ABSTRACT
Effective humoral immune responses require well-orchestrated cellular interactions between B and T follicular helper (Tfh) cells. Whether this interaction is impaired and associated with COVID-19 disease severity is unknown. Here, longitudinal acute and convalescent blood samples from 49 COVID-19 patients across mild to severe disease were analysed. We found that during acute infection activated and SARS-CoV-2-specific circulating Tfh (cTfh) cell frequencies expanded with increasing disease severity. The frequency of activated and SARS-CoV-2-specific cTfh cells correlated with plasmablast frequencies and SARS-CoV-2 antibody titers, avidity and neutralization. Furthermore, cTfh cells but not other memory CD4 T cells, isolated from severe patients induced more pronounced differentiation of autologous plasmablast and antibody production in vitro compared to cTfh cells isolated from mild patients. However, the development of virus-specific cTfh cells was delayed in patients that displayed or later developed severe disease compared to those that maintained a mild or moderate disease. This correlated with a delayed induction of high-avidity and neutralizing virus-specific antibodies. Our study therefore suggests that impaired generation of functional virus-specific cTfh cells delays the production of high-quality antibodies to combat the infection at an early stage and thereby enabling progression to more severe COVID-19 disease.
Subject(s)
COVID-19 , Acute DiseaseABSTRACT
Background: The effect of awake prone positioning on intubation rates is not established. The aim of this trial was to investigate if a protocol for awake prone positioning reduces the rate of endotracheal intubation compared with standard care among patients with moderate to severe hypoxemic respiratory failure due to COVID-19. Methods: We conducted a multicenter randomized controlled trial. Adult patients with confirmed COVID-19, high-flow nasal oxygen or noninvasive ventilation for respiratory support and a PaO2/FiO2 ratio ≤ 20 kPa were randomly assigned to a protocol targeting 16 hours prone positioning per day or standard care. The primary endpoint was intubation within 30 days. Secondary endpoints included duration of awake prone positioning, 30-day mortality, ventilator free days, hospital and intensive care unit length of stay, use of noninvasive ventilation, organ support and adverse events. The trial was terminated early due to futility. Results: Of 141 patients assessed for eligibility, 75 were randomized of whom 39 were allocated to the control group and 36 to the prone group. Within 30 days after enrollment, 13 patients (33%) were intubated in the control group versus 12 patients (33%) in the prone group (HR 1.01 (95% CI 0.46-2.21), P=0.99). Median prone duration was 3.4 hours [IQR 1.8-8.4] in the control group compared with 9.0 hours per day [IQR 4.4-10.6] in the prone group (P=0.014). Nine patients (23%) in the control group had pressure sores compared with two patients (6%) in the prone group (difference -18% (95% CI -2% to -33%); P=0.032). There were no other differences in secondary outcomes between groups.Conclusions: A protocol for awake prone positioning increased duration of prone positioning, but did not reduce the rate of intubation in patients with hypoxemic respiratory failure due to COVID-19 compared to standard care.Trial registration: ISRCTN54918435. Registered 15 June 2020 (https://doi.org/10.1186/ISRCTN54917435)
Subject(s)
COVID-19ABSTRACT
Understanding immune responses following SARS-CoV-2 infection in relation to COVID-19 severity is critical to predicting the effects of long-term immunological memory on viral spread. Here we longitudinally assessed systemic and airway immune responses against SARS-CoV-2 in a well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity; from asymptomatic infection to fatal disease. High systemic and airway antibody responses were elicited in patients with moderate to severe disease, and while systemic IgG levels were maintained after acute disease, airway IgG and IgA declined significantly. In contrast, individuals with mild symptoms showed significantly lower antibody responses but their levels of antigen-specific memory B cells were comparable with those observed in patients with moderate to severe disease. This suggests that antibodies in the airways may not be maintained at levels that prevent local virus entry upon re-exposure and therefore protection via activation of the memory B cell pool is critical.
Subject(s)
COVID-19 , Acute DiseaseABSTRACT
To understand the risk of transmission of SARS-CoV-2 in hospitalized COVID-19 patients we simultaneously assessed the presence of SARS-CoV-2 RNA, live infectious virus in the airways, and virus-specific IgG and neutralizing antibodies in sera in 36 hospitalized COVID-19 patients. SARS-CoV-2 could be cultured from four patients, all with low or undetectable antibody response. Our data suggests that the level of SARS-CoV-2 antibodies may correlate to risk for shedding live SARS-CoV-2 virus in hospitalized COVID-19 patients.
Subject(s)
COVID-19ABSTRACT
The immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFN{gamma} production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3{zeta} chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.