Original Report. Fibrosis of the Upper Lobes: A Newly Identified Late-Onset Complication After Lung Transplantation?

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1 Downloaded from by on 05/04/18 from IP address opyright RRS. For personal use only; all rights reserved Eli Konen 1,2 Gordon L. Weisbrod 1 Smita Pakhale 3 Taeong hung 1 Narinder S. Paul 1 Michael. Hutcheon 3 Received May 5, 2003; accepted after revision July 2, Department of Medical Imaging, Toronto General Hospital, University Health Network, 200 Elizabeth St., Toronto, ON ES1-401, anada. 2 Present address: Department of Diagnostic Imaging, haim Sheba Medical enter, Tel Hashomer 52621, Israel. ddress correspondence to E. Konen (konen@zahav.net.il). 3 Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto ON ES1-401, anada. JR 2003;181: X/03/ merican Roentgen Ray Society Original Report Fibrosis of the Upper Lobes: Newly Identified Late-Onset omplication fter Lung Transplantation? OJETIVE. The objective of this study was to describe the high-resolution T findings of a previously unreported rare complication observed in seven patients who had undergone lung transplantation. ONLUSION. High-resolution T findings suggestive of gradual progressive lung fibrosis, predominantly in the upper lobes with relative sparing of the basal segments, may represent a specific and rare type of rejection of still unknown cause in lung transplant recipients. L ung transplant recipients are prone to a wide range of early- and lateonset complications. Major longterm complications include the development of bronchiolitis obliterans, opportunistic infections, organizing pneumonia, recurrence of the primary disease, posttransplantation lymphoproliferative disorder, and bronchogenic carcinoma [1 6]. T plays an important role in the diagnosis and follow-up of these complications [3, 6, 7]. etween June 1, 1992, and May 31, 2002, 391 patients underwent lung transplantation (double lung, 334; single lung, 50; and heart lung, seven) at our center. s a part of the long-term follow-up of these patients, an annual high-resolution T examination was performed. From these follow-up T scans, we identified seven lung transplant recipients whose T findings showed a gradual development of parenchymal abnormalities that did not correspond radiologically or clinically to any of the known complications encountered after lung transplantation. We describe our retrospective assessment of the high-resolution T, clinical, and laboratory findings in these patients. Materials and Methods etween July 1, 2000, and June 30, 2002, we identified seven lung transplant recipients (four female and three male patients) who were referred to our department for a routine follow-up high-resolution T examination of the chest that revealed a unique pattern of lung parenchymal changes. Mean age at the time of lung transplantation was 47.7 years (range, years). The indications for lung transplantation were chronic obstructive pulmonary disease in three patients, pulmonary fibrosis in two patients, sarcoidosis in one patient, and cystic fibrosis in one patient. Six patients had undergone double lung transplantation, and one had undergone single lung transplantation. total of 44 high-resolution T scans were available for evaluation, a range of three to nine scans (mean, six scans) per patient. The scans were obtained from 3 to 92 months after lung transplantation. ll of the high-resolution T scans were retrospectively evaluated by two chest radiologists: one, a staff-grade chest radiologist and the other, a fellowship-trained chest radiologist. oth reviewers were unaware of any clinical or laboratory data. ll high-resolution T scans obtained in 1997 or later (n = 40) were evaluated on a PS (picture archiving and communication system) workstation (efilm workstation 1.7.1, Merge efilm, Toronto, anada), whereas earlier scans (n = 4) were assessed on hard-copy films. oth lungs were evaluated separately in three zones: upper lobes and right middle lobe, superior segments of lower lobes, and basal segments of lower lobes. Each zone was evaluated for the presence of the following abnormalities: peripheral interstitial opacities (interlobular septal thickening and coarse interstitial reticular opacities), traction bronchiectasis, honeycombing, and architectural JR:181, December

2 Konen et al. Downloaded from by on 05/04/18 from IP address opyright RRS. For personal use only; all rights reserved distortion. Interstitial opacities and honeycombing were graded on a four-point scale: 0, no significant abnormality; 1, abnormalities involving up to 25% of the lobar volume; 2, abnormalities involving 26 50% of the lobar volume; and 3, abnormalities involving more than 50% of the lobar volume. The severity of traction bronchiectasis and architectural distortion was subjectively scored using the following scale: 0, no bronchiectasis or distortion; 1, mild; 2, moderate; and 3, severe. Evidence of pneumothorax was also recorded. Serial volume assessments of the upper lobes were calculated on a postprocessing workstation (V Viewer, General Electric Medical Systems, Milwaukee, WI) using a modification of a previously described method [8]. The contours of the upper lobes were manually traced, and the crosssectional area was determined using the region-ofinterest function. TLE 1 verage Scores for bnormalities Seen on Follow-Up High-Resolution T Scans Obtained in Seven Patients fter Lung Transplantation Findings Segregated by Lung Segment (Grading scale, 0 3) a No. of Years Elapsed etween Surgery and T Scan > 4 No. of Patients/No. of Scans Evaluated for Each Period 5/12 4/7 5/6 5/7 5/12 Peripheral interstitial opacities Upper lobes 0.2 b Superior segments asal segments 0.4 b Traction bronchiectasis Upper lobes Superior segments asal segments Honeycombing Upper lobes Superior segments asal segments rchitectural distortion Upper lobes Superior segments asal segments Note. verage scores were calculated by adding the highest scores that the patients received at the given postoperative period and dividing that sum by the number of patients evaluated at that period. a Scale for interstitial opacities and honeycombing was based on percentage of lobar volume affected by abnormality: 0, no significant abnormality; 1, 1 25% of lobar volume; 2, 26 50%; and 3, > 50%. Scale for severity of traction bronchiectasis and architectural distortion was as follows: 0, no bronchiectasis or distortion; 1, mild; 2, moderate; and 3, severe. b Most opacities appeared within the first 3 months after transplantation and were nonspecific. They resolved slowly but completely. Results The analysis of the sequential follow-up high-resolution T scans is summarized in Table 1. Initial parenchymal abnormalities were noted on high-resolution T scans obtained months after lung transplantation (mean, 42 months). The earliest parenchymal abnormalities noted were peripheral interstitial opacities, ranging from interlobular septal thickening to coarse interstitial reticular opacities (Figs. 1 3). Some abnormalities were associated with mild peripheral ground-glass opacities (Fig. 2). Traction bronchiectasis, honeycombing, and architectural distortion all subsequently developed and appeared contemporaneously (Figs. 1, 2, and 3). In one patient who underwent a single left lung transplantation, similar changes were noticed mainly in the transplanted lung, whereas the native lung showed minimal interval changes (Fig. 4). The upper and middle lobes were affected first and to the greatest degree in all seven patients, followed by the superior segments of the lower lobes; the basal segments remained relatively spared (Table 1). omputed volumetric calculations comparing the initial and last high-resolution T scans showed a mean interval decrease of 45% in the volume of the upper lobes (range, 25 66%) (Table 2). Decreased volume showed no significant predilection for occurring in either lung. n associated pneumothorax was noted on at least one scan of five (71%) of the seven patients (Figs. 1 and 3). In two patients, the pneumothorax appeared 4 years after transplantation (one patient had a persistent asymptomatic pneumothorax after an open lung biopsy and later developed an additional spontaneous pneumothorax); in the remaining three patients, the pneumothorax appeared 5 6 years after transplantation. fter the initial radiologic changes were noted, all patients presented clinically with progressive limitation in exercise tolerance and shortness of breath. In all patients, pulmonary function tests showed a progressively restrictive pattern compared with the postoperative baseline test. In three patients, this pattern was accompanied by a mild obstructive defect. areful microbiologic evaluation did not reveal any specific causative agent. Repeated transbronchial biopsies in all patients and open lung biopsy in one patient revealed nonspecific inflammation and fibrotic changes. Discussion The high-resolution T findings for seven lung transplant recipients were suggestive of progressive upper lobe fibrosis. lthough the ages, indications for lung transplantation, and clinical findings of the patient population were diverse, the pattern of gradual high-resolution T changes was strikingly similar. The initial findings were suggestive of an interstitial lung disease but are nonspecific; these findings include interlobular septal thickening and gradual development of coarse reticular opacities, occasionally associated with mild peripheral ground-glass opacities (Figs. 1, 2, and 3). This pattern suggests an early mechanism of interstitial inflammation that might already be accompanied by elements of interstitial fibrosis, and the pathologic findings obtained in the patients support this explanation. Within a few months, more specific findings for pulmonary fibrosis appeared, including traction bronchiectasis, honeycombing, and architectural distortion of the lung parenchyma (Figs. 1, 2, 3, and 4). The changes primarily affected the upper lobes and later, to a lesser degree, the superior segments of the lower lobes, whereas the basal segments were minimally involved (Table 1). The parenchymal findings were associated with a significant reduction in lung volume, which was most 1540 JR:181, December 2003

3 Downloaded from by on 05/04/18 from IP address opyright RRS. For personal use only; all rights reserved Upper Lobe Fibrosis fter Lung Transplantation Fig year-old woman who underwent double lung transplantation 5 years earlier because of chronic obstructive pulmonary disease., xial high-resolution T scan obtained 18 months after surgery at level of distal trachea shows mild bronchial dilatation. Otherwise, no significant parenchymal abnormalities are seen., xial high-resolution T scan obtained 17 months after at level of aortic arch shows interval appearance of extensive peripheral course reticular and patchy ground-glass opacities (arrowheads), interlobular septal thickening (short arrow), and associated severe dilatation of bronchi (long arrow)., xial high-resolution T scan obtained 19 months after shows advancing bilateral coarse opacities with cystic changes, architectural distortion, and additional bilateral volume loss, all suggestive of lung fibrosis. Note interval appearance of persistent right pneumothorax that occurred after open lung biopsy. rrow indicates surgical metal clip at site of lung biopsy. Fig year-old man who underwent double lung transplantation necessitated by end-stage sarcoidosis., xial high-resolution T scan obtained 9 months after surgery at level of aortic arch shows no significant parenchymal abnormalities., xial high-resolution T scan obtained at same level 10 months after shows interval appearance of bilateral peripheral interstitial opacities (arrowheads) and interlobular septal thickening (thin arrow), with associated bronchial dilatation. Thick arrow indicates interlobar fissure., xial high-resolution T scan obtained 15 months after shows interval anterior progression of interlobar fissure (thick arrow), suggesting further volume loss of right upper lobe. Note associated traction bronchiectasis (thin arrow). JR:181, December

4 Downloaded from by on 05/04/18 from IP address opyright RRS. For personal use only; all rights reserved Konen et al. Fig year-old man who underwent double lung transplantation at age of 13 for cystic fibrosis., xial high-resolution T scan obtained at level of carina 43 months after transplantation shows normal lung parenchyma., xial high-resolution T scan obtained at same level as 12 months later shows interval appearance of bilateral diffuse peripheral interstitial opacities (arrowheads) and mild septal thickening (arrow)., xial high-resolution T scan obtained at same level as and 12 months after shows further reduction in lung volumes, bilateral course interstitial opacities with associated traction bronchiectasis (thin arrows) and cystic changes (thick arrow) suggestive of honeycombing. Note loculated pneumothorax on left hemithorax (arrowheads). striking in the upper lobes, with an average volume loss of 45% (Table 2). n associated pneumothorax was noted on at least one scan in five of our seven patients (Fig. 3); the pneumothorax was usually small and loculated, producing minimal, if any, symptoms. Neither the clinical, laboratory, nor pathologic findings were specific or helpful in determining a common pathophysiologic process in this group of patients. lso, none of the patients was treated with a pulmonary cytotoxic drug. The associated clinical picture was one of progressive dyspnea, with the results of pulmonary function tests suggestive of obstructive and restrictive patterns and pathologic analysis showing nonspecific inflammation and fibrosis. Upper lobe changes and fibrosis might be caused by mycobacterial infection; however, repeated microbio- Fig year-old woman who underwent single (left) lung transplantation at age 56 for interstitial pulmonary fibrosis., xial high-resolution T image obtained at level of distal trachea 9 months after surgery shows normal transplanted left lung. Diffuse fibrosis in native right lung with volume loss causes shifting of mediastinum to right. rrow indicates interlobar fissure., xial high-resolution T scan obtained at same level 35 months after shows interval appearance of subpleural reticular opacities mainly in left upper lobe (arrowheads), associated with traction bronchiectasis (thin arrow) and volume loss. Shift of mediastinum toward midline and interval anterior progression of interlobar fissure (thick arrow) are seen. Findings in right lung parenchyma remain mostly unchanged JR:181, December 2003

5 Upper Lobe Fibrosis fter Lung Transplantation Downloaded from by on 05/04/18 from IP address opyright RRS. For personal use only; all rights reserved TLE 2 omparison of Volumes of Upper Lobes on First and Last vailable High-Resolution T Scans in Seven Lung Transplant Recipients Volume (cm 3 ) Time Elapsed Patient Right Upper Lobe Left Upper Lobe etween First Scan Last Scan hange (%) First Scan Last Scan hange (%) Scans (mo) a N N N 1, , , , Note. N = not applicable. a ecause the patient had single lung transplantation, calculations were obtained only for the left upper lobe. logic studies showed no evidence of such infection. Recurrence of the native disease, including recurrent pulmonary fibrosis, is a wellknown complication in patients after lung transplantation and is most frequently reported in patients with sarcoidosis [3]. However, such recurrence would explain the radiologic findings in only one of our patients who underwent a lung transplantation because of end-stage lung disease resulting from sarcoidosis. Recurrent disease in two other patients, who previously had interstitial lung disease, would be expected to appear mainly in the lower lobes, not in the apices of the lungs, as observed in this cohort. literature search revealed one article with a lung transplant recipient whose radiologic images were identical to those seen in our patients [9]. Volume loss was described generally as part of the spectrum of T findings in patients with lung rejection, with no emphasis of the upper lobe predominance. Whether this particular pattern of predominantly upper lobe fibrosis represents an expression of lung rejection is unknown; the causative mechanism has not been identified. The fact that such changes affected mainly the transplanted lung in a patient who underwent single lung transplantation (Fig. 4) further suggests the hypothesis of lung rejection, as opposed to another bilateral systemic disease. heightened awareness of this condition among thoracic radiologists and respirologists who follow up lung transplant recipients might lead to a better understanding of this specific and rare pattern. In conclusion, we have described the highresolution T findings in seven lung transplant recipients who showed a unique pattern of progressively advancing pulmonary fibrosis that appeared initially in the upper lobes, and later, less prominently, in the superior segments of the lower lobes, with a relative sparing of the basal segments. linical, laboratory, microbiologic, and pathologic studies in our patients did not reveal any specific finding that could explain a common mechanism in this group of patients. Further investigation involving a larger number of lung transplant recipients with similar radiologic findings might shed more light on this rare type of lung rejection. References 1. Hertz MI, Taylor DO, Trulock EP, et al. The registry of the International Society for Heart and Lung Transplantation: nineteenth official report J Heart Lung Transplant 2002;21: rcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1999;340: ollins J, Hartman MJ, Warner TF, et al. Frequency and T findings of recurrent disease after lung transplantation. Radiology 2001;219: Mehrad, Paciocco G, Martinez FJ, Ojo T, Iannettoni MD, Lynch JP 3rd. Spectrum of spergillus infection in lung transplant recipients: case series and review of the literature. hest 2001;119: Paranjothi S, Yusen RD, Kraus MD, Lynch JP, Patterson G, Trulock EP. Lymphoproliferative disease after lung transplantation: comparison of presentation and outcome of early and late cases. J Heart Lung Transplant 2001;20: ollins J, Kazerooni E, Lacomis J, et al. ronchogenic carcinoma after lung transplantation: frequency, clinical characteristics, and imaging findings. Radiology 2002;224: ankier, Van Muylem, Knoop, Estenne M, Gevenois P. ronchiolitis obliterans syndrome in heart lung transplant recipients: diagnosis with expiratory T. Radiology 2001;218: Puybasset L, luzel P, hao N, Slutsky S, oriat P, Rouby JJ. computed tomography scan assessment of regional lung volume in acute lung injury: the T Scan RDS Study Group. m J Respir rit are Med 1998;158: Ikonen T, Kivisaari L, Taskinen E, Piilonen, Harjula L. High-resolution T in long-term follow-up after lung transplantation. hest 1997;111: JR:181, December