Publications by authors named "John McDyer"

79 Publications

Renin Angiotensin Aldosterone System Antagonism in 2019 Novel Coronavirus Acute Lung Injury.

Open Forum Infect Dis 2021 Oct 4;8(10):ofab170. Epub 2021 Apr 4.

Department of Pharmacy, AdventHealth Orlando, Orlando, Florida, USA.

It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019-associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.
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http://dx.doi.org/10.1093/ofid/ofab170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083494PMC
October 2021

Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

JAMA 2021 Oct 4. Epub 2021 Oct 4.

School of Immunology and Microbial Sciences, Kings College London, London, England.

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.

Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.

Design, Setting, And Participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021.

Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916).

Main Outcomes And Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.

Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group.

Conclusions And Relevance: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2021.18178DOI Listing
October 2021

Rate of recipient-derived alveolar macrophage development and major histocompatibility complex cross-decoration after lung transplantation in humans.

Am J Transplant 2021 Aug 24. Epub 2021 Aug 24.

Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Alveolar macrophages (AM) play critical roles in lung tissue homeostasis, host defense, and modulating lung injury. The rate of AM turnover (donor AM replacement by circulating monocytes) after transplantation has been incompletely characterized. Furthermore, the anatomic pattern of recipient-derived lung macrophages repopulation has not been reported, nor has their ability to accumulate and present donor major histocompatibility complex (a process we refer to as MHC cross-decoration). We longitudinally characterized the myeloid content of bronchoalveolar lavage (BAL) and biopsy specimens of lung transplant recipients and found a biphasic rate in AM turnover in the allograft, with a rapid turnover perioperatively, accelerated by both the type of induction immunosuppression and the presence of primary graft dysfunction. We found that recipient myeloid cells with cell surface AM phenotype repopulated the lung in a disorganized pattern, comprised mainly of large clusters of cells. Finally, we show that recipient AM take up and present donor peptide-MHC complexes yet are not able to independently induce an in vitro alloreactive response by circulating recipient T cells.
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http://dx.doi.org/10.1111/ajt.16812DOI Listing
August 2021

Early Convalescent Plasma for High-Risk Outpatients with Covid-19.

N Engl J Med 2021 Aug 18. Epub 2021 Aug 18.

From the University of Michigan, Ann Arbor (F.K.K., R.D.D., C.V.H., V.L.W.S., C.F.G., N.L.H., R.S., W.B.), Spectrum Health, Grand Rapids (J.C.R.), and Michigan State University, East Lansing (J.C.R.) - all in Michigan; the Medical University of South Carolina, Charleston (V.D.-M., S.D.Y., L.D.F., E.L.); Stanford University, Palo Alto, CA (K.S., J.M.H., S.J., J.Q.); Vitalant Research Institute, Scottsdale, AZ (L.J.D.); the National Heart, Lung, and Blood Institute, Bethesda, MD (N.E.K.); the University of Pittsburgh, Pittsburgh (A.K., J.F.M., D.J.T., C.W.C.); Harbor-UCLA Medical Center, Los Angeles (K.Y.); Cooper University Hospital, Camden, NJ (C.W.J.); Oregon Health and Science University, Portland (B.K.); Health Partners Methodist Hospital, St. Louis Park, MN (A.B.); and the University of Chicago, Chicago (D.G.B.).

Background: Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19.

Methods: In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause.

Results: A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups.

Conclusions: The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.).
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http://dx.doi.org/10.1056/NEJMoa2103784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385553PMC
August 2021

Rapid postmortem ventilation improves donor lung viability by extending the tolerable warm ischemic time after cardiac death in mice.

Am J Physiol Lung Cell Mol Physiol 2021 Oct 28;321(4):L653-L662. Epub 2021 Jul 28.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Uncontrolled donation after cardiac death (uDCD) contributes little to ameliorating donor lung shortage due to rapidly progressive warm ischemia after circulatory arrest. Here, we demonstrated that nonhypoxia improves donor lung viability in a novel uDCD lung transplant model undergoing rapid ventilation after cardiac death and compared the evolution of ischemia-reperfusion injury to mice that underwent pulmonary artery ligation (PAL). The tolerable warm ischemia time at 37°C was initially determined in mice using a modified PAL model. The donor lung following PAL was also transplanted into syngeneic mice and compared with those that underwent rapid ventilation or no ventilation at 37°C before transplantation. Twenty-four hours following reperfusion, lung histology, [Formula: see text]/[Formula: see text] ratio, and inflammatory mediators were measured. Four hours of PAL had little impact on [Formula: see text]/[Formula: see text] ratio and acute lung injury score in contrast to significant injury induced by 5 h of PAL. Four-hour PAL lungs showed an early myeloid-dominant inflammatory signature when compared with naïve lungs and substantially injured 5 h PAL lungs. In the context of transplantation, unventilated donor lungs showed severe injury after reperfusion, whereas ventilated donor lungs showed minimal changes in [Formula: see text]/[Formula: see text] ratio, histologic score, and expression of inflammatory markers. Taken together, the tolerable warm ischemia time of murine lungs at 37°C can be extended by maintaining alveolar ventilation for up to 4 h. Nonhypoxic lung undergoing warm ischemia-reperfusion injury shows an early transcriptional signature of myeloid cell recruitment and extracellular matrix proteolysis before blood-gas barrier dysfunction and significant tissue damage.
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http://dx.doi.org/10.1152/ajplung.00011.2021DOI Listing
October 2021

A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry.

Nat Commun 2021 06 23;12(1):3907. Epub 2021 Jun 23.

Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA.

SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection.
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http://dx.doi.org/10.1038/s41467-021-24156-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222394PMC
June 2021

Single cell RNA sequencing identifies IGFBP5 and QKI as ciliated epithelial cell genes associated with severe COPD.

Respir Res 2021 Apr 6;22(1):100. Epub 2021 Apr 6.

Department of Medicine, University of Pittsburgh, NW628 UPMC Montefiore, 3459 Fifth Avenue, Pittsburgh, PA, 15213, USA.

Background: Whole lung tissue transcriptomic profiling studies in chronic obstructive pulmonary disease (COPD) have led to the identification of several genes associated with the severity of airflow limitation and/or the presence of emphysema, however, the cell types driving these gene expression signatures remain unidentified.

Methods: To determine cell specific transcriptomic changes in severe COPD, we conducted single-cell RNA sequencing (scRNA seq) on n = 29,961 cells from the peripheral lung parenchymal tissue of nonsmoking subjects without underlying lung disease (n = 3) and patients with severe COPD (n = 3). The cell type composition and cell specific gene expression signature was assessed. Gene set enrichment analysis (GSEA) was used to identify the specific cell types contributing to the previously reported transcriptomic signatures.

Results: T-distributed stochastic neighbor embedding and clustering of scRNA seq data revealed a total of 17 distinct populations. Among them, the populations with more differentially expressed genes in cases vs. controls (log fold change >|0.4| and FDR = 0.05) were: monocytes (n = 1499); macrophages (n = 868) and ciliated epithelial cells (n = 590), respectively. Using GSEA, we found that only ciliated and cytotoxic T cells manifested a trend towards enrichment of the previously reported 127 regional emphysema gene signatures (normalized enrichment score [NES] = 1.28 and = 1.33, FDR = 0.085 and = 0.092 respectively). Among the significantly altered genes present in ciliated epithelial cells of the COPD lungs, QKI and IGFBP5 protein levels were also found to be altered in the COPD lungs.

Conclusions: scRNA seq is useful for identifying transcriptional changes and possibly individual protein levels that may contribute to the development of emphysema in a cell-type specific manner.
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http://dx.doi.org/10.1186/s12931-021-01675-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022543PMC
April 2021

Risk of primary graft dysfunction following lung transplantation in selected adults with connective tissue disease-associated interstitial lung disease.

J Heart Lung Transplant 2021 05 23;40(5):351-358. Epub 2021 Jan 23.

Division of Rheumatology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York. Electronic address:

Background: Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients.

Methods: We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF.

Results: A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008).

Conclusion: Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.
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http://dx.doi.org/10.1016/j.healun.2021.01.1391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102314PMC
May 2021

Transcriptional and Proteomic Characterization of Telomere-Induced Senescence in a Human Alveolar Epithelial Cell Line.

Front Med (Lausanne) 2021 9;8:600626. Epub 2021 Feb 9.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States.

Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modeled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted differences in response to telomere dysfunction. We conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the possibility of species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.
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http://dx.doi.org/10.3389/fmed.2021.600626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902064PMC
February 2021

Human Lung-Resident Macrophages Colocalize with and Provide Costimulation to PD1 Tissue-Resident Memory T Cells.

Am J Respir Crit Care Med 2021 05;203(10):1230-1244

Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Tissue-resident memory T cells (T) play a critical role in the defense against inhaled pathogens. The isolation and study of human lung tissue-resident memory T cells and lung-resident macrophages (M) are limited by experimental constraints. To characterize the spatial and functional relationship between M and human lung tissue-resident memory T cells using lung perfusion (EVLP). T and M were isolated using EVLP and intraperfusate-labeled CD45 antibody. Cells isolated after 6 hours of EVLP were analyzed using spectral flow cytometry. Spatial relationships between CD3 and CD68 cells were explored with multiplexed immunohistochemistry. Functional relationships were determined by using coculture and T-cell-receptor complex signal transduction. Lungs from 8 research-consenting organ donors underwent EVLP for 6 hours. We show that human lung T and M colocalize within the human lung, preferentially around the airways. Furthermore, we found that human lung CD8 T are composed of two functionally distinct populations on the basis of PD1 (programed cell death receptor 1) and ZNF683 (HOBIT) protein expression. We show that M provide costimulatory signaling to PD1 CD4 and CD8 lung T, augmenting the effector cytokine production and degranulation of T. EVLP provides an innovative technique to study resident immune populations in humans. Human M colocalize with and provide costimulation signaling to T, augmenting their effector function.
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http://dx.doi.org/10.1164/rccm.202006-2403OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456469PMC
May 2021

Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction.

Am J Transplant 2021 06 20;21(6):2145-2160. Epub 2020 Nov 20.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n = 24) versus non-CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.
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http://dx.doi.org/10.1111/ajt.16360DOI Listing
June 2021

Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction.

J Heart Lung Transplant 2020 12 10;39(12):1417-1425. Epub 2020 Sep 10.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address:

Background: Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes.

Methods: We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA.

Results: DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ-specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p < 0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ-specific DSAs (p = 0.03), and multiple DSAs (p = 0.02).

Conclusions: Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ-specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.
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http://dx.doi.org/10.1016/j.healun.2020.09.003DOI Listing
December 2020

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

JAMA 2020 10;324(13):1317-1329

School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions And Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2020.17022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418PMC
October 2020

A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry.

Res Sq 2020 Aug 14. Epub 2020 Aug 14.

SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identified small molecules that can reduce surface expression of TMPRSS2 using a 2,700 FDA-approved or current clinical trial compounds. Among these, homoharringtonine and halofuginone appear the most potent agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrated marked resistance to SARS-CoV-2 pseudoviral infection. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat COVID-19 infection.
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http://dx.doi.org/10.21203/rs.3.rs-48659/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430593PMC
August 2020

Circulating exosomes with lung self-antigens as a biomarker for chronic lung allograft dysfunction: A retrospective analysis.

J Heart Lung Transplant 2020 Jul 7. Epub 2020 Jul 7.

Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona. Electronic address:

Background: Exosomes isolated from plasma of lung transplant recipients (LTxRs) with bronchiolitis obliterans syndrome (BOS) contain human leukocyte antigens and lung self-antigens (SAgs), K-alpha 1 tubulin (Kα1T) and collagen type V (Col-V). The aim was to determine the use of circulating exosomes with lung SAgs as a biomarker for BOS.

Methods: Circulating exosomes were isolated retrospectively from plasma from LTxRs at diagnosis of BOS and at 6 and 12 months before the diagnosis (n = 41) and from stable time-matched controls (n = 30) at 2 transplant centers by ultracentrifugation. Exosomes were validated using Nanosight, and lung SAgs (Kα1T and Col-V) were detected by immunoblot and semiquantitated using ImageJ software.

Results: Circulating exosomes from BOS and stable LTxRs demonstrated 61- to 181-nm vesicles with markers Alix and CD9. Exosomes from LTxRs with BOS (n = 21) showed increased levels of lung SAgs compared with stable (n = 10). A validation study using 2 separate cohorts of LTxRs with BOS and stable time-matched controls from 2 centers also demonstrated significantly increased lung SAgs-containing exosomes at 6 and 12 months before BOS.

Conclusions: Circulating exosomes isolated from LTxRs with BOS demonstrated increased levels of lung SAgs (Kα1T and Col-V) 12 months before the diagnosis (100% specificity and 90% sensitivity), indicating that circulating exosomes with lung SAgs can be used as a non-invasive biomarker for identifying LTxRs at risk for BOS.
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http://dx.doi.org/10.1016/j.healun.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790863PMC
July 2020

The RNFT2/IL-3Rα axis regulates IL-3 signaling and innate immunity.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Interleukin-3 (IL-3) receptor α (IL-3Rα) is the α subunit of the ligand-specific IL-3R and initiates intracellular signaling in response to IL-3. IL-3 amplifies proinflammatory signaling and cytokine storm in murine sepsis models. Here we found that RNFT2 (RING finger transmembrane-domain containing protein 2, also TMEM118), a previously uncharacterized RING finger ubiquitin E3 ligase, negatively regulated IL-3-dependent cellular responses through IL-3Rα ubiquitination and degradation in the proteasome. In vitro, IL-3 stimulation promoted IL-3Rα proteasomal degradation dependent on RNFT2, and we identified IL-3Rα lysine 357 as a ubiquitin acceptor site. We determined that LPS priming reduces RNFT2 abundance, extends IL-3Rα half-life, and sensitizes cells to the effects of IL-3, acting synergistically to increase proinflammatory signaling. In vivo, IL-3 synergized with LPS to exacerbate lung inflammation in LPS and Pseudomonas aeruginosa-challenged mice; conversely, IL-3 neutralization reduced LPS-induced lung injury. Further, RNFT2 overexpression reduced lung inflammation and injury, whereas Rnft2 knockdown exacerbated inflammatory responses in LPS-induced murine lung injury. Last, we examined RNFT2 and IL-3Rα in human lung explants from patients with cystic fibrosis and also showed that IL-3 is elevated in mechanically ventilated critically ill humans at risk for acute respiratory distress syndrome. These results identify RNFT2 as a negative regulator of IL-3Rα and show a potential role for the RNFT2/IL-3Rα/IL-3 axis in regulating innate immune responses in the lung.
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http://dx.doi.org/10.1172/jci.insight.133652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098800PMC
February 2020

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV-associated posttransplant lymphoproliferative disorder and worse survival.

Am J Transplant 2020 05 22;20(5):1439-1446. Epub 2020 Jan 22.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.
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http://dx.doi.org/10.1111/ajt.15756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130541PMC
May 2020

Disseminated blastomycosis in coalworkers' pneumoconiosis.

Proc (Bayl Univ Med Cent) 2019 Oct 31;32(4):619-621. Epub 2019 Jul 31.

Department of Pulmonary, Allergy and Critical Care, University of Pittsburgh Medical CenterPittsburghPennsylvania.

is a thermally dimorphic fungus that can cause pulmonary, extrapulmonary, or disseminated infections. Though it can infect both immune-competent and immunocompromised hosts, the disease can be severe in immunocompromised hosts. Exposure to silica dust is associated with silicosis, and this is associated with impaired immunity and an increased risk of mycobacterial and fungal infections. The fungal infections commonly associated with pneumoconiosis are pulmonary aspergillosis, histoplasmosis, coccidioidomycosis, and cryptococcosis. However, there is a dearth of data on the association of pneumoconiosis and blastomycosis. Clinical deterioration and new cavitary lesions in patients with pneumoconiosis should alert clinicians of new pulmonary infection. Traditional sputum sampling may lead to poor diagnostic yield, because the organism is frequently surrounded by a fibrotic wall. Aggressive diagnostic testing with lung or skin biopsies may be warranted. We present the first reported case of disseminated blastomycosis in a patient with coalworkers' pneumoconiosis.
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http://dx.doi.org/10.1080/08998280.2019.1635412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793985PMC
October 2019

Early KLRG1 but Not CD57CD8 T Cells in Primary Cytomegalovirus Infection Predict Effector Function and Viral Control.

J Immunol 2019 10 25;203(8):2063-2075. Epub 2019 Sep 25.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and

CMV remains an important opportunistic pathogen in high-risk lung transplant recipients. We characterized the phenotype and function of CD8 T cells from acute/primary into chronic CMV infection in 23 (donor+/recipient-; D+R-) lung transplant recipients and found rapid induction of both KLRG1 and/or CD57 CMV-specific CD8 T cells with unexpected coexpression of CD27. These cells demonstrated maturation from an acute effector T cell (T) to an effector memory T cell (T) phenotype with progressive enrichment of KLRG1CD57CD27 cells into memory. CMV-specific KLRG1 T were capable of in vitro proliferation that diminished upon acquisition of CD57, whereas only KLRG1 expression correlated with T-bet expression and effector function. In contrast to blood T, lung mucosal T demonstrated reduced KLRG1/T-bet expression but similar CD57 levels. Additionally, increased KLRG1T were associated with early immune viral control following primary infection. To our knowledge, our findings provide new insights into the roles of KLRG1 and CD57 expression in human T cells, forming the basis for a refined model of CD8 T cell differentiation during CMV infection.
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http://dx.doi.org/10.4049/jimmunol.1900399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081945PMC
October 2019

GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis.

Am J Physiol Lung Cell Mol Physiol 2019 10 21;317(4):L510-L521. Epub 2019 Aug 21.

Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania.

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 (), as the most significantly upregulated secreted protein. expression is induced in response to telomere dysfunction and bleomycin challenge in mice. mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of , and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.
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http://dx.doi.org/10.1152/ajplung.00062.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842909PMC
October 2019

Aerosolization of Second-generation Triazoles: In Vitro Evaluation and Application in Therapy of Invasive Airway Aspergillosis.

Transplantation 2019 12;103(12):2608-2613

Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

Background: A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered.

Methods: Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions.

Results: Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (<5.4 µm) of 2.8 µm, 2.0, 86%; 3.4 µm, 2.4, 78%; and 3.0 µm, 2.3, 79% for voriconazole and 6, 12 mg/mL of posaconazole, respectively. Aspergillus fumigatus isolate from the patient was more susceptible to voriconazole, and hence aerosolized voriconazole was introduced around the third month posttransplant at 40 mg TID for 1 week, 40 mg BID for 1 week, followed by 40 mg daily thereafter, along with IV caspofungin (50 mg/d) and liposomal amphotericin B (300 mg/d). The aerosol regimen was well tolerated by the patient with undetectable trough plasma levels of voriconazole. Bronchoscopy at the fourth month revealed improvement in anastomotic plaques with reduction in bronchoalveolar lavage galactomannan values (7.48-2.15 ng/mL). This consolidated aerosolized and intravenous regimen was maintained until 2.97 years posttransplant.

Conclusions: The intravenous solutions of both second-generation triazoles showed characteristics that were suitable for aerosol delivery. Our report further adds to the therapeutic experience with the use of aerosolized voriconazole for IA in a lung transplant patient.
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http://dx.doi.org/10.1097/TP.0000000000002697DOI Listing
December 2019

Prolonged Cold Ischemia Induces Necroptotic Cell Death in Ischemia-Reperfusion Injury and Contributes to Primary Graft Dysfunction after Lung Transplantation.

Am J Respir Cell Mol Biol 2019 08;61(2):244-256

1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.

Primary graft dysfunction (PGD) is a major cause of morbidity and mortality after lung transplantation. Ischemia-reperfusion injury (IRI) is a key event that contributes to PGD, though complex interactions affect donor lungs status, such as preceding brain death (BD), hemorrhagic shock (HS), and pre-engraftment lung management, the latter recognized as important risk factors for PGD. We hypothesized that a multi-hit isogenic mouse model of lung transplantation is more closely linked to PGD than IRI alone. Left lung transplants were performed between inbred C57BL/6 mice. A one-hit model of IRI was established by inducing cold ischemia (CI) of the donor lungs at 0°C for 1, 72, or 96 hours before engraftment. Multi-hit models were established by inducing 24 hours of HS and/or 3 hours of BD before 24 hours of CI. The recipients were killed at 24 hours after transplant and lung graft samples were analyzed. In the one-hit model of IRI, up to 72-hour CI time resulted in minimal cellular infiltration near small arteries after 24-hour reperfusion. Extension of CI time to 96 hours led to increased cellular infiltration and necroptotic pathway activation, without evidence of apoptosis, after 24-hour reperfusion. In a multi-hit model of PGD, "HS + BD + IRI" demonstrated increased lung injury, cellular infiltration, and activation of necroptotic and apoptotic pathways compared with IRI alone. Treatment with an inhibitor of receptor-interacting protein kinase 1 kinase, necrostatin-1, resulted in a significant decrease of downstream necroptotic pathway activation in both single- and multi-hit models of IRI. Thus, activation of necroptosis is a central event in IRI after prolonged CI, though it may not be sufficient to cause PGD alone. Pathological evaluation of donor lungs after CI-induced IRI, in conjunction with pre-engraftment donor lung factors in our multi-hit model, demonstrated early evidence of lung injury consistent with PGD. Our findings support the premise that pre-existing donor lung status is more important than CI time alone for inflammatory pathway activation in PGD, which may have important clinical implications for donor lung retrieval.
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http://dx.doi.org/10.1165/rcmb.2018-0207OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670033PMC
August 2019

Jejuno-jejunal intussusception in a post-lung transplant patient from a gastrojejunostomy tube: A case report.

Int J Surg Case Rep 2019 31;55:129-131. Epub 2019 Jan 31.

Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States. Electronic address:

Introduction: Gastro-jejunostomy tube is used for post-pyloric feeding for critical-ill patient who cannot tolerate oral alimentation. Jejuno-jejunal intussusception is a rare complication of gastrojejunostomy tube.

Presentation Of Case: A 39-year-old male with history of severe combined immunodeficiency, Achalasia and end-stage lung disease underwent double lung transplantation. After lung transplantation, he required gastrojejunostomy(GJ) tube placement due to his esophageal disease. Four days after gastrojejunostomy tube placement, he developed jejuno-jejunal intussusception. A 15 cm segment of thickened and enlarged bowel, which consisted of the intussusception were identified laparoscopically. Surgical reduction was performed without bowel resection.

Discussion: Intussusception is uncommon in adults compared to pediatric population. In this rare case, the jejunal limb of the GJ tube placed in jejunum was the cause of jejunojejunal intussusception serving as the lead point. The GJ tube should not be placed farther down from ligaments of Treiz to prevent jejuno-jejunal intussusception.

Conclusions: A heightened index of suspicion for this rare complication should exist with a presenting patient has signs of proximal bowel obstruction and CT evidence of intussusception.
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http://dx.doi.org/10.1016/j.ijscr.2019.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365386PMC
January 2019

Cytokine-targeted therapy for the management of solid organ transplant recipients.

Hum Immunol 2019 Mar 16;80(3):184-190. Epub 2018 Dec 16.

Florida Hospital Transplant Institute, AdventHealth Orlando, 601 East Rollins St, Orlando, FL 32707, United States.

Introduction: The number of solid organ transplants completed annually continues to trend upwards each year. Despite this, maintenance immunosuppression available on the market has remained relatively stagnant. Standard triple immunosuppression, composed typically of tacrolimus, mycophenolate, and steroids, lead to many side effects that limit the use of these medications. Tacrolimus, specifically, causes nephrotoxicity that can lead to renal dysfunction requiring a kidney transplant down the road. Alternative therapies for the management of immunosuppression need to be identified to try to mitigate these adverse effects. BODY: Cytokines are responsible for facilitating T cell differentiation and lead to the activation of inflammatory mediators that can contribute to graft damage and ultimately rejection. IL-4, IL-6, IL-12/23, and IL-15 are attractive targets for medications to try to ameliorate graft rejection. Various cytokine-targeted medications are currently available on the market for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriatic arthritis, Crohn's, and multiple sclerosis.

Conclusion: This article reviews cytokine involvement in alloimmunity and the potential role cytokine-targeted therapy may play in prevention of allograft rejection in solid organ transplant recipients.
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http://dx.doi.org/10.1016/j.humimm.2018.12.006DOI Listing
March 2019

Foxp3+ T lymphocytes: immune regulators within the lung allograft.

J Clin Invest 2019 02 18;129(2):494-495. Epub 2018 Dec 18.

Antibody-mediated rejection (AMR) has emerged as an important cause of lung graft failure. In the current issue of the JCI, a study by Li et al. identifies a critical role of Foxp3+ T cells residing within lung allografts in the regulation of AMR. This study not only provides new insights into the nature of lung allografts as a primary site where T and B cell priming and immune regulation can occur, but also introduces the mouse orthotopic lung transplant as a model for studying the immunobiology of AMR. Because AMR can be so difficult to effectively treat in lung transplant recipients, the development of an animal model is a major advance in understanding the immunopathogenesis of AMR.
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http://dx.doi.org/10.1172/JCI126517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355210PMC
February 2019

Detrimental Association of Hypogammaglobulinemia With Chronic Lung Allograft Dysfunction and Death Is Not Mitigated by On-Demand Immunoglobulin G Replacement After Lung Transplantation.

Prog Transplant 2018 Dec 11:1526924818817028. Epub 2018 Dec 11.

2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Background:: Hypogammaglobulinemia (HGG), immunoglobulin G (IgG) <700 mg/dL, is associated with infections, chronic lung allograft dysfunction, and death following lung transplantation. This study evaluates the use of on-demand intravenous IgG in lung transplant recipients with HGG.

Materials And Methods:: This single-center retrospective cohort study of adult lung recipients evaluated 3 groups, no, untreated (u), or treated (t) HGG at first IgG administration or a matched time posttransplant. Primary outcome was freedom from allograft dysfunction. Secondary outcomes included development of advanced dysfunction, rejection, infection burden, and mortality.

Results:: Recipients included 484 (no HGG: 76, uHGG: 192, tHGG: 216). Freedom from chronic allograph dysfunction was highest in the non-HGG group 2 years post-enrollment (no HGG 77.9% vs uHGG 56.4% vs tHGG 52.5%; P = .002). Freedom from advanced dysfunction was significantly different 2 years post-enrollment (no HGG 90.5% vs uHGG 84.7% vs tHGG 75.4%; P = .017). Patients without HGG and those with uHGG had less mortality at 2 years post-enrollment (no HGG 84.2% vs uHGG 81.3% vs tHGG 64.8%; P < .001). Gram-negative pneumonias occurred more often in the tHGG group ( P = .02).

Conclusions:: Development of chronic lung allograft dysfunction, patient survival, rejection burden, and key infectious outcomes in lung transplant recipients were still problematic in the context of on-demand IgG therapy. Prospective studies are warranted.
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http://dx.doi.org/10.1177/1526924818817028DOI Listing
December 2018

Impaired Cytomegalovirus Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres.

Am J Respir Crit Care Med 2019 02;199(3):362-376

1 Division of Pulmonary, Allergy and Critical Care Medicine and.

Rationale: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high risk for CMV complications and effective immunity are incompletely understood.

Objectives: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control.

Methods: We studied IPF-LTRs (n = 42) and age-matched non-IPF-LTRs (n = 42) and assessed CMV outcomes. We measured lymphocyte telomere length and DNA sequencing, and assessed CMV-specific T-cell immunity in LTRs at high risk for CMV events, using flow cytometry and fluorescence in situ hybridization.

Measurements And Main Results: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared with non-IPF-LTRs (69% vs. 31%; odds ratio, 4.98; 95% confidence interval, 1.95-12.50; P < 0.001). Within this subset, IPF-LTRs who had short telomeres had the highest risk of CMV complications (P < 0.01) including relapsing-viremia episodes, end-organ disease, and CMV resistance to therapy, as well as shorter time to viremia versus age-matched non-IPF control subjects (P < 0.001). The short telomere defect in IPF-LTRs was associated with significantly impaired CMV-specific proliferative responses, T-cell effector functions, and induction of the major type-1 transcription factor T-bet (T-box 21;TBX21).

Conclusions: Because the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of LTRs has implications for risk assessment, management, and potential strategies for averting post-transplant CMV morbidities.
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http://dx.doi.org/10.1164/rccm.201805-0825OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363970PMC
February 2019

Belatacept for maintenance immunosuppression in cardiothoracic transplantation: The potential frontier.

Clin Transplant 2018 10 10;32(10):e13363. Epub 2018 Sep 10.

Norvartis Pharmaceuticals Corporation, Baltimore, Maryland.

Current immunosuppressive regimens with calcineurin inhibitors have improved the management of patients after transplantation. However, their adverse effects are linked to increased morbidity and limit the long-term survival of heart and lung transplant recipients. Belatacept, a costimulation inhibitor interfering with the interaction between CD28 on T cells and the B7 ligands on antigen presenting cells, has shown success and is currently approved for use in renal transplant recipients. Furthermore, it lacks many of the cardiovascular, metabolic, neurologic, and renal adverse of effects of calcineurin inhibitors that have the largest impact on long-term survival in cardiothoracic transplant. Additionally, it requires no therapeutic drug monitoring and is only administered once a month. Limitations to belatacept use have been observed that must be considered when comparing immunosuppression options. Despite this, maintenance immunosuppression with belatacept has the potential to improve outcomes in cardiothoracic transplant recipients, as it has with kidney transplant recipients. However, no large clinical trials investigating belatacept for maintenance immunosuppression in heart and lung transplant recipients exist. There is a large need for focused research of belatacept in cardiothoracic transplantation. Belatacept is a viable treatment option for maintenance immunosuppression, and it is reasonable to pursue more evidence in cardiothoracic transplant recipients.
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http://dx.doi.org/10.1111/ctr.13363DOI Listing
October 2018

Systematic review and meta-analysis of post-transplant lymphoproliferative disorder in lung transplant recipients.

Clin Transplant 2018 05 30;32(5):e13235. Epub 2018 Mar 30.

Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA, USA.

A systematic review of papers in English on post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random-effects model, and heterogeneity among studies was quantitated using I values. Fourteen studies published from 2005 to 2015 were included in the meta-analysis. One hundred and sixty-four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67-fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98-29.70; P = .003). pOR of death for early onset PTLD (<1 year post-LT) vs late onset (>1 year post-LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20-1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI -0.48-0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08-2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31-3.52, P = .94). This meta-analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.
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http://dx.doi.org/10.1111/ctr.13235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992057PMC
May 2018

Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients.

Am J Transplant 2018 06 6;18(6):1527-1533. Epub 2018 Apr 6.

Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.

Calcineurin inhibitors (CNIs) are the backbone of traditional immunosuppressive regimens for lung transplant recipients (LTR). The CNIs are both narrow therapeutic index drugs with significant interpatient and intrapatient variability that require therapeutic drug monitoring to ensure safety and effectiveness. We hypothesized that tacrolimus time-in-therapeutic range (TTR) affects acute and chronic rejection rates in LTRs. This was a single-center, observational, cross-sectional study of 292 adult LTRs. Subjects who received tacrolimus posttransplant for the first year were included. TTR was calculated at 1 year using protocol goal ranges (12-15 mg/mL months 0-6; 10-12 mg/mL for months 7-12). The primary outcome was acute cellular rejection (ACR) burden at 1 year. Chronic lung allograft dysfunction (CLAD), mortality, and infection rate were assessed as secondary outcomes at 1 year. Primary and secondary outcomes were assessed using logistic regression. Increasing TTR by 10% was associated with a significantly lower likelihood of high-burden ACR at 1 year on univariable (OR 0.46, 95% CI 0.40-0.54, P < .001) and multivariable (OR 0.64, 95% CI 0.47-0.86, P = .003) assessment, controlling for age and induction agent. Increasing TTR by 10% was also associated with lower rates of CLAD (P < .001) and mortality (P < .001) at 1 year. Prospective studies confirming these findings appear warranted.
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http://dx.doi.org/10.1111/ajt.14723DOI Listing
June 2018
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