Impaired SARS-CoV-2 specific T-cell response in patients with severe COVID-19

Cellular immune responses are of pivotal importance to understand SARS-CoV-2 pathogenicity. Using an enzyme-linked immunosorbent spot (ELISpot) interferon-γ release assay with wild-type spike, membrane and nucleocapsid peptide pools, we longitudinally characterized functional SARS-CoV-2 specific T-cell responses in a cohort of patients with mild, moderate and severe COVID-19. All patients were included before emergence of the Omicron (B.1.1.529) variant. Our most important finding was an impaired development of early IFN-γ-secreting virus-specific T-cells in severe patients compared to patients with moderate disease, indicating that absence of virus-specific cellular responses in the acute phase may act as a prognostic factor for severe disease. Remarkably, in addition to reactivity against the spike protein, a substantial proportion of the SARS-CoV-2 specific T-cell response was directed against the conserved membrane protein. This may be relevant for diagnostics and vaccine design, especially considering new variants with heavily mutated spike proteins. Our data further strengthen the hypothesis that dysregulated adaptive immunity plays a central role in COVID-19 immunopathogenesis

Impaired SARS-CoV-2 specific T-cell response in patients with severe COVID-19

Cellular immune responses are of pivotal importance to understand SARS-CoV-2 pathogenicity. Using an enzyme-linked immunosorbent spot (ELISpot) interferon-γ release assay with wild-type spike, membrane and nucleocapsid peptide pools, we longitudinally characterized functional SARS-CoV-2 specific T-cell responses in a cohort of patients with mild, moderate and severe COVID-19. All patients were included before emergence of the Omicron (B.1.1.529) variant. Our most important finding was an impaired development of early IFN-γ-secreting virus-specific T-cells in severe patients compared to patients with moderate disease, indicating that absence of virus-specific cellular responses in the acute phase may act as a prognostic factor for severe disease. Remarkably, in addition to reactivity against the spike protein, a substantial proportion of the SARS-CoV-2 specific T-cell response was directed against the conserved membrane protein. This may be relevant for diagnostics and vaccine design, especially considering new variants with heavily mutated spike proteins. Our data further strengthen the hypothesis that dysregulated adaptive immunity plays a central role in COVID-19 immunopathogenesis

Prediction of shock in febrile medical patients with a clinical infection

Objective: Shock in the course of fever is likely caused by septic shock. Because septic shock carries a high mortality rate, early recognition could benefit the patient. We tried to predict the development of shock in medical patients with fever and a clinical infection, on the basis of clinical and microbiological information, and to evaluate the role therein of systemic inflammatory response syndrome (SIRS) criteria: abnormal body temperature, tachycardia, tachypnea, and abnormal white blood cell counts. Design: Prospective observational study. Setting: Department of Internal Medicine at a university hospital. Patients: Patients were 212 consecutive medical patients with newly onset fever (temperature, >38.0°C axillary or >38.3°C rectally) and a clinical source of infection. Measurements and Main Results: Of the 212 patients enrolled, 14 developed shock (i.e., a decrease in systolic arterial blood pressure of >40 mm Hg) during a maximum follow-up period of 7 days after inclusion. In univariate analyses, advanced age, prior urogenital disease, an abdominal source, nosocomial infections, and bacteremia predisposed patients to shock (p < .05). For clinical variables, obtained daily for 2 days after inclusion, a low performance (p < .001), the peak respiratory rate (p < .05), the peak heart rate (p < .05), the nadir score on the Glasgow Coma Scale (p < .005), the peak and nadir white blood cell counts (p < .005), and the nadir albumin (p < .01) and peak creatinine concentrations in blood (p < .001) predicted shock development. In multivariate analysis, the presence of bacteremia, the peak respiratory rate, the nadir Glasgow Coma Scale score, and the peak white blood cell count positively and the peak erythrocyta sedimentation rate negatively contributed to prediction of shock development. In contrast, SIRS had less predictive value, mainly because of lack of predictive value of peak heart rate and temperature in multivariate models. Conclusion: In febrile medical patients with a clinical infection, the development of shock involves an interaction between circulating microbial products and the host response, which can be recognized clinically by variables easily obtained at the bedside and partly different from the set used to define SIRS

Differential vaccine-induced kinetics of humoral and cellular immune responses in SARS-CoV-2 naive and convalescent health care workers.

Effective vaccination is a key element in the exit strategy from the current severe acute respiratory syndrome- CoV coronavirus-2 (SARS-CoV-2) pandemic, and may also offer protection against severe disease from future variants of concern. Here we prospectively monitored T- cell responses over time, using ELISpot interferon-γ (INF-y) release assays, and B- cell responses, using serological tests, after vaccination and booster with BioNTech/Pfizer mRNA (Pfizer) and Janssen vector (Janssen/Johnson & Johnson) vaccines in hospital health care workers. Vaccine recipients were divided into seropositive and seronegative individuals at baseline, in order to determine the effect of natural immunity on vaccine-induced immune kinetics. We found that convalescent individuals mounted higher spike-specific INF-y-secreting T cell responses and B- cell-mediated IgG responses, after receiving the Janssen vaccine or the first dose of the Pfizer vaccine. IgG levels corresponded to the virus neutralisation capacity as measured by VNT assay. At 8 months post vaccination, spike-specific cellular immunity waned to low levels in individuals with or without prior natural immunity, whereas waning of humoral immunity occurred predominantly in naive individuals. The booster shot effectively re-induced both cellular and humoral immune responses. To conclude, our data supports the implemented single-dose mRNA booster strategy employed in the Netherlands. Furthermore, the level of pre-existing natural immunity may be factored into determining the optimal time window between future booster vaccines

Differential abundance of IgG antibodies against the spike protein of SARS-CoV-2 and seasonal coronaviruses in patients with fatal COVID-19

Abstract Infection with the novel pandemic SARS-CoV-2 virus has been shown to elicit a cross-reactive immune response that could lead to a back-boost of memory recall to previously encountered seasonal (endemic) coronaviruses (eCoVs). Whether this response is associated with a fatal clinical outcome in patients with severe COVID-19 remains unclear. In a cohort of hospitalized patients, we have previously shown that heterologous immune responses to eCoVs can be detected in severe COVID-19. Here, we report that COVID-19 patients with fatal disease have decreased SARS-CoV-2 neutralizing antibody titers at hospital admission, which correlated with lower SARS-CoV-2 spike-specific IgG and was paralleled by a relative abundance of IgG against spike protein of eCoVs of the genus Betacoronavirus. Additional research is needed to assess if eCoV-specific back-boosted IgG is a bystander phenomenon in severe COVID-19, or a factor that influences the development of an efficient anti-viral immune response

Follow-Up Study of Tuberculosis-Exposed Supermarket Customers with Negative Tuberculin Skin Test Results in Association with Positive Gamma Interferon Release Assay Results▿

We report a follow-up study of 29 subjects with negative tuberculin skin test (TST) results in association with positive gamma interferon release assay (IGRA) results, mainly due to responses to CFP-10 in the T-SPOT.TB assay, during a contact investigation. One year later, 12/29 subjects (41%) had converted to positive TST results in association with negative IGRA results

Comparison of two interferon-gamma assays and tuberculin skin test for tracing tuberculosis contacts

The tuberculin skin test (TST) has low specificity. QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB are based on interferon (IFN)-gamma responses to Mycobacterium tuberculosis-specific antigens. A novel in-tube format of QFT-G (QFT-GIT) offers logistical advantages. To compare TST, QFT-GIT, and T-SPOT.TB in bacillus Calmette-Guérin unvaccinated contacts and correlate results with measures of recent exposure. When a supermarket employee with smear-positive tuberculosis had infected most close contacts, a contact investigation among more than 20,000 customers was performed. We recruited subjects randomly on the day of TST administration (n = 469) and subjects with TST of more than 0 mm on the day of TST reading (n = 316). QFT-GIT and T-SPOT.TB were performed. Demographic data and measures of exposure were collected. TST results were analyzed at a cutoff of 10 or 15 mm. Blood tests were interpreted following the manufacturers' criteria and by varying cutoff levels. Among 785 study participants, TST results were associated with age, whereas positive IFN-gamma responses were significantly associated with cumulative shopping time, most markedly for QFT-GIT. Among participants with a TST of 15 mm or greater, sensitivity of QFT-GIT and T-SPOT.TB was 42.2 and 51.3%, respectively. Interassay agreement was 89.6% (kappa = 0.59). By varying cutoff values, agreement between the IFN-gamma assays was optimal at 93.6% (kappa = 0.71) using a cutoff of 0.20 IU/ml for QFT-GIT and 13 spots for T-SPOT.TB. Blood test results were associated with exposure, whereas the TST was not. A possible lack of sensitivity of IFN-gamma assays in detecting individuals with TST of 15 mm or greater, despite negative bacillus Calmette-Guérin vaccination status, warrants further investigation into alternative cutoff value