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Abstract
Childhood interstitial lung disease (chILD) consists of a large, heterogeneous group of individually rare disorders. chILD demonstrates major differences in disease etiology, natural history, and management when compared with the adult group. It occurs primarily secondary to an underlying developmental or genetic abnormality affecting the growth and maturity of the pediatric lung. They present with different clinical, radiologic, and pathologic features. In this pictorial review article, we will divide chILD into those more prevalent in infancy and those not specific to infancy. We will use a case based approach to discuss relevant imaging findings including modalities such as radiograph and computed tomography in a wide variety of pathologies.
Keywords: Alveolar capillary dysplasia, childhood interstitial lung disease, chronic lung disease of prematurity, congenital surfactant deficiency disorders
Childhood interstitial lung disease (chILD) consists of a large, heterogeneous group of individually rare disorders. The reported prevalence ranges from 0.13 cases/100,000 children younger than 17 years to 16.2 cases/100,000 children younger than 15 years.[1],[2],[3] ChILD demonstrates major differences in disease etiology, natural history, and management when compared with the adult group. ChILD occurs primarily secondary to an underlying developmental or genetic abnormality affecting the growth and maturity of the pediatric lung.[4] Therefore, a separate classification for chILD has been developed and updated most recently in 2013 by the chILD Research Network and recommended in the official American Thoracic Society clinical practice guideline on classification, evaluation, and management of chILD in infancy.[5]
In accordance with the “Image Gently” campaign launched by the Society for Pediatric Radiology, pediatric chest computed tomography (CT) examinations at our institution are performed with a low-dose protocol employing lower kVp, and automatic mA modulation with 1 mm × 1 mm lung algorithm reconstruction. In the appropriate patient population and indications, high-resolution chest CT including inspiratory and expiratory phases are obtained.
In this pictorial review article, we will divide chILD into those more prevalent in infancy and those not specific to infancy. We will use a case-based approach to discuss relevant imaging findings including modalities such as radiograph and CT in a wide variety of pathologies that are encountered but are rare.
Childhood Interstitial Lung Disease Entities More Prevalent in Infancy 
Alveolar capillary dysplasia
Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD-MPV) is a diffuse development disorder characterized by deficient alveolar capillaries, prominent right-to-left intrapulmonary vascular shunt, malpositioning of the pulmonary veins adjacent to the pulmonary arteries within the bronchovascular bundles, pulmonary lymphangiectasia, as well as muscular hypertrophy of the intralobular pulmonary arterioles, and resultant maldevelopment of the pulmonary lobules.[6] In addition, ACD-MPV is often associated with cardiovascular, gastrointestinal, or genitourinary system anomalies.[7] Genetic mutations and deletions within the Forkhead box transcription factor gene cluster on 16q24.1 have been reported in up to 40% of infants with ACD-MPV.[8],[9] Imaging features include progressive ground-glass opacification, with occasional pneumothorax or pneumomediastinum secondary to air leaks. Interlobular septal thickening and peribronchovascular thickening can be seen in associated lymphangiectasia [Figure 1].[1],[10] Diagnosis requires biopsy and genetic testing. It is near universally fatal secondary to progressive respiratory failure if lung transplantation is not performed in time.[11]
Figure 1: A 15-day-old term infant with respiratory distress, pathologically proven to have alveolar capillary dysplasia by bronchoscopy and tissue sample. (a) Chest radiograph shows a background of diffuse granular opacifications with peribronchial wall thickening (black arrows). (b) Axial chest computed tomography image better demonstrates diffuse ground-glass opacifications with peribronchial wall thickening (arrowhead)Pulmonary hypoplasia
Pulmonary hypoplasia is one of the alveolar growth abnormalities in which the bronchus and rudimentary lungs are present, while small airways, alveoli, and pulmonary vessels are decreased in size and number. It can be a primary phenomenon with intrinsic abnormal lung development, which is rare. Secondary pulmonary hypoplasia is much more common with compromised lung development due to intrauterine limitations on the thoracic space.[10] The most common cause of secondary pulmonary hypoplasia is congenital diaphragmatic hernia with abdominal organs occupying the thoracic space[1][Figure 2]. Additional causes of secondary pulmonary hypoplasia include severe oligohydramnios (secondary to cystic renal dysplasia, prolonged rupture of membranes, or other genitourinary and placental abnormalities) and thoracic skeletal dysplasia (such as thanatophoric dysplasia and Jeune syndrome)[12][Figure 3] and [Figure 4]. Imaging features include low lung volumes, without evidence of ground-glass opacities or cysts. In addition, the associated causes of secondary pulmonary hypoplasia usually can be found.[13]
Figure 2: (a) Axial T2 image from fetal magnetic resonance imaging demonstrates a hypoplastic right lung (white crescent outline) in the setting of a right congenital diaphragmatic hernia. (b) Coronal T2 Image from fetal magnetic resonance imaging in a different patient shows a left congenital diaphragmatic hernia with a hypoplastic left lung (white arrows)
Figure 3: A 2-day-old male infant with cystic renal dysplasia presents with shortness of breath. (a) Chest radiograph shows hypoplastic lungs and a bell-shaped thorax (black outline). (b) Ultrasound of the right kidney in the sagittal view shows increased cortical echogenicity with multiple cortical and parenchyma cysts (white arrows). The left kidney is similar in appearance (not shown). (c) Axial chest computed tomography image shows disordered lung growth and reduced chest circumference (black bracket)
Figure 4: Chest radiograph of a 12-year-old male with Jeune Syndrome shows short rib dysplasia, bell-shaped narrow chest and hypoplastic lungs (black arrows), irregular costochondral junctions (black stars), and handlebar clavicles (black lines)Chronic lung disease of prematurity
Chronic lung disease of prematurity is classically described in premature infants exposed to prolonged high-pressure mechanical ventilation and high concentrations of oxygen, resulting in airway smooth muscle hypertrophy, epithelial squamous metaplasia, peribronchial fibrosis, and hypertensive vascular changes.[14] Imaging findings include impaired lung aeration, bronchial wall thickening, coarse reticular pulmonary opacities, and cystic lucencies, with a combination of alveolar septal fibrosis, atelectasis, and hyperinflated lung, resulting in variable lung volumes.[15],[16] Oftentimes chest radiographs are sufficient to make the diagnosis [Figure 5]. However, CT is a better modality to better characterize the disease, assess for complications, and perform preoperative/pretransplant assessment[17][Figure 6].
Figure 5: Chest radiograph of a 150-day-old female infant born at 32 weeks' gestation shows interstitial coarse thickening (black arrows), overinflation (black arrowheads), and bands of atelectasis (dashed black arrows), compatible with fibrosis in the setting of chronic lung disease of prematurity
Figure 6: (a) Axial chest computed tomography image of a 5-month-old female infant born at 26 weeks' gestation shows diffuse ground-glass opacification with focal areas of air trapping (black arrows) and segmental atelectasis/scarring (white arrows). (b) Axial chest computed tomography image of a 3-year-old male born at 24 weeks' gestation shows subpleural reticulation (dashed black arrows) and scattered air trappingThere is a “new” type of chronic lung disease of prematurity seen in extremely premature (24–26 weeks gestation) infants given the improved ventilatory technique and survival.[18] These patients will have received prenatal corticosteroids and have been ventilated for shorter periods with new ventilator settings,[13] resulting in milder imaging abnormalities with less airway and vascular disease, and less fibrosis [Figure 7]. Histologically, this is seen as arrested lung development corresponding to the gestation of the infant at delivery.[19]
Figure 7: Chest radiograph of a 25-day-old female infant born at 25 weeks' gestation demonstrates scattered areas of atelectasis (white stars) compatible with the “new” type of chronic lung disease of prematurity with milder presentationTrisomy 21-related interstitial lung disease
Trisomy 21 (Down syndrome) is one of the lung growth disorders associated with chromosomal abnormalities. These patients were found to have decreased alveolar number and smaller alveolar surface area, as well as small peripheral subpleural cysts. On imaging, these cysts measure 1–2 mm in size and are subpleural along the lung periphery, fissures, and bronchovascular bundles[20],[21][Figure 8]. They have been reported to involve the anteromedial portion of the lungs.[20] Histologically, these cysts are enlarged subpleural airspaces in continuity with the proximal airways.[22] The etiology is unknown but thought to be related to pulmonary hypoplasia with Down syndrome.[23]
Figure 8: Two axial chest computed tomography images (a and b) in a 10-month-old male with trisomy 21 show extensive subpleural cysts (black arrows) peripherally and along the fissures and bronchovascular bundlesCongenital surfactant deficiency disorders
Surfactant deficiency disorders are caused by mutations in several genes, including genes for surfactant protein B, surfactant protein C, adenosine triphosphate–binding cassette transporter protein A3, thyroid transcription factor 1, and colony-stimulating factor 2 receptor (CSF2RA or CSF2RB).[5],[24] Histologically, these genetic surfactant deficiency disorders are similar irrespective of the gene involved. Typical features include type 2 pneumocyte hyperplasia and varying degrees of intra-alveolar macrophages, proteinosis, or lipoproteinosis. On imaging, these patients present with low lung volumes and diffuse ground-glass opacities. Additional findings include cysts, and interlobular septal thickening with a crazy-paving pattern. Associated pectus excavatum has also been reported, which is hypothesized to be the sequelae of chronic restrictive lung disease in the developing chest wall [Figure 9], [Figure 10], [Figure 11].
Figure 9: Chest radiograph of a term infant presenting with respiratory distress shows diffuse hazy airspace opacities (black arrows) and a pneumatocele (white outline). The patient was suspected to have a surfactant deficiency disorder and found to have adenosine triphosphate–binding cassette transporter protein A3 mutation
Figure 10: Serial axial computed tomography images through the mid lungs over a span of 7 years in a male with adenosine triphosphate–binding cassette transporter protein A3 mutation. a showed extensive ground glass opacities on the initial scan (black arrows). b performed two years later showed slightly improving ground glass opacities in the right lung (black arrows). c performed 5 years later showed continued improving ground glass opacity(black arrow). d performed 7 years later showed persistent air trapping and mosaic attenuation (black outline).
Figure 11: (a) Chest radiograph on day of life # 2 in a term infant experiencing desaturations shows nonspecific diffuse ground glass opacities. (b) Axial chest computed tomography image on day of life #9 demonstrates diffuse ground glass opacification (black outline). (c) Axial chest computed tomography image on day of life #270 shows bibasilar atelectasis and scarring (black arrows). This patient was found to have colony-stimulating factor 2 receptor B mutation Childhood Interstitial Lung Disease Entities Not Specific to Infancy Noonan-related pulmonary lymphangiectasia
Noonan syndrome is an autosomal dominant congenital disease characterized by RASopathy (Ras/mitogen-activated protein kinase) mutation. It has similar clinical features to Turner syndrome.[25] Various abnormalities of the lymphatic system have been reported in patients with Noonan syndrome including intestinal lymphangiectasis, lymphedema, and pulmonary lymphangiectasia.[26],[27] It is caused by dilation and proliferation of the lymphatic channels due to incompetent valves, or agenesis of the valves, with absence or interruption of the thoracic duct. Imaging findings include interlobular septal thickening, ground glass opacification, pleural effusions, or chylothorax [Figure 12].
Figure 12: A 5-year-old male with Noonan syndrome. (a) Axial chest computed tomography image demonstrates interlobular septal thickening (black arrows) compatible with edema. (b) Next day chest radiograph shows worsening of perihilar predominant pulmonary edema (dashed black arrows). (c) Another chest radiograph performed hours later demonstrates worsening diffuse pulmonary edema, development of right-sided pleural effusion (white arrow) and interval placement of multiple lines and tubes including endotracheal tubeBlau syndrome – “pediatric sarcoidosis”
Blau syndrome classically presents in early childhood (under the age of 4 years) as a triad of granulomatous dermatitis, arthritis, and uveitis.[28] Recent studies have shown that Blau syndrome and early-onset sarcoidosis are the familial and sporadic forms, respectively, of the same disease.[29] Blau syndrome and early-onset sarcoidosis contrast with the adult-like form of sarcoidosis, which presents in older children and adolescents, clinically manifesting with systemic features of fever, weight loss, hilar adenopathy, and pulmonary infiltration.[30] Interstitial lung disease is a major feature in adults but not in children. Pulmonary involvement is rare and includes ground glass opacities in the both upper and lower lobes, adenopathy of axillary nodes, and bronchial granulomas [Figure 13].
Figure 13: (a) Axial chest computed tomography image demonstrates “tree-in-bud” nodularity (black arrow) in this patient with pathologically proven Blau Syndrome. (b) Coned-down chest computed tomography in soft-tissue window of the same patient demonstrates left axillary adenopathy (white arrow)Bronchiolitis obliterans
Bronchiolitis obliterans is a rare, fibrosing form of chronic obstructive lung disease that follows a severe insult to the lower respiratory tract and results in narrowing and complete obliteration of the small airways. Bronchiolitis obliterans in children is most often seen following a severe lower respiratory tract infection, most commonly adenovirus. It is also a known complication following lung transplantation, bone marrow, or hematopoietic stem cell transplantation. Microscopically, this corresponds to fibrosing inflammatory processes around the lumen of the bronchioles resulting in concentric narrowing and obliteration of small airways.[1] On imaging, bronchial wall thickening, ill-defined centrilobular nodular opacities, air trapping, and central bronchiectasis are common findings [Figure 14].
Figure 14: Axial chest computed tomography image of an 8-year-old male with bronchiolitis obliterans after viral illness demonstrates bronchial wall thickening (black arrow) and scattered mosaic attenuation and air trapping (dashed black arrows)Organizing pneumonia
Organizing pneumonia (used to be described as bronchiolitis obliterans with organizing pneumonia) is histopathologically characterized by granulation tissues within small airways, alveolar ducts, and alveoli and by chronic inflammatory cell infiltration in alveolar walls.[31] When the cause is unknown, organizing pneumonia is classified as primary or cryptogenic. When a cause can be found, it is classified as secondary. Secondary causes include infection, drug reactions, collagen vascular disease, and after toxic-fume inhalation.[32] Common imaging findings include lower lung zone predominant consolidation, patchy ground glass opacities in a subpleural or bronchovascular distribution, centrilobular nodules 3–5 mm in size, bronchial wall thickening and cylindrical bronchiectasis with air bronchograms, and pleural effusions[33][Figure 15].
Figure 15: (a) Axial chest computed tomography image of a 10-year-old male with organizing pneumonia. Note the focal consolidation in the medial left lung base with bronchiectasis and air bronchograms (black arrow) and mild scattered air trapping. (b) Axial chest computed tomography image of a 2-year-old female with organizing pneumonia demonstrates the lower lung consolidations with right-sided pleural effusionAdenovirus interstitial pneumonia
Adenovirus accounts for 5%–10% of acute respiratory infections in the pediatric population while it only accounts for <1% of respiratory illnesses in adults.[34] Adenovirus has its greatest effect in the terminal bronchioles and causes bronchiolitis and bronchiectasis.[35] The bronchiolitis may be necrotizing and result in a necrotizing bronchopneumonia. This is an increasing cause of morbidity and mortality in the immunocompromised pediatric population and has been documented in those who are post liver or kidney transplantation.[36] Swyer-James-MacLeod syndrome is considered to be an acquired disease secondary to adenovirus infection in childhood.[37] Imaging findings include patchy areas of consolidation in a segmental distribution with ground glass opacities [Figure 16], lobar collapse common in children, especially the right upper lobe[38][Figure 17].
Figure 16: Axial chest computed tomography image of a 14-day-old infant with adenovirus infection shows diffuse ground glass opacification with superimposed peribronchial wall thickening (white arrows) with scatter subsegmental and bibasilar atelectasis (black arrows)
Figure 17: Chest radiograph of a 5-month-old male infant with adenovirus infection shows right upper lobe collapse (black arrows) and resultant rightward mediastinal shift (white arrow) Chronic Eosinophilic Pneumonitis Chronic eosinophilic pneumonitis is a rare pediatric respiratory disease[39] and characterized by a significant infiltration of the alveolar spaces and interstitium by eosinophils, with conservation of the normal lung structure. Respiratory symptoms usually last more than 2 weeks duration. The diagnosis is based on the demonstration of alveolar eosinophilia on bronchoalveolar lavage, and/or blood eosinophilia, with exclusion of other known causes of eosinophilia.[40] Pathology shows that exudate rich in eosinophils fills the lung interstitium and alveoli.[41] On imaging, peripheral nonsegmental pulmonary consolidations in mid to upper lung predominance are usually seen [Figure 18]. Chronic eosinophilic pneumonitis has an excellent response to steroids.
Figure 18: Axial chest computed tomography image of a 7-year-old male with chronic eosinophilic pneumonitis shows peripheral predominant airspace disease (black arrows) with interstitial thickening (white arrows) and pleural effusions (black stars) Pneumocystis Pneumonia Pneumocystis pneumonia is caused by Pneumocystis jiroveci and most commonly occurs in immunocompromised children status post allogeneic hematopoietic stem cell transplantation, solid organ transplantation, or with congenital immunodeficiency syndromes and HIV. Subclinical infection is very common in immunocompetent children; two out of three children have antibodies by the age of 4 years.[42] Imaging features on CT include ground glass opacities, predominantly in the mid lung or perihilar region with peripheral sparing, and reticular opacities or interlobular septal thickening with crazy paving pattern [Figure 19] and [Figure 20]. Poorly ventilated zones are more prone to infection. Pneumatoceles can develop in 30% of cases. In patients treated with prophylactic medications, it can have an atypical appearance such as tree in bud nodules, lymphadenopathy, and pleural effusions.[43]
Figure 19: Chest radiograph of a 4-month-old HIV-positive male infant with pneumocystis pneumonia shows bilateral hazy airspace opacities (black arrows)
Figure 20: Axial chest computed tomography image of a 10-month-old male infant with pneumocystis pneumonia shows mid-lung predominant patchy airspace opacities (black arrows) with relative subpleural sparing (dashed black arrows) Chlamydia Pneumonia Chlamydia pneumoniae is a common atypical respiratory pathogen found in children 5–15-year-old with an incubation period of approximately 21 days.[44] It causes outbreaks in closed populations such as schools and coinfection with mycoplasma or streptococcus is common. Imaging appearance is variable. Airspace consolidation with or without centrilobular or peribronchovascular nodules is often seen and nonspecific. The presence of centrilobular or peribronchovascular nodules or bronchovascular bundle thickening without consolidation and with hyperexpansion or airway dilatation is more specific to Chlamydia pneumoniae pneumonia when compared to other atypical pneumonias[45][Figure 21].
Figure 21: A 4-year-old female with chlamydia pneumonia. (a) Frontal chest radiograph shows lobar consolidation in the right middle lobe. Note how the right heart border is obscured on the frontal view (black arrow). (b) This corresponds to the consolidation in the right middle lobe on the lateral view (black star) Vaping-Associated Lung Disease Electronic cigarette or vaping product use-associated lung injury (EVALI) has become a serious public health problem with significant morbidity and mortality in young adults.[46] These patients present with respiratory symptoms such as dyspnea, as well as systemic symptoms including fever, myalgias, nausea/vomiting, and fatigue. Bronchoalveolar lavage in these patients shows increased neutrophils and lipid-laden macrophages. Imaging plays a vital role in the initial detection and evaluation of progression of EVALI. There are several imaging patterns of EVALI in adults including diffuse alveolar damage, lipoid pneumonia, acute eosinophilic pneumonia, and organizing pneumonia.[47],[48],[49] In the adolescent population, the most common reported pattern is diffuse alveolar damage, which manifests as bilateral ground-glass opacities and consolidation with subpleural and lobular sparing, in a lower lobe predominance[50][Figure 22] and [Figure 23]. The reversed halo sign (atoll sign) has been reported in pediatric patients with EVALI.[51]
Figure 22: Axial chest computed tomography image of a 19-year-old male vaping marijuana shows diffuse perihilar ground glass opacification with peripheral sparing (black arrows) and peribronchovascular sparing (dashed black arrows)
Figure 23: Axial chest computed tomography images (a and b) of a 17-year-old male with a history of vaping show a pattern consistent with diffuse alveolar damage with patchy nodular opacities in a centrilobular distribution (black arrows) and basilar consolidation (dashed black arrows) Conclusion chILDs encompass a large variety of both rare and more common pulmonary pathologies. Pathologies can be divided into two broad categories: Those associated or identified during infancy and those not specific to infancy. Genetic mutations play a large role in the pathogenesis and presentation of chILD and should be kept in mind. Knowledge of these pathologies allows for a multidisciplinary approach by pediatric radiologists, pulmonologists, and clinicians to provide appropriate and timely management.
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