Skip to main content
Insights into Imaging
Download PDF

Imaging indications and findings in evaluation of lung transplant graft dysfunction and rejection

Insights into Imaging volume 11, Article number: 2 (2020) Cite this article

Abstract

Lung transplantation is a treatment option in end-stage lung disease. Complications can develop along a continuum in the immediate or longer post-transplant period, including surgical and technical complications, primary graft dysfunction, rejection, infections, post-transplant lymphoproliferative disorder, and recurrence of the primary disease. These complications have overlapping clinical and imaging features and often co-exist. Time of onset after transplant is helpful in narrowing the differential diagnosis. In the early post transplantation period, imaging findings are non-specific and need to be interpreted in the context of the clinical picture and other investigations. In contrast, imaging plays a key role in diagnosing and monitoring patients with chronic lung allograft dysfunction. The goal of this article is to review primary graft dysfunction, acute rejection, and chronic rejection with emphasis on the role of imaging, pathology findings, and differential diagnosis.

Key points

  • Primary graft dysfunction is a syndrome of acute lung injury after lung transplant, which is characterized by development of hypoxia and diffuse pulmonary opacities in the early post-operative period without another identifiable etiology.

  • Acute cellular rejection is the most common type of acute rejection. It is frequently asymptomatic, may occur at any time after transplant, and shows non-specific imaging findings which can vary considerably. Transbronchial biopsy remains the gold standard for diagnosis.

  • Antibody-mediated rejection is less common type of acute rejection, and the diagnosis is made by integrating clinical, serologic, radiographic, and pathologic findings.

  • Bronchiolitis obliterans syndrome is the most common form of chronic lung allograft dysfunction and characterized by fibrosis/scarring that obliterates bronchioles. It typically develops after the 1st year following transplantation. Bronchiolitis obliterans syndromeis a clinical diagnosis defined by a persistent decline in FEV1 compared with baseline. Bronchiolitis obliterans manifests on CT with bronchial wall thickening, mosaic attenuation, and air trapping on expiratory images.

  • Restrictive allograft syndrome is a less common form of chronic lung allograft dysfunction. It carries a worse prognosis and is thought to be characterized pathologically by pleuroparenchymal fibroelastosis. Imaging reveals upper lobe fibrosis and signs of volume loss.

Introduction

Over the last few decades, lung transplantation has emerged as an accepted treatment option in end-stage lung disease. Diseases such as idiopathic pulmonary fibrosis, advanced emphysema, cystic fibrosis, and pulmonary arterial hypertension are being increasingly treated with lung transplantation. The number of lung transplants has been increasing over the last 20 years, with approximately 64,803 adult lung transplants performed worldwide so far. Improved survival following lung transplant has been linked to multiple factors, including improved surgical technique, drugs, and improved patient selection [1]. Despite the improved outcomes, several complications can develop during the early postoperative period as well as later in the time course, affecting quality of life and contributing to mortality. Important complications in the early postoperative course include surgical complications, infection, primary graft dysfunction, acute rejection, and in later course, chronic lung allograft dysfunction, infection, and post-transplant lymphoproliferative disorder [2, 3]. Difficulties in diagnosis arise from the non-specific clinical presentation of these entities, and the frequent coexistence of multiple complications in the same patient. Imaging plays an important role in evaluating graft dysfunction. Chest radiographs are routinely performed in the postoperative period and for periodic surveillance. Computed tomography (CT) is the imaging test of choice for evaluating lung graft complications and dysfunction. However, because CT findings can be non-specific, especially in the early postoperative period, knowledge of the clinical context, including symptoms, time course of the presentation since transplant, and correlation with other investigations such as pulmonary function tests, echocardiography, and bronchoscopy helps in narrowing the differential diagnosis (Table 1) [2,3,4]. Other imaging tools such as magnetic resonance imaging (MRI) and positron-emission tomography (PET) are helpful in specific clinical scenarios.

Table 1 Summary of role of additional common tests in the workup of graft dysfunction
Full size table

The goal of this article is to review the pathophysiology and evaluation of lung transplant graft dysfunction along a time continuum with emphasis on the role of imaging.

CT protocol

The CT protocol used depends on the clinical question that needs to be addressed. For routine follow-up and evaluation of lung parenchyma, a routine chest CT is sufficient. Use of contrast is optional and preferred if there is a clinical concern of vascular complications. For acute graft dysfunction, CT angiography can be helpful if vascular complications such as pulmonary artery stenosis/occlusion or pulmonary venous stenosis are suspected. For evaluation of chronic lung allograft dysfunction, CT protocol in patients in our institution includes high-resolution CT images from the lung apex to the diaphragm at end-inspiration with 1-mm slice thickness in 1-mm increments. End-inspiration imaging is usually followed by a free breathing imaging at different levels (mid trachea, carina, lung bases). Free breathing imaging is helpful in assessing for air way malacia and air trapping. Axial (3 × 1.5 mm), sagittal (3 × 3 mm), and coronal (3 × 3 mm) images are routinely reconstructed. Continuous axial 1-mm images are available upon request to be uploaded to a 3-dimensional workstation for further evaluation including virtual bronchoscopy if needed but not routinely reconstructed.

Hyperacute rejection

Hyperacute rejection is a type of antibody-mediated rejection. Hyperacute rejection after lung transplant is exceedingly rare in the era of sensitive pre-transplant panel reactive antibody testing. Hyperacute rejection occurs in patients with pre-formed circulating antibodies to donor human leukocyte antigen [HLA] that attack the graft. It develops during surgery or within the first 24 h after lung transplant. It can be treated with apheresis and augmented immunosuppression, but can be fatal despite treatment. Initial radiographs typically show diffuse opacities in the transplanted lung(s), typically of pulmonary edema pattern [5,6,7,8,9].

Primary graft dysfunction

Primary graft dysfunction is a syndrome of acute lung injury in the early post-transplant period. It is a major cause of early morbidity and mortality, with an incidence in the range of 30% [10]. Primary graft dysfunction is thought to result from multifactorial injury to the transplanted lung by the transplant process and other contributing factors. Transplant process-related factors include organ retrieval, preservation, implantation, and reperfusion. Acid aspiration, pneumonia, and micro-trauma from mechanical ventilation are thought to be contributing factors. The term “primary graft dysfunction” has replaced other previously used terms such as ischemia-reperfusion injury/edema, re-implantation edema/response, and primary graft failure. The main pathologic manifestation of primary graft dysfunction is diffuse alveolar damage, characterized by hyaline membranes in the acute stage (Fig. 1) and alveolar septal thickening by fibroblasts [10, 11]. The pathologic findings are identical to those seen in acute interstitial pneumonia, except that they occur in the context of lung transplantation [12]. Survivors of primary graft dysfunction have a higher incidence of development of chronic lung allograft dysfunction [10, 13, 14].

Fig. 1
figure 1

Primary graft dysfunction: imaging and transbronchial biopsy findings. The patient was 2 days status-post left lung transplant and developed increasing hypoxemia. Axial CT images (a) shows smooth interlobular septal thickening with ground-glass opacities in the transplanted left lung. These findings are typical of primary graft dysfunction but are indistinguishable from acute rejection. Transbronchial biopsy (b) from a different lung transplant patient with primary graft dysfunction showing diffuse alveolar damage. Note hyaline membranes (arrows)

Full size image

Primary graft dysfunction is characterized by the development of hypoxia and diffuse pulmonary radiographic opacities within the first 72 h after lung transplantation without another identifiable cause such a cardiogenic pulmonary edema, infection, or rejection. Assessment for this syndrome occurs at four time points, starting at the time of reperfusion of the second lung, and then at 24, 48, and 72 h. The goal of the grading system for primary graft dysfunction is to help identify patients with potentially poor outcomes. The ratio of arterial fraction of oxygen (PaO2)/fraction of inspired oxygen (FiO2) determines the severity of primary graft dysfunction. Any PaO2/FiO2 ratio with a normal chest radiograph is considered grade 0. Grades 1, 2, and 3 are characterized by diffuse pulmonary opacities on chest radiograph with PaO2/FiO2 > 300, between 200 and 300, and < 200, respectively [10].

Radiographic and CT findings of primary graft dysfunction are variable and non-specific. The most common findings are perihilar and basilar heterogeneous opacities. The opacities typically appear within 3 days after transplantation, worsen for a few days, and usually start clearing between 5 and 10 days post-transplant. Persistent or worsening opacities should raise concern for acute rejection or infection. Typically, focal clustered opacities raise the suspicion of an infectious process [2, 15,16,17]. Chest CT may show ground-glass opacities, consolidation, and interstitial and interlobular septal thickening (Fig. 1) [2, 3, 18].

Differential diagnostic considerations for graft dysfunction during the first 72 h include pulmonary edema (due to volume overload or myocardial dysfunction), pneumonia, rejection, aspiration, pulmonary, and pulmonary vein stenosis or airway anastomotic complications. Primary graft dysfunction may coexist with any of these processes. Therefore, the diagnostic workup of suspected primary graft dysfunction should include characterization of radiographic abnormalities, assessment of volume status, echocardiography, review of ventilator settings, review of donor-recipient crossmatch, and screening for donor-specific antibodies [4]. The primary role of imaging is to exclude other process that may cause symptoms or radiographic abnormalities. For example, CT angiography can be used to diagnose pulmonary embolism or arterial or venous anastomotic occlusion or stenosis (Fig. 2) [2]. Imaging also helps in selecting the most appropriate site for bronchoalveolar lavage and transbronchial biopsy [19]. Flexible bronchoscopy with bronchoalveolar lavage is usually performed in cases of early graft dysfunction with infiltrates to obtain samples for microbiologic testing, to inspect the airway, and to evaluate for bronchial anastomotic complications [4].

Fig. 2
figure 2

Left pulmonary artery anastomotic occlusion. CT-PE protocol was performed after suspecting left pulmonary artery anastomotic occlusion on initial non-enhanced CT scan performed on day 3 post bilateral lung transplant. Axial images using lung window (a and b) show diffuse and ill-defined consolidations in the left lung, predominantly in the lingula and the left lower lobe (asterisks). These findings are likely related to areas of pulmonary hemorrhage with evolving areas of pulmonary infarcts. There is associated ground glass opacities and interlobular septal thickening, best appreciated in the left upper lobe. Axial images using soft tissue window (c–e) show a total occlusion of the left pulmonary artery at the arterial anastomotic site (arrows) and a patent right pulmonary artery (asterisks). Note the enhancing left pulmonary veins within the left lung consolidation

Full size image

Acute allograft rejection

Acute rejection occurs in more than a third of lung transplant cases in the first year after transplant, and results in approximately 4% of deaths within the first 30 days after transplantation [20,21,22]. Acute cellular rejection is the most common type of acute rejection. It is caused by a T-lymphocyte-rich cellular response directed against major histocompatibility complexes (MHC) in the donor lung (also known as HLA in humans), or other donor antigens. Acute cellular rejection can occur at any time after transplant and is most commonly encountered within the first year after lung transplantation [22]. Acute rejection may present with symptoms of dyspnea, cough, or lower extremity edema. A decline in forced expiratory volume in 1 s (FEV1) may be noted on pulmonary function testing. Frequently, patients will be asymptomatic with stable pulmonary function testing, and the diagnosis is made with pathologic findings in transbronchial biopsies obtained during surveillance bronchoscopy. The pathologic findings are well-characterized [22,23,24], and include patchy lymphohistiocytic inflammatory infiltrates centered on small blood vessels (arterioles/venules). Bronchioles may also be inflamed. The International Society for Heart and Lung Transplantation (ISHLT) has laid out standardized nomenclature for grading of acute cellular rejection based on the severity of the inflammatory process and the structures involved. The vascular component, which is most common in practice, ranges from grade A0 (no rejection) to grade A4 (severe), most cases being A1 or A2. The airway component ranges from B0 (no rejection) to B2R (high grade). Acute vascular and airway rejection can be seen independently (Fig. 3), or may co-exist in the same patient [23].

Fig. 3
figure 3

Transbronchial biopsy findings in acute cellular rejection following lung transplantation. The vascular component of acute cellular rejection (a) is characterized by a lymphocyte-rich inflammatory infiltrate involving and surrounding small blood vessels within lung parenchyma. The Movat pentachrome stain (b) helps to highlight elastic layers in the blood vessel, demonstrating that inflammatory cells breach the elastic layers (black wavy lines) and involve the vascular intima (arrow). Airways involved by acute cellular rejection (c) show inflammation (long arrow). In more advanced examples, there is epithelial damage, manifested by sloughing of epithelial cells into the airway lumen (short arrow)

Full size image

Chest radiography is often ordered as a baseline test. It may show non-specific findings such as perihilar opacities and/or pleural effusion. It has low sensitivity and specificity for acute rejection, and is usually performed to look for diseases other than rejection. Chest CT is typically obtained to evaluate the severity and distribution of the disease process. The CT findings of acute cellular rejection are non-specific. They include ground-glass opacities, consolidation, and interstitial thickening with or without pleural effusions (Fig. 4) [3, 25, 26]. Significant clinical and radiographic improvement after early administration of high dose of corticosteroids provides additional supporting evidence for acute rejection [27]. Given the non-specific nature of imaging findings in acute cellular rejection, the main role of CT is to exclude other etiologies and help identifying targets for bronchoscopic tissue sampling [22, 25, 26]. Trans-bronchial biopsies are typically obtained from the lower lobes if the lungs are normal on imaging or if the disease process is diffuse. When disease is patchy on imaging, biopsies are usually taken from the radiologically abnormal areas [19].

Fig. 4
figure 4

Patient with bilateral lung transplant and mild acute cellular rejection. Axial CT images (a–d) show asymmetric (right more than left) patchy and nodular peribronchial ground glass opacities (arrows) with basilar peribronchial consolidative opacities (arrowheads) and mild bibasilar septal thickening. Transbronchial biopsy of both lower lobes showed mild acute cellular rejection (grade A2 B0)

Full size image

Antibody-mediated rejection is less common than acute cellular rejection. It is caused by antibodies against HLA antigens in the donor lung, or possibly to auto-antigens in the context of lung injury. Patients with antibody-mediated rejection usually present with respiratory symptoms that typically manifest weeks or months following transplantation. The diagnosis is extremely challenging and needs careful correlation of the clinical, radiologic, pathologic, and serologic findings (Fig. 5). The pathologic findings in this entity are poorly defined. Reported findings include acute lung injury and diffuse alveolar damage with or without capillaritis. Diagnostic criteria include detection of circulating donor specific antigen (DSA), compatible histopathologic findings, and positive immunohistochemical staining for complement component 4d (C4d). Cases with all three features are diagnosed as “definite.” The recommended designation is “probable” if 2 features are present, and “possible” if any 1 feature is present [5]. In practice, immunohistochemical staining for C4d is associated with several problems, including low sensitivity and specificity, and high background staining. There is limited data in the literature regarding the imaging findings of acute antibody-mediated rejection.

Fig. 5
figure 5

A 60-year-old male with rheumatoid arthritis–related usual interstitial pneumonia status post right lung transplant presented with shortness of breath. CT-PE protocol was performed. Axial images using soft tissue (a and b) and lung (c and d) windows show infiltrative right hilar and perihilar soft tissue density (arrows), peribronchovascular interstitial thickening, interlobular septal thickening, and ground-glass opacities within the transplanted right lung. Advanced fibrosis with exuberant honeycombing is noted in the native left lung. These findings raised concern for post-transplant lymphoproliferative disorder. Pathology and EBV PCR were negative. Flow cytometry was positive for donor specific antibody to DQ2. These findings were suggestive of antibody-mediated rejection

Full size image

The differential diagnosis of lung transplant patients with declining allograft function weeks to months after transplant includes acute rejection, infection, airway complications (airway stenosis, tracheobronchomalacia, or granulation tissue), vascular anastomotic complications, chronic rejection, and cardiac dysfunction [4, 22]. Evaluation includes a battery of laboratory testing for evidence of infection, imaging with chest radiography or CT, spirometry, and flexible bronchoscopy for bronchoalveolar lavage and transbronchial biopsy to confirm the diagnosis of acute rejection and to exclude processes such as infection, aspiration or organizing pneumonia [4, 22]. Even after a thorough evaluation, some cases can prove diagnostically challenging. The evaluation of these patients can be greatly complicated by presence of more than one process in the same patient (Fig. 6). Post-transplant lymphoproliferative disorder could rarely present early during the first weeks post lung transplant and should be considered in the differential diagnosis of persistent opacities during this period [28].

Fig. 6
figure 6

Role of multimodality imaging in a 32-year-old male status post bilateral lung transplant presenting with shortness of breath. CT images in lung window setting (a, b) show multifocal bilateral consolidations, which are predominately seen in both lower lobes. Images from flexible bronchoscopy (c, d) show mucopurulent secretions at origin of right bronchus and in right middle lobe bronchi. Still image from esophagogram (e) shows small hiatal hernia (arrow); the patient had delayed esophageal emptying. Mycoplasma IgM titers were high and the patient was felt to have mycoplasma pneumonia with co-existing aspiration pneumonia. Trans-bronchial biopsy was negative for acute rejection

Full size image

Chronic lung allograft dysfunction

Chronic lung allograft dysfunction (CLAD) following lung transplantation is a major cause of morbidity and mortality [29]. It is an umbrella term that encompasses bronchiolitis obliterans syndrome and restrictive allograft syndrome [29, 30].

Bronchiolitis obliterans syndrome/obliterative bronchiolitis

Bronchiolitis obliterans syndrome/obliterative bronchiolitis is the most common form of chronic lung allograft dysfunction and reported in 48% of patients by 5 years after transplant and 76% of patients after 10 years [1]. Obliterative bronchiolitis (also known as constrictive bronchiolitis) is a pathologic diagnosis characterized by fibrotic scarring that greatly narrows or completely obliterates bronchiolar lumens (Fig. 7). Bronchiolitis obliterans syndrome is the clinical manifestation of obliterative bronchiolitis. The hallmark of this syndrome is the presence of declining pulmonary function tests compared with baseline, in the absence of another explanation such as acute rejection, infection, pulmonary edema, or airway stenosis. Defined in this way, the diagnosis obviates the need for pathologic confirmation, which is limited by sampling issues and low sensitivity. Obliterative bronchiolitis/bronchiolitis obliterans syndrome is the most common manifestation of chronic lung allograft dysfunction [29]. Acute rejection, recurrent infections, primary graft dysfunction, HLA mismatch, cytomegalovirus pneumonitis, aspiration, and non-compliance with immunosuppressive therapy are thought to be potential risk factors for this disease [31]. Bronchiolitis obliterans syndrome often presents with non-specific symptoms; in advanced cases, patients may present with dyspnea at rest. The key feature is irreversible airflow limitation with a sustained decrease in FEV1 for > 3 weeks. The clinical staging of bronchiolitis obliterans syndrome is based on the FEV1 compared with baseline (Table 2). Pathologic examination shows obliterative bronchiolitis, as described above [29, 32]. Bronchiolar involvement in this disease is typically patchy, greatly limiting the yield of transbronchial biopsy [33]. A major role of bronchoscopy in this setting is to exclude other causes of decreased FEV1 such as acute rejection, infection, or bronchial stenosis [29].

Fig. 7
figure 7

Bronchiolitis obliterans syndrome. Axial inspiratory (a) and expiratory (b) CT images show normal-appearing transplanted lungs on inspiratory phase and areas of air-trapping on expiratory phase. CT minimum intensity projection (MinIP) image (c) of a different patient shows mosaic attenuation and bronchiectasis. Pathologic findings of obliterative bronchiolitis (D); the lumen of this bronchiole is completely obliterated by fibrous tissue (green and yellow). Residual smooth muscle bundles: red. Elastic tissue: black (Movat pentachrome stain, 100×)

Full size image
Table 2 BOS classification system
Full size table

Unlike assessment of acute rejection, imaging plays a crucial role in the diagnosis and stratification of patients with chronic lung allograft dysfunction. Chest radiography is often the first investigation and is often normal in the early stage. Volume loss with fibrotic changes can be seen in advanced disease. CT scans may be normal during early stages of the process, or may show air trapping on expiratory imaging reflecting early obliterative bronchiolitis [34]. Late stages show mosaic attenuation caused by air trapping and may be associated with bronchiectasis (Fig. 7) [35,36,37,38]. Spirometry is more sensitive in detecting the bronchiolitis obliterans syndrome than chest CT [39]. Tree-in-bud and centrilobular nodules can be seen and are thought to represent mucus impaction in distal bronchioles. Respiratory infection should be excluded based on clinical symptoms, bronchoalveolar lavage, and absence of concomitant suggestive imaging features such as consolidation before attributing these findings to the bronchiolitis obliterans syndrome [40].

Restrictive allograft syndrome

Restrictive allograft syndrome is the less common phenotype of irreversible chronic lung allograft dysfunction; it has been associated with a worse prognosis compared with bronchiolitis obliterans syndrome. It ultimately affects approximately 10% of lung transplant recipients. Patients present with restrictive lung function tests [30]. Reported pathologic findings include pleuroparenchymal fibroelastosis with or without organizing pneumonia [29, 41]. Early imaging findings include central and peripheral ground-glass opacities and organizing pneumonia (Fig. 8) [42]. Imaging features that suggest organizing pneumonia include peribronchial, perilobular, or subpleural consolidations with or without the classic reverse halo sign [43]. Peripheral fibrotic changes with upper lung predominance, volume loss, hilar retraction, and traction bronchiectasis (Fig. 8) are the classic advanced imaging findings [30, 42, 44]. Some cases may present with lower lobe or diffuse opacities and tend to have poor survival [30].

Fig. 8
figure 8

Spectrum of imaging findings in restrictive allograft syndrome. CT images (a and b) show early to intermediate changes with upper lobe ground glass opacities and mild volume loss. Chest radiograph (c) in a patient with advanced restrictive allograft syndrome showing upper lobe predominant subpleural pleuroparenchymal fibrotic changes with volume loss. CT images (d and e) in another patient with advanced restrictive allograft syndrome showing predominant subpleural fibrotic changes with associated pleural thickening

Full size image

Survival estimates range from 6 to 18 months, compared with 3–5 years in patients with bronchiolitis obliterans syndrome. It is important to note that chronic lung allograft dysfunction is a heterogeneous umbrella term, and that these phenotypes can coexist, or evolve from one to the other (Fig. 9). Evolution from obstructive to restrictive chronic lung allograft dysfunction is more common [30, 45]. The underlying severe obstruction poses a diagnostic challenge in cases that evolve from bronchiolitis obliterans syndrome to restrictive allograft syndrome. However, these cases carry a better prognosis compared with those without preceding bronchiolitis obliterans syndrome [45].

Fig. 9
figure 9

Imaging findings showing evolution of bronchiolitis obliterans to restrictive allograft syndrome. The patient initially presented with decreased FEV1 and mid-flows. Initial axial CT images (a and b) show mosaic attenuation, likely due to air-trapping. Transbronchial biopsy was negative for infection and acute rejection and the diagnosis of bronchiolitis obliterans syndrome was made. Follow-up CT images (c and d) after 3 years show evolution of changes with upper lobe predominant subpleural pleuroparenchymal fibrotic changes typical of restrictive allograft syndrome

Full size image

Additional imaging techniques that may allow early detection and monitoring of chronic lung allograft dysfunction include quantitative CT and low-dose CT volumetry. Quantitative CT is a density mapping with expiratory/inspiratory-ratio mean lung density to detect pathologic air trapping in lung transplant patients [46]. Advanced quantitative analysis of CT in lung transplant patients can improve the accuracy of diagnosis of bronchiolitis obliterans syndrome and in predicting functional parameters such as FEV [47]. Low-dose CT volumetry shows decreased lung volume in restrictive allograft syndrome, whereas patients with bronchiolitis obliterans syndrome show no significant post-transplant change [48]. Oxygen-enhanced T1-mapping MRI might become a noninvasive tool for early detection and monitoring of bronchiolitis obliterans syndrome. Oxygen is used as an inhaled contrast agent with T1 weighted images which may provide information regarding lung ventilation, perfusion, and diffusion capacity. The oxygen transfer function is a parameter using T1 relaxivity measured at room air and at 100% oxygen. Decreasing oxygen-induced relaxivity and increasing heterogeneity are suggestive features of bronchiolitis obliterans syndrome [49]. This technique requires breath hold and use of a closed facemask, which may not be well tolerated by some patients. Therefore, some simplified noncontrast-enhanced lung ventilation techniques have emerged including Fourier decomposition MRI (FD-MRI) and phase resolved functional lung MRI (PREFUL), which may have a potential applications in the future for early detection and severity assessment of chronic lung allograft dysfunction [50, 51]. The uptake of Fluorine-18-Fluorodeoxyglucose (FDG) on PET imaging may be a promising diagnostic and prognostic tool in cases of chronic lung allograft dysfunction. FDG uptake on fused PET/CT scan may distinguish restrictive allograft syndrome from bronchiolitis obliterans syndrome cases. Also, patients with restrictive allograft syndrome and areas of avid FDG uptake tend to have worse outcome [52].

Conclusion

It is important to know the various types of lung allograft dysfunction along a time continuum (Table 3). Imaging findings in the acute setting (primary graft dysfunction and acute rejection) are non-specific and need to be interpreted in conjunction with the clinical picture and other investigations. In contrast, imaging plays a key role in the diagnosis and follow-up of patients with chronic lung allograft dysfunction. Quantitative CT and T1-mapping MRI might evolve as non-invasive markers for chronic lung allograft dysfunction in the near future.

Table 3 Time onset, radiological findings, and diagnostic features of lung transplant primary graft dysfunction and different types of rejection
Full size table

Availability of data and materials

Data sharing is not applicable to this manuscript as no datasets were generated or analyzed.

References

  1. Chambers DC, Cherikh WS, Goldfarb SB et al (2018) The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: Multiorgan Transplantation. J Heart Lung Transplant 37(10):1169–1183

    Article  PubMed  Google Scholar 

  2. Krishnam MS, Suh RD, Tomasian A et al (2007) Postoperative complications of lung transplantation: radiologic findings along a time continuum. Radiographics 27(4):957–974

    Article  PubMed  Google Scholar 

  3. Habre C, Soccal PM, Triponez F et al (2018) Radiological findings of complications after lung transplantation. Insights Imaging 9(5):709–719

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ahmad S, Shlobin OA, Nathan SD (2011) Pulmonary complications of lung transplantation. Chest 139(2):402–411

    Article  PubMed  Google Scholar 

  5. Levine DJ, Glanville AR, Aboyoun C et al (2016) Antibody-mediated rejection of the lung: a consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 35(4):397–406

    Article  PubMed  Google Scholar 

  6. Frost AE, Jammal CT, Cagle PT (1996) Hyperacute rejection following lung transplantation. Chest 110(2):559–562

    Article  CAS  PubMed  Google Scholar 

  7. Choi JK, Kearns J, Palevsky HI et al (1999) Hyperacute rejection of a pulmonary allograft. Immediate clinical and pathologic findings. Am J Respir Crit Care Med 160(3):1015–1018

    Article  CAS  PubMed  Google Scholar 

  8. Bittner HB, Dunitz J, Hertz M, Bolman MR 3rd, Park SJ (2001) Hyperacute rejection in single lung transplantation--case report of successful management by means of plasmapheresis and antithymocyte globulin treatment. Transplantation 71(5):649–651

    Article  CAS  PubMed  Google Scholar 

  9. Masson E, Stern M, Chabod J et al (2007) Hyperacute rejection after lung transplantation caused by undetected low-titer anti-HLA antibodies. J Heart Lung Transplant 26(6):642–645

    Article  PubMed  Google Scholar 

  10. Snell GI, Yusen RD, Weill D et al (2017) Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 36(10):1097–1103

  11. de Perrot M, Liu M, Waddell TK, Keshavjee S (2003) Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 167(4):490–511

    Article  PubMed  Google Scholar 

  12. Mukhopadhyay S, Parambil JG (2012) Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS). Semin Respir Crit Care Med 33(5):476–485

    Article  PubMed  Google Scholar 

  13. Fiser SM, Tribble CG, Long SM et al (2002) Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome. Ann Thorac Surg 73(4):1041–1047

    Article  PubMed  Google Scholar 

  14. Bharat A, Kuo E, Steward N et al (2008) Immunological link between primary graft dysfunction and chronic lung allograft rejection. Ann Thorac Surg 86(1):189–195

    Article  PubMed  PubMed Central  Google Scholar 

  15. Anderson DC, Glazer HS, Semenkovich JW et al (1995) Lung transplant edema: chest radiography after lung transplantation--the first 10 days. Radiology 195(1):275–281

    Article  CAS  PubMed  Google Scholar 

  16. Kundu S, Herman SJ, Winton TL (1998) Reperfusion edema after lung transplantation: radiographic manifestations. Radiology 206(1):75–80

    Article  CAS  PubMed  Google Scholar 

  17. Marom EM, Choi YW, Palmer SM, DeLong DM, Stuart MD, McAdams HP (2001) Reperfusion edema after lung transplantation: effect of daclizumab. Radiology 221(2):508–514

    Article  CAS  PubMed  Google Scholar 

  18. Belmaati EO, Steffensen I, Jensen C et al (2012) Radiological patterns of primary graft dysfunction after lung transplantation evaluated by 64-multi-slice computed tomography: a descriptive study. Interact Cardiovasc Thorac Surg 14(6):785–791

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hopkins PM, Aboyoun CL, Chhajed PN et al (2002) Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant 21(10):1062–1067

    Article  PubMed  Google Scholar 

  20. Yusen RD, Edwards LB, Kucheryavaya AY et al (2015) The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report--2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant 34(10):1264–1277

    Article  PubMed  Google Scholar 

  21. Martinu T, Pavlisko EN, Chen DF, Palmer SM (2011) Acute allograft rejection: cellular and humoral processes. Clin Chest Med 32(2):295–310

    Article  PubMed  PubMed Central  Google Scholar 

  22. Martinu T, Chen DF, Palmer SM (2009) Acute rejection and humoral sensitization in lung transplant recipients. Proc Am Thorac Soc 6(1):54–65

    Article  PubMed  PubMed Central  Google Scholar 

  23. Stewart S, Fishbein MC, Snell GI et al (2007) Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant 26(12):1229–1242

    Article  PubMed  Google Scholar 

  24. De Vito DA, Hoffman LA, Iacono AT, Zullo TG, McCurry KR, Dauber JH (2004) Are symptom reports useful for differentiating between acute rejection and pulmonary infection after lung transplantation? Heart Lung 33(6):372–380

    Article  Google Scholar 

  25. Gotway MB, Dawn SK, Sellami D et al (2001) Acute rejection following lung transplantation: limitations in accuracy of thin-section CT for diagnosis. Radiology 221(1):207–212

    Article  CAS  PubMed  Google Scholar 

  26. Park CH, Paik HC, Haam SJ et al (2014) HRCT features of acute rejection in patients with bilateral lung transplantation: the usefulness of lesion distribution. Transplant Proc 46(5):1511–1516

    Article  CAS  PubMed  Google Scholar 

  27. Fuehner T, Simon A, Dierich M et al (2009) Indicators for steroid response in biopsy proven acute graft rejection after lung transplantation. Respir Med 103(8):1114–1121

    Article  CAS  PubMed  Google Scholar 

  28. Lewis AJ, Jagadeesh D, Mukhopadhyay S, Budev M, Mehta AC (2018) Corrigendum to: Post-transplant lymphoproliferative disorder presenting on post-transplant day 35 as a pulmonary parenchymal infiltrate-a case report. Oxf Med Case Reports. 2018(12):omy100

  29. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P (2014) A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant 33(2):127–133. https://doi.org/10.1016/j.healun.2013.10.022 Epub 2013 Oct 24

    Article  PubMed  Google Scholar 

  30. Sato M, Waddell TK, Wagnetz U et al (2011) Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant 30(7):735–742

    Article  PubMed  Google Scholar 

  31. Husain AN, Siddiqui MT, Holmes EW et al (1999) Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 159(3):829–833

    Article  CAS  PubMed  Google Scholar 

  32. Estenne M, Maurer JR, Boehler A et al (2002) Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 21(3):297–310

    Article  PubMed  Google Scholar 

  33. Kramer MR, Stoehr C, Whang JL et al (1993) The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial lung biopsy. J Heart Lung Transplant 12(4):675–681

  34. Bankier AA, Van Muylem A, Knoop C, Estenne M, Gevenois PA (2001) Bronchiolitis obliterans syndrome in heart-lung transplant recipients: diagnosis with expiratory CT. Radiology 218(2):533–539

    Article  CAS  PubMed  Google Scholar 

  35. Morrish WF, Herman SJ, Weisbrod GL, Chamberlain DW (1991) Bronchiolitis obliterans after lung transplantation: findings at chest radiography and high-resolution CT. The Toronto Lung Transplant Group. Radiology 179(2):487–490

    Article  CAS  PubMed  Google Scholar 

  36. Worthy SA, Park CS, Kim JS, Muller NL (1997) Bronchiolitis obliterans after lung transplantation: high-resolution CT findings in 15 patients. AJR Am J Roentgenol 169(3):673–677

    Article  CAS  PubMed  Google Scholar 

  37. Lee ES, Gotway MB, Reddy GP, Golden JA, Keith FM, Webb WR (2000) Early bronchiolitis obliterans following lung transplantation: accuracy of expiratory thin-section CT for diagnosis. Radiology 216(2):472–477

    Article  CAS  PubMed  Google Scholar 

  38. Choi YW, Rossi SE, Palmer SM, DeLong D, Erasmus JJ, McAdams HP (2003) Bronchiolitis obliterans syndrome in lung transplant recipients: correlation of computed tomography findings with bronchiolitis obliterans syndrome stage. J Thorac Imaging 18(2):72–79

    Article  PubMed  Google Scholar 

  39. Konen E, Gutierrez C, Chaparro C et al (2004) Bronchiolitis obliterans syndrome in lung transplant recipients: can thin-section CT findings predict disease before its clinical appearance? Radiology 231(2):467–473

    Article  PubMed  Google Scholar 

  40. Gunn ML, Godwin JD, Kanne JP, Flowers ME, Chien JW (2008) High-resolution CT findings of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. J Thorac Imaging 23(4):244–250

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ofek E, Sato M, Saito T et al (2013) Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol 26(3):350–356

    Article  PubMed  CAS  Google Scholar 

  42. Verleden SE, de Jong PA, Ruttens D et al (2014) Functional and computed tomographic evolution and survival of restrictive allograft syndrome after lung transplantation. J Heart Lung Transplant 33(3):270–277

    Article  PubMed  Google Scholar 

  43. Arakawa H, Kurihara Y, Niimi H, Nakajima Y, Johkoh T, Nakamura H (2001) Bronchiolitis obliterans with organizing pneumonia versus chronic eosinophilic pneumonia: high-resolution CT findings in 81 patients. AJR Am J Roentgenol 176(4):1053–1058

    Article  CAS  PubMed  Google Scholar 

  44. Konen E, Weisbrod GL, Pakhale S, Chung T, Paul NS, Hutcheon MA (2003) Fibrosis of the upper lobes: a newly identified late-onset complication after lung transplantation? AJR Am J Roentgenol 181(6):1539–1543

    Article  PubMed  Google Scholar 

  45. Verleden SE, Vos R, Vanaudenaerde BM, Verleden GM (2017) Chronic lung allograft dysfunction phenotypes and treatment. J Thorac Dis 9(8):2650–2659

    Article  PubMed  PubMed Central  Google Scholar 

  46. Solyanik O, Hollmann P, Dettmer S et al (2015) Quantification of pathologic air trapping in lung transplant patients using CT density mapping: comparison with other CT air trapping measures. PLoS One 10(10)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Mortani Barbosa EJ Jr, Shou H, Simpsom S, Gee J, Tustison N, Lee JC (2018) Quantitative computed tomography metrics from the transplanted lung can predict forced expiratory volume in the first second after lung transplantation. J Thorac Imaging 33(2):112–123

    Article  PubMed  Google Scholar 

  48. Saito T, Horie M, Sato M et al (2016) Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction. J Heart Lung Transplant 35(1):59–66

    Article  PubMed  Google Scholar 

  49. Renne J, Lauermann P, Hinrichs JB et al (2015) Chronic lung allograft dysfunction: oxygen-enhanced T1-mapping MR imaging of the lung. Radiology 276(1):266–273

    Article  PubMed  Google Scholar 

  50. Voskrebenzev A, Greer M, Gutberlet M et al (2018) Detection of chronic lung allograft dysfunction using ventilation-weighted Fourier decomposition MRI. Am J Transplant 18(8):2050–2060

    Article  CAS  PubMed  Google Scholar 

  51. Moher Alsady T, Voskrebenzev A, Greer M et al (2019) MRI-derived regional flow-volume loop parameters detect early-stage chronic lung allograft dysfunction. J Magn Reson Imaging 27(10):26799

  52. Verleden SE, Gheysens O, Goffin KE et al (2019) Role of 18F-FDG PET/CT in restrictive allograft syndrome after lung transplantation. Transplantation 103(4):823–831

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

• Imaging Institute, Cleveland Clinic, Cleveland, Ohio.

• Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland Ohio.

• Respiratory Institute, Cleveland Clinic, Cleveland, Ohio

Funding

No funding is needed or provided for writing this manuscript.

Author information

Authors and Affiliations

  1. Sections of Thoracic and Cardiovascular Imaging Laboratory, Imaging Institute, Cleveland Clinic, L-10, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Mnahi Bin Saeedan & Rahul D. Renapurkar

  2. Department of Pathology, Cleveland Clinic, Cleveland, USA

    Sanjay Mukhopadhyay

  3. Department of Pulmonary and Critical Care Medicine, Cleveland Clinic, Cleveland, USA

    C. Randall Lane

Authors
  1. Mnahi Bin Saeedan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjay Mukhopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Randall Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rahul D. Renapurkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally in writing and editing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Mnahi Bin Saeedan.

Ethics declarations

Ethics approval and consent to participate

Not applicable; this manuscript does not report on or involve the use of any animal or human data or tissue.

Consent for publication

Not applicable; this manuscript does not contain data from any individual person, please state.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bin Saeedan, M., Mukhopadhyay, S., Lane, C.R. et al. Imaging indications and findings in evaluation of lung transplant graft dysfunction and rejection. Insights Imaging 11, 2 (2020). https://doi.org/10.1186/s13244-019-0822-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13244-019-0822-7

Keywords

  • Lung transplantation complications
  • Primary graft dysfunction
  • Acute rejection
  • Chronic lung allograft dysfunction
  • Imaging findings