Diagnosis Of Pulmonary Veno-occlusive Disease Research Articles

First genetic characteristics of Polish patients with idiopathic pulmonary arterial hypertension

Abstract Introduction Pulmonary arterial hypertension (PAH) is a rare, severe disorder of multifactorial origin. Genetic alterations in BMP/SMAD pathways were previously associated with disease development, however the exact role of other genetic factors from BMP/SMAD signalling is still unclear. Purpose We aimed to search for known PAH-associated mutations and potential novel variants responsible for disease onset in Polish PAH patients. Methods We prospectively recruited 93 consecutive idiopathic PAH patients from a single pulmonary hypertension reference centre between years 2009 and 2020. Eligible patients had pre-capillary pulmonary hypertension with pulmonary vascular resistance >3 Wood units in the absence of other causes of pre-capillary pulmonary hypertension. The presence of large gene rearrangements was analyzed by the Multiplex Ligation-dependent Probe Amplification (MLPA) reactions in the ENG, ACVRL1 and BMPR2 genes (SALSA MLPA Kit, MRC-Holland). We have further sequenced a panel of selected 48 genes from BMP/SMAD and related pathways using next-generation sequencing (SureSelect XT library preparation Kit, Agilent; NextSeq 500 sequencer, Illumina) and assessed causative potential of rare variants (minor allele frequency in non-finish Europeans below 1%) with Mutation Taster web-based tool. Results We identified at least one likely-causative variant of investigated genes in 51 (54.8%) subjects. Large genomic rearrangements were found by MLPA in 2 patients in ENG and ACVRL1 (ALK1) genes. We have found mutations in BMPR2 gene in 12 patients (12.5%) from our cohort with most variants present in one sample and 3 variants present in 2 samples. Mutations were located mostly in protein kinase domain (6 variants) and Activin type I and II receptor domain (2 variants). We have found 5 likely pathogenic variants in 6 patients in genes previously associated with PAH other than BMPR2 (SMAD9, KCNA5, KCNK3, EIF2AK4). In total, potentially disease causing mutations in literature-known genes, were present in 18 patients, which accounted for 18.75% of tested cohort. Medium impact variants were also present in KCNA5, TGFBR2, AQP7, BMP6, EIF2AK4, FBP1, NOTCH1, NOTCH3, SMAD7, TBX4, TGFB2, TOPBP1, GDF5, IL6, PPARA, RXRA, KCNK3, KLF4, BMPR1B, ILK, TGFBR1, SMAD9, PPARD and TGFB3 genes. Additionally, in one patient with clinical diagnosis of pulmonary venoocclusive disease we identified an unknown homozygous frameshift variant (p.Phe1523fs/c.4567_4570delTTTG) in exon 35 of EIF2AK4 gene. Conclusions We found potentially disease causing mutations in 18,75% Polish patients diagnosed with IPAH most of them were present in BMPR2 gene which is in line with data from other European cohorts. Additionally we found an unknown mutation in the EIF2AK4 gene. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Narodowe Centrum Nauki - National Science Centre

Diagnosis of Pulmonary Veno-Occlusive Disease in the Absence of Hemodynamic Abnormalities

<h3>Introduction</h3> Sarcoidosis is a granulomatous disorder of unknown etiology that can lead to pulmonary hypertension (PH). Pulmonary veno-occlusive disease (PVOD) is a subset of PH characterized by intimal proliferation and obliteration of the intralobular veins. We present this case of a patient with sarcoidosis, who had symptoms and imaging consistent with PVOD, which preceded hemodynamic manifestations. <h3>Case Report</h3> A 52-year-old male nonsmoker presented with progressive shortness of breath, dry cough, and mild wheezing over the preceding seven months. He had no hypoxemia. He had a history of neurosarcoidosis, diagnosed nine years prior, for which he was in remission and off all immunosuppression. Physical examination was pertinent only for minimal lower extremity edema. Spirometry, diffusing capacity, 6-minute-walk-test, B-type Natriuretic Peptide (BNP), sarcoid markers, and infectious workup were normal. Chest computed tomography (CT) scan revealed interlobular septal thickening, ground glass opacities (GGOs), and lymphadenopathy, concerning for PVOD. Transthoracic echo (TTE) was normal. His right heart catheterization (RHC) was notable for a mean pulmonary artery pressure of 28 mmHg, a pulmonary capillary wedge pressure of 15 mmHg, and a pulmonary vascular resistance of 1.71 Woods units. The clinical picture was felt to represent PVOD, with imaging findings preceding hemodynamic changes. He was referred to the lung transplant program. Patient's symptoms rapidly progressed before he could undergo lung biopsy and he developed progressive hypoxemia. He underwent a successful bilateral lung transplant two weeks later. The explanted lung pathology revealed granulomatous PVOD. <h3>Summary</h3> In prior reports of sarcoidosis-associated PVOD, PH was noted on TTE or RHC correlating with symptoms well before diagnosis of PVOD. Additionally, in patients with hemodynamic or biopsy proven diagnoses of PH, the combination of GGOs, interlobular septal thickening, and mediastinal lymphadenopathy is 95% sensitive and 89% specific for PVOD. Our case suggests that CT imaging findings should raise the index of suspicion for PVOD, even in the absence of objective evidence of pulmonary vascular changes on TTE and RHC. In patients with symptoms of dyspnea, progressive hypoxemia, and these imaging findings, delayed evaluation for transplant may miss an opportunity for early intervention.

Lung Transplant Outcomes in Patients with Pulmonary Veno-Occlusive Disease

<h3>Purpose</h3> Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Prognosis of PVOD is worse than PAH. Most patients need lung transplantation. Previous study showed that PVOD patients had higher waitlist mortality compared to PAH patients. To date, there are no study report outcomes of lung transplant in this population. We would like to study the outcome and compare with IPAH patients. <h3>Methods</h3> This is a retrospective observational study. Patients with a diagnosis of PVOD and PAH underwent lung transplant between 2005 and 2018 were identified from SRTR database. Numerical data were reported in mean and standard deviation. Categorical data were reported in count and percent. T-test and Chi-square test were performed to compare variables between 2 groups. Survival was compared using Kaplan-Meier (K-M) method. <h3>Results</h3> 61 PVOD patients and 970 PAH patients underwent lung transplant were identified. There was no significant difference in age and BMI. Patients with PVOD had significant lower post-transplant systolic, diastolic and mean PA pressure and higher cardiac output. LAS at matching were not significantly different. PVOD patients had shorter time on waiting list (152.7±263.34 vs 337.56±511.14, p<0.01). Proportion of patients requiring ECMO post lung transplant were higher in PVOD group (13.11% vs 4.23%, p<0.01). Proportion of patients developing primary graft dysfunction (PGD) were lower in PVOD group (37.5% vs 61.93%, p=0.056). There was no difference of length of stay, FEV1, FVC, PCO2 post lung transplant and acute rejection between 2 groups. Survivals were not different between 2 groups using K-M method (p=0.33). <h3>Conclusion</h3> We found that PVOD patients who underwent lung transplant had shorter waiting time compared to PAH patients which suggest that disease severity of PVOD is higher than PAH. Despite that more PVOD patients required ECMO support post-operative, patient survival and other long-term outcomes such as lung function or rejection were not different between from PAH patients.

Pulmonary Capillary Hemangiomatosis and Refractory Hypoxemia During PH Therapy

<h3>Introduction</h3> Pulmonary capillary hemangiomatosis (PCH), a rare cause of pulmonary hypertension (PH), presents clinically with right heart dysfunction and may be indistinguishable from typical pulmonary arterial hypertension. Vasodilator therapy exacerbates hypoxemia in PCH despite improvement in heart failure symptoms. Lung transplant is the only definitive therapy. We present the case of a patient succumbing to progressive hypoxemia on PH therapy during lung transplant evaluation. Autopsy revealed PCH. <h3>Case Report</h3> A 42-year-old female with PH due to undifferentiated connective tissue disease presented with acute respiratory distress. She was diagnosed 2 years prior and initially treated with macitentan, tadalafil and diuretics with clinical improvement; however, worsening shortness of breath and new finding of hypoxemia developed after 1 year. Imaging revealed faint patchy nodular opacities initially attributed to UCTD-associated pneumonitis. Steroids and mycophenolate failed to achieve radiographic improvement. Repeat right heart catheterization showed continued elevation in pulmonary artery pressure and stably reduced cardiac output. Subcutaneous infusion of Treprostinil was initiated 2 months prior to admission, which worsened hypoxemia. Clinical diagnosis of pulmonary veno-occlusive disease (PVOD) vs PCH was suspected and lung transplant evaluation initiated. On admission, patient presented with syncope and was found to have refractory hypoxemia despite high-flow oxygen supplementation. Cardiogenic shock and hypoxemic respiratory failure ensued, resulting in hepatic and renal failure, leading to cardiac arrest and unsuccessful resuscitation. Autopsy showed PCH. <h3>Summary</h3> Refractory hypoxemia during up-titration of vasodilator therapy for PH should prompt clinical suspicion for atypical causes of PH such as PCH. Early lung transplant referral is essential if PCH/PVOD is suspected given its poor prognosis and potentially harmful responses associated with traditional PH therapy.

Abstract 10367: An Unusual Vasodilator Response: Recognizing a Rare Subtype of Pulmonary Arterial Hypertension

Introduction: Pulmonary veno-occlusive disease (PVOD) is a rare subtype of pulmonary arterial hypertension (PAH) caused by intimal fibrosis of the pulmonary venules and septal veins. While the hemodynamic profile is suggestive of pre-capillary pulmonary hypertension, vascular obstruction distal to the pulmonary capillary beds distinguishes PVOD from other forms of PAH. Case: A 29-year-old woman presented with progressive dyspnea and fatigue. She was tachycardic, hypotensive, and volume overloaded on exam. ECG was notable for right-axis deviation. TTE showed a dilated, hypokinetic RV and small LV with mild global hypokinesis and septal flattening throughout the cardiac cycle. A CTA chest excluded pulmonary embolism but showed diffuse centrilobular ground-glass opacities and lymphadenopathy which raised suspicion for PVOD. She underwent right heart catheterization with the following measurements (mmHg): RA 14, PA 99/56 (mean 71), PCWP 12, and CI 1.1 L/min/m 2 with PVR 28.1 WU. Following initiation of an epoprostenol infusion, she became increasingly hypoxemic with repeat CT chest demonstrating dramatic worsening of ground-glass opacities and vascular congestion. This response to a vasodilator challenge led to a clinical diagnosis of PVOD. She was urgently listed for and underwent bilateral lung transplantation. Explanted lung tissue subsequently confirmed the diagnosis. Conclusion: In most forms of PAH, vasodilators mitigate arteriolar narrowing and improve pulmonary blood flow, while in PVOD they exacerbate pulmonary capillary congestion due to increased arteriolar blood flow relative to the venous outflow due to fixed narrowing of the pulmonary venule network. Because lung biopsy is contraindicated in severe pulmonary hypertension, the clinician must recognize that worsening pulmonary edema in response to vasodilator challenge with normal PCWP is a critical clue pointing towards PVOD. Timely diagnosis is essential given the poor prognosis for this condition for which lung transplantation is the definitive treatment.

The role of cardiopulmonary exercise test in identifying pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension that shares some clinical and haemodynamic features with idiopathic pulmonary arterial hypertension (PAH). However, suspicion of PVOD is crucial, considering that PAH-specific treatment may precipitate life-threatening pulmonary oedema and lung transplant should be considered from diagnosis [1, 2]. Cardiopulmonary exercise tests provide additional data for the noninvasive diagnosis of pulmonary veno-occlusive disease <https://bit.ly/3p6Dzc5>

Une maladie veino-occlusive pulmonaire familiale avec mutation biallélique hétérozygote composite d’EIF2AK4

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Heritable and sporadic forms have been distinguished. Hypoxemia, profound reduction in the diffusion of carbon monoxide and haemodynamic confirmation of pre-capillary pulmonary hypertension are the major diagnostic criteria. Thoracic CT scanning and a response to pharmaceutical therapy provide additional information to confirm the diagnosis. A 52-year-old patient, three of whose siblings had pulmonary hypertension, was admitted with dyspnoea, malaise and palpitations. Right heart catheterisation confirmed pre-capillary pulmonary hypertension. A search for an EIF2AK4 mutation was carried out, and this showed a composite biallelic heterozygous mutation compatible with the diagnosis of familial PVOD, identical to that showed in one of his brothers. Given the signs of severity of the disease and the diagnosis of PVOD, whose response to pharmaceutical therapy is often poor, the patient was placed on a waiting list for lung transplantation. Despite a similar diagnosis in 3 brothers and follow-up proposed 11 years before the diagnosis, pulmonary hypertension appeared within a few weeks and led immediately to a severe clinical situation. Annual clinical and echocardiographic monitoring had been strongly advised to the patient, but had not allowed diagnosis at a mild or moderate stage of the disease. This clinical case shows that the identification of factors predicting the development of heritable PVOD at a pre-symptomatic stage is an important issue for clinical research.

An Uncommon Severe Case of Pulmonary Hypertension - From Genetic Testing to Benefits of Home Anticoagulation Monitoring

AbstractA 62 year-old caucasian male was admitted in our pulmonary hypertension expert center with initial diagnosis of pulmonary veno-occlusive disease for validation and specific treatment approach. Routine examinations revealed no apparent cause of pulmonary hypertension. Patient was referred for a thorax contrast enhanced multi-slice computed tomography which revealed extensive bilateral thrombi in pulmonary lower lobe arteries, pleading for chronic post embolic lesions. A right heart catheterization and pulmonary angiography confirmed the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Following the local regulations, the patient underwent thrombophilia screening including molecular genetic testing, with positive findings for heterozygous for VCORK1 -1639G&gt;A gene single nucleotide polymorphism, PAI-1 4G/5G and factor II G20210A gene. With heterozygous genetic profile of 3 mutations he has a genetic predisposition for developing a thrombophilic disease which could be involved in the etiology of CTEPH. Familial screening was extended to descendants; the unique son was tested with positive results for the same three genes. Supportive pulmonary hypertension drug therapy was initiated together with patient self-monitoring management of oral anticoagulation therapy. For optimal control of targeted anticoagulation due to a very high risk of thrombotic state the patient used a point-of-care device (CoaguChek®XS System, Roche Diagnostics) for coagulation self-monitoring.

Pulmonary Veno-Occlusive Disease as a Cause of Pulmonary Arterial Hypertension

Pulmonary veno-occlusive disease (PVOD) represents a rare form of precapillary pulmonary arterial hypertension. We present a young patient hospitalized with progressive dyspnea, with initial workup suggestive of pulmonary hypertension and unexplained noncardiogenic pulmonary edema. His subsequent clinical course was consistent with the diagnosis of PVOD.

Characteristics of patients with pulmonary venoocclusive disease awaiting transplantation.

Pulmonary venoocclusive disease (PVOD) is an uncommon cause of pulmonary arterial hypertension (PAH). However, unlike PAH, treatment options for PVOD are usually quite limited. The impact of the lung allocation score on access to transplantation for patients with PVOD and the clinical course of these patients have not been well-described. To examine the association between the diagnosis of PVOD and lung transplantation for patients on the transplant waiting list. Patients with a diagnosis of PVOD and PAH registered on the United Network for Organ Sharing wait list for transplantation from May 4, 2005 to May 3, 2013 were included. Lung transplantation was the primary outcome measure. Multivariable analyses were performed to determine the odds of dying or receiving a lung transplant after listing. Survival was compared using Kaplan-Meier and competing risks methods. Of 12,251 patients listed for lung transplantation, 49 with PVOD and 647 with PAH were identified. There were no significant differences in the lung allocation score between patients with PVOD and PAH at listing, transplant, or wait list removal for death/too sick for transplant. By 6 months, 22.6% of patients with PVOD had been removed from the wait list due to death, compared with 11.0% of patients with PAH (Chi-square P = 0.03). Patients with PVOD who died or were considered too sick for transplant were removed from the waiting list sooner after listing (22 vs. 105 d, P = 0.08). There was no difference in the proportion of patients with PVOD and PAH transplanted (50.0 vs. 47.6%, P = 0.60). In the lung allocation score era, patients with PVOD may be at higher risk for death while on the transplant waiting list. After wait list registration, close monitoring for disease progression is advised.

24-letni pacjent z chorobą zarostową żył płucnych—Opis przypadku

Pulmonary veno-occlusive disease (PVOD) is a rare cause of severe pulmonary hypertension characterised by poor prognosis. We report the case of a 24-year-old male patient with increasing dyspnea and exercise intolerance treated with calcium channel blockers and glucocorticosteroids, due to suspicion of pulmonary hypertension and interstitial lung disease, until lung biopsy was performed and a diagnosis of PVOD was established on the basis of the histological analysis of the lung biopsy sample. This case highlights that pulmonary veno-occlusive disease is a disorder that is difficult to diagnose and resistant to medical treatment, which is particularly poor prognostic factor. Due to poor response to medical therapy and high mortality in patients with PVOD, understanding the pathogenesis, differentiation with pulmonary arterial hypertension and the search for a new methods of treatment should be the key challenges for modern medicine.

A Surgical Lung Biopsy Case of Pulmonary Veno-occlusive Disease Associated with Limited Cutaneous Systemic Sclerosis

Pulmonary veno-occlusive disease (PVOD), a rare form of pulmonary arterial hypertension (PAH) characterized by a progressive obstruction of small pulmonary veins, is both difficult to diagnose and treat effectively. We reported a case of limited cutaneous systemic sclerosis complicated with PAH in which early definitive diagnosis of PVOD was made by surgical lung biopsy. A 53-year-old Japanese woman, with no history of smoking, was admitted to our hospital because of dry cough and progressive dyspnea. She had Raynaud’s phenomenon, gastroesophageal reflux and skin sclerosis and she was positive for anticentromere antibody. Chest high-resolution computed tomography (HRCT) revealed diffuse centrilobular ground-glass opacities and septal lines in addition to mediastinal lymph node enlargement; radiographic triad of HRCT signs of PVOD. PAH was found by right heart catheterization. Although limited cutaneous systemic sclerosis-associated PAH was diagnosed, histological findings obtained by surgical lung biopsy showed not only wall thickening of muscular arteries and arterioles but diffuse occlusion of pulmonary venules, that is, PVOD. In addition, pleuritis and limited, mild cellular interstitial pneumonia was also observed. First-line corticosteroid therapy and careful combination therapy with sildenafil and ambrisentan initially stabilized her symptoms and pulmonary hemodynamics, but she died due to cardiac arrest approximately 2.5 years after initiating PAH therapy. The need to establish a correct and early diagnosis of PVOD is important because of the impaired prognosis of these patients and their risk of developing severe pulmonary edema with specific PAH therapy. HRCT is a useful noninvasive diagnostic modality in the evaluation of suspected PVOD.

Multiples défauts segmentaires et sous-segmentaires de perfusion discordants avec une angiographie pulmonaire normale et une forte suspicion de maladie veino-occlusive pulmonaire

We report the case of a 55-year-old woman presenting stage-3-4 dyspnea over the last 5years with no other clinical symptoms. Pulmonary arterial hypertension (PAH) was evidenced by echocardiography. However, there was no argument for chronic thromboembolic disease during pulmonary angiography. The pulmonary scintigraphy showed homogeneous ventilation on both lung fields, with multiple bilateral segmental and subsegmental perfusion defects, however. These perfusion abnormalities with a normal pulmonary angiography led to the diagnosis of pulmonary veno-occlusive disease (PVOD) taking into account the clinical context, imaging findings, and laboratory and functional assessments. PVOD is a clinicopathological entity characterized by the occlusion or narrowing of the pulmonary veins and venules by fibrous tissue, leading to clinical manifestations that are, in many ways similar to PAH. PVOD remains poorly understood and it is difficult to diagnose and treat. However, PVOD needs to be known by clinicians and considered in the differential diagnosis of PAH.

Pulmonary Veno-occlusive Disease Following Reduced-intensity Allogeneic Bone Marrow Transplantation for Acute Myeloid Leukemia

We report a case of pulmonary veno-occlusive disease (PVOD) following allogeneic bone marrow transplantation (BMT) for the treatment of acute myeloid leukemia (AML) from an HLA mismatched mother using a reduced-intensity conditioning (RIC) regimen including gemtuzumab ozogamicin. The patient was a 21-year-old male who complained of dyspnea with hypoxemia followed by loss of consciousness. The abnormalities in chest CT and echocardiography were compatible with a diagnosis of PVOD. Treatment with 1 mg/kg of oral prednisolone resolved dyspnea and hypoxemia within a few days, and chest CT abnormalities disappeared in a week. This report is the first to describe PVOD following RIC stem cell transplantation.

Evaluation of Pulmonary Hypertension in a Child: Role of Computed Tomography

Unexplained pulmonary hypertension in pediatric patient is a diagnostic challenge. The natural history as well as management depends upon etiology of pulmonary hypertension. Despite newer insights in pathophysiology and management strategies, the outcome of pulmonary veno-occlusive disease remains dismal. The author's report a case of 12-year-old girl who presented with severe pulmonary hypertension. Stepwise evaluation and CT angiographic assessment in the index case led to definitive diagnosis of pulmonary veno-occlusive disease. This case highlights the role of cardiac imaging in localising site of pulmonary hypertension. It is important for health care professionals involved in care of patients with pulmonary hypertension to make correct diagnosis of pulmonary veno-occlusive disease for better prognostication as well as to avoid therapeutic mishaps.

Hypertension artérielle pulmonaire et sclérodermie systémique : les pièges

Although pulmonary arterial hypertension (PAH) is usually considered as a late complication in limited subsets of systemic sclerosis (SSc), PAH can also occur in diffuse SSc and in early SSc. The evaluation of the velocity of the tricuspid regurgitation on echocardiography is so far the most effective screening tool for pulmonary hypertension (PH) in SSc. Nevertheless, it is not measurable in about 20% of SSc patients ; In that case, pulmonary arterial pressure can be evaluated by using the velocity of a pulmonary insufficiency and indirect signs of PH should be analyzed: pulmonary ejection time, right heart cavities dilatation and aspect of the inferior vena cava. About 10% of SSc patients with a suspected of PAH on echocardiography have post-capillary PH at right heart catheterization mainly due to left ventricular diastolic dysfunction. In some SSc patients, PAH and post-capillary PH due to left ventricular diastolic dysfunction may be associated. This can be suspected in case of post-capillary PH with a transpulmonary gradient > 12 mmHg. Lung fibrosis is another cause of PH in SSc. The distinction between PH associated to lung fibrosis from PAH is sometimes difficult, particularly in patients with a FVC between 60 and 70% of expected. Pulmonary veno-occlusive disease is a possible cause of precapillary PH in SSc. The diagnosis of pulmonary veno-occlusive disease should be discussed in each case of PAH associated ScS due to the high risk of lung edema at the introduction of specific PAH drugs.

CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency

CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency

Pulmonale venookklusive Erkrankung – eine seltene Form der pulmonalen Hypertonie

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. So far some 200 cases have been published worldwide. Since the latest classification, agreed at a meeting in Venice in 2003, PVOD is included in the group of pulmonary arterial hypertension (PAH). It has been hypothesized that it represents endothelial dysfunction of unknown cause. Although it has many features in common with idiopathic PAH, it partially differs from it phenotypically. After exclusion of known causes of pulmonary hypertension, such as diseases of pulmonary interstitial tissue, acral clubbing and rales suggest PVOD. The findings typical in the computed tomogram of the chest include prominent septal lines, centro-acinar opacities and mediastinal lymphadenopathy. In addition to arterial lesions PVOD is particularly characterized by lesions in the venous vascular bed. PVOD has a poor prognosis. Treatment with medication approved for PAH may carry the risk of pulmonary edema. Currently the immediate listing for lung- or combined lung-heart-transplantation is recommended, once the diagnosis of PVOD has been established.

A New Classification of Pulmonary Hypertension

A New Classification of Pulmonary Hypertension

Diagnosis of pulmonary veno-occlusive disease: new criteria for biopsy

Diagnosis of pulmonary veno-occlusive disease: new criteria for biopsy