What every pediatrician needs to know about lung transplants in children

By Albert Faro, MD

Despite some formidable obstacles, lung transplantation has become an accepted treatment for children with end-stage lung disease caused by conditions such as cystic fibrosis. Do you have a patient who could benefit?

From its very modest beginnings pediatric lung transplantation has matured into an accepted therapeutic option for many children with medical conditions that result in end-stage lung disease. Between 1987 and 1998, 900 pediatric lung and heart-lung transplants were performed in the United States with 93 in 1998 alone.¹

As lung transplantation moves into the medical mainstream, pediatricians need to understand which patients can benefit from the procedure and what it involves. This brief overview discusses the indications for lung transplantation, the appropriate timing of referral, the evaluation process, the surgery and postoperative management, immunosuppression, the potential complications of lung transplantation, and its successes and failures in children.

Who is a suitable candidate?

Decisions as to who would and would not benefit from lung transplantation are based on many factors. They include past experiences (both center-specific and published reports), the scarcity of donor organs, and specific patient and parent wishes. The list of indications for lung transplantation (Table 1) has expanded to the point where virtually any child with limited life expectancy because of lung disease should be considered for referral to a transplant center. In children older than 1 year of age, cystic fibrosis (CF) is the most common indication for lung transplantation. In infants under 1 year of age, the most common reasons for transplant are congenital disorders and primary pulmonary hypertension.¹

TABLE 1
Indications for pediatric lung transplantation

Despite efforts to publicize how precious a gift organ donation is, donor organs remain scarce. The waiting period for cadaver lung transplant continues to lengthen. In 1988, 274 adults and children were waiting for lung or heart-lung transplant in the US. In 1998, the waiting list had grown to 3,422 patients, an almost 13-fold increase. The donor pool, however, has remained fairly static since 1993 at around 800 donations a year.² The arithmetic only makes sense if you add one additional variable, the patients who die on the waiting list. That number has increased almost sevenfold since 1988.

The small community of transplant physicians has a responsibility to all potential transplant recipients to ensure that patients with the best chance at long-term survival after transplantation are not dying on the list. The United Network for Organ Sharing (UNOS) has declared donated organs "a national resource to be used for the public good."³ It is thus vital to evaluate all potential recipients to make sure they do not have a contraindication that will limit their capacity to do well after transplantation.

The list of contraindications to transplantation (Table 2) varies from center to center, and what is an absolute contraindication at one site may only be a relative contraindication at another. Moreover, the list is not static. It changes over time with the introduction of new techniques or therapies.

TABLE 2
Contraindications to lung transplantation

When should a child be referred for evaluation?

The question of when to refer a child for transplant evaluation is not as easily answered as it might first appear. Kerem and colleagues set out to determine whether certain risk factors could predict which patients with CF were likely to die of respiratory failure within one or two years after being studied.⁴ They documented three factors that predicted 50% mortality at two years:

• a forced expiratory volume in one second (FEV₁) of less than 30% predicted,

• a partial pressure of arterial oxygen of less than 55 mm Hg, or

• a partial pressure of arterial carbon dioxide greater than 50 mm Hg.

For any given FEV₁, the risk of death was greater for younger patients. In addition, for any given FEV₁, the risk of death was greater for girls with CF than for boys.

More recent studies suggest that CF patients with an FEV₁ of less than 30% predicted may have median survivals of 4.6 years with 25% living more than nine years.⁵ Thus, lung function, in itself, is not a useful measure for determining the need for lung transplant. At our center we consider many factors to decide whether or not a patient should be listed for transplantation. These include lung function, rate of decline of lung function, age, sex, nutritional status, emergence of more resistant organisms, increasing rate of hospitalizations or courses of antibiotic therapy, quality of life, and, in children with pulmonary vascular disease, pulmonary artery pressures and cardiac index. Pulmonary artery pressures greater than 60 mm HG or a cardiac index less than 2 L/min/m² would be potential indications for transplant.

So, what is a clinician to do? I believe that a patient whose FEV₁ is less than 30% predicted or whose quality of life is severely impaired should be referred for evaluation. He or she may not need to receive a transplant at that point or even to be placed on the waiting list, but an evaluation by a transplant center is reasonable.

What happens during evaluation and why?

The pretransplant assessment (Table 3), like post-transplant care, is a multidisciplinary team effort. At our center, patients meet with the transplant pulmonologist; a transplant social worker; a psychiatrist or child development specialist, depending on the child's age; a nutritionist; and the transplant coordinator. Other consultations—such as cardiology, immunology, and otolaryngology—may be obtained as deemed appropriate. Laboratory tests include blood typing, serologies, renal and liver function panels, and sputum cultures. Radiographic studies include a CT scan of the chest and, in patients with CF, the sinuses, which are often diseased in such patients and may harbor infectious organisms that could compromise the transplant.

TABLE 3
Minimum pretransplant evaluation

The transplant evaluation provides an opportunity to accomplish many important objectives. Occasionally, a patient is referred to our center with end-stage lung disease of unclear etiology. We aggressively seek out the diagnosis to ascertain whether lung transplant is truly the best treatment option for that patient. Once we have completed the evaluation, we can discuss frankly the patient's prognosis and how transplantation is likely to modify that prognosis. This allows the patient and family an opportunity to discuss issues that are often too difficult or painful to talk about routinely.

The evaluation process enables us to identify problems that are not amenable to transplantation, such as the contraindications listed in Table 2, and to provide patients who are found to be suitable candidates for transplant with a plan to optimize their pretransplant care. It also helps the surgical team to decide how they will approach the patient. This is vital as we prefer to keep the period of ischemia during surgery to less than four hours to minimize the risk of ischemia-reperfusion injury. Finally, the transplant evaluation gives the patient and family an opportunity to get answers to their questions and learn exactly what they are committing to when they agree to proceed with transplantation.

The patient is listed for transplant. Now what?

In 1984 the federal government recognized a need for a national organ sharing system and UNOS won the contract. UNOS is a private, nonprofit organization that helps match donors and recipients. It also collects and stores data concerning transplantation. The US is divided into 11 geographic regions, and organs tend to be allocated within regions first. For lung transplant, three factors are prominent in determining who on the waiting list gets a lung when one becomes available. Foremost is time spent on the list. The severity of illness is not taken into account. Unlike candidates for heart or liver transplantation, being in an intensive care unit or on ionotropes does not move a patient higher on the list. The highest person on the lung transplant waiting list is the one who has accrued the most waiting time. In addition, potential recipients are matched with the donor for blood type and size, so that the person with the longest time on the list and a blood type and size that match the donor's is the one who receives a particular organ.

What type of surgery is done?

The two major types of lung transplant are heart-lung transplant and sequential double lung transplant. Most lung transplants in the US are sequential transplants. Some transplant centers, specifically in the United Kingdom, prefer to perform heart-lung transplantation because it involves fewer anastamoses. In this type of transplant, the recipient's heart, if normal, is "dominoed" into another patient requiring only a heart transplant. Sequential double lung transplant has the advantage of potentially avoiding cardiopulmonary bypass and the increased risk of bleeding and infection that is associated with it.

In a sequential double lung transplant the surgeon performs a transverse thoracosternotomy, which allows excellent visualization of the pleural space. The surgeon then replaces the patient's least functional lung, as determined during the pretransplant evaluation, while the contralateral lung provides uninterrupted ventilation. The bronchus, pulmonary artery, and pulmonary vein anastamoses are performed in that order. The surgeon then replaces the second lung. The bronchial circulation, lymphatic system, and nervous system are not reanastamosed because of the difficulty of reattaching lymphatic vessels and nerves and because the risk involved in prolonging the procedure is not worth the benefit of reestablishing bronchial circulation since the lung has a dual blood supply. Two chest tubes are placed in each pleural space and the chest is closed. A bronchoscopy is performed in the operating room to visualize the airway anastamoses. The patient is then transferred to the intensive care unit.

For patients with aseptic lung disease, single lung transplantation is an alternative. This procedure may allow one donor's gift to benefit two patients in need of a lung transplant. The surgery itself is similar to the sequential bilateral procedure except that only one lung is replaced.

Transplantation of lungs from living donors, related or unrelated to the patient, is growing in popularity. The procedure allows a friend or family member with a compatible blood type to donate a lower lobe of the lung. One donor gives a right lower lobe and another a left lower lobe. Since the lower lobes of the lungs are the largest, the recipient can lead a functional and fulfilling life after transplant with only one lobe of each lung. Donating a single lobe of one lung will not adversely affect the donors' functional capabilities, unless they are Olympic aspirants.

Using lungs from living donors offers several advantages over cadaver donation. Most notably, it changes lung transplant surgery from an emergent, any-hour-of-the-day-or-night procedure to an elective one. The surgery can be scheduled at a time best suited to the requirements of the recipient, donors, and transplant team. Since the donated lobes have not been exposed to the cardiovascular changes that occur during brain death, they are theoretically at less risk of developing ischemia-reperfusion injury. Ischemia is obviously less prolonged when organs are transported across the hall rather than across state lines, which also minimizes the risk of ischemia-reperfusion injury. Finally, living related donation provides one way of addressing the donor organ shortage, circumventing the long waiting times commonly experienced by listed patients.

A potential problem with donation by living relatives of the patient is the risk to the donors and the family unit. It is possible for three members of the same family to be undergoing thoracic surgery at the same time. The reported complications to donors thus far have been minimal, however.⁶

What about immunosuppressants?

In recent years the number of available immunosuppressive agents has exploded. This growth allows more choices in tailoring an appropriate immunosuppressive regimen for the individual patient but also fosters confusion about the appropriate roles for these potent drugs. The easiest way to approach this subject is to group the drugs into categories. Table 4 lists currently available immunosuppressants by category along with their mechanisms of action and potential side effects.

TABLE 4
Immunosuppressant drugs

The calcineurin inhibitors, cyclosporine and tacrolimus (FK 506), even with their limitations (many possible drug interactions and side effects), are the mainstay of immunosuppression and are responsible for the success of transplantation. They must never be used concurrently, however, because they act synergistically to cause nephrotoxicity. Tacrolimus is a more potent agent and seems to decrease the risk of developing bronchiolitis obliterans or chronic rejection.⁷ The incidence of acute rejection in lung transplantation, however, appears to be the same whether the patient receives cyclosporine- or tacrolimus-based immunosuppression.⁷ The choice of one agent over the other probably depends most on a transplant center's experience with that particular drug.

The number of potential drug interactions for both immunosuppressants is vast. Table 5 lists drugs that increase or decrease blood levels of cyclosporine or tacrolimus when given concomitantly. In addition, patients receiving either cyclosporine or tacrolimus should not take nonsteroidal anti-inflammatory agents such as ibuprofen because NSAIDs potentiate nephrotoxicity. The take-home message here is that the physician should not add medications to or subtract them from a patient's regimen without being aware of their impact on cyclosporine or tacrolimus levels (which are monitored at regular intervals).

TABLE 5
Cyclosporine or tacrolimus drug and food interactions

Cell toxins. This category of immunosuppressants includes azathioprine and mycophenolate mofetil (MMF). MMF theoretically should not affect other cell lines to the same extent as azathioprine, which inhibits proliferation of white blood cells and can cause bone marrow suppression. Extensive trials in lung transplant recipients comparing MMF to azathioprine are lacking.⁸

Corticosteroids interfere with several different steps in the inflammatory cascade. Classic triple-drug immunosuppression in lung transplantation has consisted of cyclosporine, azathioprine, and prednisolone. Because the lung is such a difficult organ to camouflage from the immune system, one- or two-drug immunosuppression rarely succeeds (in marked contrast to other solid organ transplants). With the introduction of tacrolimus and then MMF, the classic triad has been modified so that for many the definition of triple-drug immunosuppression means the use of any agent from each of the three categories.

Interleukin (IL)-2 receptor antagonists have just been introduced during the past two years. They are monoclonal antibodies that specifically bind to the IL-2 receptor on activated T cells. IL-2 is the major autocrine growth factor for T cells and is necessary for the viability of the activated cell.⁹

Studies of IL-2 receptor antagonists have so far focused on their use during the early post-transplant induction period. In renal transplant patients, these agents reduce the frequency of acute rejection.¹⁰ The selective immunosuppression they afford has the advantage of minimizing potential adverse effects or "collateral damage" to other arms of the patient's immune system. The immune response is a redundant one, however, with many potential pathways. Thus "sniper"-type agents are unlikely to successfully ward off an attacking army of inflammatory cells that may consist of infantry, mobile armor, battleships, and stealth fighters.

IL-2 receptor antagonists may have a vital role to play when used with other more universally immunosuppressive drugs. They may provide added efficacy in preventing rejection or allow a decrease in the dose of other immunosuppressants, reducing the likelihood of adverse effects. I suspect that over time we will see more of these types of drugs, and perhaps one day we will be able to tailor a regimen of immunosuppressants made up only of an array of such "smart bombs."

Lympholytic agents include rabbit anti-thymocyte globulin (RATG), muromonab-CD3 (OKT3), and equine antithymocyte globulin (ATGAM). This group of potent immunosuppressants induces opsonization and phagocytosis of T lymphocytes. They also modulate T cell activation. Some transplant centers use them during the induction period. This is rarely done in pediatric lung transplantation, however, because of the increased risk of infection. Lympholytics are most commonly used in cases of persistent acute rejection that do not respond to high-dose corticosteroid therapy. The adverse effects include cytokine release syndrome (consisting of chills, fever, vomiting, diarrhea, and headache), increased incidence of infection, increased risk of post-transplant lymphoproliferative disorder (PTLD), and leukopenia.

Sirolimus is the newest immunosuppressant available. Although it binds to the FK binding protein, like tacrolimus, it does not inhibit calcineurin. Because it works by a different mechanism, it can be used in conjunction with either cyclosporin or tacrolimus. Studies in renal transplant patients have shown that it effectively reduces the incidence of rejection when used with cyclosporine.¹¹ Randomized controlled trials of sirolimus in lung transplantation are only now getting underway.

What complications can occur?

Many complications can follow lung transplantation, and their likelihood can be mapped out on a timeline (Figure 1). I will not discuss complications that can occur in the early postoperative period (and are thus likely to be managed only by transplant specialists), such as ischemia-reperfusion injury, hyperacute rejection, and airway dehiscence. The complications that pediatricians are most likely to see when caring for children who have received lung transplants relate to either infection or rejection.

Acutely ill lung transplant patients often pose a challenging diagnostic dilemma. They may present with cough, dyspnea, fever, crackles on auscultation, infiltrates on chest X-ray, or decreasing lung function or hypoxia. The vexing problem is that these findings are consistent with either infection or rejection. Moreover, even if you could diagnose infection based solely on clinical signs and symptoms, how do you decide on the causative organism?

The importance of differentiating between rejection and infection is highlighted by the contrasting therapies necessary to achieve a satisfactory outcome. The appropriate management for rejection is to augment immunosuppression. If the patient is infected and not rejecting, however, the decision to augment immunosuppression could prove fatal. Treating with the wrong antimicrobial agent could prove just as costly. On the other hand, delaying therapy for acute rejection could lead to loss of the graft. The only way to make a diagnosis with confidence is to perform a bronchoalveolar lavage and a transbronchial biopsy.

Bronchiolitis obliterans, believed to be the equivalent of chronic rejection, limits the potential for long-term success after lung transplantation. Risk factors for the development of bronchiolitis obliterans include three or more episodes of acute rejection, one episode of severe acute rejection, or cytomegalovirus disease. Brochiolitis obliterans typically presents as progressive graft dysfunction, which can occur insidiously or acutely. The diagnosis can be elusive. The physical exam may be unremarkable and the chest X-ray is usually normal. High resolution CT scan of the chest may be helpful, demonstrating bronchiectasis, decreased vascular markings, and air trapping. Transbronchial biopsy has, at best, a sensitivity of 59%.¹² Thus the diagnosis of bronchiolitis obliterans syndrome is often based solely on a patient's pulmonary function and the exclusion of other diagnoses such as infection or acute rejection. Five-year survival after diagnosis is approximately 50%.¹³ Good therapeutic options are lacking.

What is the likely outcome?

One-year survival after lung transplantation has improved significantly since 1995, to 80%.¹ Three-year survival after transplant now approximates 65%, which is what the one-year survival was for patients who received transplants between 1992 and 1994. The most common causes of death in the early post-transplant period (fewer than 30 days) are graft failure, infection, and hemorrhage. In the later post-transplant period, bronchiolitis obliterans and infection are the most common reasons for death.¹

Approximately 80% of survivors will have no physical limitations one year after transplant.¹ Many studies indicate that the patient's quality of life is markedly improved.^14,15 Eventually, however, half of all survivors will develop bronchiolitis obliterans.¹³

What does the future hold?

Lung transplantation is a suitable alternative for patients with end-stage lung disease, but it is not a cure. Transplantation, rather, is a trade that by its very nature implies lifelong medical management. Patients trade their end-stage lung disease for transplant lung disease in the hopes that it can be better managed. For the right patient and family, transplant can be a second chance at life. Survival statistics have improved dramatically over the past 15 years with one-year survival rates almost doubling in recipients with CF. A variety of imposing obstacles keeps us from obtaining the long-term results we seek, however.

Rejection and specifically bronchiolitis obliterans remain major hurdles to overcome. The development of better immunosuppressants or, better yet, agents that will allow for immunotolerance would certainly improve clinical outcomes and might reduce the risk of infection. A better understanding of the mechanism of lung injury during brain death and during transition from donor to recipient may one day lead to techniques and preservative solutions that will prevent ischemia-reperfusion injury.

Finally, we must address the organ donor shortage. Too many patients die on the waiting list, and xenotransplantation is not yet the answer. The number of annual organ donations has not changed significantly since 1993. Clearly, the words "become an organ donor" either are not reaching enough people or are falling on deaf ears. As health-care professionals it is our responsibility to our patients to get the word out. I urge each of you to discuss this issue with your patients, as well as, family and friends. As it is written in the Jewish Talmud "He who saves one life, saves the world entire." Organ donation gives each of us the opportunity to save the world.

Acknowledgment: The author would like to thank James Sherman, MD, and Gary Visner, MD, for their assistance in reviewing this manuscript.

REFERENCES

1. Boucek MM, Faro A, Novick RJ, et al: The registry of the International Society of Heart and Lung Transplantation: Third official pediatric report—1999. J Heart Lung Transplant 1999;18:1151

2. United Network for Organ Sharing Registry

3. Task Force on Organ Transplantation, Department of Health and Human Services: Patient access to and payment for organ transplantation, in Report of the Task Force on Organ Transplantation. Washington, DC, Department of Health and Human Services, 1986

4. Kerem E, Reisman J, Corey M, et al: Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992;326:1187

5. Doershuk CF, Stern RC: Timing of referral for lung transplantation for cystic fibrosis: Overemphasis on FEV₁ may adversely affect overall survival. Chest 1999; 115(3):782

6. Woo MS, MacLaughlin EF, Horn MV, et al: Living donor lobar lung transplantation: The pediatric experience. Pediatr Transplant 1998;2(3):185

7. Keenan RJ, Konishi H, Kawai A, et al: Clinical trial of tacrolimus vs. cyclosporine in lung transplantation. Ann Thorac Surg 1995;60:580

8. Zuckerman A, Klepetko W, Birsan T, et al: Comparison between mycophenolate mofetil and azathioprine-based immunosuppressions in clinical lung transplantation. J Heart Lung Transplant 1999:18(5):432

9. Abbas AK, Lichtman AH, Pober JS: Cytokines, in Cellular and Molecular Immunology, ed 3. Philadelphia, WB Saunders, 1997, p 266

10. Vincenti F, Kirkman R, Light S, et al: Interleukin-2 receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 1998; 338(3):161

11. Kahan BD, Podbielski J, Napoli KL, et al: Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998;66(8):1040

12. Trulock EP: Lung transplantation. Am J Respir Crit Care Med 1997;155:789

13. Reichenspurner H, Girgis RE, Robbins RC, et al: Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg 1996; 62:1467

14. Gross CR, Savik K, Morton Bolman R, et al: Long-term health status and quality of life outcomes of lung transplant recipients. Chest 1995;108:1587

15. Ramsey SD, Patrick DL, Lewis S, et al: Improvement in quality of life after lung transplantation: A preliminary study. J Heart Lung Transplant 1995;14:870

THE AUTHOR is Clinical Assistant Professor of Pediatrics and Assistant Director of the Pediatric Lung Transplant Program, Pediatric Pulmonary Center, University of Florida, Gainesville.

Albert Faro. What every pediatrician needs to know about lung transplants in children.

Contemporary Pediatrics

2000;8:61.