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Introduction: Compared with traditional static ice storage, controlled hypothermic storage (CHS) at 4-10°C may attenuate cold-induced lung injury between procurement and implantation. In this study, we describe the first European lung transplant (LTx) experience with a portable CHS device. Methods: A prospective observational study was conducted of all consecutively performed LTx following CHS (11 November 2022 and 31 January 2024) at two European high-volume centers. The LUNGguard device was used for CHS. The preservation details, total ischemic time, and early postoperative outcomes are described. The data are presented as median (range: minimum-maximum) values. Results: A total of 36 patients underwent LTx (i.e., 33 bilateral, 2 single LTx, and 1 lobar). The median age was 61 (15-68) years; 58% of the patients were male; 28% of the transplantations had high-urgency status; and 22% were indicated as donation after circulatory death. In 47% of the patients, extracorporeal membrane oxygenation (ECMO) was used for perioperative support. The indications for using the CHS device were overnight bridging (n = 26), remote procurement (n = 4), rescue allocation (n = 2), logistics (n = 2), feasibility (n = 1), and extended-criteria donor (n = 1). The CHS temperature was 6.5°C (3.7°C-9.3°C). The preservation times were 11 h 18 (2 h 42-17 h 9) and 13 h 40 (4 h 5-19 h 36) for the first and second implanted lungs, respectively, whereas the total ischemic times were 13 h 38 (4 h 51-19 h 44) and 15 h 41 (5 h 54-22 h 48), respectively. The primary graft dysfunction grade 3 (PGD3) incidence rates were 33.3% within 72 h and 2.8% at 72 h. Intensive care unit stay was 8 (4-62)â days, and the hospital stay was 28 (13-87)â days. At the last follow-up [139 (7-446)â days], three patients were still hospitalized. One patient died on postoperative day 7 due to ECMO failure. In-hospital Clavien-Dindo complications of 3b were observed in six (17%) patients, and 4a in seven (19%). Conclusion: CHS seems safe and feasible despite the high-risk recipient and donor profiles, as well as extended preservation times. PGD3 at 72â h was observed in 2.8% of the patients. This technology could postpone LTx to daytime working hours. Larger cohorts and longer-term outcomes are required to confirm these observations.
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Introduction: Chronic rejection is a major complication post-transplantation. Within lung transplantation, chronic rejection was considered as airway centred. Chronic Lung Allograft Dysfunction (CLAD), defined to cover all late chronic complications, makes it more difficult to understand chronic rejection from an immunological perspective. This study investigated the true nature, timing and location of chronic rejection as a whole, within mouse lung transplantation. Methods: 40 mice underwent an orthotopic left lung transplantation, were sacrificed at day 70 and evaluated by histology and in vivo µCT. For timing and location of rejection, extra grafts were sacrificed at day 7, 35, 56 and investigated by ex vivo µCT or single cell RNA (scRNA) profiling. Results: Chronic rejection originated as innate inflammation around small arteries evolving toward adaptive organization with subsequent end-arterial fibrosis and obliterans. Subsequently, venous and pleural infiltration appeared, followed by airway related bronchiolar folding and rarely bronchiolitis obliterans was observed. Ex vivo µCT and scRNA profiling validated the time, location and sequence of events with endothelial destruction and activation as primary onset. Conclusion: Against the current belief, chronic rejection in lung transplantation may start as an arterial response, followed by responses in venules, pleura, and, only in the late stage, bronchioles, as may be seen in some but not all patients with CLAD.
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Rejeição de Enxerto , Transplante de Pulmão , Animais , Transplante de Pulmão/efeitos adversos , Rejeição de Enxerto/imunologia , Camundongos , Doença Crônica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Pulmão/patologia , Pulmão/imunologia , Masculino , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/patologiaRESUMO
Lung transplant (LTx) recipients are at high risk for COVID-19 related morbidity and mortality. Data regarding pre-exposure prophylaxis (PrEP) with tixagevimab-cilgavimab in this population are scarce. We therefore evaluated COVID-19 breakthrough infections and COVID-19 related complications after PrEP in a retrospective single-center study, including 264 LTx recipients who received PrEP between June 2022 and December 2022, when Omicron BA.5 was the dominant circulating SARS-CoV-2 variant. PrEP was indicated for fully vaccinated patients with poor seroconversion (anti-S <260 BAU/mL). COVID-19 breakthrough infection after PrEP occurred in 11.0% within the first 3 months, increasing to 17.4% within 6 months. Hospitalization rate rose from 27.6% to 52.9% (p = 0.046), while ICU admissions and COVID-19 mortality remained low, respectively occurring in 6.5% and 4.3% of patients with breakthrough infection within 6 months. COVID-19 breakthrough infection and associated hospitalization remained an important problem during the Omicron BA.5 surge in fully vaccinated LTx recipients with deficient seroconversion, despite PrEP with tixagevimab-cilgavimab. However, ICU admissions and COVID-19 mortality were low. Waning of neutralizing effects of PrEP and changing circulating SARS-CoV-2 variants may explain increases in COVID-19 infections and hospitalizations over time after PrEP, highlighting the need for novel, long-term effective PrEP strategies in these high-risk patients.
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Anticorpos Monoclonais , Infecções Irruptivas , COVID-19 , Profilaxia Pré-Exposição , Humanos , COVID-19/prevenção & controle , SARS-CoV-2 , Estudos Retrospectivos , Transplantados , PulmãoRESUMO
Background: Lung transplantations are highly complex procedures, often conducted in frail patients. Through the addition of immunosuppressants, healing can be compromised, primarily leading to the development of bronchopleural fistulas. Although esophageal fistulas (EFs) after lung transplantation remain rare, they are associated with significant morbidity. We aimed to investigate the clinical presentation, diagnostic approaches, and treatment strategies of EF after lung transplantation. Methods: All patients who developed EF after lung transplantation at the University Hospitals Leuven between January 2019 and March 2022 were retrospectively reviewed and the clinical presentations, diagnostic approaches, and treatment strategies were summarized. Results: Among 212 lung transplantation patients, 5 patients (2.4%) developed EF. Three patients were male and median age was 39 y (range, 34-63). Intraoperative circulatory support was required in 3 patients, with 2 needing continued support postoperatively. Bipolar energy devices were consistently used for mediastinal hemostasis. All EFs were right-sided. Median time to diagnosis was 28 d (range, 12-48) and 80% of EFs presented as recurrent respiratory infections or empyema. Diagnosis was made through computed tomography (nâ =â 3) or esophagogastroscopy (nâ =â 2). Surgical repair with muscle flap covering achieved an 80% success rate. All patients achieved complete resolution, with only 1 patient experiencing a fatal outcome during a complicated EF-related recovery. Conclusion: Although EF after lung transplantation remains rare, vigilance is crucial, particularly in cases of right-sided intrathoracic infection. Moreover, caution must be exercised when applying thermal energy in the mediastinal area to prevent EF development and mitigate the risk of major morbidity. Timely diagnosis and surgical intervention can yield favorable outcomes.
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Background: Extracorporeal life support (ECLS) is not routinely used at our center during sequential single-lung transplantation (LTx), but is restricted to anticipate and overcome hemodynamic and respiratory problems occurring peri-operatively. In this retrospective descriptive cohort study, we aim to describe our single-center experience with ECLS in LTx, analyzing ECLS-related complications. Methods: All transplantations with peri-operative ECLS use [2010-2020] were retrospectively analyzed. Multi-organ and heart-lung transplantation were excluded. Demographics, support type and indications are described. Complications are categorized according to the underlying nature and type. Data are presented as median [interquartile range (IQR)]. Kaplan-Meier was used for survival analysis. Results: The overall use of ECLS was 22% (156/703 patients) with a mean age of 52 years (IQR, 36-59 years). Transplant indications in ECLS cohort were interstitial lung disease (38%; n=60), chronic obstructive pulmonary disease (COPD) (19%; n=29), cystic fibrosis (17%; n=26) and others (26%; n=41). Per indication, 94% (15/16) of pulmonary arterial hypertension patients required ECLS, whereas only 8% (29/382) of COPD patients did. In 16% (25/156) of supported patients, veno-venous extracorporeal membrane oxygenation was initiated, while 77% (120/156) required veno-arterial support, and 7% (11/156) cardiopulmonary bypass. Thirty-day mortality was 6% (9/156). Sixteen percent (25/156) of patients were bridged to transplantation on ECLS and 24% (37/156) required post-operative support. Main reasons to use ECLS were intra-operative hemodynamic instability (53%; n=82), ventilation/oxygenation problems (22%; n=34) and reperfusion edema (17%; n=26). Overall incidence of patients with at least one ECLS-related complication was 67% (n=104). Most common complications were hemothorax (25%; n=39), need for continuous renal replacement therapy (19%; n=30), and thromboembolism (14%; n=22). Conclusions: ECLS was required in 22% of LTxs, with a reported ECLS-related complication rate of 67%, of which the most common was hemothorax. Larger databases are needed to further analyze complications and develop tailored deployment strategies for ECLS-use in LTx.
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Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and potentially life-threatening complication of acute pulmonary embolism. It is characterised by persistent fibro-thrombotic pulmonary vascular obstructions and elevated pulmonary artery pressure leading to right heart failure. The diagnosis is based on two steps, as follows: 1) suspicion based on symptoms, echocardiography and ventilation/perfusion scan and 2) confirmation with right heart catheterisation, computed tomography pulmonary angiography and, in most cases, digital subtraction angiography. The management of CTEPH requires a multimodal approach, involving medical therapy, interventional procedures and surgical intervention. This clinical-radiological-pathological correlation paper illustrates the diagnostic and therapeutic management of two patients. The first had chronic thromboembolic pulmonary disease without pulmonary hypertension at rest but with significant physical limitation and was successfully treated with pulmonary endarterectomy. The second patient had CTEPH associated with splenectomy and was considered unsuitable for surgery because of exclusive subsegmental lesions combined with severe pulmonary hypertension. The patient benefited from multimodal treatment involving medical therapy followed by multiple sessions of balloon pulmonary angioplasty. Both patients had normalised functional capacity and pulmonary haemodynamics 3-6â months after the interventional treatment. These two examples show that chronic thromboembolic pulmonary diseases are curable if diagnosed promptly and referred to CTEPH centres for specialist treatment.
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Angioplastia com Balão , Hipertensão Pulmonar , Embolia Pulmonar , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/terapia , Angioplastia com Balão/efeitos adversos , Angiografia/efeitos adversos , Tomografia Computadorizada por Raios X , Doença Crônica , Endarterectomia/efeitos adversos , Artéria PulmonarRESUMO
Background: Lung re-transplantation (re-LTx) is the only therapeutic option for selected patients with advanced allograft dysfunction. This study aims to describe our center's experience to illustrate the feasibility and safety of off-pump re-LTx avoiding clamshell incision. Methods: We performed a retrospective analysis of 42 patients who underwent bilateral re-LTx between 2007 and 2021. Patients were classified according to their surgical approach and extracorporeal life support (ECLS)-use. Demographics, surgical technique, and short- and long-term outcomes were compared between groups. Continuous data were examined with an independent-sample t-test or non-parametric test. Pearson's chi-squared and Fisher's exact were used to analyze categorical data. Results: Twenty-six patients (61.9%) underwent re-LTx by anterior thoracotomy without ECLS. Compared to the more invasive approach (thoracotomy with ECLS and clamshell with/without ECLS, n=16, 38.1%), clamshell-avoiding off-pump re-LTx patients had a shorter operative time (471.6±111.2 vs. 704.0±273.4 min, P=0.010) and less frequent grade 3 primary graft dysfunction (PGD-3) at 72 h (7.7% vs. 37.5%, P=0.038). No significant difference was found in PGD-3 incidence within 72 h, mechanical ventilation, intensive care unit (ICU) and hospital stay, and the incidence of reoperation within 90 days between groups (P>0.05). In the long-term, the clamshell-avoiding and off-pump approach resulted in similar 1- and 5-year patient survival vs. the more invasive approach. Conclusions: Our experience shows that clamshell-avoiding off-pump re-LTx is feasible and safe in selected patients on a case-by-case evaluation.
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BACKGROUND: Bronchiolitis obliterans syndrome (BOS) after lung transplantation is characterized by fibrotic small airway remodeling, recognizable on high-resolution computed tomography (HRCT). We studied the prognostic value of key HRCT features at BOS diagnosis after lung transplantation. METHODS: The presence and severity of bronchiectasis, mucous plugging, peribronchial thickening, parenchymal anomalies, and air trapping, summarized in a total severity score, were assessed using a simplified Brody II scoring system on HRCT at BOS diagnosis, in a cohort of 106 bilateral lung transplant recipients transplanted between January 2004 and January 2016. Obtained scores were subsequently evaluated regarding post-BOS graft survival, spirometric parameters, and preceding airway infections. RESULTS: A high total Brody II severity score at BOS diagnosis (P = 0.046) and high subscores for mucous plugging (P = 0.0018), peribronchial thickening (P = 0.0004), or parenchymal involvement (P = 0.0121) are related to worse graft survival. A high total Brody II score was associated with a shorter time to BOS onset (P = 0.0058), lower forced expiratory volume in 1 s (P = 0.0006) forced vital capacity (0.0418), more preceding airway infections (P = 0.004), specifically with Pseudomonas aeruginosa (P = 0.002), and increased airway inflammation (P = 0.032). CONCLUSIONS: HRCT findings at BOS diagnosis after lung transplantation provide additional information regarding its underlying pathophysiology and for future prognosis of graft survival.
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Síndrome de Bronquiolite Obliterante , Bronquiolite Obliterante , Transplante de Pulmão , Humanos , Prognóstico , Bronquiolite Obliterante/diagnóstico por imagem , Bronquiolite Obliterante/etiologia , Transplantados , Pulmão/diagnóstico por imagem , Transplante de Pulmão/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Volume Expiratório Forçado , Estudos RetrospectivosRESUMO
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. The reasons why clots do not resorb are incompletely understood, but the result is partial or complete fibrothrombotic obstruction of pulmonary arteries. A secondary microvasculopathy aggravates the pulmonary hypertension (PH) as a consequence of high flow and shear stress in the nonoccluded arteries. The treatment of CTEPH has long been purely surgical, but many patients were inoperable because of inaccessible lesions or severe comorbidities. Alternatives were developed, including medical therapy and more recently balloon pulmonary angioplasty (BPA). Depending on the generation of the obstructed vessels, the treatment will be surgical, up to the (sub)segmental level, or by BPA for more distal vessels. PH drugs are used to treat the microvasculopathy. The current paper describes the therapeutic management of inoperable patients: the medical approach with PH drugs used in mono- or combination therapy; the proper use of anticoagulants in CTEPH; the technique, indications, and results at short- and long-term of BPA; the multimodal approach for inoperable patients combining PH drugs and BPA; and the effects of rehabilitation. It shows the importance of a multidisciplinary approach to the disease.
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Angioplastia com Balão , Hipertensão Pulmonar , Embolia Pulmonar , Trombose , Humanos , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/complicações , Embolia Pulmonar/complicações , Embolia Pulmonar/terapia , Artéria Pulmonar , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/métodos , Trombose/etiologia , Doença CrônicaRESUMO
We present the case of a 78-year-old female undergoing pulmonary endarterectomy (PEA) because of suspected chronic thromboembolic pulmonary hypertension (CTEPH). During surgery firm black masses were encountered in the aortopulmonary window and on the cranial part of the right pulmonary artery (PA). After PA arteriotomy we visualized intraluminal black firm stenosing plaques at the orifices of the three right and of the left lingular and lower lobar branches. Since no dissection plane could be obtained the procedure was discontinued. Subsequent bronchoscopy visualized a submucosal dark black-blue discoloration in both main bronchi. Pathological analysis revealed anthracofibrosis, which could be explained by biomass smoke exposure in the past. We are the first to provide intravascular pictures and pathologic images of this very rare entity. Moreover, we report stenoses at the orifices of the three right-sided lobar and of the left-sided lingular and lower lobe arteries, in contrast to three previous reports that report on single locations caused by extrinsic PA compression from lymphadenopathy. Our case, however, suggests extension of fibrosis with anthracotic pigment into the PA wall. We conclude that in the absence of a clear history of exposure to carbon smoke and with consequently no diagnostic bronchoscopy, anthracofibrosis of the lungs may mimic CTEPH not only by external compression but also by extension into pulmonary vascular structures. PEA-surgery should not be attempted in these cases.
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BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition and rare complication of acute pulmonary embolism. Mechanisms underlying impaired clot resolution and in sustained fibrothrombotic obstruction of the pulmonary arterial bed remain poorly understood. Since defective angiogenesis correlated to defective clot resolution based on observations in surgical material from patients with CTEPH, we aimed to validate its crucial pathogenic role by intrathrombus inhibition of angiogenesis in a novel CTEPH rabbit model. METHODS: We aimed to compare whether intrathrombus administration of an antifibrinolytic agent, tranexamic acid, or an inhibitor of angiogenesis, SU5416, would contribute to CTEPH progression. Both products were administered on a weekly basis by autologous clot embolization in rabbits. Right ventricular pressure was monitored by telemetry, right ventricular function by transthoracic echocardiography, and a complete pulmonary hemodynamic evaluation was obtained through right heart catheterization. Markers of inflammation, endothelial dysfunction, heart failure, and fibrinolysis were measured in plasma. Pulmonary vessel remodeling was analyzed by immunohistochemistry. RESULTS: Impairing intrathrombus angiogenesis by repeatedly embolizing autologous blood clots containing SU5416 resulted in elevated mean pulmonary arterial pressure (38 mm Hg), increased indexed pulmonary vascular resistance, and enhanced right ventricular hypertrophy (80%, 1.9-fold, 36%, respectively, compared with rabbits embolized with clots containing an antifibrinolytic agent). This was caused by both obstruction of large pulmonary arteries with fibrothrombotic material and muscularization of pulmonary microvessels, and accompanied by inflammatory cell infiltration and increased circulating endothelin-1. CONCLUSIONS: The key role of angiogenesis-driven clot resolution was validated in a reliable small-animal model reproducing the major pathophysiological hallmarks of CTEPH.
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Antifibrinolíticos , Hipertensão Pulmonar , Embolia Pulmonar , Trombose , Animais , Coelhos , Antifibrinolíticos/farmacologia , Artéria Pulmonar , Doença CrônicaRESUMO
Fungal exposure and sensitization negatively affect outcomes in various respiratory diseases, however, the effect of fungal sensitization in lung transplant (LTx) recipients is still unknown. We performed a retrospective cohort study of prospectively collected data on circulating fungal specific IgG/IgE antibodies, and their correlation with fungal isolation, chronic lung allograft dysfunction (CLAD) and overall survival after LTx. 311 patients transplanted between 2014 and 2019 were included. Patients with elevated Aspergillus fumigatus or Aspergillus flavus IgG (10%) had more mold and Aspergillus species isolation (p = 0.0068 and p = 0.0047). Aspergillus fumigatus IgG was specifically associated with Aspergillus fumigatus isolation in the previous or consecutive year (AUC 0.60, p = 0.004 and AUC 0.63, p = 0.022, respectively). Elevated Aspergillus fumigatus or Aspergillus flavus IgG was associated with CLAD (p = 0.0355), but not with death. Aspergillus fumigatus, Aspergillus flavus or Aspergillus niger IgE was elevated in 19.3% of patients, but not associated with fungal isolation, CLAD or death. Mold isolation and Aspergillus species isolation from respiratory cultures were associated with CLAD occurrence (p = 0.0011 and p = 0.0005, respectively), and Aspergillus species isolation was also associated with impaired survival (p = 0.0424). Fungus-specific IgG could be useful in long-term follow-up post-LTx, as a non-invasive marker for fungal exposure, and thus a diagnostic tool for identifying patients at risk for fungal-related complications and CLAD.
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Transplante de Pulmão , Humanos , Estudos Retrospectivos , Imunoglobulina G , Imunoglobulina E , Pulmão , AloenxertosRESUMO
OBJECTIVE: To describe our experience with lung transplantation (LTx) from donors ≥70 years and compare short and long-term outcomes to a propensity-matched cohort of donors <70 years. BACKGROUND: Although extended-criteria donors have been widely used to enlarge the donor pool, the experience with LTx from older donors (≥70 years) remains limited. METHODS: All single-center bilateral LTx between 2010 and 2020 were retrospectively analyzed. Matching (1:1) was performed for the donor (type, sex, smoking history, x-ray abnormalities, partial pressure of oxygen/fraction of inspired oxygen ratio, and time on ventilator) and recipient characteristics (age, sex, LTx indication, perioperative extracorporeal life support, and cytomegalovirus mismatch). Primary graft dysfunction grade-3, 5-year patient, and chronic lung allograft dysfunction-free survival were analyzed. RESULTS: Out of 647 bilateral LTx, 69 were performed from donors ≥70 years. The mean age in the older donor cohort was 74 years (range: 70-84 years) versus 49 years (range: 12-69 years) in the matched younger group. No significant differences were observed in the length of ventilatory support, intensive care unit, or hospital stay. Primary graft dysfunction-3 was 26% in the older group versus 29% in younger donor recipients ( P = 0.85). Reintervention rate was comparable (29% vs 16%; P = 0.10). Follow-up bronchoscopy revealed no difference in bronchial anastomotic complications ( P = 1.00). Five-year patient and chronic lung allograft dysfunction-free survivals were 73.6% versus 73.1% ( P = 0.72) and 51.5% versus 59.2% ( P = 0.41), respectively. CONCLUSIONS: LTx from selected donors ≥70 years is feasible and safe, yielding comparable short and long-term outcomes in a propensity-matched analysis with younger donors (<70 years).
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Transplante de Pulmão , Disfunção Primária do Enxerto , Humanos , Idoso , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Resultado do Tratamento , Doadores de Tecidos , OxigênioRESUMO
Pulmonary vein stenosis (PVS) and pulmonary vein occlusion (PVO) represent rare complications after lung transplantation (LTx), with limited therapeutic options and a high risk of graft loss. We present 2 cases of successful endovascular transatrial stenting following double LTx. A 60-year-old woman with chronic obstructive pulmonary disease who underwent double lobar LTx was diagnosed at postoperative day 72 with a high-grade PVS on the left side. A 22-year-old woman with idiopathic pulmonary arterial hypertension who underwent double LTx was diagnosed 9 days later with PVO of the left upper lobe vein. To avoid surgical reintervention, endovascular transatrial dilatation and stenting were performed successfully in both cases. Transatrial endovascular stenting of PVS or PVO after LTx seems an effective and safe treatment option that should be considered for these life-threatening complications and executed with care.
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Pneumopatias , Transplante de Pulmão , Veias Pulmonares , Pneumopatia Veno-Oclusiva , Estenose de Veia Pulmonar , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Adulto , Estenose de Veia Pulmonar/cirurgia , Estenose de Veia Pulmonar/complicações , Veias Pulmonares/cirurgia , Pneumopatia Veno-Oclusiva/etiologia , Pneumopatia Veno-Oclusiva/cirurgia , Pulmão , Pneumopatias/complicações , Transplante de Pulmão/efeitos adversos , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Pulmonary hypertension (PH) is a chronic disorder of the pulmonary circulation that often associates with other respiratory diseases (i.e., group III PH), leading to worsened symptoms and prognosis, notably when combined with interstitial lung diseases such as pulmonary fibrosis (PF). PH may lead to right ventricular (RV) failure, which accounts for a substantial part of the mortality in chronic lung disease patients. The disappointing results of pulmonary arterial hypertension (PAH)-related therapies in patients with PF emphasize the need to better understand the pathophysiologic mechanisms that drive PH development and progression in this specific setting. In this work, we validated an animal model of group III PH associated with PF (PH-PF), by using bleomycin (BM) intratracheal instillation and characterizing the nature of induced lung and vascular remodeling, including the influence on RV structure and function. To our knowledge, this is the first work describing this dose of BM in Sprague Dawley rats and the effects upon the heart and lungs, using different techniques such as echocardiography, heart catheterization, and histology. Our data shows the successful implementation of a rat model that mimics combined PF-PH, with most features seen in the equivalent human disease, such as lung and arterial remodeling, increased mPAP and RV dysfunction.
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Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the time of lung transplantation, and control tissue was obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4-mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies and organ collection were performed 3 weeks after instillation. Only significant results (P < 0.05) are presented. In PF lung tissue, GCN2 protein expression was decreased compared with control tissue. GCN2 expression was reduced in CD31+ endothelial cells. In line with human data, GCN2 protein expression was decreased in the lung of bleomycin rats compared with saline. EIF2AK4-mutated rats treated with bleomycin showed increased parenchymal fibrosis (hydroxyproline concentrations) and vascular remodeling (media wall thickness) as well as increased right ventricular systolic pressure compared with wild-type animals. Our data show that GCN2 is dysregulated in both humans and in an animal model of combined PF and PH. The possibility of a causative implication of GCN2 dysregulation in PF and/or PH development should be further studied.
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Hipertensão Pulmonar , Fibrose Pulmonar , Animais , Humanos , Masculino , Ratos , Bleomicina , Células Endoteliais/patologia , Hipertensão Pulmonar/patologia , Pulmão/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Fibrose Pulmonar/patologia , Ratos Sprague-DawleyRESUMO
In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, the median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM). In lung transplant recipients with idiopathic inflammatory myopathy, survival was similar to that in all-cause transplantation and was worse in patients with muscle involvement compared to those with the amyopathic disease.
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Doenças Pulmonares Intersticiais , Transplante de Pulmão , Miosite , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos de Coortes , Estudos Retrospectivos , Miosite/cirurgia , Miosite/complicações , Doenças Pulmonares Intersticiais/cirurgia , Doenças Pulmonares Intersticiais/etiologia , Transplante de Pulmão/efeitos adversosRESUMO
The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung disease (ILD) and with prolonged pre-transplant survival in idiopathic pulmonary fibrosis (IPF), but no information is available regarding its prevalence in other respiratory diseases and its influence on post-transplant outcome. We included the Leuven lung transplantation cohort between 1991 and 2015 (n = 801). We assessed the minor allele frequency (MAF) of the MUC5B variant in the entire study cohort and investigated the influence of recipient MUC5B promoter polymorphism on post-transplant outcome in patients who were transplanted after 2004. MUC5B was successfully genotyped in 746 patients. The MAF was significantly higher in ILD (17.6%) compared to chronic obstructive pulmonary disease (COPD)/emphysema (9.3%), cystic fibrosis (CF)/bronchiectasis (BRECT) (7.5%) and pulmonary hypertension (PHT) (7.4%) (p < 0.001). No association was observed between rs35705950 and chronic lung allograft dysfunction (CLAD)/graft loss in the ILD population [CLAD: HR 1.37 95% CI (0.70-2.68); graft loss: HR 1.02 95% CI (0.55-1.89)], nor the entire study cohort [CLAD: HR 0.96 95% CI (0.69-1.34); graft loss: HR 0.97 95% CI (0.70-1.35)]. The MUC5B promoter polymorphism is a very specific predictive factor for the presence of pulmonary fibrosis as it is only associated with pulmonary fibrosis and not with other chronic respiratory diseases. While the MUC5B promoter variant is associated with better pre-transplant survival among IPF patients, recipient MUC5B promoter variant does not play a role in post-transplant outcome.