Context.—

Respiratory infections complicate lung transplantation and increase the risk of allograft dysfunction. Allograft lungs may have different susceptibilities to infection than native lungs, potentially leading to different disease severity in lungs of single lung transplant recipients (SLTRs).

Objective.—

To study whether infections affect allograft and native lungs differently in SLTRs but similarly in double LTRs (DLTRs).

Design.—

Using an institutional database of LTRs, medical records were searched, chest computed tomography studies were systematically reviewed, and histopathologic features were recorded per lung lobe and graded semiquantitatively. A multilobar-histopathology score (MLHS) including histopathologic data from each lung and a bilateral ratio (MLHSratio) comparing histopathologies between both lungs were calculated in SLTRs and compared to DLTRs.

Results.—

Six SLTRs died of infection involving the lungs. All allografts showed multifocal histopathologic evidence of infection, but at least 1 lobe of the native lung was uninvolved. In 4 of 5 DLTRs, histopathologic evidence of infection was seen in all lung lobes. On computed tomography, multifocal ground-glass and/or nodular opacities were found in a bilateral distribution in all DLTRs but in only 2 of 6 SLTRs. In SLTRs, the MLHSAllograft was higher than MLHSNative (P = .02). The MLHSratio values of SLTR and DLTR were significantly different (P < .001).

Conclusions.—

Allograft and native lungs appear to harbor different susceptibilities to infections. The results are important for the management of LTRs.

The median overall survival of lung transplant recipients (LTRs) is only 6.7 years, which is shorter than for other solid organ transplantations.1  Noncytomegalovirus (non-CMV) infections play a major role in graft and overall survival. Indeed, 17% to 33% of patients who die within the first year after lung transplantation and 16% to 17% who die in the years thereafter succumb because of non-CMV infections.1,2  Risk factors for infection in LTRs include immunosuppression, allograft exposure to airborne pathogens, and changes of allograft defenses, including reduced mucociliary clearance, decreased cough reflex, and interruption of lymphatic drainage.35  Infections may also mimic rejection clinically and histopathologically, potentially delaying their diagnosis.6,7 

A recent case report of a single LTR (SLTR) with COVID-19 revealed diffuse alveolar damage (DAD) only involving the allograft, whereas no acute lung injury was identified in the native lung.8  We observed similar findings in the 2 SLTRs who died of COVID-19 in our institution. Therefore, we hypothesized that infections in SLTRs may affect the allograft lung differently than the native lung, potentially implying distinct pathogeneses in these lungs. We further hypothesized that in double LTRs (DLTRs), both allografts will show similar involvement by the infection, keeping in mind that infectious changes can be patchy in lungs in general.

Patients

An institutional database of LTRs was searched for patients who died of an infectious complication involving the lungs and who underwent an autopsy at Mayo Clinic Rochester, Rochester, Minnesota (1991–2022). Additional inclusion criteria were microbiologically confirmed diagnosis of an infectious pulmonary disease and patient age 18 years or older. One patient has been previously reported.9 

Medical records were searched for demographic and clinical data as outlined in Table 1 and Supplemental Table 1 (see Supplemental Digital Content 1 at https://meridian.allenpress.com/aplm in the July 2024 table of contents.).

Table 1

Demographics, Treatment, and Outcome of Patients (N = 11)

Demographics, Treatment, and Outcome of Patients (N = 11)
Demographics, Treatment, and Outcome of Patients (N = 11)

This study was approved by the Institutional Review Board, Mayo Clinic Rochester (No. 21-002940).

Specimen Collection at Autopsy

If there was any suspicion for influenza or SARS-CoV-2 infection, respective nasopharyngeal swabbing was performed. Lung cultures were performed in a subset of cases at the discretion of the autopsy pathologist. Subsequently, all lungs were perfused with 10% buffered formalin and typically fixed for at least 1 hour before sectioning. In most patients at least 1 section from each lung lobe was sampled for microscopy.

Microbiologic Data

Data on premortem and postmortem microbiologic studies performed in each patient were obtained from the medical records. Specifically, data on all premortem microbiologic cultures, serologies, and molecular and nucleic acid testing collected during the patient's last hospitalization and prior to death were recorded. In patients with COVID-19, reverse transcription–droplet digital polymerase chain reaction was performed on formalin-fixed, paraffin-embedded lung tissue sampled at autopsy to detect SARS-CoV-2 RNA as previously described.10,11  Stains for microorganisms (Grocott methenamine silver [GMS], acid-fast Bacillus) and/or immunostains using antibodies against herpes simplex viruses (HSV) 1 and 2 (polyclonal, Cell Marque, Rocklin, California), adenovirus (clone Adeno 3, EMD Millipore Corp, Temecula, California), and/or CMV (clones CCH2 + DDG9, Dako, Carpinteria, California) were performed.

Radiology Review

A thoracic radiologist reviewed chest computed tomography (CT) studies closest to the date of death when available during the immediate premortem episode of infection blinded to histopathologic and clinical findings. The reviewer evaluated scans systematically for acute (ground-glass opacity [GGO], consolidation, interlobular septal thickening) and chronic abnormalities (emphysema, fibrosis, bronchiectasis). Comparison was made to the next most recent chest CT to assess for interval change. If no chest CT was available, a chest x-ray was reviewed.

Histopathology Review

Histopathologic slides of lungs from each autopsy were reviewed by a thoracic pathologist blinded to clinical and radiologic data. Each lung lobe was semiquantitatively scored for a variety of pertinent histopathologic features that have been reported previously to be associated with respiratory infections (Supplemental Table 2; see Supplemental Digital Content 2).1215  Hemangiomatosis-like changes were defined as a widening of alveolar septa by a proliferation of dilated and engorged capillary channels arranged perpendicularly to each other, forming a complex meshlike framework.16  Each morphologic aspect was arbitrarily scored based on focality and severity. DAD and acute fibrinous and organizing pneumonia were scored higher (score 2 if multifocal/diffuse) because these acute lung injuries are known to have a worse outcome than, for instance, organizing pneumonia (score 1.5 if multifocal/diffuse).17,18 

Semiquantitative Scoring of Histopathologic Features

A lobar histopathology score (LHS) was calculated as the sum of all scores that were given for each lung lobe. By convention, 1 point was added to each LHS to equalize the numerators and denominators for subsequent fraction calculations.

A multilobar histopathology score (MLHS) was calculated as the sum of the upper and lower LHS in each lung. Two MLHSs were generated in each patient (DLTR, 1 MLHS of the right and 1 of the left lung; SLTR, 1 MLHS of the allograft and 1 of the native lung). The right middle lobes (RMLs) were excluded from this score because tissue was not collected from these lobes in all autopsies.

An MLHS ratio was calculated by dividing the highest MLHS in each patient (either MLHSRight/Allograft or MLHSLeft/Native) by the lowest MLHS (either MLHSRight/Allograft or MLHSLeft/Native). The skewness of the ratio was considered as a measure of disease heterogeneity between the 2 lungs in individual patients. A global MLHS per autopsy (GMLHS) was calculated as the sum of the LHS of all lobes divided by the number of lobes with available tissue per patient.

Statistical Analyses

Data were summarized with frequencies and percentages or medians and ranges, as appropriate. Analyses were performed using Graph Pad Prism 7.0 (GraphPad Software Inc). The Mann-Whitney U test was used for 2-group comparisons of continuous variables. Differences were considered significant for P < .05.

Eleven LTRs died of pulmonary infection, including 6 SLTRs and 5 DLTRs. Demographics, indications for lung transplantation, and clinical details of patients are summarized in Table 1 and detailed in the Supplemental Table 1. All patients had 1 or more comorbidities as detailed in Supplemental Table 1. Patients died at a median of 28 days (range, 14–43 days) after onset of terminal illness.

A total of 9 of 10 patients (90%) met the Berlin definition for acute respiratory distress syndrome (ARDS).19  In 1 patient the clinical information was incomplete, but the patient had respiratory failure necessitating mechanical ventilation due to severe fungal pneumonia. The patient who did not meet the criteria for ARDS had severe fungal pneumonia and severe hypoxemia on continuous positive airway pressure but was not mechanically ventilated because of do-not-intubate orders. Most patients were moderately hypoxemic (Table 1). All patients received at least 1 immunomodulating agent and were treated with antibiotics, antivirals, and corticosteroids (Table 1 and Supplemental Table 1). Most patients (9 of 10; 90%) also received at least 1 antifungal agent.

Clinical Complications and Cause of Death

The most common clinical complications were acute renal failure (n = 11; 100%), shock (n = 5; 45%), pneumothorax (n = 4; 36%), and pneumomediastinum (n = 3; 27%). Treatments are summarized in Supplemental Table 1. Underlying cause of death was the pulmonary infection in all patients.

Infectious Disease Agents

The diagnosis of infection was established by premortem microbiologic testing in most patients (10 of 11; 90.9%), and by postmortem assessment in the patient with HSV-pneumonitis in whom the viral infection was clinically unsuspected. Additional microbiologic testing was performed on tissue from 9 autopsies (81.8%). More than 2 microbial agents were identified and deemed to cause disease in 8 patients (73%). The results of microbiologic testing are detailed in Table 2 and Supplemental Table 1. Autopsies confirmed the pathogenicity of all clinically suspected microorganisms except in 2 patients. One patient had COVID-19 pneumonia with superimposed bronchopneumonia due to Serratia marcescens and Stenotrophomonas maltophilia and a bronchoalveolar lavage (BAL) culture growing Scedosporium sp. One mycetoma composed of hyaline mold hyphae but without associated inflammation was seen in a honeycomb cyst of the right upper lobe (RUL) lung. This patient was probably colonized by Scedosporium sp. In another patient, cultures from the BAL and bronchial washing grew Aspergillus fumigatus, and Galactomannan antigen testing was positive in serum and BAL. No evidence of fungal infection was seen histologically on autopsy, and a left lower lobe (LLL) lung tissue culture only grew 1 colony of Aspergillus sp. However, multifocal, clinically unsuspected HSV-pneumonitis was observed in that patient (Figures 1 and 2). Further details, including the infectious disease etiologies of LTRs, are described in Table 2.

Table 2

Clinical Diagnoses, Microbiologic Findings, and Imaging and Histopathologic Features of Lung Transplant Recipients

Clinical Diagnoses, Microbiologic Findings, and Imaging and Histopathologic Features of Lung Transplant Recipients
Clinical Diagnoses, Microbiologic Findings, and Imaging and Histopathologic Features of Lung Transplant Recipients
Figure 1

Radiographic and macroscopic findings in single lung transplant recipient with fatal herpes simplex virus pneumonia (patient 4). A, Computed tomography scan reveals fibrotic changes in the right (native) lung with extensive honeycombing in the posterior right lung. The left (allograft) lung shows confluent and nodular ground-glass opacities throughout with superimposed areas of consolidation with a large amount of dependent consolidation in the left lower lobe. B, Gross specimen of the right lung is characterized by extensive fibrosis with honeycomb changes in the lower lobe and lower aspects of the middle and upper lobes. The upper lobe also shows bullous emphysema. C, Gross specimen of the left lung shows multifocal areas of consolidation and hemorrhagic change predominantly in a peripheral distribution.

Figure 1

Radiographic and macroscopic findings in single lung transplant recipient with fatal herpes simplex virus pneumonia (patient 4). A, Computed tomography scan reveals fibrotic changes in the right (native) lung with extensive honeycombing in the posterior right lung. The left (allograft) lung shows confluent and nodular ground-glass opacities throughout with superimposed areas of consolidation with a large amount of dependent consolidation in the left lower lobe. B, Gross specimen of the right lung is characterized by extensive fibrosis with honeycomb changes in the lower lobe and lower aspects of the middle and upper lobes. The upper lobe also shows bullous emphysema. C, Gross specimen of the left lung shows multifocal areas of consolidation and hemorrhagic change predominantly in a peripheral distribution.

Close modal
Figure 2

Microscopic findings in single lung transplant recipient with fatal herpes simplex virus (HSV) pneumonia (patient 4). A, The left upper lobe of the lung shows intra-alveolar fibrin with focal hyaline membranes (B, arrows) consistent with diffuse alveolar damage. C, The section from the left upper lobe also demonstrates necrotizing pneumonia with large cells with dense, intranuclear inclusions. Nuclear molding and chromatin margination beneath the nuclear membrane (stained glass appearance) are also seen. These morphologic findings are consistent with Cowdry type A inclusions, characteristic of HSV intracellular infection. D, The virus-infected cells are highlighted by HSV 1 and 2 immunostain (hematoxylin-eosin, original magnification ×100 [A]; original magnifications ×200 [B] and ×400 [C]; HSV 1 + 2, original magnification ×400 [D]).

Figure 2

Microscopic findings in single lung transplant recipient with fatal herpes simplex virus (HSV) pneumonia (patient 4). A, The left upper lobe of the lung shows intra-alveolar fibrin with focal hyaline membranes (B, arrows) consistent with diffuse alveolar damage. C, The section from the left upper lobe also demonstrates necrotizing pneumonia with large cells with dense, intranuclear inclusions. Nuclear molding and chromatin margination beneath the nuclear membrane (stained glass appearance) are also seen. These morphologic findings are consistent with Cowdry type A inclusions, characteristic of HSV intracellular infection. D, The virus-infected cells are highlighted by HSV 1 and 2 immunostain (hematoxylin-eosin, original magnification ×100 [A]; original magnifications ×200 [B] and ×400 [C]; HSV 1 + 2, original magnification ×400 [D]).

Close modal

To exclude the possibility of donor-derived infection, results of donor cultures from the 3 patients who died earliest after transplantation (1.2–6.4 months; patients 5, 8, and 10) were gathered. Donor cultures were negative for patients 8 and 10 and unavailable for patient 5. However, the donor of patient 8 was CMV positive, whereas the patient was CMV negative.

Imaging Findings Differed Between Allograft and Native Lungs in SLTRs and Were Similar Between Lungs in DLTRs

Thoracic imaging results showed the presence of GGOs and/or nodular opacities in most (4 of 5; 80%) SLTRs (Figure 1, A, and Figure 3), and all (5 of 5; 100%) DLTRs (Figure 4, A). However, in SLTRs, the changes were seen bilaterally only in 2 patients. In 1 SLTR with COVID-19 pneumonia there was extensive GGO in the mid and lower zones of the allograft but only focal areas of GGO within areas of honeycomb fibrosis of the native lung (Figure 3, A); another SLTR with HSV-pneumonitis showed multifocal confluent and nodular GGOs throughout the allograft, but only several (nonconfluent) small pulmonary nodules in the native lung. In 2 other SLTRs a few patchy ground-glass nodules were only seen in the allograft. In these 2 patients the native lungs showed dissimilar findings, including hyperinflation with emphysema in a patient with COVID-19 and honeycomb fibrosis with superimposed extensive consolidation in a patient with adenovirus pneumonia. In the SLTR with respiratory syncytial virus (RSV) and Pseudomonas aeruginosa pneumonia GGOs were not appreciated in either the allograft or the native lung. Conversely, in all DLTRs, multifocal GGOs and/or nodular opacities were seen bilaterally.

Figure 3

Radiographic and histopathologic findings in single lung transplant recipient with fatal COVID-19 (patient 2). A, Computed tomography axial planes show extensive ground-glass opacities (GGOs) in the left allograft lung. Focal areas of GGO are present within the areas of honeycomb fibrosis of the right native lung. B, Gross specimen shows parenchymal fibrosis predominantly in the periphery of the right native lung and consolidations in the left allograft lung. C, The left lower lobe of the allograft reveals an alveolar filling process. D, High-magnification microscopy shows hyaline membranes (arrow) and intra-alveolar neutrophils consistent with diffuse alveolar damage and acute bronchopneumonia. E, The right middle lobe of the native lung shows a few scattered intra-alveolar clusters of neutrophils (E, arrow, and F) (hematoxylin-eosin, original magnification ×40 [C and E]; original magnification ×400 [D and F]).

Figure 3

Radiographic and histopathologic findings in single lung transplant recipient with fatal COVID-19 (patient 2). A, Computed tomography axial planes show extensive ground-glass opacities (GGOs) in the left allograft lung. Focal areas of GGO are present within the areas of honeycomb fibrosis of the right native lung. B, Gross specimen shows parenchymal fibrosis predominantly in the periphery of the right native lung and consolidations in the left allograft lung. C, The left lower lobe of the allograft reveals an alveolar filling process. D, High-magnification microscopy shows hyaline membranes (arrow) and intra-alveolar neutrophils consistent with diffuse alveolar damage and acute bronchopneumonia. E, The right middle lobe of the native lung shows a few scattered intra-alveolar clusters of neutrophils (E, arrow, and F) (hematoxylin-eosin, original magnification ×40 [C and E]; original magnification ×400 [D and F]).

Close modal
Figure 4

Radiographic and macroscopic findings in a double lung transplant recipient with fatal influenza A pneumonia (patient 7). A, Computed tomography scan shows centrilobular nodularity throughout both lungs with associated tree-in-bud opacities and some scattered nodular areas of consolidation. B and C, Gross specimens show bilateral multinodular bronchocentric consolidations in upper and lower lobes.

Figure 4

Radiographic and macroscopic findings in a double lung transplant recipient with fatal influenza A pneumonia (patient 7). A, Computed tomography scan shows centrilobular nodularity throughout both lungs with associated tree-in-bud opacities and some scattered nodular areas of consolidation. B and C, Gross specimens show bilateral multinodular bronchocentric consolidations in upper and lower lobes.

Close modal

Bilateral multifocal consolidative opacities were more commonly found in DLTRs (3 of 5; 60%) than in SLTRs (1of 5; 20%). A summary of radiologic features and their focality is presented in Table 2 and detailed in Supplemental Table 1.

Histopathologic Features Differed Between Allograft and Native Lungs in SLTRs and Were Similar Between Lungs in DLTRs

In 10 of 11 autopsies (91%), including 5 of 6 SLTRs and 5 of 5 DLTRs, histopathologic evidence of infectious disease was seen in both lungs. However, in 4 of 6 SLTRs in which all lobes were sampled, multilobar involvement of all lung lobes was only seen in the allografts. The native lungs of these 4 SLTRs showed some histopathologic evidence of involvement by the infection, but at least 1 lobe was uninvolved. In 2 SLTRs the native RML was not sampled. In 1 of these patients with adenovirus pneumonia there was no histopathologic evidence of involvement in the native upper and lower lobes. In the other patient with Pneumocystis jirovecii and CMV pneumonia both the native upper and lower lobes had focal histologic evidence of infection. In contrast, in DLTRs, multifocal histopathologic evidence of infection was seen in all lung lobes, except in 1 patient with Staphylococcus aureus pneumonia in which the RML was uninvolved. Histopathologic findings and scores are detailed in Table 3 and Supplemental Table 1.

Table 3

Histopathologic Findings in Study Population

Histopathologic Findings in Study Population
Histopathologic Findings in Study Population

A spectrum of histopathologic findings of acute to subacute infectious processes were seen and are summarized in Tables 2 and 3 and detailed in Supplemental Table 1. Organizing pneumonia and acute bronchopneumonia were present at least focally in 1 lobe in all 11 patients. Intra-alveolar hemorrhage or hemosiderosis, and pulmonary vascular thrombi were also seen in most patients (7 of 11 [63.6%] and 6 of 11 [54.5%] patients, respectively). Examples of the gross and microscopic findings in 2 SLTRs and 1 DLTR are depicted in Figure 1, B and C; Figure 2; Figure 3, B through F; Figure 4, B and C; and Figure 5, respectively. Additional noninfectious histopathologic findings of the lungs are described in Supplemental Table 1.

Figure 5

Histopathologic findings in a double lung transplant recipient with fatal influenza A pneumonia (patient 7). A, Low-power view of the right lower lobe specimens shows a rather diffuse alveolar filling by plugs of fibroblasts associated with fibrin (B), consistent with organizing fibrinous pneumonia. B inset, Foreign body material associated with histiocytes and multinucleated giant cells is consistent with aspiration pneumonia. C, The morphologic features of the left lower lobe are similar to those of the right lower lobe, with intra-alveolar filling by fibroblasts together with fibrin (D) (hematoxylin-eosin, original magnification ×40 [A and C]; original magnification ×200 [B, B inset, and D]).

Figure 5

Histopathologic findings in a double lung transplant recipient with fatal influenza A pneumonia (patient 7). A, Low-power view of the right lower lobe specimens shows a rather diffuse alveolar filling by plugs of fibroblasts associated with fibrin (B), consistent with organizing fibrinous pneumonia. B inset, Foreign body material associated with histiocytes and multinucleated giant cells is consistent with aspiration pneumonia. C, The morphologic features of the left lower lobe are similar to those of the right lower lobe, with intra-alveolar filling by fibroblasts together with fibrin (D) (hematoxylin-eosin, original magnification ×40 [A and C]; original magnification ×200 [B, B inset, and D]).

Close modal

In SLTRs, the MLHS scores of the allografts were significantly higher than the MLHS scores of the native lungs (median [range], MLHSNative = 3.0 [2.0–7.0], MLHSAllograft = 8.0 [3.0–12.0]; P = .02). In contrast, in DLTRs, no differences were observed between the MLHSRight and MLHSLeft (median [range], MLHSRight = 8.0 [5.5–11.0], MLHSLeft = 8.0 [3.0–11.0]; P = .90). There were no differences between the MLHSallograft in SLTRs when compared to the MLHSRight and MLHSLeft of the DLTRs (P = .76 and P = .84, respectively). However, the MLHSNative in SLTRs was significantly lower than the MLHSRight, in its counterpart in DLTR (P = .04; Figure 6, A).

Figure 6

A, Comparison of multilobar histology score between native and allograft lung in single lung transplant recipients and right and left allografts in double lung transplant recipients. B, Comparison of multilobar histology score ratio between single and double lung transplant recipients.

Figure 6

A, Comparison of multilobar histology score between native and allograft lung in single lung transplant recipients and right and left allografts in double lung transplant recipients. B, Comparison of multilobar histology score ratio between single and double lung transplant recipients.

Close modal

The median MLHSratio of the SLTRs was significantly higher than the median MLHSratio of the DLTRs (median [range], SLTRs = 3.08 [1.7–4.6]; DLTRs = 1.31 [1.0–1.83]; P = .009; Figure 6, B). There was a trend toward a higher GMLHSAutopsy score for DLTRs (median [range], SLTRs = 10.25 [9.5–19.0]; DLTRs = 16.0 [8.5–22.0]; P = .18).

In SLTRs the allografts had higher MLHSs than the native lungs in all cases, except in 1 patient with RSV pneumonia and Pseudomonas aeruginosa ventilator-associated pneumonia in whom the native emphysematous lower lobe due to α1-antitrypsin deficiency (AATD) showed multiple histopathologic features of infection, whereas the allograft only revealed focal histopathologic evidence of infection (Supplemental Table 1).

LHSs were compared between different lung lobes of SLTRs and DLTRs. In all SLTRs the allograft corresponded to the left lung. The LHSRUL was significantly higher in DLTRs when compared to LHSRUL/Native of SLTRs (P = .03; Figure 7). The LHSRLL in DLTRs trended to be higher than LHSRLL/Native of SLTR (P = .05). No significant differences were found between the LHSRML scores of both groups (P = .90). In addition, no significant differences were found when evaluating the LHSLUL and LHSLLL scores of the left allograft of the SLTR and the left allograft of the DLTR (P = .70, P = .20, respectively).

Figure 7

Comparison of lobar histopathology score of the right upper lobes between single and double lung transplant recipients.

Figure 7

Comparison of lobar histopathology score of the right upper lobes between single and double lung transplant recipients.

Close modal

In our case series of 6 SLTRs who died of infection that predominantly involved the lungs we found that the extent of involvement of allograft lungs by the infection differs radiographically and histopathologically from the native lungs. Specifically, in all but 1 patient the allografts were more extensively and severely involved by the infection than the native lungs. This finding contrasted with 5 DLTRs who also died of lung infection. In those patients both lungs were similarly involved by the infection. Semiquantitative histopathologic review confirmed significant differences in the prevalence of findings between allografts and native lungs in SLTRs, but not between the 2 lungs in DLTRs. Based on our findings, consideration can be given to prolonged antimicrobial prophylaxis in SLTRs; however, this needs to be balanced with medication toxicity and cost and other risk factors for infection.

A recent report of an SLTR who died of COVID-19 also showed such a discrepancy in involvement of the native lung and the allograft.8  In that patient the allograft was reportedly heavy and showed DAD. In contrast, the native lung demonstrated changes of fibrotic interstitial lung disease and lacked evidence of infection. Because DAD or other changes related to infection can occur focally, one could intuit that the phenomenon described in that case could have just occurred by chance. However, Messika et al20  reported imaging findings during COVID-19 of 7 SLTRs; 6 patients showed unilateral GGOs in the allograft lung, and only 1 patient demonstrated bilateral involvement by COVID-19 pneumonia. The authors hypothesized that the fibrosing process of the native lung precluded a definitive identification of radiologic findings suggestive of a viral infection. In a retrospective clinical series of 32 LTRs, including 17 SLTRs who had developed COVID-19 pneumonia, a subset of LTRs had infiltrates in the allograft only, and only 1 SLTR had infiltrates merely in the native lung on chest X-ray.21  A nationwide Swedish study of LTRs with COVID-19 reported statistically significant differences in disease severity between SLTRs and DLTRs.22  Differences that would be expected in the pulmonary reserve, heterogeneity in ventilation, perfusion, compliance, and function between native and allograft lung,23  could potentially account for differences in disease severity. Because allograft lungs have a nonremodeled alveolar surface and are expected to be more compliant, they might be more prone to the seeding of airborne organisms compared with the architecturally distorted native lungs. Differences in the immune milieu between patients with single or double lung transplants may also account for variations in disease severity. Overall, these clinical studies at least suggest that differential involvement of native and allograft lungs in SLTRs by infection occurs.

Our study, although still limited in number, appears to be the largest histopathologic study of autopsy lungs that compares the distribution of acute lung injury due to infection between allograft and native lungs in SLTRs. Although we found histopathologic evidence of acute lung injury in the SLTRs with infection in both the allografts and native lungs, infection of the native lungs tended to be more focal in most patients. Different hypotheses may explain these peculiar findings. Genome-wide association and human leukocyte antigen (HLA) region fine-mapping studies have identified susceptibility loci for multiple common infections. Susceptibility to viral infections has been mainly associated with variation in class I molecules, whereas susceptibility to bacterial infections has been largely associated with variation in class II molecules.24  Therefore, expected differences in HLA configurations between the donor allograft and the recipient native lung may, at least in part, explain the differential susceptibility of the organs to infection by different microorganisms.

In addition, because the allograft and native lungs have different genetic configurations, the expected differences in cellular expression of receptors between the allograft and native lung could account for regional differences of tissue infectivity. For example, data derived from 1051 lung tissue samples of the Human Lung Tissue Expression Quantitative Trait Loci Study revealed wide-ranging individual differences in tissue gene expression of ACE2 and 2 host cell proteases, TMPRSS2 and ADAM17, which are cofactors for SARS-CoV-2 cell entry.25  Single-cell sequencing data have also revealed ACE2-expressing cell ratio heterogeneity between individuals, which could explain differences in susceptibility to viral infections (in that specific study to SARS-CoV-2) between individuals.26  Furthermore, in end-stage fibrotic lungs, differences in microanatomic abnormalities27,28  and in cellular populations29  may alter the density of cells that are susceptible to viral infections.

Physiologic changes that occur because of transplantation of the allograft lung, such as interruption of lymphatic drainage or mucociliary clearance,4,5  are known to alter the pulmonary host defenses that are critical for pathogen clearance and could also explain the differences in infection focality. Differences in lung mechanics and inflation in native and allograft lungs that are seen in SLTRs30,31  may also potentially lead to differences in the inoculum of microorganisms that get distributed to distal areas of the lung. Damaged fibrotic or emphysematous lungs may not be amenable to produce the same changes secondary to infection and that are usually seen in a structurally normal lung. The native lung disease may also play a role in the susceptibility to tissue infectivity. In 1 of our SLTRs with severe AATD, the native lung was more involved than the allograft. It has been postulated that patients with severe AATD may have an increased susceptibility to COVID-1932,33 or other microorganisms because of dysfunctional anomalous α1-antitrypsin proteins altering viral entry34  or phagocytosis.35 

Limitations of this study include its single-center observational design, small cohorts, differences in number of hematoxylin-eosin slides evaluated in different disease types, and the retrospective nature contributing to missing data. Furthermore, CT had been used for specific imaging indications, including unexplained clinical worsening per American College of Radiology guidelines, possibly introducing selection bias toward more severe disease. In addition, many of these patients had comorbidities, some of which also led to changes that are similar to those observed in infection (eg, aspiration pneumonia). Conceivably, donor-derived infection of the recipient is a possibility. Furthermore, differential occurrence of pathogens is observed in different posttransplantation periods.36  In our study, in 2 patients who died within 6 months of transplantation, donor cultures were negative. However, in 1 of these patients the donor was CMV positive whereas the patient was CMV negative at time of transplantation. Therefore, the CMV infection in that patient was likely donor derived. The other patient had an infection with Pseudomonas, which can cause nosocomial pneumonia but is not considered donor derived. The third patient who died within 6 months of transplantation had infections with Aspergillus and Pneumocystis; those infections are usually not associated with donor infections but are considered opportunistic infections. Therefore, although donor cultures were not available for that patient, infections were likely not donor derived. All other patients died more than 12 months after transplantation, at which time infections are in general considered community acquired.36  Also, morphologic features of infection can mimic rejection.6,7  For instance, perivascular chronic inflammation, a morphologic feature of acute cellular rejection, has been described in COVID-19 pneumonia and other infections.7  Similarly, chronic inflammation in the submucosa of small airways, indicating acute small airways rejection in allografts, has also been reported for instance in COVID-19 pneumonia.7  Overall, the morphologic distinction between acute rejection and infection can be challenging and, in some patients, impossible solely based on morphology, and correlation with microbiology test results is necessary. Because of these known difficulties the grading scheme of rejection by the International Society of Heart and Lung Transplantation relies on the absence of concurrent infection and recommends grading of rejection only after the rigorous exclusion of infection.37  Furthermore, infection and rejection may occur together.

Our data suggest that allograft and native lungs harbor different susceptibilities to infections. Larger, possibly multi-institutional studies are needed to validate our results and to elucidate pathogenic mechanisms that may explain the differences between native and allograft lungs. The results are important for the management and treatment of lung transplant recipients.

We thank Jolene Tuchek for assisting with administrative tasks and with the biobank slide repository of the Department of Pathology at Mayo Clinic, Rochester.

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Author notes

Villalba is currently with the Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, at the Centers for Disease Control and Prevention, Atlanta, Georgia. Villalba and Cheek-Norgan contributed equally to this study.

Two supplemental digital content files are available for this article at https://meridian.allenpress.com/aplm in the July 2024 table of contents.

Competing Interests

The authors have no relevant financial interest in the products or companies described in this article.

Previously presented as an abstract at the 12th Pulmonary Pathology Society Biennial Meeting; June 25-27, 2022; Cork, Ireland.

Supplementary data