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(Chest. 2006;130:1481-1488.)
© 2006 American College of Chest Physicians

Sarcoidosis-Associated Pulmonary Hypertension*

Outcome With Long-term Epoprostenol Treatment

Kimberly A. Fisher, MD; David M. Serlin, MD; Kevin C. Wilson, MD; Robert E. Walter, MD; Jeffrey S. Berman, MD and Harrison W. Farber, MD, FCCP

* From The Pulmonary Center, Boston University School of Medicine, Boston, MA.

Correspondence to: Kimberly A. Fisher, MD, UMass Memorial Medical Center-University Campus, 55 Lake Ave North, Worcester, MA 01655; e-mail: FisherK{at}ummhc.org

Abstract

Rationale: Pulmonary hypertension is a known complication of sarcoidosis and is associated with increased mortality. Little is known about the outcome of sarcoidosis-associated pulmonary hypertension, including response to treatment.

Objective: To determine the characteristics and outcome of patients with sarcoidosis-associated pulmonary hypertension treated with IV epoprostenol.

Design: Retrospective chart review of all cases of pulmonary hypertension with a concomitant diagnosis of sarcoidosis evaluated in the Boston University Pulmonary Hypertension Center from 2000 to 2004.

Measurements: Data collected included patient demographics, sarcoidosis stage, pulmonary function, echocardiography results, treatment, baseline and posttreatment hemodynamic measurements, and clinical outcome.

Results: Eight patients were identified; four of the patients had stage IV pulmonary sarcoidosis. Pulmonary function test results were notable for severe diffusion impairment (mean diffusion capacity of the lung for carbon monoxide, 30% of predicted), with only mild-to-moderate restrictive physiology (mean FVC, 59% of predicted). Seventy-five percent of patients required supplemental oxygen at the time of presentation. All patients had moderate or severe pulmonary hypertension and were New York Heart Association (NYHA)/World Health Organization (WHO) class III or IV. A vasodilator trial with epoprostenol was performed in seven of the eight patients; six of the seven patients had a significant hemodynamic response (> 25% reduction in pulmonary vascular resistance). All but one of the responders (five of six patients) continued on therapy. Average clinical improvement was one to two NYHA/WHO classes at a mean follow-up of 29 months (range, 15 to 49 months).

Conclusions: In patients with sarcoidosis-associated pulmonary hypertension, the severity of pulmonary vascular disease occurs out of proportion to lung function abnormalities. The majority of our patients responded to epoprostenol; survival may be improved in this group.

Key Words: granulomatous disease • prostanoid therapy • pulmonary circulation • pulmonary vascular disease

Pulmonary hypertension is a well-described complication of sarcoidosis. When all stages of sarcoidosis are considered, studies12 have demonstrated elevated pulmonary artery pressure (PAP) in 6 to 23% of patients at rest, and as many as 43% with exertion.2 The increase in PAP is typically mild to moderate but can be severe.345678 Advanced sarcoidosis is more commonly complicated by pulmonary hypertension. Shorr and coworkers9 recently reviewed right-heart catheterization (RHC) data from 363 sarcoidosis patients awaiting lung transplantation and found that 73.8% had pulmonary hypertension. Furthermore, the presence of pulmonary hypertension has been shown to be an independent risk factor of mortality from sarcoidosis in patients awaiting lung transplantation.10

Treatment of pulmonary arterial hypertension associated with sarcoidosis is controversial and based on limited data. While some case reports71112 describe regression of pulmonary hypertension with steroid treatment, others3513 describe no improvement or even worsening despite steroid therapy. Recently, Nunes et al14 reported a series of 22 patients with sarcoidosis-associated pulmonary hypertension; of the 10 patients treated with corticosteroids in this series, 3 patients had documented decreases in systolic PAP in response to steroids. Reports of acute vasoreactivity in response to epoprostenol suggest a role for long-term treatment with vasodilators in the management of sarcoidosis-associated pulmonary hypertension.41516 However, the safety and long-term efficacy of IV epoprostenol in patients with sarcoidosis-associated pulmonary hypertension is not known.

In the current report, we describe the acute response to epoprostenol and the outcome with long-term administration of epoprostenol in patients with sarcoidosis-associated pulmonary hypertension. Of note, this study was not designed to evaluate the prevalence of pulmonary hypertension in patients with sarcoidosis, but to describe the response of patients with sarcoidosis-associated pulmonary hypertension to epoprostenol treatment. To our knowledge, this is the largest group of patients with sarcoid-associated pulmonary hypertension treated with long-term epoprostenol therapy.

Materials and Methods

Design and Data Collection
In accordance with the protocol approved by the Institutional Review Board, we retrospectively reviewed all cases of pulmonary hypertension evaluated in the Boston University Pulmonary Hypertension Center between January 2000 and October 2004 and identified patients with a concurrent diagnosis of sarcoidosis. Data collected included patient demographics, sarcoidosis stage, treatment, pulmonary function, echocardiography results, baseline and posttreatment hemodynamics, complications of vasodilator therapy, and long-term clinical outcome.

Patients
All patients with known diagnoses of both sarcoidosis and pulmonary hypertension were identified. The diagnosis of sarcoidosis was confirmed by review of the medical record, including compatible historical information and/or pathology findings. Patients were classified as having sarcoidosis-associated pulmonary hypertension if they had a mean PAP (mPAP) ≥ 25 mm Hg at RHC and did not have evidence of connective tissue disease, portal hypertension, elevated pulmonary capillary wedge pressure, congenital or valvular heart disease, HIV disease, history of anorexigen use, thromboembolic disease, or obstructive sleep apnea.

In one patient, the diagnosis of sarcoidosis-associated pulmonary hypertension was based on Doppler echocardiographic findings of pulmonary hypertension (right ventricular dilation, hypokinesis, and estimated pulmonary artery systolic pressure > 40 mm Hg in the setting of normal left ventricular size and function). This patient, however, died prior to invasive confirmation of pulmonary arterial hypertension and vasodilator challenge and is excluded from the analysis below.

Acute Vasodilator Testing
Informed consent for RHC was obtained from all patients. The patients were admitted to the medical ICU at Boston Medical Center for insertion of a pulmonary artery catheter (right internal jugular or left subclavian vein approach). After insertion, baseline hemodynamic measures were obtained. Per protocol, IV epoprostenol was then initiated at 2 ng/kg/min, and increased by 2 ng/kg/min every 15 min, until signs or symptoms of systemic toxicity (headache, jaw pain, nausea, vomiting, flushing, or systemic hypotension) developed. Hemodynamic measurements were performed prior to each incremental dose increase.

Long-term Vasodilator Treatment
Long-term IV epoprostenol therapy was administered via a centrally inserted tunneled catheter immediately following the vasoreactivity testing. No patient was a candidate for oral calcium-channel blockers because all patients had severe pulmonary hypertension based on pulmonary vascular resistance (PVR) and New York Heart Association (NYHA)/World Health Organization (WHO) functional class. Dose adjustments were made as dictated by patient symptoms (especially exertional dyspnea) and clinical status. Patients were treated with supplemental oxygen as required to maintain oxygen saturation ≥ 90%. All patients treated with long-term vasodilators also received anticoagulation with warfarin to a international normalized ratio of 2 to 3.

Immunosuppressive Therapy
Corticosteroid or immunosuppressive therapy was initiated or continued based on standard indications for treatment of sarcoidosis (ie, hypercalcemia, pulmonary, ocular, or CNS involvement).

Statistical Analysis
Our primary outcome measure was the acute percentage change in PVR, with change in right atrial pressure and cardiac output as secondary outcomes. The Wilcoxon signed-rank test was used to assess the significance of the change with an {alpha} level of p = 0.05.

Results

Patients
Eight patients with sarcoidosis-associated pulmonary hypertension were identified (Table 1 ). In 75% of cases, sarcoidosis was diagnosed based on accepted clinical findings and biopsy results demonstrating noncaseating granulomas. Two patients were considered to have sarcoidosis based on typical clinical features (hilar lymphadenopathy, upper lobe fibrosis, typical eye involvement) in the absence of biopsy. Of the five patients reported who underwent long-term epoprostenol treatment, all had biopsy-proven sarcoidosis. Mean age was 48.5 years (range, 39 to 71 years), with equal numbers of men and women. In most patients (six of eight patients), the diagnosis of sarcoidosis preceded the diagnosis of pulmonary hypertension by an average of 16.7 years (range, 0 to 28 years). However, in two cases, the diagnoses of pulmonary hypertension and sarcoidosis were established simultaneously. Seven patients had pulmonary disease, four being Scadding stage IV. Pulmonary function testing (Table 2 ) demonstrated severe diffusion impairment (mean diffusing capacity of the lung for carbon monoxide, 30% of predicted; range, 9 to 73% of predicted), with only mild-to-moderate restrictive physiology (mean total lung capacity, 70% of predicted; range, 44 to 95% of predicted). All patients underwent Doppler echocardiography prior to RHC; seven of eight patients had an elevated estimated pulmonary arterial systolic pressure, and all patients had evidence of right ventricular dilatation and dysfunction, with preserved left ventricular function. No patient had echocardiographic evidence of diastolic dysfunction or restrictive cardiomyopathy. Seventy-five percent of patients required supplemental oxygen at the time of presentation. All patients had significant functional limitation and were NYHA/WHO class III or IV.


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  		Table 1. Patient Characteristics

 

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  		Table 2. Baseline Pulmonary Function Test Results

 
All patients were treated with immunomodulatory therapy (Table 3 ), although the exact doses and temporal relation to epoprostenol initiation varied. Steroid therapy was initiated or increased in three patients (patients 1, 4, and 6) for the treatment of interstitial lung disease within days of starting epoprostenol. Three patients (patients 3, 5, and 7) remained on their baseline prednisone dose or had it tapered after initiation of epoprostenol. Patient 2 was started on steroid therapy 1 month prior to epoprostenol initiation, without improvement in symptoms. Two patients were treated with hydroxychloroquine; one of these patients had also previously received methotrexate. See Table 3 for further details of immunomodulatory medications.


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  		Table 3. Immunomodulatory Treatment*

 
Acute hemodynamic data
Seven patients underwent RHC and acute vasodilator testing. Baseline hemodynamic data (Table 4 ) demonstrated moderate or severe pulmonary hypertension (mean PVR, 1,176 dyne · s · cm-5) with a pulmonary capillary wedge pressure ≤ 15 mm Hg in all patients. Six of seven patients (86%) were acutely vasoreactive, as defined by a 25% reduction in PVR, in response to the maximally tolerated dose of epoprostenol (mean dose, 9 ng/kg/min). On average, there was a decrease in PVR (45%, p = 0.02) and mPAP (11%, p = 0.08), and a significant increase in cardiac output (mean, 2.02 L/m; 44%; p = 0.03) and cardiac index (66%, p = 0.03). All seven patients who underwent acute vasodilator testing exhibited a decrease in systemic vascular resistance (SVR) from a mean initial SVR of 2,147 dyne · s · cm-5 to a mean lowest SVR of 1,069 dyne · s · cm-5 (a 50% decrease). In addition, the average mean arterial pressure decreased from 103 to 81 mm Hg (average, 21% decrease). In two patients, this resulted in a clinically significant decrease in systemic BP that limited acute up-titration of epoprostenol but did not affect long-term use of epoprostenol in these patients.


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  		Table 4. Acute Hemodynamic Response to Epoprostenol Infusion

 
Long-term Patient Outcome
An overview of patient treatment and outcome is presented in Figure 1 . Prostanoid therapy was initiated in all seven patients who underwent RHC and acute vasodilator testing. Six of the patients were treated with IV epoprostenol, and one patient (patient 7) elected to be treated with subcutaneous treprostinil. One of the patients (patient 5) had a cardiac arrest within hours of epoprostenol initiation; thus, data on long-term treatment with epoprostenol are available on five patients. Average follow-up duration is 29 months (range, 15 to 49 months). The mean dose of epoprostenol is 55.6 ng/kg/min. All patients who received long-term epoprostenol therapy are currently alive, and all patients have improved by one to two NYHA/WHO classes (Table 5 ). One patient underwent successful orthotopic lung transplantation after 16 months of vasodilator therapy. The patient treated with subcutaneous treprostinil discontinued treatment after 1 month because of intractable site pain, refused other therapy, and subsequently died.


Figure 1
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  		Figure 1. Overview of patient treatment and outcome. pt./pts. = patient/patients; RHF = right-heart failure; SQ = subcutaneous; w/in = within.

 

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  		Table 5. Clinical Response to Long-term Prostanoid Therapy*

 
Complications
Side effects of IV epoprostenol included jaw pain, headache, and flushing, especially at the time of dose increases. There were no central line infections or epoprostenol-associated thrombocytopenia.

During the initiation of IV epoprostenol, acute respiratory failure requiring mechanical ventilation due to cardiogenic pulmonary edema developed in patient 6, as evidenced by chest radiography and elevation of pulmonary capillary wedge pressure to 30 mm Hg. This resolved with aggressive diuresis and temporary reduction in epoprostenol dose. In spite of a slow increase in epoprostenol dose, this patient has had no recurrent pulmonary edema. Patient 5 had a cardiac arrest 4 h after initiation of epoprostenol and died. Patient 4 transiently desaturated at the time of epoprostenol initiation, requiring temporary increase in the fraction of inspired oxygen from 3 L by nasal cannula to a 50% face mask. None of the other patients had desaturation requiring increased oxygen during epoprostenol initiation or at long-term follow-up.

Discussion

We report a series of patients with sarcoidosis-associated pulmonary hypertension, including their clinical characteristics and their outcome with both short-term and long-term IV epoprostenol treatment. In keeping with previous reports,124814 the majority of our patients had evidence of pulmonary fibrosis and required supplemental oxygen, suggesting that pulmonary parenchymal destruction and hypoxia account, at least in part, for the observed pulmonary hypertension in these patients.

However, we believe that sarcoidosis-associated pulmonary hypertension is due to more than just parenchymal destruction and hypoxia. Studies17181920 examining the degree of pulmonary hypertension in patients with other types of advanced lung disease (eg, COPD, cystic fibrosis, and interstitial lung diseases) have found average systolic PAPs of 37 to 46 mm Hg. In contrast, the average systolic PAP in our cohort of patients was 88 mm Hg, suggesting that causative mechanisms in addition to parenchymal destruction and hypoxia exist in sarcoidosis-associated pulmonary hypertension. Shorr and coworkers21 have similarly found higher mean PAPs in patients with sarcoidosis awaiting lung transplantation compared to those with idiopathic pulmonary fibrosis awaiting lung transplantation. Further supporting our belief that additional etiologies exist in sarcoidosis-associated pulmonary hypertension, we found a wide range of time between the diagnosis of sarcoidosis and the presentation of pulmonary vascular disease (0 to 30 years), and we found that two of our patients had moderate-to-severe pulmonary hypertension despite having only stage I to II sarcoidosis with minimal restrictive physiology by pulmonary function testing and normal oxygen saturation. This is in keeping with the findings of Sulica et al,8 in which only 60% of patients with sarcoidosis-associated pulmonary hypertension had radiographic evidence of pulmonary fibrosis. Nunes et al14 recently reported a series of 22 patients with sarcoidosis-associated pulmonary hypertension in whom they specifically found extrinsic arterial compression by lymphadenopathy in three patients, and pulmonary venoocclusive disease in five patients, conclusively demonstrating mechanisms other than fibrosis that give rise to pulmonary hypertension in patients with sarcoidosis.

Acute vasoreactivity in response to epoprostenol and inhaled nitric oxide (iNO) has previously been described in sarcoidosis-associated pulmonary hypertension.451516 Preston et al4 reported a larger acute reduction in mPAP and PVR (18% and 31%, respectively) in response to iNO than in response to epoprostenol (6% and 25%), and surmised that the mechanism of disease in these patients may make them more responsive to iNO than epoprostenol. Our report does not compare iNO and epoprostenol; however, we found a mean acute decrease in PVR greater than that found by Preston et al4 in response to epoprostenol, suggesting that patients with sarcoidosis-associated pulmonary hypertension may well be quite responsive to epoprostenol (Fig 2 ). By contrast, none of the 22 patients with sarcoidosis-associated pulmonary hypertension described by Nunes et al14 were acutely vasoresponsive. This marked difference in findings illustrates the heterogeneity of sarcoidosis-associated pulmonary hypertension.


Figure 2
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  		Figure 2. Acute hemodynamic response to IV epoprostenol in individual patients. Red lines indicate mean values; p values are calculated using the Wilcoxon ranked-sign test. Left, a: p < 0.02 for percentage change in PVR. Center, b: p < 0.03 for percentage change in central venous pressure (CVP). Right, c: p < 0.03 for percentage change in cardiac index (CI).

 
All five of our patients successfully treated with long-term epoprostenol infusion are alive at most recent follow-up. All patients have improved by one to two functional NYHA/WHO classes with long-term epoprostenol treatment. These findings differ from the experience of Preston et al4 with long-term iNO, in which three patients treated with iNO died of progressive right-heart failure within 4 to 5 months, one patient died suddenly after 1 year of treatment, and only three patients treated with long-term iNO had an improved functional class. It is unlikely that the results we observed are due to less severe pulmonary vascular disease at the initiation of therapy. The baseline mean PVR in our study was 1,176 dyne · s · cm-5, compared to 896 dyne · s · cm-5 in the study by Preston et al,4 with patients of similar functional class (NYHA/WHO class III and IV). Thus, although comparisons between studies are difficult, long-term treatment with epoprostenol may offer a better outcome than iNO.

The concomitant initiation of corticosteroids and epoprostenol in three of our patients makes it difficult to exclude completely a steroid-induced regression of granulomatous disease as contributing to several of the favorable clinical responses. However, the sequence of steroid therapy and clinical improvement make this less likely. In two of the three patients (patients 1 and 4), steroids were started days to weeks after the initiation of epoprostenol, at which time a dramatic clinical response to epoprostenol had already been noted. In the remainder of the patients, pulmonary hypertension either developed while receiving long-term corticosteroid therapy (patients 3, 5, and 7), or failed to improve in spite of an extended course of prednisone (patient 2) prior to epoprostenol initiation. These findings are in keeping with the variable responses of sarcoidosis-induced pulmonary hypertension to corticosteroids that have been published35711121314 and include improvement, worsening, and clinical stability.

Systemic administration of prostacyclin can increase intrapulmonary shunting and worsen ventilation/perfusion mismatch leading to hypoxia.222324 This is of particular concern in patients with preexisting fibrotic lung disease in whom such a complication could dramatically worsen arterial oxygenation. Arterial blood gas data were not available on the patients in our series; as such, we cannot exclude small decreases in the PaO2. However, it is notable that only one of the seven patients who underwent an acute vasodilator trial with IV epoprostenol had a clinically significant decrease in oxygenation, presumably due to worsened ventilation/perfusion mismatch. In this case (patient 4), the desaturation was temporary (< 8 h) and resolved spontaneously.

Several serious complications were observed with acute epoprostenol administration in patients with sarcoidosis-associated pulmonary hypertension. Pulmonary edema complicating epoprostenol infusion has been described in patients with pulmonary postcapillary disease, including pulmonary venoocclusive disease,25 pulmonary capillary hemangiomatosis,2627 scimitar syndrome,28 scleroderma,2930 and decreased left ventricular compliance (unpublished observations; H. Farber, MD; May 2006). Cardiac involvement with an elevated left ventricular end-diastolic and/or pulmonary capillary wedge pressure has been reported in patients with sarcoidosis.31323334 We hypothesize that patient 6 had occult myocardial involvement that was unmasked by the increase in cardiac output with short-term administration of epoprostenol, leading to the development of acute pulmonary edema. Alternatively, extensive granulomatous involvement of the pulmonary veins leading to postcapillary pulmonary hypertension and simulating pulmonary venoocclusive disease has been described in sarcoidosis.614 Such a mechanism could explain the development of elevated pulmonary capillary wedge pressure and subsequent pulmonary edema, shortly after starting epoprostenol, in patient 6. However, in this case, improvement with diuretics and continued epoprostenol would not be expected, thus making occult myocardial involvement more likely. We cannot explain with certainty the cardiac arrest and subsequent death of patient 5 4 h after starting epoprostenol. However, an asystolic arrest secondary to hypoxia from acute pulmonary edema due to underlying venoocclusive disease is possible.

The primary limitations of this report are the small sample size and retrospective nature of the study. In addition, the concomitant treatment with corticosteroids in several cases poses a potential confounder. Nevertheless, this represents the largest reported series of patients with sarcoidosis-associated pulmonary hypertension treated with vasodilators and the longest-term follow-up to date. As such, our experience adds to the currently limited knowledge of sarcoidosis-associated pulmonary hypertension and may provide a therapeutic option for these patients with high mortality.

In summary, we found acute vasoreactivity in response to epoprostenol in patients with sarcoidosis-associated pulmonary hypertension. This translated into functional improvement with long-term epoprostenol administration. These data suggest a promising role for epoprostenol in the treatment of sarcoidosis-associated pulmonary hypertension, either alone or as bridge to lung transplantation. This is of particular importance, as pulmonary hypertension is an independent risk factor for mortality among patients with sarcoidosis awaiting lung transplantation.10 Our experience highlights the potential for serious complications of vasodilator therapy in patients with sarcoidosis-associated pulmonary hypertension. However, the dramatic improvement in pulmonary hemodynamics, functional status, and potential for improved survival in the majority of treated patients suggests that patients with sarcoidosis-associated pulmonary hypertension may benefit from treatment with pulmonary vasodilators.

Footnotes

Abbreviations: iNO = inhaled nitric oxide; mPAP = mean pulmonary artery pressure; NYHA = New York Heart Association; PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance; RHC = right-heart catheterization; SVR = systemic vascular resistance; WHO = World Health Organization

The authors have no conflicts of interest to disclose.

Received for publication December 20, 2005. Accepted for publication May 14, 2006.

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