- Email: [email protected]
Heart Transplantation in Children with Mitochondrial Disease
ORIGINAL ARTICLES Heart Transplantation in Children with Mitochondrial Disease Jeffrey G. Weiner, MD, MSCI1, Andrea N. Lambert, MD1, Cary Thurm, PhD2, Matt Hall, PhD2, Jonathan H. Soslow, MD, MSCI1, Tyler E. Reimschisel, MD, MHPE3, David W. Bearl, MD, MA1, Debra A. Dodd, MD1, Brian Feingold, MD, MS4, and Justin Godown, MD1 Objectives To compare the outcomes and comorbidities of children with mitochondrial disease undergoing heart transplantation with children without mitochondrial disease. Study design Using a unique linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, pediatric heart transplantation recipients from 2002 to 2016 with a diagnosis of cardiomyopathy were included. Post heart transplantation survival and morbidities were compared between patients with and without mitochondrial disease. Results A total of 1330 patients were included, including 47 (3.5%) with mitochondrial disease. Survival after heart transplantation was similar between patients with and without mitochondrial disease over a median follow-up of 4 years. Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P = .009), require a longer duration of mechanical ventilation after heart transplantation (3 days vs 1 day; P < .001), and have a longer intensive care unit stay after heart transplantation (10 vs 6 days; P = .007). The absence of a hospital readmission within the first post-transplant year was similar among patients with and without mitochondrial disease (61.7% vs 51%; P = .14). However, patients with mitochondrial disease who were readmitted demonstrated a longer length of stay compared with those without (median, 14 days vs 8 days; P = .03). Conclusions Patients with mitochondrial disease can successfully undergo heart transplantation with survival comparable with patients without mitochondrial disease. Patients with mitochondrial disease have greater risk for post-heart transplantation morbidities including stroke, prolonged mechanical ventilation, and longer intensive care unit and readmission length of stay. These results suggest that the presence of mitochondrial disease should not be an absolute contraindication to heart transplantation in the appropriate clinical setting. (J Pediatr 2019;-:1-6).
M
itochondrial disease is associated with the development of cardiomyopathy in up to 40% of patients.1 Mitochondrial disease is rare when considered individually, but as a group of conditions it is diagnosed with an estimated incidence of 1 in 5000 live births.2 Hypertrophic cardiomyopathy is the most common presentation of heart disease in this population, but dilated cardiomyopathy and left ventricular noncompaction also occur.1,3 In patients with mitochondrial disease, cardiomyopathy is the leading cause of death. Patients with mitochondrial disease and cardiomyopathy have a reported mortality of 82% at 16 years of age, compared with 5% mortality in those without evidence of cardiac involvement.1 The presence of cardiomyopathy may prompt consideration of heart transplantation in children with mitochondrial disease. However, there are limited data on heart transplantation outcomes in this population and the presence of mitochondrial disease may be considered a contraindication to heart transplantation by some centers.4 The aim of this project was to use a novel linkage between administrative and clinical registry data to identify and compare heart transplantation outcomes for children with mitochondrial disease compared with those without.
Methods This was a nested case-control study using a national cohort of patients with linked clinical and administrative data to compare transplantation outcomes in patients with and without mitochondrial disease.
ECMO ICU ICD PHIS SRTR
Extracorporeal membranous oxygenation Intensive care unit International Classification of Diseases Pediatric Health Information System Scientific Registry of Transplant Recipients database
From the 1Department of Pediatric Cardiology, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 2Children’s Hospital Association, Lenexa, KS; 3Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Nashville, TN; and the 4Department of Pediatrics and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, PA Supported through internal funding from the Katherine Dodd Faculty Scholar Program at Vanderbilt University (to J.G.). Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institute of Health (6T32HL105334-06 [to J.W.] and K23HL123938 [to J.S.] [Bethesda, Maryland]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.10.016
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
This study used a unique linkage between the Scientific Registry of Transplant Recipients database (SRTR; Hennepin Healthcare Research Institute, Minneapolis, Minnesota) and the Pediatric Health Information System (PHIS; Children’s Hospital Association, Lenexa, Kansas) administrative and billing database. Records were linked at the patient level using indirect identifiers, the results of which have been validated for accuracy and previously described.5 The SRTR data system includes data on all donors, waitlisted candidates, and transplant recipients in the US, submitted by the members of the Organ Procurement and Transplantation Network. The Health Resources and Services Administration, US Department of Health and Human Services provides oversight to the activities of the Organ Procurement and Transplantation Network and SRTR contractors. SRTR data are derived from multiple sources, including the Organ Procurement and Transplantation Network, transplant programs, organ procurement organizations, histocompatibility laboratories, the Centers for Medicare and Medicaid Services, and the National Technical Information Service’s Death Master File. The SRTR database includes data from every organ transplant and waitlist addition within the US since October 1987. The PHIS database is an administrative database that collects clinical and resource used data for hospital encounters from more than 50 large children’s hospitals. Data collected includes encounter-level diagnosis and procedural International Classification of Diseases (ICD)-9 and ICD-10 codes, payer information, and detailed billing data for inpatient hospitalizations, observation, ambulatory surgery, and emergency department visits.5 All pediatric patients who underwent heart transplantation with a diagnosis of cardiomyopathy were identified from the linked database for inclusion (2002-2016). For the purposes of this study, patients with ICD-9 or ICD-10 codes specific to mitochondrial disease (Table I; available at www.jpeds. com) at any encounter are designated as having mitochondrial disease, although confirmatory testing was not necessarily performed. The SRTR database did not contain codes for mitochondrial disease and was not used to identify patients with mitochondrial disease. Pretransplant clinical characteristics and post-transplant outcome data were derived from the linked dataset. The primary outcomes of interest included survival to discharge, graft survival, and freedom from readmission. Immediate postoperative outcomes assessed before discharge from the heart transplantation hospitalization included: rejection, pacemaker placement, cardiac reoperation, other surgical reoperation, chylothorax, use of extracorporeal membranous oxygenation (ECMO), dialysis, need for inhaled nitric oxide, intensive care unit (ICU) and total hospital length of stay, length of mechanical ventilation, and stroke. ICD codes indicating muscle weakness were also examined owing to the potential for a higher incidence in the mitochondrial disease population. Details of outcome identification are provided in Table II (available at www.jpeds.com). 2
Volume -
- 2019
Statistical Analyses Patient characteristics and outcomes after heart transplantation were compared between patients with and without mitochondrial disease. Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using the Fisher exact test, with a prespecified 2-sided alpha level of 0.05 considered the standard for statistical significance. To evaluate post-transplant graft survival, survival curves were generated using the Kaplan-Meier method (censoring at death, retransplantation, or last known follow-up) and compared using the log-rank test with a prespecified alpha level of 0.05 considered the standard for statistical significance. The Kaplan-Meier method was similarly used to evaluate freedom from readmission within the first post-transplant year among patients with and without mitochondrial disease. Power analysis and sample size calculations were not performed, because this was a retrospective analysis of all available data. All statistical analyses were performed in SAS version 9.4 (SAS Institute; Cary, North Carolina) or STATA version 15 (StataCorp LLC; College Station, Texas). To account for the observation that patients with mitochondrial disease were younger, smaller, and hospitalized longer preoperatively, the primary analysis was repeated using a matched control group. The control group was randomly selected (5 controls for every 1 subject) after matching for age (12 months), the need for ventricular assist device support, and the need for ventilator support at the time of heart transplantation. This project was approved by SRTR, PHIS, and the Vanderbilt University Institutional Review Board.
Results A total of 1330 patients with cardiomyopathy were identified from the linked database and included in the analysis. Of this group, 47 patients (3.5%) were identified with mitochondrial disease diagnosis codes (Figure 1; available at www.jpeds. com). The first occurrence of an ICD code defining mitochondrial disease was noted before the transplant admission in 14 patients (30%). For the remaining patients, the first occurrence of an ICD code defining mitochondrial disease occurred during (n = 25 [53%]) or after (n = 8 [17%]) the transplant admission. Patients with mitochondrial disease also had higher incident muscle weakness than those without (29.8% vs 3.5%; P < .001). Patient demographics and pretransplant clinical characteristics are shown in Table III. Patients with mitochondrial disease were significantly younger than those without (median age, 22 months vs 89 months; P = .004). Patients with mitochondrial disease were also significantly smaller at time of heart transplantation than those without (median weight, 11 kg vs 23 kg; P = .001). Of patients with mitochondrial disease, 39 (83%) had dilated cardiomyopathy, 6 (13%) had hypertrophic cardiomyopathy, and 1 patient each had left ventricular Weiner et al
- 2019
ORIGINAL ARTICLES
Table III. Pretransplant clinical characteristics Characteristics Male Age (months) at heart transplantation Weight (kg) at heart transplantation Type of cardiomyopathy Dilated Restrictive Hypertrophic Other Status at heart transplantation 1A 1B 2 IV Inotrope requirement VAD before heart transplantation ECMO before heart transplantation Pretransplant length of stay (days) iNO before heart transplantation Muscle weakness
Without mitochondrial disease (n = 1283)
With mitochondrial disease (n = 47)
650 (50.7) 89 (14-168) 23 (9-50)
26 (55.3) 22 (8-74) 11 (7-20)
1008 (78.6) 154 (12) 73 (5.7) 48 (3.7)
39 (83.0) 0 (0) 6 (12.7) 2 (4.3)
1105 (86.1) 111 (8.7) 67 (5.2) 642 (50) 368 (28.7) 58 (4.5) 23 (1-60) 46 (3.6) 45 (3.5)
42 (89.4) 1 (2.1) 4 (8.5) 21 (44.7) 17 (36.2) 0 (0) 41 (12-82) 2 (4.3) 14 (29.8)
P value .56 .004 .001 .006
.15
.55 .26 .26 .004 .69 <.001
iNO, inhaled nitric oxide; VAD, ventricular assist device. For categorical variables, Fisher exact test used. For continuous variables, Wilcoxon rank-sum used. Values are number (%) or median (IQR). Bold values indicate P < 0.05.
noncompaction and histiocytoid cardiomyopathy. No patients with mitochondrial disease carried a diagnosis of restrictive cardiomyopathy. Patients with mitochondrial disease had a significantly longer hospital length of stay before heart transplantation (median, 41 days vs 23 days; P = .004). There were no significant differences in sex, United Network for Organ Sharing listing status, use of mechanical circulatory support, inotropic support, or inhaled nitric oxide at the time of heart transplantation between those with and without mitochondrial disease. Unmatched outcomes after heart transplantation are shown in Table IV. The in-hospital mortality after heart transplantation was not different between those with and without mitochondrial disease (2.1% vs 1.8%; P = .58).
Patients with mitochondrial disease had a significantly higher prevalence of postoperative stroke (11.1% vs 2.7%; P = .009), longer length of stay after heart transplantation (median, 23 vs 15 days; P < .001), longer ICU length of stay (median, 10 days vs 6 days; P = .007), and longer duration of mechanical ventilation after heart transplantation (median, 3 days vs 1 day; P < .001). Patients requiring mechanical support (either ventricular assist device support or ECMO) before transplantation had a significantly higher prevalence of stroke after heart transplantation than patients without pretransplant mechanical stroke (Table V; available at www.jpeds.com). When adjusting for the use of mechanical support before heart transplantation, mitochondrial disease is independently associated with
Table IV. Unadjusted outcomes after heart transplantation Outcomes In-hospital mortality Stroke ECMO after heart transplantation Nitric oxide Dialysis Rejection Pacemaker Chylothorax Cardiac surgery Noncardiac surgery Tracheostomy Post heart transplantation hospital length of stay (days) ICU length of stay (days) Time requiring mechanical ventilation (days) Time requiring inhaled nitric oxide (days) Readmission within 1 year of heart transplantation Readmission length of stay (days)
No mitochondrial disease (n = 1283)
Mitochondrial disease (n = 47)
P value
23 (1.8) 34 (2.7) 99 (7.7) 567 (44.3) 35 (2.74) 131 (11.2) 6 (0.5) 38 (3.0) 49 (4.9) 93 (9.4) 20 (1.6) 15 (11-24)
1 (2.1) 5 (11.1) 3 (6.4) 17 (36.2) 1 (2.3) 4 (8.5) 0 (0) 0 (0) 2 (5.6) 5 (13.2) 2 (4.3) 23 (13-47)
.58 .009 0.51 .29 0.66 .81 0.81 .64 .69 .39 .18 <.001
6 (4-13) 1 (1-4)
10 (4-28) 3 (2-9)
.007 <.001
3 (2-4) 29 (61.7)
.43 .14
14 (8-23)
.03
3 (2-5) 644 (51) 8 (4-19)
For categorical variables, Fisher exact test used. For continuous variables, Wilcoxon rank-sum used. Values are number (%) or median (IQR). Bold values indicate P < 0.05.
Heart Transplantation in Children with Mitochondrial Disease
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Figure 2. Kaplan-Meier survival analysis comparing freedom from death or retransplantation between recipients of heart transplant with and without mitochondrial disease.
higher prevalence of stroke after heart transplantation (Table VI; available at www.jpeds.com). No statistically significant differences were noted between the 2 groups in terms of the need for ECMO, inhaled nitric oxide, pacemaker placement, dialysis, cardiac or noncardiac surgery, or in the prevalence of chylothorax or rejection before hospital discharge after heart transplantation. There was no difference in post-transplant graft survival in patients with mitochondrial disease compared with those without (P = .57) with a median follow-up of 4 years (range, 1-11 years) (Figure 2). In the first year after hospital discharge, there was no difference in the frequency of readmission between patients with and without mitochondrial disease (61.7% vs 51%; P = .14). Similarly, no significant difference was shown in time to readmission for patients with mitochondrial disease compared with those without (P = .22) (Figure 3). However, when readmitted to the transplant hospital, patients with mitochondrial disease had a significantly longer length of stay compared with those without (median, 14 days vs 8 days; P = .03). Results of the secondary matched analysis are summarized in the supplemental material. When matched for age, ventricular assist device support, and ventilator support, the prevalence of stroke after heart transplantation remained 4
significantly higher in the mitochondrial disease group (11.1% vs 2.1%; P = .01) (Table VII; available at www. jpeds.com). Similar to the primary analysis, there was no difference in post-transplant graft survival between patients with and without mitochondrial disease (P = .75) when using a matched control group (Figure 4; available at www. jpeds.com).
Discussion There are limited prior data describing transplant outcomes in patients with mitochondrial disease. Case reports and case series describe successful transplantation in patients with cardiomyopathy secondary to mitochondrial disease.6-11 Bates et al describe a series of 5 patients with cellular evidence of mitochondrial disease (using endomyocardial biopsy before transplantation), but with no manifestation of disease in other organs. These patients had normal courses after heart transplantation.7 In addition, several cases of heart transplantation in patients with mitochondrial disease with isolated cardiac disease have been reported.6,8 Other case reports exist that highlight transplantation in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes who also had successful outcomes.9,12 Conversely, Parikh et al caution against solid organ transplantation in this Weiner et al
- 2019
ORIGINAL ARTICLES
Figure 3. Kaplan-Meier survival curve comparing freedom from readmission in the first year after transplant between patients with and without mitochondrial disease.
population, citing postoperative complications and graft failure in 6 of 11 heart transplant recipients.4 Patients in our analysis likely represent a select cohort with minimal comorbidities. Patients with mitochondrial disease and significant extracardiac manifestations are more likely to be precluded from transplant candidacy. The use of an mitochondrial disease code was made in only 30% of patients during a hospitalization before heart transplantation with the majority of patients receiving this diagnostic code during or after their heart transplantation admission. This finding suggests that, for some patients, transplant providers may have been unaware of the mitochondrial disease diagnosis at the time of listing for heart transplantation. Although our data support that heart transplantation in this group can achieve similar outcomes to patients without mitochondrial disease, these data may not be generalizable to patients with mitochondrial disease and significant extracardiac comorbidities, and careful assessment of transplant candidacy for each patient is warranted. When considering morbidity patterns in these patients, it is notable that patients with mitochondrial disease demonstrate a significantly higher prevalence of stroke after heart transplantation than those without. Multiple possible explanations could account for this finding. Several mitochondrial diseases, most notably mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, confer a higher risk of metabolic stroke. It is also possible that having any level of impaired mitochondrial function, coupled with the stress of heart failure, cardiopulmonary bypass, and postoperative recovery can increase the risk of stroke-like episodes. Patients with mitochondrial disease required a longer duration of mechanical ventilation in the post-transplant period and had longer post-transplant total and ICU lengths
of stay. Although the etiology for these findings cannot be precisely determined in our analysis, the presence of muscle weakness (whether apparent or subclinical) in patients with mitochondrial disease may prolong the need for postoperative positive pressure ventilation, resulting in a longer posttransplant length of stay. Patients with mitochondrial disease did demonstrate a significantly higher incidence of muscle weakness, supporting this as a possible etiology for our findings. Given that we found no difference in other posttransplant complications including rejection, dialysis, ECMO, pacemaker, and cardiac or noncardiac reoperation, it is reasonable to consider the significant difference in mechanical ventilation time as a likely contributor to the prolonged length of stay. Although the length of stay after transplantation is increased in patients with mitochondrial disease, readmission after transplantation are similar between groups. However, when patients with mitochondrial disease are readmitted to the hospital, they again demonstrate a significantly longer length of stay compared with patients without mitochondrial disease. The etiology of this finding is unclear and warrants further investigation. The greater prevalence of metabolic stroke and muscle weakness in patients with heart transplantation with mitochondrial disease should inform physicians in their perioperative management of this population. As an example, this population may benefit from different ventilation strategies given their propensity for impaired respiratory mechanics. It can be hypothesized that the higher prevalence of metabolic stroke is a result of metabolic demand and impaired respiratory chain metabolism, for which prophylaxis would be difficult. Knowledge of this risk can be used to inform counseling before heart transplantation and to prepare
Heart Transplantation in Children with Mitochondrial Disease
5
THE JOURNAL OF PEDIATRICS
www.jpeds.com
the ICU for careful neurologic monitoring after heart transplantation. There are inherent limitations to this study. The diagnosis of mitochondrial disease is challenging, and assessment of these diagnoses using ICD codes may introduce error owing to miscoding. This may result in patients with mitochondrial disease who were not identified, or patients without mitochondrial disease incorrectly labelled as having mitochondrial disease. Unfortunately, there are limited options to validate this classification within the linked database. Although the linkage between SRTR and PHIS provides a platform to assess transplantation outcomes in this population, it does not contain data from all pediatric transplant centers. Therefore, it may miss some patients with mitochondrial disease who have undergone heart transplantation. In addition, the SRTR-PHIS linkage does not include patients who were listed but not transplanted; therefore, waitlist outcomes for this group are not known. Also, there is likely a selection bias in patients with mitochondrial disease listed, with only the “healthiest” patients progressing to transplantation. Although ICD coding allowed identification of patients with probable mitochondrial disease, there may be inaccuracies in coding and limited options to verify these data. Additionally, “mitochondrial disease” is a heterogeneous term representing a host of rare diseases with similar cellular physiology but potentially variable pathology; comparing postoperative morbidity among these patients may be biased by a preponderance of one specific diagnosis. Unfortunately, ICD-9 codes do not allow identification of specific forms of mitochondrial disease. This improved with ICD-10 coding, but only a minority of our patients had these codes, limiting our ability to define specific forms of mitochondrial disease. When considering stroke, data were not available to compare those with metabolic stroke (more inherent in the mitochondrial disease population) to embolic or ischemic stroke. These results suggest that a diagnosis of mitochondrial disease alone should not serve as an absolute contraindication to heart transplantation. However, because of the likely selection bias in our cohort, these data may not be generalizable to all patients with mitochondrial disease and each patient
6
Volume -
should be evaluated on an individual basis to determine transplant candidacy. n Submitted for publication Aug 5, 2019; last revision received Sep 19, 2019; accepted Oct 9, 2019. Reprint requests: Jeffrey G. Weiner, MD, MSCI, Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center, Department of Pediatric Cardiology, 2200 Children’s Way, Suite 5230 DOT, Nashville, TN 37232-9119. E-mail: [email protected]
References 1. Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO, Neish SR, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004;114:925-31. 2. Bannwarth S, Procaccio V, Lebre AS, Jardel C, Chaussenot A, Hoarau C, et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet 2013;50:704-14. 3. Limongelli G, Tome-Esteban M, Dejthevaporn C, Rahman S, Hanna MG, Elliott PM. Prevalence and natural history of heart disease in adults with primary mitochondrial respiratory chain disease. Eur J Heart Fail 2010;12:114-21. 4. Parikh S, Karaa A, Goldstein A, Ng YS, Gorman G, Feigenbaum A, et al. Solid organ transplantation in primary mitochondrial disease: proceed with caution. Mol Genet Metab 2016;118:178-84. 5. Godown J, Thurm C, Dodd DA, Soslow JH, Feingold B, Smith AH, et al. A unique linkage of administrative and clinical registry databases to expand analytic possibilities in pediatric heart transplantation research. Am Heart J 2017;194:9-15. 6. Golden AS, Law YM, Shurtleff H, Warner M, Saneto RP. Mitochondrial electron transport chain deficiency, cardiomyopathy, and long-term cardiac transplant outcome. Pediatr Transplant 2012;16:265-8. 7. Bates MG, Nesbitt V, Kirk R, He L, Blakely EL, Alston CL, et al. Mitochondrial respiratory chain disease in children undergoing cardiac transplantation: a prospective study. Int J Cardiol 2012;155:305-6. 8. Santorelli FM, Gagliardi MG, Dionisi-Vici C, Parisi F, Tessa A, Carrozzo R, et al. Hypertrophic cardiomyopathy and mtDNA depletion. Successful treatment with heart transplantation. Neuromuscul Disord 2002;12:56-9. 9. Bhati RS, Sheridan BC, Mill MR, Selzman CH. Heart transplantation for progressive cardiomyopathy as a manifestation of MELAS syndrome. J Heart Lung Transplant 2005;24:2286-9. 10. Schmauss D, Sodian R, Klopstock T, Deutsch MA, Kaczmarek I, Roemer U, et al. Cardiac transplantation in a 14-yr-old patient with mitochondrial encephalomyopathy. Pediatr Transplant 2007;11:560-2. 11. Bonnet D, Rustin P, Rotig A, Le Bidois J, Munnich A, Vouhe P, et al. Heart transplantation in children with mitochondrial cardiomyopathy. Heart 2001;86:570-3. 12. Fayssoil A. Heart diseases in mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome. Congest Heart Fail 2009;15:284-7.
Weiner et al
- 2019
ORIGINAL ARTICLES
Figure 1. Identifying the patient population. Flow diagram describing the patient selection process.
Heart Transplantation in Children with Mitochondrial Disease
6.e1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Figure 4. Kaplan-Meier survival analysis comparing freedom from death or retransplantation between recipients of heart transplant with mitochondrial disease and age- and support-matched controls.
Table I. Identifying the patient population ICD-9/10 codes 277.87* E78.71 E88.40 E88.41 E88.42 E88.49 G71.3 H49.81 H49.811 H49.812 H49.813 H49.819
Diagnosis Disorders of mitochondrial metabolism Barth syndrome Mitochondrial metabolism disorder, unspecified MELAS syndrome MERRF syndrome Other mitochondrial metabolism disorders Mitochondrial myopathy, not elsewhere classified Kearns-Sayre syndrome Kearns-Sayre syndrome, right eye Kearns-Sayre syndrome, left eye Kearns-Sayre syndrome, bilateral Kearns-Sayre syndrome, unspecified eye
MELAS, mitochondrial encephalopathy, lactic acidosis, and stroke; MERRF, mitochondrial encephalopathy with ragged red fibers. ICD-9 and -10 codes shown in this Table were used to query the linked PHIS and SRTR database. Patients with any combination of the above diagnoses at pretransplantation, transplantation, or post-transplantation hospitalizations were included for analysis. *Denotes ICD-9. Other codes listed are ICD-10.
6.e2
Weiner et al
- 2019
ORIGINAL ARTICLES
Table II. Identifying patient outcomes Outcomes Muscle weakness Chylothorax Stroke Dialysis Pacemaker Rejection Cardiac reoperation Other operation iNO after transplantation In-hospital mortality ECMO post-transplant Total LOS ICU LOS Days of ventilation Days of iNO Readmission LOS Status and date of last known follow-up
SRTR
PHIS
– – REC_POSTX_STROKE REC_POSTX_DIAL REC_POSTX_PACEMAKER REC_POSTX_DRUG_TREAT_REJ REC_POSTX_CARDIAC_REOP REC_POSTX_SURG – – – – – – – – X
ICD-9: 728.87, V46.3, 359.89, ICD-10: M62.81, Z99.3, G71.3, G71.8, G72.89 ICD-9: 457.8, ICD-10: I89.8 – – – – – – CTC code: 521173 PHIS flag CTC code: 521180-521182 X X X X X
iNO, inhaled nitric oxide; LOS, length of stay. ICD-9 and -10 and SRTR codes shown in this Table were used to query the linked PHIS and SRTR database to identify patient characteristics before transplantation and outcomes after transplantation. X denotes that length of stay data was derived from the respective data bank.
Table V. Univariate analysis of stroke and mechanical support Variables VAD (n = 381) ECMO (n = 58) No mechanical support (n = 893)
Stroke
No stroke
P value
21 (5.5) 8 (13.7) 13 (1.5)
360 (94.5) 50 (86.3) 880 (98.5)
.001 <.001 <.001
VAD, ventricular assist device. ECMO in this Table refers to ECMO use before heart transplantation. Data were compared using Fisher exact test. Values are number (%). Bold values indicate P < 0.05.
Heart Transplantation in Children with Mitochondrial Disease
Table VI. Multivariable analysis of stroke Variables
aOR
95% CI
P value
Mitochondrial disease ECMO before transplantation VAD before transplantation
5.37 8.6 3.23
1.9-14.7 3.62-20.4 1.67-6.26
<.001 <.001 <.001
ECMO in this Table refers to ECMO use before heart transplantation. Data were analyzed using multivariable logistic regression with the binary outcome “postoperative stroke.” Bold values indicate P < 0.05.
6.e3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Table VII. Matched control group secondary analysis Variables Age at heart transplantation (months) Weight at heart transplantation (kg) In-hospital mortality Stroke ECMO after heart transplantation Nitric oxide Dialysis Rejection Pacemaker Chylothorax Cardiac surgery Noncardiac surgery Total hospital length of stay (days) ICU length of stay (days) Time requiring mechanical ventilation (days) Time requiring inhaled nitric oxide (days) Readmission within 1 year of heart transplantation Readmission length of stay (days)
Controls (n = 235)
Mitochondrial disease (n = 47)
P value
20 (9-78) 11 (7-23) 5 (2.1) 5 (2.1) 23 (9.8) 109 (46.6) 6 (2.6) 19 (8.5) (0) 8 (3.4) 12 (6.7) 20 (11.2) 59 (24-97) 7 (4-15) 2 (1-6) 3 (2-5) 130 (55.3)
22 (8-74) 11 (7-20) 1 (2.1) 5 (11.1) 3 (6.4) 17 (36.2) 1 (2.3) 4 (8.5) 0 (0) 0 (0) 2 (5.6) 5 (13.2) 69 (28-140) 10 (4-28) 3 (2-9) 3 (2-4) 29 (61.7)
.99 .88 0.67 .01 .59 .20 0.69 0.62 0.5 .36 .58 .78 .10 .11 .15 .43 .52
8 (4-24)
14 (8-23)
.11
Patients with mitochondrial disease codes matched 5:1 with controls for age (12 months, VAD, and ECMO support before heart transplantation). For categorical variables, Fisher exact test used. For continuous variables, Wilcoxon rank-sum used. Values are number (%) or median (IQR). Bold values indicate P < 0.05.
6.e4
Weiner et al
M
itochondrial disease is associated with the development of cardiomyopathy in up to 40% of patients.1 Mitochondrial disease is rare when considered individually, but as a group of conditions it is diagnosed with an estimated incidence of 1 in 5000 live births.2 Hypertrophic cardiomyopathy is the most common presentation of heart disease in this population, but dilated cardiomyopathy and left ventricular noncompaction also occur.1,3 In patients with mitochondrial disease, cardiomyopathy is the leading cause of death. Patients with mitochondrial disease and cardiomyopathy have a reported mortality of 82% at 16 years of age, compared with 5% mortality in those without evidence of cardiac involvement.1 The presence of cardiomyopathy may prompt consideration of heart transplantation in children with mitochondrial disease. However, there are limited data on heart transplantation outcomes in this population and the presence of mitochondrial disease may be considered a contraindication to heart transplantation by some centers.4 The aim of this project was to use a novel linkage between administrative and clinical registry data to identify and compare heart transplantation outcomes for children with mitochondrial disease compared with those without.
Methods This was a nested case-control study using a national cohort of patients with linked clinical and administrative data to compare transplantation outcomes in patients with and without mitochondrial disease.
ECMO ICU ICD PHIS SRTR
Extracorporeal membranous oxygenation Intensive care unit International Classification of Diseases Pediatric Health Information System Scientific Registry of Transplant Recipients database
From the 1Department of Pediatric Cardiology, Monroe Carell Jr. Children’s Hospital, Nashville, TN; 2Children’s Hospital Association, Lenexa, KS; 3Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Nashville, TN; and the 4Department of Pediatrics and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, PA Supported through internal funding from the Katherine Dodd Faculty Scholar Program at Vanderbilt University (to J.G.). Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institute of Health (6T32HL105334-06 [to J.W.] and K23HL123938 [to J.S.] [Bethesda, Maryland]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.10.016
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
This study used a unique linkage between the Scientific Registry of Transplant Recipients database (SRTR; Hennepin Healthcare Research Institute, Minneapolis, Minnesota) and the Pediatric Health Information System (PHIS; Children’s Hospital Association, Lenexa, Kansas) administrative and billing database. Records were linked at the patient level using indirect identifiers, the results of which have been validated for accuracy and previously described.5 The SRTR data system includes data on all donors, waitlisted candidates, and transplant recipients in the US, submitted by the members of the Organ Procurement and Transplantation Network. The Health Resources and Services Administration, US Department of Health and Human Services provides oversight to the activities of the Organ Procurement and Transplantation Network and SRTR contractors. SRTR data are derived from multiple sources, including the Organ Procurement and Transplantation Network, transplant programs, organ procurement organizations, histocompatibility laboratories, the Centers for Medicare and Medicaid Services, and the National Technical Information Service’s Death Master File. The SRTR database includes data from every organ transplant and waitlist addition within the US since October 1987. The PHIS database is an administrative database that collects clinical and resource used data for hospital encounters from more than 50 large children’s hospitals. Data collected includes encounter-level diagnosis and procedural International Classification of Diseases (ICD)-9 and ICD-10 codes, payer information, and detailed billing data for inpatient hospitalizations, observation, ambulatory surgery, and emergency department visits.5 All pediatric patients who underwent heart transplantation with a diagnosis of cardiomyopathy were identified from the linked database for inclusion (2002-2016). For the purposes of this study, patients with ICD-9 or ICD-10 codes specific to mitochondrial disease (Table I; available at www.jpeds. com) at any encounter are designated as having mitochondrial disease, although confirmatory testing was not necessarily performed. The SRTR database did not contain codes for mitochondrial disease and was not used to identify patients with mitochondrial disease. Pretransplant clinical characteristics and post-transplant outcome data were derived from the linked dataset. The primary outcomes of interest included survival to discharge, graft survival, and freedom from readmission. Immediate postoperative outcomes assessed before discharge from the heart transplantation hospitalization included: rejection, pacemaker placement, cardiac reoperation, other surgical reoperation, chylothorax, use of extracorporeal membranous oxygenation (ECMO), dialysis, need for inhaled nitric oxide, intensive care unit (ICU) and total hospital length of stay, length of mechanical ventilation, and stroke. ICD codes indicating muscle weakness were also examined owing to the potential for a higher incidence in the mitochondrial disease population. Details of outcome identification are provided in Table II (available at www.jpeds.com). 2
Volume -
- 2019
Statistical Analyses Patient characteristics and outcomes after heart transplantation were compared between patients with and without mitochondrial disease. Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using the Fisher exact test, with a prespecified 2-sided alpha level of 0.05 considered the standard for statistical significance. To evaluate post-transplant graft survival, survival curves were generated using the Kaplan-Meier method (censoring at death, retransplantation, or last known follow-up) and compared using the log-rank test with a prespecified alpha level of 0.05 considered the standard for statistical significance. The Kaplan-Meier method was similarly used to evaluate freedom from readmission within the first post-transplant year among patients with and without mitochondrial disease. Power analysis and sample size calculations were not performed, because this was a retrospective analysis of all available data. All statistical analyses were performed in SAS version 9.4 (SAS Institute; Cary, North Carolina) or STATA version 15 (StataCorp LLC; College Station, Texas). To account for the observation that patients with mitochondrial disease were younger, smaller, and hospitalized longer preoperatively, the primary analysis was repeated using a matched control group. The control group was randomly selected (5 controls for every 1 subject) after matching for age (12 months), the need for ventricular assist device support, and the need for ventilator support at the time of heart transplantation. This project was approved by SRTR, PHIS, and the Vanderbilt University Institutional Review Board.
Results A total of 1330 patients with cardiomyopathy were identified from the linked database and included in the analysis. Of this group, 47 patients (3.5%) were identified with mitochondrial disease diagnosis codes (Figure 1; available at www.jpeds. com). The first occurrence of an ICD code defining mitochondrial disease was noted before the transplant admission in 14 patients (30%). For the remaining patients, the first occurrence of an ICD code defining mitochondrial disease occurred during (n = 25 [53%]) or after (n = 8 [17%]) the transplant admission. Patients with mitochondrial disease also had higher incident muscle weakness than those without (29.8% vs 3.5%; P < .001). Patient demographics and pretransplant clinical characteristics are shown in Table III. Patients with mitochondrial disease were significantly younger than those without (median age, 22 months vs 89 months; P = .004). Patients with mitochondrial disease were also significantly smaller at time of heart transplantation than those without (median weight, 11 kg vs 23 kg; P = .001). Of patients with mitochondrial disease, 39 (83%) had dilated cardiomyopathy, 6 (13%) had hypertrophic cardiomyopathy, and 1 patient each had left ventricular Weiner et al
- 2019
ORIGINAL ARTICLES
Table III. Pretransplant clinical characteristics Characteristics Male Age (months) at heart transplantation Weight (kg) at heart transplantation Type of cardiomyopathy Dilated Restrictive Hypertrophic Other Status at heart transplantation 1A 1B 2 IV Inotrope requirement VAD before heart transplantation ECMO before heart transplantation Pretransplant length of stay (days) iNO before heart transplantation Muscle weakness
Without mitochondrial disease (n = 1283)
With mitochondrial disease (n = 47)
650 (50.7) 89 (14-168) 23 (9-50)
26 (55.3) 22 (8-74) 11 (7-20)
1008 (78.6) 154 (12) 73 (5.7) 48 (3.7)
39 (83.0) 0 (0) 6 (12.7) 2 (4.3)
1105 (86.1) 111 (8.7) 67 (5.2) 642 (50) 368 (28.7) 58 (4.5) 23 (1-60) 46 (3.6) 45 (3.5)
42 (89.4) 1 (2.1) 4 (8.5) 21 (44.7) 17 (36.2) 0 (0) 41 (12-82) 2 (4.3) 14 (29.8)
P value .56 .004 .001 .006
.15
.55 .26 .26 .004 .69 <.001
iNO, inhaled nitric oxide; VAD, ventricular assist device. For categorical variables, Fisher exact test used. For continuous variables, Wilcoxon rank-sum used. Values are number (%) or median (IQR). Bold values indicate P < 0.05.
noncompaction and histiocytoid cardiomyopathy. No patients with mitochondrial disease carried a diagnosis of restrictive cardiomyopathy. Patients with mitochondrial disease had a significantly longer hospital length of stay before heart transplantation (median, 41 days vs 23 days; P = .004). There were no significant differences in sex, United Network for Organ Sharing listing status, use of mechanical circulatory support, inotropic support, or inhaled nitric oxide at the time of heart transplantation between those with and without mitochondrial disease. Unmatched outcomes after heart transplantation are shown in Table IV. The in-hospital mortality after heart transplantation was not different between those with and without mitochondrial disease (2.1% vs 1.8%; P = .58).
Patients with mitochondrial disease had a significantly higher prevalence of postoperative stroke (11.1% vs 2.7%; P = .009), longer length of stay after heart transplantation (median, 23 vs 15 days; P < .001), longer ICU length of stay (median, 10 days vs 6 days; P = .007), and longer duration of mechanical ventilation after heart transplantation (median, 3 days vs 1 day; P < .001). Patients requiring mechanical support (either ventricular assist device support or ECMO) before transplantation had a significantly higher prevalence of stroke after heart transplantation than patients without pretransplant mechanical stroke (Table V; available at www.jpeds.com). When adjusting for the use of mechanical support before heart transplantation, mitochondrial disease is independently associated with
Table IV. Unadjusted outcomes after heart transplantation Outcomes In-hospital mortality Stroke ECMO after heart transplantation Nitric oxide Dialysis Rejection Pacemaker Chylothorax Cardiac surgery Noncardiac surgery Tracheostomy Post heart transplantation hospital length of stay (days) ICU length of stay (days) Time requiring mechanical ventilation (days) Time requiring inhaled nitric oxide (days) Readmission within 1 year of heart transplantation Readmission length of stay (days)
No mitochondrial disease (n = 1283)
Mitochondrial disease (n = 47)
P value
23 (1.8) 34 (2.7) 99 (7.7) 567 (44.3) 35 (2.74) 131 (11.2) 6 (0.5) 38 (3.0) 49 (4.9) 93 (9.4) 20 (1.6) 15 (11-24)
1 (2.1) 5 (11.1) 3 (6.4) 17 (36.2) 1 (2.3) 4 (8.5) 0 (0) 0 (0) 2 (5.6) 5 (13.2) 2 (4.3) 23 (13-47)
.58 .009 0.51 .29 0.66 .81 0.81 .64 .69 .39 .18 <.001
6 (4-13) 1 (1-4)
10 (4-28) 3 (2-9)
.007 <.001
3 (2-4) 29 (61.7)
.43 .14
14 (8-23)
.03
3 (2-5) 644 (51) 8 (4-19)
For categorical variables, Fisher exact test used. For continuous variables, Wilcoxon rank-sum used. Values are number (%) or median (IQR). Bold values indicate P < 0.05.
Heart Transplantation in Children with Mitochondrial Disease
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Figure 2. Kaplan-Meier survival analysis comparing freedom from death or retransplantation between recipients of heart transplant with and without mitochondrial disease.
higher prevalence of stroke after heart transplantation (Table VI; available at www.jpeds.com). No statistically significant differences were noted between the 2 groups in terms of the need for ECMO, inhaled nitric oxide, pacemaker placement, dialysis, cardiac or noncardiac surgery, or in the prevalence of chylothorax or rejection before hospital discharge after heart transplantation. There was no difference in post-transplant graft survival in patients with mitochondrial disease compared with those without (P = .57) with a median follow-up of 4 years (range, 1-11 years) (Figure 2). In the first year after hospital discharge, there was no difference in the frequency of readmission between patients with and without mitochondrial disease (61.7% vs 51%; P = .14). Similarly, no significant difference was shown in time to readmission for patients with mitochondrial disease compared with those without (P = .22) (Figure 3). However, when readmitted to the transplant hospital, patients with mitochondrial disease had a significantly longer length of stay compared with those without (median, 14 days vs 8 days; P = .03). Results of the secondary matched analysis are summarized in the supplemental material. When matched for age, ventricular assist device support, and ventilator support, the prevalence of stroke after heart transplantation remained 4
significantly higher in the mitochondrial disease group (11.1% vs 2.1%; P = .01) (Table VII; available at www. jpeds.com). Similar to the primary analysis, there was no difference in post-transplant graft survival between patients with and without mitochondrial disease (P = .75) when using a matched control group (Figure 4; available at www. jpeds.com).
Discussion There are limited prior data describing transplant outcomes in patients with mitochondrial disease. Case reports and case series describe successful transplantation in patients with cardiomyopathy secondary to mitochondrial disease.6-11 Bates et al describe a series of 5 patients with cellular evidence of mitochondrial disease (using endomyocardial biopsy before transplantation), but with no manifestation of disease in other organs. These patients had normal courses after heart transplantation.7 In addition, several cases of heart transplantation in patients with mitochondrial disease with isolated cardiac disease have been reported.6,8 Other case reports exist that highlight transplantation in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes who also had successful outcomes.9,12 Conversely, Parikh et al caution against solid organ transplantation in this Weiner et al
- 2019
ORIGINAL ARTICLES
Figure 3. Kaplan-Meier survival curve comparing freedom from readmission in the first year after transplant between patients with and without mitochondrial disease.
population, citing postoperative complications and graft failure in 6 of 11 heart transplant recipients.4 Patients in our analysis likely represent a select cohort with minimal comorbidities. Patients with mitochondrial disease and significant extracardiac manifestations are more likely to be precluded from transplant candidacy. The use of an mitochondrial disease code was made in only 30% of patients during a hospitalization before heart transplantation with the majority of patients receiving this diagnostic code during or after their heart transplantation admission. This finding suggests that, for some patients, transplant providers may have been unaware of the mitochondrial disease diagnosis at the time of listing for heart transplantation. Although our data support that heart transplantation in this group can achieve similar outcomes to patients without mitochondrial disease, these data may not be generalizable to patients with mitochondrial disease and significant extracardiac comorbidities, and careful assessment of transplant candidacy for each patient is warranted. When considering morbidity patterns in these patients, it is notable that patients with mitochondrial disease demonstrate a significantly higher prevalence of stroke after heart transplantation than those without. Multiple possible explanations could account for this finding. Several mitochondrial diseases, most notably mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, confer a higher risk of metabolic stroke. It is also possible that having any level of impaired mitochondrial function, coupled with the stress of heart failure, cardiopulmonary bypass, and postoperative recovery can increase the risk of stroke-like episodes. Patients with mitochondrial disease required a longer duration of mechanical ventilation in the post-transplant period and had longer post-transplant total and ICU lengths
of stay. Although the etiology for these findings cannot be precisely determined in our analysis, the presence of muscle weakness (whether apparent or subclinical) in patients with mitochondrial disease may prolong the need for postoperative positive pressure ventilation, resulting in a longer posttransplant length of stay. Patients with mitochondrial disease did demonstrate a significantly higher incidence of muscle weakness, supporting this as a possible etiology for our findings. Given that we found no difference in other posttransplant complications including rejection, dialysis, ECMO, pacemaker, and cardiac or noncardiac reoperation, it is reasonable to consider the significant difference in mechanical ventilation time as a likely contributor to the prolonged length of stay. Although the length of stay after transplantation is increased in patients with mitochondrial disease, readmission after transplantation are similar between groups. However, when patients with mitochondrial disease are readmitted to the hospital, they again demonstrate a significantly longer length of stay compared with patients without mitochondrial disease. The etiology of this finding is unclear and warrants further investigation. The greater prevalence of metabolic stroke and muscle weakness in patients with heart transplantation with mitochondrial disease should inform physicians in their perioperative management of this population. As an example, this population may benefit from different ventilation strategies given their propensity for impaired respiratory mechanics. It can be hypothesized that the higher prevalence of metabolic stroke is a result of metabolic demand and impaired respiratory chain metabolism, for which prophylaxis would be difficult. Knowledge of this risk can be used to inform counseling before heart transplantation and to prepare
Heart Transplantation in Children with Mitochondrial Disease
5
THE JOURNAL OF PEDIATRICS
www.jpeds.com
the ICU for careful neurologic monitoring after heart transplantation. There are inherent limitations to this study. The diagnosis of mitochondrial disease is challenging, and assessment of these diagnoses using ICD codes may introduce error owing to miscoding. This may result in patients with mitochondrial disease who were not identified, or patients without mitochondrial disease incorrectly labelled as having mitochondrial disease. Unfortunately, there are limited options to validate this classification within the linked database. Although the linkage between SRTR and PHIS provides a platform to assess transplantation outcomes in this population, it does not contain data from all pediatric transplant centers. Therefore, it may miss some patients with mitochondrial disease who have undergone heart transplantation. In addition, the SRTR-PHIS linkage does not include patients who were listed but not transplanted; therefore, waitlist outcomes for this group are not known. Also, there is likely a selection bias in patients with mitochondrial disease listed, with only the “healthiest” patients progressing to transplantation. Although ICD coding allowed identification of patients with probable mitochondrial disease, there may be inaccuracies in coding and limited options to verify these data. Additionally, “mitochondrial disease” is a heterogeneous term representing a host of rare diseases with similar cellular physiology but potentially variable pathology; comparing postoperative morbidity among these patients may be biased by a preponderance of one specific diagnosis. Unfortunately, ICD-9 codes do not allow identification of specific forms of mitochondrial disease. This improved with ICD-10 coding, but only a minority of our patients had these codes, limiting our ability to define specific forms of mitochondrial disease. When considering stroke, data were not available to compare those with metabolic stroke (more inherent in the mitochondrial disease population) to embolic or ischemic stroke. These results suggest that a diagnosis of mitochondrial disease alone should not serve as an absolute contraindication to heart transplantation. However, because of the likely selection bias in our cohort, these data may not be generalizable to all patients with mitochondrial disease and each patient
6
Volume -
should be evaluated on an individual basis to determine transplant candidacy. n Submitted for publication Aug 5, 2019; last revision received Sep 19, 2019; accepted Oct 9, 2019. Reprint requests: Jeffrey G. Weiner, MD, MSCI, Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center, Department of Pediatric Cardiology, 2200 Children’s Way, Suite 5230 DOT, Nashville, TN 37232-9119. E-mail: [email protected]
References 1. Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO, Neish SR, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004;114:925-31. 2. Bannwarth S, Procaccio V, Lebre AS, Jardel C, Chaussenot A, Hoarau C, et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet 2013;50:704-14. 3. Limongelli G, Tome-Esteban M, Dejthevaporn C, Rahman S, Hanna MG, Elliott PM. Prevalence and natural history of heart disease in adults with primary mitochondrial respiratory chain disease. Eur J Heart Fail 2010;12:114-21. 4. Parikh S, Karaa A, Goldstein A, Ng YS, Gorman G, Feigenbaum A, et al. Solid organ transplantation in primary mitochondrial disease: proceed with caution. Mol Genet Metab 2016;118:178-84. 5. Godown J, Thurm C, Dodd DA, Soslow JH, Feingold B, Smith AH, et al. A unique linkage of administrative and clinical registry databases to expand analytic possibilities in pediatric heart transplantation research. Am Heart J 2017;194:9-15. 6. Golden AS, Law YM, Shurtleff H, Warner M, Saneto RP. Mitochondrial electron transport chain deficiency, cardiomyopathy, and long-term cardiac transplant outcome. Pediatr Transplant 2012;16:265-8. 7. Bates MG, Nesbitt V, Kirk R, He L, Blakely EL, Alston CL, et al. Mitochondrial respiratory chain disease in children undergoing cardiac transplantation: a prospective study. Int J Cardiol 2012;155:305-6. 8. Santorelli FM, Gagliardi MG, Dionisi-Vici C, Parisi F, Tessa A, Carrozzo R, et al. Hypertrophic cardiomyopathy and mtDNA depletion. Successful treatment with heart transplantation. Neuromuscul Disord 2002;12:56-9. 9. Bhati RS, Sheridan BC, Mill MR, Selzman CH. Heart transplantation for progressive cardiomyopathy as a manifestation of MELAS syndrome. J Heart Lung Transplant 2005;24:2286-9. 10. Schmauss D, Sodian R, Klopstock T, Deutsch MA, Kaczmarek I, Roemer U, et al. Cardiac transplantation in a 14-yr-old patient with mitochondrial encephalomyopathy. Pediatr Transplant 2007;11:560-2. 11. Bonnet D, Rustin P, Rotig A, Le Bidois J, Munnich A, Vouhe P, et al. Heart transplantation in children with mitochondrial cardiomyopathy. Heart 2001;86:570-3. 12. Fayssoil A. Heart diseases in mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome. Congest Heart Fail 2009;15:284-7.
Weiner et al
- 2019
ORIGINAL ARTICLES
Figure 1. Identifying the patient population. Flow diagram describing the patient selection process.
Heart Transplantation in Children with Mitochondrial Disease
6.e1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Figure 4. Kaplan-Meier survival analysis comparing freedom from death or retransplantation between recipients of heart transplant with mitochondrial disease and age- and support-matched controls.
Table I. Identifying the patient population ICD-9/10 codes 277.87* E78.71 E88.40 E88.41 E88.42 E88.49 G71.3 H49.81 H49.811 H49.812 H49.813 H49.819
Diagnosis Disorders of mitochondrial metabolism Barth syndrome Mitochondrial metabolism disorder, unspecified MELAS syndrome MERRF syndrome Other mitochondrial metabolism disorders Mitochondrial myopathy, not elsewhere classified Kearns-Sayre syndrome Kearns-Sayre syndrome, right eye Kearns-Sayre syndrome, left eye Kearns-Sayre syndrome, bilateral Kearns-Sayre syndrome, unspecified eye
MELAS, mitochondrial encephalopathy, lactic acidosis, and stroke; MERRF, mitochondrial encephalopathy with ragged red fibers. ICD-9 and -10 codes shown in this Table were used to query the linked PHIS and SRTR database. Patients with any combination of the above diagnoses at pretransplantation, transplantation, or post-transplantation hospitalizations were included for analysis. *Denotes ICD-9. Other codes listed are ICD-10.
6.e2
Weiner et al
- 2019
ORIGINAL ARTICLES
Table II. Identifying patient outcomes Outcomes Muscle weakness Chylothorax Stroke Dialysis Pacemaker Rejection Cardiac reoperation Other operation iNO after transplantation In-hospital mortality ECMO post-transplant Total LOS ICU LOS Days of ventilation Days of iNO Readmission LOS Status and date of last known follow-up
SRTR
PHIS
– – REC_POSTX_STROKE REC_POSTX_DIAL REC_POSTX_PACEMAKER REC_POSTX_DRUG_TREAT_REJ REC_POSTX_CARDIAC_REOP REC_POSTX_SURG – – – – – – – – X
ICD-9: 728.87, V46.3, 359.89, ICD-10: M62.81, Z99.3, G71.3, G71.8, G72.89 ICD-9: 457.8, ICD-10: I89.8 – – – – – – CTC code: 521173 PHIS flag CTC code: 521180-521182 X X X X X
iNO, inhaled nitric oxide; LOS, length of stay. ICD-9 and -10 and SRTR codes shown in this Table were used to query the linked PHIS and SRTR database to identify patient characteristics before transplantation and outcomes after transplantation. X denotes that length of stay data was derived from the respective data bank.
Table V. Univariate analysis of stroke and mechanical support Variables VAD (n = 381) ECMO (n = 58) No mechanical support (n = 893)
Stroke
No stroke
P value
21 (5.5) 8 (13.7) 13 (1.5)
360 (94.5) 50 (86.3) 880 (98.5)
.001 <.001 <.001
VAD, ventricular assist device. ECMO in this Table refers to ECMO use before heart transplantation. Data were compared using Fisher exact test. Values are number (%). Bold values indicate P < 0.05.
Heart Transplantation in Children with Mitochondrial Disease
Table VI. Multivariable analysis of stroke Variables
aOR
95% CI
P value
Mitochondrial disease ECMO before transplantation VAD before transplantation
5.37 8.6 3.23
1.9-14.7 3.62-20.4 1.67-6.26
<.001 <.001 <.001
ECMO in this Table refers to ECMO use before heart transplantation. Data were analyzed using multivariable logistic regression with the binary outcome “postoperative stroke.” Bold values indicate P < 0.05.
6.e3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Table VII. Matched control group secondary analysis Variables Age at heart transplantation (months) Weight at heart transplantation (kg) In-hospital mortality Stroke ECMO after heart transplantation Nitric oxide Dialysis Rejection Pacemaker Chylothorax Cardiac surgery Noncardiac surgery Total hospital length of stay (days) ICU length of stay (days) Time requiring mechanical ventilation (days) Time requiring inhaled nitric oxide (days) Readmission within 1 year of heart transplantation Readmission length of stay (days)
Controls (n = 235)
Mitochondrial disease (n = 47)
P value
20 (9-78) 11 (7-23) 5 (2.1) 5 (2.1) 23 (9.8) 109 (46.6) 6 (2.6) 19 (8.5) (0) 8 (3.4) 12 (6.7) 20 (11.2) 59 (24-97) 7 (4-15) 2 (1-6) 3 (2-5) 130 (55.3)
22 (8-74) 11 (7-20) 1 (2.1) 5 (11.1) 3 (6.4) 17 (36.2) 1 (2.3) 4 (8.5) 0 (0) 0 (0) 2 (5.6) 5 (13.2) 69 (28-140) 10 (4-28) 3 (2-9) 3 (2-4) 29 (61.7)
.99 .88 0.67 .01 .59 .20 0.69 0.62 0.5 .36 .58 .78 .10 .11 .15 .43 .52
8 (4-24)
14 (8-23)
.11
Patients with mitochondrial disease codes matched 5:1 with controls for age (12 months, VAD, and ECMO support before heart transplantation). For categorical variables, Fisher exact test used. For continuous variables, Wilcoxon rank-sum used. Values are number (%) or median (IQR). Bold values indicate P < 0.05.
6.e4
Weiner et al