Chronic Lung Allograft Dysfunction: Review of CT and Pathologic Findings

Abstract

Chronic lung allograft dysfunction (CLAD) is the most common cause of mortality in lung transplant recipients after the 1st year of transplantation. CLAD has traditionally been classified into two distinct obstructive and restrictive forms: bronchiolitis obliterans syndrome and restrictive allograft syndrome. However, CLAD may manifest with a spectrum of imaging and pathologic findings and a combination of obstructive and restrictive physiologic abnormalities. Although the initial CT manifestations of CLAD may be nonspecific, the progression of findings at follow-up should signal the possibility of CLAD and may be present on imaging studies prior to the development of functional abnormalities of the lung allograft. This review encompasses the evolution of CT findings in CLAD, with emphasis on the underlying pathogenesis and pathologic condition, to enhance understanding of imaging findings. The purpose of this article is to familiarize the radiologist with the initial and follow-up CT findings of the obstructive, restrictive, and mixed forms of CLAD, for which early diagnosis and treatment may result in improved survival.

Supplemental material is available for this article.

© RSNA, 2021

Summary

Chronic lung allograft dysfunction may manifest with a spectrum of imaging and pathologic findings and a combination of obstructive and restrictive functional abnormalities. Awareness of the spectrum of CT findings is important to minimize diagnostic delay and improve patient outcomes.

Essentials

• ■ Obstructive chronic lung allograft dysfunction (CLAD) is characterized by concentric narrowing of the bronchiolar lumen by intramural or submucosal fibrous tissue, resulting in airway luminal compromise manifesting predominantly as bronchial wall thickening, mosaic perfusion, and expiratory airtrapping on CT images.

• ■ Restrictive CLAD is characterized by a chronic fibrosing pneumonia pattern and a spectrum of acute lung injury at pathologic analysis, with correlating pleuroparenchymal fibroelastosis and a spectrum of heterogeneous CT findings, including nonresolving subpleural and perilobular consolidation with or without an organizing pneumonia reaction pattern.

• ■ Initial imaging features of restrictive CLAD including septal thickening, ground-glass nodules, and consolidation are nonspecific, may be subtle and overlap with CT findings in other common pathologic conditions among patients after transplant, and warrant short-interval follow-up imaging.

• ■ Lung transplant recipients can develop a combination of obstructive and restrictive functional, pathologic, and imaging abnormalities (ie, mixed-phenotype CLAD).

Introduction

Lung transplant has become the mainstay treatment for end-stage lung disorders for select individuals, but the long-term outcome remains relatively poor, with a 58.6% 5-year survival rate, a median posttransplant survival of 6.7 years, and a conditional median survival of 8.8 years (1). Allograft failure is said to account for at least 40% of deaths after the 1st year after lung transplant (2,3), which is considerably higher compared with the percentages associated with other solid-organ transplants (4). A substantial contributor to the relatively poor long-term outcomes of lung transplant is chronic lung allograft dysfunction (CLAD) (5), which is an overarching designation for chronic and progressive physiologic deficits encompassing both obstructive and restrictive physiologic phenotypes. The pathologic spectrum of findings in CLAD may involve airways and acute, subacute, and chronic interstitial and airspace disease, or combinations of these findings. Knowledge of the underlying pathologic condition in CLAD is crucial to understanding the CT findings. The purpose of this article is to familiarize the radiologist with the spectrum of initial CT manifestations and progression of CLAD, which may result in earlier diagnosis and potentially lead to improved survival.

Definition of CLAD

CLAD is defined as a substantial and persistent physiologic decline, documented by a greater-than-20% decline in forced expiratory volume in 1 second (FEV₁) compared with the baseline reference value (3), and may be subcategorized as having a predominately obstructive pattern, restrictive pattern, or mixed obstructive and restrictive pattern on spirometric images (3). A number of potential pathologic processes may also cause chronic loss of allograft function, including surgical factors (eg, lobectomy, chest wall surgery, or phrenic nerve damage), mechanical factors (eg, persistent pleural effusion; airway stenosis; weight gain; myopathy; or persistent edema because of heart, kidney, or liver failure), localized infection with chronic scarring, disease recurrence from the underlying transplant indication (eg, lymphangioleiomyomatosis or sarcoidosis), drug toxicity, tumor infiltration, pulmonary arterial stricture or emboli, effects of aspiration, and others, but these processes do not form part of the CLAD spectrum and must be ruled out before a diagnosis of CLAD can be made (1,3).

Obstructive CLAD

Obstructive CLAD remains the most common phenotype of chronic rejection (65%–75%) (6), with 48% of patients who have undergone lung transplant demonstrating some degree of obstructive CLAD within 5 years of transplant (7), resulting in a median survival interval after diagnosis of 3–5 years (7). This form of CLAD has traditionally been associated with the entity of bronchiolitis obliterans (BO) syndrome, defined as the physiologic correlate for a histologic diagnosis of BO (also known as obliterative or constrictive bronchiolitis) (8), and for some time was considered the prime entity behind pulmonary allograft dysfunction. Obstructive CLAD develops insidiously 3 months after transplantation, with patients typically presenting with dyspnea on exertion and nonproductive cough (6). Pulmonary function tests demonstrate irreversible FEV₁ decline of less than 80% of the baseline level (9), with early or greater FEV₁ decline associated with decreased survival (10). Obstructive CLAD is diagnosed in patients with a sustained and unexplained decrease in FEV₁ level greater than 20% (ie, FEV₁ ≤ 80% of the baseline level 3 months after transplant in the absence of infection or another identifiable cause when two separate measures 3 weeks apart meet the threshold) (11).

There are three distinct clinical phenotypes of BO syndrome: (a) BO with early presentation (within 2 years of lung transplant) (12), accelerated progression (FEV₁ decrease > 100 mL per month), and poor prognosis; (b) BO with a more insidious decline of FEV₁ and a better prognosis (13–15); and (c) neutrophilic reversible airway disease (16), which responds to azithromycin therapy and is also known as azithromycin-responsive allograft dysfunction (17). Female sex, pretransplant diagnosis of idiopathic pulmonary fibrosis, single-lung transplantation, and rapid onset are factors that are associated with accelerated progression, poorer prognosis, and poorer pulmonary function after the onset of obstructive CLAD (15). Neutrophilic reversible airway disease does not occur as frequently now because azithromycin is universally initiated immediately after the lung transplant surgery and is no longer considered a form of CLAD (18).

Pathologic Characterization of Obstructive CLAD

Patient clinical data for figures in this article are provided in Tables E1 and E2 (supplement). Ethical approval for this study was obtained from the institutional review board at Vancouver General Hospital. Because this was a retrospective descriptive study that did not expose patients to additional harm or interventions, the institutional review board at Vancouver General Hospital (Vancouver, Canada) waived the need for informed consent.

The essential manifestation of obstructive CLAD is that of BO (often referred to in the literature as constrictive bronchiolitis) and, as expected, histopathologic manifestations are essentially airway based (19–21). BO is characterized by concentric narrowing of the bronchiolar lumen by intramural and submucosal fibrous tissue, resulting in airway luminal compromise (Fig 1, C; Fig 2, B). Histologic assessment of samples from biopsies, resections, or autopsy may demonstrate a spectrum of findings ranging from partial (subtotal) luminal encroachment by paucicellular sclerotic fibrous tissue, active fibroplasia with or without accompanying immune-cell infiltrates, or complete obliteration with remnant fibrous scars. Lesion distribution within the lung allograft is heterogeneous, leading to low sensitivity of diagnostic transbronchial biopsies (22–24), previously reported to be as low as 17.1% (24), necessitating clinical definition based on pulmonary function tests and supplemented by imaging findings (9).

Figure 1:

Obstructive chronic lung allograft dysfunction in a 61-year-old man. A, No airtrapping on CT images obtained on posttransplant day 221, with appropriate increased bilateral attenuation on expiratory (EXP) images evolving to, B, severe airtrapping on CT images obtained on posttransplant day 991, manifested by bilateral areas of increasing lucency at expiration. C, At transbronchial biopsy specimen assessment, subepithelial connective tissue (arrows) were apparent in portions of these two membranous bronchioles, identifiable because of their smooth muscle walls (arrowheads on C). Although hemosiderin-containing macrophages can be seen in some airspaces in the lower portion of the biopsy specimen, the alveolar walls are of relatively normal thickness. Bar = 0.5 mm. Additional patient information is found in Tables E1 and E2 (supplement). INS = inspiratory.

Figure 2:

A, Mixed-phenotype chronic lung allograft dysfunction in a 30-year-old man. CT images obtained on posttransplant day 1833 show predominantly peribronchovascular reticulation with nodular thickening of the interlobular septa (ILS), perilymphatic nodules, and associated architectural distortion. The expiratory image obtained on day 1833 demonstrates new moderate airtrapping with a lower-than-expected increase in attenuation and lack of volume reduction. B, Low-power images of the left lower lobe from the explant in A. The pleura (P) shows mild fibrosis. Bands of fibrous tissue, presumably the residua of unresolved organizing pneumonia, extend from the subpleural zone and penetrate the underlying parenchyma following the ILS (arrows). Some of the centrilobular airways demonstrate changes of constrictive obliterative bronchiolitis (arrowheads). Movat pentachrome staining is used. The horizontal bar is equivalent to 2 mm. C, From a different area of the left lower lobe, this medium-power micrograph of a membranous bronchiole (Br) demonstrates the classic finding of constrictive obliterative bronchiolitis, in which the subepithelial zone, of normal to negligible thickness, is expanded by a myofibroblastic matrix (double arrow), causing a severe reduction in luminal patency. Movat pentachrome staining is used. The horizontal bar is equivalent to 0.5 mm. D, Microscopic section from a chronic lung allograft dysfunction explant shows uniform alveolar wall thickening and architectural sparing changes of nonspecific interstitial pneumonia. The airspaces contain scattered inflammatory cells and occasionally contain some edematous fluid. The horizontal bar is equivalent to 0.5 mm. E, Superimposed on a background of nonspecific interstitial pneumonia, the parenchyma shows a combination of alveolar macrophage accumulation, simulating a desquamative interstitial pneumonia pattern (*) with airspace cholesterol granulomas (arrow), suggesting a component of obstructive pneumonitis. Some of the tissue compaction is likely due to atelectasis. Hematoxylin-eosin staining is used. Additional patient information is found in Tables E1 and E2 (supplement). ils = interlobular septal thickening, PA = pulmonary artery.

CT Findings of Obstructive CLAD

Airtrapping on expiratory images is considered the most reliable CT finding of obstructive CLAD (88% accuracy) when more than 32% of the lungs are involved (25), with mosaic perfusion resulting from hypoxic vasoconstriction and vascular oligemia appearing within areas of airtrapping (26). On noncontrast CT studies, mosaic perfusion can be seen as heterogeneous attenuation with low-attenuation areas because of underlying airway obstruction (27) and reduced size of the pulmonary vasculature within the hyperlucent lung area. To assess airtrapping, inspiratory and expiratory CT examinations are performed. Airtrapping is identified on end-expiratory CT images as parenchymal areas with a lower-than-normal increase in attenuation and a lack of volume reduction (28) (Fig 3). Airtrapping can progress over time, in line with declining lung function at spirometry (Fig 1).

Figure 3:

Obstructive chronic lung allograft dysfunction in a 64-year-old man. CT images obtained 18 years after transplant show bilateral mosaic attenuation on inspiratory images characterized by intermittent areas of lucency (★) because of underlying airway obstruction and reduced caliber of pulmonary vasculature and subtle relative increased attenuation (arrows), accentuated on expiratory images, with the lower-than-normal increase in attenuation and lack of volume reduction consistent with moderate airtrapping. Additional patient information is found in Tables E1 and E2 (supplement).

Centrilobular and tree-in-bud nodules may be seen in obstructive CLAD resulting from distal bronchiole impaction but are a nonspecific finding that may be seen in other posttransplant complications, such as infection (29).

Before the manifestation of obstructive CLAD on spirometric images, CT is of limited diagnostic value, with bronchiectasis, bronchial wall thickening, and mosaic attenuation having poor sensitivity (4%–25%) (27). Both bronchiectasis and bronchial wall thickening have been shown to have relatively low sensitivity in the diagnosis of BO syndrome during all periods (24%–36% and 4%–40%, respectively) but have been shown to have higher specificity (80%–96% for both findings) (27). Previous studies have similarly shown bronchiectasis (30–33) and bronchial wall thickening (31–33) to have low sensitivity and have shown bronchiectasis to have higher specificity (30,31). When obstructive CLAD is present on spirometric images, the extent of airtrapping on CT images correlates reasonably well with the decrease in FEV₁ (29), but CT analysis may under- or overestimate the severity of airflow obstruction (34–39). Airtrapping can be graded as mild, moderate, or severe, depending on the subjective assessment of the extent of lung involvement (40); however, the apparent severity can vary depending on the expiratory effort, thus limiting the value of CT during serial evaluation. Parametric response mapping (voxel-to-voxel comparison of inspiratory and expiratory CT images) has been shown to be useful for monitoring the progression of BO in patients with lung transplants and for prediction of survival (41).

Restrictive CLAD

The restrictive form of CLAD, essentially synonymous with restrictive allograft syndrome, introduced by Sato et al (42), is found in 25%–35% of patients with CLAD and evinces a prognosis worse than that of the obstructive form, developing a median of 0.5–1.5 years after transplant (43). In these cases, the principle pathologic condition is that of various forms of interstitial fibrosis. Current proposals advocate that restrictive allograft syndrome be defined as the restrictive phenotype of CLAD, by using the following physiologic and radiologic definitions: (a) a persistent and greater-than-20% decline in FEV₁ compared with the posttransplant baseline value, which is computed as the mean of the best two postoperative FEV₁ measurements performed at least 3 weeks apart; (b) a concomitant greater-than-10% decline in total lung capacity compared with the posttransplant baseline value, which is computed as the mean of the two total lung-capacity measurements performed at the time of or near to the best two postoperative FEV₁ measurements; and (c) the presentation of persistent opacities on chest images (3). Currently, three clinical subsets are recognized: (a) acute hypoxemic respiratory failure clinically similar to adult respiratory distress syndrome and a pathologic condition that demonstrates acute and/or organizing lung injury patterns; (b) stepwise decrements in lung function, with periodic exacerbations of respiratory decline interspersed with periods of relative stability; and (c) gradually progressive functional decline in the face of radiographic changes, which demonstrates the best prognosis (3,18,44). As a cohort, patients with restrictive CLAD have a more guarded prognosis than those with obstructive CLAD because these patients have a median survival of 1.5 years compared with patients with obstructive CLAD, who have a median survival of approximately 3 years (42).

Pathologic Characterization of Restrictive CLAD

The chronic fibrosing pneumonia pattern, both grossly and microscopically, observed in most cases of restrictive CLAD is virtually identical to that observed in the entity of pleuroparenchymal fibroelastosis (45), one of the rare forms of idiopathic interstitial pneumonia (46). It features variable pleural fibrosis and a distinctive parenchymal alteration consisting of a well-demarcated subpleural band of intra-alveolar fibrosis and elastosis (47,48) in which there is a visual sense of preserved alveolar architecture, with collagenous fibrosis filling vestigial alveolar spaces and reduplicated elastic fibers continuing to outline the alveolar walls (Fig 4). Although the pathologic events culminating in pleuroparenchymal fibroelastosis remain speculative, the microscopic impression is that of poorly or partly organized alveolar exudates that have become transfixed in place and static in their final form. This histologic manifestation has been described in restrictive CLAD (47,49–52).

Figure 4:

Representative images of pathologic patterns that can be seen in restrictive chronic lung allograft dysfunction. A, Scanned microscopic section from pleuroparenchymal fibroelastosis that shows the classic subpleural band of fibroelastosis with sharp demarcation from the deeper lung parenchyma (arrows). There are lumina of ectatic, caliber-persistent airways (*) as they extend toward and into the subpleural fibroelastotic zone. Pulmonary artery is shown (★). The horizontal bar is equivalent to 5 mm. Hematoxylin-eosin staining was used. B, Magnified image shows the typical picture of pleuroparenchymal fibroelastosis with partially preserved, thickened alveolar wall elastica (arrows) encircling airspaces filled with inert organized fibrosis. Hematoxylin-eosin staining was used. C, In this micrograph, the elastic tissue is highlighted in black (arrows), enclosing old organizing collagenous alveolar exudates (*). Movat pentachrome staining was used. Additional patient information is found in Tables E1 and E2 (supplement).

In addition to the particular pattern of fibroelastosis described above, other parenchymal changes have been described in restrictive CLAD and are often concurrent. Acute fibrinous and organizing pneumonia (AFOP) (53) (16,54) and diffuse alveolar damage (42,49) were identified (acute and/or organizing diffuse alveolar damage) in 13 of 16 patients with restrictive CLAD with a pleuroparenchymal fibroelastosis pattern; in seven of those patients, the diffuse alveolar damage pattern appeared to merge with zones of intra-alveolar fibrosis and elastosis. Von der Thüsen et al (52) found a spectrum of changes, including organizing pneumonia, AFOP, nonspecific interstitial pneumonia, capillaritis, and BO, and described a subset of fibrosis-induced emphysema, a pattern that may confer better survival.

CT Findings of Restrictive CLAD

CT findings in restrictive CLAD include peripheral consolidations, pleural thickening, central or peripheral ground-glass opacities, septal lines, subpleural reticulation and thickening, bronchiectasis, architectural distortion, and volume loss with an upper-lobe predominance (9). CT findings may be present before the development of a restrictive ventilatory defect (55) and may therefore be helpful in early diagnosis and management. Initial imaging features of restrictive CLAD such as septal thickening, ground-glass nodules, and consolidation are nonspecific, may be subtle, and may overlap with CT findings in other common pathologic conditions, including infection, among patients after transplant. Dubbeldam et al (18) found that these often initially nonspecific findings persisted at follow-up CT and described two distinct subgroups of patients with restrictive CLAD according to the evolution of CT findings, with a more slowly progressing group overlapping with previously reported pleuroparenchymal fibroelastosis and upper-lobe fibrosis (examples provided in Figs 4 and 5) and a more rapidly progressing group possibly overlapping with previously reported AFOP (example provided in Fig 6). Patient outcome differences have also been reported according to the distribution of the radiographic findings. Significantly shorter survival has been associated with basal predominant and diffuse patterns of interstitial fibrotic changes on CT images compared with apical predominant findings (56). An example of basal predominant parenchymal changes in a patient with restrictive CLAD is provided in Figure 7.

Figure 5:

Restrictive chronic lung allograft dysfunction in a 58-year-old man. CT images obtained on posttransplant day 730 show subpleural patchy consolidation and ground-glass opacities in the posterior right upper lobe, which increases on day 961, with subsequent progressive worsening of interlobular septal thickening, pleuroparenchymal consolidation, fissural retraction, and volume loss in the right upper lobe, with similar but less marked changes in the left upper lobe at day 1194. Additional patient information is found in Tables E1 and E2 (supplement).

Figure 6:

Rapidly progressive restrictive chronic lung allograft dysfunction in a 21-year-old woman. CT images obtained on posttransplant day 371 demonstrate mild focal, slightly nodular interlobular septal thickening in the right upper lobe. Worsening coarse interlobular septal thickening, new patchy bilateral peripheral peribronchovascular and subpleural ground-glass opacities, and nodular consolidation is shown on day 485. Findings are consistent with progressive biapical fibrosis with an organizing pneumonia reaction pattern because of rapidly progressive restrictive chronic lung allograft dysfunction. The transbronchial biopsy specimen shows complete densification by a mixture of arborizing intra-alveolar organizing airspace exudates (*) instead of open alveolar spaces and shows some residual airspace fibrin (arrow), both indicating a phase of organizing subacute lung injury (acute fibrinous and organizing pneumonia). Hematoxylin-eosin staining was used. The horizontal bar is equivalent to 200 µm. Additional patient information is found in Tables E1 and E2 (supplement).

Figure 7:

Restrictive chronic lung allograft dysfunction in a 48-year-old woman. CT images obtained on posttransplant day 1213 show basal predominant sweeping peribronchovascular and perilobular consolidation and ground-glass opacities, in keeping with an organizing pneumonia reaction pattern, with worsening traction bronchiectasis (arrows) and volume loss on images obtained on day 1711. Elevation of the right hemidiaphragm contributes to volume loss with diaphragmatic paralysis, a known posttransplant complication. Additional patient information is found in Tables E1 and E2 (supplement).

The CT correlate of pleuroparenchymal fibroelastosis is characterized by apical predominant pleural thickening, which is typically asymmetric and variable in extent (57); dense subpleural consolidation; traction bronchiectasis; architectural distortion; and volume loss (46,58). A scoring system for the severity of pleuroparenchymal fibroelastosis has been proposed on the basis of the presence of cylindrical versus cystic bronchiectasis, the extent of pleuroparenchymal and blotchy opacities, and the degree of volume loss (59). The clinical value of this scoring system has yet to be assessed in restrictive CLAD. An example of pleuroparenchymal fibroelastosis in the setting of restrictive CLAD is provided in Figure 5.

Mixed-Phenotype CLAD

It is increasingly being reported that patients can demonstrate combined obstructive and restrictive CLAD, which is called mixed-phenotype CLAD (60,61). Sato et al (42) originally reported that patients with CLAD could transition from one phenotype to another. In the presence of previous obstructive CLAD, a decline in total lung capacity may be the most reliable pulmonary function test to detect evolution from obstructive CLAD to mixed-phenotype CLAD (60). Apical predominance of pleural and interstitial opacities and pleuroparenchymal fibroelastosis have been reported in patients with mixed-phenotype CLAD (60).

Examples in patients who initially developed obstructive CLAD with progressive airtrapping on CT images and subsequent development of restrictive CLAD are provided in Figures 2, 8–9. These cases show progression of airtrapping and bronchiectasis over time with the development of fibrotic changes, but only Figure 8 shows the classic imaging features of restrictive CLAD (ie, pleuroparenchymal fibroelastosis).

Figure 8:

A, Mixed-phenotype chronic lung allograft dysfunction in a 33-year-old woman. CT images obtained on posttransplant day 808 show patchy subpleural consolidation and ground-glass opacities in the right upper lobe. CT images obtained on day 1286 show right upper lobe–predominant patchy ground-glass opacities and subpleural reticulation with volume loss. CT images obtained on day 1617 show progressive bilateral apical pleural thickening, subpleural fibrosis with traction bronchiectasis, volume loss, and architectural distortion, which are consistent with pleuroparenchymal fibroelastosis. B, CT images obtained on day 362 show right-middle-lobe airtrapping because of bronchial stenosis (not shown). CT images obtained on day 1557 show bilateral bronchiectasis and markedly worse bilateral airtrapping, evidenced by a lower-than-normal increase in attenuation and a lack of volume reduction, which are consistent with deteriorating accompanying obstruction. Additional patient information is found in Tables E1 and E2 (supplement).

Figure 9:

Mixed-phenotype chronic lung allograft dysfunction in a 37-year-old man. CT studies obtained on posttransplant days 1817 and 2328 show worsening bilateral airtrapping manifested by a lower-than-anticipated decrease in volume and increased attenuation at expiration. CT images obtained on day 1817 show new focal peripheral consolidation in the posterior right upper lobe, which decreases in extent but fails to resolve on day 2328. Worsening volume loss and associated retraction of the oblique fissure is shown on images obtained on day 2328. Additional patient information is found in Tables E1 and E2 (supplement).

Acute cellular rejection, manifested in its early stages as perivascular and peribronchiolar lymphocytic infiltrates, can be identified in restrictive and mixed-phenotype cases (60). BO is recognized as accompanying other pathologic entities in restrictive CLAD, including up to 100% in some studies (23,47,49,52,54,60,62). In restrictive CLAD, airway obliteration may be the result of both classic constrictive bronchiolitis and external compression, or even complete effacement, by the process of intra-alveolar fibrosis and elastosis (63).

As the various cases illustrate, the clinical, radiologic, and histologic manifestations of CLAD are heterogeneous and may progress slowly over several years or more rapidly within months. The Table summarizes findings in the subtypes of CLAD.

Spirometric, CT, and Pathologic Findings in Obstructive and Restrictive CLAD

Dysfunctions Associated with CLAD

AFOP Lung Injury

Originally described by Bealsey et al (53), AFOP represents a severe form of acute lung injury. In the initial study, patients had a clinical course and mortality rate that were similar to those of patients with diffuse alveolar damage, although a subset demonstrated a more subacute presentation and recovered without mechanical ventilation. Etiologic factors were similar to those of diffuse alveolar damage cohorts; some cases were idiopathic.

Paraskeva et al (16) described a series of lung transplant recipients with this type of lung allograft injury and a poor prognosis. It has been rarely reported as a separate entity by other centers, with incidence varying from 1% to 11% (16,65,66). AFOP has been described as an accompanying histologic feature in restrictive CLAD. Although spirometric criteria for AFOP do not exist, an FEV₁ decline greater than 20% and a restrictive physiologic profile are typically present (16,67,68). A causal relationship between AFOP and obstructive and restrictive CLAD has previously been proposed (68), and it remains to be seen whether AFOP merely represents a form of lung injury predisposing a patient to developing CLAD or whether AFOP represents its own distinct phenotype (65,69).

Pathologic characterization of AFOP.—AFOP has a distinct microscopic appearance as ball-like fibrin exudates that fill or substantially occupy alveolar spaces (Fig 10). Alveolar septa are typically slightly widened, are lined with reactive type 2 pneumocytes, and may harbor a lymphocytic cellular interstitial pneumonitis. Hyaline membranes are not considered a feature and, if identified, suggest a diagnosis of diffuse alveolar damage. Likewise, overt fibroblastic organization of the intra-alveolar aggregates would result in a diagnosis of organizing pneumonia. Substantial tissue eosinophilia would raise the possibility of acute eosinophilic pneumonia. The conceptual position of AFOP relative to classic diffuse alveolar damage and organizing pneumonia remains the subject of investigation. Clinicians should recognize that intra-alveolar fibrin may attend other localized infectious, inflammatory, or neoplastic lesions. Care must be exercised to avoid overinterpreting descriptions of airspace fibrin and/or AFOP in pathologic reports of small biopsies as generalizable to situations in which intra-alveolar fibrin manifests as a diffuse lung injury pattern. Indeed, pathologists should only diagnose AFOP by using surgical biopsy, resection, or autopsy specimens (70).

Figure 10:

Hematoxylin-eosin–stained section from a lung at autopsy in a patient with chronic lung allograft dysfunction (imaging not available). A, Scanned micrograph shows typical features of acute fibrinous and organizing pneumonia (AFOP) associated with organizing alveolar fibroelastosis. The changes are distributed on both sides of an interlobular septum (ILS) in a perilobular pattern. Fibrinous pleuritis with edema has widened the pleura (pl). The horizontal bar is equivalent to 1.25 mm. B, Higher-magnification image of the region of AFOP shows compact fibrin balls occupying alveolar spaces (arrow) that can be seen separating away from the alveolar septa.

Because of its alveolar filling pattern and the fact that it may be seen in direct apposition to established fibroelastosis, it is tempting to speculate that AFOP may be one of the direct antecedents of intra-alveolar fibrosis and elastosis. Because AFOP may also be found in conjunction with organizing pneumonia, it is not unreasonable to speculate that there may be an intermediate phase of organizing pneumonia in some cases that eventuate in intra-alveolar fibrosis and elastosis and pleuroparenchymal fibroelastosis.

CT findings of AFOP.—CT findings previously described in the setting of AFOP after lung transplant include ground-glass opacities and interlobular septal thickening that indicate an underlying alveolar process, bilateral predilection (71), with consolidation and peripheral fibrosis identified less commonly.

Eosinophilia

Peripheral blood eosinophilia and/or elevated bronchoalveolar lavage eosinophils have been reported in association with acute lung allograft rejection (72–76), and bronchoalveolar lavage eosinophilia greater than 2% is associated with worse outcome after lung transplant (77). Bronchoalveolar lavage eosinophilia can be detected at the time of acute lung allograft dysfunction (with or without classic findings of acute cellular rejection and interstitial eosinophilic infiltrates) preceding the development of CLAD or during the progression of CLAD. Worse prognosis and a significantly decreased graft survival occurred with peripheral blood eosinophilia in patients with restrictive CLAD (56).

CT findings of eosinophilia.—CT features of acute eosinophilic pneumonia consist mainly of bilateral ground-glass opacities, interlobular septal thickening, and thickening of bronchovascular bundles commonly associated with small pleural effusions (78,79). Bilateral ground-glass opacities and tree-in-bud nodules have been reported in a patient with graft eosinophilia after lung transplant (80), but overall there is a paucity of data on CT findings in eosinophilia in lung transplant. Examples of eosinophilic lung allograft dysfunction are provided in Figures 11 and 12.

Figure 11:

Mixed-phenotype chronic lung allograft dysfunction in a 26-year-old woman. CT images obtained on posttransplant day 1447 demonstrate a multifocal bilateral upper lobe and peripherally predominant peribronchovascular ground-glass opacities and interlobular septal thickening (arrowheads), accompanied by elevated bronchoalveolar lavage and peripheral blood eosinophilia consistent with an eosinophilic pneumonia pattern, which resolves at follow-up CT on day 1611. CT images obtained on day 1651 demonstrate increased bronchial wall thickening and new multifocal peripheral consolidation with a reverse halo sign (arrow), in keeping with the organizing pneumonia pattern in the apicoposterior segment of the left upper lobe. Additional patient information is found in Tables E1 and E2 (supplement).

Figure 12:

Mixed-phenotype chronic lung allograft dysfunction in a 68-year-old man. CT images obtained on posttransplant day 1096 demonstrate nodular subpleural consolidation in the apical right upper lobe (arrow). CT images obtained on day 1321 show new upper lobe–predominant perilobular ground-glass opacities and dense consolidation with associated bronchial dilatation and volume loss, as well as an organizing pneumonia reaction pattern with improved but persistent findings on images obtained on day 1350 (arrowheads). Additional patient information is found in Tables E1 and E2 (supplement).

Neutrophilic Reversible Airway Disease

It has been suggested that neutrophilic reversible airway disease can be diagnosed when patients have an FEV₁ level that is less than 80% of the baseline level for at least 3 weeks and have bronchoalveolar lavage neutrophil levels greater than 15% without infection (81) with an increase in FEV₁ of at least 10% after 3 to 6 months of azithromycin treatment (compared with FEV₁ at the start of treatment, on the basis of two separate measurements with at least 3 weeks in between) (82). Although neutrophilic reversible airway disease can occur any time after transplant, it typically occurs early (within 3–6 months) (83).

Although patients with neutrophilic reversible airway disease respond to azithromycin, these patients have been shown to have an overall poorer survival (84), and underlying pathophysiologic condition is not well understood. Patients who respond to azithromycin have been shown to have significantly higher levels of inflammatory cytokines (IL-1, IL-8, MCP-1, RANTES), matrix remodeling factors (MMP-8, MMP-9), growth factors (HGF, PDGF), markers of oxidative stress (MPO) (85), and bile acid (previously noted to result in allograft neutrophilia) in bronchoalveolar lavage specimens (85–87). Azithromycin suppresses inflammation (88), and patients who respond to azithromycin are known to have neutrophilic reversible airway disease or azithromycin responsive allograft dysfunction (9,85), an entity distinct from BO, characterized by active inflammation and neutrophilic infiltration. Because azithromycin is universally initiated immediately after lung transplant, fewer patients develop neutrophilic reversible airway disease, and it is no longer considered a form of CLAD (18).

CT findings of neutrophilic reversible airway disease.— Imaging findings in neutrophilic reversible airway disease include the presence of centrilobular micronodules and tree-in-bud opacities, airtrapping (common), mucous plugging, airway wall thickening, bronchial wall thickening, bronchial dilatation, and consolidation, which improve during and after treatment with azithromycin (89).

MRI Assessment of CLAD

Several MRI techniques have been used to assess CLAD, with the ability to assess regional function changes enabling detection of graft abnormalities before FEV₁ deterioration. With inhalation of gaseous contrast media containing hyperpolarized xenon or helium, biochemical and spatial information can be obtained by mapping metabolic activity during molecule degradation (90). This technique has shown superior sensitivity for the detection of regional hypoventilation compared with CT (91) but is limited because of cost and long preparation time. Quantitative oxygen-enhanced T1 mapping has been used to assess lung composition and CLAD severity (92); this technique is limited by the need for a closed face mask and breath holds. Fourier decomposition MRI uses rapidly acquired images during normal respiration to distinguish between periodic signal variations of blood inflow and perfusion (high frequency) and ventilation (low frequency) (93). Fourier decomposition MRI–derived parameters demonstrated potential in quantitative CLAD diagnosis and assessment by enabling estimation of the regional fractional-ventilation and ventilation-defect percentages (94). More recently, Moher Alsady et al (95) used the phase-resolved functional lung MRI contrast-free technique (96) to generate flow–volume loops and yield parameters of ventilation dynamics, which were shown to be sensitive enough for the detection of early CLAD.

Pathogenesis of CLAD

The pathogeneses of both obstructive and restrictive CLAD remain elusive and are likely the result of synergy among many pathways. These involve the innate immune processes (eg, acute lung injury, primary graft dysfunction, reflux or aspiration, and infection) and adaptive immunity generating alloimmune and autoimmune responses against lung structural proteins (self-antigen manifestation following tissue destruction and exposure to cryptogenic autoantigens) (97). Many risk factors are common to both obstructive and restrictive CLAD, including acute cellular rejection, lymphocytic bronchiolitis, community-acquired respiratory viral infections, bacterial and fungal colonization (particularly by Pseudomonas aeruginosa) (98), cytomegalovirus mismatch, and bronchoalveolar lavage neutrophilia, and bronchoalveolar lavage and blood eosinophilia (3,77,99). The relationship between acute lung allograft injury patterns and the development of CLAD has been examined (100). Acute cellular rejection was found to be the only early‐onset (<6 months after transplant) allograft injury that was associated with CLAD development. The pathogenesis of acute rejection represents an alloimmune response by preformed alloreactive memory T cells. Late (>6 months after transplant) parenchymal and vascular injury patterns of diffuse alveolar damage, organizing pneumonia, and acute rejection predicted the development of restrictive CLAD, whereas the airway‐centric injury pattern (lymphocytic bronchiolitis) predicted obstructive CLAD development in this study. It was hypothesized that diffuse alveolar damage, organizing pneumonia, and lymphocytic bronchiolitis would be initiated by exposure‐related insults (eg, aspiration, infection, and pollution), which would be followed by alloimmune responses demonstrating the complex interaction of the innate and adaptive immune systems in response to injury, leading to CLAD (100).

For the production of the typical lesion of BO in obstructive CLAD, a host of initiating factors are thought to alter the metabolism of the airway epithelial cells, activating the epithelial-mesenchymal transformative pathway. Infection, including viruses (101) acting through toll-like receptors (102); reflux or aspiration of gastric or bile acids (103,104); injurious factors acquired through primary graft dysfunction events (105); and rejection of allograft (106) are a few of the potential factors associated with BO. Following the appropriate interactions, airway epithelial cells are then stimulated to release an array of soluble factors that lead to the recruitment of myofibroblasts and generation of matrix-transforming growth factor β, platelet-derived growth factor, insulin-like growth factor 1, fibronectin, S100A4, and matrix metalloproteinase (107,108).

A humoral alloimmune response has been found to play an important role in the mechanism of BO. In solid-organ transplantation, donor-specific anti–human leukocyte antigen antibodies and non–human leukocyte antigen antibodies are known to contribute to antibody-mediated rejection (109,110) and increase the risk of developing obstructive CLAD (110–113) and the risk of death (114). When exposed to anti–human leukocyte antigen antibodies, human airway epithelial cells secrete fibroblast growth factors, inducing epithelial cell proliferation and apoptosis (111). Neutrophilic infiltration of allografts has also been associated with the presence of anti–human leukocyte antigen antibodies (115). There is a substantial body of literature that supports donor-specific antibodies and antibody-mediated rejection as playing clinically significant roles in the pathogenesis of restrictive CLAD (116–119). Clinical details of the depicted cases according to figures presented in this article are provided in Tables E1 and E2 (supplement).

Translating from molecular events to pathologic expression, the role of acute lung injury patterns such as organizing pneumonia, diffuse alveolar damage, and AFOP as the direct antecedents to intra-alveolar fibrosis and elastosis or pleuroparenchymal fibroelastosis has been examined. These pathologic processes, unified by variable expressions of airspace fibrin, reflect degrees of alveolar septal injury and leakage of cells and proteins into the alveolar space. Both of these processes have been identified in patients with CLAD (16,42,49,52).

Finally, an obstructive airway component creating a predisposition for developing the intra-alveolar fibroelastotic sequelae of restrictive CLAD should not be discounted. Airway injury could result in a predisposition to overall pleuroparenchymal fibroelastosis by both mechanisms of diminished clearance of pathogenic substances and mechanisms retarding the expectoration of any accumulated alveolar secretions and exudates distributed in the subtended alveolar parenchyma. The formation of BO lesions is commonly found in patients with restrictive CLAD and may be a contributing culprit rather than just an associated parallel process.

Management of CLAD

A detailed description of treatment for CLAD subtypes is beyond the scope of this article. There are few treatment options that exist for CLAD, and the treatments that are available have been reported in obstructive CLAD primarily and have demonstrated limited efficacy. To our knowledge, formal treatment guidelines for restrictive CLAD do not exist and management is largely experimental (64). As mentioned above, neutrophilic reversible airway disease is rarely encountered because azithromycin is initiated immediately after lung transplant surgery and is therefore no longer considered a form of CLAD (18). Montelukast is a cysteinyl leukotriene inhibitor that may be useful in patients with the obstructive CLAD phenotype in which neutrophilia is absent and azithromycin is unlikely to be effective (120), and it has previously been shown to slow the rate of FEV₁ decline (121,122). Extracorporeal photopheresis includes the removal of a fraction of the patient’s blood and isolation of leukocytes, which are then exposed to ultraviolet light in the presence of 8-methoxypsoralen, which results in leukocyte apoptosis and regulatory T-cell induction (123). Obstructive CLAD phenotype (124) and early CLAD (125) have been associated with a better response to extracorporeal photopheresis, whereas the restrictive CLAD phenotype and bronchoalveolar lavage neutrophilia have been associated with poorer response rates (126).

Alemtuzumab (a CD52 antagonist) has been shown to improve interstitial changes and lung function in patients with restrictive CLAD (127). Moniodis et al (128) showed that extracorporeal photopheresis and alemtuzumab slow the rate of CLAD progression equally. Cytolytic therapy with rabbit antithymocyte globulin has been shown to be effective in the treatment of obstructive and restrictive CLAD, with therapy demonstrating clinically significant reversal of lung function decline (129). Given the similar pathogenesis of CLAD and idiopathic pulmonary fibrosis, antifibrotic treatments may have benefit in the treatment of CLAD (130–132). In Europe, a randomized clinical trial is currently recruiting patients to test pirfenidone efficacy in CLAD, with studies involving nintedanib also in development (120). Because of relationship between gastroesophageal reflux and CLAD, an expert panel previously recommended fundoplication consideration in patients with CLAD and confirmed gastroesophageal reflux (133). Because of evolving treatment strategies, earlier recognition of CLAD is imperative for prompt treatment instigation and improved patient outcomes.

Conclusion

The clinical, radiologic, and histologic manifestations of CLAD are heterogeneous and may progress slowly over several years or more rapidly within months.

Knowledge of the underlying pathologic condition and pathogenesis of CLAD is key to understanding the imaging findings. Features on images might precede the clinical manifestation of the allograft injury. Tissue samples obtained with transbronchial biopsies have limited value in characterizing these lesions; therefore, subtle findings at CT imaging could alert the clinician to follow the changes closely and correlate the findings with other clinical findings. Emerging MRI techniques for the early detection and quantification of CLAD severity have been described and hold promise for future patient monitoring in clinical practice, particularly because of the absence of ionizing radiation with MRI and the often-frequent need for imaging in this patient cohort. We highlighted the importance of early CT findings and the evolution of CT findings in CLAD, which, if detected early on, may impact treatment decisions and improve patient outcomes.