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It is known that people receiving immune suppressive therapy, such as recipients of solid-organ transplants, have a suboptimal response to SARS-CoV-2 vaccination. In a randomized, double-blind trial, a third dose of the mRNA-1273 vaccine was compared with placebo. The third dose of vaccine produced a significant boost in neutralizing antibodies.

Availability of organs is a limiting factor for lung transplantation, leading to substantial mortality rates on the wait list. Use of organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), would increase organ donation, but these organs are generally not offered for transplantation due to a high risk of transmission. Here, we develop a method for treatment of HCV-infected human donor lungs that prevents HCV transmission. Physical viral clearance in combination with germicidal light-based therapies during normothermic ex-vivo Lung Perfusion (EVLP), a method for assessment and treatment of injured donor lungs, inactivates HCV virus in a short period of time. Such treatment is shown to be safe using a large animal EVLP-to-lung transplantation model. This strategy of treating viral infection in a donor organ during preservation could significantly increase the availability of organs for transplantation and encourages further clinical development. Organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), are not offered for transplantation due to a high risk of transmission. Here, Galasso et al. develop a method for treatment of HCV-infected human donor lungs that is safe and prevents HCV transmission in the pig model.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and encompasses a spectrum from simple steatosis to steatohepatitis (NASH). There is currently no approved pharmacologic therapy against NASH, partly due to an incomplete understanding of its molecular basis. The goal of this study was to determine the key differentially expressed genes (DEGs), as well as those genes and pathways central to its pathogenesis. We performed an integrative computational analysis of publicly available gene expression data in NASH from GEO (GSE17470, GSE24807, GSE37031, GSE89632). The DEGs were identified using GEOquery, and only the genes present in at least three of the studies, to a total of 190 DEGs, were considered for further analyses. The pathways, networks, molecular interactions, functional analyses were generated through the use of Ingenuity Pathway Analysis (IPA). For selected networks, we computed the centrality using igraph package in R. Among the statistically significant predicted networks (p-val < 0.05), three were of most biological interest: the first is involved in antimicrobial response, inflammatory response and immunological disease, the second in cancer, organismal injury and development and the third in metabolic diseases. We discovered that HNF4A is the central gene in the network of NASH connected to metabolic diseases and that it regulates HNF1A, an additional transcription regulator also involved in lipid metabolism. Therefore, we show, for the first time to our knowledge, that HNF4A is central to the pathogenesis of NASH. This adds to previous literature demonstrating that HNF4A regulates the transcription of genes involved in the progression of NAFLD, and that HNF4A genetic variants play a potential role in NASH progression.

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 6 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.

Immunocompromised patients are predisposed to severe COVID-19. Here we compare homotypic and heterotypic humoral and cellular immune responses to Omicron BA.1 in organ transplant patients across a diverse clinical spectrum. We perform variant-specific pseudovirus neutralization assays for D614G, and Omicron-BA.1, -BA.2, and Delta variants. We also measure poly-and monofunctional T-cell responses to BA.1 and ancestral SARS-CoV-2 peptide pools. We identify that partially or fully-vaccinated transplant recipients after infection with Omicron BA.1 have the greatest BA.1 neutralizing antibody and BA.1-specific polyfunctional CD4 + and CD8 + T-cell responses, with potent cross-neutralization against BA.2. In these patients, the magnitude of the BA.1-directed response is comparable to immunocompetent triple-vaccinated controls. A subset of patients with pre-Omicron infection have heterotypic responses to BA.1 and BA.2, whereas uninfected transplant patients with three doses of vaccine demonstrate the weakest comparative responses. These results have implications for risk of infection, re-infection, and disease severity among immune compromised hosts with Omicron infection. Immunocompromised individuals are predisposed to severe SARS-CoV-2 infection, with transplant recipients typically displaying impaired immune response to pathogens, due to typical life-long immunosuppressive treatment. In this work, the authors evaluate the immune response to Omicron subvariants BA.1 and BA.2 in organ transplant recipients across a diverse clinical spectrum.

Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe COVID-19 outcomes among recipients of organ transplants across Canada. We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen. A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing (n = 190), compared with not needing (n = 319), supplemental oxygen included age (median 62.6 yr, interquartile range [IQR] 52.5–69.5 yr v. median 55.5 yr, IQR 47.5–66.5; p < 0.001) and number of comorbidities (median 3, IQR 2–3 v. median 2, IQR 1–3; p < 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants (n = 48) were more likely to have severe disease with a high mortality rate (n = 15, 31.3%) compared with recipients of other organ transplants, including kidney (n = 48, 14.8%), heart (n = 1, 4.4%), liver (n = 9, 11.4%) and kidney–pancreas (n = 3, 12.0%) transplants (p = 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02–1.07) and number of comorbidities (OR 1.63, 95% CI 1.30–2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly. Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants.

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.

There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of χ 2 tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3·6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22·4%) given antivirals later (p=0·007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009–10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. None.

Influenza is a major cause of morbidity and mortality in immunosuppressed persons, and vaccination often confers insufficient protection. IL-28B, a member of the interferon (IFN)-λ family, has variable expression due to single nucleotide polymorphisms (SNPs). While type-I IFNs are well known to modulate adaptive immunity, the impact of IL-28B on B- and T-cell vaccine responses is unclear. Here we demonstrate that the presence of the IL-28B TG/GG genotype (rs8099917, minor-allele) was associated with increased seroconversion following influenza vaccination (OR 1.99 p = 0.038). Also, influenza A (H1N1)-stimulated T- and B-cells from minor-allele carriers showed increased IL-4 production (4-fold) and HLA-DR expression, respectively. In vitro, recombinant IL-28B increased Th1-cytokines (e.g. IFN-γ), and suppressed Th2-cytokines (e.g. IL-4, IL-5, and IL-13), H1N1-stimulated B-cell proliferation (reduced 70%), and IgG-production (reduced>70%). Since IL-28B inhibited B-cell responses, we designed antagonistic peptides to block the IL-28 receptor α-subunit (IL28RA). In vitro, these peptides significantly suppressed binding of IFN-λs to IL28RA, increased H1N1-stimulated B-cell activation and IgG-production in samples from healthy volunteers (2-fold) and from transplant patients previously unresponsive to vaccination (1.4-fold). Together, these findings identify IL-28B as a key regulator of the Th1/Th2 balance during influenza vaccination. Blockade of IL28RA offers a novel strategy to augment vaccine responses.

Background. Cytomegalovirus (CMV) load measurement is used to assess the efficacy of treatment of CMV disease, but lacks standardization. Using the World Health Organization (WHO) international standard for reporting, we correlated viral load with CMV disease resolution. Methods. CMV load was quantified in plasma using a test calibrated to the WHO standard. Three predictive rules were predefined to determine association between CMV DNAemia and outcome: (1) pretreatment CMV DNA of <18 200 (4.3 log 10 ) IU/mL; (2) viral load declines of 1.0, 1.5, 2.0, and 2.5 log 10 IU/mL from baseline to days 7, 14, and 21 of treatment, respectively; and (3) viral suppression <137 (2.1 log 10 ) IU/mL at days 7, 14, and 21. Analysis was performed using Cox proportional hazard models. Results. Of 267 patients, 251 had CMV disease resolution by day 49 of treatment. Patients with pretreatment CMV DNA of <18 200 (4.3 log 10 ) IU/mL had faster time to disease resolution (adjusted hazard ratio [AHR], 1.56; P = .001). Patients with CMV load suppression (<137 IU/mL [<2.1 log 10 ]) at days 7, 14, and 21 had faster times to clinical disease resolution (AHRs, 1.61, 1.73, and 1.64, and P = .005, <.001, and <.001, respectively). Relative CMV load reductions from baseline were not significantly associated with faster resolution of CMV disease. Conclusions. Patients with pretreatment CMV DNA of <18 200 (4.3 log 10 ) IU/mL are 1.5 times more likely to have CMV disease resolution. CMV suppression (<137 [2.1 log 10 ] IU/mL), as measured by a test calibrated to the WHO Standard, is predictive of clinical response to antiviral treatment. Clinical Trials Registration. NCT00431353.