Objectives: The effect of prior cigarette use by lung transplant donors and recipients on posttransplant survival is poorly defined, especially in subjects with cystic fibrosis. We sought to determine if donor or recipient cigarette smoking is associated with differential postlung transplant outcomes in cystic fibrosis patients, including survival.

Materials and Methods: The United Network for Organ Sharing database was searched to analyze a large sample of cystic fibrosis patients with a history of lung transplant. The primary endpoint of the study was overall survival after transplant based on either recipient or donor history of smoking cigarettes.

Results: There was a significant decrease in survival for cystic fibrosis patients who received lungs from a donor with a history of smoking (P = .026), but no difference in survival for recipients with a personal history of smoking. Nearly 60% of subjects who received lungs from a smoking donor died during the study. Donor smoking history was correlated with survival in a univariate (HR 1.2, [1.04-1.3]), but not multivariate model. Donor smoking history also was associated with increased treatment for rejection within the first year after transplant (P = .005).

Conclusions: More than 20 pack-year history of donor smoking may affect lung transplant outcomes (eg, survival and acute rejection) in patients with cystic fibrosis. Caution must be exercised when choosing suitable organ donors for cystic fibrosis patients requiring a lung transplant.

Key words : Lung disease, Registry, Tobacco, Trans-plantation

Introduction

Cystic fibrosis (CF) is a life-limiting disease characterized by progressive respiratory function deterioration with chronic respiratory tract infections.¹ Lung transplant (LTx) is a therapeutic option for end-stage or acutely declining CF lung disease.² As such, CF is the second most frequent indication for bilateral LTx worldwide.³ While LTx in CF is associated with improved median survival compared with other transplant indications, optimization of posttransplant outcomes and determination of risk factors for acute allograft rejection is ongoing in CF.

Cigarette smoking by LTx donors and recipients is an understudied potential risk factor for post-transplant survival in CF. Historically, smoking has been negatively associated with pretransplant organ yields,⁴ questioning use of donor organs from cigarette smokers. Also, donor cigarette use has been associated with cardiac allograft vasculopathy in heart transplant recipients,⁵ but not specifically lung allograft dysfunction. However, because of shortages in transplantable organs, former smokers are often considered as lung donors. Recent analyses have shown that single and double-lung transplants are thought to be safely performed for all indications using donors with heavy smoking histories.^6,7 These studies did not specifically look at outcomes for CF patients, a population that inherently may be more sensitive to receiving lungs damaged by cigarette smoke. Cigarette smoke is known to affect ciliary function and mucus clearance,^8,9 allowing for potential continued chronic lung infections in CF patients from seeding of transplanted lungs with chronic upper airway bacteria.

Transplant recipient smoking history also is important in CF, as a single-center study demon-strated that 16% of CF patients had a history of smoking cigarettes¹⁰ before LTx. In support of these recipient studies, a single-center study of LTx recipients of all indications demonstrated that preoperative recipient smoking history was not a risk factor for airway complications during the first year after a transplant.¹¹ However, recipient smoking has been linked with posttransplant lung cancer development in 1 series, with 1 of the patients affected having a diagnosis of CF.¹² Those investigators reported that 2.6% of recipients developed lung cancer. Additionally, there is a single case reported of donor-acquired small cell lung cancer following LTx in a CF patient whose donor was a former smoker.¹³

Therefore, because of concerns of cigarette smoking effects specifically in CF patients after LTx, we undertook an analysis of the United Network for Organ Sharing (UNOS) registry to determine if donor or recipient cigarette smoking is associated with differential post LTx outcomes including survival.

Materials and Methods

UNOS database
This study was approved by The Ohio State University Wexner Medical Center Institutional Review Board, with a waiver of the need for individual consent (IRB#2012H0306). Data were obtained from the Organ Procurement and Transplant Network Standard Transplant Analysis and Research Database, which is maintained by UNOS. Data included patient characteristics, demographics, and specific clinical outcomes for donor, pretransplant recipient, and posttransplant recipient. We retrospectively examined eligible recipients of a deceased-donor LTx who had a diagnosis of CF from January 1, 1987, to September 6, 2013. Recipients with a history of retransplant were excluded from the analyses. We grouped lung transplant recipients and donors according to a history of cigarette use defined in the database as > 20 pack-years. The primary endpoint of the study was overall survival after transplant, based on either recipient or donor history of cigarette use. Secondary endpoints included the effect of recipient and donor cigarette use on acute rejection within the first year.

Statistical analyses
All analyses were performed using Stata/MP, version 13.0 (College Station, TX: StataCorp LP). For every analysis, a P value < .05 was considered statistically significant. Continuous variables are expressed as means ± standard deviation (SD), and categorical variables as counts with percentages. Chi-square testing was used for bivariate analyses. Survival duration was analyzed from the date of the transplant until the date of death or censoring. Crude differences in overall survival across recipient or donor cigarette use categories were assessed using Kaplan-Meier estimates of the survival function, and log-rank tests were performed to test for differences in survival functions. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for both univariate and multivariate models. All variables included in these models were selected based on clinical relevance to the study.

The univariate models included donor and recipient history of cigarette use, donor and recipient gender and race, type of transplant (ie, single or double lung), history of infection (defined as acute infection requiring intravenous drug therapy within 2 weeks before the transplant), pulmonary hyper-tension before the transplant, lung function before the transplant measured as forced expiratory value in 1 second (FEV1) and forced vital capacity, recipient’s educational level and insurance status, and posttransplant factors including treatment for rejection within 1 year, creatinine level, body mass index (BMI), and ischemic time. Medicare and Medicaid insurance use are associated with lower socioeconomic status in the United States. The multivariate model included donor and recipient history of cigarette use, donor and recipient gender and race, type of transplant, history of infection before transplant, FEV1, and forced vital capacity before the transplant, recipient’s insurance status, treatment for rejection within 1 year, creatinine level, BMI, and ischemic time. Pulmonary hypertension and recipient’s educational status were excluded from the multivariate model because of missing data.

Results

Cohort demographics
We used a total of 3616 cases of patients with CF, after a LTx that were eligible for analyses. Details of the sample size and exclusion process for all analyses are presented in Table 1. Study cohort demographics are presented in Table 2. Recipients of LTx with a history of CF were primarily white (95.1%) and male (52.4%), while the majority of donors also were white (67.1%) and male (56.7%). The majority of the recipients’ (37.2%) highest educational level was equivalent to high school or a general educational development attainment; and 60.8% of recipients had private insurance coverage for their transplant.

Past history of cigarette smoking was reported in 5.3% of recipients, and 16.4% of donors; 57% of subjects had a history of pulmonary hypertension before the LTx, and 41.1% were treated for acute rejection within the first year after the transplant. Subjects’ mean percentage of predicted FEV1 was 26.5% and BMI 19.1 before the LTx.

Survival data
Kaplan-Meier survival curves are presented for recipients with and without cigarette use (Figure 1) and for donors with and without cigarette use (Figure 2). There were 1746 total deaths during the study. Comparable numbers of recipients with (28%, 25/90) and without (29.8%, 480/1610) prior cigarette use died during the study. There was no significant difference in the Kaplan-Meier survival estimate for transplanted CF patients with a history of cigarette use (P = .6). However, there was a significant decrease in survival for CF patients who received lungs from a donor with a history of cigarette use (P = .026). Of subjects whose donor had a history of smoking cigarettes, 326/548 (59.5%) died, compared with 1215/2792 subjects (43.5%) whose donor did not smoke cigarettes.

Hazard modeling
Results of the univariate Cox proportional hazard modeling are presented in Table 3. Donor, but not recipient, history of cigarette use had a significant effect on survival (HR 1.2; 95% CI: 1.02-1.3; P = .03). Smoking donors were more likely to be white (P < .001) than other races. Other negative associations with survival in the univariate model included black donors (HR 1.2; 95% CI: 1.05-1.4; P = .008), acute infection before transplant (HR 1.2, 95 CI: 1.04-1.3; P = .006), Medicaid use (HR 1.4; 95% CI: 1.3-1.6; P < .001), Medicare use (HR 1.2; 95% CI: 1.01-1.3; P = .042), and treatment for rejection within 1 year of transplant (HR 1.5; 95% CI: 1.3-1.7; P < .001). Significant positive associations with survival included history of double lung transplant (HR 0.4; 95% CI: 0.2-0.7; P = .001), recipient’s educational status of a college degree or beyond (HR 0.5; 95% CI: 0.4-0.7; P < .001), higher BMI (HR 0.98; 95% CI: 0.96 - 0.99), and lower ischemic time at transplant (HR 0.97; 95% CI: 0.94-0.99; P = .048).

Multivariate Cox proportional hazard model results are presented in Table 4. Overall subject characteristics are similar to the univariate analysis. Most of the significant variables from the univariate analysis were not significantly associated with survival in the multivariate analysis, except for treatment for rejection within 1 year of transplant (HR 1.5; 95% CI: 1.1-2.1; P = .01) and Medicaid use (HR 1.4; 95% CI: 1.1-1.8; P = .006). Double LTx (HR 0.2; 95% CI: 0.05-0.8; P = .026) and higher BMI (HR 0.9; 0.92-0.99; P = .017) were positively associated with survival. Neither recipient nor donor history of cigarette use was associated with increased mortality in the multivariate model.

The effect of donor and recipient smoking history on the frequency of acute rejection within the first year after the transplant also was examined. Recipient history of smoking was not associated with increased acute rejection in a bivariate model (P = .5), but donor history of smoking was associated with increased acute rejection within the first year (P = .005). Of those treated for acute rejection within the first year after the LTx, 18% were subjects whose donor had previously smoked, compared with 13.6% of subjects without acute rejection whose donor had previously smoked cigarettes (P = .005).

Discussion

Smoking within the previous 6 months is a contraindication for LTx eligibility; however, past use of cigarettes beyond the most recent 6 months currently is not an absolute or relative contra­indication for LTx.^2,14 Additionally, although an “ideal” lung donor has a smoking history of less than 20 years,¹⁵ that benchmark often is not achieved, as evidenced by the 16.4% of donors listed in this study with a history of cigarette use. There are currently no studies that directly quantify how much past donor smoking is safe when accepting lungs for transplant; however, retrospective reviews have shown that more than 40 pack-years negatively influences outcomes in non-CF patients.¹⁶

Previously, a single-center study did not demonstrate differences in all diagnosis posttransplant outcomes from donors who smoked more than 20 years.¹⁷ Donor history of smoking has also been shown not to affect late transplant outcomes.¹⁸ Additionally in all recipients of lung transplant, patients who received lungs from smoking donors had a lower hazard of death than those who remained on the waiting list.¹⁹ In our current study, we used a large database of post LTx CF patients to determine a negative effect on posttransplant outcomes from donors with a smoking history greater than 20 pack-years. This finding should be considered by clinicians regarding lung allocation for patients with CF, who represent a specific population at risk of complications from smoking-induced dysfunction.

Interestingly, we did not find any correlations with survival in those patients with CF with a personal history of smoking. This may be because of the small number of recipients (90) who had reported a history of cigarette smoking. Based on other evidence in CF, it remains prudent to recommend cessation of all tobacco products for at least 6 months in patients with CF before an LTx as substance abuse or dependence remains an absolute contraindication.¹⁴

In the setting of organ transplant, several factors affect the decision to accept organs for a patient with end-stage disease, including status of the recipient and donor, condition of the organ, donor-recipient compatibility, and transplant center factors. Often decisions can be made at a time of critical condition, so several factors are influencing organ allocation. Based on the results of the present study, caution should be taken in accepting lungs with a greater than 20 donor pack-year history of smoking for patients with CF because of a decreased survival after an LTx and an increased risk of acute allograft rejection. However, there may be other factors involved, as donor history of smoking did not remain significant in our multivariable model.

Additional factors may predispose CF patients to more negative effects associated with receipt of donor lungs from past smokers. Cigarette smoking is associated with systemic decreases in cystic fibrosis transmembrane conductance regulator function,²⁰ contributing to phenotypic symptoms comparable to a CF-like state in smokers. Additionally, secondhand smoke has been shown to affect nutritional, micro­biological, and airway functioning in children with CF,²¹ further providing evidence of the toxic effect of smoke on CF lungs. Some of these factors may account for the fact that we did find outcome differences in this population, where others did not in the general population of recipients of LTx.

In addition to the effect of smoking in CF, acute allograft rejection was a significant risk of past donor smoking. Exact reasons for this cannot be determined from the current study, but recent studies have shown that smoking after a transplant mimics a chronic rejection state²²; however, not specifically acute rejection. Contrasting our data, a meta-analysis of all postsurgical outcomes in non-CF current smokers did not show an increase in acute rejection.²³ However, CF patients represent a unique group of patients with differing immune responses, therefore making our findings relevant. Chronic rejection could not be assessed in this study based on the recent changes in nomenclature and previous coding in UNOS. Overall, further research on the effects of donor smoking history on allograft functioning in CF is needed.

This study has several limitations. The use of registry data is prone to several biases including coding errors and missing data. Precise donor smoking history also was not available including nicotine metabolites, and therefore smokers may have classified themselves as nonsmokers for reasons of social desirability. This misclassification error would have biased the study toward the null hypothesis. Additionally, the retrospective nature of the study prevents us from determining direct correlation amongst findings. Finally, cystic fibrosis transmembrane conductance regulator status is not routinely known for all donors, precluding analysis of the risk of carrier status on any outcomes. Despite these shortcomings, we feel that the large collection of patients helps shed some light on a subject mostly addressed in single-center studies in the past.

In summary, donor, but not recipient, history of cigarette use greater than 20 pack-years is associated with decreased survival in a univariate model and increased acute rejection in all models after LTx in patients with CF. This study provides useful information to assist clinicians who make allocation decisions for CF patients.

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