Improvements in nutrition, antimicrobial therapy, and strategies for airway clearance have extended the life expectancy and improved the quality of life for patients of all ages with cystic fibrosis (CF).1 This disease remains lethal, however, with life expectancy now at 30 years of age in the United States. The most common cause of death is respiratory failure because of progressive bronchiectasis with gram-negative bacteria1 (a particular and somewhat unusual subset of the bacteria that cause lower respiratory infections.)

By 1998, nearly 1,000 CF patients worldwide with end-stage lung disease had undergone either heart-lung transplantation or bilateral sequential lung transplantation, with survival rates comparable to those of transplant recipients with other underlying diseases.2 Surgical techniques have advanced considerably since 1983, when the first CF recipient underwent heart-lung transplantation in Pittsburgh. Bilateral sequential lung transplantation has become the surgical procedure of choice in most centers worldwide because of its technical feasibility and the limited availability of heart-lung blocs.3,4 The living-donor lobar lung transplantation technique pioneered by Starnes5 in the early 1990s has become an alternative to bilateral sequential lung transplantation in selected patients in some transplantation centers.

Indications and Contraindications
The indication for lung transplantation is the same in the CF candidate as in other patients: progressive lung disease with both a poor quality of life and a low likelihood of survival beyond the time that donor organs are expected to be available.2 Markers of severity of CF-associated lung disease that have proven useful in the timing of referral for lung transplantation include an increased frequency of pulmonary exacerbations requiring intravenous antibiotic therapy, progressive weight loss in adults or failure to grow in children, an increasingly antibiotic-resistant microbial profile in respiratory cultures, worsening gas exchange with oxygen dependence and/or hypercapnia, and a forced expiratory volume in 1 second of less than 30 percent of the predicted value.

Although a consensus conference on lung transplantation for patients with CF2 has developed criteria for indications and contraindications, there are significant differences in approach to the contraindications to lung transplantation for CF among transplantation centers worldwide. Many centers will not accept a patient for referral who is in frank respiratory failure, and many centers are now either wary of or likely to turn down potential recipients with Burkholderia cepacia as their predominant respiratory pathogen. There are broad differences in approach to patients with malnutrition, associated liver disease, cortico-steroid dependence, or fungal or non- tuberculous mycobacterial infections.

Pretransplantation Care
Because of success in lung transplantation and the relatively delicate status of the lungs in brain-dead potential donors, a serious organ shortage has developed in virtually every nation where organ transplantation is performed. Waiting times range from 6 months to almost 3 years, depending on geographic location, the transplantation center, and the age, size, and blood type of the CF patient. The mortality of CF patients on the waiting list varies from less than 5 percent to 50 percent worldwide.2 At St Louis Children’s Hospital, where 67 CF patients aged less than 21 years have undergone lung transplantation since 1991, mortality on the waiting list recently exceeded 10 percent for the first time.

After referral and listing for transplantation, pretransplantation care issues become complex and crucial. Close communication between the referring CF center and the transplantation program is of great importance during this time. Augmentation of nutritional support and physical rehabilitation is often clinically indicated and recommended. At St Louis Children’s Hospital, modification reduction of corticosteroid therapy, if prescribed, is recommended during this period as well. Changes in antimicrobial resistance patterns and trends in gas exchange are critically important to note during this period, especially if the living-donor lobar lung transplantation option is possible. Return visits to the transplantation center are scheduled every 6 months during the waiting period, and relocation is recommended when the candidate’s name nears the top of our recipient list. After relocation to St Louis, the patient is seen weekly at the transplantation clinic and physical rehabilitation is accelerated. If sinus surgery is clinically indicated, the patient is referred to otolaryngologists during this period.

Surgery and Recovery
The time of transplantation is one of high drama after a long, uncertain wait. The transplantation surgery usually lasts 4 to 6 hours. Operative mortality in most centers is extremely low (less than 5 percent).2 Issues of pleural adhesions, hemorrhage, cardiopulmonary bypass, and size matching are easier to deal with if the surgeon is experienced in lung transplantation and has a gift for situational problem-solving.

At first, the postoperative period is one of clinical stabilization, continuation of aggressive antimicrobial therapy, and initiation of analgesia, sedation, and immunosuppressant medication. Most centers continue to use the standard combination of cyclosporine, azathioprine, and cortico-steroids for short-term and long-term immunosuppression. Some centers have begun to use tacrolimus in lieu of cyclosporine and mycophenolate mofetil instead of azathioprine.

Clinical recovery depends on several factors, including the extent of injury to the engrafted lungs from reperfusion, the underlying nutritional and physical condition of the patient, the presence of early infection within the graft, and the vigor of respiratory drive. Extubation typically takes place within 48 hours in uncomplicated cases and older patients, but prolonged intubation and mechanical ventilation within the intensive care unit may be required for patients with complications. More than 90 percent of patients are successfully extubated and discharged without supplemental oxygen at St Louis Children’s Hospital and the affiliated lung transplant program at Barnes-Jewish Hospital also in St Louis. The median hospital stay at the St Louis Children’s Hospital is 2 to 3 weeks after surgery (with a small but significant group of outliers). During this initial hospitalization, teamwork among the surgeon, transplantation pulmonologist, intensivists, and other members of the transplantation team is critically important.

Living-Donor Lobar Transplantation
Because of the high mortality rate among CF patients waiting for transplantation and the success of living-donor use in kidney and, more recently, liver transplantation, the living-donor lobar lung transplantation technique was developed in the early 1990s. CF has been the underlying disease in the vast majority of recipients of living-donor lobes. In this scenario, a patient with progressive disease and a low likelihood of surviving until cadaveric organs become available is evaluated and must meet the usual criteria for lung transplantation.

Two donors with nearly perfect physical and mental health, and whose motives are judged by an independent psychologist to be altruistic and uncoerced, are selected. At the time of surgery, three thoracic surgeons in three operating rooms work simultaneously. The transplantation surgeon performs the usual dissection of the recipient’s native lungs and isolates the bronchi and vessels at the sites intended for anastomoses. The harvesting surgeons perform thoracotomies, isolate a lower lobe from each of the two donors, and await communication for the timing of harvest. Ischemic time can usually be limited to approximately 1 hour, which decreases the chance of reperfusion injury in the donated lobes. Ideally, the donors will be taller and have larger lung volumes than the recipient so the resultant lung volumes and anastomotic caliber of bronchi and vessels will cause only minimal problems.

The details of coordination, the need for precise collaboration, and the surgical skills required are daunting. As a result, despite relatively encouraging results published by Starnes,6 few transplantation centers have embraced living-donor lobar lung transplantation. To the author’s knowledge, only two centers have performed 10 or more of these procedures, of which St Louis Children’s Hospital is one.

The challenges faced after transplantation are considerable. Major areas of concern are recovery, infection, graft rejection, and return to a near-normal lifestyle. Recovery depends on both graft function and recipient factors (physical, mental, and spiritual). Compulsive monitoring of graft function, overall physiological function of the patient, and complications fill the days and weeks after transplantation.

For the RCP caring for these patients, several features must be dealt with.7 The surgical (clamshell) incision is broad and complicates the usual techniques for chest physiotherapy, necessitating the use of methods adapted to the unique needs and tolerance of each individual. Thoracostomy tubes are often left in place for many days after surgery, since the surgery requires the severing of lymphatic channels that normally play an important role in handling the flow of fluid across the pleural space. Bronchial denervation results in a permanent loss of afferent neural input from the distal airway, and the cough reflex is consequently attenuated. Patients need to learn new techniques for the detection and clearance of lower-airway mucus secretions. Bronchial anastomotic narrowing, although avoided in the majority of recipients through the use of current surgical techniques, further complicates mucus clearance in some individuals. Hemidiaphragm paralysis occurs in approximately 15 percent to 20 percent of our recipients and predisposes patients to atelectasis and poor mucus clearance. Fortunately, in the majority of these cases, the phrenic-nerve injury is ischemic and function recovers within the first months after transplantation.

Infection of the transplanted lungs is a particular concern in CF patients for at least two reasons.8 Virtually all lung transplant recipients with CF have aggressive gram-negative microorganisms, most commonly Pseudomonas aeruginosa, in their native airways. These organisms often develop a high level of resistance to commonly administered antibiotics. The remaining trachea and upper respiratory tract, notably the paranasal sinuses, continue to have CF within the local environment. This fosters attachment and survival of these organisms after transplantation. The proximity of these organisms, the likelihood of aspiration of pharyngeal secretions during sleep in many (if not all) individuals, the defective cough mechanism, and the lifelong use of immunosuppressant medication make the CF lung transplant recipient a candidate for serious lower respiratory infections in the future.

Our practice has been known to use intravenous antipseudomonal antibiotics immediately after transplantation. Specific agents are chosen on the basis of careful antibiotic sensitivity testing of the patient’s own microbial flora. After successful extubation (and, often, after bronchoscopic inspection of the bronchial anastomoses and bronchoalveolar lavage cultures), the intravenous antibiotics are discontinued in favor of aerosolized tobramycin or colistin depending on the antibiotic profile of the organisms. The inhaled antibiotics are continued for the first few weeks and are reintroduced as indicated later, often during intercurrent viral respiratory infections. We have a high index of suspicion for bacterial lower-respiratory infection and a low threshold for the use of flexible fiberoptic bronchoscopy in these patients.

Various viral infections pose additional threats to lung transplant recipients with CF. Community-acquired respiratory viruses can produce serious infection, most notably respiratory syncytial virus, parainfluenza virus, influenzas A and B, and adenovirus. We have had two CF lung transplant recipients die of early onset adenovirus pneumonia. With antiviral therapies increasingly available, a high index of suspicion and early diagnosis and treatment are critically important. In addition, the herpes-family viruses pose problems for lung transplant recipients. This family, which includes herpes simplex, varicella, cytomegalovirus (CMV), and Epstein-Barr virus (EBV), has “immortality” in common: after primary infection, the virus remains in the host, in latent form, with the potential for reactivation. CMV has been known for decades as an especially severe pathogen in organ transplantation patients. Fortunately, ganciclovir, foscarnet, and hyperimmune globulin have provided the therapeutic tools to minimize morbidity and mortality in the current era. On the other hand, EBV infection, either primary or in reactivation, is strongly correlated with the development of posttransplantation lymphoproliferative disease, an often-lethal complication that is difficult to prevent or treat.

Graft rejection has been described in two forms: acute vascular rejection and chronic airway rejection. Acute vascular rejection is common in the first weeks and months after transplantation and is usually heralded by a change in the patient’s clinical examinations or objective measures of respiratory health. Signs of acute graft rejection are low-grade fever, bilateral interstitial infiltrates visible on chest radiographs, inspiratory crackles noted on auscultation of the lungs, a drop in lung function, and a modest degree of desaturation detected using pulse oximetry. Because these findings are quite nonspecific, diagnosis by transbronchial biopsy is the practice of most transplantation physicians in most clinical situations.

In these cases, the histopathological findings demonstrate perivascular lymphocytic cuffing in mild rejection, and extension of the lymphocytic inflammation into the interstitium and airways in more severe degrees of rejection. Treatment consists of high-dose systemic cortico-steroid therapy with monitoring for clinical response. Bronchoscopy is routinely repeated, with transbronchial biopsy performed 2 weeks after each course of high-dose corticosteroid therapy. Repeated episodes of acute rejection are the most important risk factor for bronchiolitis obliterans, the histologic picture of chronic rejection. Although we believe that other insults and processes can also lead to bronchiolitis obliterans in these patients, chronic rejection clearly appears to be the leading etiology. Bronchiolitis obliterans is not easily treated and is often relentlessly progressive, although the natural history of progression varies markedly among individuals. The latest and most long-term follow-up study9 suggests that 50 percent or more of survivors of lung or heart-lung transplantation have, 5 years after surgery, bronchiolitis obliterans, as diagnosed using histopathological or clinical criteria. Bronchiolitis obliterans remains the single greatest hurdle faced by patients, families, and transplantation caregivers in their continuing struggle for success.

The purpose of organ transplantation is to restore physiologic function to improve the patient’s quality of life. Organ transplant recipients, provided they survive the early months after surgery, have to live with daily medications, some form of surveillance of their health, and the uncertainty of survival for the remainder of their lives. Some individuals have enough resources, family support, insurance coverage, and intrinsic strength to make the transition back to school or to work without difficulty. Others, because of complications or other factors, have enormous difficulties finding some functional normality. An excellent understanding by the patient and family of the ongoing care issues, an open communication line to the transplantation center, and the availability of caregivers at home who are willing to be educated and participate as important members of the care team for the transplant recipient can contribute to success.

Organ transplantation has come a long way since the 1950s, when the first human kidney transplantation was performed. Although surgical techniques and immunologic understanding of graft rejection have improved dramatically, survival rates and longevity have not yet improved to an acceptable level. For these reasons, research into newer immunosuppressant medications and approaches must continue. It seems reasonable to hope and expect that the enormous investment of societal resources in organ transplantation over the past 50 years, the courage of transplant recipients, and the vision of transplantation physicians and caregivers will be rewarded in the 21st century by improved survival.

George Mallory, Jr, MD, is a pediatric pulmonologist at St Louis Children’s Hospital and associate professor of pediatrics at Washington University School of Medicine, St Louis.

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6. Starnes VA, Barr MI, Schenkel FA, et al. Experience with living donor lobar transplantation for indication other than cystic fibrosis. J Thorac Cardiovasc Surg. 1997;114:917-921.

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9. Hosenpud JD, Bennett LE, Keck BM, et al. Registry of the International Society for Heart and Lung Transplantation: fourteenth official report. J Heart Lung Transplant. 1997;16:691-712.