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An overview of paediatric lung transplantation
PAEDIATRIC RESPIRATORY REVIEWS (2004) 5, 249–254 doi:10.1016/j.prrv.2004.04.005
RECENT ADVANCES
An overview of paediatric lung transplantation Marlyn S. Woo Cardiothoracic Transplant Center, Childrens Hospital Los Angeles and Keck School of Medicine at the University of Southern California, Los Angeles, California, USA KEYWORDS paediatric; lung transplant; living donor lobar; bronchiolitis obliterans; outcome; lung growth; medical non-adherence
Summary Paediatric lung transplantation is indicated in selected children with end-stage lung disease that is not amenable to conventional medical or surgical therapy. The indications and complications differ from adult lung transplant patients. Due to the long waiting times for suitable cadaveric lungs, other types of lung transplantation, such as living donor lobar and split-lung procedures, have been utilised in paediatric patients. Unlike adult candidates, cystic fibrosis and primary pulmonary hypertension are the primary indications. Most recipients are in the adolescent age group. Complications that occur with greater frequency in paediatric lung recipients include somatic growth and graft function, post-transplant lymphoproliferative disease and medical non-adherence. While long-term outcome remains similar between adult and paediatric lung transplant recipients, there is a lower risk of bronchiolitis obliterans in very young recipients and in those who receive living donor lobar lung transplantation. Research into these clinical problems is hampered by the fact that only a small number of paediatric transplants are performed at each centre. Hence, improvement in outcome for these children will be dependent on developing methods to produce better tolerance, understanding the mechanisms/treatment of bronchiolitis obliterans and multi-centre studies that focus on the problems that primarily affect the paediatric lung transplant recipient. ß 2004 Elsevier Ltd. All rights reserved.
INTRODUCTION
INDICATIONS
Lung transplantation is no longer considered an experimental procedure for children with end-stage lung disease. The number of children undergoing lung transplantation has been increasing steadily since Cooley’s heart–lung transplant into a 2-month-old infant in 1968. However, children comprise only a small proportion of all lung transplant procedures. As a result, the published literature related to paediatric lung transplantation consists primarily of single-centre reports based on relatively few patients. The vast majority of these reports are descriptive or retrospective analyses. Although children have different primary indications and somewhat different complications, survival is comparable with adult recipients.1
For children, the most common indication for lung transplantation is cystic fibrosis. Hence, it is not surprising that most paediatric lung transplant patients are adolescents (Fig. 1).1 Other disease processes leading to lung transplant referral include primary pulmonary hypertension, nontransplant-associated bronchiolitis obliterans (OB) and congenital heart disease (Table 1).1 Less common causes for referral include alveolar capillary dysplasia, surfactant protein B deficiency, pulmonary veno-occlusive disease, pulmonary arteriovenous malformations, idiopathic pulmonary haemosiderosis and idiopathic pulmonary fibrosis. Unfortunately, these lung diseases all have a predilection for abrupt, rapid clinical deterioration that lead to high risk of death while awaiting a cadaveric lung transplant. Unlike candidates for heart or liver transplantation, lung transplant candidates have the double disadvantage of organ allocation based on length of time on the waiting list, as well as a lower number of suitable organs available from cadaveric
Correspondence to: Marlyn S. Woo, Division of Paediatric Pulmonology; Mailstop #83, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA Tel.: þ1 323 669 2101; fax: þ1 323 664 9758; E-mail: [email protected] 1526–0542/$ – see front matter
ß 2004 Elsevier Ltd. All rights reserved.
250
M. S. WOO
Table 2 Recipient criteria for living donor lobar lung transplantation.
Figure 1 Age distribution of paediatric lung transplant recipients. Paediatric lung transplants from January 1986 to June 2002.
organ donors. It has been estimated that less than 25% of multi-organ donors provide cadaveric lungs.2 Limited data suggest that outcomes from the use of organs falling outside of the standard criteria for lung donor quality may be acceptable.3 However, there is a reluctance to place ‘suboptimal’ lungs into children. For this reason, other lung transplant procedures, such as living donor lobar4 and splitlung procedures,5 have been utilised for patients who would not be expected to survive to receive a suitable cadaveric transplant.
LIVING DONOR LOBAR LUNG TRANSPLANTATION Although available in only a few centres around the world, living donor lobar lung transplantation has been performed successfully in over 150 patients. It is performed primarily in candidates who are not expected to survive to receive cadaveric lungs. Candidates for living donor lobar proceTable 1 tion.
Primary indications for paediatric lung transplanta-
Diagnosis Cystic fibrosis Primary pulmonary hypertension Congenital heart disease Idiopathic pulmonary fibrosis Pulmonary vascular disease Re-transplant (non-OB) Re-transplant (OB) OB (not transplant-related) Bronchiectasis COPD/emphysema Other
Age <1 year
Age 1–10 years
7%
34.1% 14.6%
48.9% 12.2% 7.3%
11.6% 7.3% 3.7% 4.9% 6.1% 3.7%
1.2% 14.6%
1.2% 11.6%
OB, bronchiolitis obliterans; COPD, chronic obstructive pulmonary disease.
End-stage lung disease that has failed medical management No significant liver disease No significant kidney disease No multiply-resistant organisms No active or recent psychiatric disease Adequate psychosocial support No medical compliance problems (by candidate or caregivers) Age > 7 years (depends on height) HIV negative Availability of at least two suitable donors (for bilateral lobar procedure) HIV, human immunodeficiency virus.
dures must meet the same criteria as those for cadaveric lung transplant. In fact, all living donor lobar candidates are also listed for cadaveric organs. The indications, surgical procedure and paediatric outcomes for living donor lobar transplant have been published previously.4,6 However, it is important to note that this type of transplant should not be left for ‘emergency’ or last-minute referral. Both the lung transplant candidate and the prospective lobar donors would be placed at risk without a careful and thorough evaluation. Indications for referral for living donor lobar lung transplantation, as well as guidelines for lobar donor candidates, are listed in Tables 2 and 3.
COMPLICATIONS Irrespective of the type of procedure, all lung transplant patients are at risk from complications related to their surgery and immunosuppressive medication. The cause of morbidity is related to the time after lung transplantation Table 3
Candidates for living donor lobar donation.
No coercion (emotional or financial) Must have prior relationship with proposed recipient/family ABO compatible with prospective donor Preferably at least 4 inches taller than prospective donor Age 18–55 years Non-smoking No significant past medical history No recent viral infections (no active EBV, hepatitis) Normal echocardiogram and electrocardiogram Normal coronary angiography (if indicated) Normal chest radiograph Oxygen tension > 80 mmHg on room air FEV1 and FVC > 85% predicted No significant pulmonary pathology on CT scan (must be completely normal on donor side) No previous thoracic surgery on donor side EBV, Epstein–Barr virus; CT, computed tomography.
AN OVERVIEW OF PAEDIATRIC LUNG TRANSPLANTATION
Table 4 Paediatric lung transplant morbidity at 1 and 5 years after transplant. Condition
Within 1 year
Within 5 years
Hypertension Renal dysfunction Abnormal creatinine <2.5 mg/dl Creatinine >2.5 mg/dl Chronic dialysis Renal transplant Hyperlipidaemia Diabetes Bronchiolitis obliterans
37.7% 7.6% 5.1% 1.6% 0.6% 0.3% 0.9% 21% 14.7%
73.7% 24.1% 12.1% 6.9% 3.4% 1.7% 1.7% 31% 20.5%
(Table 4).1 This article will focus on problems that are more common in children than adult lung transplant patients.
Linear growth and lung graft function A problem unique to paediatric lung transplant recipients is lung growth and graft function. There have been many reports of lung transplant recipients who received transplants in infancy and childhood and who subsequently underwent significant somatic growth. Those without evidence of OB often have spirometry values within the normal range. Animal studies suggest that lungs transplanted into immature recipients do grow.7,8 Using serial imaging measurements, a small retrospective study found that airway growth in humans does occur.9 However, assessment of alveolar growth in humans is difficult. Routine measurements of pulmonary function primarily assess volumes of gas exchanged. Changes in these values may reflect an increase in the average volume of each alveolar unit rather than an increase in the number of alveoli. However, pulmonary function measurements following lung transplant can return to the normal range in infants10 and older children,11 suggesting that an increase in lung volume and gas exchange proportionate to somatic growth occurs. Measurement of the diffusing capacity for carbon monoxide (DLCO) provides a better estimate of gas exchange surface area but is not easily measured in infants. However, a significant increase in DLCO has been demonstrated in paediatric recipients of cadaveric and living donor lobar transplants.12 It is important to note, however, that the DLCO values did not continue to increase with linear growth in living donor lobar recipients, suggesting that the increase in lung volume was secondary to hyperinflation rather than new lung growth.12 The most important long-term factor impacting pulmonary allograft function in paediatric lung transplant recipients is OB. At 5 years after transplant, roughly half of lung transplant recipients will have signs of OB. Basic science and clinical research is ongoing, yet the aetiology of OB remains unknown.
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Post-transplant lymphoproliferative disease This poorly differentiated B-cell lymphoma is more common in paediatric patients who tend to be Epstein–Barr-virus naive at the time of transplantation. While it usually arises in the transplanted lung (nodule or density), it can also occur in the small bowel and central nervous system. Treatment consists of reduction in immunosuppression and, in more extensive cases, treatment with chemotherapy.13,14
Medical non-adherence Non-adherence to medical therapy, particularly not taking immunosuppressive medication regularly, is a common cause of graft failure/rejection in adolescent solid organ transplant recipients. Possible medical non-adherence should be considered in all patients who have widely fluctuating immunosuppression levels, recurrent acute rejection, complaints of Cushingoid appearance or weight gain, depression, missed routine clinic appointments or caregivers finding loose medication tablets/capsules (under cushions, in trash receptacles, etc.). Early referral to child psychiatry or psychology is important, as well as family counselling.
OUTCOME Just as the causes of morbidity are related to the time after transplant surgery, the primary causes of mortality change with the time since transplantation (Table 5).1 However, the factor most responsible for preventing long-term success of lung transplantation is OB. OB accounts for more than 40% of deaths that occur more than 1 year after transplant.15 The diagnosis of OB is made by tissue findings of small airways with lymphocytic infiltration, fibromyxoid deposits, subepithelial fibrosis and (in the advanced stages) total fibrous obliteration.16 It is often a focal process that is difficult to diagnose with transbronchial biopsy and even with open lung biopsy.17 To permit earlier treatment/intervention of OB, a set of clinical criteria for ‘OB syndrome’ (BOS) was developed based on unexplained obstructive decline in pulmonary function.18 A recent revision of the BOS clinical criteria recognised that percent predicted values rather than absolute Table 5
Primary cause of death after lung transplantation.
0–30 days
31 days–1 year
Graft failure Other Infection (non-CMV) Cardiovascular Technical
Infection (non-CMV) Bronchiolitis Graft failure Infection (non-CMV) Other Graft failure Bronchiolitis CMV Acute rejection Lymphoma
CMV, cytomegalovirus.
>1 year
Other Lymphoma Cardiovascular
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values should be used in assessment of the decline in FEV1 in paediatric recipients.19 Most clinical studies aimed at identifying risk factors for OB are generally retrospective, involving primarily adult populations. Acute rejection is the most consistently identified risk factor. Patients experiencing more frequent20 or more severe21 rejection episodes were more likely to develop OB. Paediatric living donor lobar recipients are noted to have a lower incidence of OB, probably due to the less frequent and less severe rejection episodes.22 Other studies supporting an immune mechanism for the aetiology of OB showed increased incidence in patients with lymphocytic bronchitis and bronchiolitis,23 human leukocyte antigen (HLA) mismatches24 and anti-HLA antibodies.25 Patients with decreased donor alloreactive (peripheral microchimerism and absence of donor antigen reactivity in bronchoalveolar lavage lymphocytes) had a lower incidence of OB.26,27 Infection, particularly with cytomegalovirus (CMV), has also been implicated in the aetiology of OB. There are several single-centre retrospective reports implicating CMV.25,28–31 In one centre, the use of ganciclovir prophylaxis against CMV infection reduced the incidence of OB in the first year after transplant.32 Indirect evidence suggests a role for community acquired viral infections in the development of OB.33,34 Besides infection, chronic aspiration related to gastroparesis has also been raised as a risk factor leading to OB.35 This association is supported by another clinical study which suggested that fundoplication improves lung function in patients with reflux.36 While there appears to be a number of reports linking bacterial infections with OB, there is no clear evidence that bacterial infections cause OB.28,37–39 Nonetheless, chronic infection seems to play a role in the development of OB40 and bacterial infection is a significant cause of death in OB patients.41 Very young children who underwent lung transplantation under the age of 3 years may have a lower risk for the development of OB. One retrospective, single-centre study found a decreased incidence of acute rejection in infants.42 A retrospective analysis of the author’s centre’s paediatric living donor lobar transplant recipients also found a lower incidence of OB.22 This lower incidence did not appear to be related to the degree of HLA matching but rather to the shorter ischaemic times for the living donor lobar grafts.22 There are no effective treatments for OB. At early detection/diagnosis of OB or BOS, therapy usually consists of augmentation of immunosuppression. The data supporting this therapy are mostly anecdotal or single-centre uncontrolled series. Reported treatments for OB include anti-thymocyte preparations,43 cyclophosphamide,44 methotrexate,45 photopheresis46 and total lymphoid irradiation.47 While all studies reported that some patients showed benefit, none were uniformly beneficial for all affected patients and none reversed OB. The use of tacrolimus as ‘rescue’ therapy may slow the decline in
M. S. WOO FEV1.48,49 A recent small uncontrolled pilot study suggested that azithromycin was beneficial,50 but a double-blinded, placebo-controlled study using inhaled fluticasone propionate showed no benefit.51 Another retrospective study of patients prescribed statins for hypercholesterolaemia found a lower incidence of OB and a better long-term survival.52 With the lack of effective medical therapy for OB, treatment is usually limited to re-transplantation. Given the scarcity of suitable organs and the growing number of lung transplant candidates, lung re-transplantation is fraught with medical and ethical challenges.
CONCLUSIONS Paediatric lung transplant recipients face many of the same challenges that confront adult recipients. There is a need to increase the donor lung pool for all lung transplant candidates. Better strategies to achieve effective and prolonged tolerance while minimising the toxicity of immunosuppressive agents will improve long-term function and prevent the cumulative morbidity associated with current regimens. Discovering the mechanism of OB, as well as earlier detection, will help us achieve longer graft function for all lung transplant recipients. However, we need more sensitive methods than decline in FEV1 for detecting OB and its response to therapy. There are issues that are unique to the child who undergoes lung transplant surgery. Research in paediatric lung transplantation is limited by the relatively small number of transplants performed at each centre. Multi-centre clinical studies are needed to determine the most appropriate monitoring and treatment regimens for paediatric lung transplant patients. In this manner, we can improve the outcomes of all children who undergo lung transplantation.
PRACTICE POINTS Cystic fibrosis and primary pulmonary hypertension are the primary indications for paediatric lung transplantation Less than 25% of multi-organ cadaveric donors can provide lungs for transplant Organ shortage has led to alternatives to cadaveric lungs: living donor lobar and split-lung procedures Paediatric and adult lung transplant recipients face many of the same complications Morbidity type is related to time after lung transplant Paediatric lung transplant recipients have complications that are not as common in adult recipients: linear growth and lung graft function, increased risk of post-transplant lymphoproliferative disease and medical nonadherence
AN OVERVIEW OF PAEDIATRIC LUNG TRANSPLANTATION
Cause of morbidity is also related to time after transplant surgery Mortality in the peri-operative period is primarily due to graft failure Mortality in the first year after transplant is primarily caused by non-CMV infection OB is the primary cause of death and the chief obstacle to long-term survival in lung transplant recipients who survive for more than 1 year after surgery There is no effective treatment for OB
RESEARCH DIRECTIONS Optimising the available cadaveric donor pool Producing better graft tolerance while reducing the side-effects of infection, hypertension and renal dysfunction OB: mechanisms, detection and effective therapy Unique challenges of transplant in children require multi-centre studies to determine the best monitoring and treatment regimens
REFERENCES 1. Boucek MM, Edwards LB, Keck BM et al. The Registry of the International Society for Heart and Lung Transplantation: Sixth Official Pediatric Report – 2003. J Heart Lung Transplant 2003; 22: 636–652. 2. Follette D, Rudich S, Bonacci C, Allen R, Hoso A, Albertson T. Importance of an aggressive multidisciplinary management approach to optimize lung donor procurement. Transplant Proc 1999; 31: 169– 170. 3. Straznicka M, Follette DM, Eisner MD, Roberts PF, Menza RL, Babcock WD. Aggressive management of lung donors classified as unacceptable: excellent recipient survival one year after transplantation. J Thorac Cardiovasc Surg 2002; 124: 250–258. 4. Starnes VA, Barr ML, Cohen RG. Lobar transplantation: indications, technique, and outcome. J Thorac Cardiovasc Surg 1994; 108: 403–411. 5. Couetil JP, Tolan MJ, Loulmet DF et al. Pulmonary bipartitioning and lobar transplantation: a new approach to donor organ shortage. J Thorac Cardiovasc Surg 1997; 113: 529–537. 6. Woo MS, MacLaughlin EF, Horn MV et al. Living donor lobar lung transplantation: the pediatric experience. Pediatr Transplantation 1998; 2: 185–190. 7. Binns OA, DeLima NF, Buchanan SA et al. Mature pulmonary lobar transplants grow in an immature environment. J Thorac Cardiovasc Surg 1997; 114: 186–194. 8. Ibla JC, Shamberger RC, DiCanzio J, Zurakowski D, Koka BV, Lillehei CW. Lung growth after reduced size transplantation in a sheep model. Transplantation 1999; 67: 233–240. 9. Ro PS, Bush DM, Kramer SS, Mahboubi S, Spray TL, Bridges ND. Airway growth after pediatric lung transplantation. J Heart Lung Transplant 2001; 20: 619–624. 10. Cohen AH, Mallory GB, Ross K et al. Growth of lungs after transplantation in infants and in children younger than 3 years of age. Am J Respir Crit Care Med 1999; 159: 1747–1751.
253
11. Sweet SC, Spray TL, Huddleston CB et al. Pediatric lung transplantation at St. Louis Children’s Hospital, 1990–1995. Am J Respir Crit Care Med 1997; 155: 1027–1035. 12. Sritippayawan S, Keens TG, Horn MV et al. Does lung growth occur when mature lobes are transplanted into children? Pediatr Transplantation 2002; 6: 500–504. 13. Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplantation 2002; 6: 456–464. 14. Straathof KC, Savoldo B, Heslop HE, Rooney CM. Immunotherapy for post-transplant lymphoproliferative disease. Br J Haematol 2002; 118: 728–740. 15. Boucek MM, Edwards LB, Keck BM et al. The Registry of the International Society for Heart and Lung Transplantation: Fifth Official Pediatric Report – 2001–2002. J Heart Lung Transplant 2002; 21: 827–840. 16. Yousem SA, Berry GJ, Cagle PT et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 1996; 15: 1–15. 17. Weill D, McGiffin DC, Zorn GL Jr et al. The utility of open lung biopsy following lung transplantation. J Heart Lung Transplant 2000; 19: 852–857. 18. Cooper JD, Billingham M, Egan T et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993; 12: 713–716. 19. Estenne M, Maurer JR, Boehler A et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002; 21: 297–310. 20. Sharples LD, Tamm M, McNeil K, Higenbottam TW, Stewart S, Wallwork J. Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation – early risk factors. Transplantation 1996; 61: 560–566. 21. Berry GJ, Brunt EM, Chamberlain D et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990; 9: 593–601. 22. Woo MS, MacLaughlin EF, Horn MV, Szmuszkovicz JR, Barr ML, Starnes VA. Bronchiolitis obliterans is not the primary cause of death in pediatric living donor lobar lung transplant recipients. J Heart Lung Transplant 2001; 20: 491–496. 23. Reichenspurner H, Girgis RE, Robbins RC et al. Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg 1996; 62: 1467–1472. 24. Chalermskulrat W, Neuringer IP, Schmitz JL et al. Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation. Chest 2003; 123: 1825–1831. 25. Smith MA, Sundaresan S, Mohanakumar T et al. Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome. J Thorac Cardiovasc Surg 1998; 116: 812–820. 26. Zeevi A, Rabinowich H, Yousem SA et al. Presence of donor-specific alloreactivity in histologically normal lung allografts is predictive of subsequent bronchiolitis obliterans. Transplant Proc 1991; 23: 1128–1129. 27. McSherry C, Jackson A, Hertz MI, Bolman RM III, Savik K, Reinsmoen NL. Sequential measurement of peripheral blood allogeneic microchimerism levels and association with pulmonary function. Transplantation 1996; 62: 1811–1818. 28. Bando K, Paradis IL, Similo S et al. Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management. J Thorac Cardiovasc Surg 1995; 110: 4–13. 29. Keenan RJ, Lega ME, Dummer JS et al. Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation. Transplantation 1991; 51: 433–438.
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30. Keller CA, Cagle PT, Brown RW, Noon G, Frost AE. Bronchiolitis obliterans in recipients of single, double, and heart-lung transplantation. Chest 1995; 107: 973–980. 31. Kroshus TJ, Kshettry VR, Savik K, John R, Hertz MI, Bolman RM. Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg 1997; 114: 195–202. 32. Duncan SR, Grgurich WF, Iacono AT et al. A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation. Am J Respir Crit Care Med 1994; 150: 146–152. 33. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002; 21: 559–566. 34. Hohlfeld J, Niedermeyer J, Hamm H, Schafers HJ, Wagner TO, Fabel H. Seasonal onset of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996; 15: 888–894. 35. Berkowitz N, Schulman LL, McGregor C, Markowitz D. Gastroparesis after lung transplantation. Potential role in postoperative respiratory complications. Chest 1995; 108: 1602–1607. 36. 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. 37. Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant 2002; 21: 271–281. 38. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002; 21: 559–566. 39. Husain S, Singh N. Bronchiolitis obliterans and lung transplantation: evidence for an infectious etiology. Semin Respir Infect 2002; 17: 310–314. 40. Metras D, Viard L, Kreitmann B et al. Lung infections in pediatric lung transplantation: experience in 49 cases. Eur J Cardiothorac Surg 1999; 15: 490–494. 41. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002; 166: 440–444.
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42. Ibrahim JE, Sweet SC, Flippin M et al. Rejection is reduced in thoracic organ recipients when transplanted in the first year of life. J Heart Lung Transplant 2002; 21: 311–318. 43. Date H, Lynch JP, Sundaresan S, Patterson GA, Trulock EP. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J Heart Lung Transplant 1998; 17: 869–875. 44. Verleden GM, Buyse B, Delcroix M et al. Cyclophosphamide rescue therapy for chronic rejection after lung transplantation. J Heart Lung Transplant 1999; 18: 1139–1142. 45. Dusmet M, Maurer J, Winton T, Kesten S. Methotrexate can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996; 15: 948–954. 46. O’Hagan AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999; 115: 1459–1462. 47. Diamond DA, Michalski JM, Lynch JP, Trulock EP III. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation. Int J Radiat Oncol Biol Phys 1998; 41: 795–800. 48. Roman A, Bravo C, Monforte V, Reyes L, Canela M, Morell F. Preliminary results of rescue therapy with tacrolimus and mycophenolate mofetil in lung transplanted patients with bronchiolitis obliterans. Transplant Proc 2002; 34: 146–147. 49. Ross DJ, Lewis MI, Kramer M, Vo A, Kass RM. FK 506 ’rescue’ immunosuppression for obliterative bronchiolitis after lung transplantation. Chest 1997; 112: 1175–1179. 50. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003; 168: 121–125. 51. Whitford H, Walters EH, Levvey B et al. Addition of inhaled corticosteroids to systemic immunosuppression after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002; 73: 1793–1799. 52. Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003; 167: 1271–1278.
RECENT ADVANCES
An overview of paediatric lung transplantation Marlyn S. Woo Cardiothoracic Transplant Center, Childrens Hospital Los Angeles and Keck School of Medicine at the University of Southern California, Los Angeles, California, USA KEYWORDS paediatric; lung transplant; living donor lobar; bronchiolitis obliterans; outcome; lung growth; medical non-adherence
Summary Paediatric lung transplantation is indicated in selected children with end-stage lung disease that is not amenable to conventional medical or surgical therapy. The indications and complications differ from adult lung transplant patients. Due to the long waiting times for suitable cadaveric lungs, other types of lung transplantation, such as living donor lobar and split-lung procedures, have been utilised in paediatric patients. Unlike adult candidates, cystic fibrosis and primary pulmonary hypertension are the primary indications. Most recipients are in the adolescent age group. Complications that occur with greater frequency in paediatric lung recipients include somatic growth and graft function, post-transplant lymphoproliferative disease and medical non-adherence. While long-term outcome remains similar between adult and paediatric lung transplant recipients, there is a lower risk of bronchiolitis obliterans in very young recipients and in those who receive living donor lobar lung transplantation. Research into these clinical problems is hampered by the fact that only a small number of paediatric transplants are performed at each centre. Hence, improvement in outcome for these children will be dependent on developing methods to produce better tolerance, understanding the mechanisms/treatment of bronchiolitis obliterans and multi-centre studies that focus on the problems that primarily affect the paediatric lung transplant recipient. ß 2004 Elsevier Ltd. All rights reserved.
INTRODUCTION
INDICATIONS
Lung transplantation is no longer considered an experimental procedure for children with end-stage lung disease. The number of children undergoing lung transplantation has been increasing steadily since Cooley’s heart–lung transplant into a 2-month-old infant in 1968. However, children comprise only a small proportion of all lung transplant procedures. As a result, the published literature related to paediatric lung transplantation consists primarily of single-centre reports based on relatively few patients. The vast majority of these reports are descriptive or retrospective analyses. Although children have different primary indications and somewhat different complications, survival is comparable with adult recipients.1
For children, the most common indication for lung transplantation is cystic fibrosis. Hence, it is not surprising that most paediatric lung transplant patients are adolescents (Fig. 1).1 Other disease processes leading to lung transplant referral include primary pulmonary hypertension, nontransplant-associated bronchiolitis obliterans (OB) and congenital heart disease (Table 1).1 Less common causes for referral include alveolar capillary dysplasia, surfactant protein B deficiency, pulmonary veno-occlusive disease, pulmonary arteriovenous malformations, idiopathic pulmonary haemosiderosis and idiopathic pulmonary fibrosis. Unfortunately, these lung diseases all have a predilection for abrupt, rapid clinical deterioration that lead to high risk of death while awaiting a cadaveric lung transplant. Unlike candidates for heart or liver transplantation, lung transplant candidates have the double disadvantage of organ allocation based on length of time on the waiting list, as well as a lower number of suitable organs available from cadaveric
Correspondence to: Marlyn S. Woo, Division of Paediatric Pulmonology; Mailstop #83, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA Tel.: þ1 323 669 2101; fax: þ1 323 664 9758; E-mail: [email protected] 1526–0542/$ – see front matter
ß 2004 Elsevier Ltd. All rights reserved.
250
M. S. WOO
Table 2 Recipient criteria for living donor lobar lung transplantation.
Figure 1 Age distribution of paediatric lung transplant recipients. Paediatric lung transplants from January 1986 to June 2002.
organ donors. It has been estimated that less than 25% of multi-organ donors provide cadaveric lungs.2 Limited data suggest that outcomes from the use of organs falling outside of the standard criteria for lung donor quality may be acceptable.3 However, there is a reluctance to place ‘suboptimal’ lungs into children. For this reason, other lung transplant procedures, such as living donor lobar4 and splitlung procedures,5 have been utilised for patients who would not be expected to survive to receive a suitable cadaveric transplant.
LIVING DONOR LOBAR LUNG TRANSPLANTATION Although available in only a few centres around the world, living donor lobar lung transplantation has been performed successfully in over 150 patients. It is performed primarily in candidates who are not expected to survive to receive cadaveric lungs. Candidates for living donor lobar proceTable 1 tion.
Primary indications for paediatric lung transplanta-
Diagnosis Cystic fibrosis Primary pulmonary hypertension Congenital heart disease Idiopathic pulmonary fibrosis Pulmonary vascular disease Re-transplant (non-OB) Re-transplant (OB) OB (not transplant-related) Bronchiectasis COPD/emphysema Other
Age <1 year
Age 1–10 years
7%
34.1% 14.6%
48.9% 12.2% 7.3%
11.6% 7.3% 3.7% 4.9% 6.1% 3.7%
1.2% 14.6%
1.2% 11.6%
OB, bronchiolitis obliterans; COPD, chronic obstructive pulmonary disease.
End-stage lung disease that has failed medical management No significant liver disease No significant kidney disease No multiply-resistant organisms No active or recent psychiatric disease Adequate psychosocial support No medical compliance problems (by candidate or caregivers) Age > 7 years (depends on height) HIV negative Availability of at least two suitable donors (for bilateral lobar procedure) HIV, human immunodeficiency virus.
dures must meet the same criteria as those for cadaveric lung transplant. In fact, all living donor lobar candidates are also listed for cadaveric organs. The indications, surgical procedure and paediatric outcomes for living donor lobar transplant have been published previously.4,6 However, it is important to note that this type of transplant should not be left for ‘emergency’ or last-minute referral. Both the lung transplant candidate and the prospective lobar donors would be placed at risk without a careful and thorough evaluation. Indications for referral for living donor lobar lung transplantation, as well as guidelines for lobar donor candidates, are listed in Tables 2 and 3.
COMPLICATIONS Irrespective of the type of procedure, all lung transplant patients are at risk from complications related to their surgery and immunosuppressive medication. The cause of morbidity is related to the time after lung transplantation Table 3
Candidates for living donor lobar donation.
No coercion (emotional or financial) Must have prior relationship with proposed recipient/family ABO compatible with prospective donor Preferably at least 4 inches taller than prospective donor Age 18–55 years Non-smoking No significant past medical history No recent viral infections (no active EBV, hepatitis) Normal echocardiogram and electrocardiogram Normal coronary angiography (if indicated) Normal chest radiograph Oxygen tension > 80 mmHg on room air FEV1 and FVC > 85% predicted No significant pulmonary pathology on CT scan (must be completely normal on donor side) No previous thoracic surgery on donor side EBV, Epstein–Barr virus; CT, computed tomography.
AN OVERVIEW OF PAEDIATRIC LUNG TRANSPLANTATION
Table 4 Paediatric lung transplant morbidity at 1 and 5 years after transplant. Condition
Within 1 year
Within 5 years
Hypertension Renal dysfunction Abnormal creatinine <2.5 mg/dl Creatinine >2.5 mg/dl Chronic dialysis Renal transplant Hyperlipidaemia Diabetes Bronchiolitis obliterans
37.7% 7.6% 5.1% 1.6% 0.6% 0.3% 0.9% 21% 14.7%
73.7% 24.1% 12.1% 6.9% 3.4% 1.7% 1.7% 31% 20.5%
(Table 4).1 This article will focus on problems that are more common in children than adult lung transplant patients.
Linear growth and lung graft function A problem unique to paediatric lung transplant recipients is lung growth and graft function. There have been many reports of lung transplant recipients who received transplants in infancy and childhood and who subsequently underwent significant somatic growth. Those without evidence of OB often have spirometry values within the normal range. Animal studies suggest that lungs transplanted into immature recipients do grow.7,8 Using serial imaging measurements, a small retrospective study found that airway growth in humans does occur.9 However, assessment of alveolar growth in humans is difficult. Routine measurements of pulmonary function primarily assess volumes of gas exchanged. Changes in these values may reflect an increase in the average volume of each alveolar unit rather than an increase in the number of alveoli. However, pulmonary function measurements following lung transplant can return to the normal range in infants10 and older children,11 suggesting that an increase in lung volume and gas exchange proportionate to somatic growth occurs. Measurement of the diffusing capacity for carbon monoxide (DLCO) provides a better estimate of gas exchange surface area but is not easily measured in infants. However, a significant increase in DLCO has been demonstrated in paediatric recipients of cadaveric and living donor lobar transplants.12 It is important to note, however, that the DLCO values did not continue to increase with linear growth in living donor lobar recipients, suggesting that the increase in lung volume was secondary to hyperinflation rather than new lung growth.12 The most important long-term factor impacting pulmonary allograft function in paediatric lung transplant recipients is OB. At 5 years after transplant, roughly half of lung transplant recipients will have signs of OB. Basic science and clinical research is ongoing, yet the aetiology of OB remains unknown.
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Post-transplant lymphoproliferative disease This poorly differentiated B-cell lymphoma is more common in paediatric patients who tend to be Epstein–Barr-virus naive at the time of transplantation. While it usually arises in the transplanted lung (nodule or density), it can also occur in the small bowel and central nervous system. Treatment consists of reduction in immunosuppression and, in more extensive cases, treatment with chemotherapy.13,14
Medical non-adherence Non-adherence to medical therapy, particularly not taking immunosuppressive medication regularly, is a common cause of graft failure/rejection in adolescent solid organ transplant recipients. Possible medical non-adherence should be considered in all patients who have widely fluctuating immunosuppression levels, recurrent acute rejection, complaints of Cushingoid appearance or weight gain, depression, missed routine clinic appointments or caregivers finding loose medication tablets/capsules (under cushions, in trash receptacles, etc.). Early referral to child psychiatry or psychology is important, as well as family counselling.
OUTCOME Just as the causes of morbidity are related to the time after transplant surgery, the primary causes of mortality change with the time since transplantation (Table 5).1 However, the factor most responsible for preventing long-term success of lung transplantation is OB. OB accounts for more than 40% of deaths that occur more than 1 year after transplant.15 The diagnosis of OB is made by tissue findings of small airways with lymphocytic infiltration, fibromyxoid deposits, subepithelial fibrosis and (in the advanced stages) total fibrous obliteration.16 It is often a focal process that is difficult to diagnose with transbronchial biopsy and even with open lung biopsy.17 To permit earlier treatment/intervention of OB, a set of clinical criteria for ‘OB syndrome’ (BOS) was developed based on unexplained obstructive decline in pulmonary function.18 A recent revision of the BOS clinical criteria recognised that percent predicted values rather than absolute Table 5
Primary cause of death after lung transplantation.
0–30 days
31 days–1 year
Graft failure Other Infection (non-CMV) Cardiovascular Technical
Infection (non-CMV) Bronchiolitis Graft failure Infection (non-CMV) Other Graft failure Bronchiolitis CMV Acute rejection Lymphoma
CMV, cytomegalovirus.
>1 year
Other Lymphoma Cardiovascular
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values should be used in assessment of the decline in FEV1 in paediatric recipients.19 Most clinical studies aimed at identifying risk factors for OB are generally retrospective, involving primarily adult populations. Acute rejection is the most consistently identified risk factor. Patients experiencing more frequent20 or more severe21 rejection episodes were more likely to develop OB. Paediatric living donor lobar recipients are noted to have a lower incidence of OB, probably due to the less frequent and less severe rejection episodes.22 Other studies supporting an immune mechanism for the aetiology of OB showed increased incidence in patients with lymphocytic bronchitis and bronchiolitis,23 human leukocyte antigen (HLA) mismatches24 and anti-HLA antibodies.25 Patients with decreased donor alloreactive (peripheral microchimerism and absence of donor antigen reactivity in bronchoalveolar lavage lymphocytes) had a lower incidence of OB.26,27 Infection, particularly with cytomegalovirus (CMV), has also been implicated in the aetiology of OB. There are several single-centre retrospective reports implicating CMV.25,28–31 In one centre, the use of ganciclovir prophylaxis against CMV infection reduced the incidence of OB in the first year after transplant.32 Indirect evidence suggests a role for community acquired viral infections in the development of OB.33,34 Besides infection, chronic aspiration related to gastroparesis has also been raised as a risk factor leading to OB.35 This association is supported by another clinical study which suggested that fundoplication improves lung function in patients with reflux.36 While there appears to be a number of reports linking bacterial infections with OB, there is no clear evidence that bacterial infections cause OB.28,37–39 Nonetheless, chronic infection seems to play a role in the development of OB40 and bacterial infection is a significant cause of death in OB patients.41 Very young children who underwent lung transplantation under the age of 3 years may have a lower risk for the development of OB. One retrospective, single-centre study found a decreased incidence of acute rejection in infants.42 A retrospective analysis of the author’s centre’s paediatric living donor lobar transplant recipients also found a lower incidence of OB.22 This lower incidence did not appear to be related to the degree of HLA matching but rather to the shorter ischaemic times for the living donor lobar grafts.22 There are no effective treatments for OB. At early detection/diagnosis of OB or BOS, therapy usually consists of augmentation of immunosuppression. The data supporting this therapy are mostly anecdotal or single-centre uncontrolled series. Reported treatments for OB include anti-thymocyte preparations,43 cyclophosphamide,44 methotrexate,45 photopheresis46 and total lymphoid irradiation.47 While all studies reported that some patients showed benefit, none were uniformly beneficial for all affected patients and none reversed OB. The use of tacrolimus as ‘rescue’ therapy may slow the decline in
M. S. WOO FEV1.48,49 A recent small uncontrolled pilot study suggested that azithromycin was beneficial,50 but a double-blinded, placebo-controlled study using inhaled fluticasone propionate showed no benefit.51 Another retrospective study of patients prescribed statins for hypercholesterolaemia found a lower incidence of OB and a better long-term survival.52 With the lack of effective medical therapy for OB, treatment is usually limited to re-transplantation. Given the scarcity of suitable organs and the growing number of lung transplant candidates, lung re-transplantation is fraught with medical and ethical challenges.
CONCLUSIONS Paediatric lung transplant recipients face many of the same challenges that confront adult recipients. There is a need to increase the donor lung pool for all lung transplant candidates. Better strategies to achieve effective and prolonged tolerance while minimising the toxicity of immunosuppressive agents will improve long-term function and prevent the cumulative morbidity associated with current regimens. Discovering the mechanism of OB, as well as earlier detection, will help us achieve longer graft function for all lung transplant recipients. However, we need more sensitive methods than decline in FEV1 for detecting OB and its response to therapy. There are issues that are unique to the child who undergoes lung transplant surgery. Research in paediatric lung transplantation is limited by the relatively small number of transplants performed at each centre. Multi-centre clinical studies are needed to determine the most appropriate monitoring and treatment regimens for paediatric lung transplant patients. In this manner, we can improve the outcomes of all children who undergo lung transplantation.
PRACTICE POINTS Cystic fibrosis and primary pulmonary hypertension are the primary indications for paediatric lung transplantation Less than 25% of multi-organ cadaveric donors can provide lungs for transplant Organ shortage has led to alternatives to cadaveric lungs: living donor lobar and split-lung procedures Paediatric and adult lung transplant recipients face many of the same complications Morbidity type is related to time after lung transplant Paediatric lung transplant recipients have complications that are not as common in adult recipients: linear growth and lung graft function, increased risk of post-transplant lymphoproliferative disease and medical nonadherence
AN OVERVIEW OF PAEDIATRIC LUNG TRANSPLANTATION
Cause of morbidity is also related to time after transplant surgery Mortality in the peri-operative period is primarily due to graft failure Mortality in the first year after transplant is primarily caused by non-CMV infection OB is the primary cause of death and the chief obstacle to long-term survival in lung transplant recipients who survive for more than 1 year after surgery There is no effective treatment for OB
RESEARCH DIRECTIONS Optimising the available cadaveric donor pool Producing better graft tolerance while reducing the side-effects of infection, hypertension and renal dysfunction OB: mechanisms, detection and effective therapy Unique challenges of transplant in children require multi-centre studies to determine the best monitoring and treatment regimens
REFERENCES 1. Boucek MM, Edwards LB, Keck BM et al. The Registry of the International Society for Heart and Lung Transplantation: Sixth Official Pediatric Report – 2003. J Heart Lung Transplant 2003; 22: 636–652. 2. Follette D, Rudich S, Bonacci C, Allen R, Hoso A, Albertson T. Importance of an aggressive multidisciplinary management approach to optimize lung donor procurement. Transplant Proc 1999; 31: 169– 170. 3. Straznicka M, Follette DM, Eisner MD, Roberts PF, Menza RL, Babcock WD. Aggressive management of lung donors classified as unacceptable: excellent recipient survival one year after transplantation. J Thorac Cardiovasc Surg 2002; 124: 250–258. 4. Starnes VA, Barr ML, Cohen RG. Lobar transplantation: indications, technique, and outcome. J Thorac Cardiovasc Surg 1994; 108: 403–411. 5. Couetil JP, Tolan MJ, Loulmet DF et al. Pulmonary bipartitioning and lobar transplantation: a new approach to donor organ shortage. J Thorac Cardiovasc Surg 1997; 113: 529–537. 6. Woo MS, MacLaughlin EF, Horn MV et al. Living donor lobar lung transplantation: the pediatric experience. Pediatr Transplantation 1998; 2: 185–190. 7. Binns OA, DeLima NF, Buchanan SA et al. Mature pulmonary lobar transplants grow in an immature environment. J Thorac Cardiovasc Surg 1997; 114: 186–194. 8. Ibla JC, Shamberger RC, DiCanzio J, Zurakowski D, Koka BV, Lillehei CW. Lung growth after reduced size transplantation in a sheep model. Transplantation 1999; 67: 233–240. 9. Ro PS, Bush DM, Kramer SS, Mahboubi S, Spray TL, Bridges ND. Airway growth after pediatric lung transplantation. J Heart Lung Transplant 2001; 20: 619–624. 10. Cohen AH, Mallory GB, Ross K et al. Growth of lungs after transplantation in infants and in children younger than 3 years of age. Am J Respir Crit Care Med 1999; 159: 1747–1751.
253
11. Sweet SC, Spray TL, Huddleston CB et al. Pediatric lung transplantation at St. Louis Children’s Hospital, 1990–1995. Am J Respir Crit Care Med 1997; 155: 1027–1035. 12. Sritippayawan S, Keens TG, Horn MV et al. Does lung growth occur when mature lobes are transplanted into children? Pediatr Transplantation 2002; 6: 500–504. 13. Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplantation 2002; 6: 456–464. 14. Straathof KC, Savoldo B, Heslop HE, Rooney CM. Immunotherapy for post-transplant lymphoproliferative disease. Br J Haematol 2002; 118: 728–740. 15. Boucek MM, Edwards LB, Keck BM et al. The Registry of the International Society for Heart and Lung Transplantation: Fifth Official Pediatric Report – 2001–2002. J Heart Lung Transplant 2002; 21: 827–840. 16. Yousem SA, Berry GJ, Cagle PT et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 1996; 15: 1–15. 17. Weill D, McGiffin DC, Zorn GL Jr et al. The utility of open lung biopsy following lung transplantation. J Heart Lung Transplant 2000; 19: 852–857. 18. Cooper JD, Billingham M, Egan T et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993; 12: 713–716. 19. Estenne M, Maurer JR, Boehler A et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002; 21: 297–310. 20. Sharples LD, Tamm M, McNeil K, Higenbottam TW, Stewart S, Wallwork J. Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation – early risk factors. Transplantation 1996; 61: 560–566. 21. Berry GJ, Brunt EM, Chamberlain D et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990; 9: 593–601. 22. Woo MS, MacLaughlin EF, Horn MV, Szmuszkovicz JR, Barr ML, Starnes VA. Bronchiolitis obliterans is not the primary cause of death in pediatric living donor lobar lung transplant recipients. J Heart Lung Transplant 2001; 20: 491–496. 23. Reichenspurner H, Girgis RE, Robbins RC et al. Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg 1996; 62: 1467–1472. 24. Chalermskulrat W, Neuringer IP, Schmitz JL et al. Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation. Chest 2003; 123: 1825–1831. 25. Smith MA, Sundaresan S, Mohanakumar T et al. Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome. J Thorac Cardiovasc Surg 1998; 116: 812–820. 26. Zeevi A, Rabinowich H, Yousem SA et al. Presence of donor-specific alloreactivity in histologically normal lung allografts is predictive of subsequent bronchiolitis obliterans. Transplant Proc 1991; 23: 1128–1129. 27. McSherry C, Jackson A, Hertz MI, Bolman RM III, Savik K, Reinsmoen NL. Sequential measurement of peripheral blood allogeneic microchimerism levels and association with pulmonary function. Transplantation 1996; 62: 1811–1818. 28. Bando K, Paradis IL, Similo S et al. Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management. J Thorac Cardiovasc Surg 1995; 110: 4–13. 29. Keenan RJ, Lega ME, Dummer JS et al. Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation. Transplantation 1991; 51: 433–438.
254
30. Keller CA, Cagle PT, Brown RW, Noon G, Frost AE. Bronchiolitis obliterans in recipients of single, double, and heart-lung transplantation. Chest 1995; 107: 973–980. 31. Kroshus TJ, Kshettry VR, Savik K, John R, Hertz MI, Bolman RM. Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg 1997; 114: 195–202. 32. Duncan SR, Grgurich WF, Iacono AT et al. A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation. Am J Respir Crit Care Med 1994; 150: 146–152. 33. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002; 21: 559–566. 34. Hohlfeld J, Niedermeyer J, Hamm H, Schafers HJ, Wagner TO, Fabel H. Seasonal onset of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996; 15: 888–894. 35. Berkowitz N, Schulman LL, McGregor C, Markowitz D. Gastroparesis after lung transplantation. Potential role in postoperative respiratory complications. Chest 1995; 108: 1602–1607. 36. 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. 37. Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant 2002; 21: 271–281. 38. Billings JL, Hertz MI, Savik K, Wendt CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002; 21: 559–566. 39. Husain S, Singh N. Bronchiolitis obliterans and lung transplantation: evidence for an infectious etiology. Semin Respir Infect 2002; 17: 310–314. 40. Metras D, Viard L, Kreitmann B et al. Lung infections in pediatric lung transplantation: experience in 49 cases. Eur J Cardiothorac Surg 1999; 15: 490–494. 41. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002; 166: 440–444.
M. S. WOO
42. Ibrahim JE, Sweet SC, Flippin M et al. Rejection is reduced in thoracic organ recipients when transplanted in the first year of life. J Heart Lung Transplant 2002; 21: 311–318. 43. Date H, Lynch JP, Sundaresan S, Patterson GA, Trulock EP. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J Heart Lung Transplant 1998; 17: 869–875. 44. Verleden GM, Buyse B, Delcroix M et al. Cyclophosphamide rescue therapy for chronic rejection after lung transplantation. J Heart Lung Transplant 1999; 18: 1139–1142. 45. Dusmet M, Maurer J, Winton T, Kesten S. Methotrexate can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996; 15: 948–954. 46. O’Hagan AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999; 115: 1459–1462. 47. Diamond DA, Michalski JM, Lynch JP, Trulock EP III. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation. Int J Radiat Oncol Biol Phys 1998; 41: 795–800. 48. Roman A, Bravo C, Monforte V, Reyes L, Canela M, Morell F. Preliminary results of rescue therapy with tacrolimus and mycophenolate mofetil in lung transplanted patients with bronchiolitis obliterans. Transplant Proc 2002; 34: 146–147. 49. Ross DJ, Lewis MI, Kramer M, Vo A, Kass RM. FK 506 ’rescue’ immunosuppression for obliterative bronchiolitis after lung transplantation. Chest 1997; 112: 1175–1179. 50. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003; 168: 121–125. 51. Whitford H, Walters EH, Levvey B et al. Addition of inhaled corticosteroids to systemic immunosuppression after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002; 73: 1793–1799. 52. Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003; 167: 1271–1278.