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Eur J Cardiothorac Surg 1999;15:490-495
© 1999 Elsevier Science NL
a Cardiothoracic Surgery Service, La Timone Children's Hospital, Boulevard Jean Moulin-13385, Marseilles Cedex 05, France
b Department of Anesthesia and Intensive Care, La Timone Children's Hospital, Boulevard Jean Moulin-13385, Marseilles Cedex 05, France
Received 26 May 1998; received in revised form 13 January 1999; accepted 1 February 1999.
Corresponding author. Tel.: +33-4-9138-6676; fax: +33-4-9147-8170; e-mail: dmetras@ap-hm
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Abstract |
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 Top Abstract Introduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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Key Words: Pediatric • Lung • Transplantation • Pulmonary • Infections
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Introduction |
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TopAbstractIntroduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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They can be responsible for progressive dysfunction of the graft and obliterative bronchiolitis (OB), reaching 40% of the transplanted lungs [5], a major cause of late mortality after the first year. However, interestingly, lung infections have not been reported to be more frequent in transplantation for cystic fibrosis (CF) than for non-septic pulmonary disease [6] [7].
Since 1988, we have performed 49 lung transplantations in 43 children, 35 for cystic fibrosis and eight for non-septic diseases. We report here the infectious complications observed and their impact on early and late graft dysfunction and deaths.
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Materials and methods |
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TopAbstractIntroduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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Immunosuppressive protocol
The protocols have evolved with time. From 1988 to 1993, an induction was done with rabbit anti-thymocyte globulin (RATG). (initially for 1 week, then in 1993 for 3 days). Since 1994, RATG induction was abandoned, as in many other programs, in an effort to decrease infections.
Steroids were initially withheld for 2 weeks and subsequently given on a maintenance dose. Since 1994, they were used on day 1 at 8 mg/kg per day, tapered to 0.6 mg/kg per day on day 3, then decreased each week to reach 0.2 mg/kg per day.
Intravenous Cyclosporin was started during the 1st post-operative day, when the renal function and diuresis were considered satisfactory, to reach 400 to 500 ng/ml monoclonal radio immunoassay (RIA) in the whole blood. Oral or enteral administration was started between the 4th and 10th day to reach similar trough levels during the 1st year.
Azathioprin started at the dose of 2 mg/kg was progressively adapted to tend to reach a white blood count (WBC) below 5000.
Antibiotic prophylaxy
All patients with CF had multiple pre-operative bacterial and fungal tracheobronchial contamination (Table 2). Patients with Burkolderia cepacia (n=3) were not considered as contra indicated for transplantation, despite multiple antibiotic resistance.
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Although systematically done, cultures of the bronchial secretion of the donor did not lead to significant changes in the AB treatment.
In non-CF patients, a shorter, 2-day double-AB regimen was used with Ceftazidine and Vancomycine, in view of the frequent carriage of methicillin-resistant Staphylococus.
Antifungal prophylaxy
After an initial period without systematic prophylaxy, we now routinely use Fluconazole during 10–15 days, 6–8 mg/kg per day. In addition, local decontamination by oral Amphotericin B is also used.
Pneumocystis
Trimethoprime (8 mg/kg per day), Sulfamethazole (40 mg/kg per day) are given after the 1st month, 3 days/week during 9 months.
Toxoplasmosis
Pyrimethamine (1 mg/kg per week) during 6 weeks is given in case of a sero-positive donor and sero-negative recipient.
Cytomegalovirus (CMV)
Despite our efforts to match donors and recipients, 40% of the patients had a CMV mismatch, 12 negative patients receiving a positive donor.
Prophylaxy has evolved with time, according to the matching of patients, to our results and according to the reports of literature.
Initially, polyvalent immunoglobulins were given. Then IV Acyclovir (500 mg/m2 per day) was given during 10 days.
Since 1992, IV Gancyclovir (GCVIV) is given (10 mg/kg per day or more according to blood level) if the donor or recipient is seropositive, presently for 3 months. If both are negative, only Acyclovir is given. Specific immunoglobulins are not given on a routine basis, mainly due to a problem of availability in France.
Post-transplantation routine surveillance
Post-transplantation, regular bacteriology and viral laboratory tests were performed: twice in the 1st week, weekly during the following month, twice a month until the 6th month, then every month until the 1st year.
These controls included: blood tests with white cells count, and Protein C Reactive (PCR).
Bacterial identification, culture and antibiogram of bronchial secretion. Viremia, genic amplification, leucocytes antigenemia, urine and sputum CMV research. Serologies: CMV, EBV, HSV, Candida, Aspergillus, Toxoplasmosis.
Broncho-alveolar-lavage (BAL) were done on day 2, then every week in the 1st month and subsequently if required by clinical, radiological, or lung function tests anomaly.
On all BAL, a systematic research of all viral, bacteriologic, mycotic and parasitic agents was carried out.
Concerning the respiratory tract: chest X-ray, CT Scans, blood gazes, frequent functional studies, bronchoscopy with BAL are also carried out routinely. Transbronchial biopsy (TBB) was done after 2 weeks for the first one, then at month 1 and 3, subsequently only in case of pulmonary clinical event. During a TBB, three–five samples were taken in one or two ipsilateral tubes.
The diagnosis of a bacterial infection was accepted when, after a clinical and laboratory episode (fever, sputum, modification of breath sounds, X-ray, WBC, PCR), endoscopy, BAL and/or TBB demonstrated clear signs of infection.
During the 1st post-operative month, acute rejection episodes were diagnosed mainly on clinical or X-ray grounds, rarely with biopsy specimen obtained by TBB. The classical rejection grading of the IHLTS were used.
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Results |
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TopAbstractIntroduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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Overall infectious episodes
Among 49 pediatric lung transplantations, only five patients had no infection. There were 3.2 infectious episodes per year, 75% localized to the lungs. The number of infectious episodes (viral or bacterial) in the first 3 months, in the following 9 months, and beyond the 1st year have been compared according to the immunosuppression protocols used, and in particular the diminution and then suppression of RATG induction. Despite a slight decrease in the number of infectious episodes, the numbers did not reach statistical difference.
Also, the treatment of acute rejection episodes (1.5 rejection episode/patient per year) was not correlated with a subsequent increase of infectious episodes.
Bacterial infections
There were 53 bacterial infectious episodes (Table 3). The majority occurred in the 1st year (80%) and most (42%) during the first 3 months.
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Thirty-eight episodes of bacterial lung infection occurred in 16 patients (Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococus pneumoniae, Klebsiella pneumoniae, Mycobacterium kansasii). In five patients they occurred in the presence of a silastic intra-bronchial stent, mostly in our initial experience.
Local infection (abscess of thoracotomy wound or mediastinitis) occurred twice, successfully treated by prolonged antibiotic treatment associated with debridement. No particular naso–sinus infection occurred.
Viral infections
Syncitial respiratory virus (SRV)
Two episodes occurred at 5 and 6 months post-transplant, without major consequence, treated with nebulized ribavirin. The other one was not treated and resolved spontaneously.
Ebstein–Barr virus (EBV)
Seven episodes occurred, three times it was a reactivation in three sero-positive patients.
In four cases they were asymptomatic. One case had symptoms of acute abdominal episode needing laparotomy. It showed an infiltration of the colic wall, (unfortunately no biopsy was taken). This disappeared with diminution of immunosuppression.
Three lymphoproliferative syndromes on the transplanted lungs occurred in seronegative recipients with seropositive donors. Immunosuppression was decreased and a cellular lytic chemotherapy was undertaken. Two patients died after 1 month, showing no regression of the lesions. In one patient, the lung lesions disappeared but the patient died 2 months later of a lung CMV infection.
Various virus infections
One pneumonitis with herpes simplex virus was cured by Acyclovir. There were three adenovirus infections, one of them leading to the death of the patients 2 months after a retransplantation. They were treated with non-specific antiviral chemotherapy (Gancyclovir and Foscavir). Three minor febrile episodes with para-influenzae virus occurred without major consequence.
CMV pneumonitis
There were 16 patients who suffered from one or several episodes of CMV pulmonary infection. The occurrence of CMV pneumonitis relationships to the serologic status of the donor and recipient are shown in Table 4. The risk of developing a pneumonitis with a positive donor was found to be significantly higher (P<0.02) than with a negative donor.
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The diagnosis was done in all cases by histology after TBB and frequently without the appearance of viremia or CMV isolation by PCR genic amplification. In only 4/16 patients, positive viremia occurred before the pneumonitis. Viral isolation in the BAL was done in only 10/16 cases, by vial-shell or PCR.
The incidence of CMV pneumonitis was evaluated in relation with the various immunosuppressive protocols and CMV prophylaxis. It appears that there is no significant correlation between these factors.
Outcome of the patients with CMV pneumonitis: Fourteen of the 16 patients presenting a CMV pneumonitis died despite maximal treatment. One patient was cured of the pneumonitis, one was successfully retransplanted after viral cure but with functional destruction of the lung. It is now 4 years after the patients successful BSLT retransplantation. The pathology of the explanted lung was essentially fibrosis, rather than active inflammatory or necrotic process.
The actuarial survival curves show a difference of survival in negative recipient and donor, better than any other combination, but more significant is negative donor (40% survival at 3 years) upon positive donor (17% at 3 years).
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Discussion |
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TopAbstractIntroduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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Infections have been reported to be responsible for death in 40% of the patients during the 1st months after transplantation [1]. The overall rate of infectious episodes in our experience is grossly similar to other series [2] [6]. The diagnosis of early infection is difficult, and bronchoscopy and BAL are the best tools to make this diagnosis sure. Of the bacterial infections, 96.5% have been evidenced by these tools.
It is well recognized that lung transplantation is more at risk of lung infectious than other types of transplant for a number of reasons: highly septic organs, with a frequently uncontrolled infection, direct communication of the transplanted organ with the outside world, decreased spontaneous ability of the lung to clear secretion's, persistence of septic foci in CF patients, poor nutritional status of the CF recipient.
The level of immunosuppression, particularly its increment in the presence of infection, has been incriminated in the appearance of infections, particularly CMV [10]. Although we have not observed this correlation, we have suppressed the induction with RATG, as others [10] [11].
The bacterial infections have been reported to be the most frequent particularly in pediatric lung transplantation, 54% in the Pittsburgh experience [4], 48% in Stanford [1]. Our figure of 53% is grossly similar.
Among these infections, the majority are pulmonary (56% in our experience). In the Toronto experience [12] they occurred in 75% in the first 2 post-operative months.
The presence of Pseudomonas aeruginosa, is constant in CF candidates for transplantation (89% according to the Chapel Hill group [13], 95% in our experience. They were responsible for the large majority of pulmonary infections (66% of bacterial infections in our experience). Interestingly, they have been shown by the group of Cambridge [6] to be equally present in non-CF transplanted patients.
Although none of these early infectious have led to the death of our patients, they were associated with OB in six of our eight patients with OB, leading to their death. The Pittsburgh group has shown [5] that multiresistant Pseudomonas decrease 1 year survival (46%), versus the AB sensitive ones (84%).
The presence of Cepacia is considered by some as a contra-indication to transplantation [14]. We have transplanted three patients with pre-operative Cepacia. There was no major post-operative Cepacia infection, but the patients had a late death with carriage of various infectious agents (CMV two cases, Staphylococus, two cases; Alkaligenes xylosoxydans, one case; Pseudomonas aeruginosa, three cases).
In our experience CMV infection appears to be the most threatening problem, directly or indirectly responsible for 60% of the deaths.
Two types of infections can occur after transplantation in a seropositive recipient: (a) Reactivation corresponding to the replication of the endogenous virus worn by the seropositive recipient. (b) Superinfection caused by the donor's virus in a seropositive recipient.
If the recipient is seronegative, a primo-infection can occur either by the donor's virus if seropositive (70–88% of recipients can develop this infection in the first 3 months [15]). It can also occur in case of both negative recipient and donor.
CMV produces not only pulmonary lesions per se, but also favors chronic rejection [16], bacterial and fungal infection, leading to irreversible lung lesions and dysfunction, even after eradication of the virus with Gancyclovir.
In our experience, the viral laboratory findings have had less sensitivity than histology findings.
In our experience, CMV infections have led to dramatic mid-term and/or long-term results. Despite numerous efforts, reducing immunosuppression and increasing the duration of Gancyclovir prophylaxis to 3 months, it remains a major problem for us. Comparing the 3 years survival of all different combinations of donor and recipient status, we reach only a significant difference between positive and negative donor irrespective of recipient condition (40 vs. 17%).
The prevention of CMV pulmonary infections, followed by death or chronic lung dysfunction leading to retransplant or death is a difficult one. Its seems that prolonged prophylaxy with Gancyclovir associated with hyperimmune immunoglobulin may be the best strategy [17]. The CMV recipient–donor matching and even the use of exclusively negative donors is questionable. It would reduce considerably the already limited pool of lung donors by 50%.
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Conclusion |
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TopAbstractIntroduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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By contrast, viral, and particularly CMV infections have led to the death of patients, either by their direct effect in lung infections or leading to chronic lung dysfunction, occasionally associated with rejection. They remain a extremely difficult problem overwhelming all other infectious complications.
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Footnotes |
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Appendix A. Conference discussion |
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TopAbstractIntroduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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Dr. Metras: Yes, I think so. We have a little less infection, but it is not yet solved. I must say that we have been intrigued by the fact that the Hannover group, for example, does not care about matching with CMV and doesn't even look at the donor CMV condition. So we have sent somebody to Hannover and carried out the same protocol, exactly as your protocol on a patient 2 weeks later with a positive donor and negative recipient. He went home after 2 weeks and died after 2 months from severe CMV lung infection. So I think at home it is an unsolved problem.
Dr Pettersson: What is the age difference between the Marseille material and the Hannover material? What is the mean age of your group?
Dr Metras: The mean age is 11 in our group.
Dr Pettersson: And yours?
Dr A. Haverich (Hannover, Germany): It was 28.
Dr Pettersson: So that's a major difference.
Dr Metras: I think so.
Dr Haverich: I do think it is a major difference because in the pediatric population of our cystics I think the infections are also much more severe to treat. Also the question that I would have, in your prophylactic protocol you said that you would only give anti-CMV prophylaxis in those patients with a positive donor and a negative recipient. I do not think that with a 60% incidence of CMV conversion in the donor-plus/recipient-plus match that you should not give a very high-dose prophylaxis in those patients also.
Dr Metras: No. Maybe I wasn't clear enough. I said that if the donor or the recipient is CMV-positive, they have a 3-month prophylaxis. It is only the negative/negative who do not have systematic Gancyclovir prophylaxis.
Dr S. Mattila (Helsinki, Finland): These are excellent results in this group of patients, which is more difficult than the adults. I would like to ask you about your attitude toward the Pseudomonas infection and also to get a comment from the Hannover group, because we have a feeling in our material in Helsinki that it is almost impossible to totally eradicate the Pseudomonas from the bronchial tree, and it seems to have nothing to do with the real infections with the patient. So I would like to ask, is that only our feeling, or how did you treat your patients, because in both series most of the patients were Pseudomonas-infected prior to transplantation.
Dr Metras: I agree totally with you that Pseudomonas cannot be eradicated. None of those patients had an eradication of Pseudomonas. The only thing is that apparently it is, in general, adequately controlled by multiple antibiotics, and even in some cases of multiresistant Pseudomonas they did not develop severe Pseudomonas infection leading to death, although they were very often associated in the progressive lung dysfunction, but they did not die directly of an infection process.
Dr L. Hamilton (Newcastle Upon Tyne, UK): Thank you for a realistic and therefore, a very valuable paper. Just to answer your question, we match as closely as possible for CMV status in our lung transplants.
Both papers this morning have raised the question of retransplantation. Could I just ask for your current views on the question of retransplantation? Certainly, in adults we no longer offer retransplantation in the lung patients, could I ask about children?
Dr Metras: Our view is that, of course, retransplantation is very controversial, we know about that, but it is very difficult to refuse to consider an individual patient for retransplantation, and I think that it has to be chosen by the group, in terms of possibilities of having reasonable results, possibilities of having a lung for these patients, and also sometimes personal contact with the family and the patient. I must tell you that you have seen that we have performed seven retransplantations in six patients. We have performed, in one patient, two retransplantations. The patient was transplanted 8 years ago with a double-lung en bloc transplant, underwent obliterative bronchiolitis, 1 year later was transplanted with a heart–lung block, and then 5 years later again developed obliterative bronchiolitis. We were really hesitating. We transplanted him with a single lung and he is now in good condition 2 years after this transplant. He is a very clever guy and not infected. So it is difficult to say no.
Dr Haverich: If I could comment on that, to refuse to do lung transplantation as a reoperation in the adult population, I think this is a very difficult issue that cannot actually be answered by the surgeons. I think for this question we have to sit together with psychologists and social workers and with family psychiatrists and so on, because this has to be defined. I could turn this around. You probably say it's because of the poor results of retransplantation, and then I could ask you why do you do Fontan recipients for heart transplantation with the known poor results and do not restrict it to pediatric cardiomyopathy where the results would be much better. I think it is a very difficult question and it is beyond surgical discussion alone.
I would ask one final question because I think, especially in the pediatric age group, this is extremely important, and the question is who takes care of those patients who are at home and get sick, at what speed do they get into the hospital, and what department do they end up in?
Dr Metras: Well, that's a big problem, but usually the cystic fibrosis patients are taken care of by centers that deal with them before the transplant, and usually they are the referring doctors for a problem after the transplant if they live around there, otherwise they directly call us in the hospital. But I agree that sometimes it has led to retardation of treatment when it was an underestimated problem by the GP. This is a big problem.
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References |
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TopAbstractIntroduction
Materials and methodsResultsDiscussion
Conclusion
Appendix A. Conference...References |
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This article has been cited by other articles:
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  B. Bech, T. Pressler, M. Iversen, J. Carlsen, N. Milman, K. Eliasen, M. Perko, and H. Arendrup Long-term outcome of lung transplantation for cystic fibrosis -- Danish results Eur. J. Cardiothorac. Surg., December 1, 2004; 26(6): 1180 - 1186. [Abstract] [Full Text] [PDF]
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 R. M. ARIS, J. C. ROUTH, J. J. LIPUMA, D. G. HEATH, and P. H. GILLIGAN Lung Transplantation for Cystic Fibrosis Patients with Burkholderia cepacia Complex . Survival Linked to Genomovar Type Am. J. Respir. Crit. Care Med., December 1, 2001; 164(11): 2102 - 2106. [Abstract] [Full Text] [PDF]
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