Sepsis is caused by a dysregulated host response to an infection that leads to cascading cell death and eventually organ failure. In this study, the role of inflammatory response serum secretory phospholipase A2 (sPLA2) and albumin in sepsis was investigated by determining the activities of the two proteins in serial serum samples collected on different days from patients with sepsis after enrollment in the permissive underfeeding versus standard enteral feeding protocols in an intensive care unit. Serum sPLA2 and albumin showed an inverse relationship with increasing sPLA2 activity and decreasing albumin membrane-binding activity in patients with evolving complications of sepsis. The activities of sPLA2 and albumin returned to normal values more rapidly in the permissive underfeeding group than in the standard enteral feeding group. The inverse sPLA2–albumin activity relationship suggests a complex interplay between these two proteins and a regulatory mechanism underlying cell membrane phospholipid homeostasis in sepsis. The decreased albumin–membrane binding activity in patients’ serum was due to its fatty acid-binding sites occupied by pre-bound fatty acids that might alter albumin’s structure, binding capacities, and essential functions. The sPLA2–albumin dual serum assays may be useful in determining whether nutritional intervention effectively supports the more rapid recovery of appropriate immune responses in critically ill patients with sepsis.

Abstract Background Recombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151–202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks. Methods Patients who completed the randomized PRM-151–202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis). Results All 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, − 6.2% (− 7.7; − 4.6) and − 5.7% (− 8.0; − 3.3) for percent predicted FVC and − 36.3 m (− 65.8; − 6.9) and − 28.9 m (− 54.3; − 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128. Conclusions Long-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect. Trial registration NCT02550873; EudraCT 2014-004782-24.

Age-dependent conformational stability of human serum albumin was determined by the method of fluorescent bilayer liposome assay. After pre-heating at 80 °C, albumin in the sera of 74-year-old healthy subjects exhibited hydrophobic effects on liposomes and made liposomal membrane phospholipids more susceptible to hydrolysis by the lipolytic enzyme phospholipase A2. In contrast, albumin in the sera of 24-year-old individuals was stable at 80 °C and displayed no increased hydrophobic effects on liposomes. The results suggest that albumin in the sera of 74-year-old subjects is more easily converted to a misfolded form in which its protein structure is altered when compared to albumin in the sera of 24-year-old individuals. Misfolded albumin can lose its ability to carry out its normal homeostatic functions and may promote alterations in membrane integrity under inflammatory conditions. However, our investigation has limitations that include the lack of testing sera from large numbers of individuals across a broad range of age to validate our preliminary observations of age-dependent differences in albumin stability and its interactions with liposomes.

Meyer and Avery comment on the implications of a study by Hostetler et al. (page 2864), in which screening of a large group of lung transplant candidates revealed that some lacked humoral immunity to measles, mumps, and varicella, especially younger patients and those with cystic fibrosis.

As the COVID-19 pandemic has swept the world, the provision of health care for conditions that are unrelated to COVID-19 has been extensively disrupted. This is especially the case for patients in need of solid organ transplantation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have complicated the approach that transplant centres must take to ensure that recipients are not placed at risk of potentially fatal outcomes or severe allograft dysfunction should they become infected with SARS-CoV-2. Many DNA and RNA viruses pose both immediate and delayed-onset, potentially serious risks for lung transplant recipients,1Danziger-Isakov L Verschuuren E Manuel O Viral infections in lung transplantation.in: Vigneswaran WT Garrity Jr, ER Odell JA Lung transplantation: principles and practice. CRC Press, Boca Raton, FL2016: 293-306Crossref Google Scholar and disruption of host–virus relationships after solid organ transplantation can lead to both reactivation of latent viruses residing in donor tissues and new infections. Additionally, lung transplant recipients who have had successful transplantations are at risk of developing community-acquired respiratory virus infections, which have been linked to both acute and chronic lung allograft dysfunction.2Clausen ES Zaffiri L Infection prophylaxis and management of viral infection.Ann Transl Med. 2020; 8: 415Crossref PubMed Google Scholar Infection with the novel SARS-CoV-2 is associated with substantial morbidity and mortality, and many survivors of COVID-19 have long-term or permanent detrimental health effects.3Wiersinga WJ Rhodes A Cheng AC Peacock SJ Prescott HC Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review.JAMA. 2020; 324: 782-793Crossref PubMed Scopus (3313) Google Scholar Airborne transmission is the predominant route of disease spread4Dos Santos WG Natural history of COVID-19 and current knowledge on treatment therapeutic options.Biomed Pharmacother. 2020; 129110493Crossref PubMed Scopus (116) Google Scholar and it has become clear that virus-containing aerosols can linger in ambient air for hours before settling out via gravity. Asymptomatic infected individuals can be important vectors of virus spread, and should solid organ transplant recipients become infected with SARS-CoV-2, they might be at increased risk of severe disease and a fatal outcome compared with the general population.5Pereira MR Mohan S Cohen DJ et al.COVID-19 in solid organ transplant recipients: initial report from the US epicenter.Am J Transplant. 2020; 20: 1800-1808Crossref PubMed Scopus (631) Google Scholar However, community-acquired SARS-CoV-2 infections in lung transplant recipients can have a benign clinical course.6Koczulla RA Sczepanski B Koteczki A et al.SARS-CoV-2 infection in two patients following recent lung transplantation.Am J Transplant. 2020; 20: 2928-2932Crossref PubMed Scopus (21) Google Scholar SARS-CoV-2 rapidly replicates once it gains access to respiratory epithelium.3Wiersinga WJ Rhodes A Cheng AC Peacock SJ Prescott HC Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review.JAMA. 2020; 324: 782-793Crossref PubMed Scopus (3313) Google Scholar, 4Dos Santos WG Natural history of COVID-19 and current knowledge on treatment therapeutic options.Biomed Pharmacother. 2020; 129110493Crossref PubMed Scopus (116) Google Scholar It can then spread via the circulation as it infects endothelial cells, not only causing respiratory dysfunction—organising pneumonia, diffuse alveolar damage, intravascular clotting, and acute respiratory distress syndrome (ARDS)—but potentially causing severe dysfunction of other organs, including heart, brain, gastrointestinal tract, and kidneys.7Gavriatopoulou M Korompoki E Fotiou D et al.Organ-specific manifestations of COVID-19 infection.Clin Exp Med. 2020; 20: 493-506Crossref PubMed Scopus (326) Google Scholar Viral loads can be very large and virus shedding can persist for many weeks.8To KK Tsang OT Leung WS et al.Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.Lancet Infect Dis. 2020; 20: 565-574Summary Full Text Full Text PDF PubMed Scopus (2327) Google Scholar Transplanting lungs from a SARS-CoV-2-positive donor into a SARS-CoV-2-naive recipient or transplanting donor lungs into a patient whose irreversible respiratory failure has occurred as a consequence of severe ARDS with pulmonary fibrosis associated with COVID-19 are two potential scenarios in which a SARS-CoV-2 primary infection or SARS-CoV-2 reactivation could cause life-threatening complications and a poor outcome for lung transplant recipients. In The Lancet Respiratory Medicine, Laurens Ceulemans and colleagues9Ceulemans LJ Van Slambrouck J De Leyn P et al.Successful double-lung transplantation from a donor previously infected with SARS-CoV-2.Lancet Respir Med. 2020; (published online Dec 1.)https://doi.org/10.1016/S2213-2600(20)30524-5Summary Full Text Full Text PDF PubMed Scopus (42) Google Scholar report a successful double-lung transplantation using lungs from a SARS-CoV-2 IgG antibody-positive donor who had recovered from a presumed case of symptomatic COVID-19 3 months before transplantation. The SARS-CoV-2-naive recipient had a typical post-transplantation course, and although a lung biopsy done at the time of implantation showed the presence of SARS-CoV-2 RNA by PCR testing, post-transplantation nasopharyngeal swab testing, repeated PCR tests of bronchoalveolar lavage specimens, viral culture of bronchoalveolar lavage and donor lung tissue to detect viral replication, and serum anti-SARS-CoV-2 antibodies were negative. The good transplantation outcome and absence of virus activation despite the intense immunosuppression regimen given to the recipient suggest that transplanting organs harvested from a donor whose SARS-CoV-2 infection has resolved can be safely performed. Although many patients succumb to respiratory failure with acute COVID-19 pneumonia, a substantial number of survivors with refractory ARDS develop severe, non-resolving pulmonary fibrosis that leaves them persistently ventilator-dependent and unlikely to survive without a lung transplant. Lang and colleagues10Lang C Jaksch P Hoda MA et al.Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient.Lancet Respir Med. 2020; 8: 1057-1060Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar reported using lung transplantation as a salvage therapy for a patient with severe, treatment-refractory COVID-19-induced ARDS requiring prolonged extracorporeal membrane oxygenation support. Repeated nasopharyngeal swabs and bronchoalveolar lavage specimens before transplantation were PCR positive, but Vero cell cultures did not show viable virus. Although post-transplant PCR on multiple sequential nasopharyngeal swab and bronchoalveolar lavage specimens remained positive before turning negative after day 10, Vero cell cultures were negative, suggesting that infective virus was no longer present, and the recipient had a good transplantation outcome. What lessons do these case reports provide? As new cases of COVID-19 are exponentially on the rise in the general population in many countries, it is increasingly likely that donors might have a history of previous infection, either resolved or still active, when assessed for transplantation suitability. Potential donors must be thoroughly screened for active SARS-CoV-2 infection, but transplanting lungs from a donor whose infection has resolved and whose respiratory function is not compromised can be safe, possibly even if SARS-CoV-2 RNA persists in lung tissue. Additionally, when lung transplantation is considered in patients with end-stage ARDS or fibrosis caused by COVID-19, although PCR from respiratory tract specimens might be persistently positive up to and shortly after transplantation, active infection with shedding of viable virus is not necessarily observed, as shown by Lang and colleagues,10Lang C Jaksch P Hoda MA et al.Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient.Lancet Respir Med. 2020; 8: 1057-1060Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar and lung transplantation can be safely performed. Experienced transplant teams need to adequately screen donor lungs for active SARS-CoV-2 infection, and transplant candidates whose transplant indication is refractory COVID-19 ARDS must be carefully selected. Because there is still much to learn concerning the effect of the SARS-CoV-2 virus on lung transplantation outcomes, a careful approach with attention to short-term and long-term follow-up after transplantation is essential. Although effective vaccines might soon be available and vaccination combined with other strategies will hopefully curb and eventually stop the COVID-19 pandemic, infections will probably continue to affect world populations for months to years. Evolving experience in the era of SARS-CoV-2 at lung transplantation centres around the world will provide guidance for developing best practices to deal with the threat that this novel virus poses to successful solid organ transplantation. I report grants from the US National Institutes of Health, Genentech/Roche, Galapagos, Parion, Biogen, and Promedior, outside of the submitted work. Successful double-lung transplantation from a donor previously infected with SARS-CoV-2In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resulting respiratory disease, COVID-19, emerged.1 As the pandemic continues, with more than 62 million people with documented SARS-CoV-2 infection, a growing number of potential organ donors will have been infected. Since SARS-CoV-2 resides primarily in the respiratory tract, lung transplantation has the highest concern in terms of donor-derived viral transmission and impaired graft quality. Therefore, graft acceptance for lung transplantation should carefully be balanced against the longer waiting time for the recipient. Full-Text PDF

Organising pneumonia (OP) is currently recognised as a nonspecific lung injury response that is associated with a variety of imaging patterns obtained with high-resolution computed tomography (HRCT) of the chest and is characterised histopathologically by the presence of inflammatory cells and a connective tissue matrix within distal airspaces of the lungs. OP is associated with many conditions that include connective tissue disorders, various infections, drug reactions, hypersensitivity pneumonitis and aspiration. When OP cannot be linked to an associated condition and appears to be idiopathic, it is termed cryptogenic organising pneumonia.

Aging-related protein misfolding and aggregation may play critical roles in the pathogenesis of numerous diseases. In the brain, extracellular aggregated amyloid-β (Aβ) is closely related to the death of neurons in individuals with Alzheimer's disease (AD). Albumin-Aβ binding is important in preventing Aβ fibril aggregation. However, because albumin is the most abundant and important antioxidant in the circulation, aging-related oxidative stress could have a significant effect on the molecular conformation and binding capacities of albumin. To investigate the link between misfolded albumin and AD, we developed fluorescent assays to determine the effects of misfolded albumin on membrane integrity in the presence of a lipolytic, inflammatory response-like enzyme, secretory phospholipase A2 (sPLA2). We found that misfolded albumin increased degradation of phospholipids in highly fluid bilayer membranes in the presence of sPLA2 due to hydrophobic effects of misfolded albumin. High amounts of misfolded albumin were present in sera of elderly (average 74 years) versus young (average 24 years) subjects (p < 0.0001). Albumin in cerebrospinal fluid (CSF) of elderly subjects, though present in small concentrations, had a 2- to 3-fold increased capacity to promote sPLA2-catalyzed membrane phospholipid degradation as compared with the same amount of albumin in serum (p < 0.0001). In addition, the fatty acid binding capacity of albumin in CSF from female subjects was considerably lower than values obtained for men, especially for individuals diagnosed with AD (p = 0.0006). This study suggests that inflammation, misfolded albumin and/or other dysfunctional proteins, and changes in membrane fluidity could alter cell membrane integrity and homeostasis and contribute to the pathogenesis of aging-related dementia and AD.

Aging-related misfolded proteins appear to play critical roles in neurodegenerative diseases including Alzheimer's disease (AD). A fluorescent liposome assay was used to determine whether differences in the binding activity of albumin with fatty acids (FA) derived from the hydrolysis of liposome phospholipids [catalyzed by secretory phospholipase A2 (sPLA2)] were linked to aging and AD. All components were mixed either at 0oC (Assay-1) or 24oC (Assay-2) prior to being assayed in a microplate reader at 25oC. Albumin-FA-binding activity (Alb-FA-BA) increased markedly after albumin was partially denatured. The specific activity of Alb-FA-BA (per μg albumin) in the sera of healthy young control (HYC) (n = 18, average age 24), healthy older control subjects (HOC), and age-matched individuals with mild cognitive impairment (MCI) or patients with AD (each group n = 10, average age = 74) determined by Assay-2 was 2.0, 3.6, 3.5, and 3.3-times higher than that determined by Assay-1, respectively, (p < 1 x 10−6), likely due to increasing liposomal membrane fluidity in Assay-2. Serum Alb-FA-BA of HOC, MCI and AD was 50% higher than that of HYC in Assay-2 (p = 2.4 x 10−9), perhaps due to higher content of misfolded albumin in the sera from older subjects. The specific activity of Alb-FA-BA of HOC, MCI and AD in cerebrospinal fluid (CSF) was nearly twice as high as the values determined by either Assay-1 or Assay-2 for serum, suggesting a higher proportion of misfolded albumin in CSF versus serum. The results of this study suggest that aging-related misfolding of albumin or protein (i.e. oligomers) may elicit membrane degradation in the presence of an inflammatory response and active sPLA2 combined with high membrane fluidity. We suggest that such interactions may represent an important mechanism in the pathogenesis of aging-related dementia and AD.

FOR RELATED ARTICLE, SEE PAGE 64Lung transplantation is the only potentially therapeutic option that can extend survival and improve quality of life for patients with progressive and ultimately fatal lung disorders that do not respond to nontransplant therapies. Relatively stringent eligibility criteria keep many patients with end-stage lung disease from becoming candidates who can be listed for transplantation, however.1Weill D. Benden C. Corris P.A. et al.A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2015; 34: 1-15Abstract Full Text Full Text PDF PubMed Scopus (880) Google Scholar In addition, if potential candidates meet inclusion and exclusion criteria and are then placed on the transplant waitlist, a shortage of donor lungs prevents many waitlisted patients from receiving a life-saving lung transplant, especially those who are in urgent need of a transplant and at high risk of dying while awaiting a transplant. FOR RELATED ARTICLE, SEE PAGE 64 The lung allocation score (LAS) was implemented in the United States in 2005 with the hope of decreasing the risk of death without receiving a transplant while waitlisted candidates await a lung offer,2Egan T.M. Murray S. Bustami R.T. et al.Development of the new lung allocation system in the United States.Am J Transplant. 2006; 6: 1212-1227Crossref PubMed Scopus (585) Google Scholar and the LAS uses a comprehensive array of patient- and disease-specific variables (Table 1) to balance the degree of urgency for transplantation with the likelihood of posttransplant survival.3George M.P. Pipeling M.R. Prognostic markers and the LAS for lung transplantation: impact of new revisions for successful outcome.in: Raghu G. Carbone R.G. Lung Transplantation: Evolving Knowledge and New Horizons. Springer, Cham, Switzerland2018: 93-109Crossref Google Scholar Its use has been correlated with a reduction in the number of active waitlisted candidates as well as the number of patient deaths while on the waitlist.4McCurry K.R. Shearon T.H. Edwards L.B. Lung transplantation in the United States, 1998-2007.Am J Transplant. 2009; 9: 942-958Crossref PubMed Scopus (69) Google Scholar Additionally, the death rate did not appear to increase as patients with higher degrees of urgency were listed.4McCurry K.R. Shearon T.H. Edwards L.B. Lung transplantation in the United States, 1998-2007.Am J Transplant. 2009; 9: 942-958Crossref PubMed Scopus (69) Google Scholar, 5Egan T.M. Edwards L.B. Effect of the lung allocation score on lung transplantation in the United States.J Heart Lung Transplant. 2016; 35: 433-439Abstract Full Text Full Text PDF PubMed Scopus (164) Google ScholarTable 1Criteria/Values Used to Calculate the Lung Allocation Score (LAS)aSome values are adjusted according to disease group; group A = obstructive lung disease; group B = pulmonary vascular disease; group C = cystic fibrosis or immunodeficiency disorders; group D = restrictive lung disease.,bThe LAS calculation incorporates three different measures (waiting list urgency, posttransplant survival, and transplant benefit) to derive a raw allocation score that is then normalized on a continuous scale of 0 to 100.Adapted from https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_10; accessed 4 February 2019.▪ Lung diagnosis code▪ Age, y▪ BMI▪ Functional status▪ FVC, percent predicted▪ Requirement for supplemental oxygen▪ 6-min walk distance, ft▪ Pulmonary artery systolic pressure, mm Hg▪ Mean pulmonary artery pressure, mm Hg▪ Cardiac index, L/min/m2▪ Central venous pressure, mm Hg▪ Ventilation status▪ Pco2, mm Hg (current, highest, lowest)▪ Presence of diabetes▪ Serum creatinine, mg/dL (current, highest, lowest)▪ Total bilirubin, mg/dL (current, highest, lowest)a Some values are adjusted according to disease group; group A = obstructive lung disease; group B = pulmonary vascular disease; group C = cystic fibrosis or immunodeficiency disorders; group D = restrictive lung disease.b The LAS calculation incorporates three different measures (waiting list urgency, posttransplant survival, and transplant benefit) to derive a raw allocation score that is then normalized on a continuous scale of 0 to 100. Open table in a new tab As techniques for supporting lung transplant candidates with very advanced or acutely deteriorating clinical status have evolved (including advances in providing intensive care support and using mechanical ventilation or extracorporeal life support to bridge patients to transplant), LAS values are likely to climb over time as clinicians try to find a “sweet spot” that balances mortality risk without a transplant with the risk of early death from myriad posttransplant complications that can cut survival short after a recipient has undergone a lung transplant. But candidates with very high LAS values, which have been suggested to correlate with worse posttransplant survival by a number of investigators, may have significantly worse posttransplant survival than candidates with lower scores.6Russo M.J. Iribarne A. Hong K.N. et al.High lung allocation score is associated with increased morbidity and mortality following transplantation.Chest. 2010; 137: 651-657Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 7Merlo C.A. Weiss E.S. Orens J.B. et al.Impact of U.S. Lung Allocation Score on survival after lung transplantation.J Heart Lung Transplant. 2009; 28: 769-775Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar This may especially be the case for candidates with a transplant indication of pulmonary fibrosis,8Weiss E.S. Allen J.G. Merlo C.A. et al.Lung allocation score predicts survival in lung transplantation patients with pulmonary fibrosis.Ann Thorac Surg. 2009; 88: 1757-1764Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar but a more recent investigation suggested that posttransplant mortality is improving in recipients with very high LAS values.9Crawford T.C. Grimm J.C. Magruder J.T. et al.Lung transplant mortality is improving in recipients with a lung allocation score in the upper quartile.Ann Thorac Surg. 2017; 103: 1607-1613Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar In this issue of CHEST, Li and colleagues10Li S.S. Miller R. Tumin D. et al.Lung allocation score thresholds prioritize survival after lung transplantation.Chest. 2019; 156: 64-70Abstract Full Text Full Text PDF Scopus (19) Google Scholar examined the United Network for Organ Sharing Registry to identify first-time adult lung transplant candidates who had LAS values ≥40 and were waitlisted between May 2005 and December 2016. The goal was to identify whether an “LAS ceiling” could be identified that may define an upper limit threshold for LAS values where prioritization based on the LAS value did not have an effect on survival. Survival benefit was calculated by including all waitlisted patients regardless of whether they received a transplant, and using a Cox proportional hazards regression approach with receipt of a lung transplant considered to represent an instantaneous reduction in risk of mortality and a piecewise-constant, time-varying covariate, they modeled lung transplant survival benefit while stratifying lung recipients by LAS value deciles ranging from 30 to > 90. Their ultimate goal was to identify an LAS decile threshold where further increase in the LAS value did not correlate in a statistically significant increase in lung transplant benefit. In addition, because major categories of lung diseases have been shown to have varying benefit from a lung transplant,11Vock D.M. Durheim M.T. Tsuang W.M. et al.Survival benefit of lung transplantation in the modern era of lung allocation.Ann Am Thorac Soc. 2017; 14: 172-181Crossref PubMed Scopus (73) Google Scholar the data were also analyzed by dividing the cohort into groups with obstructive lung disease, pulmonary vascular disease, cystic fibrosis (CF), and restrictive lung disease while excluding prior recipients listed for retransplantation. Eighty-three percent of the entire study population (N = 21,748) had LAS values < 50, 8.2% died while waitlisted, 73% received a transplant, and 28% of recipients died post-transplant. Receipt of a lung transplant relative to time of being placed on the waitlist was particularly protective for patients with an initial LAS value of 70 to 79 and LAS ≥ 90; smoothed estimates of transplant benefit supported a stable benefit for lung transplantation for patients with a LAS value ≥ 70. Additionally, analysis of the four diagnosis groups identified a stable benefit for LAS ≥ 50 for patients with CF. These data support a somewhat lower mortality benefit for candidates with LAS < 70 compared with those with higher LAS values, and the ceiling appeared to be even lower for CF with a breakpoint of LAS = 50. Why do the findings of this examination of United Network for Organ Sharing Registry data differ from previously published reports? As the authors point out, earlier studies linking high LAS values to increased mortality assessed absolute posttransplant survival.6Russo M.J. Iribarne A. Hong K.N. et al.High lung allocation score is associated with increased morbidity and mortality following transplantation.Chest. 2010; 137: 651-657Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 7Merlo C.A. Weiss E.S. Orens J.B. et al.Impact of U.S. Lung Allocation Score on survival after lung transplantation.J Heart Lung Transplant. 2009; 28: 769-775Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 8Weiss E.S. Allen J.G. Merlo C.A. et al.Lung allocation score predicts survival in lung transplantation patients with pulmonary fibrosis.Ann Thorac Surg. 2009; 88: 1757-1764Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In contrast, the current study compared survival benefit following transplantation as compared with candidates remaining on the waitlist with the assumption that transplant provided an instantaneous survival benefit. Survival benefit of transplant for increasingly ill candidates (as reflected by high to very high LAS values) has been improving over time9Crawford T.C. Grimm J.C. Magruder J.T. et al.Lung transplant mortality is improving in recipients with a lung allocation score in the upper quartile.Ann Thorac Surg. 2017; 103: 1607-1613Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar as advances have been made in critical illness support measures as strategies that can bridge patients to transplant with a variety of emerging supportive measures including extracorporeal life support are increasingly used.12Meyer K.C. Recent advances in lung transplantation.F1000Res. 2018; 7Crossref Scopus (3) Google Scholar The LAS has undergone various revisions since its initial adoption in 2005, and more revisions driven by data derived from registry analyses are needed. The current analysis by Li and colleagues suggests that higher scores are correlated with greater benefit, that survival benefit for transplantation (vs continued waitlisting or no transplant) appears to be equalized for all candidates with a LAS ≥ 70 (or ≥ 50 for patients with CF), and that priority for organ offers should be equalized for the relatively small number of patients with LAS values above these thresholds. However, using such thresholds to transplant increasingly ill and complex patients may also significantly increase costs of providing posttransplant care and lead to more frequent readmissions to hospital and more attenuated quality of life. Additional research is needed to verify the findings of Li and colleagues, and how the LAS can best be used to provide the greatest good for the greatest number of lung transplant candidates should be continually reevaluated as registry data continues to accrue over time. Lung Allocation Score Thresholds Prioritize Survival After Lung TransplantationCHESTVol. 156Issue 1PreviewThe lung allocation score (LAS) prioritizes lung transplant (LTx) candidates with poor transplant-free survival and expected survival benefit from LTx. Although patients with the highest LAS have the shortest waiting time, mortality benefit is unclear in this group, raising criticism that the LAS inappropriately prioritizes critically ill candidates. We aim to identify a threshold above which increasing LAS values do not predict increasing survival benefit. Full-Text PDF

Background Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. Methods Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. Findings Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of -3.6% per year and in 6-min walking distance of -10.5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from -8.7% per year in weeks 0-28 to -0.9% per year in weeks 28-52, p<0.0001) and 6-min walking distance (from -54.9 m per year to -3.5 m per year, p=0.0224). Interpretation Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Lung transplantation can improve quality of life and prolong survival for individuals with end-stage lung disease, and many advances in the realms of both basic science and clinical research aspects of lung transplantation have emerged over the past few decades. However, many challenges must yet be overcome to increase post-transplant survival. These include successfully bridging patients to transplant, expanding the lung donor pool, inducing tolerance, and preventing a myriad of post-transplant complications that include primary graft dysfunction, forms of cellular and antibody-mediated rejection, chronic lung allograft dysfunction, and infections. The goal of this manuscript is to review salient recent and evolving advances in the field of lung transplantation.

The cause of the formation of amyloid-ß plaques, which play a critical role in neuronal death in Alzheimer's disease (AD), is unknown. The objective of this study was to investigate the level of protein unfolding in the sera of patients with AD. Sera were collected from young healthy adults, healthy older adults without evidence of cognitive impairment, patients with mild cognitive impairment (MCI), and patients with AD. We used a previously developed fluorescent liposome assay (Translational Medicine 2015; 5:1-9) to determine the albumin-fatty acid binding activity (Alb-FA-BA) as a marker of the level of protein unfolding; protein unfolding is recognized as an initial step involved in amyloid aggregation and plaque formation. The Alb-FA-BA was markedly augmented after albumin was exposed to increased temperature up to 80oC or to ß-mercaptoethanol. The increased Alb-FA-BA was likely due to increasing unfolded albumin forms that appeared under these conditions. Sera of patients with AD had significantly higher Alb-FA-BA than the healthy older control group (149.740 ± 3.805 vs. 130.821 ± 4.894, p = 0.0018, n = 24), the young healthy control group (123.051 ± 4.660, p < 0.0001, n = 25), and subjects with MCI (128.399 ± 3.520, p = 0.0005, n = 24). However, total serum albumin levels from all samples were approximately the same. A molecular weight (MW) < 10k factor in the serum was isolated to a partially pure form that stimulated Alb-FA-BA. The MW < 10k factor isolated from patients with AD stimulated Alb-FA-BA significantly more than the factor from the older control and MCI subject groups (161.146 ± 7.236, 124.385 ± 6.075, and 141.410 ± 4.897, respectively, p = 0.0124 for AD vs. older control, p = 0.0295 for AD vs. MCI) (n = 11 for each group). High Alb-FA-BA in the AD sera may indicate the presence of an increased content of unfolded albumin induced by the MW < 10k factor. The Alb-FA-BA and the MW < 10k factor could be useful biomarkers for AD.

IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC >= 50% and >= 90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] >= 25% and >= 90% predicted; and distance of >= 150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES The primary end pointwas the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, + 2.3[90% CI, 1.1 to 3.5]; P =.001). No significant treatment differences were observed in total lung volume (difference, 93.5mL[90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2%[90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1%[90% CI, -2.2 to 4.3]), or measurement of DLCO (difference, -0.4[90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, + 31.3 m[90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). CONCLUSIONS AND RELEVANCE In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety.

Objective: Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock. Design: Retrospective analysis of a pediatric septic shock database. Setting: Twenty-nine PICUs in the United States. Patients: Eight hundred ninety children 10 years and younger with septic shock. Interventions: None. Measurements and Main Results: We considered the minimum, maximum, and mean chloride values during the initial 7 days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration greater than or equal to 110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of greater than or equal to two organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 patients (25%) with a complicated course and 93 mortalities (10%). Seventy patients had a minimum chloride greater than or equal to 110 mmol/L, 179 had a mean chloride greater than or equal to 110 mmol/L, and 514 had a maximum chloride greater than or equal to 110 mmol/L. A minimum chloride greater than or equal to 110 mmol/L was associated with increased odds of complicated course (odds ratio, 1.9; 95% CI, 1.1–3.2; p = 0.023) and mortality (odds ratio, 3.7; 95% CI, 2.0–6.8; p < 0.001). A mean chloride greater than or equal to 110 mmol/L was also associated with increased odds of mortality (odds ratio, 2.1; 95% CI, 1.3–3.5; p = 0.002). The secondary analysis yielded similar results. Conclusion: Hyperchloremia is independently associated with poor outcomes among children with septic shock.

Objectives: International experts recently characterized interstitial pneumonia with autoimmune features (IPAF) as a provisional diagnosis for patients with interstitial lung disease who have characteristics of autoimmune disease but do not meet criteria for a specific autoimmune disease. We describe clinical characteristics of IPAF patients and examine responses to mycophenolate as a therapy for IPAF. Methods: This retrospective cohort included adult patients meeting European Respiratory Society/American Thoracic Society classification criteria for IPAF. Sociodemographic, clinical, and pulmonary function test data were abstracted for patients with and without mycophenolate treatment and followed longitudinally from interstitial lung disease diagnosis for change in pulmonary function test results. Results: We identified 52 patients who met criteria for IPAF. Of 52 IPAF patients, 24 did not receive mycophenolate and 28 did, with median time to mycophenolate treatment 22 months. Changes in FVC% and percentage predicted lung diffusion capacity for carbon monoxide (D-LCO%) between the mycophenolate-treated and untreated groups were not significantly different (FVC% change P=0.08, D-LCO% change P=0.17). However, there was a trend toward more rapid baseline decline of both FVC% and D-LCO% in the mycophenolate-treated cohort before vs after mycophenolate therapy. The slope of both FVC% and D-LCO% values improved after onset of mycophenolate exposure for the treated group, although this finding was not statistically significant. Conclusion: Patients with IPAF might benefit from mycophenolate therapy. Larger prospective clinical trials are needed to evaluate the efficacy of mycophenolate for patients who meet criteria for IPAF.