Acute lung injury is characterized by injury to the lung epithelium that leads to impaired resolution of pulmonary edema and also facilitates accumulation of protein-rich edema fluid and inflammatory ...cells in the distal airspaces of the lung. Recent in vivo and in vitro studies suggest that mesenchymal stem cells (MSC) may have therapeutic value for the treatment of acute lung injury. Here we tested the ability of human allogeneic mesenchymal stem cells to restore epithelial permeability to protein across primary cultures of polarized human alveolar epithelial type II cells after an inflammatory insult. Alveolar epithelial type II cells were grown on a Transwell plate with an air-liquid interface and injured by cytomix, a combination of IL-1β, TNFα, and IFNγ. Protein permeability measured by 131I-labeled albumin flux was increased by 5-fold over 24 h after cytokine-induced injury. Co-culture of human MSC restored type II cell epithelial permeability to protein to control levels. Using siRNA knockdown of potential paracrine soluble factors, we found that angiopoietin-1 secretion was responsible for this beneficial effect in part by preventing actin stress fiber formation and claudin 18 disorganization through suppression of NFκB activity. This study provides novel evidence for a beneficial effect of MSC on alveolar epithelial permeability to protein.
Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have ...developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.
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•A postmortem bedside surgical procedure was developed for COVID-19 and control patients•Ciliated cells are the main target cell type for SARS-CoV-2 in the respiratory mucosa•Sustentacular cells (non-neuronal) are the main target cell type in the olfactory mucosa•No evidence for infection of olfactory sensory neurons or olfactory bulb parenchyma
Postmortem samples of respiratory and olfactory mucosa and whole olfactory bulbs are harvested immediately after the death of COVID-19 patients revealing ciliated cells and sustentacular cells but not olfactory sensory neurons as the main target cell types for SARS-CoV-2 infection and replication.
Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) are associated with chronic lung allograft dysfunction (CLAD) and mortality post lung transplantation, but data concerning ...prevalence, time of onset, persistence and effects on long-term outcome remain scarce.We assessed the association between HLA antibodies and CLAD-free and graft survival in a cohort of 362 patients. We stratified our analysis according to DSA status, persistence of antibodies and timing of antibodies (pre-transplant, early or late post-transplant).Within our cohort, 61 (17%) patients developed DSAs (mostly against HLA-DQ), which was associated with worse CLAD-free and graft survival (p<0.0001 and p=0.059, respectively). Persistent (hazard ratio (HR) 3.386, 95% CI 1.928-5.948; p<0.0001) as well as transient (HR 2.998, 95% CI 1.406-6.393; p=0.0045) DSAs were associated with shorter CLAD-free survival compared with patients without DSAs. Persistent DSAs (HR 3.071, 95% CI 1.632-5.778; p=0.0005) but not transient DSAs were negatively associated with graft survival compared with patients without DSAs, likely due to the higher incidence of restrictive CLAD. HLA non-DSAs and pre-transplant HLA antibodies had no effect on post-transplant outcome.We demonstrated an important difference in prognosis between persistent and transient DSAs. Moreover, the observed association between DSAs and restrictive CLAD suggests an overlap between antibody-mediated rejection and restrictive CLAD that needs further investigation.
Lung transplantation (LTx) is now a very established treatment for patients with end-stage lung diseases. However, shortage of suitable donors is still a major limitation for realizing the full ...success of this therapy. Donor lungs from both brain death donors (BDD) and circulatory death donors (DCD) are often injured as a result of brain injury-related cytokine storm, aspiration, infection, fluid overload, ventilator-associated lung injury, and warm ischemia, which prevents them safely being used for transplantation 1. Attempts to transplant injured donor lungs can lead to high incidence of severe primary graft dysfunction (PGD) and associated short- and long-term consequences to recipients 2. Therefore, utilization rates of lungs from multi-organ donors is low, ranging from 5% to 20%. One of the most attractive strategies to increase donor lung utilization is by improving assessment and treatment of the organ once it is removed from the hostile peri-procurement environment of the donor. In order to achieve this, normothermic ex vivo lung perfusion (EVLP) has been developed over the last 10 years.
Summary
Normothermic regional perfusion (NRP) in donation after circulatory death (DCD) is a safe alternative to in situ cooling and rapid procurement. An increasing number of countries and centres ...are performing NRP, a technically and logistically challenging procedure. This consensus document provides evidence‐based recommendations on the use of NRP in uncontrolled and controlled DCDs. It also offers minimal ethical, logistical and technical requirements that form the foundation of a safe and effective NRP programme. The present article is based on evidence and opinions formulated by a panel of European experts of Workstream 04 of the Transplantation Learning Journey project, which is part of the European Society for Organ Transplantation.
Normothermic regional perfusion (NRP) in donation after circulatory death (DCD) is a safe alternative to in situ cooling and rapid procurement. This consensus document provides evidence‐based recommendations on the use of NRP in uncontrolled and controlled DCDs. It also offers minimal ethical, logistical and technical requirements that form the foundation of a safe and effective NRP programme. The present article is based on evidence and opinions formulated by a panel of European experts of Workstream 04 of the Transplantation Learning Journey project, which is part of the European Society for Organ Transplantation.
Abstract
OBJECTIVES
Hearts donated after circulatory determination of death are usually preserved with normothermic machine perfusion prior to transplantation. This type of preservation is costly, ...requires bench time adding to warm ischaemia, and does not provide a reliable evaluation of the unloaded donor heart. We report on 4 successful donation after circulatory death (category III) hearts transplanted after thoraco-abdominal normothermic regional perfusion (NRP) and static cold storage.
METHODS
After life sustaining therapy was withdrawn and death was declared, perfusion to thoraco-abdominal organs was restored using extracorporeal circulation via cannulas in the femoral artery and vein and clamping of supra-aortic vessels. After weaning from extracorporeal circulation, cardiac function was assessed. Once approved, the heart was retrieved and stored using classic static cold storage. Data are expressed as median min–max.
RESULTS
Donor and recipient ages were 44 years 12–60 (n = 4) and 53 years 14–64 (n = 4), respectively. Time from the withdrawal of life sustaining therapy to start of NRP was 22 min 18–31. Cold storage time was 72 min 35–129. Thirty-day survival was 100% with a left ventricle ejection fraction of 60% 50–60.
CONCLUSIONS
Donation after circulatory death heart transplantation using thoraco-abdominal NRP and subsequent cold storage preservation for up to 129 min was safe for 4 procedures and could be a way to expand the donor heart pool while avoiding costs of machine preservation.
Long-term survival after lung transplantation (LTx) is hampered by development of chronic lung allograft dysfunction (CLAD).
is an established risk factor for CLAD. Therefore, we investigated the ...effect of
eradication on CLAD-free and graft survival.Patients who underwent first LTx between July, 1991, and February, 2016, and were free from CLAD, were retrospectively classified according to
presence in respiratory samples between September, 2011, and September, 2016.
-positive patients were subsequently stratified according to success of
eradication following targeted antibiotic treatment. CLAD-free and graft survival were compared between
-positive and
-negative patients; and between patients with or without successful
eradication. In addition, pulmonary function was assessed during the first year following
isolation in both groups.CLAD-free survival of
-negative patients (n=443) was longer compared with
-positive patients (n=95) (p=0.045). Graft survival of
-negative patients (n=443, 82%) was better compared with
-positive patients (n=95, 18%) (p<0.0001). Similarly,
-eradicated patients demonstrated longer CLAD-free and graft survival compared with patients with persistent
Pulmonary function was higher in successfully
-eradicated patients compared with unsuccessfully eradicated patients (p=0.035).
eradication after LTx improves CLAD-free and graft survival and maintains pulmonary function. Therefore, early
detection and eradication should be pursued.
Summary
In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We systematically reviewed ...outcomes of solid organ transplantation after RP by searching PubMed, Embase, and Cochrane libraries. Eighty‐eight articles reporting on outcomes of liver, kidney, pancreas, heart, and lung transplants or donor/organ utilization were identified. Meta‐analyses were conducted when possible. Methodological quality was assessed using National Institutes of Health (NIH)‐scoring tools. Case reports (13/88), case series (44/88), retrospective cohort studies (35/88), retrospective matched cohort studies (5/88), and case‐control studies (2/88) were identified, with overall fair quality. As blood viscosity and rheology change below 20 °C, studies were grouped as hypothermic (HRP, ≤20 °C) or normothermic (NRP, >20 °C) regional perfusion. Data demonstrate that RP is a safe alternative to in situ cold preservation (ISP) in uncontrolled and controlled DCDs. The scarce HRP data are from before 2005. NRP appears to reduce post‐transplant complications, especially biliary complications in controlled DCD livers, compared with ISP. Comparisons for kidney and pancreas with ISP are needed but there is no evidence that NRP is detrimental. Additional data on NRP in thoracic organs are needed. Whether RP increases donor or organ utilization needs further research.
This systematic review and meta‐analyses summarizes all available evidence on regional perfusion in donation after circulatory death donors. It found that regional perfusion is feasible and safe and reduces some complications after transplantation of organs that underwent regional perfusion.
Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well‐established treatment for a variety of ...chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We reviewed posttransplant outcome of ARDS patients from three high‐volume European transplant centers. Demographics and clinical data were collected and analyzed. Viral infection was the main reason for ARDS (n = 7/13, 53.8%). All patients were admitted to ICU and required mechanical ventilation, 11/13 were supported with ECMO at the time of listing. They were granted a median LAS of 76 (IQR 50–85) and waited for a median of 3 days (IQR 1.5–14). Postoperatively, median length of mechanical ventilation was 33 days (IQR 17–52.5), median length of ICU and hospital stay were 39 days (IQR 19.5–58.5) and 54 days (IQR 43.5–127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with a median duration of 2 days (IQR 2–7). 30‐day mortality was 7.7%, 1 and 5‐year survival rates were calculated as 71.6% and 54.2%, respectively. Given the lack of alternative treatment options, the herein presented results support the concept of offering live‐saving LTx to carefully selected ARDS patients.
In the largest cohort study from 3 European high‐volume centers, lung transplantation as a rescue therapy in 13 highly selected patients with acute respiratory distress syndrome bridged on mechanical ventilation or ECMO between August 1998 and May 2020, 30‐day mortality was 7.7% with 1‐year and 5‐year survival rates of 71.6% and 54.2%, respectively.
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