Andras Khoor, MD
Lung transplantation may offer a longer survival and improved quality of life to patients with end-stage lung disease. Common indications for single lung, bilateral (double) lung, and heart-lung transplantation are listed in Table 13.1. Bilateral lung transplantation is the norm for cystic fibrosis, but of interest, the proportion of bilateral lung transplantation procedures has been rising for other major indications as well.1 Benchmark survival rates for adult lung transplant recipients are 89% at 3 months, 80% at 1 year, 65% at 3 years, 54% at 5 years, and 31% at 10 years after transplantation.1
Unfortunately, the number of patients who can benefit from lung transplantation is limited by the availability of donor organs. Historically, waiting time was the main determinant of donor lung allocation in the United States. In 2005 a lung allocation score was implemented, dramatically changing the way donor lungs are distributed.2 Under the new system, priority for transplantation is determined by medical urgency and expected outcome. Allocating lungs for transplant based on urgency and benefit instead of waiting time is associated with fewer waitlist deaths, more transplants performed, and a change in distribution of recipient diagnoses to patients more likely to die on the waiting list.3 In recent years, novel strategies—including living-donor single-lobe transplantation and ex vivo lung perfusion4-6—have been developed to increase the donor lung pool. Ex vivo lung perfusion allows an increased use of donor lungs through two major processes: first, a more complete assessment of questionable lungs prior to transplant and, second, the treatment and repair of injured lungs toward clinical acceptability.6
Complications of lung transplantation may be related to (1) the operation itself (primary graft dysfunction, anastomotic complications), (2) the host’s immunologic response to the allograft (rejection), and (3) the immunosuppressive therapy used to prevent rejection (infection, posttransplantation lymphoproliferative disorders [PTLDs]). Other complications, such as organizing pneumonia and recurrence of the original disease, may also occur. To aid the differential diagnosis, posttransplant time intervals can be divided arbitrarily into immediate (within 4 days), early (4 days to 1 month), and late (beyond 1 month) posttransplantation periods.7 Differential diagnostic possibilities for each of these periods are listed in Table 13.2.
Table 13.1 Most Common Indications for Lung Transplant Procedures
|
Transplant Procedure Most Common Indications |
|
|
Adult single lung |
Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis α1-Antitrypsin deficiency emphysema |
|
Adult bilateral (double) lung |
Cystic fibrosis Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis α1-Antitrypsin deficiency emphysema Idiopathic pulmonary arterial hypertension |
|
Adult heart-lung |
Congenital heart disease Idiopathic pulmonary arterial hypertension Cystic fibrosis |
|
Pediatric lung |
Cystic fibrosis Primary pulmonary hypertension Congenital heart disease Interstitial pneumonitis Surfactant protein B deficiency |
Figure 13.1 Acute diffuse alveolar damage due to harvest injury. The key to the diagnosis is the presence of hyaline membranes.
Table 13.2 Complications of Lung Transplantation
|
Posttransplantation Period |
Operation-Related Complications |
Rejection |
Immunosuppression-Related Complications |
Other Complications |
|
Immediate (within 4 days) |
Primary graft dysfunction Arterial anastomotic obstruction Venous anastomotic obstruction Airway dehiscence |
Acute antibody-mediated rejection |
Bacterial pneumonia |
|
|
Early (4 days to 1 month) |
Arterial anastomotic obstruction Venous anastomotic obstruction Airway dehiscence Large airway stenosis |
Acute rejection |
Infection (bacterial, viral, fungal, Pneumocystis jirovecii) |
|
|
Late (beyond 1 month) |
Large airway stenosis |
Acute rejection Chronic airway rejection |
Infection (bacterial, viral, fungal, P jirovecii) Posttransplantation lymphoproliferative disorders |
Organizing pneumonia Recurrence of the primary disease |
Posttransplantation transbronchial biopsy may be performed for a specific clinical indication or for surveillance of acute rejection. The role of surveillance biopsy in lung transplant patients remains controversial.8,9 At least five pieces of well-expanded alveolated lung parenchyma are required for the assessment of acute rejection.10 the histopathologic findings most commonly encountered in a posttransplantation transbronchial biopsy include acute rejection, cytomegalovirus (CMV) infection, airway-centered inflammation, pneumonia, bronchiolitis obliterans, harvest injury, invasive aspergillosis, and PTLDs.8,11
Operation-Related Complications
Primary Graft Dysfunction
Despite many advances in organ preservation, surgical technique, and perioperative care, primary graft dysfunction—also known as harvest injury, ischemia-reperfusion injury, early graft dysfunction, and reimplantation response—contributes significantly to both the morbidity and mortality for lung transplantation.12 Primary graft dysfunction affects an estimated 10% to 25% of pulmonary allografts and can range in clinical severity from a transient decrease in oxygenation to complete graft failure.13 the International Society for Heart and Lung Transplantation (ISHLT) has proposed a definition and grading scheme based on the chest film and PaO2/FiO2 ratio.14
Time Period
Primary graft dysfunction becomes apparent within 72 hours after transplantation.
Clinical Presentation
Primary graft dysfunction has many features in common with other forms of acute lung injury, including severe hypoxemia and pulmonary edema.
Radiologic Findings
Chest radiographs show panlobar alveolar infiltrates.
Diagnosis
The diagnosis of primary graft dysfunction is based on the radiographic and PaO2/FiO2 criteria as well as on the exclusion of clinically similar conditions such as acute antibody-mediated rejection (AMR), venous anastomotic obstruction, cardiogenic pulmonary edema, and pneumonia.14 In selected cases, a lung biopsy may be helpful.15
Pathologic Findings
Mild cases may show alveolar and interstitial edema with scattered neutrophils.16 the histologic correlate of severe primary graft dysfunction is diffuse alveolar damage.15 the acute phase of diffuse alveolar damage is characterized by hyaline membranes, interstitial edema, occasional fibrin thrombi, and scattered neutrophils in the alveolar septa (Fig. 13.1). In the organizing phase, hyaline membranes are incorporated into the alveolar septa, which become thickened by fibroblast-rich connective tissue (Fig. 13.2).
Figure 13.2 Organizing diffuse alveolar damage resulting from harvest injury. In the absence of residual hyaline membranes, the history can aid the diagnosis.
Histologic Differential Diagnosis
Diffuse alveolar damage is a nonspecific histologic pattern that can be elicited by various insults in the posttransplantation setting (Box 13.1). Immunofluorescent studies are helpful in separating primary graft dysfunction from acute AMR. Acute AMR is characterized by alveolar septal deposits of immunoglobulin G and complement (particularly C4d), which are absent in primary graft dysfunction. Acute rejection is not a major concern during the immediate posttransplantation period. Any infection can manifest as diffuse alveolar damage in an immunocompromised patient; There fore it is always prudent to perform special stains to rule out acid-fast bacilli and fungal organisms.
Treatment, Prognosis, and Prevention
The treatment is supportive and may include mechanical ventilation. A retrospective analysis by Christie and associates showed that in patients with and without primary graft dysfunction, 30-day mortality rates are 42.1% and 6.1%, respectively.17 Primary graft dysfunction is also associated with an increased risk of obliterative bronchiolitis.17 For the prevention of primary graft dysfunction, research studies have focused on improving lung preservation techniques by optimizing the volume, temperature, pressure, and components of preservation solutions as well as inflation and ventilation parameters of the organs during transport.13 So far, these studies have had modest clinical impact.
Arterial Anastomotic Obstruction
The incidence of pulmonary arterial anastomotic obstruction after lung transplantation is relatively low.18,19 Causes include narrowed anastomosis, with or without thrombus formation resulting from suboptimal surgical anastomoses and excessive length of donor or recipient pulmonary artery with kinking or torsion of the anastomosis.18,19
Time Period
Arterial anastomotic obstruction usually occurs during the first week after transplantation.
Clinical Presentation
Signs and symptoms include dyspnea, hypoxemia, and elevated pulmonary arterial pressure.
Diagnosis
The diagnosis is suggested by reduced perfusion in the allograft by ventilation-perfusion (V/Q) scan and can be confirmed by echocardiogram or pulmonary angiography. Large areas of infarction may be present Pathologic confirmation is usually not required.
Venous Anastomotic Obstruction
Minor abnormalities of the pulmonary venous anastomosis are relatively common complications of lung transplantation.19,20 Occlusive thrombu: formation is relatively rare but may have catastrophic consequences including allograft failure and stroke.
Time Period
Venous anastomotic obstruction usually presents in the immediat posttransplantation period but has been reported to occur as late a: the eighth postoperative day.18,19
Clinical Presentation
Pulmonary venous obstruction after lung transplantation should b suspected in every case of persistent pulmonary edema in the firs postoperative days, often associated with a frothy blood-stained secretion from the endotracheal tube.19,21
Radiologic Findings
Chest radiography reveals diffuse unilateral interstitial edema.
Diagnosis
Transesophageal echocardiography with color-flow Doppler imaging is virtually diagnostic, demonstrating a marked reduction of the flow in the affected pulmonary vein.19,21
Pathologic Findings
The specimen from the surgical revision may include a thrombus. Biopsy of the lung obtained at the same time may show congestion and venou engorgement.
Treatment
Venous anastomotic obstruction is considered a surgical emergency and revision of the anastomosis with removal of any associated thrombus is required to prevent irreversible injury to the lung allograft.
Airway Dehiscence
In the early years of lung transplantation, airway dehiscence due to ischemia of the donor bronchus was a major cause of morbidity and death. Improved surgical techniques, reduced immunosup pression, and better allograft preservation have reduced the incidence of airway complications.22 Currently most centers report a 7% to 18% complication rate with a related mortality rate of 2% to 4%.22
Time Period
Airway dehiscence may develop in the first few weeks afte transplantation.
Diagnosis
Ischemia and necrosis of the bronchus can be diagnosed by direct visualization with a bronchoscope.
Pathologic Findings
Biopsies show coagulation necrosis of the bronchial mucosa, submucosa, and cartilage. Superimposed bacterial or fungal infection may produce neutrophilic infiltrates, there by enhancing necrosis and dehiscence of the anastomosis.
Treatment
Treatment is based on the severity of the problem, ranging from a “wait and see” policy to stent placement, reconstructive surgery, pneumonectomy, or retransplantation.23
Large Airway Stenosis
Large airway (bronchial) stenosis is the most common airway complication. The incidence is estimated to be between 1.6% and 32%.22 It is usually seen after necrosis or dehiscence or in healing or treated infections. “Telescoped” anastomosis is associated with a 7% incidence of airway stenosis.
Nonanastomotic large airway stenosis has also been described.24,25 the pathogenesis of this lesion is unclear, but it may represent a response to ischemic damage, alloreactive injury, or infection.
Time Period
Bronchial stenosis usually occurs a few months after the transplantation procedure but has been described as early as 8 days.26
Clinical Presentation
Clinical findings include dyspnea, retained secretions, recurrent pneumonia, and a decline in spirometry, all of which can mimic chronic airway rejection.
Diagnosis
Bronchoscopic examination provides the diagnosis, with biopsies providing confirmatory histology.
Pathologic Findings
Common findings include prominent granulation tissue, fibrosis, and squamous metaplasia.
Treatment
Treatment options include mechanical dilation with the rigid bronchoscope, balloon bronchoplasty, and stenting.23,27,28
Pulmonary Allograft Rejection and Related Entities
With the exception of monozygotic twins, donors and recipients are genetically different and express different histocompatibility antigens. As a result, allografts are rejected by the recipient’s immune system. Multiple immunologic processes are involved, creating a spectrum of rejection responses. A “working formulation for the classification of pulmonary allograft rejection” was introduced by the ISHLT in 1990.29 the working formulation was first revised in 1996.30 the currently accepted scheme for grading pulmonary allograft rejection was approved by the ISHLT board of directors in 2007 (Box 13.2).10 the differences between the 1996 and 2007 schemes are relatively minor and are related to airway inflammation and chronic airway rejection.
Since the 2007 revision,10 a new clinical concept of chronic lung allograft dysfunction (CLAD) has emerged.31 In addition to obstructive CLAD—also known as bronchiolitis obliterans syndrome (BOS)—restric- tive CLAD or restrictive allograft syndrome (RAS) has also been recognized by transplant pulmonologists.31 Pathologic correlates of BOS and RAS are obliterative bronchiolitis and pulmonary pleuroparenchymal fibroelastosis (PPFE), respectively.32
Acute AMR is a controversial subject and is discussed at the end of this section.
Acute (Cellular) Rejection
The term acute rejection without a qualifier is used to describe acute cellular rejection. This is a cell-mediated process, in contrast to the antibody-mediated process of antibody-mediated (humoral) rejection. Most lung transplant recipients experience episodes of acute rejection.
Time Period
Acute rejection may occur as early as 3 days and as late as several years after transplantation. The majority of acute rejection episodes begin within the first 3 months after transplantation.
Clinical Presentation
Clinical features may include low-grade fever, cough, dyspnea, crackles, and adventitious sounds on auscultation. Features suspicious for rejection include a more than 10% decrease in the forced expiratory volume in 1 minute (FEV1) and hypoxemia.
Radiologic Findings
Radiologic abnormalities include perihilar or lower lung zone alveolar and interstitial infiltrates, septal lines, subpleural edema, peribronchial cuffing, and pleural effusion. In cases of a single-lung transplant, the V/Q lung scan will show decreased perfusion to the allograft.
Diagnosis
Clinical features may suggest acute rejection, but a transbronchial biopsy is usually required to confirm the diagnosis and rule out infection. If biopsy from multiple sites is technically impossible, lower lobe biopsies are preferred because they appear to be more informative.33
Pathologic Findings
The hallmark of acute rejection is the presence of perivascular mononuclear cell infiltrates. If small airway inflammation is present, it should be noted (see later discussion).
Acute rejection is graded according to the density and extent of the perivascular infiltrates and the presence or absence of secondary pneumocyte damage (Table 13.3). Rejection-type infiltrates usually involve more than one vessel, but a single perivascular infiltrate should be evaluated by the same criteria as for multiple infiltrates, as follows: 1. Minimal acute rejection (grade A1) is characterized by infrequent two- to three-cell-thick perivascular mononuclear cell infiltrates (Fig. 13.3).
Table 13.3 Grading Acute Rejection
|
Grade of Acute Rejection |
Histologic Criteria |
Cellular Composition |
Comments |
|
A0—none |
Normal pulmonary parenchyma |
||
|
A1—minimal |
Perivascular mononuclear cell infiltrates, 2-3 cells thick (not obvious at low magnification) |
Small round, plasmacytoid, and transformed lymphocytes |
The perivascular infiltrates are usually infrequent |
|
A2—mild |
Perivascular mononuclear cell infiltrates, >3 cells thick (easily seen at low magnification) |
Same as A1, with macrophages, and eosinophils |
The perivascular infiltrates are usually frequent Endothelialitis and airway inflammation are often present |
|
A3—moderate |
Perivascular mononuclear cell infiltrates, similar to A2, with extension into alveolar septa and airspaces |
Same as A2, with occasional neutrophils |
Endothelialitis and airway inflammation are usually present |
|
A4—severe |
Diffuse mononuclear cell infiltrates, similar to A3, with prominent pneumocyte damage |
Same as A3 |
The pneumocyte damage is commonly associated with hyaline membranes |
Figure 13.3 Minimal acute rejection (A1) with a sparse perivascular mononuclear cell infiltrate.
Figure 13.4 In mild acute rejection (A2), the mononuclear cell infiltrate is denser and is more than three cell layers thick. However, it is limited to the perivascular area.
Figure 13.5 In moderate acute rejection (A3), the perivascular infiltrate extends into the alveolar septa.
2. In mild acute rejection (grade A2), the perivascular mononuclear cell infiltrates become thicker, denser, and usually more frequent (Fig. 13.4).
3. In moderate acute rejection (grade A3), the infiltrates extend into the alveolar septa and airspaces (Fig. 13.5).
4. In severe acute rejection (grade A4), the mononuclear cell infiltrates are associated with pneumocyte damage. The latter often manifests as diffuse alveolar damage with hyaline membranes (Fig. 13.6). The composition of the cellular infiltrates also changes with increasing severity of rejection. In minimal acute rejection, the perivascular infiltrates are composed predominantly of small, round, plasmacytoid, and transformed lymphocytes. As the rejection advances in intensity, the infiltrates contain more activated lymphocytes, macrophages, eosinophils, and neutrophils. Subendothelial and peribronchiolar infiltrates become more pronounced.
In higher-grade rejection, the inflammatory cells permeate the vessels with extension to the endothelium, giving rise to endothelialitis. In 30% of mild and 60% of moderate acute rejection, there is also associated airway inflammation.
A rare form of acute rejection also exists; it is characterized by abundant eosinophils, which may obscure the mononuclear cells in the perivascular infiltrates.
Histologic Differential Diagnosis
Perivascular and interstitial mononuclear cell infiltrates are not specific for acute rejection.8 Differential diagnostic considerations include infections, especially CMV pneumonia and Pneumocystis jirovecii pneumonia,34-36 and PTLDs.37,38 Some histologic features may favor infection over acute rejection (Table 13.4). Cultures and special stains may be helpful in the diagnosis of mycobacterial, fungal, and P. jirovecii infections. Viral pneumonias can be confirmed by cultures as well as serologic, immunohistochemical, or molecular hybridization techniques.
Figure 13.6 In severe acute rejection (A4), the perivascular infiltrates lead to lung injury. The latter manifests as fibrinous exudates and hyaline membranes in this case. (A) Lower magnification. (B) Higher magnification.
Table 13.4 Histologic Features Favoring Infection Over Acute Rejection
|
Histologic Features |
Infection Favored |
|
Predominant alveolar septal infiltrates as compared with perivascular infiltrates |
Any infection |
|
Abundant neutrophils |
Bacterial pneumonia, CMV pneumonia, or candidiasis |
|
Abundant eosinophils |
Fungal infection |
|
Nuclear or cytoplasmic inclusions |
Viral pneumonia |
|
Multinucleation |
Respiratory syncytial virus or parainfluenza virus pneumonia |
|
Punctate zones of necrosis |
Herpes simplex virus, varicella zoster virus, or CMV pneumonia |
|
Granulomatous inflammation |
Mycobacterial, fungal, or Pneumocystis jirovecii infection |
|
Frothy intraalveolar exudates |
P jirovecii pneumonia |
|
CMV, Cytomegalovirus. |
In some cases, histologic features of acute rejection and infection coexist. In these cases, the pathologist should attempt to decide which is dominant and guide the clinician by favoring one over the other. Follow-up biopsy after appropriate antimicrobial therapy is also recommended so that any acute rejection component can be reassessed.10 the differential diagnosis between acute rejection and PTLDs is discussed later.
Treatment and Prognosis
The treatment of acute rejection typically consists of bolus therapy with intravenous steroids, which may be supplemented by temporary increases in the maintenance immunosuppression regimen. In at least 80% of the cases, acute rejection is successfully treated. However, 15% to 20% of acute rejection episodes persist or recur, presenting a particularly difficult management problem for the clinician. When this occurs, intensified immunosuppression with one or more agents is usually attempted. However, it has been shown that patients with persistent, recurrent, or late (occurring at least 3 months after transplantation) acute rejection are at increased risk for developing chronic airway rejection.39 Recent studies have indicated that an increased risk may exist even with minimal acute rejection.40,41
Table 13.5 Grading Airway Inflammation
|
Grade Airway Inflammation |
|
|
B0—no airway inflammation |
None |
|
B1R—low-grade small airway inflammation |
Mononuclear cells in the submucosa (can be infrequent and scattered or forming band-like infiltrates) Occasional eosinophils may be seen |
|
B2R—high-grade small airway inflammation |
Mononuclear cells in the submucosa with greater numbers of eosinophils Epithelial damage and intraepithelial lymphocytic infiltration Ulceration and fibrinopurulent exudates may occur |
|
BX—ungradable |
Sampling problems, infection, tangential cutting, other problems |
Airway Inflammation: Lymphocytic Bronchiolitis
The 2007 working formulation has collapsed the four previous B grades into two (grade 1R, or low-grade, and grade 2R, or high-grade) and has retained B0 (no airway inflammation) and BX (ungradable). Another change from the previous working formulation is that the B grade designation applies only to small airways (bronchioles). Airway inflammation may be a harbinger of chronic airway rejection.42,43
Pathologic Findings
Criteria for grading airway inflammation are listed in Table 13.5.
Histologic Differential Diagnosis
Infection, particularly that caused by viral, bacterial, mycoplasmal, fungal, and chlamydial organisms, may mimic the airway inflammation related to acute rejection.35
Obliterative Bronchiolitis
Obliterative bronchiolitis, also known as chronic airway rejection, obstructive CLAD, and BOS, is the most significant long-term complication of lung transplantation, with a prevalence of 30% to 50% and an associated mortality rate of 25%.44 the terminology is somewhat confusing because obliterative bronchiolitis of chronic airway rejection is usually referred to as bronchiolitis obliterans, or BOS, in the clinical lung transplantation literature. It is important to recognize that obliterative bronchiolitis or bronchiolitis obliterans of chronic airway rejection is both clinically and histologically distinct from the (sub)acute lung injury pattern once known as bronchiolitis obliterans organizing pneumonia (BOOP). To make this distinction clear, the nomenclature has been changed, and the currently preferred term for BOOP is organizing pneumonia.45,46
Time Period
Obliterative bronchiolitis is most frequently diagnosed between 9 and 15 months after transplantation.47 It rarely develops during the first 3 months but has been reported as early as 2 months after transplantation.47
Clinical Presentation
Obliterative bronchiolitis often develops insidiously with vague general symptoms and nonproductive cough. Later, progressive dyspnea on exertion becomes the dominant complaint. At this later stage, pulmonary function tests show a decline in the FEV1 as compared with a previously established posttransplantation baseline.
Radiologic Findings
Chest radiographs are typically unremarkable until later in the disease, when a variable pattern of bronchiectasis is accompanied by airway tapering/obliteration and zones of hyperinflation. These changes reflect the peculiar nature of chronic airway rejection: proximal bronchiectasis (dilatation) with distal obliterative bronchiolitis (constriction).
Diagnosis
Transbronchial biopsy is an insensitive method for the detection of obliterative bronchiolitis.10 An ad hoc ISHLT working group has concluded that FEV1 is the most reliable and consistent indicator of chronic airway rejection.48
Pathologic Findings
The term obliterative bronchiolitis refers to hyalinized fibrous plaques present in the submucosa of small airways.10,16 ttey lead to partial or complete luminal compromise (Fig. 13.7). The scar tissue may be concentric or eccentric and may be associated with destruction of the smooth muscle wall. The 1996 working formulation retained the designation of active versus inactive obliterative bronchiolitis, depending on the presence and degree of accompanying inflammation.30 However, the consensus in 2007 was that the distinction between active and inactive was no longer useful and that the condition should be designated merely as C0, indicating a biopsy with no evidence of obliterative bronchiolitis, and C1, indicating that obliterative bronchiolitis is present in the biopsy.10 Obliterative bronchiolitis often produces mucostasis or postobstructive (endogenous lipid) pneumonia.10,16
Histologic Differential Diagnosis
Transplant-related obliterative bronchiolitis involves the small airways. Large airway fibrosis is a nonspecific finding and should not be considered as evidence of chronic airway rejection. The organizing pneumonia pattern is manifested as fibromyxoid connective tissue plugs within the lumina of bronchioles and alveoli.49 ’Hiese loose edematous airspace-filling plugs should be distinguished from the densely eosinophilic submucosal scars of transplant bronchiolitis obliterans.
Treatment and Prognosis
Augmented immunosuppression appears to be of some benefit in treating bronchiolitis obliterans, but it is far from optimal. It is suggested that cyclosporine be switched to tacrolimus, and a trial of azithromycin is also recommended.50 Referral to an experienced surgeon to evaluate the gastroesophageal junction for fundoplication is suggested for patients who also have confirmed gastroesophageal reflux.50 Survival is higher among patients who undergo retransplantation for obliterative bronchiolitis than for those who undergo retransplantation for other reasons, but it is lower compared with patients undergoing primary lung transplantation.50
Accelerated Graft Vascular Sclerosis
The clinicopathologic significance of accelerated graft vascular sclerosis or chronic vascular rejection is not entirely clear. However, chronic vascular changes may coincide with the presence of obliterative bronchiolitis in lung transplant recipients and with the presence of accelerated coronary artery disease in combined heart-lung transplant recipients.51,52
Figure 13.7 Bronchiolitis obliterans. Scar tissue obliterates the lumen of a bronchiole, which can be recognized by the presence of smooth muscle and elastic fibers in the wall. (A) Hematoxylin and eosin stain. (B) Verhoeff-Van Gieson stain.
Figure 13.8 Chronic vascular rejection (accelerated vascular sclerosis). Intimal proliferation occludes the lumen of a muscular pulmonary artery, which can be recognized by the presence of two elastic laminae. (A) Hematoxylin and eosin stain. (B) Verhoeff-Van Gieson stain.
Diagnosis
Accelerated graft vascular sclerosis is not applicable to transbronchial biopsies but may be noted in surgical lung samples.10
Pathologic Findings
In accelerated graft vascular sclerosis, there is fibrointimal thickening in arteries and veins (Fig. 13.8). There may also be an “active” inflammatory component consisting of subendothelial, intimal, or medial, predominantly lymphoid mononuclear cell infiltrates.
Pulmonary Pleuroparenchymal Fibroelastosis
As mentioned earlier, two clinical forms of CLAD have been identified: BOS and RAS.31 Pathologic correlates of BOS and RAS are obliterative bronchiolitis and PPFE, respectively.32 PPFE was first described as an idiopathic lung disease.53 In 2013 idiopathic PPFE was included in the updated American ’ttoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias as a rare entity.46 However, PPFE has also been reported in association with alkylating drugs, bone marrow transplantation, and, most importantly, lung transplantation.32,54,55
Time Period
Pulmonary allograft recipients surviving for at least 3 months were included in the study of Sato et al.56 Similar to obliterative bronchiolitis, PPFE is unlikely to occur during the first 3 months after transplantation.
Clinical Presentation
Patients present with CLAD.
Radiologic Findings
Chest computed tomography (CT) shows upper lobe dominant fibrosis, interstitial opacities, ground-glass opacities, and traction bronchiectasis.56-58
Diagnosis
RAS is defined as CLAD with an irreversible decline in total lung capacity to below 90% of baseline.56 Low-dose CT volumetry may be a useful tool to differentiate RAS from BOS in bilateral lung and heart-lung transplant patients with CLAD.58
Pathologic Findings
Lungs with PPFE show varying degrees of pleural fibrosis.32 Beneath the fibrotic pleura There is elastotic connective tissue, which appears to represent thickening of the alveolar septal elastic network. The subpleural fibroelastosis involves predominantly the upper lobes. A sharp demarcation is often seen between the affected and unaffected lung parenchyma, and fibroblastic foci may be noted at the interface. Findings of PPFE are often accompanied by diffuse alveolar damage and obliterative bronchiolitis.32
Histologic Differential Diagnosis
Histologic differential diagnoses include apical cap. Similar to PPFE, apical caps are composed of elastotic connective tissue. Separation of the two entities requires correlation of the clinical, radiologic, and pathologic findings. In a recent review, usual interstitial pneumonia (UIP) is mentioned as the main differential diagnosis for PPFE.59 However, although PPFE is composed of elastotic connective tissue, the fibrosis in UIP is more collagenous. Furthermore, it is unlikely that UIP would involve the transplanted lung.
Treatment and Prognosis
Patients with RAS have significantly worse median survival than patients with BOS.56,60 Currently, retransplantation may be the only option for these patients.
Antibody-Mediated Rejection
AMR is caused by donor-specific antihuman leukocyte antigen antibodies (DSAs). These antibodies, which may develop before or after transplantation, bind to target antigens and activate the complement system.61,62 Early observations of AMR were based on hyperacute rejection, in which preexistent antibodies lead to complement activation and rapid graft loss. With improved cross-matching before transplantation, the incidence of hyperacute rejection has decreased. On the other hand, improvements in DSA detection have increased the recognition of AMR after the immediate posttransplant period.61,63,64
Time Period
AMR is arbitrarily divided into hyperacute (occurring intraoperatively or within 24 hours of surgery), acute (often mimicking acute cellular rejection), and chronic (potentially manifesting as an occult cause of CLAD) forms.65
Clinical Presentation
AMR can be clinical with measurable allograft dysfunction, such as hypoxemia and decreased FEV1, or subclinical, with normal allograft function.65,66 Patients with clinical AMR may have symptoms such as dyspnea, cough, fever, and malaise, or they may be asymptomatic.
Radiologic Findings
Imaging studies may show lung infiltrates.
Diagnosis
The diagnosis of pulmonary AMR remains a challenge and requires the correlation of clinical, radiologic, pathologic, serologic, and microbiologic findings.67 Key diagnostic criteria include lung biopsy findings consistent with AMR, positive immunohistochemical staining for complement 4d (C4d), and detection of circulating DSAs.65 A diagnosis of definite AMR can be made, if all three criteria are met. Two of the three criteria are required for a probable and one of the three criteria is required for a possible AMR diagnosis. Allograft dysfunction may bring the attention to AMR but is not required for the diagnosis (clinical vs. subclinical AMR). When There is measurable pulmonary allograft dysfunction, other potential causes of the dysfunction such as infection need to be excluded.
Pathologic Findings
Histology and immunohistochemistry for C4d, along with DSA detection, are key elements of the diagnosis of pulmonary AMR.68 the most common histologic finding described in association with AMR is capillary inflammation, which encompasses neutrophilic capillaritis and neutrophilic margination.10,69,70 Neutrophilic capillaritis is defined as alveolar septal infiltrates composed of neutrophils and the presence of neutrophilic karyorrhectic debris and fibrinous exudates.68 Fibrin thrombi in capillaries may or may not be observed. Neutrophilic margination is defined as a collection of neutrophils within the interstitial capillaries.68 Karyorrhectic debris and fibrinous exudates are not seen. In addition to neutrophilic capillaritis and margination, acute lung injury/diffuse alveolar damage and endothelialitis also show correlation with circulating DSAs.69 Other reported histologic findings include high-grade acute cellular rejection (grade A3 or A4), persistent and recurrent acute cellular rejection (any A grade), high-grade lymphocytic bronchiolitis (grade B2R), persistent low-grade lymphocytic bronchiolitis (grade B1R), and obliterative bronchiolitis (grade C1).68 Unfortunately, none of the histologic findings are sufficiently sensitive or specific for AMR.67
Although it has low sensitivity and specificity in the setting of lung transplantation, immunohistochemistry for C4d may provide supportive evidence for AMR.65,67,71 C4d studies can be performed using immunoperoxidase and immunofluorescence techniques. Both techniques require careful interpretation due to nonspecific background staining.67 Diffuse staining of greater than 50% of the alveolar septal capillaries is considered positive.68
Histologic Differential Diagnosis
No histologic findings are specific for AMR. For example, neutrophilic capillaritis, neutrophilic margination, and acute lung injury can also be seen in infection and severe acute cellular rejection.10 There fore it is important that histologic findings be interpreted in a clinicopathologic context and infection be excluded before a diagnosis of AMR is made.
Prevention, Treatment, and Prognosis
One of the major goals of donor selection is to avoid hyperacute rejection due to preexistent antibodies.61 Since harmful DSAs can also develop after transplantation, DSA testing should be performed promptly if AMR is suspected.72
Currently, there is no standard protocol for the treatment of AMR. Intravenous immunoglobulin (IVIG) is often applied to reduce antibody- mediated immunity.73 Rituximab is an anti-CD20 monoclonal antibody that causes B cell depletion and can be applied in conjunction with IVIG.61 Plasmapheresis can also lead to clinical improvements.66 However, because of the potential side effects, it is usually reserved for severe cases.
Infection
Pulmonary infections are the most common cause of morbidity in the lung transplant population. Prompt recognition and treatment are necessary to prevent poor outcomes.
Bacterial Infections
Cystic fibrosis patients frequently show airway colonization with gramnegative bacteria both before and after lung transplantation. Recent data suggest that colonization with gram-negative bacteria may play a role in the pathogenesis of chronic airway rejection.74
Bacterial infections of the lower respiratory tract may manifest as acute bronchitis or bronchopneumonia. Gram-negative infections, especially those caused by Pseudomonas species, account for about 75% of bacterial pneumonias. Other reported bacterial pathogens include a wide range of nosocomial organisms. Legionellosis is rarely reported.75
Time Period
Bacterial infections can occur shortly after transplantation, presumably due to transmission of bacteria from the donor. Nevertheless, the risk of bacterial infection persists throughout the lifetime of the allograft.
Clinical Presentation
The clinical findings include fever, cough, purulent sputum, shortness of breath, rales on auscultation, hypoxemia, leukocytosis, and decline in spirometry.
Radiologic Findings
New or increasing infiltrates on chest radiograph are common manifestations of bacterial pneumonias.
Diagnosis
Most of the clinical features of transplant-associated pneumonia are nonspecific and largely modified by the patient’s immunocompromised status. Bronchoalveolar lavage (BAL) and transbronchial biopsy are often performed in the evaluation of new infiltrates. Culture results are often an important part of the diagnostic work-up.
Pathologic Findings
In acute bronchitis, neutrophils infiltrate the bronchial mucosa. This pathologic change may be associated with mucosal ulceration and intraluminal neutrophils. As in the normal host, acute pneumonia is recognized by the presence of neutrophils within the alveolar spaces (Fig. 13.9).
Histologic Differential Diagnosis
The composition of inflammatory infiltrates distinguishes bacterial infection from acute rejection. Bacterial infection is characterized by the presence of neutrophils, whereas mononuclear cells (mainly lymphoid cells) are seen predominantly in acute rejection.
Treatment and Prognosis
Organism-specific management is essential. Any regimen of broadspectrum antibiotics instituted before identification of an organism should include agents effective against Pseudomonas species.
Figure 13.9 Acute pneumonia. Neutrophil granulocytes are present in the alveolar spaces.
Figure 13.10 Cytomegalovirus pneumonia. Mononuclear cells infiltrate the alveolar septa diffusely, with no perivascular accentuation.
Viral Infections
CMV infection remains a serious problem in lung transplant recipients. Donor-recipient mismatch, with the donor being seropositive and the recipient seronegative for CMV, poses the highest risk for the development of CMV pneumonia. Seropositive recipients of a seropositive or seronegative donor are at intermediate risk of acquiring active CMV pneumonia, and seronegative recipients of a seronegative donor are at lowest risk. Universal ganciclovir prophylaxis is a strategy aimed at reducing CMV infection and delaying the development of obliterative bronchiolitis. However, the optimal duration of ganciclovir prophylaxis remains unclear. If the prophylaxis is discontinued, the incidence of CMV pneumonia is around 57%.76 A recent study has suggested that indefinite ganciclovir prophylaxis may prevent CMV pneumonia in 98% of lung transplant recipients.76
Herpes simplex virus (HSV) infections are also a potential problem in lung transplantation. The frequency of HSV infections has also been reduced remarkably with the routine use of ganciclovir prophylaxis.
Other viruses responsible for respiratory infections include adenovirus, respiratory syncytial virus, influenza virus, parainfluenza virus, and varicella zoster virus.77,78
Time Period
Before universal ganciclovir prophylaxis, CMV infection generally occurred between 2 weeks and 4 months after transplantation. HSV infection typically began as oral ulcers or tracheitis during the first month after transplantation.
Clinical Presentation
Fever, malaise, myalgias, chills, abdominal discomfort, cough, and shortness of breath are frequent symptoms of CMV pneumonia. Physical examination may reveal crackles or may be normal. Other features include hypoxemia and decline in spirometry values. Fortunately, pneumonia caused by HSV is now rare, thanks to routine prophylaxis. The clinical features are similar to those of CMV pneumonia.
Radiologic Findings
Chest radiographs may show reticular or reticulonodular infiltrates but may be clear in up to two-thirds of patients.
Figure 13.11 Cytopathic effects characteristic of cytomegalovirus infection. Both nuclear and cytoplasmic inclusions are present, but the latter are less apparent.
Diagnosis
The diagnosis of viral pneumonia is often impossible on clinical grounds alone. BAL and transbronchial biopsy play important roles in establishing the diagnosis.
Pathologic Findings
Recognizing tissue responses and cytopathic effects may help in identifying viral infections (see Chapter 6). Tissue responses to viral pathogens range from minimal nonspecific inflammation to diffuse alveolar damage. Most cases of CMV infection show interstitial pneumonia with a mixed lymphocytic and polymorphonuclear cell infiltrate (Figs. 13.10 and 13.11).34 Zonal necrosis may be seen with herpes simplex, varicella zoster, and CMV pneumonia (Figs. 13.12 and 13.13). CMV may also be associated with neutrophilic microabscesses. Necrotizing bronchiolitis may be a feature of adenovirus, influenza virus, and respiratory syncytial virus infections. Some characteristic viral cytopathic effects are listed in Table 13.6. These cytopathic effects, however, can be sparse or absent.
Immunohistochemistry, in situ hybridization, and polymerase chain reaction techniques can be used to identify many viruses and have largely replaced electron microscopy in this role (Fig. 13.14).
Figure 13.12 Herpes simplex virus pneumonia with an area of necrosis.
Figure 13.13 Higher-power view of involved lung in herpes simplex pneumonia, showing a nuclear inclusion.
Table 13.6 Viruses and Their Cytopathic Effects
|
Virus |
Cytopathic Effects |
|
Cytomegalovirus |
Cytomegaly, nuclear and cytoplasmic inclusions |
|
Herpes simplex virus |
Nuclear inclusions |
|
Varicella zoster virus |
Nuclear inclusions |
|
Adenovirus |
Smudge cells, nuclear inclusions |
|
Respiratory syncytial virus |
Occasional multinucleation, cytoplasmic inclusions |
|
Influenza virus |
None |
|
Parainfluenza virus |
Occasional multinucleation, cytoplasmic inclusions |
Histologic Differential Diagnosis
The histologic differential diagnosis of viral pneumonia includes acute rejection.34 Both processes can exhibit perivascular and interstitial mononuclear cell infiltrates. However, perivascular infiltrates predominate in acute rejection, and alveolar septal infiltrates are more prominent in viral infection (Table 13.4). The presence of CMV inclusions is indicative of CMV pneumonia, but attention to other histologic details is necessary to exclude concurrent acute rejection and bronchiolitis obliterans, which are frequently associated with CMV infection.
Figure 13.14 Herpes simplex virus infection. Paraffin immunoperoxidase studies reveal herpes simplex virus-positive cells.
Fungal Infections
Fungal infections are less frequent than other infections in the transplant recipient but carry a high mortality rate when they do occur. The fungal species most commonly encountered in lung transplant biopsies include Aspergillus and Candida.79 Cryptococcosis, histoplasmosis, coccidioidomycosis, and mucormycosis have also been reported.79,80 Fungal organisms may colonize the respiratory tract or cause overt infection.80 Prolonged antibiotic therapy predisposes patients to disseminated candidiasis.
Time Period
Fungal infections have a bimodal presentation: early onset between 2 weeks and 2 months after transplantation, secondary to difficult postsurgical periods and prior colonizations, and late onset, primarily secondary to chronic rejection and terminal renal insufficiency.80
Clinical Presentation
The clinical picture is not specific. Fungal pneumonias may manifest with fever, leukocytosis, and hypoxemia.
Radiologic Findings
Radiographically, pulmonary infiltrates with consolidation or cavitary nodules may be seen.
Diagnosis
The diagnosis is most often made by a combination of clinical features and the recovery of fungal organisms from BAL, transbronchial biopsy, blood, or other body fluids.
Pathologic Findings
Fungal species may be a source of bronchial anastomotic infections (Figs. 13.15 and 13.16). Aspergillus pneumonia is characterized by hemorrhagic infarction and sparse inflammatory cell infiltrates (Figs. 13.17 and 13.18). Long, septate hyphae, with 45-degree branching points, invade blood vessels and permeate alveolar septa. Candida infection produces neutrophilic infiltrates and is associated with abscess formation. Clusters of pseudohyphae and yeast forms are often found in the centers of abscesses.
Figure 13.15 Bronchial mucosal necrosis and associated Aspergillus infection. There is no significant inflammation.
Figure 13.16 Grocott methenamine silver stain of material from the same case as in Fig. 13.15 reveals fungal organisms compatible with Aspergillus species.
Figure 13.17 Aspergillus pneumonia with an area of infarction.
Figure 13.18 Grocott methenamine silver stain of material from the same case as in Fig. 13.17 shows vasoinvasive fungal elements compatible with Aspergillus species.
Pneumocystis jirovecii Pneumonia
Although recent studies have strongly suggested that P. jirovecii (formerly known as P. carinii) is a fungus, we discuss P. jirovecii pneumonia separately from other fungal infections for didactic purposes. Without prophylaxis, P. jirovecii pneumonia occurs in nearly all lung transplant recipients.81 ttanks to the routine use of prophylaxis, it is rarely seen today in this patient population.
Time Period
Historically, infections have been most common around the seventh posttransplantation week.
Clinical Presentation
The clinical presentation is nonspecific and includes cough, fever, dyspnea, and hypoxemia.
Radiologic Findings
Radiographically, diffuse pulmonary infiltrates are seen.
Diagnosis
Because P. jirovecii cannot be grown in culture, the diagnosis is usually made by identification of the organisms in lavage fluid. Rarely, transbronchial lung biopsy is required.
Pathologic Findings
The classic histologic picture of interstitial pneumonia with frothy intraalveolar exudates, seen in patients with acquired immunodeficiency syndrome, is rarely encountered in lung transplant recipients (Figs. 13.19 and 13.20). In these patients, P jirovecii pneumonia more often manifests as diffuse alveolar damage and the organisms are typically embedded in the prominent hyaline membranes (Fig. 13.21). Granulomatous inflammation is a less common manifestation of infection with P. jirovecii.
Posttransplantation Lymphoproliferative Disorders
PTLD lesions are lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in an allograft recipient.82 Characteristics of PTLDs vary somewhat with allograft types and with immunosuppressive regimens. PTLDs are relatively more common among pulmonary allograft recipients as a result of higher levels of immunosuppression.37 In this population, the occurrence rate for PTLDs may be as high as 5%.
Figure 13.19 Pneumocystis jirovecii pneumonia, bronchoalveolar lavage. Frothy exudate can be seen.
Figure 13.20 Grocott methenamine silver stain of material from the same case as in Fig. 13.19 reveals Pneumocystis jirovecii organisms.
Figure 13.21 Pneumocystis jirovecii pneumonia. Both frothy intraalveolar exudates and hyaline membranes are visible.
A majority of PTLDs are associated with primary or reactivated Epstein-Barr virus (EBV) infection and appear to represent EBV-induced B cell or rarely T-cell proliferations. EBV-seronegative recipients who develop primary EBV infection have a higher incidence of PTLD. Approximately 20% of patients with PTLDs are EBV-seronegative. The etiology of EBV-negative cases is unknown, but the fact that some of them respond to decreased immunosuppression suggests that they are also related to decreased immune competence.
Time Period
PTLD most commonly develops in the first year after lung transplantation.83
Clinical Presentation
Primary EBV infection often presents as a mononucleosis-like illness with fever and sore throat. Pulmonary involvement by PTLD may cause shortness of breath or may be discovered incidentally on a routine chest radiograph. Simultaneous involvement of extrapulmonary sites may result in diarrhea, due to involvement of the gastrointestinal tract, and dysphagia, due to involvement of the tonsils. Physical examination may reveal lymphadenopathy, enlarged tonsils, splenomegaly, and crackles on chest auscultation. In some cases, the physical examination may be entirely normal.
Radiologic Findings
Thoracic abnormalities are present in most lung transplant recipients with PTLD.84 the most common radiologic finding is multiple pulmonary nodules. Other manifestations include a solitary nodule, multifocal alveolar infiltrates, and hilar or mediastinal adenopathy.
Diagnosis
The diagnosis is usually suspected on the basis of the clinical and radiologic findings, but histologic diagnosis is required.
Pathologic Findings
The spectrum of PTLDs ranges from early lesions to polymorphic PTLD to lymphomas.85,86 Several classification schemes have been proposed, but the World Health Organization classification is now widely accepted and is presented in Box 13.3.82
Specimen evaluation for the diagnosis of PTLD should include a routine morphologic examination, immunophenotyping, preservation of tissue for potential molecular genetic studies, and detection of EBV infection.82,87 Flow cytometry or frozen section immunohistochemistry is more useful in determining cell lineage and clonality than paraffin section immunohistochemistry. If immunophenotyping studies show polytypic immunoglobulin, clonality can be further assessed by molecular genetic studies that are capable of identifying polyclonal or monoclonal gene rearrangement. EBV infection can be detected using immunohistochemistry for latent membrane protein (LMP-1), but in situ hybridization for EBV-encoded nuclear RNA is considered the gold standard.
Early Lesions
Early lesions of PTLD include plasmacytic hyperplasia and infectious mononucleosis-like lesions. ’Hiese lesions usually arise in lymph nodes or Waldeyer ring and only rarely involve true extranodal sites such as the lung. ’Hiey are characterized by some degree of architectural preservation of the involved tissue,82 but they differ from typical reactive follicular hyperplasia in having a diffuse proliferation of plasma cells. Plasmacytic hyperplasia is distinguished by numerous plasma cells and rare immu- noblasts; an infectious mononucleosis-like lesion has the typical morphologic features of infectious mononucleosis in the lymph node, namely paracortical expansion and numerous immunoblasts in a background of T cells and plasma cells.
Immunophenotypic studies show an admixture of polyclonal B cells, plasma cells, and T cells. EBV-positive immunoblasts are typically present.
Polymorphic Posttransplantation Lymphoproliferative Disorders
Polymorphic PTLDs are destructive lesions that efface the architecture of lymph nodes or form destructive extranodal masses.82 In contrast to most lymphomas, polymorphic PTLDs show the full extent of B-cell maturation and are composed of immunoblasts, plasma cells, small and intermediate-sized lymphocytes, and centrocyte-like cells. Scattered large, bizarre cells (atypical immunoblasts) and areas of necrosis may also be present. Polymorphic PTLDs were at one time subdivided into polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma. Today this separation is not deemed necessary because both have similar clinical features. Immunophenotyping studies typically show a mixture of B and T cells. Most of the cases are monoclonal, at least by molecular genetic studies. EBV-positive immunoblasts are present in a majority of the cases.
Monomorphic B-Cell Posttransplantation Lymphoproliferative Disorders
Monomorphic B-cell PTLDs are characterized by nodal architectural effacement or tumoral growth in extranodal sites, with confluent sheets of large transformed cells.82 These tumors should be diagnosed as B-cell lymphomas and should be classified according to lymphoma classification guidelines. However, PTLD should also appear in the differential diagnosis. A majority of B-cell PTLDs have morphologic features of diffuse large B-cell lymphoma (Figs. 13.22-13.24). A minority may be classified as Burkitt lymphoma, plasma cell myeloma, or plasmacytomalike lesions. Immunophenotyping studies of monomorphic B-cell PTLD show B-cell-associated antigen expression (CD19, CD20, CD79a). Many cases coexpress antigens usually associated with T cells (CD43, CD45RO). A majority of cases are monoclonal and EBV-positive. Monomorphic B-cell PTLDs often contain oncogene or tumor suppressor gene alterations (N-ras gene codon 61 point mutation, p53 gene mutation, or c-myc gene rearrangement).88,89
Monomorphic T-Cell Posttransplantation Lymphoproliferative Disorders
T-cell lymphomas have been reported in allograft recipients. Similar to monomorphic B-cell PTLDs, monomorphic T-cell PTLDs have sufficient atypia to be recognized as neoplastic and should be classified according to the standard lymphoma classification. Monomorphic T-cell PTLDs express pan-T-cell antigens. Most of the reported cases are EBV-negative.
Figure 13.22 Panoramic view of monomorphic B-cell posttransplantation lymphoproliferative disorder showing a mass-like lesion in the pulmonary parenchyma.
Figure 13.23 Higher magnification of involved lung in B-cell posttransplantation lymphoproliferative disorder showing morphologic features of a diffuse large B-cell lymphoma.
Figure 13.24 In situ hybridization studies performed on involved lung in B-cell posttransplantation lymphoproliferative disorder reveal numerous cells that are positive for Epstein-Barr virus-encoded nuclear RNA.
Classic Hodgkin Lymphoma-Type Posttransplantation Lymphoproliferative Disorder
Classic Hodgkin lymphoma-type PTLD is the least common form of PTLD.82 the diagnosis is based on classic morphologic and immuno- phenotypic features, preferably including both CD15 and CD30 expression. This type of PTLD is almost always EBV-positive. Because Reed-Sternberg-like cells may also be seen in some polymorphic and monomorphic PTLDs, the distinction between classic Hodgkin lymphoma-type PTLD and Hodgkin lymphoma-like PTLD may be difficult in some cases. However, the latter are better categorized as either polymorphic or monomorphic PTLDs.
Histologic Differential Diagnosis
Acute rejection may be considered in the differential diagnosis of PTLDs, especially in small biopsy samples. Detection of EBV infection is very helpful in this respect. A sheet-like monomorphous infiltrate with a mononuclear composition of more than 25% B cells and more than 30% large lymphoid cells also favors PTLD over acute rejection.38
Treatment and Prognosis
Therapy of PTLD must be tailored to the individual patient. Newer modalities such as anti-CD20 monoclonal antibody therapy (with rituximab) complement the standard stepwise approach that begins with a reduction of immunosuppression.90 the role of chemotherapy continues to be defined, and in some cases early recourse to this approach may be desirable. Survival varies by age and extent of disease, with pediatric patients and those with localized disease tending to fare better.
Other Complications
Cryptogenic Organizing Pneumonia
Cryptogenic organizing pneumonia, previously known as idiopathic BOOP, occurs as a response to acute lung injury. In lung transplant recipients, it is commonly associated with aspiration, infection, and acute rejection.49,91-93 However, organizing pneumonia is not a component of, and does not necessarily predispose to, chronic airway rejection (obliterative bronchiolitis).
Time Period
The time from transplantation to onset of cryptogenic organizing pneumonia ranges from 2 to 43 months.
Clinical Presentation
The clinical findings are nonspecific and may include cough, dyspnea, fever, hypoxemia, and a decline in pulmonary function.
Radiologic Findings
The chest film may be normal in appearance or show localized or diffuse infiltrates.
Diagnosis
Cryptogenic organizing pneumonia is a clinical diagnosis that requires histopathologic confirmation by transbronchial or surgical lung biopsy (i.e., the presence of organizing pneumonia).
Pathologic Findings
Fibromyxoid plugs of granulation tissue are seen within small airways and airspaces, typically in a patchy distribution (Fig. 13.25).
Figure 13.25 Organizing pneumonia with intraalveolar fibroblastic plugs.
Histologic Differential Diagnosis
In organizing diffuse alveolar damage, the fibroblastic proliferation involves the interstitium rather than the airspaces, and remnants of hyaline membranes may be seen.49 However, organizing pneumonia and diffuse alveolar damage are both acute lung injury patterns, and features of both may be present in a given case. Airspace fibromyxoid tissue can also be seen in organizing infectious pneumonia and healing rejection, especially higher-grade rejection following steroid therapy. Separation of organizing pneumonia from transplant obliterative bronchiolitis has been discussed earlier.
Recurrence of the Primary Disease
A relatively small percentage of transplant patients are at risk for recurrence of their primary disease following lung transplantation. Sarcoidosis is the most common disease to recur.94 Other reported cases include recurrence of lymphangioleiomyomatosis,95-97 diffuse panbronchiolitis,98 giant cell interstitial pneumonia,99 desquamative interstitial pneumonia,91,100 intravenous talc granulomatosis,101 and adenocarcinoma.102
Clinical Features
Recurrence of the primary disease is usually an incidental finding on transbronchial biopsy or autopsy. However, symptomatic cases have also been described.
Diagnosis
The diagnosis depends on transbronchial or other biopsy samples.
Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.
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1. Which of the following statements concerning contemporary lung transplantation is/are TRUE?
A. Widespread use in the United States is restricted by organ availability.
B. It is cost-effective for the management of most chronic lung diseases.
C. Complications are mainly related to acute rejection.
D. Transbronchial biopsy in transplant recipients is restricted to surveillance for rejection.
E. All of the above
ANSWER: A
2. Which of the following is NOT an expected complication of lung transplantation during the first 3 months post transplant?
A. Infection
B. Aspiration
C. Harvest injury
D. Acute rejection
E. Obliterative bronchiolitis
ANSWER: E
3. All of the following terms refer to primary graft dysfunction EXCEPT:
A. Harvest injury
B. Ischemia-reperfusion injury
C. Early graft dysfunction
D. Primary organ failure
E. Reimplantation response
ANSWER: D
4. Which of the following statements about acute antibody-mediated rejection is/are TRUE?
A. It does not occur in lung transplantation.
B. It is a synonym for acute graft rejection.
C. It is characterized by immunoglobulin G (IgG) and C4d septal deposits.
D. Optimal treatment remains uncertain.
E. All of the above are true.
ANSWER: D
5. Which of the following is the most common airway complication of primary graft dysfunction?
A. Infection
B. Humoral rejection
C. Large airway stenosis
D. Posttransplantation lymphoproliferative disorder
E. None of the above
ANSWER: C
6. The 2007 International Society for Heart and Lung Transplantation Revised Working Formulation for allograft rejection includes which of the following major categories?
A. Humoral rejection, airway inflammation, chronic airway rejection, chronic vascular rejection
B. Reperfusion injury, acute rejection, chronic airway rejection, chronic vascular rejection
C. Acute rejection, graft failure, chronic airway rejection, chronic venous rejection
D. Acute rejection, humoral rejection, chronic airway rejection, chronic vascular rejection
E. Acute rejection, airway inflammation, chronic airway rejection, chronic vascular rejection
ANSWER: E
7. Radiologic findings of acute rejection include:
A. Perihilar alveolar and interstitial infiltrates
B. Lower lung zone alveolar and interstitial infiltrates
C. Pleural effusion
D. Septal lines
E. All of the above
ANSWER: E
8. The hallmark histopathologic feature of acute rejection is:
A. Hyaline membranes
B. Acute inflammation
C. Perivascular mononuclear cell infiltrates
D. Organizing pneumonia
E. All of the above
ANSWER: C
9. Minimal acute cellular rejection (grade A1) is characterized by:
A. Greater than five perivascular infiltrates in two or more biopsies
B. A single vessel containing 5 to 10 mononuclear cells
C. Infrequent perivascular mononuclear lymphoid cells two to three cells deep
D. At least five perivascular infiltrates of 10 or more cells
E. None of the above
ANSWER: C
10. Which of the following is/are histopathologic feature(s) in lung biopsies that favor infection over acute rejection?
A. Intraalveolar exudates
B. Granulomas
C. Predominant alveolar septal infiltrates
D. Abundant eosinophils
E. All of the above
ANSWER: E
11. True or false: Perivascular and interstitial mononuclear cell infiltrates are specific for rejection.
A. True
B. False
ANSWER: B
12. True or false: Rejection and infection may coexist in the transplant recipient.
A. True
B. False
ANSWER: A
13. True or false: Lymphocytic bronchiolitis is the characteristic histopathology of chronic airway rejection.
A. True
B. False
ANSWER: B
14. True or false: the current four grades of airway inflammation (B0, B1R, B2R, BX) are unchanged from previous International Society for Heart and Lung Transplantation Working Formulations.
A. True
B. False
ANSWER: B
15. True or false: the clinicopathologic significance of chronic vascular rejection remains unclear.
A. True
B. False
ANSWER: A
16. What is this?
A. Pulmonary embolus
B. Bronchiolitis obliterans
C. Chronic vascular rejection
D. Secondary amyloidosis
E. None of the above
ANSWER: C
17. What is this more likely to represent in the setting of lung transplantation?
A. Acute humoral rejection
B. Herpes simplex pneumonia
C. Acute cellular rejection
D. Cytomegalovirus pneumonia
E. None of the above
ANSWER: D
18. What is this more likely to represent in the setting of lung transplantation?
A. Acute humoral rejection
B. Herpes simplex pneumonia
C. Posttransplantation lymphoproliferative disorder
D. Cytomegalovirus pneumonia
E. None of the above
ANSWER: D
19. What is this more likely to represent in the setting of lung transplantation?
A. Acute humoral rejection
B. Herpes simplex pneumonia
C. Mild acute cellular rejection (grade A1)
D. Severe acute cellular rejection (grade A4)
E. None of the above
ANSWER: D
20. What is this more likely to represent in the setting of lung transplantation?
A. Acute humoral rejection
B. Minimal acute rejection (grade A1)
C. Severe acute cellular rejection (grade A4)
D. Cytomegalovirus pneumonia
E. None of the above
ANSWER: B
Case 1
eSlide 13.1
Clinical History
A 68-year-old male, 10 months after lung transplantation for idiopathic pulmonary fibrosis, returns to the lung transplant clinic for surveillance bronchoscopy. He has no major complaints. The slide is from a transbronchial biopsy performed during the bronchoscopy procedure.
Pathologic Findings
Two of the five biopsy specimens show perivascular mononuclear cell infiltrates. One of these infiltrates is more than three cell layers thick. In addition, chronic bronchitis is also seen.
Diagnosis
Mild acute rejection (grade A2).
Discussion
Although the role of surveillance bronchoscopy in the follow-up care of lung transplant patients is somewhat controversial, acute cellular rejection is a relatively common finding in both protocol and diagnostic biopsies. Since acute rejection is a risk factor for obliterative bronchiolitis, recognition is important. Perivascular mononuclear cell infiltrates are characteristic of this process. See the section titled Acute (Cellular) Rejection.
Case 2
eSlide 13.2
Clinical History
A 22-year-old female, 4 years after bilateral lung transplantation for cystic fibrosis, undergoes retransplantation for chronic respiratory failure. The slide is from the explanted right lung allograft.
Pathologic Findings
The alveolar parenchyma is largely preserved, but the bronchioles are abnormal. They show luminal narrowing due to scar tissue between the muscle layer and the epithelium. One of the bronchioles is completely obliterated and can be recognized only by its muscle layer.
Diagnosis
Obliterative bronchiolitis.
Discussion
Obliterative bronchiolitis is the most significant long-term complication of lung transplantation. Clinically, it presents as chronic dysfunction of the lung allograft and is associated with a high mortality rate. Histologically, partial or complete obstruction of the bronchiolar lumina is seen. The obliterating scar tissue may or may not be inflamed. In case of complete obstruction, bronchioles can be recognized by their muscle layer, their elastic layer (elastic stain), or the accompanying pulmonary artery. See the section titled Obliterative Bronchiolitis.
Case 3
eSlide 13.3
Clinical History
A 52-year-old female, 2 months after bilateral lung transplantation for interstitial pneumonia with autoimmune features (IPAF), is on mechanical ventilation owing to primary graft dysfunction. She has a fever. A transbronchial biopsy is performed.
Pathologic Findings
The lung biopsy shows diffuse alveolar thickening due to a mononuclear cell infiltrate and patchy organizing pneumonia. Scattered alveolar epithelial cells exhibit enlarged nuclei with intranuclear inclusions.
Diagnosis
Cytomegalovirus pneumonia.
Discussion
Cytomegalovirus infection remains a substantial issue for lung transplant recipients. It may also contribute to the development of obliterative bronchiolitis. Seronegative recipients of a seropositive donor are at highest risk. Histologically, the most typical finding is chronic interstitial pneumonia with the characteristic cytopathic effect. In some cases, perivascular infiltrates are seen mimicking acute rejection. Immunohistochemical studies for cytomegalovirus confirm the diagnosis. See the section titled Viral Infections.
Case 4
eSlide 13.4
Clinical History
A 55-year-old male, 3 months after bilateral lung transplantation for idiopathic pulmonary fibrosis, returns to the lung transplant clinic with chest congestion. A transbronchial biopsy is performed.
Pathologic Findings
The lung biopsy shows effaced pulmonary parenchyma with an infiltrate composed of large atypical lymphoid cells. In paraffin immunoperoxidase studies, the neoplastic cells are diffusely positive for CD20. CD3 reveals scattered reactive T cells. The Ki-67 labeling index is 100%. Epstein-Barr virus in situ hybridization is positive with a diffuse staining pattern.
Diagnosis
Diffuse large B-cell lymphoma consistent with monomorphic posttransplant lymphoproliferative disorder (PTLD).
Discussion
Lung transplant recipients receive a high level of immunosuppression and There fore are prone to Epstein-Barr virus-related PTLDs. Histologically, PTLDs range from early lesions to polymorphic PTLDs to monomorphic PTLDs/lymphomas. In addition to histology, studies for clonality and Epstein-Barr virus play a role in the diagnosis. See the section titled Posttransplantation Lymphoproliferative Disorders.
Case 5
eSlide 13.5
Clinical History
A 66-year-old male, 1 month after bilateral lung transplantation for idiopathic pulmonary fibrosis, undergoes surveillance bronchoscopy. The slide is from a transbronchial biopsy performed during the bronchoscopy procedure.
Pathologic Findings
Histologic sections show foci of airspace-filling fibroblastic plugs. Diagnosis
Organizing pneumonia.
Discussion
Organizing pneumonia is a relatively common finding in posttransplant lung biopsies. It may be of unknown etiology (i.e., cryptogenic organizing pneumonia). However, after lung transplantation, it may also be related to aspiration, infection, and acute rejection. Histologically, airspaces are focally filled with fibroblastic plugs (Masson bodies). See the section titled Cryptogenic Organizing Pneumonia.