Lung Transplant in Children

REVIEW ARTICLE

Lung transplant in children

José J. Camargo*, Grupo de Transplante Pulmonar da Santa Casa de Porto Alegre, RS, Brazil

Abstract Objective: this article presents a review of the main aspects related to lung transplant in children and shows the experience of the first medical team to perform this procedure in Latin America. Sources: literature review of scientific articles, using the Medline and Lilacs databases. Summary of the findings: the article was organized into topics. Similarities and differences regarding lung transplant in adults were identified. Specific problems presented by children subjected to transplant are discussed, and special emphasis is given to a specific situation: lung transplant with living related donors. Conclusions: advances in adult lung transplant for the treatment of parenchymatous or vascular lung diseases have been successfully employed in the pediatric population during the last few years.

J Pediatr (Rio J) 2002;78(Suppl. 2):S113-S122: lung transplant, infancy, indications and results.

Introduction The first lung transplants for the treatment of children cardiac disorders caused by pulmonary hypertension with lung parenchyma disorders or problems related to its decreased with the replacement of the diseased lungs, vessels were indeed cardiopulmonary transplants, following cardiopulmonary transplants became less frequent and were a current trend in the 1980s, which considered only recommended in those cases of pulmonary hypertension cardiopulmonary transplant to be more appropriate to treat associated with heart defects that could not be surgically patients with end-stage lung diseases that had or could have corrected and, sporadically, in cases of vascular lung disease some cardiac involvement. with left ventricle failure (usually with previous heart With the advent of unilateral and bilateral lung transplant, surgery). which is undoubtedly simpler, and the demonstration that Nowadays, bilateral lung transplant is the most widely used in the pediatric population, partly because cystic fibrosis is the most frequent indication for transplants in children, but also because there is some concern with graft * Professor of Thoracic Surgery, Fundação Faculdade Federal de Medicina de Porto Alegre. Coordinator, Transplant Center, Santa Casa de Porto growth and with occasional underfunction of the organs Alegre. donated by extremely small individuals.1

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Other indications for lung transplant include idiopathic Relative contraindications pulmonary fibrosis, primary pulmonary hypertension or Continued use of corticoid (> 0.5 mg/kg/day of pulmonary hypertension secondary to congenital heart prednisone) results in difficult bronchial healing and is a defects and an array of less frequent parenchyma diseases relative contraindication, since the dose of corticoid can (Figure 1). usually be reduced way below this limit. Many transplant centers regard the need for mechanical ventilation as a relative contraindication; however, the experience of centers specialized in transplants in children younger than six months shows that most of them were on mechanical ventilation and that this did not influence the success of the transplant, even in the presence of such cardiorespiratory dysfunction.3 The experience of this group revealed that the prompter availability of a donor, given the need for mechanical ventilation, had some impact on the survival rate. Therefore, the use of lobes from living donors has allowed saving the lives of children with remote chances of survival who were waiting for organs from dead donors.4 Life expectancy without the transplant is difficult to determine in the pediatric population, but in general, the inclusion of potential candidates in waiting lists follows reasonably safe rules, which vary according to the underlying disease.

Cystic fibrosis In cystic fibrosis, the rehabilitation programs, especially

CF: cystic fibrosis, BO: bronchiolitis obliterans, ILF: idiopathic lung fibrosis, based on continued physical therapy, adequate antibiotic PPH: primary pulmonary hypertension. therapy and proper nutrition, have increased the mean age of cystic fibrosis patients. However, the following criteria Figure 1 - Analysis of 200 consecutive cases of transplantation have been used to indicate the best time for lung transplant: at Cleveland Clinic and at Barnes Hospital, em Saint Louis – Postbronchodilator FEV1 of less than 20% predicted for adults, and less than 30% predicted for children and women at any age;

– Resting hypoxemia (PaO2 of less than 55-60 mmHg); – hypercapnia (PaCO2 of less than 50 mmHg); – relevant secondary pulmonary hypertension (PMAP of less than 35 mmHg or PSAP of less than 45 mmHg); – hard-to-control weight loss, despite aggressive Indications management (nasoenteral tube, jejunostomy, etc.); The indications for lung transplant in children are often – repeated hospital admissions due to frequent and similar to those observed in adults2, including: untreatable infections, suggesting loss of control over – severe respiratory insufficiency; the disease. – lack of response to other forms of clinical or surgical Cystic fibrosis is the main indication for lung transplant treatments; in industrialized countries given the higher prevalence of – life expectancy shorter than two years, compatible with the disease among Anglo-Saxons. Some exclusion criteria the length of time on the waiting list; for potential candidates are not a common sense, such as colonization by Burkholderia cepacia, for which some – no other comorbidities (especially hepatic, renal and services refuse to recommend transplantation alleging high CNS); risk, whereas other specialized centers do not see any – psychological and emotional profile compatible with significant difference in outcome as a result of this agent. the requirements of a highly complex procedure; An identical situation occurs in relation to the colonization – adequate socioeconomic and family support conditions. by Aspergillus. Lung transplant in children - Camargo JJ et alii Jornal de Pediatria - Vol. 78, Supl.2, 2002 S115

In a different way, the involvement of other organs such – presence of hypoxemia, aggravated by exercise; as the pancreas and liver may determines an increase in – vital capacity of less than 60% predicted; postoperative risk and sometimes requires the transplantation – gradual deterioration, despite clinical treatment; of both lung and liver, an exception procedure that has thrived in several specialized centers.5 – signs of secondary pulmonary hypertension. An important aspect in the preparation for transplantation The growing need for oxygen supply and the gradual due to cystic fibrosis is the aggressive treatment against weight loss are important so that the severity of the situation malnutrition, often present at the moment of inclusion in the is known and transplantation can be recommended. waiting list. Malnutrition is one aggravating factor that adds In patients with fibrosis in which the lungs are metabolic difficulties to the losses of chronic infections and symmetrically affected (which is usually common), there is to the energy consumption that results from the enhanced a preference for left lung transplant due to the easy spatial respiratory effort. A follow-up with an experienced adaptation of the new organ, placed in a retracted pleural nutritionist, the prescription of diets extremely rich in cavity, to match the reduction in size of the fibrotic organ. proteins and calories and the use of more aggressive methods, Without opposition of the liver, left lung transplantation such as nasoenteral tube and gastrostomy or jejunostomy (if allows a fast descent of the hemidiaphragm, with total nasoenteral intubation is not possible), have been currently expansion of the newly implanted organ. used with the aim of eliminating this severe condition, The selection of the side is always based on the lowest which is reason enough for exclusion from the waiting list functional participation of a given lung, established on the or could result in failure if transplantation is carried out. initial assessment by means of perfusion scintigraphy (Figure Another relevant aspect is the effective previous control 2). of sinus disease, often expressed in the form of pansinusitis. As expected, the greatest difficulty in carrying out a The colonization by the same bacteria found in the lower transplant in children is to have a donor with compatible airways is inevitable in this population; however, patients size. Such difficulty is exacerbated in fibrosis, and is with retention of secretions that might be an entry point for characterized by increased chest retraction caused by pulmonary sepsis in the postoperative period are not allowed parenchyma disease, which allows the use of donors 20% to be in the waiting list. Large sinusotomies have locally smaller than the recipient. controlled infection, minimizing the risk of aspiration of Approximately one third of transplanted fibrotic patients gross pus by the upper airways. Sinusotomy, albeit use extracorporeal membrane oxygenation (ECMO). This considered a small surgery, requires general anesthesia and necessity is predictable because of previous pulmonary the patient usually has difficulty resuming respiratory hypertension and because of the need for high doses of physical therapy, which could cause serious postsurgical oxygen. complications. In these cases, an intensive preoperative treatment with multiple antibiotics and rigorous physical Anyway, the need for ECMO is defined in the therapy are mandatory, with 4 to 6 daily sessions. intraoperative period at the moment of clamping the pulmonary artery for pneumonectomy. Since the use of As patients with cystic fibrosis are permanently colonized extracorporeal circulation increases morbidity and mortality, by multiresistant bacteria, invariably Pseudomonas, and several maneuvers have been suggested in order to avoid many times associated with Staphylococcus, the use of at them, among which we have the use of nitric oxide, which least one antibiotic drug should be maintained, preferably has proved efficient in many cases from the moment of one that has not been exposed to the bacterial resistance of anesthesia. When, despite the use of nitric oxide, the systolic these patients so that the risks of postoperative infection can pressure of the pulmonary artery, after its clamping, exceeds be dealt with to some advantage. 60 mmHg, the patient should be submitted to ECMO, so as to prevent edema of the native lung, which is inevitable when this pressure is maintained during pneumonectomy and graft implantation. In addition, many patients with this Pulmonary fibrosis pressure level, acutely established by the clamping of the In pulmonary fibrosis, even though life expectancy is pulmonary artery, have a hemodynamic imbalance, showing expressed in years from the moment of diagnosis (mean of low blood pressure, tachycardia, arrhythmia and 6.5 years), there are cases in which the disease develops desaturation, thus making the use of ECMO imperative. faster despite the adequate clinical treatment. As the The availability of modern equipment, which allows blood evolution of the disease varies from patient to patient, it is filtration, with removal of the volume at the end of the currently recommended that a patient with the confirmed procedure, is crucial to mitigate the risks involved in diagnosis of fibrosis be investigated by a lung transplant extracorporeal circulation. Comparatively, the patients that group. use ECMO spend a longer time on mechanical ventilation The following elements indicate the moment of selection in the postoperative period, being more slowly weaned than for transplantation: those patients who do not require ECMO. S116 Jornal de Pediatria - Vol. 78, Supl.2, 2002 Lung transplant in children - Camargo JJ et alii

Figure 2 - a) 12-year-old female patient with idiopathic lung fibrosis, with 4-year evolution, O2 dependent for 18 months. b) Perfusional lung scintigraphy showing that the functional participation of the right lung is only 12%. c) Radiological control one year after the unilateral transplantation on the right

Pulmonary hypertension PPH when drugs are used in combination, as is the case of The life expectancy related to this condition is the most prostacyclin and sildenafil, especially when the patient difficult to predict, especially because many patients have does not respond specifically to one of them, or when the sudden death due to severe arrhythmia. patient develops tolerance of the drug. To arrive at a final conclusion, further studies have to be carried out. Currently, The higher morbidity and mortality after transplantation we can safely affirm that lung transplants are no longer the due to primary pulmonary hypertension (PPH) and the fact first therapeutic option for patients with pulmonary that the results in the medium and long term are worse than hypertension. This option is therefore recommended for those of other treatable diseases have encouraged the search those patients who did not respond to vasodilator therapy or for alternative clinical solutions to this disease. After defining for those who failed to respond after some time during the that the use of anticoagulation increases life expectancy of treatment. these patients, important advances have been made in the use of vasodilators, initially calcium blockers and more The following criteria have been suggested as signs for recently, prostacyclin.6 the inclusion in waiting list for lung transplant: A recent review of primary pulmonary hypertension in – class III or IV in NYHA; children7 showed that life expectancy in five years is 97% – lack of response to the regular use of vasodilators; against 35% among those who responded and did not – PMAP of greater than 80 mmHg; respond to the use of calcium blockers. On the other hand, – heart rate of less than 2.5 l/seg/m2; the continuous use of intravenous prostacyclin, in children – pressure of atrium D greater than 10 mmHg; in whom calcium blocker had failed, the life expectancy in five years was 92%, compared to 29% for children who did – venous saturation of less than 63%. not respond to prostacyclin or who did not have the drug Technically speaking, the modern tendency is bilateral available. The same study revealed that the results obtained sequential transplant, with extracorporeal circulation ab from IV prostacyclin were comparable to those obtained initio, although in unilateral transplant the results may be through transplantation in a three-year follow-up. satisfactory. The preference for bilateral transplant is due to Before the advent of continuous infusion of prostacyclin, the fact that, if an early graft dysfunction occurs (reperfusion 30-40% of the patients with PPH succumbed while they injury, edema due to overhydration, rejection or infection), waited for transplantation. This new therapy effectively perfusion will be maintained almost exclusively for the eliminated this dramatic situation, now regarding transplanted lung, which will result in severe desaturation transplantation not as an ab initio solution, but as a viable by severe shunting. This is due to the rigidity of the vascular alternative to those patients who do not respond to network of the native lung, which determines that blood vasodilators or to those who, after an initial response, failed flow predominate in the transplanted lung due to its higher to respond satisfactorily. There are several case reports that resistance, even in the presence of occasional graft suggest there might be greater success with the treatment of dysfunctions.8 Lung transplant in children - Camargo JJ et alii Jornal de Pediatria - Vol. 78, Supl.2, 2002 S117

Despite the systematic use of prophylactic measures, The thorax/lower lobe ratio of each potential donor can such as water restriction, elevated decubitus with be defined nearly with mathematical accuracy by means of transplanted lung facing upwards, positive expiratory helical tomography for measurement of lung volume, pressure, inhaled or intravenous vasodilators and deep according to the technique developed at our service,11 sedation with or without curarization, inexplicable and fast- which traces a line in the middle of the zone with highest developing crises of pulmonary hypertension might also vascular rarefaction observed on CT, thus identifying the occur, with massive pulmonary edema. scissura, establishing the geographical limits of the lobe, Even though the described difficulties can be effectively and calculating its volume, which is then compared with the managed nowadays, there is a common agreement that, volume of the recipient’s chest cavity (Figure 3). whenever possible, transplantation due to pulmonary The assessment of donors is resumed with an extensive hypertension should be bilateral. clinical and laboratory evaluation with the aim of confirming the good health of each candidate, including a complete functional assessment of the lungs and eliminating potential Lobar transplant donors with total pulmonary capacity of less than 85% The pioneering experiment conducted by Starnes9 predicted. attempted to solve the problem with obtaining adequate- Aside from the serological tests for herpes, CMV, sized organs for extremely small recipients. Since pediatric toxoplasmosis, Chagas disease, HIV, among others, the donors are even more rare and as there is a growing demand candidates are also submitted to fibrobronchoscopy and from critically ill recipients, especially among those with pulmonary arteriography corresponding to the side to be cystic fibrosis, lobar transplant, from family-related donors, used for donation with the intention of ruling out some has become a daring and, at the same time, intelligent anatomical anomalies that could impair the use of the lobe. proposal. The technique proposed by Starnes9 uses the lower The ideal candidate for transplant using living donors is lobes (right and left) removed from different donors (usually that patient with end-stage lung disease, often with cystic from father and mother) in order to replace one and the other fibrosis, in general, a child or an adolescent with a chest lung, respectively (Figure 4). cavity about the size of the lobe of an adult. The recipient The anatomical similarities of the lower lobe to the can be neither so small that the lobe of an adult cannot fit corresponding lung greatly facilitate the technique of lobar into the chest cavity, nor so big that a lower lobe of an adult transplant. Our recent experience with seven pediatric cannot fill the pleural cavity. As the matter only concerns patients who received lower lobes from living donors spatial adequacy, some lobar transplants have been confirms this observation. performed in adults with a small thorax. Donors should be blood-related, preferably the parents, so that immunological similarity can be used to the maximum advantage. Such similarity is certainly responsible for the favorable outcome in this group of patients. When this situation is present, the assessment of the three candidates involved starts with blood typing and determination of size compatibility as to the thorax/lower lobe ratio of each of the potential donors. In regard to the ABO system, the same criteria used for emergency blood transfusions should be applied, although there should ideally be a perfect compatibility between the recipient and each of the donors. The second item, that is, size compatibility, is essential because, if organs larger than the recipient’s chest cavity are implanted, severe hemodynamic problems may occur as a result of cardiac compression.10 On the other hand, the attempt to reduce the volume of lobes to be implanted was not successful since it causes hematomas on the lobe, which tend to expand due to the effect of anticoagulation (essential in ECMO) and certainly compromise the initial function of the implanted lobes. A slightly smaller lung volume is desirable when the recipient has some pulmonary hyperinflation as a result of Figure 3 - Volumetry of the lower left lobe the underlying disease. established by helicoidal CT S118 Jornal de Pediatria - Vol. 78, Supl.2, 2002 Lung transplant in children - Camargo JJ et alii

requirements and occasional functional losses, such as reperfusion injury, acute rejection and infection, among others;14 – episodes of acute rejection in the postoperative period are frequent and may be intense despite the kinship, which is attributed to the great immunological competence, characteristic of childhood, especially after the age of three. However, as the management of acute rejection with current drugs has been effective, this behavior does not interfere with the outcome; Figure 4 - a) X-rays of a 12-year-old boy with bronchiolitis – since under these circumstances we have two donors, obliterans and severe hyperinflation. FEV1: 12% of acute rejections in 30% of the cases are unilateral or, if expected. b) Radiological control 2.5 years after the bilateral, they are asymmetric, showing that the transplantation of two lobes (lower lobes from recipient’s body tends to recognize the transplanted parents). Patient resumed normal life. FEV1: 97% of expected (during this period the patient grew 13 cm, organs as foreign bodies, in a different way and at and the vital capacity increased 290 ml) different times. When rejections affect both lobes at the same time, and with the same intensity, functional involvement may be severe (Figure 5); – the late detection of bronchiolitis obliterans, which is knowingly a chronic rejection, is quite rare in this group From the technical point of view, the transplant is in which donors are obligatorily from the same family. carried out sequentially in three operating rooms located In the experiment conducted by Starnes, the comparison side by side, with left lower lobectomy of the first donor and between transplant recipients and dead donors, in terms corresponding pneumonectomy of the recipient, performed of survival rate, was widely favorable to the first group. simultaneously so that the length of ischemia is as short as The immunological tolerance enhanced by kinship possible. The lobe removed from the donor is preserved in certainly has a significant participation in late results. a basin, using a model of inflation and perfusion that While in conventional transplants life expectancy in perfectly simulates preservation in a dead donor. five years is only 50%, with blood-related donors, life Lobar transplant should begin on the side that is expectancy rises to 72%, in five years; functionally less participative, according to scintigraphy, – Starnes et al.15,16 compared 14 transplant recipients, or by the left side in case of symmetric disease, with the with living donors, with 11 recipients with dead donors attempt to avoid the need for prolonged ECMO. and found that episodes of acute rejection and pulmonary During the implantation of the second lobe, we have functional tests (FEV1 and FEV25-75%) were used elective ECMO so as not to submit the newly implanted comparable in both groups in one year, but in 24 months, contralateral lobe to full blood flow, which could cause the differences were substantial: the group of living reperfusion injury. donors had no case of bronchiolitis obliterans (BO) In the postoperative period, the recipient is often whereas 86% of the patients who received organs from extubated earlier, which has been a reality in half of our a dead donor showed some sign of bronchiolitis. The cases. subsequent report of the experience of this group, extended to 53 cases, revealed the persistence of the previously observed differences. The low incidence of Outcome after bilobar transplant BO and infection as the main cause of death in the group of living donors led the authors to consider a slighter Over time, the experience with this population has immunosuppression scheme and a heavier antibiotic allowed for some observations: therapy for this group.17 The authors regard lung – the surgery on donors has been conducted with the transplant with living donors as the ideal procedure for presumable morbidity of a lobectomy, with the advantage children;15 that the patient is absolutely healthy. In the experiment – another interesting aspect is the growth of the transplanted carried out by Saint Louis, postsurgical complications organ, keeping up with the pace of the recipient. The 12 were more frequent in the donors, but the group with presence of growth hormone in pediatric recipients greater experience in lobar transplant has reported few explains why a mature organ, implanted in a developing intercurrent events (flutter, reintervention due to recipient, sustains growth.19 The experiment conducted bleeding, persistent air escape for over five days) and no by Ro et al.18 showed that the true growth of the airway 17 interference with the patient’s final rehabilitation; detected by computed tomography revealed that – the transplant should be bilobar, since a single lobe implanted lobes grow, following the pace of growth of offers enough parenchyma to meet postoperative the recipient’s body. Lung transplant in children - Camargo JJ et alii Jornal de Pediatria - Vol. 78, Supl.2, 2002 S119

Figure 5 - a) 14-year-old male patient with severe cystic fibrosis. b) Severe bilateral and symetric rejection after transplantation of two lobes with family donors (father and mother). c) Late radiological control (1 year) with excellent functional result (FEV1: 107% of expected)

Peculiarities of lung transplant in very small children Acute rejection is as frequent in children as in adults, Despite the predictable difficulties in finding small although it is seemingly less prevalent in children aged less 22,23 donors, there are some pioneering experiments with lung than three years. transplants in very small children. Recently, the Saint Louis The episodes of rejection are more frequent in the first group20 reported an experiment with 19 transplant recipients six months, but may occur at any time. aged less than six months. In most cases (13 patients), the The incidence of chronic rejection or bronchiolitis disease was parenchymatous, while another six presented obliterans (BO) is high among children. The Saint Louis vascular lung disease. All of them were submitted to bilateral and Pittsburgh groups, which revealed 24% and 50% of BO transplantation, and although surgical mortality was higher in adults, showed this late complication in 27% and 18% of (32% or 6/19 patients) than that observed in older children, pediatric transplant recipients.22,24 On the other hand, the the late survival rate was comparable to other pediatric reasons for the high rate of BO after cardiopulmonary groups (44% in a maximum follow-up period of six years). transplantation due to cystic fibrosis, described in up to Bronchial complications and episodes of acute rejection 48% of the cases followed up during three years25 are not are equally comparable; however, chronic rejection seems clear, although the malabsorption of cyclosporin in cystic to be less frequent in this group, especially, with bronchiolitis fibrosis and the natural growth factors have been regarded obliterans in only two out of 13 survivors (15%), in a three- as occasionally responsible for higher rates of chronic year follow-up. The residual functional capacity and the rejection. pulmonary functional tests have gradually increased, suggesting lung growth concomitant with body growth. The level of activity and the quality of life are usually optimal after lung transplantation in children. The pulmonary functional assessment usually reaches an excellent peak in Postoperative outcome six months. In the experiment by Pittsburg, only two of 26 survivors did not return to normal physical activity,24 and The data collected from the Saint Louis International 21 21 of 22 survivors in the initial experiment by Saint Louis Lung Transplant Registry showed that children have as presented good walking condition.4 good an outcome as that of adults, with a survival rate of 67% in their first year, and 57% in the second year, with slight variations from one center to another. The Saint Louis group did not reveal any difference in risk when compared Complications to children with more or less than three years of age at the Infectious complications are more frequent in pediatric time of transplantation.22 transplants, similarly to what occurs in adults, and are more The necessity of mechanical ventilation before common in the postoperative period of lung transplantations transplantation, the need for high doses of oxygen than in any other solid organ transplant. supplementation, the presence of aortopulmonary collateral For still unclear reasons, some infections, such as that vessels and prolonged length of ischemia have been caused by the respiratory syncytial virus, adenovirus and repeatedly cited as elements of surgical risk, with impact on parainfluenza, may lead to severe and sometimes fatal early postoperative death. infections. S120 Jornal de Pediatria - Vol. 78, Supl.2, 2002 Lung transplant in children - Camargo JJ et alii

The previous serology for cytomegalovirus (CMV) is bronchiolitis obliterans by chronic rejection were observed negative in most children, increasing the risk of severe among them. infections when these patients are already In general, the incidence of bronchiolitis obliterans has immunocompromised and have primary infection by CMV. been reported in as much as 50% of pediatric patients, If a CMV-negative patient receives an organ from a CMV- which seems to be paradoxical, given that many centers positive donor, the risk is quite high, especially in the form report less acute rejection in these patients, but apparently of pneumonia. other factors favor the occurrence of bronchiolitis obliterans, The use of prophylactic ganciclovir and probably the as the frequent viral infections by CMV, and the difficulties use of CMV hyperimmune immunoglobulin may delay the in maintaining a uniform immunosuppression in this age onset and mitigate the severity of the infection caused by group, in function of the higher speed of hepatic elimination CMV.26 of cyclosporin and tacrolimus in this population, thus Similarly to what occurs in adults, ganciclovir is an requiring higher doses and regular administration. efficient drug for CMV infections, especially when they Most children have not come into contact with the manifest themselves as isolated infections. The association Epstein-Barr (EBV) virus, which results in the enhanced with other agents, especially fungal ones, significantly risk of this viral infection if they receive an organ from a increases mortality. test-positive donor, and presumably, a higher probability of Infections caused by Aspergillus are problematic in developing lymphoproliferative disease in the future. In the pediatric patients. The sources of contamination include experiments carried out by St. Louis and Pittsburgh, the fungal aspiration from contaminated environments, occurrence of lymphoproliferative disease was 9% and 22,24 colonization of suture lines, and endogenous airway 22%, respectively. colonization in patients with cystic fibrosis. The infection The most frequent primary site is the transplanted organ, may be characterized by tracheobronchitis, pneumonia, but other areas, such as the CNS, have been described. An aspergilloma or invasive aspergillosis. The prophylactic interesting aspect of these experiments is the report that, use of inhaled amphotericin or oral itraconazole may reduce aside from the primary infection by the Epstein-Barr virus, the risks of infection by Aspergillus. many children received enhanced immunosuppression with In patients with cystic fibrosis, the regular colonization cytolytic agents, which seems to favor this late complication. of upper airways by gram-negative bacteria increases the Likewise, the yet incipient experience with tacrolimus risk of contamination of the graft by these bacteria, especially suggests that the incidence of lymphoproliferative disease when there is some kind of injury in the transplanted organ. is more commonly observed with this drug than with 28 When the initial outcome is favorable, the rule is that the cyclosporin. graft remains sterile, but with the presence of reperfusion Transbronchial biopsy, considered an essential tool for injury, acute rejection or viral infections, the risk of bacterial the follow-up of adult transplant recipients, is problematic proliferation in the transplanted organ increases a lot, from in very small children due to the difficult treatment of such the germs found in the upper airway. a small airway and to the nonexistence of appropriate clips A similar situation is observed in the late postoperative for the collection of samples. On the other hand, the period of cystic fibrosis, when the sputum test after occurrence of bleeding and pneumothorax is more common 27 transplantation is often negative, and remains sterile for among pediatric patients. several months or years, if evolution occurs normally, but Another problem that is characteristic of a pediatric with early recolonization by pseudomonas if there are signs patient is venous access, which is usually overcome with the of bronchiolitis obliterans. use of total or partial impantable vascular access. The Bronchial complications due to the smaller diameter of impantable vascular accesses should be removed after a few the upper airways in pediatric patients are slightly less months so that they will not become a source of bacterial frequent in this population, as expected, and are characterized colonization. by cicatricial stenosis or bronchomalacia. Bronchomalacia, albeit less frequent among children, is difficult to control due the occlusive tendency of the small airway, especially Specific problems of cystic fibrosis in expiration. Repeated dilations and, less frequently, the Cystic fibrosis, a leading indication for lung transplants use of bronchial stents might be necessary.27 in many internationalcenters, is associated with several problems in the postoperative period: – pancreatic insufficiency and the resulting malabsorption Peculiarities of pediatric transplantation of food causes many patients to have osteoporosis, First of all, a distinction between pediatric patients which tends to worsen with the daily use of prednisone younger and older than three years has to be drawn. In the in the postoperative period. Bone marrow compression experience of Barnes Hospital,22 children younger than and pathological fractures may represent serious three years have less rejection than others, and no cases of difficulties in these patients;29 Lung transplant in children - Camargo JJ et alii Jornal de Pediatria - Vol. 78, Supl.2, 2002 S121

– predisposition to intestinal constipation, also attributed Follow-up of pediatric transplant recipients in the long to pancreatic insufficiency, usually worsens after term transplantation as a result of patient’s immobility, The pediatric patient, just as the adult one, returns to his/ sedation with narcotics and reduction of intestinal her city of origin after postoperative recovery has been well motility determined by azathioprine. The prophylaxis established, with adequate immunosuppression and and early detection of this complication can avoid preserved pulmonary function. intestinal perforation and unnecessary and risky The family is informed that any clinical change must be surgeries; reported because it may mean the onset of a remarkable – the inevitable colonization of the airway of a cystic complication, especially of CMV infection, or incipient patient by P. aeruginosa and similar germs poses an manifestations of bronchiolitis obliterans. A permanent additional risk to infection of the graft by these bacteria. contact between the pediatrician and the transplantation Some centers, such as that in Toronto, considers the center is crucial for the successful follow-up of the patient. previous colonization by Burkholderia cepacia an Any change in medication should be jointly analyzed, absolute contraindication for transplantation.30 Other due to the frequent interaction of drugs that could change centers do not go so far as to contraindicate the transplant, the immunosuppressive action. but admit that the presence of this agent increases the The patient has to return to the transplantation center on morbidity and mortality in the early postoperative period. a regular basis for periodical follow-ups, transbronchial Other microorganisms, such as Stenotrophomonas biopsy and occasional adjustments to immunosuppressant maltophilia (Xanthomonas), Alcaligenes xylosoxidans drugs. After six months, it should be possible to define the and Aspergillus fumigatus, often persist in the respiratory transplant recipient as a rejector or non-rejector. Based on epithelium of the trachea and of the facial sinuses, and these elements, the administration of drugs may be represent a great therapeutic challenge in occasionally reduced, and an ideal dosage that ensures the immunocompromised patients; prophylaxis of rejections with minimal adverse effects should be attempted. – the tendency of chronification of sinusitis by the germs mentioned above asserts the importance of an appropriate The routine of physical exercises and nutritional pretransplant preparation, by means of large sinusotomies rehabilitation, quite often implemented before the transplant, and an aggressive treatment with antibiotics in the should be maintained and intensified, with the aim of postoperative period. This tendency has been ascribed allowing as normal a lifestyle as possible. to the immunological imbalance caused by Avoiding exposure to harmful elements, such as tobacco uncontrollable chronic sinusitis with propensity for and dust, is very important; however, this concern should chronic rejection, observed in patients transplanted due not interfere with school activities and other activities that to cystic fibrosis,22 since systemic inflammation may are normal for the patient’s age. alter the P-450 metabolism of immunosuppressants, especially of cyclosporin A;

– other problems result from the difficult absorption of the drugs and require different strategies for the treatment Conclusions of these patients. It is not clear whether cyclosporin and Lung transplant has increasingly established itself as a tacrolimus have a different metabolism in cystic fibrosis, reliable therapeutic option for those children with end-stage but the elimination of prednisone is faster, and many respiratory diseases, with a survival rate similar to that of antibiotics, especially aminoglycosides, should be given adults. Cystic fibrosis is the most frequent indication for in higher doses and at shorter intervals than what is transplantation in children, followed by vascular lung recommended for other transplant recipients; diseases and idiopathic pulmonary fibrosis. Infectious complications, especially the viral ones, are frequent, and – the absorption of cyclosporin, hampered by the initial the lymphoproliferative disease is more common in children, formulation, significantly improved with the probably because many of them are subject to primary development of Neoral (Sandoz, East Hanover, NJ), a infection by the Epstein-Barr virus after transplantation. microemulsion that is better absorbed by all patients, Other complications, such as hypertension, including the cystic ones; hypercholesterolemia, renal dysfunction and airway stenosis, – presumably due to the great variability in the absorption are similar to those described in adults. Children with cystic of cyclosporin, cystic patients are at a greater risk for fibrosis have to cope with some difficulties related to the neurological complications in the postoperative period underlying disease, but life expectancy after transplantation than other patients.31 has increased as surgical experience is improved. S122 Jornal de Pediatria - Vol. 78, Supl.2, 2002 Lung transplant in children - Camargo JJ et alii

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