Pulmonary Veno-occlusive Disease Research Articles

Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a disorder with a large genetic component. Biallelic mutations of EIF2AK4, which encodes the kinase GCN2, are causal in two ultra-rare subtypes of PAH, pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis. EIF2AK4 variants of unknown significance have also been identified in patients with classical PAH, though their relationship to disease remains unclear. To provide patients with diagnostic information and enable family testing, the functional consequences of such rare variants must be determined, but existing computational methods are imperfect. We applied a suite of bioinformatic and experimental approaches to sixteen EIF2AK4 variants that had been identified in patients. By experimentally testing the functional integrity of the integrated stress response (ISR) downstream of GCN2, we determined that existing computational tools have insufficient sensitivity to reliably predict impaired kinase function. We determined experimentally that several EIF2AK4 variants identified in patients with classical PAH had preserved function and are therefore likely to be non-pathogenic. The dysfunctional variants of GCN2 that we identified could be subclassified into three groups: misfolded, kinase-dead, and hypomorphic. Intriguingly, members of the hypomorphic group were amenable to paradoxical activation by a type-1½ GCN2 kinase inhibitor. This experiment approach may aid in the clinical stratification of EIF2AK4 variants and potentially identify hypomorophic alleles receptive to pharmacological activation.

3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension.

Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure. Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function. Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments. 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

PULMONARY VENO–OCCLUSIVE DISEASE ASSOCIATED WITH METHAMPHETAMINE ABUSE: A FIRST CASE DESCRIPTION

Abstract Background Recreational methamphetamine is widely used worldwide (about 35 million people), mainly as 3,4–Methylenedioxymethamphetamine (MDMA). A definite association has been established between methamphetamine and pulmonary arterial hypertension (PAH). This drug–associated form of PAH shares histological, clinical and hemodynamic characteristics, prognosis and treatment strategies with idiopathic PAH. However, the association between MDMA and a rarer and devasting form of PAH with concomitant venous involvement (pulmonary veno–occlusive disease, PVOD), has never been reported. Notably, initiation of PAH–specific treatment in PVOD may lead to catastrophic consequences. Case Description A 32–year–old man was fast–track referred to our PH Centre in December 2023, due to high echocardiographic probability of pulmonary hypertension (PH). After interrogation, he admitted the regular use of MDMA. No other risk factor for PAH was found. Right heart catheterization showed a pre–capillary PH (mean pulmonary artery pressure 35 mmHg; wedge pressure 12 mmHg; pulmonary vascular resistance 5.9 WU) with low cardiac output (2.2 L/min/m2) and no acute response to vasoreactivity testing. Exercise capacity was severely reduced (oxygen consumption 19.6 mL/Kg/min, 50% of predicted) due to absent stroke volume reserve, accompanied by augmented exercise hyperventilation (VE/VCO2 slope 60) and exercise–induced desaturation (SaO2 94 à 77%), this latter not explained by a right–to–left shunt. Diffusion capacity of the lung was severely reduced (DLCO 28%). Chest CT and perfusion scan excluded both thromboembolic etiology and parenchymal lung disease. A diagnosis of PVOD was made, based on the presence of pre–capillary PH, oxygen desaturation, extreme exercise hyperventilation and very low DLCO, even in the absence of pathognomonic CT features. Counselling for stopping MDMA abuse was offered. Cautious monotherapy with macitentan was started and was well tolerated. A genetic testing for EIF2AK4 is ongoing. Contact with transplant center has been performed. A follow–up RHC has been planned before careful therapy up–titration. Conclusions This is the first case reported of the potential association between methamphetamines and PVOD. Due to the large worldwide use of MDMA, this link should be considered because of its prognostic and therapeutic implications. The diagnosis of PVOD is a clinical one, needing a high index of suspicion especially in the absence of chest CT findings.

Effect of epoprostenol-induced thrombocytopaenia on lung transplantation for pulmonary arterial hypertension.

Preoperative intravenous epoprostenol therapy can cause thrombocytopaenia, which may increase the risk of perioperative bleeding during lung transplantation. This study aimed to determine whether lung transplantation can be safely performed in patients with epoprostenol-induced thrombocytopaenia. From June 2008 to July 2022, we performed 37 lung transplants in patients with pulmonary arterial hypertension (PAH), including idiopathic PAH (n = 26), congenital heart disease-associated PAH (n = 7), pulmonary veno-occlusive disease (n = 3) and peripheral pulmonary artery stenosis (n = 1) at our institution. Of these, 26 patients received intravenous epoprostenol therapy (EPO group), whereas 11 patients were treated with no epoprostenol (no-EPO group). We retrospectively analysed the preoperative and postoperative platelet counts and post-transplant outcomes in each group. Preoperative platelet counts were relatively lower in the EPO group than in the no-EPO group (median EPO: 127000 vs no-EPO: 176000/μl). However, blood loss during surgery was similar between the 2 groups (EPO: 2473 ml vs no-EPO: 2615 ml). The platelet counts significantly increased over 1 month after surgery, and both groups showed similar platelet counts (EPO: 298000 vs no-EPO: 284000/μl). In-hospital mortality (EPO: 3.9% vs no-EPO: 18.2%) and the 3-year survival rate (EPO: 91.4% vs no-EPO: 80.8%) were similar between the 2 groups. Patients with PAH treated with intravenous epoprostenol showed relatively lower platelet counts, which improved after lung transplantation with good post-transplant outcomes.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial

A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Lung Transplantation in Pulmonary Arterial Hypertension: The Portuguese Experience

In patients with pulmonary arterial hypertension (PAH), refractory to medical therapy, lung transplantation emerges as an option. This study describes the outcomes of 8 PAH patients who underwent lung transplantation. A retrospective, single-center study was conducted among patients with PAH who underwent lung transplantation in our center. Patients had a median age of 46 years, with female sex predominance (75%). Causes of HAP were pulmonary veno-occlusive disease (n = 5, 62.5%), idiopathic PAH (n = 2, 25%), and heritable PAH (n = 1, 12.5%). Pre-transplant hemodynamics revealed a median mean pulmonary artery pressure of 58.5 mm Hg (48-86). All patients received bilateral lung transplants with extracorporeal membrane oxygenation support, displaying immediate post-transplant hemodynamic improvement. Primary graft dysfunction grade 3 (PGD 3) was observed in 75% of patients. Five patients (62.5%) died, with a 72.9% survival at 12 months and 29.2% at 24 months post-transplantation. Our study reveals the complexity and challenges of lung transplants in patients with PAH. Despite notable immediate hemodynamic improvements, high rates of PGD 3 and the survival rate remain a concern. Further research to define optimal peri and post-transplant management to improve survival is required.

Outcomes and risk assessment in pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension (PAH). Although European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines advise assessing PAH severity at baseline and during follow-up, no existing risk assessment methods have been validated for PVOD. This study aimed to identify prognostic factors, examine the impact of treatment strategies and evaluate risk assessment methods for PVOD patients. The study analysed all incident PVOD patients included in the French Pulmonary Hypertension Registry between 2006 and 2021. Survival was assessed based on initial treatment strategy and risk status and compared to a matched (age, sex, pulmonary vascular resistance) PAH group. Six risk assessment methods (number of four low-risk and three noninvasive low-risk variables, ESC/ERS guidelines three-strata and four-strata models, REVEAL 2.0 and Lite 2) were applied at baseline and early follow-up, and their accuracy was compared using Harrell's c-statistic. Among the 327 included PVOD patients, survival rates at 1, 3 and 5 years were 86%, 50% and 27%, respectively. Multivariate analysis showed that only 6-min walk distance was associated with survival, with no significant difference based on initial treatment strategy. All six risk assessment methods could discriminate mortality risk, and the ESC/ERS four-strata model was the most accurate at both baseline and follow-up (C-index 0.64 and 0.74). PVOD survival rates were consistently lower than PAH when comparing baseline risk status using the ESC/ERS four-strata model. PVOD is associated with poor outcomes, and initial treatment strategies do not significantly affect survival. Risk assessment methods can be useful in predicting survival for PVOD patients.

Sarcoidosis-Associated Pulmonary Hypertension

Sarcoidosis is characterized by non-necrotizing granulomatous aggregations affecting a range of organs, with thoracic structures involved in 90% to 95% of cases. This granulomatous disease can impact the pulmonary vasculature via different mechanisms resulting in sarcoidosis-associated pulmonary hypertension (SAPH). These include postcapillary disease (left heart disease), immune-mediated granulomatous vasculopathy, hypoxemia, thromboembolism, pulmonary vascular compression and/or stenosis by mediastinal lymph nodes/fibrosis, or sarcoidosis-related portal hypertension. SAPH is a serious complication, especially in those with end-stage lung disease. A thorough evaluation is crucial to delineate the predominant mechanism of PH in the affected individual. The management of SAPH is complex and necessitates a personalized, multifaceted approach, targeting the specific mechanisms and underlying pathologies. Such patients are best served at specialized Pulmonary Hypertension and Sarcoidosis Centers. A notable phenotype within SAPH is the “pulmonary arteriopathy” group, characterized by milder parenchymal disease and a favorable response to PAH-targeted therapy, whereas patients with active granulomatous inflammation are likely to respond to immunosuppression. Several PAH therapies have been used to treat SAPH, however, clear direction on the use of PAH therapies in SAPH is still lacking. Patients receiving pulmonary vasodilators should be carefully monitored for potential deterioration in gas exchange or development of pulmonary edema, which could suggest underlying left heart disease or pulmonary veno-occlusive disease. Timely referral for lung transplant evaluation is crucial for those with SAPH and severe parenchymal lung disease, ensuring a comprehensive and patient-centered care approach. Much work remains to be done to understand the exact pathogenesis of SAPH, as well as to develop therapies that clearly improve outcomes for these patients.

Applicability of the 3-Strata ESC/ERS risk model at baseline in pulmonary veno-occlusive disease

Abstract Introduction The risk of death or lung transplantation in Pulmonary Arterial Hypertension (PAH) is influenced by many factors. The recently published European Society of Cardiology/ European Respiratory Society (ESC/ERC) Guidelines for the study and management of PAH recommend the use of a multiparametric 3-strata model for risk stratification at diagnosis [1]. Heritable pulmonary veno-occlusive disease (PVOD) is an especially infrequent form of PAH caused by homozygous variants in the gene encoding the Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 (EIF2AK4). PVOD has a dramatically low long-term survival. There is no evidence confirming the applicability of the risk scores in PVOD. Our aim was to evaluate the usefulness of the 3-strata ESC/ERC score at diagnosis in patients with heritable PVOD. Methods We considered patients with the diagnosis of heritable PVOD included in the Spanish registry of PAH (REHAP) between 2011 and 2022. The diagnosis required a homozygous variant in EIF2AK4, and a diagnostic right heart catheterization (RHC). The other group was composed of patients with PAH and pathogenic or likely pathogenic variants in the gene BMPR2. The prognostic evaluation was done when these patients were included in the registry. All participants signed informed consent. Results In the 2011-2022 period up to 32 cases of PVOD in 23 unrelated families and 28 cases in 23 families were collected. 10 patients were excluded due to incomplete RHC at diagnosis. The baseline characteristics of the population can be seen in the Table. After a median follow-up of 16.9 months, up to 15 patients with PVOD needed lung transplantation (46.9%), and 6 patients died (18.7%). On the contrary, only 4 patients needed lung transplantation and one died in the BMPR2 group after a median follow-up of 97.1 months. Most of the included PVOD patients had an intermediate risk of mortality after the application of the 3-strata European model (62.5%), and only one case (3.1%) was categorized as high-risk. There was a non-significant tendency for patients with BMPR2 variants to have lower risk levels. The application of the 3-strata model at diagnosis in patients with PVOD demonstrated a good global prognostic capacity (C Index of 0.707). In our PVOD population, those patients at intermediate risk had a hazard ratio of 9.53 (2.15-42.17, p=0.003) when compared with patients at low risk. Similarly, those patients at high risk at diagnosis had a hazard ratio of 9.49 (0.86-104.69, p=0.066) when compared with patients at intermediate risk (Figure). Conclusions The application of the ESC/ERC three-strata risk tool in patients with PVOD demonstrates a good global prognostic capacity. Nevertheless, the risk of death or lung transplantation can be higher than predicted in this population, enhancing the need for an early evaluation for lung transplantation.Figure

The prevalence and significance of the EIF2AK4 variants in the patients with pulmonary arterial hypertension

Abstract Background Eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) has been reported to be the causative gene of pulmonary veno-occlusive disease (PVOD).[1] Although some patients with pulmonary arterial hypertension (PAH) also carry the EIF2AK4 variants, its importance remains unclear. Purpose The purpose of this study was to evaluate the prevalence and significance of EIF2AK4 variants in patients with PAH. Methods The whole exome sequencing were performed in total 162 patients with idiopathic or heritable PAH. The clinical data including the high-resolution CT scanning, pulmonary function test, laboratory data at diagnosis, and therapeutic response to pulmonary vasodilator were evaluated. Results We identified the heterozygous variants of EIF2AK4 in 6 (3.7%) patients. Among them, 2 patients also had bone morphogenetic protein receptor type 2 (BMPR2) variants which were defined as pathogenic by American College of Medical Genetics and Genomics classification. The other 4 patients did not have known PAH associated gene variants. Although the typical findings of PVOD such as interlobular septal thickening and enlarged mediastinal lymph nodes, were not identified by the CT scanning, the median percent diffusing capacity for carbon monoxide of patients with EIF2AK4 heterozygous variants was reduced to 45.6%. In addition, 4 of 6 patients received prostacyclin injection therapy because oral combination therapy was ineffective, and 2 patients died. Moreover, none of the 6 patients reached mean pulmonary arterial pressure≤30 mmHg despite the combination therapy. We also identified homozygous EIF2AK4 variants in 2 patients with PAH. They did not have the known causative variants of PAH. CT scanning at diagnosis did not detect any characteristic of PVOD in either of the two patients. Although the pulmonary vasodilator was initiated without induction of pulmonary edema, one patient was refractory to the therapy. Conclusions The genetic analysis is crucial for accurate diagnosis even in patients diagnosed with PAH because heterozygous or homozygous variants in EIF2AK4 could be involved in the disease pathology.

Retrospective analysis of confirmed cases of pulmonary veno-occlusive disease: a single tertiary referral center study

Abstract Background Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that primarily results in intimal fibrosis of the pulmonary venules and veins, the venous lesions are often associated with changes in interlobular septa, lung parenchyma, and pulmonary arterioles and arteries. Purpose We sought to study the clinical characteristics of patients with confirmed PVOD at a single large referral center. Methods We retrospectively reviewed data from a total of 675 patients with pulmonary hypertension (identified by ICD codes or search of text) from 2017 and 2022 from a database obtained from electronic medical records at our institution. Patients with group 2 pulmonary hypertension were excluded. Only 29 cases were confirmed by histology or genetic testing. Results Out of the 29 patients confirmed with PVOD, 28 (96.5%) had a characteristic histology (lung biopsy (55.1%), explanted lung for transplant (27.5%) and autopsy (13.7%)) and 1 (3.4%) had a positive genetic test for EIF2AK4 biallelic mutation. The age at diagnosis was 53±16 years, 14 (48.2%) were men, 2 (6.8%) had systemic scleroderma, 2 (6.8%) had psoriasis, 2 (6.8%) were exposed to cytotoxic agents, 16 (55.1%) were smokers and 2 (6.8%) had a family history of pulmonary hypertension. All patients had computed tomography of the chest but only 12 (41.3%) had all 3 typical features found in PVOD (ground glass opacities, interlobular septal thickening, and lymphadenopathy). The most common feature was interlobular septal thickening in 26 (89.6%), followed by ground glass opacities present in 25 (86.2%) and lymphadenopathy in 12 (41.3%) of the patients. At diagnosis, mean pulmonary artery pressure was 45±15 mmHg and pulmonary vascular resistance was 9±6 WU. The median DLCO was 41 (34-58) %. On echocardiogram, 14 (48.2%) had severely enlarged right ventricle (RV), RV function was ≥moderately reduced in 17 (58.6%), RV systolic pressure was 63±20 mmHg and 6 (20.6%) had pericardial effusion. Out of 21 (72.4%) patients who received pulmonary vasodilators, 4 (13.7%) received single agent. 10 (34.4%) received 2 agents, 6 (20.6%) 3 agents, and 1 (3.4%) received 4 agents. 35.7% of these treated patients reported an improvement or initial worsening of symptoms with subsequent improvement afterwards. 18 (62%) patients with PVOD died, 12 (41.3%) had a lung transplant and 6 (20.6%) were still alive without the transplant until the day data was collected. Mean duration from diagnosis to death and lung transplantation was 446 ± 405 days and 274±479 days respectively. Conclusion PVOD is a rare and lethal cause of pulmonary hypertension. When suspected, a trial of medical therapy should be initiated carefully. The evaluation for lung transplant should be considered early given its high mortality.

Abstract 17370: Activation of Endothelial GCN2 Kinase Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and pulmonary vascular remodeling that result in right heart failure. Published studies show that recessive mutations in the EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) resulting in reduction of GCN2 are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients and EIF2AK4 mutation was also found in PAH patients although very rare. Objective: To determine the role of endothelial GCN2 kinase in the pathogenesis of PAH. Results: Employing Eif2ak4 -/- mice, we found that loss of GCN2 induced neither spontaneous PVOD nor pulmonary hypertension (PH). In response to chronic hypoxia, loss of GCN2 inhibited hypoxia-induced PH and pulmonary vascular remodeling. RNA-sequencing analysis of mouse lung samples indicated Endothelin-1 as the downstream target of GCN2 in regulating pulmonary vascular remodeling and PH. In cultured human lung microvascular endothelial cells, GCN2 was phosphorylated and activated in response to hypoxia, which mediated hypoxia-induced Endothelin-1 expression through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Endothelial cell-targeted nanoparticle delivery of plasmid DNA expressing Endothelin-1 selectively in endothelial cells in Eif2ak4 -/- mice markedly reversed the phenotype in response to hypoxia. Furthermore, nanoparticle delivery of the CRIPSR/Cas9 system-mediated knockout of Eif2ak4 in adult C57BL/6 mice also attenuated hypoxia-induced PH. Additionally, monocrotaline-induced vascular remodeling and PH in rats were inhibited by GCN2 inhibitor A-92 treatment. In lung samples of idiopathic PAH patients, we observed endothelial GCN2 hyperphosphorylation of pulmonary vascular lesions, without marked differences in GCN2 mRNA and protein levels compared to normal donor lungs. Conclusion: These studies demonstrate that endothelial GCN2 activation mediates pulmonary vascular remodeling and PAH development through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients without GCN2 loss of function mutations.

A Rare Case of Pulmonary Veno-Occlusive Disease, Pulmonary Capillary Hemangiomatosis

A 40-year-old male with past medical history of chronic pain on methadone for a few years, hypertension, and obesity presented with worsening dyspnea and was found to have significant hypoxemia. A CT-angiogram of the chest showed extensive diffuse bilateral pulmonary infiltrates with bilateral hilar and mediastinal lymphadenopathy.

Improvement in survival of acute myeloid leukemia and myelodysplastic syndrome patients following allogeneic transplant: a long-term institutional experience

BackgroundAllogeneic stem cell transplant (allo-SCT) plays a key role in the treatment of patients with both acute myeloid leukemia (AML) and myelodysplastic (MDS). Outcomes of allo-SCT have improved with optimization of transplant practices. We sought to evaluate trends in survival in AML and MDS patients undergoing allo-SCT at our institution from 1984 to 2018.MethodsA retrospective analysis of 900 consecutive AML and MDS patients undergoing allo-SCT was performed. Patients were divided by year of transplant for analysis. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints included non-relapse mortality (NRM), graft-versus-host disease (GVHD), GVHD-free relapse free survival (GRFS), and transplant complications.ResultsWe found a significant improvement in survival from 1984 to 2018 with 5-year PFS and OS improving from 17% to 49% and 17% to 53%, respectively (statistically significant difference since 2004; p<0.001). There was a significant difference in rates of grade II-IV aGVHD (p<0.001) and chronic GVHD at day +365 with cumulative incidence of both highest from 2014-2018, however, NRM improved across the years with 5- year NRM decreasing from 45% to 21%. Rates of pulmonary infections, hemorrhagic cystitis, veno-occlusive disease, and fungal infections also decreased across the years (p<0.001).ConclusionsWe found a significant improvement in survival of AML and MDS patients undergoing allo-HCT over the past several decades. This likely reflects improvements in transplant practices and general supportive care. Post-transplant relapse remains the leading cause of transplant failure in this group.

Echocardiographic Study of Ventricular Septal Defect in 1- to 12-Year-Old Children Visiting a Tertiary Care Center in Patna, India.

Background Symptoms of serious heart problems present at birthoften appear during the first few days, weeks, or months of a child's life. Shunt formation between the left and right ventricle is a crucial component of the pathophysiology of ventral septal defects. Objectives We aim to determine the most frequent types of ventricular septal defect (VSD) by echocardiography and whether there is any gender variation in the type of ventricular septal defect. Material and methods A total of 100 children who were clinically suspected of or diagnosed with VSD at the age of 1-12 years were enrolled in this study. The septum of the atrioventricular (AV) canal, the muscular septum, and the parietal band of the distal conal septum were evaluated by color Doppler. Ventricular septal defect (VSD) size and kind are similarly impacted by the 2D echo mode. The size and site of the VSD, associated congenital anomaly, and significant morphological changes in ventricular cavities, gender discrimination, and relation-specific types of ventricular septal defect were observed. Results A total of 100 VSD children presentedwith clinical symptoms of fast breathing, retraction of the chest, cough, cyanosis, fever, difficulty during feeding, cyanotic spell, chest pain, and edema at 65%, 62%, 54%, 52%, 54%, 29%, 9%, 11%, and 4%, respectively. Conclusion Early diagnosis is essential for effective medical care of diseases such as infective endocarditis (IE), which is present in some cases of VSD, and the avoidance of persistent pulmonary veno-occlusive disease (PVOD).

The chest CT signs for pulmonary veno-occlusive disease correlate with pulmonary haemodynamics in systemic sclerosis.

Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relation between clinical signs of PVOD and severing of pulmonary vasculopathy in SSc. This study comprised 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities (mPAP > 20 mmHg, PVR > 2 W.U. or PAWP > 15 mmHg). The chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0-1 group and the 2-3 group, according to the number of chest CT signs for PVOD, including 1) mediastinal lymph node enlargement, 2) thickened interlobular septal wall, and 3) ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function, and serum biomarkers were compared between the two groups. Mediastinal lymph node enlargement, thickened interlobular septal wall, and ground glass opacity were observed in 11 (21%), 32 (62%), and 11 (21%) patients, respectively. The 2-3 group (n = 15) had higher mPAP (p= 0.02) while lower DLco/VA (p= 0.02) compared with the 0-1 group (n = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide, and Krebs von den Lunge-6 were not different between the two groups. The CT signs for PVOD had positive correlation with mPAP but negative correlation with DLco in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein.

Pulmonary veno-occlusive disease with vanished pulmonary consolidation.

Pulmonary veno-occlusive disease (PVOD) is an extremely rare cause of pulmonary hypertension. Previously reported computed tomography (CT) findings of PVOD included centrilobular ground-glass opacities, a mosaic pattern, and septal lines; however, chest CT revealing pulmonary consolidation disappearance with repositioning has not been reported.

Bilateral lung transplantation for pediatric pulmonary arterial hypertension: perioperative management and one-year follow-up.

Bilateral lung transplantation (LuTx) remains the only established treatment for children with end-stage pulmonary arterial hypertension (PAH). Although PAH is the second most common indication for LuTx, little is known about optimal perioperative management and midterm clinical outcomes. Prospective observational study on consecutive children with PAH who underwent LuTx with scheduled postoperative VA-ECMO support at Hannover Medical School from December 2013 to June 2020. Twelve patients with PAH underwent LuTx (mean age 11.9 years; age range 1.9-17.8). Underlying diagnoses included idiopathic (n = 4) or heritable PAH (n = 4), PAH associated with congenital heart disease (n = 2), pulmonary veno-occlusive disease (n = 1), and pulmonary capillary hemangiomatosis (n = 1). The mean waiting time was 58.5 days (range 1-220d). Three patients were bridged to LuTx on VA-ECMO. Intraoperative VA-ECMO/cardiopulmonary bypass was applied and VA-ECMO was continued postoperatively in all patients (mean ECMO-duration 185 h; range 73-363 h; early extubation). The median postoperative ventilation time was 28 h (range 17-145 h). Echocardiographic conventional and strain analysis showed that 12 months after LuTx, all patients had normal biventricular systolic function. All PAH patients are alive 2 years after LuTx (median follow-up 53 months, range 26-104 months). LuTx in children with end-stage PAH resulted in excellent midterm outcomes (100% survival 2 years post-LuTx). Postoperative VA-ECMO facilitates early extubation with rapid gain of allograft function and sustained biventricular reverse-remodeling and systolic function after RV pressure unloading and LV volume loading.

Positive vasoreactive response in patients with genetically confirmed pulmonary veno-occlusive disease: case report

Positive vasoreactive response in patients with genetically confirmed pulmonary veno-occlusive disease: case report

Pneumatocele after lung transplantation

Pneumatoceles are a known complication of pneumonia or trauma, especially in young children. A 44-year-old male with pulmonary veno-occlusive disease and pulmonary hypertension underwent double lung transplantation with cardiopulmonary support. The patient had experienced severe primary graft dysfunction and bilateral lower lobe pneumonia. Posttransplant bronchoalveolar lavage fluid identified Staphylococcus aureus and Burkholderia cepacia. We started trimethoprim-sulfamethoxazole, meropenem, and minocycline. We also switched him to a prone position every 12 h for 3 days. The respiratory condition gradually improved with systemic therapy, prone position, oxygenation with ventilator, and venous-venous extracorporeal membrane oxygenation. Pneumatocele developed at the site of pneumonia. Although the pneumatocele was gradually increasing the size, we decided to continue conservative treatment. The pneumatocele spontaneously ruptured, and asymptomatic pneumothorax developed. We performed percutaneous drainage for pneumothorax, and the pneumatocele resolved. After he was discharged from the hospital, that pneumatocele shrank and disappeared. Pneumatocele can occur at the site of pneumonia after lung transplantation. It may be curable with conservative treatment, but the possibility of sudden rupture and pneumothorax should be considered.