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Ann Thorac Surg 1995;60:1341-1346
© 1995 The Society of Thoracic Surgeons
Divisions of Cardiothoracic Surgery and General Surgery, Department of Surgery, and Division of Respiratory and Critical Care, Department of Medicine, Washington University School of Medicine, Barnes Hospital, St. Louis, Missouri
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Abstract |
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Methods. A retrospective analysis was done of 212 consecutive lung transplantations performed at Barnes Hospital between July 1988 and March 1994 to characterize the prevalence and course of BOS. One hundred eighty-seven transplant recipients survived at least 3 months after transplantation, putting them at risk for BOS. Recipients free of BOS (group I) were distinguished from those with BOS (group II) based on the presence of declining spirometry (forced expiratory volume in 1 second persistently less than 80% of previous baseline) or histologic obliterative bronchiolitis in group II.
Results. There were 110 transplantations in group I (59%) and 77 in group II (41%). At follow-up, BOS was detected using the following criteria: declining forced expiratory volume in 1 second alone, 40 of 77 (52%); positive histologic results alone, 7 of 77 (9.1%); and both, 30 of 77 (38.9%). Declining spirometry was the most common initial sign of BOS onset (57 of 77, 74%). There were no differences between groups with respect to age, sex, indication for transplantation, or type of transplantation performed. The mortality rate was significantly higher with BOS (group II, 22 of 77 [28.6%] versus group I, 8 of 110 [7.3%]; p = 0.001) and was not related to either the type of transplantation performed or the indication for transplantation. Follow-up of group II (mean 35.1 months; range, 7.1 to 63.7 months) showed a delay until BOS onset (16.1 ± 1.2 months); when BOS was fatal, death ensued within 11.5 ± 2.4 months of its onset. Comparison of the first and last quartiles of recipients in this series (QTR1 versus QTR4, 53 patients in each) demonstrated a higher prevalence of BOS in QTR1 (24 with BOS of 43 at risk [55.8%] versus QTR4, 5 with BOS of 52 at risk [9.6%]; p < 0.001) and a worse BOS functional score in QTR1 (2.2 ± 0.2 versus QTR4, 0.8 ± 0.2; p = 0.007).
Conclusions. (1) Bronchiolitis obliterans syndrome is truly a clinical syndrome, not simply a pathologic entity; (2) BOS displays considerable latency in onset and progression; (3) lung transplant recipients must therefore be followed up for a sufficient interval to determine the actual prevalence and mortality rate of BOS; and (4) the prevalence and mortality rates of BOS are higher than previously appreciated, exceeding 50% and 40%, respectively.
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Introduction |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Lung transplantation is now an established modality in the treatment of selected patients with end-stage lung disease. A number of lung transplantation programs, including our own [1], have reported operative mortality rates of less than 10%. Despite this improvement in early survival, the long-term outlook for lung allograft recipients is clouded by a late-onset syndrome of chronic lung allograft dysfunction. This syndrome, believed (but not proved) to be a manifestation of chronic allograft rejection, has emerged as the main source of late mortality and morbidity for these patients.
In the context of lung transplantation, this entity was first described in 1984 by the Stanford group [2]. They observed a process characterized by declining forced expiratory volume in 1 second (FEV1) and histologic features of obliterative bronchiolitis (OB) in a significant number of their heart-lung allograft recipients. Based on the early clinical experience in heart-lung transplantation, OB was believed to affect 10% to 54% of long-term survivors of this procedure [3]. As experience with isolated lung transplantation accumulated, OB was also encountered in recipients of single and bilateral lung transplants. Early follow-up reports suggested that OB might occur somewhat less frequently in isolated lung transplantation, perhaps in about 20% of long-term survivors [4]. We performed this retrospective analysis of our own experience with the following goals:(1) to determine the prevalence of this syndrome in our lung transplant recipient population (for this purpose, we defined this entity as ``bronchiolitis obliterans syndrome'' [BOS] and used the corresponding definitions and conventions of the 1993 report of the International Society for Heart and Lung Transplantation [5]); (2) to characterize the clinical features and progression of BOS; and (3) to estimate the mortality rate of BOS given the limited therapeutic options currently available.
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Patients and Methods |
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Definition of Bronchiolitis Obliterans Syndrome
The following conventions of the 1993 International Society for Heart and Lung Transplantation report [5] were adopted.
(1) Recipients were considered evaluable (``at risk'' for developing BOS) only if they survived at least 3 months after their transplantation [5]. Twenty-one of 208 recipients (10%) died within 3 months of their procedure and were excluded. The remaining 187 patients at risk for BOS formed the population for this analysis.
(2) The diagnosis of BOS (see below) rests on functional data (from pulmonary function testing) and pathologic data (from bronchoscopy with transbronchial lung biopsy) obtained from the recipient periodically during follow-up. Although we do not adhere to a rigid protocol, a general schedule for these surveillance procedures in our program is as follows.
Pulmonary function testing relies on the FEV1 [5]. Spirometry is obtained weekly for the first 3 months posttransplantation, then monthly for the remainder of the first year, and then every 2 to 3 months thereafter [10]. A baseline FEV1 value was documented for all evaluable recipients. This baseline value was the average of the two highest consecutive FEV1 measurements obtained 3 to 6 weeks apart after transplantation and was used to determine the fractional change in FEV1 later in follow-up.
Transbronchial lung biopsy is obtained at 2 to 3 weeks after transplantation; at approximately 3, 6, and 12 months; and then annually after 1 year [10]. Bronchoscopy with transbronchial lung biopsy is also performed whenever clinically indicated, particularly in the first several months posttransplantation. The main value of transbronchial lung biopsy is to identify a specific treatable lesion when clinical or spirometric decline is encountered during follow-up [5]. However, the presence of OB [12] is sought and is used as another criterion for the diagnosis of BOS (see below).
(3) Recipients were determined to be free of BOS (and placed in group I) if their FEV1 remained at 80% or more of their baseline value and there was no histologic evidence of OB (BOS stage 0a; see below).
(4) Recipients were defined as having BOS (and placed in group II) if there was a sustained and significant fractional decline in their FEV1 after 3 months from the date of the transplantation. (The decline in FEV1 was considered sustained and significant when the average of two FEV1 values, obtained at least 1 month apart, was less than 80% of the previously established baseline value.) Recipients were also considered positive for BOS if OB was documented histologically.
(5) The conventions for BOS numeric stages (a means of quantifying the severity of BOS) and subcategory designations [5] were used, as summarized in Table 1
. For each numeric stage, the subcategory designation ``a'' signifies no histologic evidence of OB, whereas the designation ``b'' signifies histologic presence of OB. Therefore, according to this convention, all patients in group I (free of BOS) are denoted as being in stage 0a.
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Clinical variable analysis included age, sex, diagnosis (indication for transplantation), and type of transplantation performed (single lung transplantation [SLT] versus bilateral lung transplantation [BLT]). Distributions were determined for groups I and II to look for a possible association between any of these variables and the development of BOS.
Absolute mortality was compared between group I and group II. Also analyzed were the mean interval (in months) until BOS was fatal in group II recipients and the distribution of deaths according to the type of transplantation performed (SLT versus BLT) and according to the recipient's underlying diagnosis in the two groups.
Data Analysis
Whenever applicable, data are presented as mean ± standard error of the mean. Statistical comparison of values between the groups was performed using the unpaired t test, Fisher's exact test, or the Mann-Whitney nonparametric test, when appropriate. Values were considered significantly different at p values less than 0.05.
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Results |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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). The criteria signifying the onset of BOS were declining spirometry in 57 of 77 (74%), a biopsy specimen positive for OB in 14 of 77 (18.2%), and both simultaneously in 6 of 77 (7.8%). However, at completion of follow-up, only 40 of 77 recipients with BOS (52%) had evidence of declining spirometry alone, 30 of 77 (38.9%) had evidence of both declining spirometry and histologic OB, and only 7 of 77 (9.1%) had a biopsy specimen positive for OB as the sole criterion of BOS.
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). Because this suggested a degree of latency, a quartile analysis was performed, as summarized in Table 2. In this analysis, the prevalence, the mean interval until onset of BOS, and the mean BOS stage were compared between the four consecutive quartiles of patients making up this series. The principal reason for performing this comparison was the difference in the durations of recipient follow-up between these quartiles; for example, quartile 1 (QTR1, the first of the four consecutive quartiles) offered a range of 46 to 72 months of follow-up, whereas quartile 4 (QTR4, the last quartile) offered a range of only 4 to 17 months of follow-up. In progressing from QTR1 to QTR4, the following were noted: (1) a decrease in the prevalence of BOS (QTR1, 24 with BOS of 43 at risk [55.8%] versus QTR4, 5 with BOS of 52 at risk [9.6%]; p < 0.001), (2) a shorter duration until onset of BOS (QTR1, 17.5 ± 2.1 months versus QTR4, 5.6 ± 0.9 months; p < 0.001), and (3) a lower mean BOS stage (QTR1, 2.21 ± 0.21 versus QTR4, 0.80 ± 0.20; p = 0.007).
Clinical indices were compared between groups I and II. Mean age (group I, 43.6 ± 1.1 years versus group II, 41.9 ± 1.4 years; p = 0.34) and sex distribution (group I, males 52% versus group II, males 38%; p = 0.073) did not differ between the groups. Figure 1A, which shows the distribution of the indications for transplantation in groups I and II, demonstrates no difference between groups with respect to the underlying diagnosis (p = 0.360). There was a nearly identical distribution of the various types of procedures in the two groups: group I, 55 SLT (50%), 54 BLT (49.1%), and one en bloc double lung transplantation (0.9%) versus group II, 39 SLT (50.7%), 37 BLT (48.1%), and 1 double lung transplantation (1.2%) (p = 0.962). These data are depicted in a slightly different manner in Figure 1B, which shows a comparable distribution of the four BOS stages along with the percentage of recipients free of BOS (stage 0a) in recipients of SLT and BLT (p = 0.406).
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). In patients with BOS who died, fatality ensued within 11.5 ± 2.4 months of the onset of BOS. In comparing groups I and II with respect to deaths, there was no significant difference between groups with regard to the type of transplantation performed (Fig 2B) or the underlying diagnosis (Fig 2C).
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Comment |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Our data suggest strongly that BOS is a clinical syndrome that is not always demonstrable as a pathologic entity. In our analysis, the initial feature heralding the onset of BOS was declining spirometry alone in 57 of 77 recipients at risk (74%); ultimately, 40 of 77 (52%) were still defined as having BOS solely on the basis of physiologic decline. The initial sign of BOS was histologic evidence of OB in only 14 of 77 (18.2%), and ultimately, only 7 of 77 (9.1%) were deemed as having BOS solely on this basis. These findings may explain the conflicting opinions expressed in early reports dealing with the prevalence of this entity [3]. Kramer and associates [13] reviewed their experience with 16 patients with advanced BOS (defined by physiologic decline) and showed that only seven of 42 specimens (15.2%) of transbronchial lung biopsies obtained from these patients were positive for OB. In addition to demonstrating the low sensitivity of transbronchial lung biopsy in detecting OB, their data lend support to the general belief that a comprehensive definition of this entity should include the use of physiologic indices, as proposed by Cooper and co-workers [5], and not only histologic documentation of OB. Open lung biopsy will increase the detection of histologic OB, but is obviously a more invasive alternative and not practical for routine patient surveillance. Open lung biopsy is better restricted to the evaluation of serious graft dysfunction after all other less invasive approaches have failed to distinguish between infection and rejection. In our experience, virtually all patients who died of this syndrome were found to have OB at autopsy even when it was not detected before death, providing the ultimate correlation between the observed functional decline and this pathologic ``hallmark.''
One of the questions arising from this study is: What is the significance of a biopsy specimen positive for OB in the recipient who has been clinically and physiologically stable previously? It would be useful to know whether this histologic change is a predictor of later functional decline, because the fibrosis of OB is irreversible once established. This situation applied to 14 recipients in this study. We found that 7 of these 14 (50%) later had physiologic decline, and 3 of these 7 died of BOS. However, it was intriguing that the other 7 remained in BOS stage 0b throughout their posttransplantation course and that 6 of these 7 recipients are alive without signs of physiologic decline 8 to 42 months (mean, 27.3 months) after transplantation. The data from this small subgroup, in the context of our entire analysis, might lead one to speculate that histologic OB can be identified in virtually all lung allografts given sufficiently meticulous tissue sampling, but that the true prevalence of clinical graft dysfunction is still only about 50% overall. The reason that only a subgroup of recipients manifests graft dysfunction remains an unanswered but important question.
Our analysis showed that overall, in 41% of recipients at risk, BOS developed after a mean interval of about 16 months after transplantation. However, our quartile analysis yielded several noteworthy observations. First, the number of recipients at risk for BOS increased from QTR1 (43 at risk of 53 transplantations) to QTR4 (52 at risk of 53 transplantations). This chronologic improvement in early survival is due to a number of factors. First, en bloc double lung transplantation was used frequently in our early experience. This procedure is associated with an increased operative mortality rate [9] and was soon replaced by the bilateral sequential technique. Furthermore, there has been a general improvement in virtually all facets of intraoperative and perioperative patient care as a result of greater clinical experience. Second, a true appreciation of the prevalence, severity, and latency of BOS is derived from the early quartiles, which provided the longest duration of follow-up. Our data showed that the prevalence and the mean BOS numeric stage were both significantly higher in QTR1 than in QTR4. Thus, although our analysis of the BOS group overall suggests that the prevalence of this syndrome is 41%, it may actually exceed 50% (based on the 55.8% and 66.7% prevalences observed in QTR1 and QTR2, respectively, in comparison with the 9.6% prevalence seen in QTR4). Similarly, the adverse effect of BOS on graft function was more apparent with longer follow-up, with a mean BOS stage of 2.21 ± 0.21 in QTR1, compared with 0.80 ± 0.20 in QTR4. Also, although the BOS group overall demonstrated a mean interval until onset of the syndrome of 16.1 months, this interval may actually be slightly longer (based on the 17.5- and 19.1-month intervals seen in QTR1 and QTR2, respectively). (The short interval until BOS onset of only 5.6 months seen in QTR4 was likely the result of having a limited duration of follow-up of a small number of recipients with BOS in this most recent quartile.) In summary, our findings confirm the notion held by many that BOS is indeed a progressive, late-onset syndrome of graft dysfunction. Unfortunately, the data also suggest, in contrast to earlier reports [4], that BOS eventually affects a large percentage of long-term survivors, perhaps even the majority.
There is considerable evidence from previous clinical [14–16] and experimental [17, 18] studies that BOS has an immunologic basis, leading to the widely held belief that it represents a chronic immune response directed against the lung allograft. Although the current study was not intended to be a detailed analysis of risk factors, our comparison of groups I and II showed that BOS affects all subgroups of lung allograft recipients without distinction for recipient age, sex, the type of transplantation performed, or the underlying diagnosis. In a previous study of the first 112 consecutive lung transplantations performed at our institution [19], we performed a more formal analysis of several clinical and immunologic variables in comparing 54 recipients free of BOS and 40 recipients with BOS, using the same BOS criteria as in the current study. That study revealed a significant correlation between the development of lymphocytotoxic anti–human lymphocyte antigen antibodies and the development of BOS [19], similar to the association demonstrated by previous investigators between the development of such antibodies and chronic cardiac allograft rejection [20]. That correlation [19] demonstrated further that lung transplant recipients in whom BOS develops give evidence of allosensitization, and may also imply a mechanistic role for these antibodies in the genesis of BOS. We are currently updating that analysis to determine further the significance of that finding.
The true pathogenesis of BOS is unknown, but because it is believed to arise from an immune response to the allograft, we and other centers [21, 22] have treated it empirically using augmented immunosuppression protocols. This has consisted of bolus treatment with corticosteroids as well as antilymphocytic agents. Despite the use of these modalities, our analysis has shown that absolute mortality rates are significantly higher for lung transplant recipients with BOS and that this mortality does not correlate with the type of transplantation or the underlying diagnosis. Once again, the true mortality rate of BOS may be better reflected through the quartile analysis (data not shown); although the mortality in group II overall was 22 of 77 (28.6%), it was 10 of 24 (42%) in QTR1. Our study did not show a significant difference in mortality between QTR1 (10 of 24, 42%) and QTR4 (1 of 5, 20%; p = 0.622 versus QTR1), but this was likely the result of the small number of patients in QTR4.
In conclusion, our data suggest that BOS is indeed a clinical syndrome of lung allograft dysfunction that is frequently associated with histologic evidence of OB, that it displays considerable latency in its onset and progression, that it is far more prevalent among recipients of isolated lung transplants than has been proposed by previous investigators, and that despite all currently available treatment modalities, it carries a high mortality rate. It is the greatest source of late mortality and morbidity in lung transplant recipients and is the greatest obstacle to long-term survival in clinical lung transplantation today.
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Acknowledgments |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Sundaresan, Division of Cardiothoracic Surgery, Washington University School of Medicine, Suite 3107 Queeny Tower, One Barnes Hospital Plaza, St. Louis, MO 63110.
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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