Multimodality Thoracic Imaging of Juvenile Systemic Sclerosis: Emphasis on Clinical Correlation and High-Resolution CT of Pulmonary Fibrosis

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1 Pediatric Imaging Review Valeur et al. Multimodality Imaging of Juvenile Systemic Sclerosis Pediatric Imaging Review Natalie S. Valeur 1 Anne M. Stevens 2 Mark R. Ferguson 3 Eric L. Effmann 3 Ramesh S. Iyer 1,3 Valeur NS, Stevens AM, Ferguson MR, Effmann EL, Iyer RS Keywords: cardiac MRI, fibrosis grading systems, gastroesophageal reflux, high-resolution CT, juvenile systemic sclerosis, pulmonary arterial hypertension, pulmonary fibrosis DOI: /AJR Received December 23, 2013; accepted after revision July 29, Department of Radiology, University of Washington Medical Center, Seattle, WA. 2 Department of Rheumatology, Seattle Children s Hospital, Seattle, WA. 3 Department of Radiology, Seattle Children s Hospital, 4800 Sand Point Way NE, Seattle, WA Address correspondence to R. S. Iyer (riyer@uw.edu). This article is available for credit. AJR 2015; 204: X/15/ American Roentgen Ray Society Multimodality Thoracic Imaging of Juvenile Systemic Sclerosis: Emphasis on Clinical Correlation and High-Resolution CT of Pulmonary Fibrosis OBJECTIVE. Juvenile systemic sclerosis is a rare multisystem autoimmune disorder characterized by vasculopathy and multiorgan fibrosis. Cardiopulmonary complications are the leading cause of morbidity and mortality. Although pulmonary fibrosis is the complication that is most common and well described, cardiovascular and esophageal involvement may also be observed. In this article, common thoracic findings in juvenile systemic sclerosis will be discussed. We will focus on chest CT, including CT findings of pulmonary fibrosis and associated grading methods, as well as cardiac MRI and esophageal imaging. CONCLUSION. Radiologists play a pivotal role in the initial diagnosis and follow-up evaluation of pediatric patients with systemic sclerosis. Treatment decisions and prognostic assessment are directly related to imaging findings along with clinical evaluation. S ystemic sclerosis, a category of scleroderma, is an autoimmune connective tissue disorder that leads to fibrosis of multiple organ systems, most notably the skin; proliferative small-vessel vasculopathy; and obliterative microvascular disease [1 3]. Juvenile systemic sclerosis is a rare subset of systemic sclerosis that occurs in patients younger than 16 years old [4]. The development of pulmonary fibrosis in patients with juvenile systemic sclerosis is a significant prognostic indicator; these patients should be rigorously screened for subclinical pulmonary disease because early involvement may dictate a different clinical course and may concurrently affect management decisions [5]. Chest radiography is often considered a screening tool, but this modality is insensitive for detecting pulmonary involvement. Although CT has a much higher sensitivity for detecting pulmonary abnormalities than radiography, the higher radiation dose of CT is concerning in this particular patient cohort who may undergo several imaging examinations throughout childhood [2]. This article will review the underlying cause of systemic sclerosis, clinical presentation, nonimaging and imaging evaluations, the spectrum of imaging findings with a focus on high-resolution CT (HRCT), differential diagnostic considerations for pulmonary disease, treatment, and future directions. This article will also address the less common but prognostically important thoracic manifestations of pulmonary hypertension and cardiac fibrosis. Cause Juvenile systemic sclerosis is a rare autoimmune disorder with a reported incidence of 1.36 cases per 1 million children. The strongest known risk factor is a family history of systemic sclerosis [4, 6]. There is little reported radiology-pathology correlation because biopsies are rarely performed in children with suspected juvenile systemic sclerosis; thus, the pathogenesis of interstitial lung disease in systemic sclerosis is not yet fully elucidated, but interstitial lung disease in this setting appears to result from an initial microvascular injury that is followed by inflammation and fibrosis. The initial vascular and endothelial injury leads to the production of prothrombotic molecules, such as thrombin, endothelin-1, and vascular endothelial growth factor, and culminates in the stimulation of fibroblasts [7]. The end result is inflammation within the alveoli and production of an extracellular matrix composed of collagen and fibronectin [7, 8]. Some authors have suggested gastroesophageal reflux disease (GERD) as a cause of pulmonary fibrosis, but this hypothesis has not yet been validated [8]. 408 AJR:204, February 2015

2 Multimodality Imaging of Juvenile Systemic Sclerosis Clinical Presentation Systemic sclerosis typically affects middle-aged women in their fifth and sixth decades of life; however, when disease onset occurs in patients younger than 16 years old, it is classified as juvenile systemic sclerosis [4]. Juvenile systemic sclerosis comprises 3 10% of systemic sclerosis cases [2, 9, 10], with an average age at symptom onset of 8 9 years old and a female-to-male ratio of 4:1 [5]. Almost all pediatric patients present with skin involvement, and a majority present with arthritis (64 79%), Raynaud phenomenon (72 84%), and gastrointestinal involvement (65 69%) [4, 11, 12]. The main prognostic factor in both the juvenile and adult populations is the involvement of the cardiopulmonary system, with the development of interstitial lung disease, pulmonary arterial hypertension, and heart failure [1, 5, 7, 13, 14]. Of all the potential cardiopulmonary complications, pulmonary fibrosis is the most common in both children and adults. Up to 90% of patients have manifestations of fibrosis that are visible on imaging, and these imaging findings are concordant with findings at autopsy, the latter of which has shown a 74 95% prevalence [2]. Detecting early pulmonary involvement clinically in children may be challenging because they are often asymptomatic until the disease is advanced; however, detection of pulmonary involvement remains critical because interstitial lung disease can develop early and lead to restrictive lung disease [5, 9, 14]. Although systemic sclerosis in the adult population is considered to have a high mortality [3], the largest study to date on juvenile systemic sclerosis performed by Martini et al. [10] reported a mean survival at 5 years from diagnosis of 88.0% and an average life expectancy of years. Other studies have reported survival at 20 years from diagnosis as between 69% and 82% [15, 16]. From these data, two possible courses of disease have been suggested: a more common insidious disease course with a low mortality rate and a more rare course of rapidly progressive disease with early development of internal organ failure, particularly heart failure. Pulmonary fibrosis is often cited as the leading cause of mortality in adults with systemic sclerosis [3, 5]; however, Martini et al. [10] found the leading cause of death in juvenile systemic sclerosis to be cardiac failure, accounting for 62.5% of deaths in their study, followed by respiratory failure, renal failure, and infection. Independent risk factors associated with increased mortality in their study were pulmonary fibrosis evident on chest radiography, elevated creatinine level, and pericarditis. A short interval between symptom onset and disease diagnosis was associated with a better prognosis [10]. In the Martini et al. [10] study, juvenile systemic sclerosis patients with a fatal outcome showed rapid disease progression that resulted in death typically within 5 years of symptom onset and diagnosis. Nonimaging Evaluation The detection of lung involvement in juvenile systemic sclerosis has increased over time, likely in part because of the increased use of screening tests. In a 1959 study by Scalapino, pulmonary fibrosis was estimated to occur in 9% of children with systemic sclerosis. In more recent studies that include symptoms (dyspnea) and radiologic and functional diagnostics, investigators report pulmonary fibrosis in up to 20 55% of children with juvenile systemic sclerosis [15, 16, 17, 18]. The most sensitive method for the detection of pulmonary fibrosis in patients with juvenile systemic sclerosis is not clear. Although bronchoalveolar lavage can detect inflammation within the alveoli, it has not been found to be helpful in predicting treatment response or progression [7]. Pulmonary function tests (PFTs) of patients with juvenile systemic sclerosis reveal low forced vital capacity (FVC) in 42 65% of patients and low values for the diffusing capacity of the lung for carbon monoxide (Dlco) in 13 27% of patients. These PFTs yield greater sensitivity for detecting disease than relying on symptoms alone, radiography, or HRCT [11, 19]. In addition, low FVC has been correlated with honeycombing and ground-glass changes on HRCT and low Dlco values with fibrosing alveolitis, albeit in small cohorts that need to be further validated [2, 20]. PFTs are noninvasive, are readily available, and do not involve ionizing radiation and therefore are a simple initial screening tool. One major disadvantage of PFTs is that the range of normal values is generally large from 80% to 120% predicted based on age, sex, and height [13, 16]. Thus, a value just below the normal lower limit may actually reflect a marked decrease from the patient s true baseline if that value was originally at the upper limit of normal [21, 22]. Imaging Evaluation Chest Radiography The imaging evaluation of suspected interstitial lung disease typically begins with chest radiography given its balance of wide availability and ease of use with decreased costs and lower radiation dose compared with HRCT [23, 24]. Radiographic images obtained in full inspiration and without motion are critical for high diagnostic quality and are most difficult to obtain in infants. In these patients, magnification in the anteroposterior projection is less problematic, allowing supine imaging with kvp, mas, and a source-to image receptor distance of 40 cm [24]. Chest High-Resolution CT Patient preparation At our institution, a tertiary care multidisciplinary children s hospital, we perform HRCT of the chest with spirometry assistance in children with confirmed or suspected pulmonary fibrosis. The technique is optimal for patients who are 5 years old or older and compliant with breathing instructions. This technique requires a close partnership with colleagues from the PFT laboratory. The goals of spirometryassisted CT are to optimize inspiratory and expiratory effort and minimize respiratory artifact. The technique evolved from evaluating patients with cystic fibrosis and has been shown to reliably produce high-quality CT images in children as young as 4 years old [25 27]. At our institution, before a patient undergoes chest CT, he or she goes to the PFT laboratory to receive coaching to perform full inspiration and expiration using spirometry assistance. This visit before CT serves two functions: to familiarize the child with the equipment and breathing instructions and to obtain baseline PFT values in a comfortable environment. The child is then transported to the CT suite accompanied by the spirometry equipment and pulmonary technologist. The patient undergoes the HRCT examination of the chest while being continuously monitored by spirometry. The inspiration and expiration levels during CT are compared with those obtained in the preceding PFT laboratory visit to ensure adequate respiratory effort during scanning. The typical goal during imaging is to achieve 95% of the slow vital capacity recorded in the PFT laboratory to optimize CT diagnostic quality. HRCT of the chest in infants and young children who cannot follow breathing instructions can be more challenging. Advances in CT scanner speeds have decreased the need for sedation in most pediatric patients. Nevertheless, motion artifact remains a limitation with such studies. General anesthesia AJR:204, February

3 Valeur et al. TABLE 1: High-Resolution Chest CT Inspiratory Sequence Protocols at Our Institution Slice Thickness (mm) Patient Weight (kg) Scan Range a (mm) kvp ma (Range) Scan Time (s) with either endotracheal intubation or a laryngeal mask airway is an effective method for obtaining motion-free images but is invasive and incurs procedural risk. Atelectasis is a common problem in intubated infants because of increased chest wall compliance, immature collateral ventilation pathways, and loss of intercostal muscular tone [23]. Infants younger than 6 months old are often imaged successfully after feeding and swaddling using standard thoracic CT examinations. However, imaging during quiet respiration often does not achieve the full inspiration and expiration phases needed for an optimal HRCT study. Decubitus positioning has been described as an alternative to the expiratory sequence. In this technique, the decubitus lung simulates expiration, whereas the nondependent lung resembles an inspiratory phase. Potential disadvantages with decubitus imaging include misregistration artifacts and interrupting sedation [23, Pitch Acquisition Sequence (Bone Algorithm) Axial Mediastinal Reconstruction (Soft-Tissue Algorithm) 28]. Respiratory-gated CT allows accurate timing of scanning, with peak inspiration and expiration during quiet breathing, but involves specialized equipment that is not widely available [23]. Cine CT, performed either with electron beam CT or with helical CT, is another alternative to the expiratory sequence that may be helpful in free-breathing young children. Cine CT is performed by acquiring multiple cine images from the same slice level, selecting representative inspiratory and expiratory images, and measuring lung density in the same region at different phases in the respiratory cycle [29]. Finally, controlled-ventilation chest CT using positive pressure ventilation is another technique to minimize motion blurring and can be performed using either of two techniques. The first technique involves hyperventilating a sedated infant with positive pressure via a face mask. This method results in hypocarbia and stimulation of the Axial Pulmonary Reconstruction (Bone Algorithm) Projections and Slice Thicknesses for Multiplanar Reformats b Coronal, 2 mm; axial, 1 and 2 mm; coronal and axial c, 3-mm MIP Coronal 3 mm; axial 1 and 2 mm; coronal and axial c, 3-mm MIP Coronal, 3 mm; axial 1 and 2 mm; coronal and axial c, 3-mm MIP Coronal, 3 mm; axial 1 and 3 mm; coronal and axial c, 3-mm MIP Coronal, 3 mm; axial 1 and 3 mm; coronal and axial c, 5-mm MIP Coronal, 3 mm; axial 1 and 2 mm; coronal and axial c, 3-mm MIP Coronal and sagittal, 3 mm; coronal and axial c, 5-mm MIP Coronal and sagittal c, 3 mm; coronal and axial c, 5-mm MIP Coronal and sagittal c, 3 mm; coronal and axial c, 5-mm MIP Coronal and sagittal c, 3 mm; coronal and axial c, 5-mm MIP Coronal and sagittal c, 3 mm; coronal and axial c, 5-mm MIP Coronal and sagittal c, 3 mm; coronal and axial c, 5-mm MIP Note The expiratory sequence for all weights consists of five 1.25-mm axial slices acquired at 20- to 30-mm intervals, extending from 1 cm above the aortic arch to 1.5 cm above the diaphragmatic dome. Bismuth shields are used for all female patients to reduce radiation to breast tissue. MIP = maximum intensity projection. a Craniocaudal. b Reconstructed from acquisition with bone algorithm. c Both of these reconstructions are included with the examination protocol. Hering-Breuer reflex, which prevents pulmonary overinflation through a transient respiratory pause. HRCT then ensues with either sustained positive pressure or pulmonary deflation to obtain inspiratory or expiratory images, respectively [23, 24, 30]. The second technique does not use hyperventilation; rather, this method relies on alternating positive pressure ventilation in a paralyzed and intubated patient. The application of constant positive pressure ventilation results in lung volumes maintained near total lung capacity, thus simulating a breath-hold in inspiration. Subsequently withholding positive pressure ventilation then allows passive exhalation to the patient s functional residual capacity [24]. Imaging parameters We use a 64- MDCT scanner and perform helical acquisitions of the lungs in full inspiration with a mm slice thickness. Our scanning parameters are dependent on patient weight and are listed in Table 1. We use a pitch of 410 AJR:204, February 2015

4 Multimodality Imaging of Juvenile Systemic Sclerosis 1.375:1 and a scanning time of second. The general parameters include kvp, ma, and a noise index of Axial slices of the thorax are also performed using a soft-tissue kernel with a slice thickness of mm, depending on patient size. Finally, for the expiratory sequence, five equally spaced 1.25-mm-thick axial slices are acquired from approximately 1 cm above the aortic arch to 1.5 cm above the dome of the diaphragm. These expiratory slices are typically acquired at 20- to 30-mm intervals. Bismuth shields are used for all female patients to reduce radiation to breast tissue. The achieved dose for each HRCT examination is typically 2 4 mgy. Postprocessing techniques Axial 1-mm and coronal 3-mm slices are reconstructed with a bone (sharpening convolution kernel) algorithm. Maximum-intensity-projection reformatted images in lung windows are also performed in 5-mm slices in both axial and coronal projections for the inspiratory sequence. We apply a 20 30% iterative reconstruction to our acquisition sequence to balance noise and optimize image quality. Pulmonary Fibrosis Chest Radiography As we mentioned earlier, chest radiography has a poor sensitivity for lung parenchymal changes secondary to systemic sclerosis in children. Although 74 95% of patients have fibrosis at autopsy [2], only 18 39% of patients show radiographic abnormalities [2, 19, 31]. Given its limitations in this setting, chest radiography should not be considered an adequate screening study for the detection or exclusion of fibrosis and is usually followed by HRCT for further evaluation. Abnormalities on chest radiography in patients with juvenile systemic sclerosis include low lung volumes, interstitial prominence or thickening, cardiomegaly with or without pericardial effusions, pleural effusions, enlargement of the pulmonary arteries, and mediastinal lymphadenopathy [2]. High-Resolution CT HRCT offers the greatest sensitivity and specificity for pulmonary parenchymal changes resulting from systemic sclerosis. HRCT exhibits a high sensitivity, revealing pulmonary disease in up to 90% of pediatric patients with juvenile systemic sclerosis [2]. These abnormal imaging findings may be unsuspected both clinically, particularly in pediatric patients, and radiographically. Pulmonary fibrosis is common in all systemic sclerosis patients, so early imaging detection is valuable information for clinical providers [2]. Findings on HRCT parallel the histopathologic findings, with the predominant pathologic pattern being an interstitial process akin to nonspecific interstitial pneumonia (NSIP) [2]. The most common CT abnormality in patients with pulmonary fibrosis is parenchymal ground-glass opacity (GGO) with a variable reticular pattern; GGOs are often found peripherally and in the lower lobes with an apicobasal gradient [2, 32] (Figs. 1 4). Within the upper lobe, there may also be an anteroposterior gradient, with the anterior pleura and parenchyma affected to a greater degree. The fine intralobular fibrosis seen in NSIP is beyond the resolution capabilities of HRCT, producing the GGOs frequently seen [22]. Subpleural sparing may be observed in the lower lobes posteriorly, similar to other interstitial lung diseases characterized by NSIP pathologically (Fig. 5). There may be associated bronchiectasis or subpleural nodules [2, 5, 33]. In addition to GGOs and traction bronchiectasis, pleuroparenchymal cystic changes may also be present. Parenchymal cysts with associated architectural distortion, which is referred to as honeycombing, is most frequent in the anterior upper lobes and the lower lobes. Large single-layer 1- to 2-cm subpleural cysts can also be seen in the anterior upper lobes, which may represent paraseptal emphysema or subpleural bullae, and may be specific to juvenile systemic sclerosis [2]. Although GGOs and cystic changes are the most common findings, interlobular septal thickening can also be present in a polygonal pattern or manifest perpendicular to the pleura, the latter of which leads to a reticular pattern [14]. Early fibrosis may be subtle and may be identified in only the peripheral upper or lower lobes (Fig. 6). An acute process such as infection, aspiration, or hemorrhage may also obscure underlying fibrosis (Fig. 7). Atelectasis often masks or mimics posterior lung fibrotic changes on HRCT. For juvenile systemic sclerosis and other conditions exhibiting pulmonary fibrosis, radiologists may play an active role during the examination to assess whether atelectasis is hindering diagnostic accuracy. If there is an abundance of atelectasis, the inspiratory sequence may have to be performed again while the patient is in the prone position. Although prone acquisition may be routine in healthier older children and in adults, this position may pose challenges for the anesthesia team monitoring a young ill child and should therefore be incorporated into the decision to repeat the examination. CT may also reveal mediastinal lymphadenopathy, esophageal dilatation, and pleural effusions. The incidences of these findings are lower in the pediatric population than in adults with scleroderma, possibly because of a shorter disease duration in children [2, 14]. Grading Because pulmonary fibrosis is a leading cause of mortality in patients with systemic sclerosis and the primary medical treatment is aggressive immunosuppression, a systematic method to assess disease extent and progression is ideal. The Scleroderma Lung Study [34] found a relationship between the extent of pulmonary fibrosis and changes in PFT results, with increasing GGOs corresponding well to low FVC and low Dlco values. Radiologists can thus make broad observations regarding disease severity and changes over time that are consistent with the clinical course of these patients [7]. Multiple grading systems have been proposed in an effort to quantify pulmonary fibrosis in a more granular and reproducible fashion. Some methods entail assessing the lungs at multiple different levels, such as the method described by Desai et al. [32] in In that grading scheme, five levels are chosen: 1, the origin of the great vessels; 2, the carina; 3, pulmonary venous confluence; 4, between 3 and 5; and 5, 1 cm above the right diaphragm dome. Five parameters are recorded at each level. First, the degree of interstitial lung disease (GGO and reticulation) as a proportion of lung parenchyma is estimated to the nearest 5%. Second, the relative proportions of the reticular pattern and ground-glass pattern contributing to the interstitial lung disease are evaluated. Third, the coarseness of fibrosis is evaluated semiquantitatively on a 4-point scale. Fourth, the extent of emphysema is assessed to the nearest 5%. Fifth, the overall interstitial lung disease is characterized as predominantly reticular opacities, equally reticular and GGOs, or predominantly GGOs. Two observers would grade each study, and if their measurements at any level differed by more than 20%, by more than one grade for coarseness of fibrosis, or by overall quality of interstitial lung disease, a consensus was reached. In the final analysis, the extent of interstitial lung disease and the extent of emphysema are ob- AJR:204, February

5 Valeur et al. TABLE 2: Pulmonary Imaging Findings in Systemic Disorders a Systemic Disorders tained by averaging the scores from the two observers at each level; the extent of GGO is assessed by dividing the extent of GGO by the overall extent of interstitial lung disease; and the coarseness score is obtained by summing all levels, with adjustments made if one or more levels is given a score of zero [32]. Another pulmonary fibrosis grading system, which was proposed by Goh et al. [21], uses a broad radiologic assessment and incorporates PFTs in ambiguous cases; it is relatively straightforward to use, and the results correlate with clinical mortality [22]. Given that GGOs involving more than 20% of lung parenchyma have been associated with an increase in mortality, this value was chosen as a threshold mark [7]. The extent of disease based on the amount of GGOs and reticulation was graded as more than 20% or less than 20%. Patients with imaging findings showing that less than 20% of lung parenchyma was involved with either GGOs or reticulation were considered to have pulmonary disease of limited extent and had no statistically significant increased risk of mortality. In contradistinction, patients with greater than 20% of the lung parenchyma involved with either GGO or reticulation were deemed to have extensive disease and had a statistically significant increased rate of disease progression and mortality rate (p = 0.001). For indeterminate or borderline cases, an FVC criterion with a threshold value of 70% was incorporated [21, 22]. Research into the development of a computer-aided diagnosis system has also been Nodules (Some Cavitary) Ground-Glass Opacity Airspace Opacities Diffuse Alveolar Hemorrhage proposed in an effort to decrease intra- and interobserver variations and standardize quantifiable findings [35]. No fibrosis grading systems exclusive to systemic sclerosis in the pediatric population have been described or studied to date. Differential Diagnosis Differential considerations for pulmonary fibrosis from juvenile systemic sclerosis may be subdivided into two broad categories: systemic disorders with pulmonary involvement (including juvenile systemic sclerosis) and primary pediatric interstitial lung disease. The topic of interstitial lung disease in childhood is beyond the scope of this article, and we defer discussion of these disorders to other more detailed resources [24, 36, 37]. Systemic conditions with abnormal lung findings on imaging include vasculitides, connective tissue disorders, sickle cell disease, Langerhans cell histiocytosis, and lysosomal storage disorders; these imaging manifestations are summarized in Table 2. Wegener polyangiitis is the most common form of pulmonary vasculitis in children. It typically presents with a triad of necrotizing granulomatous lesions in the upper and lower respiratory tract and glomerulonephritis [38]. Nodules, some of which are cavitary, are the pulmonary imaging hallmark of Wegener polyangiitis and are seen in 90% of patients [14]. Although nodules are seen in both Wegener polyangiitis and juvenile systemic sclerosis, they are seen more frequently in the former. Juvenile idiopathic arthritis Interstitial Disease Pleural or Pericardial Disease Lung Cysts Wegener polyangiitis ++++ (90%) Microscopic polyangiitis (57%) + + Churg-Strauss syndrome (75%) +++ (75%) Juvenile arthritis (60%) Systemic lupus erythematosus Systemic sclerosis ++ (64%) +++ (73%) ++++ (91%) + Mixed connective tissue disease Dermatomyositis ++ + Acute chest syndrome Langerhans cell histiocytosis Gaucher disease or Niemann-Pick disease Note Plus signs indicate that finding is present with frequency proportional to number of plus signs attributed; dash ( ) indicates finding is generally not seen. a This table was reprinted with permission from [59]: O Donovan JC, Lee EY, Effmann EL. Systemic conditions with lung involvement. In: Coley BD, ed. Caffey s pediatric diagnostic imaging, 12th ed. Philadelphia, PA: Elsevier Saunders, 2013:606. exhibits pleural and pericardial effusions on HRCT more commonly than fibrosis. However, when pulmonary parenchymal involvement does occur with juvenile idiopathic arthritis, GGOs progressing to concurrent septal thickening are observed [14, 39, 40]. Other pediatric connective tissue disorders besides systemic sclerosis include systemic lupus erythematosus, dermatomyositis, and mixed connective tissue disease. They may all progress to pulmonary fibrosis, although much less commonly than with juvenile systemic sclerosis. Systemic sclerosis also has a higher incidence of nodules and GGOs than other connective tissue diseases [37]. Acute chest syndrome in sickle cell disease patients usually produces nonspecific airspace consolidation in contradistinction to systemic sclerosis. Chronic pulmonary findings of sickle cell disease on HRCT may include parenchymal bands, septal thickening, and architectural distortion, and honeycombing is unusual in these patients [37, 41]. Additional Imaging Findings Pulmonary Arterial Hypertension Pulmonary arterial hypertension (PAH) in juvenile systemic sclerosis patients may develop as either a primary or a secondary process. In primary cases, PAH develops from microcirculation vasculopathy and increased pulmonary vascular resistance and eventually may result in right heart failure (Fig. 8) [5]. Secondary PAH develops secondarily from chronic interstitial lung disease (Fig. 8). The development of PAH from 412 AJR:204, February 2015

6 Multimodality Imaging of Juvenile Systemic Sclerosis either cause typically heralds a poor prognosis, with heart-lung or lung transplant as the definitive treatment [2]. The traditional reference standard for the diagnosis of PAH is right heart catheterization, showing a mean pulmonary arterial pressure of greater than 25 mm Hg and a normal pulmonary capillary wedge pressure (< 15 mm) [5]. However, the preferred less invasive modality for the diagnosis of PAH is now Doppler echocardiography [5]. The prevalence of PAH is slightly less in patients with juvenile systemic sclerosis (< 10%) than in patients with adult-onset systemic sclerosis (8 12%) [5]. The diagnosis of PAH may be suggested on a standard unenhanced or contrastenhanced CT examination when the diameter of the main pulmonary artery exceeds 29 mm. This value has been adopted from studies of adults in the literature because criteria for pulmonary artery caliber in pediatric patients have not been firmly established. Similarly, the diagnosis may also be suggested when the main pulmonary artery exceeds the aorta in diameter in the same axial slice [42] (Figs. 8 and 9). HRCT is helpful to identify and characterize associated pulmonary fibrosis, which can contribute to the development of or can exacerbate existing pulmonary hypertension [2]. Esophageal Dysfunction In adult patients with systemic sclerosis the esophagus is a commonly afflicted organ, second only to the skin. Esophageal disease is found in up to 50 90% of adults and is caused by early neurovascular damage with subsequent fibrosis of the smooth-muscle layer [8]. Methodical esophageal peristalsis is lost; it is replaced by hypomotility, disorderly contractions, and a relaxed lower esophageal sphincter [43]. Patients experience severe GERD, erosive esophagitis, strictures, and Barrett esophagus (i.e., metaplasia from normal squamous to columnar cells lining the esophagus). This latter condition brings about an increased risk of malignant degeneration to adenocarcinoma [8, 43]. Gastrointestinal Tract Involvement In patients with juvenile systemic sclerosis, gastrointestinal tract involvement ranges from 8% at diagnosis in older cohorts depending mostly on symptom reports to 74% in more recent cohorts [10, 16, 17 19, 44]. Systemic sclerosis involving the gastrointestinal tract is reported in a variety of ways, including patient reports of dysphagia, heartburn, diarrhea, or weight loss; esophageal dysmotility; and radiographic evidence of GERD [31, 45]. Overall, gastrointestinal tract involvement in patients with juvenile systemic sclerosis was not different from adult populations with systemic sclerosis [16, 17]. GERD is believed by some authors to contribute to the development of interstitial lung disease [2, 8]. This assertion has been supported by histologic findings, the distribution of GGOs on CT, and a reported association between reduced PFT results and the presence of GERD [2, 8]. On HRCT, esophageal disease in children may manifest as dilatation and excess intraluminal debris; however, these findings are nonspecific and may be seen in healthy children. Nevertheless, we believe it is important to raise the possibility of esophageal disease in juvenile systemic sclerosis patients when these findings are present because recognition and medical management may relieve gastrointestinal symptoms and mitigate the progression of pulmonary fibrosis [8]. Esophageal dysfunction can be readily assessed with fluoroscopic esophagography. In children with systemic sclerosis, esophagography may show a dilated esophagus, a patulous gastroesophageal junction, esophageal hypomotility, esophageal dysmotility, or gastroesophageal reflux (Fig. 10). Sequelae of advanced disease such as strictures, mucosal irregularities, and ulceration may also be revealed. Another highly sensitive modality for the detection of gastroesophageal reflux is scintigraphy. For scintigraphy, the patient ingests a meal with 99m Tc labeled sulfur colloid. Although lacking the anatomic detail of fluoroscopy, the scintigraphic esophago gram may be used to evaluate both esophageal transit and the presence of reflux [43] (Fig. 10). Additional potential advantages of a nuclear medicine examination include relatively favorable dosimetry, greater concordance with normal physiology than the ingestion of barium, and the ability to quantify the degree of reflux [46]. Cardiac Involvement Cardiac involvement is rarer than pulmonary fibrosis in both children and adults with systemic sclerosis, but the implications are of critical importance, particularly in the pediatric population. In a study by Scalapino et al. [16], the mortality rates from cardiac causes were higher in the juvenile population (15%) than in adults (7%); in addition, cardiac disease was the leading source of mortality in a large study of juvenile systemic sclerosis by Martini et al. [10]. Systemic sclerosis can affect many cardiac components, including the conduction system, myocardium, pericardium, and even the valves [47]. The most common cardiac clinical manifestations in juvenile systemic sclerosis are pericarditis (10%), arrhythmias (10%), and heart failure (7%) [10, 48]. Cardiac involvement is thought to be caused by microvascular disease leading to ischemia. Histologic studies show patchy myocardial fibrosis with concentric intimal hypertrophy of the coronary arteries [48]. At autopsy, myocardial fibrosis is found in 50 80% of cases but is rarely clinically symptomatic [49]. Cardiac manifestations of systemic sclerosis have been characterized with much greater detail in adult patients than in pediatric patients. Decreased systolic function is considered specific for cardiac involvement in patients with systemic sclerosis, with an incidence of % at rest and up to 46% with exercise [47]. The presence of diastolic dysfunction is more widely seen (17.7%) in patients with scleroderma [47], but this finding is nonspecific and confounding comorbidities likely play a role in the adult population. Currently, Doppler echocardiography is the most widely used diagnostic imaging method to evaluate for cardiac disease in patients with systemic sclerosis. However this modality is unable to directly depict cardiac fibrosis; instead, the resultant wall motion dysfunction is observed. The same is true for scintigraphic cardiac perfusion studies that use 99m Tc or 201 Tl sestamibi and tetrofosmin [5, 48]. Cardiac MRI is gaining recognition for its ability to reveal ventricular morphology and function, perfusion, and the presence of myocarditis or fibrosis in a single study [48]. Cardiac assessment using MRI includes assessment of the overall morphology and function of the heart; evaluation for increased myocardial signal intensity on T2- weighted imaging, a finding that suggests edema; left ventricular thinning (wall thickness 4 mm); right ventricular hypertrophy (wall thickness 5 mm); and abnormally increased end-diastolic volume of either the left or right ventricle. The presence and extent of myocardial fibrosis may be evaluated for by assessing for late gadolinium enhancement (Fig. 11) because IV gadolinium is retained in the fibrotic tissue but washes out rapidly from normal myocardium. In patients with systemic sclerosis, disease distribution is patchy and scattered, often AJR:204, February

7 Valeur et al. mid-myocardial in location, as opposed to correlating with coronary artery distribution as is typical for large-vessel ischemic changes. In their 2009 study involving 52 adult-onset systemic sclerosis patients, Hachulla et al. [49] described at least one cardiac abnormality in 75% of patients, which is similar to findings seen at autopsy and exceeds the prevalence suggested by echocardiography (48%) [23]. Patients with disease of longer duration had more cardiac abnormalities including a greater distribution of late myocardial enhancement, which indicates a progressive course of cardiac involvement [49]. Although cardiac MRI may not be available for all patients, Doppler echocardiography and the serum brain natriuretic peptide value can be widely used as screening tools for cardiac involvement by systemic sclerosis. If available, cardiac MRI may be considered in select patients to evaluate myocardial perfusion, cardiac fibrosis, cardiac function, and ventricular volumes. Therapy For many pediatric patients, progression of interstitial lung disease is most rapid in the first 5 years, rendering early detection and observation critical for therapy decisions [7]. Over time, the basilar-predominant groundglass attenuation may improve or resolve with medication management. However, in many patients, there is interval progression to overt pulmonary fibrosis with the development of interlobular septal thickening and cystic changes including honeycombing that is worse in the apices [2, 22]. The fact that an early diagnosis is associated with a better prognosis suggests that early treatment may prevent morbidity and mortality in juvenile systemic sclerosis, although this hypothesis has not been directly tested [10]. Currently, there are no consensus guidelines regarding specific medication regimens for children with systemic sclerosis with thoracic involvement. Recommendations for the treatment of adults with systemic sclerosis based on the consensus of a task force [50] have been published. No clinical trials have been conducted for patients with juvenile systemic sclerosis; however, a panel of 18 pediatric juvenile systemic sclerosis experts agreed on nine recommendations through the Delphi survey, including the use of cyclophosphamide to treat interstitial lung disease [51]. Many patients with pulmonary fibrosis are treated with monthly IV cyclophosphamide and variable combinations of steroids, methotrexate, and rituximab. By identifying the presence of pulmonary fibrosis, the radiologist plays an important role in allowing the treating rheumatologist to initiate therapy. The Scleroderma Lung Study [34] showed that patients with a greater extent of pulmonary fibrosis early in the disease course have a more favorable response to treatment. This more favorable response to treatment may be because there is a higher degree of reversible inflammation that can be successfully countered using antiinflammatory treatments [2, 7]. With this principle to guide therapy, it is recommended that patients with pulmonary fibrosis detected on HRCT and patients with PFT results indicating respiratory compromise be given immunomodulatory treatment, in addition to patients with a new diagnosis and those with severe or progressive disease. The treating rheumatologist will then adjust this immunomodulatory medication regimen depending on the patient s imaging manifestations on serial HRCT and the degree of impaired or restricted function on PFTs. The radiologist can add value to care delivery by assessing changes in parenchymal disease over time and in response to specific therapies. Future Directions Pulmonary disease is common in patients with juvenile systemic sclerosis and remains a leading cause of mortality in these children. Available treatments have the potential to slow disease progression, especially when administered early, but these therapies are associated with risks and identification of high-risk patients is necessary [52]. A critical but unanswered question is at what threshold to institute treatment [21]. PFTs are widely available and may be readily and easily applied. However, the broad range of normal values makes it challenging for physicians to characterize the efficacy of therapy, particularly in patients with minimal disease at baseline [21]. Ideally, quantification of disease on HRCT would correlate well with clinical disease burden. However, the extent of disease on imaging is not always predictive of patient prognosis [52]. Further studies assessing treatment indications are needed and will likely assimilate PFTs, imaging, and possibly other clinical parameters such as bronchoalveolar lavage. The role of HRCT in stratifying those patients at risk of disease progression is unclear and may change with the integration of computeraided detection and improvements in HRCT techniques [3, 22, 35, 53]. The ability to identify reversible lesions is also a key target for future studies, and exploring the utility of serial CT may prove beneficial. There has been relatively minimal work to date assessing serial HRCT studies in these patients. Serial HRCT findings may be particularly relevant in patients with minimal or slowly progressing disease, and the benefits of serial CT must be weighed against the costs of ionizing radiation [21, 22, 52]. Although patients with no pulmonary disease detected on baseline CT have a very good prognosis, more recent studies show that GGOs may in fact be irreversible; thus, further research into the progression of GGOs to reticulation and bronchiectasis and whether treatment influences this course may be helpful [3, 34, 52]. Finally, during the past 2 decades, MRI using hyperpolarized noble gases has garnered increased attention as a novel strategy to evaluate pulmonary structure and function. The lungs are typically difficult to assess with MRI because of low proton density, motion artifacts, and susceptibility artifacts. This unique contrast-enhanced technique allows direct visualization of airspaces through inhalation of the hyperpolarized gases 3 He and 129 Xe. Much of the preliminary work in hyperpolarized gas MRI has been performed with helium because it is almost entirely confined to the lungs once inhaled and has no adverse effects. However, 3 He is expensive and has a limited supply. Xenon-129 has a reduced signal compared with 3 He because of its smaller magnetic moment, but 129 Xe is more abundant and less expensive. Preliminary results with 129 Xe have been very favorable with respect to safety and tolerability. In addition, the blood and tissue solubility of xenon may be leveraged to measure the diffusive capacity of the respiratory membrane, including xenon levels dissolved in lung tissue and RBCs. In patients with systemic sclerosis and in those with other chronic pulmonary disorders, MRI with hyperpolarized gas may provide a quantifiable imaging method to evaluate disease severity and response to therapy. There has been relatively limited clinical translation of this technique because of the technical challenges and high costs of polarizing the gas. However, the lack of ionizing radiation and ability to provide both anatomic and functional data are promising features for future use [54 57]. Continued advances in cardiac MRI techniques will allow for even 414 AJR:204, February 2015

8 Multimodality Imaging of Juvenile Systemic Sclerosis greater evaluation of the involvement of systemic sclerosis within the heart. Specifically, the diffuse nature of inflammation and fibrosis may be better interrogated with native T1 mapping of myocardium as well as extracellular volume quantification [58]. Conclusion Radiologists play a pivotal role in the initial diagnosis and follow-up evaluation of pediatric patients with systemic sclerosis. Treatment decisions and prognostic assessment are directly related to imaging findings along with clinical findings. Patients with juvenile systemic sclerosis often present with subclinical pulmonary disease, further highlighting the gap in detection and diagnosis addressed by radiology. The radiologist adds value by serving as a consultant for the judicious use of HRCT, including the use of dose reduction techniques. HRCT is strongly recommended to evaluate for lung disease as a baseline and for monitoring response to therapy. The radiologist s role includes documenting the extent of interstitial lung disease, including GGOs, interlobular septal thickening, and cystic pleuroparenchymal changes. Secondary findings such as pulmonary artery enlargement as a manifestation of PAH and esophageal dilatation also have important treatment implications in patients with juvenile systemic sclerosis. Finally, as cardiac imaging becomes more available, the radiologist has the opportunity to detect and quantify a rare but potentially lethal disease complication. Thus, there are several avenues by which multimodality thoracic imaging may guide management of this complex multisystem disorder. References 1. Daoussis D, Liossis SNC, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology 2010; 49: Seely JM, Jones LT, Wallace C, et al. Systemic sclerosis: using high-resolution CT to detect lung disease in children. 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9 Valeur et al. fibrosis on serial thoracic high-resolution CT scan phy: the Framingham Heart Study. Circ Cardiovasc derma in childhood. Rheum Dis Clin North Am than placebo: findings from the Scleroderma Imaging 2012; 5: ; 34: , ix Lung Study. Chest 2009; 136: Clements PJ, Becvar R, Drosos AA. Assessment 52. Launay D, Remy-Jardin M, Michon-Pasturel U, et 35. Kim HG, Tashkin DP, Clements PJ, et al. A com- of gastrointestinal involvement. Clin Exp Rheu- al. High resolution computed tomography in fi- puter-aided diagnosis system for quantitative matol 2003; 21(suppl 29):S15 S18 brosing alveolitis associated with systemic sclero- scoring of extent of lung fibrosis in scleroderma patients. Clin Exp Rheumatol 2010; 28(5 suppl 62):S26 S Brody AS. Imaging considerations: interstitial lung disease in children. Radiol Clin North Am 2005; 43: Zucker EJ, Guillerman RP, Fishman MP, Casey AM, Lillehel CW, Lee EY. Diffuse lung disease. In: Coley BD, ed. Caffey s pediatric diagnostic imaging, 12th ed. Philadelphia, PA: Elsevier Saunders, 2013: O Donovan JC, Lee EY, Effmann EL. Systemic conditions with lung involvement. In: Coley BD, ed. Caffey s pediatric diagnostic imaging, 12th ed. Philadelphia, PA: Elsevier Saunders, 2013: Kim EA, Lee KS, Johkoh T, et al. Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings. RadioGraphics 2002; 22:S151 S Sohn DI, Laborde HA, Bellotti M, Seijo L. Juvenile rheumatoid arthritis and bronchiolitis obliterans organized pneumonia. Clin Rheumatol 2007; 26: Aquino SL, Gamsu G, Fahy JV, et al. Chronic pulmonary disorders in sickle cell disease: findings at thin-section CT. Radiology 1994; 193: Truong QA, Massaro JM, Rogers IS, et al. Reference values for normal pulmonary artery dimensions by noncontrast cardiac computed tomogra- 44. Foeldvari I, Zhavania M, Birdi N, et al. Favourable outcome in 135 children with juvenile systemic sclerosis: results of a multi-national survey. Rheumatology (Oxford) 2000; 39: Weber P, Ganser G, Frosch M, et al. Twenty-four hour intraesophageal ph monitoring in children and adolescents with scleroderma and mixed connective tissue disease. J Rheumatol 2000; 27: Tolin RD, Malmud LS, Reilley J, Fisher RS. Esophageal scintigraphy to quantitate esophageal transit (quantitation of esophageal transit). Gastroenterology 1979; 76: Lambova S. Cardiac manifestations in systemic sclerosis. World J Cardiol 2014; 6: Meune C, Vignaux O, Kahan A, Allanore Y. Heart involvement in systemic sclerosis: evolving concept and diagnostic methodologies. Arch Cardiovasc Dis 2010; 103: Hachulla AL, Launay D, Gaxotte V, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis 2009; 68: Kowal-Bielecka O, Landewé R, Avouac J, et al.; EUSTAR Co-Authors. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009; 68: Zulian F. Systemic sclerosis and localized sclero- sis. J Rheumatol 2006; 33: Gohari Moghadam K, Gharibdoost F, Parastandechehr G, Salehian P. Assessments of pulmonary involvement in patients with systemic sclerosis. Arch Iran Med 2011; 14: Kirby M, Parraga G. Pulmonary functional imaging using hyperpolarized noble gas MRI: six years of start-up experience at a single site. Acad Radiol 2013; 20: Salerno M, Altes TA, Mugler JP, et al. Hyperpolarized noble gas MR imaging of the lung: potential clinical applications. Eur J Radiol 2001; 40: Mugler JP 3rd, Altes TA. Hyperpolarized 129 Xe MRI of the human lung. J Magn Reson Imaging 2013; 37: Lilburn DM, Pavlovskaya GE, Meersmann T. Perspectives of hyperpolarized noble gas MRI beyond 3 He. J Magn Reson 2013; 229: Ntusi NA, Piechnik SE, Francis JM, Ferreira VM, Rai AB, Matthews PM, et al. Subclinical myocardial inflammation and diffuse fibrosis are common in systemic sclerosis a clinical study using myocardial T1-mapping and extracellular volume quantification. J Cardiovasc Magn Reson 2014; 16: O Donovan JC, Lee EY, Effmann EL. Systemic conditions with lung involvement. In: Coley BD, ed. Caffey s pediatric diagnostic imaging, 12th ed. Philadelphia, PA: Elsevier Saunders, 2013:606 (Figures start on next page) 416 AJR:204, February 2015

10 Multimodality Imaging of Juvenile Systemic Sclerosis A Fig year-old girl with systemic sclerosis and pulmonary fibrosis. A C, Axial unenhanced CT images of thorax show reticular and ground-glass opacities and multiple small nodules in patchy distribution, with most abnormalities in lung periphery. Pleural and parenchymal cystic changes are greatest within anterior upper lobes (A) and lower lobes and are worse on left than right (B and C). D, Posteroanterior chest radiograph shows bilateral reticular opacities and scattered small cysts. Heart is mildly enlarged. C D B AJR:204, February

11 Valeur et al. A Fig year-old girl with systemic sclerosis and pulmonary fibrosis. A and B, Axial contrast-enhanced CT images in arterial phase reveal upper lobe patchy peripheral ground-glass and reticular opacities and severe lower lobe parenchymal cystic changes. Small bilateral pleural effusions are also noted. Basal-predominant fibrosis is typical of juvenile systemic sclerosis. Enlargement of pulmonary arteries from pulmonary hypertension is visible in A but is better shown in Figure 7. This examination was performed in arterial phase because of suspicion for pulmonary embolism. Fig. 3 7-year-old girl with systemic sclerosis and pulmonary fibrosis. Axial unenhanced CT image shows patchy ground-glass opacities affecting periphery of both lungs. Fig. 4 9-year-old girl with systemic sclerosis and pulmonary fibrosis. Axial unenhanced CT image reveals patchy ground-glass opacities, which are greatest in anterior right lung, and bilateral lower lobe parenchymal cystic changes, which are greater on left than right. Image is slightly degraded by respiratory artifact. B 418 AJR:204, February 2015

12 Multimodality Imaging of Juvenile Systemic Sclerosis Fig year-old girl with early pulmonary fibrosis. Axial unenhanced CT image shows bilateral lower lobe ground-glass opacities in curvilinear distribution with posterior subpleural parenchymal sparing (arrowheads). This pattern of subpleural sparing may be seen in other interstitial lung diseases pathologically characterized by nonspecific interstitial pneumonia. A Fig year-old girl with systemic sclerosis and early fibrosis. A, Axial unenhanced high-resolution CT (HRCT) image shows bilateral subpleural reticulation, ground-glass attenuation, and small parenchymal cysts (arrowheads). B, Axial HRCT image acquired at level of lower lobes shows mild focal ground-glass opacity (arrow), which may represent either early fibrosis or atelectasis. B A B Fig. 7 5-year-old boy with pulmonary hemorrhage obscuring early fibrosis. A and B, Axial contrast-enhanced CT images at level of upper (A) and lower (B) lobes exhibit geographic pattern of ground-glass opacities (GGOs) with interlobular septal thickening; latter finding is more conspicuous in right lung apex. GGOs are largely centered around bronchovascular bundles, which is a finding typical of hemorrhage. Combination of GGOs and reticular pattern has been referred to as crazy paving, nonspecific appearance likened to a tiled patio or sidewalk. (Fig. 7 continues on next page) AJR:204, February

13 Valeur et al. E C Fig. 7 (continued) 5-year-old boy with pulmonary hemorrhage obscuring early fibrosis. C and D, CT images in soft-tissue windows show extensive mediastinal (arrows, C), subcarinal (black arrow, D), and bilateral peribronchial (white arrows, D) lymphadenopathy. E and F, Unenhanced CT images obtained 3 months after A D reveal mild anterior subpleural reticulation and small cysts (arrows) indicating presence of mild underlying fibrosis that was obscured by prior hemorrhage. D F 420 AJR:204, February 2015

14 Multimodality Imaging of Juvenile Systemic Sclerosis Fig year-old girl with systemic sclerosis and primary pulmonary arterial hypertension. A, Axial contrast-enhanced CT image in soft-tissue windows shows enlargement of main (M), right (R), and left (L) pulmonary arteries. B, CT image in lung windows reveals clear pulmonary parenchyma. A Fig year-old girl with systemic sclerosis and secondary pulmonary arterial hypertension (same patient as in Fig. 2). Oblique reformatted contrast-enhanced CT image shows enlargement of main (M), right (R), and left (L) pulmonary arteries. Pleuroparenchymal fibrotic changes are again noted but are better seen in Figure 2. B AJR:204, February

15 Valeur et al. A Fig year-old girl with systemic sclerosis and esophageal involvement. A, Left posterior oblique fluoroscopic spot image from esophagography shows patulous contrast-filled esophagus. B and C, Planar images obtained at two different time points from 99m Tc-labelled sulfur colloid examination reveal that tracer (arrows) is in distal esophagus; in this case, the appearance indicates gastroesophageal reflux. A Fig year-old man with systemic sclerosis and cardiac involvement. A, Short-axis phase-sensitive inversion recovery image from cardiac MRI shows patchy transmural late gadolinium enhancement (arrows) involving inferolateral wall near heart base. B, Axial oblique magnitude image from phase-contrast MRI shows relative enlargement of central pulmonary arteries (main [M], right [R], and left [L]); these findings are compatible with pulmonary hypertension. Other cardiac MR images of this patient also showed decreased systolic function of right and left ventricles and enlargement of right and left ventricles. FOR YOUR INFORMATION This article is available for CME and Self-Assessment (SA-CME) credit that satisfies Part II requirements for maintenance of certification (MOC). To access the examination for this article, follow the prompts associated with the online version of the article. B B C 422 AJR:204, February 2015