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A 63-Year-Old Woman With Neurofibromatosis Type 1 and Pulmonary Hypertension With Worsening Hypoxemia
[
Pulmonary, Critical Care, and Sleep Pearls
]
A 63-Year-Old Woman With Neurofibromatosis Type 1 and Pulmonary Hypertension With Worsening Hypoxemia Udit Chaddha, MD; Ioan Puscas, DO; Ashley Prosper, MD; Sivagini Ganesh, MD; and Bassam Yaghmour, MD
A 63-year-old woman with a history of neurofibromatosis type-1 (NF-1) and pulmonary arterial hypertension (PAH) thought to be secondary to the NF-1 presented with a few weeks of worsening dyspnea on exertion. She took no medications other than sildenafil for her pulmonary hypertension (PH). She denied tobacco, alcohol, and illicit or anorectic drug use. She had previously worked as a waitress. Her mother and her brother had NF-1 but no PH or lung disease. CHEST 2017; 152(4):e89-e93
CASE PRESENTATION:
Physical Examination Findings Her oxygen saturation was 92% on 40% FIO2 delivered by high-flow nasal cannula. Physical examination revealed scattered skin neurofibromas and some bibasilar lung crackles. Cardiac examination was significant for a loud pulmonic component of S2 and a left parasternal holosystolic murmur.
Diagnostic Studies Routine blood work was largely unremarkable. Diffuse reticular nodular opacities seen on chest radiography (Fig 1) prompted chest CT scanning, which revealed diffuse centrilobular ground-glass nodules, along with scattered small cysts and interlobular septal thickening (Fig 2). Prominent cardiomegaly and pulmonary artery enlargement were also seen. Transthoracic echocardiography demonstrated a severely dilated right atrium and ventricle with depressed right ventricular (RV) function. A pulmonary artery catheter was placed, with hemodynamic measurements demonstrating severe PAH, with a mean pulmonary artery pressure of
AFFILIATIONS: From the Division of Pulmonary, Critical Care, and Sleep Medicine (Drs Chaddha, Puscas, Ganesh, and Yaghmour), and the Department of Radiology (Dr Prosper), Keck School of Medicine of the University of Southern California, Los Angeles, CA. CORRESPONDENCE TO: Udit Chaddha, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Keck School of Medicine of the
chestjournal.org
60 mm Hg, pulmonary vascular resistance of 14 Wood units, a pulmonary capillary wedge pressure of 15 mm Hg, and a cardiac index of 2.1 L/min/m2. Vasoreactivity testing with inhaled nitric oxide was negative. The patient was prescribed dobutamine for inotropic support and IV treprostinil, in addition to the sildenafil, for the severe PAH. Titrating the treprostinil up resulted in worsening pulmonary edema and hypoxemia, with an 80% FIO2 supplemental oxygen requirement. The paradoxical response to IV vasodilator therapy with increasing pulmonary edema and the precapillary hemodynamic features made us pursue an open lung biopsy, which demonstrated moderate to severe pulmonary arteriosclerosis with arterial medial hypertrophy consistent with her PH (Fig 3). The biopsy also revealed several areas of alveolar capillary engorgement and tortuosity confirmed with CD31 immunostaining (Fig 4).
University of Southern California, 2020 Zonal Ave, Los Angeles, CA 90033; e-mail: [email protected] Copyright Ó 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2017.05.014
e89
Figure 1 – Portable chest radiograph demonstrating diffuse faint reticular nodular opacities throughout the lung parenchyma, cardiomegaly, and an enlarged main pulmonary artery. Also seen is a peripherally inserted central catheter in the right arm.
Figure 3 – H&E staining of lung biopsy sample reveals arterial hypertrophy (white arrows).
Figure 2 – A, B, Axial (A) and coronal (B) CT section demonstrating scattered centrilobular ground-glass nodules and small cysts.
e90 Pulmonary, Critical Care, and Sleep Pearls
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152#4 CHEST OCTOBER 2017
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Figure 4 – A, B, H&E (A) and CD31 endothelial marker (B) staining demonstrating areas of capillary hemangiomatosis (white arrows).
What is the diagnosis?
chestjournal.org
e91
Diagnosis: Pulmonary capillary hemangiomatosis Discussion Pulmonary capillary hemangiomatosis (PCH) is a rare condition first described by Wagenvoort in 1978, characterized by a multilayer thin-walled microvessel proliferation and capillary infiltration into the peribronchial and perivascular interstitium, the parenchyma, and the pleura, that masquerades as PAH. PCH occurs with equal frequency among men and women, with published reports in infants as well as persons up to 70 years old. Most cases are sporadic, and there are no clearly identified risk factors. Association with conditions like connective tissue diseases has been occasionally reported. To the best of our knowledge, there have been no previous reports of an association between PCH and NF-1. In 1988, Langleban first described a familial form of PCH. In 2013, EIF2AK4 mutations were described separately in patients with PCH and pulmonary venoocclusive disease (PVOD). Thus, it is important to offer genetic testing and counseling to family members of patients with PCH to allow earlier detection and intervention. Capillary infiltration of surrounding vessels and tissue distinguishes PCH from another closely related condition, PVOD. Endothelial cell markers such as CD31 or CD34 help highlight the proliferative capillary endothelial cells. The secondary venoocclusion from capillary invasion into vein walls causes the PH in PCH. Pulmonary arteries often show intimal thickening and medial hypertrophy. PCH manifests as PH, with an indolent onset of signs and symptoms slowly progressing to cor pulmonale. Signs and symptoms, such as progressive dyspnea, hypoxemia, and RV dysfunction, are nonspecific and indistinguishable from other causes of PH, although hemoptysis and hemorrhagic pleural effusions are more commonly reported in this population and are thought to result from hemorrhage due to the fragile capillary walls. CT imaging findings are diffuse, generally spare the periphery, and include thickened subpleural septal lines, mediastinal adenopathy, and nodular centrilobular ground-glass opacities (as capillary proliferation is centered around bronchovascular bundles). The presence of this triad should heighten the suspicion for this entity in patients with PAH. Other imaging changes consistent with PH, such as pulmonary artery and
e92 Pulmonary, Critical Care, and Sleep Pearls
right-sided heart enlargement, are also seen. The cysts seen in the patient were possibly a consequence of her NF-1. Pulmonary artery hemodynamics in PCH are indistinguishable from the precapillary hemodynamics of other causes of PAH. In general, these patients are comparatively more hypoxemic and have lower diffusion capacity of the lung for carbon monoxide (DLCO), likely from capillary proliferation-related alveolar septal filling and vascular narrowing. The striking clinical, radiographic, hemodynamic, and histologic similarities between PCH and PVOD and the recent discovery of the EIF2AK4 mutation in both entities has raised questions about whether they represent different points on the spectrum of the same disease and has led to their grouping into the same PH subclass—group 1. Histologic changes are not always limited to the veins in PVOD or to the capillaries in PCH. Although the diagnosis of both entities often requires histopathologic confirmation, a surgical biopsy is not always feasible. There are a few reports of PCH diagnosed with transbronchial biopsy; given its patchy nature, if pursued, multiple biopsy samples should be taken. In the setting of PAH with worsening hypoxemia and pulmonary edema after the initiation of vasodilator therapy, with specific physiological (lower than expected DLCO), radiological (typical CT findings), or genetic testing (EIF2AK4 mutations) findings, PCH or PVOD can be diagnosed without performing a biopsy. Lung transplantation is considered the only definitive treatment, with at least one published case of recurrence after transplantation. Pulmonary vasodilators have, by and large, been reported to cause worsening often catastrophic hypoxemia from pulmonary edema, presumably from increased perfusion in the presence of downstream vascular occlusion. However, there have also been patients who seemed to have benefited from vasodilator therapy. Thus, vasodilators can be used in PCH but with a high degree of caution. The rationale for the variability in vasodilator tolerance remains speculative. Survival beyond 5 years is rare, with a reported median survival of about 3 years. Death occurs from progression to cor pulmonale and, eventually, to RV failure and cardiovascular collapse.
Clinical Course The patient in our study was weaned from IV vasodilator therapy with a dramatic improvement in her
[
152#4 CHEST OCTOBER 2017
]
oxygen saturation, after which she only required oxygen delivered by a simple nasal cannula. She continued to require dobutamine for RV inotropy. Cardiac MRI demonstrated severe RV dilatation and hypertrophy and an RV ejection fraction of 21%.
3. In patients undergoing pulmonary artery catheterization, the findings of pulmonary hypertension with precapillary hemodynamics and clinical worsening with vasoreactivity testing should alert the clinician to the possibility of PCH/PVOD.
Although her oxygen requirement had decreased, her pulmonary reserve was still low, and she would become desaturated on walking just a few steps. She was also maintained on digoxin and low doses of diuretics.
4. Lung transplantation is considered the only definitive therapy for PCH. Vasodilators should generally be avoided because of the well-reported paradoxical response of worsening pulmonary edema with their use. However, their successful use, with caution, has been reported in a few cases.
Given her advanced disease, she was considered for transplantation. Our center does not perform combined heart-lung transplantations, and due to her poor RV function she was not considered a candidate for isolated lung transplantation. Her medical records were forwarded to other regional centers for consideration of combined heart-lung transplantation; however, we were unable to find a center willing to perform the transplantation. Although her condition remained unchanged, her poor functional and oxygen status and her dependence on inotropic agents meant that her quality of life remained poor. After extensive discussions with the palliative care team, she reassessed her goals of care and elected to go home to spend time in a more familiar environment. She continued to be in good spirits for a short time after discharge but eventually died of her progressive cor pulmonale 3 months after discharge.
Clinical Pearls 1. A diagnosis of PCH should be considered in patients with PAH who have worsening hypoxemia and pulmonary edema after the initiation of vasodilator therapy and a radiographic pattern of centrilobular ground-glass nodules, subpleural septal lines, and mediastinal lymphadenopathy. Although testing for specific genetic mutations (EIF2AK4) can be considered, histopathologic confirmation with a lung biopsy is often necessary. 2. In addition to typical signs and symptoms of PAH, patients with PCH may present with a constellation of clinical findings, including hemoptysis, hemorrhagic pleural effusions, and a lower than expected DLCO.
chestjournal.org
Acknowledgments Financial/nonfinancial disclosures: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Reading Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. Havlik DM, Massie LW, Williams WL, Crooks LA. Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases. Am J Clin Pathol. 2000;113(5):655-662. Almagro P, Julià J, Sanjaume M, et al. Pulmonary capillary hemangiomatosis associated with primary pulmonary hypertension: report of 2 new cases and review of 35 cases from the literature. Medicine (Baltimore). 2002;81(6):417-424. 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. Lee C, Suh RD, Krishnam MS, et al. Recurrent pulmonary capillary hemangiomatosis after bilateral lung transplantation. J Thorac Imaging. 2010;25(3):W89-W92. Ogawa A, Miyaji K, Yamadori I, et al. Safety and efficacy of epoprostenol therapy in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Circ J. 2012;76(7):1729-1736. O’Keefe MC, Post MD. Pulmonary capillary hemangiomatosis: a rare cause of pulmonary hypertension. Arch Pathol Lab Med. 2015;139(2): 274-277. Galiè N, Humbert M, Vachiery JL, et al. 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). Eur Respir J. 2015;46(4):903-975. Chaisson NF, Dodson MW, Elliott CG. Pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease. Clin Chest Med. 2016;37(3):523-534.
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Pulmonary, Critical Care, and Sleep Pearls
]
A 63-Year-Old Woman With Neurofibromatosis Type 1 and Pulmonary Hypertension With Worsening Hypoxemia Udit Chaddha, MD; Ioan Puscas, DO; Ashley Prosper, MD; Sivagini Ganesh, MD; and Bassam Yaghmour, MD
A 63-year-old woman with a history of neurofibromatosis type-1 (NF-1) and pulmonary arterial hypertension (PAH) thought to be secondary to the NF-1 presented with a few weeks of worsening dyspnea on exertion. She took no medications other than sildenafil for her pulmonary hypertension (PH). She denied tobacco, alcohol, and illicit or anorectic drug use. She had previously worked as a waitress. Her mother and her brother had NF-1 but no PH or lung disease. CHEST 2017; 152(4):e89-e93
CASE PRESENTATION:
Physical Examination Findings Her oxygen saturation was 92% on 40% FIO2 delivered by high-flow nasal cannula. Physical examination revealed scattered skin neurofibromas and some bibasilar lung crackles. Cardiac examination was significant for a loud pulmonic component of S2 and a left parasternal holosystolic murmur.
Diagnostic Studies Routine blood work was largely unremarkable. Diffuse reticular nodular opacities seen on chest radiography (Fig 1) prompted chest CT scanning, which revealed diffuse centrilobular ground-glass nodules, along with scattered small cysts and interlobular septal thickening (Fig 2). Prominent cardiomegaly and pulmonary artery enlargement were also seen. Transthoracic echocardiography demonstrated a severely dilated right atrium and ventricle with depressed right ventricular (RV) function. A pulmonary artery catheter was placed, with hemodynamic measurements demonstrating severe PAH, with a mean pulmonary artery pressure of
AFFILIATIONS: From the Division of Pulmonary, Critical Care, and Sleep Medicine (Drs Chaddha, Puscas, Ganesh, and Yaghmour), and the Department of Radiology (Dr Prosper), Keck School of Medicine of the University of Southern California, Los Angeles, CA. CORRESPONDENCE TO: Udit Chaddha, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Keck School of Medicine of the
chestjournal.org
60 mm Hg, pulmonary vascular resistance of 14 Wood units, a pulmonary capillary wedge pressure of 15 mm Hg, and a cardiac index of 2.1 L/min/m2. Vasoreactivity testing with inhaled nitric oxide was negative. The patient was prescribed dobutamine for inotropic support and IV treprostinil, in addition to the sildenafil, for the severe PAH. Titrating the treprostinil up resulted in worsening pulmonary edema and hypoxemia, with an 80% FIO2 supplemental oxygen requirement. The paradoxical response to IV vasodilator therapy with increasing pulmonary edema and the precapillary hemodynamic features made us pursue an open lung biopsy, which demonstrated moderate to severe pulmonary arteriosclerosis with arterial medial hypertrophy consistent with her PH (Fig 3). The biopsy also revealed several areas of alveolar capillary engorgement and tortuosity confirmed with CD31 immunostaining (Fig 4).
University of Southern California, 2020 Zonal Ave, Los Angeles, CA 90033; e-mail: [email protected] Copyright Ó 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2017.05.014
e89
Figure 1 – Portable chest radiograph demonstrating diffuse faint reticular nodular opacities throughout the lung parenchyma, cardiomegaly, and an enlarged main pulmonary artery. Also seen is a peripherally inserted central catheter in the right arm.
Figure 3 – H&E staining of lung biopsy sample reveals arterial hypertrophy (white arrows).
Figure 2 – A, B, Axial (A) and coronal (B) CT section demonstrating scattered centrilobular ground-glass nodules and small cysts.
e90 Pulmonary, Critical Care, and Sleep Pearls
[
152#4 CHEST OCTOBER 2017
]
Figure 4 – A, B, H&E (A) and CD31 endothelial marker (B) staining demonstrating areas of capillary hemangiomatosis (white arrows).
What is the diagnosis?
chestjournal.org
e91
Diagnosis: Pulmonary capillary hemangiomatosis Discussion Pulmonary capillary hemangiomatosis (PCH) is a rare condition first described by Wagenvoort in 1978, characterized by a multilayer thin-walled microvessel proliferation and capillary infiltration into the peribronchial and perivascular interstitium, the parenchyma, and the pleura, that masquerades as PAH. PCH occurs with equal frequency among men and women, with published reports in infants as well as persons up to 70 years old. Most cases are sporadic, and there are no clearly identified risk factors. Association with conditions like connective tissue diseases has been occasionally reported. To the best of our knowledge, there have been no previous reports of an association between PCH and NF-1. In 1988, Langleban first described a familial form of PCH. In 2013, EIF2AK4 mutations were described separately in patients with PCH and pulmonary venoocclusive disease (PVOD). Thus, it is important to offer genetic testing and counseling to family members of patients with PCH to allow earlier detection and intervention. Capillary infiltration of surrounding vessels and tissue distinguishes PCH from another closely related condition, PVOD. Endothelial cell markers such as CD31 or CD34 help highlight the proliferative capillary endothelial cells. The secondary venoocclusion from capillary invasion into vein walls causes the PH in PCH. Pulmonary arteries often show intimal thickening and medial hypertrophy. PCH manifests as PH, with an indolent onset of signs and symptoms slowly progressing to cor pulmonale. Signs and symptoms, such as progressive dyspnea, hypoxemia, and RV dysfunction, are nonspecific and indistinguishable from other causes of PH, although hemoptysis and hemorrhagic pleural effusions are more commonly reported in this population and are thought to result from hemorrhage due to the fragile capillary walls. CT imaging findings are diffuse, generally spare the periphery, and include thickened subpleural septal lines, mediastinal adenopathy, and nodular centrilobular ground-glass opacities (as capillary proliferation is centered around bronchovascular bundles). The presence of this triad should heighten the suspicion for this entity in patients with PAH. Other imaging changes consistent with PH, such as pulmonary artery and
e92 Pulmonary, Critical Care, and Sleep Pearls
right-sided heart enlargement, are also seen. The cysts seen in the patient were possibly a consequence of her NF-1. Pulmonary artery hemodynamics in PCH are indistinguishable from the precapillary hemodynamics of other causes of PAH. In general, these patients are comparatively more hypoxemic and have lower diffusion capacity of the lung for carbon monoxide (DLCO), likely from capillary proliferation-related alveolar septal filling and vascular narrowing. The striking clinical, radiographic, hemodynamic, and histologic similarities between PCH and PVOD and the recent discovery of the EIF2AK4 mutation in both entities has raised questions about whether they represent different points on the spectrum of the same disease and has led to their grouping into the same PH subclass—group 1. Histologic changes are not always limited to the veins in PVOD or to the capillaries in PCH. Although the diagnosis of both entities often requires histopathologic confirmation, a surgical biopsy is not always feasible. There are a few reports of PCH diagnosed with transbronchial biopsy; given its patchy nature, if pursued, multiple biopsy samples should be taken. In the setting of PAH with worsening hypoxemia and pulmonary edema after the initiation of vasodilator therapy, with specific physiological (lower than expected DLCO), radiological (typical CT findings), or genetic testing (EIF2AK4 mutations) findings, PCH or PVOD can be diagnosed without performing a biopsy. Lung transplantation is considered the only definitive treatment, with at least one published case of recurrence after transplantation. Pulmonary vasodilators have, by and large, been reported to cause worsening often catastrophic hypoxemia from pulmonary edema, presumably from increased perfusion in the presence of downstream vascular occlusion. However, there have also been patients who seemed to have benefited from vasodilator therapy. Thus, vasodilators can be used in PCH but with a high degree of caution. The rationale for the variability in vasodilator tolerance remains speculative. Survival beyond 5 years is rare, with a reported median survival of about 3 years. Death occurs from progression to cor pulmonale and, eventually, to RV failure and cardiovascular collapse.
Clinical Course The patient in our study was weaned from IV vasodilator therapy with a dramatic improvement in her
[
152#4 CHEST OCTOBER 2017
]
oxygen saturation, after which she only required oxygen delivered by a simple nasal cannula. She continued to require dobutamine for RV inotropy. Cardiac MRI demonstrated severe RV dilatation and hypertrophy and an RV ejection fraction of 21%.
3. In patients undergoing pulmonary artery catheterization, the findings of pulmonary hypertension with precapillary hemodynamics and clinical worsening with vasoreactivity testing should alert the clinician to the possibility of PCH/PVOD.
Although her oxygen requirement had decreased, her pulmonary reserve was still low, and she would become desaturated on walking just a few steps. She was also maintained on digoxin and low doses of diuretics.
4. Lung transplantation is considered the only definitive therapy for PCH. Vasodilators should generally be avoided because of the well-reported paradoxical response of worsening pulmonary edema with their use. However, their successful use, with caution, has been reported in a few cases.
Given her advanced disease, she was considered for transplantation. Our center does not perform combined heart-lung transplantations, and due to her poor RV function she was not considered a candidate for isolated lung transplantation. Her medical records were forwarded to other regional centers for consideration of combined heart-lung transplantation; however, we were unable to find a center willing to perform the transplantation. Although her condition remained unchanged, her poor functional and oxygen status and her dependence on inotropic agents meant that her quality of life remained poor. After extensive discussions with the palliative care team, she reassessed her goals of care and elected to go home to spend time in a more familiar environment. She continued to be in good spirits for a short time after discharge but eventually died of her progressive cor pulmonale 3 months after discharge.
Clinical Pearls 1. A diagnosis of PCH should be considered in patients with PAH who have worsening hypoxemia and pulmonary edema after the initiation of vasodilator therapy and a radiographic pattern of centrilobular ground-glass nodules, subpleural septal lines, and mediastinal lymphadenopathy. Although testing for specific genetic mutations (EIF2AK4) can be considered, histopathologic confirmation with a lung biopsy is often necessary. 2. In addition to typical signs and symptoms of PAH, patients with PCH may present with a constellation of clinical findings, including hemoptysis, hemorrhagic pleural effusions, and a lower than expected DLCO.
chestjournal.org
Acknowledgments Financial/nonfinancial disclosures: None declared. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Reading Langleben D, Heneghan JM, Batten AP, et al. Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med. 1988;109(2):106-109. Havlik DM, Massie LW, Williams WL, Crooks LA. Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases. Am J Clin Pathol. 2000;113(5):655-662. Almagro P, Julià J, Sanjaume M, et al. Pulmonary capillary hemangiomatosis associated with primary pulmonary hypertension: report of 2 new cases and review of 35 cases from the literature. Medicine (Baltimore). 2002;81(6):417-424. 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. Lee C, Suh RD, Krishnam MS, et al. Recurrent pulmonary capillary hemangiomatosis after bilateral lung transplantation. J Thorac Imaging. 2010;25(3):W89-W92. Ogawa A, Miyaji K, Yamadori I, et al. Safety and efficacy of epoprostenol therapy in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Circ J. 2012;76(7):1729-1736. O’Keefe MC, Post MD. Pulmonary capillary hemangiomatosis: a rare cause of pulmonary hypertension. Arch Pathol Lab Med. 2015;139(2): 274-277. Galiè N, Humbert M, Vachiery JL, et al. 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). Eur Respir J. 2015;46(4):903-975. Chaisson NF, Dodson MW, Elliott CG. Pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease. Clin Chest Med. 2016;37(3):523-534.
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