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From the Archives of the AFIP

Lung Disease in Premature Neonates: Radiologic-Pathologic Correlation¹

¹ From the Department of Radiologic Pathology, Armed Forces Institute of Pathology, 6825 16th St NW, Washington, DC 20306 (G.A.A.); Department of Radiology, Pennsylvania Hospital, Philadelphia, Pa (G.A.A.); Division of Neonatology, Schneider Children’s Hospital, North Shore Long Island Jewish Health System, New Hyde Park, NY (S.E.C.); Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Md (J.T.S.); and Department of Radiology, Children’s Hospital of Philadelphia, Pa (R.I.M.). Received February 4, 2005; accepted March 7. S.E.C. participated in a speakers’ bureau for iNO Therapeutics, Clinton, NJ, and was a sponsored speaker for Viasys, Yorba Linda, Calif; all remaining authors have no financial relationships to disclose. Address correspondence to G.A.A. (e-mail: gagrons{at}mac.com).

	Abstract

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 
Pulmonary disease is the most important cause of morbidity in preterm neonates, whose lungs are often physiologically and morphologically immature. Surfactant deficiency in immature lungs triggers a cascade of alveolar instability and collapse, capillary leak edema, and hyaline membrane formation. The term respiratory distress syndrome (RDS) has come to represent the clinical expression of surfactant deficiency and its nonspecific histologic counterpart, hyaline membrane disease. Historically, chest radiographs of infants with RDS predictably demonstrated decreased pulmonary expansion, symmetric generalized reticulogranular lung opacities, and air bronchograms. Refinements in perinatal medicine, including antenatal glucocorticoid administration, surfactant replacement therapy, and increasingly sophisticated ventilatory strategies have decreased the prevalence of RDS and air leak, altered familiar radiographic features, and lowered the threshold of potential viability to a gestational age of approximately 23 weeks. Alveolar paucity and pulmonary interstitial thickness in these profoundly premature neonates impair normal gas exchange and may necessitate prolonged mechanical ventilation, increasing the risk of lung injury. Bronchopulmonary dysplasia (BPD), alternatively termed chronic lung disease of infancy, is a disorder of lung injury and repair originally ascribed to positive-pressure mechanical ventilation and oxygen toxicity. Before the advent of surfactant replacement therapy, chest radiographs of infants with classic BPD demonstrated coarse reticular lung opacities, cystic lucencies, and markedly disordered lung aeration that reflected alternating regions of alveolar septal fibrosis and hyperinflated normal lung parenchyma. In the current era of surfactant replacement, BPD is increasingly a disorder of very low-birth-weight neonates with arrested alveolar and pulmonary vascular development, minimal alveolar septal fibrosis and inflammation, and more subtle radiographic abnormalities.

	LEARNING OBJECTIVES FOR TEST 6

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 
After reading this article and taking the test, the reader will be able to:

• Describe the anatomic and pathophysiologic features of pulmonary immaturity.
  
• Recognize the radiologic manifestations of neonatal lung disease related to premature delivery and its treatment complications.
  
• Discuss the impact of evolving perinatal medical management on radiologic patterns of disease.
  

	Introduction

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 
Approximately 487,000 infants were delivered before completing 37 weeks gestation in the United States in 2002, a population that represents 12.1% of all live births and a 14% increase since 1990 (1). The increase in the preterm birth rate is related in part to the steep rise in the number of multiple births over the past 2 decades (2). Many premature newborns require treatment in a neonatal intensive care unit at an annual national cost that exceeds $4 billion. Of the many complications of prematurity, including intracranial hemorrhage, necrotizing enterocolitis, sepsis, and retinitis, lung disease remains the most common cause of neonatal morbidity.

During the past decade, dramatic changes in the medical management of premature infants have lowered the threshold of potential viability to 23–24 weeks of gestation. Below this age, developmental immaturity of multiple organ systems precludes survival. Death often results from pulmonary immaturity, which leads to severe tissue damage and dysfunctional gas exchange in an air-breathing environment. The improved survival of very low-birth-weight neonates, the ubiquity of surfactant replacement therapy, and refinements in mechanical ventilation have transformed the natural history of acute and chronic pulmonary insufficiency in premature newborns and have altered familiar radiologic patterns of disease. This article examines the clinical, pathologic, and radiologic features of pulmonary immaturity, the impact of evolving therapeutic strategies, and the changing face of chronic lung disease of prematurity.

	Normal Lung Development

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 
A deeper understanding of anatomic and physiologic pulmonary immaturity in the premature neonate is predicated on a review of normal lung development. Intrauterine lung maturation has been divided into five phases: embryonic, pseudoglandular, acinar or canalicular, saccular, and alveolar (3).

During the embryonic phase (26 days to 6 weeks gestation), an endodermlined outpouching or "lung bud" derived from the primitive fore-gut divides and branches dichotomously to form the early tracheobronchial tree (Figs 1, 2). Initially, the primitive airways are surrounded by loose mesenchyme supplied by primitive systemic arteries. The pulmonary arteries arise from the sixth aortic arch near the end of the embryonic period, penetrate the mesenchyme, and ultimately replace the systemic vessels.

View larger version (48K): [in this window] [in a new window] [Download PPT slide]   Figure 1.  Normal development of the major airways. Schematic shbows induction of dichotomous branching of the lung bud (arrow) by contact with primitive mesenchyme (arrowhead). (Illustration by Aletta Ann Frazier, MD, Department of Radiologic Pathology, Armed Forces Institute of Pathology.)

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 2.  Embryonic phase of normal respiratory tract development. Photomicrograph (original magnification, x100; hematoxylineosin [H-E] stain) of the developing lungs of a 4-mm embryo at approximately 30 days gestation shows the primary bronchial buds (arrows) surrounded by primitive mesenchyme.

View larger version (198K): [in this window] [in a new window] [Download PPT slide]   Figure 3.  Immature lung in the pseudoglandular phase. Photomicrograph (original magnification, x15; H-E stain) of the lungs at 13 weeks gestation shows blind-ending terminal bronchioles (arrows) surrounded by immature lung parenchyma, which has begun to organize into lobules and clusters of primitive acini (arrowheads).

View larger version (168K): [in this window] [in a new window] [Download PPT slide]   Figure 4.  Immature lung in the canalicular (acinar) phase. Photomicrograph (original magnification, x425; H-E stain) of the lungs shows blood-filled capillaries (arrow) that lie immediately beneath the surface of alveolar duct structures lined by cuboidal epithelium (early type II pneumocytes (arrowhead). (Reprinted, with permission, from reference 6.)

View larger version (143K): [in this window] [in a new window] [Download PPT slide]   Figure 5.  Saccular phase of lung development. Photomicrograph (original magnification, x350; H-E stain) of the lungs reveals saccules subdivided by secondary crests (arrows) composed of thinning type I cells immediately adjacent to capillary beds.

View larger version (177K): [in this window] [in a new window] [Download PPT slide]   Figure 6.  Alveolar phase of lung development. Photomicrograph (original magnification, x25; H-E stain) of the normal lung at 38 weeks gestation shows mature alveolar ducts and alveolar saccules with delicate septa, resulting in a thin air-blood barrier.

View larger version (99K): [in this window] [in a new window] [Download PPT slide]   Figure 7.  Endogenous surfactant delivery. Diagram of a type II pneumocyte demonstrates migration of lamellar bodies (arrow) from the nucleus to the apical cell surface, where surfactant (in pink) is released into the alveolus by exocytosis. (Diagram by Aletta Ann Frazier, MD, Department of Radiologic Pathology, Amred Forces Institute of Pathology.)

	Neonatal Respiratory Distress Syndrome

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 
Clinical Features
Respiratory distress syndrome (RDS) is the clinical expression of surfactant deficiency in neonates. Alveolar instability and collapse results in decreased functional residual capacity and increased dead space. Impaired oxygenation and metabolic acidosis increase pulmonary vascular resistance, which in turn increases the likelihood of right-to-left shunting through the ductus arteriosus, augments ventilation-perfusion mismatch, and exacerbates hypoxemia. The deleterious effects of relative surfactant deficiency may be compounded by qualitative defects in extant surfactant when it is inactivated by acinar fluid from capillary leak, hemorrhage, aspirated meconium, or alveolar epithelial injury (7).

In 2002, the overall rate of RDS was 6.1 cases per 1,000 neonates, or approximately 24,000 newborns, representing a decrease since the highest levels were reported for 1994–1995 (1). Most neonates with RDS are premature, and their deficiency of endogenous surfactant is related to a relative lack of mature type II pneumocytes. Term infants of mothers with poorly controlled diabetes may also present with RDS, because fetal hyperinsulinism interferes with the glucocorticoid axis that governs surfactant biosynthesis (21). Other risk factors for RDS include fetal asphyxia, maternal or fetal hemorrhage, and multiple gestations. RDS is more common and severe in male neonates and occurs more commonly in whites than blacks (22).

Neonates with RDS typically present with non-specific tachypnea, expiratory grunting, nasal flaring, cyanosis, and substernal and intercostal retractions (Fig 8). Grunting is the sound produced by breathing against a partially closed glottis as a neonate with RDS augments alveolar distention by increasing expiratory pressure.

View larger version (54K): [in this window] [in a new window] [Download PPT slide]   Figure 8.  Clinical features of neonatal respiratory distress. Drawing depicts a representative preterm newborn with RDS exhibiting substernal and intercostal retractions, nasal flaring, and circumoral cyanosis. (Illustration by Aletta Ann Frazier, MD, Department of Radiologic Pathology, Armed Forces Institute of Pathology.)

View larger version (203K): [in this window] [in a new window] [Download PPT slide]   Figure 9.  Surfactant deficiency in a premature infant. Histologic features. Photomicrograph (original magnification, x75; H-E stain) shows collapsed acini surrounding dilated alveolar ducts lined by smooth homogeneous hyaline membranes (arrows).

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 10.  Surfactant deficiency in a premature infant. Gross pathologic features. Photograph of an autopsy specimen demonstrates small atelectatic lungs with focal hemorrhage (arrow) visible on the pleural surface.

Advances in Clinical Management of RDS
Despite the increased rate of preterm delivery in the United States, recent advances in perinatal medical management have decreased the incidence and severity of RDS. Clinical innovations that have substantially modified the natural history of RDS include antenatal corticosteroid administration, surfactant replacement therapy, and increasingly sophisticated use of assisted ventilation in the delivery room and intensive care nursery (6).

Corticosteroid treatment of pregnant women at risk of premature delivery was introduced in 1972 to enhance structural and biochemical lung maturity in neonates (25). Randomized controlled trials have shown that antenatal corticosteroid administration reduces the incidence of RDS in infants born at 29–34 weeks gestation, but the trial results have not confirmed a definite benefit in infants born at 24–28 weeks gestation (21). However, a large randomized trial of pregnant patients with intact membranes at 24–28 weeks gestation showed a significant reduction in the incidence of high-grade neonatal intracranial hemorrhage (26), and meta-analysis suggests significant benefit of antenatal corticosteroids for reducing the incidence of RDS, intracranial hemorrhage, necrotizing enterocolitis, and neonatal mortality (27). The National Institutes of Health consensus conference statements on antenatal corticosteroid use recommend that all pregnant women should be considered eligible for a single course of corticosteroids during 24–34 weeks gestation (21,28,29). Although the effect of prenatal glucocorticoid administration on RDS in pregnancies less than 24 weeks gestation remains unclear, a course of antenatal steroids is deemed reasonable (30).

After delivery, administration of exogenous surfactant synergizes with antenatal corticosteroid therapy to improve oxygenation, decrease the need for mechanical ventilation, and reduce mortality in neonates with respiratory failure from RDS (31). The efficacy and safety of surfactant replacement therapy have been established in multiple randomized controlled clinical trials (32–47). Surfactant is delivered into the tracheobronchial tree as a liquid bolus through an endotracheal tube. During administration, the infant is turned from side to side to facilitate uniform acinar distribution of surfactant throughout both lungs. Nebulized surfactant delivery, which would eliminate the reliance on tracheal intubation, is under investigation but has not yet been proved effective and is not commercially available (48).

Four surfactant preparations have currently been approved by the U.S. Food and Drug Administration: Exosurf Neonatal (colfosceril palmitate; Glaxo Wellcome, Research Triangle Park, NC), a synthetic formulation; Survanta (beractant; Ross Products Division, Abbott Laboratories, Columbus, Ohio) and Infasurf (calfactant; Forest Laboratories, New York, NY), natural surfactants composed of modified bovine lung extract; and Curosurf (poractant alfa; Chiesi Farmaceutici, Parma, Italy), a porcine-derived minced lung extract. Both modified natural and synthetic surfactant formulations are effective in the treatment and prevention of RDS. However, a meta-analysis of comparative trials indicates that use of natural surfactant results in greater early improvement in the requirement for ventilator support, less frequent pneumothorax, decreased mortality, and a marginal decrease in the risk of chronic lung disease associated with treatment of RDS (49).

Two treatment strategies for surfactant delivery have emerged. In prophylactic treatment, surfactant is administered immediately in the delivery room or very soon thereafter in an effort to prevent RDS in preterm neonates. In rescue (selective) treatment, surfactant is given after the diagnosis of RDS has been established clinically and radiographically. In a comparison of prophylactic surfactant delivery and rescue therapy for confirmed RDS, data analysis of clinical outcomes in eight studies was recently performed in accordance with the standards of the Cochrane Neonatal Review Group (50). The reviewers concluded that, when compared with selective treatment of established RDS, prophylactic surfactant administration to neonates considered at risk for developing RDS (preterm infants less than 30–32 weeks gestation) was associated with a decreased risk of pneumothorax, less frequent interstitial air leak, and decreased mortality. However, the precise criteria by which an infant should be judged "at risk" for developing RDS and thus selected for prophylactic surfactant administration remain unclear. Currently, neonatologists often use their own center’s demographics to make this decision. Because early treatment is more effective, infants not given surfactant prophylactically can be immediately treated if signs of respiratory distress develop.

Before the advent of surfactant replacement therapy, mechanical ventilation was the primary intervention to combat the physiologic consequences of surfactant deficiency in infants with RDS. Positive-pressure ventilation distends collapsed acini while delivering air with high oxygen content (51). However, mechanical ventilation is associated with untoward cardiovascular and pulmonary consequences, including diminished cardiac output, decreased systemic venous return, compromised pulmonary blood flow, air leak complications, and chronic lung disease (52). Current treatment protocols advocate use of ventilatory assistance according to the severity of the lung disease, thus optimizing tissue oxygenation and carbon dioxide removal while minimizing cardiovascular depression, overdistention of small airways, and oxygen toxicity. Neonates with mild RDS often are treated with early nasal continuous positive airway pressure (CPAP). If needed, surfactant can be given and extubation performed very soon thereafter. Thus for some infants, tracheal intubation may be brief or avoided altogether (52,53).

Strategies of mechanical ventilation used today attempt to minimize lung injury by avoiding both atelectasis and overdistention, as well as by optimizing blood gas tensions to avoid hypocarbia and oxygen toxicity. Modern conventional infant ventilators synchronize the mechanical breaths with the infant’s own respiratory effort. Lung injury can be minimized by careful attention to appropriate tidal volumes and adequate end expiratory pressure (54). High-frequency oscillatory ventilation (HFOV) is an alternative to conventional ventilation. The HFOV apparatus delivers small tidal volumes often equal to or less than the infant’s dead space. These volumes are generated by a piston or diaphragm that moves rapidly back and forth, providing both an active inspiratory and expiratory phase and facilitating carbon dioxide removal. Frequencies commonly used in infants are 8–12 Hz. The oscillations are superimposed on a constant mean airway pressure chosen to optimally recruit and oxygenate the lung. Adequate gas exchange thus may occur at substantially lower peak inspiratory pressures than required with conventional mechanical ventilation. Recently, a large, randomized, multicenter clinical trial was conducted in the United States in very low-birth-weight infants with RDS who still required substantial ventilator support after receiving surfactant. Infants were assigned to either early HFOV or conventional synchronized mechanical ventilation. The investigators found a small but significant improvement in pulmonary outcome in the infants managed with HFOV, with no difference between the groups with regard to extrapulmonary complications of prematurity (55). Other investigators, who used somewhat different protocols and HFOV equipment, have found no difference in pulmonary outcome (56).

Surfactant replacement therapy and mechanical ventilation are not universally effective in premature infants with RDS, possibly because of uneven surfactant distribution or concurrent sepsis, acidosis, or patent ductus arteriosus. Extracorporeal membrane oxygenation (ECMO), a form of cardiopulmonary bypass, is reserved for treating reversible respiratory failure refractory to conventional ventilatory measures (57). However, because ECMO requires anticoagulation and because premature infants are at increased risk for intracranial hemorrhage, many treatment centers restrict use of ECMO to newborns of at least 34 weeks gestational age. Because ECMO requires large cannula sizes, the procedure cannot be performed in most infants weighing less than 2000 g.

Radiologic Features
The radiographic findings in untreated RDS predictably reflect the generalized acinar collapse that results from surfactant deficiency. Thus, chest radiography demonstrates decreased lung expansion, symmetric generalized consolidation of variable severity, effacement of normal pulmonary vessels, and air bronchograms. The familiar "reticulogranular" texture of the lung opacities in RDS represents the summation of collapsed alveoli, transudation of fluid into the interstitium from capillary leak, and distention by air of innumerable bronchioles that remain more compliant than surfactant-deficient lung (Fig 11) (58). These radiographic findings are usually present shortly after birth but occasionally do not reach maximum severity until 12–24 hours of life (22). In severe cases of RDS, dense bilateral symmetric lung consolidation (so-called white out) may completely efface the cardiomediastinal and diaphragm contours. Before the widespread use of exogenous surfactant therapy, the chest radiographs of infants with RDS who required only short-term assisted ventilation typically demonstrated granularity that evolved to generalized hazy opacities to clearing over several days to 2–3 weeks (22).

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   Figure 11.  Mild RDS. Magnified radiograph of the right lung of a preterm neonate shows effacement of vascular definition by diffuse reticulogranular opacities. Peripheral air bronchograms (arrows) are visible at the medial lung base. The minor fissure (arrowheads) is slightly thickened.

Several explanations have been proposed for asymmetric radiographic improvement following surfactant therapy (65): (a) maldistribution of surfactant into the right mainstem bronchus, (b) insufficient surfactant requiring additional applications, and (c) regional differences in aeration before surfactant treatment.

"Classic" chest radiographic findings (Fig 12) are less commonly observed in neonates with RDS since surfactant replacement therapy became ubiquitous. Emerging radiographic patterns associated with surfactant administration may complicate image interpretation, particularly when surfactant has been administered before baseline imaging. Asymmetric multifocal areas of opacity may be mistaken for neonatal pneumonia or meconium aspiration syndrome (Fig 13). Localized overaeration of selective acinar populations may produce cystic lucencies that mimic interstitial air leak (22). Asymmetric unilateral improvement in RDS, typically resulting in a hyperlucent right lung with contralateral mediastinal shift, may nominally resemble a tension pneumothorax (Fig 14). Finally, pulmonary hemorrhage, a rare complication following surfactant treatment, is typically heralded by acute respiratory decompensation that occurs after initial clinical improvement and produces sudden dense airspace consolidation on radiographs (Fig 15). Although the precise mechanism of pulmonary hemorrhage following surfactant therapy remains unclear, it has been suggested that improved ventilation and decreased pulmonary vascular resistance following surfactant administration promotes left-to-right shunting through the ductus arteriosus, producing hemorrhagic pulmonary edema (67).

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 12a.  Symmetric surfactant effect in a 36-week-gestationalage infant of a diabetic mother. (a) Pretreatment radiograph shows diminished lung expansion, diffuse bilateral reticulogranular opacities, and air bronchograms, findings consistent with severe RDS. (b) Repeat radiograph, obtained 6 hours after endotracheal administration of one dose of surfactant, reveals marked improvement in lung aeration and vascular definition.

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   Figure 12b.  Symmetric surfactant effect in a 36-week-gestationalage infant of a diabetic mother. (a) Pretreatment radiograph shows diminished lung expansion, diffuse bilateral reticulogranular opacities, and air bronchograms, findings consistent with severe RDS. (b) Repeat radiograph, obtained 6 hours after endotracheal administration of one dose of surfactant, reveals marked improvement in lung aeration and vascular definition.

View larger version (166K): [in this window] [in a new window] [Download PPT slide]   Figure 13.  Asymmetric surfactant effect in a 2-day-old, 32-week-gestational age newborn with RDS. Frontal chest radiograph demonstrates multifocal residual consolidations that mimic pneumonia or meconium aspiration syndrome.

View larger version (159K): [in this window] [in a new window] [Download PPT slide]   Figure 14.  Asymmetric distribution of endotracheal surfactant into the right mainstem bronchus in a 1-day-old preterm neonate with RDS. Frontal radiograph of the chest shows a clear hyperexpanded right lung, shift of mediastinal structures to the left, and persistence of diffuse left lung opacification.

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 15a.  Pulmonary hemorrhage in a 26-week-gestationalage neonate following prophylactic surfactant therapy. (a) Frontal chest radiograph obtained after one dose of surfactant and during treatment with nasal CPAP shows hyperinflated lungs with faint symmetric residual opacities. (b) Repeat radiograph, obtained after 24 hours for evaluation of sudden respiratory decompensation and bloody endotracheal aspirates, shows dense bilateral airspace consolidation.

View larger version (156K): [in this window] [in a new window] [Download PPT slide]   Figure 15b.  Pulmonary hemorrhage in a 26-week-gestationalage neonate following prophylactic surfactant therapy. (a) Frontal chest radiograph obtained after one dose of surfactant and during treatment with nasal CPAP shows hyperinflated lungs with faint symmetric residual opacities. (b) Repeat radiograph, obtained after 24 hours for evaluation of sudden respiratory decompensation and bloody endotracheal aspirates, shows dense bilateral airspace consolidation.

Today, it is not uncommon to encounter profoundly premature newborns weighing substantially less than 1000 g, whose initial chest radiographs may appear normal or display only subtle haziness or interstitial thickening (Figs 16, 17) (22). Despite the absence of granular lung opacities typically associated with RDS, alveolar paucity in extremely low-birth-weight neonates often necessitates continued ventilator support, subjecting the lungs to the deleterious effects of high oxygen concentration and positive pressure. Over several days to weeks, the chest radiographs of these infants may evolve from normal or near-normal appearance to diffuse haziness to a coarse, irregular pattern of chronic lung disease (Fig 17) (22).

View larger version (159K): [in this window] [in a new window] [Download PPT slide]   Figure 16.  Immature lungs in a profoundly premature neonate delivered at a gestational age of 22 weeks and 6 days. Anteroposterior chest radiograph obtained on the first postnatal day shows diffuse fine interstitial thickening.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 17a.  Immature lungs in a 24-week-gestational-age neonate with a birth weight of 530 g. (a) Anteroposterior radiograph obtained on the second postnatal day shows clear lungs. (b) Repeat radiograph, obtained at 48 days, shows coarse parenchymal opacities with no regions of disordered aeration or cystic lucency, findings consistent with uniform fibrosis in "new" BPD.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 17b.  Immature lungs in a 24-week-gestational-age neonate with a birth weight of 530 g. (a) Anteroposterior radiograph obtained on the second postnatal day shows clear lungs. (b) Repeat radiograph, obtained at 48 days, shows coarse parenchymal opacities with no regions of disordered aeration or cystic lucency, findings consistent with uniform fibrosis in "new" BPD.

	Bronchopulmonary Dysplasia

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

Since its original description almost 4 decades ago, the epidemiology, clinical presentation, and radiologic features of BPD have changed substantially. In the original series published by North-way et al (71), surviving infants with BPD initially presented with severe RDS and had an average gestational age and birth weight of 34 weeks and 2235 g, respectively. Since the introduction of surfactant replacement therapy for RDS, antenatal glucocorticoid treatment, and refinements in assisted ventilation, BPD is now uncommon in larger and more mature infants with a gestational age exceeding 30 weeks or weighing more than 1200 g at birth (72). However, these clinical advances have also improved survival for extremely low-birth-weight infants (<1000 g), who often do not have radiographic evidence of RDS and whose lung injury is not necessarily initiated by oxygen delivery and mechanical ventilation (73).

Traditionally, the diagnosis of BPD was assigned to infants who received mechanical ventilation and oxygen delivery for a minimum of 3 days during the first 2 weeks of life, who exhibited clinical signs of respiratory compromise beyond 28 days, who required supplemental oxygen beyond 28 days of age to maintain a PaO₂ above 50 mm Hg, and who developed the characteristic radiographic abnormalities originally described by Northway (74,75). This restrictive definition has been applied in an effort to identify patients who will have significant pulmonary dysfunction during the first year of life (76).

The original criteria for the diagnosis of BPD have grown less reliable as increasingly immature infants have survived. Low-birth-weight infants may fulfill the diagnostic requirements for BPD at 28 days of life but no longer meet the criteria as they approach 40 weeks postmenstrual age (defined as gestational age at birth plus chronologic age) (76,77). In a retrospective study of 119 infants with birth weights less than 1500 g and with follow-up data available for 2 years after birth, Shennan and colleagues (78) found that the requirement for supplemental oxygen at 36 weeks postmenstrual age was a superior predictor of abnormal outcome. On the basis of this revised definition, approximately 30% of infants with birth weight less than 1000 g develop BPD (79). It has also been recognized that radiologic abnormalities in this subset of very immature infants who meet the proposed new clinical requirements for BPD are frequently dissimilar to those originally described by Northway (75). Consequently, the designation chronic lung disease of infancy has gained favor to describe the form of BPD encountered in very low-birth-weight infants (80).

A workshop organized by the National Institute of Heart Disease, the National Heart, Lung, and Blood Institute, and Office of Rare Diseases was recently convened to review the definition of BPD, propose new diagnostic criteria, and establish future research priorities (72). By consensus, the workshop participants elected to retain the term bronchopulmonary dysplasia as the best descriptor of the chronic lung disease peculiar to premature infants. A new definition of BPD (Table) was developed for infants with gestational age less than 32 weeks and greater than 32 weeks based on time of clinical assessment and clinical severity.

Alveolar septal fibrosis is the predominant residual feature in the condition known as longstanding healed BPD (84). In 1986, Stocker (84) recognized that the severity of alveolar septal fibrosis in long-standing healed BPD varied from acinus to acinus in the same patient. He postulated that intraluminal plugs of inflammatory debris related to acute necrotizing bronchiolitis in terminal airways protected some acinar populations from the untoward effects of high oxygen tensions and positive-pressure ventilation, while adjacent unprotected acini underwent uniform alveolar septal fibrosis (Fig 18). According to this theory, eventual removal of the occlusive plugs by alveolar macrophages produced alternating populations of hyperinflated but otherwise normal alveoli and scarred alveoli, leading to a "cobblestone" appearance of the lung surface and cleavage of the visceral pleura by multiple deep pseudofissures (Fig 19).

View larger version (56K): [in this window] [in a new window] [Download PPT slide]   Figure 18.  Proposed model for the pathogenesis of long-standing healed BPD. Schematic 1 represents three normal acini (a, b, c), each supplied by a terminal bronchiole. As shown in schematic 2, during positive-pressure ventilation and oxygen delivery for treatment of surfactant deficiency, hyaline membranes or occlusive debris from necrotizing bronchiolitis (arrow) "protects" acinus a from alveolar septal injury, whereas varying degrees of partial occlusion of the bronchioles to acini b and c permit alveolar septal necrosis from barotrauma-volutrauma and oxygen toxicity. Schematic 3 depicts the phase following resolution of bronchiolar obstruction, in which acinus a hyper-expands and continues to develop new alveoli, acinus b has undergone septal fibrosis and is inhibited from further alveolar development, and acinus c has atrophied. (Illustration by Aletta Ann Frazier, MD, Department of Radiologic Pathology, Armed Forces Institute of Pathology.) (Adapted, with permission, from reference 85.)

View larger version (152K): [in this window] [in a new window] [Download PPT slide]   Figure 19a.  Long-standing "healed" BPD, pathologic features. (a) Photomicrograph (original magnification, x30; H-E stain) demonstrates diffuse alveolar septal fibrosis within an acinus (bottom) adjacent to another acinus (top) with hyperexpanded but otherwise normal alveoli. (b) Photomicrograph (original magnification, x100; H-E stain) depicts a continuous band of hyperplastic smooth muscle (arrow) surrounding a bronchiole. (c) Photograph of the pleural surface of a lung at 1 month of age shows alternating populations of hyperexpanded and collapsed acini de-fined by irregular pseudofissures (arrows).

View larger version (189K): [in this window] [in a new window] [Download PPT slide]   Figure 19b.  Long-standing "healed" BPD, pathologic features. (a) Photomicrograph (original magnification, x30; H-E stain) demonstrates diffuse alveolar septal fibrosis within an acinus (bottom) adjacent to another acinus (top) with hyperexpanded but otherwise normal alveoli. (b) Photomicrograph (original magnification, x100; H-E stain) depicts a continuous band of hyperplastic smooth muscle (arrow) surrounding a bronchiole. (c) Photograph of the pleural surface of a lung at 1 month of age shows alternating populations of hyperexpanded and collapsed acini de-fined by irregular pseudofissures (arrows).

View larger version (103K): [in this window] [in a new window] [Download PPT slide]   Figure 19c.  Long-standing "healed" BPD, pathologic features. (a) Photomicrograph (original magnification, x30; H-E stain) demonstrates diffuse alveolar septal fibrosis within an acinus (bottom) adjacent to another acinus (top) with hyperexpanded but otherwise normal alveoli. (b) Photomicrograph (original magnification, x100; H-E stain) depicts a continuous band of hyperplastic smooth muscle (arrow) surrounding a bronchiole. (c) Photograph of the pleural surface of a lung at 1 month of age shows alternating populations of hyperexpanded and collapsed acini de-fined by irregular pseudofissures (arrows).

Perinatal factors that influence lung maturation likely play an important role in the pathogenesis of BPD in the era of surfactant therapy. Exposure to chronic low-grade chorioamnionitis, a common clinical problem associated with preterm delivery, is known to increase the risk of lung injury (86). In particular, the genital mycoplasma Ureaplasma urealyticum, the most common contaminant of amniotic fluid, has been associated with the development of BPD (87–89). In this clinical setting, antenatal exposure to proinflammatory cytokines in amniotic fluid may prime the lung for postnatal injury, which is subsequently amplified by even gentle mechanical ventilation and oxygen exposure (9). In 1999, Jobe (9) coined the term new BPD to distinguish the emerging type of chronic lung injury in very immature infants from the condition originally described by Northway. In 2003, Hodgman (90) suggested that the "new" BPD and the condition originally described in 1960 by Wilson and Mikity (70) are the same entity, each attributable to an aberrant response of the immature lung to early air breathing rather than damage from barotrauma and oxygen toxicity. Although its pathogenesis is multifactorial and incompletely understood, accumulating evidence strongly suggests that the new BPD is fundamentally an inhibition of acinar and vascular growth during a vulnerable stage of lung development (Fig 20) (9).

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   Figure 20.  New BPD in very low-birth-weight infants. (Reprinted, with permission, from reference 9.)

View larger version (55K): [in this window] [in a new window] [Download PPT slide]   Figure 21.  Arrested acinar development in post-surfactant BPD. Schematics of a trio of acini show oversimplified anatomy due to alveolar paucity with either thin alveolar septa (center) or uniform mild fibrosis (right), compared with normal alveolar growth and development (left). (Illustration by Aletta Ann Frazier, MD, Department of Radiologic Pathology, Armed Forces Institute of Pathology.) (Adapted, with permission, from reference 85.)

View larger version (205K): [in this window] [in a new window] [Download PPT slide]   Figure 22.  BPD in a surfactant-treated infant. Photomicrograph (original magnification, x50; H-E stain) shows expanded, simplified alveolar ducts, saccules, and alveoli with little or no alveolar septal fibrosis.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 23a.  "Classic" severe BPD in a 3-month-old premature infant. (a) Frontal radiograph shows heterogeneous aeration, coarse strandlike areas of opacity, and intervening cystic lucencies. (b) Axial CT scan demonstrates right upper lobe regional air trapping anteriorly, architectural distortion with fibrotic subpleural parenchymal bands (arrows) and subsegmental atelectasis posteriorly, and diffuse coarse reticular opacities in the left lung.

View larger version (175K): [in this window] [in a new window] [Download PPT slide]   Figure 23b.  "Classic" severe BPD in a 3-month-old premature infant. (a) Frontal radiograph shows heterogeneous aeration, coarse strandlike areas of opacity, and intervening cystic lucencies. (b) Axial CT scan demonstrates right upper lobe regional air trapping anteriorly, architectural distortion with fibrotic subpleural parenchymal bands (arrows) and subsegmental atelectasis posteriorly, and diffuse coarse reticular opacities in the left lung.

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Figure 24.  BPD in a 33-day-old preterm infant. Frontal chest radiograph demonstrates uniform distribution of reticular opacities and small cystic lucencies.

In those infants who do develop the bubbly lungs characteristic of severe BPD, chest radiographs may show severely disordered lung aeration manifesting as a heterogeneous pattern of opaque strands, cystic lucencies of varying size, and regional air trapping (Fig 23). Chest CT demonstrates these alterations with greater sensitivity than radiography, particularly in older survivors of BPD, and may demonstrate regional air trapping; reticular and linear areas of opacity representing thickened interlobular septa, subsegmental atelectasis, and fibrosis; segmental or lobar atelectasis; vascular attenuation with reduced bronchoarterial diameter ratios; bronchial wall thickening without bronchiectasis; and bullae or pneumatoceles (100–103). The linear areas of opacity with a triangular pleural base seen on CT scans (Fig 23) have been attributed to the pseudofissures found in gross lung specimens of patients with severe BPD (Fig 19 ) (102).

Treatment
In many infants, BPD results in substantial long-term morbidity, including increased airway reactivity, development of obstructive airway disease, poor growth, and an increased frequency of re-hospitalization (104). Some lung function abnormalities may persist until adulthood (105). In very severe cases, death may result from progressive respiratory failure, cor pumonale, or superimposed infection.

There are currently few effective treatment options for BPD. Administration of postnatal corticosteroids, especially dexamethasone, has been associated with several short-term benefits, including decreased frequency of BPD and decreased duration of mechanical ventilation (104). However, recent data suggest that use of postnatal corticosteroids may lead to neurodevelopmental impairment and cerebral palsy (106). Because of these concerns, the American Academy of Pediatrics and the Canadian Pediatric Society recommend use of postnatal corticosteroids only in severe cases or as part of a clinical trial (107). Although there may be a place for use of postnatal corticosteroids in the prevention and treatment of BPD, the optimal dosage, formulation, timing, and method of administration have yet to be determined.

Other treatments such as bronchodilator therapy and diuretics have had some success in improving pulmonary function (104,108). No therapy to date has been shown to improve long-term outcome or decrease mortality. Newer treatment options such as inhaled nitric oxide may provide some benefit, but they have yet to be fully evaluated (109). Currently, treatment is supportive and includes optimizing nutrition, prevention of injurious mechanical ventilation, judicious use of oxygen, and timely treatment of superimposed infections.

	Air Leak Phenomena

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 
Mechanical ventilation is an important risk factor contributing to air leak in premature infants treated for lung disease. Once attributed to high airway pressure alone (barotrauma), recent work has established that airway overdistention (volutrauma) produces this type of lung injury (110). Rupture at bronchioloalveolar junctions permits passage of gas into the perivascular and peribronchial spaces, a condition that has been termed pulmonary interstitial emphysema (PIE) (7). Although this nomenclature is retained in this article, PIE should be distinguished from the formal pathologic definition of emphysema, which is characterized by permanent expansion of airspaces distal to the terminal bronchiole, alveolar septal destruction, and an absence of fibrosis.

Once PIE is established, gas may dissect centrifugally along bronchovascular sheaths or lymphatic channels to form subpleural blebs, which may rupture into the pleural space and produce pneumothorax (Fig 25). Centripetal migration of interstitial gas may produce pneumomediastinum (Fig 26) or pneumopericardium. In rare cases, systemic air embolism occurs during mechanical ventilation in neonates with RDS. The pathogenesis of this almost universally fatal disorder is controversial (110,111). Theories include the formation of alveolar to vascular fistulae in the setting of PIE and passage of lymphatic gas into the right side of the heart.

View larger version (123K): [in this window] [in a new window] [Download PPT slide]   Figure 25a.  Acute PIE. (a) Photograph of a sectioned lung specimen shows linear (arrow) and irregular (arrowhead) collections of interstitial gas adjacent to compressed bronchovascular bundles. (Reprinted, with permission, from reference 6.) (b) Cut specimen shows that following centrifugal migration of interstitial gas, subpleural blebs (arrow) collect within interlobular septa.

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   Figure 25b.  Acute PIE. (a) Photograph of a sectioned lung specimen shows linear (arrow) and irregular (arrowhead) collections of interstitial gas adjacent to compressed bronchovascular bundles. (Reprinted, with permission, from reference 6.) (b) Cut specimen shows that following centrifugal migration of interstitial gas, subpleural blebs (arrow) collect within interlobular septa.

View larger version (123K): [in this window] [in a new window] [Download PPT slide]   Figure 26.  Pneumomediastinum, gross pathologic features. Photograph of an autopsy specimen with the lungs removed shows multiple collections of gas (arrow) within loose mediastinal connective tissue.

View larger version (154K): [in this window] [in a new window] [Download PPT slide]   Figure 27.  Unilateral acute PIE in a premature infant who underwent positive-pressure ventilation for RDS. Frontal radiograph shows a profusion of irregular cystic lucencies within the left lung. Granular consolidation of the right lung is consistent with uncomplicated RDS.

View larger version (176K): [in this window] [in a new window] [Download PPT slide]   Figure 28.  "Pseudocyst" in a premature infant who underwent mechanical ventilation. Frontal chest radiograph shows a large, rounded, right juxtahilar gas collection with a smooth thin wall (arrowheads).

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 29a.  Persistent PIE, pathologic features. (a) High-power photomicrograph (original magnification, x300; H-E stain) shows a cyst wall (arrowheads) composed of fibrotic connective tissue lined by multinucleated foreign body giant cells (arrow). (Reprinted, with permission, from reference 6.) (b) Photograph of the sectioned surgical specimen shows the lung parenchyma compressed by multiple intercommunicating air-filled cysts delimited by smooth membranes.

View larger version (95K): [in this window] [in a new window] [Download PPT slide]   Figure 29b.  Persistent PIE, pathologic features. (a) High-power photomicrograph (original magnification, x300; H-E stain) shows a cyst wall (arrowheads) composed of fibrotic connective tissue lined by multinucleated foreign body giant cells (arrow). (Reprinted, with permission, from reference 6.) (b) Photograph of the sectioned surgical specimen shows the lung parenchyma compressed by multiple intercommunicating air-filled cysts delimited by smooth membranes.

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figure 30a.  Diffuse persistent PIE in a 3-week-old girl with a history of positive-pressure mechanical ventilation. (a) Frontal chest radiograph shows overexpansion of most of the left lung by multiple cystic lucencies, producing contralateral mediastinal displacement and left retrocardiac compressive atelectasis. (b) Axial CT scan shows multiple collections of interstitial gas in the left upper lobe that surround lines (arrows) and dots (arrowheads) of soft-tissue attenuation. (c) Photograph of the resected left upper lobe shows the surface of the lung blistered by multiple subpleural cysts (arrows).

View larger version (111K): [in this window] [in a new window] [Download PPT slide]   Figure 30b.  Diffuse persistent PIE in a 3-week-old girl with a history of positive-pressure mechanical ventilation. (a) Frontal chest radiograph shows overexpansion of most of the left lung by multiple cystic lucencies, producing contralateral mediastinal displacement and left retrocardiac compressive atelectasis. (b) Axial CT scan shows multiple collections of interstitial gas in the left upper lobe that surround lines (arrows) and dots (arrowheads) of soft-tissue attenuation. (c) Photograph of the resected left upper lobe shows the surface of the lung blistered by multiple subpleural cysts (arrows).

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   Figure 30c.  Diffuse persistent PIE in a 3-week-old girl with a history of positive-pressure mechanical ventilation. (a) Frontal chest radiograph shows overexpansion of most of the left lung by multiple cystic lucencies, producing contralateral mediastinal displacement and left retrocardiac compressive atelectasis. (b) Axial CT scan shows multiple collections of interstitial gas in the left upper lobe that surround lines (arrows) and dots (arrowheads) of soft-tissue attenuation. (c) Photograph of the resected left upper lobe shows the surface of the lung blistered by multiple subpleural cysts (arrows).

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 31a.  Localized persistent PIE in a 1-year-old boy delivered at 27 weeks gestational age. (a) Frontal chest radiograph shows a circumscribed lucent lesion at the medial right lung base with a smooth, lobulated, thin wall (arrows). (b) Axial CT scan shows an aggregate of thin-walled, gas-containing cysts in the right lower lobe that contains lines (arrows) and dots (arrowheads) of soft-tissue attenuation. (c) Photograph of the cut surface of the resected specimen shows a broncho-vascular bundle (arrows) surrounded by gas within a multiloculated cystic mass.

View larger version (136K): [in this window] [in a new window] [Download PPT slide]   Figure 31b.  Localized persistent PIE in a 1-year-old boy delivered at 27 weeks gestational age. (a) Frontal chest radiograph shows a circumscribed lucent lesion at the medial right lung base with a smooth, lobulated, thin wall (arrows). (b) Axial CT scan shows an aggregate of thin-walled, gas-containing cysts in the right lower lobe that contains lines (arrows) and dots (arrowheads) of soft-tissue attenuation. (c) Photograph of the cut surface of the resected specimen shows a broncho-vascular bundle (arrows) surrounded by gas within a multiloculated cystic mass.

View larger version (123K): [in this window] [in a new window] [Download PPT slide]   Figure 31c.  Localized persistent PIE in a 1-year-old boy delivered at 27 weeks gestational age. (a) Frontal chest radiograph shows a circumscribed lucent lesion at the medial right lung base with a smooth, lobulated, thin wall (arrows). (b) Axial CT scan shows an aggregate of thin-walled, gas-containing cysts in the right lower lobe that contains lines (arrows) and dots (arrowheads) of soft-tissue attenuation. (c) Photograph of the cut surface of the resected specimen shows a broncho-vascular bundle (arrows) surrounded by gas within a multiloculated cystic mass.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 32a.  Bilateral pneumothoraces. (a) Anteroposterior chest radiograph shows juxtamediastinal lucencies and bisagittal compression of the lobes of the thymus (arrows), producing a "figure 8" configuration contour. A "deep sulcus sign" (arrowhead) is seen in the right lung. (b) On a radiograph obtained after spontaneous resolution of air leak, the mediastinal contour appears normal.

View larger version (183K): [in this window] [in a new window] [Download PPT slide]   Figure 32b.  Bilateral pneumothoraces. (a) Anteroposterior chest radiograph shows juxtamediastinal lucencies and bisagittal compression of the lobes of the thymus (arrows), producing a "figure 8" configuration contour. A "deep sulcus sign" (arrowhead) is seen in the right lung. (b) On a radiograph obtained after spontaneous resolution of air leak, the mediastinal contour appears normal.

View larger version (165K): [in this window] [in a new window] [Download PPT slide]   Figure 33.  Bilateral pneumothoraces. Frontal chest radiograph obtained with the infant rotated toward the right reveals the anterior junction line (arrowheads) outlined by pleural gas. Both diaphragm leaflets and the right aspect of the cardiothymic silhouette are abnormally well defined.

View larger version (154K): [in this window] [in a new window] [Download PPT slide]   Figure 34.  Pneumomediastinum. Frontal chest radiograph shows the lobes of the thymus (arrows), which are displaced superolaterally by a large central lucent area.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 35.  Extensive air leak in a premature neonate who received positive-pressure assisted ventilation for treatment of RDS. Frontal chest radiograph demonstrates a thin pericardial membrane (straight white arrows), which is defined medially by intrapericardial gas and laterally by pleural or mediastinal gas. Extrapleural gas outlines the medial aspect of the left diaphragm (black arrows). Bilateral pneumothoraces produce deep sulcus signs (curved arrows). Mediastinal gas tracks into the cervical soft tissues and right lateral chest wall (arrowheads). The tip of the endotracheal tube enters the right mainstem bronchus.

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   Figure 36.  Systemic air embolism in the setting of diffuse bilateral PIE. Frontal radiograph of the chest and abdomen shows elevation and compression of the base of the heart (white arrowheads) by tension pneumopericardium. The cardiac chambers are filled with gas, and intraluminal gas is demonstrated in the inferior vena cava (straight arrow), hepatic veins (black arrowhead), and abdominal aorta surrounding the tip of the umbilical artery catheter (curved arrow). Both lungs are overexpanded by innumerable cystic lucencies representing PIE. (Courtesy of Gael J. Lonergan, MD, Austin Radiological Association, Austin, Tex.)

	Conclusions

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 
Advances in perinatal medicine and neonatology have altered the natural history of lung disease in premature neonates, while introducing a new era of radiologic complexity. Radiologists may face new or perplexing expressions of once-predictable disease processes. Proper interpretation of chest radiographs in preterm neonates with structural and physiologic pulmonary immaturity requires an appreciation of the surfactant effect, an understanding of the impact of increasingly sophisticated ventilation strategies, and familiarity with evolving patterns of chronic lung disease.

	Footnotes

 

Abbreviations: BPD = bronchopulmonary dysplasia, CPAP = continuous positive airway pressure, H-E = hematoxylineosin, HFOV = high-frequency oscillatory ventilation, PIE = pulmonary interstitial emphysema, RDS = respiratory distress syndrome

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official nor as reflecting the views of the Departments of the Army or Defense.

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Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Normal Lung Development Neonatal Respiratory Distress... Bronchopulmonary Dysplasia Air Leak Phenomena Conclusions References

 

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