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Neonatal Respiratory Distress Syndrome

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-.

Neonatal Respiratory Distress Syndrome

Authors

Sudeep Yadav1; Brian Lee2; Ranjith Kamity3.

Affiliations
1 BP Koirala Institute of Health Science
2 NYU Winthrop Hospital
3 NYU Winthrop Hospital

Last Update: July 19, 2020.

Introduction
Neonatal respiratory distress syndrome, or RDS, is a common cause of respiratory distress in a newborn, presenting
within hours after birth, most often immediately after delivery. RDS primarily affects preterm neonates, and
infrequently, term infants. The incidence of RDS is inversely proportional to the gestational age of the infant, with more
severe disease in the smaller and more premature neonates. While treatment modalities, including antenatal
corticosteroids, surfactants, and advanced respiratory care of the neonate, have improved the outcomes for patients
affected by RDS, it continues to be a leading cause of morbidity and mortality in the preterm infant.

Etiology
Neonatal respiratory distress syndrome (RDS) occurs from a deficiency of surfactant, due to either inadequate surfactant
production, or surfactant inactivation in the context of immature lungs. Prematurity affects both these factors, thereby
directly contributing to RDS.

Fetal Lung Development

It is essential to review fetal lung development and surfactant production to understand the etiology of RDS. The normal
process of fetal lung development occurs in stages, known as embryonic, pseudo glandular, canalicular, saccular, and
alveolar stages.[1]

During the embryonic period, the lung bud first appears at 26 days as a ventral protrusion of the fetal esophagus.[2] The
lung bud further penetrates and divides throughout the surrounding mesenchyme, initially forming the mainstem bronchi
by 37 days. The mainstem bronchi branch further leading to the development of subsegmental bronchi by 48 days.
Pulmonary vasculature develops along with the developing lung and the pulmonary artery forms as a branch of the sixth
aortic arch by 37 days.

The pseudo glandular stage starts around the fifth week of gestation and ends at the 16th week, and is the stage at which
neuroepithelial cells, cartilage, ciliated cells, goblet cells, and basal cells develop in the proximal pulmonary epithelium.
During this stage, the airways branch 15 to 20 times by the 18th week of gestation.[2]

The canalicular stage, beginning the 16th week and ending around the 25th week, marks the beginning of the
development of the pulmonary acinus, the formation of a blood-air barrier, and surfactant production via type 2 cells,
culminating in a lung potentially viable for gas exchange. The increasing number and size of capillaries continue to
vascularize the mesenchyme. Together with the growth of the bronchioles, this thins the mesenchymal space between
the respiratory epithelial basement membranes and the vascular epithelium. Eventually, these capillary and respiratory
epithelial basement membranes fuse, forming a rudimentary blood-air barrier.[3] At 20 weeks, lamellar bodies begin to
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form in the cytoplasm of the glycogen-laden cuboidal epithelium of the bronchioles, and these cells differentiate into
type 2 cells, which are capable of producing surfactant.

During the saccular stage, from around the 24th week to the 32nd week of gestation, the terminal saccule forms,
developing the respiratory bronchioles, which have a wall thickness that allows for gas exchange. It is at this stage that
the premature infant is potentially viable in extrauterine life.[3]

At 32 weeks, the alveolar stage begins, and alveoli start to form as the respiratory bronchioles develop septations,
increasing the surface area for gas exchange. By term age, the lung contains 50 to 150 million alveoli.

Surfactant

The pulmonary surfactant covers the inner lining of normal alveoli. In the fetus, however, the developing alveoli are
filling with fetal lung fluid, which does not contribute to gas exchange. During fetal life, surfactant production begins in
the alveolar type 2 cells around 20 weeks gestation. Surfactant is predominantly lipid-dense, comprising of around 70%
to 80% phospholipids, 10% protein, and 10% neutral lipids. The surfactant consists of four surfactant-specific proteins
(SP); SP-A, SP-B, SP-C, and SP-D. SP-A and SP-D are involved in regulating inflammatory processes in the lung.[4]
[5] SP-B is required for the formation of normal lamellar bodies in the type 2 cells and is also involved in the processing
of SP-C. SP-C is a protein that might work with SP-B to improve surfactant deposition and function within the alveoli
by lowering surface tension.[6] Inside the alveolar type 2 cells, surfactant synthesis starts with phospholipids in the
endoplasmic reticulum. The phospholipids transfer through the Golgi apparatus into the lamellar bodies. Surfactant
lipoprotein complex (SP-A, SP-B, SP-C, and phospholipids) forms inside lamellar bodies at the apical surface of type 2
cells, which are subsequently released into alveoli by exocytosis.

The lung experiences force due to the elasticity of the chest wall and lung parenchyma, and the surface tension of air-
fluid interfaces in both the small airways and alveoli. Surfactant lipoprotein complex is significant as it decreases the
surface tension on the small airways and alveoli, which prevents both the collapse of alveoli and entering of interstitial
fluid into the airspace.[7] The type 2 cells reabsorb the secreted surfactant complex from the airspace. The surfactant
molecules are recycled back by endocytosis into multivesicular bodies and eventually into lamellar bodies. This process
of recycling endogenous and exogenous surfactants from alveoli is responsible for maintaining the surfactant pool.[8] In
addition to the lower quantity of surfactant, preterm infants also have decreased surfactant activity due to its
composition.

Genetics

Monozygotic twins have a higher incidence of RDS compared to dizygotic twins, and an increased incidence of RDS
has also been reported in families, thus supporting an underlying genetic predisposition.[9] Infants with genetic causes
of surfactant protein deficiency can also present with varying degrees of RDS. Rare recessive mutations of the SP-B
gene causing SP-B deficiency can present in the neonatal period with severe RDS and progress to severe respiratory
failure.[10] On the other hand, SP-C gene mutations are seen in about 0.1% of the population and present with
interstitial lung disease, usually beyond the first month of life. Neonatal RDS is also associated with deletions in ATP
binding cassette sub-family A, member 3 (ABCA-3). Although about 4% of the population reportedly carries this
deletion, the exact incidence of fatal RDS in this population is unknown.[11][12]

Epidemiology
As the most common cause of respiratory distress in premature infants, RDS occurs in about 24,000 infants born in the
United States annually. It is also the most common complication of prematurity leading to significant morbidity in late
preterm neonates and even mortality in very low birth weight infants. The exact definition of RDS is imprecise, thus
requiring a careful analysis of statistical data. The most important risk factors are prematurity and low birth weight.
Other risk factors include white race, male gender, late preterm delivery, maternal diabetes, perinatal hypoxia and
ischemia, and delivery in the absence of labor.[13] The incidence of RDS increases with decreasing gestational age at
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birth. In one study of babies born between 2003 and 2007 at various National Institute of Child Health and Human
Development (NICHD) Neonatal Research Network centers, 98% of babies born at 24 weeks had RDS, while at 34
weeks, the incidence was 5%, and at 37 weeks was less than 1%.[14]

Pathophysiology
Neonatal respiratory distress syndrome is caused by surfactant deficiency, especially in the context of immature lungs.
The deficiency of surfactant increases the surface tension within the small airways and alveoli, thereby reducing the
compliance of the immature lung. The delicate balance of pressures at the air-fluid interface is essential to prevent the
collapse of the alveolus or the filling of the alveolus with fluid. The pathophysiology of RDS can be described using
LaPlace law, denoted as:

P=2T/R

where P is pressure, T is surface tension, and R is the radius. Laplace law describes the relationship between the pressure
difference across the interface of two static fluids to the shape of the surface. As the surface tension increases at the
alveolar level, the amount of pressure required to maintain alveolar shape increases. With reduced surfactant production,
atelectasis occurs throughout the lung, causing reduced gas exchange. Widespread and repeated atelectasis eventually
damages the respiratory epithelium, causing a cytokine-mediated inflammatory response. As pulmonary edema develops
as a result of the inflammatory response, increasing amounts of protein-rich fluid from the vascular space to leak into the
alveoli, which further inactivate surfactant.[15][16] Furthermore, many infants with RDS require mechanical ventilation,
which may have deleterious effects on the lung.

Overdistension of the alveoli during positive pressure ventilation leads to further damage and inflammation. Besides,
oxidative stress generated both by high oxygen tensions from mechanical ventilation and inflammatory processes within
the lung also promotes the conversion of surfactant into an inactive form through protein oxidant damage and lipid
peroxidation.[17][18][19] Thus RDS can cause hypoxemia through alveolar hyperventilation, diffusion abnormality,
ventilation-perfusion mismatch, intrapulmonary shunting, or a combination of these mechanisms. This hypoxemia and
tissue hypoperfusion ultimately lead to increased anaerobic metabolism at a cellular level with resultant lactic acidemia.

Histopathology
Historically, neonatal respiratory distress syndrome was known as hyaline membrane disease, owing to an eosinophilic
membrane that lines the distal airspaces, usually terminal bronchioles or alveolar ducts, in autopsies of neonates with
RDS. Macroscopically, lung tissue from infants with RDS appears similar to hepatic tissue with a ruddy appearance. The
hyaline membrane mentioned above is composed of fibrin, cellular debris from lung epithelium, red blood cells, and
leukocytes. Microscopic histological examination may also reveal pulmonary tissue with few dilated alveoli among
diffuse areas of atelectasis.[20]

History and Physical

The infant with neonatal respiratory distress syndrome is often born premature and presents with signs of respiratory
distress usually immediately after delivery, or within minutes of birth. The infant may present with decreased breath
sounds and possibly diminished peripheral pulses. Upon clinical examination, such neonates have signs and symptoms
of increased work of breathing, including tachypnea, expiratory grunting, nasal flaring, retractions (subcostal,
subxiphoid, intercostal, and suprasternal) and use of accessory muscles, as well as cyanosis and poor peripheral
perfusion. Auscultation reveals uniformly decreased air entry. In untreated RDS, the symptoms will progressively
worsen over 48 to 72 hours towards respiratory failure, and the infant may become lethargic and apneic.[21] The infant
may also develop peripheral extremity edema and show signs of decreased urine output.

Evaluation
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Since the definition of neonatal respiratory distress syndrome is imprecise, prompt diagnosis and treatment require an
overall assessment of prenatal and delivery history to identify perinatal risk factors, clinical presentation, radiographic
findings, and evidence of hypoxemia on blood gas analysis. As described above, the clinical presentation consists of
non-specific respiratory symptoms, including tachypnea, nasal flaring, grunting, retractions, and cyanosis, with
decreased air entry on auscultation.

Chest Radiography

Chest radiography findings pathognomonic of RDS include homogenous lung disease with diffuse atelectasis,
classically described as having a ground-glass reticulo-granular appearance with air bronchograms, as well as low lung
volumes. The air-tissue interface formed between microalveolar collapse in the background with the air-filled larger
airways in the foreground creates the classic appearance of air bronchograms.

Arterial Blood Gas Analysis

Arterial blood gas analysis may show hypoxemia that responds to increased oxygen supplementation and hypercapnia.
Serial blood gases may show evidence of worsening respiratory and metabolic acidosis, including lactic acidemia in
infants with worsening RDS.

Other Investigations

An echocardiogram may show the presence of a patent ductus arteriosus that might complicate the clinical course of
RDS. Complete blood counts may show evidence of anemia and abnormal leukocyte counts, suggesting infection. At
times, a workup for infectious etiologies may be necessary, including blood, cerebrospinal fluid, and tracheal cultures
(when appropriate).

Treatment / Management
The goals of optimal management of neonatal respiratory distress syndrome include decreasing incidence and severity
using antenatal corticosteroids, followed by optimal management using respiratory support, surfactant therapy, and
overall care of the premature infant.

Antenatal corticosteroids (discussed later in the topic)

Monitoring oxygenation and ventilation

Assisted ventilation of the neonate

Exogenous surfactant therapy

Supportive care, including thermoregulation, nutritional support, fluid and electrolyte management, antibiotic
therapy, etc.[22][23]

Monitoring Oxygenation and Ventilation

Serial blood gas monitoring may be necessary to optimize oxygenation and ventilation. Ideally, the neonates undergo
blood gas monitoring using an umbilical or peripheral arterial catheter placed using a sterile technique. The partial
pressure of arterial oxygen (PaO2) on an arterial blood gas is maintained between 50 to 80 mmHg, and partial pressure
of arterial carbon dioxide (PaCO2) is maintained between 40 to 55 mmHg, with the pH >7.25.

Non-invasive pulse oximetry is now the standard of care to monitor oxygen saturation (SaO2). Unclear higher limits
often limit the utility of pulse oximetry, since PaO2 could be significantly higher at the SaO2 levels >95%. Non-invasive
capnography and transcutaneous carbon dioxide monitoring are used as adjuncts for monitoring ventilation.

Assisted Ventilation of the Neonate

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The goals of assisted ventilation are to reduce atelectasis by providing a constant distending positive airway pressure.
The current preferred strategy is the early initiation of continuous positive airway pressure (CPAP) with selective
surfactant administration.[24] In most institutions, non-invasive modalities are preferred over invasive ventilation as
they decrease the risk of mortality, and bronchopulmonary dysplasia (BPD) compared to invasive ventilation with or
without surfactant.[25][26]

Continuous Positive Airway Pressure (CPAP): Nasal CPAP is an initial intervention in preterm infants with RDS or
risk of RDS without respiratory failure. Multiple modalities are available for CPAP delivery, including ventilator derived
CPAP as well as a less expensive bubble CPAP device. Infants who received CPAP fared as well as infants who received
prophylactic surfactant therapy along with mechanical ventilation in the SUPPORT trial (Surfactant Positive Airway
Pressure and Pulse Oximetry Randomized Trial),[27] and those who received early CPAP had a reduced need for
surfactant therapy. Also, the incidence of BPD decreased with the use of CPAP.[22] The goals of treatment include
keeping SpO2 between 90-95%, and PaCO2 between 45-65 mmHg.

Non-invasive Respiratory Support: Nasal Intermittent Positive Pressure Ventilation (NIPPV) appears superior to
CPAP alone for decreasing extubation failure, the need for intubation in preterm infants, but the same in cost and safety.
[28] The primary difference in NIPPV and CPAP is that NIPPV requires a ventilator to provide positive pressure
ventilation, while CPAP may use a less expensive device such as bubble CPAP to deliver the appropriate pressures.

High Flow Nasal Canula: Heated humidified high-flow nasal cannulas (HFNC) are also used in some centers as an
alternative to CPAP to provide positive distending pressure ventilation to neonates with RDS. As seen in a clinical trial
by Roberts et al., HFNC was found to be inferior to CPAP.[29]

Mechanical Ventilation: Patients who do not respond to CPAP, develop respiratory acidosis (PH < 7.2 and PaCo2 > 60-
65 mm of Hg), hypoxemia (PaO2 < 50 mm of Hg or Fio2 > 0.40 on CPAP), or severe apnea are managed with
endotracheal intubation and mechanical ventilation. The goals of mechanical ventilation include providing adequate
respiratory support while balancing the risks of barotrauma, volutrauma, and oxygen toxicity. Time-cycled pressure
limited ventilation is the preferred initial mode of ventilation in preterm infants with RDS. High-frequency oscillatory
ventilation (HFOV) and high-frequency jet ventilation (HFJV) are often used as rescue modalities when requiring high
conventional ventilator support or concerns for pulmonary air leaks. Other strategies include the use of high-frequency
ventilation empirically in extremely preterm infants to minimize lung injury.

Exogenous Surfactant Therapy

The targeted treatment for surfactant deficiency is intratracheal surfactant replacement therapy via an endotracheal tube.
Surfactant administered within 30 to 60 minutes of the birth of a premature neonate is found to be beneficial. Surfactant
hastens recovery and decreases the risk of pneumothorax, interstitial emphysema, intraventricular hemorrhage (IVH),
BPD, and neonatal mortality in the hospital and at one year. However, neonates who receive surfactant for established
RDS, have an increased risk of apnea of prematurity. According to European census guidelines, the surfactant is
administered to immature babies with FiO2 > 0.3, and mature babies with FiO2 > 0.4. Currently, there are no clinically
significant advantages of using one type over another when used in similar doses:[30]

Beractant: This is a modified natural surfactant prepared from minced bovine lungs with the additives

Poractant alfa: This is a modified natural surfactant derived from minced porcine lung extract

Calfactant: This is a natural surfactant obtained from lavaging calf lung alveoli and contains 80%
phosphatidylcholine with only 1% protein

Synthetic surfactant: Clinical trials are ongoing

Surfactant is administered either by standard endotracheal intubation, which needs experienced practitioner or through
less invasive surfactant administration (LISA) technique like aerosolized nebulized surfactant preparations, laryngeal/
mask, pharyngeal instillation, and thin intratracheal catheters.[31][32][33][34][35] The standard technique of surfactant
administration by endotracheal intubation and mechanical ventilation may result in transient airway obstruction,
pulmonary injury, pulmonary air leak, and airway injury.[36][37] Emerging evidence shows that the LISA technique is
associated with a lower rate of BPD, death, and need for mechanical ventilation compared to surfactant administration
through endotracheal intubation.[38] Still, further investigations are required to prefer the LISA technique as the
standard technique of surfactant administration in place of endotracheal intubation. If the neonates maintain adequate
respiratory drive with FiO2 <0.3, it should be planned to stop surfactant and switch to CPAP. Oxygen saturation (>90%),
thermoregulation (36.5 to 37.5 C), and fluid and nutrition status should be monitored.

Supportive Care

Preterm infants with apnea of prematurity may require caffeine therapy. Caffeine can also be administered to preterm
infants < 28 weeks with extremely low birth weight (BW <1000 g) to increase respiratory drive and enhance the use of
CPAP. There was a low incidence of BPD and earlier extubation in preterm infants who received caffeine compared to
placebo.[39]

Optimal fluid and electrolyte management is critical in the initial course of RDS. Some neonates may require volume
resuscitation using crystalloids as well as vasopressors for hypotension. Furthermore, the overall care of a preterm infant
also includes optimizing thermoregulation, nutritional support, blood transfusions for anemia, treatment for
hemodynamically significant PDA, and antibiotic therapy as necessary.

Differential Diagnosis
There are numerous causes of neonatal respiratory distress syndrome, including transient tachypnea of the newborn,
pulmonary air leak disorders (pneumothorax, pneumomediastinum), neonatal pneumonia, meconium aspiration,
persistent pulmonary hypertension of the newborn, and the broad categories of cyanotic congenital heart disease and
interstitial lung disease.[21]

Infants with transient tachypnea of the newborn have impaired resorption of the fetal lung fluid and have marked
tachypnea soon after birth, but symptoms generally improve after 24 hours. Chest radiograph shows perihilar
streaking, representing perihilar interstitial edema, without the diffuse reticulo-granular ground glass appearance
of RDS.

Pulmonary air leak syndromes such as pneumothorax and pneumomediastinum may also present as respiratory
distress, but the onset of symptoms may be more acute. Other clinical clues include chest rise asymmetry, and
diminished breath sounds on one side of the chest. Hyperlucent areas on chest radiography can be appreciated if
the air leak is significant. Pulmonary interstitial emphysema affects infants who are mechanically ventilated;
symptoms of respiratory distress often occur later than expected with RDS, and the trapped air within the
perivascular tissues has a characteristic appearance of cystic lucencies on chest radiography.

Bacterial pneumonia, especially related to Group B Streptococcus in a newborn is often clinically and
radiographically indistinguishable from RDS. The preferred treatment includes empirical antibiotics in addition to
respiratory management.

Infants with cyanotic congenital heart disease may have similar symptoms clinically, but will not have the diffuse
reticulo-granular ground glass appearance on chest radiography. The radiological findings depend on the
underlying anatomic abnormality.

Prognosis
Prognosis of infants managed with antenatal steroids, respiratory support, and exogenous surfactant therapy is excellent.
Mortality is less than 10%, with some studies showing survival rates of up to 98% with advanced care. Increased
/
survival in developed countries is in stark comparison to babies who received no intervention in low-income countries,
where the mortality rate for premature infants with RDS is significantly higher, at times close to 100%.[40] With
adequate ventilatory support alone, surfactant production eventually begins, and once surfactant production begins along
with the onset of diuresis, RDS improves within 4 or 5 days. Untreated disease leading to severe hypoxemia in the first
days of life can result in multiple organ failure and death.

Complications
Complications of neonatal respiratory distress syndrome are related mainly to the clinical course of RDS in neonates and
the long term outcomes of the neonates. While surfactant therapy has decreased the morbidity associated with RDS,
many patients continue to have complications during and after the acute course of RDS.

Acute complications due to positive pressure ventilation or invasive mechanical ventilation include air-leak syndromes
such as pneumothorax, pneumomediastinum, and pulmonary interstitial emphysema. There is also an increase in the
incidence of intracranial hemorrhage and patent ductus arteriosus in very low birth weight infants with RDS, although
independently linked to prematurity itself.

BPD is a chronic complication of RDS. The pathophysiology of BPD involves both arrested lung development as well
as lung injury and inflammation. Besides a surfactant deficiency, the immature lung of the premature infant has
decreased compliance, decreased fluid clearance, and immature vascular development, which predisposes the lung to
injury and inflammation, further disrupting the normal development of alveoli and pulmonary vasculature. Also,
oxidative stress from hyperoxia secondary to mechanical ventilation, and decreased anti-oxidant capabilities of the
premature lung, both lead to further damage to the lung through the increased production on TGF-β1 and other pro-
inflammatory cytokines.[41]

Neurodevelopmental delay is another complication of RDS, especially with infants who received mechanical ventilation
long-term.[42] The incidence of cerebral palsy also was increased in infants with RDS, with decreasing incidence as
gestational age increased. The length of time on mechanical ventilation correlates with increased rates of both cerebral
palsy and neurodevelopmental delay.

Deterrence and Patient Education

While the goal of preventing preterm birth altogether continues to be investigated, RDS can be reduced by the
administration of antenatal corticosteroids. Administration of antenatal corticosteroids significantly reduces the
incidence of RDS and the need for mechanical ventilation. The use of antenatal corticosteroids decreased the incidence
of RDS in a review of 21 studies and 4083 infants with a reduction in neonatal and fetal death in a review of 3627
infants in 13 studies.[43] It has also been shown to reduce infant mortality and periventricular leukomalacia. Of note,
there were no statistically significant increases in maternal mortality with the administration of antenatal corticosteroids.

The beneficial effect of antenatal corticosteroid use after 34 weeks of gestation is controversial due to the lack of
information in long term developmental outcomes.[44] Maternal antenatal corticosteroids are recommended for possible
preterm delivery in the next seven days between 23rd and 34th week gestational age.[45] Some institutions offer
antenatal corticosteroids at 22 weeks if anticipating delivery within the next week. Despite multiple interventions
targeting various etiologies, the goal of preventing preterm birth remains elusive.

Enhancing Healthcare Team Outcomes

The clinical presentation of neonatal respiratory distress overlaps with a wide range of respiratory illnesses occurring in
the newborn period. However, a basic history, laboratory workup, and imaging can help confirm the diagnosis. The
management of RDS requires the coordination of care between numerous teams, including physicians, nurses,
respiratory therapists, nutritionists, and pharmacists. Several comorbidities further complicate the clinical course of
neonates with RDS requiring a high level of clinical expertise. These include respiratory complications (pneumothorax, /
pneumomediastinum, and pulmonary interstitial emphysema), patent ductus arteriosus, pulmonary hypertension, and
sepsis.

Clear goals of care must be established from the onset of birth, from the initial stabilization of the infant in the delivery
room to the long-term goals of care. A team led by the neonatologist manages the patient primarily, and at times,
consulting a pulmonologist to establish long-term care after the patient's discharge from the NICU. Specialized neonatal
nursing care is central to optimizing care of such critical newborns. A trained respiratory therapist is equally essential in
managing a wide range of ventilatory strategies used by the medical team. These strategies may include various modes
of non-invasive ventilation, conventional mechanical ventilation, as well as high-frequency ventilation. Infants that
progress towards BPD continue to require a holistic approach with dedicated interprofessional healthcare teams aimed at
achieving better outcomes.

Questions
To access free multiple choice questions on this topic, click here.

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Figures

This is a chest radiograph of a preterm neonate with respiratory distress syndrome showing diffuse ground glass
haziness bilaterally with air bronchograms. Contributed by Ranjith Kamity, MD

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