Imaging of pulmonary infections after lung transplantation: a pictorial essay of early and late computed tomography findings

Pulmonary infections are among the most common complications after lung transplants and a major cause of morbidity and mortality in these patients. Computed tomography is one of the main non-invasive diagnostic tools for detecting lung infections but characterizing the correct etiology may be very challenging. Indeed, although several pathogens show typical patterns at imaging, others, such as bacteria, may demonstrate quite unspecific features. Therefore, additional parameters, like the timing of the infection, should be evaluated to support the radiologists in narrowing the differential diagnoses. In fact, it has been demonstrated that several pathogens, like Candida albicans, usually occurring within the first month after the transplant, frequently occur at specific time points. Thus, aim of this review is to make radiologists and clinicians familiar with the computed tomography patterns of pulmonary infections occurring after lung transplant, considering the etiology and the time of onset, according to the extensive experience gained in our tertiary center.


Introduction
Pulmonary infections are a leading cause of morbidity and mortality after lung transplant (LT) and may occur at any time [1][2][3][4]. LTs carry an intrinsic high risk of infection because of the direct communication of the transplanted organ with the atmosphere [5]. Additional factors associated with the surgical procedures (e.g., impaired mucociliary function due to allograft denervation, administration of immunosuppressive drug therapy) [6], the donor (e.g., insufficient donor arterial oxygen tension, positive donor sputum) and the recipient (e.g., older than 40 years) [1,6] may play a significant role for the onset of infections in the early and late postoperative phase.
Together with the clinical and laboratory evaluations, radiological imaging, especially computed tomography (CT), is crucial for the early detection and characterization of pulmonary infections in LT [1][2][3][4]. Indeed, specific patterns at CT such as nodules with a peripheral rim of groundglass due to Aspergillosis [1,7] or diffuse bilateral groundglass areas with sub-pleural sparing due to Pneumocystis jirovecii may suggest a confident diagnosis. Even if in some cases, such as with bacterial infections, the imaging features might be relatively unspecific, making the diagnostic process more challenging [1][2][3], the temporal relationship between the LT and the onset of the lesions may narrow down the list of differential diagnoses. In fact, it is well known that specific agents, such as the Pseudomonas aeruginosa, which is more frequent during the early postoperative phase, tend to occur at specific time points.
Thus, the aim of this review is to make radiologists and clinicians familiar with the CT patterns pulmonary infections occurring after LT considering the etiology and the time of onset of the disease.

Pulmonary infections after lung transplant
Since different agents are associated with the occurrence of pulmonary infections at different time points after LT, a subdivision in early (up to 1 month), primary late (1-4 months), and secondary late (after 4 months) infections, according also to the different etiologies, has been applied ( Fig. 1) [1,2].

Bacterial infections
Bacterial infections are the most common postoperative infections in LT recipients, especially during the early phase (i.e., 1 month). Nevertheless, it should be considered that they may also occur later on during recipients' life [8,9].
Gram-negative bacilli, such as Klebsiella species and Pseudomonas aeruginosa, followed by Gram-positive, like Staphylococcus aureus, are the most frequent agents [6]. Pulmonary Actinomycosis, even if rare, should be considered among the differential diagnoses especially in case of mediastinitis [10]. It has also to be highlighted that recipients with cystic fibrosis carry a higher risk of infections due to Pseudomonas aeruginosa and Burkholderia cepacia complex.

Fungal infection
Candida species often colonize the airways of LT recipients. Very aggressive infections usually occur during the first month after the LT, either as postoperative complications due to a prolonged stay in the intensive care unit or because of a colonized donor organ [11][12][13]. CT patterns of fungal infections include patchy and confluent pulmonary infiltrates, nodules (i.e., occasionally miliary), mass-like foci or airspace consolidation, and interstitial involvement. In case of single LTs, fungal pneumonia mainly affects the transplanted lung (Fig. 6). Very aggressive infections may also cause candidemia, mediastinitis, or necrosis of the anastomosis [8].

Viral infections
Respiratory viral infections are a very important cause of morbidity and mortality in LT recipients [14].
Cytomegalovirus (CMV) is the second-most common cause of pneumonia and the most common opportunistic infection in LT patients [1,15], even if it has to be considered that the current prophylaxis with antiviral drugs is reducing its occurrence [16]. Overall, CMV pulmonary infections have a peak incidence at 1-4 months (i.e., range 1-12 months) rarely occurring in the first two weeks after the LT [1]. Primary pulmonary infections due to CMV are usually very severe and may occur in seronegative recipients receiving a graft from a seropositive donor. On the contrary, secondary infections, commonly less severe, are mainly diagnosed in seropositive recipients either infected by a different CMV strain or undergoing a reactivation due to immunosuppression [8].
In addition to CMV, community-acquired viruses, such as respiratory syncytial, parainfluenza, influenza virus, and adenovirus, may infect LT recipients especially between 2 weeks and 2 years after the LT, with a rate of occurrence between 8 and 14% [1].
Other less common viral pathogens are herpes simplex (i.e., the incidence is constantly decreasing because of prophylaxis), varicella zoster (i.e., mainly causing muco-cutaneous involvement), and Epstein-Barr virus (i.e., especially important because it may then cause lymphoproliferative disorders) [8].
CT findings of viral infections include ground-glass, air-space consolidations, tree-in-bud opacities, airway dilatation, bronchial wall thickening, and pleural effusion (Fig. 7) [1,8,17]. Severe infections may present with a crazy paving pattern (i.e., ground-glass opacity with superimposed interlobular septal thickening and intra-lobular reticular thickening) (Fig. 8). The CMV pneumonia is also associated with a high risk of superimposed bacterial and fungal infections. Thus, it needs to be taken into consideration that findings due to the additional infection could overlap with the above-mentioned viral features at imaging (Fig. 9).

Fungal infection
Aspergillosis is the most common fungal infection in LT recipients [7,18] and it usually occurs 1-6 months after the LT (i.e., peak incidence within the first 3 months after the LT) [1].
Ulcerative tracheobronchitis is the earliest and most common expression of the disease, and it may cause anastomotic dehiscence. Its diagnosis is easily reached at CT with the detection of focal bronchial wall defects and perianastomotic air collections (Fig. 10) [19].
Aspergilloma, necrotizing pneumonia, invasive pulmonary disease, disseminated infection, or empyema may also be due to Aspergillus infection. Invasive pulmonary infections tend to occur in the later phase after LT and are mainly associated with the dissemination to other organs. Typical features at CT imaging of Aspergillus infection include focal nodular and mass-like consolidations, cavitation, nodules (i.e., solitary or multiple) surrounded by a rim of

Bacteria
Among the bacterial infections occurring in the secondary late period after LT, those due to Mycobacterium tuberculosis are quite frequent (i.e., estimated prevalence between 2 and 3.8%) [1,8], and are usually caused by the reactivation of a focus in the native lung or by transmission via the allograft.

Fungal infection
Prior to the trimethoprim/sulfamethoxazole prophylaxis, Pneumocystis jirovecii pneumonia (PJP) was diagnosed in around 90% of the LT recipients and the first 6 months after the LT were at very high risk (i.e., highest peak between the second and sixth month). Nowadays, PJP is very uncommon during the first year after LT and it mainly occurs later on [16].
Typical PJP findings at CT are represented by bilateral ground-glass opacities with sub-pleural sparing and predilection for the upper lobes. Less frequently, focal areas of consolidation and thickening of the interlobular septa or diffuse micro-nodules are evident at imaging (Fig. 15). A cystic form of PJP may also occur and these patients carry a high risk of pneumothorax or pneumomediastinum [16].

Conclusion
Pulmonary infections are very common after LT and CT imaging plays a crucial role. Therefore, a deep knowledge of the typical CT findings caused by the most common different pathogens and their usual timing of colonization are essential to support the clinicians in the diagnostic and therapeutic process.

Conflict of interest
The authors have no conflicts of interest to declare that are relevant to the content of this article.

Ethical Standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The authors did not receive support from any organization for the submitted work.
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