppressive medication. The presence of acidic stomach contents can be confirmed by first placing the distal channel into the stomach and then removing it to the distal esophagus. Alternatively, the distal channel is left in the stomach so the percentage of time the gastric contents are acidic can be determined.

Multichannel intraluminal impedance with pH monitoring (MII-pH) is a newer technique that has certain advantages over traditional pH monitoring. It can measure the change in electrical impedance along the length of the esophagus. It can track the movement of gas or liquid boluses, both anterograde and retrograde; detect both acid and nonacid liquid boluses; determine if the bolus is being swallowed or refluxed; and determine how high along the esophagus the bolus moves. It is better able than is pH monitoring to detect pharyngeal-level reflux, and in one study in infants, it detected a large number of events that correlated with respiratory symptoms on sleep study, only 12% of which were acid. Unfortunately, MII-pH is not as widely available due to startup costs and technical support for the procedure.

Both studies will diagnose GERD, but neither study, even with pharyngeal channels, can detect aspiration. These studies must be used in conjunction with direct evidence of aspiration.

Gastroesophageal Scintigraphy/“Milk Scan”

Milk scan has been used as a physiologic means of determining aspiration of GERD. Technetium-99m is mixed with a child’s milk or food, and the child is allowed to eat. Serial radiologic images are then captured to detect tracer in the lungs. Unfortunately, this test does not clearly distinguish between aspiration from swallowing and aspiration from GERD. It also seems to have a low sensitivity. In one study, positive scans were found in only 6% of children with cerebral palsy, a group of children who have a much higher prevalence of aspiration, based on is VFSS and salivagrams. This test, however, is much less invasive than bronchoscopy and does not require a great deal of radiation, allowing multiple uses if necessary. In children with a gastrostomy, it can distinguish between GERD and swallowing dysfunction if the radiotracer is given via the tube.

Dye Studies

In the case of aspiration of GERD, dye studies are helpful only if the child has a gastrostomy or jejunostomy and a tracheostomy tube. Dye can be mixed with tube feedings and detected with tracheal suctioning. If aspiration is seen, it is accurate and helpful. If not, it may be falsely negative. In assessing salivary aspiration in a child with a tracheostomy, dye is placed on a child’s tongue and detected by suctioning stained secretions from the tracheostomy. Its sensitivities and specificities are similar to those when dye is mixed with oral or tube feedings; if aspiration is seen, it is accurate, but false negatives occur regularly.

Radionuclide Salivagram/“Spit Scan”

This test is often considered the gold standard for detection of salivary aspiration. Its accuracy, however, has not been evaluated. Similar to gastroesophageal scintigraphy, this test involves using a small amount of radiotracer placed on the tongue, in the buccal pouch, or as a continuous infusion. Subsequent detection in the lower airways or lungs can diagnose aspiration of the oral secretions. The test is usually readily available and may be used because of its simplicity, noninvasive nature, nonreliance on oral feeding, and low radiation exposure. Studies have shown positive salivagrams in 26% to 28% of children suspected of aspirating oral secretion, but none of these studies had any confirmatory tests, most being done prior to use of FEES. This test also has poor agreement with VFSS and milk scan, but it has been used successfully in one case to titrate nocturnal tracheal positive pressure. It also has been correlated with abnormal chest radiographs. There is no doubt that the salivagram can detect salivary aspiration. It appears, however, that many children who might, at least intermittently, aspirate their saliva are missed with this test.

Chest Radiograph

Radiographic testing is not diagnostic of recurrent pulmonary aspiration and cannot distinguish among the types of aspiration. It can, however, give evidence of pulmonary inflammation or damage and help us to assess the pulmonary impact of the aspiration.

Chest radiographs may show peribronchial thickening, atelectasis, scattered infiltrates, or hyperinflation. In advanced cases, bronchiectasis may also be present. Radiographs obtained during acute aspiration pneumonia are more likely to show active disease with segmental or lobar infiltrate, especially in dependent areas of the lung (Fig. 504-1).

High-Resolution Computed Tomography of the Chest

High-resolution computed tomography (HRCT) scanning gives more precise information about lung damage than do plain radiographs (Fig. 504-2). These scans demonstrate the detail of bronchiectasis, “tree-in-bud” opacities, and air trapping more clearly. These findings often are seen in children who aspirate, especially in dependent portions of the lung. Findings may be present before clinical symptoms of chronic lung disease are present, so obtaining an HRCT should be considered in most children with potential chronic pulmonary aspiration. Any single HRCT is a single point in time. Serial HRCT can follow progression or resolution of lung damage with time and interventions. High-resolution technique is preferred because it provides more detail.

TREATMENT

In large-volume aspiration, if the material aspirated was particulate, flexible or rigid bronchoscopy may be useful to remove the particulate matter; otherwise, the management is largely supportive. Once the aspiration event has occurred, the airway epithelial damage is present, like a burn. There is no way to neutralize the acid to prevent injury. Supplemental oxygen for hypoxemia, mechanical ventilation for respiratory failure, and intravenous fluids to support vascular volume all are indicated. The use of systemic corticosteroids in both animal models and human trials of aspiration pneumonitis has had mixed results. Generally, steroids are not recommended. Empiric antibiotic use in aspiration pneumonitis is common but has not been rigorously evaluated. Good outcomes have been reported in patients who did not receive antibiotics, but given the reported rates of bacterial superinfection as high as 50% and the difficulty assessing whether infection is a contributing component, antibiotics usually are used. A general rule is that antibiotics are not necessary until signs or symptoms of superimposed bacterial infection are present. With bacterial superinfection, there is often increased or new fever; worsening respiratory symptoms with cough, wheeze, crackles, or respiratory distress; increased leukocytosis; or new findings on chest radiograph. This complication is seen more frequently in individuals with predisposing risk factors such as tooth or gum disease, intubation, indwelling lines, immunosuppression, or chronic gastric acid suppression. The source of bacteria usually is the mouth but might also be stomach contents. Organisms vary by age, underlying condition, and prior antibiotic use. Initial treatment should be with penicillin, ampicillin, and antibiotics geared toward anaerobes. Clindamycin and metronidazole may be used in conjunction with penicillin to improve its efficacy. If the aspiration pneumonia has occurred in an institutionalized individual or one with significant underlying medical problems, including long-term antibiotic use, additional treatment with second- or third-generation cephalosporins may be warranted. Immunocompromised children may need very broad antibiotic coverage until cultures are able to guide specific therapy. Supplemental chest percussion and postural drainage may be useful if atelectasis or pneumonia is present. Drainage of pleural effusions or empyemas is indicated.

For treatment of swallowing dysfunction with aspiration, feeding therapy is vital. Speech-language pathologists and occupational therapists often serve as these professionals. There is no medication that will help swallowing itself. Feeding modalities include thickening liquids and limiting certain consistencies, positioning to aid swallow, and pacing feeds. Using certain nipples on bottles, straws, and sippy cups may all help pacing. If feeding cannot be accomplished safely, a child may need to be taken off all oral feeding. Motility issues may contribute to swallowing dysfunction and must be addressed. Certain anatomic issues such as cricopharyngeal achalasia and laryngoesophageal clefts will lead to aspiration from swallow and can be surgically addressed. Silent aspiration may also occur due to central lesions, and diagnosing and treating these lesions are important.

For GERD with aspiration, medical treatment is the first line of treatment. It includes the use of thickened feeds, which has been shown to decrease nonacid reflux events by MII-pH. Pharmaceuticals include histamine blockers, such as ranitidine and famotidine, and proton pump inhibitors, such as omeprazole. Acid blockade renders gastric contents more neutral, decreasing their toxicity to the airway if aspirated, but it does not prevent aspiration of GERD. Prokinetic agents are also used, but choices in the United States are limited, and effectiveness is questionable. Metoclopramide has not had widely proven efficacy and has side effects that may limit its use. Erythromycin also is used, at both antimicrobial and low-dose options mainly in infants, with mixed results but without significant side effects. It has had some efficacy on antral gastric motility. Domperidone is available as a promotility agent outside the United States, but it also has not been demonstrated to be clearly effective against GERD, and concerns have been expressed about cardiac side effects. No pharmacologic agents have been tested specifically against aspiration.

For children who have failed medical therapy for GERD, fundoplication is the surgical option of choice. Generally, fundoplications are successful with good outcomes, but surgical complications are still possible. When fundoplications are too tight, they can impede movement of food, liquid, and saliva into the stomach, leaving it in the distal esophagus and increasing the likelihood of aspiration. Improvement of pulmonary symptoms with fundoplication occurs in 48% to 92% of children. Recurrence of GERD occurs in approximately 10%, but in most cases, repeat fundoplication can be performed successfully. Children with neurologic disorders have a higher rate of failure of fundoplication, approximately 25%. These are the same children who are at higher risk for aspiration, so reevaluation for GERD is warranted if symptoms persist. Evaluation for complicating pathology, including dysmotility and eosinophilic esophagitis, should be performed before fundoplication because these children are most likely to have complications such as retching and failure to improve from surgery. In children who have failed fundoplication for GERD or who have contraindications to fundoplication, another option is feedings into the jejunum. Placement of a surgical jejunostomy will allow for full feeds with reduced risk of GERD and aspiration. Aspiration of gastric secretions is still possible. If temporary feeding into the jejunum is necessary, placement of a nasoduodenal tube or gastrojejunal tube is possible, but these tubes obstruct the pylorus and/or lower esophageal sphincter, impeding passage through these openings. They are also prone to displacement, requiring radiologically guided replacement. All duodenal or jejunal feedings must be done as a continuous drip, and jejunal tubes carry the risk of inducing intussusception.

A final option in extreme cases of GERD with aspiration for which other options have all failed is esophagogastric separation with permanent gastrostomy tube for feeding and esophageal drainage into the jejunum. Unfortunately, even with this procedure, there seem to be complications because a high number of these children appear to mishandle their oral secretions, aspirating them instead of gastric contents.

The first line of therapy for aspiration of saliva is pharmacologic to reduce salivary flow. Some studies have evaluated behavioral modification to control drooling, with positive results, but none of them actually decreases salivary flow. Reduction of salivary flow can be accomplished by anticholinergics. Glycopyrrolate administered orally at a dose of 0.04 to 0.1 mg/kg/dose will reduce the amount of saliva but may have diminishing effects the longer a child takes it. Glycopyrrolate also is associated with anticholinergic side effects such as flushing, urinary retention, constipation, behavior changes, and mucus plugging that may cause some children stop taking it. Mucus plugging is the most concerning because it may cause respiratory distress or even be life-threatening. Using antihistamines such as cetirizine for drooling has had anecdotal success. Scopolamine patches tend to be more successful than are antihistamines, with fewer side effects. Because treatment usually is accomplished with a patch, titration can be difficult. Generally, a single patch is applied every 72 hours, although partial patches also have been tried. No studies have shown that medical treatment actually prevents aspiration or resultant lung damage even though it reduces salivary flow.

Injection of botulinuum toxin into the salivary glands can paralyze the glands and reduce saliva production. All studies of this therapy have demonstrated improvement of sialorrhea, but length of response varies. There does seem to be a need for repeat therapy as the toxin wears off; no long-term studies of efficacy of repeated doses have been done. There has not been any study of the impact of injection of botulinuum toxin on aspiration or lung disease.

Surgical options include ligation of salivary ducts or removal of certain salivary glands. This therapy can serve to decrease salivary flow permanently. Ligation of the ducts of the parotid and submandibular glands or excision of the submandibular glands and ligation of the parotid ducts have been used with good success in children. Two studies have also shown a reduction in hospitalizations and lower respiratory tract infections in children who have undergone the procedures. Prospective studies and comparisons with other techniques such as botulinum injection still need to be assessed.

Another option is insertion of a tracheostomy tube. It alone does not decrease salivation and cannot prevent aspiration. It does allow for suctioning of aspirated saliva to hopefully prevent pneumonia. Some children who aspirate saliva require tracheostomy for upper airway obstruction and other reasons. There is evidence that swallowing is affected in children with tracheostomy, which may render children more prone to aspiration. If a child is placed on positive-pressure ventilation, aspiration may be less likely to occur because of the positive pressure in the lower airway impeding passive influx of saliva.

The definitive treatment for salivary aspiration is physical separation of the upper airway from the lower airway. It is accomplished by separating the larynx from the trachea with the trachea diverted to a permanent stoma. A complete laryngectomy may also be performed. This surgery will prevent aspiration of saliva and may allow for oral feedings, but it will prevent phonation and may not be reversible. It has been associated with a decrease in the incidence of pneumonias in children. It should be considered in children with intractable aspiration who are experiencing progressive lung damage or life-threatening pneumonias.

PREVENTION

The most appropriate way to prevent aspiration syndromes is to treat the underlying risk factors and contributors. Start by recognizing that all children potentially aspirate. However, certain underlying conditions render aspiration more likely to occur (see Table 504-1). Proactive suspicion involves asking questions of caregivers about the presence of symptoms (see Table 504-2). Diagnosis and treatment of potential swallowing disorders, GERD, and salivary aspiration, as described above, must occur. Speech-language pathologists, occupational therapists, physical therapists, and feeding therapists all are integral to helping children swallow effectively and should be used proactively. Keeping the lungs clear is an important concept that will prevent complications. Use of adequate pulmonary toilet with manual chest physiotherapy, oscillating chest wall therapy, and cough assist treatments may be necessary not only for treatment but also for prevention. Certain pulmonary medications, such as bronchodilators, inhaled corticosteroids, or even cyclic antibiotics for pulmonary infection prophylaxis, may help. Even prophylactic invasive or noninvasive mechanical ventilation during sleep may prevent pulmonary aspiration.

A corollary to prevention is close monitoring. These children should have regular visits with their primary care practitioner and need to have regular pulse oximetry, chest physical exams, chest radiography, and pulmonary function testing if possible. Deterioration should trigger further evaluation. HRCT scan of the chest should judiciously be repeated to check progression of any lung disease. Use of other tools as repeat evaluations should be used as deemed necessary.

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INTRODUCTION

Asthma is a chronic condition associated with significant health and economic burden to patients, families, and society. Its symptoms of cough, wheeze, shortness of breath, and chest tightness are associated with variable airflow limitation that is at least partly reversible. Asthma is estimated by the World Health Organization to affect 150 million people worldwide, and its global pharmacotherapeutic costs exceed $5 billion per year. Although patients suffering from asthma share similar clinical symptoms, the disease itself is heterogeneous in terms of phenotypes and natural history. This heterogeneity is compounded by combinations of environmental exposures that occur in utero, in early life, and across the life span, which contribute to the difficulty in both studying and treating asthma. This challenge is especially evident in children, for whom asthma remains the leading cause of emergency care and hospitalization rates continue to rise.

EPIDEMIOLOGY

Currently, there are no national measures of the incidence of asthma and the rate at which it develops over time. However, the prevalence of asthma has been tracked by the National Health Interview Survey (NHIS), which is used to produce annual health estimates based on self-report of a nationally representative sample. Prevalence identifies the population in need of effective measures to control asthma symptoms. Between 1980 and 1995, the prevalence of asthma among children 0 to 17 years of age more than doubled, from 3.6% in 1980 to 7.5% at the peak of the trend in 1995. Although the prevalence rate has leveled off since then, prevalence remains high, and in 2005, 12.7% of children had been diagnosed with asthma at some point in their lifetime (9 million children), of whom 70% were reported to currently have asthma (6.5 million). Although some countries have seen a decline in asthma-related hospitalizations and deaths, the global burden for patients from exacerbations and day-to-day symptoms has increased by almost 30% in the past 20 years. Nearly two-thirds of these children who currently have asthma reported at least 1 attack in the previous 12 months. Ambulatory care use for asthma has continued to grow since 2000, while the overall rate of ambulatory care use for children has not increased. Despite increased overall healthcare utilization and the fact that there are means to prevent attacks or exacerbations among children with asthma, the majority of children with asthma still suffer from attacks. Furthermore, the burden of avoidable emergency department visits and hospitalizations for asthma is high and has remained resistant to intervention. It is estimated that at least 70% of all children who have asthma have persistent asthma.

In a recent systematic review, all existing childhood asthma prediction models were assessed for their potential to identify preschool children who will develop asthma at school age. Twelve prediction models were identified, and no single model was able to predict asthma development.

Racial disparities in childhood asthma are extensive. Children of American Indian or Alaska Native descent have current asthma prevalence rates 25% higher and black children 60% higher than those of white children. African Americans are 4 times more likely to be hospitalized and 5 times more likely to die of asthma than are non-African Americans. When race and ethnicity are considered, Puerto Rican children have the highest prevalence of all groups, 140% higher than that of non-Hispanic white children. In light of these differing prevalence rates, the lower rate for ambulatory care visits among black children compared with white children suggests that black children may be underutilizing ambulatory care. Rates in adverse outcomes such as emergency department visits, hospitalizations, and death are substantially higher for black children. The disparity in asthma mortality rates between black and white children has increased in recent years. The relative importance of urban residence, low socioeconomic status, or minority (particularly black and Hispanic) status as independent risk factors for increased asthma morbidity and mortality remains controversial.

PATHOGENESIS

Asthma Heterogeneity: Role of Phenotypes and Endotypes

The concepts underlying asthma pathogenesis have changed dramatically over the last 5 years, and our understanding of this complex disease continues to evolve. It is now clear that asthma is not a single disease but rather a syndrome that can be caused by numerous distinct biologic mechanisms. Epidemiologic, clinical, genetic, genomic, immunologic, and molecular approaches have been used to classify clinically relevant variants of asthma, with the goal of maximizing the efficacy of treatment. This effort has led to the concept of “phenotype” versus “endotype.” A disease phenotype describes observable characteristics and consists of common patterns of clinical observations; phenotypic variants of asthma can be identified by natural history (age of onset, age of remission), sex, lung function, bronchial reactivity, exacerbation frequency, and severity of clinical symptoms (eg, symptom, physiology, behavior, biochemical marker, natural history). Cluster analyses of well-characterized asthma cohorts have identified several distinct clinical phenotypes in adults and children. However, these phenotypes have limited ability to improve management or guide treatment choices because the phenotypes often overlap and do not relate to specific underlying pathophysiologic mechanisms. This gap in understanding led to concerted efforts to define asthma endotypes. An asthma “endotype” is a disease subtype that is defined by a distinct functional or pathobiologic mechanism. Molecular biomarkers are used to define asthma endotypes. The biomarkers can include patterns of allergic sensitization, serum factors or proteins, metabolites, genetic/genomic and epigenetic markers, immunologic patterns, and sputum or blood cellularity. The linkage to pathogenic mechanisms renders recognition of endotypes especially valuable, as knowledge of pathogenic mechanisms of specific variants of asthma may serve as a more precise guide to treatment. Molecular differences likely exist even within endotypes, as well as overlap in inflammatory features among endotypes.

Inflammation has a central and consistent role in the pathophysiology of asthma, regardless of the severity or subtype of asthma. Airway inflammation in asthma is found in patients with mild, moderate, and severe disease. The pathologic features of the asthmatic airways include denudation of the airway epithelium, mucus overproduction, goblet cell hyperplasia, basement membrane thickening with variable subepithelial fibrosis, bronchial smooth muscle hyperplasia, and cellular infiltration with eosinophils, lymphocytes, and neutrophils (Fig. 505-1). Airway narrowing and subsequent airflow limitation lead to clinical symptoms in acute exacerbations of asthma whereby bronchoconstriction occurs quickly to narrow the airways in response to exposure to a variety of triggers including allergens, irritants, and viral infection. In some persons who have asthma, airflow limitation may be only partially reversible due to permanent changes in the airway that increase airflow obstruction and airway responsiveness, known as airway remodeling (which may have occurred antenatally).

The inflammatory response in the airways of patients with asthma is caused by genetic and environmental interactions that prompt an orchestrated series of events initiated by an interplay between the airway epithelium and the innate and adaptive immune system, driving a chronic inflammatory response (Fig. 505-2). Environmental factors are critical determinants of the development, persistence, and progression of asthma. Specific exposures in susceptible children during critical stages in development (especially during early life while the respiratory and immune systems are maturing) give rise to changes in developmental trajectories, which are in part mediated by changes in epigenetic markers and multigene regulation. The resulting asthma-related endotypes and intermediate phenotypes precede and may predict the development of the different clinical expressions of asthma.

The immunohistopathologic features of asthma include epithelial injury and infiltration of inflammatory cells, consisting of eosinophils, lymphocytes, mast cells, neutrophils, and phagocytes. Inflammatory mediators released by these cells include cytokines, chemokines, lipid mediators, and proteases, which are the effectors of chronic inflammation. Differing asthma phenotypes, including eosinophilic asthma, neutrophilic asthma, and mixed eosinophilic and neutrophilic asthma, have been described based on the nature or pattern of inflammation. The recruitment of eosinophils and neutrophils is dependent on cytokines and chemokines, and recent data suggest that the specific T-cell types may be important in characterizing clinically relevant endotypes.

Eosinophilic Asthma

The most predominant and clearly described endotype is eosinophilic asthma, which accounts for approximately 50% to 60% of the total asthma population. Most of these patients can be controlled on moderate to high doses of inhaled corticosteroids (ICS), but 5% to 10% have severe disease that requires oral corticosteroids to control the eosinophilic airway inflammation. In these patients, eosinophils are often increased in the blood (≥ 400/mL) when asthma is severe or uncontrolled. Type 2 innate lymphoid cells (ILC-2s) have been implicated in the pathogenesis of this form of asthma. ILC-2s become activated in response to the epithelial cell–derived cytokines interleukin (IL)-33, IL-25, or thymic stromal lymphopoietin (TSLP) and release mediators associated with a T_H2 response. ILC-2s have been reported to secrete 40-fold more IL-5 and 10-fold more IL-13 than T cells. IL-5 and IL-13 that are locally produced by steroid-insensitive ILC-2s may contribute to persistent sputum eosinophilia in patients who may have normal blood eosinophils. The release of these cytokines is induced by proteases, which are present in various allergens, viruses, and bacteria.

Other biomarkers have been suggested to identify eosinophilic asthma. Forced exhaled nitric oxide (FeNO) is possibly the most widely used method in clinical practice for the evaluation of airway inflammation because of the availability of a Food and Drug Administration–approved device (NIOX, Aerocrine, Sweden). However, the degree of correlation between FeNO and sputum eosinophils is low. A systematic review found that tailoring treatment based on FeNO failed to reduce the number of exacerbations, both in adults and children, and could potentially be harmful, as it was associated with use of higher ICS doses in children.

Neutrophilic Asthma and Mixed Eosinophilic/Neutrophilic Asthma

The presence of neutrophils in asthma is often characterized by more severe asthma, poor asthma control, a greater need for more potent and multipronged treatment approaches, and treatment resistance, especially to corticosteroids. The presence of eosinophils varies in “neutrophilic” asthma, but recent studies suggest that most patients have airway neutrophilia in combination with persistent airway eosinophilia, regardless of atopic status. The mixed cellular inflammatory state is accompanied by the presence of mixed cytokines. The presence of IL-17A is consistent with the neutrophilic infiltrate because IL-17A induces the expression of neutrophilic chemokines, resulting in neutrophil influx. Recently, exposure to numerous environmental factors including traffic-related air pollution (TRAP) and fungi has been shown to result in T_H17 responses and severe asthma characterized by neutrophils and eosinophils.

Frequent Exacerbator

Exacerbations of asthma, including those that require emergency department care or hospitalization, occur variably in patients across all levels of severity. Although patients with severe asthma are more likely to have frequent exacerbations compared with patients suffering from mild and moderate disease, a proportion of asthmatics with milder phenotypes are exacerbation prone. These observations suggest that patients with frequent exacerbations may represent a separate phenotype of disease with potentially unique pathogenetic mechanisms. In line with this suggestion is that although improving baseline asthma control with inhaled glucocorticosteroids can reduce the risk of exacerbations in patients with atopic asthma, a decrease in asthma symptoms does not always reduce the number or severity of exacerbations. Recent evidence supports that it is a distinct endotype. In a genome-wide association study, CDHR3 was identified as a susceptibility locus for this phenotype. CDHR3 has been reported to serve as a receptor for human rhinovirus (HRV) type C strains.

ENVIRONMENTAL RISK FACTORS FOR CHILDHOOD ASTHMA

The impact of the environment, including lifestyle factors (eg, obesity, diet/nutrition), on the incidence and morbidity rates of asthma is increasingly being recognized. The increasing prevalence and marked variations in the proportion of children with asthma in different countries and in migrating populations over this relatively short period of time cannot be explained by genetic differences alone and strongly implicate environmental causations.

Allergens

The association of asthma and allergy has been long recognized, first in cross-sectional studies and more recently in prospective studies. Immunoglobulin (Ig) E–mediated hypersensitivity to environmental allergens is present in the majority of children and young adults with asthma, and exposure to allergens appears to be involved in the initial development of asthma, as well as the exacerbation of existing asthma. Exposure to allergens is linked to sensitization, which is a risk factor for development of asthma. However, the role of allergens in the development of asthma is complex and is yet to be fully defined. Numerous epidemiologic studies have shown that children who grow up on traditional farms are protected from allergic sensitization and asthma. Studies support that the protection may be due to activation and modulation of innate immune responses by microbial exposures. Similarly, observations from longitudinal birth cohort studies have revealed that exposure to dogs in early life also protects against the development of asthma. Environmental influences may have different effects on disease during specific “windows of opportunity” or times when the child is most vulnerable. Allergy testing is recommended for patients who have persistent asthma.

Secondhand Smoke

Despite the overall decrease in tobacco use in the United States over the last decade, the prevalence of cigarette smoking remains high in urban populations. An estimated 50% to 75% of children have detectable levels of serum cotinine, a nicotine metabolite. Families with lower incomes and education levels have disparately higher levels of parental reported secondhand smoke (SHS) exposures. Fifty-nine percent of urban asthmatic children enrolled in the National Cooperative Inner-City Asthma Study and 48% of urban asthmatic children enrolled in the Inner-City Asthma Study live in households having at least 1 cigarette smoker. In the National Cooperative Inner-City Asthma Study, a household member was smoking during 10% of the home visits, and 48% of urine samples collected from asthmatic children had cotinine/creatine ratios that were consistent with significant tobacco smoke exposure in the last 24 hours. Among children who have asthma, exposure to SHS is associated with increased symptoms, decreased lung function, and greater use of health services. As SHS has many associated adverse health effects in children, it is important for clinicians to collect unbiased, precise, and accurate exposure histories. Questions posed to collect these histories in the clinical setting must be both comprehensive and concise to enable targeted interventions. In addition to inquiring about maternal smoking, recent studies reveal that it is important to ask questions about the number of smokers living in the home, the number of hours per day the child is exposed to smoke, and whether anyone ever smokes in the car with the child. Furthermore, the possibility that an older asthmatic child may be an active smoker should not be discounted.

Air Pollution

Exposure to TRAP and, in particular, diesel exhaust particles (DEPs), a major component of TRAP, has been associated with childhood asthma symptoms and exacerbations. A comprehensive and systematic review of worldwide traffic emissions and health science by a Special Panel convened by the Health Effects Institute (HEI) found sufficient evidence that exposure to TRAP causes exacerbation of asthma in children (HEI Special Report 17, Boston, MA: Health Effects Institute, 2010). Exposure to TRAP has been shown to enhance allergen-specific memory, thereby potentiating secondary allergen recall responses and promoting exacerbations. Ultra-fine DEPs reach small airways including the alveolar/gas exchange regions of the lung, exacerbating respiratory disease symptoms. This exposure is highly significant because in large cities in North America, up to 45% of the population resides in zones that are most impacted by TRAP, and more than 30% of schools are located in high TRAP-exposure areas. Further, although truck engines are being designed to decrease particle exposures, air quality and engine exhaust control policies implemented in 2005 to 2010 have not produced significant changes in TRAP levels. DEPs are composed of elemental carbon cores with large surface areas capable of binding organic polycyclic aromatic hydrocarbons, transition metals, and airborne allergens, all of which have the potential to induce reactive oxygen species and inflammation. DEPs can interact directly with allergens and have been shown to augment allergen-induced responses. In addition, DEPs absorb other metals and toxic gases produced by diesel engines, such as polycyclic aromatic hydrocarbons, which have direct detrimental effects on the lungs. Other components of TRAP, including ozone, nitrogen dioxide, and polycyclic hydrocarbons, have also been implicated as contributors to asthma symptoms.

Respiratory Infections

Numerous respiratory viruses in infancy have been associated with the subsequent development of asthma. HRV infection has been associated with the majority of exacerbations of asthma in pediatric patients. HRV is a positive-sense, single-stranded picornavirus that is subcategorized into A, B, and C strains, with HRV-A and HRV-C implicated in most exacerbations. The mechanism for the propensity of HRV infection to trigger exacerbation of asthma remains ill-defined for all viral strains. Most exacerbations of asthma caused by HRV occur in those who are atopic, and the risk for wheezing with HRV is strongly associated with high levels of total and allergen-specific IgE and with the presence of T_H2-related airway inflammation prior to an infection. Some studies suggest that decreased production of interferon in response to viral infection in the setting of T_H2 inflammation may contribute to exacerbations of asthma. The impact of viral infection on outcomes is not restricted to HRV. Further understanding of the viral mechanisms that contribute to persistent recurrent wheezing is needed.

Fungal Exposure

Fungi are ubiquitous in indoor and outdoor environments and have been associated with childhood asthma. Overwhelming and mounting evidence links mold exposure and asthma, and the mechanistic basis for the association has often been attributed to fungal sensitization. However, in addition to their ability to act as allergens, fungi have direct immunomodulatory activities. β-Glucans account for as much as 60% of the weight of the cell wall and can bind and signal directly through dectin-1, promoting fungal immunity by inducing dendritic cells to polarize T cells toward T_H17 cells. Exposure to a fungus has been shown to promote the development of severe allergic asthma and render it more resistant to steroids. This reaction may be mediated via the induction of T_H17 responses by β-glucans independent of sensitization.

GENETIC CONTRIBUTION TO ASTHMA PATHOGENESIS

Although environmental influences are important in the development of asthma, a strong genetic predisposition exists. The single most important factor in predicting asthma among infants and young children with wheezing is a family history of allergy. A recent meta-analysis of 71 twin studies estimated the heritability of asthma to be 0.54 (standard error, 0.048). It is now evident that the pathogenesis of asthma is dependent on the occurrence of multilayered gene–environment interactions over time. A particular asthma gene may be relevant only in the context of a specific environmental exposure during a key developmental period or age in a given population. In other words, environmental exposures that occur at the right time in a given individual may increase the penetrance of a given asthma susceptibility genotype, resulting in the development or progression of asthma. The same genetic susceptibility will not be evident in an individual who was not exposed to the relevant environmental factor or was exposed at a time when he/she was not fully susceptible to the negative health effects of the exposures. Accordingly, studies that focus on smaller, specific asthma phenotypes and endotypes have begun to yield identification of genetic risk alleles with larger effect sizes. The genetic underpinnings of different asthma phenotypes and endotypes are likely to be completely distinct and need to be studied independently.

CLINICAL MANIFESTATIONS

Asthma is characterized by respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity. The symptoms may occur during the daytime and/or nighttime and may be triggered by exposure to exercise, allergens, irritants (TRAP, SHS, perfumes, paint fumes), cold weather, or other factors. The clinical manifestations of asthma often are shaped by the presence of comorbid conditions. Compared to children without asthma, children with asthma had higher prevalences of allergic rhinitis, eczema, and food allergy. The term multimorbidity may be more appropriate than is comorbidity because the primary allergic disease often is not clearly identifiable. Although the concept of multimorbidity of allergic diseases has been known for years, recent studies have shed important insights on allergic multimorbidity.

Comorbid Conditions

Allergic Multimorbidity

The atopic or allergic march describes the sequential progression of different allergic conditions frequently observed in children with IgE-antibody responses against common environmental allergens (atopy). Eczema or atopic dermatitis (AD) may predate the development of other allergic disorders later in life. An estimated one-third to half of patients with AD will develop asthma; however, the mechanisms that promote disease progression remain unclear. Atopic sensitization has been reported to be a major determinant of AD progression to respiratory allergy; however, the mechanisms of disease progression are far more complex. The discovery of the filaggrin loss-of-function mutations has provided genetic evidence linking skin barrier deficiency to eczema and asthma. The skin matrix protein filaggrin promotes keratin aggregation; abnormal function of this protein has been associated with eczema, asthma, and allergic rhinitis. Furthermore, a genome-wide association study of eczema followed by childhood asthma implicated several new susceptibility loci.

The importance of monosensitization versus polysensitization in allergic disease multimorbidity also has been demonstrated. Data reveal that mono- and polysensitization represent 2 different phenotypes of IgE-associated diseases. Polysensitization, as compared to nonsensitization and monosensitization, is associated with a higher frequency of family history of allergic disease (asthma and rhinitis), a higher prevalence of symptoms of asthma and rhinitis, a higher prevalence of multimorbidity, a broader sensitization to different allergens, and the persistence of allergic diseases with a lower probability of remission. Thus, it has been suggested that sensitization should be considered as a qualitative and quantitative trait (monosensitization and polysensitization), as important clinical differences exist between monosensitized and polysensitized subjects. Epidemiologic studies confirm that sensitization among genetically susceptible populations to allergens, including house dust mites, pet dander, Alternaria mold, and cockroaches, confers risk for childhood asthma. Sensitization to outdoor pollens has been associated with seasonal asthma. Further, recent data suggest that polysensitization defined in part by food sensitization may have additional clinical impact.

Allergic Rhinitis

The upper and lower airways exist as a continuum and show similar histopathologic changes, including epithelial damage, thickening of the basement membrane, and a predominantly eosinophilic cellular infiltrate, when inflamed. Segmental bronchial allergen challenge causes inflammatory changes in both nasal and bronchial mucosa. Exposure of sensitized subjects to allergens leads to increased inflammation and airway hyperresponsiveness. Anti-inflammatory treatment aimed at the upper airway results in decreased markers of lower airway inflammation. Furthermore, treatment of allergic rhinitis with antihistamines and intranasal steroids has been reported to decrease emergency department visits for asthma.

Sinusitis

Similar to rhinitis, sinusitis can contribute to asthma symptoms. An association was observed between the extent of sinusitis, markers of lower airway inflammation, exhaled nitric oxide, and decreases in pulmonary function. Further, in children with asthma, treatment of the concurrent sinusitis with intranasal corticosteroids and antibiotics resulted in an improvement in respiratory symptoms and decreased airway inflammation.

Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in patients who have asthma and have the presence or a history of pulmonary infiltrates; it is rarely seen in children with asthma. The classic clinical presentation of ABPA includes transient migratory lung shadows on chest x-ray or computed tomography (CT), peripheral blood eosinophilia, fever, and sputum containing brown plugs or flecks (Aspergillus recovered in 50% of cases). These patients should be referred to a specialist.

Gastroesophageal Reflux Disease

Symptoms of gastroesophageal reflux disease (GERD) may be seen in children who have asthma. According to the National Guidelines, medical management of GERD should be instituted for patients who have asthma (especially nocturnal symptoms) and complain of frequent heartburn or pyrosis; however, some recent studies have not noted any benefit of GERD therapy.

Obesity

The parallel rise in the prevalence of asthma and obesity suggests that they are related. Obesity has been associated with persistence and severity of asthma in both children and adults. Compared with nonasthmatics, body mass index (BMI) in asthmatics was higher in 3 cross-sectional US health surveys. Further support for an association between asthma and obesity is provided by prospective studies, which show that the risk for developing asthma is increased with increasing BMI. Indeed, a recent meta-analysis confirmed that obesity is a strong risk factor for incident asthma. Notably, as obese asthmatics lose weight, their asthma symptoms and lung function improve. Weight loss following gastric bypass surgery improved self-reported severity of asthma. Epidemiologic studies that have controlled for potential effects of diet and physical activity when examining the relationship of obesity to onset of asthma observed that the effects of obesity on asthma appear to be independent of diet and physical activity, although these 3 factors are clearly interrelated.

Obstructive Sleep Apnea

Nocturnal asthma and obstructive sleep apnea (OSA) may have similar clinical symptoms. Nocturnal symptoms in asthma frequently are underdiagnosed, and OSA may be prevalent in nocturnal asthma. A high prevalence of OSA has been reported in patients who have unstable asthma. Evaluation for OSA is recommended in patients with unstable, poorly controlled asthma, particularly those who are overweight or obese. Congestion of the nasopharynx due in part to allergic rhinitis, with resultant mouth breathing, may heighten the expressions of both OSA and asthma. Patients who have unstable asthma and sleep apnea demonstrated improvement when treated with nasal continuous positive airway pressure (CPAP). In contrast, nocturnal nasal CPAP in individuals who have asthma and who do not have apnea is associated with disrupted sleep. Thus, confirmation of diagnosis is important.

Aspirin Sensitivity

The classic aspirin triad (also known as Samter’s triad) of asthma, aspirin intolerance, and nasal polyposis most commonly develops in adulthood. However, as many as 5% of children with asthma may have aspirin-induced symptoms. Avoidance of nonsteroidal anti-inflammatory drugs should be considered in children with severe persistent asthma.

Anxiety and Affective Disorders

Estimates of the prevalence of internalizing disorders, such as anxiety and affective disorders, are significantly above the prevalence in the general pediatric population. These disorders are common illnesses in childhood but are often unnoticed because of their subtle features. Recognizing the presence of these disorders is important, as they may contribute to asthma symptoms and poor quality of life. Significantly higher rates of internalizing difficulties have been reported among children with severe asthma compared with those who have mild or intermittent asthma. Further, depression was an identified risk factor among severely asthmatic children who died of asthma. It is important to assess for the presence of maternal anxiety and depression as well because these conditions in the mother may contribute to severe asthma.

DIAGNOSIS OF ASTHMA

History and Symptoms

Asthma is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow limitation. The diagnosis of asthma should be based on a history of characteristic symptom patterns and evidence of variable airflow limitation, from bronchodilator reversibility testing or other tests. A diagnosis of asthma should be considered if any of the following clinical indicators are present: wheezing (however, asthma can occur in the absence of wheezing); recurrent cough; recurrent chest tightness or difficulty breathing; worsening symptoms with exercise or at night; or worsening symptoms during viral infection, exposure to furry pets, changes in weather, exposure to pollen, or environmental tobacco smoke (all known triggers for asthma). Improvement of symptoms after treatment with a bronchodilator is suggestive of asthma, but a lack of improvement does not rule out the diagnosis. Pulmonary function testing is recommended if any of the indicators are present.

The history of symptoms varies with age. An infant or young child often has a history of recurrent wheeze or persistent cough with colds, whereas older children often complain of chest tightness or persistent cough/wheeze. Triggers for childhood asthma often include viral infections (especially RSV and HRV), allergen exposure, irritants (environmental tobacco smoke, pollution), weather changes, stress or emotional factors, gastroesophageal reflux, aspirin sensitivity, hormonal factors such as menses, and exercise.

Per the Global Initiative for Asthma (GINA) guidelines, there is an increased probability that symptoms are due to asthma if more than 1 type of symptom (wheeze, shortness of breath, cough, chest tightness) is present, symptoms are worse at night or in the early morning, symptoms vary over time and in intensity, and/or symptoms are triggered by exposure to viral infections, exercise, allergens, changes in weather, or irritants. There is a decreased probability that symptoms are due to asthma in isolated cough with no other respiratory symptoms. If the cough is associated with chronic production of sputum or with dizziness, light-headedness or peripheral tingling, or chest pain, then additional workup for other causes is warranted.

Physical Examination

The upper respiratory tract, chest, and skin are the focus of the physical examination for childhood asthma. Physical findings that increase the probability of asthma include hyperexpansion of the thorax, use of accessory muscles of breathing, wheezing during normal breathing or elicited by forced exhalation (typical of airflow obstruction), rhinitis, swollen pale nasal turbinates, and the presence of AD/eczema. The absence of these findings does not rule out asthma because the disease is by definition variable, and signs of airflow obstruction are often absent between attacks. Wheezing may be absent during severe exacerbations of asthma due to severely reduced airflow. It is important to note that the presence of wheezing is nonspecific and may also be heard with upper airway dysfunction, respiratory infections, tracheomalacia, or inhaled foreign body. Crackles and inspiratory wheezing are not features of asthma. Examination of the nose may reveal signs of allergic rhinitis or nasal polyposis.

Pulmonary Function Tests

In a patient with typical respiratory symptoms, obtaining evidence of excessive variability in expiratory lung function is an essential component of the diagnosis of asthma. Pulmonary function tests (PFTs) should be attempted in children ≥ 5 years old with symptoms suggestive of asthma because medical history and physical examination are not reliable means of excluding other diagnoses or of characterizing the status of lung impairment. These measurements help to determine whether there is airflow obstruction, its severity, and whether it is reversible over the short term. Demonstration of reversibility of airflow obstruction following inhalation of a bronchodilator is central to the definition of asthma. Examination of the volume-time curve and the shape of the flow-volume loop provides an estimate of the adequacy of the patient’s effort in performing the test. Airflow obstruction is indicated by a reduction in the values for both the forced expiratory volume in 1 second (FEV₁) and the FEV₁ expressed as a ratio of forced vital capacity (FEV₁/FVC) relative to appropriate reference or predicted values. If obstruction is detected on the baseline PFT, a bronchodilator (albuterol) should be administered and the PFT repeated in 20 minutes. An improvement of 12% or greater and an absolute change of at least 200 mL in the FEV₁ is consistent with a diagnosis of asthma; however, neither this finding nor any other single test or measure is adequate to diagnose asthma. In addition to the PFT results, the patient’s history and symptoms, along with the exclusion of other possible diagnoses, are needed to establish a diagnosis of asthma.

Methacholine challenge testing (MCT) usually is considered when asthma is a serious possibility and traditional methods, most notably spirometry performed before and after administration of a bronchodilator, have not established or eliminated the diagnosis. Bronchoprovocation testing should be carried out by a trained individual in an appropriate facility. Although a positive test is consistent with asthma, MCT is more useful in excluding a diagnosis of asthma than in establishing one. The end point is the provocative concentration that results in a 20% fall in FEV₁ (PC20). A PC20 of 8 mg/mL or lower is indicative of bronchial hyperresponsiveness; however, the interpretation of the MCT is complicated and depends on the pretest probability. Methacholine concentrations between 8 and 16 mg/mL are consistent with bronchial hyperresponsiveness. Pulmonary function measures often do not correlate directly with symptoms. One study reports that one-third of the children who had moderate-to-severe asthma were reclassified to a more severe asthma category when pulmonary function reports of FEV₁ were considered in addition to frequency of symptoms. Conversely, in another study, children who were classified as having mild-to-moderate asthma by symptoms had normal FEV₁.

Exercise-Induced Asthma

Exercise-induced bronchoconstriction is a transient narrowing of the airways that affects 40% to 90% of asthmatic children and adolescents. Prevention is essential as it causes limitations in daily life activities in as many as 30% of children. The mechanisms underlying exercise-induced asthma (EIA) are not known. The optimal method for diagnosis of EIA is to perform a standardized exercise challenge test. A diagnosis of EIA cannot be made with an MCT, and EIA cannot be excluded by a negative response to methacholine. Vigorous exercise should be avoided for at least 4 hours before testing, as prior exercise has been found to exert a protective effect. The preferred modes of exercise are the motor-driven treadmill with adjustable speed and grade or the electromagnetically braked cycle ergometer. The presence of exercise-induced bronchoconstriction is defined by plotting forced expiratory volume (FEV), as a percentage of the preexercise baseline FEV, at each postexercise interval. A 15% decrease is an accepted abnormal response. Effective recognition and treatment of EIA are critical parts of managing asthma, especially considering that quality of life in children with asthma has been found to correlate with shortness of breath during exercise.

EIA is best treated with ICSs to control inflammation as well as pretreatment before exercise with short-acting or long-acting bronchodilators. The use of β₂-agonists before exercise will prevent EIA in more than 80% of patients. Short-acting agents confer protection for 2 to 3 hours, whereas long-acting agents may be protective for as long as 12 hours. However, frequent or chronic use of long-acting β₂-agonists for EIA is not recommended as the protective effect wanes with frequent use and they may disguise poorly controlled persistent asthma. Other agents including leukotriene receptor antagonists and cromolyn are alternative therapies for EIA but are not as effective as is a steroid combined with β₂-agonists. A mask or scarf over the mouth may attenuate cold-induced EIA. Objective testing for EIA is important. A European study showed that 50% of those treated for EIA did not have asthma or EIA.

DIFFERENTIAL DIAGNOSIS OF ASTHMA IN CHILDHOOD

A diagnosis of asthma requires an exclusion of other possible diagnoses. In hospitalized children, a chest x-ray should be strongly considered. Radiographic findings in asthma range from normal to hyperinflation with peribronchial interstitial infiltrates and atelectasis. In a 3-year study of hospitalized children with asthma, 76% had evidence of hyperinflation, whereas 20% had infiltrates, pneumonia, and/or atelectasis.

The differential diagnosis of asthma in children is summarized in Table 505-1. It is important to note that any of these alternative diagnoses may be found together with asthma. A sweat test should be considered in children with recurrent wheezing and associated symptoms of failure to thrive, diarrhea, steatorrhea, nasal polyps, chronic or pan-sinusitis, and/or digital clubbing. An x-ray should also be done in these circumstances.

Several conditions can coexist with asthma or mimic asthma symptoms and include rhinitis/sinusitis, GERD, OSA, obesity, and aspirin sensitivity (discussed earlier). Radiographic imaging of the sinuses should be considered for children with persistent nocturnal cough, nasal symptoms, and dental pain. Similarly, the presence of the other conditions should be evaluated if indicated and treated if present.

Cough Variant Asthma

Cough-variant asthma is considered as an asthma subset in which chronic cough is the only symptom. Triggers for cough-variant asthma often include exercise and cold air or changes in weather. MCT or exercise-tolerance testing should be used to establish the presence of bronchial hyperresponsiveness to avoid overtreatment.

Vocal Cord Dysfunction

Vocal cord dysfunction (VCD) often mimics asthma. VCD is characterized by episodic dyspnea and wheezing caused by intermittent paradoxical vocal cord adduction during inspiration. The cause of VCD is not well understood. Although VCD is clearly distinct from asthma, it frequently is confused with asthma, leading to inappropriate medication of affected individuals with antiasthma medications. Asthma medications are not effective in treating VCD; thus, VCD should be considered in patients who are resistant to treatment. It is important to note, however, that VCD and asthma often coexist and that VCD may complicate management of the asthma. Elite athletes, in particular, are prone to both exercise-induced bronchospasm and VCD, so careful workup is warranted for athletes who present with exercise-related breathlessness. VCD can be difficult to diagnose. Flattening of the inspiratory flow loop on spirometry in addition to the symptoms is strongly suggestive of the diagnosis, but abnormalities of the inspiratory loop may be absent between episodes. The diagnosis of VCD comes from direct observation of paradoxical vocal cord movement by flexible laryngoscopy during an acute episode. Most patients with VCD cannot voluntarily induce an episode. Therapy generally consists of speech therapy and relaxation techniques.

ASSESSMENT OF ASTHMA CONTROL

Once the diagnosis of asthma has been made, it is important to characterize the patient’s asthma in order to design the most optimized therapeutic strategy for that patient. It involves (1) identifying triggers for the patient’s asthma; (2) identifying comorbidities that may be contributing to the patient’s asthma symptoms; (3) assessing treatment issues, particularly inhaler technique and adherence; and (4) assessing asthma control and severity, including assessment of symptoms and future risk (summarized in Table 505-2). Per the GINA guidelines, the level of asthma control is the extent to which the manifestations of asthma can be observed in the patient or have been reduced or removed by treatment. It is determined by interactions of the genetic background, environmental and psychosocial factors, and treatments.

Identification of Asthma Triggers

The evaluation of a patient with asthma should include identification of the patient’s asthma triggers, such as exposure to allergens (eg, pets, seasonal pollens), irritants (eg, environmental tobacco smoke, air pollution), fungi, or respiratory viruses. It is important to elicit the location and duration of the exposure as well as the relationship of the exposure to the symptoms.

Assessment of Asthma Control and Severity

The concept of asthma control should be discussed as patients often understand the concept of “asthma control” differently from health professionals. The frequency or severity of symptoms that patients regard as unacceptable or bothersome will vary from patient to patient and may not align with the current guidelines regarding the goals of asthma treatment. Further, a patient may state that his/her symptoms do not interfere with daily activities but neglect to mention that they have excluded exercise from their daily activities due to symptoms.

Asthma severity is the intrinsic intensity of disease. Assessment of patients who have confirmed asthma includes classification of severity because the selection of drug class and dose of therapy should correspond to the level of asthma severity. This initial assessment of asthma severity is made immediately after diagnosis and before treatment based on the symptom burden, lung function, and exacerbations (Fig. 505-3). Asthma severity is a dynamic variable and can change over time. After initiation of treatment, it can be determined retrospectively from the level of treatment required to control symptoms and exacerbations. Classification of severity is based on the spirometry and frequency of symptoms over the previous month per the patient history. According to the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, classification of severity should include parameters of both impairment (assessment of the frequency and intensity of symptoms and functional limitations that a patient is experiencing or has recently experienced) and risk (occurrence of either exacerbations of asthma or the loss of pulmonary function over time) since these domains may respond differentially to treatment. The term asthma control is used in the GINA guidelines and also encompasses both current impairment and risk.

Assessment of the impairment domain can be elicited by careful, directed history and measurement of lung function. Spirometry is the preferred method for measuring lung function to classify severity. Analysis of a large, longitudinal study of children confirmed a relationship between the severity of airflow obstruction, especially FEV₁, and the risk of developing exacerbations. However, even children with really severe asthma may have normal spirometry. Recent data have suggested that, in contrast to FEV₁ measures, FEV₁/FVC may be a more sensitive marker of asthma severity in children. Peak expiratory flow (PEF) monitoring has not been found to be a reliable variable for classifying severity but may be helpful in some children. Short-term PEF monitoring may be used to establish a baseline for action plans. After starting ICS, personal best PEF (from twice-daily readings) is reached on average within 2 weeks. Average PEF continues to increase, and diurnal PEF variability to decrease, for about 3 months. Excessive variation in PEF suggests suboptimal asthma control and increases the risk of having exacerbations. Long-term PEF monitoring is now generally recommended only for patients with severe asthma who have impaired perception of airflow limitation.

In the history, it is important to ascertain the frequency of nighttime symptoms and awakenings, the frequency of short-acting bronchodilator use for quick relief of symptoms, the number of work or school days missed, the child’s ability to engage in normal activities including sports activities, and quality-of-life assessments. Standardized questionnaires such as the Asthma Control Test, the Childhood Asthma Control Test, the Asthma Control Questionnaire, and others have been developed to facilitate and standardize the assessment of the impairment domain of asthma control.

More recently, tools that integrate impairment and risk (symptoms and exacerbations) and, as such, more comprehensively represent asthma control and severity have been developed. These measures include the Composite Asthma Severity Index (CASI) and the GINA symptom control tool. In well-treated asthma populations, symptom scores lose their discriminatory ability. With the addition of controller treatment, lung function measures, and exacerbations to symptom scores, CASI allows for the measurement of asthma activity even in well-treated populations. This measure of asthma severity provides a means to discriminate among individuals who may have well-controlled symptoms but continue to have frequent exacerbations or persistently low airflow limitation. Some of the available tools that can be used for initial and ongoing monitoring of childhood asthma are presented in Table 505-3.

A history of previous exacerbations requiring emergency department (ED) visits, hospitalization, or intensive care unit (ICU) admission can help identify a patient’s risk for having future exacerbations. Symptoms, exacerbations, spirometry (especially FEV₁ percent predicted value or FEV₁/FVC), and quality of life over time are currently the best available measures of asthma control. It is important to note that patients at any level of severity, even intermittent asthma, can have severe exacerbations.

Many biomarkers have been proposed. Serum IgE has been implicated in severity of asthma including exacerbation severity. Mounting evidence supports that allergic sensitization, especially polysensitization, is a risk factor for persistence of the asthma. However, no biomarkers are recommended in the current guidelines.

Assessment and monitoring of asthma control and severity should be performed regularly because the course of asthma is variable. Asthma may persist or remit with time. Although childhood asthma is a significant risk factor for persistent asthma in adults, 40% to 60% of children with asthma remit by the time they reach adulthood. Remission is more likely to occur in children with milder disease (less frequent and less severe symptoms), who have less atopic sensitization, normal lung function, mild airway hyperresponsiveness, and no comorbid allergic disease. In contrast, persistence is strongly associated with polysensitization, more severe disease (more frequent and severe symptoms), abnormal lung function, and a greater degree of airway hyperresponsiveness.

TREATMENT

The primary goal of therapy is to reduce impairment and risk. Reducing impairment is focused on prevention of symptoms, resulting in decreased need for relief use of a short-acting bronchodilator, maintenance of normal activity level, normal pulmonary function, and patient satisfaction with control. Reducing risk is focused on prevention of exacerbations and loss of lung function. Treatment should include identification and education regarding the individual patient’s asthma triggers, as well as pharmacologic treatment optimized for maximal effectiveness with minimal/no side effects.

There are 2 types of asthma medications: controller medications, which are taken daily to provide long-term control, and quick-relief medications. Patients who have persistent asthma require both classes of medication. Long-term control medications include ICSs, inhaled long-acting bronchodilators, leukotriene modifiers, theophylline, and immunomodulators. These medications act predominantly by decreasing airway inflammation. A summary of a childhood asthma treatment plan algorithm is shown in Figure 505-4.

Asthma severity is the intrinsic intensity of the disease process and dictates which step to initiate treatment. Treatment is selected based on each patient’s level of severity based on the frequency and severity of symptoms, frequency and severity of exacerbations, and lung function (see Fig. 505-3). Severity can also be defined retrospectively by identifying the level of treatment required to control symptoms. At each treatment step in asthma management, different medication options are available. For each treatment step, a preferred controller medication is recommended that provides the best benefit-to-risk ratio (including cost) for both symptom control and risk reduction. Choice of the preferred controller is based on group mean data from efficacy studies in well-characterized populations. In addition, to population-level recommendations, patient-level medication choices termed personalized or precision medicine choices have increased in the literature. They take into account patient’s characteristics (phenotypes) or endotypes that predict a clinically important difference in treatment response compared with other patients, along with the patient’s preferences and practical issues (cost, family issues, health literacy, and adherence). At present, most research activity about individualized treatment is focused on severe asthma.

OVERALL STRATEGY FOR ASTHMA TREATMENT

Detailed strategies for prescribing asthma medications are proposed in all guidelines. Age is an important feature and should be taken into account. In adolescents, compliance is an important consideration, and treatments should be selected carefully based on the patient’s lifestyle and wishes. Medication for acute relief of symptoms (typically, a short-acting inhaled β₂-agonist) should be available to all asthma patients, irrespective of age, severity, or control. The type and extent of controller therapy is selected based on step classification, which is dependent on asthma severity (see Fig. 505-3).

• Step 1: For intermittent asthma, no controller medication is proposed.

• Step 2: Mild persistent asthma entails the use of 1 controller medication.

• Steps 3/4: ICSs can be increased to a medium/high dose, and/or a second controller medication can be added. For children age 5 to 12 years, the guidelines recommend either doubling the ICS dose or adding a long-acting β-agonist (LABA). Omalizumab may also considered at this step by the National Asthma Education and Prevention Program.

• Steps 5/6: In cases for which control cannot be achieved with the maximum dose of ICSs and additional medication, the final resort is the use of oral corticosteroids. Biologic therapies should be considered.

CONTROLLER MEDICATIONS

Inhaled Corticosteroids

ICSs are the most effective long-term therapy available for patients with persistent asthma. Corticosteroids exert their effects by binding to glucocorticoid receptors in the cytoplasm of target cells. ICSs have a variety of anti-inflammatory effects on many different cell types, which may contribute to their success in the treatment of asthma. They include modulation of anti-inflammatory proteins including cytokines, adrenergic receptor expression, cytokine expression, inflammatory receptors, and adhesion molecules. In addition, steroids markedly reduce the number of circulating eosinophils by decreasing their survival. They inhibit the release of inflammatory mediators from alveolar macrophages, the production of inflammatory cytokines and chemokines by human airway epithelial cells, and mucus secretion by goblet cells.

ICSs are very effective as preventive therapy, leading to reduced severity of symptoms, improvement in asthma control and quality of life, improvement in lung-function measures, diminished airway hyperresponsiveness, and prevention of exacerbation frequency and severity. Sensitivity to ICSs varies among patients. Corticosteroid responsiveness is decreased in smokers and persons who have asthma with predominantly neutrophilic inflammation. In addition, African American children with poorly controlled asthma are at increased risk for having corticosteroid insensitivity.

High, medium, and low doses of ICS for children are summarized in Table 505-4. Studies comparing ICS therapy to other single-control medications reveal that in patients with mild or moderate persistent asthma, treatment with ICS demonstrates greater improvements in lung function, symptom scores, frequency and severity of exacerbations, and relief use of bronchodilators. According to the Expert Panel Report 3, in patients ≥ 12 years old who require more than low-dose ICS alone to control asthma (ie, step 3 care or higher), combination therapy with a LABA along with ICS is preferred. In a study of children who have uncontrolled asthma despite the use of low-dose ICS, a randomized trial comparing step-up therapies revealed that LABA step-up was superior to increasing the ICS dose or adding a leukotriene receptor antagonist (LTRA). However, some children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy. Several studies show that for patients who have mild or moderate persistent asthma, use of higher doses of ICS negligibly improves asthma control compared with lower doses. However, in other studies, higher doses have demonstrated added benefit. Once asthma is well controlled for at least 3 months, stepping down therapy should be considered. Several studies have shown that for most patients whose asthma has been well controlled by high-dose ICS alone, a 50% reduction in dose can be tolerated without a loss of control. However, there is significant variability in response, and the ICS should be decreased cautiously. The patient/family should be given a plan if symptoms worsen while the ICSs are being decreased. Each patient/family should be given a written asthma action plan based on signs and symptoms and/or PEF. It is particularly important to provide an action plan for those with moderate or severe asthma or those at higher risk for exacerbations. Written action plans are particularly recommended for patients who have moderate or severe persistent asthma, a history of severe exacerbations, or poorly controlled asthma.

ICSs are well tolerated and safe at the recommended dosages. Oral candidiasis (thrush) is rare in patients on low-dose ICS but is a common adverse effect of high-dose ICS (Expert Panel Report 3). To minimize this risk, use the lowest dose of ICS that provides control and advise patients to rinse their mouths (rinse and spit) after inhalation of the ICS. In addition, use of a spacer or valved holding chamber with a non–breath-activated metered-dose inhaler (MDI) will reduce the risk of developing thrush. Dysphonia is another side effect of ICS therapy, especially at higher doses, although it is less common in children. Use of a spacer or valved holding chamber will minimize risk. Reflex cough and bronchospasm have been reported after use of ICS. These effects can be reduced by optimizing the inhaler technique and using a spacer or valved holding chamber. The side effect that is most worrisome in children is the potential effect on linear growth. Longitudinal studies have shown that a reduction in growth velocity may occur in children or adolescents as a result of ICS therapy; however, these studies are difficult to interpret because poorly controlled asthma may delay growth in children. Per the Expert Panel Report 3, the available cumulative data regarding children suggest that although low/medium ICS doses may decrease growth velocity, the effects are small and nonprogressive. Combination therapy should be initiated when high-dose ICSs are necessary to control symptoms in order to reduce the dose of ICS and minimize possible dose-related long-term effects on growth. Low- and medium-dose ICSs appear to have no serious adverse effects on bone mineral density in children. Disseminated varicella has been reported in children who have severe persistent asthma and are taking immunosuppressive doses of systemic corticosteroids. Children on immunosuppressive doses of corticosteroids who have not been immunized against varicella and are exposed to varicella infection are candidates for oral antiviral therapy. In children, low- and medium-dose ICS therapy has not been found to have a significant effect on the incidence of subcapsular cataracts or glaucoma. In a study of children, ICS at dosages from 400 to 1000 μg/d (budesonide) did not affect fasting glucose or glycosolated hemoglobin. However, ICS at high doses can be associated with systemic side effects including cushingoid features and growth suppression, as well as effects related to hypothalamic–pituitary axis suppression, which can result in adrenocortical atrophy and glucocorticoid insufficiency. Presentation may be with severe hypoglycemia. Clinicians should be aware of the possibility of clinical adrenal suppression in children with asthma on high doses of ICS and should consider adrenal function monitoring in these children.

Oral Corticosteroids

Oral corticosteroids should be used for only the most severe asthma patients who are not controlled on the other therapies due to the considerable side effects of systemic steroids. These patients should be referred to a specialist for management.

Long-Acting β₂-Agonists

In a study of children who have uncontrolled asthma despite the use of low-dose ICS, a randomized trial comparing step-up therapies revealed that LABA step-up was superior to increasing the ICS dose or adding an LTRA. Salmeterol and formoterol are β₂-agonists that bind to β₂-adrenergic receptors and result in relaxation of airway smooth muscle. Both produce clinically relevant cardiovascular effects (tachycardia, QTc interval prolongation, and hypokalemia) at doses approximately 4 to 5 times those recommended. Due to their increased lipophilicity prolonging retention in lung tissue, a single dose results in a bronchodilation effect for approximately 12 hours. Formoterol has a more rapid onset of bronchodilation (similar to albuterol). They should not be used alone for treatment of persistent asthma but rather in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma (step 3 or higher in children ≥ 5 years of age). These drugs should not be used for the treatment of an acute exacerbation.

Although LABAs have previously been associated with an increased risk of asthma-related deaths and an increased numbers of severe asthma exacerbations, a recent trial prospectively evaluated the safety of salmeterol in a fixed-dose combination in children and found that salmeterol did not confer increased risk over fluticasone alone. In children ≥ 5 years of age who have moderate persistent asthma that is not well-controlled on ICS, the option to escalate therapy should be taken after consideration of other factors, including inhaler technique, optimizing education, and monitoring adherence, which is a contributor to lack of response to treatment in a majority of cases. In the cases for which escalation of therapy is warranted, there is no evidence for the use of a combination ICS plus LABA inhaler as first-line therapy, but this treatment should be considered in children requiring more than low doses to achieve control. LABA inhalers should never be used as monotherapy and carry a US Food and Drug Administration (FDA) warning stating this in the United States.

Leukotriene Receptor Antagonists

Leukotrienes are products of arachidonic acid metabolism released from mast cells, eosinophils, and basophils. LTRAs are effective in improving symptoms and lung function and preventing exacerbations at all ages. They are less efficacious than is ICS in clinical trials and, as such, are recommended as second choice after low-dose ICS for the initial step of chronic treatment. They may also be effective add-on medications, but less so than are LABAs. Some guidelines suggest that LTRA may be particularly useful when a patient has rhinitis or exercise-induced symptoms. Some evidence suggests the effectiveness of LTRA for children with exercise-induced asthma. Although ICSs are the preferred controller therapy for persistent asthma, LTRAs are an alternative treatment for mild persistent asthma in children younger than 12 years old. They can also be used as adjunct therapy with ICS for children younger than 12 years old. In children ≥ 12 years of age, the preferred adjunct therapy is an LABA. The use of LTRAs as adjunctive therapy in moderate or severe asthma has not been studied adequately in children. Hepatic dysfunction, including some cases of fulminate hepatic failure, has been reported as a side effect of zafirlukast. Patients should stop taking zafirlukast if any signs or symptoms of hepatitis occur.

Tiotropium

Tiotropium is a long-acting once-daily anticholinergic initially approved for the treatment of persistent asthma in children age 12 and older. Tiotropium has been studied as an add-on therapy to ICSs in adolescents and children. An improvement in lung function has been demonstrated in symptomatic pediatric and adolescent patients with asthma with the addition of tiotropium to ICS, improving peak and trough FEV₁ and morning and evening PEF. In adults with severe asthma, the addition of tiotropium significantly increased the time to the first severe exacerbation and improved lung function.

Methylxanthines

Methylxanthines also can be used as step-up treatment to ICS, although the addition of theophylline to ICS produces a small improvement in lung function similar to doubling the dose of ICS. Studies on the use of methylxanthines in combination with ICS (with or without LABA) in severe asthma are lacking. Theophylline is proposed as add-on therapy for children age 12 and older with severe asthma.

Cromolyn Sodium and Nedocromil

Cromolyn sodium and nedocromil are mast cell stabilizers. They are not the preferred treatment for any category of asthma. They are still included in some guidelines as alternative treatment for mild persistent asthma but are less effective than is ICS in improving outcomes and are no longer available in many countries.

Biologic Therapies in Asthma

For the majority of asthmatic patients, disease control is achieved within the first 3 treatment steps, which include the use of ICSs either alone or in combination with LABAs or LTRA. This approach has provided a safe and effective mode of treatment. However, some patients do not respond fully to these treatment choices, and for those patients, additional therapy options are needed along with referral to a specialist. The next choices are limited and have begun to extend into the use of biologics.

Anti-IgE

Omalizumab is a recombinant DNA-derived humanized monoclonal antibody directed against the Cε3 domain of IgE. It blocks the ability of IgE to bind to its high-affinity receptor (FcεRI) on mast cells, basophils, eosinophils, Langerhans cells, and dendritic cells. The use of this antibody results in reduction of the serum concentration of free IgE and attenuates the allergic response to inhaled allergens in sensitized individuals. Omalizumab is currently recommended as a potential adjunctive therapy in patients ≥ 12 years old who have allergies and severe persistent asthma (step 5) that is not controlled with the combination of high-dose ICS and LABAs.

In clinical trials of patients with moderate or severe persistent allergic asthma (IgE > 30 IU/mL) incompletely controlled with ICS, addition of omalizumab to ICS therapy produced a reduction in asthma exacerbations, improved quality of life, and resulted in a small improvement in lung function in some studies. Omalizumab has also been demonstrated to have a modest steroid-sparing effect.

Anaphylactic reactions are estimated in 0.2% of treated patients, which resulted in an FDA alert in 2007. These reactions occur for the most part within 2 hours of the first 3 injections of omalizumab; however, reactions can occur at any time. Thus, administration of omalizumab should be performed only in settings equipped for the identification and treatment of anaphylaxis. Adverse effects reported from omalizumab in the trials have also included injection-site pain and bruising in as many as 20% of patients.

Anti–IL-5

Eosinophils are a frequent finding in asthmatic inflammation, and a high blood eosinophil count often reflects inflammation and disease severity in asthma. A reduction of sputum eosinophils by ICS reduces the frequency of exacerbations and usually indicates an establishment of disease control. IL-5 is the key cytokine that promotes terminal differentiation, survival, migration, and activation of eosinophils; thus, anti–IL-5 is a reasonable target for asthma treatment. In November 2015, the FDA approved mepolizumab for use with other asthma medicines for the maintenance treatment of asthma in patients age 12 years and older.

The safety and efficacy of mepolizumab were established in 3 double-blind, randomized, placebo-controlled trials in patients with severe asthma on currently available therapies. Mepolizumab or placebo was administered to patients every 4 weeks as an add-on asthma treatment. Compared with those on a placebo, patients receiving mepolizumab had fewer exacerbations requiring hospitalization and/or ED visits and a longer time to the first exacerbation. In addition, patients with severe asthma receiving mepolizumab experienced greater reductions in their daily maintenance oral corticosteroid dose while maintaining asthma control, compared with patients receiving placebo. Treatment with mepolizumab did not result in a significant improvement in lung function. The effects of IL-5 modulation are limited to patients who are already on corticosteroid treatment but have persistent eosinophilia despite taking corticosteroids and continue to experience exacerbations. The most impressive results have been seen in patients with significant peripheral blood eosinophilia at baseline.

The most common side effects of mepolizumab include headache, injection-site reactions, back pain, and weakness (fatigue). Hypersensitivity reactions can occur within hours or days of being treated with mepolizumab. Herpes zoster infections (shingles) have also been reported in patients receiving mepolizumab.

Other Biologics on the Horizon

In a study of adult atopic asthmatic patients who were uncontrolled with ICS, treatment with anti–IL-13 improved lung function compared to placebo. Studies with humanized monoclonal antibodies directed at IL-4Rα have shown initial promise, with a reduction in exacerbation frequency, as well as improvements in asthma control. TSLP is an epithelial-derived cytokine that is produced in response to proinflammatory stimuli and mechanical stress and leads to the induction of T_H2-related cytokines. A humanized anti-TSLP monoclonal antibody has shown some initial promise and is under investigation.

QUICK-RELIEF MEDICATIONS

Quick-relief medications are used to provide prompt relief of acute symptoms. These medications include short-acting β₂-agonists (SABAs) and anticholinergics (ipratropium bromide). SABAs relax airway smooth muscle, thereby resulting in a rapid increase in airflow and symptomatic relief. These agents exist as racemic mixtures, and the R-enantiomers have been shown to possess the majority of the therapeutic activity. However, there has been no consistent added benefit of the R-enantiomer versus the racemic mixture. SABAs are very effective in the treatment of acute symptoms and are the preferred and recommended treatment. However, regular use is not recommended because it has not been shown to have added benefit when compared to as-needed use with regard to asthma control. Use of SABAs > 2 times per week may signify that the asthma is not well controlled and controller therapy should be adjusted accordingly. Increasing use of SABAs has been associated with increased risk of having an acute exacerbation requiring hospitalization and increased risk for death.

Ipratropium has been shown to be effective only in the ED setting. Studies of children with asthma requiring hospitalization have failed to show any benefit by the addition of ipratropium to their treatment regimens after the transition from the ED to the inpatient setting.

TREATMENT OF ACUTE ASTHMA IN CHILDREN

Severe exacerbations of asthma can be life threatening. Care must be prompt, and rapid recognition of a severe exacerbation is critical as it requires close observation for deterioration, frequent treatment, and transfer to an ED. The assessment of the severity of an acute asthma exacerbation is an important guide to treatment. All clinicians treating patients who have asthma should be prepared to treat an asthma exacerbation, be familiar with the symptoms and signs of severe and life-threatening exacerbations, and have procedures for facilitating immediate transfer to an ED. Clinical signs characterizing a severe episode include the use of accessory muscles, limited ability to speak, preference to sit upright, a paradoxical pulse of > 25 mm Hg, a heart rate of > 130 bpm, a respiratory rate of > 25 breaths/min, a PEF of less than 50% of predicted, and an oxygen saturation < 92%. If any of these signs are present, the patient should be transferred to an ED immediately.

A brief history should include ascertainment of the onset of the exacerbation, identification of any potential triggers, current medications and timing of the most recent dose, comorbid conditions, and the number of previous ED visits and hospitalizations (including ICU and need for intubation) for asthma. The physical exam should focus on assessment of the severity of the exacerbation and possible complications including pneumonia, pneumothorax, or pneumomediastinum. Most patients who have an asthma exacerbation do not require any initial laboratory studies. Chest radiography is not recommended for routine assessment but should be obtained if a complicating process, such as a pneumothorax, pneumomediastinum, pneumonia, or lobar atelectasis, is suspected. The differences in the anatomy and physiology of the lungs of infants and young children place them at greater risk for respiratory failure; thus, it is important to monitor oxygen saturation (SaO₂) by pulse oximetry.

According to the National Guidelines outlined in the Expert Panel Report 3, initial treatment for an acute exacerbation should include oxygen to maintain an SaO₂ > 92%, and 3 treatments of an SABA (each 2.5–5.0 mg albuterol) spaced every 20 to 30 minutes should be given. Systemic corticosteroids (1–2 mg/kg/d up to a maximum 60 mg/d for 3–10 days) are recommended for patients who have moderate or severe exacerbations and do not respond completely to initial therapy. Once-daily and multiple-daily dosing approaches are comparable in clinical outcomes. There appears to be no significant difference in the efficacy of oral corticosteroids or parenteral corticosteroids on the length of hospital stay in children with acute asthma exacerbations. Parenteral administration should be used in the child who is unable to tolerate oral medications due to vomiting. Given its longer biologic duration of action, dexamethasone may be preferred in the ED management of acute asthma. A meta-analysis concluded there was no difference in the relative risk of relapse between dexamethasone (intramuscular or oral, 1 or 2 doses) and prednisone/prednisolone (oral for 5 days) and that children treated with dexamethasone were less likely to experience emesis. A 5- to 10-day course following ED discharge is recommended to prevent early relapse. Improvement from an asthma exacerbation usually is gradual, and even when symptoms have resolved, evidence of inflammation in the airways has been shown to continue for to 2–3 weeks. When systemic corticosteroids are administered for asthma exacerbations, the child should continue to receive maintenance ICS to reinforce the importance of this medication, although studies have not addressed the clinical utility of this practice. Intramuscular depot injections of corticosteroids have been shown to be effective in preventing relapse after discharge from the ED. Thus, this option may be considered as an alternative to oral corticosteroids for patients who are at high risk of nonadherence. Systemic corticosteroids can speed resolution of airflow obstruction and reduce the rate of relapse. There are considerable side effects of systemic corticosteroids, but little information is available regarding the side effects of brief courses. One epidemiologic study suggests that children 4 to 17 years of age who require more than 4 courses of oral corticosteroids (average duration 6.4 days) as treatment for underlying disease have an increased risk of having a fracture. Another study concluded that multiple short courses of oral corticosteroids (median 4 courses in the preceding year) in the treatment of asthma in children 2 to 17 years of age were not associated with any lasting effect on bone metabolism, bone mineralization, or adrenal function. In another study, children who received 4 or more bursts of oral corticosteroids for acute asthma exacerbations in the previous year demonstrated a subnormal response of the hypothalamic–pituitary–adrenal axis to hypoglycemic stress or adrenocorticotropic hormone.

Ipratropium bromide, an inhaled anticholinergic agent, is a useful additional treatment for acute asthma and should be considered for patients who have severe exacerbations. Ipratropium exerts its effects by blocking cholinergic receptors, leading to diminished bronchomotor tone, mucosal edema, and secretions. It is not effective when administered alone, but in combination with SABA, it can improve lung function and reduce hospitalization rates in children with moderate-to-severe exacerbations. National Asthma Education and Prevention Program guidelines recommend 2 or 3 doses of 250 to 500 μg via nebulization or 2 to 3 puffs of 17 μg/puff administered via MDI. Ipratropium treatment has not been shown to have any benefit outside of the ED setting and is not recommended in the inpatient setting or as an outpatient.

For severe exacerbations unresponsive to the initial treatments, adjunct treatments can be considered. Studies in children and adults have demonstrated that adjunct intravenous magnesium sulfate (25–75 mg/kg up to 2 g in children) reduces hospitalization rates in ED patients with severe asthma exacerbations. Magnesium sulfate has not been shown to be beneficial in mild or moderate exacerbations. Heliox (a mixture of helium and oxygen) may improve gas exchange in patients with severe obstruction, although studies have been conflicting regarding its efficacy. Some studies have observed no added benefit with heliox, whereas others have found a significant improvement in pulmonary index and a trend toward reduced incidence of hospitalizations in children with moderate-to-severe exacerbations who received heliox-driven albuterol nebulization.

ASTHMA EDUCATION

An important component of asthma management is education. Evidence is abundant that asthma self-management education is effective in improving outcomes of chronic asthma. The value of establishing the child-family-physician partnership for optimal asthma management has been shown in randomized controlled trials. Specific training in self-management skills is necessary to produce behavior that modifies the outcomes of chronic illnesses including asthma. Patients must actively participate in their own care by learning how to use strategies and to minimize exposure to triggers and adjust treatments to improve disease control. Patient’s self-management should be partnered with the care provided by the healthcare team with the goal of reducing the impact of asthma on related morbidity, functional ability, and quality of life. The benefits of equipping patients and families with the necessary tools for self-assessment, optimization of medications, and actions to prevent exacerbations include reduction in incidence of urgent care visits and hospitalizations, reduction of asthma-related healthcare costs, and improvement in health status. This training includes education regarding the goals of therapy, the different types of medication (controller versus quick relief), the importance of taking the medications as prescribed, the actions to be taken for worsening symptoms, and the correct inhaler technique. Mismatches between parent reports and provider intentions regarding asthma treatment have been reported to occur for more than half of asthmatic children. Efforts should focus on ways to reduce mismatches. The Expert Panel recommends that clinicians provide patients with asthma self-management education that includes asthma information, training in asthma management skills, self-monitoring, a written asthma action plan, and regular ongoing assessment by a physician. Physicians should involve patients and families in the decisions about the types of self-monitoring. Written asthma action plans are particularly recommended for patients who have moderate or severe persistent asthma, a history of severe exacerbations, or poorly controlled asthma.

Inhaler Technique

Poor inhaler technique leads to poor asthma control, increased risk of exacerbations, and increased adverse effects. Most patients (up to 70–80%) are unable to use their inhaler correctly. Unfortunately, many healthcare providers are unable to demonstrate how to correctly use the inhalers they prescribe. Most people with incorrect technique are unaware that they have a problem. Both spacers and valved holding chambers are intended to retain large particles emitted from the MDI, reduce deposition in the oropharynx, and promote inhalation of a higher proportion of small, respirable particles.

In vitro and in vivo studies comparing various spacers and valved holding chambers with the same MDI have demonstrated significant variation in the respirable dose emitted from the devices and 2- to 5-fold difference in systemic availability of the drug. Valved holding chambers are preferred in children because they have 1-way valves that do not allow the child to exhale into the device. Thus, the child does not need to coordinate actuation and inhalation. Checking and correcting inhaler technique using a standardized checklist takes only 2 to 3 minutes and leads to improved asthma control. A physical demonstration with a placebo inhaler is preferred to improve inhaler-use technique. After training, proper inhaler-use technique diminishes with time, so checking and retraining must be repeated regularly. Pharmacists and nurses are key partners in asthma education and can provide highly effective inhaler-skills training. Training is equally important with dry powder devices and breath-actuated devices.

Asthma Education Partnerships

Visits to the ED and hospitalizations for asthma exacerbation are important opportunities for providing asthma education for a population of children with exacerbations. The Expert Panel concluded that it is important to assess inhaler-use techniques for all prescribed medications and reinforce correct technique before patients are discharged home. Further, the Expert Panel recommends that patients should be referred for a follow-up asthma care appointment within 1 to 4 weeks of discharge. The follow-up appointment should include patient education and asthma self-management education. Some studies support that better outcomes may result for patients referred from the ED to asthma specialists.

Several studies suggest that comprehensive school-based education programs about asthma can improve health and quality of life in children with persistent asthma. Further, asthma education incorporating technology that includes video gaming media has been shown to be useful in improving knowledge of asthma self-management and quality of life for high-risk children who have asthma.

Studies of community-based asthma interventions and education have revealed that asthma-education programs delivered by trained community residents are feasible and can result in changes in behavior and improved quality of life. Similarly, home-based interventions show significant promise for the treatment of childhood asthma. The home may be a useful point of care to assess and identify potential challenges to optimal asthma control including adherence obstacles, environmental exposures, and psychosocial factors, which may not be evident in a clinical setting. This information could be used to tailor personalized interventions including strategies to increase adherence and reduce household allergens.

ADHERENCE

Poor adherence is defined as the failure of treatment to be taken as agreed upon by the patient and the healthcare provider. There is considerable evidence regarding the importance of poor adherence in chronic diseases. As many as 50% of adults and children on long-term therapy for asthma fail to take medications as directed. In clinical practice, poor adherence may be identified by checking the date of the last prescription, checking the expiration date on the inhaler, and monitoring the electronic inhaler. In some health systems, pharmacists can assist in identifying poorly adherent patients by monitoring dispensing records. It is important to elicit patients’ beliefs and concerns about asthma and asthma medications in order to understand the reasons behind their medication-taking behavior. They include both intentional and unintentional factors and may be related to side effects of the medication as well as psychosocial factors including maternal depression, home environment, ethnicity, health literacy, and numeracy. A patient’s concerns about side effects may or may not be valid, but either way, the impact on their adherence is the same. Interventions that have been shown to improve adherence in asthma management include shared decision-making for medication choices and dosing regimens, medication reminders, less frequent dosing regimens, and home visits.

The essential components of effective, guided asthma self-management are self-monitoring of symptoms, a written asthma action plan that outlines how to recognize and respond to worsening asthma, and ongoing assessment of asthma control and management by a healthcare provider. Self-management education that includes these 3 components dramatically reduces asthma morbidity in adults and children.

OTHER TREATMENT CONSIDERATIONS

Environmental Allergen Avoidance

Avoidance of environmental allergens is one of the goals of asthma management. Allergic sensitization is common among asthmatics (60% in adults and as high as 90% of children). Sensitized asthmatic subjects challenged with extracts of the aeroallergens to which they are sensitive display symptoms of acute asthma. Asthmatic symptoms and objective measurements of lung function improve when patients avoid allergens to which they are sensitive.

Specific strategies for allergen avoidance are dependent on the allergen. The allergen that has been best studied is the house dust mite. The key target for control of dust mite exposure is bedding because of the high level of mite allergen exposure in mattresses, as well as the proximity of the patient to the source of dust mite and the prolonged period of time that is spent in this one site. Studies examining the effectiveness of dust mite–proof encasings for bedding have shown long-term reductions in the amount of allergen recovered, as well as in the allergen concentrations. Another recommendation is weekly washing of all sheets and bedding in hot water at a temperature of greater than 130°F in order to kill dust mites. Other recommendations for decreasing exposure to dust mites include removal of ­wall-to-wall carpeting, replacement with hardwood floors or tiled floor surfaces, and implementation of methods to decrease humidity.

Control of pet allergens represents a unique problem. Almost all residences contain detectable cat and dog allergen regardless of whether there is a cat or dog in the home. Although the mean level in houses without cats is significantly lower than that found in houses with pets, the lower level is still sufficient to cause symptoms in some individuals. Cats carry very large amounts of allergen, and only a tiny fraction becomes airborne. The transfer of allergen from houses to public places, schools, and daycare centers occurs by means of clothing. Optimal strategy for controlling cat allergens is relocation of the cat to another environment, which results in a drop in allergen levels by as much as 70%, although it takes years for the levels to decline to levels found in homes without a cat. Other measures, such as frequent washing of the cat, air filtration, and treatment with drugs or emollients, have not been shown to be effective.

Sensitivity and exposure to cockroaches are common findings among patients who have asthma and live in inner cities. In a study of asthma in an inner-city area, asthma severity increased with increasing levels of cockroach antigen in the bedrooms of sensitized children. Cockroach control measures are recommended if the patient is sensitive to cockroaches and infestation is present in the home.

The data for other environmental control measures including control of molds are still not definitive but support that decreasing exposure may be beneficial. As a routine part of their asthma care, patients/families should be counseled concerning the negative effects of smoking and environmental tobacco smoke. Notably, smoking out of doors does not adequately reduce exposure for children. There is insufficient evidence to recommend indoor air cleaning devices.

Immunotherapy

According to the Expert Panel Report 3, allergen immunotherapy should be considered for patients who have persistent asthma, evidence of allergen sensitization, and a history supporting a relationship between asthma symptoms and allergen exposure. Clinical studies have demonstrated that immunotherapy is effective in reducing asthma symptoms caused by exposure to grass, cat, house dust mite, ragweed, Cladosporium, and Alternaria. A meta-analysis of 75 randomized, placebo-controlled studies has confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication and improvement in bronchial hyperreactivity. Furthermore, immunotherapy may prevent the development of asthma in children with allergic rhinitis. The course of allergen immunotherapy is typically 3 to 5 years in duration. Immunotherapy carries a risk of allergic reactions including severe anaphylaxis, and these risks are more frequent among patients with poorly controlled asthma. Thus, immunotherapy should be administered only in a physician’s office equipped to handle anaphylaxis.

Assessment of Control

Periodic assessments of asthma control measures (see Table 505-2) are recommended to determine if the goals of therapy are being met and if adjustments in therapy are needed. The frequency of visits to a clinician for review of asthma control is a matter of clinical judgment, but should be, as a general rule, at least every 6 months. Patients with poorly controlled and/or severe persistent asthma and those who need additional supervision to help them follow their treatment plan should be seen more often.

Ongoing assessment of control should include monitoring of signs and symptoms of asthma, pulmonary function, quality of life/­functional status, history of asthma exacerbations, adherence to therapy, and potential side effects from medication. Per the Expert Panel Report 3, clinicians should use self-assessment tools to determine the patient’s/family’s assessment of the control of the asthma. Several multidimensional instruments have been developed to assess control (see Table 505-3).

Spirometry is recommended at the time of initial assessment, after the patient’s asthma symptoms have stabilized, and then every 1 to 2 years. It is also recommended during periods of progressive or prolonged loss of asthma control. Although spirometry is the preferred method to assess pulmonary function, peak flow monitoring should be considered for patients who have moderate or severe persistent asthma, patients who have a history of severe exacerbations, and patients who have difficulty accurately perceiving their level of airflow obstruction and worsening asthma. PEF is dependent on effort and technique; thus, it is important to review the technique frequently with the patient.

It is important to examine how the disease expression and control are affecting the patient’s quality of life. Correlations between asthma symptoms and quality of life are often in the low-to-moderate range, while correlations with pulmonary function measures are even weaker. Thus, the impact of the disease on the patient must be assessed directly and cannot reliably be inferred from the pulmonary function or symptoms.

A history of previous exacerbations, especially in the past year, is the strongest predictor of future severe exacerbations. Thus, it is critical to ascertain a careful history of exacerbations including the frequency, rate of onset, severity (length of hospital stay, use of corticosteroids, ICU, intubation), and causes of exacerbations. Referral to an asthma specialist should be considered in patients whose asthma is severe or difficult to control as outlined in Table 505-5.

Severe Asthma

With the development of effective asthma-control medications, most children with asthma can attain and maintain good asthma control. Unfortunately, a small group of severe asthmatic children will continue to have symptoms despite maximal medical therapy. Whereas most children with asthma achieve good symptom control when treated with low- to medium-dose ICS, children with severe asthma have sustained symptoms despite treatment with high doses of ICSs or oral corticosteroids. Although this group is comprised of only 5% to 10% of all children with asthma, it accounts for nearly 50% of all asthma-related expenditures.

Most definitions of severe asthma have included frequent day and nighttime symptoms, need for rescue bronchodilator therapy several times a day, and an FEV₁ less than 60% of predicted. The European Respiratory Society/American Thoracic Society Task Force Report on severe asthma simplified the definition of severe asthma by stating that severe asthma requires treatment with high-dose ICS plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy. Children with severe asthma may fall into 2 categories: difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis and/or comorbidities and/or poor adherence due to adverse psychological or environmental factors. In contrast, treatment-resistant asthma (also called refractory asthma) is defined as difficult asthma despite management of these factors. It is important to recognize that a child may have difficult-to-treat and treatment-resistant asthma. Although difficult-to-treat asthma is relatively common, only a fraction of these patients will have true refractory asthma. The true prevalence of refractory childhood asthma is difficult to determine as studies often do not account for inhaler technique and adherence.

Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with LABAs and other add-on therapies such as LTRAs and methylxanthines. It is important to identify and address the influences that render asthma difficult to control including reviewing the diagnosis and the removal of causal or aggravating factors. With the development of highly effective medications, children with severe asthma are less likely to be steroid-dependent, have better baseline lung function, require far less rescue albuterol, and are less growth-suppressed. Despite these gains, children with severe asthma continue to have frequent exacerbations, and osteopenia continues to be a common steroid-induced adverse effect.

Extrapolating adult severity classifications to children is difficult for a number of reasons. Adults with asthma are more likely to exhibit a persistent pattern, whereas children may have a pattern of rapidly evolving, frequent, and often severe exacerbations. Children have severe exacerbations triggered by viral infections and/or exposure to allergens that can result in healthcare utilization but then often remain asymptomatic between these episodes. Lung-function measurements also show different patterns, are age-dependent, and may be within normal limits despite significant symptom burden and medication use. In children, the distal airways are more affected, and increased distal lung resistance explains the often unimpaired FEV₁ values. Other measures of lung function such as FEV₁/FVC, forced expiratory flow at 25% to 75% of predicted, or the degree of airway responsiveness to bronchodilators may relate better to asthma severity.

Most children with severe asthma present in school age. Among school-aged and adolescent children, those with severe asthma were more likely to have higher serum IgE levels, increased allergic sensitization (especially to mold), increased load of aeroallergen sensitization earlier in life, a higher prevalence of AD, and greater bronchial hyperresponsiveness, and to report being of African American or more than one race than were children with milder disease. Adolescents are at an increased risk of having a higher prevalence of severe asthma and death from asthma due to reduced adherence to treatment and increased risk-taking behaviors.

SUGGESTED READINGS

INTRODUCTION

Preschool wheeze affects at least one-third of all children younger than 5 years old, and a disproportionate number of preschool children use healthcare resources for wheezing episodes compared to school-aged children with asthma. However, despite this high prevalence, it remains a significant management challenge. Establishing a diagnosis is difficult, with almost complete reliance on accurate parental symptom reporting, and there are no objective tests to assess lung function or airway inflammation. These patients have a relatively poor response to traditional asthma medications, and we cannot predict or prevent who will progress to asthma.

CONFIRMING THE DIAGNOSIS

History

The presence of wheeze must be confirmed before any treatment is initiated. Unfortunately, establishing its presence can be a challenge, especially if the child is seen when he or she is well. The history relies on accurate parental reporting, but parents’ and physicians’ understandings of wheeze may be very different. Another factor is the influence of language and culture; there is not an equivalent word for “wheeze” in all languages, and many parents may not understand what is implied by the term and may respond incorrectly. The most important aspect of the history is, therefore, to ask open-ended questions and to allow the parents to describe the symptoms. Asking “Does your child have noisy breathing or difficulty in breathing?” may be a good start, followed by asking the parents to describe any noises that they hear. The use of terms such as “whistling” have been adopted especially for epidemiologic questionnaires; however, they may also be too directive and significantly influence the way parents respond. It is, therefore, best to minimize the use of any specific or leading words. It is important to remember that difficulty in breathing or breathlessness may be more apparent to parents than are overt noises. In the current era of smartphones, the best way to determine whether a child has true wheezing may be to ask the parents to record and/or take a video of their child during an episode. Numerous algorithms using smartphone technology to allow objective recognition of wheeze in the clinic are being generated; however, none is in routine clinical use. A good alternative is to use a video questionnaire containing clips of videos of varying noises including wheeze, upper airway noises, and stridor that can be shown to parents to try to objectively confirm wheeze. It is important to ensure that upper airway and rattily chest noises are not misinterpreted as wheeze. The presence of a cough often is equally as apparent as the presence of wheeze, and enquiry about the nature of the cough, specifically whether it is moist- or wet-sounding, rather than dry or tight, is essential to direct appropriate management.

Given the difficulties inherent in the objective confirmation of wheeze (or bronchospasm, which is not the same thing) when a child is well, the primary care physician or general pediatrician who may see the child when acutely unwell should be asked to document the presence or absence of wheeze. Doctor-diagnosed wheeze is thus a term often used in questionnaires used in epidemiologic studies.

Examination

The findings on examination depend on whether the child is acutely unwell. Tachypnea, increased work of breathing, respiratory distress, low oxygen saturation, and widespread wheeze on auscultation all are consistent with an acute episode of preschool wheeze. Unusual features include focal signs on auscultation of the chest rather than diffuse bilateral wheeze or the presence of stridor. However, in an elective setting, examination usually is normal. Abnormal clinical signs are unusual when the child is well and suggest an alternative diagnosis (Table 506-1).

DIFFERENTIAL DIAGNOSES

The single most important aspect of the management of a preschool child presenting with wheezing is to carefully consider alternative diagnoses before initiating treatment, especially in younger children. Between one-third and one-half of children aged younger than 18 months with recurrent severe wheezing who underwent clinically indicated bronchoscopy had upper airway abnormalities such as malacia, compared with approximately 10% in older children. Another explanation for wheezing in this age group, especially younger children, is aspiration, either secondary to gastroesophageal reflux or an unsafe swallow. A list of differential diagnoses and unusual symptoms and signs that should cause concern and question the diagnosis of simple preschool wheeze has been provided in Table 506-1.

A particular symptom pattern that can cause confusion is the presence of a moist or wet cough together with wheeze or noisy breathing. This symptom pattern could be termed wheeze plus and may suggest the presence of protracted bacterial bronchitis (PBB). The clinical features that suggest PBB and its management are summarized below.

Protracted Bacterial Bronchitis

PBB is characterized by the presence of a persistent wet cough for at least 4 weeks, often associated with the presence of wheezing or rattily breathing. It is essential to ensure that clinical features suggesting an alternative diagnosis such as cystic fibrosis or other chronic suppurative lung disease are absent (see Table 506-1) and there are no obvious radiologic abnormalities such as bronchiectasis. Suggested criteria for diagnosing PBB are summarized in Table 506-2. In cases for which bronchoscopy is undertaken in children with suspected PBB, significantly more have lower airway infection with common respiratory viruses and bacteria compared to controls. Therefore, in the presence of a chronic and persistent wet cough, with no clinical features suggesting an alternate diagnosis, a clinical diagnosis of PBB can be made and a prolonged course of oral broad-spectrum antibiotics such as amoxicillin/clavulanate should be trialed. The duration of therapy remains uncertain and can range from 2 to 6 weeks. The British Thoracic Society Guidelines suggest a 4- to 6-week trial of treatment, but in the absence of additional investigations, it is more appropriate to have a 2-week trial of therapy initially to assess response and, if there is no response, to proceed to further investigations.

CLINICAL WHEEZE PHENOTYPES

Clinical wheeze phenotypes have been identified from cohort studies that have followed children from birth through school age and beyond. The first such cohort was the Tucson Children’s Respiratory Study and included transient/early wheeze (0–3 years), persistent wheeze (0–6 years), and late-onset wheeze (3–6 years), but these phenotypes could be applied only retrospectively once the child had reached the age of 6. Subsequently, other European cohorts (Prevention and Incidence of Asthma and Mite Allergy [PIAMA] and Avon Longitudinal Study of Parents and Children [ALSPAC] cohorts) have confirmed and extended these patterns. The data have confirmed that only one-third of all preschool children who wheeze develop asthma by school age. Therefore, using the “asthma” label in this age group increases confusion and should be avoided. Data from cohorts have also been used to develop clinical indices that might help to predict which child will develop asthma by school age. The Asthma Predictive Index (API) was derived from the Tucson data, and, subsequently, a modified Asthma Predictive Index (mAPI; Table 506-3) was derived, which can be applied to all children older than age 1 year. Numerous risk factors for future development of asthma have been identified from birth cohorts and include maternal or paternal atopy and early atopic sensitization in the child. However, the clinical utility of these childhood-asthma prediction models remains unclear. The greatest limitation of all currently available predictive models is that although they have a good negative predictive value and exclude children who are unlikely to develop asthma with good accuracy, none has a positive predictive value better than 50%, which means the ability to accurately identify those children who will go on to develop asthma remains no better than tossing a coin.

Clinical phenotypes derived from birth cohorts do not adequately inform management of preschool wheezing because they can be applied only retrospectively. Furthermore, the mAPI was designed to predict which children are at high risk of developing asthma by school age and whether treatment with regular inhaled steroids might modify the natural progression; it does not predict which children will respond to treatment. Therefore, clinical phenotypes that guide management have been proposed. Two main patterns of wheeze have been defined by the European Respiratory Society: episodic viral wheeze and multiple-trigger wheeze. Episodic viral wheeze is most commonly related to an upper respiratory infection. In contrast, multiple-trigger wheeze occurs both during acute episodes of infection and “to a lesser degree” at other times, often during exercise. The advantages of this classification include the ability to prospectively assign a phenotype at the time of consultation, regardless of the age of the child; the use of only the child’s clinical history without objective tests; and no reliance on family history. However, there are several limitations to this approach. First, it relies on parents distinguishing symptom patterns, and there may be over- or underreporting. Second, clinical phenotypes may change within 3 months. Third, disregard for severity or frequency of episodes may mean management is suboptimal. And finally, the underlying infectious cause of an acute episode is not considered. Although it was previously thought that most episodes are precipitated by viral infections, it is now recognized that an equal number are also caused by bacterial infection.

TREATMENT OF PRESCHOOL WHEEZE

Prevention of Progression To Asthma

There are no disease-modifying agents that prevent progression of preschool wheeze to asthma. Early use of inhaled steroids does not affect this progression. Therefore, it is important to be clear what the term preschool wheeze actually means. There is a tendency to use the terms preschool wheeze and asthma interchangeably, but for children age 5 and younger, the diagnostic label of “asthma” should be avoided because it is hard to confirm this diagnosis without the availability of objective tests, including lung function tests, to show reversible airflow obstruction or airway hyperresponsiveness. In addition, the term asthma suggests the presence of airway inflammation, but many preschool wheezers do not have inflamed airways. Also, preschool children, even those with multiple-trigger wheezing, do not respond to “usual” asthma medications in the same way as do school-aged children, particularly when acutely unwell. Short courses of oral corticosteroids, the standard treatment for school-aged children with an asthma exacerbation, have a variable, if any, response in preschool children (see below). In addition, response to maintenance therapy with inhaled steroids is extremely variable in preschool children.

Management of Current Symptoms

Having confirmed the presence of wheeze and ensured that all differential diagnoses for wheezing in preschool children have been excluded as far as possible, approaches to management can be considered, which can be divided into the management of the acute wheezy episode and management to try to minimize daily symptoms and future exacerbations.

Management of Acute Episodes

Bronchodilators

At present, the mainstay of management of an acute episode of wheezing is bronchodilator therapy. Evidence for efficacy and choice of bronchodilator in this age group is scant. It is apparent that there is significant variability across centers in the dose, timing, route, and frequency of bronchodilators used with differing severities of episodes. A trial of inhaled β₂-agonists via a spacer should be undertaken, and anticholinergics such as ipratropium bromide may also be added if symptoms are severe or there is little response to β₂-agonists. The most important aspect is to ensure use of correct device and technique in order to achieve maximal drug delivery. Nebulizers should be reserved for those who require oxygen, and intravenous treatment may also be used if symptoms are severe.

Oral Corticosteroids

Although a short course of oral steroids is effective in treating acute asthma in older children, there is limited evidence supporting this intervention among preschool children. Specifically, preschool children who have viral-induced episodes of wheeze, even when severe enough to require hospitalization, have no benefit from a short course of oral steroids, whether considering length of hospital stay, symptoms, or severity of episode. At least 3 randomized trials evaluating oral corticosteroids for wheezing episodes in preschool children have failed to demonstrate efficacy. A post hoc analysis of 2 additional large randomized trials in more than 1500 episodes of significant lower respiratory tract wheezing confirmed that oral steroids did not reduce the severity of symptoms or duration of episodes. There is universal agreement that the role, if any, of oral steroids for treating acute wheezing episodes in preschool children remains unconfirmed (see later Table 506-5). However, in practice, the severity of the episode must guide whether oral steroids are used. They should be avoided in a child at home who is responding to bronchodilators. In contrast, the threshold for use is lower in a hospitalized child with worsening or severe symptoms despite use of bronchodilators.

High-Dose Inhaled Steroids

There is some evidence that high-dose inhaled steroids are beneficial during an acute exacerbation of preschool wheeze. A randomized trial of fluticasone 750 μg twice daily for a week or up to 10 days initiated at home at the onset of a viral respiratory illness showed a significant reduction in the primary outcome of rescue oral steroid use. However, this benefit came at a significant cost, which was a smaller gain in height during the 1-year trial period in the fluticasone group, and the effects on adrenal function were only crudely assessed. A Cochrane Review of the use of high-dose inhaled steroids for acute viral wheeze also has documented improvement in the duration of symptoms and severity of exacerbation. However, given the very high doses used, the treatment duration of up to 10 days, and the fact that some children may have episodes as frequently as every 2 weeks, there is the potential of using very high-dose inhaled steroids almost continuously with this regimen, and for this reason, it cannot be recommended.

Leukotriene Receptor Antagonists

An alternative strategy that can be considered is the use of leukotriene receptor antagonists (LTRAs) at the onset of symptoms, including the onset of coryza, and before the start of wheezing. A recent large, multicenter, randomized trial that assessed the efficacy of intermittent montelukast in children age 10 months to 5 years with acute wheeze (WAIT trial) showed no benefit in unscheduled healthcare visits. However, there was a subgroup with the 5/5 ALOX5 genotype who did benefit. Because there is a subgroup of preschool wheezers who respond to intermittent LTRA, it is worth giving a trial for parents to initiate at home to determine efficacy in the individual child. However, if there is no benefit, then this approach should be stopped. Parents must be warned of the very dramatic adverse effects of LTRAs on behavior or in causing nightmares in a small proportion of children, which may necessitate stopping treatment.

Intermittent Inhaled Steroids or LTRA for Acute Episodes

One trial compared the efficacy of intermittent montelukast, intermittent inhaled budesonide (0.5 mg twice daily nebulized), and placebo at the onset of symptoms for acute viral wheeze. The primary outcome of episode-free days over a 12-month period was similar, but all secondary outcomes improved equally with LTRA or budesonide.