The Risk Factors of Mortality
Results of Cox proportional hazards models were presented in Table 6. Compared with non-ReTX patients, ReTX recipients had nearly 2 times the risk for death within 1 year posttransplant. Older age, female sex, hospitalization 15 days or longer, cardiac index at listing, eGFR less than 60 mL/min per 1.73 m2, 6-minute walk distance less than 400 ft, and donor/recipient height ratio less than 1 were independently associated with a higher risk for 1-year mortality in the entire lung transplant cohort. Ages 65 years or older remained significant in ReTX recipients. The Cox proportional hazards models that were run in all patients had a moderate C statistic of 0.68 (Table 6). The stratification analysis by age groups in the retransplant cohort indicated that the number of death within 1 year after retransplant was 8 (38%) of 21 patients 50 years or older (median age of the retransplant cohort) versus 11 (39%) of 28 patients (P = 0.93) younger than 50 years. Meanwhile, 3 (60%) of 5 patients 65 years or older died within 1 year versus 16 (36%) of 44 patients (P = 0.30) younger than 65 years (data not shown). Of 49 ReTX patients, 43 (88%) received a single lung ReTX on the different side or double lung ReTX. Only 6 (12%) received a single lung ReTX on the same side of the primary lung transplantation. There was no significant difference in the mortality within 5 years after transplant by the side the single lung ReTX occurred (30/43, 69.8% vs 4/6, 66.7%, P = 0.99, data not shown).
Analysis of our 6-year cohort showed that lung ReTX recipients had good short-term outcomes, especially for 30 and 90 days, where survival rates dropped from 94% to 88%, respectively, which were similar to the survival rate of primary lung transplantation recipients (95% and 91%, respectively). However, mortality declined dramatically after 90 days with the 1-year survival of 61.3% (vs 81.9% in non-ReTX patients, P < 0.001). The 1-year survival of our ReTX is comparable to that of the historic control cohort described by Sommer et al,4 who were not retransplanted following the minimally invasive protocol (63.2%). Notably, Sommer et al suggested that the short- and midterm outcome of the ReTX patients could be substantially improved with the minimally invasive protocol. In fact, their minimally invasive ReTX cohort had a comparable 1-year survival to that of our primary lung transplantation cohort (80.6% vs 81.9%).4 Perioperative bleeding, severe infection, PGD and airway dehiscence were the major causes of early mortality within 90 days after ReTX. Surgical complications in the perioperative period after Re-TX were bleeding and airway complications. In general, lung ReTX recipients carry higher mortality risk because of technically challenging issues including chest wall bleeding due to significant adhesions. Moreover, these patients have a high prevalence of bleeding after the surgery due to coagulopathy due to cardiopulmonary bypass pump runs, or renal insufficiency. Prolonged operation times, increased use of blood products and cardiopulmonary bypass can also be major contributing factors to mortality and morbidity. Severe airway complications are associated with infection, rejection, surgical techniques or persistent ischemia and use of vasoconstrictor agents. Complete dehiscence of the anastomosis can be associated with high morbidity and mortality.5
Surgical anastomotic techniques plus allograft infection, with positive cultures for aggressive microbes such as Pseudomonas have a significant impact on airway complications and can be a substantial treatment challenge. Infection after lung ReTX has a significant impact on early and late mortality in our lung retransplant recipients. There were 3 deaths due to pneumonia and septic shock, which accounted for 16% of the 1-year ReTx mortality. These data clearly elucidate that infection poses a high risk for a poor outcome. Pretransplant immunosuppression may potentially be responsible for the higher rate of serious infection in these patients.6,7 Increasingly potent immunosuppressive agents given for induction and maintenance therapy have dramatically reduced the incidence of rejection of transplanted organs while increasing patients' susceptibility to opportunistic infections. Literature review suggests bacterial infections comprise more than half of all infectious complications after lung transplant.8 Aguilar-Guisado and coworkers reported a cohort study of 85 episodes of pneumonia in 236 lung transplants and identified bacterial pneumonia (82.7%) as being more frequent than fungal (14%) and viral pneumonia (10.4%). The most frequent microorganisms in each etiological group were Pseudomonas aeruginosa (n = 14, 24.6%), cytomegalovirus (CMV; n = 6, 10.4%) and Aspergillus spp. (n = 5, 8.8%).9 The etiology of pneumonia in lung transplantation is varied and includes 4 overlapping sources: donor-derived infections, recipient-derived infections, nosocomial infections, and community-acquired infections.10 A significant number of the early episodes of bacterial pneumonia are derived from donor lungs.8 Although infection and surgical complications account for most of recipient deaths in 90 days in our lung retransplant recipients, infection and chronic rejection accounted for the most retransplant recipient deaths between 90 days to 1 year.11
Our univariate analysis suggests that recipients who require dialysis have a significantly greater increased mortality risk after lung transplant. Of 4 recipients who had pretransplant dialysis, 2 were ReTX candidates and offered ReTX with acceptable renal function (eGFR>60 mL/min per 1.73 m2). Given the small number of recipients receiving pretransplant dialysis (n = 4), this variable was not included in the Cox proportional hazards model. Although pretransplant dialysis has not been well described as a risk factor for poorer survival after lung transplantation, pretransplant eGFR less than 60 mL/min per 1.73 m2, has been recognized as a risk factor for mortality in lung transplant recipients.12 This observation clearly indicates that lung ReTX should be avoided in patients on current dialysis unless concomitant renal transplantation is available as a reasonable therapeutic option, which may reduce the high mortality for this high-risk specific subgroup.
In our cohort, BOS and R-CLAD were the leading causes of death in the ReTX after the first year of lung transplantation.13-16 We had 4 recipients who had respiratory failure due to R-CLAD within the first year after lung ReTX. R-CLAD accounted for about 21% of the total deaths in the first year. Major risk factors related with R-CLAD including allograft acute rejection, CMV infection, human leukocyte antigen (HLA) mismatching, non-CMV infection, and allograft ischemic time.17,18 Further investigations are needed to discern why the development of R-CLAD occurs so early after lung ReTX and quickly leads to graft dysfunction or failure within the first year after ReTX. In addition, some significant differences of the patients' condition at baseline (ReTX patients were more likely to be females, have a lower BMI, and eGFR, have a higher rate of previous steroid use, and history of diabetes compared with non-ReTX patients) may also contribute to the ReTX patients' poor outcomes via the increase of infections and higher levels of immune suppression at or before the transplant.
Our study indicates mortality for ReTX is comparable to mortality rates for primary lung transplant recipients in the short term (within 90 days after transplantation), but had poor results at 1 year. These outcomes are similar with national data.2 Although survival after lung ReTX has had definite improvement in recent years,19-21 outcome measures such as mortality are still poorer compared with outcome measures after primary lung transplantation. Moreover, donor organs are scarce and in high demand, thus outcome measures must be weighed in the decision algorithm.
ReTX carries a high risk of operative complications and poorer overall outcomes. Hence, patients who are considered for ReTX must meet strict criteria to ensure the best possible outcomes for our patients. Therefore, our lung retransplant protocol is based on current data and the scarcity of donor organs and was recently revised. Based on these new revised criteria, patients being considered for lung retransplant undergo the same stringent evaluation as the initial lung transplant evaluation. Patients and families are counseled that not all patients who have had a transplant in the past are appropriate candidates for ReTX. The evaluation also includes a psychosocial and economic evaluation to identify any concerns that would hinder our goal to provide the best outcomes and survival for our lung transplant patients. Ages 65 years or older, being female, having posttransplant length of stay 15 days or longer, eGFR less than 60, 6-minute walk distance less than 400 ft, and donor/recipient height ratio less than 1, considered a surrogate for donor-recipient lung size match in our analysis, have been identified by the Cox proportional hazards model as risk factors for having higher risk for 1-year mortality, in which ages 65 years or older remained significant after stratification for ReTX group. Although preoperative ICU stay and mechanical ventilation were included in the initial multivariate model, these 2 variables were not significant and were removed from the final model. The risk factors identified associated with poor posttransplant outcome by our multivariable Cox proportional hazard model has some practical implementations: (1) more careful consultations and extensive evaluations should be done before making a decision regarding lung retransplant for the “high risk” patients, (2) if a lung retransplant is done on a patient having one of the risk factors (such as older than 65 year, female, eGFR<60, 6 minute walk distance <400 and donor/recipient height ratio < 1), the patient would need greater attention and more aggressive medical support measures should be allocated. In addition, certain medical support should be considered to improve the modifiable parameters (such as 6-minute walk distance or carefully choose a matched donor lung size) that would ultimately improve the patient's posttransplant survival. However, given the small number of event in ReTX patients, stratification analysis by non-ReTX versus ReTX for the Cox proportional hazards model was not conducted. Although only 5 (10.2%) patients in our retransplant cohort are 65 years or older, these patients had higher mortality (3/5, 60%), a 24% increase compared with patients younger than 65 years. However, this findings should be interpreted with caution given the small sample size of the retransplant cohort. Although preoperative ICU stay and mechanical ventilation were included in the initial multivariate model, these 2 variables were not significant and were removed from the final model. Improving the 6-minute walk distance, carefully choosing a size-matched donor lung, and more aggressive postop medical supports would be among the approaches to improve patient survival. The implementation of minimally invasive procedures should also be taken into consideration for ReTX patients.4 In our center, 24/49 (49.0%) of patients received bilateral ReTX. Medical and surgical issues drive review board decisions toward offering single versus double ReTX. Single lung ReTX was offered more in older recipients, obstructive CLAD phenotype, and primary single lung transplants with graft failure where the remaining native lung was removed and transplanted. Double lung retransplants were offered for younger patients, restrictive CLAD phenotype, concomitant chronic infections or colonization, sicker patients in ICU with severe graft dysfunction. Surgical considerations predisposing to single lung transplants included presence of diaphragm paralysis, significant pleuroparenchymal chest wall adhesions or loculation and ipsilateral or double lung retransplants were generally avoided. However, there was no significant difference in the outcome between groups of single versus bilateral retransplantation (data not shown).
Lung retransplantation is a treatment option for highly selected patients. Outcomes of lung retransplantation are good in the short-term, but long-term survival results in lung retransplant recipients are poor. Severe PGD, infections and surgical issues are the main causes of death during the early postoperative (90 days) period. Chronic rejection still is the major cause of death in lung transplantation long-term follow-up. Those individuals who undergo lung retransplantation for chronic rejection have a better survival than those with early graft failure/acute rejection. Lung retransplantation indication should be evaluated more vigorously, especially in patients older than 65 years, female, having eGFR less than 60 mL/min per 1.73 m2 or 6-minute walk distance less than 400 ft. Although some risk factors are not modifiable (such as older age or sex), improving the modifiable parameters (such as 6-minute walk distance or careful choices of a matched donor lung size) would be among the approaches to improve the patient's posttransplant survival.
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© 2018 The Authors. Published by Wolters Kluwer Health, Inc.
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