Clinical and Hemodynamic Responses to Imatinib in Pulmonary Veno-Occlusive Disease/Pulmonary Capillary Hemangiomatosis: A Retrospective Pilot Study of Five Cases and Review of the Literature.

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are rare types of pulmonary arterial hypertension with dismal prognoses; there is no established medical treatment for these conditions. Possible efficacy of imatinib against these conditions has been reported in 15 cases; however, how and in whom imatinib is effective remain unknown. METHODS: We retrospectively evaluated clinical data from consecutive patients with PVOD/PCH treated with imatinib at our institution. The diagnosis of PVOD/PCH was established using the following criteria: pre-capillary pulmonary hypertension; diffusion capacity of the lung for carbon monoxide < 60%; and two or more high-resolution computed tomography findings of interlobular septal thickening, centrilobular opacities, and mediastinal lymphadenopathy. The dose of pulmonary vasodilators remained unchanged during the assessment of imatinib. RESULTS: The medical records of five patients with PVOD/PCH were reviewed. The patients were aged 67 ± 13 years, their diffusion capacity of the lung for carbon monoxide was 29 ± 8%, and their mean pulmonary artery pressure was 40 ± 7 mmHg. Imatinib was administered at 50-100 mg/day; consequently, the World Health Organization functional class improved in one patient. In addition, imatinib improved the arterial oxygen partial pressure in this and another patient (these two also experienced a decreased mean pulmonary artery pressure and pulmonary vascular resistance after imatinib usage). CONCLUSIONS: This study indicated that imatinib improves the clinical condition, including pulmonary hemodynamics, of some patients with PVOD/PCH. In addition, patients with a certain high-resolution computed tomography pattern or PCH-dominant vasculopathy may respond favorably to imatinib.

A case of glucocorticoid-resistant adult Still's disease complicated by pulmonary hypertension and interstitial lung disease.

Adult Still's disease (ASD) is rarely complicated by pulmonary hypertension (PH). A 76-year-old woman experienced ASD relapse with repeated exacerbation of PH and interstitial lung disease. Although she had been treated with immunosuppressive agents and pulmonary vasodilators, the ASD relapsed with fever, rash, increased inflammatory responses and exacerbated interstitial lung disease, and PH. The pathology of PH appeared to encompass groups 1 [pulmonary arterial hypertension (PAH)], 1' [pulmonary veno-occlusive disease (PVOD)], and 3. Remission induction therapy with high-dose glucocorticoid and tocilizumab was administered, and switching or adding pulmonary vasodilators was also attempted. As the disease activity of ASD decreased, the mean pulmonary arterial pressure and pulmonary vascular resistance improved. PH is an extremely rare form of organ dysfunction in individuals with ASD. Like other systemic autoimmune diseases, PH (PAH or PVOD) can determine the prognosis of ASD. Because of PH's rarity, it is important to sufficiently evaluate its pathology, considering the possibility that PH is not clinically classified as PAH (group 1), and to administer immunosuppressive therapy and vasodilators according to the pathology.

Good response to pulmonary arterial hypertension-targeted therapy in 2 pulmonary veno-occlusive disease patients: A case report.

RATIONALE: Pulmonary veno-occlusive disease (PVOD) is a kind of rare and fatal pulmonary arterial hypertension (PAH). Different from other subtypes of PAH, PVOD patients have a very poor prognosis because of the progressive nature of pulmonary vascular involvement and fatal pulmonary edema induced by PAH-targeted drugs. Lung transplantation is the only choice for these patients. PATIENT CONCERNS: We reported 2 cases of PVOD which was misdiagnosed as idiopathic pulmonary arterial hypertension initially due to the lack of typical findings of PVOD. Right heart catheterization was done. The results showed severe PAH with mean pulmonary artery pressure at 76 mmHg and 68 mmHg. DIAGNOSIS: The diagnosis of idiopathic pulmonary arterial hypertension was corrected by eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) mutation screening. Biallelic mutations (c.1387delT (p. Arg463fs); c.989-990 delAA (p. Lys330fs)) were detected by next-generation sequencing for whole exome from blood sample. The presence of biallelic EIF2AK4 mutation was sufficient to confirm the diagnosis of PVOD. INTERVENTIONS: The 2 patients had good response to PAH-targeted therapy (Ambrisentan 10 mg once a day and tadalafil 20 mg once a day) in the following 1 year. OUTCOMES: Because the patients had a good response to targeted drugs, the treatment of the 2 cases was unchanged. Over 1-year period, they still have a good response to PAH-targeted drugs. There was no sign of pulmonary edema. LESSONS: All these results may indicate that PVOD is not so rare and typical findings of PVOD are lacking in some patients. EIF2AK4 mutation screening by next-generation sequencing maybe useful to differentiate PVOD from other PAH subtypes. PVOD is a heterogeneity population and different patients have different characteristics including response to PAH-targeted therapy. How to pick off this portion of patients timely is the core issue. Further study is necessary to answer this question.

GCN2 Regulates ATF3-p38 MAPK Signaling Transduction in Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a fatal disease of pulmonary vascular lesions leading to right heart failure. Heritable PVOD (hPVOD) is related to biallelic mutation of EIF2AK4 (encoding GCN2), but its molecular mechanism remains unclear. In this study, we aimed to investigate the pathogenesis of PVOD and to find potential drug targets for PVOD. GCN2 dysfunction led to an enhanced transcription of collagen I gene (col1a1 and col1a2) through decreasing ATF3-dependent p38 phosphorylation inhibition in PVOD, which promotes the collagen I synthesis in pulmonary arterial smooth muscle cells (PASMCs) and eventually leads to increased collagen deposition in pulmonary artery. Four GCN2 knockout (KO) cell lines (exon 15 or 33 mutation) were successfully constructed by epiCRISPR system. Two induced pluripotent stem cells (iPSCs) were generated by reprogramming peripheral blood mononuclear cells (PBMCs) of PVOD patient. It was also comfirmed that GCN2 dysfunction could lead to increased expression of collagen I in lateral plate mesoderm lineage-smooth muscle cells (LM-SMCs) differentiated from both GCN2 KO cell lines and iPSCs. SB203580 (a specific inhibitor of p38) improved hemodynamics and pulmonary vascular remodeling in mitomycin C (MMC)-induced PVOD rats by right ventricle echocardiography. On the whole, we proposed that GCN2 deficiency decreased ATF3-dependent p38 phosphorylation inhibition in PVOD development and suggested a potential therapeutic reagent of SB203580 for the treatment of the disease.

Targeted therapy in pulmonary veno-occlusive disease: time for a rethink?

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) is a rare condition with poor prognosis, and lung transplantation is recommended as the only curative therapy. The role of pulmonary arterial hypertension targeted therapy in PVOD remains controversial, and long-term effects of targeted therapy have been rarely reported. This study aims to retrospectively evaluate the role of targeted therapy in PVOD patients and the long-term outcome. METHODS: PVOD patients with good responses to targeted therapies were analyzed, and data pre- and post- targeted therapies were compared. An overview of the effects of targeted therapies on PVOD patients was also conducted. RESULTS: Five genetically or histologically confirmed PVOD patients received targeted therapies and showed good responses. Their mean pulmonary arterial pressure by right heart catheterization was 62.0 ± 11.7 mmHg. Two receiving monotherapy got stabilized, and three receiving sequential combination therapy got improved, cardiac function and exercise capacity significantly improved after treatments. No pulmonary edema occurred. The mean time from the first targeted therapy to the last follow up was 39.3 months, and the longest was 9 years. A systematic review regarding the effects of targeted therapies on PVOD patients indicated majorities of patients got hemodynamics or 6-min walk distance improved, and 26.7% patients developed pulmonary edema. The interval from targeted drugs use to death ranged from 71 min to over 4 years. CONCLUSIONS: Cautious use of targeted therapy could safely and effectively improve or stabilize hemodynamics and exercise capacity of some patients without any complications. PVOD patients could live longer than expected.

Beneficial Effects of Imatinib in a Patient with Suspected Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH). The prognosis of PVOD patients remains poor, since no effective medical therapy is yet available. Imatinib is a tyrosine kinase inhibitor specific for platelet-derived growth factor receptor and is expected as a treatment option for pulmonary arterial hypertension (PAH). Recently, it has been reported that imatinib improved functional capacity of a patient with PVOD. We here report a patient with suspected PVOD who has been successfully treated with imatinib and is alive for 6 years after diagnosis. A 57-year-old woman was admitted to a hospital for severe dyspnea. Echocardiography suggested the presence of PH, because tricuspid regurgitation pressure gradient was elevated. The patient was then transferred to our hospital by an ambulance ahead of schedule due to fever and worsening dyspnea. Because the patient had no left heart disease, we diagnosed that she had PAH associated with severe right heart failure. We immediately started treatment with nitric oxide (NO) for her severe hypoxia; however, it caused pulmonary edema. We suspected PVOD from CT characteristics and pulmonary edema after PAH-targeted vasodilator therapy, and then started oral imatinib treatment. In response to imatinib, her pulmonary edema gradually improved. Since then, the patient has been alive for 6 years with imatinib and pulmonary vasodilators. At present, lung transplantation is the only effective therapy for PVOD with limited availability. We therefore propose that imatinib may be a treatment option for PVOD and a bridge to lung transplantation.

Use of vasodilators for the treatment of pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: A systematic review.

BACKGROUND: There are several medications available to treat pulmonary arterial hypertension (PAH): PAH-targeted drugs. However, in patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD/PCH), rare diseases that cause pulmonary hypertension, the effectiveness and safety of vasodilators, including PAH-targeted drugs, are unclear. METHODS: We searched English-language publications listed in three electronic databases (PubMed, Cochrane Library, and the Japan Medical Abstracts Society). Reports with efficacy outcomes (survival, improvement in 6-minute walk distance, and pulmonary vascular resistance) and data on development of pulmonary edema after administration of vasodilators to patients with PVOD/PCH were selected (1966 to August 2015). RESULTS: We identified 20 reports that met our criteria. No randomized controlled or prospective controlled studies were reported. The survival time ranged from 71 minutes to 4 years or more after initiation of vasodilators. Most of the reported cases showed an improvement in the 6-minute walk distance and pulmonary vascular resistance. Pulmonary edema was reported in 15 articles, some cases of which were lethal. CONCLUSIONS: The present study demonstrates the potential efficacy and difficulties in the use of vasodilators in patients with PVOD/PCH; however, drawing a firm conclusion was difficult because of the lack of randomized controlled trials. Further research is needed to ascertain if vasodilator use is beneficial and safe in patients with PVOD/PCH.

Good response to PAH-targeted drugs in a PVOD patient carrying Biallelic EIF2AK4 mutation.

Pulmonary veno-occlusive disease (PVOD) is a rare and fatal cause of pulmonary arterial hypertension (PAH). Different from other types of PAH, PVOD patients have a dismal prognosis because of the progressive nature of pulmonary vascular involvement and fatal pulmonary edema induced by PAH-targeted drugs. Lung transplantation is the only choice for these patients. In a recent article published in the journal, Yang and his colleagues found pulmonary edema was not demonstrated in 2 of the 6 PVOD patients injected with prostacyclin analogues (a kind of PAH-targeted drug). Regretfully, none of these 6 patients underwent microscopic examination of lung tissues. Here, we reported a sporadic PVOD patient evidenced by pathology and EIF2AK4 biallelic mutation. The patient was followed over the course of 3 years in our center. During the 3 years, he was admitted into our hospital for many times for the acute exacerbation of pulmonary hypertension. However, after treatment with many kinds of PAH-targeted drugs, the pulmonary hypertension was in control and he feel better every time. The present patient displayed different treatment response comparing with previous reports. It suggests that PVOD is a heterogeneity population and different patients have different characteristics including clinical manifestation, genomics, treatment response et al. How to pick off this portion of patients timely is the core issue. Lots of important works are necessary to answer this question. However, we can see a glimmer of hope form this patient at least.

A 77-Year-Old Woman With Acute Shortness of Breath and Chest Pain.

CASE PRESENTATION: A 77-year-old woman presented to the hospital with symptoms of progressive shortness of breath with associated right-sided pleuritic pain. The patient had begun noting dyspnea on exertion, limiting her ability to go on hikes over the few days prior to admission. Her medical history is significant for carcinoid tumor status postresection in 2012 without recurrence. She has no history of thromboembolism or clotting disorders, and she has no history of smoking or drug abuse. Current medications include amlodipine, celecoxib, hydrochlorothiazide, and rosuvastatin.

Efficacy and safety of long-term imatinib therapy for patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are categorized as Group 1' in the clinical classification of pulmonary hypertension. No medical therapy has been proven to be effective in patients with PVOD/PCH. Imatinib is a molecular targeted drug and was expected to be effective in patients with pulmonary arterial hypertension. We evaluated its efficacy and safety in patients with PVOD/PCH. METHODS: In the present observational study, 9 patients with PVOD/PCH received imatinib. Clinical data including exercise capacity and hemodynamics at baseline and at follow-up were compared. Survival rate of patients treated with imatinib was compared to those of 7 patients who did not treated with imatinib. RESULTS: Imatinib was prescribed at doses of 100-400 mg/day and was well-tolerated. At follow-up, World Health Organization functional class and brain natriuretic peptide levels significantly improved. Mean pulmonary arterial pressure was significantly reduced (from 56.8 ± 8.3 to 43.7 ± 9.0 mmHg) with preserved cardiac index. Patients were treated with imatinib for 797.2 ± 487.0 days. Seven patients (77.8%) died and 2 patients (22.2%) underwent lung transplantation. Mean survival time in patients treated with imatinib therapy was 1493.7 ± 196.3 days (95% confidence interval, 1108.9-1878.5 days), significantly longer than those without imatinib treatment (713.0 ± 258.1 days, log-rank test, P = 0.04). CONCLUSIONS: Imatinib improved exercise capacity, hemodynamics and survival in patients with PVOD/PCH. In patients with PVOD/PCH, who have no effective medical therapy available, imatinib might function as a bridge to lung transplantation, and may become a potential therapeutic option to improve their survival.

Experiencia única con macitentán y sildenafilo en el tratamiento de la enfermedad venooclusiva pulmonar / The first experience of pulmonary veno-occlusive disease treatment with macitentan and sildenafil

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A case report of PVOD patient combined with pulmonary embolism: Anticoagulation or not?

RATIONALE: Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH). Oral anticoagulation is confined to patients with idiopathic PAH (IPAH), but no oral anticoagulation has been recommended for PVOD, because occult pulmonary hemorrhage was a common finding in PVOD. PATIENT CONCERNS: We report a case of PVOD, who was misdiagnosed as IPAH for 5 years with worsening dyspnea and two episodes of pulmonary embolism (PE). DIAGNOSES: He was confirmed as PVOD combined with PE by biopsy of the explanted lung specimen. INTERVENTIONS: He took oral anticoagulation, warfarin, to treat his first-time PE in July 2010, and his disease was kept stable for about 4 years, until he discontinued the anticoagulation therapy by himself sometime in 2014. Later on, a life-threatening PE recurred in January 2015, so he resumed the anticoagulation therapy. OUTCOMES: Fortunately, the bilateral sequential lung transplantation that was performed in July 2015 in time saved his life. He has been living well without dyspnea and the echocardiography showed the normalizations of the once increased pulmonary arterial pressure and the once enlarged right ventricle of his heart. In addition, to the best of my knowledge, he was the first PVOD patient receiving lung transplantation in China. LESSONS: We recommend that PVOD patients combined with PE should be treated with anticoagulation therapy indefinitely to prevent the recurrence of life-threatening PE until they get a chance for lung transplantation.

Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience.

BACKGROUND: X-linked hyper-IgM syndrome (X-HIGM) due to mutations in the gene encoding CD40 ligand results in failure of Ig class switching and an increased propensity for recurrent sinopulmonary and other infections, and thus decreased life expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is curative, but long-term follow-up data are limited. PROCEDURES: We conducted a retrospective analysis of seven patients who have undergone allogeneic HSCT for HIGM syndrome at Duke University Medical Center. RESULTS: Median age at transplant was 5.2 years (range 0.7-19.3). None of the patients had active hepatic or pulmonary disease immediately prior to transplant, but all had a history of serious infections. Five patients received myeloablative conditioning, and two patients received reduced intensity conditioning. Graft sources included bone marrow, peripheral blood, and unrelated umbilical cord blood. Post-transplantation complications included veno-occlusive disease, hemorrhagic cystitis, adenoviremia, and cryptosporidium recurrence in one patient each. Two patients developed acute GVHD grades II-IV that resolved promptly with treatment and none developed extensive chronic GVHD. All patients are intravenous IgG-independent and 6/7 have normal antibody titers. Immunoglobulin (Ig) A levels normalized in all but one patient and T and B cell numbers and function are otherwise normal in all. All patients are alive at a median follow-up of 9.7 (range 9.7-16.1) years post-transplantation with predominantly donor chimerism and no recurrent infections. CONCLUSIONS: Allogeneic HSCT results in excellent survival and sustained immune reconstitution in patients with CD40 ligand deficiency using both myeloablative and reduced intensity conditioning approaches and various graft sources, including bone marrow, peripheral blood, and umbilical cord blood.