Search

Abstract Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single cell RNA-seq on 286 blood samples from 108 age- and sex-matched COVID-19 patients, including 73 with early samples. We examine discrete cell subtypes and continuous cell states longitudinally, and we identify upregulation of type I IFN-stimulated genes (ISGs) as the predominant early signature of subsequent worsening of symptoms, which we validate in an independent cohort and corroborate by plasma markers. However, ISG expression is dynamic in progressors, spiking early and then rapidly receding to the level of severity-matched non-progressors. In contrast, cross-sectional analysis shows that ISG expression is deficient and IFN suppressors such as SOCS3 are upregulated in severe and critical COVID-19. We validate the latter in four independent cohorts, and SOCS3 inhibition reduces SARS-CoV-2 replication in vitro. In summary, we identify complexity in type I IFN response to COVID-19, as well as a potential avenue for host-directed therapy.

Introduction Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including administration of booster doses, continues to be the most effective method for controlling COVID-19-related complications including progression to severe illness and death. However, there is mounting evidence that more needs to be done to protect individuals with compromised immune function. Areas covered Here, we review the effectiveness of COVID-19 vaccination in immunocompromised patients, including those with primary immunodeficiencies, HIV, cancer (including hematological malignancies), solid organ transplant recipients, and chronic kidney disease, as reported in systematic reviews/meta-analyses published over a 12-month period in PubMed. Given the varied responses to vaccination in patients with compromised immune function, a major goal of this analysis was to try to identify specific risk-factors related to vaccine failure. Expert opinion COVID-19 remains a global problem, with new variants of concern emerging at regular intervals. There is an ongoing need for optimal vaccine strategies to combat the pandemic. In addition, alternative treatment approaches are needed for immunocompromised patients who may not mount an adequate immune response to current COVID-19 vaccines. Identification of high-risk patients and the introduction of newer antiviral approaches such as monoclonal antibodies will offer physicians therapeutic options for such vulnerable individuals.

Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks.

Abstract A cost-minimization analysis was conducted for Klebsiella pneumoniae liver abscess (KLA) patients enrolled in a randomized controlled trial which found oral ciprofloxacin to be non-inferior to intravenous (IV) ceftriaxone in terms of clinical outcomes. Healthcare service utilization and cost data were obtained from medical records and estimated from self-reported patient surveys in a non-inferiority trial of oral ciprofloxacin versus IV ceftriaxone administered to 152 hospitalized adults with KLA in Singapore between November 2013 and October 2017. Total costs were evaluated by category and payer, and compared between oral and IV antibiotic groups over the trial period of 12 weeks. Among the subset of 139 patients for whom cost data were collected, average total cost over 12 weeks was $16,378 (95% CI, $14,620–$18,136) for the oral ciprofloxacin group and $20,569 (95% CI, $18,296–$22,842) for the IV ceftriaxone group, largely driven by lower average outpatient costs, as the average number of outpatient visits was halved for the oral ciprofloxacin group. There were no other statistically significant differences, either in inpatient costs or in other informal healthcare costs. Oral ciprofloxacin is less costly than IV ceftriaxone in the treatment of Klebsiella liver abscess, largely driven by reduced outpatient service costs. Trial registration: ClinicalTrials.gov Identifier NCT01723150 (7/11/2012).

Background. Immunocompromised individuals have been excluded from landmark studies of messenger RNA vaccinations for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In such patients, the response to vaccination may be blunted and may wane more quickly compared with immunocompetent patients. We studied the factors associated with decreased antibody response to SARS-CoV-2 vaccination and risk factors for subsequent breakthrough infections in liver transplant (LT) patients undergoing coronavirus disease 2019 vaccination with at least 2 doses of messenger RNA vaccine from April 28, 2021, to April 28, 2022. Methods. All LT recipients received at least 2 doses of the BNT162b2 (Pfizer BioNTech) vaccine 21 d apart. We measured the antibody response against the SARS-CoV-2 spike protein using the Roche Elecsys immunoassay to the receptor-binding domain of the SARS-CoV-2 spike protein, and the presence of neutralizing antibodies was measured by the surrogate virus neutralization test (cPass) before first and second doses of vaccination and also between 2 and 3 mo after the second dose of vaccination. Results. Ninety-three LT recipients who received 2 doses of BNT162b2 were included in the analysis. The mean time from LT was 110 ± 154 mo. After 2-dose vaccination, 38.7% of LT recipients (36/93) were vaccine nonresponders on the cPass assay compared with 20.4% (19/93) on the Roche S assay. On multivariable analysis, increased age and increased tacrolimus trough were found to be associated with poor neutralizing antibody response (P = 0.038 and 0.022, respectively). The use of antimetabolite therapy in conjunction with tacrolimus approached statistical significance (odds ratio 0.21; 95% confidence interval, 0.180-3.72; P = 0.062). Breakthrough infection occurred in 18 of 88 LT recipients (20.4%). Female gender was independently associated with breakthrough infections (P

Objectives: To examine the prevalence and characteristics of HIV-tuberculosis (TB) co-infected patients in Singapore, an intermediate TB-burden country.Methods: Retrospective data across 11 years was obtained from the National University Hospital (NUH), a quaternary hospital and the National Centre for Infectious Diseases (NCID), the national HIV center.Results: From December 2005 to December 2016, 4015 HIV-infected patients were managed at NUH and NCID, of whom, respectively, 48 and 272 were diagnosed with active TB disease. Only 2 patients (0.6%) were screened for latent TB infection on HIV diagnosis. Mean CD4 count at TB diagnosis was 125.0 ± 153.9 cells/mm3. More patients with HIV diagnosed ≥6 weeks before TB (41%) were associated with CD4 counts >200 cells/mm3 than patients with TB diagnosed ≥6 weeks before HIV (2%). Of 124 (38.6%) HIV-TB patients with CD4 count ≤50 cells/mm3, only 18 (14.2%) started anti-retroviral therapy (ART) in

Summary: Virus-specific humoral and cellular immunity act synergistically to protect the host from viral infection. We interrogate the dynamic changes of virological and immunological parameters in 12 patients with symptomatic acute SARS-CoV-2 infection from disease onset to convalescence or death. We quantify SARS-CoV-2 viral RNA in the respiratory tract in parallel with antibodies and circulating T cells specific for various structural (nucleoprotein [NP], membrane [M], ORF3a, and spike) and non-structural (ORF7/8, NSP7, and NSP13) proteins. Although rapid induction and quantity of humoral responses associate with an increase in disease severity, early induction of interferon (IFN)-γ-secreting SARS-CoV-2-specific T cells is present in patients with mild disease and accelerated viral clearance. These findings provide support for the prognostic value of early functional SARS-CoV-2-specific T cells with important implications in vaccine design and immune monitoring.

Background: The seasonal influenza vaccine is less effective in older people and a single dose is unlikely to provide the year-round protection necessary for tropical climates which have year-round influenza virus activity. This study aims to assess the effect of a trivalent inactivated influenza vaccine (IIV3) booster at 180 days on haemagglutination-inhibition (HI) antibody titres for each of the influenza strains present in the administered vaccine in older people aged 65 years or above in Singapore.Methods/design: This is a single-centre, randomised, observer-blind, active-comparator controlled, parallel-group, phase IV trial in 200 adults aged 65 years or older. Study participants will be assigned to one of two groups in a 1:1 ratio and followed for 1 year, with five scheduled visits. The control group will receive IIV3 at day 1, and an active comparator (Tetanus-diphtheria-pertussis vaccine) at day 180. Participants in the experimental group will receive IIV3 containing the same strains at day 1 and day 180. Endpoints are immunological, and include measures of HI titres, microneutralisation titres (MN) and cell-mediated immunity from first vaccination up to day 360.Discussion: If superiority of 6-monthly influenza vaccination is demonstrated, this study could form the basis for a larger clinical trial with influenza infection as the primary endpoint.Trial Registration: ClinicalTrials.gov, ID: NCT02655874 . Registered on 12 January 2016. [ABSTRACT FROM AUTHOR]

Background: COVID-19, is associated with vascular dysfunction, arterial stiffness and worse outcomes in diabetes mellitus (DM) (1). We hypothesise that longer-term impact in COVID-19 DM patients will be worse when compared to other metabolic conditions, 1 year after recovery from COVID-19. Methods: We recruited 63 patients belonging to the three groups: group 1 - recovered COVID-19 DM-type 2, n = 14; Group 2- recovered COVID-19, non-diabetes hypertension or hyperlipidemia, n = 29 and Group 3- non-COVID-19 DM, n = 14. Data collected: 1. Demographics, 2. Anthropometry, 3. Metabolic profile, 4. Reactive Hyperaemia index (LnRHI), Augmentation index (AI@75), Heart Rate variability (HRV) (RHI-EndoPAT), 5. Carotid-femoral Pulse-Wave-velocity (cfPWV), central pulse pressure (CPP) (Sphygmocor); 6. Autofluorescence-Advanced glycation end-products (AGE-Reader); 7. Carotid intima-media thickness (CIMT). We performed one-way ANOVA to compare differences in the three groups. Results: Demographics and anthropometry (BMI and waist circumference) were comparable in all three groups. When compared to Groups 2 and 3, In Group 1: Troponin and the red cell distribution width (RDW) was higher (p < 0.05); Sphygmocor based cfPWV & CPP, was higher (p < 0.001); RHI-EndoPAT based AI (@75) was higher and HRV(SDNN) was lower (p < 0.05); AGE was higher (p < 0.01) (see Fig. 1). Conclusion: Measures of arterial-stiffness (cf-PWV & AI@75) and HRV are more significantly impaired in DM when compared to hypertension/hyperlipidemia, one year post COVID-19 recovery. These measures are higher when compared to similar matched diabetes patients with no history of COVID-19 infection. COVID-19 DM patients need to be followed up to study long-term impact on vascular complications and autonomic neuropathy. [ABSTRACT FROM AUTHOR]