The clinical syndrome of transient tachypnea of the newborn (TTN) is caused by persistence of fetal lung fluid in the neonate. Other terms for this syndrome include wet lung disease, transient respiratory distress of the newborn, and neonatal retained fluid syndrome. Transient tachypnea is the most common of the various causes of respiratory distress in term newborns (Table 2-1).¹ Factors that are associated with an increased risk for transient tachypnea include prolonged labor, cesarean section, narcotic depression, maternal asthma, and maternal diabetes.^2,3 Typically, the infant is clinically normal immediately after delivery, but becomes tachypneic over the next few hours. Despite the signs of mild to moderate respiratory distress, there is usually normal oxygenation. As the name indicates, TTN is typically a self-limited process.

In the fetus, lung fluid is produced by type II pneumocytes. This fluid is cleared from the neonatal lung by capillary resorption, lymphatic resorption, and expulsion via the airways. The pathophysiology of transient tachypnea involves compromised clearance of fetal lung fluid.⁴ The association with cesarean section delivery presumably relates to the lack of normal physiological expulsion of fluid from the lungs by the extrinsic compression that occurs during vaginal delivery. These infants may also have a diminished catecholamine surge – a result of lack of exposure to all stages of labor. There is evidence that diminished β-adrenergic responsiveness may be a factor in some affected neonates. Proper function of the β-adrenergic response system is important for the successful transition of the neonate from fetal life to breathing air. Other conditions that result in diminished clearance of lung fluid in the newborn are hypoalbuminemia, elevated pulmonary venous pressure, diminished respiratory drive (sedation), endothelial cell damage (oxygen toxicity), and bronchial obstruction.⁵

The clinical findings in neonates with transient tachypnea include a rapid respiratory rate, mild retractions, and expiratory grunting. Occasionally, there is mild cyanosis that is promptly relieved by supplemental oxygen administration. The tachypnea develops within the first several hours of life. The respiratory rate is usually normal for the first hour, with gradual subsequent increase. In most affected infants, the tachypnea peaks between 6 and 36 hours after birth and then slowly returns to normal by the third or fourth day. Pneumothorax can complicate the clinical course (Figure 2-1). Physical examination may reveal an overexpanded chest; the lungs are typically clear to auscultation. Unlike respiratory distress syndrome, there are no substantial abnormalities on blood gas analysis or blood pH assesment.⁶

Some infants with transient tachypnea follow a more prolonged course than described above, and sometimes require supplemental oxygen. Some of these infants have evidence of global myocardial dysfunction on echocardiography. In severely affected infants, echocardiography shows signs of pulmonary hypertension and biventricular myocardial dysfunction. With classic mild TTN, there is minimal left ventricular overload. Complete clinical recovery is to be expected regardless of the echocardiographic pattern.⁷

Chest radiographs of neonates with TTN show prominent and ill-defined pulmonary vascular markings, edematous interlobar and interlobular septa, and small pleural effusions (usually with small fluid collections in the costophrenic sulci and interlobar fissures) (Figure 2-2). Engorged lymphatics account for at least some of the interstitial opacities. These findings involve both lungs, but frequently are more pronounced on the right. Mild hyperinflation is usually present. Alveolar opacification is occasionally present early in the course. The heart is normal or only minimally enlarged; the presence of cardiomegaly portends a prolonged clinical course.^8,9

There are several important considerations in the radiographic differential diagnosis of TTN. Conditions that can potentially mimic transient tachypnea on the initial chest radiograph include mild respiratory distress syndrome, congestive heart failure, neonatal polycythemia, total anomalous pulmonary venous connection, and primary pulmonary lymphangiectasia. Correlation of the findings on serial radiographs with the clinical factors allows a correct diagnosis in most instances.

When present, the observation of hyperinflation is helpful in differentiating transient tachypnea from early or mild respiratory distress syndrome. Respiratory distress syndrome is typically associated with generalized underaeration of the lungs, in the absence of mechanical ventilation. Because of the slow clearance of pulmonary fluid by premature infants, imaging during the first 2 hours of life of an infant with mild respiratory distress syndrome shows diffuse alveolar fluid and normal lung volumes. A more radiographically distinct pattern of hypoaeration and granular parenchymal lung densities usually is present by 4 to 6 hours of age. Occasionally, infants with transient tachypnea do not have evidence of hyperaeration, and additional serial radiographs are necessary to demonstrate the clearance of the lung fluid. A lack of hyperaeration is usually because of a superimposed abnormality that causes respiratory depression, such as sedation, hypoxia, hypothermia, or central nervous system pathology.

Because mild cardiomegaly can be one of the radiographic features of TTN, the appearance can be confused with that of congestive heart failure. The neonate with congenital heart disease of sufficient severity to result in pulmonary vascular congestion and edema usually has distinct cardiomegaly, while transient tachypnea results in borderline or minimal cardiac enlargement in combination with prominent linear vascular markings radiating from the hila. Infants with transient tachypnea also have normal blood gas values and improve promptly with oxygen therapy.

Neonatal respiratory distress syndrome (RDS) is a pulmonary abnormality of premature infants in which there is poor aeration of alveoli, predominantly a result of surfactant deficiency. Other terms for this disorder include hyaline membrane disease and surfactant deficiency disease. Surfactant deficiency is the most common serious pulmonary abnormality of premature infants. The prevalence of RDS is inversely proportional to the gestational age and birth weight. Between 60% and 80% of infants born at less than 28 weeks of gestational age develop RDS, whereas only 15% to 30% of those born between 32 and 36 weeks of gestational age are affected. Additional risk factors for this complication in premature infants include precipitous delivery, asphyxia, maternal diabetes, multifetal pregnancies, cold stress, and a history of RDS in siblings. Males are affected more frequently than females. Genetic alterations in surfactant proteins (SP-A, SP-B) influence the risk for RDS.¹⁰

The primary factor in the pathophysiology of RDS is deficiency of surfactant. Pulmonary surfactant reduces the surface tension of the alveolar air–liquid interface.¹¹ This serves to provide mechanical stability of the alveoli and prevent atelectasis. Synthesis of surfactant takes place within alveolar epithelial type II cells. The largest component of surfactant (>50%) is the surface tension reducing agent dipalmitoyl phosphatidylcholine. The other components include unsaturated phosphatidylcholines, phosphatidylglycerol, cholesterol, and protein; the functions of these components in surfactant are unknown. The metabolism of surfactant is under hormonal control, and appears to involve interplay between β-adrenergic agonists, cyclic adenosine monophosphate, and prostaglandins. In neonatal RDS, the produced surfactant is abnormal with respect to its chemical and physical properties.¹²

The high alveolar surface tension that occurs in neonates with deficient surfactant results in a propensity for collapse of small air spaces at end-expiration. Additional factors include the small size of the respiratory units and the compliant chest wall of the ill premature infant. The alveoli within the atelectatic lung are perfused but not ventilated, resulting in hypoxia. Small tidal volumes, increased physiological dead space and poor lung compliance result in hypercarbia. Hypercarbia, hypoxia, and acidosis cause pulmonary arterial vasoconstriction and secondary right-to-left shunting through the foramen ovale and ductus arteriosus. The diminished pulmonary blood flow leads to ischemic injury of alveolar cells, including the surfactant-producing type II pneumocytes. This process results in the accumulation of proteinaceous material within the alveolar spaces. Epithelial cell damage related to high oxygen concentrations in ventilated lungs is an additional factor that interferes with surfactant synthesis.

The clinical presentation of RDS typically occurs within minutes of birth, with tachypnea, grunting, retractions, and nasal flaring. Cyanosis and dyspnea are progressive and respond poorly to oxygen administration. The severity of the clinical manifestations typically peaks at approximately 3 days, after which there is gradual improvement. The risk for mortality during the acute phase of the illness is primarily related to complications from air leaks, pulmonary hemorrhage, and intracranial hemorrhage.

Radiographic manifestations of RDS are usually present on images of the symptomatic neonate obtained soon after birth. Rarely, initial radiographs are normal and the characteristic radiographic findings do not develop until several hours later. This disorder is essentially excluded when a symptomatic neonate has a normal chest radiograph obtained beyond 8 hours of life. Radiographs of the neonate with RDS typically show fine reticular and granular lung opacities, and global underaeration (Figures 2-3 and 2-4). In some infants, there is a ground-glass pattern of lung opacification. The abnormality involves the entire lung, but is frequently more prominent at the bases. This radiographic pattern is predominantly a result of alveolar atelectasis. Air bronchograms may be lacking in the early stages of the process (grade 1 disease). At this stage, the alveolar atelectasis preferentially involves the posterior (dependent) portions of the lungs. With progression, the reticular and granular opacities become more prominent, because of coalescence of smaller atelectatic areas, and scattered air bronchograms become visible (grade 2 disease). Progressive increase in opacification occurs in the anterior aspects of the lungs, resulting in obscuration of the cardiac silhouette. Because many of the larger bronchi are located in the mid and anterior aspects of the lungs, air bronchograms are more pronounced during this phase (grade 3 disease). In severely affected infants, the lungs are poorly inflated, diffusely opacified, and contain prominent air bronchograms (grade 4 disease).

Therapy for children with mild manifestations of RDS consists of supportive care. Acidosis, hypoxia, hypotension, and hypothermia are managed medically. Supplemental oxygen is administered. Infants with severe RDS, and those who develop complications, usually require assisted mechanical ventilation. Exogenous surfactant administration and antenatal corticosteroid therapy have a major impact on improving survival and morbidity in RDS.¹³

Therapy influences the radiographic findings in children with RDS. With tracheal intubation and positive pressure ventilation, the lungs become hyperinflated. The granular parenchymal lung opacities become less apparent, and peripheral air bronchograms become more pronounced. Radiographic improvement occurs in the great majority of infants treated with exogenous surfactant (Figure 2-5). In some instances, the radiographic clearing is asymmetric or nonuniform. Improvement is sometimes more rapid in the right lung, possibly as a consequence of facilitation of surfactant delivery to the right lung because of the orientation of the right main bronchus (Figure 2-6). Unilateral improvement in lung aeration can lead to contralateral mediastinal shift. However, asymmetry of lung opacities in these children can also result from a pneumothorax or pneumomediastinum related to mechanical ventilation. Pulmonary hemorrhage is a rare complication of surfactant therapy. Infants with pulmonary hemorrhage typically have acute respiratory decompensation, blood-tinged tracheal secretions, and abrupt onset of dense airspace consolidation on radiographs.¹⁴

Potential complications in children with RDS include those related to the disease itself and those related to medical treatment. These infants are at risk for fluid overload, pulmonary edema, patent ductus arteriosus, pulmonary hemorrhage, superimposed infection, and barotrauma. With the exception of barotrauma, the radiographic findings with the other entities are often nonspecific and difficult to differentiate from lung opacification because of the underlying surfactant deficiency. A common clue to the presence of a complicating condition is failure of radiographic improvement by the third or fourth day of life.

Excessive right-to-left shunting through a patent ductus arteriosus occurs in some infants with RDS. The delayed closure of the ductus is related to hypoxia, acidosis, elevated pulmonary pressure, systemic hypotension, and local release of prostaglandins. Left-to-right shunting through a patent ductus can occur as the acute phase of RDS resolves and the pulmonary vascular resistance decreases. This left-to-right shunting can lead to left ventricular volume overload and pulmonary edema (Figure 2-7). Spontaneous closure of the ductus frequently occurs in response to supportive medical therapy. Pharmacological closure can be induced by the use of indomethacin, which inhibits prostaglandin synthesis. Patients who fail medical therapy are candidates for surgical closure.

Air leaks caused by positive-pressure ventilation and oxygen therapy can occur in infants with RDS. Rupture at the level of the terminal bronchioles and terminal air sacs leads to leakage of air into the intralobar septa, producing pulmonary interstitial emphysema. The radiographic indicator of this complication is the presence of fine linear interstitial lucencies, which may involve a single lobe, one lung, or both lungs (Figure 2-8). With increased distention, air-filled cysts may become visible. The lungs are hyperinflated. Air leak can also result in pneumomediastinum, pneumothorax, or pneumopericardium (Figures 2-9 and 2-10).

Group B streptococcal sepsis is an important consideration in the differential diagnosis of RDS. Indicators of this diagnosis include the presence of Gram-positive cocci in gastric or tracheal aspirates, a history of maternal colonization, the identification of streptococcal antigen within the urine, and marked neutropenia. Transient tachypnea is distinguished from RDS by its short and mild clinical course, responsiveness to supplemental oxygen administration, and pulmonary overaeration on chest radiographs. Congenital alveolar proteinosis may have a clinical and radiographic appearance that is indistinguishable from that of severe RDS. Diffuse pulmonary hemorrhage can mimic the radiographic appearance of RDS; this diagnosis should be considered if there are pleural effusions. Pulmonary hemorrhage can also occur as a complication of surfactant therapy for RDS. There is often clinical evidence of hemorrhage in these infants — that is, frothy blood-tinged fluid in the endotracheal tube. Infants of diabetic mothers, particularly those with severe hypoglycemia, sometimes have radiographic findings similar to those of RDS, with bilateral reticular densities; helpful differentiating features include cardiomegaly and hepatosplenomegaly. Pulmonary lymphangiectasia that presents in the newborn usually results in diffuse ground-glass opacities and bilateral pleural effusions.

Bronchopulmonary dysplasia (BPD) is a distinct clinical entity that occurs as a therapy-related complication in infants who are undergoing treatment for respiratory failure. The features include pulmonary fibrosis, nonuniform aeration, and respiratory insufficiency. Bronchopulmonary dysplasia can be defined as the triad of oxygen dependence, characteristic radiographic findings, and respiratory symptoms that persist beyond 28 days of life in an infant who suffered respiratory failure in the perinatal period. An alternative clinical definition is oxygen dependency in a premature infant at an age greater than 36 weeks after conception. More recently introduced terms for BPD are chronic lung disease of infancy and chronic lung disease of prematurity. The pathological features of BPD include manifestations of alveolar maldevelopment, with or without areas of pulmonary fibrosis.^15–17

Although most commonly associated with RDS (respiratory distress syndrome), BPD can also occur with other conditions that are treated with supplemental oxygen therapy and mechanical ventilation, including meconium aspiration syndrome, immature lung syndrome, congenital heart disease, and neonatal pneumonia. Risk factors for BPD include low gestational age, male sex, patent ductus arteriosus, radiographic evidence of pulmonary interstitial emphysema, elevated pulmonary artery pressure, and high peak expiratory pressure. Because of advancements in therapy for premature infants, BPD is now uncommon in infants with a gestational age of greater than 30 weeks or a birthweight of greater than 1200 g.

The pathophysiology of BPD involves the response of immature lungs to oxygen toxicity and barotrauma from positive-pressure ventilation. Highly concentrated oxygen is toxic to the pulmonary capillaries and alveolar cells, with tissue injury occurring through the formation of reactive oxygen intermediates and peroxidation of membrane lipids. Premature infants, who have severely reduced antioxidant defenses, are particularly sensitive to the toxic effects of oxygen. The cellular damage leads to abnormal microvascular permeability, pulmonary edema, and acute necrotizing tracheobronchitis. These effects are intensified by positive-pressure ventilation, which forces oxygen into unventilated acini. Direct lung injury also occurs in the form of barotrauma at the level of the acini and small airways. Inflammation caused by prenatal and/or postnatal infections or antenatal exposure to proinflammatory cytokines in amniotic fluid is a likely contributing factor in most patients. With modern therapeutic techniques, oxygen toxicity and barotrauma have diminished importance in the pathophysiology of BPD. Many of these children apparently have an aberrant response of the immature lung to early air breathing that causes inhibition of acinar and vascular growth.^18–20

The lung is affected in a nonuniform fashion in BPD. Local bronchiolar obstruction protects some acini from barotrauma and exposure to concentrated oxygen. These initially protected acini may later become normal when recanalization of the bronchiolar lumen allows aeration, or they may become hyperexpanded. Those acini that are exposed to high pressures and concentrated oxygen typically go on to develop persistent interstitial fibrosis in the alveolar septa; some of these acini become completely obliterated and permanently nonfunctional. Acini that are distal to partially obstructed bronchioles sustain damage of intermediate severity. Surfactant therapy, however, results in a more uniform pattern of acinar ventilation.

Northway et al described 4 radiographic stages of BPD. During stage I (2 to 3 days of age), chest radiographs show manifestations of severe RDS, with diffuse granular lung opacities and prominent central air bronchograms. The lungs are underinflated. Stage II occurs between 4 and 10 days of age; the lungs become densely consolidated, with a coarse reticulonodular pattern. Stage III occurs over the next 10 days, and is characterized by the onset of hyperinflation and the appearance of numerous air-filled cysts of various sizes. Stage IV occurs at 20 to 30 days of age and is characterized by diffuse emphysema, with interspersed strand-like densities and areas of atelectasis (Figure 2-11). Cardiomegaly and cor pulmonale may develop during this stage.

Because of advances in therapy, the classic progressive stages of BPD described by Northway et al are rarely identified in current practice.²¹ Unlike the classic pathophysiology that involved barotrauma and oxygen toxicity, current forms of the condition are predominantly related to immaturity, perinatal infection and inflammation, persistent patency of the ductus arteriosus, and disrupted alveolar and capillary development. The most common radiographic finding is the persistence of fine, diffuse, granular opacities in a ventilated infant who fails to exhibit the expected clinical signs of improvement by the third or fourth day of life. Respiratory distress persists in conjunction with hypoxia, hypercarbia, and oxygen dependence. Interstitial emphysema may be noted on radiographs. There is gradual progression on serial radiographs to a pattern characterized by hyperinflation and numerous small round air filled cystic areas alternating with irregular opacities (Figure 2-12). This corresponds to Northway stage IV; however, the findings are usually more symmetrical and the cystic areas are smaller and more uniform than with classic stage IV BPD. Other potential radiographic patterns of late-phase BPD include generalized overaeration with coarse interstitial opacities and diffuse fine infiltrates without emphysema (Figure 2-13). The histological features during the progression from RDS to BPD consist of progressive alveolar coalescence, microatelectasis, interstitial edema, coarse focal basement membrane thickening, and bronchial and bronchiolar mucosal metaplasia and hyperplasia.

The treatment of BPD includes fluid restriction, diuretic therapy, steroid therapy (early in the course), maintenance of adequate oxygenation, nutritional support, and prompt detection and treatment of infection.²² The most common fatal complications of BPD are right-sided heart failure and viral necrotizing bronchiolitis. Most infants with BPD undergo a slow clinical recovery during the first year of life. Survivors of neonatal BPD often exhibit manifestations of chronic pulmonary dysfunction during childhood, such as recurrent episodes of coughing, wheezing, dyspnea, and pneumonia. Cardiovascular sequelae can also occur, including pulmonary hypertension, systemic hypertension, left ventricular hypertrophy, and exercise intolerance.²³

A variety of strategies are used to diminish the risk for the development of BPD in premature infants. The treatment of maternal infection, administration of prenatal glucocorticoids, and postnatal surfactant replacement therapy improve survival of preterm infants, but the effectiveness of these interventions in preventing progression to BPD is unclear. Techniques that appear to be effective in mitigating the severity of BPD include the administration of retinol (vitamin A), the use of high-frequency oscillatory ventilation, early aggressive nutrition, the treatment of a patent ductus arteriosus, and administration of glucocorticoids. The routine use of glucocorticoids is discouraged, however, because of potential neurodevelopmental side effects.^22,24

Chest radiographs usually show gradual improvement during the first few years of life in children who survive BPD as infants. The radiographic findings of BPD in the postneonatal period include hyperinflation, focal hyperlucencies, and linear scars (Figure 2-14). Generalized pulmonary interstitial thickening is a less common finding. The late CT manifestations of BPD include extensive areas of reduced lung attenuation (the size and number of vessels are reduced), widespread bronchial wall thickening, and a decreased bronchus-to-pulmonary-artery ratio (the airways appear of reduced diameter) (Figure 2-15). Bronchiectasis does not occur. Linear opacities and bullae are sometimes present. A mosaic pattern can occur. Triangular subpleural opacities, with the apices directed centrally, have been described; these may be contiguous with well-defined linear opacities (Figure 2-16). Most older children and adults with a history of BPD have residual pulmonary abnormalities identifiable on CT.^25–28

Lobar hyperinflation can occur as a complication of BPD. This is termed acquired lobar emphysema or persistent acquired lobar overinflation. The pathogenesis is multifactorial, and includes the effects of barotrauma and oxygen toxicity. An additional factor may be repeated trauma to the bronchial walls by suction catheters, resulting in luminal narrowing by granulation tissue and distal air trapping. The importance of this latter mechanism is supported by the observed predilection for involvement of the right lower and right middle lobes.

Acquired lobar emphysema is usually associated with severe neonatal respiratory distress that required prolonged ventilatory support and high peak inspiratory pressures. The time course for the initial development of lobar hyperinflation ranges from a few weeks to several months of age. Radiographs show lobar hyperinflation, atelectasis in adjacent lung, and mediastinal shift. The clinical course of acquired lobar emphysema ranges from complete spontaneous resolution to persistent severe hyperinflation requiring surgical resection. Successful treatment of severe early onset lobar overaeration with selective intubation and high frequency oscillatory ventilation of the unaffected lung has been reported.^29–33

Immature lung syndrome (chronic pulmonary insufficiency of prematurity) is a respiratory disorder of the newborn that occurs in very small premature infants (birth weight <1500 g; gestational age <26 weeks). Immature lung syndrome is clinically and radiographically distinct from RDS. Unlike RDS, the onset of respiratory distress in infants with immature lung syndrome typically does not occur until the end of the first week of life. These infants suffer apneic spells. There is a progressive increasing requirement for supplemental oxygen administration. Manifestations of BPD are less common in infants with immature lung syndrome than in those with RDS. The overall prognosis of immature lung syndrome is poor.

The pathophysiology of immature lung syndrome is incompletely understood. Despite the extreme prematurity that is usually associated with this disorder, surfactant is present. This may be a result of the stimulation of early production of surfactant in response to fetal stress. The presence of surfactant likely accounts for the typical delay in the clinical onset of respiratory distress. The surfactant, however, may be of insufficient quantity or quality to maintain alveolar ventilation. Other possible pathophysiological factors include fluid overload and thoracic cage insufficiency.

During the early asymptomatic phase of immature lung syndrome, chest radiographs are normal except for pulmonary hypoaeration. The appearance of ill-defined, fluffy parahilar opacities correlates with the development of symptomatic respiratory distress (Figure 2-17). Unlike RDS, air bronchograms are absent or minimal (Figure 2-18). The radiographic findings usually are relatively stable for 1 to 2 months, after which there is slow clearing of the parenchymal opacities. Air-block complications can occur, but are less common than in children with classic RDS. Many of these premature infants develop manifestations of BPD.^16,34,35