NeoQuest July 2023: Respiratory Distress in a Term Neonate

A 12-day-old term male infant with no significant past medical history presents to the emergency department with respiratory distress. His respiratory rate is 70 breaths per minute, and his heart rate is 120 beats per minute with a pre-ductal oxygen saturation of 90%. On physical exam, he has retractions and grunting, with equal air entry bilaterally on auscultation. After obtaining a chest radiograph (Figure 1A), a computed tomography of the chest is performed for further diagnostic imaging (Figure 1B). 

Figure 1. Diagnostic imaging of the chest of the infant in the vignette reveals (A) hyperlucent cystic lesions on plain radiograph and B) multiple cystic lung lesions of the bilateral lobes communicating with the tracheobronchial tree with no evidence of systemic collaterals feeding the lesion on high-resolution computed tomography with angiography. Mekarthi A, Subramanian S, Murki S, Singh A, Veerlapati R. A term neonate with persistent respiratory distress. Neoreviews. 2023;24(7):e448–451

Of the following, the stage of embryonic lung development most likely altered in this infant is:

1. Alveolar
2. Canalicular
3. Embryonic
4. Pseudoglandular
5. Saccular

Answer: D. Pseudoglandular  

Explanation:

The presentation of a term infant with respiratory distress and radiographic evidence of multiple cystic lung lesions communicating with the tracheobronchial tree without systemic blood supply should raise suspicion for congenital pulmonary airway malformation (CPAM).^1–3 The development of CPAM results from a failure of maturation of the conducting airways and bronchiolar structures during the pseudoglandular stage (7–17 weeks gestation) of lung development (Figure 2) (Option D).^1–3 CPAMs are characterized by non-functional cystic lung tissue that communicates with the tracheobronchial tree and is supplied by the pulmonary circulation.^1,2 CPAMs are the most common type of bronchopulmonary malformation, with an incidence of 1 in 10,000 live births.³ CPAMs have been classified into five major histopathological subtypes (types 0 through 4) for differentiation of clinical features, potential for malignancy, and prognosis. CPAMs can be associated with cardiac or renal anomalies, recurrent respiratory infections, and malignancies such as pleuropulmonary blastoma and rhabdomyosarcoma.^1–4

Figure 2. Stages of lung development and associated pulmonary disorders. Figure adapted from: Reuter S, Moser C, Baack M. Respiratory distress in the newborn. Pediatr Rev. 2014;35(10):417-429; and McBride W. Congenital lesions of the lung. Neoreviews. 2016;17(5):e263–270

Embryonic defects in the alveolar stage (>36 weeks gestation) of lung maturation can result in compromised development of respiratory alveoli, resulting in disorders such as congenital lobar emphysema (CLE) (Figure 2) (Option A). CLE occurs secondary to endoluminal obstruction from mucosal hyperproliferation and lobar hyperexpansion, leading to an inability to fully decompress the obstructed lobe upon exhalation. Infants with CLE present with radiographic findings consistent with lobar hyperexpansion and mediastinal shift (Figure 3), findings that were not present in the infant in this vignette.³

Figure 3. Chest radiograph of an infant with congenital lobar emphysema demonstrating hyperexpansion of the affected left lung with a mediastinal shift to the patient’s right. Image from: Vachharajani A, Herco M. A term infant with respiratory distress at birth. Neoreviews. 2019;20(7):e428–31

Developmental alterations of the lung in the canalicular phase (17–26 weeks gestation) result in disorders such as alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) (Figure 2) (Option B). ACD/MPV is characterized by a malposition of pulmonary veins adjacent to the pulmonary arteries and lobular maldevelopment (Figure 4).^6–9 Infants with ACD/MPV may present with severe respiratory distress, evidence of pulmonary hypertension on echocardiogram, and non-specific chest radiograph findings including diffuse haziness and ground glass opacities, in contrast to the cystic lucencies on the chest radiograph in this vignette.⁶

Figure 4. Histological findings in ACD/MPV, where congested misaligned pulmonary veins (V) are positioned adjacent to thickened pulmonary arteries (Ar) within acinar parenchyma. Pulmonary capillaries (C) are dysplastic, decreased in number, and abnormally positioned away from the alveolus (A). Image adapted from: Alsaleem M, Hpa N, Kozielski R. Case 3: term infant with severe respiratory failure. Neoreviews. 2020;21(5):e349-52

Alterations in the embryonic stage (0–7 weeks gestation) of lung development can manifest as pulmonary agenesis (Figure 2) (Option C).¹⁰ On chest radiographs, infants with pulmonary agenesis will demonstrate a complete homogeneity of the affected side, which was not present in the infant presented in this vignette (Figure 5).¹⁰ The presence of pulmonary agenesis can be an isolated finding, but it is more commonly associated with other congenital anomalies (tracheoesophageal fistula, heterotaxy syndromes with cardiac malpositions, aortic stenosis, and total/partial anomalous venous connections) and/or as part of the VACTERL spectrum.¹⁰

Figure 5. Chest CT of an infant with complete aplasia of the right lung with absence of the right pulmonary artery. Image adapted from: Kalamdani P, Manerkar S, Bhisikar S, Mondkar J. Case 2: severe respiratory distress at birth: a rare cause. Neoreviews. 2019;20(9):e524–6

Developmental disruption in the saccular stage (26–36 weeks gestation) of lung maturation can impact normal saccular formation at the end of terminal bronchioles and disrupt the initiation of surfactant production by type II pneumocytes (Option E). Defects in the saccular phase can contribute to surfactant deficiency and the development of bronchopulmonary dysplasia in preterm infants (Figure 2).^8,9 Preterm infants with deficiencies in surfactant production and respiratory distress syndrome often present with diffuse, homogenous, reticulogranular opacification of bilateral lung fields noted on chest radiograph, which is not consistent with the imaging of the infant in this vignette.^1,8

Did you know?

• The dimensions of congenital lung malformations (CLMs) measured by fetal ultrasound are characterized by using the CLM volume ratio (CVR), which is the (length x width x height × 0.52)/head circumference (in centimeters).² A CVR value greater than 1.6 is associated with a 3- to 4-fold increased risk of developing hydrops.²

What are some of the prenatal management strategies for a fetus with a congenital lung malformation?
For an overview of various prenatal and postnatal surgical interventions for CLMs, refer to the management strategies described in King A, Olutoye OO, Lee TC, Keswani SG. Surgical management of congenital lung malformations. Neoreviews. 2023;24(2):e84–e96²

What is the differential diagnosis for an infant with a prolonged oxygen requirement and persistent tachypnea with suspected interstitial lung disease?
For an overview of interstitial lung diseases in infancy, refer to Table 1 in Arzuaga BH, Mathai T, Khan O. Children’s interstitial lung diseases in early infancy. Neoreviews. 2013;14(11):e562–566⁶

NeoQuest July Authors:

Srirupa Hari Gopal, MBBS, FAAP, Baylor College of Medicine
Lila S. Nolan, MD, FAAP, Washington University School of Medicine 

References:

1. Mekarthi A, Subramanian S, Murki S, Singh A, Veerlapati R. A term neonate with persistent respiratory distress. Neoreviews. 2023;24(7):e448–451
2. King A, Olutoye OO, Lee TC, Keswani SG. Surgical management of congenital lung malformations. Neoreviews. 2023;24(2):e84–e96
3. McBride W. Congenital lesions of the lung. Neoreviews. 2016;17(5):e263–270
4. Hensley A, Kracer B. Term infant with respiratory distress and desaturations. Neoreviews. 2013;14(2):e100–103
5. Vachharajani A, Herco M. A term infant with respiratory distress at birth. Neoreviews. 2019;20(7):e428–431
6. Arzuaga BH, Mathai T, Khan O. Children’s interstitial lung diseases in early infancy. Neoreviews. 2013;14(11):e562–566
7. Alsaleem M, Hpa N, Kozielski R. Case 3: term infant with severe respiratory failure. Neoreviews. 2020;21(5):e349–352
8. Schittny JC. Development of the lung. Cell Tissue Res. 2017;367(3):427–444
9. Reuter S, Moser C, Baack M. Respiratory distress in the newborn. Pediatr Rev. 2014;35(10):417–429
10. Kalamdani P, Manerkar S, Bhisikar S, Mondkar J. Case 2: severe respiratory distress at birth: a rare cause. Neoreviews. 2019;20(9):e524–526