Publications by authors named "Deepali Kumar"

157 Publications

A call to routinely test lower respiratory tract samples for SARS-CoV-2 in lung donors.

Am J Transplant 2021 Mar 23. Epub 2021 Mar 23.

Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1111/ajt.16576DOI Listing
March 2021

Characteristics and outcomes of patients with COVID-19 admitted to hospital and intensive care in the first phase of the pandemic in Canada: a national cohort study.

CMAJ Open 2021 Jan-Mar;9(1):E181-E188. Epub 2021 Mar 8.

Division of Infectious Diseases, Department of Medicine (Lee), McGill University, Montréal, Que.; Ajmera Transplant Centre (Kumar), University Health Network, Toronto, Ont.; Department of Critical Care Medicine (Dechert), Brantford General Hospital, Brantford, Ont.; Department of Medicine (Sandhu), St. Michael's Hospital, Toronto, Ont.; School of Rehabilitation Science (Kho, O'Grady), McMaster University, Hamilton, Ont.; St. Joseph's Healthcare (Kelly), Hamilton, Ont.; Island Health Authority (Ovakim), Victoria, BC; Department of Anesthesiology and Department of Medicine - Critical Care Division (Carrier), Centre hospitalier de l'Université de Montréal, Montréal, Que.; Department of Medicine (Daneman), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont.; Faculté de médecine de l'Université de Montréal (Tessier-Grenier), Université de Montréal, Montréal, Que.; Vancouver Island Health Authority (Wood), Victoria, BC; Department of Medicine (Gu), McGill University, Montréal, Que.; Children's Hospital of Eastern Ontario Research Institute (O'Hearn), Ottawa, Ont.; Department of Community Health Sciences (Stelfox), University of Calgary, Calgary, Alta.; UBC Faculty of Medicine (Douglas), University of British Columbia, and Island Health, Vancouver, BC; Department of Medicine (Fowler), University of Toronto, Toronto, Ont.; Faculty of Medicine (Solomon), McGill University, Montréal, Que.; Department of Pediatrics (Goco) and of Critical Care Medicine (Guerguerian), The Hospital for Sick Children, Toronto, Ont.; Department of Medicine (Hsu), McGill University, Montréal, Que.; Divisions of Infectious Diseases and Medical Microbiology (Cheng), McGill University Health Centre, Montréal, Que.; Department of Medicine (Swanson), University of Victoria, Victoria, BC; Department of Medicine (Hall), Dalhousie University, Halifax, NS; Department of Medicine (Pitre), McMaster University, Hamilton, Ont.; Department of Pediatrics (Jouvet), Sainte-Justine Hospital, Université de Montréal, Montréal, Que.; Ottawa Hospital Research Institute (Pharand), Ottawa, Ont.; Department of Critical Care Medicine (Fiest), Cumming School of Medicine, University of Calgary, Calgary, Alta.; Faculty of Medicine, University of British Columbia, and Island Health (Reel), Victoria, BC; Department of Medicine (Tsang), McMaster University, Hamilton, Ont., and Niagara Health (Tsang), St. Catharines, Ont.; Grand River Hospital (Kruisselbrink), Kitchener, Ont.; Department of Family Medicine and Emergency Medicine (Archambault), Université Laval, Laval, Que.; Department of Medicine (Rishu), Sunnybrook Health Sciences Centre, Toronto, Ont.; Department of Medicine (Codan), University of Calgary, Calgary, Alta.; Departments of Medicine (Rewa, Sligl), of Critical Care Medicine (Kutsogiannis) and of Pediatrics (Joffe), University of Alberta, Edmonton, Alta.; Department of Medicine (Shadowitz), Sunnybrook Health Sciences Centre, Toronto, Ont.; Department of Medicine (Sarfo-Mensah), The Ottawa Hospital/Ottawa Hospital Research Institute, Ottawa, Ont.; Department of Medicine (Lamontagne), Université de Sherbrooke, Sherbrooke, Que.; Department of Pediatrics (Menon), University of Ottawa, Ottawa, Ont.; McGill University Health Centre (Atique), Montréal, Que.; William Osler Health System (Richardson), Toronto, Ont.; Joseph Brant Hospital (Reeve), Burlington, Ont.; Department of Pediatrics (Murthy), University of British Columbia, Vancouver, BC.

Background: Clinical data on patients admitted to hospital with coronavirus disease 2019 (COVID-19) provide clinicians and public health officials with information to guide practice and policy. The aims of this study were to describe patients with COVID-19 admitted to hospital and intensive care, and to investigate predictors of outcome to characterize severe acute respiratory infection.

Methods: This observational cohort study used Canadian data from 32 selected hospitals included in a global multisite cohort between Jan. 24 and July 7, 2020. Adult and pediatric patients with a confirmed diagnosis of COVID-19 who received care in an intensive care unit (ICU) and a sampling of up to the first 60 patients receiving care on hospital wards were included. We performed descriptive analyses of characteristics, interventions and outcomes. The primary analyses examined in-hospital mortality, with secondary analyses of the length of hospital and ICU stay.

Results: Between January and July 2020, among 811 patients admitted to hospital with a diagnosis of COVID-19, the median age was 64 (interquartile range [IQR] 53-75) years, 495 (61.0%) were men, 46 (5.7%) were health care workers, 9 (1.1%) were pregnant, 26 (3.2%) were younger than 18 years and 9 (1.1%) were younger than 5 years. The median time from symptom onset to hospital admission was 7 (IQR 3-10) days. The most common symptoms on admission were fever, shortness of breath, cough and malaise. Diabetes, hypertension and cardiac, kidney and respiratory disease were the most common comorbidities. Among all patients, 328 received care in an ICU, admitted a median of 0 (IQR 0-1) days after hospital admission. Critically ill patients received treatment with invasive mechanical ventilation (88.8%), renal replacement therapy (14.9%) and extracorporeal membrane oxygenation (4.0%); 26.2% died. Among those receiving mechanical ventilation, 31.2% died. Age was an influential predictor of mortality (odds ratio per additional year of life 1.06, 95% confidence interval 1.03-1.09).

Interpretation: Patients admitted to hospital with COVID-19 commonly had fever, respiratory symptoms and comorbid conditions. Increasing age was associated with the development of critical illness and death; however, most critically ill patients in Canada, including those requiring mechanical ventilation, survived and were discharged from hospital.
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http://dx.doi.org/10.9778/cmajo.20200250DOI Listing
March 2021

Prospective observational study and serosurvey of SARS-CoV-2 infection in asymptomatic healthcare workers at a Canadian tertiary care center.

PLoS One 2021 16;16(2):e0247258. Epub 2021 Feb 16.

University Health Network, Toronto, Ontario, Canada.

Health care workers (HCWs) are at higher risk for SARS-CoV-2 infection and may play a role in transmitting the infection to vulnerable patients and members of the community. This is particularly worrisome in the context of asymptomatic infection. We performed a cross-sectional study looking at asymptomatic SARS-CoV-2 infection in HCWs. We screened asymptomatic HCWs for SARS-CoV-2 via PCR. Complementary viral genome sequencing was performed on positive swab specimens. A seroprevalence analysis was also performed using multiple assays. Asymptomatic health care worker cohorts had a combined swab positivity rate of 29/5776 (0.50%, 95%CI 0.32-0.75) relative to a comparative cohort of symptomatic HCWs, where 54/1597 (3.4%) tested positive for SARS-CoV-2 (ratio of symptomatic to asymptomatic 6.8:1). SARS-CoV-2 seroprevalence among 996 asymptomatic HCWs with no prior known exposure to SARS-CoV-2 was 1.4-3.4%, depending on assay. A novel in-house Coronavirus protein microarray showed differing SARS-CoV-2 protein reactivities and helped define likely true positives vs. suspected false positives. Our study demonstrates the utility of routine screening of asymptomatic HCWs, which may help to identify a significant proportion of infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886177PMC
February 2021

Safety and immunogenicity of adjuvanted recombinant subunit herpes zoster vaccine in lung transplant recipients.

Am J Transplant 2021 Feb 10. Epub 2021 Feb 10.

Transplant Infectious Diseases and Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada.

Lung transplant recipients are at high risk for herpes zoster and preventive measures are a significant unmet need. We investigated the safety and immunogenicity of two doses of a recombinant zoster vaccine (RZV) in lung transplant recipients (≥50 years). We enrolled 50 patients of which 49 received at least one vaccine dose. Anti-glycoprotein E (gE) antibody levels (n = 43) increased significantly compared to baseline (median optical density [OD] 1.96; interquartile range [IQR]: 1.17-2.89) after the first (median OD 3.41, IQR 2.54-3.81, p < .0001) and second vaccine dose (median OD 3.63, IQR 3.39-3.86, p < .0001). gE-specific polyfunctional CD4+ T cell frequencies (n = 38) also increased from baseline (median 85 per 10 CD4+ T cells; IQR: 46-180) to the first (median 128 per 10 CD4+ T cells; IQR: 82-353; p = .023) and after the second dose (median 361 per 10 CD4+ T cells; IQR: 146-848; p < .0001). Tenderness (83.0%; 95%CI: 69.2-92.4%) and redness (31.9%; 95%CI: 19.1-47.1%) at injection site were common. One rejection episode within 3 weeks of vaccination was observed. This is the first study demonstrating that RZV was safe and elicited significant humoral and cell-mediated immunity in lung transplant recipients. RZV is a new option for the prevention of shingles in this population.
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http://dx.doi.org/10.1111/ajt.16534DOI Listing
February 2021

Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial.

Lancet Respir Med 2021 Feb 5. Epub 2021 Feb 5.

Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada; University Health Network, University of Toronto, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Background: To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19.

Methods: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259.

Findings: Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15-16·73; p=0·029). Of those with baseline viral load above 10 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49-31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported.

Interpretation: Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding.

Funding: The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
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http://dx.doi.org/10.1016/S2213-2600(20)30566-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906707PMC
February 2021

Evaluation of Recombinant Herpes Zoster Vaccine for Primary Immunization of Varicella-seronegative Transplant Recipients.

Transplantation 2021 Jan 19. Epub 2021 Jan 19.

1 Pediatric Infectious Diseases Unit, Geneva University Hospitals and Faculty of Medicine, 4 rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland 2 Division of Infectious Diseases, Inselspital, Freiburgstrasse 18, 3010 Bern, Switzerland 3 Ajmera Transplant Centre, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada 4 Centers for Disease Control and Prevention, Division of Viral Diseases, 1600 Clifton Road, Atlanta, GA 30333, USA.

Background: Immunization of VZV-seronegative solid organ transplant (SOT) patients using the live-attenuated varicella vaccine is generally contraindicated, leaving no widely applicable immunization option. The recombinant subunit herpes zoster vaccine (RZV) is indicated for VZV seropositive persons to prevent shingles but could potentially also protect VZV-seronegative persons against varicella. We performed a safety and immunogenicity evaluation of RZV in VZV-seronegative SOT recipients as an option for protection.

Methods: VZV-seronegative adult SOT patients with no history of varicella/shingles vaccine or disease were given 2 doses of RZV vaccine 2-6 months apart. Blood was drawn prevaccination (V1), prior to the second dose (V2) and 4 weeks after second dose (V3). Humoral (anti-gE) and cell-mediated immunity was evaluated, with polyfunctional cells defined as cells producing ≥2 cytokines.

Results: Among 31 eligible VZV-seronegative SOT patients screened, 23 were enrolled. Median age was 38 years and median time since transplant procedure was 38 years. The most frequent transplant types were liver (35%) and lung (30%). Median anti-gE levels significantly increased from V1 to V3 (p=0001) and V2 to V3 (p<0001), even though only 55% had a positive seroresponse. Median polyfunctional CD4 T-cells counts increased from V1 to V2 (54/10 vs 104/10 cells; p=0041), and from V2 to V3 (380/10; p=0002). Most adverse events were mild with no rejection episodes.

Conclusion: RZV was safe and elicited significant humoral and cellular responses in VZV-seronegative SOT patients, and has the potential to be considered as a preventive strategy against primary varicella.
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http://dx.doi.org/10.1097/TP.0000000000003621DOI Listing
January 2021

Evaluating the role of STAT3 in CD4+ T-cells in susceptibility to invasive aspergillosis.

Infect Immun 2021 Feb 1. Epub 2021 Feb 1.

Transplant Infectious Diseases, Ajmera Transplant Center, University Health Network, University of Toronto, Toronto, Canada

We aimed to determine whether T cell-specific STAT3 deletion influences the immune response to in the immunosuppressed context in CD4 mice. Immunosuppressed and non-immunosuppressed CD4 mice and littermate Stat3 mice infected with in an aerosol chamber and mice weight, activity, appearance and respiratory rate was monitored daily for 21 days to evaluate their survival. infection was confirmed by lung fungal culture counts, histology, and galactomannan test. Cytokines were measured 3 days post infection in BAL and serum. Immunosuppressed CD4 mice began succumbing to infection by day 4, and by day 7, only 30% of mice survived. Immunosuppressed Stat3 mice started to succumb to the disease on day 5, and 40% of mice remained by day 7. The non-immunosuppressed control Stat3 and CD4 mice maintained their weight over study period, without any evidence of infection by by histology. In the BAL, TNFα, IL-6, IFNγ, IL-17A, and IL-22 levels were elevated in Stat3 immunosuppressed mice compared to immunosuppressed CD4 mice three days post-infection. STAT3 in CD4+ T cells modulates the production of cytokines in the IL-17 pathway in immunosuppressed mice. However, it has no meaningful effect on the clearance of nor the concomitant increase in susceptibility to infection.
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http://dx.doi.org/10.1128/IAI.00035-21DOI Listing
February 2021

Natural influenza infection produces a greater diversity of humoral responses than vaccination in immunosuppressed transplant recipients.

Am J Transplant 2021 Jan 23. Epub 2021 Jan 23.

Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

The humoral immune response to influenza virus infection is complex and may be different compared to the antibody response elicited by vaccination. We analyzed the breadth of IgG and IgA responses in solid organ transplant (SOT) recipients to a diverse collection of 86 influenza antigens elicited by natural influenza A virus (IAV) infection or by vaccination. Antibody levels were quantified using a custom antigen microarray. A total of 120 patients were included: 80 IAV infected (40 A/H1N1 and 40 A/H3N2) and 40 vaccinated. Based on hierarchical clustering analysis, infection with either H1N1 or H3N2 virus showed a more diverse antibody response compared to vaccination. Similarly, H1N1-infected individuals showed a significant IgG response to 27.9% of array antigens and H3N2-infected patients to 43.0% of antigens, whereas vaccination elicited a less broad immune response (7.0% of antigens). Immune responses were not exclusively targeting influenza hemagglutinin (HA) proteins but were also directed against conserved influenza antigens. Serum IgA responses followed a similar profile. This study provides novel data on the breadth of antibody responses to influenza. We also found that the diversity of response is greater in influenza-infected rather than vaccinated patients, providing a potential mechanistic rationale for suboptimal vaccine efficacy in this population.
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http://dx.doi.org/10.1111/ajt.16503DOI Listing
January 2021

Development and Validation of a Multiplex, Bead-based Assay to Detect Antibodies Directed Against SARS-CoV-2 Proteins.

Transplantation 2021 01;105(1):79-89

Division of Laboratory Medicine, Department of Pathology, Emory University, Atlanta, GA.

Background: Transplant recipients who develop COVID-19 may be at increased risk for morbidity and mortality. Determining the status of antibodies against SARS-CoV-2 in both candidates and recipients will be important to understand the epidemiology and clinical course of COVID-19 in this population. While there are multiple tests to detect antibodies to SARS-CoV-2, their performance is variable. Tests vary according to their platforms and the antigenic targets which make interpretation of the results challenging. Furthermore, for some assays, sensitivity and specificity are less than optimal. Additionally, currently available serological tests do not exclude the possibility that positive responses are due to cross reactive antibodies to community coronaviruses rather than SARS-CoV-2.

Methods: This study describes the development and validation of a high-throughput multiplex antibody detection assay.

Results: The multiplex assay has the capacity to identify, simultaneously, patient responses to 5 SARS-CoV-2 proteins, namely, the full spike protein, 3 individual domains of the spike protein (S1, S2, and receptor binding domain), and the nucleocapsid protein. The antibody response to the above proteins are SARS-CoV-2-specific, as antibodies against 4 common coronaviruses do not cross-react.

Conclusions: This new assay provides a novel tool to interrogate the spectrum of immune responses to SAR-CoV-2 and is uniquely suitable for use in the transplant setting. Test configuration is essentially identical to the single antigen bead assays used in the majority of histocompatibility laboratories around the world and could easily be implemented into routine screening of transplant candidates and recipients.
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http://dx.doi.org/10.1097/TP.0000000000003524DOI Listing
January 2021

The economic impact of increased length of stay associated with surgical site infections in liver transplantation on Canadian healthcare costs.

Clin Transplant 2021 Jan 29;35(1):e14155. Epub 2020 Nov 29.

Multi-Organ Transplant Program, and Division of Infectious Diseases, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Background: Complications after liver transplantation cause additional healthcare costs. The objective of this study was to contrast the length of stay (LOS) costs for recipients with and without surgical site infections (SSIs).

Methods: This retrospective observational cohort study was conducted at a transplant center in Canada, between February 2011 and August 2014. The difference in the LOS costs was assessed by the Mann-Whitney U test, while multiple linear regression analysis was used to identify the variables that may have impacted on the costs.

Results: Two hundred and twenty-nine liver transplant recipients were enrolled. Thirty-six recipients developed SSIs (36/229, 15.7%). The median LOS costs in recipients with and without SSIs were $39,456 Canadian dollars (interquartile range $25,696- 59,722) and $31,084 Canadian dollars (interquartile range $22,712-49 610), respectively (p = .072). There was a trend that the costs were higher for those recipients with versus those without SSIs (p = .088). Transfusion of ≥ 5 units of red cells and dialysis before transplantation impacted on cost.

Conclusion: There was a trend for higher healthcare facility costs for recipients with SSIs. Red cell transfusions and greater dialysis use before transplant were factors associated with the cost. Implementation of cost reduction strategies targeting high-cost recipients is necessary.
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http://dx.doi.org/10.1111/ctr.14155DOI Listing
January 2021

Long-lasting cluster of nosocomial pneumonia with a single Pneumocystis jirovecii genotype involving different organ allograft recipients.

Clin Transplant 2020 12 27;34(12):e14108. Epub 2020 Oct 27.

Multiorgan Transplant Program, London Health Sciences Center, Western University, London, ON, Canada.

Pneumocystis pneumonia (PCP) outbreaks may occur in solid organ transplant (SOT) patients. Transmissibility of Pneumocystis jirovecii among SOT and non-SOT patients has not been investigated. Ten SOT (ie, 4 heart, 4 kidney, 2 liver allograft recipients) and 11 non-SOT (ie, 7 HIV-infected, 3 hematologic malignancies, and 1 stem cell transplant) patients with PCP were admitted to London Health Sciences Center (LHSC) from October 2014 to August 2016. We investigated the course of illness and outcome of PCP in SOT and non-SOT patients. Post-transplant PCP was frequently an acute-onset disease (90% vs. 18.2%, p = .01) requiring ICU admission (70% vs. 20%, p = .03) and hemodialysis (60% vs. 0, p = .003). Mortality was more frequent in SOT patients (40% vs. 18.1%, p = .36). Multilocus sequence typing (MLST) demonstrated circulation of a single genotype of P. jirovecii among SOT patients. However, 8 different genotypes were detected from non-SOT patients. Reinstitution of prophylaxis successfully controlled post-transplant cluster until end of observation period in October 2019. No transmission was detected from non-SOT patients to SOT recipients. Detection of a single P. jirovecii genotype from all SOT recipients highlights the likelihood of nosocomial transmission. No source control method is recommended by current guidelines. Improvement of preventive strategies is required.
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http://dx.doi.org/10.1111/ctr.14108DOI Listing
December 2020

Influenza Virus Infection and Transplantation.

Transplantation 2020 Oct 8. Epub 2020 Oct 8.

Infectious Diseases, Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

Influenza infection poses significant risk for solid organ transplant recipients who often experience more severe infection with increased rates of complications, including those relating to the allograft. Although symptoms of influenza experienced by transplant recipients are similar to that of the general population, fever is not a ubiquitous symptom and lymphopenia is common. Annual inactivated influenza vaccine is recommended for all transplant recipients. Newer strategies such as using a higher dose vaccine or multiple doses in the same season appear to provide greater immunogenicity. Neuraminidase inhibitors are the mainstay of treatment and chemoprophylaxis although resistance may occur in the transplant setting. Influenza therapeutics are advancing, including the recent licensure of baloxavir; however, many remain to be evaluated in transplant recipients and are not yet in routine clinical use. Further population-based studies spanning multiple influenza seasons are needed to enhance our understanding of influenza epidemiology in SOT recipients. Specific assessment of newer influenza therapeutics in transplant recipients and refinement of prevention strategies are vital to reducing morbidity and mortality.
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http://dx.doi.org/10.1097/TP.0000000000003486DOI Listing
October 2020

Ex-vivo delivery of monoclonal antibody (Rituximab) to treat human donor lungs prior to transplantation.

EBioMedicine 2020 Oct 16;60:102994. Epub 2020 Sep 16.

Ajmera Transplant Center, University Health Network, PMB 11-175, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada. Electronic address:

Background: Ex-vivo lung perfusion (EVLP) is an innovative platform for assessing donor lungs in the pre-transplant window. In this study, we demonstrate an extension of its utility by administering the anti-CD20 monoclonal antibody, Rituximab, during EVLP. We hypothesized that this would lead to targeted depletion of allograft B-cells which may provide significant clinical benefit, including the potential to reduce latent Epstein-Barr virus (EBV) and decrease the incidence of post-transplant lymphoproliferative malignancies.

Methods: Twenty human donor lungs rejected for transplantation were placed on EVLP with (n = 10) or without (n = 10) 500 mg of Rituximab. Safety parameters such as lung physiology and inflammatory cytokines were evaluated. We measured the delivery efficacy through flow cytometry, immunohistochemistry and ELISA. An in-vitro culture assay, in the presence of complement, was further conducted to monitor whether B-cell depletion would occur in Rituximab-perfused samples.

Findings: Rituximab was successfully delivered to human lungs during EVLP as evidenced by flow cytometric binding assays where lung tissue and lymph node biopsies demonstrated occupied CD20 epitopes after perfusion with the antibody. Lymph nodes from Rituximab perfusions demonstrated a 10.9 fold-reduction in CD20+ staining compared to controls (p = 0.0003). In lung tissue, Rituximab resulted in an 8.75 fold-reduction in CD20+ staining relative to controls (p = 0.0002). This decrease in CD20+ binding illustrates the successful delivery and occupation of epitopes after perfusion with the Rituximab. No apparent safety concerns were seen as exhibited by markers associated with acute cell injury (e.g., proinflammatory cytokines), cell death (e.g., TUNEL staining), or pulmonary physiology. In a post-perfusion tissue culture model, the addition of complement (human serum) resulted in evidence of B-cell depletion consistent with what would be expected with posttransplant activation of bound Rituximab.

Interpretation: Our experiments illustrate the potential of EVLP as a platform to deliver monoclonal antibody therapies to treat donor lungs pretransplant with the goal of eliminating a latent virus responsible for considerable morbidity after lung transplantation.

Funding: Supported by the University Health Network Transplant Center.
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http://dx.doi.org/10.1016/j.ebiom.2020.102994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501077PMC
October 2020

Case 29-2020: A 66-Year-Old Man with Fever and Shortness of Breath after Liver Transplantation.

N Engl J Med 2020 09;383(12):1168-1180

From the Departments of Medicine (J.A.F., M.B.R.) and Radiology (E.W.Z.), Massachusetts General Hospital, and the Departments of Medicine (J.A.F., M.B.R.) and Radiology (E.W.Z.), Harvard Medical School - both in Boston; the Division of Infectious Diseases and Transplant Center, University Health Network and University of Toronto, Toronto (D.K.); the Transplantation and Clinical Virology Unit, Department of Biomedicine, University Hospital Basel, Basel, Switzerland (H.H.H.); and the Nephrology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy (U.M.).

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http://dx.doi.org/10.1056/NEJMcpc2004982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510944PMC
September 2020

Tacrolimus Impairs Kupffer Cell Capacity to Control Bacteremia: Why Transplant Recipients Are Susceptible to Infection.

Hepatology 2020 Aug 6. Epub 2020 Aug 6.

Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.

Background And Aims: Kupffer cells (KCs) are the resident intravascular phagocyte population of the liver and critical to the capture and killing of bacteria. Calcineurin/nuclear factor of activated T cells (NFAT) inhibitors (CNIs) such as tacrolimus are used to prevent rejection in solid organ transplant recipients. Although their effect on lymphocytes has been studied extensively, there are limited experimental data about if and how CNIs shape innate immunity, and whether this contributes to the higher rates of infection observed in patients taking CNIs.

Approach And Results: Here, we investigated the impact of tacrolimus treatment on innate immunity and, more specifically, on the capability of Kupffer cells (KCs) to fight infections. Retrospective analysis of data of >2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of Staphylococcus aureus infection. Using a mouse model of acute methicillin-resistant S. aureus (MRSA) bacteremia, most bacteria were sequestered in the liver and we found that bacteria were more likely to disseminate and kill the host in tacrolimus-treated mice. Using imaging, we unveiled the mechanism underlying this observation: the reduced capability of KCs to capture, phagocytose, and destroy bacteria in tacrolimus-treated animals. Furthermore, in a gene expression analysis of infected KCs, the triggering receptor expressed on myeloid cells 1 (TREM1) pathway was the one with the most significant down-regulation after tacrolimus treatment. TREM1 inhibition likewise inhibited KC bacteria capture. TREM1 levels on neutrophils as well as the overall neutrophil response after infection were unaffected by tacrolimus treatment.

Conclusions: Our results indicate that tacrolimus treatment has a significant impact directly on KCs and on TREM1, thereby compromising their capacity to fend off infections.
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http://dx.doi.org/10.1002/hep.31499DOI Listing
August 2020

High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis.

Leuk Lymphoma 2020 12 25;61(13):3198-3208. Epub 2020 Jul 25.

Department of Medicine, Division of Medical Oncology and Hematology, University of Toronto, Toronto, ON, Canada.

We explore risk factors and impacts of post-transplant EBV-Reactivation (EBV-R) and PTLD in 270 patients that underwent RIC alloHCT using ATG-PTCy and cyclosporine for GVHD prophylaxis. Twenty-five (12%) patients had probable ( = 7) or proven ( = 18) PTLD. Patients were managed with reduction of immunosuppression and 22 with weekly rituximab (375 mg/m IV). ORR was 84%; 8 (32%) recipients died, and one-year OS and NRM of patients with PTLD was 59.7% and 37%, respectively. One hundred seventy-two (63.7%) recipients had EBV-R. One-year OS and RFS of patients with EBV-R were 68.2% and 60.6%, and of EBV-Negative patients were 62.1% and 50.1%, respectively. High incidence but low mortality of EBV-R and PTLD was documented. EBV-R induced a protective effect on RFS in multivariable analysis (HR 0.91,  = .011). Therefore, EBV-R may have a protective effect on RFS in this setting. Further research is necessary to evaluate the interplay of EBV-R, immune reconstitution, and post-transplant outcomes.
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http://dx.doi.org/10.1080/10428194.2020.1797010DOI Listing
December 2020

T-cell responses following Natural Influenza Infection or Vaccination in Solid Organ Transplant Recipients.

Sci Rep 2020 06 22;10(1):10104. Epub 2020 Jun 22.

Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

Little is known about cell-mediated immune responses to natural influenza infection in solid organ transplant (SOT) patients. The aim of our study was to evaluate the CD4 and CD8 responses to influenza A and B infection in a cohort of SOT patients. We collected peripheral blood mononuclear cells at influenza diagnosis and four weeks later from 31 SOT patients during the 2017-2018 influenza season. Infection-elicited influenza-specific CD4 and CD8 T-cell responses were measured using flow cytometry and intracellular cytokine staining and compared to responses following influenza vaccine in SOT patients. Natural infection was associated with a significant increase in CD4 T-cell responses. For example, polyfunctional cells increased from 21 to 782 and from 193 to 1436 cells per 10 CD4 T-cells among influenza A/H3N2 and B-infected patients (p = 0.006 and 0.004 respectively). Moreover, infection-elicited CD4 responses were superior than vaccine-elicited responses for influenza A/H1N1 (931 vs 1; p = 0.026), A/H3N2 (647 vs 1; p = 0.041) and B (619 vs 1; p = 0.004). Natural influenza infection triggers a significant increase in CD4 T-cell responses in SOT patients. Infection elicits significantly stronger CD4 responses compared to the influenza vaccine and thereby likely elicits better protection against reinfection.
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http://dx.doi.org/10.1038/s41598-020-67172-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308384PMC
June 2020

Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.

Lancet Gastroenterol Hepatol 2020 07 6;5(7):649-657. Epub 2020 May 6.

Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Background: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors.

Methods: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing.

Findings: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 logIU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV.

Interpretation: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors.

Funding: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.
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http://dx.doi.org/10.1016/S2468-1253(20)30081-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391837PMC
July 2020

KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation.

Transplantation 2020 Apr;104(4S1 Suppl 1):S11-S103

The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Canada.

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.
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http://dx.doi.org/10.1097/TP.0000000000003136DOI Listing
April 2020

Summary of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation.

Transplantation 2020 04;104(4):708-714

The Ottawa Hospital and Ottawa Hospital Research Institute, Ottawa, Canada.

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence. The strengths of recommendations are provided in the full report. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.
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http://dx.doi.org/10.1097/TP.0000000000003137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147399PMC
April 2020

CMV immune monitoring-Where do we go from here?

Am J Transplant 2020 08 15;20(8):1961-1962. Epub 2020 Apr 15.

Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1111/ajt.15875DOI Listing
August 2020

COVID-19: A global transplant perspective on successfully navigating a pandemic.

Am J Transplant 2020 Jul 12;20(7):1773-1779. Epub 2020 Apr 12.

Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

The COVID-19 pandemic has rapidly evolved and changed our way of life in an unprecedented manner. The emergence of COVID-19 has impacted transplantation worldwide. The impact has not been just restricted to issues pertaining to donors or recipients, but also health-care resource utilization as the intensity of cases in certain jurisdictions exceeds available capacity. Here we provide a personal viewpoint representing different jurisdictions from around the world in order to outline the impact of the current COVID-19 pandemic on organ transplantation. Based on our collective experience, we discuss mitigation strategies such as donor screening, resource planning, and a staged approach to transplant volume considerations as local resource issues demand. We also discuss issues related to transplant-related research during the pandemic, the role of transplant infectious diseases, and the influence of transplant societies for education and disseminating current information.
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http://dx.doi.org/10.1111/ajt.15876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228301PMC
July 2020

Coronavirus disease 2019: Implications of emerging infections for transplantation.

Am J Transplant 2020 07 16;20(7):1768-1772. Epub 2020 Mar 16.

Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA.

The recent identification of an outbreak of 2019- novel Coronavirus is currently evolving, and the impact on transplantation is unknown. However, it is imperative that we anticipate the potential impact on the transplant community in order to avert severe consequences of this infection on both the transplant community and contacts of transplant patients.
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http://dx.doi.org/10.1111/ajt.15832DOI Listing
July 2020

Late Onset Invasive Pulmonary Aspergillosis in Lung Transplant Recipients in the Setting of a Targeted Prophylaxis/Preemptive Antifungal Therapy Strategy.

Transplantation 2020 12;104(12):2575-2581

Multi-Organ Transplant Program, Division of Infectious Diseases, University Health Network, University of Toronto, Toronto, ON, Canada.

Background: Invasive pulmonary aspergillosis (IPA) is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). It is unclear how a targeted prophylaxis/ preemptive antifungal therapy strategy impacts the incidence of IPA beyond the first-year posttransplant.

Methods: This is a retrospective cohort of LTRs from January 2010 to December 2014. We included all LTRs who survived beyond the first year and followed them until death or 4 years postoperatively. Incidence of probable/proven IPA and Aspergillus colonization were assessed as per International Society for Heart and Lung Transplantation (ISHLT) criteria. Patients with risk factors, positive Aspergillus cultures, or galactomannan (GM) received targeted prophylaxis/preemptive therapy within the first-year posttransplant.

Results: During the study period, 350 consecutive LTRs underwent 1078 bronchoscopies. Positive bronchoalveolar lavage for GM or Aspergillus cultures was reported for 15% (52/350) of LTRs between 2 and 4 years after transplantation. Among them, the median time to positive Aspergillus culture or GM positivity was 703 days (interquartile range, 529-754 d). The incidence rate of IPA and Aspergillus colonization was 30 of 1000 patient-y, and 63 of 1000 patient-y, respectively. The mortality rate was significantly higher in patients with IPA than without IPA (107/1000 patient-years versus 18/1000 patient-years; P < 0.0001). Rate of first-year colonization and IPA was 33% and 9%, respectively. Among the 201 patients who had a negative bronchoscopy during the first year posttransplant, only 6 (3%) developed IPA during the follow-up.

Conclusions: A targeted prophylaxis/preemptive therapy strategy within the first-year posttransplant resulted in 4% incidence of IPA at 4-years after transplantation. However, IPA was associated with higher mortality.
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http://dx.doi.org/10.1097/TP.0000000000003187DOI Listing
December 2020

Cytomegalovirus (CMV) Cell-Mediated Immunity and CMV Infection After Allogeneic Hematopoietic Cell Transplantation: The REACT Study.

Clin Infect Dis 2020 Dec;71(9):2365-2374

Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients. CMV cell-mediated immunity (CMV-CMI) as determined by a peptide-based enzyme-linked immunospot (ELISPOT) CMV assay may identify patients at risk for clinically significant CMV infection (CS-CMVi).

Methods: The CS-CMVi was defined as CMV viremia and/or disease necessitating antiviral therapy. CMV-CMI was characterized as high when the intermediate-early 1 (IE-1) antigen spot counts (SPCs) were >100 (cutoff 1) or when the IE-1 and phosphoprotein 65 antigen SPCs were both >100 SPCs per 250 000 cells (cutoff 2), and a low CMV-CMI when SPCs were below these thresholds. In this prospective multicenter study, we evaluated CMV-CMI every 2 weeks from the pretransplant period until 6 months posttransplantation in 241 allo-HCT recipients with positive CMV serostatus. The primary endpoint was CS-CMVi occurring within 2 weeks of the last measurement of CMV-CMI.

Results: CS-CMVi occurred in 70 allo-HCT recipients (29%). CMV-CMI was low in patients who experienced CS-CMVi (94%), whereas those who had a high CMV-CMI were less likely to have CS-CMVi (P < .0001). Patients with CS-CMVi had higher all-cause mortality (P = .007), especially those with low CMV-CMI (P = .035). On multivariable analysis, CMV-CMI, sex, race, antithymocyte globulin, and steroid use were independent predictors of CS-CMVi, and the time from transplant to engraftment was the only predictor of mortality.

Conclusions: Measurement of CMV-CMI using a novel ELISPOT assay would be useful clinically to monitor allo-HCT recipients and distinguish between those at risk of developing CS-CMVi and requiring antiviral prophylaxis or therapy and those who are protected.
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http://dx.doi.org/10.1093/cid/ciz1210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713694PMC
December 2020

Letermovir as Salvage Therapy for Cytomegalovirus Infection in Transplant Recipients.

Transplantation 2020 02;104(2):404-409

Transplant Infectious Diseases, University Health Network, Toronto, ON, Canada.

Background: Letermovir, a new viral terminase complex inhibitor, has been approved for the prevention of cytomegalovirus (CMV) infection in hematopoietic stem cell transplant patients. However, data on the efficacy and safety of letermovir for the treatment of CMV infection in transplant recipients remain scarce.

Methods: We performed a single-center retrospective study of stem cell and organ transplant recipients who received letermovir for the treatment of CMV infection from November 2017 to October 2018.

Results: Six patients were included, and 5 were evaluable. All received letermovir in the context of a refractory or resistant CMV infection including asymptomatic CMV viremia (n = 3), CMV syndrome (n = 1), and CMV pneumonitis and colitis (n = 1). The 3 asymptomatic patients experienced a decrease of the viral load (VL) to <200 IU/mL after letermovir therapy. One patient displayed a partial VL response (2-log of VL reduction) but a good clinical response, and one who received a suboptimal dose of letermovir experienced an increase of viremia. There were no treatment-related adverse effects.

Conclusions: We demonstrate mixed efficacy in patients with refractory CMV infection suggesting that letermovir may be a useful therapeutic adjunct, potentially in combination with other antivirals.
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http://dx.doi.org/10.1097/TP.0000000000002785DOI Listing
February 2020

Innate and Adaptive Immune Correlates of Chronic and Self-limiting EBV DNAemia in Solid-organ Transplant Recipients.

Transplantation 2020 11;104(11):2373-2382

Multi-Organ Transplant Program, Department of Medicine, University Health Network, Toronto, ON, Canada.

Background: Epstein-Barr virus (EBV) DNAemia is a major risk factor for posttransplant lymphoproliferative disorder; however, immune correlates of EBV DNAemia in the transplant setting are limited.

Methods: Peripheral blood mononuclear cells were collected from 30 transplant recipients with self-limiting EBV DNAemia (SLD; n = 11) or chronic EBV DNAemia (CD; n = 19) at enrollment and 4-8 weeks later. Mass cytometry was used to characterize innate and T-cell immune correlates of EBV DNAemia. Furthermore, flow cytometry was used to measure the frequency of EBV-specific T-cell responses between groups following stimulation with an EBV-infected cell lysate.

Results: Unsupervised analysis of the innate compartment (CD3CD19 cells) identified 5 CD11c clusters at higher abundance in the SLD group (false discovery rate ≤ 1%). These clusters expressed CD11b, CD45RO, CD14, CD123, CD127, and CD38, among others. Unsupervised profiling of the T-cell compartment (CD3CD19) revealed 2 CD4 T-cell clusters at higher frequency among those with SLD (false discovery rate ≤ 1%), which expressed CD45RA, CCR7, CD27, CD28, and CD40L-suggestive of a naive T cell (TN). Manual biaxial gating confirmed increased frequencies of conventional dendritic cells (3.1% versus 2.1%; P = 0.023) and CD4 TN (4.4% versus 1.9%; P = 0.018) among those with SLD. Last, frequencies of interferon-γ-producing EBV-specific CD4 T cells were significantly lower in the CD group relative to those with SLD (4243 versus 250 cells/10 cells; P = 0.015).

Conclusions: CD is associated with a reduction of CD11c cells, CD4 TN, and interferon-γ-producing EBV-specific CD4 T cells, suggesting an interplay between innate and adaptive immune compartments may be important for regulating EBV DNAemia.
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http://dx.doi.org/10.1097/TP.0000000000003130DOI Listing
November 2020

Clinical predictors of progression and clearance of low-level CMV DNAemia in solid organ transplant recipients.

Transpl Infect Dis 2020 Feb 19;22(1):e13207. Epub 2019 Nov 19.

Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada.

Background: Low-level CMV DNAemia is common and in the absence of treatment may either progress to higher viral loads that require therapy, or may spontaneously resolve. The clinical predictors of progression and spontaneous viral clearance are not well defined.

Methods: We performed a retrospective cohort study of organ transplant recipients who had untreated low-level CMV DNAemia (<1000 IU/mL). Outcomes were evaluated for 8 weeks after initial viral detection, and progression to CMV high viral load was defined as CMV viral load ≥1000 IU/mL. CMV DNAemia doubling time was calculated for a subset of patients with sufficient viral load timepoints.

Results: Of the 297 patients analyzed, 118/297 (39.7%) patients progressed to a high viral load and the remaining cleared DNAemia spontaneously (46.8%) or remained at low level (13.4%). In multivariate analysis, progression was significantly more likely in lung transplant recipients (odds ratio 3.09) and less likely in those with an episode of previously treated CMV infection (odds ratio 0.081). In a subset of 27 patients with progression, the doubling time for CMV DNAemia was a median of 6.1 days (range 2.4-21.8).

Conclusion: We found that previous CMV infection significantly decreased the likelihood of low-level DNAemia progression suggesting that CMV immunity plays a role in progression vs spontaneous clearance.
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http://dx.doi.org/10.1111/tid.13207DOI Listing
February 2020

Vaccination Guidelines for Patients with Immune-Mediated Disorders on Immunosuppressive Therapies-Executive Summary.

J Can Assoc Gastroenterol 2019 Dec 1;2(4):149-152. Epub 2019 Feb 1.

Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

The use of immunosuppressive therapies for immune-mediated disease (IMD) is associated with an elevated risk of infections and related comorbidities. While many infectious diseases can generally be prevented by vaccines, immunization rates in this specific patient population remain suboptimal, due in part to uncertainty about their efficacy or safety under these clinical situations. To address this concern, a multidisciplinary group of Canadian physicians with expertise in dermatology, gastroenterology, infectious diseases and rheumatology developed evidence-based clinical guidelines on vaccinations featuring 13 statements that are aimed at reducing the risk of preventable infections in individuals exposed to immunosuppressive agents.
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http://dx.doi.org/10.1093/jcag/gwy069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785689PMC
December 2019

Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial.

Lancet Respir Med 2020 02 9;8(2):192-201. Epub 2019 Oct 9.

Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.

Background: A substantial proportion of organ donors test positive for hepatitis C virus (HCV) infection. To date, only a few studies have evaluated the safety of using lungs from these donors for transplantation, and no direct interventions to donor organs have been done with the aim of preventing HCV transmission via organ transplantation. We aimed to assess the safety and efficacy of lung transplantation in humans from HCV-positive donors to HCV-negative recipients after application of ex-vivo lung perfusion (EVLP) plus ultraviolet C (UVC) perfusate irradiation.

Methods: We did a single centre, prospective, open-label, non-randomised trial in which donor lungs from HCV-viraemic donors (HCV-positive) were transplanted into HCV-negative recipients at Toronto General Hospital, University Health Network (Toronto, ON, Canada). Donors were younger than 65 years old and tested positive for HCV by nucleic acid testing. Donors who tested positive for hepatitis B virus, HIV, human T-lymphotropic virus 1 or 2 were excluded. Recipients were on the lung transplant waiting list without significant liver disease (stage 2 fibrosis or higher were excluded) or active HCV infection. Before implantation, all HCV-positive donor lungs were treated with EVLP with or without UVC perfusate irradiation to reduce the concentration of HCV RNA and infectivity. For the first week after transplantation, patients' HCV RNA blood concentrations were measured once daily, then once per week for 12 weeks. All patients received 12 weeks of oral sofosbuvir 400 mg plus velpatasvir 100 mg, starting at least 2 weeks after transplantation. The primary endpoint was a composite of survival and HCV-free status at 6 months after transplantation in all patients who received HCV-positive lungs. Patient outcomes such as survival, time in hospital, and incidence of acute rejection were compared between those receiving HCV-positive lungs and all patients who received HCV-negative lung transplants during the study period. The study is registered with ClinicalTrials.gov, NCT03112044.

Findings: From Oct 1, 2017, to Nov 1, 2018, 209 patients had a transplantation; of 27 donors who were HCV-positive and initially considered, 22 were suitable for transplantation. The remaining 187 donors were HCV-negative. Before implantation, 11 of the HCV-positive donor lungs were treated with EVLP alone and the other 11 were treated with EVLP plus UVC. Lung disease, urgency status, and positive donor-recipient HLA crossmatch were similar between the patients who received HCV-positive and HCV-negative lungs. 20 (91%) patients in the HCV-positive group developed HCV viraemia within the first week after transplantation and had sofosbuvir plus velpatasvir treatment, starting at a median of 21 days after transplantation (IQR 16·76-24·75). Donor organ treatment with EVLP plus UVC was associated with significantly lower recipient viral loads in blood within the first week after transplantation than with EVLP alone (median of 167 IU/mL [IQR 20-12 000] vs 4390 IU/mL [1170-112 000] at day 7; p=0·048) and prevented transmission in two (18%) of 11 patients. All 20 infected patients achieved negative HCV PCR within 6 weeks of treatment initiation. The primary endpoint of survival and HCV-free status at 6 months after transplantation was achieved in 19 (86%) of 22 patients in the HCV-positive group. 6-month survival was 95% in recipients receiving lungs from HCV-viraemic donors versus 94% in recipients receiving lungs from HCV-negative donors. The most common grade 3-4 adverse events in the HCV-positive group were respiratory complications (five [23%]) and infections (four [18%]). Serious adverse events requiring admission to hospital occurred in ten (45%) patients. One (5%) patient who did not develop HCV infection died at day 31 from multiorgan failure related to pseudomonas sepsis. Two patients presented with HCV relapse within 3 months after sofosbuvir plus velpatasvir completion and required retreatment.

Interpretation: Early and intermediate clinical outcomes were not significantly different between patients receiving viraemic HCV donor lungs and HCV-negative donor lungs. Donor organ treatment with UVC perfusate irradiation during EVLP significantly decreased HCV viral loads within the first 7 days after transplantation and shows the proof-of-concept for a novel approach of minimising viral load ex vivo before transplantation, with intent of preventing donor-recipient transmission.

Funding: Canadian Institutes of Health Research.
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http://dx.doi.org/10.1016/S2213-2600(19)30268-1DOI Listing
February 2020