eMedicine Specialties > Pediatrics: Surgery > Transplantation

Lung Transplantation: Treatment

Author: Albert Faro, MD, Assistant Professor, Department of Pediatrics, Division of Allergy and Pulmonary Medicine, Washington University School of Medicine
Coauthor(s): Gary A Visner, DO, Chief, Division of Pediatric Pulmonology, Associate Professor, Department of Pediatrics, University of Florida College of Medicine
Contributor Information and Disclosures

Updated: May 30, 2008

Treatment

Medical Therapy

Treatment varies depending on the primary diagnosis. The goal of therapy for patients on the transplant waiting list is to optimize their medical care in preparation for the upcoming surgery and to correct deficiencies discovered during the evaluation. This approach may include improving the patient's nutritional status, providing pulmonary rehabilitation, and trying to decrease the number of pulmonary exacerbations for which intravenous (IV) antibiotics are needed.

If the patient has psychosocial contraindications to transplantation, the authors attempt to correct those conditions by providing their families the assistance they need to successfully care for their child. If that assistance is ineffective and if transplantation is otherwise deemed appropriate, one must give careful consideration to involving the appropriate state authorities for alternative placement of the child. However, at some centers, the need for placement is considered a contraindication to transplantation.

Advances in the treatment of pulmonary vascular disease have changed the outlook for many patients with IPH. In some patients with IPH, medical therapy with epoprostenol has delayed or obviated lung transplant. Other pulmonary vasodilators, such as sildenafil and bosentan, have also been effective in treating these patients.

Surgical Therapy

Surgical intervention prior to transplant may vary depending on the primary diagnosis. For instance, patients with CF and end-stage lung disease may develop pneumothoraces. Before the advent of transplantation, these patients routinely underwent pleurodesis to prevent recurrences. However, pleurodesis potentially complicates transplantation surgery and is a relative contraindication. In fact, before one proceeds with any thoracic procedure, the transplant center should be consulted because such procedures may disqualify the patient from future transplantation surgery. Any thoracic procedure before transplantation may increase the risk of bleeding and intraoperative or immediate postoperative mortality.

Other surgical interventions that may be contemplated prior to transplant include the placement of a gastrostomy-tube for nutritional resuscitation.

Preoperative Details

Recipient

After a patient is listed for lung transplantation, if they are age 12 years or older, the timing of the transplantation depends on their lung allocation score (LAS). The LAS was put established in 2005.7 This new allocation system factors in the risk of mortality while on the waiting list and the benefit of transplantation. In addition, this new system allows pediatric donor lungs to be preferentially offered to pediatric recipients within the region before being offered to a wider pool.

Clinical findings and laboratory values used to determine the LAS include the following:

  • Age
  • Underlying diagnosis
  • Forced vital capacity
  • Oxygen levels at rest
  • Six-minute walk test results
  • Ventilator use
  • Functional status (NYHA Class)
  • Systolic pulmonary artery pressure
  • Pulmonary capillary wedge pressure
  • Body mass index
  • Diabetes diagnosis
  • Creatinine levels

In, children younger than 12 years, lungs are still allocated based on waiting time; organs are given to the child with the most time accrued on the list who also matches the donor’s blood type and body size.

Donor
The potential lung donor should meet certain criteria; however, these criteria are mostly derived from experience and not from controlled trials. 

Characteristics of ideal donors include the following:8

  • Age younger than 55 years: Data suggests poorer outcomes with older donors, especially when combined with ischemic times longer than 6 hours.
  • ABG results that include a ratio of arterial oxygen pressure to fraction of inspired oxygen (PaO2/FiO2) of more than 300 mm Hg and a positive end-expiratory pressure (PEEP) of 5 cm H2 O: Data is inadequate to support or refute this cutoff. Studies mainly focus on interventions to increase donor PaO2/FiO 2 to more than 300 mm Hg to harvest the organ. 
  • Normal chest radiography findings: The use of donors with abnormal chest radiography findings has not been studied. If findings suggest atelectasis, aggressive airway clearance and the use of bronchoscopy to remove mucus plugs may salvage an otherwise unusable lung. However, if findings suggest a contusion, the lung should not be accepted.
  • Ischemic time of 4-6 hours: Reports describe successful outcomes with ischemic times of 6-11 hours. Poor outcomes are clearly associated with older donors and prolonged ischemic times.
  • Height and/or predicted total lung capacity (TLC) ± 20% of recipient: Data demonstrate no adverse results on outcomes when using donor lungs within 75-125% of recipient TLC.
  • Negative Gram stain findings: Infection is a major source of early posttransplant morbidity and mortality; however, evidence suggests that positive sputum Gram stain findings do not correlate with the development of pneumonia. Data suggests that the amount of purulent secretions may be important in predicting posttransplant outcome.
  • A history of smoking less than 20 packs per year: No data support or refute this criteria. Concerns include the development of malignancy posttransplant as well as the potential for increased risk of poor perioperative outcome.
  • No history of cancer: Little data is available regarding donors with a past history of malignancy. The potential risk is likely based on histology, tumor stage, and length of cancer-free survival. Primary CNS tumors rarely spread. Risk factors include medulloblastoma or glioblastoma, previous craniotomy, ventricular shunt, and tumor radiation. Renal cell carcinoma is the most common type of cancer transmitted from donors.
  • Mechanical ventilation for less than 3 days: Mechanical ventilation for longer than 2 days is a risk factor for the development of ventilator-associated pneumonia. However, donors with prolonged courses who have normal radiography findings and good gas exchange may be better donors because the sequelae of aspiration may not be evident within the first 24-48 hours.

Intraoperative Details

The most common pediatric surgical technique in the United States now consists of a bilateral sequential procedure with telescoping anastomoses. This procedure may allow the surgeon to avoid the need for cardiopulmonary bypass, reducing the risk of infection and bleeding. In a sequential bilateral lung transplantation, the surgeon performs a transverse thoracosternotomy, allowing for excellent visualization of the pleural space. The patient's least functional lung, as determined during the transplantation evaluation, is removed first, while the contralateral lung provides uninterrupted ventilation. The bronchus, pulmonary artery, and pulmonary vein anastomoses are performed in that order. The bronchial circulation, lymphatic system, and nervous system are not reanastomosed.

Because of the relative difficulties of double-lumen endotracheal tube use in small children and the prevalence of pulmonary hypertension in that cohort, cardiopulmonary bypass is often used in younger children.

Living lobar donation allows a family member or friend to donate a lower lobe of their lung. One donor donates a right lower lobe, and another donates a left lower lobe. Using lungs from living donors offers several advantages over using lungs from deceased donors. Most notably, lung transplantation surgery is changed from an emergency procedure to an elective one. The surgery can be scheduled at a time best suited to the requirements of the recipient, donors, and transplantation team, thus potentially decreasing the risk of ischemia-reperfusion injury. Also, the risk of BO may be lower in the living lobar recipient.

Postoperative Details

Typical Postoperative Course

If all goes well, the typical postoperative course consists of a 2-week hospitalization period. The goal is to extubate patients within 24-48 hours of transplantation to minimize barotrauma and further oxidant injury. While intubated, patients may require frequent bronchoscopy to evaluate the anastomotic site and to suction debris and secretions (secondary to the reimplantation response) from the airway. Chest tubes are typically removed when they are draining less than 100 mL of fluid per day and when no air leak is present.

When all pressors are discontinued and the patient is extubated, they can be transferred from intensive care. Appropriate IV antibiotics and other warranted antimicrobials are continued for approximately 2 weeks. Physical therapy is initiated in the intensive care unit and progressively becomes more strenuous as the patient becomes ambulatory.

Discharge to posttransplantation housing varies by center. At St. Louis Children's Hospital housing is near the hospital, and patients continue to attend regular sessions of physical therapy. One month after surgery, they undergo surveillance bronchoscopy with transbronchial biopsy. The timing of surveillance procedures vary from center to center.

Immunosuppressants

Induction therapy
A well-established risk factor for the development of BO is a history of acute rejection. This has led to the institution of induction regimens at many centers. Most often, the agents used for induction are potent immunosuppressants that may potentially increase the risk for infection or malignancy to strike. The most recent ISHLT Registry report indicates that approximately half of the pediatric lung transplant recipients receive some form of induction. Consensus has not been reached on whether induction therapy should be used, and centers who use induction therapy have not reached a consensus as to the best agent to use. In general, induction agents can be divided into lympholytic agents and interleukin (IL)-2 receptor antagonists.

  • Lympholytic agents
    • These drugs induce opsonization and phagocytosis of T lymphocytes and modulate T-cell activation.
    • These preparations contain antibodies to human lymphocytes and are derived from animal serum. They include rabbit antithymocyte globulin (RATG [Thymoglobulin]), muromonab-CD3 (OKT3 [Orthoclone]), and equine antithymocyte globulin (lymphocyte immune globulin [ATGAM]).
    • These agents are used by some transplant centers for induction therapy immediately after transplantation; they are typically administered for 3-5 days. In other instances, they are used to treat steroid-resistant rejection and are typically administered for 10-14 days.
    • Results from trials comparing induction agents suggest that patients receiving OKT-3 have a higher incidence of infection. RATG and ATGAM are fairly similar, although RATG infusions may be better tolerated. In a single-center prospective trial, RATG did decrease the incidence of acute rejection. No study has documented that any of these agents have a beneficial impact on the incidence of BO. 
    • Potential adverse effects include cytokine release syndrome (ie, chills, fever, vomiting, diarrhea, headache), increased incidence of infection, increased risk of posttransplantation lymphoproliferative disorder (PTLD), and leukopenia.
    • Alemtuzumab (Campath), a newer monoclonal antibody, binds to the CD52 surface antigen and has been used in renal transplant recipients.
  • IL-2 receptor antagonists
    • These agents are monoclonal antibodies that specifically bind to the IL-2 receptor on activated T cells.
    • They include basiliximab (Simulect) and daclizumab (Zenapax). The 2 agents differ in their half-lives (ie, longer for daclizumab) and in the number of doses necessary. They are used for induction therapy immediately after transplantation.
    • These agents appear to reduce the frequency of acute rejection in adult lung transplant recipients. A retrospective study in pediatric lung transplant recipients found no difference in acute rejection or BO compared with controls.
    • They are typically well tolerated.

Maintenance immunosuppression

  • Calcineurin inhibitors
    • Cyclosporine and tacrolimus are the 2 drugs available for use in this category. These powerful agents are the mainstay of immunosuppression and are responsible for the success of transplantation. However, because of an array of potential adverse effects and drug interactions, they have limitations. Drug levels are monitored on a regular basis. Doses for lung transplant recipients are usually maintained at higher levels (ie, cyclosporine 300-350 ng/mL; tacrolimus 10-12 ng/mL) than those for other organ recipients. The serum levels require maintenance at levels high enough to prevent rejection without causing debilitating toxicities. The cytochrome P450 (CYP) 3A isoenzyme in the liver metabolizes both drugs.
    • Cyclosporine binds cyclophilin in the cytoplasm of the T cell, which then binds calcineurin, a Ca2 + phosphatase, blocking it from activating transcription factors and ultimately preventing the expression of IL-2. IL-2 is a growth factor for T cells. Without it, the magnitude of T-cell response is greatly diminished.
    • Tacrolimus, a macrolide antibiotic, binds a different immunophilin, the FK-binding protein. This complex also binds calcineurin and prevents IL-2 expression. It is more potent than cyclosporine.
    • Both drugs are metabolized in the liver and can increase the risk of infection, nephrotoxicity, neurotoxicity, GI disturbances, electrolyte derangements, malignancy, and hypertension. 
    • Multiple trials have compared these 2 agents; they are equal in prevention of BO and improvement of survival. However, the adverse effect profiles are clearly different. Cyclosporine may cause gingival hyperplasia and hirsutism, whereas tacrolimus may cause more hyperglycemia.
    • Most pediatric lung transplant centers now preferentially use tacrolimus-based regimens as their primary immunosuppression because it has a more manageable adverse effect profile in children and because of the potential impact on adherence. Numerous agents may cause changes in the serum levels of cyclosporine and tacrolimus when coadministered.
    • The following are examples of drugs likely to increase cyclosporine or tacrolimus serum levels secondary to decreased hepatic metabolism by inhibiting the CYP3A4 isoenzyme:
      • Cimetidine
      • Erythromycin
      • Clarithromycin
      • Diltiazem
      • Verapamil
      • Itraconazole
      • Voriconazole
      • Fluconazole
      • Ketoconazole
      • Grapefruit juice
    • The following are examples of drugs likely to decrease cyclosporine or tacrolimus serum levels by either inducing hepatic metabolism via CYP3A4 or decreasing bioavailability of the drugs:
      • Rifampin
      • Phenytoin
      • Carbamazepine
      • Phenobarbital
      • Ethambutol
      • St John's wort
      • Antacids
    • Nonsteroidal anti-inflammatory drugs (NSAIDs) can potentiate the nephrotoxicity of these agents and should never be used concurrently. Renal prostacyclin synthesis is important in maintaining glomerular filtration rate and renal blood flow. NSAIDs suppress renal thromboxane-A2 production, which attenuates the effects of reduced vasodilatory prostaglandins. In addition, tacrolimus and cyclosporine should never be used together as they potentiate their nephrotoxicities.
    • Initial single-center studies suggest that aerosolized cyclosporine may provide a substantial survival advantage to lung transplant recipients receiving the drug.9 Further studies are necessary.
  • Cell toxins
    • This category of immunosuppressant agents includes azathioprine (Imuran) and mycophenolate mofetil (MMF, [Cellcept]). Azathioprine prevents the proliferation of T cells by inhibiting purine biosynthesis. Its use is limited because of its toxicity on other cell types. MMF inhibits an enzyme responsible for balancing purine nucleotides in lymphocytes and affects only the de novo pathway of purine biosynthesis. Other cell types are theoretically protected from the full effects of this agent because they can synthesize purine nucleotides via the salvage pathway. Several studies that compared azathioprine with MMF in lung transplant recipients have not shown a clear clinical benefit of one agent over the other.10
    • Dosing is often determined by WBC count. The goal is to maintain a total leukocyte count of 4000-7000/mcL and an absolute neutrophil count of more than 1500/mcL. MMF serum levels can be measured, and data support maintaining levels at more than 3 mcg/mL.
    • Potential adverse effects for both of these agents include myelosuppression, infection, and nausea. In addition, azathioprine may cause hepatotoxicity and rash. MMF may cause diarrhea and an increased risk of lymphoproliferative disorders. Allopurinol should be used cautiously in patients on azathioprine. The dose of azathioprine should be reduced by 50-75% to minimize the potentiation of toxicity when used in concert with allopurinol.
  • Corticosteroids
    • Corticosteroids are the oldest group of immunosuppressant agents. They interfere with several different steps in the inflammatory cascade. They interfere with transcription factors such as NF-kappa B and AP-1, blocking cytokine production. They also cause lymphocyte apoptosis.
    • Corticosteroids possess many potential adverse effects, including increased risk of infection, hyperglycemia, hypertension, cataract formation, bone loss, GI disorders, mood alteration, acne, growth suppression, and amenorrhea. At high doses, corticosteroids may cause alterations in serum levels of the calcineurin inhibitors.
  • Rapamycin and its derivatives
    • This family of drugs consists of sirolimus (rapamycin, [Rapamune]) and everolimus (40-0-[2-hydroxyethyl]-rapamycin [RAD]). Although they bind to the FK-binding protein, like tacrolimus, they do not inhibit calcineurin. Their effects occur later in the cell cycle by inhibiting cytokine-induced signal transduction pathways. Because sirolimus and RAD work by different mechanisms, they can be used with cyclosporine or tacrolimus.
    • One study in lung transplant recipients examined the use of sirolimus as rescue therapy; renal dysfunction was the most common indication. In these 23 adult lung transplant recipients, only 2 episodes of acute rejection were documented over a median follow-up period of 107 days.
    • Sirolimus may have a beneficial effect in patients with chronic rejection because it inhibits proliferation of endothelial and smooth muscle cells in vitro and appears to inhibit vascular injury in vivo. RAD also inhibits smooth muscle proliferation.
    • Initially, rapamycin was available only as a suspension, but a tablet form is now available. It is routinely dosed once daily, but evidence indicates that in children more desirable drug levels are maintained with a twice-daily dosing regimen. Dosing is adjusted to achieve serum levels of 8-13 mcg/L.
    • Potential adverse effects of sirolimus include hyperlipidemia and myelosuppression. Lipid profiles must be regularly monitored. It has no role in the early postoperative period because it may interfere with wound healing and cause anastomotic dehiscence. Sirolimus is also associated with the development of interstitial pneumonitis.

Follow-up

Outpatient care posttransplant varies somewhat from center to center. After discharge from St. Louis Children's Hospital, patients are seen in clinic twice a week and regularly attend pulmonary rehabilitation sessions. To prevent complications, or to identify them early, numerous parameters are monitored on a routine basis. Standard laboratory and imaging studies are performed on a routine basis. 

In addition, therapeutic drug monitoring has become a standard for transplant care. Many of the immunosuppressive medications have a narrow therapeutic index, and patients have variable pharmacokinetics. This appears to be particularly relevant in preventing side effects from the agents. Patients are instructed to monitor their lung function, blood pressure, temperature, and weight daily and to call with any changes.

Rejection or infection frequently results in loss of lung function. For children old enough to perform spirometry, FEV1 may be monitored on a daily basis in order to detect early changes in lung function. For younger children, home oximetry may be used on a daily basis.

Bronchoscopy

As mentioned above, patients undergo their initial bronchoscopic examination while intubated within 24 hours of transplant. At the authors' center, the first routine surveillance transbronchial biopsy is performed one week after transplantation. At some centers, this procedure may not be performed until one month after transplantation.

At St. Louis Children's Hospital, the authors routinely perform surveillance transbronchial biopsy at one week and 1, 2, 3, 6, 9, 12, and 18 months after transplantation. Other centers have different monitoring schedules, including some adult centers who perform biopsies only when clinically indicated. The optimal monitoring system has yet to be clearly elucidated and should be an area of further study.

Patient education

For excellent patient education resources, visit eMedicine's Lung and Airway Center and Procedures Center. Also, see eMedicine's patient education articles Heart and Lung Transplant and Bronchoscopy.

Complications

Primary Graft Dysfunction

Acute lung injury of newly transplanted lungs has been called numerous names; however, the term primary graft dysfunction (PGD) was the consensus selection of the ISHLT.11 PGD is an acute lung injury in the transplanted lung in the immediate postoperative period.12  It results from numerous donor factors, including the very act of dying, which may cause abrupt changes in blood pressure and the release of inflammatory mediators that potentially damage donor organs. These changes are not well understood

However, in renal transplantation, evidence suggests a reduced incidence of ischemia-reperfusion injury in living related donation compared with cadaveric donation. Additional factors related to the risk of developing PGD include inherent donor lung characteristics, preservation process, pulmonary ischemia and reperfusion, and, possibly, recipient factors (eg, primary pulmonary hypertension).

The incidence of PGD varies from 10-50%, depending on the definition. The ISHLT also developed a classification of PGD based on severity using PaO2/FiO2 and chest radiography findings at different time points within the first 72 hours. Contributing factors that may need to be excluded include hyperacute rejection, cardiogenic pulmonary edema, pulmonary venous obstruction, pneumonia, and, possibly, transfusion-related acute lung injury. Based on this new classification, the incidence of severe PGD (PaO 2 /FiO 2 <200 48 h posttransplant) appears to be approximately 15%; more importantly, severe PGD is associated with an increase in both early and late graft failure and mortality. 

PGD occurs within hours and as long as 2 days posttransplantation; it is characterized by poor oxygenation with pulmonary infiltrates on radiographs. Additional characteristics include pulmonary edema, low lung compliance, and increased pulmonary vascular resistance; the histologic examination may reveal diffuse alveolar disease. 

Ischemia-reperfusion injury with an increase in oxygen free radicals is believed to play a critical role in the pathophysiology of PGD. This results in a proinflammatory condition with inflammatory cell activation, release of cytokines and chemokines, and endothelial cell dysfunction, resulting in a dysregulation of vasoactive mediators and prothrombotic and fibrinolytic factors. 

In general, patients with severe PGD are treated similarly to patients with acute respiratory distress syndrome. In patients with capillary leak associated with PGD, excessive fluid should be avoided while maintaining perfusion and adequate oxygenation to vital organs. Typically, protective ventilator strategies using pressure-controlled ventilation with PEEPs and smaller tidal volumes are used to prevent volutrauma and barotraumas to the newly transplanted lungs.  

Because pulmonary vascular resistance is often increased, nitric oxide is frequently used to treat PGD. Nitric oxide may also improve perfusion to areas of lung that are being ventilated. Similarly, prostaglandins may be used; experimental data suggests a beneficial role for exogenous surfactant therapy. When patients require high concentrations of supplemental oxygen (which may contribute to further formation of oxygen radicals) or when they have ventilatory pressures high enough to yield barotrauma or compromise systemic blood return and pressure, the early use of extracorporeal membrane oxygenation (ECMO) should be initiated to provide rest to the lung. 

Airway Complications

Airway dehiscence was once a common complication of lung transplantation. With the evolution of surgical techniques, this is now rare. However, the development of airway stenosis and bronchomalacia, probably secondary to ischemia-reperfusion injury, is not unusual.13 If the narrowing is severe enough to cause compromise, the affected area can often be successfully treated by performing balloon dilatation. Theoretically, this should be more of a problem in young children; however, one study suggests that the incidence of this complication is the same among young children and older children.

Infection

The likelihood of the development of certain infections can be suggested by the period after transplantation in which they appear. For example, bacteria are the likely causes of infections that occur immediately after transplantation. Opportunistic infections, such as those due to Pneumocystis carinii, CMV, and Nocardia species, are not usually observed until after the first month after transplantation. One exception to this rule is fungal infections. Chronic airway colonization with fungi such as Aspergillus species is not uncommon in patients with CF. If left untreated, these patients may become critically ill soon after transplant.

Clinically, these patients may present with fever, cough, dyspnea, crackles on auscultation, infiltrates on chest radiographs, decreased lung function, or hypoxia.

Bacterial infections

IV antibiotics are started intraoperatively. If CF or septic lung disease is present, antibiotics are initiated based on the results of the most recent sputum culture. If aseptic lung disease is present, patients are routinely given drugs with broad-spectrum coverage.

Viral infections

Potential causative agents include CMV,14 respiratory syncytial virus (RSV), human metapneumovirus, EBV, influenza, herpes, varicella, and adenovirus. CMV poses a clinical challenge for the transplant physician. CMV can cause acute life-threatening illness, such as pneumonitis or hepatitis and is also linked to the development of BO in lung transplant recipients.15 Children who are CMV seronegative at the time of transplantation and who receive organs from a seropositive donor are at the highest risk. Virtually all centers administer prophylaxis against CMV, though the ideal regimen is debated.

RSV infection may be fatal in as many as 12% of all lung transplant recipients. RSV can also potentially trigger acute rejection. Appropriate management in patients with a lung transplant requires further study. The roles of RSV hyperimmune globulin (RespiGam), ribavirin, and palivizumab (Synagis) in this setting are not well defined.

Similarly, adequate therapies for adenoviral pneumonia in transplant recipients are lacking. One series studied patients who received Cidofovir (1 mg/kg) 3 days per week for 4 weeks, with probenecid and IV hydration.16 Three of the 4 survived the infection, and none developed nephrotoxicity with this regimen; however, 2 of the survivors developed BO.

All of the authors' transplant recipients are annually immunized against influenza. If a patient has symptoms that suggest influenza, they are routinely started on therapy. Amantadine and rimantadine were not recommended by the Centers for Disease Control and Prevention (CDC) for the 2005-2006 influenza season because of resistance. Laboratory testing by the CDC on the predominant strain of influenza (H3N2) currently circulating in the United States showed that it was resistant to these drugs.

EBV infection is discussed below.

Fungal infections

As noted above, lung transplant patients with CF often have chronic colonization with Aspergillus species. However, any immunocompromised lung transplant recipient is at risk for developing fungal infections. Candida albicans and Aspergillus species are the most common fungal organisms isolated in this group. Patients with these infections may present with pneumonia but may also present with mediastinitis, wound infections, or mycotic aneurysms.

Options for therapy have rapidly increased over the past 5 years with the emergence of newer azoles and echinocandins. Because many patients already have some degree of renal dysfunction from life-long exposure to aminoglycosides, and because the calcineurin inhibitors are nephrotoxic, amphotericin B and intravenous voriconazole should be used cautiously.

In a randomized trial, voriconazole was shown to be superior to amphotericin in treating invasive A spergillus infection and has the advantage that of being used orally in stable patients.17 Although effective, itraconazole has somewhat more unpredictable bioavailabilty. Posaconazole has recently become available and also has potent activity against Aspergillus infection.

The major drawback for any of the azoles is their interaction with cyclosporine, tacrolimus, and sirolimus. In fact, voriconazole is contraindicated in patients on sirolimus, and large downward dose adjustments of the calcineurin inhibitors are indicated when any of the azoles are instituted. Caspofungin is less likely to impact immunosuppressant levels, but tacrolimus levels should still be monitored because they may be lowered by caspofungin. Because caspofungin's mechanism of action differs, combination with azole therapy is potentially available.

One study reported superiority of this combination compared with intravenous liposomal amphotericin B in 90-day survival and renal function; however, strong evidence for use of combination therapy is still lacking. The liposomal form of amphotericin B is less nephrotoxic than amphotericin B and is still indicated for serious fungal infections. In stable patients, nebulized liposomal amphotericin B is an option, although good randomized studies are lacking. In the setting of lung transplantation, the nebulized form of the drug is most commonly used for prophylaxis. However, optimal duration for prophylaxis is not yet established. 

Other opportunistic infections

P carinii is a rare pathogen in lung transplant recipients because patients routinely receive prophylaxis with trimethoprim-sulfamethoxazole starting approximately one week after transplantation.

Surgical Complications

Chylothorax may occur. Damage to the thoracic duct may occur intraoperatively, resulting in a collection of chyle in the pleural space. Treatment is usually conservative, with a decrease in dietary long-chain fatty acids. Surgical intervention is rarely necessary.

Damage to the phrenic nerve may occur intraoperatively, resulting in diaphragmatic paralysis. The nerve is cut only in rare circumstances, but bruising is not uncommon, and nerve function usually returns within 3 months. However, in the meantime, patients may experience unilateral paralysis usually without significant symptoms.

Immunologic Complications

Acute rejection

Acute rejection remains a fairly common complication after lung transplant, although it is not as common as it once was. The lungs are prone to rejection for various reasons. The lungs have a large endothelial surface. The entire cardiac output perfuses the lungs, thereby exposing them to all of the circulating immune effector cells. In addition, the lung has its own array of immune effector cells. Finally, the lungs are constantly exposed to inhaled antigens.

Patients with clinically acute rejection present in the same manner as patients with infections with cough, fever, decreased lung function, and radiographic changes. Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy is the only definitive way to differentiate rejection from infection.

Rejection is treated with high-dose methylprednisolone (10 mg/kg IV each day for 3 d at the authors' center). Repeat biopsy is performed 2-4 weeks after therapy. If no improvement occurs, the patient may be given a second course of high-dose methylprednisolone or may be treated with a lympholytic agent for 10-14 days.

Bronchiolitis obliterans

BO is an inflammatory injury to the small airways, which is presumed to result from chronic rejection in lung transplantation. BO is a histopathologic diagnosis. Because the process is initially patchy, transbronchial biopsy samples often do not suggest the diagnosis, necessitating open lung biopsy. Therefore, a corresponding clinical syndrome was defined that corresponds to the histopathologic diagnosis and is termed BO syndrome (BOS).

A patient has BOS when an otherwise unexplained drop in lung function occurs after acute rejection, infection, and airway complications have been ruled out. Risk factors for BOS include recurrent acute rejection (>3 episodes) or an episode of severe acute rejection. CMV disease had been associated with the development of BO in many older studies before the advent of routine CMV prophylaxis. An association between gastroesophageal reflux (GER) and BOS has also been demonstrated. Clinical features of BO include deteriorating lung function that occurs more than 3 months after transplantation. BO is characterized by irreversible obstruction of the small airways. Patients may report dyspnea and wheezing.

Physical examination may reveal distant breath sounds, basilar crackles, or unremarkable findings. Chest radiography findings may be normal or may reveal hyperinflation. High-resolution CT scanning of the chest may demonstrate bronchiectasis, decreased vascular markings, and airtrapping. Histologically, BO is characterized by a proliferation of fibroblasts into the airway lumen, ultimately forming intraluminal granulation tissue and total obliteration of the lumen. The airway injury is initially patchy and inhomogeneous, adding to the difficulty of making a pathologic diagnosis with routine surveillance transbronchial biopsy.

In the past, no therapy could reverse the condition, although some therapies, including augmentation of immunosuppression, seemed to halt further deterioration of the airway obstruction at least temporarily. However, emerging evidence suggests that patients with early stages of BOS and GER may dramatically benefit from fundoplication.18  BOS develops in nearly one half of all lung transplant recipients.

Infant lung transplant recipients seem to have significantly less acute rejection and BO than older children. In addition, mechanical ventilation pretransplantation does not appear to negatively impact infant outcomes.

Malignancy

Because of immunosuppressive agents, lung transplant recipients are at increased risk for malignancies. The most common in children is PTLD.19 The spectrum of disease severity widely varies, with the most severe being true malignancy. Primary infection with EBV after transplant is the primary risk factor. Therefore, children, who are more likely than adults to be EBV seronegative at the time of transplant, are at increased risk. Furthermore, pediatric lung transplant recipients are at high risk, with an incidence of as much as 19% in one series.

The first therapeutic step is to decrease immunosuppression. This results in regression of the lesion in about 50% of patients. Other potential therapies are poorly studied. The literature is replete with case reports, but randomized controlled trials comparing interventions are lacking. If reduced immunosuppression is unsuccessful, potential therapies include treatment with anti–B-cell antibodies (eg, rituximab), interferon-alfa with or without IV immunoglobulin (IVIG), surgical resection, radiotherapy, and cytotoxic chemotherapy.

The prognosis for patients with PTLD is poor. The risk for developing BO after having had PTLD is significant. The interventions described above may substantially improve outcomes for these patients.

More on Lung Transplantation

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Workup: Lung Transplantation
Treatment: Lung Transplantation
Follow-up: Lung Transplantation
Multimedia: Lung Transplantation
References
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References

  1. Aurora P, Whitehead B, Wade A, Bowyer J, Whitmore P, Rees PG. Lung transplantation and life extension in children with cystic fibrosis. Lancet. Nov 6 1999;354(9190):1591-3. [Medline].

  2. Bowdish ME, Barr ML, Schenkel FA. A decade of living lobar lung transplantation: perioperative complications after 253 donor lobectomies. Am J Transplant. Aug 2004;4(8):1283-8. [Medline].

  3. Sritippayawan S, Keens TG, Horn MV. Does lung growth occur when mature lobes are transplanted into children?. Pediatr Transplant. Dec 2002;6(6):500-4. [Medline].

  4. Liou TG, Adler FR, Fitzsimmons SC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol. Feb 15 2001;153(4):345-52. [Medline].

  5. Aris RM, Routh JC, LiPuma JJ. Lung transplantation for cystic fibrosis patients with Burkholderia cepacia complex. Survival linked to genomovar type. Am J Respir Crit Care Med. Dec 1 2001;164(11):2102-6. [Medline].

  6. Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. May 29 2008;358(22):2319-31. [Medline].

  7. Egan TM, Murray S, Bustami RT, Shearon TH, McCullough KP, Edwards LB. Development of the new lung allocation system in the United States. Am J Transplant. 2006;6(5 Pt 2):1212-27. [Medline].

  8. Gabbay E, Williams TJ, Griffiths AP, et al. Maximizing the utilization of donor organs offered for lung transplantation. Am J Respir Crit Care Med. Jul 1999;160(1):265-71. [Medline].

  9. [Best Evidence] Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med. Jan 12 2006;354(2):141-50. [Medline].

  10. Palmer SM, Baz MA, Sanders L. Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection. Transplantation. Jun 27 2001;71(12):1772-6. [Medline].

  11. Trulock EP, Christie JD, Edwards LB, Boucek MM, Aurora P, Taylor DO. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart-lung transplantation report-2007. J Heart Lung Transplant. Aug 2007;26(8):782-95. [Medline].

  12. Daud SA, Yusen RD, Meyers BF, Chakinala MM, Walter MJ, Aloush AA. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. Mar 1 2007;175(5):507-13. [Medline].

  13. Choong CK, Sweet SC, Zoole JB, Guthrie TJ, Mendeloff EN, Haddad FJ. Bronchial airway anastomotic complications after pediatric lung transplantation: incidence, cause, management, and outcome. J Thorac Cardiovasc Surg. Jan 2006;131(1):198-203. [Medline].

  14. Danziger-Isakov LA, DelaMorena M, Hayashi RJ. Cytomegalovirus viremia associated with death or retransplantation in pediatric lung-transplant recipients. Transplantation. May 15 2003;75(9):1538-43. [Medline].

  15. Danziger-Isakov LA, Faro A, Sweet S, Michaels MG, Aurora P, Mogayzel PJ Jr. Variability in standard care for cytomegalovirus prevention and detection in pediatric lung transplantation: survey of eight pediatric lung transplant programs. Pediatr Transplant. Dec 2003;7(6):469-73. [Medline].

  16. Doan ML, Mallory GB, Kaplan SL, et al. Treatment of adenovirus pneumonia with cidofovir in pediatric lung transplant recipients. J Heart Lung Transplant. Sep 2007;26(9):883-9. [Medline].

  17. Husain S, Paterson DL, Studer S, Pilewski J, Crespo M, Zaldonis D. Voriconazole prophylaxis in lung transplant recipients. Am J Transplant. Dec 2006;6(12):3008-16. [Medline].

  18. Davis RD, Lau CL, Eubanks S. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. Mar 2003;125(3):533-42. [Medline].

  19. Cohen AH, Sweet SC, Mendeloff E. High incidence of posttransplant lymphoproliferative disease in pediatric patients with cystic fibrosis. Am J Respir Crit Care Med. Apr 2000;161(4 Pt 1):1252-5. [Medline].

  20. Liou TG, Adler FR, Cox DR, Cahill BC. Lung transplantation and survival in children with cystic fibrosis. N Engl J Med. Nov 22 2007;357(21):2143-52. [Medline].

  21. Okazaki M, Krupnick AS, Kornfeld CG, Lai JM, Ritter JH, Richardson SB. A mouse model of orthotopic vascularized aerated lung transplantation. Am J Transplant. Jun 2007;7(6):1672-9. [Medline].

  22. Dobbin C, Maley M, Harkness J. The impact of pan-resistant bacterial pathogens on survival after lung transplantation in cystic fibrosis: results from a single large referral centre. J Hosp Infect. Apr 2004;56(4):277-82. [Medline].

  23. Elizur A, Sweet SC, Huddleston CB, Gandhi SK, Boslaugh SE, Kuklinski CA. Pre-transplant mechanical ventilation increases short-term morbidity and mortality in pediatric patients with cystic fibrosis. J Heart Lung Transplant. Feb 2007;26(2):127-31. [Medline].

  24. Faro A, Mallory GB, Visner GA, Elidemir O, Mogayzel PJ Jr, Danziger-Isakov L. American Society of Transplantation executive summary on pediatric lung transplantation. Am J Transplant. Feb 2007;7(2):285-92. [Medline].

  25. Faro A, Visner G. The use of multiple transbronchial biopsies as the standard approach to evaluate lung allograft rejection. Pediatr Transplant. Aug 2004;8(4):322-8. [Medline].

  26. Garrity ER Jr, Villanueva J, Bhorade SM. Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody. Transplantation. Mar 27 2001;71(6):773-7. [Medline].

  27. Glanville AR, Estenne M. Indications, patient selection and timing of referral for lung transplantation. Eur Respir J. Nov 2003;22(5):845-52. [Medline].

  28. Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review. J Am Soc Nephrol. Jun 1999;10(6):1366-80. [Medline].

  29. Hadjiliadis D, Steele MP, Chaparro C, Singer LG, Waddell TK, Hutcheon MA. Survival of lung transplant patients with cystic fibrosis harboring panresistant bacteria other than Burkholderia cepacia, compared with patients harboring sensitive bacteria. J Heart Lung Transplant. Aug 2007;26(8):834-8. [Medline].

  30. Haworth SG. Primary pulmonary hypertension in childhood. Arch Dis Child. Nov 1998;79(5):452-5. [Medline].

  31. Huddleston CB, Sweet SC, Mallory GB. Lung transplantation in very young infants. J Thorac Cardiovasc Surg. Nov 1999;118(5):796-804. [Medline].

  32. Ibrahim JE, Sweet SC, Flippin M. Rejection is reduced in thoracic organ recipients when transplanted in the first year of life. J Heart Lung Transplant. Mar 2002;21(3):311-8. [Medline].

  33. Kaditis AG, Gondor M, Nixon PA. Airway complications following pediatric lung and heart-lung transplantation. Am J Respir Crit Care Med. Jul 2000;162(1):301-9. [Medline].

  34. Kaditis AG, Phadke S, Dickman P. Mortality after pediatric lung transplantation: autopsies vs. clinical impression. Pediatr Pulmonol. May 2004;37(5):413-8. [Medline].

  35. Khalifah AP, Hachem RR, Chakinala MM. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med. Jul 15 2004;170(2):181-7. [Medline].

  36. Khalifah AP, Hachem RR, Chakinala MM, Schechtman KB, Patterson GA, Schuster DP. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med. Jul 15 2004;170(2):181-7. [Medline].

  37. Khalifah AP, Hachem RR, Chakinala MM, Yusen RD, Aloush A, Patterson GA. Minimal acute rejection after lung transplantation: a risk for bronchiolitis obliterans syndrome. Am J Transplant. Aug 2005;5(8):2022-30. [Medline].

  38. Knoop C, Haverich A, Fischer S. Immunosuppressive therapy after human lung transplantation. Eur Respir J. Jan 2004;23(1):159-71. [Medline].

  39. Kroshus TJ, Kshettry VR, Savik K. Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg. Aug 1997;114(2):195-202. [Medline].

  40. Laube BL, Karmazyn YJ, Orens JB, Mogayzel PJ Jr. Albuterol improves impaired mucociliary clearance after lung transplantation. J Heart Lung Transplant. Feb 2007;26(2):138-44. [Medline].

  41. Martinu T, Howell DN, Davis RD, Steele MP, Palmer SM. Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary retransplant recipients. Chest. Apr 2006;129(4):1016-23. [Medline].

  42. Meyer DM, Bennett LE, Novick RJ. Effect of donor age and ischemic time on intermediate survival and morbidity after lung transplantation. Chest. Nov 2000;118(5):1255-62. [Medline].

  43. Nevins TE. Non-compliance and its management in teenagers. Pediatr Transplant. Dec 2002;6(6):475-9. [Medline].

  44. Nogee LM. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu Rev Physiol. 2004;66:601-23. [Medline].

  45. Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. Jul 2006;25(7):745-55. [Medline].

  46. Pierre AF, Sekine Y, Hutcheon MA. Marginal donor lungs: a reassessment. J Thorac Cardiovasc Surg. Mar 2002;123(3):421-7; discussion, 427-8. [Medline].

  47. Reams BD, Musselwhite LW, Zaas DW, Steele MP, Garantziotis S, Eu PC. Alemtuzumab in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation. Am J Transplant. Dec 2007;7(12):2802-8. [Medline].

  48. Schubert M, Venkataramanan R, Holt DW. Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients. Am J Transplant. May 2004;4(5):767-73. [Medline].

  49. Sharples LD, McNeil K, Stewart S. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant. Feb 2002;21(2):271-81. [Medline].

  50. Sweet SC. Pediatric living donor lobar lung transplantation. Pediatr Transplant. Nov 2006;10(7):861-8. [Medline].

  51. Sweet SC. Pediatric lung transplantation: update 2003. Pediatr Clin North Am. Dec 2003;50(6):1393-417, ix. [Medline].

  52. Sweet SC, Faro A. Not so fast--don't deprive children with cystic fibrosis of the option for lung transplantation. Am J Respir Crit Care Med. Jan 15 2006;173(2):246-7; author reply 247-8. [Medline].

  53. Trulock EP. Lung transplantation. Am J Respir Crit Care Med. Mar 1997;155(3):789-818. [Medline].

  54. Waltz DA, Boucek MM, Edwards LB, Keck BM, Trulock EP, Taylor DO. Registry of the International Society for Heart and Lung Transplantation: ninth official pediatric lung and heart-lung transplantation report--2006. J Heart Lung Transplant. Aug 2006;25(8):904-11. [Medline].

  55. Wells A, Faro A. Special considerations in pediatric lung transplantation. Semin Respir Crit Care Med. Oct 2006;27(5):552-60. [Medline].

  56. Woo MS, MacLaughlin EF, Horn MV. Bronchiolitis obliterans is not the primary cause of death in pediatric living donor lobar lung transplant recipients. J Heart Lung Transplant. May 2001;20(5):491-6. [Medline].

  57. Yu AD, Garrity ER. Lung transplantation: recipient selection. Chest Surg Clin N Am. Aug 2003;13(3):405-28, v. [Medline].

  58. Zuckermann A, Reichenspurner H, Birsan T. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg. Apr 2003;125(4):891-900. [Medline].

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Further Reading

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Keywords

lung transplantation, lung transplant, lobar transplantation, living related donation, living-donor lung transplant, deceased donor lung transplant, heart-lung transplant, lung disease, end-stage lung disease, congenital lung disease, primary pulmonary hypertension, cystic fibrosis, CF, chronic lung disease, bronchiolitis obliterans, BO, congenital cardiac disease, pulmonary fibrosis, congenital heart disease, CHD, surfactant abnormalities, idiopathic pulmonary hypertension, idiopathic pulmonary hypertension, IPH, respiratory insufficiency, respiratory failure, syncope, diabetes mellitus, cor pulmonale, congenital alveolar proteinosis, pleurodesis

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Contributor Information and Disclosures

Author

Albert Faro, MD, Assistant Professor, Department of Pediatrics, Division of Allergy and Pulmonary Medicine, Washington University School of Medicine
Albert Faro, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Transplantation, and International Society for Heart and Lung Transplantation
Disclosure: Nothing to disclose.

Coauthor(s)

Gary A Visner, DO, Chief, Division of Pediatric Pulmonology, Associate Professor, Department of Pediatrics, University of Florida College of Medicine
Gary A Visner, DO is a member of the following medical societies: International Society for Heart and Lung Transplantation
Disclosure: Nothing to disclose.

Medical Editor

Richard G Ohye, MD, Director, Pediatric Cardiac Transplantation, Fellowship Program Director, Pediatric Cardiac Surgery, Assistant Professor, Department of Surgery, Section of Cardiac Surgery, University of Michigan Medical Center
Richard G Ohye, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Chest Physicians, American College of Surgeons, Association for Academic Surgery, International Society for Heart and Lung Transplantation, and Society of Thoracic Surgeons
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Brian F Gilchrist, MD, Chief, Division of Pediatric Surgery, Tufts-New England Medical Center; Associate Professor, Department of Surgery, Tufts University School of Medicine
Disclosure: Nothing to disclose.

CME Editor

Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center
Ron Shapiro, MD is a member of the following medical societies: American College of Surgeons, American Society of Transplant Surgeons, Association for Academic Surgery, Central Surgical Association, and Society of University Surgeons
Disclosure: Astellas Honoraria Speaking and teaching; Brystol Meyer Squibb StemCell Data Monitoring Committee Consulting fee Review panel membership

Chief Editor

Mary C Mancini, MD, PhD, Director of Cardiothoracic Transplantation, Professor, Department of Surgery, Louisiana State University Health Sciences Center
Mary C Mancini, MD, PhD is a member of the following medical societies: American Heart Association, American Medical Association, American Thoracic Society, Association for Academic Surgery, Association for Surgical Education, International College of Surgeons, International Society for Heart and Lung Transplantation, New York Academy of Sciences, Phi Beta Kappa, and Southern Thoracic Surgical Association
Disclosure: Nothing to disclose.

 
 
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