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* From the Divisions of Pulmonary, Allergy and Critical Care Medicine (Drs. Arcasoy, Christie, and Kotloff and Ms. Blumenthal) and Cardiothoracic Surgery (Drs. Pochettino, Rosengard, and Bavaria), University of Pennsylvania Medical Center, Philadelphia, PA.
Correspondence to: Selim M. Arcasoy, MD, FCCP, Assistant Professor of Medicine, Hospital of the University of Pennsylvania, Pulmonary, Allergy and Critical Care Division, 832 West Gates, 3600 Spruce St, Philadelphia, PA 19104-4283; e-mail: arcasoy{at}mail.med.upenn.edu
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Retrospective cohort study.
Setting: Tertiary-care university hospital.
Patients: Forty-three patients with sarcoidosis who have been listed for lung transplantation at the University of Pennsylvania Medical Center.
Methods: A multivariable explanatory analysis using a Cox proportional hazards model was performed to determine risk factors that are independently associated with mortality while patients await transplantation.
Results: Twenty-three of the 43 patients (53%) died while
awaiting transplantation. The survival rate of listed patients (as
determined by the Kaplan-Meier method) was 66% at 1 year, 40% at 2
years, and 31% at 3 years. In a univariate analysis, the following
factors were significantly associated with death on the waiting list:
PaO2 
60 mm Hg (relative risk [RR], 3.4;
95% confidence interval [CI], 1.2 to 9.3); mean pulmonary artery
pressure 
35 mm Hg (RR, 3.2; 95% CI, 1.1 to 9.5); cardiac index
2 L/min/m2 (RR, 2.8; 95% CI, 1.2 to 6.6), and right
atrial pressure (RAP) 15 mm Hg (RR, 7.6; 95% CI, 3.0 to 19.3).
Multivariable analysis revealed that RAP 15 mm Hg was the only
independent prognostic variable (RR, 5.2; 95% CI, 1.6 to 16.7;
p = 0.006). Twelve patients underwent lung transplantation. Survival
after transplantation determined by the Kaplan-Meier method was 62% at
both 1 and 2 years, and 50% at 3 years.
Conclusions: Patients with advanced sarcoidosis awaiting lung transplantation have a high mortality rate with a median survival of < 2 years. Mortality is most closely linked to elevated RAP. While earlier referral may diminish the mortality rate of patients on the waiting list for transplantation, further improvements in posttransplantation outcomes will be necessary to ensure that this procedure truly bestows a survival benefit.
Key Words: lung transplantation • mortality • pulmonary hypertension • sarcoidosis
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and spontaneous remission of clinically overt disease are commonly encountered, a chronic course occurs in 10 to 30% of patients, at times resulting in significant impairment of lung function. Mortality rates of 1 to 6% have been reported, 1 2 3 with the majority of deaths in the United States attributable to respiratory failure. The treatment of symptomatic pulmonary sarcoidosis mainly involves corticosteroids or other anti-inflammatory and immunosuppressive agents, but advanced disease that is unresponsive to medical therapy is considered to be an indication for lung transplantation. Given the significant risks and mortality rate associated with transplantation, this option ideally should be reserved for patients who are not only severely impaired but in imminent danger of dying from their disease. Because of the often protracted and variable course of sarcoidosis, determining the optimal timing of transplantation is problematic. Although certain clinical features of sarcoidosis have been identified as markers of a chronic course, accurate predictors of intermediate-term mortality in patients with advanced disease have not been well-defined.1 3 In the absence of such disease-specific prognostic indexes, the recently published international guidelines for the selection of lung transplant recipients4 recommend that the same criteria utilized for the listing of patients with idiopathic pulmonary fibrosis be applied to those with pulmonary fibrosis secondary to sarcoidosis, despite the seemingly disparate courses followed by these two disorders.4 5
To better characterize the natural history of advanced sarcoidosis, we performed a retrospective cohort study of all patients with sarcoidosis who have been placed on the list for lung transplantation at our institution since 1991. Our specific aim was to identify prognostic factors associated with an increased risk of early mortality that could assist in determining the appropriate timing of referral for lung transplantation. A secondary goal was to examine outcomes following lung transplantation to provide insight into the risk/benefit ratio associated with transplantation in this complex patient population.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Statistical Analysis
Demographic, clinical, and physiologic parameters derived from
the transplant evaluation were chosen for consideration as potential
risk factors. Potential risk factors were initially analyzed for
significant association with mortality on the waiting list utilizing
the log rank test for categoric variables and the Cox proportional
hazards model for continuous variables. When appropriate, continuous
variables were dichotomized according to clinically relevant or
published cutoff points and inspection of the data. To assess the
strength of association of clinical variables with mortality on the
waiting list when adjusted for the potential confounding effects of
other significant variables, a multivariable explanatory analysis using
the Cox proportional hazards model was performed. Risk factors with a
level of significance defined as p < 0.2 in univariate analysis were
adjusted for in the multivariable explanatory model. To avoid model
overfitting, significant risk factors were tested for independent
association with outcome by adjusting for confounding variables one at
a time. Confounding was defined as a difference of > 15%
between the unadjusted and adjusted relative risks (RRs). Risk factors
were adjusted for all significant confounding variables, and summary
adjusted RRs are reported. A p value < 0.05 following adjustment for
all confounding variables was considered to be significant. Collinear
variables were not individually adjusted for in the multivariable
analysis.
Overall survival was analyzed by the Kaplan-Meier technique, and differences in survival were assessed for statistical significance by the log rank test. In analyzing the survival of the 43 patients listed for transplantation, time 0 was the date of listing and censoring was performed at the time of transplantation. For the 12 patients who underwent transplantation, posttransplantation survival was analyzed with time 0 defined as the date of transplantation.
Comparisons of hemodynamic variables at listing and transplantation were made using the paired Student’s t test. All statistical analyses were performed using computer software packages (StatView, version 5.0.1; SAS Institute; Cary, NC; and STATA, version 6.0; STATA Corp; College Station, TX).
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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60 mm Hg) was present in
56% of patients who died compared to 31% of those who remained alive
(unadjusted RR of mortality, 3.4; 95% confidence interval [CI], 1.2
to 9.3; p = 0.01). Eighty-three percent of patients who died had a
mean PAP of 35 mm Hg compared to 40% of living patients
(unadjusted RR of mortality, 3.2; 95% CI, 1.1 to 9.5; p = 0.02). A
cardiac index of 2 L/min/m2 was present in
52% of patients who died compared with only 11% of patients who were
alive (unadjusted RR of mortality, 2.8; 95% CI, 1.2 to 6.6;
p = 0.02). Finally, severe elevation of RAP (ie, 15 mm
Hg) was present in 45% of deceased patients compared with no patients
who survived on the waiting list (unadjusted RR of mortality, 7.6; 95%
CI, 3.0 to 19.3; p < 0.0001).
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60 mm Hg, the survival rate
was 31% at both 1 and 2 years compared to 94% and 53%, respectively,
for patients with PaO2 > 60 mm
Hg (p = 0.01). One-year and 2-year survival rates of patients with a
mean PAP 35 mm Hg were 51% and 25%, respectively, compared to
93% and 78%, for patients whose mean PAP was < 35 mm Hg
(p = 0.02). Patients with a cardiac index 2 L/min/m2
had 1-year and 2-year survival rates of 39% and 23%, respectively,
compared to 84% and 51% for patients with a higher cardiac index
(p = 0.02). Last, for patients with a RAP 15 mm Hg, the 1-year
and 2-year survival rates were 20% and 0%, respectively, as compared
to 83% and 57%, respectively, for patients with a lower RAP
(p < 0.0001; Fig 2
).
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35 mm Hg,
PaO2 60 mm Hg, cardiac index
2 L/min/m2, RAP 15 mm Hg, PVR, and 6-min
walk test distance. The adjusted RRs are presented in Table 3
. When
adjusted for other significant variables, a RAP 15 mm Hg was the
only variable independently associated with the death of patients on
the waiting list, with a RR of 5.2 (95% CI, 1.6, 16.7; p = 0.006).
PAP, PaO2, and cardiac index did not
maintain their significant association with mortality when adjusted for
confounding.
Posttransplantation Course
Twelve of the 43 patients underwent transplantation an average of
494 ± 105 days (range, 45 to 1,319 days) after being placed on the
list for transplantation (Table 4
). Four patients underwent single-lung transplantation, and eight
patients underwent bilateral lung transplantation. Hemodynamic data
derived from the insertion of a pulmonary artery catheter at the time
of transplantation were available for review in 10 of the 12 patients
who underwent transplantation. The mean PAP at the time of
transplantation was 41 ± 15 mm Hg compared to 29 ± 11 mm Hg at
the time of listing (p < 0.005). All but one patient demonstrated
progressive elevation of the mean PAP during the waiting period (Fig 3
). The mean RAP increased to a lesser degree, from 7 ± 3 mm Hg at the
time of listing to 9 ± 4 mm Hg at the time of transplantation
(p = 0.53).
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Discussion |
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Although the natural history of sarcoidosis has been scrutinized previously, the prognostic factors that have been identified have been relatively imprecise and therefore of limited clinical utility.1 2 3 6 7 8 Acute clinical manifestations and earlier radiographic stages have been associated with a high rate of remission and favorable prognosis.3 6 9 In contrast, black race, lupus pernio, chronic uveitis, cystic bone lesions, age of onset of > 40 years, chronic hypercalcemia, nephrocalcinosis, radiographic patterns of stage III or IV disease, and splenomegaly have been associated with a higher likelihood of chronic or progressive disease but have not been well-correlated with mortality per se.2 3 10 11 In their study group of 254 patients, Vestbo and Viskum12 reported that the presence of respiratory symptoms at the time of initial presentation was a significant predictor of mortality from sarcoidosis. In contrast to our study looking at short-term mortality, the median follow-up in the study by Vestbo and Viskum12 was 27 years, with an overall mortality rate of only 13%. Baughman and coworkers8 reviewed their 7-year experience with 479 patients with sarcoidosis, identifying fibrosis seen on chest radiographs and a vital capacity of < 1.5 L as predictive of death from respiratory failure. However, the utility of these radiographic and functional indexes was limited by low positive predictive values, which were only 21% and 24%, respectively. Furthermore, the short-term prognosis of patients with a vital capacity of < 1.5 L was still relatively favorable, with a survival rate (Kaplan-Meier method) at 3 years of approximately 70%. In our study, we did not detect any association between pulmonary function parameters and death but this likely reflects the fact that we restricted our analysis to a more homogeneous group with advanced disease and severe impairment in lung function. Similar to our approach, Judson13 reviewed the course of 10 patients with sarcoidosis listed for lung transplantation at the Medical University of South Carolina and documented a 40% mortality rate. His analysis also failed to identify pulmonary function parameters as predictive of outcome, although definitive conclusions were limited by the small size of the study population. Interestingly, Judson commented that the four patients who died had "poorer gas exchange and more severe pulmonary hypertension" than those who survived, factors that were identified in our study as statistically associated with an increased risk of death.
A striking finding of our study was the prognostic importance of right ventricular hemodynamics. We found pulmonary hypertension and elevated right ventricular filling pressures to be common features of patients with advanced sarcoidosis. In this regard, the mean PAP for the entire group was 41 ± 16 mm Hg and the mean RAP was 11 ± 6 mm Hg. Furthermore, pulmonary hypertension progressed over time, as demonstrated by repeat hemodynamic studies at the time of transplantation. Both mean PAP and RAP were found to be associated with an increased risk of death in univariate analysis. By multivariable analysis, only RAP was found to be independently associated with increased mortality, suggesting that the lethal effects may be attributable not to the magnitude of pulmonary hypertension but to its impact on right ventricular performance. Although pulmonary hemodynamics have been shown to be of prognostic importance in patients with primary pulmonary hypertension and COPD, their prognostic value in diffuse parenchymal disease has been unclear.14 15 In a study of 67 patients with chronic interstitial lung disease who were referred for lung or heart-lung transplantation, Harari and colleagues16 were unable to identify any correlation between hemodynamic parameters and pretransplant survival. Notably, however, none of the patients in their study had sarcoidosis.
More than half of our patients died while awaiting transplantation,
indicating that listing frequently occurred too late in the course of
disease. Under the current allocation system in the United States,
donor lungs are distributed by time accrued rather than medical
urgency, and the median waiting period now is approximately 2
years.17
The decision to list a patient must factor in
this prolonged waiting time and, therefore, must often be based not on
imminent need but on anticipated need for transplantation in
the intermediate term. Our study clearly demonstrates that patients
with established right ventricular dysfunction at the time of listing,
as evidenced by a RAP 15 mm Hg, are unlikely to survive until
transplantation, since none of these patients survived for 2 years. In
a subset of 10 patients who had serial assessments of hemodynamics, we
also have demonstrated the propensity of pulmonary hypertension to
worsen over a relatively brief period of time. Based on these
observations, we would recommend that serial evaluation of pulmonary
hemodynamics be incorporated into the routine monitoring of patients
with advanced sarcoidosis. The development of pulmonary hypertension,
in conjunction with significant limitation in exercise tolerance,
should prompt the strong consideration of listing for transplantation
before the onset of significant right ventricular dysfunction.
From 1988 to 1999, a total of 392 patients with sarcoidosis were listed for lung transplantation in the United States, 149 of whom subsequently underwent lung transplantation. One-year, 2-year, and 3-year posttransplant survival rates (determined by the Kaplan-Meier method) of these patients were 67%, 59%, and 50%, respectively (S. Buckingham, United Network for Organ Sharing; personal communication; June 2000). These survival rates closely approximate those that we have reported in the current series and are comparable to outcomes achieved in association with idiopathic pulmonary fibrosis, primary pulmonary hypertension, and cystic fibrosis both nationwide and within our own program.17 Whether transplantation actually confers a survival advantage over the natural history of advanced sarcoidosis is uncertain. Direct comparison of the post-transplant survival rate of patients in our study to the survival rate of patients on the waiting list (with censoring of patients at the time of transplantation) suggests a potential for improved survival associated with transplantation. However, firm conclusions are limited by the small number of at-risk patients in each group beyond the first year and by the interdependence of the two patient populations (ie, 12 patients were common to both the listed patient group and the group that had received transplants). Time-dependent nonproportional hazards analysis of a larger cohort of patients, as has been performed on other advanced lung disease populations,18 may provide more definitive insight into this question but is beyond the scope of the current study.
The posttransplantation course of our patients was distinguished by a seemingly high incidence of lethal invasive Aspergillosis, with three of five deaths attributable to this complication. In two of these cases, native lung aspergillomas could be directly implicated as the source of infection. In one case, soiling of the pleural space by a mycetoma occurred at the time of explantation, and the patient rapidly developed widespread infection within the thoracic cavity despite immediate administration of IV amphotericin therapy. In the second case involving the recipient of a single lung, widespread infection of the allograft with Aspergillus was demonstrated on postmortem examination to have arisen from an aspergilloma in the contralateral native lung that was not apparent on routine chest radiography. The experience of other centers with this problem has been variable. Pigula and colleagues19 encountered invasive aspergillosis in four of nine transplant recipients with sarcoidosis who survived beyond the first month. In contrast, aspergillosis was not found in any of 12 patients who received transplants at a major British center.20 Based on our experience, we favor the performance of bilateral transplantation for those patients with Aspergillus recovered on preoperative sputum cultures or with CT evidence of aspergillomas (even when unilateral) in an attempt to remove all devitalized tissue that might be harboring this organism. Additionally, we currently exclude patients with peripheral aspergillomas associated with marked pleural reaction for fear that the likelihood of pleural contamination during explantation would be high.
Two of the 12 patients in our series developed evidence of recurrent sarcoidosis. Others have reported varying rates of recurrence involving as many as two thirds of patients in one study.19 20 21 22 23 24 25 26 27 28 29 The propensity for sarcoidosis to recur in the context of immunosuppression is surprising, particularly since T-cell activation has been implicated as a major component of disease pathogenesis.30 Nevertheless, recurrence is typically of little clinical consequence and should not influence the decision to extend transplantation to this patient population.
In conclusion, patients with advanced sarcoidosis awaiting lung transplantation at our center had a high mortality rate, with approximately half of the patients dying prior to transplantation. Marked elevation in RAP, reflecting right ventricular dysfunction, was the strongest predictor of death. While the listing of patients with sarcoidosis prior to the onset of right ventricular dysfunction will diminish the mortality rate on the waiting list for lung transplantation, further improvement in posttransplantation outcomes will be necessary to ensure that this procedure truly bestows a survival benefit.
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Footnotes |
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This research was supported by the Craig and Elaine Dobbin Pulmonary Research Fund.
This article was presented in part at the American Thoracic Society Meeting, Toronto, Canada, in May 2000.
Received for publication November 13, 2000. Accepted for publication March 27, 2001.
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