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Noninfectious complications following lung transplantation

Noninfectious complications following lung transplantation
Literature review current through: May 2024.
This topic last updated: Apr 11, 2022.

INTRODUCTION — Lung transplantation is an important therapeutic option for select patients with end-stage lung disease and offers the potential for improved quality of life and long-term survival. Unfortunately, the lung transplant recipient is at risk for developing numerous infectious and noninfectious complications that threaten these objectives, including anastomotic problems, allograft rejection, primary graft dysfunction, phrenic nerve injury, pleural complications, venous thromboembolism, post-transplant malignancy, and recurrent primary disease.

General noninfectious complications of lung transplantation will be reviewed here. Other transplant-related complications, such as airway anastomotic complications, gastroesophageal reflux, reduced muscle strength, infection, and allograft rejection, are discussed separately. (See "Airway complications after lung transplantation" and "Physiologic changes following lung transplantation" and "Fungal infections following lung transplantation" and "Bacterial infections following lung transplantation" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Viral infections following lung transplantation" and "Evaluation and treatment of acute cellular lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

ALLOGRAFT REJECTION — Acute and chronic lung transplant rejection are discussed separately. (See "Evaluation and treatment of acute cellular lung transplant rejection" and "Evaluation and treatment of antibody-mediated lung transplant rejection" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

ANASTOMOTIC COMPLICATIONS — Lung transplantation involves completion of three anastomoses: airway, pulmonary arterial, and pulmonary vein-to-left atrium.  

Airway anastomotic complications — Airway anastomotic complications are discussed separately. (See "Airway complications after lung transplantation".)

Vascular anastomotic complications — Complications of the arterial and venous anastomoses are less frequently seen than airway anastomotic complications but may have devastating effects. Vascular obstruction includes narrowing of the lumen, kinking, thrombus, and external compression.

Pulmonary artery obstruction — A systematic review identified 1696 lung transplants with a prevalence of pulmonary artery obstruction of 3.66 percent (95% CI 2.80-4.50) [1]. Most were due to narrowing of the pulmonary artery lumen (stenosis). Pulmonary artery stenosis occurs more commonly late after lung transplantation. Causes include excessive length of donor and recipient segments, distortion due to short donor length, technical narrowing, and twisting of the anastomosis [2].

Symptoms such as shortness of breath and signs of pulmonary hypertension and right heart failure (eg, systemic hypotension, peripheral edema) or hypoxemia suggest this diagnosis.

Echocardiographic evidence of increased right ventricular pressure or right ventricular dysfunction may be present [3]. Quantitative ventilation/perfusion scanning shows blood flow that is unequally distributed between lungs after bilateral transplantation or disproportionate flow to the native lung after single lung transplantation. Computed tomography (CT) angiography and dynamic magnetic resonance (MR) angiography may also suggest the diagnosis; however, pulmonary angiography is usually necessary to confirm the diagnosis of pulmonary artery anastomotic stenosis (including documentation of a >10 mmHg pressure gradient) and allows therapeutic measures such as balloon dilatation and stent placement [3-5]. Surgical reconstruction is the final option for narrowing not amenable to other interventions [6].

Distortion or kinking of the pulmonary artery — Kinking of the pulmonary artery has been described in case reports and has a similar presentation as pulmonary artery stenosis [7,8]. In one case, the kink was associated with decreased flow in the pulmonary vein, as assessed by transesophageal echocardiography [7]. Percutaneous placement of a metallic stent was beneficial in both cases. Occlusion by thrombus and rarely external compression can be seen.

Pulmonary cuff dysfunction — Pulmonary cuff dysfunction includes pulmonary vein thrombosis and pulmonary vein stenosis. Pulmonary vein thrombosis typically occurs in the early postoperative period, but it has also been reported two weeks postoperatively [9]. Thrombus formation at the pulmonary venous/left atrial cuff suture line carries the risk of systemic embolization and cerebrovascular accident [10]. Thrombi may also obstruct pulmonary venous outflow and cause severe pulmonary edema refractory to medical management [11,12].

A systematic review found a prevalence of pulmonary cuff dysfunction of 2.5 percent (95% CI 1.8-3.4), which may be an underestimate [13]. A prospective cohort study evaluated the incidence of pulmonary venous thrombosis in 87 consecutive lung transplant recipients, by performing transesophageal echocardiography within 48 hours of the transplant procedure [11]. Thirteen (15 percent) had evidence of pulmonary venous/left atrial clot. This subset of patients had a significantly increased risk of death (90-day mortality rate of 38 percent).

Clinical features include hypoxemia, decreased lung compliance, and diffuse radiographic opacities in the allograft, although some clinically-unsuspected pulmonary venous thrombi are detected by routine transesophageal echocardiography [14,15]. Pulmonary artery and central venous pressures may be elevated. The superior veins appear to be the most commonly affected [13]. The differential diagnosis includes pulmonary vein stenosis, primary graft dysfunction, myocardial dysfunction, infection, and acute rejection [15]. The diagnosis is typically made by transesophageal echocardiography by measuring peak pulmonary cuff velocities, the presence of turbulent flow, elevated pressure gradient across the anastomosis, or pulmonary vein diameter (also measured by computed tomography) [16]. Peak systolic velocities >100 cm/s, a loss of systolic flow predominance, or turbulence by color-flow Doppler may indicate obstruction, and peak systolic velocities >170 cm/s and elevated baseline velocity indicate likely obstruction [16]. Peak velocities may be affected by many factors and need to be considered in the clinical setting.

There is no standardized approach to managing pulmonary vein thrombosis after lung transplantation. If the bleeding risk is not prohibitive, patients with symptomatic thrombi may benefit from systemic anticoagulation and, possibly, fibrinolytic therapy [15]. Refractory hypoxemia and/or hemodynamic instability may require emergent surgical thrombectomy, but outcomes are usually poor [17,18]. On the other hand, two patients with small venous anastomotic thrombi and lack of accelerated flow velocity were monitored without specific therapy and the thrombi resolved spontaneously.

Pulmonary vein stenosis is usually diagnosed in the late post-operative period using TEE or chest computed tomography. If detected intra-operatively, revision of the pulmonary cuff in the operating room may be required.

PHRENIC NERVE AND DIAPHRAGMATIC DYSFUNCTION — The reported incidence of diaphragmatic paralysis following lung transplantation generally ranges from 3 to 23 percent [19-22]. In a prospective cohort study of patients with normal phrenic nerve conduction studies pre-operatively, 43 percent of lung transplant recipients had evidence of phrenic nerve injury (abnormal phrenic nerve conduction study and diaphragmatic ultrasound) within three post-operative weeks, with bilateral lung recipients having twice the incidence of single lung recipients [23]. The lack of a “gold standard” definition makes it difficult to compare studies. (See "Heart-lung transplantation in adults", section on 'Phrenic nerve dysfunction'.)

The pathogenesis of phrenic nerve dysfunction is thought to include mechanical injury from intraoperative retraction of the sternum, manipulation of the pericardium, and mediastinal dissection, and also ischemia, inflammation, or thermal injury when cold topical cardioplegia is used. Right lung graft placement and mediastinal adhesions were associated with a higher risk of phrenic nerve injury in a multivariate analysis by hemithorax (rather than by patient) [23]. Patients with phrenic nerve injury have increased reintubation rates and more noninvasive ventilation [23]. Phrenic nerve injury following lung transplantation results in longer intensive care unit and hospital stays and longer duration of mechanical ventilation [19,20,23-26].

A retrospective cohort study showed that 23 percent of patients who received bilateral lung transplant had diaphragmatic elevation post-operatively [22]. Patients with persistent diaphragmatic elevation had lower spirometric measures at discharge and one year, but no difference in mechanical ventilation and ICU duration, although patients with permanent diaphragmatic elevation had a longer hospital stay [22].

Diaphragm paralysis should be suspected when a patient has dyspnea, hypoxemia, hypoventilation, atelectasis, hemidiaphragm elevation on an upright chest radiograph, or difficulty weaning from the ventilator postoperatively [24]. The diagnosis of unilateral diaphragmatic paralysis is usually made by fluoroscopic examination of the diaphragm, while bilateral paralysis may be strongly suspected based on the clinical setting, bilateral elevation of the diaphragm, supine and sitting spirometry, and diaphragmatic electromyography (EMG). The diagnosis and management of diaphragm paralysis is discussed separately. (See "Diagnosis and management of nontraumatic unilateral diaphragmatic paralysis (complete or partial) in adults" and "Diagnostic evaluation of adults with bilateral diaphragm paralysis" and "Treatment of bilateral diaphragmatic paralysis in adults".)

PLEURAL COMPLICATIONS — Pleural complications are commonly seen after lung transplantation and include pneumothorax, bronchopleural fistula, pleural effusion, hemothorax, empyema, and chylothorax. These complications are discussed separately. (See "Pleural complications in lung transplantation".)

PRIMARY GRAFT DYSFUNCTION — Primary graft dysfunction (also known as primary graft failure, severe ischemia-reperfusion injury, or reimplantation response) is a severe, acute lung injury syndrome occurring in the first 72 hours after lung transplantation. It is characterized by diffuse radiographic opacities in the allograft and an increased alveolar-arterial oxygen gradient. Primary graft dysfunction is discussed separately. (See "Primary lung graft dysfunction".)

VENOUS THROMBOEMBOLISM — Lung transplant recipients, like other patients undergoing major surgery, are at increased risk of venous thromboembolism (VTE). The reported incidence of pulmonary embolism ranges from 5 to 15 percent, while venous thrombosis was found in 20 to 45 percent when both upper and lower extremity thrombi were included [27-31]. VTE most commonly occurs early after transplant with most events occurring in first weeks to months after transplantation [32,33].

Risk factors for VTE among lung transplant recipients include older age, prior VTE, male sex, prolonged mechanical ventilation and ICU stay, diabetes, pneumonia, extracorporeal membrane oxygenation (ECMO), and cardiopulmonary bypass [28-30,33,34]. A significant proportion of VTEs are associated with a central venous catheter [31]. Patients with VTE within 30 days of transplantation are more likely to have had interruption of prophylaxis within the first five days after surgery and to have received cardiopulmonary bypass, independent of other variables [31]. Other bivariate predictors of early VTE in this study included ECMO, longer ICU stay, and need for hemodialysis. Another retrospective cohort study showed that female sex, prior history of VTE, hospitalization at the time of transplant, and placement of three or more central venous catheters were associated with an increased risk of early VTE, whereas the use of prophylaxis or anticoagulation were protective [35]. Another study showed increased prevalence of VTE after institution of routine screening [36]. A randomized trial of tacrolimus/sirolimus/prednisone versus tacrolimus/azathioprine/prednisone after lung transplantation suggested an increased risk of venous thromboembolism in those assigned to sirolimus (17 percent) compared with patients assigned to azathioprine (3 percent) [37].

Pulmonary vascular reserve tends to be limited during the recovery phase; as a result, an embolus to the transplanted lung can have serious consequences [38]. The presentation of thromboembolism is nonspecific, so a high index of suspicion is necessary when a transplant recipient presents with dyspnea, hypoxemia, or exercise desaturation. The diagnosis is typically obtained by computed tomography pulmonary angiography (CTP) or a ventilation-perfusion scan if radiographic contrast is contraindicated. The treatment is the same as for VTEs in general, although the risk of hemothorax may be greater in the early post-operative period. The diagnosis and treatment of VTE are discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

Standard methods of VTE prophylaxis should be used, although they (and longer periods of prophylaxis) have not been prospectively evaluated in this population [32]. Interruption of prophylaxis during the first five post-operative days (for >12 hours) was independently associated with an increased risk for VTE within 30 days of lung transplant [31]; however, this association could be confounded by other factors. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Deep venous thrombosis associated with an indwelling central venous catheter in a lung transplant recipient is evaluated and managed with conventional approaches. In particular, there should be a high index of suspicion for the development of this complication in patients who required placement of large cannulas for ECMO for pre- and/or post-transplant support. (See "Catheter-related upper extremity venous thrombosis in adults" and "Extracorporeal life support in adults in the intensive care unit: Overview".)

MALIGNANCY — Solid organ transplant recipients have a two-fold increased risk for developing malignancy [39,40]. Among five-year lung transplant survivors, malignancy has been reported to be the proximate cause of death in more than 17 percent of lung transplant recipients [41]. (See "Malignancy after solid organ transplantation".)

Lung cancer — Since the major indications for lung transplantation are diseases associated with smoking and the associated greater risk of lung cancer (eg, emphysema, idiopathic pulmonary fibrosis), single-lung recipients appear to be at higher risk for developing lung cancer (in the native lung) compared with bilateral lung recipients [42-49].

Lung cancer may also represent recurrent disease in patients who were transplanted for multifocal or diffuse bronchoalveolar carcinoma, now defined by the term adenocarcinoma in situ and pathologically as either lepidic predominant adenocarcinoma or mucinous adenocarcinoma [50-54]. A retrospective, multicenter study of 2168 consecutive lung transplant recipients (975 single-lung, 1211 bilateral-lung or heart-lung) from 1981 to 2001 reported a 2 percent incidence of bronchogenic carcinoma among single lung recipients [55]. All cases developed in the native lung, and none were reported in patients who received bilateral or heart-lung transplants. In a separate study, lung cancer was identified in 12 of 520 lung recipients, and eleven were in the native lung [44]. The rate of lung cancer in these studies does not appear to be greater than what has been observed in high-risk patients (smokers, chronic obstructive pulmonary disease [COPD]/idiopathic pulmonary fibrosis [IPF] patients), but the risk is greater than in the general population [55-58]. In a review of data from the US Scientific Registry of Transplant Recipients, lung transplant recipients were found to have 5.5 fold increased risk of lung cancer compared with the general population [39]. More recent studies suggest that 1 to 2 percent of patients have incidentally discovered cancers in the lung explant [59,60].

Bronchogenic carcinoma arising in the lung allograft is a rare occurrence, likely due to the careful donor selection process in which older age, history of significant tobacco use and evidence of parenchymal lung disease designate organs that are not suitable for transplantation [61]. The increasing demand for organs, however, has resulted in consideration of extended criteria lung donors that may have history of greater tobacco exposure. It remains to be seen if the incidence of donor-derived lung cancer will increase in the future [62,63]. (See "Lung transplantation: Deceased donor evaluation", section on 'Expanded donor criteria'.)

While the risk of developing lung cancer after lung transplantation relates largely to conventional risk factors, lung cancers that do arise appear to behave more aggressively under the influence of immunosuppression [43]. In fact, tumor progression may be so rapid that it can be difficult to distinguish from an infectious process [48]. Whether it is the loss of antitumor immune surveillance in the immunosuppressed host or specific properties of administered immunosuppressive drugs that promote tumor growth is uncertain [64,65].

The evaluation of pulmonary nodules is discussed separately. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

Post-transplantation lymphoproliferative disorders — The diverse lymphoproliferative diseases (including lymphoma) that arise after transplantation are referred to collectively as post-transplantation lymphoproliferative disorders (PTLD). They comprise a morphologically and clonally heterogeneous group of abnormal B-cell proliferative responses that have been associated with Epstein-Barr virus (EBV) infection, ranging from benign processes such as infectious mononucleosis-like illnesses and polyclonal hyperplasia to aggressive malignant monoclonal lymphomas.

PTLD typically arises from recipient lymphoid cells and occurs in approximately 1 to 8 percent of lung transplant recipients, rates higher than in other solid organ (heart, liver, kidney) transplant populations [66-71]. In an analysis of the International Society of Heart and Lung Transplantation (ISHLT) Registry, the incidence of PTLD at 10 years from transplantation was 4.1 percent with almost half of the cases developing in the first post-transplant year [71].

Early-onset PTLD is typically associated with EBV, while cases developing beyond five years after transplant are more commonly EBV-negative [72,73]. Among the neoplasms that arise after lung transplantation, PTLD is second in frequency to nonmelanoma skin cancers. The clinical manifestations, diagnosis, and treatment of PTLD are discussed in detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

The following discussion is limited to issues specifically related to lung transplant recipients. The clinical presentation of PTLD may vary depending on timing after transplantation with intrathoracic or lung allograft involvement more commonly seen in cases presenting within the first year after transplantation. Extrathoracic manifestations are more common with later onset presentations [52,74]. PTLD in lung transplant recipients with intrathoracic involvement may present as single or multiple pulmonary nodules or masses, mediastinal adenopathy and pleural effusions [75-77]. Diffuse lymphadenopathy as well as gastrointestinal, genitourinary, breast, cutaneous, and central nervous system involvement have also been reported [76,78-84].

In a review of the ISHLT registry, increasing age was a risk factor for PTLD among lung transplant recipients between 45 and 62 years at the time of transplant [71]. Conversely, younger age was a risk factor for recipients <45 or >62 years of age. The risk of PTLD is markedly increased in transplant recipients who are Epstein-Barr virus (EBV)-seronegative before transplantation and then acquire a primary EBV infection in the post-transplant setting [85-88]. Thus, the risk of PTLD is higher in children and young adults and is likely the reason for increased rates in lung transplant recipients with cystic fibrosis (CF), although CF-specific risk factors may also play a role [89,90]. In a single-center retrospective study of 28 patients with PTLD, transplantation for IPF was identified as an independent risk factor for EBV-associated PTLD [91].

Induction therapy and a greater intensity of maintenance immunosuppression are associated with development of PTLD [71,85,87,91,92]. The risk of PTLD is uncertain with use of novel immunosuppressive agents. In particular, when the off-label use of belatacept (a selective T-lymphocyte costimulation blocker) is considered in lung transplantation, the clinician should be aware that an increased incidence of PTLD has been reported in patients receiving this medication in renal transplantation [93-95]. (See "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Calcineurin inhibitor (CNI)-related toxicity' and "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Calcineurin inhibitor-related toxicity'.)

The initial treatment of PTLD after lung transplantation usually involves reduction in the intensity of maintenance immunosuppression to allow recovery of recipient EBV-specific cytotoxic T-lymphocytes. However, reduced immunosuppression increases the risk of developing allograft rejection [69,96]. Beyond reduction in immunosuppression, treatment with the chimeric human-mouse CD20 monoclonal antibody rituximab is well tolerated and associated with response rates of 50 to 80 percent [76,80,97]. Other options for patients who do not respond to rituximab or relapse after initial response includes cytotoxic chemotherapy, radiation therapy, or a combination of these [76,98-100]. Chemotherapy is typically reserved for refractory disease and EBV (-), CD20 (-) tumors. For bulky disease, especially in the GI tract, surgical intervention to reduce the risk of gut perforation may be considered. Adoptive immunotherapy which involves the transfer of cytotoxic T lymphocytes from recipient (autologous) or HLA-matched EBV positive donors are currently under investigation [101,102]. A more detailed discussion of specific therapies is reviewed separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

The role of prophylactic antiviral therapy in lung transplant recipients is not well-established, but many pediatric centers monitor EBV-seronegative recipients for evidence of viral activation. Prophylactic antiviral therapy at the time of early detection of primary EBV infection is discussed separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Prevention'.)

In the future, novel approaches targeting latent EBV infection in the donor lungs ex vivo prior to transplantation may reduce risk of donor-acquired EBV infection and PTLD [103].

Skin cancer — Lung transplant recipients are at increased risk of developing skin cancer, most commonly squamous cell carcinoma [104-106]. The risk may be greater after lung transplantation compared with other solid organ transplant recipients, due to the greater intensity of immunosuppression needed to prevent rejection [104]. In one series, the cumulative incidences for any skin cancer were 31 percent and 47 percent at 5 and 10 years posttransplantation, respectively [105].

Risk factors for skin cancer include male sex, increasing age, high sun exposure, fair skin, and previous nonmelanoma skin cancers [104,107]. Additionally, infections with oncogenic viruses likely play an important role in development of cutaneous malignancies with some studies reporting that the majority of squamous skin cancers in the transplant population are associated with HPV infection [108].

Use of the antifungal medication voriconazole to treat or prevent aspergillus and other fungal infections has been reported to increase risk of squamous cell skin cancer in transplant recipients [109,110]. In an international, retrospective cohort study of 900 lung transplant recipients, voriconazole exposure >30 days was identified as an independent risk factor for squamous cell cancer (hazard ratio [HR] = 2.4) [111]. Increased dose and duration of voriconazole treatment was associated with greater risk. In particular, treatment for more than 180-days had an adjusted HR of 3.5 for squamous cell cancer. The mechanism by which voriconazole may induce skin cancer has not been fully elucidated. Notably, this drug is associated with several acute and chronic phototoxic reactions and actinic keratosis. Its major metabolite, voriconazole N-oxide (VNO), may sensitize keratinocytes to ultraviolet A radiation and generate toxic reactive oxygen species that damage cellular DNA [112].  

All transplant recipients should receive education on the high risk of developing skin cancer after transplantation. During post-transplant visits, the importance of limiting sun exposure, using sun-protective clothing, and applying high sun protection factor (SPF) sunscreen while outdoors should be emphasized. At minimum, routine annual consultation with a transplant dermatologist for skin surveillance is advised [113,114]. Patients with multiple risk factors may need more frequent evaluation. Prevention and management of skin cancer in solid organ transplant recipients is discussed separately. (See "Prevention and management of skin cancer in solid organ transplant recipients".)

RECURRENT PRIMARY DISEASE — A number of diseases have been reported to recur in the lung allograft, including:

Sarcoidosis [115-120]

Lymphangioleiomyomatosis [121-123]

Diffuse panbronchiolitis [124]

Pulmonary alveolar proteinosis [125,126]

Desquamative interstitial pneumonia [127]

Pulmonary Langerhans cell histiocytosis [128-131]

Bronchioloalveolar carcinoma [50,51,132]

Idiopathic pulmonary hemosiderosis [133,134]

Giant cell interstitial pneumonitis [135]

Alpha-1 antitrypsin deficiency [136,137]

Pulmonary veno-occlusive disease [138]

Polymyositis-associated interstitial lung disease [139]

Sarcoidosis in particular has had a high recurrence rate in some small series [140]. It is often an incidental finding with noncaseating granulomas identified on lung biopsy specimens and is not associated with poorer outcomes.

GRAFT-VERSUS-HOST DISEASE — Graft-versus-host disease (GVHD) results from an immunologic attack by viable donor lymphocytes on recipient tissue and is manifested clinically by dysfunction of the skin, liver, gastrointestinal tract, and bone marrow (table 1). GVHD is common following hematopoietic stem cell transplantation and is a rare complication of lung transplantation [141-144]. (See "Pathogenesis of graft-versus-host disease (GVHD)".)

Clinical manifestations of GVHD include a maculopapular skin rash, severe cytopenias (especially neutropenia), cholestatic hepatitis, gastroenteritis and fever [141,145,146]. GVHD should be considered when these clinical findings are present; however, severe drug reactions and infections may have similar presentations. The diagnosis is confirmed by skin biopsy and by chimerism studies on peripheral blood, which quantify the percentage of circulating lymphocytes of donor and recipient origin. GVHD in lung transplant recipients appears to have a high mortality rate [141]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Prevention of graft-versus-host disease".)

Risk factors for GVHD after lung transplantation have not been well described. It is hypothesized that severe impairment of recipient cell-mediated immune surveillance supports donor-derived immune cell survival. In a case report, a lung transplant recipient with pulmonary fibrosis associated with a loss of function mutation in telomerase reverse transcriptase (TERT) was found to have acute GVHD [147]. It was proposed that telomerase dysfunction resulting in impaired cell-mediated immunity increased risk for acute GVHD. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Telomerase-related genes'.)

DRUG-INDUCED PULMONARY TOXICITY — Pulmonary toxicity due to medications is infrequent but needs to be considered when a lung recipient develops dyspnea, deteriorating oxygen saturation, and radiographic opacities. As an example, pulmonary toxicity is associated with use of mechanistic target of rapamycin (mTOR) inhibitors such as sirolimus or everolimus. The pathogenesis is unknown and toxicity is not clearly dependent on serum levels [148,149].

Symptoms usually develop within six months of initiating mTOR therapy, although later presentations have been reported. Patients typically present with dry cough, progressive dyspnea, fatigue and weakness. Fever and hemoptysis may also be present [150]. Radiographic abnormalities include bilateral interstitial opacities, alveolar consolidation and nodular opacities, which may persist for several months after drug cessation [149,151,152]. Lymphocytic alveolitis and, less commonly, alveolar hemorrhage are seen on analysis of bronchoalveolar lavage fluid. Histologic findings include organizing pneumonia (also known as bronchiolitis obliterans organizing pneumonia or BOOP), interstitial lymphocytic infiltrates, and sometimes alveolar hemorrhage [149,150,153]. Since mTOR inhibitor-associated pulmonary toxicity is potentially reversible (especially if recognized and treated early), it is important to consider it in the differential diagnosis of deteriorating lung function [154]. MTOR inhibitors may also be associated with increased risk of venous thromboembolism, thus the diagnosis of pulmonary embolism should be considered in patients with new onset dyspnea or hypoxemia [37]. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Rapamycin and analogs'.)

Other agents used commonly in transplant recipients that have been associated with lung injury include rituximab, amiodarone, and daptomycin. As transplant recipients are typically on numerous medications, drug-related toxicities should be considered in the differential diagnosis [155-157]. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Rituximab' and "Amiodarone pulmonary toxicity" and "Daptomycin: An overview", section on 'Eosinophilic pneumonia'.)

EXTRAPULMONARY COMPLICATIONS

Hyperammonemia — Severe hyperammonemia has been reported as a rare and frequently fatal cause of coma in the early post-transplant period, affecting approximately 1 to 4 percent of lung transplant recipients [158-162]. In addition to hepatic failure or urea cycle enzyme deficiencies, systemic infection with Mycoplasma hominis or Ureaplasma is a unique cause of hyperammonemia in lung transplant recipients. These microbes metabolize urea as an energy source and produce ammonia as a by-product. Treatment of hyperammonemia in these patients requires prompt initiation of antibiotics. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Ammonia'.)

Pathogenesis – The role of Mycoplasma and Ureaplasma in hyperammonemia was illustrated in the following studies. In a case report, a lung transplant recipient with fatal hyperammonemia was found to have Mycoplasma hominis infection in the blood and in various tissues (trachea, lung, small bowel, colon) [163]. In a subsequent study, investigators found Ureaplasma urealyticum or U. parvum infection in lung transplant recipients with hyperammonemia syndrome, but did not detect these organisms in any of the 20 lung transplant recipients with normal ammonia concentrations [161]. Donor factors associated with Mycoplasma and/or Ureaplasma included younger age, female sex, and cannabis use [164]. Administration of Ureaplasma-directed antimicrobials to the patients with hyperammonemia syndrome resulted in biochemical and clinical resolution of the disorder. It is not known why this condition is seen in the post-transplant setting.

Clinical features – Patients present with lethargy, somnolence, agitation, or seizures.

Evaluation – While the role of screening is unclear, serum ammonia levels should be measured in lung transplant recipients presenting with clinical findings consistent with this condition (eg, unexplained lethargy, agitation, seizure). If ammonia levels are elevated, blood, sputum, and bronchoalveolar (BAL) specimens should be tested for Mycoplasma and Ureaplasma by polymerase chain reaction (PCR) and culture. (See "Mycoplasma hominis and Ureaplasma infections", section on 'Diagnosis'.)

Treatment – While awaiting culture and PCR results in a recipient with a consistent clinical presentation, empiric therapy should be initiated against Mycoplasma hominis and Ureaplasma species. M. hominis is usually susceptible to tetracyclines; Ureaplasma species are generally susceptible to macrolides, fluoroquinolones, and tetracyclines. Combination antibiotic therapy is considered prudent given the risk of resistant organisms being present initially or developing during therapy [161]. Antimicrobial therapy is described in greater detail separately. (See "Mycoplasma hominis and Ureaplasma infections", section on 'Ureaplasma spp'.)

Additional interventions such as elimination of exogenous nitrogen sources from feedings, hemodialysis to clear ammonia from the blood stream, and administration of intravenous sodium benzoate and sodium phenylacetate to serve as alternatives to urea for the excretion of nitrogenous wastes may also be of benefit [165-167]. (See "Intermittent dialysis and continuous modalities for patients with hyperammonemia".)

Prophylactic screening of prospective donors and recipients – Some have proposed administering prophylactic antibiotics directed against these infections to the prospective donor and recipient until screening culture and PCR results are available; however, the risks and benefits of this approach are unknown [168,169].

Cardiac complications — Several cardiac complications may develop after lung transplantation. Early recognition and prompt treatment are essential to improving patient outcomes.

Atrial dysrhythmias – Atrial dysrhythmias are quite common after lung transplantation. The incidence of atrial arrhythmias (most commonly atrial fibrillation) early in the postoperative period ranges from 25 to 35 percent [170-175]. Risk factors include older age, male sex, left atrial enlargement, prior atrial fibrillation, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, regurgitant valvulopathy, coronary artery disease, prior coronary artery bypass graft procedure, diastolic dysfunction, and the use of cardiopulmonary bypass [170-172,174,176,177].

The surgical anastomosis between the donor left atrial cuff/pulmonary veins and recipient left atrium seems to be an important site for the development of the macro-reentry circuit of atrial flutter [178]. Atrial dysrhythmias usually respond to conventional therapies such as antiarrhythmic medications and cardioversion. Nevertheless, this complication is associated with prolonged hospital stays and increased mortality [171,173]. Medical therapy can often be discontinued within six weeks to three months after transplantation with low risk for recurrence [175,179]. Studies have shown a low risk of atrial fibrillation late after lung transplantation, whereas atrial flutter and other atrial tachycardias are more common [171,180]. In patients referred for electrophysiology study, catheter ablation of atrial arrhythmias a mean of 9.5 ± 6.7 years after lung transplantation appeared to be effective [181].

Hemodynamic instability – Hypotension is quite common in the immediate post-transplant period and usually responds well to judicious administration of volume, vasopressors, and inotropes. Intraoperative coronary artery air embolism, cardiac manipulation during the procedure, postoperative coronary artery embolism of small thrombi from the left atrial pulmonary venous anastomosis, or infarction from pre-existing coronary artery disease can cause myocardial injury, but clinically significant myocardial injury resulting in left ventricular dysfunction or biventricular failure is uncommon. In contrast, a pre-transplant diagnosis of severe pulmonary arterial hypertension is associated with increased risk of life threatening hemodynamic instability. Severe right ventricular dysfunction, requirement for cardiopulmonary bypass with attendant risk of hemorrhage, and increased incidence of early graft failure contribute to this risk [182].

Coronary artery disease – Over the long-term, risk factors for coronary artery disease develop in many lung transplant recipients [41]. Among five-year survivors in the Registry of the International Society for Heart and Lung Transplantation, the prevalence of risk factors was very high: systemic hypertension, 82 percent; hyperlipidemia, 59 percent; renal insufficiency, 55 percent with 3 percent requiring dialysis; and diabetes mellitus, 40 percent. In a single-center, retrospective study of 126 recipients without hypertension, hypercholesterolemia, or diabetes mellitus before transplantation, at least one cardiovascular risk factor had developed in 90 percent of the recipients by three years after transplantation [183]. Most of these risk factors are, directly or indirectly, related to the post-transplantation immunosuppressive medications. Thus, to a certain extent, these risk factors are unavoidable, but they should be controlled as well as possible with the standard modalities of diet, exercise, and drug therapy. Perhaps surprisingly, a study comparing lung transplant recipients with mild asymptomatic coronary artery disease (who were not previously revascularized or revascularized during lung transplantation) had a 6 percent risk of progression requiring intervention post-transplant [184]. Age, atrial fibrillation, and a diagnosis of IPF were independent predictors of postoperative cardiac events.

Pericarditis – Several case reports have described constrictive pericarditis developing in bilateral lung transplant recipients six months to nine years following transplantation [185-190]. Patients typically present with dyspnea, orthopnea, and lower extremity edema. Infectious and malignant causes of pericarditis must be sought and excluded [188,191-193]. Treatment is usually pericardiectomy [189]. The diagnosis and management of constrictive pericarditis are discussed separately. (See "Constrictive pericarditis: Diagnostic evaluation".)

Diabetes mellitus — New onset diabetes mellitus occurs in approximately 20 percent of lung transplant recipients followed for one year and more than 30 percent at five years [41,183,194-196]. Risk factors for post-transplant diabetes mellitus include glucocorticoid and calcineurin use, older age, obesity (body mass index >30) and diagnosis of cystic fibrosis [196,197]. Patients receiving tacrolimus have a greater likelihood of developing diabetes than those receiving cyclosporine, although glucose intolerance is not considered a reason to switch from tacrolimus to cyclosporine. The presence of diabetes mellitus is associated with an increased risk of death in lung transplant recipients [196,198-200]. International consensus guidelines for the evaluation and management of post-transplantation diabetes mellitus (PTDM) are discussed separately, [201,202]. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)

Renal insufficiency — Acute renal failure (ARF) is commonly seen after lung transplantation [203-207]. In a retrospective analysis, 424 of 657 lung transplant recipients had at least one episode of acute kidney injury (AKI) in the first two weeks following transplantation [203]. In a cohort from the University of Alberta, 69 percent had AKI early after lung transplantation [208]. In a separate study, 166 out of 296 (56 percent) consecutive transplant recipients developed acute renal insufficiency, although only 8 percent needed dialysis [204]. ARF requiring renal replacement therapy (RRT) was associated with an increased risk for early mortality. Independent predictors of post-transplant severe ARF were preoperative diagnoses of pulmonary hypertension and idiopathic pulmonary fibrosis, reduced baseline glomerular filtration rate (GFR), mechanical ventilation >24 hours and use of intravenous amphotericin B. A validated risk score for ARF after lung transplantation includes race, diagnosis, BMI, diabetes mellitus (DM), pre-operative GFR, intensive care unit/extracorporeal membrane oxygenation (ECMO) pre-transplant, and other factors [209]. The presence of AKI is a risk factor for mortality, independent of primary grant dysfunction [208,210,211].

Chronic kidney disease (CKD) has been reported in 5 percent of lung recipients within three years of transplantation and approximately 15 percent at six years [212]; higher estimates (68 percent at five years) are seen using a lower threshold to define CKD (GFR <60 mL/min/1.73 m2). In the International Society of Heart Lung Transplant Registry, a creatinine >2.5 mg/dL was noted in 15 percent of lung transplant recipients at five years post-transplant [213]. Chronic renal failure is also associated with increased mortality [212,214]. Depending on the study and patient population, implicated risk factors for chronic renal insufficiency include age, a history of smoking [214,215], sex, early post-transplant ARF, use of calcineurin inhibitors and other nephrotoxic drugs, hypertension, sarcoidosis, and diabetes [216-218]. Equations for estimation of GFR are the best predictors of the risk of CKD after lung transplantation [218,219]. Risk factors, prevention, and treatment of post-transplant nephrotoxicity are discussed separately. (See "Kidney function and non-kidney solid organ transplantation", section on 'Lung transplantation' and "Kidney function and non-kidney solid organ transplantation", section on 'Prevention and treatment strategies' and "Cyclosporine and tacrolimus nephrotoxicity", section on 'Incidence' and "Assessment of kidney function", section on 'Assessment of GFR'.)

Kidney transplant for CKD after lung transplantation (usually for calcineurin inhibitor-induced renal failure) has been performed successfully [220].

Pneumatosis intestinalis and pneumoperitoneum — Pneumatosis intestinalis (PI) refers to the presence of gas within the wall of the small or large intestine. A single center study reported that over an 11-year period, 10 of 373 consecutive lung recipients developed PI. Outcomes were generally good (100 percent short-term survival), although two of these patients did have high lactate levels and required bowel resection [221]. While reported risk factors include glucocorticoid therapy, infectious colitis and sepsis, it may be a benign finding in asymptomatic patients. In a separate series of 321 bilateral lung transplants, pneumatosis intestinalis (PI) was identified on imaging studies in seven asymptomatic patients [222]; three of the six patients also had pneumoperitoneum. No definite cause for these findings was identified and the radiographic findings resolved spontaneously at a mean of 24 days. (See "Pneumatosis intestinalis".)

Neurologic complications — Neurologic complications are common after lung transplant, affecting 92 percent of patients in one cohort over a 10-year period with 31 percent developing severe complications [223,224]. Neurologic complications have been reported to increase hospital length of stay and in some reports are associated with increased mortality. Delirium and encephalopathy are the most frequently reported neurologic complications and typically occur in the early post-operative period [224-226].

Reversible posterior leukoencephalopathy (RPLS) is a rare, serious neurologic complication associated with immunosuppressive therapy, especially calcineurin inhibitors, and should be considered in the differential diagnosis of altered mental status in transplant recipients [227,228]. (See "Reversible posterior leukoencephalopathy syndrome".)

Cerebrovascular accidents have been reported to occur in approximately 5 to 10 percent of lung recipients [223,224,229,230]. In addition to the well-recognized atherothrombotic mechanisms of stroke, two embolic mechanisms unique to this patient population must also be considered. Failure to fully de-gas the pulmonary vascular tree and cardiac chambers after completion of the vascular anastomosis can lead to air embolism immediately upon lung reperfusion or in the early postoperative period. In addition, formation of thrombus at the left atrial anastomotic site can result in embolic stroke days to weeks after transplantation (see 'Vascular anastomotic complications' above). The increasing use of extracorporeal membrane oxygenation (ECMO) to support patients with cardiopulmonary failure pre- and post-transplantation is an additional risk factor for stroke [231]. (See "Extracorporeal life support in adults in the intensive care unit: Overview" and "Lung transplantation: Preanesthetic consultation and preparation" and "Lung transplantation: Procedure and postoperative management".)

Clinical and radiographic findings consistent with multiple areas of brain infarction should prompt performance of transesophageal echocardiography. If thrombus is documented, systemic anticoagulation should be initiated in the absence of other contraindications. (See 'Pulmonary cuff dysfunction' above.)

Other complications — Lung transplant recipients may develop a panoply of other medical and surgical problems. Most of these are not unique to lung transplantation, but instead are side effects of the immunosuppressive medications or general medical problems that are aggravated by the post-transplantation regimen [64,232].

Prominent problems include:

Osteoporosis [232-235]. (See "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation".)

Obesity [236-239]. (See "Obesity in adults: Etiologies and risk factors".)

Anemia, thrombotic microangiopathy (TMA) syndromes [240]. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Chronic pain [241].

Gastroparesis and gastroesophageal reflux disease (GERD) [242,243]. (See "Physiologic changes following lung transplantation", section on 'Oropharyngeal dysphagia, gastroesophageal reflux, and gastroparesis'.)

Hypercholesterolemia and hypertriglyceridemia [183,213]. Hyperlipidemia is reported in 59 percent of lung transplant recipients within five years after transplant [213]. (See "Lipid abnormalities after kidney transplantation".)

Diverticulitis, cholecystitis, gastrointestinal perforation [244-247].

Distal intestinal obstruction syndrome in patients with cystic fibrosis – Distal intestinal obstruction syndrome (DIOS) is characterized by an acute complete or partial obstruction of the ileocecum by intestinal contents and may occur with increased frequency following lung transplantation [248-250]. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Distal intestinal obstruction syndrome'.)

Weakness of respiratory and limb muscles. (See "Physiologic changes following lung transplantation", section on 'Respiratory and skeletal muscle function'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)

SUMMARY AND RECOMMENDATIONS

Vascular anastomotic complications – Complications of the pulmonary artery and pulmonary vein/left atrium anastomoses, such as thrombus formation, stenosis, and arterial kinking, occur less frequently than airway anastomotic complications, but may have devastating effects. (See 'Vascular anastomotic complications' above.)

Diaphragmatic dysfunction – Diaphragmatic dysfunction due to phrenic nerve injury complicates approximately 3 to 23 percent of lung transplantations. Diaphragm paralysis should be suspected in patients with postoperative dyspnea, hypoxemia, hypoventilation, atelectasis, unilateral or bilateral diaphragm elevation on an upright chest radiograph, and/or difficulty weaning from the ventilator postoperatively. (See 'Phrenic nerve and diaphragmatic dysfunction' above and "Diagnosis and management of nontraumatic unilateral diaphragmatic paralysis (complete or partial) in adults" and "Diagnostic evaluation of adults with bilateral diaphragm paralysis" and "Treatment of bilateral diaphragmatic paralysis in adults".)

Venous thromboembolism – Lung transplant recipients are at increased risk of venous thromboembolism (VTE). A high index of suspicion for VTE is necessary when a transplant recipient presents with dyspnea, hypoxemia, or exercise desaturation. (See 'Venous thromboembolism' above.)

Post-lung transplant malignancy – Lung transplant recipients have an increased risk for developing malignancy. As lung diseases associated with cigarette smoking are frequent indications for lung transplant, it is not surprising that lung cancer occurs in the native lung in approximately 2 percent of single lung recipients. Overall, lung transplant recipients have a 5.5 fold increased risk of lung cancer compared with the general population. (See 'Malignancy' above.)

Post-transplantation lymphoproliferative disorders – The risk of post-transplantation lymphoproliferative disorders (PTLD) in lung transplant recipients is approximately 5 percent, but is substantially higher in transplant recipients who are Epstein-Barr virus (EBV)-seronegative before transplantation and acquire a primary EBV infection in the post-transplant setting. Notably, the incidence of PTLD not associated with EBV infection is increasing. The clinical presentation of PTLD may vary depending on timing after transplantation with intrathoracic or lung allograft involvement more commonly seen in cases presenting within the first year after transplantation while extrathoracic manifestations are more common with later presentations. (See 'Post-transplantation lymphoproliferative disorders' above and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Recurrence of primary lung disease – A number of diseases have been reported to recur in the lung allograft, including sarcoidosis, lymphangioleiomyomatosis, diffuse panbronchiolitis, pulmonary alveolar proteinosis, desquamative interstitial pneumonia, pulmonary Langerhans cell histiocytosis, bronchioloalveolar carcinoma, and idiopathic pulmonary hemosiderosis. (See 'Recurrent primary disease' above.)

Graft-versus-host disease – Graft-versus-host disease (GVHD) results from an attack by viable donor lymphocytes from the lung allograft on recipient tissues (eg, skin, gastrointestinal tract, liver, bone marrow) and is a rare complication of lung transplantation. (See 'Graft-versus-host disease' above.)

Drug-induced pulmonary toxicity – Pulmonary toxicity due to medications (eg, sirolimus, rituximab) is an infrequent adverse effect following lung transplantation, but needs to be considered when a lung recipient develops dyspnea, deteriorating oxygen saturation, and radiographic opacities. (See 'Drug-induced pulmonary toxicity' above.)

Extrapulmonary complications – Lung transplant recipients are at risk for other complications due to adverse effects of immunosuppressive medications or their underlying disease, including hyperammonemia due to systemic infection with Mycoplasma hominis or Ureaplasma, atrial dysrhythmias, hemodynamic instability, coronary artery disease, diabetes mellitus, renal insufficiency, pneumatosis intestinalis, and stroke. (See 'Extrapulmonary complications' above.)

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Topic 4656 Version 30.0

References

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