[
Original Research Pulmonary Vascular Disease
]
Pulmonary Venoocclusive Disease in Childhood Cornelia Woerner, MD; Ernest Cutz, MD; Shi-Joon Yoo, MD, PhD; Hartmut Grasemann, MD; and Tilman Humpl, MD, PhD
Pulmonary venoocclusive disease (PVOD) is a rare lung disease, diagnosed in 5% to 10% of patients with pulmonary hypertension (PH). The incidence, prevalence, and etiology of PVOD in children are not well defined. The mortality remains high, related, at least partly, to the limited treatment options.
BACKGROUND:
This retrospective analysis (1985-2011) summarizes symptoms, associated factors, treatment, and outcomes of nine pediatric patients (five girls, four boys) with histologic confirmation of PVOD.
METHODS:
PH was diagnosed at a mean age of 13.5 years (range, 8-16 years), followed by the definitive diagnosis of PVOD at a mean age of 14.3 years (range, 10-16 years). Symptoms such as decreased exercise tolerance (n 5 6) and/or shortness of breath (n 5 9) preceded the diagnosis by 21 months on average; the mean survival time after diagnosis was 14 months (range, 0-47 months). CT scans of the lungs showed typical radiologic features. Treatment included supplemental home oxygen (n 5 5), diuretics (n 5 9), warfarin (n 5 4), and pulmonary vasodilators (n 5 4). Four children were listed for lung transplantation, and three have undergone transplantation. Eight patients died, including two after lung transplantation. One patient with lung transplant survived with good quality of life.
RESULTS:
PVOD is an important differential diagnosis for pediatric patients with PH. CT scanning is a valuable tool to image lung abnormalities; the definitive diagnosis can only be made by examination of lung biopsy specimens, which subjects the patient to additional risk. Early listing for lung transplantation is essential, as the mean survival time is only 14 months. CHEST 2014; 146(1):167-174
CONCLUSIONS:
Manuscript received January 22, 2013; revision accepted January 2, 2014; originally published Online First February 6, 2014. ABBREVIATIONS: NYHA 5 New York Heart Association; PAP 5 pulmonary artery pressure; PFT 5 pulmonary function test; PH 5 pulmonary hypertension; PVOD 5 pulmonary venoocclusive disease AFFILIATIONS: From the Department of Pediatrics, Division of Cardiology (Drs Woerner, Yoo, and Humpl), Department of Laboratory Medicine and Pathobiology (Dr Cutz), Department of Pediatrics, Division of Respiratory Medicine (Dr Grasemann), Department of Critical Care Medicine (Dr Humpl), and Department of Medical Imaging (Dr Yoo), University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
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The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Tilman Humpl, MD, PhD, The Hospital for Sick Children, Critical Care and Cardiology, 555 University Ave, Toronto, ON, M5G 1X8, Canada; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0172 FUNDING/SUPPORT:
167
Pulmonary venoocclusive disease (PVOD) is a rare lung disease that affects the postcapillary venous pulmonary vasculature and accounts for 5% to 10% of cases with “idiopathic” pulmonary arterial hypertension.1-5 It carries a high risk of developing right-sided heart failure secondary to elevated pulmonary artery pressure (PAP) followed by death. Histopathologic findings in PVOD have previously been well characterized.2 The main features include involvement of preseptal venules and small septal veins with varying degree of luminal obliteration due to intimal fibrous proliferation that can be loose initially and later becoming dense or sclerotic. The media of the veins can become arterialized with an
increase in smooth muscle cells and elastic fibers in their walls. Further progression may lead to pulmonary arterioles with medial hypertrophy, capillary angiectasia, and even capillary proliferation. Parenchymal changes begin with interstitial edema and can progress to fibrosis.2 Incidence, prevalence, and etiology of PVOD are not well defined, treatment is limited, and the mortality remains high.
Materials and Methods
test, pulmonary function test (PFT), CT scan of the lung, cardiac catheterization, bronchoscopy, lung biopsy specimen examination, and autopsy.
The cardiology, radiology, and pathology databases were searched for patients with clinical suspicion of PVOD between 1985 and 2011. Final patient selection for this study was based on histologic confirmation of PVOD. Patients with clinical signs of PVOD but without histologic findings were excluded. Paper and electronic patient charts were reviewed, and data including initial symptoms, age at presentation with symptoms, time of diagnosis, additional diagnoses, risk factors, New York Heart Association (NYHA) functional class, and physical examination at presentation were collected. Additionally, the results of the following investigations were evaluated: ECG, echocardiogram, chest radiograph, 6-min walk
Results Nine patients were identified; demographic data are shown in Table 1. The average time interval from onset of symptoms until the diagnosis of pulmonary hypertension (PH) and PVOD was 14 months and 21 months, respectively (range, , 1 month to 7 years). The mean survival time after diagnosis with PVOD was 14 months (range, , 1-47 months). Initial symptoms included fatigue, decreased exercise tolerance, and shortness of breath on exertion. Other symptoms were cough, dizziness, chest pain with exercise, palpitations, syncope, and nonspecific symptoms such as headache, poor appetite, pallor, perioral cyanosis, and hemoptysis (Table 2). Four children were previously diagnosed with a different pulmonary disease: three with bronchial asthma and one with allergic alveolitis. Additional diagnoses affecting other organs were present in three children and included bilateral renal dysplasia, ichthyosis, velopharyngeal incompetence, severe developmental delay, and congenital heart disease. One patient was diagnosed with Myhre syndrome, confirmed by mutational analysis of SMAD4.14 168 Original Research
There are a number of reports about adult patients,3,6-8 but, to our knowledge, only a few case reports exist about children.9-13 We undertook a single-center retrospective review to summarize symptoms, associated factors, treatment, and outcomes in children with PVOD.
The lung samples were fixed in buffered formalin and embedded in paraffin. In addition to routine stains with hematoxylin and eosin, we also used special stains, including elastic trichrome to visualize vascular changes, stain for iron for assessment of hemosiderosis, or stains for microorganisms where indicated. Due to the small number of patients and the large variation in their clinical course, statistical analysis was not performed. This study was approved by the Research Ethics Board at the Hospital for Sick Children, Toronto, Ontario, Canada (No. 100010504).
Two patients received long-term immunosuppressive treatment (tacrolimus and tacrolimus, azathioprine and prednisone) after (nonlung) solid organ transplantation. Other risk factors, such as tobacco consumption, were not documented. One patient was taking an antidepressant drug, three patients were treated with bronchodilators (puffers), and three were not on any medications. The physical examination was unremarkable in one patient; the others presented with abnormal findings (Table 2). NYHA class at presentation ranged from I to TABLE 1
] Demographic Data of Patients With PVOD
Demographic
Variable
Age at diagnosis, alive or postmortem, mean (range), y
14.3 (10-16)
Age at diagnosis of pulmonary hypertension, mean (range), y
13.5 (8-16)
Age at onset of symptoms, mean (range), y
12.4 (7-15)
Sex, female:male
5:4
Postmortem diagnosis, No.
3
PVOD 5 pulmonary venoocclusive disease.
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169
…
9
…
1
1
…
1
1
1
1
…
Decreased Exercise Tolerance
1
1
1
1
1
1
1
1
1
Shortness of Breath
…
…
1
…
…
…
…
…
…
Syncope
…
…
1
…
…
…
…
…
1
Palpitations
…
…
…
1
…
…
1
…
…
Chronic Cough
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
1
1
1
1
0
0
1
1
0
C/PM
1
1
1
1
0
1
1
1
0
BWT
0
1
0
1
0
1
0
1
1
NLO
1
1
1
1
1
1
1
1
1
MPA
1
1
1
1
0
1
1
1
1
PAHIL
…
1
…
…
…
1
1
1
1
Loud S2
0
1
1
0
0
0
0
0
0
DV
…
…
…
…
…
…
…
1
1
RV Heave
1
1
1
0
0
1
0
1
0
MM/E
…
…
1
…
…
…
…
…
1
Murmur
0
1
1
0
0
0
0
0
0
PE
…
1
…
…
…
…
…
…
1
Elevated JVP
CM
Marked
Mild
Mild
Mild
Moderate
Mild
Marked
Moderate
92
88
87
96
93
85
90
98
98
RVH
II
III
IV
II
III
II
III
III
III
NYHA Class
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Severe
Moderate
Severe
Tc Saturation, %
Moderate
1
1
…
…
1
…
1
…
…
Crackles
BWT 5 bronchial wall/peribronchial thickening; CM 5 cardiomegaly; C/PM 5 Increased interstitial or streaky markings, central and/or abutting to the pleural surfaces; DV 5 diminished vascularity in the periphery; GGO 5 ground-glass opacity; MM/E 5 mediastinal and hilar edema or mass; MPA 5 dilated mean pulmonary artery segment; NLO 5 nodular or mottled lung opacity; PAHIL 5 dilated central pulmonary arteries at hilum; PE 5 pleural effusion; RVH 5 right ventricular hypertrophy. See Table 1 legend for expansion of other abbreviation.
1
GGO
] CT Scan Findings of Patients With PVOD
1
Patient
TABLE 3
JVP 5 jugular venous pressure; NYHA 5 New York Heart Association; RV 5 right ventricular; Tc 5 transcutaneous.
…
8
…
5
…
…
4
1
…
3
7
1
2
6
…
Chest Pain
] Symptoms and Clinical Findings of Patients at Initial Presentation
1
Patient
TABLE 2
IV (Table 2). Transcutaneous oxygen saturation ranged from 85% to 98% on room air (mean, 92%). Hypocapnia was present in 66% (n 5 6); the pH was within normal limits.
haziness of both lungs, or blurring of vessel margins suggestive of pulmonary venous hypertension in eight of nine cases. CT scan findings are summarized in Table 3 and illustrated in Figure 1.
PFTs were performed in seven patients at our institution and revealed a restrictive pattern in all cases (in one patient, the PFT was done at another hospital, and the results were not available). In all patients, the FVC and FEV1 were decreased, with a mean of 50% (range, 20%-81%) and 51% (range, 18%-81%), respectively. The diffusing capacity of the lung for carbon monoxide was reduced in the four patients tested (67%, 62%, 26%, and 83%), ranging from 5.9 mL/min/mm Hg to 14.2 mL/min/mm Hg. Five children completed a 6-min walk test with a mean distance of 263 m (range, 19-382 m).
A diagnostic cardiac catheterization with acute vasodilator testing was performed in four patients and showed elevated PAP (Table 4). During testing with pulmonary vasodilators, one patient developed acute pulmonary edema.
Eight patients had abnormal ECG findings, with frequent right-axis deviation, signs of right atrial enlargement, and right ventricular hypertrophy. Transthoracic echocardiography showed a dilated right ventricle with flattening or bowing of the interventricular septum, suggesting elevated right ventricular pressure in all patients. The estimated right ventricular systolic pressure ranged from more than one-half systemic to systemic (n 5 5) to suprasystemic (n 5 3). In one patient, only mean PAP could be estimated and exceeded 25 mm Hg. The initial chest radiograph showed a prominent pulmonary arterial segment of the left heart border in all cases and increased interstitial markings, ground-glass
Bronchoscopy with BAL was performed in only two patients and did not reveal significant findings. Four children underwent elective lung biopsy; two had samples taken from the explanted lungs at the time of transplantation, and three patients had the diagnosis of PVOD established at autopsy (Table 5). The main histologic findings included extensive changes of PVOD similar to those previously described.1,2,13,15-17 These changes were characterized by extensive and diffuse occlusion of pulmonary veins by fibrous tissue, which, in some areas, was loose and edematous, while in others it was dense and sclerotic (Fig 2A). The intimal thickening involving venules and small veins exhibited an eccentric pattern resembling organizing arterial thrombi. In most cases, the pulmonary arterioles showed moderate to severe medial thickening without plexiform lesions. In addition, several cases showed variable interstitial thickening with focal fibrosis and moderate to marked pulmonary hemosiderosis (Table 5). In the two patients who underwent solid organ transplantation, the lung biopsy specimens, in addition to
Figure 1 – Classic image findings of pulmonary venoocclusive disease in a 16-year-old patient. A, Frontal chest radiograph shows mild cardiomegaly with markedly dilated main pulmonary arterial segment of the left upper heart border due to pulmonary hypertension. Both lungs are diffusely hazy and show increased interstitial markings with blurred vessel margins. B, CT images reconstructed in axial and coronal planes show diffuse ground-glass opacity with a mosaic pattern, thickened septal lines extending to the pleura (black arrows), and peribronchial thickening (white arrows). Note that there are low density areas in the mediastinum and hila (asterisks), which represent soft tissue edema or lymphatic dilatation. Extensive edematous tissue in the posterior mediastinum is well appreciated in the coronal plane. The pulmonary arteries in the mediastinum and hila are dilated.
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TABLE 4
] Hemodynamic Findings in Cardiac
Catheterization in Patients With PVODa
Patient
mPAP, mm Hg
PVRi, WU3m2
PCWP
1
50 (80/40)
18.1
7
2
42 (62/30)
11.3
3
67 (85/55)
…
4
74 (96/55)
37
3 13 8
mPAP 5 mean pulmonary artery pressure; PCWP 5 pulmonary capillary wedge pressure; PVRi 5 pulmonary vascular resistance indexed for body surface area; WU 5 Wood Units. See Table 1 legend for expansion of other abbreviation. aBaseline with 100% oxygen and inhaled nitric oxide (40 parts per million).
prominent involvement of pulmonary veins by PVOD, also showed granulomatous inflammatory changes with aggregates of multinucleated giant cells in the alveoli, alveolar septae, or both (Figs 2B, 2C). In contrast to other patients with PVOD, the pulmonary arteries in these two patients appeared relatively unaffected (Fig 2B). Special stains for acid-fast bacilli and fungal organisms were negative. These changes were interpreted as most likely representing extrinsic allergic alveolitis or a drug reaction. The therapeutic approach was heterogeneous because patients were diagnosed over a relatively long time span and had a variable clinical disease course and severity. In some, the definite diagnosis was not established prior to biopsy or autopsy. Five children received oxygen, four were started on diuretics as initial treatment, and four were treated with warfarin. The patient diagnosed with allergic alveolitis received pulse steroid therapy. In four patients, pulmonary vasodilators were added TABLE 5
(inhaled nitric oxide, sildenafil, epoprostenol) in the absence of a definitive diagnosis of PVOD, leading to acute deterioration in one, and no improvement or subacute worsening in the others. Five patients were assessed for lung transplantation and four were listed. One patient died while awaiting heartlung transplantation, and three underwent lung transplantation with waiting times of 27 to 240 days. One patient and family declined assessment for lung transplantation, and three patients were not eligible. Two of the listed patients required mechanical support. One patient was supported with extracorporeal membrane oxygenation and converted to an interventional lung assist (Novalung GmBH), and the other was semiurgently cannulated to the interventional lung assist; both underwent lung transplantation. Following lung transplantation, one patient is alive; the two deaths were related to rejection and multiorgan failure.
Discussion While there are several reports regarding adults with PVOD, to our knowledge, this is the first reported series of children with this disease. In 1934, Höra15 published findings of an adult patient followed by a detailed pathologic description emphasizing differences between “classical” pulmonary arterial hypertension and PVOD.16 Further cases were reported,17,18 including the first pediatric patient in 1967,9 and several adult case series.1,3,19 The underlying cause and the pathophysiology of PVOD remain unclear. Associations of PVOD with
] Pathology Findingsa in Patients With PVOD
Patient
PVOD
PH
Hemosiderosis
Parenchymal Disease or Other Findings
1
31
2-31
None
None
2
31
21
1-21
None
3
31
2-31
1-21
Interstitial fibrosis/DAD
4
31
21
2-31
Interstitial fibrosis, focal
5
31
31
21
Interstitial fibrosis, BOOP
6
31
11
11
Granulomatous/giant cell
7
31
21
2-31
Focal fibrosis, thrombosis
8
31
1-21
2-31
None
9
…
…
…
…
Biopsy performed
31
11
11
Granulomatous/giant cells
Explanted lung
31
11
31
Interstitial fibrosis/no giant cells
BOOP 5 bronchiolitis obliterans organizing pneumonia; DAD 5 diffuse alveolar damage; PH 5 pulmonary hypertension. See Table 1 legend for expansion of other abbreviation. aSemiquantitative histologic evaluation: 11 5 minimal to mild, 21 5 moderate, 31 5 severe.
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connective tissue and autoimmune diseases, HIV infection, bone marrow transplantation, sarcoidosis, and pulmonary Langerhans cell granulomatosis have been described,20-23 but were not found in the patients. Occurrence of PVOD after solid organ transplantation is most likely drug induced, not accounting for a different disease. There are case reports of affected siblings, suggesting a genetic association.10 Furthermore, mutation in bone morphogenetic protein receptor II was discovered in a patient with biopsy specimen-proven PVOD.24 Interestingly, one of the patients was diagnosed with Myrhe syndrome, a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness, and cognitive delay.14 Studies have identified mutations in SMAD4 as a cause of this syndrome.25 The patient with Myhre syndrome appears to be the first recognized case of this disorder associated with pulmonary vascular disease, specifically PVOD; a manuscript is in preparation about this case. It is of interest to note that SMAD4 plays a critical role in the BMPR2/SMAD signaling implicated in the pathogenesis of familial PH.26 Other possible risk factors include tobacco use, chemotherapy, appetite-suppressing agents, and thoracic radiation.3,27-29 Histology in two of our cases revealed prominent granulomatous inflammation suggestive of hypersensitivity reaction or drug effect, and both of these patients underwent preceding solid organ transplantation and were receiving immunosuppressive medication. We are not aware of previous reports of PVOD associated with granulomatous interstitial inflammation in this setting. The onset of the disease varies between a few months of age to the seventh decade of life; however, in the patient group, clinical signs became apparent between 8 and 16 years of age. PVOD does not appear to be sex specific,3 which is also reflected in the almost equal sex distribution in our series.
Figure 2 – Histologic images from two patients are presented. A, Low magnification view of lung biopsy specimen showing fibrous obliteration of medium size PVs as well as small peripheral pulmonary venules (arrows). A bronchovascular bundle contains normal BR and PA with thickened media. Small peripheral branches of pulmonary artery appear relatively normal (arrowheads) (Elastic trichrome). B, Low power view of lung biopsy specimen with PVs showing striking fibrous and fibrointimal proliferation causing total lumenal obliteration. In contrast, PAs are widely open. A small BR contains an aggregate of macrophages. Adjacent lung parenchyma shows interstitial thickening, congestion, and recent hemorrhage (Elastic trichrome). C, A close up view from Figure 1B showing lung parenchyma with focal aggregates of multinucleated giant
172 Original Research
Shortness of breath and decreased exercise tolerance were the major clinical signs; however, other symptoms like chronic cough, pulmonary edema, hemoptysis, and exertional syncope are also possible. The time between onset of symptoms and diagnosis varies.
cells (arrows) in interstitium and alveolar space. Note the complete obliteration of a small pulmonary venule outlined by elastic (black) and collagen (green) in the wall (Elastic trichrome). BR 5 bronchiole; GC 5 giant cell; PA 5 pulmonary artery; PV 5 pulmonary vein.
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In the adult population, it is reported as an average of 49 months30 and averaged 21 months in our cohort. Transthoracic echocardiography remains also in the pediatric population a useful tool to assess the presence of elevated right-sided pressures and exclude underlying cardiac causes. Right-sided heart catheterization provides detailed hemodynamic information (PAP, pulmonary capillary wedge pressure, and indexed pulmonary vascular resistance), and also allows pulmonary vasoreactivity testing. The triad of severe PH and radiographic pulmonary edema in the presence of a normal pulmonary artery wedge pressure is highly suggestive of PVOD and was present in the majority of the patients. Several diagnostic tools (arterial blood gas analysis, PFT, highresolution CT scan of the chest, and BAL) may help explore the underlying cause, but are not always performed in children. The gold standard for a definitive diagnosis of PVOD remains histology, but a lung biospy is invasive and often associated with a high risk in patients with PH.31,32 In our series, all patients with PFTs had decreased FEV1 and FVC, in contrast to the reports in adults.33 High-resolution CT scans often reveal three typical radiologic features: centrilobular ground-glass opacities, septal lines (interlobular septal thickening), and mediastinal lymph node enlargement.34,35 Ground-glass opacities were seen in all of the present patients; however, septal thickening and nodular/mottled lung opacities were not consistently present, underlining the difficulties in making the diagnosis by imaging alone. Interestingly, CT imaging for the diagnostic workup of pediatric patients with PH was only used in 41% of a large patient cohort, with 74% being reported as abnormal.36 Despite thorough noninvasive tests, the accurate diagnosis of PVOD was not recognized in three of the patients (30%) until postmortem examination. Especially if medical treatment of PH fails, PVOD should be strongly considered,7 as it is often misdiagnosed as
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idiopathic arterial hypertension.8 As epidemiologic data suggest, a proportion of 5% to 25% of primary PH will fulfill criteria for PVOD if fully investigated; the prevalence of only six pediatric patients (1.7%) in a large current registry37 suggests underdiagnosis of the disease. The use of pulmonary vasodilators (inhaled nitric oxide, epoprostenol, sildenafil) leads to improvement in some patients. Given the risk of pulmonary edema as a result of the relatively greater degree of vasodilatation in the precapillary vessels compared with the postcapillary vessels with resultant increased transcapillary hydrostatic pressure, this treatment avenue should be used with caution.38 Pulmonary edema may also present later despite a favorable (or uncomplicated) response during cardiac catheterization prior to initiation of therapy. Mechanical lung-assist devices might be an additional option in these situations. At present, the only therapeutic option is lung transplantation; hence, early diagnosis and assessment are crucial. Holcomb et al1 reported 72% mortality in the first year and nearly 100% within 2 years of diagnosis. In our cohort, the mean survival after diagnosis was 14 months. In conclusion, PVOD is an important differential diagnosis in children with PH and may be underdiagnosed. CT imaging is an important tool to narrow down the etiology of PH, but definitive diagnosis in most cases can only be made by histology. With small numbers of patients, variable workup, and heterogeneous nature of the disease, a multicenter registry approach may be helpful to further define disease characteristics and to evaluate treatment benefits. Currently, with limited therapeutic options and the progressive nature of the disease, the overall prognosis is very poor. However, multicenter studies of carefully titrated vasodilator therapy should be considered in the future. With the short mean survival time following diagnosis, early mechanical support and/or early listing for lung transplantation must be considered, as the average waiting time frequently exceeds the individual’s remaining lifespan. Given delay in diagnosis, clinical course, and overall outcome, early recognition of PVOD is essential.
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Acknowledgments Author contributions: T. H. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. C. W. served as principal author. C. W. and T. H. contributed to data acquisition; C. W., E. C., S.-J. Y., H. G., and T. H. contributed to data analysis and interpretation; T. H. contributed to study conception and design; C. W. contributed to the drafting of the submitted article; E. C., S.-J. Y., H. G., and T. H. contributed to the revision of the manuscript for important intellectual content; and E. C., S.-J. Y., H. G., and T. H. approved the final version. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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26.
27.
28.
29.
30.
31.
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33.
34.
35.
36.
37.
38.
Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet. 2011;44(1):85-88. Yang J, Davies RJ, Southwood M, et al. Mutations in bone morphogenetic protein type II receptor cause dysregulation of Id gene expression in pulmonary artery smooth muscle cells: implications for familial pulmonary arterial hypertension. Circ Res. 2008;102(10):1212-1221. Joselson R, Warnock M. Pulmonary veno-occlusive disease after chemotherapy. Hum Pathol. 1983;14(1):88-91. Knight BK, Rose AG. Pulmonary venoocclusive disease after chemotherapy. Thorax. 1985;40(11):874-875. Kramer MR, Estenne M, Berkman N, et al. Radiation-induced pulmonary veno-occlusive disease. Chest. 1993;104(4):1282-1284. Lantuéjoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30(7):850-857. Jaklitsch MT, Linden BC, Braunlin EA, Bolman RM III, Foker JE. Open-lung biopsy guides therapy in children. Ann Thorac Surg. 2001;71(6):1779-1785. Kreider ME, Hansen-Flaschen J, Ahmad NN, et al. Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease. Ann Thorac Surg. 2007;83(3): 1140-1144. Montani D, Kemp K, Dorfmuller P, Sitbon O, Simonneau G, Humbert M. Idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: similarities and differences. Semin Respir Crit Care Med. 2009;30(4):411-420. Resten A, Maitre S, Humbert M, et al. Pulmonary hypertension: CT of the chest in pulmonary venoocclusive disease. AJR Am J Roentgenol. 2004;183(1):65-70. Ozsoyoglu AA, Swartz J, Farver CF, Mohammed TL. High-resolution computed tomographic imaging and pathologic features of pulmonary veno-occlusive disease: a review of three patients. Curr Probl Diagn Radiol. 2006;35(6):219-223. Beghetti M, Berger RM, Schulze-Neick I, et al; TOPP Registry Investigators. Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice. Eur Respir J. 2013;42(3): 689-700. Berger RM, Beghetti M, Humpl T, et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. 2012;379(9815):537-546. Montani D, Jaïs X, Dorfmuller P, Simonneau G, Sitbon O, Humbert M. Goal-oriented therapy in pulmonary veno-occlusive disease: a word of caution. Eur Respir J. 2009;34(5):1204-1206.
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Original Research Pulmonary Vascular Disease
]
Pulmonary Venoocclusive Disease in Childhood Cornelia Woerner, MD; Ernest Cutz, MD; Shi-Joon Yoo, MD, PhD; Hartmut Grasemann, MD; and Tilman Humpl, MD, PhD
Pulmonary venoocclusive disease (PVOD) is a rare lung disease, diagnosed in 5% to 10% of patients with pulmonary hypertension (PH). The incidence, prevalence, and etiology of PVOD in children are not well defined. The mortality remains high, related, at least partly, to the limited treatment options.
BACKGROUND:
This retrospective analysis (1985-2011) summarizes symptoms, associated factors, treatment, and outcomes of nine pediatric patients (five girls, four boys) with histologic confirmation of PVOD.
METHODS:
PH was diagnosed at a mean age of 13.5 years (range, 8-16 years), followed by the definitive diagnosis of PVOD at a mean age of 14.3 years (range, 10-16 years). Symptoms such as decreased exercise tolerance (n 5 6) and/or shortness of breath (n 5 9) preceded the diagnosis by 21 months on average; the mean survival time after diagnosis was 14 months (range, 0-47 months). CT scans of the lungs showed typical radiologic features. Treatment included supplemental home oxygen (n 5 5), diuretics (n 5 9), warfarin (n 5 4), and pulmonary vasodilators (n 5 4). Four children were listed for lung transplantation, and three have undergone transplantation. Eight patients died, including two after lung transplantation. One patient with lung transplant survived with good quality of life.
RESULTS:
PVOD is an important differential diagnosis for pediatric patients with PH. CT scanning is a valuable tool to image lung abnormalities; the definitive diagnosis can only be made by examination of lung biopsy specimens, which subjects the patient to additional risk. Early listing for lung transplantation is essential, as the mean survival time is only 14 months. CHEST 2014; 146(1):167-174
CONCLUSIONS:
Manuscript received January 22, 2013; revision accepted January 2, 2014; originally published Online First February 6, 2014. ABBREVIATIONS: NYHA 5 New York Heart Association; PAP 5 pulmonary artery pressure; PFT 5 pulmonary function test; PH 5 pulmonary hypertension; PVOD 5 pulmonary venoocclusive disease AFFILIATIONS: From the Department of Pediatrics, Division of Cardiology (Drs Woerner, Yoo, and Humpl), Department of Laboratory Medicine and Pathobiology (Dr Cutz), Department of Pediatrics, Division of Respiratory Medicine (Dr Grasemann), Department of Critical Care Medicine (Dr Humpl), and Department of Medical Imaging (Dr Yoo), University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
journal.publications.chestnet.org
The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Tilman Humpl, MD, PhD, The Hospital for Sick Children, Critical Care and Cardiology, 555 University Ave, Toronto, ON, M5G 1X8, Canada; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0172 FUNDING/SUPPORT:
167
Pulmonary venoocclusive disease (PVOD) is a rare lung disease that affects the postcapillary venous pulmonary vasculature and accounts for 5% to 10% of cases with “idiopathic” pulmonary arterial hypertension.1-5 It carries a high risk of developing right-sided heart failure secondary to elevated pulmonary artery pressure (PAP) followed by death. Histopathologic findings in PVOD have previously been well characterized.2 The main features include involvement of preseptal venules and small septal veins with varying degree of luminal obliteration due to intimal fibrous proliferation that can be loose initially and later becoming dense or sclerotic. The media of the veins can become arterialized with an
increase in smooth muscle cells and elastic fibers in their walls. Further progression may lead to pulmonary arterioles with medial hypertrophy, capillary angiectasia, and even capillary proliferation. Parenchymal changes begin with interstitial edema and can progress to fibrosis.2 Incidence, prevalence, and etiology of PVOD are not well defined, treatment is limited, and the mortality remains high.
Materials and Methods
test, pulmonary function test (PFT), CT scan of the lung, cardiac catheterization, bronchoscopy, lung biopsy specimen examination, and autopsy.
The cardiology, radiology, and pathology databases were searched for patients with clinical suspicion of PVOD between 1985 and 2011. Final patient selection for this study was based on histologic confirmation of PVOD. Patients with clinical signs of PVOD but without histologic findings were excluded. Paper and electronic patient charts were reviewed, and data including initial symptoms, age at presentation with symptoms, time of diagnosis, additional diagnoses, risk factors, New York Heart Association (NYHA) functional class, and physical examination at presentation were collected. Additionally, the results of the following investigations were evaluated: ECG, echocardiogram, chest radiograph, 6-min walk
Results Nine patients were identified; demographic data are shown in Table 1. The average time interval from onset of symptoms until the diagnosis of pulmonary hypertension (PH) and PVOD was 14 months and 21 months, respectively (range, , 1 month to 7 years). The mean survival time after diagnosis with PVOD was 14 months (range, , 1-47 months). Initial symptoms included fatigue, decreased exercise tolerance, and shortness of breath on exertion. Other symptoms were cough, dizziness, chest pain with exercise, palpitations, syncope, and nonspecific symptoms such as headache, poor appetite, pallor, perioral cyanosis, and hemoptysis (Table 2). Four children were previously diagnosed with a different pulmonary disease: three with bronchial asthma and one with allergic alveolitis. Additional diagnoses affecting other organs were present in three children and included bilateral renal dysplasia, ichthyosis, velopharyngeal incompetence, severe developmental delay, and congenital heart disease. One patient was diagnosed with Myhre syndrome, confirmed by mutational analysis of SMAD4.14 168 Original Research
There are a number of reports about adult patients,3,6-8 but, to our knowledge, only a few case reports exist about children.9-13 We undertook a single-center retrospective review to summarize symptoms, associated factors, treatment, and outcomes in children with PVOD.
The lung samples were fixed in buffered formalin and embedded in paraffin. In addition to routine stains with hematoxylin and eosin, we also used special stains, including elastic trichrome to visualize vascular changes, stain for iron for assessment of hemosiderosis, or stains for microorganisms where indicated. Due to the small number of patients and the large variation in their clinical course, statistical analysis was not performed. This study was approved by the Research Ethics Board at the Hospital for Sick Children, Toronto, Ontario, Canada (No. 100010504).
Two patients received long-term immunosuppressive treatment (tacrolimus and tacrolimus, azathioprine and prednisone) after (nonlung) solid organ transplantation. Other risk factors, such as tobacco consumption, were not documented. One patient was taking an antidepressant drug, three patients were treated with bronchodilators (puffers), and three were not on any medications. The physical examination was unremarkable in one patient; the others presented with abnormal findings (Table 2). NYHA class at presentation ranged from I to TABLE 1
] Demographic Data of Patients With PVOD
Demographic
Variable
Age at diagnosis, alive or postmortem, mean (range), y
14.3 (10-16)
Age at diagnosis of pulmonary hypertension, mean (range), y
13.5 (8-16)
Age at onset of symptoms, mean (range), y
12.4 (7-15)
Sex, female:male
5:4
Postmortem diagnosis, No.
3
PVOD 5 pulmonary venoocclusive disease.
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169
…
9
…
1
1
…
1
1
1
1
…
Decreased Exercise Tolerance
1
1
1
1
1
1
1
1
1
Shortness of Breath
…
…
1
…
…
…
…
…
…
Syncope
…
…
1
…
…
…
…
…
1
Palpitations
…
…
…
1
…
…
1
…
…
Chronic Cough
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
1
1
1
1
0
0
1
1
0
C/PM
1
1
1
1
0
1
1
1
0
BWT
0
1
0
1
0
1
0
1
1
NLO
1
1
1
1
1
1
1
1
1
MPA
1
1
1
1
0
1
1
1
1
PAHIL
…
1
…
…
…
1
1
1
1
Loud S2
0
1
1
0
0
0
0
0
0
DV
…
…
…
…
…
…
…
1
1
RV Heave
1
1
1
0
0
1
0
1
0
MM/E
…
…
1
…
…
…
…
…
1
Murmur
0
1
1
0
0
0
0
0
0
PE
…
1
…
…
…
…
…
…
1
Elevated JVP
CM
Marked
Mild
Mild
Mild
Moderate
Mild
Marked
Moderate
92
88
87
96
93
85
90
98
98
RVH
II
III
IV
II
III
II
III
III
III
NYHA Class
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Severe
Moderate
Severe
Tc Saturation, %
Moderate
1
1
…
…
1
…
1
…
…
Crackles
BWT 5 bronchial wall/peribronchial thickening; CM 5 cardiomegaly; C/PM 5 Increased interstitial or streaky markings, central and/or abutting to the pleural surfaces; DV 5 diminished vascularity in the periphery; GGO 5 ground-glass opacity; MM/E 5 mediastinal and hilar edema or mass; MPA 5 dilated mean pulmonary artery segment; NLO 5 nodular or mottled lung opacity; PAHIL 5 dilated central pulmonary arteries at hilum; PE 5 pleural effusion; RVH 5 right ventricular hypertrophy. See Table 1 legend for expansion of other abbreviation.
1
GGO
] CT Scan Findings of Patients With PVOD
1
Patient
TABLE 3
JVP 5 jugular venous pressure; NYHA 5 New York Heart Association; RV 5 right ventricular; Tc 5 transcutaneous.
…
8
…
5
…
…
4
1
…
3
7
1
2
6
…
Chest Pain
] Symptoms and Clinical Findings of Patients at Initial Presentation
1
Patient
TABLE 2
IV (Table 2). Transcutaneous oxygen saturation ranged from 85% to 98% on room air (mean, 92%). Hypocapnia was present in 66% (n 5 6); the pH was within normal limits.
haziness of both lungs, or blurring of vessel margins suggestive of pulmonary venous hypertension in eight of nine cases. CT scan findings are summarized in Table 3 and illustrated in Figure 1.
PFTs were performed in seven patients at our institution and revealed a restrictive pattern in all cases (in one patient, the PFT was done at another hospital, and the results were not available). In all patients, the FVC and FEV1 were decreased, with a mean of 50% (range, 20%-81%) and 51% (range, 18%-81%), respectively. The diffusing capacity of the lung for carbon monoxide was reduced in the four patients tested (67%, 62%, 26%, and 83%), ranging from 5.9 mL/min/mm Hg to 14.2 mL/min/mm Hg. Five children completed a 6-min walk test with a mean distance of 263 m (range, 19-382 m).
A diagnostic cardiac catheterization with acute vasodilator testing was performed in four patients and showed elevated PAP (Table 4). During testing with pulmonary vasodilators, one patient developed acute pulmonary edema.
Eight patients had abnormal ECG findings, with frequent right-axis deviation, signs of right atrial enlargement, and right ventricular hypertrophy. Transthoracic echocardiography showed a dilated right ventricle with flattening or bowing of the interventricular septum, suggesting elevated right ventricular pressure in all patients. The estimated right ventricular systolic pressure ranged from more than one-half systemic to systemic (n 5 5) to suprasystemic (n 5 3). In one patient, only mean PAP could be estimated and exceeded 25 mm Hg. The initial chest radiograph showed a prominent pulmonary arterial segment of the left heart border in all cases and increased interstitial markings, ground-glass
Bronchoscopy with BAL was performed in only two patients and did not reveal significant findings. Four children underwent elective lung biopsy; two had samples taken from the explanted lungs at the time of transplantation, and three patients had the diagnosis of PVOD established at autopsy (Table 5). The main histologic findings included extensive changes of PVOD similar to those previously described.1,2,13,15-17 These changes were characterized by extensive and diffuse occlusion of pulmonary veins by fibrous tissue, which, in some areas, was loose and edematous, while in others it was dense and sclerotic (Fig 2A). The intimal thickening involving venules and small veins exhibited an eccentric pattern resembling organizing arterial thrombi. In most cases, the pulmonary arterioles showed moderate to severe medial thickening without plexiform lesions. In addition, several cases showed variable interstitial thickening with focal fibrosis and moderate to marked pulmonary hemosiderosis (Table 5). In the two patients who underwent solid organ transplantation, the lung biopsy specimens, in addition to
Figure 1 – Classic image findings of pulmonary venoocclusive disease in a 16-year-old patient. A, Frontal chest radiograph shows mild cardiomegaly with markedly dilated main pulmonary arterial segment of the left upper heart border due to pulmonary hypertension. Both lungs are diffusely hazy and show increased interstitial markings with blurred vessel margins. B, CT images reconstructed in axial and coronal planes show diffuse ground-glass opacity with a mosaic pattern, thickened septal lines extending to the pleura (black arrows), and peribronchial thickening (white arrows). Note that there are low density areas in the mediastinum and hila (asterisks), which represent soft tissue edema or lymphatic dilatation. Extensive edematous tissue in the posterior mediastinum is well appreciated in the coronal plane. The pulmonary arteries in the mediastinum and hila are dilated.
170 Original Research
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TABLE 4
] Hemodynamic Findings in Cardiac
Catheterization in Patients With PVODa
Patient
mPAP, mm Hg
PVRi, WU3m2
PCWP
1
50 (80/40)
18.1
7
2
42 (62/30)
11.3
3
67 (85/55)
…
4
74 (96/55)
37
3 13 8
mPAP 5 mean pulmonary artery pressure; PCWP 5 pulmonary capillary wedge pressure; PVRi 5 pulmonary vascular resistance indexed for body surface area; WU 5 Wood Units. See Table 1 legend for expansion of other abbreviation. aBaseline with 100% oxygen and inhaled nitric oxide (40 parts per million).
prominent involvement of pulmonary veins by PVOD, also showed granulomatous inflammatory changes with aggregates of multinucleated giant cells in the alveoli, alveolar septae, or both (Figs 2B, 2C). In contrast to other patients with PVOD, the pulmonary arteries in these two patients appeared relatively unaffected (Fig 2B). Special stains for acid-fast bacilli and fungal organisms were negative. These changes were interpreted as most likely representing extrinsic allergic alveolitis or a drug reaction. The therapeutic approach was heterogeneous because patients were diagnosed over a relatively long time span and had a variable clinical disease course and severity. In some, the definite diagnosis was not established prior to biopsy or autopsy. Five children received oxygen, four were started on diuretics as initial treatment, and four were treated with warfarin. The patient diagnosed with allergic alveolitis received pulse steroid therapy. In four patients, pulmonary vasodilators were added TABLE 5
(inhaled nitric oxide, sildenafil, epoprostenol) in the absence of a definitive diagnosis of PVOD, leading to acute deterioration in one, and no improvement or subacute worsening in the others. Five patients were assessed for lung transplantation and four were listed. One patient died while awaiting heartlung transplantation, and three underwent lung transplantation with waiting times of 27 to 240 days. One patient and family declined assessment for lung transplantation, and three patients were not eligible. Two of the listed patients required mechanical support. One patient was supported with extracorporeal membrane oxygenation and converted to an interventional lung assist (Novalung GmBH), and the other was semiurgently cannulated to the interventional lung assist; both underwent lung transplantation. Following lung transplantation, one patient is alive; the two deaths were related to rejection and multiorgan failure.
Discussion While there are several reports regarding adults with PVOD, to our knowledge, this is the first reported series of children with this disease. In 1934, Höra15 published findings of an adult patient followed by a detailed pathologic description emphasizing differences between “classical” pulmonary arterial hypertension and PVOD.16 Further cases were reported,17,18 including the first pediatric patient in 1967,9 and several adult case series.1,3,19 The underlying cause and the pathophysiology of PVOD remain unclear. Associations of PVOD with
] Pathology Findingsa in Patients With PVOD
Patient
PVOD
PH
Hemosiderosis
Parenchymal Disease or Other Findings
1
31
2-31
None
None
2
31
21
1-21
None
3
31
2-31
1-21
Interstitial fibrosis/DAD
4
31
21
2-31
Interstitial fibrosis, focal
5
31
31
21
Interstitial fibrosis, BOOP
6
31
11
11
Granulomatous/giant cell
7
31
21
2-31
Focal fibrosis, thrombosis
8
31
1-21
2-31
None
9
…
…
…
…
Biopsy performed
31
11
11
Granulomatous/giant cells
Explanted lung
31
11
31
Interstitial fibrosis/no giant cells
BOOP 5 bronchiolitis obliterans organizing pneumonia; DAD 5 diffuse alveolar damage; PH 5 pulmonary hypertension. See Table 1 legend for expansion of other abbreviation. aSemiquantitative histologic evaluation: 11 5 minimal to mild, 21 5 moderate, 31 5 severe.
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171
connective tissue and autoimmune diseases, HIV infection, bone marrow transplantation, sarcoidosis, and pulmonary Langerhans cell granulomatosis have been described,20-23 but were not found in the patients. Occurrence of PVOD after solid organ transplantation is most likely drug induced, not accounting for a different disease. There are case reports of affected siblings, suggesting a genetic association.10 Furthermore, mutation in bone morphogenetic protein receptor II was discovered in a patient with biopsy specimen-proven PVOD.24 Interestingly, one of the patients was diagnosed with Myrhe syndrome, a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness, and cognitive delay.14 Studies have identified mutations in SMAD4 as a cause of this syndrome.25 The patient with Myhre syndrome appears to be the first recognized case of this disorder associated with pulmonary vascular disease, specifically PVOD; a manuscript is in preparation about this case. It is of interest to note that SMAD4 plays a critical role in the BMPR2/SMAD signaling implicated in the pathogenesis of familial PH.26 Other possible risk factors include tobacco use, chemotherapy, appetite-suppressing agents, and thoracic radiation.3,27-29 Histology in two of our cases revealed prominent granulomatous inflammation suggestive of hypersensitivity reaction or drug effect, and both of these patients underwent preceding solid organ transplantation and were receiving immunosuppressive medication. We are not aware of previous reports of PVOD associated with granulomatous interstitial inflammation in this setting. The onset of the disease varies between a few months of age to the seventh decade of life; however, in the patient group, clinical signs became apparent between 8 and 16 years of age. PVOD does not appear to be sex specific,3 which is also reflected in the almost equal sex distribution in our series.
Figure 2 – Histologic images from two patients are presented. A, Low magnification view of lung biopsy specimen showing fibrous obliteration of medium size PVs as well as small peripheral pulmonary venules (arrows). A bronchovascular bundle contains normal BR and PA with thickened media. Small peripheral branches of pulmonary artery appear relatively normal (arrowheads) (Elastic trichrome). B, Low power view of lung biopsy specimen with PVs showing striking fibrous and fibrointimal proliferation causing total lumenal obliteration. In contrast, PAs are widely open. A small BR contains an aggregate of macrophages. Adjacent lung parenchyma shows interstitial thickening, congestion, and recent hemorrhage (Elastic trichrome). C, A close up view from Figure 1B showing lung parenchyma with focal aggregates of multinucleated giant
172 Original Research
Shortness of breath and decreased exercise tolerance were the major clinical signs; however, other symptoms like chronic cough, pulmonary edema, hemoptysis, and exertional syncope are also possible. The time between onset of symptoms and diagnosis varies.
cells (arrows) in interstitium and alveolar space. Note the complete obliteration of a small pulmonary venule outlined by elastic (black) and collagen (green) in the wall (Elastic trichrome). BR 5 bronchiole; GC 5 giant cell; PA 5 pulmonary artery; PV 5 pulmonary vein.
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In the adult population, it is reported as an average of 49 months30 and averaged 21 months in our cohort. Transthoracic echocardiography remains also in the pediatric population a useful tool to assess the presence of elevated right-sided pressures and exclude underlying cardiac causes. Right-sided heart catheterization provides detailed hemodynamic information (PAP, pulmonary capillary wedge pressure, and indexed pulmonary vascular resistance), and also allows pulmonary vasoreactivity testing. The triad of severe PH and radiographic pulmonary edema in the presence of a normal pulmonary artery wedge pressure is highly suggestive of PVOD and was present in the majority of the patients. Several diagnostic tools (arterial blood gas analysis, PFT, highresolution CT scan of the chest, and BAL) may help explore the underlying cause, but are not always performed in children. The gold standard for a definitive diagnosis of PVOD remains histology, but a lung biospy is invasive and often associated with a high risk in patients with PH.31,32 In our series, all patients with PFTs had decreased FEV1 and FVC, in contrast to the reports in adults.33 High-resolution CT scans often reveal three typical radiologic features: centrilobular ground-glass opacities, septal lines (interlobular septal thickening), and mediastinal lymph node enlargement.34,35 Ground-glass opacities were seen in all of the present patients; however, septal thickening and nodular/mottled lung opacities were not consistently present, underlining the difficulties in making the diagnosis by imaging alone. Interestingly, CT imaging for the diagnostic workup of pediatric patients with PH was only used in 41% of a large patient cohort, with 74% being reported as abnormal.36 Despite thorough noninvasive tests, the accurate diagnosis of PVOD was not recognized in three of the patients (30%) until postmortem examination. Especially if medical treatment of PH fails, PVOD should be strongly considered,7 as it is often misdiagnosed as
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idiopathic arterial hypertension.8 As epidemiologic data suggest, a proportion of 5% to 25% of primary PH will fulfill criteria for PVOD if fully investigated; the prevalence of only six pediatric patients (1.7%) in a large current registry37 suggests underdiagnosis of the disease. The use of pulmonary vasodilators (inhaled nitric oxide, epoprostenol, sildenafil) leads to improvement in some patients. Given the risk of pulmonary edema as a result of the relatively greater degree of vasodilatation in the precapillary vessels compared with the postcapillary vessels with resultant increased transcapillary hydrostatic pressure, this treatment avenue should be used with caution.38 Pulmonary edema may also present later despite a favorable (or uncomplicated) response during cardiac catheterization prior to initiation of therapy. Mechanical lung-assist devices might be an additional option in these situations. At present, the only therapeutic option is lung transplantation; hence, early diagnosis and assessment are crucial. Holcomb et al1 reported 72% mortality in the first year and nearly 100% within 2 years of diagnosis. In our cohort, the mean survival after diagnosis was 14 months. In conclusion, PVOD is an important differential diagnosis in children with PH and may be underdiagnosed. CT imaging is an important tool to narrow down the etiology of PH, but definitive diagnosis in most cases can only be made by histology. With small numbers of patients, variable workup, and heterogeneous nature of the disease, a multicenter registry approach may be helpful to further define disease characteristics and to evaluate treatment benefits. Currently, with limited therapeutic options and the progressive nature of the disease, the overall prognosis is very poor. However, multicenter studies of carefully titrated vasodilator therapy should be considered in the future. With the short mean survival time following diagnosis, early mechanical support and/or early listing for lung transplantation must be considered, as the average waiting time frequently exceeds the individual’s remaining lifespan. Given delay in diagnosis, clinical course, and overall outcome, early recognition of PVOD is essential.
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Acknowledgments Author contributions: T. H. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. C. W. served as principal author. C. W. and T. H. contributed to data acquisition; C. W., E. C., S.-J. Y., H. G., and T. H. contributed to data analysis and interpretation; T. H. contributed to study conception and design; C. W. contributed to the drafting of the submitted article; E. C., S.-J. Y., H. G., and T. H. contributed to the revision of the manuscript for important intellectual content; and E. C., S.-J. Y., H. G., and T. H. approved the final version. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
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