Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations.

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

BACKGROUND: SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials. METHODS: ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined. DISCUSSION: This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

Threat of COVID-19 impacting on a quaternary healthcare service: a retrospective cohort study of administrative data.

OBJECTIVES: The threat of a pandemic, over and above the disease itself, may have significant and broad effects on a healthcare system. We aimed to describe the impact of the SARS-CoV-2 pandemic (during a relatively low transmission period) and associated societal restrictions on presentations, admissions and outpatient visits. DESIGN: We compared hospital activity in 2020 with the preceding 5 years, 2015-2019, using a retrospective cohort study design. SETTING: Quaternary hospital in Melbourne, Australia. PARTICIPANTS: Emergency department presentations, hospital admissions and outpatient visits from 1 January 2015 to 30 June 2020, n=896 934 episodes of care. INTERVENTION: In Australia, the initial peak COVID-19 phase was March-April. PRIMARY AND SECONDARY OUTCOME MEASURES: Separate linear regression models were fitted to estimate the impact of the pandemic on the number, type and severity of emergency presentations, hospital admissions and outpatient visits. RESULTS: During the peak COVID-19 phase (March and April 2020), there were marked reductions in emergency presentations (10 389 observed vs 14 678 expected; 29% reduction; p<0.05) and hospital admissions (5972 observed vs 8368 expected; 28% reduction; p<0.05). Stroke (114 observed vs 177 expected; 35% reduction; p<0.05) and trauma (1336 observed vs 1764 expected; 24% reduction; p<0.05) presentations decreased; acute myocardial infarctions were unchanged. There was an increase in the proportion of hospital admissions requiring intensive care (7.0% observed vs 6.0% expected; p<0.05) or resulting in death (2.2% observed vs 1.5% expected; p<0.05). Outpatient attendances remained similar (30 267 observed vs 31 980 expected; 5% reduction; not significant) but telephone/telehealth consultations increased from 2.5% to 45% (p<0.05) of total consultations. CONCLUSIONS: Although case numbers of COVID-19 were relatively low in Australia during the first 6 months of 2020, the impact on hospital activity was profound.

Clinical trials for the prevention and treatment of COVID-19: current state of play.

Since coronavirus disease 2019 (COVID-19) emerged in Wuhan, China in December 2019 and spread around the world, over 1100 clinical studies have been registered globally on clinical trials registries, including over 500 randomised controlled trials. Such rapid development and launch of clinical trials is impressive but presents challenges, including the potential for duplication and competition. There is currently no known effective treatment for COVID-19. In order to focus on those studies most likely to influence clinical practice, we summarise the 31 currently registered randomised trials with a target sample size of at least 1000 participants. We have grouped these trials into four categories: prophylaxis; treatment of outpatients with mild COVID-19; treatment of hospitalised patients with moderate COVID-19; and treatment of hospitalised patients with moderate or severe disease. The most common therapeutic agent being trialled currently is hydroxychloroquine (24 trials with potential sample size of over 25 000 participants), followed by lopinavir-ritonavir (seven trials) and remdesevir (five trials) There are many candidate drugs in pre-clinical and early phase development, and these form a pipeline for future large clinical trials if current candidate therapies prove ineffective or unsafe.