As research continues and experience grows, lung transplantation survival rates are expected to increase

a04a.jpg (9383 bytes)Prior to the introduction of lung and heart-lung transplantation, patients with certain lung diseases such as end-stage emphysema or cystic fibrosis (CF) had very little hope of deliverance from the suffering associated with these diseases and the insidious decline in lung function that eventually claimed their lives. As this surgical procedure was perfected and as medications that reduce organ rejection and fight infection improved, there was a dramatic effect on the quality of life after transplantation and a decrease in the mortality rates1 associated with these and other lung diseases. Transplantation is not, however, a cure for these diseases; long-term survival is still an elusive goal for the patients and care providers who are pursuing it. Many diagnostic tests and presurgical and postsurgical treatments involve respiratory care, so understanding this medical event is important to the knowledgeable RCP.

Transplantation Surgeries
The surgical procedures for lung transplantation include single-lung transplantation; heart-lung transplantation, involving the total replacement of both lungs plus the heart; sequential double-lung transplantation, in which the surgeon removes and replaces the first lung while the other lung continues to function (after which the second lung is removed and replaced with the other donor lung); and lower-lobe transplantation, in which two living donors each donate a lower lobe to the recipient.

Single-lung transplantation allows one donor to provide a single lung to each of two recipients. Sequential double-lung transplantation permits a donor to provide the lungs to one patient and the heart to another. Since lower-lobe transplantation involves removal of just one lobe, the living donors usually have very little reduction in lung function or exercise tolerance.2 Xenotransplantation (transplantation from one species to another) is considered to be a possibility for the lung in the future, given the chronic shortage of donors and the growing number of possible recipients. Animal-to-human heart-transplantation procedures have been performed, but there has been no animal-to-human transplantation involving the lungs. In December 2000, the International Society for Heart and Lung Transplantation3 (ISHLT) issued guidelines related to animal-to-human organ transplantation, discussing many of the issues surrounding these procedures and the research needed for the future. Another area of research involves keeping donor lungs viable for transplantation once they have been removed from the donor.

Transplantation and disease
Lung transplantation began showing a measure of success in the 1980s, with the procedure for bilateral lung transplantation being introduced in 1988.4 The pool of candidates seeking a transplant has grown considerably. In 1988, there were 274 adults and children on the waiting list for a lung or heart-lung transplant in the United States; by 1998, that list grew to include 3,422 individuals.2 According to the figures released from the United Network for Organ Sharing5 (UNOS), as of March 1, 2002, there were 3,824 patients waiting for lung transplants. UNOS also reported that 956 lung-transplantation procedures were performed in 2000.

There is a chronic shortage of donors, which limits the number of transplantation procedures. For those who have been put on the waiting list, the risk of dying varies according to the type of lung disease. Patients with chronic obstructive pulmonary disease (COPD) who are on the waiting list have the lowest risk of dying, compared with patients with CF, pulmonary fibrosis, or pulmonary hypertension.6 Patient referral for placement on the transplantation waiting list is also linked to the underlying disease; referrals are done using disease-specific criteria to screen for those who have an increased risk of dying. Table 1 summarizes the international guidelines for the selection of lung-transplant candidates. These came from a committee set up by the ISHLT and were released in 1998.1,7

Chronic Obstructive Pulmonary Disease
• Forced expiratory volume in 1 second (FEV1) <25% of predicted value after bronchodilator use
• Clinically significant hypoxemia, hypercapnia, or pulmonary hypertension: rapid decline in lung function or frequent severe exacerbations

Cystic Fibrosis
• FEV1 <30% of predicted value
• FEV1 >30% of predicted value with rapid decline in lung function, frequent severe exacerbations, or progressive weight loss
• Female sex and age <18 years with FEV1 >30% of predicted value

Idiopathic Pulmonary Fibrosis
• Symptomatic disease unresponsive to therapy
• Vital capacity <60% to 70% of predicted value and/or diffusing capacity (corrected for alveolar volume) <50% to 60% of predicted value
• Evidence of resting or exercise-induced hypoxemia

Primary Pulmonary Hypertension
• New York Heart Association (NYHA) functional class III or IV (in category III, the patient shows a marked limitation of physical activity, but is comfortable at rest. In category IV, the patient has an inability to carry on any physical activity without discomfort and may have symptoms even at rest10)
• Mean pulmonary artery pressure >55 mm Hg
• Mean right atrial pressure >15 mm Hg
• Cardiac index <2 L/min per m2
• Failure of medical therapy, especially intravenous epoprostenol, to improve NYHA functional class or hemodynamic indices

Table 1. Disease-specific guidelines for referral for the most common lung- transplantation procedures. Adapted from N Engl J Med6 and Am J Respir Crit Care Med.9

Donor lungs are in short supply for several reasons. First, not many members of the general population have taken action to declare themselves donors. Second, the lung is very fragile and can be damaged before being harvested by too much fluid administration, aspiration, or ventilator-associated pneumonia; pulmonary function may already be compromised by a history of smoking. Because of these problems, only 20% of organ donors have suitable lungs.1 Third, the lung is very susceptible to ischemia and must be transplanted within approximately 6 hours of being harvested. This problem geographically limits the possible recipients of a given donor lung due to time constraints that apply to traveling with the harvested organ.1

Currently, the most common disease that calls for lung transplantation is emphysema (accounting for more than 45% of cases), with CF being the second most common at 15% to 20% of cases. These are followed by pulmonary fibrosis (10% to 15%) and pulmonary hypertension (5%).8 Other diseases that have involved transplantation include primary pulmonary hypertension, congenital heart disease (Eisenmenger syndrome), sarcoidosis, and histiocytosis X.9 The average time that a patient spends on the waiting list before receiving a transplant is 2 years, but there are many patients who do not survive the wait. Unlike patients on waiting lists for heart or liver transplants, who are assigned priority based on severity of illness, lung-transplant candidates are given priority based only on the length of time that they have waited.2

Diagnostic Screening
The international guidelines1,6 recommend using a battery of diagnostic tests to screen potential candidates for referral to the transplantation list. These tests include full pulmonary-function testing; exercise performance measurement using a standardized test such as the 6-minute walk; electrocardiography; echocardiography or pharmacological stress echocardiography for patients at high risk for coronary artery disease; high-resolution CT of the thorax in cases involving parenchymal disease, pleural disease, or previous thoracic surgical procedures; 24-hour creatinine clearance testing; and liver-function studies.

The international guidelines provide information on contraindications for referral to the transplantation waiting list. Absolute contraindications include:

• major organ dysfunction (particularly renal dysfunction, since immunosuppressive drugs tend to have a negative impact on the kidneys);
• HIV infection;
• active malignancy within the previous 2 years (except basal cell and squamous cell carcinoma of the skin, and with certain other tumors carrying a 5-year waiting period);
• a positive test for antigen to hepatitis B;
• hepatitis C with proven liver disease;
• progressive neuromuscular disease.

Relative contraindications include symptomatic osteoporosis (transplantation is linked to bone loss and high fracture rates, despite efforts to prevent osteoporosis); severe musculoskeletal disease such as kyphoscoliosis; weight that remains at a level of less than 70% or more than 130% of ideal body weight; and addictive behavior involving alcohol, tobacco, or narcotics within the previous 6 months. Other relative contraindications are psychosocial problems that cannot be resolved and are highly likely to have a negative impact on patient outcomes; documented noncompliance with medical care; and reliance on invasive ventilation.
Patients receiving noninvasive ventilation who meet all other criteria are eligible for transplantation, as are patients colonized by fungi or atypical mycobacteria. Adequately treated tuberculosis is not a contraindication.

Predicting COPD Mortality
Recent work is attempting to improve on the international guidelines. This research identifies those patients with the greatest risk of dying in a given time frame. This provides physicians with better criteria for placing patients on the transplant waiting list, and it can help them determine the best time for that referral to occur. Martinez and Kotloff6 reviewed and summarized research in lung transplantation related to COPD and found several notable points. For example, a forced expiratory volume in 1 second (FEV1) result that is less than 30% of the predicted postbronchodilator volume is a threshold for increased risk of mortality. Hypoxemia also appears to be a weak predictor of mortality, but hypercarbia (resting Paco2 of more than 48 mm Hg and/or an increase of more than 5 mm Hg in Paco2 despite long-term oxygen therapy) shows a clear predictive value. Decreased exercise capacity (despite maximal pulmonary rehabilitation) is another factor associated with mortality. A 6-minute walk test resulting in a distance traveled of 91 m 152 m may be a reliable threshold. Females have a better prognosis than males, and comorbidities of hypertension, diabetes mellitus, and ischemic heart disease have been found to increase mortality. Poor nutritional status, as indicated by a low body-mass index, is another independent predictor of mortality in COPD.

Predicting CF Mortality
Research done by Kerem et al10 and published in 1992 was the only major study on CF available to the group that produced the international guidelines.7,10,11 In December 2001, Liou et al4 published research that examined the survival of lung-transplantation patients with CF. Using data on patients in the CF Foundation Patient Registry, the researchers established a list of variables to create a model that would predict 5-year survival rates for CF patients. After screening the patient registry (containing 27,849 patients), they established an acceptable study group of 11,630 patients. They found that, using the 1998 guidelines (FEV1 of less than 30% of the predicted value), 1,458 patients were identified as potential transplant recipients. These patients had a wide range of predicted survival (from 6% to 94%, based on the new prediction model) over a 5-year course. The researchers then applied the newly created prediction model to the study group. After scoring each case, they arranged the patients into five groups based on 5-year predicted survival. Group 1 had a 5-year predicted survival of less than 30%; group 2, 30% to 49%; and groups 3, 4, and 5 had 50% to 100% predicted 5-year survival. The results established that group 1 members had the highest survival benefit if they received their transplants, group 2 had a neutral survival benefit, and groups 3 through 5 had reduced survival after transplantation.

• Sex (females have a higher risk)
• Forced expiratory volume in 1 second divided by forced vital capacity
• Weight-for-age score (indication of nutritional status)
• Pancreatic sufficiency
• Diabetes mellitus
• Staphylococcus aureus infection
• Burkholderia cepacia infection
• Number of acute exacerbations of CF (zero to five)
• Number of acute exacerbations of B. cepacia
Table 2. Variables for predicting 5-year survival in cystic fibrosis patients.

Compared with the 1,458 patients targeted for transplantation using the recommended criteria, 309 CF patients who would have the greatest 5-year survival benefit were identified by this research.4 Thus, using the Group 1 criteria to place patients on the transplant list would reduce the number of CF referrals, make the wait for a transplant decrease, and increase the opportunity for other patients to receive a transplant. Table 2 gives the variables used in the model.

Postsurgical Course
After patients have received a lung transplant, the first year is critical for survival. This is the period with the highest risk for surgical complications, rejection, and infection. The risk of acute rejection is highest in the first 3 months after surgery. Once a patient has survived the first year after surgery, he or she is likely to survive for 3 or more years, with a dramatic change in quality of life.12 Patients with double-lung transplantation procedures transition from having a high risk of dying due to respiratory failure to having nearly normal pulmonary function results for spirometry and an exercise tolerance that approaches 50% of the standard age-specific prediction.7 Rejection and/or infection will appear in some patients after transplantation, however; as a result, survival rates drop from 75% after 1 year to 50% after 5 years to around 25% after 10 years. These declines are due to three factors: first, patients must take immunosuppressant medications that leave them at increased risk for opportunistic infection; second, the transplanted lungs have lost the normal cough reflex due to denervation; and third, the lung is in open communication with the environment and is vulnerable to infection through this exposure.

Bacterial pneumonias, cytomegalovirus infections, fungal infections, and respiratory syncytial virus infections are often prime suspects when infection is present. The micro-organisms attack the transplanted organs, calling for antibiotic therapy and, often, increased use of steroids (in addition to damaging delicate lung tissue). When a transplantation patient presents with cough, fever, crackles on auscultation, infiltrates, or hypoxia, the differential diagnosis may be either rejection or infection. Bronchoalveolar lavage (BAL) and transbronchial biopsy provide the diagnostic clues.

Bronchiolitis obliterans is of particular concern and is considered to be a chronic rejection of the transplanted organ. Bronchiolitis obliterans is difficult to differentiate and may be acute and obvious or chronic and hidden. High-resolution CT scanning may reveal clues such as bronchiectasis, decreased vascular markings, and air trapping.8 BAL during bronchoscopy can help diagnose bronchiolitis obliterans when lymphocytosis and neutrophilia are found with no sign of infection.13 To fight rejection, patients must take immunosuppressive agents for the rest of their lives. Clinicians usually prescribe cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone.1 These agents suppress the immune system to ward off rejection, but have many negative interactions with other prescribed medications, which creates difficulties in trying to treat other problems. The immunosuppressive agents also have some toxic effects on the kidney and liver and must be used with care to avoid damaging these organs.

Lung transplantation is a trade-off, with a better future and a short period of fairly normal health balanced against a long-term future that still remains dim. Regardless of the disease that caused the need for a transplant, infection and rejection usually bring an end to life during the 5 to 10 years after surgery. With research ongoing in keeping donor lungs viable and with the possibility of xenotransplantation, more patients will be able to receive a transplant. As research continues and experience grows, lung-transplantation survival rates are expected to increase. Meanwhile, RCPs must be prepared to provide high-quality diagnostic testing and care, accompanied by genuine compassion, to those who are waiting and to those who have received lung transplants.

William C. Pruitt, RRT, is an instructor, Department of Cardiorespiratory Care, University of South Alabama, Mobile.

1. Arcasoy S, Kotloff R. Medical progress: lung transplantation. N Engl J Med. 1999;340:1081-1091.
2. Faro A. What every pediatrician needs to know about lung transplants in children. Contemporary Pediatrics. 2000;17:61-70.
3. Cooper D, Keogh A, Brink J, et al. Report of the xenotransplantation advisory committee of the international society for heart and lung transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases. Journal of Heart and Lung Transplantation. 2000;19:1125-1165.
4. Liou T, Adler F, Cahil B, et al. Survival effect of lung transplantation among patients with cystic fibrosis. JAMA. 2001;286:2683-2689.
5. United Network for Organ Sharing. Available at: Accessed March 14, 2002.
6. Martinez F, Kotloff R. Prognostication in chronic obstructive pulmonary disease: implications for lung transplantation. Seminars in Respiratory and Critical Care Medicine. 2002;22:489-498.
7. Maurer J, Frost A, Glanville A, et al. International guidelines for the selection of lung transplant candidates. Am J Respir Crit Care Med. 1998;158:335-339.
8. Kerstjens H, Groen H, van der Bij W. Recent advances: respiratory medicine. BMJ. 2001;323:1349-1353.
9. Marczin N, Riedel B. Exhaled nitric oxide during lung transplantation. Lancet. 1997;350:1681-1682.
10. Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Engl J Med. 1992;326:1187-1191.
11. Maurer J. Editorial: patient selection for lung transplantation. JAMA. 2001;286:2720.
12. American College of Chest Physicians. Why lung transplants are needed. Available at: Accessed March 14, 2002.
13. Tiroke A, Bewig B, Haverich A. Bronchoalveolar lavage in lung transplantation: state of the art. Clin Transplant. 1999;13:131-158.