Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern.

Background: Recent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies according to the variant of concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. Methods: The MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of early treatments with bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with mild-to-moderate SARS-CoV-2 infection. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was coronavirus disease 2019 (COVID-19) progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. Results: Overall, 319 patients were included. Among 141 patients infected with Delta, no COVID-19 progression was recorded, and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.90). Among 170 patients infected with Omicron (80.6% BA.1 and 19.4% BA.1.1), two COVID-19 progressions were recorded, both in the bamlanivimab/etesevimab group, and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared with the bamlanivimab/etesevimab and casirivimab/imdevimab groups (HR 0.53 and HR 0.45, 95% CI 0.36-0.77 and 95% CI 0.30-0.67, p<0.01). Conclusions: Our data suggest that, among adult outpatients with mild-to-moderate SARS-CoV-2 infection due to Omicron BA.1 and BA.1.1, early treatment with sotrovimab reduces the time to recovery compared with casirivimab/imdevimab and bamlanivimab/etesevimab. In the same population, early treatment with casirivimab/imdevimab may maintain a role in preventing COVID-19 progression. The generalisability of trial results is substantially limited by the early discontinuation of the trial and firm conclusions cannot be drawn. Funding: This trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). The VOC identification was funded by the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 101016167. Clinical trial number: NCT05205759.

Impact of COVID-19 and Antibiotic Treatments on Gut Microbiome: A Role for Enterococcus spp.

OBJECTIVE: Several studies showed the substantial use of antibiotics and increased risk of antimicrobial resistant infections in patients with COVID-19. The impact of COVID-19-related treatments and antibiotics on gut dysbiosis has not been clarified. DESIGN: The prospective cohort study included hospitalized COVID-19 patients (April-December 2020). The gut microbiome composition was analysed by 16S sequencing. The gut diversity and changes in opportunistic bacteria (OBs) or symbionts were analysed according to clinical parameters, laboratory markers of disease progression, type of non-antibiotic COVID-19 treatments (NACT) and type, WHO AWaRe group, and duration of antibiotic therapy (AT). RESULTS: A total of 82 patients (mean age 66 ± 13 years, 70% males) were enrolled. The relative abundance of Enterococcus was significantly correlated with duration of hospitalization, intensive care unit stay, O2 needs, and D-dimer, ferritin, and IL-6 blood levels. The presence of Enterococcus showed the highest number of correlations with NACT, AT, and AT + NACT (e.g., hydroxychloroquine ± lopinavir/ritonavir) and increased relative abundance with AWaRe Watch/Reserve antibiotics, AT duration, and combinations. Abundance of Dorea, Agathobacter, Roseburia, and Barnesiella was negatively correlated with AT and corticosteroids use. Patients with increased IL-6, D-dimer, and ferritin levels receiving AT were more likely to show dysbiosis with increased abundance of Enterococcus and Bilophila bacteria and decreased abundance of Roseburia compared with those not receiving AT. CONCLUSION: Microbiome diversity is affected by COVID-19 severity. In this context, antibiotic treatment may shift the gut microbiome composition towards OBs, particularly Enterococcus. The impact of treatment-driven dysbiosis on OBs infections and long-term consequences needs further study to define the role of gut homeostasis in COVID-19 recovery and inform targeted interventions.

Provision of, and access to, sexual and reproductive health services during Covid-19: qualitative research with staff and clients/patients in England

BackgroundThe Covid-19 pandemic put unprecedented pressure on health services, including sexual and reproductive healthcare (SRH). Timely access to SRH prevents poor outcomes for individuals, and for population health. To inform future pandemic preparedness, we explored experiences of providing and accessing SRH services in England (within a multi-country, WHO-funded study).MethodsIn-depth interviews with a purposive sample of staff (about Covid-19’s impact on staff and services) and clients aged 18+ (about experiences of seeking/receiving care) of three contrasting SRH services in southeast England: a sexual health clinic, an abortion provider, and a sexual assault referral centre (SARC). Descriptive Thematic Analysis.ResultsStaff (n=8) interviews consistently revealed three themes: (i) Service disruption: severe disruption occurred during the March-July 2020 lockdown, but where feasible SRH services were transferred to telephone (e.g. consultations) and post (e.g. some contraceptive methods, medical abortion, STI self-sampling). Some core services (e.g. STI treatment, SARC services) continued in person. Access was widened during subsequent lockdowns. (ii) Staff impact: staff reported working from home, or providing services in person often with shortages of protective equipment, or redeployment to acute hospital care. Impacts included stress, loneliness, and (for redeployees) mismatches between skill-sets and new responsibilities. (iii) Adjustment and resilience: staff reported continual adjustment in mode of service delivery and breadth of services provided. Remote service delivery was generally welcomed, but considered more time-consuming to deliver. Colleagues’ absences were burdensome and stressful for staff.Provisional themes from clients (n=10, recruitment ongoing) include: (i) Perceptions of services as Covid-safe: despite reporting varying concerns about Covid-19’s severity and personal vulnerability. (ii) Navigating new routes to care: whilst some clients reported being able to access care rapidly and easily, services delivered in person were not always promptly available, which could be distressing.DiscussionPrompt access to SRH could not always be maintained, despite efforts by staff/services. Remote delivery of some elements of SRH is popular with staff and clients. Staff concerns contrast with clients’ perceptions of SRH services as Covid-safe.People who did not use SRH – for whom perceived risk of Covid-19 may have been a barrier to seeking care – should be included in future research. When services were under particular pressure due to staff shortages, referral for client interviews slowed. Experiences of seeking/receiving care at these especially challenging times may therefore be under-explored.Interviews repeated later in 2022 will capture change over time. A quantitative Health Facility Assessment will complement our qualitative findings.

Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections: The ORCHESTRA Prospective Cohort Study.

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p < 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05-0.27, p < 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08-5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03-1.08, p < 0.001), and male gender (aOR:1.97, 95%CI: 1.04-3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p < 0.001) in immunocompromised and elderly patients >75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.

Clinical efficacy of different monoclonal antibody regimens among non-hospitalised patients with mild to moderate COVID-19 at high risk for disease progression: a prospective cohort study.

This study aimed to compare the clinical progression of COVID-19 in high-risk outpatients treated with the monoclonal antibodies (mAb) bamlanivimab, bamlanivimab-etesevimab and casirivimab-imdevimab. This is an observational, multi-centre, prospective study conducted from 18 March to 15 July 2021 in eight Italian tertiary-care hospitals including mild-to-moderate COVID-19 outpatients receiving bamlanivimab (700 mg), bamlanivimab-etesevimab (700-1400 mg) or casirivimab-imdevimab (1200-1200 mg). All patients were at high risk of COVID-19 progression according to Italian Medicines Agency definitions. In a patient subgroup, SARS-CoV-2 variant and anti-SARS-CoV-2 serology were analysed at baseline. Factors associated with 28-day all-cause hospitalisation were identified using multivariable multilevel logistic regression (MMLR) and summarised with adjusted odds ratio (aOR) and 95% confidence interval (CI). A total of 635 outpatients received mAb: 161 (25.4%) bamlanivimab, 396 (62.4%) bamlanivimab-etesevimab and 78 (12.2%) casirivimab-imdevimab. Ninety-five (15%) patients received full or partial SARS-CoV-2 vaccination. The B.1.1.7 (Alpha) variant was detected in 99% of patients. Baseline serology showed no significant differences among the three mAb regimen groups. Twenty-eight-day all-cause hospitalisation was 11.3%, with a significantly higher proportion (p 0.001) in the bamlanivimab group (18.6%), compared to the bamlanivimab-etesevimab (10.1%) and casirivimab-imdevimab (2.6%) groups. On MMLR, aORs for 28-day all-cause hospitalisation were significantly lower in patients receiving bamlanivimab-etesevimab (aOR 0.51, 95% CI 0.30-0.88 p 0.015) and casirivimab-imdevimab (aOR 0.14, 95% CI 0.03-0.61, p 0.009) compared to those receiving bamlanivimab. No patients with a history of vaccination were hospitalised. The study suggests differences in clinical outcomes among the first available mAb regimens for treating high-risk COVID-19 outpatients. Randomised trials are needed to compare efficacy of mAb combination regimens in high-risk populations and according to circulating variants.

Harmonization and standardization of data for a pan-European cohort on SARS- CoV-2 pandemic.

The European project ORCHESTRA intends to create a new pan-European cohort to rapidly advance the knowledge of the effects and treatment of COVID-19. Establishing processes that facilitate the merging of heterogeneous clusters of retrospective data was an essential challenge. In addition, data from new ORCHESTRA prospective studies have to be compatible with earlier collected information to be efficiently combined. In this article, we describe how we utilized and contributed to existing standard terminologies to create consistent semantic representation of over 2500 COVID-19-related variables taken from three ORCHESTRA studies. The goal is to enable the semantic interoperability of data within the existing project studies and to create a common basis of standardized elements available for the design of new COVID-19 studies. We also identified 743 variables that were commonly used in two of the three prospective ORCHESTRA studies and can therefore be directly combined for analysis purposes. Additionally, we actively contributed to global interoperability by submitting new concept requests to the terminology Standards Development Organizations.

Determinants of persistence of symptoms and impact on physical and mental wellbeing in Long COVID: A prospective cohort study.

BACKGROUND: Residual symptoms can be detected for several months after COVID-19. To better understand the predictors and impact of symptom persistence we analyzed a prospective cohort of COVID-19 patients. METHODS: Patients were followed for 9 months after COVID-19 onset. Duration and predictors of persistence of symptoms, physical health and psychological distress were assessed. RESULTS: 465 patients (54% males, 51% hospitalized) were included; 37% presented with at least 4 symptoms and 42% complained of symptom lasting more than 28 days. At month 9, 20% of patients were still symptomatic, showing mainly fatigue (11%) and breathlessness (8%). Hospitalization and ICU stay vs. non-hospitalized status increased the median duration of fatigue of 8 weeks. Age > 50 years (OR 2.50), ICU stay (OR 2.35), and presentation with 4 or more symptoms (OR 2.04) were independent predictors of persistence of symptoms at month 9. A total of 18% of patients did not return to optimal pre-COVID physical health, while 19% showed psychological distress at month 9. Hospital admission (OR 2.28) and persistence of symptoms at day 28 (OR 2.21) and month 9 (OR 5.16) were independent predictors of suboptimal physical health, while female gender (OR 5.27) and persistence of symptoms at day 28 (OR 2.42) and month 9 (OR 2.48) were risk factors for psychological distress. CONCLUSIONS: Patients with advanced age, ICU stay and multiple symptoms at onset were more likely to suffer from long-term symptoms, which had a negative impact on both physical and mental wellbeing. This study contributes to identify the target populations and Long COVID consequences for planning long-term recovery interventions.

Long-Term Patient-Centred Follow-up in a Prospective Cohort of Patients with COVID-19.

INTRODUCTION: To better define COVID-19 long-term impact we prospectively analysed patient-centred outcomes, including general health and symptom duration. METHODS: Barthel index (BI), St. George's Respiratory Questionnaire adapted to patients with COVID-19 (aSGRQ) and WHO Clinical Progression Scale (CPS) were measured at enrolment and at 6 weeks from the onset of symptoms. Persistence of most frequently reported symptoms was assessed at 6 weeks and, among symptomatic patients, at 12 weeks from the onset of symptoms. Predictors of impaired general health over time were identified using an ordinal multilevel multivariate model. RESULTS: A total of 448 patients (55% men, median age 56 years) were enrolled. WHO-CPS showed mild, moderate and severe disease in 48%, 42% and 10% of patients at admission and mild disease in all patients at follow-up, respectively. BI and aSGRQ were normal in 96% and 93% patients before COVID-19 but only in 47% and 16% at COVID-19 diagnosis and in 87% and 65% at 6-week follow-up. Male gender was identified by all three assessments as a predictor of impaired general health (BI, OR 2.14, p < 0.0001; aSGRQ, OR 0.53, p = 0.003; WHO-CPS, OR 1.56, p = 0.01). Other predictors included age, ICU admission and comorbidities (e.g. cardiovascular disease and cancer) for BI, hospital admission for aSGRQ, age and presence of comorbidities for WHO-CPS. At 6- and 12-week follow-up, 39% and 20% of patients, respectively, were still reporting symptoms. Fatigue and breathlessness were the most frequently reported symptoms. CONCLUSIONS: Long-term follow-up facilitates the monitoring of health impairment and symptom persistence and can contribute to plan tailored interventions.