ALTERATIONS OF PULMONARY FUNCTION IN CHILDREN

Infections

Infections of the upper airway (Table 34-1) are common in children; some have the potential to cause life-threatening emergencies. Recognition and rapid evaluation of these problems are crucial pediatric care skills.

Croup

Classic croup is an acute laryngotracheobronchitis and is the most common cause of acute upper respiratory obstruction in young children.⁹ It occurs most often in children from 6 months to 5 years of age, with peak incidence in the second year of life.¹⁰ In 85% of cases, croup is caused by a virus, most commonly parainfluenza; however, other viruses such as influenza A or respiratory syncytial virus (RSV) also can cause croup.⁹ Rhinovirus, adenovirus, measles, and the atypical bacteria Mycoplasma pneumoniae also have been associated with causation. The incidence of croup is highest in late autumn and winter, corresponding to the parainfluenza and RSV seasons, respectively. Croup is more common in boys than girls. In a significant portion of affected children, croup is a recurrent problem during childhood, and there is a family history of croup in about 15% of cases.

PATHOPHYSIOLOGY The pathophysiology of viral croup is caused primarily by subglottic edema from the infection. The mucous membranes of the larynx are tightly adherent to the underlying cartilage, whereas those of the subglottic space are looser and thus allow accumulation of mucosal and submucosal edema (Figure 34-7). Furthermore, the cricoid cartilage is structurally the narrowest point of the airway, making edema in this area critical. As illustrated in Figure 34-8, increased resistance to airflow leads to increased work of breathing, which generates more negative intrathoracic pressure, which in turn may exacerbate dynamic collapse of the upper airway.

CLINICAL MANIFESTATIONS Typically there is a prodrome of rhinorrhea, sore throat, and low-grade fever for a few days. The child then develops the characteristic harsh (seal-like) barking cough, hoarse voice, and inspiratory stridor. Most cases are mild and resolve spontaneously after several more days. Occasionally, however, UAO becomes severe and requires urgent management.

Spasmodic croup is another clinical entity that is characterized by similar hoarseness, barking cough, and stridor but is of sudden onset, usually at night and without viral prodrome. It often resolves as quickly as it develops. The etiology is unknown although an association with a history of atopy has been observed.¹⁰

EVALUATION AND TREATMENT The degree of symptoms determines the level of treatment. Most children have a barking cough and viral symptoms and may need no specific treatment. However, the presence of stridor (especially at rest), retractions, or agitation suggests a sicker child. A number of clinical tools are used to assess the severity of croup in children. The tool most often used is the Westley croup score, which provides a cumulative score for the degree of stridor, retractions, air entry, cyanosis, dyspnea, and level of consciousness in the child.⁹ Severity also is classified into mild, moderate, and severe.

Croup therapy has been the subject of debate for years. Nonpharmacologic treatment options include steam inhalation, ice masks, and oxygen. The first two, however, lack scientific studies to support or refute their benefit. The consensus from numerous controlled studies is that oral, intravenous, or nebulized corticosteroids have a significant effect on croup-related hospitalizations and are cost effective.⁹ Symptoms improve faster, less sleep is lost by children, less stress is experienced by parents, and fewer children have a need for return healthcare visits when corticosteroids are used.¹¹ The emergent use of nebulized epinephrine is indicated when significant respiratory distress is present. Epinephrine stimulates α- and β-adrenergic receptors and is thought to decrease airway secretions and mucosal edema. However, its effect lasts only 2 hours and should be considered a temporizing measure until concomitantly given steroids begin to take effect. Thus children who are given nebulized epinephrine should be observed for 2 to 3 hours to ensure that they will remain stable, and close follow-up is mandatory. Heliox (helium-oxygen mixture of 80:20 or 70:30) can be used for severe cases of croup, although this is not considered part of the routine treatment regimen.^9,10

Acute Epiglottitis

Acute epiglottitis is a severe, life-threatening, rapidly progressive infection of the structures above the insertion point of the glottis, which include the epiglottis, aryepiglottic folds, arytenoid soft tissue, and the uvula. Historically, cases were nearly always caused by H. influenzae type B (Hib). Since the advent of Hib immunization, the overall incidence of acute epiglottitis has decreased to only 10% to 20% of previous levels.^9,12 Current pediatric cases usually represent vaccine failures or are caused by alternative pathogens, such as groups A, B, C, F, and G streptococci, Streptococcus pneumoniae, Candida species. S. aureus, and viral pathogens.¹² Hib still accounts for approximately 25% of the cases seen in children.¹² Thermal injuries, trauma, and posttransplant lymphoproliferative disorder also have been reported as causes of epiglottitis.¹²

CLINICAL MANIFESTATIONS In the classic form of the disease, a child between 2 and 6 years of age suddenly develops high fever, irritability, sore throat, a “hot potato voice,” inspiratory stridor, and severe respiratory distress. The child appears ill and classically will adopt a forward-leaning position (tripod position) with drooling and dysphagia (inability to swallow). Examination of the throat may trigger laryngospasm and cause respiratory collapse. Death may occur in a few hours. Pneumonia, cervical lymph node inflammation, otitis, and, rarely, meningitis or septic arthritis may occur during the course of epiglottitis.

EVALUATION AND TREATMENT Despite its decreasing incidence, all pediatric practitioners must be familiar with epiglottitis and understand it is a life-threatening emergency. The essentials are recognition, avoidance of disturbing the child (which could worsen the obstruction), and securing the airway. Tracheal intubation should be accomplished by the most experienced personnel (usually an anesthesiologist and/or otolaryngologist) using fiberoptic laryngoscopy. Subsequent culture of the airway is obtained and intravenous broad-spectrum antibiotics are administered promptly. Therapy is reevaluated after culture results return. Corticosteroids also are generally used in treatment regimens although there are no published randomized trials to support this practice.^9,12,13 Despite the severe presentation of epiglottitis, resolution with treatment is usually rapid, with intubation rarely needed for more than a couple of days. When Hib epiglottitis is diagnosed, the American Academy of Pediatrics (AAP) recommends that postexposure prophylaxis with rifampin be administered to household contacts (specific to certain ages of children present).¹³ When caused by microorganisms other than H. influenzae, as is now the usual situation, epiglottitis may present in ages outside the typical range and with more gradual rather than fulminant onset, thus making diagnosis less obvious. Such cases also may respond more slowly to treatment.

Aspiration of Foreign Bodies

Most children who aspirate a foreign object (foreign body aspiration) are between 1 and 3 years of age. More than 100,000 cases occur each year.¹⁴ Often the aspiration either is not witnessed or does not seem significant to the parent, thus medical care is often not pursued until after the first 24 hours. At the time of aspiration, the child may cough, choke, gag, or wheeze, and stridor or cyanosis occasionally occurs. This may be followed by a quiescent interval of minutes to even weeks or months before symptoms reappear from resulting local irritation, granulation, bronchial obstruction, or infection (pneumonia or bronchiectasis). Pronounced inspiratory stridor, cough, and wheezing are typical symptoms that prompt the parents to seek medical attention. Examples of common aspirated objects include nuts, sunflower seeds, hot dog chunks, popcorn, coins, and small toys or toy parts. Meat or food impactions are more common in adolescents. Items of particular concern are batteries and multiple magnets. In general, foreign bodies require early intervention secondary to their propensity to cause respiratory symptoms and complications, including esophageal erosions or aortoesophageal fistula.

The symptom history is often the most critical aid in diagnosis.^14,15 Symptoms are determined by the size of the object and the site in which it is located, as well as the child’s age and size (see Figure 34-4). Foreign bodies lodged in the upper trachea typically produce inspiratory stridor, whereas those located in the lower intrathoracic airways more commonly produce wheezing. About 75% of aspirated foreign bodies lodge in a bronchus. Children with an unexplained persistent cough and refractory parenchymal infiltrates also should be considered for unrecognized foreign body aspiration.¹⁶ Many objects are not radiopaque; however, if the object has completely occluded a lung segment, atelectasis will be visible on a chest radiograph. Occasionally, air will accumulate distal to the obstruction if the object is causing a ball-valve effect. This effect can sometimes be documented by inspiratory and expiratory chest films (Figure 34-9). In a younger child, bilateral decubitus films may show failure to compress the obstructed lung when in the “down” position.

Most foreign bodies can be removed by bronchoscopy and only rarely is a pulmonary lobectomy required. Soft particles such as food as well as hard objects must be removed because infectious processes will otherwise occur. Objects lodged in the laryngeal or subglottic regions are particularly dangerous because of their potential for complete or near-complete airway occlusion.

Other Causes of Upper Airway Compromise

Obstructive Sleep Apnea

Obstructive sleep apnea syndrome (OSAS) is a breathing disorder defined by prolonged partial and/or intermittent complete UAO during sleep with disruption of normal ventilation and normal sleep patterns.³⁷ Childhood OSAS is common with an estimated prevalence of 2% to 3% among middle-school children and as many as 13% of children ages 3 to 6 years. Prevalence is estimated to be two to four times higher in vulnerable populations (blacks, Hispanics, and preterm infants).³⁸ Unlike adults, OSAS in children occurs equally among males and females. Possible influences early in life may include passive smoke exposure, socioeconomic status, and snoring together with genetic modifiers such as those that promote airway inflammation.

PATHOPHYSIOLOGY The pathophysiology of childhood OSAS is likely to be multifactorial in origin. In otherwise healthy children, the most common predisposing factor is adenotonsillar hypertrophy, which causes physical impingement on the nasopharyngeal airway. OSAS often occurs in overweight or obese children as well as in those with orthodontic/craniofacial anomalies or neurologic disorders. Allergy and asthma also may contribute to this condition. In addition to physical narrowing, other mechanisms have been suggested, such as abnormalities in the motor tone of the upper airways (frequently an issue in neurologically impaired children) or abnormal arousal mechanisms.³⁹ Recent studies have documented that children with sleep disordered breathing (SDB) have increased inflammation in the upper airway and elevated serum levels of C-reactive protein that are relationally proportional to the severity and frequency of UAO.⁴⁰ Lastly, genetic susceptibility likely plays a role in neurocognitive dysfunction associated with this condition.

CLINICAL MANIFESTATIONS OSAS may present with a history of snoring and labored breathing, restlessness, and sweating during sleep, which can be continuous or intermittent. There may be episodes of increased respiratory effort but no audible airflow, often terminated by snorting, gasping, repositioning, or arousal. Affected children are often chronic mouth breathers and have large tonsils. They also may exhibit nocturnal enuresis and intrusive nap habits.⁴¹ Unlike adults, no correlation between OSAS and sleep position has been noted in children. Similar to adults, it appears that there also may be a correlation between OSAS and elevated blood pressure. This is further linked to increased body mass index (BMI) and episodes of desaturation and apnea/hypopnea.⁴² Children who are overweight or obese often have severe OSAS and adopt the prone sleeping position to facilitate improved airway patency and are at a 4.6-fold increase for sleep apnea compared with healthy children.³⁸

OSAS can result in chronic hypoxemia and hypercapnia affecting multiple organ systems. Significant morbidity is associated with OSAS including cognitive, neurobehavioral (inattention, hyperactivity, aggression, conduct problems, attention deficit/hyperactivity disorder [ADHD]/emotional [mood]) impairment, excessive daytime sleepiness, impaired school performance, and poor quality of life.³⁸ Left untreated it also can cause cardiovascular disease, particularly left ventricular hypertrophy, and insulin resistance, as well as pulmonary complications (upper and lower respiratory tract infections) and reduced somatic growth.^{38,41,43–45}

EVALUATION AND TREATMENT All parents should be asked if their child exhibits snoring, a symptom that is often not spontaneously reported to a healthcare provider. The history and physical examination are the most effective means of diagnosis.⁴⁶ Screening tools and sleep questionnaires may be helpful in evaluating the presence of SDB.⁴¹ Radiographic image of the upper airway may reveal upper airway narrowing caused by adenoidal hypertrophy and magnetic resonance imaging (MRI) and acoustic reflectometry may detect reduced upper airway dimensions.^38,41 The most definitive evaluation (“gold standard”) is the polysomnographic sleep study, which documents obstructed breathing and physiologic impairment. If obstructive sleep apnea caused by tonsillar enlargement is documented or strongly suspected clinically, children are most often referred for tonsillectomy and adenoidectomy (T&A). For severely affected children who do not respond to T&A or who have different problems, such as obesity that cannot be rapidly remedied, continuous positive airway pressure (CPAP) delivered through a tight-fitting nasal mask may be used during sleep. Treatment is important to prevent associated morbidities. Successful medical or surgical treatment results in improvement in physical, behavioral, and emotional difficulties as well as quality of life.^41,47

Neonatal Respiratory Distress Syndrome

Respiratory distress syndrome (RDS) of the newborn, also known as hyaline membrane disease (HMD), is a major cause of morbidity and mortality in premature newborns.⁴⁸ The epidemiology, pathophysiology, and clinical presentation of RDS are outlined in Box 34-2. The major predisposing factor is prematurity because the immature lung is not well structured for gas exchange and has not yet developed adequate surfactant production and secretion. Occasionally RDS is seen in other situations, most notably infants of diabetic mothers. An additional factor that increases risk is cesarean delivery. It is more common in boys than girls and in whites than nonwhites. The incidence of RDS (in the absence of preventive treatment) is approximately 50% to 60% at 29 weeks of gestation and decreases significantly by 36 weeks. Preterm births account for up to 12% of all births⁴⁹ and approximately 10% of newborns who require some assistance to begin breathing at birth.⁵⁰ Antenatal stress on the fetus may accelerate lung maturation and decrease RDS risk. In special circumstances, such as elective early delivery (e.g., for maternal health reasons), RDS risk is assessed by sampling amniotic fluid for quantification of secreted surfactant lipids, the basis of the lecithin/sphingomyelin (L/S) ratio (value of 2 or greater predicts low risk). Another common test looks for presence of the lipid phosphatidylglycerol, which also reflects lung maturity.

PATHOPHYSIOLOGY RDS is a state of pulmonary insufficiency that in its natural course commences at or shortly after birth. Severity tends to increase over the first 2 days of life.⁵¹ It is caused primarily by surfactant deficiency and, secondarily, by a deficiency in alveolar surface area for gas exchange. Premature infants are born with many underdeveloped and small alveoli that are difficult to inflate. Those that are available for gas exchange do not have adequate surfactant, which is necessary at the air interface to maintain alveolar distention at end-expiration. The net effect is atelectasis (see Figure 34-11), which causes significant hypoxemia, and is difficult for the neonate to overcome because it requires a significant negative inspiratory pressure to open the alveoli with each breath. The chest wall is weak and highly compliant, making it difficult to overcome this increased work of breathing. This results in a decrease in tidal volume causing alveolar hypoventilation and hypercapnia. Hypoxia and hypercapnia cause pulmonary vasoconstriction, which increases intrapulmonary resistance and shunting (Figure 34-12). To make the situation more complex, prolonged hypoxemia activates anaerobic glycolysis, which produces lactic acid and thus causes metabolic acidosis. Alveolar hypoventilation makes it impossible to get rid of excess carbon dioxide (CO₂), and combined metabolic and respiratory acidosis develops. Lowered pH causes further vasoconstriction. This results in hypoperfusion of the lung and a decrease in effective pulmonary blood flow. Increased pulmonary vascular resistance causes a partial return to fetal circulation, with right-to-left shunting of blood through the ductus arteriosus and foramen ovale (see Figures 34-11 and 34-12). With inadequate pulmonary circulation and alveolar perfusion, the oxygen content of the blood continues to decrease, pH decreases, and materials needed for surfactant production are not circulated to the alveoli. Capillary permeability increases, resulting in the leakage of plasma proteins. Fibrin deposits in the air spaces create the appearance of hyaline membranes for which the disorder is named. The plasma proteins leaked into the air space have the additional adverse effect of interfering with the function of surfactant that may be present. The pathogenesis of RDS is summarized in Figure 34-12.

CLINICAL MANIFESTATIONS Signs of RDS appear within minutes of birth. Some neonates require immediate resuscitation because of asphyxia or initial severe respiratory distress. Tachypnea (respiratory rate more than 60 breaths per minute), expiratory grunting or whining, intercostal and subcostal retractions, nasal flaring, and poor color are the most striking clinical manifestations of RDS. The natural course is characterized by progressive hypoxemia and dyspnea. Apnea and irregular respirations occur as the infant tires. The severity of the hypoxemia and the difficulty in providing adequate supplemental oxygenation give rise to the Vermont Oxford Neonatal Network definition of RDS as a PaO₂ less than 50 mmHg in room air, central cyanosis in room air, or a need for supplemental oxygen to maintain PaO₂ greater than 50 mmHg, as well as the classic chest film appearance.⁵¹ Within the first 6 hours of life, a chest radiograph will reveal air-filled bronchi (air bronchograms) silhouetted against lung fields that have a “ground glass” appearance associated with alveolar consolidation. RDS can progress to death in severe cases, but in most cases the clinical manifestations reach a peak within 3 days, after which there is gradual improvement with appropriate treatment.

EVALUATION AND TREATMENT Diagnosis is made on the basis of clinical manifestations, chest radiographs, and, occasionally, confirmatory analysis (e.g., L/S ratio) of amniotic fluid or tracheal aspirates. The ultimate treatment for RDS would be prevention of premature birth, but in the meantime other significant advances in treatment have been made.

The first is antenatal treatment with glucocorticoids for women in preterm labor. Glucocorticoids induce a significant and rapid acceleration of lung maturation and stimulation of surfactant production in the fetus, and there is extensive evidence that maternal steroid therapy significantly reduces the incidence of RDS, central nervous system hemorrhage, and neonatal mortality.^49,52 This treatment is currently recommended in the setting of preterm labor at 24 to 34 weeks of gestation unless delivery is imminent; ideally, dosing continues for 48 hours while attempts are made to halt labor. It remains unclear whether repeated courses of steroids are safe in this setting.⁵¹

The second major advance in RDS treatment has been exogenous surfactant, either synthetic or purified from animal sources and instilled down an endotracheal tube (ETT). This may be administered in prophylactic or rescue protocol. Unfortunately, liquid dosing down the ETT may result in peridosing adverse events like hypoxia, hypercapnia, and changes in cerebral blood flow. There has been recent progress in administering surfactant by less invasive methods such as through nebulization or nasal CPAP. These modalities result in more uniform distribution of the drug than through the ETT.⁵³ Current protocols recommend prophylactic administration of surfactant to infants weighing less than 1000 g beginning within 15 to 30 minutes of birth, after the infant is stabilized. Repeat dosing is usually given every 12 hours during the first few days. There is usually a dramatic improvement in oxygenation. For infants weighing more than 1000 g, surfactant replacement is based on clinical need. Because of concerns about intervention-induced lung injury, guidelines for surfactant administration are being reconsidered (see What’s New? Pulmonary Resuscitation of the Newborn—Setting the Stage for Injury?).

Systematic reviews of randomized, controlled trials have confirmed that surfactant replacement improves oxygenation as well as reduces the incidence of RDS, death, pneumothorax, and pulmonary interstitial emphysema.⁵⁴ Therapy with surfactant should be considered complementary to antenatal glucocorticoids, which promote not only accelerated surfactant synthesis but also enhanced structural development of the lung and beneficial effects on mechanisms of fluid clearance from the lung. These two therapies together appear to have an additive effect on improving lung function. Supplemental inositol also may promote maturation of surfactant and prevent adverse neonatal outcomes in preterm infants.⁵⁵

The third advance in RDS treatment has been in supportive care. Newborns with RDS need oxygen and often ventilatory support such as CPAP or mechanical ventilation. Strategies that are lung protective, such as greater reliance on nasal CPAP, permissive hypercapnia, lower oxygen saturation targets, modulation of tidal volume (V_T) settings, use of nitric oxide, and use of high-frequency oscillation, are being evaluated.⁵⁶ Nitric oxide has found acceptance for treatment of persistent pulmonary hypertension of the newborn and for hypoxic respiratory failure in term and near-term infants although the precise mechanisms of how it may improve lung function are yet unclear.^57,58 The use of nitric oxide in moderately ill, ventilated premature infants appears safe in infants between 1000 and 1250 g birth weight. Benefits include decreased oxygen use and fewer days of ventilation, prevention of bronchopulmonary dysplasia (BPD), and neurologic protection. Additional therapies, such as antioxidants, late surfactant doses, caffeine, and improved ventilatory strategies (including steroids surrounding the time of extubation), can provide additional benefit in these vulnerable infants.^59,60 Other key components of supportive care include prophylactic antibiotics, temperature control, fluid and nutritional management, maintenance of blood pressure, and management of patent ductus arteriosus.⁵¹

The extremely preterm lung is particularly vulnerable to injury. Mechanical ventilation may interfere with alveolarization and surfactant metabolism and may aggravate the proinflammatory state (as reflected by abnormal cytokine profiles) that is believed to accompany premature birth and RDS. Injury from oxygen toxicity also is a concern and is mediated through reactive oxygen species.⁶¹ This combination of factors may lead to subsequent development of chronic lung disease or bronchopulmonary dysplasia.^62,63 The use of CPAP rather than intubation may reduce these complications.⁶⁴ Most infants with RDS survive with treatment. However, the incidence of subsequent chronic lung disease is significant among very low-birth-weight infants.

Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), often used synonymously with chronic lung disease of infancy, is the most common chronic lung disease of infancy in the United States. It is the term used for persisting lung disease following premature birth and perinatal respiratory support. When originally described by Northway and colleagues in 1967, the term was applied to premature infants (30 to 37 weeks’ gestation) who had survived acute RDS but continued to have pulmonary dysfunction and oxygen dependence, which was attributed to injury from postnatal mechanical ventilation and oxygen therapy.⁶⁵ The terms of definition and evolution of disease have changed notably since the original description of the disease. Premature infants are now consistently surviving at 23 to 26 weeks and have different mechanisms of lung injury.⁶⁶

In the current era of neonatology, the widespread use of antenatal glucocorticoids and postnatal surfactant has lessened the incidence and severity of RDS, and BPD is occurring almost exclusively in the smallest premature infants (23 to 28 weeks’ gestation) who have received mechanical ventilation. Surprisingly, some of these tiny infants who develop BPD have had few or no clinical signs of RDS at birth or have initially received only low levels of supplemental oxygen or ventilatory support.⁶⁷ Nevertheless, a highly significant predictor of subsequent BPD remains the need for mechanical ventilation on the day of birth. The presence of antenatal chorioamnionitis, postnatal sepsis, or a patent ductus arteriosus may confer additive risk of developing BPD.

The reported incidence of BPD is widely variable because of the lack of consistent diagnostic criteria, but is most common in infants delivered at gestational ages less than 30 weeks or who have birth weights of less than 1500 g. There are approximately 60,000 infants born at less than 1500 g in the United States on an annual basis. About 20% to 30% of these infants develop BPD. Because BPD is a multisystem condition, it also is associated with developmental disorders in other systems, such as growth retardation, pulmonary hypertension, neurodevelopmental delays (e.g., cerebral palsy), hearing defects, and retinopathy of prematurity.^66,68

PATHOPHYSIOLOGY In preterm infants born at less than 28 weeks of gestation, the fetal lung is in the canalicular stage of development (16 to 28 weeks), a critical period during which type II epithelial cells appear, capillaries grow into the future distal alveolar regions, and the interstitium begins to condense. Ultimately the alveoli must have a very thin interface between the air space and the capillary for appropriate gas exchange. The extensive network of alveoli develop by septation within the terminal respiratory unit, beginning in the saccular stage, which starts at approximately 26 to 28 weeks.

Prior to the widespread use of surfactant therapy, BPD was a disease characterized by airway injury, inflammation, and parenchymal fibrosis. Now, after the initiation of surfactant therapy, what is called new BPD is most often a form of arrested lung development.⁶⁹ The characteristic pathologic changes seen in new BPD are fewer and larger alveoli with less functional surface area, and reduced and dysplastic capillary ingrowth to the alveolar region. There may be accompanying pulmonary hypertensive changes, interstitial fibrosis, and smooth muscle hyperplasia, but certainly to a much lesser degree than that associated with classic BPD. Airway epithelial lesions are negligible. The pathophysiology of BPD is diagrammed in Figure 34-13.

Genetic susceptibility and hereditary influences on gene expression that are pivotal for surfactant synthesis, vascular development, and inflammatory regulation have been documented as being associated with new BPD.⁶⁶ To a significant extent, cytokines may mediate the abnormal alveolarization and injury response that lead to BPD, although this has not been directly proven. In the case of intrauterine infection, inflammatory mediators may prime the lung for an exaggerated path of injury after birth. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and IL-8, are elevated in the amniotic fluid or tracheal aspirates of preterm infants who later develop BPD. Interestingly, the predominant mediators of new BPD are profibrotic and angiogenic cytokines rather than proinflammatory cytokines.⁷⁰ Antenatal and postnatal exposures also play into the progression of this “developmental disorder.” In the antenatal period, the use of steroids, chorioamnionitis, or the presence of intrauterine growth restriction influences the development and progression of BPD. Postnatally, administration of steroids, nutritional issues, as well as mechanical ventilator damage and pulmonary edema, influence progression of BPD.

Ventilation-perfusion matching is compromised as a result of structural underdevelopment, pulmonary hypertension, increased lung fluid content, airway injury, and smooth muscle hypertrophy, as well as adverse chest wall dynamics. Thus infants with BPD exhibit an increased oxygen requirement, increased work of breathing, and in the most severe cases, right-sided heart failure.

CLINICAL MANIFESTATIONS The current clinical definition of BPD includes the need for supplemental oxygen at 36 weeks’ postmenstrual age, and for at least 28 days after birth, with a graded severity dependent on required respiratory support at term (divided into mild, moderate, and severe based on oxygen requirements and ventilatory needs). The affected infant exhibits hypoxemia caused by ventilation-perfusion mismatch and diffusion defects. Work of breathing is elevated, resulting in hypercapnia. The ability to feed may be impaired. Intermittent bronchospasm with wheezing, mucous plugging, and pulmonary hypertension characterize the clinical course of the most severely affected babies. Dusky spells may occur with agitation or reflux because of several contributing factors, including nonhomogeneous ventilation, air trapping, bronchospasm, laryngospasm, sudden increases in pulmonary vascular resistance, or occasionally, pneumothorax.

Infants with severe BPD require prolonged, assisted ventilation with cautious weaning. Prevention of lung damage with “gentle ventilation” (see lung protective strategies of ventilation in RDS section, p. 1335) or early nasal CPAP, or both, are used in clinical situations when permitted. Use of CPAP has resulted in fewer days of oxygen and ventilator requirement by reducing the amount of lung injury as compared with mechanical ventilation.^71,72 Additionally, oxygen supplementation at lower than previously accepted values (89% to 94% saturations) is a means to reduce oxidant injury to the lungs and retinal vasculature.⁷¹ Inhaled nitric oxide is also a treatment option in some circumstances and has been associated with improved neurologic outcomes in preterm infants; however, routine use of this therapy needs further follow-up for long-term effects on the pulmonary and developmental systems.^73–75 Diuretics are used to control pulmonary edema. Bronchodilators are used to reduce airway resistance. Early anti-inflammatory therapies, such as steroids, may facilitate weaning but introduce significant risks, such as abnormal neurodevelopment. The current recommendation is to avoid using steroids when clinical situations permit until further studies can identify which individuals are most likely to benefit without serious steroid-associated complications.^75,76 Azithromycin also may have a role in controlling the inflammatory portion of this disease process as it does in other pulmonary diseases; however, research in this area is ongoing.⁷⁷ Caffeine citrate is commonly used and has been associated with decreased rates of BPD. Other therapies in the early stages of investigation include targeted cytokine and anticytokine therapies, antioxidants, and antiproteinases. Infection is a constant threat because of invasive lines, the endotracheal tube, and a compromised immune system. Nutritional needs are high and must be met to promote growth and healing. Most infants can be fed enterally. Early supplemental vitamin A and/or amino acids, which play a role in normal lung development, may be required in low-birth-weight infants and have resulted in as much as a 12% reduction in development of BPD.^71,75,78

Death from BPD is usually caused by infection or respiratory failure. Recurrent cough and wheezing are frequent in survivors with BPD, as well as a high susceptibility to repeated respiratory infections and their complications. Measures to prevent viral infections and avoid environmental exposures are critical to the care and treatment of these children. Infants who survive are often discharged with home oxygen therapy (some on ventilators). In addition to respiratory management, good nutrition is essential to recovery. Gradual improvement is usually noted in the first 2 years, but pulmonary function may remain abnormal for many years, and there is an increased incidence of asthma during childhood. Characteristic abnormalities on pulmonary function testing include expiratory airflow obstruction and air trapping. For some children, improvement is seen from school age onward, with gradually diminishing clinical symptoms and improved pulmonary function.⁶⁶

Respiratory Infections

Infections may be localized to the bronchioles and bronchi, alveoli, interstitium, or pleura. The cause and site of infections are related to the age of the child, seasonal variables, and environmental exposures. Infants and young children tend to have more viral infections, especially during late autumn to early spring. Environmental factors may play a role such as the presence of siblings and daycare exposure.

Aspiration Pneumonitis

Aspiration pneumonitis is caused by a foreign substance, such as food material, secretions (e.g., saliva or gastric contents), or chemical compounds entering the lung and causing inflammation. The aspiration of meconium from amniotic fluid can occur at birth. Meconium contains bile salts from the fetal intestinal tract that cause inflammation. Neurologically compromised children or children undergoing sedation or anesthesia may aspirate oral secretions (containing anaerobic bacteria) or stomach contents. Children with neurologic compromise, other underlying diseases such as chronic lung disease/BPD, anatomic tracheoesophageal, or craniofacial abnormalities may present with chronic pulmonary aspiration (CPA). Left unaddressed, CPA can result in progressive lung disease, bronchiectasis, and respiratory failure and is the leading cause of death in children with severe neurologic compromise.¹⁰¹ The severity of lung injury after an acute aspiration incident is determined by the amount of material aspirated, the pH of the aspirated material, and the presence of pathogenic bacteria. Very low pH or very high pH causes a significant inflammatory response. With hydrocarbon ingestions, lung injury is determined by the volatility and viscosity of the aspirated substance. A low-viscosity substance, such as gasoline or lighter fluid, is the most toxic; high-viscosity hydrocarbons, such as petroleum jelly or mineral oil, are much less likely to cause pneumonitis. Treatment for aspiration pneumonitis depends on the material aspirated but generally includes broad-spectrum antibiotic therapy. Strategies for prevention of aspiration are an important part of the therapeutic plan at every well-child visit.

Bronchiolitis Obliterans

Bronchiolitis obliterans (BO), a relatively rare diagnosis in children, is fibrotic obstruction of the respiratory bronchioles and alveolar ducts secondary to intense inflammation. The inflammation leads to narrowing, complete obliteration, or both of the airway lumen. Pathologically, there are two forms: proliferative and constrictive; the latter results in the obliteration of the lumen and is the more common form. Most cases of bronchiolitis obliterans in children are associated with viral pulmonary infections, such as influenza, adenoviral infection, pertussis (whooping cough), measles, parainfluenza, RSV, human immunodeficiency virus (HIV) or M. pneumoniae. BO may occur after allograft transplantation (lung, heart-lung, and bone marrow) as a manifestation of graft-versus-host disease. It also is associated with collagen vascular disease, toxic fume inhalation, chronic hypersensitivity pneumonitis, Crohn disease, and Stevens-Johnson syndrome.^102,103 For reasons that are unclear, BO seems to occur more frequently in the Southern Hemisphere, although it is certainly noted in other parts of the world as well. Genetic factors influence susceptibility; however, these factors have yet to be clarified.¹⁰³ Initially cough, respiratory distress, and cyanosis occur, followed by a brief period of improvement. The progression of disease is then reflected by tachypnea, sputum production, increased anterior/posterior diameter, crackles, wheezing, and hypoxemia.¹⁰⁴

There is no specific treatment for BO. Supportive care is usually given with mechanical ventilation, although there is evidence that this also may contribute to the progression of the disease. Use of antiviral agents may be warranted in managing those with viral infection. For transplant recipients, augmentation of immunosuppressive therapies and treatment with anti-inflammatory agents are showing promise in reducing airway inflammation, thus improving pulmonary function.¹⁰⁵ Clinical progression can be quite variable depending on the predisposing condition. Some children experience partial recovery, whereas others follow a course of steady decline in lung function.

Asthma

Asthma is an obstructive airway disease characterized by reversible airflow obstruction, bronchial hyperreactivity, and inflammation. The onset of asthma generally occurs early in life and is associated with identifiable risk factors.¹⁰⁶ The prevalence of asthma is significantly higher in children than adults and is the most prevalent chronic disease in childhood, affecting 5% to 13% of all children. In the prepubertal years, more boys than girls are affected. Although statistics suggest that asthma has become more prevalent in the past two decades, some of this increase may be related to improved awareness of the diagnosis of the condition.¹⁰⁷ Populations most affected include those living in an urban setting, ethnic minorities, and those of low-socioeconomic status.¹⁰⁸ There also may be associations between those children living with a single mother and having multiple siblings that result in reduction in treatment and worsened outcomes from asthma.¹⁰⁹ Asthma-related deaths almost always occur outside the hospital setting. The severity and persistence of asthma are influenced by age at disease onset, genetics, behavior, atopy, air pollution, level of allergen exposure, environmental tobacco smoke, gastroesophageal reflux, and respiratory infections.¹⁰⁶ Additional confounding variables that affect disparity in asthma morbidity and therapy are lack of health insurance, poor access to asthma specialists, inappropriate utilization of healthcare resources, and inadequate medical care.¹⁰⁸ Inner-city black and Hispanic children have higher morbidity and mortality rates than white children.¹⁰⁸ After decades of rising mortality rates, there has been a decrease in the number of children dying of this disease in recent years.¹¹⁰

The wide spectrum of clinical disease in asthma probably reflects a complex interaction between genetic susceptibility and environmental factors, including allergens (e.g., air pollution, dust mite and cockroach allergen, tobacco smoke) and infections, particularly viral respiratory infections (e.g., rhinovirus).^108,111 The genetics of asthma are complex. Population genomic screening has led to the identification of many candidate genes or chromosomal regions that are associated with asthma. Included in the long list of asthma-associated genes are those that code for increased levels of immune and inflammatory mediators (e.g., IL-4, IgE, and leukotrienes), nitric oxide, and transmembrane proteins in the endoplasmic reticulum.^111,112 In addition, genes may impart associated phenotypes, such as bronchial hyperresponsiveness (BHR), sensitization to allergens, and responsiveness to asthma therapies. For example, a specific polymorphism in the gene for the β-adrenergic receptor that is prevalent in black children is associated with poor response to β-adrenergic inhaled medication.¹⁰⁸

Environmental exposures such as allergens, viruses, smoke, and air pollutants interact with an individual’s genetic vulnerabilities to induce the onset of clinical asthma.^{106,111,113,114} One hypothesis for the high prevalence of asthma in westernized cultures is called the “hygiene hypothesis.” This theory suggests that certain early childhood respiratory viral infections could favor the Th₂-predominant phenotype and contribute to inducing asthma in susceptible individuals. It also suggests that lack of sufficient early exposure to other types of infections (e.g., hepatitis) also favors the Th₂ phenotype in the airways and permits induction of asthma.¹¹⁵ Asthma develops because the Th₂ response (in which CD4 T-helper [Th] cells produce specific cytokines, such as IL-4, IL-5, and IL-13) promotes an atopic/allergic response in the airways as opposed to a Th₁ response characteristic of delayed-type hypersensitivity and phagocyte-mediated host defense. IL-4 and IL-13 are particularly important for B-cell switching to favor IgE production, and IL-5 is crucial for local differentiation and enhanced survival of eosinophils within the airways. This theory about the origins of asthma is consistent with many of the epidemiologic and pathophysiologic features of childhood asthma, but is not yet proven.

PATHOPHYSIOLOGY The pathophysiology of asthma in children is similar to that for adults (see Chapter 33, Figure 33-11, p. 1285). However, good criteria for predicting adult asthma in persons with childhood asthma remains unclear.^116,117 For acute allergen-induced asthma, the paradigm of the early asthmatic response remains useful (Figure 34-14, A and 34-15). This begins immediately after exposure and lasts up to 2 hours. The allergen binds to preformed IgE on the surface of mucosal mast cells, and crosslinking of these IgE molecules triggers degranulation of the mast cell, releasing mediators such as histamine, leukotrienes, prostaglandins, platelet-activating factor, chemotactic chemokines, and certain cytokines (e.g., IL-1).¹⁰⁶ These mediators cause airway smooth muscle constriction (bronchospasm), increased vascular permeability (mucosal edema), and mucus secretion. The late asthmatic response starts 4 to 8 hours after exposure and may persist up to 24 hours (Figure 34-14, B). The response is characterized by inflammatory cell recruitment (neutrophils, eosinophils, basophils, and T lymphocytes) that was triggered earlier by chemotactic factors and up-regulation of endothelial adhesion molecules. Another wave of mediator release occurs, again inciting bronchospasm, edema, and mucus secretion. Epithelial damage and impaired mucociliary function may be seen because of direct toxic effects of cellular products such as major basic protein from eosinophils. This local injury stimulates local nerve endings, which may aggravate bronchoconstriction and mucus secretion through autonomic pathways (Figure 34-15).

Although allergen-associated immune and inflammatory processes are considered the primary etiologic processes in asthma, neutrophilic airway inflammation likely accounts for a portion of asthma cases. Those individuals with a predominance of inflammatory neutrophils (rather than eosinophils) have allergies less often and are less responsive to steroids.^106,111 As the inflammatory process continues, bronchospasm develops which narrows the airways especially during expiration. Mucous plugging, edema, and cellular infiltration lead to further airway narrowing. A partial obstruction is present that creates a “ball-valve” effect, leading to segmental hyperinflation, which may become extreme and compromise effective tidal volume. Measures of expiratory flow rates, such as forced expiratory volume in 1 second (FEV₁) and peak flow, are markedly reduced.

Examination of postmortem lung specimens of individuals who died from asthma reveals abnormalities consistent with acute and chronic changes in the airways. These include extensive mucous plugging, mucosal edema, and denudation of bronchial and bronchiolar epithelium. Eosinophilia is present in the submucosa, and a multicellular inflammatory infiltrate accumulates in the airways. Thickening of the basement membrane, airway smooth muscle hypertrophy, and mucous gland hypertrophy are often noted. In chronic asthma, chronically increased numbers of inflammatory cells may lead to long-term changes, such as goblet cell hyperplasia and airway wall remodeling (subepithelial fibrosis, smooth muscle hypertrophy).

The typical arterial blood gas abnormalities in acute asthma are hypoxemia, hypocarbia, and respiratory alkalosis. Because bronchial obstruction is nonuniform, ventilation is likewise uneven, causing ventilation mismatch and hypoxemia. The degree of hypoxemia is usually mild, however, and arterial saturations of less than 90% indicate severe airway obstruction. Pulmonary circulation may be altered by regional hypoxic vasoconstriction, as well as the effect of increased intra-alveolar pressure (caused by expiratory airway obstruction and alveolar hyperinflation) to decrease perfusion of alveolar capillaries. Typically, respiratory rate is elevated to compensate for hypoxemia and reduces arterial PCO₂ (respiratory alkalosis). If airway resistance and hyperinflation become severe, increased respiratory rate can no longer compensate for decreasing V_T causing a reduction in minute ventilation and a gradual rise in arterial PCO₂, thus even a normal PaCO₂ value should be of concern if respiratory distress is significant. Retention of CO₂ is a late finding, usually occurring only if FEV₁ falls to around 15% to 20% of predicted values, and reflects inadequate alveolar ventilation and increased functional dead space. With severe and prolonged airway obstruction (status asthmaticus), the end result of the pathophysiologic processes may be respiratory failure with acute CO₂ retention and respiratory acidosis. Metabolic acidosis may accompany life-threatening asthma, especially when left ventricular filling and thus cardiac output become compromised because of severe hyperinflation.

CLINICAL MANIFESTATIONS In a typical acute asthma attack, the major complaints are cough, wheeze, and shortness of breath. Signs of a preceding upper respiratory infection, such as rhinorrhea or low-grade fever, may be present. In children, 70% to 80% of acute wheezing episodes are associated with viral respiratory infections. In infants and toddlers younger than 2 years old, the most common of these is RSV. In older children and adults, the major viral trigger is rhinovirus. In fact, rhinovirus is reportedly associated with 60% to 80% of asthma exacerbations in school-age children.¹¹⁸

On physical examination, expiratory wheezing that is often described as high pitched and musical is found, along with prolongation of the expiratory phase of the respiratory cycle. Sometimes hyperinflation is visible. Respiratory rate is elevated, as is heart rate. Nasal flaring and accessory muscle use are evident, with retractions in the substernal, subcostal, intercostal, suprasternal, or sternocleidomastoid areas. Infants may appear to be “head bobbing” because of sternocleidomastoid muscle use. Pulsus paradoxus (decrease in systolic blood pressure of more than 10mmHg during inspiration) may be present. The child may appear anxious or diaphoretic, important signs of respiratory compromise.

Findings in chronic asthma may include hyperinflation of the thorax (barrel chest) or pectus excavatum. Clubbing should not be seen in those with asthma and, if present, should trigger evaluation for other conditions, such as cystic fibrosis.

EVALUATION AND TREATMENT Asthma is often underdiagnosed and untreated, especially in preschool-age children. The fact that many of the symptoms overlap with other respiratory illness, like bronchitis or upper respiratory infections, may confuse the diagnosis. Because of the changing appearance of asthma in some children, tools to help confirm diagnosis are recommended. The modified asthma predictive index (API) is recommended by the National Institutes of Health (NIH) guidelines. Diagnosis is based on episodes of wheezing noted on an annual basis as well as concurrent risk factors. The major historical and physical factors that contribute to the diagnosis of asthma are parental history of asthma, physician-diagnosed atopic dermatitis, and evidence of sensitization to aeroallergens. Minor factors include evidence of sensitization to foods, 4% or greater peripheral blood eosinophilia, or wheezing not associated with upper respiratory illnesses.¹⁰⁶ To firmly establish the diagnosis, objective information is gathered by medical history, physical examination, and, when the child is 5 or older, pulmonary function testing (spirometry).

Characteristic abnormalities of spirometry would be reduced expiratory flow rates, namely FEV₁ and to an even greater extent, the midexpiratory flow rate (or forced expiratory flow rate between 25% and 75% [FEF_25%-75%] of total exhaled volume); also the ratio of FEV₁ to forced vital capacity (FVC) would be typically decreased. Unlike asthmatic adults, however, asthmatic children often have normal or near-normal spirometry between attacks. Other potentially useful supportive diagnostic findings would include evidence of air trapping on lung volume measurement (by plethysmography), documentation of bronchial hyperreactivity (in response to challenge such as exercise or inhaling methacholine) or increased expiratory flow rates in response to an inhaled bronchodilator. Often it is not feasible to obtain the above tests on children, so in practice an empiric trial of asthma-directed medications is commonly initiated, using clinical symptoms (wheeze, cough, exercise tolerance, handling of respiratory infections, etc.) as a guideline. During a significant asthma attack, individuals may be too dyspneic to perform spirometry, and it may precipitate excessive coughing.

For home management of asthma, peak flowmeters are often used. Peak flow measures are less reliable and less reproducible than those obtained by spirometry but can be helpful. For serial tracking, peak flow measurements should be obtained at consistent times of day because of the natural diurnal variation in peak flow, which is usually lowest at approximately 4 AM and highest at approximately 4 PM. Once a baseline value has been established on the basis of repeated measurements over a period of time, decreases in peak flow can be interpreted meaningfully to help assess the child and modify treatment in the face of increased symptoms or intercurrent illness.

The goal of asthma therapy is to achieve long-term control by reduction in impairment and risk.¹⁰⁶ Management of asthma medications in children is often difficult because remission is common. Care providers must periodically assess asthma control in children to decide if a “step up” (increase) or “step down” (decrease) is indicated in their asthma therapy. Algorithms can help assess asthma control and offer information about how to adjust therapy accordingly. Key features to assess include nighttime awakenings, interference with normal activities, use of short-acting beta₂ agonist, lung function, and exacerbations requiring oral steroids. Before therapy is augmented, reassessment of inhaler technique, adherence, environmental controls, and comorbidities should occur. For a reduction in therapy, the child’s asthma should be well controlled for a minimum of 3 months.¹⁰⁶

For management of intermittent (formerly called mild) asthma, rapid-acting bronchodilators, such as albuterol (a β₂-adrenergic agonist) or levalbuterol, may be sufficient with addition of oral systemic steroids for more significant attacks to decrease inflammatory responses in the lung.¹⁰⁶ Inhaled ipratropium bromide is an anticholinergic agent that contributes to bronchodilation by inhibiting vagal tone; it is sometimes used together with albuterol for acute treatment or sometimes as an alternative, though generally considered less potent for those who cannot tolerate β₂-adrenergic agonists because of side effects. Environmental controls and monitoring would also be included in the treatment plan for children as noted below.

There are a growing number of options for management of persistent asthma depending on chronicity and severity of symptoms, as well as on individual compliance issues. Guidelines have been outlined and widely distributed by an NIH expert panel.¹⁰⁶ In addition to medications, environmental controls are instituted. There also is a new focus on child-parent education and monitoring control of symptoms more closely and by a variety of methods. For individuals with persistent symptoms, daily “controller” medication is recommended. The most widely preferred controller therapy remains inhaled corticosteroids (ICS), although there is some debate about their safety in children younger than 2 years of age.¹¹⁹ Montelukast (an oral leukotriene receptor antagonist) is frequently used as supplemental therapy or, for milder allergic or exercise-induced asthma, as monotherapy.¹²⁰ Inhaled cromolyn and nedocromil remain available anti-inflammatory therapies, but their use has declined in the United States in favor of other therapies. Long-acting β₂-adrenergic agonists, such as salmeterol, also may be applied to pediatric asthma except in the youngest children. All classifications of asthma also require intermittent use of a short-acting bronchodilator during times of exacerbation or illness. Depending on the severity of symptoms, short courses of oral systemic corticosteroids also are prescribed. For allergic asthma, immunotherapy has been shown to be an important tool in reducing asthma symptoms and exacerbations, and can now be given sublingually.¹²¹ Anti-IgE therapy is indicated for select individuals with severe asthma.¹²² There also may be utility in using inhaled nitric oxide as an objective measure to determine asthma relapse after cessation of ICS.¹²³ Research in the area of pediatric asthma is targeted at evaluating the effects of vitamin D supplementation on wheezing; the associations between asthma and other underlying illnesses, such as sickle cell disease; the role of intermittent inhaled steroid use; and the effect of functional polymorphisms of antioxidant genes in regard to air pollution (in vitro).¹¹¹

Regardless of the type of asthma, written asthma action plans and extensive child and family education is necessary for everyone. Asthma management education is necessary for children and their parents to ensure disease control and compliance. Follow-up care is needed every 3 to 6 months to evaluate control and need for change in the treatment plan.

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a condition that can result from either a direct or indirect pulmonary insult. It is defined as respiratory failure of acute onset characterized by severe hypoxemia that is refractory to treatment with supplemental oxygen, bilateral infiltrates on chest x-ray, and no evidence of heart failure.¹²⁴ Individuals with conditions such as pneumonia, aspiration, near-drowning, and smoke inhalation or a systemic insult such as sepsis, multiple trauma, or burns are susceptible to triggering this process. All of these clinical scenarios activate an inflammatory response that causes alveolocapillary injury. ARDS accounts for approximately 10% of total patient days and one third of all deaths in pediatric intensive care units. The overall mortality in children is less than that experienced by the adult population but can be as high as 40%, depending on age and associated conditions and complications.¹²⁵ Children younger than 5 years appear to have diminished mortality compared with those older than 5 years of age. Children with underlying disease processes, such as Down syndrome,¹²⁶ systemic lupus erythematosus, and those who have undergone lung transplantation have decreased survival. Genetic predisposition to developing ARDS has been documented in adults; however, this is less well characterized in the pediatric population.¹²⁷

PATHOPHYSIOLOGY The hallmark of ARDS is lung inflammation. Destruction of the capillary-alveolar unit leads to activation of a number of systems and mediators (Figure 34-16), including complement, cytokines, arachidonic acid metabolites, platelet-activating factor, reactive oxygen species, and others (specifically TNF, interferon-alpha, and lipopolysaccharide).¹²⁸ Sources of these mediators include neutrophils, activated platelets, macrophages, and injured endothelium. Early, during the inflammatory or exudative phase of ARDS, there is pulmonary neutrophil influx along with intraluminal fibrin and platelet aggregation. Injury to the endothelial barriers results in capillary leak and noncardiogenic pulmonary edema. The presence of inflammatory mediators and edema fluid in the alveoli inactivates surfactant, contributing further to alveolar collapse.¹²⁵ This fluid also has procoagulant activity, leading to fibrin clotting within air spaces. Similarly, the pulmonary microcirculation is compromised by the formation of thrombi composed of fibrin, platelets, and leukocytes.

The early accumulation of edema fluid in the air spaces results in decreased lung compliance, decreased functional residual volume, and increased dead space. Ventilation-perfusion mismatching, intrapulmonary shunting, and hypoxemia occur. Diffuse pulmonary thrombosis contributes further to the formation of pulmonary edema by increasing capillary hydrostatic pressure and may lead to pulmonary hypertension.

In the fibroproliferative phase, type II alveolar cells proliferate, and there is alveolar septal thickening and collagen deposition. Interstitial fibrosis can be evident as early as 10 days after the initial insult. Similarly, vascular changes may occur, including obliteration of the microcirculation and thickening of the walls of pulmonary arterioles and arteries, which can lead to chronic pulmonary hypertension in survivors.

CLINICAL MANIFESTATIONS ARDS develops acutely after the initial insult, usually within 24 hours (although occasionally it is delayed up to a few days). There is progressive respiratory distress and severe hypoxemia with poor response to oxygen supplementation. Initially, hyperventilation occurs, but CO₂ retention may ultimately develop because of inadequate functional air space, atelectasis, decreased pulmonary compliance, and respiratory muscle fatigue. Severity of the clinical course is modified by comorbid factors, such as the presence of sepsis or multisystem organ failure, and whether complications develop, such as nosocomial pneumonia.

EVALUATION AND TREATMENT Treatment of ARDS remains supportive in nature. Any underlying condition, such as sepsis, must be treated. The goals of therapy are to preserve and restore oxygen delivery, minimize acute lung injury, and decrease mortality by avoiding iatrogenic pulmonary complications. Most individuals with ARDS require mechanical ventilation and often high levels of positive end-expiratory pressure to promote alveolar recruitment, stabilization, and redistribution of alveolar edema fluid into the interstitium. Various ventilation strategies may be used for ARDS, such as low tidal volumes, prone positioning, inverse inspiratory/expiratory ratio, high-frequency oscillatory ventilation, and airway pressure release ventilation.^129–131 Liquid ventilation through perfluorocarbons instilled in the lungs is being investigated. These fluids have low surface tension and are efficient carriers of oxygen and CO₂. Other therapies, such as surfactant and nitric oxide, offer promise, but their efficacy is still being evaluated in the treatment of pediatric ARDS.¹³⁰ Surfactant appears to improve oxygenation and increase survival time in some investigations, whereas in others its benefits remain inconsequential.^125,132 Systemic corticosteroids have proven effective for decreasing postextubation stridor and may reduce reintubation rates.^130,131

Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive inherited disorder that is associated with defective epithelial ion transport. CF affects primarily whites (approximately 1 in 3200) and is one of the most common lethal genetic diseases in this ethnic group. Approximately 30,000 individuals in the United States and 70,000 worldwide manifest the disease. The incidence in blacks is 1:15,000 and in Asian Americans is 1:31,000.¹³³ Estimated symptomless carrier frequency is higher affecting 10 million or 1 in 29 whites in the United States. Approximately 1000 new cases of CF are diagnosed each year, and the median age at diagnosis is 6 months; 75% of cases are diagnosed by 1 year of age. Approximately 10% of cases are not diagnosed until after age 10; however, these cases usually have milder symptoms. The median age of survival in the United States is 36.5 years of age (2005 data).¹³³

PATHOPHYSIOLOGY On a simplistic level, CF is characterized by abnormal secretions that cause obstructive problems within the respiratory, digestive, and reproductive tracts. However, research suggests that there may be additional CF-associated primary defects, such as an intrinsic proinflammatory state and abnormal local immune defenses in the lungs. The CF gene (CFTR) has been located on chromosome 7. Its mutation results in the abnormal expression of cystic fibrosis transmembrane conductance regulator (CFTCR) protein, which is a cyclic adenosine monophosphate (cAMP)–activated chloride channel present on the surface of many types of epithelial cells, including those lining airways, bile ducts, pancreas, sweat ducts, and vas deferens. Despite knowing that chloride transport is a fundamental abnormality, the exact disease mechanisms in CF have still not been clearly defined at the cellular and end-organ levels.

Although CF is a multiorgan disease, the lungs are the most critical site of involvement, and respiratory failure is almost always the cause of death. The typical features of CF lung disease are mucous plugging, chronic inflammation, and infection. The abnormalities primarily involve the airways, with progressive bronchiectasis that becomes widespread. Parenchymal involvement occurs much later and includes microabscess formation, patchy consolidation and pneumonia, peribronchial fibrosis, and cyst formation (Figure 34-17). The pathophysiology for these changes is outlined in a simplified form in Figure 34-18. Peripheral bullae may develop because of obstruction and airway wall weakening, and pneumothorax can occur. Hemoptysis, sometimes life threatening, may occur because of erosion of enlarged bronchial arteries that develop in response to the inflammation associated with bronchiectasis. Over a long period of time, pulmonary vascular remodeling occurs because of localized hypoxia and arteriolar vasoconstriction; pulmonary hypertension and cor pulmonale may develop with end-stage disease.

The mucus plugging seen in CF probably results from the combination of increased production of mucus, altered physicochemical properties of the mucus, and reduced mucociliary clearance.¹³⁴ Mucus-secreting airway cells (goblet cells and submucosal glands) are increased in number and size. Dysregulation of the airway epithelial sodium channel (ENaC) causes abnormal chloride secretion and exaggerated sodium absorption, resulting in depletion of the airway surface liquid volume and therefore dehydration of airway mucus.¹³⁵ This appears to facilitate mucus adherence to the epithelium, subsequent impairment of ciliary mobility, and retention of bacteria that can then form biofilms. Finally, after secretion, CF mucus becomes even more viscous because of deoxyribonucleic acid (DNA) and filamentous (F) actin released from degraded neutrophils, which are present in very high numbers in CF airways.

Chronic, intense neutrophil-dominated inflammation occurs in CF airways, and plays a critical role in long-term damage.¹³⁶ Abnormal cytokine profiles have been documented in CF airway fluids, including deficient IL-10 and excessive IL-1, IL-8, and TNF-α, all changes conducive to promoting inflammation. Neutrophils are present in great excess in CF airways and release damaging oxidants, such as myeloperoxidase¹³⁶ and proteases in massive amounts that overwhelm local antiprotease defenses. One protease in particular, neutrophil elastase, has the following detrimental effects: (1) direct damage to lung structural proteins, such as elastin; (2) induction of airway cells to produce IL-8, a strong attractant for neutrophils and thus a means for augmenting a local “vicious cycle” of inflammation; (3) destruction of IgG and complement components important for opsonization and phagocytosis of pathogens; and (4) direct stimulation of mucus secretion by mucus-producing cells. Other contributors to CF pathogenesis are being explored including errant epithelial oxidant defense with exposure to airborne bacteria, major vault protein migration with pseudomonas infection, and antiprotease activity relating to the inflammatory process.¹³⁷

Children with CF have a propensity for chronic endobronchial infection that remains poorly understood. It is likely that local factors in the CF airway microenvironment favor bacterial colonization because no systemic immune defect has been found. Staphylococcus aureus is common, and Pseudomonas aeruginosa ultimately colonizes airways in 75% of children with CF. Infecting colonies of Pseudomonas appear to adopt a mucoid phenotype and organize themselves into adherent biofilms, making it difficult for antibiotics and local defenses to reach them. Pseudomonas acquisition has been linked with more rapid decline in pulmonary function.¹³⁸ Persistence of infection incites chronic local inflammation, airway damage, bronchiectasis, microabscess formation, and foci of hemorrhagic pneumonia. New evidence suggests that anaerobes present in the CF lung may contribute to the cycle of infection and ongoing inflammation. The amount of smooth muscle present in the airway in this group of children, increased from normal, is also a contributor to the chronic inflammatory process.^139,140

CLINICAL MANIFESTATIONS The most common manifestations are respiratory and gastrointestinal, including the pancreas and biliary tract. Respiratory symptoms at presentation may include persistent (but not necessarily severe) cough or wheeze, sputum production, and recurrent or severe pneumonia. More subtle respiratory tract presentations of CF include chronic sinusitis and nasal polyps. With appropriate treatment, cough, sputum production, and exercise limitation do not usually reach debilitating levels during childhood. Digital clubbing may appear quite early and in the absence of significant pulmonary impairment. Development of barrel chest or persistent crackles occurs much later in the course of the disease.

Classic gastrointestinal manifestations include meconium ileus at birth, which is almost pathognomonic for CF. Approximately 15% to 20% of individuals with CF present with this. Another classic presentation is failure to thrive and malabsorptive symptoms, such as frequent loose and oily stools. Metabolic abnormalities, trace element deficiencies, fat-soluble vitamin alterations, and electrolyte imbalances may occur early in the course of disease.¹³⁷ Rectal prolapse is an occasional presenting sign that should always prompt testing for CF. About 10% of CF patients do not experience gastrointestinal problems and are termed “pancreatic sufficient.” Several specific CFTR mutations are predictive of this milder phenotype. Males with CF are typically infertile (98%). Other complications of CF may include liver disease (approximately 5%), diabetes mellitus (10% to 25%), and decreased bone mineral density as early as preschool age.¹³⁷

Overall severity of CF lung disease is highly variable. Even affected siblings may have disparate courses despite identical CFTR mutations, environment, and treatment strategy. We now know that some genetic variants significantly influence survival among children with the same mutations.¹³³ Mutations in the CFTR gene have been classified based on the type of defect. Classes 1 through 3 are associated with more severe disease and 4 and 5 with milder pulmonary disease (generally pancreatic sufficient). Mortality rates correlate respectively with the classes noted above. Researchers continue to explore identification of “gene modifiers,” other than CFTR, that may serve to lessen or aggravate the degree of CF lung disease and increase or decrease the risk of developing other CF complications, such as severe liver disease.¹⁴¹ Other variables that have long been associated with decline in pulmonary status for those with CF and, thus earlier demise, include colonization with P. aeruginosa, female sex, and poor nutritional status.¹⁴²

EVALUATION AND TREATMENT The standard method of diagnosis has been the sweat test, which will reveal sweat chloride concentration in excess of 60 mEq/L. Genotyping for CFTR mutations is also available as an alternative or supplemental method but may fail to confirm up to 10% of cases because of a lack of ability to screen for every described CF-associated mutation. There are more than 1500 specific mutations, but most standard laboratory panels include fewer than 100 mutations.¹³³ Newborn screening for CF is currently mandated in 32 of the 50 states in the United States and will continue to expand, on a voluntary, state-by-state basis subsequent to recent recommendations developed by the Centers for Disease Control and Prevention (CDC) and an advisory panel of CF experts¹⁴³ (see What’s New? Newborn Screening for Cystic Fibrosis).

Treatment is primarily focused on pulmonary health and nutrition. Because the pulmonary decline in CF is slow and insidious, and because of the early onset of chronic inflammation and infection, treatment strategies begin immediately at diagnosis and are modified over time as disease progresses. Pulmonary therapies include techniques to promote mucus clearance, such as chest physical therapy and related equipment (such as the high-frequency chest wall oscillation vest) and an assortment of handheld positive expiratory pressure (PEP) devices. Aerosol therapy includes bronchodilators and nebulized deoxyribonuclease (DNase), which acts to liquefy mucus and may even have anti-inflammatory effects.¹⁴⁴ Antibiotic practices vary, with prophylactic and treatment strategies being used. Increasing emphasis has been placed on delaying and controlling Pseudomonas colonization, such as the maintenance use of inhaled antibiotics.¹⁴⁵ Macrolide antibiotics, such as azithromycin, have been reported to improve pulmonary function through improvement in the airway inflammation process.¹³⁶ Hypertonic saline also has proven beneficial to improve airway surface water, thus improving mucus viscosity.¹⁴⁶ Ibuprofen has been shown to improve lung function in several clinical trials.^137,147 Intravenous antibiotics are used to treat major exacerbations of pulmonary infection, which may be either subacute or acute. Individuals with end-stage lung disease may consider double lung transplant as a life-lengthening measure.¹⁴⁸

Nutritional problems are extremely common in CF, and poor nutrition is correlated with worse outcomes including progression of lung disease and onset of additional complications such as decreased bone mineral density.¹⁴⁹ Elements of aggressive nutritional support include meticulous monitoring of growth parameters, controlling fat malabsorption, ensuring adequate caloric intake, and keeping overall health stable. Approximately 90% of children with CF have pancreatic insufficiency. This is the result of abnormal ion transport causing decreased fluid and bicarbonate secretion from the pancreatic acinar cells, which leads to thickened secretions plugging the smaller pancreatic ducts, and eventual autodigestion or

atrophy of the acinar cells. Therefore, patients must take exogenous pancreatic enzymes with meals and snacks in order to absorb nutrients and control malabsorptive symptoms. Fat-soluble vitamins (A, D, E, and K) must be supplemented. Caloric needs are high, especially with advancing lung disease, and high-calorie supplements or even gastrostomy feeding may be warranted.

Future treatments for CF in trial phases are aimed at improving inhaled antibiotic therapy (duramycin, denufosol and dry powder tobramycin), a vaccine against Pseudomonas, and the use of growth hormone. Gene transfer and stem cell therapies also are being investigated.¹⁵⁰

There is a growing contingent of adults with CF living into their 40s and 50s. Care for these individuals shifts away from a pediatric focus because their care needs are unique and often extremely complex. Challenges noted in this specialty area are pregnancy and details about balancing disease management and adult life issues.