REVIEW Pediatric lung transplantation: 10 years of experience Priscila C. L. B. Camargo,I Eduardo Z. S. Pato,II Silvia V. Campos,I Jose´ E. Afonso Jr.,I Rafael M. Carraro,I Andre´ N. Costa,I Ricardo H. O. B. Teixeira,I Marcos N. Samano,III,* Paulo M. Peˆgo-FernandesII IHospitaldasCl´ınicasdaFaculdadedeMedicinadaUniversidadedeSa˜oPaulo(HCFMUSP),HeartInstitute(Incor),PulmonologyDivision,Sa˜oPaulo/SP, Brazil.IIFaculdadedeMedicinadaUniversidadedeSa˜oPaulo(USP),Sa˜oPaulo/SP,Brazil.IIIHospitaldasClı´nicasdaFaculdadedeMedicinadaUniversidade deSa˜oPaulo(HCFMUSP),HeartInstitute(Incor),ThoracicSurgeryDivision,Sa˜oPaulo/SP,Brazil. Lungtransplantationisawell-establishedtreatmentforadvancedlungdiseases.Inchildren,thediseasesthat most commonly lead to the need for a transplantation are cystic fibrosis, pulmonary hypertension, and bronchiolitis.However,thenumberofpediatriclungtransplantationsbeingperformedislowcomparedwith thenumberof transplants performedintheadult agegroup. Theobjective ofthisstudy was todemonstrate ourexperiencewithpediatriclungtransplantsovera10-yearperiodinaprograminitiallydesignedforadults. KEYWORDS: Lung Transplantation; Pediatrics;Cystic Fibrosis;Bronchiectasis; Bronchiolitis. CamargoPC,PatoEZ,CamposSV,AfonsoJr.JE,CarraroRM,CostaAN,etal.Pediatriclungtransplantation:10yearsofexperience.Clinics. 2014;69(S1):51-54. E-mail:[email protected] *correspondingauthor Tel.:55112661-5248 & INTRODUCTION The aim of this study was to describe the pediatric lung transplantationexperiencesattheHeartInstitute(InCor)of Lung transplantation (LTx) is now a well-established Faculdade deMedicina daUniversidade de Sa˜oPaulo. therapyfortreatingvariouschroniclungdiseasesthatlead tosevererespiratoryfailure.LTxhasimprovedsignificantly & PATIENTS AND METHODS since it began in 1963 with James Hardy (1). An increasing numberofstudieshavefocusedonstudyingtheindications, Aretrospectiveanalysisofthemedicalrecordsofpatients techniques, immunosuppressive drugs, and criteria for undergoing lung transplantation at the Heart Institute donation. The first pediatric LTx occurred in 1987 in a 16- (Incor) of Hospital das Cl´ınicas da Faculdade de Medicina year-old boywith familial pulmonary fibrosis(2). de Sa˜o Paulo was performed for the period from January The annual number of pediatric lung transplants per- 2003toOctober 2013. formed is significantly lower than that of adult transplant surgeries performed each year. According to a 2013 report & RESULTS from the International Society of Heart and Lung Trans- plantation,from1986toJune2012,inpatientsyoungerthan FromFebruary2003toOctober2013,192lungtransplants 18 years, 1875 lung transplants and 667 double heart and were performed at our institution (11 patients 18 years lungtransplantationswerereported(3),whereastherewere old and younger). The recipient distribution by age and 3640transplanted adultsin 2011(4). diagnosisis showninFigure1. ThemostcommonindicationforLTxinpatientsupto18 All 11 pediatric patients underwent bilateral sequential years old is cystic fibrosis (3), a fact that is also demon- LTx;twopatientsrequiredcardiopulmonarybypassduring strated in this study. Other indications for LTx include surgery. To date, the longest surviving pediatric transplant bronchiolitis obliterans, bronchiectasis, pulmonary arterial patient underwent surgery 5 years ago when he was 11 hypertension, idiopathic fibrosis, interstitial lung diseases, yearsold. andsurfactant proteinabnormalities (5). Two patients suffered immediate postoperative death less than one month post transplantation. The first patient, whose initial diagnosis was idiopathic pulmonary arterial hypertension, developed primary graft dysfunction and died on the 4th postoperative day. This patient was six Copyright (cid:2) 2014CLINICS–ThisisanOpenAccessarticledistributedunder years old and required cardiopulmonary bypass. The thetermsoftheCreativeCommonsAttributionNon-CommercialLicense(http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non- second patient, a 17-year-old adolescent diagnosed with commercial use, distribution, and reproduction in any medium, provided the bronchiolitis obliterans associated with secondary pulmon- originalworkisproperlycited. aryhypertension,alsounderwentcardiopulmonarybypass; Nopotentialconflictofinterestwasreported. the patient developed refractory hemodynamic instability DOI:10.6061/clinics/2014(Sup01)10 anddied threedays post-surgery. 51 PediatricLungTransplantation CLINICS2014;69(S1):51-54 CamargoPCLBetal. Figure1-Distributionofrecipientsaccordingtoageanddiagnosis. One patient with an initial diagnosis of bronchiectasis disease (4,5). Furthermore, in Brazil, the prevalence of died three years after undergoing transplantation for bronchiectasis (notsecondarytocysticfibrosis)isconsider- chronicgraftdysfunctionwithclinicalrestrictivesyndrome. able, andthis conditionfrequently requires LTx. A 16-year-old patient with an initial diagnosis of post- Intheadultpopulation,themainindicationsareemphy- infectiousbronchiolitisobliteranssyndromelaterdeveloped semaand idiopathicpulmonary fibrosis(4). obliterative bronchiolitis and underwent retransplantation The pediatric contraindications for the procedure are three yearsafterthe initial procedure. identical to those in the adult population and include In our institution, induction therapy is performed systemicdiseaseswithextrapulmonarycomplications,mali- with 10mg/kg intravenous methylprednisolone, with gnancy, HIV infection, and severe renal impairment. The basiliximab in the case of initial suppurative disease. The absence of social support, transportation issues, or poor maintenance immunosuppression combines corticosteroids adherence to treatment are also important conditions that (prednisone), calcineurin inhibitor (cyclosporine or tacroli- preclude LTx (7). mus), and a cellular activation inhibitor (azathioprine or The number of pediatric transplants performed in our mycophenolate sodium). study group, although small, corresponded to approxi- The complications related to the immunosuppressive mately 5.7% of the total number of transplants performed, regimenwereinfection(inthemajorityofcases)andrever- whichdidnotdifferfromtheliterature(3).Thesurvivalrate sible posterior leukoencephalopathy (one case) in a patient was also similar to that of the international registry, but a initially diagnosed with cystic fibrosis. This patient was on longer follow-up is necessary, as illustrated by the patient cyclosporineandshowedneurologicalsymptomseightdays with a longer follow-up who underwent surgery 5 years after the procedure, progressing to acute subdural hemor- earlier. rhage.Currently,hehasmotorneurologicaldeficitwithout Thelownumberofdonorsandviableorgansfordonation other complications. is a significant complicating factor that has affected the Inourstudy,themostcommoninfectionfoundafterthefirst pediatric andadult LTx program. month of transplant was due to citomegalovirus (CMV), As in the adult population, there are three main types followedbyrespiratoryviralinfectionsandbacterialinfections. of postoperative complications: immediate complications, Figure 2 shows the survival rate based on the time after occurring in the first days after transplantation; early com- transplantation forpatients 18yearsold andyounger. plications, occurring within three months posttransplanta- tion; andlatecomplications (8). & DISCUSSION The immediate postoperative complications are hyper- acute rejection, primary graft dysfunction, reperfusion LTxisawell-establishedtherapyforpatientswithchronic injury, and surgical complications, such as anastomotic lung disease and end-stage vascular pulmonary disease. dehiscence andbleeding. Indications for LTx in the pediatric population are rare Hyperacute rejection is an uncommon condition. Today, becauseterminalillnessesinthisagegroupareuncommon virtual crossmatching performedpreoperatively inpatients (5).Mostpatientsyoungerthan18yearswhoundergolung withahighreactivepanelidentifiesanypossibleincompat- transplantationareolderthan11years(3,6),whichwasalso ibility that could preclude transplantation between the found in ourstudygroup. recipient and donor. Hyperacute rejection has a poor The main indications for LTx in the pediatric population prognosis, and treatment should be started immediately are pulmonary cystic fibrosis, interstitial lung disease if the prospective crossmatch is positive. The treatment associatedwithpulmonaryfibrosis,andcongenitalvascular consists of plasmapheresis in the operating room and 52 CLINICS2014;69(S1):51-54 PediatricLungTransplantation CamargoPCLBetal. Figure2-SurvivalCurve–KaplanMeier. during the postoperative period, with the administration can be present during the entire posttransplant follow- of intravenous immunoglobulin and thymoglobulin as an up period. The use of maintenance medications has other additional potential indication for retransplantation (8,9). undesirableeffects,includingmetabolicchanges(hypergly- Anotherimportantcomplicationisprimarygraftdysfunc- cemia and dyslipidemia) and nephrotoxicity. In our study tion,whichoccurredinoursettingandcanoccurwithin72 group, one patient had reversible posterior leukoence- hourspost-surgery.Primarygraftdysfunctionisdefinedby phalopathy, a disease that is often associated with the use alowrelationshipbetweenPaO2andFiO2,withorwithout of calcineurin inhibitors and that has variable outcomes radiographic changes. The complication is described in (16,17). It involves a wide spectrum of neurological Table 1. International data show that cardiopulmonary manifestations, such as a decreased level of consciousness, bypass is used more frequently in pediatric LTx compared seizures, and visual disturbances that are frequently withadultLTx,anditsuseisrelatedtothedevelopmentof associated with ischemic changes mainly in parietal and primary graft dysfunction, smoking status of the donor, occipital lesions, as evidenced by MRI. The reversibility of presenceofreperfusioninjury,andbodymassindexofthe lesions is case dependent. Patient management usually recipient (8,10,11). In acute respiratory distress syndrome, consists of reducing or changing the calcineurin inhibitor. clinical management consists of protective ventilation Ourcaseshowedreversibilityofthechangesaftertheinitial and, in some cases, the use of extracorporeal membrane change in the immunosuppressant agent, but the patient oxygenation (10,12,13). developed hemorrhagic transformation and persistent Acuterejection,infection,sideeffectsofimmunosuppres- motor deficiency. sive drugs, and surgical complications, such as stenosis of Bronchiolitis obliterans syndrome is the main late the bronchial anastomosis, are some immediate postopera- complication; it corresponds to chronic graft dysfunction. tive complications; they frequently occur in the first three Bronchiolitisobliteranssyndromeisdefinedbya20%drop months afterLTx. intheforcedexpiratoryvolume(FEV1)valueinonesecond Clinically, diagnosing acute rejection and respiratory compared with the patient’s baseline, and it is diagnosed infections can be challenging, and they require different using the best three FEV1 values previously taken after treatments. The diagnosis of acute rejection is made using thedevelopmentoffixedairflowobstructiononspirometry histological findings that show perivascular mononuclear and in the absence other factors that may influence the cellinfiltrate.Theintensityandextentoftheacuterejection collection method (18). The differential diagnosis includes determinesitsclassification(14).Whenindicated,treatment other causes of FEV1 decline, such as anastomotic stenosis consists of adjusting the immunosuppression, including or respiratory infections. In some cases, the patient may changingorincreasingthedoseoftheimmunosuppressive present with severe dysfunction and end-stage pulmonary maintenanceregimen,administeringhighdosesofcorticos- disease, and any indication for retransplantation should be teroids (in some cases), and using intravenous thymoglo- carefully evaluated (5). In our study group, retransplanta- bulin in more severe or refractory cases (15). The infection tionwasindicated threeyearsafter thefirstprocedureina treatment is basedon etiological agents. patientwho underwent transplantation at age16. Infectionsareoftenrelatedtotheuseofimmunosuppres- The indications for LTx in a pediatric population are sivedrugs,andinfectionsareonetypeofcomplicationthat less common than those in an adult population. Certain Table1- Classification of Primary graft dysfunction -Adaptedfrom ISHLT(International Societyof Heart andLung Transplantation Registries) (10). Grades PaO/FiO Persistantpulmonaryinfiltrationatradiographicimagewithpulmonaryedema 2 2 0 .300 Absence 1 .300 Present 2 200-300 Present 3 ,200 Present 53 PediatricLungTransplantation CLINICS2014;69(S1):51-54 CamargoPCLBetal. peculiarities, such as the prevalence of different diseases, 2006update—aconsensusreportfromthePulmonaryScientificCouncil oftheInternationalSocietyforHeartandLungTransplantation.J.Heart indicatetheprocedureanddirectitsperioperativemanage- LungTransplant.2006;25(7):745-55,http://dx.doi.org/10.1016/j.healun. ment, although the postoperative complications and treat- 2006.03.011. mentsaresimilartothosefoundinpatientsolderthan18.In 8. SolomonM,GrasemannH,KeshavjeeS.Pediatriclungtransplantation. oursetting,theindications,prevalenceofpediatricLTx,and Pediatr. Clin North Am. 2010;57(2):375-91, http://dx.doi.org/10.1016/ j.pcl.2010.01.017. survivalratesweresimilartothoseintheinternationaldata, 9. Frost AE, Jammal CT, Cagle PT. 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