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Commentary

Imaging in Lung Transplantation: So Near and Yet So Far

Young, Katherine MD1; Ali, Hakim Azfar MD1

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doi: 10.1097/TP.0000000000003457
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Lung transplantation has evolved into a mainstream modality of treatment for end-stage lung disease. Despite the advances, “graft failure,” infection, and malignancy are still the principal causes of morbidity and mortality in lung transplant recipients (LTRs).1 Early identification of these complications is desirable but often difficult; in light of this, a multifaceted surveillance and diagnostic approach is usually undertaken which includes a combination of lung function assessment, imaging as well as invasive measures like bronchoscopy.2 Routine imaging in LTRs plays a pivotal role in detecting infectious and malignant complications3 but presently has a limited use in detecting graft dysfunction related to rejection. The most referenced use is demonstration of mosaic air trapping suggestive of bronchiolitis obliterans phenotype of chronic lung allograft dysfunction (CLAD) on airway protocol computed tomography (CT) scan.2 Given the current void in the utility of imaging, more advanced noninvasive diagnostic tools are of great interest.3

Hybrid 18F-fluorodeoxyglucose positron emission tomography with CT (18F-FDG PET/CT) is routinely used in oncologic patients for staging and response assessment of disease.3,418F-FDG PET/CT provides valuable functional information based on the glucose uptake and glycolysis of cancer cells and depicts metabolic abnormalities alongside a simultaneous CT for accurate anatomical localization of the lesions. In recent years, there has been interest in using 18F-FDG PET/CT as a diagnostic modality in solid organ transplant (SOT) recipients when other imaging modalities have proven inconclusive. Areas of interest include various malignancies including posttransplant lymphoproliferative disorders, infections, and graft dysfunction.3,4

In the current issue of Transplantation, Van Rompaey and colleagues report high diagnostic yield of 18F-FDG PET and PET/CT for malignancy in LTRs.5 In this single-center, retrospective, observational study, the major indication for 18F-FDG PET/CT referral was malignancy, followed by CLAD with restrictive allograft syndrome (RAS) phenotype, and infection/inflammation not otherwise specified.5 Due to the large number of referrals for malignancy (80.8%), the analysis primarily focuses on the diagnostic performance of 18F-FDG PET/CT in malignancy. Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 91.4%, 82.3%, 75.3%, and 94.2% respectively.5 These findings are comparable to earlier retrospective studies that investigated the clinical utility of 18F-FDG PET/CT in diagnosing malignancy in SOTs; however, in these prior studies LTRs were underrepresented compared with other SOTs.3 This topic is of clinical interest given LTRs are at a 3–5-fold increased risk of malignancy compared with the general population and early diagnosis could have huge clinical implications.3

While the high sensitivity and negative predictive value is no surprise and is consistent with findings in nontransplant populations,6 it drives home the point that 18F-FDG PET is an attractive diagnostic tool to “rule-out” malignancy in LTRs in the right clinical context.3,5

The greatest limitation of this study acknowledged by the authors is that it has a single-center, retrospective design over a period of time, which may or may not have been subject to different diagnostic or therapeutic strategies. Given these limitations, prospective studies are needed to further elucidate these findings and delineate the value of 18F-FDG PET/CT scans for evaluating different sizes and phenotypes of pulmonary abnormalities (solid, subsolid, and ground glass) as well as for distribution of lesions in LTRs. This will be interesting to look at within the context of the more common inflammatory and infectious etiologies frequently seen in LTRs as well as the high prevalence of diabetes in this population. Furthermore, given the heterogeneity of management protocols at various lung transplant centers, structured formal recommendations may be difficult to define.

Another interesting feature from the study includes the incidental detection of abnormalities in about 15% of patients with over half of these findings revealing a malignant or infectious cause and hence clinically relevant.5 While intriguing, this should serve as hypothesis generating and will need to be explored.

From 2002 onwards, 18F-FDG PET/CT has been one of the fastest growing medical imaging modalities, rivaling the growth of magnetic resonance imaging during the 1980s and 1990s.7 With improvements in various modalities of imaging, there has been renewed attention towards study of early segmental ventilation and perfusion anomalies in various lung diseases as well as LTRs. The recognition of CLAD phenotypes with radiological abnormalities, specifically RAS, which is typically characterized by upper lobe infiltrates,2 has further increased this interest.

Van Rompaey’s cohort includes 31 (13.2%) patients who had 18F-FDG PET or PET/CT for the indication of RAS. In addition to being a small patient cohort, the poor specificity and broad confidence intervals for sensitivity precludes the current use of 18F-FDG PET/CT as a stand-alone study for the diagnosis of RAS.5 Interestingly, in another paper this group of authors demonstrated a higher standard uptake valuemax in fibrotic areas in RAS compared to bronchiolitis obliterans phenotype and the data suggest that these patients with “hot” fibrotic areas may have worse outcomes.4 As we further study the role of FDG-PET in LTR, we should consider looking at pathologic correlates as well as the degree and cellular basis of glucose uptake in a comparative study between acute rejection, CLAD phenotypes, and other inflammatory conditions.

Previous studies have suggested the neutrophilic FDG uptake seen in infection or in inflammatory conditions such as pneumonitis8 differs from the FDG uptake in the lymphocytic process of acute rejection and can thereby distinguish these entities.9 Some animal models of rejection have shown FDG analog uptake predominantly by CD8 T cells in the setting of rejection.10

The technology is still far from prime time use in CLAD but data furthers the case for additional research to explore the utility of PET/CT in CLAD adding control groups with alternate pathology. This should be in conjunction with further elucidation of the cellular sources of glucose utilization in RAS as compared to non-RAS CLAD and other etiologies such as infection and inflammation.

For now, the use of 18F-FDG PET/CT in LTRs will have to be in the right clinical context and take into account a variety of factors including symptoms, signs, microbiology, and biopsy results.4,9

REFERENCES

1. Chambers DC, Cherikh WS, Harhay MO, et al.; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation report-2019; focus theme: donor and recipient size match. J Heart Lung Transplant. 2019; 38:1042–1055
2. Bin Saeedan M, Mukhopadhyay S, Lane CR, et al. Imaging indications and findings in evaluation of lung transplant graft dysfunction and rejection. Insights Imaging. 2020; 11:2
3. Wareham NE, Lundgren JD, Da Cunha-Bang C, et al. The clinical utility of FDG PET/CT among solid organ transplant recipients suspected of malignancy or infection. Eur J Nucl Med Mol Imaging. 2017; 44:421–431
4. Verleden SE, Gheysens O, Goffin KE, et al. Role of 18F-FDG PET/CT in restrictive allograft syndrome after lung transplantation. Transplantation. 2019; 103:823–831
5. Van Rompaey W. Diagnostic yield of 18F-FDG PET after lung transplantation: a single-center, retrospective cohort study. Transplantation. 2020; 47:529–536
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8. Jones HA, Clark RJ, Rhodes CG, et al. In vivo measurement of neutrophil activity in experimental lung inflammation. Am J Respir Crit Care Med. 1994; 149:1635–1639
9. Jones HA, Donovan T, Goddard MJ, et al. Use of 18FDG-pet to discriminate between infection and rejection in lung transplant recipients. Transplantation. 2004; 77:1462–1464
10. Chen DL, Wang X, Yamamoto S, et al. Increased T cell glucose uptake reflects acute rejection in lung grafts. Am J Transplant. 2013; 13:2540–2549
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