Is lung transplantation survival better in infants? Analysis of over 80 infants

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1 Is lung transplantation survival better in infants? Analysis of over 80 infants Muhammad S. Khan, MD, a,b Jeffrey S. Heinle, MD, a,b Andres X. Samayoa, MD, a,b Iki Adachi, MD, a,b Marc G. Schecter, MD, c George B. Mallory, MD, c and David L.S. Morales, MD d From the a Michael E. DeBakey Department of Surgery, Baylor College of Medicine; b Division of Congenital Heart Surgery, Texas Children s Hospital; c Section of Pulmonology, Department of Pediatrics, Baylor College of Medicine and Texas Children s Hospital, Houston Texas; and d Congenital Heart Surgery, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio. KEYWORDS: lung transplantation; infants; pediatrics; outcomes; survival BACKGROUND: There have been 41,600 pediatric lung transplantations (LTx) performed worldwide with a trend toward improved outcomes over the last 25 years. The majority of these LTxs have been in older children and adolescents. Less than 4 infant (defined as r12 months of age) LTxs per year have been performed over the past 20 years, mostly in the USA. However, infant LTx outcomes have not been well documented in a multi-institutional longitudinal fashion. METHODS: The United Network of Organ Sharing database was queried from October 1987 to July Of the 1,003 pediatric LTxs reported, 84 (8%) were infants. All combined transplantations were excluded. RESULTS: Eighty-one infants received 84 LTxs, of which 95% had a bilateral LTx. Median age and weight at LTx was 4 months (range 0 to 11 months) and 5.3 kg (2.7 to 11.8 kg), respectively. Median ischemic time was 5.2 hours (2.0 to 10.8 hours). Overall Kaplan Meier graft survival was similar for infants compared with other pediatric age group (OPA: 41 to 18 years) LTx recipients (half-life 4.0 years vs 3.4 years, p ¼ 0.7). Conditional 1-year graft survival for infants was significantly higher than OPA (half-life 7.4 years vs 5.0 years, p ¼ 0.024). Early (1987 to 2000, n ¼ 46) and late (2001 to 2011, n ¼ 38) era graft survival was not significantly different. Graft survival in pre-ltx ventilated infants was significantly better than pre-ltx ventilated OPA (half-life 6.1 years vs 0.9 year, p ¼ 0.004) and was not statistically different from pre-ltx infants not on ventilatory support (half-life 6.1 years vs 2.2 years, p ¼ 0.152). Cox regression of 5 variables (weight, donor arterial PO 2, pre-tx ventilator, organ ischemic time, center experience) showed that survival was associated with increased center experience (p ¼ 0.03). CONCLUSION: Infants undergoing LTx have outcomes similar to those of all other pediatric LTx patients. J Heart Lung Transplant 2013;32:44 49 r 2013 International Society for Heart and Lung Transplantation. All rights reserved. Pediatric lung transplantation (LTx) is an accepted therapy for selected infants, children and adolescents with end-stage lung and pulmonary vascular disease. There have Reprint requests: Muhammad S. Khan, MD, Division of Congenital Heart Surgery, Texas Children s Hospital, 6621 Fannin Street, WT19345H, Houston, TX Telephone: Fax: address: mshoaibkhan@hotmail.com /$ - see front matter r 2013 International Society for Heart and Lung Transplantation. All rights reserved. been 41,600 pediatric LTxs performed worldwide starting in October The vast majority of pediatric LTxs have been performed in older children and adolescents 1 with significantly fewer infant LTxs being reported. From 2000 through 2011, the median number of infant LTxs in the USA has been 4 per year. In contrast, there has been a median of 87 infant heart transplantations and 150 infant liver transplantations in the USA over the same time

2 Khan et al. Infant LTx in the USA 45 period. 2 Also, the number of centers performing infant LTx, according to the United Network of Organ Sharing (UNOS), has decreased over the 25 years with only 2 centers in the USA having performed infant LTx in the last 5 years. 2 Reports on overall pediatric LTx have shown a trend toward better outcomes related to improved early survival over time. 1,3 Infants, however, have been found in some reviews to have worse outcomes when compared with other age groups. 1 Single-center experiences with infant LTx have been published with variable results. The largest series was from St. Louis Children s Hospital, reporting 36 infants whose outcomes were no different than those of older children. 4 A general review of the UNOS database of all pediatric LTxs did not find a significant effect of age on graft or patient survival. 3 Despite this, LTx for infants has not been widely adopted. Because infant LTx outcomes have not been well documented in a multi-institutional longitudinal fashion, the objective of this study was to examine in detail the outcomes of all infant LTxs reported to the UNOS database in the last 25 years. Methods In 1984, the U.S. Congress created the Organ Procurement and Transplantation Network (OPTN) under the National Organ Transplant Act. The OPTN is a unified transplantation network administered by a private, non-profit organization, UNOS, which maintains a database of all transplantations in the USA. We used the UNOS database in this study. Approval for use of the OPTN data from the institutional review board at Baylor College of Medicine was obtained prior to the start of our investigation. The current study is a retrospective review of the OPTN data of all pediatric LTx patients from October 1987 to July For purposes of comparison, the pediatric cohort was divided into 2 groups based on age at primary LTx, defining infant LTx at the age r12 months and other pediatric age group (OPA) LTxs at the age 412 months but r216 months (18 years). Multi-organ transplantations (heart lung, lung liver, lung kidney) were excluded from the study cohort. Relevant variables, such as recipient gender, age and weight at LTx, diagnosis, waitlist time, use of ventilator and steroids prior to LTx and lung graft survival times, were analyzed and compared between the 2 age groups. Furthermore, differences in LTx graft survival were studied over the 25-year study period, divided into early (1987 to 2000) and late (2001 to 2011) eras. Graft survival was also analyzed with regard to centers that were more experienced with infant LTx (45 infant LTx) versus those with less experience (r5 infant LTxs). Waitlist removals were also looked at for different pediatric age groups from the OPTN data. Frequencies were calculated for categorical variables and means with standard deviations or medians with minimums and maximums were reported for the continuous variables. Categorical variables were compared using chi-square tests. Continuous variables were compared using Student s t-test and analysis of variance with Tukey s method to control for multiple comparisons. Survival analysis was carried out with Kaplan Meier and life-table methods and survival was compared between groups using the logrank test. A Cox regression model was used to determine the association between different risk factors and survival. p o 0.05 was considered statistically significant. Results Eighty-one infants received a total of 84 LTxs, 95% with bilateral LTxs, 42 (52%) were female, and 63 (78%) were Caucasian. Median age at LTx was 4 months (range 0 to 11 months) with a median weight at LTx of 5.4 kg (2.7 to 11.8 kg). There were 2 neonatal (within the first month Table 1 Characteristics of Infants and Other Pediatric Age Group (OPA) Lung Transplant (LTx) Recipients Characteristics Infants (n ¼ 84) OPA (n ¼ 919) p-value Median age at LTx (range) 4.0 mo (0 to 11 mo) 14 y (1 to 18 y) o Median weight at LTx (range) 5.3 kg (2.7 to 11.8 kg) 34.2 kg (4.9 to 95.7 kg) o Female (%) 44 (52) 541 (59) 0.25 Caucasian (%) 66 (79) 748 (81) 0.5 Bilateral LTx (%) 80 (95) 794 (86) 0.07 Era Early era (1987 to 2000) 46 (55) 437 (48) 0.2 Late era (2001 to 2011) 38 (45) 482 (52) Median ischemic time (range) 5.2 h (2.0 to 10.8 h) 5.1 h (0.5 to 12.0 h) 0.8 Mean waitlist time SD (days) o Pre-LTx steroid use (%) 29 (34) 289 (31) 0.8 Pre-LTx ventilator use (%) 60 (71) 116 (13) o Pre-LTx ECMO use (%) 4 (5) 13 (1.4) Centers performing LTx NA o5 LTxs from 2000 to 2011 (%) 7 (70) 30 (29) LTxs from 2000 to 2011 (%) 3 (30) 74 (71) Patient status at 5 years (%) Alive 24 (36) 237 (32) 0.9 Retransplanted 6 (9) 80 (11) Dead 37 (55) 415 (57) Bold indicates statistical significance. ECMO, extracorporeal membrane oxygenation; LTx, lung transplantation; NA, not applicable.

3 46 The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 Table 2 Proportion of Waitlist Withdrawals for Death by Age in Pediatric Lung Transplant Candidates, 1995 to 2011 Age (years) Transplants Waitlist death removals o Ratio LTx:death removal of life) LTxs performed during the study period. The most common diagnosis in patients requiring LTx was congenital diseases (n ¼ 20, 24%) surfactant dysfunction disorders (n ¼ 16, 19%) and idiopathic pulmonary hypertension (n ¼ 11, 13%). Median ischemic time was 5.2 hours (2.0 to 10.8 hours). Sixty infants or 71% were on mechanical ventilation at the time of transplantation. The median follow-up time was 2.8 years (8 days to 16 years). There were 45 (54%) deaths in the cohort. The 3 most common causes of death were graft failure in 12 (27%), respiratory failure in 9 (20%) and infection in 7 (16%). The cause of death was bronchiolitis for 1 (1%) patient. Of the 4 patients on pre- LTx extracorporeal membrane oxygenation (ECMO), 3 died within 3 months after LTx. Ten (12%) infants were retransplanted; 3 patients received their second LTx before 1 year of age. The waitlist time was found to be significantly shorter for infants than for OPA recipients (p o ) (Table 1). On the other hand, from 1995 through 2011, during which there were 76 infant LTxs, there were 52 waitlist withdrawals for death (Table 2). Of the 84 donors, 56 (67%) were infants, 45 (54%) were females, and 53 (63%) were Caucasians. The median weight at donation was 7.0 kg (2.3 to 56 kg) with a mean donor-torecipient weight ratio of and a mean height ratio of The most common cause of death in donors was head trauma (n ¼ 46, 55%) followed by anoxia (n ¼ 24, Figure 2 Lung transplantation (LTx) 1-year-conditional graft survival in infants and other pediatric age group (OPA) recipients. 29%). The mean PaO 2 at time of donation was mm Hg. Overall Kaplan Meier graft survival was similar for infants vs OPA recipients (half-life: 4.0 years vs 3.3 years, p ¼ 0.5) (Figure 1). However, conditional 1-year graft survival for infants was significantly better than for OPA recipients (half-life: 7.4 years vs 5.1 years, p ¼ 0.014) (Figure 2). Early (1987 to 2000, n ¼ 46) and late era (2001 to 2011, n ¼ 38) LTx graft survival was not significantly different for infants (late vs early era half-life: 4.6 years vs 3.1 years, p ¼ 0.6). A sub-group analysis of graft survival in ventilated patients showed that infants did significantly better than OPA recipients (half-life 6.1 years vs 0.9 year, respectively, p ¼ 0.004) (Figure 3). Although not statistically significant, graft survival of ventilated infants was found to be better Figure 1 Lung transplantation (LTx) graft survival in infants and other pediatric age group (OPA) recipients. Figure 3 Lung transplantation (LTx) graft survival in ventilated infants and other pediatric age group (OPA) recipients.

4 Khan et al. Infant LTx in the USA 47 than that of those not on mechanical ventilatory support at the time of LTx (half-life: 6.1 years vs 2.2 years, p ¼ 0.152). Cox regression of 5 variables showed a significant association between increased graft survival and more experienced centers in infant LTx (Table 3). Discussion Infant lung transplantation in the USA remains a rare surgical event with a median of 4 such transplants performed yearly, predominantly in 2 pediatric lung transplant centers. The low incidence of infant lung transplantation is likely explained by perceived unique challenges in this population. The much larger number of infant heart and liver transplants performed annually suggests that donor availability is unlikely to be a convincing explanation for the low numbers. Infants with end-stage lung disease have distinct underlying diagnoses, the most common of which are surfactant dysfunction disorders and congenital diseases. 1 Such etiologies have been thought to negatively impact survival after lung transplantation. 5 Many infants undergoing LTx have been intubated since birth and a small subset may have been or continue to be on ECMO support as well. 5 These pre-ltx critical states have been demonstrated to increase morbidity and mortality in pediatric LTx. 6 Also, the small size of these infants makes surgery more technically demanding, especially bronchial anastomoses. Post-surgery complications such as airway malacia and severe infection, especially susceptibility to primary viral infection, have been reported more frequently among infants. 7,8 Challenges in managing patients during long-term follow-up with lung biopsies and pulmonary function tests also exist for infants, which can potentially delay diagnosis and treatment of acute or chronic allograft dysfunction. 9 In this analysis we have focused on isolated LTx. Over the same 25-year observation period, there were 16 infant heart lung transplants. This group of patients is distinct enough that their inclusion would have affected the insights into infant LTx, which has been the primary focus of this investigation. Despite these issues and challenges, this analysis of the UNOS database demonstrates that LTx graft survival for infants is comparable to that of older children. Also, as with infants undergoing heart transplantation, 10 if the infants receiving LTx survive the early-phase hazard (first year), they have better conditional survival than the remainder of children undergoing LTx. Unlike the overall group of children undergoing LTx, where there is survival improvement over the passage of time, infants as a group have demonstrated improved survival from the pre- to post-2000 era. Furthermore, there has not been an increase in the number of infant LTxs done, perhaps because less active centers have stopped performing infant LTx. It is noteworthy that the infant cohort was found to be more frequently on pre-transplant ventilation (71% of the total) and ECMO support (5%), and hence in a more critical pre-ltx condition. Interestingly, the severity of their lung disease did not appear to impact graft survival in infants. In fact, they are the only age group in which pre-ltx ventilation was not associated with decreased survival. These results suggest that chronic respiratory failure and ICU location should not be considered contraindications in and of themselves in candidates selected for infant LTx. We can only speculate that the intrinsic recuperative potential of infants permits recovery from extended critical illness and major surgery in a way superior to older children and adolescents. Table 2 shows that a higher proportion of infants have died on the waitlist than in other pediatric age groups. Thus, although the wait time can be relatively short for infant LTx and the outcome despite mechanical ventilation in a significant proportion of transplanted infants is relatively good, this patient group is quite ill and has high waitlist mortality. The results of the current study are not entirely surprising in that earlier published studies have also shown that the infant LTx cohort has survival similar to that of all other pediatric LTx recipients. 3 It is impossible to discern the impact of underlying disease because the diseases that lead to infant lung transplant are so distinct from those of older children and adolescents. Furthermore, the limited nature of the OPTN data makes analysis of morbidity and true mechanisms of graft failure and death impossible. Nonetheless, the improved conditional 1-year graft survival for younger patients may be explained in a variety of ways. It is known that allograft rejection is a major cause of mortality and morbidity after thoracic transplantation in children. 11 Some studies have demonstrated that infant LTx grafts have lower rates of acute rejection and bronchiolitis obliterans. 12,13 Table 3 Cox Regression Analysis of Characteristics Impacting Lung Graft Survival in Infants 95% CI for Exp(B) Variables Significance Hazard ratio Lower Upper Weight PaO Ischemic time Ventilator support Less experienced center a a This was a binary variable: Z5 infant LTxs as a more experienced center and o5 infant LTxs as a less experienced center.

5 48 The Journal of Heart and Lung Transplantation, Vol 32, No 1, January 2013 A study of over 200 heart and LTxs demonstrated that age o1 year was a protective factor against early, late and multiple episodes of rejection. 13 It has been proposed that the immune systems of infants are more tolerant of transplanted organs than the immune systems of older children. 13 It can be surmised that the fewer rejection episodes seen in infants would contribute to improved graft survival. Another example of how immunologic immaturity and immune tolerance in infants may positively impact post-transplant graft function is the first (only) reported success of an ABO-incompatible LTx in an infant. 14 ABO-incompatible cardiac transplantation in infants is already a well-practiced strategy at many centers. The success of ABO-incompatible transplantation in infancy has been explained by different mechanisms, including elimination of donor-specific B lymphocytes, 15 development of resistance by graft cell to humoral injury, 16 and ineffective antibody binding to donor cells. 17 Proportionally more infants were on ECMO support prior to LTx than older children. However, with only 4 infants in this particular cohort, 3 of whom died after LTx, it is impossible to make general conclusions. Survival has been reported to be worse for pediatric patients bridged by ECMO to LTx, 6 and the current study has provided no evidence to the contrary. LTx in infants is an infrequently used therapy and curiously, over time, fewer centers have been performing infant LTx. Ten pediatric lung transplant centers have performed infant LTx in the last 25 years with only 3 centers ever performing 45 infant LTxs. Within the past 5 years, only 2 centers in the USA have been actively performing LTx in infants. Our multivariable regression analysis showed that the only variable significantly associated with mortality was low center experience with infant LTx (o5 infant LTxs). Centers with more robust experiences tend to have better outcomes, a finding common in the solid-organ transplant studies. This may be due to the more specialized needs of such small patients, which are better provided at experienced centers with a full multidisciplinary team. The definition of being an experienced center (45 transplants) in the current study is not widely agreed upon and definitions may vary. However, it needs to be acknowledged that with the passage of time fewer centers are performing lung transplantation in infants. Although there can be a multitude of reasons, a steep learning curve resulting in poor outcomes in the beginning due to a lack of experience may be a significant real or perceived barrier for a program to begin or resume transplanting infants. One study of pediatric LTx utilizing the UNOS database showed a significant improvement in graft survival in the recent era. 3 A similar analysis of infants did not a show a statistically significant improvement over the years. This again points toward the decline in the number of centers willing to perform LTx in infants. The need for reevaluating guidelines of donor and recipient selection and post-transplant management seems obvious. Another notable finding is the significantly shorter LTx waitlist time for infants compared with older children. This difference cannot be explained by the lung allocation system (LAS) in the USA, introduced in Duetolackof sufficient numbers to create a statistically sound model, organ allocation for patients o12 years of age did not change and is still based primarily on waiting time. 9 Interestingly, as indicated previously, over the 25 years, there has been a relatively large number of listed infants removed from the waitlist due to death. Because so few infant LTxs are performed each year, any infant listed for LTx may be the only transplant recipient on the list nationally. Furthermore, the most active centers, located in Missouri and Texas, are centrally located in the USA, so potential donors from the east to west coast may be possible. Last, the Organ Donation Breakthrough Collaborative, initiated in the USA several years ago, has generated a significant increase in awareness, organ procurement organization activity and organ donation. 19 These factors may contribute to a shorter waitlist time for infants, which may improve survival when analyzing all patients listed for transplantation. This study included an analysis of a national database which may have limitations in terms of accuracy and certainly with respect to completeness of data. Customized definitions for experienced centers and era analysis were used, which may have impacted our results. Age was only available in months and not days in the database, which could also have led to labeling errors. In conclusion, our data analysis has demonstrated that LTx can be a viable and beneficial management strategy for selected infants with end-stage lung disease. Our analysis also shows that commonly considered contraindications to transplantation, including compromised immunity, need for mechanical ventilation and waitlist time, do not seem to diminish survival after infant LTx. Overall, survival for infant LTx is similar to that of older children and teenagers undergoing LTx, whereas late (41 year conditional) survival and survival in certain uniformly high-risk cohorts (pre-ltx mechanical ventilation) appear to be better in the infant population compared with all other children undergoing LTx. Also, the waitlist time for infants, which has been a concern for many, is relatively short, albeit at the same time that death on the waitlist is relatively high. These results will hopefully encourage more centers to utilize LTx as an effective strategy to care for selected infants with end-stage lung disease. Disclosure statement The authors have no conflicts of interest to disclose. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This work was supported in part by the Health Resources and Services Administration (Contract C). The findings were presented at the 32nd annual meeting and scientific sessions of the International Society for Heart and Lung Transplantation, April 2012, Prague, Czech Republic. References 1. Benden C, Aurora P, Edwards LB, et al. The registry of the International Society for Heart and Lung Transplantation: fourteenth

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