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Published online before print October 1, 2001, 10.1148/radiol.2212010381
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(Radiology. 2001;221:508-514.)
© RSNA, 2001

Thoracic Imaging

Reperfusion Edema after Lung Transplantation: Effect of Daclizumab1

Edith M. Marom, MD, Yo Won Choi, MD, Scott M. Palmer, MD, MHS, David M. DeLong, PhD, Mark D. Stuart, BS and H. Page McAdams, MD

1 From the Departments of Radiology (E.M.M., D.M.D., H.P.M.) and Medicine (S.M.P., M.D.S.), Duke University Medical Center, Box 3808, Durham, NC 27710; and Department of Radiology, Hanyang University Hospital, Seoul, Korea (Y.W.C.). Received January 29, 2001; revision requested March 12; revision received April 4; accepted May 2. Address correspondence to E.M.M. (e-mail: marom001@mc.duke.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine if daclizumab, an interleukin-2 antagonist, reduced the severity of reperfusion edema in lung transplant recipients.

MATERIALS AND METHODS: Eighty-five patients who were to undergo 86 consecutive lung transplants were included; 43 (50%) received daclizumab in addition to conventional immunosuppression. Patients were assigned to one of the following groups: control, right allograft; control, left allograft; daclizumab treated, right allograft; daclizumab treated, left allograft. Radiographs obtained in the first 5 postoperative days were evaluated for degree of edema. Mean daily edema scores and curves for control and daclizumab-treated groups were compared. Differences in survival at 1, 3, 6, and 12 months after transplantation, days of mechanical ventilation, and the ratio of arterial oxygenation to inspired oxygen level at 1, 3, and 5 days after transplantation were also compared.

RESULTS: Mean daily edema scores, edema curves, survival, days of mechanical ventilation, and ratio of arterial oxygenation to inspired oxygen level at 1 and 3 days after transplantation did not significantly differ between daclizumab-treated and control groups. A trend toward improved survival in the daclizumab-treated group was noted.

CONCLUSION: Daclizumab had no effect on the radiographic or immediate clinical manifestations of reperfusion edema in lung transplant recipients. Additional follow-up is needed to determine if daclizumab offers any long-term benefit in terms of reduced rejection rates or survival.

Index terms: Lung, edema, 60.458, 60.711 • Lung, effects of drugs on • Lung, transplantation, 60.711


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Reperfusion edema, also known as the reimplantation response, is defined as the morphologic, radiologic, and functional change that occurs in the lung allograft immediately after transplantation (1). It is a form of noncardiogenic pulmonary edema that occurs in nearly all pulmonary allografts in the first few days after transplantation (2,3). Clinically, reperfusion edema manifests with hypoxemia and pulmonary opacities on chest radiographs (4). The opacities are usually heterogeneous in nature and perihilar and lower lobe in distribution (2,3,5). They typically develop in the first few hours after lung transplantation, worsen and peak a few days following transplantation, and then begin to resolve in most patients (3,6,7). However, severe edema persists in up to 15% of all lung transplant recipients and can result in primary graft failure, the second most common cause of early mortality in lung transplant recipients (8).

The pathogenesis of reperfusion edema is not clearly understood and is probably multifactorial. Putative causes include increased vascular permeability due to allograft ischemia and reperfusion (9,10), decreased surfactant production, interruption of lymphatic drainage (11,12), uptake of calcium by cells (13), free radical production (14,15), and possibly the vasoconstrictive effects of prostaglandin E2 (16). Mediators of reperfusion injury may include neutrophil-derived oxygen free radicals, various cytokines, the complement system, and, possibly, interleukin-2 (IL-2) (17,18).

Daclizumab is a molecularly engineered protein that competitively inhibits IL-2 binding (19). The addition of daclizumab to conventional immunosuppression has been shown to decrease the incidence of acute allograft rejection in renal and cardiac transplant recipients (20–23). Its utility in lung transplantation is currently being investigated. One retrospective report suggests that the use of an anti–IL-2 agent (either daclizumab or basiliximab) does not decrease acute rejection in lung recipients but is associated with improved pulmonary function at 3 and 6 months after transplantation (24).

The reason for improved pulmonary function in patients treated with anti–IL-2 receptor therapy is unknown. We hypothesize, however, that inhibition of the IL-2 receptor might lead to improved pulmonary function by reducing ischemia reperfusion injury after lung transplantation. It has been known for many years that patients treated with IL-2 can develop pulmonary edema caused by increased vascular permeability—the so-called vascular leak syndrome (25–30). Daclizumab, therefore, by virtue of its action as an IL-2 antagonist, might reduce the severity of reperfusion edema in lung transplant recipients. The purpose of this study was to determine if the addition of daclizumab to conventional immunosuppressive therapy reduced the severity of reperfusion edema in lung transplant recipients.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
Eighty-eight patients who underwent 90 consecutive lung transplant procedures from October 17, 1997, to September 27, 1999, were considered eligible for this retrospective study. This period was chosen so that equal numbers of patients treated with daclizumab and patients not treated with daclizumab (control group) were included. Our institutional review board approved the study and waived the requirement for patient consent. Patients were excluded if they developed histologically proved acute rejection or infection during the first 6 days after transplant. Infection was defined as a positive culture in conjunction with histologic proof and/or strong clinical suspicion. Three patients were excluded due to infection by Staphylococcus aureus (n = 2) or parainfluenza virus (n = 1). No patient was excluded because of acute rejection. One patient was excluded because a large ipsilateral pleural effusion that precluded radiography of the allograft in the immediate posttransplant period. One of these excluded lung transplantation procedures occurred in a patient who had undergone lung transplantation twice. Thus, the final study group consisted of 85 patients who underwent 86 consecutive lung transplantation procedures (38 bilateral, 30 unilateral left, 18 unilateral right); a total of 124 allografts were evaluated (61 control group, 63 daclizumab-treated group). Of the patients who received daclizumab, 20 had undergone bilateral, 13 unilateral left, and 10 unilateral right lung transplantation. Of the control group, 18 had undergone bilateral, 17 unilateral left, and 8 unilateral right lung transplantation. Recipients were 18–66 years old (mean age, 47 years). Indications for transplantation were chronic obstructive pulmonary disease (n = 36), cystic fibrosis (n = 15), {alpha}1-antitrypsin deficiency (n = 9), idiopathic interstitial fibrosis (n = 7), second transplantation (n = 5), emphysema (n = 3), bronchiectasis (n = 3), sarcoidosis (n = 3), primary pulmonary hypertension (n = 2), eosinophilic granuloma (n = 1), agammaglobulinemia (n = 1), and acute respiratory distress syndrome (n = 1).

Allograft Preparation
Pulmonary allografts were harvested and flushed with University of Wisconsin solution (Viaspan; Dupont Pharmaceuticals, Wilmington, Del and 500 µg of prostaglandin E2). The preservation solution most commonly used was modified Euro-Collins solution (Baxter Healthcare, Deerfield, IL); the allografts were immersed in this solution at 4°C for transport.

Immunosuppressive Therapy
The first 43 (50%) patients (control group), who underwent transplantation from October 17, 1997, to December 1, 1998, received only conventional immunosuppressive drugs. The next 43 (50%) patients (daclizumab-treated group), who underwent transplantation from December 2, 1998, until September 27, 1999, received daclizumab in addition to conventional immunosuppressive drugs, as part of their routine clinical treatment. Preoperative immunosuppression consisted of oral administration of 2.0–2.5 mg cyclosporine per kilogram of body weight 4 hours before transplantation, 500 mg of methylprednisolone, and 2 mg/kg azathioprine intravenously administered at the time of reperfusion. Postoperative immunosuppression consisted of 125 mg methylprednisolone intravenously administered every 12 hours for four doses, followed by 20 mg/day prednisone, tapered by 5 mg every 3 months if the patient remained free of rejection. Postoperative cyclosporine was either administered intravenously or orally with the dose strictly adjusted to maintain a level between 250–300 ng/mL (measured by using high-performance liquid chromatography) during the first 6 months after transplantation. Postoperative azathioprine was administered (intravenously until oral medications were tolerated) at a dose of 2 mg/kg daily. Daclizumab (Zenepax; Hoffman-LaRoche, Nutley, NJ) was intravenously administered at a dose of 1 mg/kg in the operating room at the time of lung transplantation and on postoperative day 4 for a total of two doses.

Clinical Evaluation
All patients underwent standard follow-up after lung transplantation, which included daily chest radiographs for the first 6 postoperative days. Lower airway secretions obtained by using suction were cultured daily while the patients were intubated and thereafter if there was clinical suspicion of infection. Patients underwent fiberoptic bronchoscopy with transbronchial biopsy when clinically suspected of having rejection or infection (n = 3). All culture specimens were directly examined and cultured for bacterial, fungal, and viral infection. Specimens were directly examined after Gram staining, potassium hydroxide preparation, and direct immunofluorescent staining for respiratory viruses (respiratory syncytial virus; influenza A and B; adenovirus; parainfluenza 1, 2, and 3). Cultures were processed for bacteria, fungi, cytomegalovirus, and adenovirus.

In addition, patient medical records were retrospectively reviewed for the following information: survival in the first posttransplantation year; number of postoperative days on mechanical ventilation during the study period; and the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FIO2) on 1, 3, and 5 days after transplantation, which is a quantitative assessment of the severity of oxygenation impairment (31).

Survival for each group was assessed at 1, 3, 6, and 12 months after transplantation by using Kaplan-Meier analysis. Overall survival was assessed with the log-rank test. The number of postoperative days on mechanical ventilation during the study period and the PaO2/FIO2 ratios on days 1, 3, and 5 posttransplantation were compared between groups by using the Wilcoxon rank sum test.

Radiographic Evaluation
Daily chest radiographs were obtained in all patients for the duration of their hospital stay. During the first 2 postoperative days, supine anteroposterior chest radiographs were obtained (Computed Radiography System 7000; Philips Medical Systems, Shelton, Conn). This method of radiography was continued for as long as the patient was confined to a bed. After the 2nd postoperative day, those patients able to stand underwent posteroanterior chest radiography with either a dedicated digital thoracic system (Thoravision System; Philips Medical Systems, Hamburg, Germany) with a selenium drum detector or a conventional chest radiographic unit (InSight; Eastman Kodak, Rochester, NY) with an asymmetric screen-film system for thoracic radiography.

For the purpose of this study, six daily chest radiographs obtained in the first 5 days after transplantation (day 0 to day 5) were selected for review. When more than one chest radiograph was available per day, radiographs were chosen so that the time intervals between them would remain evenly distributed. The radiographs were serially evaluated by two thoracic radiologists (E.M.M., Y.W.C.) who were blinded to the immunosuppressive regimen. The patient name and radiograph acquisition date were concealed to exclude bias related to the date of transplantation and, therefore, drug regimen. Evaluation was performed by using hard-copy images. Each transplanted lung was divided into four zones (upper, midle, lower, and perihilar [3]), and the degree of edema in each zone was assessed by using a four-point scale: 0 for normal lung, 1 for minimal opacity not obscuring lung vessels, 2 for opacity partially obscuring lung vessels, 3 for opacity completely obscuring lung vessels. Differences in score were resolved by consensus.

To assess the effect of daclizumab on radiographic findings of edema, we performed two types of analysis. For the first analysis, we calculated the total daily edema score for each allograft by summing the lung zone scores for each day. The data were then grouped according to the side of the allograft (right or left) and type of immunosuppression: control group, right lung allograft; control group, left lung allograft; daclizumab-treated group, right lung allograft; and daclizumab-treated group, left lung allograft. For the purpose of this analysis, bilateral transplants were divided into right and left lung allografts and grouped appropriately. We then calculated a mean edema score for each group on each posttransplantion day (day 0–5) by summing the total edema scores for that day and dividing by the number of allografts in each group. The resulting mean daily edema scores for the two right lung allograft groups (control vs daclizumab treated) were then compared by using a two-group t test; the mean daily edema scores for the two left lung allograft groups (control vs daclizumab treated) were compared in a similar fashion.

For the second analysis, curves relating the mean daily edema score to day after transplantation were generated for each of the four groups. To compare edema curves quantitatively, we calculated the coefficients of the first three orthogonal polynomials that described each curve. The first coefficient was the area under the curve and reflected the total amount of edema depicted on radiographs. The second coefficient was the linear trend of the curve and reflected the rate of edema resolution. The third coefficient, or quadratic, reflected the tendency of the curve to form a single peak. The coefficients of the two right lung allograft curves (control group vs daclizumab-treated group) were compared by using a two-group t test. The coefficients of the two left lung allograft curves (control group vs daclizumab-treated group) were then compared in a similar fashion. The coefficients were also compared after correction for the covariates of age, sex, and type of transplantation (unilateral vs bilateral).

To correct for possible differences due to radiographic technique, the mean frequency of supine and upright radiographs was computed for each patient and these means were compared by using the Wilcoxon rank sum test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Radiographic Data
Analysis of the radiographic data showed that evidence of reperfusion edema was seen in all patients, regardless of group. Radiographic opacities predominated in the perihilar and lower lung zones, generally peaked in severity by the first postoperative day, and began to improve thereafter (Figs 1, 2). Typical radiographic findings of reperfusion edema are shown in Figure 3.



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  		Figure 1. Graph shows mean edema score versus day after transplantation for right lung allografts. There was no significant difference between control (dotted line) and daclizumab-treated (solid line) groups.

 


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  		Figure 2. Graph shows mean edema score versus day after transplantation for left lung allograft. There was no significant difference between control (dotted line) and daclizumab-treated (solid line) groups.

 


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  		Figure 3a. Reperfusion edema in 45-year-old man after left single lung transplantation for emphysema. Patient received daclizumab. (a) Anteroposterior chest radiograph obtained in the first few hours after transplantation demonstrates mild perihilar opacities in left lung allograft (arrows). Allograft was scored as follows: upper zone = 1, perihilar zone = 2, middle zone = 1, lower zone = 2; daily edema score = 6. (b) Anteroposterior chest radiograph obtained 24 hours after a shows increasing opacity in the left lung allograft, compatible with worsening edema. Allograft was scored as follows: upper zone = 1, perihilar zone = 3, mid zone = 2, lower zone = 3; daily edema score = 9. (c) Posteroanterior chest radiograph obtained 72 hours after b shows marked interval decrease in opacities in left lung allograft. Allograft was scored as follows: upper zone = 0, perihilar zone = 1, mid zone = 0, lower zone = 1; daily edema score = 2.

 


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  		Figure 3b. Reperfusion edema in 45-year-old man after left single lung transplantation for emphysema. Patient received daclizumab. (a) Anteroposterior chest radiograph obtained in the first few hours after transplantation demonstrates mild perihilar opacities in left lung allograft (arrows). Allograft was scored as follows: upper zone = 1, perihilar zone = 2, middle zone = 1, lower zone = 2; daily edema score = 6. (b) Anteroposterior chest radiograph obtained 24 hours after a shows increasing opacity in the left lung allograft, compatible with worsening edema. Allograft was scored as follows: upper zone = 1, perihilar zone = 3, mid zone = 2, lower zone = 3; daily edema score = 9. (c) Posteroanterior chest radiograph obtained 72 hours after b shows marked interval decrease in opacities in left lung allograft. Allograft was scored as follows: upper zone = 0, perihilar zone = 1, mid zone = 0, lower zone = 1; daily edema score = 2.

 


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  		Figure 3c. Reperfusion edema in 45-year-old man after left single lung transplantation for emphysema. Patient received daclizumab. (a) Anteroposterior chest radiograph obtained in the first few hours after transplantation demonstrates mild perihilar opacities in left lung allograft (arrows). Allograft was scored as follows: upper zone = 1, perihilar zone = 2, middle zone = 1, lower zone = 2; daily edema score = 6. (b) Anteroposterior chest radiograph obtained 24 hours after a shows increasing opacity in the left lung allograft, compatible with worsening edema. Allograft was scored as follows: upper zone = 1, perihilar zone = 3, mid zone = 2, lower zone = 3; daily edema score = 9. (c) Posteroanterior chest radiograph obtained 72 hours after b shows marked interval decrease in opacities in left lung allograft. Allograft was scored as follows: upper zone = 0, perihilar zone = 1, mid zone = 0, lower zone = 1; daily edema score = 2.

 
There was no significant difference in mean daily edema scores for control and daclizumab-treated, right or left lung allograft groups (P > .3). There was little visual difference in mean edema curves generated for control and daclizumab-treated, right (Fig 1) or left (Fig 2) lung allograft groups. There was no significant difference in total amount of edema between control or daclizumab-treated, right or left lung allograft groups (first polynomial, P > .79). There was no significant difference in rate of edema resolution between control or daclizumab-treated, right or left lung allograft groups (second polynomial, P > .76). There was no significant difference in the tendency of the curves to peak between control or daclizumab-treated, right or left lung allograft groups (third polynomial, P > .8). When the coefficients were adjusted for age, sex, or type of transplantation, no significant differences were found (P > .12 in all cases). The mean frequency of supine and upright radiographs did not significantly differ between control and daclizumab-treated groups (P = .93).

Clinical Data
Kaplan-Meier survival curves for the control and daclizumab-treated groups are shown in Figure 4. No statistically significant survival difference between groups was demonstrated at 1, 3, 6, and 12 months after transplantation (P values of .24, .33, .37, and .39, respectively) or in the overall survival (P = .16).



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  		Figure 4. One-year posttransplantation Kaplan-Meier survival curves. No significant survival differences were observed between control (dotted line) and daclizumab-treated (solid line) groups at 1, 3, 6, and 12 months after transplant. Note, however, a trend toward improved survival in the daclizumab-treated group.

 
The number of postoperative days on mechanical ventilation did not differ significantly (P = .56) between groups. Patients in the control groups were mechanically ventilated for 3.5 days ± 2.2 (mean ± SD) and patients in the daclizumab-treated groups were mechanically ventilated for 3.2 days ± 2.1.

The PaO2/FIO2 ratio on postoperative day 1 was available in 83 patients and did not differ significantly between groups (P = .52); mean ratios were 3.19 ± 1.5 and 3.27 ± 1.24 for the control (n = 42) and daclizumab-treated groups (n = 41), respectively. The PaO2/FIO2 ratio on postoperative day 3 was available in 54 patients and did not differ significantly between groups (P = .09); mean ratios were 2.68 ± 1.98 and 3.07 ± 1.22 for the control (n = 26) and daclizumab-treated groups (n = 28), respectively. The PaO2/FIO2 ratio on postoperative day 5 was available in only 45 patients. Mean ratios on day 5 were 2.58 ± 1.25 and 3.17 ± 0.86 for the control (n = 19) and daclizumab-treated groups (n = 26), respectively. This difference was significant (P = .03).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
IL-2, a cytokine produced by T lymphocytes, is responsible for the growth and differentiation of T and B lymphocytes. IL-2 is important in the organ rejection process because it stimulates cytotoxic T cells to attack the allograft (32). In addition, IL-2–activated helper T cells secrete chemical messengers that activate and recruit additional inflammatory cells, such as neutrophils, to the allograft. Engineered antibody products such as daclizumab are directed at the IL-2 receptor and are designed to selectively block activation of antigen-specific T lymphocytes. It does so by binding the alpha subunit of the receptor and inhibiting the binding of IL-2 (19,33). This mechanism is attractive for prevention of acute rejection because the alpha subunit to which daclizumab binds is expressed by only a small percentage of T and B lymphocytes; thus, daclizumab has little adverse effect on the overall immune system (34). The addition of this agent to standard immunosuppression regimens may lead to more rapid tapering of prednisone, further decreasing the overall level of immunosuppression and potentially reducing the incidence of posttransplantation infection. Thus, daclizumab theoretically combats acute rejection without increasing the patient’s susceptibility to infection. The addition of daclizumab to standard immunosuppression protocols in renal and heart transplant recipients has been shown to reduce the incidence of acute rejection without increasing (and sometimes even decreasing) the incidence of infection (20–23). However, in these studies (20–22), daclizumab did not significantly affect renal or heart graft survival at 12 months. Preliminary data in lung transplant recipients suggests improved pulmonary function may occur in patients treated with anti–IL-2 receptor therapy, although the reason for this improvement is unknown (24).

Several lines of reasoning suggest that IL-2 may play an important role in the pathogenesis of reperfusion edema in lung transplant recipients. First, up to 50% of patients treated with IL-2 develop increased vascular permeability pulmonary edema, although at doses higher than those produced locally in the lung (25–27,35). Endothelial damage in these patients is caused not by IL-2 itself, but rather by IL-2–activated leukocyte-induced mediators such as neutrophil-derived oxygen free radicals (27,36,37). Second, neutrophil activation and free radical production are believed to be important in the pathogenesis of reperfusion edema (14,15). Increased numbers of neutrophils are often noted in bronchoalveolar lavage fluid obtained from lung allografts affected by reperfusion edema (38). IL-2–activated helper T cells secrete chemical messengers essential for neutrophil recruitment to the lung. Third, a significant increase in IL-2 levels has been reported (39) in bronchoalveolar fluid obtained within 24 hours of implantation in an animal model of lung transplantation. For these reasons we postulated that daclizumab, by competitively inhibiting IL-2 binding, might decrease the severity of reperfusion edema in lung transplant recipients.

In our study, however, we observed no significant differences between control and daclizumab-treated groups in the radiographic appearance or quantitative assessment of reperfusion edema. Daclizumab did not affect the overall amount of edema depicted on radiographs or the rate of resolution of edema. There was also no significant difference between control or daclizumab-treated groups in mean number of days of mechanical ventilation, mean PaO2/FIO2 ratios on postoperative days 1 and 3, or mean survival at 1, 3, 6, and 12 months after transplantation. We thus conclude that daclizumab has no important effect on either the radiographic or immediate clinical manifestations of reperfusion edema in lung transplant recipients. Although previous authors, as noted earlier, have suggested a role for IL-2 in the pathogenesis of reperfusion lung injury, blocking the IL-2 receptor did not seem to affect reperfusion edema in our study. This may be because the pathogenesis of reperfusion lung injury involves a complex cascade of multiple overlapping pathways, only one of which involves IL-2 (13,16,32,40). Thus, blocking the IL-2 receptor may not reduce reperfusion injury because of the redundancy of the immune system.

Several arguments may be raised to rebut our negative conclusions. The tests we used might not have been sensitive enough to detect a small effect of daclizumab. Chest radiography, for example, is limited in its ability to depict and allow quantification of excess lung water. Although results of animal studies have shown a significant relationship between the amount of extravascular lung water and pulmonary edema on chest radiographs, excess lung water can be diagnosed only when it is greater than 35% of normal (41). Also, studies assessing reperfusion edema by chest radiography in humans (2) and dogs (42) have shown poor correlation between radiographic findings and physiologic abnormalities. Thus, chest radiographs may not have detected a subtle daclizumab effect in our study. However, a clinically important effect would likely have resulted in an appreciable change in the radiographic appearance, or quantitative assessment, of reperfusion edema in our study.

One might also argue that the clinical tests we used were not sensitive enough to detect a subtle daclizumab effect. Interestingly, the mean PaO2/FIO2 ratios at day 5 did show a significant trend toward improved oxygenation in the daclizumab-treated groups. While this finding is possibly due to a subsample selection bias at day 5, it might indicate a subtle daclizumab effect. In addition, although survival differences between groups were not statistically significant, analysis of the survival curves (Fig 4) suggests at least a trend toward improved survival in the daclizumab-treated groups. Thus, it is possible that daclizumab did have a subtle effect on reperfusion lung injury, but that the relative infrequency of severe injury and the small size of the study group may have limited our power to detect this effect. Nevertheless, the weight of evidence from our study suggests that daclizumab had no clinically important effect on reperfusion edema.

Finally, it is possible that daclizumab does affect reperfusion edema, but that the dose and dosing schedule used in this study were not sufficient to cause this effect. The dose used in this study was similar to that used in studies with heart and renal transplant recipients. The dosing schedule was chosen to reflect the long in vivo half-life of daclizumab. However, it is possible that a larger dose or different dosing schedule is needed to cause a radiographically or clinically appreciable change in reperfusion edema after lung transplantation.

Our study had several potential limitations. First, definitive diagnosis of reperfusion edema is difficult because it is a diagnosis of exclusion (2,4). We therefore limited our study to the first 5 postoperative days to minimize the possibility of acute rejection or infection affecting the radiographic and clinical findings. Furthermore, we excluded patients with documented infection or acute rejection from the study. However, since routine surveillance transbronchial biopsies were not performed in the majority of patients, we cannot be absolutely certain that some patients did not experience acute rejection or infection in the period considered. Although infection and acute rejection are rare in the first few days after transplantation, we cannot absolutely exclude this possibility. Second, this was a retrospective cohort study, not a prospective randomized comparison of daclizumab-treated and untreated groups. Since the two groups were collected consecutively, not simultaneously, it is possible that differences in surgical technique, transplant indications, or clinical status prior to transplantation may have affected these results, particularly with respect to survival. However, because the overall length of the study was relatively short and surgical and clinical management procedures did not change substantially in this period, we do not believe that the study design substantially biased our results.

In conclusion, the addition of daclizumab to conventional immunosuppressive therapy did not significantly affect the severity of reperfusion edema in lung transplant recipients as assessed by using chest radiography. Daclizumab also had no important effect on the immediate clinical manifestations of reperfusion edema. Further studies are needed to determine if daclizumab reduces the incidence of acute rejection or infection after lung transplantation and has a significant effect on survival.


   FOOTNOTES
 
Abbreviations: FIO2 = fraction of inspired oxygen, IL-2 = interleukin-2, PaO2 = partial pressure of arterial oxygen

Author contributions: Guarantors of integrity of entire study, E.M.M., H.P.M.; study concepts, E.M.M., H.P.M., S.M.P., D.M.D., Y.W.C.; study design, H.P.M., E.M.M., S.M.P., D.M.D.; literature research, E.M.M., data acquisition, E.M.M., Y.W.C., M.D.S.; data analysis/interpretation, E.M.M., H.P.M., Y.W.C., D.M.D.; statistical analysis, D.M.D.; manuscript preparation, E.M.M., H.P.M.; manuscript definition of intellectual content, E.M.M., H.P.M., S.M.P.; manuscript editing, E.M.M., H.P.M.; manuscript revision/review, E.M.M., H.P.M., S.M.P., D.M.D., M.D.S.; manuscript final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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