Detection of specific RBD+ IgG+ memory B cells by flow cytometry in healthcare workers and patients with inborn errors of immunity after BNT162b2 m RNA COVID-19 vaccination.

Introduction: Inborn errors of immunity (IEI) are a heterogeneous group of diseases caused by intrinsic defects of the immune system. Estimating the immune competence of immunocompromised patients for an infection risk assessment or after SARS-CoV-2 vaccination constituted a challenge. Methods: The aim of this study was to determine the humoral responses of patients with IEI through a comprehensive analysis of specific receptor-binding domain-positive (RBD+) IgG+ memory B cells (MBCs) by flow cytometry, together with routine S-specific IgG antibodies and QuantiFERON SARS-CoV-2 (T-cell response), before the vaccine and 3 weeks after a second dose. Results and discussion: We first analyzed the percentage of specific RBD+ IgG+ MBCs in healthy healthcare workers. Within the control group, there was an increase in the percentage of specific IgG+ RBD+ MBCs 21 days after the second dose, which was consistent with S-specific IgG antibodies.Thirty-one patients with IEI were included for the pre- and post-vaccination study; IgG+ RBD+ MBCs were not evaluated in 6 patients due to an absence of B cells in peripheral blood. We detected various patterns among the patients with IEI with circulating B cells (25, 81%): an adequate humoral response was observed in 12/25, consider by the detection of positive S-specific IgG antibodies and the presence of specific IgG+ RBD+ MBCs, presenting a positive T-cell response; in 4/25, very low S-specific IgG antibody counts correlated with undetectable events in the IgG+ RBD+ MBC compartment but with positive cellular response. Despite the presence of S-specific IgG antibodies, we were unable to detect a relevant percentage of IgG+ RBD+ MBCs in 5/25; however, all presented positive T-cell response. Lastly, we observed a profound failure of B and T-cell response in 3 (10%) patients with IEI, with no assessment of S-specific IgG antibodies, IgG+ RBD+ MBCs, and negative cellular response. The identification of specific IgG+ RBD+ MBCs by flow cytometry provides information on different humoral immune response outcomes in patients with IEI and aids the assessment of immune competence status after SARS-CoV-2 mRNA vaccine (BNT162b2), together with S-specific IgG antibodies and T-cell responses.

Admission Hemoglobin as a Prognostic Factor for Major Adverse Kidney Events in Hospitalized Patients with Covid-19 and Acute Kidney Injury

Introduction: AlthoughCOVID-19 and anemia are associated with higher risk for Acute Kidney Injury (AKI), to the best of our knowledge no studies have analyzed the association of admission hemoglobin with Major Adverse Kidney Events (MAKE) in patients with COVID-19 and AKI. Method(s): Retrospective cohort study of 412 hospitalized patients with severe COVID-19. MAKE was defined as a composite of 28-day mortality, progression to AKI stage 3, and renal replacement therapy. A COX regression analysis was used to determine the independent association of hemoglobin level with risk of MAKE. Result(s): The mean age of the 412 patients was 55+/-15 years, 35.9% were male, had a mean Body Mass Index (BMI) of 28.2+/-5.5 kg/m2, and median in-hospital stay was 10 (6-17) days. Overall, patients had a mean hemoglobin level of 12.8+/-2.8g/dL, and 62.1%, 23.8%, 8.7%, and 5.3% presented a 24-hour hemoglobin >13g/dL, 10-13g/dL, 9.9-8g/dL, and < 8g/dL, respectively. Likewise, the 28-day mortality was 20.4%, 22.3% progressed to AKI stage 3 and 9.5% required RRT. The univariate analysis showed that a 24-hour hemoglobin >13 g/dL had a lower risk for 28-day mortality (HR=0.634 [0.503-0.800]), AKI at any stage (0.457 [0.304-687]), progression to AKI stage 3 (0.666 [0.527-0.841]) and RRT requirement (0.626 [0.489-0.801]). After COX regression analysis, a hemoglobin >13g/dL was associated with lower risk to present MAKE (0.541 [0.338-0.866]), independently of age, sex, BMI, diabetes, hypertension, chronic kidney disease, mechanical ventilation, and proinflammatory markers. Conclusion(s):A hemoglobin >13 g/dL level was independently associated with lower risk to present MAKE in hospitalized patients with severe COVID-19. [Formula presented] Conclusion(s): A hemoglobin >13 g/dL level was independently associated with lower risk to present MAKE in hospitalized patients with severe COVID-19. No conflict of interestCopyright © 2023

CHRONIC THROMBOEMBOLIC DISEASE AFTER ACUTE PULMONARY EMBOLISM RELATED TO SARSCoV-2

During SARS-CoV-2 infection, acute pulmonary embolism (PE) worsens the patient's clinical status. However, after resolution of the acute phase, the impact of residual thrombotic lesions in pulmonary vasculature remains unknown. In this line, chronic thromboembolic disease (CTD) consists of persistent thrombotic lesions and involves long-term functional limitations, including those for patients with a CTD with or without chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to evaluate the prevalence of CTD after hospitalization for SARSCoV-2 pneumonia and PE. Also, we evaluated the clinical and functional characteristics of these patients. Forty-two patients diagnosed of PE in the course of SARS-CoV-2 pneumonia were included. In all patients, CT angiography (n=35) and/or pulmonary V/Q scan (n=19) was obtained between 3 to 4 months after discharge. Remaining symptoms, pulmonary function and exercise capacity also were evaluated. Eleven patients (26%) showed persistent thrombotic lesions without residual SARS-CoV-2 pneumonia images. Within this former group, 36% (n=4) had exertional dyspnea as expression of CTD. Only one patient (9%) developed CTEPH. The only related factor with persistent thrombotic lesions was older age (>70 years). Exercise capacity and pulmonary function were not significantly different between symptomatic and non-symptomatic patients. Residual thrombotic lesions are a frequent finding after SARS-CoV-2 infection, however the prevalence of CTD and CTEPH are similar to SARS-CoV-2 non-related acute pulmonary embolism. In this patients, the current recommendations for pulmonary embolism monitoring after discharge could be applied.

Was there any delay in the treatment of breast cancer patients because of the COVID-19 stringency measures? : Francisco Estupiñán

Background Healthcare systems across Europe reorganized services to provide attention to COVID-19 patients. In the event of the surge of cases, countries were forced to cancel or postpone non-urgent care. The objective of this work is to investigate whether there were time-to-treatment delays in breast cancer due to April-May 2020 restrictions, and whether the delays were permanent and different across countries. Methods Design: Quasi-experimental pre-post study with a historical control. Population: Virtually the universe of breast cancer patients receiving elective surgery, radiotherapy, hormonal therapy or chemotherapy since January 2017 (until December 2021) in the participant regions - Belgium, Marché (IT), Riga (LV), Portugal, Wales, and Aragon (ES). The main endpoint is the change in the median time-to-treatment before and after an empirical joint-point. The study variables are detailed here https://doi.org/10.5281/zenodo.5148022. Analysis: Distributed generalized additive models using https://cran.r-project.org/package=mgcv. Results Preliminary results show that the impact in March-April 2020 time-to-treatment evolved differently across countries. For instance, while the median time from diagnosis to surgery, as the first treatment, increased from approximately 39 days (2018-2019) to more than 45 days (2020-2021) in Wales, in the Marche region (IT) the median time decreased from 52 days in 2017-2019 to 47 days in 2020. Complete analyses for the rest of the participant countries are currently undergoing. Conclusions We have observed differences in time to treatment in women with breast cancer across countries;however, the magnitude and direction of the effect has been uneven across countries.

Building a federated research infrastructure for a policy-rapid response

Background Mobilizing real world data from multiple data hubs in multiple countries to carry out policy-oriented research, requires orchestrating the governance of workflows, being compliant with legal and ethical requirements, and semantic harmonization and technological interoperability. In the context of PHIRI, policy-oriented research has to provide insight to policy-makers to cope with pandemics. Methods PHIRI builds this concept on the deployment of four use cases throughout a federated research infrastructure. A central hub orchestrates all the elements encompassing the development of such an infrastructure;so, a common governance model, common methodology pursuing semantic interoperability, and the development and deployment of technological solution containing ETL processes, data quality assessment solutions and data analyses, all packaged to be rolled out in the different data hubs composing the federation. Results A prototype orchestrating those workflows is being followed in four use cases: indirect effects of the pandemic on vulnerable populations, delayed breast cancer treatments due to the pandemic, perinatal health affections along the COVID19 crisis, effects of the pandemic on mental health care. A prototype of the technological platform supporting interoperable federated analyses has been prepared. Conclusions It is pertinent, feasible and reliable using a federated research infrastructure leveraging real world data from many data hubs in many countries to answer research queries on the COVID19 pandemic.

Research use cases measuring the impact of COVID-19 on population health

Background Wide variations in COVID-19 infection and outcomes exist across Europe and within countries. PHIRI will look at COVID-19 impacts in specific subgroups by conducting research through use cases of immediate relevance for public health policies focusing on indirect effects of the pandemic related to healthcare and other policies to contain the pandemic. Furthermore, the use cases represent pilot activities for the benefits and added value of a research infrastructure by bringing together data from different European countries. Methods Four research use cases will focus on selected aspects of vulnerable population groups and risk factors, delayed medical care in cancer, perinatal health outcomes, as well as mental health outcomes and are selected based on public health importance, geographic coverage, feasibility of producing actionable insights and relevance for the PHIRI infrastructure. The use cases will demonstrate how a broad variety of secondary data (e.g. administrative and survey data) can be pooled and/or reused in a distributed way across Europe. Results The outputs of the use cases will be processed by formalizing data models, data management processes and analytical pipelines in an interoperable way to feed in the federated research infrastructure. The use cases facilitate research by making scalable, reproducible methods available within PHIRI and by publishing the FAIRified use cases analysis results on the Health Information Portal. They will provide outcomes to guide policy makers in preparedness and response scenarios and will ensure the development of a format for the timely dissemination of use case results to the targeted groups. Conclusions PHIRI will provide insights in real life use cases to generate immediate results on key health impacts of COVID-19 on population health to underpin decision making and will drive the development of the federated research infrastructure that allows rapid cycle analysis.

COVID-19 in hospitalized HIV-positive and HIV-negative patients: A matched study

Background: We compared the characteristics and clinical outcomes of hospitalized patients with COVID-19 with and without HIV infection (HIV-pos and HIV-neg) in Spain during the first wave of the pandemic. Methods: HIV-pos were identified by reviewing clinical records and laboratory registries of 10,922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to June 30, 2020. Each HIV-pos was matched with 5 HIV-neg of the same age and sex randomly selected from COVID-19@Spain, a multicenter cohort of 4,035 patients hospitalized with PCR confirmed COVID-19 in Spain (Clin Microbiol Infect 2020;26:1525-36). Data were collected with the ISARIC-WHO Core case report form (https://isaric.org/document/COVID-19-crf/). The COVID-19 SEIMC score (predictive of 30-day mortality), based on age, sex, dyspnea, O2 saturation, neutrophil-to-lymphocyte ratio, and estimated glomerular filtration rate, was calculated at admission in all patients (ESCMID Conference on Coronavirus Disease, 2020, Abstract#00513). Outcomes included the need for mechanical ventilation and all-cause in-hospital mortality. Results: Forty-five patients with PCR confirmed COVID-19 were identified in CoRIS, 21 of which were hospitalized. A total of 105 age/sex-matched controls were selected from COVID-19@Spain. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In HIV-pos, 19.1% were IDUs, 95.2% were on ART, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4+ count was 595 (349-798) cells/mm3. No statistically significant differences were found between groups in number and type of comorbidities, presenting signs and symptoms, laboratory parameters, and radiology findings. The median (Q1-Q3) COVID-19 SEIMC score on admission was 4 (2-7) and 5 (3-7) in HIV-pos and HIV-neg, respectively;P=.890. Corticosteroids were administered to 33.3% and 27,4% HIV-pos and HIV-neg, respectively;P=.58. Remdesivir was administered to 0 and 2.9% of HIV-pos and HIV-neg, respectively;P=.426. During admission, 9.5% HIV-pos and 23.3% HIV-neg underwent mechanical ventilation;P=.158. In-hospital mortality was 9.5% in HIV-pos and 11.4% in HIV-neg;P=.800. Conclusion: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes in patients hospitalized with COVID-19. (Figure Presented).

Prevalence and factors associated with SARS-CoV-2 antibodies in a Spanish HIV cohort

Background: Within a prospective cohort of people with HIV (PWH) in Spain, we assessed the prevalence of SARS-CoV-2 antibodies (Ab), the proportion of asymptomatic COVID-19, and identified predictors of infection. Methods: We determined SARS-CoV-2 Ab in plasma samples collected from April 1st to September 30th, 2020, from enrollees in the Spanish HIV Research Network Cohort (CoRIS), a prospective national cohort of PWH, naive to ART at study entry, seen for the first time from January 1st, 2004. Samples were stored at-80°C in the Spanish HIV BioBank, and serology was performed using the Platelia SARS-CoV-2 Total Ab assays (BioRad, Hercules, CA, USA). Illness severity (NIH criteria) was assessed by medical records review and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes, non-AIDS related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, and N(t)RTI backbone. Results: During the study period, blood samples were collected and stored in the HIV BioBank from 1,076 consecutive PWH in CoRIS: 88.0% male at birth, median age 43 yr., 72.3% MSM, 97.7% on ART, median CD4+ 688 cells/mm3, 91.4% undetectable HIV viral load. SARS-CoV-2 Ab were detected in 91 PWH, for a seroprevalence of 8.5% (95%CI: 6.9%-10.3%). A total of 41 PWH (45.0%) had asymptomatic infections;the disease was mild in 43 (47.3%), moderate in 4 (4.4%), severe in 3 (3.3%), and 0 critical. Seven PWH (7.7%) were hospitalized. COVID-19 was confirmed by RT-PCR in 22 (24.2%) PWH. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American (LA) Countries vs. Spain (adjusted odds ratio [aOR]: 2.34, 95%CI: 1.42-3.85;P=.001);arterial hypertension (aOR: 1.63, 95%CI: 1.00-2.67;P=.050);and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) vs tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR: 0.32, 95%CI: 0.12-0.84;P=.021). (Table). Conclusion: A large proportion of SARS-CoV-2 infections among PWH were asymptomatic. Birth in LA-countries and arterial hypertension were associated with increased risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggest that TDF/FTC may prevent SARS-CoV-2 infection among PWH. (Figure Presented).

Hepatotoxicity associated with acute tocilizumab treatment in patients with sarscov-2 infection

Background and importance Tocilizumab (TCZ) has been proposed to mitigate the cytokine storm syndrome associated with SARS-CoV-2. However, acute administration of this drug has been shown to cause serious adverse effects at the level of the liver, including acute liver failure. Aim and objectives To evaluate the liver toxicity profile associated with the acute use of TCZ in patients with SARS-CoV-2 infection. Material and methods A retrospective single centre study, lasting 2 months (March to April 2020), was conducted in all patients with a clinical suspicion/diagnosis confirmed of SARSCoV-2 infection and who had received treatment with TCZ. The following variables were collected: age, sex, posology scheme of TCZ, admission to the intensive care unit (ICU), need for orotracheal intubation (OTI) and death during the hospital stay. The hepatic profile was analysed for levels of hepatic transaminases (GOT/AST and GPT/ALT) and total bilirubin (TOT BL) pre and post completion of treatment with TCZ. Alteration of liver parameters was classified as mild (1- 3 × upper limit of normality (UPN)), moderate (3-5 × UPN) and severe (≥5 × UPN). Results During the study period, 44 patients with SARS-CoV-2 infection were treated with TCZ (65.9% men (n=29);mean age 62.3 years (31-82)). The posology scheme of TCZ used was the following: single dose (68.2%, n=30), double dose (18.2%, n=8) and triple dose (11.6%, n=6). Two patients (4.5%) received a 50% reduced dose because of previous liver failure. During admission, 56.8% (n=25) of patients required a stay in the ICU. 36.4% (n=16) needed OTI. 9.1% (n=4) died during admission. Liver profile analysis showed that 72.7% of patients (n=32) presented with normal levels of GPT/ALT and GOT/AST before treatment. 59.1% (n=26) presented with normal levels of BL TOT and 4.5% (n=2) had high levels. In 34.1% (n=15) there were no data. After treatment with TCZ, 86.3% (n=38) developed hepatotoxicity. Elevation of GPT/ALT was observed: mild (42.1%), moderate (28.9%) and severe (28.9%);elevation of GOT/AST: mild (44.7%), moderate (31.6%) and severe (13.2%). 42.9% (n=12) presented with high levels of BL TOT after receiving TCZ. Conclusion and relevance The study showed how a high proportion of patients with SARS-CoV-2 infection developed severe liver toxicity after the use of the drug. However, future studies will be needed to clarify the involvement of SARSCoV-2 itself in the development of hepatotoxicity.