Lung transplantation may offer 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 12-1. 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 Living donor single lobe transplantation may be a viable alternative to cadaveric lung transplantation for selected patients.² Benchmark survival rates for adult lung transplant recipients are 88% at 3 months, 78% at 1 year, 63% at 3 years, 51% at 5 years, and 28% at 10 years after transplantation.¹

Table 12-1 Most Common Indications for Lung Transplant Procedures

Transplant Procedure	Most Common Indications
Adult single lung	Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis α₁-Anti-trypsin deficiency emphysema
Adult bilateral/double lung	Cystic fibrosis Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis α₁-Anti-trypsin 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

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 (LAS) was implemented, dramatically changing the way donor lungs are distributed.³ Under the new system, priority for transplantation is determined by medical urgency and expected outcome. Early evaluations of the new system indicate that the waiting time and waitlist mortality rate are decreased, the number of transplants is increased, and the post-transplantation survival is unchanged.⁴

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, post-transplantation lymphoproliferative disorders [PTLDs]). Other complications, such as organizing pneumonia and recurrence of the original disease, may also occur. To aid the differential diagnosis, post-transplant time intervals can be divided arbitrarily into immediate (within 4 days), early (4 days to 1 month), and late (beyond 1 month) post-transplantation periods.⁵ Differential diagnostic possibilities for each of these periods are listed in Table 12-2.

Table 12-2 Complications of Lung Transplantation

Post-transplantation 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.^6,⁷ At least five pieces of well-expanded alveolated lung parenchyma are required for the assessment of acute rejection.⁸ The histopathologic findings most commonly encountered in a post-transplantation transbronchial biopsy include acute rejection, cytomegalovirus infection, airway-centered inflammation, pneumonia, bronchiolitis obliterans, harvest injury, invasive aspergillosis, and PTLDs.^6,⁹

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. Primary graft dysfunction affects an estimated 10% to 25% of pulmonary allografts and can range in clinical severity from transient decrease in oxygenation to complete graft failure.¹⁰ The International Society for Heart and Lung Transplantation (ISHLT) has proposed a definition and a grading scheme based on the chest film and Pao₂/Fio₂ ratio.¹¹

Pathologic Findings

Mild cases may show alveolar and interstitial edema with scattered neutrophils.¹³ The histologic correlate of severe primary graft dysfunction is diffuse alveolar damage.¹² 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. 12-1). In the organizing phase, hyaline membranes are incorporated into the alveolar septa, which become thickened by fibroblast-rich connective tissue (Fig. 12-2).

Figure 12-1 Acute diffuse alveolar damage due to harvest injury. The key to the diagnosis is the presence of hyaline membranes.

Figure 12-2 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 post-transplantation setting (Box 12-1). Immunofluorescent studies are helpful in separating primary graft dysfunction from acute antibody-mediated rejection. Acute antibody-mediated rejection is characterized by alveolar septal deposits of IgG and complement (particularly C4d), which are absent in primary graft dysfunction. Acute rejection is not a major concern during the immediate post-transplantation period. Any infection can manifest as diffuse alveolar damage in an immunocompromised patient; therefore, it is always prudent to perform special stains to rule out acid-fast bacilli and fungal organisms.

Box 12-1 Common Causes of Diffuse Alveolar Damage in the Pulmonary Allograft

Harvest injury

Acute antibody-mediated rejection

Severe acute rejection

Infection

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 those without primary graft dysfunction, 30-day mortality rates are 42.1% and 6.1%, respectively.¹⁴ Primary graft dysfunction is also associated with an increased risk of obliterative bronchiolitis.¹⁵ For 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, and inflation and ventilation parameters of the organs during transport.¹⁰ 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.¹⁶ 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.¹⁶

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.¹⁷ Occlusive thrombus formation is relatively rare but may have catastrophic consequences, including allograft failure and stroke.

Time Period

Venous anastomotic obstruction usually presents in the immediate post-transplantation period but has been reported to occur as late as the eighth postoperative day.¹⁶

Clinical Presentation

Pulmonary venous obstruction after lung transplantation should be suspected in every case of persistent pulmonary edema in the first postoperative days, often associated with a frothy blood-stained secretion from the endotracheal tube.¹⁸

Radiologic Findings

Chest radiograph 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.¹⁸

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 venous 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 immunosuppression, and better allograft preservation have reduced the incidence of airway complications.¹⁹ Currently, most centers report a 7% to 18% complication rate with a related mortality rate of 2% to 4%.¹⁹

Time Period

Airway dehiscence may develop in the first few weeks after 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, thereby enhancing necrosis and dehiscence of the anastomosis.

Treatment

Surgical options are limited, but may include anastomotic revision, retransplantation, or stent placement.

Large Airway Stenosis

Large airway (bronchial) stenosis is the most common airway complication. The incidence is estimated to be between 1.6% and 32%.¹⁹ 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.^20,²¹ 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.²²

Clinical Presentation

Clinical findings include dyspnea, retained secretions, recurrent pneumonia, and 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

Airway stenting is often used as the primary management option for airway complications after lung transplantation.²³

Rejection

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 1990.²⁴ The working formulation was first revised in 1996.²⁵ The currently accepted scheme for grading pulmonary allograft rejection was approved by the ISHLT board of directors in 2007 (Box 12-2).⁸ The differences between the 1996 and 2007 schemes are relatively minor and are related to airway inflammation and chronic airway rejection. Acute antibody-mediated rejection is a controversial subject and is not included in the 2007 working formulation. For the sake of completeness, however, it 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 acute 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 usually is 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.²⁶

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 12-3). 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. 12-3).

2. In mild acute rejection (grade A2), the perivascular mononuclear cell infiltrates become thicker, denser, and usually more frequent (Fig. 12-4).

3. In moderate acute rejection (grade A3), the infiltrates extend into the alveolar septa and air spaces (Fig. 12-5).

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. 12-6).

Table 12-3 Grading Acute Rejection

Figure 12-3 Minimal acute rejection (A1) with sparse perivascular mononuclear cell infiltrate.

Figure 12-4 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 12-5 In moderate acute rejection (A3), the perivascular infiltrate extends into the alveolar septa.

Figure 12-6 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.

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 through 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, 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 cytomegalovirus pneumonia and Pneumocystis jiroveci pneumonia,²⁷^–²⁹ and PTLDs.³⁰ Some histologic features may favor infection over acute rejection (Table 12-4). Cultures and special stains may be helpful in the diagnosis of mycobacterial, fungal, and Pneumocystis jiroveci infections. Viral pneumonias can be confirmed by cultures as well as serologic, immunohistochemical, or molecular hybridization techniques.

Table 12-4 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 jiroveci infection
Frothy intra-alveolar exudates	Pneumocystis jiroveci pneumonia