A little history...

Before we begin with the definition  of lung allograft dysfunction and deal specifically with the radiological appearances of the chronic form, it might be useful to review the recent evolution of knowledge regarding this subject in order to clarify some terms commonly used.

Initial studies of patients with decline in allograft function after lung transplantation showed typically histopathological changes of bronchiolitis obliterans (BO). This histopathological pattern was considered the result of underlying alloimmune mechanisms leading to chronic rejection.

Unfortunately, the pathological evidence of BO in these patients is not easy as it requires a significant amount of representative tissue, difficult to establish from the relatively limited sampling of lung tissue obtained from transbronchial lung biopsy.

Hence, an International Society for Heart and Lung Transplantation (ISHLT) committee introduced in 1993 the term bronchiolitis obliterans syndrome (BOS) as a clinical surrogate reflecting the chronic forced expiratory volume in 1 second (FEV1) decline due to the development of BO (3). As long as histopathological diagnosis of BO is difficult, an easier to perform and more available marker is introduced to monitor these patients.

Unfortunately, this clinical surrogate, although useful, was found to be limited due to the accumulated experience and the evolution of new therapies. As a consequence, an update in the diagnosis of BOS was introduced in 2002 (4).

Despite this update a significant cohort of patients had chronic FEV1 decline for which the previous definition of BOS was not the best descriptor. In order to include these patients a new classification system for chronic lung allograft dysfunction was proposed in 2014 (5).

Lung allograft dysfunction (LAD)

LAD is defined as a decline in FEV1 or forced vital capacity (FVC) >10% of baseline figures, considering baseline as the best post-operative FEV1 or FVC value. This decline may be an acute (ALAD) or chronic (CLAD) phenomenon.

ALAD may caused by various conditions including acute rejection, infections, pulmonary thromboembolism. Many of the conditions leading to ALAD may be reversible with treatment and restore FEV1 or FVC values to >90% baseline. If these values are not restored to normality after 3 weeks CLAD should be suspected (5).

Chronic lung allograft dysfunction (CLAD)

CLAD is defined as a “transplanted lung that does not achieve or no longer maintains normal function for an arbitrarily defined period of time” (5).

CLAD will be suspected in patients with persistent (more than three weeks) decline of FEV1 or FVC ≤ 90 % baseline. If the FEV1 or FVC decline further to ≤ 80% of baseline values despite treatment or without identifying a cause CLAD will be stablished and a specific cause or phenotype of CLAD should be identified.

Among the specific causes that may lead to a situation of suspected or stablished CLAD stand out infection, anastomotic stricture, neoproliferative diseases, persistent acute rejection and disease recurrence. So, in spite of the use of the word chronic, CLAD should not be considered a permanent situation as long as lung function decline caused by some of the conditions is reversible and may be restored to normal upon correct treatment.

It is important to stress that CLAD should not be considered a final diagnosis but a simple descriptor of persistent lack of normal lung function and once the detection of suspected CLAD is made, a whole battery of extended tests, including full pulmonary function test, chest CT, bronchoalveolar lavage and transbronchial biopsy, should be performed with the goal of identifying specific and treatable causes of allograft dysfunction or the phenotype of CLAD. 

If no specific diagnosis is reached after extensive investigation and the CLAD situation persists more than three weeks it is important to define the CLAD phenotype for every patient. This phenotype classification is stablished with the results of extended pulmonary function testing and divided in an obstructive phenotype or bronchiolitis obliterans syndrome (BOS) and a restrictive phenotype or restrictive allograft syndrome (RAS).

As a summary, Figure 2 depicts a flow chart to evaluate a patient with lung transplantation and decline in pulmonary function tests.

Fig. 2: Flow chart to evaluate lung allograft recipient with pulmonary function impairment. Modified from Verleden et al.

Obstructive CLAD. BOS

Obstructive CLAD is defined by persistent decline in FEV1 measurements equal or superior to 20% baseline and also with a decreased FEV1/FVC ratio denoting an obstructive condition.

The pathological process underlying this obstructive phenotype will be the obliterative bronchiolitis pattern described previously in patients with chronic rejection and BOS.

Radiologically, this phenotype, being an obstructive condition, will be mainly characterized by the presence of mosaic attenuation pattern related to patched areas of air trapping in expiratory images. A minimum percentage of one third of air trapping visible at end-expiratory CT scans has been proposed for the CT diagnosis of BOS (6). Obtaining good inspiratory and expiratory images is crucial to make a correct diagnosis specially in initial BOS and an adequate training of the patient in inspiratory and expiratory effort by the technician before the images are obtained is most advisable.

Fig. 3: Inspiratory and expiratory CT in patient with bilateral transplantation due to fibrotic hypersensitivity pneumonitis 18 months ago. Notice bibasal patched areas of air trapping in expiratory images with no relevant abnormalities in inspiratory images. Baseline FEV: 1.95 l. Current FEV1:1.72 l

Correlation between the extent of air trapping in CT evaluation and the deterioration of respiratory functional test is fairly good although of limited clinical relevance in the management of these patients as long as functional test are relatively cheap and easily available.

Fig. 4: Inspiratory and expiratory CT in patient with bilateral transplantation due to idiopathic pulmonary fibrosis 13 years ago. Baseline FEV1: 3.6 l. Patchy areas of air trapping are evident in both lower lobes and to a lesser extent in right upper lobe becoming more evident as FEV1 deteriorates.

The definition of BOS requires a persistent decline in FEV1 but this decline is not mean to be definitive. Reversibility of BOS has been traditionally considered an exception. This is a logical assumption if we consider bronchiolitis obliterans, irreversible small-airways occupation from a pathological point of view, as the pathological substrate of BOS. But this airways occupation is not necessarily fibrotic and hence irreversible, specially in early stages of BOS.

Up to 40% of patients that meet the criteria of BOS may present response to treatment with azithromycin with an increase in FEV1 of at least 10% with some patients recovering completely the FEV1 values to baseline figures (7).

Neutrophilia in bronchoalveolar lavage is associated with good response to therapy.

The radiological features of azithromycin-responsive allograft dysfunction (ARAD) patients were similar to non-responders with the presence of centrilobular small nodules as the most significant differential sign present in 54% of responders and in about one third of non-responders (8).

Fig. 5: Inspiratory and expiratory CT in patient with unilateral transplantation due to idiopathic pulmonary fibrosis 7 years ago. Baseline FEV1: 2.00 L. FEV 1 deterioration 6 years after surgery with FEV1 falling to 1.29 L with patchy areas of air trapping in CT examination (A). After azithromycin treatment FEV1 recovered to 1.78 with CT images reflecting a lesser extent in air trapping areas.

This particular behavior poses different questions regarding wether this condition, ARAD, constitutes an early phase of BOS or a completely different diagnosis and about BO as its pathological substrate.

Restrictive CLAD. RAS

Restrictive allograft dysfunction (RAS) is defined as persistent FEV 1 decline of > 20% accompanied by a decline in forced vital capacity (FVC) and total lung capacity (TLC). Depending on the relative decline of these three measurements the findings may lie outside the definition of BOS that requires an obstructive ventilatory defect. A restrictive ventilatory pattern may be suggested even if total lung capacity is not available when FEV 1 and FVC decline simultaneously giving a normal or even an increased FEV1/FVC ratio (5).

The radiological appearance in this group of patients is characterized by the progressive development of reticular and ground glass opacities with loss of volume and lung distortion suggestive of lung fibrosis.

Fig. 6: Inspiratory, coronal reconstruction and expiratory CT in patient with bilateral transplantation due to Langerhans cell histiocytosis 4 years ago. Baseline FEV 1: 2.92 L. Baseline FVC: 3.25. Notice reticular abnormalities with upper lobes predominance with no significant air trapping in end-expiratory images (Bottom row). Pulmonary functional tests showed progressive worsening with FEV 1: 2.39 and FVC: 2.74 48 months after surgery. FEV 1/FVC ratio remained slightly increased with a value of 118% confirming the diagnoses of RAS.

The progression pattern of RAS has been described as a stair-step pattern with acute exacerbations followed by interval periods during which fibrosis progresses (9). The acute exacerbations are characterized radiologically by the presence of ground glass opacities and consolidation similar to the features found in acute respiratory distress syndrome (ARDS) and with diffuse alveolar damage (DAD) as a common pathological substrate.

Fig. 7: Axial and coronal CT images in patient with left lung transplantation due to NSIP. Ground glass opacities appear at the left upper lobe 19 months after surgery (red arrow) followed by substitution of the ground glass opacification by a reticular pattern (blue arrows) with bronchiolar retraction (green arrows) and slight loss of volume consistent with fibrotic changes in relation to RAS.

Some patients developing RAS phenotype may initially present a FEV1 decline consistent with the diagnosis of BOS with the restrictive pattern, radiologically and at functional lung tests, appearing subsequently. This evolution may take a prolonged period of time but appearance of reticular opacities at CT seems predictive of the conversion from BOS to RAS phenotype.

Conversely, patients with initial RAS phenotype may develop features consistent with BOS. Hence, coexistence of both phenotypes is not exceptional.

Fig. 8: Axial, expiratory and coronal CT images in patient with bilateral transplantation due to hypersensitivity pneumonitis 3 years ago. Baseline FEV 1: 2.52 L. Baseline FVC: 3.16 L. CT images obtained at 16, 26 and 29 months show progressive appearance of faint subpleural reticular opacities in left upper lobe (red arrow) and irregular bronchial dilatation (blue arrow) with more evident air trapping in lower lobes in expiratory CT. The lung function values showed parallel decline in FEV 1 (1.91 L) and FVC (2.16 L) with a normal FEV1 / FVC ratio.

The RAS phenotype has showed a worse survival when compared to the BOS phenotype (10).

Specific causes of late lung allograft dysfunction

Acute rejection

Acute rejection usually occurs during the first three weeks after trasplantation with a peak of incidence between days 5 and 10. Despite most patients experience several episodes of acute rejection within the first three months, acute rejection may appear also later. Repeated episodes of acute rejection have been associated with an increased risk for the development of CLAD (11).

The imaging features are similar to those of reimplantation response in an early postoperative phase but this differential is not an issue in a late phase. The most challenging differential in this phase is established with infection. CT findings include patchy or diffuse ground glass opacities and interlobular septal thickening.

Fig. 9: Chest radiograph and CT images in patient with bilateral lung transplantation due to COPD two years ago. Chest radiograph obtained 5 months after surgery in A shows faint lineal opacities in both lungs with no consolidation. Ches CT shows bilateral interlobular septal thickening with minimum areas of ground glass opacities (red circles). After corticosteroid therapy chest radiograph and CT show complete resolution of the septal thickening confirming diagnosis of acute rejection. Notice incidental small pulmonary herniation on the left side (red arrow).

The presence of nodules and areas of consolidation may also be present, making the differential diagnosis with infection even more difficult. Transbronchial biopsy is performed in these cases to confirm diagnosis and to rule out infection.

The range of clinical presentation is wide ranging from asymptomatic patients to patients presenting with fever, dyspnea and leukocytosis. Decline in FVC and FEV 1 is usually present. Response to corticosteroids and immunosuppresion is characteristically described in this group of patients.

Bronchial stenosis

Bronchial anastomotic stenosis is usually seen within 4 months of lung transplantation. Narrowing secondary to stricture, with a significant stenosis defined as a reduction superior to 50% of the lumen, is easily assessed with inspiratory CT but evaluation in axial, coronal and sagittal planes is necessary to make the diagnosis. Despite confirmation of diagnosis relies on bronchoscopy, CT is valuable to plan therapeutic procedures including bronchoscopic stent implantation.

Bronchial stricture is seen in up to 10% of cases but this percentage is decreasing with improvement in surgical techniques and donor preservation techniques. An increase incidence of stricture development has been described with the use of the telescope anastomosis technique (12).

Fig. 10: Inspiratory, expiratory, coronal minIP reformation and virtual bronchoscopy in patient with bilateral lung transplantation due to idiopathic pulmonary fibrosis 4 years ago. Notice irregularity at the bronchial stenosis at the inspiratory image immediately after surgery in relation to bronchial wall overlapping secondary to telescope technique (red arrow). 5 months after surgery a significant stenosis (red circle and arrow) is seen with left lung air trapping in expiratory image (blue arrow). After repeated treatments of balloon dilatation a bronchial stent is inserted one year after surgery. CT obtained three months later shows nonsignificant stenosis secondary to granulation tissue (green circle and arrow) that progresses to a significant stenosis 3 years later (yellow circle and arrow). A second bronchial stent was deployed at the stricture point with normalization of the bronchial caliber.

Lymphoproliferative disorders

Posttransplantation lymphoproliferative disorders is a spectrum of diseases ranging from benign polyclonal lymphoid proliferation to high grade lymphoma.

Incidence is approximately 5% with most cases occurring within the first year with a peak incidence at 4 months.

Imaging in these cases is not different from other cases of lymphoma in the general population with multiple pulmonary nodules and masses as the most frequent appearance. Extrapulmonary involvement, including hilar or mediastinal lymph nodes enlargement and pleural and pericardial effusions, is less common.

Fig. 11: CT and PET-CT images in patient with bilateral lung transplantation due to COPD. Four months after surgery small solid nodules are seen in both lungs (red circles). Four months later multiple solid and hypermetabolic nodules and masses develop with no extrapulmonary involvement. High grade lymphoma.

Disease recurrence

Disease recurrence is uncommon (1% of lung transplant recipients). Among the diseases reported to recur in the transplanted lung sarcoidosis is the most commonly cited with lymphangioleiomyomatosis and Langerhans cell histiocytosis being less common.

Fig. 12: CT images in patient with bilateral lung transplantation due to Langerhans cell histiocytosis four years ago. Presurgical CT shows irregular cystic lesions with bilateral air collections related to repetition pneumothoraces. Postoperative CT shows no abnormalities in lung parenchyma. Two years later small and irregular cystic lesions are visible in both lungs suggesting Langerhans cell histiocytosis.

Transbronchial biopsy complications

Transbronchial biposies are routinely performed in the follow-up evaluation of patients with lung transplantation. Solid and cavitary nodules with surrounding ground glass opacities may be identified up to four weeks after transbronchial biopsy. The temporal relationship to the biopsy and the unilateral and regular distribution of the lesions make the diagnosis easier and prevent confusion with fungal infection.

Fig. 13: CT images in patient with bilateral lung transplantation due to cystic fibrosis. Four days after transbronchial biopsy several solid nodules, one of them with cavitation, are seen in the periphery of the right lung surrounded by ground glass opacities reflecting perilesional bleeding. Only three days later the size of the nodules has slightly decreased with no cavitation and with improvement of the ground glass opacities. Postbiopsy lesions.

Alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is an exceptionally rare complication after lung transplantation with less than ten cases reported. 

PAP is characterized by the accumulation of surfactant lipids and proteins in the alveolar spaces. Primary PAP is the result of autoantibodies to granulocyte macrophage-colony stimulating factor resulting in macrophage dysfunction and impaired surfactant processing. Secondary PAP is the result of macrophage dysfunction in the absence of these autoantibodies and has been described  in relation to hematologic disorders, immunodeficiency, infections and inhalation diseases. In PAP after lung transplantation the etiology is thought to be related to a defect in macrophage function caused by immunosuppresion therapy (13).

The radiological appearance in PAP after lung transplantation does not differ from other forms of PAP with “crazy-paving” pattern (interlobular septal thickening superimposed to ground glass opacities) as the most salient radiological sign.

Fig. 14: CT images in patient with right lung transplantation due to NSIP five years ago. CT examination performed one month after surgery shows no graft abnormalities. Six months later CT images showed diffuse ground glass opacities in the pulmonary graft in the context of CMV infection. Two months later CT showed persistence of the abnormalities despite correct treatment and clinical improvement. BAL lavage confirmed diagnosis of PAP. Follow-up CT eight months after lung transplantation shows more clearly the typical “crazy-paving” pattern.