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Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn

Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn
Author:
Richard Martin, MD
Section Editor:
Joseph A Garcia-Prats, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Jun 2022. | This topic last updated: Mar 31, 2020.

INTRODUCTION — Respiratory distress syndrome (RDS), formerly known as hyaline membrane disease, is a common problem in preterm infants. This disorder is caused primarily by deficiency of pulmonary surfactant in an immature lung. RDS is a major cause of morbidity and mortality in preterm infants.

The pathophysiology and clinical features of RDS will be presented here. The management of RDS and other disorders of perinatal transition are discussed separately. (See "Management of respiratory distress syndrome in preterm infants" and "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis" and "Persistent pulmonary hypertension of the newborn" and "Transient tachypnea of the newborn".)

LUNG DEVELOPMENT — Knowledge of the normal fetal lung development is central to understanding the pathophysiology of neonatal RDS, which is due to inadequate surfactant activity resulting from lung immaturity.

Normal fetal alveolar development occurs in the following stages [1]:

Embryonic period – At approximately 26 days gestation, the embryonic stage begins with the first appearance of the fetal lung, which appears as a protrusion of the foregut. The initial branching of the lung occurs at 33 days gestation forming the prospective main bronchi, which begin to extend into the mesenchyme. Further branching forms the segmental bronchi as the lung enters the next stage of development.

Pseudoglandular stage – In the pseudoglandular stage (5th to 16th weeks of gestation), 15 to 20 generations of airway branching occur starting from the main segmental bronchi and ending as terminal bronchioles. At the end of the pseudoglandular stage, the airways are surrounded by a loosely packed mesenchyme, which includes a few blood vessels, and is lined by glycogen-rich and morphologically undifferentiated epithelial cells with a columnar to cuboidal shape. In general, epithelial differentiation is centrifugal, so the proximal airways are lined with the most differentiated cells, with progressively less differentiation in the more distal tubules.

Canalicular stage – During the canalicular stage (16th to 25th weeks of gestation), the transition from previable to a potential viable lung occurs as the respiratory bronchioles and alveolar ducts of the gas exchange region of the lung are formed. The surrounding mesenchyme becomes more vascular and condenses around the airways. The closer vascular proximity ultimately results in fusion of the capillary and epithelial basement membranes. After 20 weeks gestation, cuboidal epithelial cells begin to differentiate into alveolar type II cells with formation of cytoplasmic lamellar bodies [2]. The presence of lamellar bodies indicates the production of surfactant, which is produced from glycogen and stored in the lamellar bodies.

Saccular stage – At the beginning of the saccular stage (approximately 24 weeks gestation), there is potential for viability because gas exchange is possible due to the presence of large and primitive forms of the future alveoli. In this stage, formation of alveoli (ie, alveolarization) occurs by the outgrowth of septae that subdivide terminal saccules into anatomic alveoli, where air exchange occurs. The number of alveoli in each lung increases from zero at 32 weeks gestation to between 50 and 150 million alveoli in term infants and 300 million in adults. Alveolar growth continues for at least two years after birth at term.

Pulmonary surfactant — The primary cause of RDS is deficiency of pulmonary surfactant, which is developmentally regulated. The fetal lung is filled with fluid and provides no respiratory function until birth. In preparation for air breathing, surfactant is expressed in the lung starting around the 20th week of gestation [3]. Surfactant reduces the alveolar surface tension, thereby facilitating alveolar expansion and reducing the likelihood of alveolar collapse atelectasis.

Because of the developmental regulation of surfactant production, the most common cause of surfactant deficiency is preterm delivery. In addition, mutations in the genes encoding surfactant proteins SP-B and SP-C [4,5] and the adenosine triphosphate (ATP)-binding cassette (ABC) transporter A3 (ABCA3) [6-8] may cause surfactant deficiency and/or dysfunction, and hereditary respiratory failure in infants born at term. (See "Genetic disorders of surfactant dysfunction", section on 'SFTPC sequence variants'.)

Pulmonary surfactant is a complex mixture that is mostly composed of lipids (90 percent), primarily phospholipids, and approximately 10 percent proteins.

Lipid – Approximately 70 percent of the lipid in surfactant is phosphatidylcholine species. Of this, approximately 60 percent is disaturated palmitoylphosphatidyl choline, the main component of surfactant that lowers alveolar surface tension [9].

Protein – Four surfactant-specific proteins have been identified, and their functions have been partly elucidated [1,10-12]. They include the hydrophobic surfactant proteins SP-B and SP-C, and the hydrophilic proteins SP-A and SP-D.

SP-A, a member of the collectin protein family, is an innate host defense protein and a regulator of inflammation in the lung. This protein facilitates phagocytosis of pathogens and their clearance from the airspace by macrophages. Patients with a deficiency of SP-A have not been identified. SP-A levels are low in surfactant from preterm lungs and increase with corticosteroid exposure. Mice that lack SP-A have normal lung function and surfactant metabolism, indicating that SP-A is not critical to the regulation of surfactant metabolism. SP-A is not present in currently available surfactants used for treatment of RDS.

SP-B facilitates surface absorption of lipids and, as a result, contributes to the surface tension-lowering ability of surfactant. Animals with antibodies to SP-B develop respiratory failure. Homozygous SP-B deficiency is extremely rare and essentially lethal in term human infants [4]. SP-B and SP-C are both components found in commercial preparations of surfactants.

Humans with SP-C deficiency do not have respiratory distress at birth, but develop progressive interstitial pulmonary fibrosis as infants and into early childhood [5]. SP-C deficient mice have normal lung and surfactant function at birth. However, the mice develop progressive interstitial lung disease and emphysema as they age. In this animal model, the misprocessed SP-C results in SP-C deficiency in the airspaces and injury to the type II cell. SP-B and SP-C probably work cooperatively to optimize rapid adsorption and spreading of phospholipids on a surface and to facilitate surface tension lowering and alveolar stability on surface area compression at low lung volume.

SP-D is a hydrophilic protein and, like SP-A, a member of the collectin protein family. It also functions as an innate host defense molecule by binding pathogens and facilitating their clearance. The absence of SP-D results in increased surfactant lipid pools in the airspaces and emphysema, but no major deficits in surfactant function in mice [13]. Treatment of preterm lambs with recombinant surfactant protein D has been shown to inhibit lung inflammation, which reduces surfactant inactivation, and may hold promise for future human investigation [14].

Synthesis, secretion, and absorption — Surfactant is synthesized within the alveolar type II cells starting with phospholipid synthesis in the endoplasmic reticulum, then is processed through the Golgi apparatus to the lamellar bodies. Phospholipids combine with the surfactant proteins SP-B and SP-C to form the surfactant lipoprotein complex within the lamellar bodies. Lamellar bodies localize to the apical surface of the type II cell and are released into the alveoli by exocytosis.

As the lamellar bodies unravel within the alveoli, the surfactant complex forms a lipoprotein array (includes SP-A, SP-B, and SP-C proteins, and phospholipids) called tubular myelin that contributes to the surface film within the alveoli and airways and reduces alveolar surface tension [1]. Secreted surfactant moves from the airspaces back to type II cells, where it is recycled back into the cell by an endocytotic process into multivesicular bodies and subsequently lamellar bodies. Recycling of endogenous and exogenous surfactant is an important contributor to the surfactant pool [15].

Prematurity — In the preterm infant, both a decrease in the quantity and quality of surfactant contributes to decreased surfactant activity, resulting in RDS.

In addition to low surfactant production seen with decreasing gestational age, the surfactant produced in preterm infants compared with surfactant from term infants has reduced activity because of differences in lipid and protein composition [16]:

Surfactant from immature lungs compared with surfactant from mature lungs contains larger amounts of phosphatidylinositol (10 versus 2 percent of the surfactant composition) and smaller amounts of phosphatidylglycerol (less than 1 versus 10 percent). The more mature form of surfactant with the higher phosphatidylglycerol content has greater surface activity. The phosphatidylglycerol content begins to rise in amniotic fluid after 35 weeks gestation and is used as a marker for fetal lung maturity.

Several other techniques are available to assess fetal lung maturation. These include lecithin/sphingomyelin (L/S) ratio and lamellar body counts. As discussed above, surfactant production is first noted around 20 weeks gestation with the appearance of lamellar bodies within the epithelial cells of the airways. Clinically, lamellar body counts in the amniotic fluid may also be used to measure fetal lung maturity and surfactant production. (See "Assessment of fetal lung maturity", section on 'Phosphatidylglycerol'.)

The protein content of surfactant from preterm lung is low relative to the amount of surfactant lipid. In general, type II cells with lamellar bodies appear in the human lung after 20 weeks with very little surfactant protein mRNA expression until later in gestation. The expression of the four surfactant proteins varies with gestational age: SP-A increases after 32 weeks gestation, SP-B increases after 34 weeks gestation, SP-C mRNA is highly expressed at the tip of branching airways during early lung development, and expression of SP-D mRNA is low until late gestation.

The administration of antenatal glucocorticoids reduces the risk of RDS in preterm infants because it improves neonatal lung function by enhancing maturational changes in lung architecture and by inducing enzymes that stimulate phospholipid synthesis and release of surfactant. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Mechanism of action' and "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

PATHOPHYSIOLOGY

Overview — The primary abnormality in RDS is surfactant deficiency. In the premature lung, inadequate surfactant activity results in high surface tension leading to instability of the lung at end-expiration, low lung volume, and decreased compliance. These changes in lung function cause hypoxemia due to a mismatch between ventilation and perfusion primarily due to collapse of large portions of the lung (atelectasis), with additional contributions of ventilation/perfusion mismatch from intrapulmonary and extrapulmonary right-to-left shunts.

Surfactant deficiency also leads to lung inflammation and respiratory epithelial injury, which may result in pulmonary edema and increased airway resistance. These factors further exacerbate lung injury and worsen lung function. At the same time, abnormal fluid absorption results in inefficient clearing of liquid in the injured lung, leading to edema lung that also impedes gas exchange.

Surfactant deficiency — In preterm infants, surfactant deficiency is the primary cause of RDS because the loss of surfactant leads to an increase in the amount of pressure needed to open alveoli, and alveolar instability at low volume resulting in alveolar collapse and diffuse atelectasis. (See 'Prematurity' above.)

The relationship of the inflating pressure, surface tension, and radius of curvature is illustrated by the model of a distal alveolus as a sphere connected to a distal airway described by LaPlace's law. According to LaPlace's law, the pressure (P) necessary to keep the sphere open is proportional to the surface tension (T) and inversely proportional to the radius (R) of the sphere, as shown by the formula:

                                     P = 2T/R

If the surface tension is high and the alveolar volume is small (ie, the radius is low), as occurs at end-expiration, the pressure necessary to keep the alveolus open is high. If this increased pressure cannot be generated, the alveolus collapses. Diffuse atelectasis occurs when alveolar collapse occurs throughout the lung, which leads to hypoxemia. Pulmonary surfactant reduces the surface tension, even at low volumes, leading to a decrease in the required pressure, thus maintaining alveolar volume and stability (figure 1).

Inflammation and lung injury — The role of inflammation in the pathogenesis of RDS is suggested by animal experiments in which surfactant deficiency was associated with the rapid accumulation of neutrophils in the lung and evidence of pulmonary edema [17]. In this model, depletion of neutrophils prevented pulmonary edema. In addition, as noted above, surfactant deficiency causes atelectasis that may lead to injury of the respiratory epithelium and the alveolar capillary endothelium, which can trigger a cytokine-mediated inflammatory response. Further injury may be caused by positive pressure ventilatory support or excessive oxidant exposure [18-23]. The inflammation and lung injury may, in turn, lead to accumulation of protein-rich pulmonary fluid that can deactivate any surfactant that is present, thereby further exacerbating the underlying surfactant deficiency [24].

Pulmonary edema — In infants with RDS, pulmonary edema often occurs because of the following contributory factors:

Inflammation and lung injury. (See 'Inflammation and lung injury' above.)

Reduced pulmonary fluid absorption − In the fetus, lung fluid is actively transported into the potential airspaces in a process mediated by chloride channels. In preparation for birth and air-breathing, the lung shifts from a secretory to an absorptive mode. Fluid absorption is mediated by sodium channels expressed on epithelial cells (ENaC). However, ENaC expression increases with gestational age in parallel with the surge in surfactant production. In preterm infants, an inadequate number of ENaC may result in fluid retention, similar to what is seen in infants with transient tachypnea of the newborn [25,26].

Low urine output − Infants with RDS typically have low urine output contributing to fluid retention in the first few days, which may exacerbate pulmonary edema. Some infants have hyponatremia due to increased free water. Infants recovering from RDS typically have a spontaneous diuresis on the second to fourth day, followed by improved pulmonary function.

Surfactant inactivation — In addition to decreased surfactant production and synthesis of a less active surfactant, surfactant inactivation further reduces the effective surfactant pool size. Factors that contribute to surfactant inactivation include:

Meconium and blood in the alveoli can inactivate surfactant activity, which is more typically an issue in term infants with meconium aspiration than in preterm infants with surfactant deficiency.

Proteinaceous edema and inflammatory products increase the conversion rate of surfactant into its inactive vesicular form. This conversion can be accelerated by oxidant and mechanical stress associated with mechanical ventilation, especially if high tidal volumes and lack of positive end-expiratory pressure (PEEP) are used [21,27].

Pulmonary function and gas exchange — The major negative effects of surfactant deficiency on pulmonary function are low compliance and low lung volume (functional residual capacity), and are primarily due to atelectasis, although both pulmonary edema and inflammation may be contributing factors. Total lung resistance is slightly increased, probably as a result of airway compression by interstitial edema and damage to the airways by the increased pressure needed to expand the poorly compliant alveoli [28-31].

Exogenous surfactant therapy prevents or corrects these pulmonary functional abnormalities (ie, low lung compliance and volume, and increased lung resistance). (See "Management of respiratory distress syndrome in preterm infants", section on 'Surfactant therapy'.)

Hypoxemia — The hypoxemia that occurs in RDS is due primarily to mismatch of ventilation and perfusion with intrapulmonary right-to-left shunting of blood past substantial regions of the lung that are poorly ventilated. Extrapulmonary shunting also occurs typically across the foramen ovale and patent ductus arteriosus.

The proportion of hypoxemia due to shunting versus poor alveolar ventilation depends upon the extent of hypoxic pulmonary vasoconstriction and the relative size of the underventilated region. Although minute ventilation may be increased, alveolar ventilation is decreased as most of the lung is collapsed and poorly ventilated. Poor ventilation is reflected in elevated values of arterial partial pressure of carbon dioxide (PaCO2), and a resultant respiratory acidosis. Metabolic acidosis also may be present due to lactic acid production from anaerobic metabolism, in response to hypoxemia and compromised tissue perfusion.

INCIDENCE — The incidence of RDS increases with decreasing gestational age (GA). The risk is highest in extremely preterm infants, as illustrated by a study from the National Institute of Child Health and Human Development Neonatal Research Network that found a 93 percent incidence of RDS in a cohort of 9575 extremely preterm infants (GA 28 weeks or below) born between 2003 and 2007 [32].

Although the incidence is lower, RDS still occurs in a significant number of late preterm infants (GA between 34 weeks and 36 weeks and 6 days). In a report from the Safe Labor Consortium of 233,844 deliveries from 2002 and 2008, RDS was diagnosed in 10.5, 6, 2.8, 1, and 0.3 percent for infants born at 34, 35, 36, 37, and ≥38 weeks gestation, respectively [33]. In late preterm and term infants, male sex is associated with an increased risk of RDS (adjusted odds ratio [AOR] 1.7, 95% CI 1.45-1.93), and being White is also associated with increased risk, as opposed to being of Asian (AOR 0.57, 95% CI 0.47-0.7), Black (AOR 0.66, 95% CI 0.5-0.87), or Hispanic race/ethnicity (AOR 0.76, 95% CI 0.64-0.9) [34].

CLINICAL MANIFESTATIONS — The clinical manifestations of RDS result primarily from abnormal pulmonary function and hypoxemia. Because RDS is primarily a developmental disorder of deficient surfactant production, it presents within the first minutes or hours after birth. If untreated, RDS progressively worsens over the first 48 hours of life. In some cases, infants may not appear ill immediately after delivery, but develop respiratory distress and cyanosis within the first few hours of age. These infants may have a borderline amount of surfactant that is consumed or becomes inactivated.

The affected infant is almost always preterm and exhibits signs of respiratory distress that include:

Tachypnea.

Nasal flaring, which reflects the use of accessory respiratory muscles and lowers total respiratory system resistance.

Expiratory grunting, which results from exhalation through a partially closed glottis and slows the decrease in end-expiratory lung volume.

Intercostal, subxiphoid, and subcostal retractions, which occur because the highly compliant rib cage is drawn in during inspiration by the high intrathoracic pressures required to expand the poorly compliant lungs.

Cyanosis due to right-to-left intra- and extra-pulmonary shunting. (See 'Hypoxemia' above.)

On physical examination, auscultated breath sounds are decreased, and infants may be pale with diminished peripheral pulses. The urine output often is low in the first 24 to 48 hours and peripheral edema is common.

Clinical course — Prior to surfactant use, uncomplicated RDS typically progressed for 48 to 72 hours. This was associated with an improvement in respiratory function as endogenous surfactant production increased. RDS typically resolves by one week of age. A marked diuresis typically preceded the improvement in lung function. The natural history of RDS is greatly modified by treatment with exogenous surfactant, which dramatically improves pulmonary function, leading to the resolution of symptoms, and shortens the clinical course. In addition, the use of continuous positive airway pressure (CPAP) has also improved the clinical course of RDS, even in infants who do not receive surfactant therapy. (See "Management of respiratory distress syndrome in preterm infants", section on 'Surfactant therapy' and "Management of respiratory distress syndrome in preterm infants", section on 'Nasal continuous positive airway pressure (nCPAP)'.)

Laboratory findings — Chest radiography is generally obtained for all neonates with respiratory distress. The radiographic features of neonatal RDS (low lung volume and the classic diffuse reticulogranular ground glass appearance with air bronchograms) in a preterm infant with respiratory distress fulfill the clinical diagnosis criteria for RDS (image 1). (See 'Diagnosis' below.)

Other laboratory findings associated with, but not diagnostic for, RDS include:

Arterial blood gas measurements typically show hypoxemia that responds to administration of supplemental oxygen. The partial pressure of carbon dioxide (PCO2) initially is normal or slightly elevated, but usually increases as the disease worsens.

As the disease progresses, infants may develop hyponatremia. This results from water retention, and usually improves with fluid restriction. Attentive fluid management prevents hyponatremia, and as a result, this finding is less commonly observed.

DIAGNOSIS — The diagnosis of RDS is based on a clinical picture of a preterm infant with the onset of progressive respiratory failure shortly after birth (manifested by an increase in the work of breathing and an increase in the oxygen requirement), in conjunction with a characteristic chest radiograph. The chest radiographic features of RDS include a low lung volume and the classic diffuse reticulogranular ground glass appearance with air bronchograms (image 1). This radiographic pattern results from alveolar atelectasis contrasting with aerated airways. Pulmonary edema may contribute to the diffuse appearance. Pneumothorax and air leaks are uncommon findings in the initial chest radiography, and are more frequently observed when lung compliance improves. (See 'Clinical manifestations' above and "Pulmonary air leak in the newborn".)

Differential diagnosis — The differential diagnosis for RDS includes other causes of respiratory distress, which are distinguished from RDS by their clinical features, radiographic features, and course. The initial evaluation and management of neonates with respiratory distress are discussed separately. (See "Overview of neonatal respiratory distress and disorders of transition".)

Transient tachypnea of the newborn (TTN) – TTN is generally seen in more mature infants (ie, term or late preterm infants) compared with RDS. Patients with TTN have milder respiratory distress and improve more quickly than those with RDS. Only extremely severe cases of TTN, which are rare, require mechanical ventilation. (See "Transient tachypnea of the newborn".)

Bacterial pneumonia – It is often difficult to differentiate between infants with RDS and those with bacterial pneumonia because of overlap of both clinical and radiographic findings. As a result, blood cultures and, possibly, tracheal cultures should be obtained in all preterm infants who present with respiratory distress. Empirical antibiotics are given to infants at risk for infection pending culture results and clinical course. (See "Neonatal pneumonia".)

Air leak – Air leak (eg, pneumothorax) may be a complication of RDS, an isolated problem, or associated with another underlying disorder. It is detected by chest radiography. (See "Pulmonary air leak in the newborn".)

Cyanotic congenital heart disease – Most patients with cyanotic congenital heart disease (CCHD) have milder respiratory distress than that seen in patients with RDS. In addition, CCHD is usually differentiated from RDS by the absence of the characteristic diffuse reticulogranular ground glass appearance with air bronchograms on chest radiograph. If lung function and the chest radiograph do not improve with respiratory support and surfactant administration, an echocardiogram should be performed to rule out structural heart disease or persistent pulmonary hypertension of the newborn (PPHN) in infants with severe arterial hypoxemia. (See "Cardiac causes of cyanosis in the newborn".)

Interstitial (diffuse) lung disease – A number of interstitial and diffuse lung diseases may present in the neonatal period, including genetic disorders of surfactant dysfunction, lung growth abnormalities, and pulmonary interstitial glycogenosis. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

Non-pulmonary systemic disorders, such as hypothermia, hypoglycemia, anemia, polycythemia, or metabolic acidosis, may present with respiratory distress. Differentiation from RDS is based on the history, physical findings and appropriate laboratory evaluation.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: When a baby is born premature (The Basics)" and "Patient education: Transient tachypnea of the newborn (The Basics)")

SUMMARY AND RECOMMENDATIONS

Respiratory distress syndrome (RDS), formerly also known as hyaline membrane disease, is a common problem in preterm newborn infants.

RDS is caused primarily by deficiency of pulmonary surfactant in an immature lung. Other contributing factors to lung injury include inflammation and pulmonary edema. (See 'Pulmonary surfactant' above and 'Pathophysiology' above.)

Surfactant deficiency causes alveolar collapse leading to low lung compliance and volume and ventilation and perfusion mismatch resulting in hypoxemia. (See 'Pulmonary function and gas exchange' above.)

The incidence of RDS increases with decreasing gestational age (GA). Extremely preterm infants (GA 28 weeks or below) are at the greatest risk for RDS, with an incidence of over 90 percent. (See 'Incidence' above.)

The clinical manifestations of RDS are primarily due to abnormal pulmonary function and hypoxemia in a preterm infant. RDS presents within the first minutes or hours of birth with signs of respiratory distress, such as tachypnea, nasal flaring, expiratory grunting, intercostal, subcostal, and subxiphoid retractions, and cyanosis. Additional findings may include decreased ausculatory breath sounds, pallor, and diminished perfusion. (See 'Clinical manifestations' above.)

Typically RDS progresses over the first 48 to 72 hours of life with increased respiratory distress, and begins to resolve after 72 hours. Subsequent improvement is coincident with increased production of endogenous surfactant with resolution of symptoms by one week of age. The use of antenatal steroids, exogenous surfactant, and/or continuous positive airway pressure dramatically improves pulmonary function and shortens the clinical course. (See 'Clinical course' above.)

The diagnosis of RDS is based on clinical findings of a preterm infant with onset of progressive respiratory failure shortly after birth and a characteristic chest radiograph, which demonstrates low lung volume and diffuse reticulogranular ground glass appearance with air bronchograms (image 1). (See 'Diagnosis' above.)

The differential diagnosis of RDS includes other causes of respiratory distress in the newborn including transient tachypnea of the newborn (TTN), bacterial pneumonia, air leak, cyanotic congenital heart disease (CCHD), interstitial (diffuse) lung disease, and non-pulmonary systemic disorders. These disorders are distinguished from RDS based on differences in clinical presentation, chest radiograph findings, and clinical course. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen E Welty, MD, and Firas Saker, MD, FAAP, who contributed to an earlier version of this topic review.

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