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Corresponding author at: Departments of Cardiology and Clinical Science, National Hospital Organization Okayama Medical Center, 1711-1 Tamasu, Kita-ku, Okayama 701-1192, Japan.
Department of Clinical Science, National Hospital Organization Okayama Medical Center, Okayama, JapanDepartment of Cardiology, National Hospital Organization Okayama Medical Center, Okayama, Japan
Establishment of diagnosis and treatment of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH) has been a challenge.
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It is necessary to make an early clinical diagnosis of PVOD/PCH.
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We developed a prediction score to clinically diagnose PVOD/PCH.
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PVOD/PCH score may help distinguish PVOD/PCH from idiopathic pulmonary arterial hypertension.
Abstract
Background
Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are rare causes of pulmonary hypertension. Although diagnosis is based on pathological findings, an early diagnosis is crucial because of poor prognosis compared to other types of pulmonary hypertension. Furthermore, vasodilators may cause fatal pulmonary edema in patients with PVOD/PCH. This study aimed to identify specific characteristics for patients with PVOD/PCH to clinically diagnose PVOD/PCH.
Methods
Clinical data were obtained at baseline and were compared between 19 patients with PVOD/PCH and 55 patients with idiopathic/heritable pulmonary arterial hypertension. Receiver operating characteristic analyses were used to determine characteristics specific for patients with PVOD/PCH and a scoring system to diagnose PVOD/PCH was developed.
Results
Patients with PVOD/PCH had a smoking history and were predominantly male. Six-minute walk distance was significantly lower and oxygen desaturation was severe during the walk. Diffusion capacity of carbon monoxide was significantly low. Radiological findings included ground glass opacity on chest high-resolution computed tomography (CT) in all patients with PVOD/PCH, and thickened septal lines in 90% of the patients. Lung perfusion scintigraphy showed defect in >70% of the patients. Pulmonary edema after initiation of vasodilation therapy was frequently observed in PVOD/PCH patients. Based on these results, we identified nine important clinical characteristics and a novel scoring system was designed to clinically diagnose PVOD/PCH: male sex, smoking history, 6-minute walk distance < 285 m, minimum SpO2 < 92% during the 6-minute walk test, %DLco < 34%, ground glass opacity and thickening of the interlobular septa in high-resolution CT, defects in the perfusion lung scan, and pulmonary edema due to vasodilators. Score ≥ 5 points had 95% sensitivity and 98% specificity to predict PVOD/PCH (area under the curve: 0.991; 95% CI: 0.976–1.000).
Conclusions
Our novel prediction rule for diagnosing PVOD/PCH may offer an early clinical diagnosis of these diseases.
Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) have been considered to be rare causes of pulmonary hypertension. However, because of advances in pulmonary hypertension treatments, more cases with PVOD/PCH have been recognized. Approximately 10% of patients who were clinically diagnosed with pulmonary arterial hypertension (PAH) were diagnosed with PVOD/PCH by histological studies [
], the prognoses of patients with PVOD/PCH are still poor. Patients reportedly die within 1–2 years after clinical diagnoses of pulmonary hypertension [
] because of the difficulty in diagnosis and lack of effective treatment for this condition. PAH-targeted therapies sometimes cause fatal pulmonary edema in patients with PVOD/PCH (Fig. 1) [
]. Establishment of diagnosis and treatment of PVOD/PCH has been a challenge in the clinical practice of pulmonary hypertension. Although the definite diagnosis is based on pathological findings [
], it is necessary to make an early clinical diagnosis considering the poor prognosis of PVOD/PCH. Despite reports regarding the clinical characteristics of patients with PVOD/PCH [
], the diagnosis remains challenging. This study aimed to identify characteristics specific for PVOD/PCH and help distinguish patients with PVOD/PCH from those with idiopathic/heritable PAH (I/HPAH) based on clinical data and radiological findings.
Fig. 1Representative radiographical images of pulmonary edema induced by epoprostenol. (A) Chest X-ray of a patient with pulmonary veno-occlusive disease (PVOD) on admission shows cardiomegaly, dilatation of pulmonary arteries, and Kerley B lines. (B) Chest X-ray of a patient with PVOD after administration of epoprostenol (0.5 ng/kg/min) shows severe pulmonary edema.
Patients with PVOD/PCH and I/HPAH who underwent treatment at National Hospital Organization Okayama Medical Center (Okayama, Japan) between May 2003 and January 2015 were included in this study. A comprehensive diagnosis was made according to a standard diagnostic algorithm, including physical examination, blood chemical analysis, radiographic examination, pulmonary function test results, and right heart catheterization [
]: precapillary pulmonary hypertension confirmed by right heart catheterization, presence of radiological abnormalities characteristic of PVOD/PCH on high-resolution computed tomography (HRCT) of the chest (centrilobular ground glass opacities, thickening of interlobular septa, or lymphadenopathy), and low diffusion capacity of carbon monoxide (DLco). Furthermore, if patients demonstrate severe desaturation on exertion or develop pulmonary edema after administration of PAH-targeted therapies, we consider the possibility of PVOD/PCH is high. Pathological examination was performed on lung tissue obtained during autopsy or lung transplantation. Study protocol was approved by the Institutional Review Board (H25-RINKEN-03).
Data collection
Data were retrospectively collected from patient records and analyzed. Baseline demographic information was collected, including age, sex, smoking history, World Health Organization (WHO) functional class, plasma levels of B-type natriuretic peptide (BNP), hemodynamic parameters (mean pulmonary arterial pressure, cardiac index, and pulmonary vascular resistance), 6-minute walk distance (6MWD), oxygen saturation (SpO2), and pulmonary function test results. Results of HRCT scans and ventilation-perfusion lung scans were also evaluated. Furthermore, if treated with PAH-targeted therapies, the presence of pulmonary edema was recorded.
Statistical analysis
Continuous data are expressed as mean (standard deviation) or median (range), and categorical data are expressed as number (%). Differences between continuous and categorical variables were analyzed by unpaired t-test or Kruskal–Wallis test, and chi-square test, respectively. Receiver operating characteristic analyses were used to determine cut-off values for selected variables. Kaplan–Meier survival curves were used to analyze event rates for all-cause death. Patients who underwent lung transplantation were censored at the time of the operation. The follow-up period for monitoring patient survival ended on July 1, 2015. Differences between survival curves were assessed using the log-rank test. Statistical analysis was performed using the IBM SPSS Statistics 20 (IBM, Armonk, NY, USA). Statistical significance was defined as p < 0.05.
Results
Characteristics of patients with PVOD/PCH
There were 19 patients clinically suspected to have PVOD/PCH during this study period. In nine patients (47%) with PVOD/PCH, pathological studies confirmed the diagnosis. Two patients had PCH, while the additional seven patients had PVOD. There were 55 patients diagnosed as having I/HPAH. Diagnoses were later confirmed by pathological studies in nine patients (16%) with I/HPAH. Mean survival time of patients with PVOD/PCH was significantly worse than that of patients with I/HPAH [3.3 ± 0.5 years (95% CI, 2.3–4.2 years) vs. 22.6 ± 4.4 years (95% CI, 14.0–31.3 years), log-rank test, p < 0.001] (Fig. 2).
Fig. 2Overall survival. Survival of patients with pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) (red line) was significantly worse than that of idiopathic/heritable pulmonary arterial hypertension (I/HPAH) (blue line) (log-rank test, p < 0.001).
Baseline demographics were compared between PVOD/PCH and I/HPAH (Table 1). Patients with PVOD/PCH were predominantly male and the average age at diagnosis was higher than that of patients with I/HPAH. Approximately 70% of patients had a smoking history. No patients had history of exposure to organic solvents or alkylating agents. Although hemodynamic parameters were similar in both groups, patients with PVOD/PCH showed severely impaired exercise capacity. The 6MWD was significantly shorter than that of patients with I/HPAH. It is notable that patients with PVOD/PCH showed significant desaturation of oxygen during walking test, reduced to as low as 84% of oxygen saturation. In spirometric analysis, both PVOD/PCH and I/HPAH patients did not demonstrate obstructive or constrictive respiratory disorder. However, patients with PVOD/PCH showed significantly low DLco. Pulmonary edema occurred in more than 70% of patients with PVOD/PCH after initiating PAH-targeted drugs, although this rarely occurred in patients with I/HPAH.
Table 1Clinical characteristics at baseline.
PVOD/PCH (n = 19)
I/HPAH (n = 55)
p-Value
Age at diagnosis (years)
46.6 ± 18.5
31.7 ± 16.7
0.002
Male, n (%)
14 (74)
15 (27)
<0.001
Smoking history, n (%)
13 (68)
9 (16)
<0.001
WHO-FC (I/II/III/IV)
0/0/7/12
1/10/32/12
0.006
BNP (pg/mL)
505.8 (14.9–1702.0)
153.2 (5.8–1687.6)
0.017
mPAP (mmHg)
59.2 ± 17.3
59.9 ± 16.1
0.873
CI (L/min/m2)
2.3 ± 0.5
2.3 ± 0.8
0.879
PVR (dyne s/m5)
1172 ± 417
1338 ± 629
0.342
6MWD (m)
128 (0–360)
383 (0–495)
<0.001
Baseline SpO2 (%)
97 (89–98)
98 (95–100)
<0.001
Minimum SpO2 (%)
84 (68–95)
95 (84–100)
<0.001
ΔSpO2 (%)
11.8 ± 5.3
3.8 ± 3.6
<0.001
%VC (%)
93.2 ± 14.8
94.5 ± 17.7
0.801
FEV1.0% (%)
75.4 ± 11.0
79.0 ± 8.2
0.179
%DLco (%)
22.2 (14.0–53.2)
57.8 (19.6–90.0)
<0.001
Pulmonary edema, n (%)
14 (74)
1 (2)
<0.001
High-resolution CT, n (%)
Ground glass opacity
19 (100)
21 (38)
<0.001
Thickening of interlobular septa
17 (89)
8 (15)
<0.001
Lymphadenopathy
6 (32)
4 (7)
0.020
Pleural effusion
4 (21)
4 (7)
0.168
Nodular shadow
7 (37)
4 (7)
0.006
Defect in perfusion lung scan, n (%)
14 (74)
7 (13)
<0.001
Results are expressed as mean (SD), median (range), or n (%). WHO-FC, World Health Organization functional class; BNP, brain natriuretic peptide; mPAP, mean pulmonary arterial pressure; CI, cardiac index; PVR, pulmonary vascular resistance; 6MWD, 6-minute walk distance; SpO2, oxygen saturation; VC, vital capacity; FEV1.0, forced expiratory volume 1.0 (s); DLco, diffusion capacity of carbon monoxide.
There were many characteristics for PVOD/PCH in radiographical findings, as previously reported. The chest HRCT scans showed ground glass opacity in all patients with PVOD/PCH (Table 1). Thickening of the interlobular septa was seen in approximately 90% of patients with PVOD/PCH. Representative HRCT scans show characteristic abnormalities in patients with PVOD/PCH (Fig. 3Aa and b), although patients with I/HPAH rarely demonstrated abnormalities in HRCT scans (Fig. 3Ac). Perfusion scintigraphy showed defects in 14 patients with PVOD/PCH (74%). The defect was frequently observed in the upper lobes (Fig. 3Ba), which is different from the mottled pattern seen in patients with I/HPAH (Fig. 3Bb).
Fig. 3Representative radiographical images. (A) High-resolution computed tomography (CT) scan image. (a) High-resolution CT scan of a patient with pulmonary veno-occlusive disease (PVOD) shows ground glass opacity and thickening of interlobular septa. (b) High-resolution CT scan of a patient with pulmonary capillary hemangiomatosis shows nodular shadow and thickening of interlobular septa. (c) High-resolution CT scan of a patient with idiopathic pulmonary arterial hypertension without abnormalities. (B) Ventilation-perfusion scintigraphy. (a) Ventilation scan (left panel) of a patient with PVOD shows no defect but perfusion scan (right panel) shows defect in bilateral upper lobes. (b) Ventilation scan (left panel) of a patient with idiopathic pulmonary arterial hypertension shows no defect but perfusion scan (right panel) shows mottled pattern of defects.
We used receiver operating characteristic analysis to determine important clinical parameters. Table 2 shows the calculated area under the curve (AUC) for each clinical parameter shown in Table 1 to predict the diagnosis of PVOD/PCH. Based on the calculation, we selected nine parameters that might be helpful in diagnosing PVOD/PCH. Among the parameters related to the 6MWD, two parameters that showed greater AUC (6MWD and minimum oxygen saturation measured during the test) were chosen. Clinical characteristics specific to PVOD/PCH were the following values: male sex (AUC: 0.732), smoking history (AUC: 0.737), 6MWD (AUC: 0.897), oxygen desaturation during the 6-minute walk test (AUC: 0.919), %DLco (AUC: 0.953), chest HRCT scan findings [ground glass opacity (AUC: 0.820) and thickening of the interlobular septa (AUC: 0.860)], defects in the perfusion lung scan (AUC: 0.891), and pulmonary edema after treatment with PAH-targeted drugs (AUC: 0.989) (Table 3). We calculated the optimal cut-off value for 6MWD, minimum SpO2 during exercise, or %DLco using receiver operating characteristic analysis. We further calculated predictive values to clinically diagnose PVOD/PCH based on these nine parameters. Pulmonary edema after vasodilation therapy counted for 2 points because it was highly specific to PVOD/PCH. Other parameters were scored as 1 point each and the highest possible score of the sum of the values was 10 points. The mean value of the score in our cohort was 7.7 ± 1.9 points for PVOD/PCH and 1.5 ± 1.3 points for I/HPAH (p < 0.001) (Fig. 4). There was no significant difference in PVOD/PCH score between 9 patients with pathological diagnosis and 10 patients without pathological diagnosis (p = 0.066). We calculated the optimal cut-off value for PVOD/PCH score to predict the diagnosis of PVOD/PCH using receiver operating characteristic analysis. A score ≥5 points had a sensitivity of 95% and specificity of 98% to predict PVOD/PCH (AUC: 0.991; 95% CI: 0.976–1.000).
Table 2Clinical characteristics important for diagnosing PVOD/PCH.
Clinical parameters
Area under curve
Age
0.715
Male sex
0.732
Smoking history
0.737
WHO-FC
0.682
BNP
0.678
6MWD
0.897
Baseline SpO2
0.735
Minimum SpO2
0.919
ΔSpO2
0.894
%VC
0.504
FEV1.0%
0.597
%DLco
0.953
Ground glass opacity
0.820
Thickening of interlobular septa
0.860
Lymphadenopathy
0.614
Pleural effusion
0.562
Nodular shadow
0.641
Defect in perfusion lung scan
0.891
Pulmonary edema
0.989
WHO-FC, World Health Organization functional class; BNP, brain natriuretic peptide; 6MWD, 6-minute walk distance; SpO2, oxygen saturation; VC, vital capacity; FEV1.0, forced expiratory volume 1.0 (s); DLco, diffusion capacity of carbon monoxide.
Fig. 4Histogram of pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) score. Distribution of score was different between patients with (A) PVOD/PCH and (B) idiopathic/hereditary pulmonary arterial hypertension (I/HPAH).
Since pathological diagnosis of PVOD/PCH is difficult to obtain ante mortem because lung biopsy bears high risk in patients with pulmonary hypertension, establishing an early clinical diagnosis of PVOD/PCH is imperative in the clinical practice of pulmonary hypertension. We retrospectively analyzed clinical characteristics of patients with PVOD/PCH compared to those of I/HPAH, and identified nine characteristics that are important to clinically diagnose PVOD/PCH. The PVOD/PCH score consists of these nine clinical parameters that showed high discriminative capacity for diagnosing PVOD/PCH and could therefore be useful for identifying patients with high probability of PVOD/PCH without performing pathological studies.
PVOD consists of extensive and diffuse occlusion of pulmonary venules and veins, while PCH is characterized by localized capillary proliferation within the lung, where capillaries invade pulmonary interstitium, vessels, and, less commonly, airways [
], are reported to contribute to the pathogenesis of PVOD/PCH. Although the precise mechanism of PVOD/PCH is largely unknown, it is obvious that this disease entity is different from I/HPAH. However, in clinical practice, sometimes the differential diagnosis of PVOD/PCH and I/HPAH is difficult.
Furthermore, there is little chance to survive for patients with PVOD/PCH. There is no established medical treatment for PVOD/PCH and lung transplantation is the only curative treatment. If patients are candidates for transplantation, they should be listed as soon as possible because of rapid disease progression [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
]. PAH-targeted therapies must be initiated with great caution in patients with PVOD/PCH in centers with extensive experience in pulmonary hypertension due to the risk of developing pulmonary edema [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
]. Since there is an obstruction in pulmonary veins and capillaries in these patients, hydrostatic pressure may increase with PAH-targeted drugs, which dilate pulmonary arteries. Only when used at experienced centers, epoprostenol may be tolerated in PVOD/PCH patients by gradual increase with concomitant use of diuretics and may be a candidate drug as a bridge therapy for lung transplantation [
]. In this situation, to clinically diagnose PVOD/PCH as soon as possible, clinical characteristics specific for PVOD/PCH identified in the present study may be useful. In comparison of clinical parameters of PVOD/PCH and I/HPAH, low DLco and characteristic findings of HRCT and ventilation-perfusion scan were found for PVOD/PCH as previously reported [
] and are controversial. In the present study, abnormality in lung perfusion scan suggests PVOD/PCH.
There are some limitations in the present study. This study is retrospective, performed at a single center, and has a small sample size. We cannot exclude selection bias due to the nature of the study design. We also do not have pathological confirmation of diagnosis in all patients. Although all the clinical diagnoses matched with the pathological diagnosis obtained, we cannot rule out the possibility of misdiagnoses in patients whose lung tissues were not pathologically examined.
Conclusions
In the present study, characteristic parameters to diagnose PVOD/PCH were identified based on clinical data and radiological findings and a scoring system was developed. Clinical diagnosis based on our novel score may help an early clinical diagnosis of these diseases and offer an appropriate therapeutic strategy for patients with PVOD/PCH. To confirm that the diagnostic accuracy of these features and establish whether the scoring system using them can serve as a reliable diagnostic tool, it is indispensable to calculate scores in other cohorts of patients with a pathological diagnosis, although it may be difficult because of the rareness of the disease.
Conflicts of interest
A.O. has received lecture fees from Actelion Pharmaceuticals Japan Ltd., GlaxoSmithKline KK, Nippon Shinyaku Co., Ltd., and Pfizer Japan Inc.
Y.T. has no conflicts to declare.
H.M. has received lecture fees from Actelion Pharmaceuticals Japan Ltd., AOP Orphan Pharmaceuticals AG, Bayer Yakuhin Ltd., GlaxoSmithKline KK, Nippon Shinyaku Co., Ltd., and Pfizer Japan Inc.
Acknowledgments
This work was partly supported by the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development [27280401].
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
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