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(By Isabel P. Neuringer, MD; Worakij Chalermskulrat, MD; and Robert M. Aris, MD)
Objectives
1. To understand the spectrum of health issues encountered by long-term lung transplantation survivors.
2. To describe the epidemiology of problems in long-term lung transplantation survivors.
3. To recognize immunosuppressant-related toxicities in long-term lung transplantation survivors.
4. To review renal, hematologic, endocrine, infectious-disease, GI, and neurologic complications after lung transplantation.
5. To review diagnostic and therapeutic interventions in long-term survivors of lung transplantation.
Key words:
calcineurin inhibitor; cytomegalovirus; diabetes; distal intestinal obstruction syndrome; encephalopathy; leukopenia; lung transplantation; nephrotoxicity; osteoporosis; respiratory virus
Abbreviations
CF = cystic fibrosis; CMV = cytomegalovirus; QOL = quality of life
This review will address special problems that occur in long-term survivors of lung transplantation. Many of the problems affecting long-term survivors are not well defined in terms of incidence or prevalence because many patients relocate and receive their "late" care in their hometowns some distance from the transplant center and thus are missed by the tracking registry and by the academic physicians who write many of the reports about these problems.
Because the overall 5- and 10-year survival rates after lung transplant are 45% and 25%, respectively, a relatively large number of patients have become intermediate- to long-term survivors. This is particularly true for patients who receive transplants before the age of 50 years and those with cystic fibrosis (CF), because 33% and 40%, respectively, will enjoy survival at their 10-year anniversary. In addition, because more than half of lung transplants are performed in individuals 50 years old and older, this population, composed predominantly of patients with COPD and idiopathic pulmonary fibrosis, is also at risk for health problems that are not intrinsically linked to the operation or immunosuppression. This results in a 10-year survival rate that is an absolute 10 percentage points lower for patients aged > 50 years compared with those < 50 years (30% vs 20%). While a review of health problems affecting older individuals is beyond the scope of this manuscript, practitioners need to be aware of the potential for a common health problem (eg, heart disease, stroke, cancer) to present typically or atypically (due to immunosuppressants or other medications) in this group. Last, this review will concentrate on the epidemiology of problems seen in long-term survivors, because the presentation and treatment of ommon problems will be similar regardless of whether they present early or late after transplantation. In addition, when applicable, we will include a full discussion of unique problems in this patient population.
Renal Insufficiency:
The predominant renal injury after lung transplantation is attributed to the calcineurin inhibitors, tacrolimus and cyclosporin, which cause renal and systemic vasoconstriction and toxic damage to renal tubular epithelium.1 At 1, 5, and 7 years after lung transplant, 26, 38, and 42% of lung transplant patients, respectively, experience a rise in serum creatinine, and 1.9, 3.4, and 5.4% of these patients, respectively, require chronic dialysis.2 This figure may actually underestimate the concurrent frequency of adjustment and/or discontinuation of medications as a result of renal insufficiency. At a single center, serum creatinine doubled in one third of patients by year 1 and in half of all patients by year 5, and was associated with diastolic blood pressure >90 mm Hg and a rise in serum creatinine early after transplant.
Interestingly, serum creatinine did not rise as quickly in patients taking tacrolimus.3 The substitution of sirolimus for a calcineurin inhibitor, accompanied by reduced dosage of the calcineurin inhibitor, offers a potential renoprotective strategy, such that selected patients discontinued dialysis in one study.4 Mammalian target of rapamycin inhibitors (commonly known as mTOR inhibitors), however, can paradoxically potentiate nephrotoxicity when used in conjunction with full dosages of calcineurin inhibitors, as observed in transplantation of other solid organs, and therefore appropriate caution must be exercised.5
Malignancy:
While exact incidence figures are not known, malignancy affects ~5% of all lung transplant recipients in the first postoperative year. More than half of these early malignancies are lymphomas, a third are skin cancers, and the rest are solid tumors in other organs.2 Immunosuppressants are likely to be causal in lymphomagenesis in the first year. Two thirds of these lymphoma victims survive.2,6 Thus, malignancy causes death in ~1.4% of all lung transplant recipients in the first year. As patients live beyond the first year, the annualized death rate of malignancy remains the same, but lymphomas become less common (~20% of all cancer) and are replaced largely by skin cancers, which account for more than half of all malignancies beyond 1 year.
Solid tumors increase by a small percentage (from ~20% in the first year to ~25% in each of the next 4 years), but they account for the majority of cancer deaths after 1 year. Beyond 5 years, cancer will likely result in death in about 1 in 10 patients cumulatively over the following years if the current statistics are projected forward.
Few data on skin cancer have come directly from the lung transplant population. Most of the data are from composite solid organ transplant or cardiothoracic transplant programs.7 In general, skin cancer after transplantation is made up of squamous carcinomas (which represent 50 to 70% of the total), basal cell carcinomas (20 to 40% of the total), and melanomas (~5% of the total). Merkel cell carcinoma is also more common after transplant but constitutes <1% of all skin cancers. The ratio of basal cell to squamous cell carcinomas is deeply reversed after transplant in comparison with the normal population, in which the ratio is ~5:1, and melanomas are twice as common after transplant in comparison with the normal population. The higher incidence of skin cancers and the alteration in this ratio is due to the immunosuppression, with azathioprine being at least as important as calcineurin inhibitors, if not more so, in the genesis of skin cancer following transplant. In addition to a higher incidence rate for skin cancer after transplantation, aggressive skin cancer (defined as cases that have spread to local nodes or beyond or that recur after presumably curative therapy) is also considerably more common, accounting for as many as 15% of all skin cancers and 40% of all major malignancies after transplant.7
Squamous cell cancers are more commonly poorly differentiated after transplant and have been linked to level of immunosuppression as well as the more typical risk factors present in the nontransplant population (solar keratoses, light skin pigmentation, and sun exposure). A subgroup of patients with squamous cell skin carcinoma will develop aggressive malignancies with spread to regional nodes and beyond at the time of diagnosis. Many of these tumors will not be controlled with surgery and radiation. Basal cell carcinomas occur at younger ages (typically one to two decades earlier) in transplant recipients and are more likely to be extracephalic in location compared with the nontransplant population. Histologically, superficial basal cell carcinomas are more frequent in transplant recipients than in control groups. Melanomas are not only more common after transplant but also are more invasive, with ~70% having tumors of Clark's level III or greater (or >0.76 mm by Breslow's technique). Cutaneous melanomas are associated with lymph node metastases in 20% and death in 30%. Melanomas of unknown origin, constituting 5% of all melanomas, resulted in death >50% of the time, whereas rare ocular melanomas caused death in only 20%.
With the exceptions noted above, most of the common malignancies seen in the general population (breast, colon, lung, prostate, leukemia) are not increased in incidence after solid organ transplant. However several unusual cancers are more common, including Kaposi's sarcoma, renal carcinomas, in situ carcinomas of the uterine cervix, hepatobiliary carcinomas, anogenital carcinomas, and various other sarcomas. As immunosuppression and potentially oncogenic viruses play a major role in causing these cancers, reducing immunosuppression to the lowest level compatible with good allograft function and prophylactic antiviral agents may be useful in the prevention and possibly even the treatment of some of these cancers. A comprehensive cancer-screening algorithm has recently been promulgated, but interestingly, the cost effectiveness is lower for screening transplant recipients (in this case, renal transplant patients) than in the general population, because the risk of dying from nonmalignant causes outweighs the higher risk of malignancy and its associated poorer outcomes in transplant recipients.8
Endocrine Problems: Osteoporosis and Diabetes
Osteoporosis and fractures are very common after lung transplantation. Immunosuppressant therapy, which plays a large role in lung transplantation, contributes to significant bone loss, fractures, and kyphosis in patients with end-stage lung disease, many of whom already suffer from severe osteoporosis before transplant.9
Transplant recipients develop high-turnover osteoporosis, marked by elevated levels of bone breakdown and formation markers. Longitudinal studies of lung transplant recipients have shown that spine and femur bone mineral density decreases 2 to 5% in the first year after transplant as a result of the stress of the operation, immunosuppressant therapy, and immobility. These figures are generally consistent with bone mineral density losses that occur after transplantation of the kidney, heart, and liver. More importantly, patients who have received lung transplants have alarmingly high rates of pathologic fractures, ranging from 37 to 42%, with some patients having multiple fractures. This is in part due to the overlapping of low bone density and bone quality and the increased activity levels that come with marked improvements in lung function. Interventions with bisphosphonates have been shown to be effective in controlled clinical trials.10
Diabetes affects about one in three lung transplant recipients beyond the first year after lung transplantation.11 Corticosteroids clearly play a causal role in posttransplant diabetes by causing insulin resistance; this effect is dose related, so dose reduction can be ameliorating. Calcineurin inhibitors (tacrolimus is five times more diabetogenic than cyclosporin), which cause direct islet toxicity, are a key causative factor in the pathogenesis as well.
Patients with CF and pancreatic insufficiency may be at higher risk for diabetes owing to the natural course of pancreatic failure, which leads to endocrine insufficiency as they get older. Diabetes is one of the most serious long-term complications of transplantation, particularly if the condition is poorly controlled. Transplant recipients in whom diabetes develops are at greater risk of graft rejection, graft loss, infection, and both microvascular and macrovascular complications. In addition, the annual attributable costs of developing new-onset diabetes after organ transplantation are between $12,000 and $22,000.
The diagnosis of posttransplant diabetes follows the standard guidelines of a fasting glucose level >126 mg/dL, but, in addition, any casual serum glucose >200 mg/dL makes the diagnosis as well. The natural history of diabetes after transplantation shares many similarities with type 2 diabetes in that the onset can be insidious; individuals may experience glucose intolerance and may be asymptomatic for years before symptoms clinically manifest. Furthermore, posttransplantation hyperglycemia and diabetes are not always permanent and may normalize, sometimes without treatment, within weeks or months. Management of posttransplant diabetes is similar to general diabetes management, but clinicians have the option of altering the immunosuppressive regimen (eg, lowering the prednisone dose or discontinuing tacrolimus) to assist in glucose control.
Infections:
Infections gradually decrease over time after transplant, but never reach the level of a nonimmunosuppressed host.2,12 They lead to or contribute to hospitalization in 20% of the lung transplant population by year 5 vs 40% in year1. Infections in long-term survivors of lung transplantation also differ from early infections; over the long term, there are lower rates of pneumonia/bacteremia from nosocomial pathogens (Pseudomonas, Staphylococcus, Enterococcus, other Gram-negative rods, and Candida) and cytomegalovirus (CMV). Patients with CF may be at higher risk for infection than other patient groups; this issue remains controversial, with studies supporting and challenging this contention. Community-acquired infections (bacterial and viral) tend to predominate in most patients who are doing well, but CF patients are still at risk for reinfecting their allografts with Gram-negative rods and Staphylococcus from reservoirs in their native airways or sinuses. Patients who develop chronic graft rejection or obliterative bronchiolitis are at high risk for infection with Pseudomonas, other Gram-negative rods, Staphylococcus, and Aspergillus due to alterations in epithelial integrity and reduced local host defense. Legionella, Nocardia, Listeria, Cryptococcus, endemic mycoses, Mycobacterium tuberculosis and nontuberculous mycobacteria can all cause infection in lung transplant recipients, but each is rare, affecting < 1% of all patients. In general, these infections must be diagnosed early, using invasive procedures if needed, and treated aggressively in long-term transplant survivors with specific antimicrobial agents with or without reduction in immunosuppression (a decision that is based on the severity of disease).
The respiratory viruses include rhinovirus, influenza A and B, respiratory syncytial virus, parainfluenza 1, 2, and 3, and adenovirus. The clinical importance of infection with these viruses in the solid organ transplant population is not well defined. In lung or heart-lung recipients, the prevalence of respiratory viral infections ranges from 0 to 20%.12 Similarities among these viral pathogens include seasonality, transmission from person to person, relatively short incubation periods, acquisition in the community or nosocomially, use of the respiratory tract as the portal of entry and site of disease expression, and varying ranges of clinical severity. The majority of infections are associated with acute upper respiratory tract symptoms, fever, pulmonary function decline, and hypoxia. The risk of complications from these viruses varies considerably between the particular virus and type of transplant, but concern arises that they may alter host immune responses and lead to a deterioration in allograft function from acute and/or chronic rejection. In case reports and series of patients with community-acquired viral infections, researchers have not been able to determine a casual link with bronchiolitis obliterans syndrome because of the high prior probability of suffering from bronchiolitis obliterans syndrome (BOS), the long latency period between some community-acquired viral infections and BOS, and the variable pattern of immune activation induced by different community-acquired viral infections. Nonetheless, occasional reports of community-acquired viral pneumonia culminating in death have been reported in lung transplant recipients, especially with adenovirus. Adenovirus infections in the immunosuppressed patient are often more severe and persist longer than those occurring in normal hosts. Antiviral therapy, although largely unproven, is often used in transplant recipients to facilitate recovery.
Hematologic Problems
The most common hematologic problems in lung transplant recipients are anemia and leukopenia, which occur in the vast majority of patients at some point. Anemia is usually caused by immunosuppressants (mycophenolate is a more common cause than the others), chronic disease, iron deficiency (largely from too much phlebotomy for laboratory tests), or renal insufficiency. Leukopenia is usually related to DNA synthesis inhibitors or rapamycin. Doses of these medications can be adjusted to keep the total white blood cell count above 4.0x109 cells/L and the hematocrit above 30%.
Thrombocytopenia occurs in some patients but is usually of a mild degree. The exception is the minority (<1%) of patients will develop thrombotic thrombocytopenic purpura/hemolytic uremic syndrome and experience either very low platelet counts (often <20,000/L) or a rapidly falling platelet count. In thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, accompanying symptoms and signs include mental status changes, fever, hemolytic anemia with schistocytes on the peripheral smear, and renal insufficiency. More than 95% of the cases occur in the first posttransplant year and result from calcineurin inhibition.13 Late cases have been reported and under-reporting may occur if this syndrome is confused with severe sepsis, a very likely entity on the differential diagnosis list of a very ill immunosuppressed host. Key differentiating features are the very low or rapidly falling platelet count and evidence of hemolysis. Prompt plasma exchange is the treatment of choice and has lowered mortality from 90% to 10%.
Gastrointestinal Disorders:
GI problems after lung transplant commonly cause both functional and pathologic disorders, resulting in a myriad of disease manifestations, often necessitating surgical intervention. In addition to intolerance of the medical regimen, lung transplant recipients may experience any of a spectrum of GI problems, including peptic ulcer disease, reflux, esophagitis, gastritis, gastroparesis, cholecystitis, colitis (inflammatory and viral), and diarrhea.
Aspiration secondary to reflux and altered cough reflex has increasingly become implicated in predisposing to chronic allograft dysfunction,14 and in an effort to prevent deterioration of lung function, fundoplication has been advocated.15 Maurer16 reviewed colonic disease at her center and cited a 13% incidence of colonic complications excluding chronic diarrhea, with the spectrum of disease including diverticultis, infectious colitis, GI malignancy, megacolon, and colonic perforation. Approximately 30% of patients with colonic pathology died from their illness.16 CMV infection contributes to diarrheal illnesses after lung transplant, but can also present as esophagitis or hepatitis. A negative serum CMV viral load may not, in our experience, eliminate the existence of active CMV disease in the GI tract, and therefore at our institution esophagogastroduodenoscopy and/or colonoscopy are often required to finalize the diagnosis.
In patients with CF, underlying GI problems are exacerbated posttransplant, including reflux disease, impaired GI motility, malabsorption, and distal intestinal obstruction syndrome. Distal intestinal obstruction syndrome can affect about one in five patients, and occurs most often in the perioperative setting.17 Prompt recognition of delayed bowel function and treatment with GoLYTELY (polyethylene glycol 3350 and electrolytes for oral solution; Braintree Laboratories, Inc; Braintree, MA), cathartics such as MiraLax (polyethylene glycol 3350; Braintree Laboratories, Inc; Braintree, MA), and enemas can prevent the development of bowel obstruction. The accumulation of undigested food resulting in a gastric bezoar requires the addition of enzyme supplementation, bicarbonate, and motility agents to encourage slow resolution over time.
Liver, Biliary, and Pancreatic Complications
A significant proportion of the liver function laboratory abnormalities observed in lung transplant patients are medication related. Cyclosporin, to a greater extent than tacrolimus, has lithogenic effects, causing injury to the hepatic membrane, and reducing bile acid flow and bile secretion. Metabolized in the liver and secreted in bile, cyclosporin may induce the formation of gallstones resulting in cholecystitis; this occurred in 4% of patients with CF after lung transplant, and 5.7% of cardiothoracic organ transplant patients.17,18 Azathioprine has associated hepatotoxicity, which often causes pancreatitis; however, as with most drug-induced abnormalities in laboratory findings, the toxic effects resolve with drug discontinuation. Liver test abnormalities are frequently seen in patients with CF and in addition to medication-related effects, and may reflect a degree of underlying hepatic steatosis. The relatively indolent progression of CF-related liver disease, however, has little impact on health after lung transplant, according to one case series.19
Neurologic Sequelae:
Neurologic complications after lung transplantation generally result from calcineurin inhibitor-mediated headache, seizure, and encephalopathy; acute thromboembolic CNS events; and infectious CNS lesions. Headache is the most common side effect of calcineurin inhibitors, although cortical blindness, posterior reversible leukoencephalopathy, and acute cerebellar edema may also occur. Calcineurin-inhibitor CNS toxicity may be due to hypoperfusion and localized ischemia from endothelial injury and vascular edema.20 A clear association between dosage and toxicity, however, is difficult to predict, as calcineurin-inhibitor neurotoxicity may not necessarily be associated with elevated serum drug level.21 Poorly controlled hypertension can potentiate calcineurin-inhibitor toxicity, causing headache and seizures.
Quality of Life:
Living with end-stage lung disease is associated with low quality of life (QOL), depression, and anxiety. Lung transplant recipients have dramatic improvements in a large number of QOL indices (including most dimensions of the Nottingham Health Profile, Karnofsky score, level of anxiety, depression, and feeling of well-being) immediately after transplantation.22 Double lung recipients seem to have a better QOL after transplant, but some of this effect may be related to age. Unfortunately, these indicators are slowly eroded late after transplant, with more patients experiencing dyspnea, anxiety, depression, and a lower level of well-being. The number of patients suffering from renal insufficiency, diabetes, osteoporosis, hyperlipidemia, other drug-induced adverse events and BOS increased coincident with these lower QOL scores. Nonetheless, patients experience a stable and better overall QOL after transplantation at most, if not all, time points in comparison with end-stage lung disease patients. While specific therapies have not been used to treat patients with depression and anxiety in controlled trials after transplant, a large percentage of patients are treated with serotonin reuptake inhibitors and long-acting anxiolytics either acutely or chronically to address these problems.
Conclusions:
As the number of long-term survivors of lung transplantation continues to grow, physicians have an opportunity to better understand the factors that predispose patients to renal insufficiency, diabetes, chronic rejection, and malignancy, and thereby optimize treatment for the next generation of lung transplant patients. Knowledge gained from the experience of long-term survivors will provide insight into how caregivers can anticipate complications in susceptible patients, distinguish issues common to different end-stage lung disease states, adjust clinical regimens accordingly, and improve outcomes in the future. The survival of this cohort of patients also confirms that long-term graft acceptance ultimately can be achieved. Thus, this unique group of patients, many of whom have functional tolerance to their transplanted lungs, may ultimately shed light on how to accomplish long-term graft acceptance therapeutically.
Acknowledgment
This work was supported by the National Heart Lung Blood Institute, the Cystic Fibrosis Foundation, and the Verne Caviness GCRC at the University of North Carolina at Chapel Hill.
References
1. Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care 2001; 7:384-389
2. Trulock EP, Edwards LB, Taylor DO, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-first official adult lung transplant report-2004. J Heart Lung Transplant 2004; 23:804-815
3. Ishani A, Erturk S, Hertz MI, et al. Predictors of renal function following lung or heart-lung transplantation. Kidney Int 2002; 61:2228-2234
4. Snell GI, Levvey BJ, Chin W, et al. Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment. J Heart Lung Transplant 2002; 21:540-546
5. Formica RN Jr, Lorber KM, Friedman AL, et al. The evolving experience using everolimus in clinical transplantation. Transplant Proc 2004; 36:495S-499S
6. Aris RM, Maia DM, Neuringer IP, et al. Post-transplantation lymphoproliferative disorder in the Epstein-Barr virus-naive lung transplant recipient. Am J Respir Crit Care Med 1996; 154:1712-1717
7. Veness MJ, Quinn DI, Ong CS, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer 1999; 85:1758-1764
8. Kiberd BA, Keough-Ryan T, Clase CM. Screening for prostate, breast and colorectal cancer in renal transplant recipients. Am J Transplant 2003; 3:619-625
9. Aris RM, Neuringer IP, Weiner MA, et al. Severe osteoporosis before and after lung transplantation. Chest 1996; 109:1176-1183
10. Trombetti A, Gerbase MW, Spiliopoulos A, et al., Bone mineral density in lung-transplant recipients before and after graft: prevention of lumbar spine post-transplantation-accelerated bone loss by pamidronate. J Heart Lung Transplant 2000; 19:736-743
11. Legendre C, Marchetti P, Markell M, et al. New-onset diabetes after transplantation: 2003 International consensus guidelines; proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003. Transplantation 2003; 75:SS3-SS24
12. Davidson J, Wilkinson A, Dantal J, et al. Infectious complications of lung transplantation. Transpl Infect Dis 2001; 3:128-137
13. Singh N, Gayowski T, Marino IR. Hemolytic uremic syndrome in solid-organ transplant recipients. Transpl Int 1996; 9:68-75
14. Young LR, Hadjiliadis D, Davis RD, et al. Lung transplantation exacerbates gastroesophageal reflux disease. Chest 2003; 124:1689-1693
15. Davis RD Jr, Lau CL, Eubanks S, et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg 2003; 125:533-542
16. Maurer JR. The spectrum of colonic complications in a lung transplant population. Ann Transplant 2000; 5:54-57
17. Gilljam M, Chaparro C, Tullis E, et al. GI complications after lung transplantation in patients with cystic fibrosis. Chest 2003; 123:37-41
18. Lord RV, Ho S, Coleman MJ, et al. Cholecystectomy in cardiothoracic organ transplant recipients. Arch Surg 1998; 133:73-79
19. Klima LD, Kowdley KV, Lewis SL, et al. Successful lung transplantation in spite of cystic fibrosis-associated liver disease: a case series. J Heart Lung Transplant 1997; 16:934-938
20. Coley SC, Porter DA, Calamante F, et al. Quantitative MR diffusion mapping and cyclosporine-induced neurotoxicity. AJNR Am J Neuroradiol 1999; 20:1507-1510
21. Goldstein LS, Haug MT 3rd, Perl J 2nd, et al. Central nervous system complications after lung transplantation. J Heart Lung Transplant 1998; 17:185-191
22. Gross CR, Savik K, Bolman RM 3rd, et al. Long-term health status and quality of life outcomes of lung transplant recipients. Chest 1995; 108:1587-1593
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