Background There is significant heterogeneity within the primary graft dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung dysfunction and ...patterns of resolution. Methods Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 h after transplantation were included. Latent class analysis (LCA) was used to statistically identify classes based on changes in PGD International Society for Heart & Lung Transplantation grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death. Results Of 1,255 subjects, 361 had grade 3 PGD within the first 72 h after transplantation. LCA identified three distinct phenotypes: (1) severe persistent dysfunction (class 1), (2) complete resolution of dysfunction within 72 h (class 2), and (3) attenuation, without complete resolution within 72 h (class 3). Increased use of cardiopulmonary bypass, greater RBC transfusion, and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (hazard ratio, 2.39; 95% CI, 1.57-3.63; P < .001). Conclusions There are distinct phenotypes of resolution of dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas those with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of graft dysfunction.
Abstract
While seizure activity may be electrographically widespread, increasing evidence has suggested that ictal discharges may in fact represent travelling waves propagated from a focal seizure ...source. Interictal epileptiform discharges (IEDs) are an electrographic manifestation of excessive hypersynchronization of cortical activity that occur between seizures and are considered a marker of potentially epileptogenic tissue. The precise relationship between brain regions demonstrating IEDs and those involved in seizure onset, however, remains poorly understood. Here, we hypothesize that IEDs likewise reflect the receipt of travelling waves propagated from the same regions which give rise to seizures.
Forty patients from our institution who underwent invasive monitoring for epilepsy, proceeded to surgery and had at least one year of follow-up were included in our study. Interictal epileptiform discharges were detected using custom software, validated by a clinical epileptologist.
We show that IEDs reach electrodes in sequences with a consistent temporal ordering, and this ordering matches the timing of receipt of ictal discharges, suggesting that both types of discharges spread as travelling waves. We use a novel approach for localization of ictal discharges, in which time differences of discharge receipt at nearby electrodes are used to compute source location; similar algorithms have been used in acoustics and geophysics. We find that interictal discharges co-localize with ictal discharges. Moreover, interictal discharges tend to localize to the resection territory in patients with good surgical outcome and outside of the resection territory in patients with poor outcome. The seizure source may originate at, and also travel to, spatially distinct IED foci.
Our data provide evidence that interictal discharges may represent travelling waves of pathological activity that are similar to their ictal counterparts, and that both ictal and interictal discharges emerge from common epileptogenic brain regions. Our findings have important clinical implications, as they suggest that seizure source localizations may be derived from interictal discharges, which are much more frequent than seizures.
The significance of interictal epileptiform discharges (IEDs) in patients with epilepsy is incompletely understood. Diamond et al. show that both ictal discharges and IEDs are travelling waves which emerge from common epileptogenic brain regions. These findings may underscore a new role for IEDs in seizure source localization.
See Schevon and Michalak (https://doi.org/10.1093/brain/awad108) for a scientific commentary on this article.
In 2005, the International Society for Heart and Lung Transplantation published a standardized definition of primary graft dysfunction (PGD), facilitating new knowledge on this form of acute lung ...injury that occurs within 72 h of lung transplantation. PGD continues to be associated with significant morbidity and mortality. This article will summarize the current literature on the epidemiology of PGD, pathogenesis, risk factors, and preventive and treatment strategies.
Since 2011, several manuscripts have been published that provide insight into the clinical risk factors and pathogenesis of PGD. In addition, several transplant centers have explored preventive and treatment strategies for PGD, including the use of extracorporeal strategies. More recently, results from several trials assessing the role of extracorporeal lung perfusion may allow for much-needed expansion of the donor pool, without raising PGD rates.
This article will highlight the current state of the science regarding PGD, focusing on recent advances, and set a framework for future preventive and treatment strategies.
In November 2017, the donation service area (DSA) was removed as the primary unit of US donor lung allocation. Our primary objective was to evaluate the effect of this change on recipient ...characteristics, the use of pretransplant extracorporeal membrane oxygenation (ECMO), and on index hospitalization length of stay (LOS) and early posttransplant complications. We also assessed whether these outcomes differed in high and low competition centers, as defined by the Herfindahl‐Hirschman Index. Following DSA removal, there was a 9‐day decrease in median waitlist time (P = .001) and an increase in median lung allocation score (40 vs 42, P < .0001) but no difference in the need for pretransplant ECMO (incidence rate ratio = 1.16, P = .12). Median LOS increased from 17 to 19 days in the post‐DSA era (P = .01). There was no difference in posttransplant outcomes, including prolonged ventilation, new dialysis, or early survival, in the general cohort or between competition groups. High competition centers saw an 18.5‐minute increase in ischemic time compared to low competition centers (P = .04) but did not differentially increase single lung transplants or pretransplant ECMO utilization. Overall, DSA elimination was associated with increased posttransplant LOS but no significant differences in pretransplant ECMO or other posttransplant outcomes. Effects were largely similar at low and high competition centers.
In a retrospective cohort study comparing United States lung transplants performed in the year before versus after elimination of donation service area in the lung allocation algorithm, the authors report no effect on pretransplant resource utilization but an increase in postoperative length of stay.
The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging ...coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID50 > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens.
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•Iterative structure-based design of SARS-CoV-2 ferritin nanoparticle immunogens•Elicitation of potent neutralizing activity against SARS-CoV-2, VoCs, and SARS-CoV-1•Passively transferred immune-IgG protects K18-hACE2 mice from SARS-CoV-2 challenge
Joyce et al. generate four categories of engineered SARS-CoV-2 ferritin nanoparticle immunogens using structure-based vaccine design that recapitulate the prefusion SARS-CoV-2 spike, S1, and RBD. These immunogens induce robust and protective neutralizing antibody responses against SARS-CoV-2 and elicit potent neutralization against variants of concern and the heterologous SARS-CoV-1.
The goal of this case report is to describe the process, challenges, and opportunities of implementing rehabilitation for individuals who were critically ill and required both mechanical ventilation ...(MV) and extracorporeal membrane oxygenation (ECMO) support following a coronavirus 2019 (COVID-19) infection in an academic medical center.
This administrative case report is set in a heart and vascular intensive care unit, a 35-bed critical care unit that provides services for patients with various complex cardiovascular surgical interventions, including transplantation. Patients were admitted to the heart and vascular intensive care unit with either COVID-19 acute respiratory distress syndrome or pulmonary fibrosis for consideration of bilateral orthotropic lung transplantation. The authors describe the process of establishing rehabilitation criteria for patients who, by previously established guidelines, would be considered too ill to engage in rehabilitation.
The rehabilitation team, in coordination with an interprofessional team of critical care providers including physicians, respiratory care providers, perfusionists, and registered nurses, collaborated to implement a rehabilitation program for patients with critical COVID-19 being considered for bilateral orthotropic lung transplantation. This was accomplished by (1) reviewing previously published guidelines and practices; (2) developing an interdisciplinary framework for the consideration of rehabilitation treatment; and (3) implementing the framework for patients in our heart and vascular intensive care unit.
In response to the growing volume of patients admitted with critical COVID-19, the team initiated and developed an interprofessional framework and successfully provided rehabilitation services to patients who were critically ill. While resource-intensive, the process demonstrates that rehabilitation can be implemented on a case-by-case basis for select patients receiving extracorporeal membrane oxygenation and MV, who would previously have been considered too critically ill for rehabilitation services.
Rehabilitating patients with end-stage pulmonary disease on extracorporeal membrane oxygenation and MV support is challenging but feasible with appropriate interprofessional collaboration and knowledge sharing.
Pathobiology of frailty in lung disease Koons, Brittany; Greenland, John R.; Diamond, Joshua M. ...
Translational research : the journal of laboratory and clinical medicine,
07/2020, Letnik:
221
Journal Article
Recenzirano
Odprti dostop
Frailty is a clinical state of vulnerability to stressors resulting from cumulative alterations in multiple physiological and molecular systems. Frailty assessment in patients with chronic disease is ...useful for identifying those who are at increased risk for poor clinical and patient reported outcomes. Due to biobehavioral changes purported to cause both frailty and certain chronic lung diseases, patients with lung disease appear susceptible to frailty and prone to developing it decades earlier than community dwelling healthy populations. Herein, we review the literature and potential pathobiological mechanisms underpinning associations between frailty in lung disease and age, sex, comorbidity and symptom burden, severity of lung disease, inflammatory biomarkers, various clinical parameters, body composition measures, and physical activity levels. We also propose a multipronged program of future research focused on improving the accuracy and precision of frailty measurement in lung disease, identifying blood-based biomarkers and measures of body composition for frailty, determining whether subphenotypes of frailty with distinct pathobiology exist, and developing personalized interventions that target the specific underlying mechanisms causing frailty.
Primary Graft Dysfunction Natalini, Jake G; Diamond, Joshua M
Seminars in respiratory and critical care medicine,
06/2021, Letnik:
42, Številka:
3
Journal Article
Recenzirano
Primary graft dysfunction (PGD) is a form of acute lung injury after transplantation characterized by hypoxemia and the development of alveolar infiltrates on chest radiograph that occurs within 72 ...hours of reperfusion. PGD is among the most common early complications following lung transplantation and significantly contributes to increased short-term morbidity and mortality. In addition, severe PGD has been associated with higher 90-day and 1-year mortality rates compared with absent or less severe PGD and is a significant risk factor for the subsequent development of chronic lung allograft dysfunction. The International Society for Heart and Lung Transplantation released updated consensus guidelines in 2017, defining grade 3 PGD, the most severe form, by the presence of alveolar infiltrates and a ratio of PaO
:FiO
less than 200. Multiple donor-related, recipient-related, and perioperative risk factors for PGD have been identified, many of which are potentially modifiable. Consistently identified risk factors include donor tobacco and alcohol use; increased recipient body mass index; recipient history of pulmonary hypertension, sarcoidosis, or pulmonary fibrosis; single lung transplantation; and use of cardiopulmonary bypass, among others. Several cellular pathways have been implicated in the pathogenesis of PGD, thus presenting several possible therapeutic targets for preventing and treating PGD. Notably, use of ex vivo lung perfusion (EVLP) has become more widespread and offers a potential platform to safely investigate novel PGD treatments while expanding the lung donor pool. Even in the presence of significantly prolonged ischemic times, EVLP has not been associated with an increased risk for PGD.
Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre‐ and posttransplant mortality, but this risk is not ...explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age‐associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with posttransplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging‐associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.
The authors review the potential impact on lung transplant candidate evaluation of assessing frailty and other age‐associated dysfunction using the Fried frailty phenotype, cumulative deficits, sarcopenia, cognition, depression, nutrition, and immunosenescence.
Lung Transplantation Ahya, Vivek N; Diamond, Joshua M
The Medical clinics of North America
103, Številka:
3
Journal Article
Recenzirano
Lung transplantation is an appropriate therapeutic option for select patients with end-stage lung diseases and offers the possibility of improved quality of life and longer survival. Unfortunately, ...the transplant recipient is at risk for numerous immunologic, infectious, and medical complications that threaten both of these goals. Median survival after lung transplantation is approximately 6 years. Optimizing outcomes requires close partnership between the patient, transplant center, and primary medical team. Early referral to a transplant center should be considered for patients with idiopathic pulmonary fibrosis and related interstitial lung diseases due to risk of acute exacerbation and accelerated development of respiratory failure.
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