Blood Transcriptomes of SARS-CoV-2-Infected Kidney Transplant Recipients Associated with Immune Insufficiency Proportionate to Severity.

BACKGROUND: Among patients with COVID-19, kidney transplant recipients (KTRs) have poor outcomes compared with non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort. METHODS: We ascertained clinical data by chart review. A single sample of blood was collected for transcriptome analysis. Total RNA was poly-A selected and RNA was sequenced to evaluate transcriptome changes. We also measured cytokines and chemokines of serum samples collected during acute infection. RESULTS: A total of 64 patients with COVID-19 in KTRs were enrolled, including 31 with acute COVID-19 (<4 weeks from diagnosis) and 33 with post-acute COVID-19 (>4 weeks postdiagnosis). In the blood transcriptome of acute cases, we identified genes in positive or negative association with COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways but downregulation of T cell and adaptive immune activation pathways. This finding was independent of lymphocyte count, despite reduced immunosuppressant use in most KTRs. Compared with acute cases, post-acute cases showed "normalization" of these enriched pathways after 4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of immunosuppression. Analysis of the non-KTR cohort with COVID-19 showed significant overlap with KTRs in these functions. Serum inflammatory cytokines followed an opposite trend (i.e., increased with disease severity), indicating that blood lymphocytes are not the primary source. CONCLUSIONS: The blood transcriptome of KTRs affected by COVID-19 shows decreases in T cell and adaptive immune activation pathways during acute disease that, despite reduced immunosuppressant use, associate with severity. These pathways show recovery after acute illness.

Differences in Humoral and Cellular Vaccine Responses to SARS-CoV-2 in Kidney and Liver Transplant Recipients.

The antibody and T cell responses after SARS-CoV-2 vaccination have not been formally compared between kidney and liver transplant recipients. Using a multiplex assay, we measured IgG levels against 4 epitopes of SARS-CoV-2 spike protein and nucleocapsid (NC) antigen, SARS-CoV-2 variants, and common coronaviruses in serial blood samples from 52 kidney and 50 liver transplant recipients undergoing mRNA SARS-CoV-2 vaccination. We quantified IFN-γ/IL-2 T cells reactive against SARS-CoV-2 spike protein by FluoroSpot. We used multivariable generalized linear models to adjust for the differences in immunosuppression between groups. In liver transplant recipients, IgG levels against every SARS-CoV-2 spike epitope increased significantly more than in kidney transplant recipients (MFI: 19,617 vs 6,056; P<0.001), a difference that remained significant after adjustments. Vaccine did not affect IgG levels against NC nor common coronaviruses. Elicited antibodies recognized all variants tested but at significantly lower strength than the original Wuhan strain. Anti-spike IFN-γ-producing T cells increased significantly more in liver than in kidney transplant recipients (IFN-γ-producing T cells 28 vs 11 spots/5x105 cells), but this difference lost statistical significance after adjustments. SARS-CoV-2 vaccine elicits a stronger antibody response in liver than in kidney transplant recipients, a phenomenon that is not entirely explained by the different immunosuppression.

Modelling the DFT structural and reactivity study of feverfew and evaluation of its potential antiviral activity against COVID-19 using molecular docking and MD simulations.

Abstract: The unavailability of a proper drug against SARS-CoV-2 infections and the emergence of various variants created a global crisis. In the present work, we have studied the antiviral behavior of feverfew plant in treating COVID-19. We have reported a systematic in silico study with the antiviral effects of various phytoconstituents Borneol (C10H18O), Camphene (C10H16), Camphor (C10H16O), Alpha-thujene (C10H16), Eugenol (C10H14O), Carvacrol (C10H14O) and Parthenolide (C15H20O3) of feverfew on the viral protein of SARS-CoV-2. Parthenolide shows the best binding affinity with both main protease (Mpro) and papain-like protease (PLpro). The molecular electrostatic potential and Mulliken atomic charges of the Parthenolide molecule shows the high chemical reactivity of the molecule. The docking of Parthenolide with PLpro give score of -8.0 kcal/mol that validates the good binding of Parthenolide molecule with PLpro. This complex was further considered for molecular dynamics simulations. The binding energy of the complex seems to range in between -3.85 to -11.07 kcal/mol that is high enough to validate the stability of the complex. Free energy decomposition analysis have been also performed to understand the contribution of residues that reside into the binding site. Good binding affinity and reactivity response suggested that Parthenolide can be used as a promising drug against the COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02067-6.

Coronavirus Disease 2019 in Solid Organ Transplant: A Multicenter Cohort Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well described. METHODS: We performed a multicenter cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS: Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (interquartile range [IQR] 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 1.7-5.5, P < .001], congestive heart failure [aOR 3.2, 95% CI 1.4-7.0, P = .004], chronic lung disease [aOR 2.5, 95% CI 1.2-5.2, P = .018], obesity [aOR 1.9, 95% CI 1.0-3.4, P = .039]) and presenting findings (lymphopenia [aOR 1.9, 95% CI 1.1-3.5, P = .033], abnormal chest imaging [aOR 2.9, 95% CI 1.1-7.5, P = .027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. CONCLUSIONS: Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.

DFT and MD simulation investigation of favipiravir as an emerging antiviral option against viral protease (3CLpro) of SARS-CoV-2.

As per date, around 20 million COVID-19 cases reported from across the globe due to a tiny 125 nm sized virus: SARS-CoV-2 which has created a pandemic and left an unforgettable impact on our world. Besides vaccine, medical community is in a race to identify an effective drug, which can fight against this disease effectively. Favipiravir (F) has recently attracted too much attention as an effective repurposed drug against COVID-19. In the present study, the pertinency of F has been tested as an antiviral option against viral protease (3CLpro) of SARS-CoV-2 with the help of density functional theory (DFT) and MD Simulation. Different electronic properties of F such as atomic charges, molecular electrostatic properties (MEP), chemical reactivity and absorption analysis have been studied by DFT. In order to understand the interaction and stability of inhibitor F against viral protease, molecular docking and MD simulation have been performed. Various output like interaction energies, number of intermolecular hydrogen bonding, binding energy etc. have established the elucidate role of F for the management of CoV-2 virus for which there is no approved therapies till now. Our findings highlighted the need to further evaluate F as a potential antiviral against SARS-CoV-2.

In Silico Investigation of Phytoconstituents of Medicinal Herb 'Piper Longum' Against SARS-CoV-2 by Molecular Docking and Molecular Dynamics Analysis.

Unavailability of treatment for the SARS-CoV-2 virus has raised concern among the population worldwide. This has led to many attempts to find alternative options to prevent the infection of the disease, including focusing on vaccines and drugs. The use of natural products and herbal extracts can be a better option in beating the virus and boosting up immunity. In the present paper, we have done a systematic in silico study of papain-like protease of COVID-19 virus with the chemical constituents of herbal plant Piper Longum. Screening of the pharmacokinetic properties is done with thirty-two phytoconstituents of Piper Longum which help us in selecting the most active components of the plant. After selection molecular docking is performed with Aristololactam (C17H11NO4), Fargesin (C21H22O6), l-asarinin (C20H18O6), Lignans Machilin F (C20H22O5), Piperundecalidine (C23H29NO3), and Pluviatilol (C20H20O6). Molecular dynamic (MD) is also performed with the inhibitor-receptor complex which suggest significant inhibition and a stable complex of I-Asarinin with PLpro. Docking scores and simulation results suggest that I-Asarinin can act as a potential drug like candidate against COVID-19.

Influence of patient characteristics and immunosuppressant management on mortality in kidney transplant recipients hospitalized with coronavirus disease 2019 (COVID-19).

The influence of patient characteristics and immunosuppression management on COVID-19 outcomes in kidney transplant recipients (KTRs) remains uncertain. We performed a single-center, retrospective review of all adult KTRs admitted to the hospital with confirmed COVID-19 between 03/15/2020 and 05/15/2020. Patients were followed from the date of admission up to 1 month following hospital discharge or study conclusion (06/15/2020). Baseline characteristics, laboratory parameters, and immunosuppression were compared between survivors and patients who died to identify predictors of mortality. 38 KTRs with a mean baseline eGFR of 52.5 ml/min/1.73 m2 were hospitalized during the review period. Maintenance immunosuppression included tacrolimus (84.2%), mycophenolate (89.5%), and corticosteroids (81.6%) in the majority of patients. Eleven patients (28.9%) died during the hospitalization. Older age (OR = 2.05; 1.04-4.04), peak D-dimer (OR = 1.20; 1.04-1.39), and peak white blood cell count (OR = 1.11; 1.02-1.21) were all associated with mortality among KTRs hospitalized for COVID-19. Increased mortality was also observed among KTRs with concomitant HIV infection (87.5% vs. 36.1%; p < .01). Conversely, immunosuppression intensity and degree of reduction following COVID-19 diagnosis were not associated with either survival or acute allograft rejection. Our findings potentially support a strategy of individualization of immunosuppression targets based on patient-specific risk factors, rather than universal immunosuppression reduction for KTRs at risk from COVID-19.

SARS-CoV-2 Infections among Recent Organ Recipients, March-May 2020, United States.

We conducted public health investigations of 8 organ transplant recipients who tested positive for severe acute respiratory syndrome coronavirus 2 infection. Findings suggest the most likely source of transmission was community or healthcare exposure, not the organ donor. Transplant centers should educate transplant candidates and recipients about infection prevention recommendations.

Incidence and Outcomes of COVID-19 in Kidney and Liver Transplant Recipients With HIV: Report From the National HOPE in Action Consortium.

BACKGROUND: Transplant recipients with HIV may have worse outcomes with coronavirus disease 2019 (COVID-19) due to impaired T-cell function coupled with immunosuppressive drugs. Alternatively, immunosuppression might reduce inflammatory complications and/or antiretrovirals could be protective. METHODS: Prospective reporting of all cases of SARS-CoV-2 infection was required within the HOPE in Action Multicenter Consortium, a cohort of kidney and liver transplant recipients with HIV who have received organs from donors with and without HIV at 32 transplant centers in the United States. RESULTS: Between March 20, 2020 and September 25, 2020, there were 11 COVID-19 cases among 291 kidney and liver recipients with HIV (4%). In those with COVID-19, median age was 59 y, 10 were male, 8 were kidney recipients, and 5 had donors with HIV. A higher proportion of recipients with COVID-19 compared with the overall HOPE in the Action cohort were Hispanic (55% versus 12%) and received transplants in New York City (73% versus 34%, P < 0.05). Most (10/11, 91%) were hospitalized. High-level oxygen support was required in 7 and intensive care in 5; 1 participant opted for palliative care instead of transfer to the intensive care unit. HIV RNA was undetectable in all. Median absolute lymphocyte count was 0.3 × 103 cells/µL. Median CD4 pre-COVID-19 was 298 cells/µL, declining to <200 cells/µl in 6/7 with measurements on admission. Treatment included high-dose steroids (n = 6), tocilizumab (n = 3), remdesivir (n = 2), and convalescent plasma (n = 2). Four patients (36%) died. CONCLUSIONS: Within a national prospective cohort of kidney and liver transplant recipients with HIV, we report high mortality from COVID-19.

Treatment with convalescent plasma in solid organ transplant recipients with COVID-19: Experience at large transplant center in New York City.

Solid organ transplant (SOT) recipients may be at higher risk for poor outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Convalescent plasma is an investigational therapy that may benefit immunosuppressed patients by providing passive immunity. Convalescent plasma was administered to hospitalized patients with coronavirus disease-2019 (COVID-19) at an academic transplant center in New York City. Eligible patients were hospitalized and required to have positive nasopharyngeal polymerase chain reaction (PCR) diagnosis of SARS-CoV-2 infection, be at least 18 years old, and have either dyspnea, blood oxygen saturation ≤ 93% on ambient air, respiratory frequency ≥ 30 breaths/min, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, or lung infiltrates > 50%. Thirteen SOT recipients received convalescent plasma from April 9, 2020, to May 17, 2020. The median time from symptom onset to plasma infusion was 8 days. Eight of 13 patients (62%) had de-escalating oxygenation support by day 7 post-convalescent plasma. Nine (69%) patients were discharged, 1 (7%) patients remain hospitalized, and 3 (23%) patients died. This series supports the need for additional studies on convalescent plasma use in SOT recipients with COVID-19 to better determine efficacy and identify patients who are likely to benefit.

Kidney transplantation using lymphocyte depleting induction and standard maintenance immunosuppression at the height of the SARS-CoV-2 pandemic in New York City: A single-center experience.

BACKGROUND: Concerns have been raised regarding proceeding with kidney transplantation using standard immunosuppression in COVID-19 endemic areas. METHODS: We performed a single-center review of all adult kidney transplants performed during the COVID-19 pandemic in New York City. Patients were managed with standard immunosuppression protocols, including lymphocyte depleting induction and trough-guided tacrolimus. Retrospective data were collected for 3 months from the date of transplantation or until study conclusion (5/7/2020). The primary outcomes assessed included patient and allograft survival as well as COVID-19 related hospital readmission. RESULTS: 30 kidney transplants were performed during the height of the COVID-19 pandemic. After a median follow-up of 51.5 days, 93.3% of patients were alive with 100% death-censored allograft survival. 9 patients were readmitted to the hospital during the study period, 4 (13.3%) related to infection with COVID-19. Infections were mild in 3/4 patients, with one patient developing severe disease leading to respiratory failure. Patients readmitted with COVID-19 were numerically more likely to be African American, have a BMI > 30 kg/m2, have a lymphocyte count ≤ 300 cells/mL, and be on maintenance corticosteroids. CONCLUSIONS: Kidney transplantation in areas endemic to COVID-19 using standard induction and maintenance immunosuppression appears to be associated with a modest risk for severe COVID-19 related disease.