Quality of life and intrinsic capacity in patients with post-acute COVID-19 syndrome is in relation to frailty and resilience phenotypes

Background. The objective of this study was to characterize frailty and resilience in people evaluated for Post-Acute COVID-19 Syndrome (PACS), in relation to quality of life (QoL) and Intrinsic Capacity (IC). Methods. This cross-sectional, observational, study included consecutive people previously hospitalized for severe COVID-19 pneumonia attending Modena (Italy) PACS Clinic from July 2020 to April 2021. Four frailty-resilience phenotypes were built: 'fit/resilient', 'fit/non-resilient', 'frail/resilient' and 'frail/non-resilient'. Frailty and resilience were defined according to frailty phenotype and Connor Davidson resilience scale (CD-RISC-25) respectively. Study outcomes were: QoL assessed by means of Symptoms Short form health survey (SF-36) and health-related quality of life (EQ-5D-5L) and IC by means of a dedicated questionnaire. Their predictors including frailty-resilience phenotypes were explored in logistic regressions. Results. 232 patients were evaluated, median age was 58.0 years. PACS was diagnosed in 173 (74.6%) patients. Scarce resilience was documented in 114 (49.1%) and frailty in 72 (31.0%) individuals. Table 1 shows demographic, anthropometric and clinical characteristics, comorbidities and patient-reported outcomes according to four frailty-resilience phenotypes. With regards to study outcomes, Figure 1 depicts in radar graphs, mean scores of each domain of SF-36 (1A), EQ-5D5L (1B) and IC (1C). Figures shows polygon areas for each frailty/resilience phenotypes. Progressive increase of mean scores of each domain are plotted in the vertices of polygons, from the lowest (near the center) in frail and non-resilient, to highest (towards periphery) in fit and resilient. Multivariate logistic analyses were used to identify predictors of the total scores of SF-36 (Figure 2A), EQ-5D5L (Figure 2B) and IC (Figure 2C). Conclusion. Resilience is complementary to frailty in the identification of clinical phenotypes with different impact on wellness and QoL. Frailty and resilience should be evaluated in hospitalized COVID-19 patients to identify vulnerable individuals to prioritize urgent health interventions in people with PACS. Funding. This study is supported by a Gilead Sciences Inc. unrestricted grant.

Metabolic associated fatty liver disease is highly prevalent in the post-acute COVID syndrome

Background and Aims : Recently a proposal has been advanced to change the traditional definition of Non-Alcoholic Fatty Liver Disease to Metabolic Associated Fatty Liver Disease (MAFLD), to reflect the cluster of metabolic abnormalities that may be more closely associated with cardiovascular risk. Long COVID is a smoldering inflammatory condition, characterized by a number of symptom clusters. This study aims to determine the prevalence of MAFLD in patients with post-acute COVID syndrome (PACS) and its association with other PACS-cluster phenotypes. Method(s): We included 235 patients followed at a single university outpatient clinic. The diagnosis of PACS was based on >=1 cluster of symptoms: respiratory, neurocognitive, musculoskeletal, psychological, sensory, dermatological. The outcome was prevalence of MAFLD detected by transient elastography during the first post-discharge follow-up outpatient visit. The prevalence of MAFLD at the time of hospital admission was calculated retrospectively using the hepatic steatosis index. Result(s): Of 235 patients, 162 (69%) were men (median age 61). The prevalence of MAFLD was 55.3% at follow-up and 37.3% on admission (P<0.001). Insulin resistance (OR=1.5, 95%CI: 1.14-1.96), body mass index (OR=1.14, 95%CI: 1.04-1.24), and the metabolic syndrome (OR=2.54, 95%CI: 1.13-5.68), were independent predictors of MAFLD. The number of PACS clusters was inversely associated with MAFLD (OR=0.86, 95%CI: 0.76-0.97). Thirty-one patients (13.2%) had MAFLD with no other associated PACS clusters. All correlations between MAFLD and other PACS clusters were weak. Conclusion(s): MAFLD was highly prevalent after hospital discharge and may represent a specific PACS-cluster phenotype, with potential long-term metabolic and cardiovascular health implications. Copyright © 2022

suPAR evaluation in patients with SARS-CoV-2 infection: our experience

Introduction Elevated soluble urokinase Plasminogen Activator Receptor (suPAR) is a biomarker associated with adverse outcomes. We aimed to investigate the associations among plasma suPAR levels (testing the cut-offs <=4 and >=6 ng/mL that supports patient discharge/hospitalisation, respectively) with other biomarkers such as PCR, PCT, IL-6 and with sex, age, discharge/death and WHO disease severity in patients tested positive for SARS-CoV-2. Methods We performed an observational cohort study of 99 patients (37 females, 62 males) presenting with COVID-19 symptoms at Department of Infectous and Critical Care of our Hospital in April 2020. Plasma suPAR was measured using suPARnostic kit (Virogates, Denmark), an immunoturbidimetric method on Abbott Alinity i platform. Patients were followed for development of mechanical ventilation, mortality or discharged. Statistical analysis was performed using Principal Component Analysis (PCA) that can be applied to datasets to obtain a simplified model for stratifying patients by reducing the number of variables. PCA weights the variables according to their relative importance. This method, in our case, can aid in determining key variables in management of patients affected by SARS-CoV-2. Results The mean age was 58 years;women had a higher concentration average of suPAR (8.9 vs 8.3 ng/mL) but the subdivision by sex did not determine any clustering. All variables showed a positive correlation with disease severity, better with IL-6 and suPAR (IL-6=25.3%, suPAR=24%, age=16.4%, PCT=15.4%, PCR=17.2%), allowing a subdivision of 3 groups (severe/ critic: IL-6=227.65 pg/mL, suPAR=9.26 ng/mL;moderate: IL-6=48.1 pg/mL, suPAR=7.35 ng/mL, paucisymptomatic: IL-6=3.7 pg/mL, suPAR=2.78 ng/mL). Combining the variables and discharge/death outcome showed positive correlation although this did not result any clear clustering (n.78 discharged: IL-6=214 pg/mL, suPAR=8.23 ng/mL;n.14 dead: IL-6=286 pg/mL, suPAR=11.31 ng/mL). Discussion Our data show that suPAR levels increase as the disease worsens. Statistical analyses demonstrated that suPAR levels are positively correlated with age and IL-6 levels. Therefore, further evaluation of suPAR plasma levels in different symptoms of COVID-19 patients could still provide important indications for early admission and treatment.

DO ALL CRITICALLY ILL COVID-19 PATIENTS BENEFIT from INTENSIFYING with TOCILIZUMAB?

Background: Treatment guidelines recommend the use of tocilizumab in patients with a current CRP >7.5 mg/dl. Recent data showed that survival benefit might be greater in those with higher CRP levels. We aimed to estimate the causal effect of intensification with tocilizumab on mortality overall and after stratification for PaO2/FiO2 ratio, CRP levels. Methods: Observational cohort study of patients with severe COVID-19 pneumonia. Primary endpoint was day-28 mortality. Survival analysis was conducted to estimate the conditional and average causal effect of tocilizumab intensification vs. glucocorticoids alone using Kaplan-Meier curves and Cox regression models with a time-varying variable for the intervention. Analysis was controlled for age, ethnicity, duration of symptoms, at hospital admission (baseline, BL) PaO2/FiO2 ratio, CRP (BL and current), Charlson comorbidity index and post-BL use of remdesivir and invasive mechanical ventilation. The hypothesis of the existence of effect measure modification by CRP and PaO2/FiO2 ratio was tested by including an interaction term in the model. Results: 992 patients median age 69 years, 72.9% males, 597 (60.2%) treated with monotherapy and 395 (31.8%), adding tocilizumab upon respiratory deterioration were included. At BL, median CRP was 6.0 mg/dl (IQR 3.0-15.0) and median PaO2/FiO2 ratio was 261 mmHg (200-303). The two groups differed for median values of: CRP (6 vs 7 mg/dL;p<.001)), IL-6, (27.6 vs 175.0 mg/L;p<.001) LDH (525 vs 622 U/L;p<.001), lymphocytes (939 vs 835/mm3;p<.001) and PaO2/FiO2 ratio (276 vs 235 mmHg;p<.001) at BL. In the unadjusted analysis there was no statistically significant difference in mortality between the two groups, but there was strong evidence for an effect of the intensification after controlling for key BL and post-BL confounders, consistent with the estimate in trials (adjusted hazard ratio (aHR)=0.59, 95% CI:0.38-0.90). Although the study was not powered to detect interactions (p>0.57) there was a signal for intensification to have a larger effect in subsets, especially participants with high levels of CRP at intensification (Figure). Conclusion: Our data suggest that intensification with tocilizumab confers reduced survival benefit in those intensifying with a CRP of 0-7.5 mg/dl. It also provides substantial benefit even in patients who are intensified with a CRP>15 mg/dl. Large randomised studies are needed to establish an exact cut-off for clinical use.

Association between respiratory distress time and invasive mechanical ventilation in COVID-19 patients: A multicentre regional cohort study.

AIM: To determine whether the duration of respiratory distress symptoms in severe COVID-19 pneumonia affects the need for invasive mechanical ventilation and clinical outcomes. MATERIALS AND METHODS: An observational multicentre cohort study of patients hospitalised in five COVID-19-designated ICUs of the University Hospitals of Emilia-Romagna Region. Patients included were adults with pneumonia due to SARS-CoV-2 with PaO2/FiO2 ratio <300 mmHg, respiratory distress symptoms, and need for mechanical ventilation (invasive or non-invasive). Exclusion criteria were an uncertain time of respiratory distress, end-of-life decision, and mechanical respiratory support before hospital admission. MEASUREMENTS AND MAIN RESULTS: We analysed 171 patients stratified into tertiles according to respiratory distress duration (distress time, DT) before application of mechanical ventilation support. The rate of patients requiring invasive mechanical ventilation was significantly different (p < 0.001) among the tertiles: 17/57 patients in the shortest duration, 29/57 in the intermediate duration, and 40/57 in the longest duration. The respiratory distress time significantly increased the risk of invasive ventilation in the univariate analysis (OR 5.5 [CI 2.48-12.35], p = 0.003). Multivariable regression analysis confirmed this association (OR 10.7 [CI 2.89-39.41], p < 0.001). Clinical outcomes (mortality and hospital stay) did not show significant differences between DT tertiles. DISCUSSION: Albeit preliminary and retrospective, our data raised the hypothesis that the duration of respiratory distress symptoms may play a role in COVID-19 patients' need for invasive mechanical ventilation. Furthermore, our observations suggested that specific strategies may be directed towards identifying and managing early symptoms of respiratory distress, regardless of the levels of hypoxemia and the severity of the dyspnoea itself.

Hyalinose segmentaire et focale post-vaccination anti-SARS-CoV-2 : une association fortuite ?

Déclaration de liens d’intérêts: Les auteurs déclarent ne pas avoir de liens d’intérêts.

Aggravation d’une maladie rénale chronique : la COVID-19, complice ou coupable ?

Introduction La COVID-19 peut être associée à une hyalinose segmentaire et focale (HSF) collapsante nommée COVAN de mauvais pronostic. Description Nous rapportons quatre cas de patients ayant présenté une aggravation de leur insuffisance rénale chronique (IRC) dans les suites d’une infection COVID-19. Méthodes Entre novembre 2020 et avril 2021, quatre patients d’origine Africaine âgés de 47 à 74 ans, suivis dans notre service, ont été hospitalisés pour une aggravation de leur IRC. Leur néphropathie sous-jacente était une néphroangiosclérose (n=2), un diabète (n=1), une HSF collapsante (n=1) prouvée par ponction biopsie rénale (PBR). Lors du suivi, leur clairance était en moyenne de 47mL/min/1,73m2 avec une protéinurie négative ou<1,6g/g. Résultats Les patients ont été hospitalisés pour une aggravation majeure de leur IRC. À l’admission, la clairance moyenne était de 18mL/min/1,73m2 associée à une protéinurie de rang néphrotique. Une infection COVID-19 a été retrouvée dans les deux mois précédents chez deux des quatre patients. Tous avaient une sérologie COVID-19 positive, ainsi que les allèles à risque du gène ApoL1 (homozygote G1/G1 ou hétérozygote G1/G2). Deux patients ont eu une PBR retrouvant une HSF collapsante. La PBR n’a pas été réalisée chez les autres en raison d’une hypotrophie rénale. Durant le suivi, deux patients sont restés stables, un a nécessité le recours à l’hémodialyse et le dernier a été traité par corticoïdes 0,5mg/kg/j, permettant une diminution de la protéinurie et une amélioration partielle de la fonction rénale. La particularité de notre série est l’existence d’une IRC sous-jacente régulièrement suivie. Il reste à déterminer si la présence d’une IRC constitue un facteur favorisant la survenue d’une COVAN (Tableau 1). Conclusion L’aggravation rapide d’une IRC et d’une protéinurie doit maintenant faire rechercher une antériorité d’infection par la COVID-19. La COVAN est probablement sous-estimée chez ces patients pour lesquels la PBR n’est la plupart du temps pas effectuée.

LBA73 The ORF1ab of SARS-CoV-2 encodes an immunodominant epitope restricted by HLA-A*01:01

Background: A large global effort is ongoing to develop vaccines against SARS-CoV-2, the causative agent of COVID-19. While there is accumulating information on the antibody response against SARS-CoV-2, less is known about the SARS-CoV-2 antigens that are targeted by CD8 T cells. Such knowledge will be of high value to gain fundamental insights into the antigenic landscape of SARS-CoV-2 recognized by CD8 T cells, to develop tool allowing focused analysis of the SARS-CoV-2 specific T cell responses directly ex vivo, and to understand whether current vaccine designs are covering the CD8 T cell recognized antigens. Methods: To address this issue, we have analyzed samples from 18 COVID-19 patients for CD8 T cell recognition of 500 predicted SARS-CoV-2-derived epitopes restricted to 10 common HLA-A and HLA-B alleles. For each HLA allele, the top 50 epitopes were selected based on predicted binding affinity and likelihood of successful proteasomal processing. To probe for CD8 T cell recognition of the selected epitope-HLA complexes, we made use of our in-house technology based on multiplexing of peptide HLA (pHLA) multimers conjugated to fluorescent dyes. Results: In addition to previous studies showing CD8 T cell reactivity towards epitopes derived from the spike protein of SARS-CoV-2, we have identified several CD8 T cell recognized epitopes derived from the ORF1ab, including one epitope displaying clear immunodominant properties across patients positive for HLA-A*01:01. Investigation of the functional status of part of the identified responses (including 4 responses specific for the immunodominant epitope) revealed that the T cell responses were highly dysfunctional. In addition the SARS-CoV-2 specific CD8 T cell responses displayed an increased expression of NKG2A in comparison with bulk CD8 T cells, which may explain their dysfunctional state. Conclusions: Our data suggest that part of the ORF1ab encodes multiple CD8 T cell antigens including one immunodominant epitope. Noteworthy these epitopes were derived from a part of the viral genome that is not included in the majority of vaccine candidates in development, and this may potentially influence their clinical activity and safety profile. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV-2 infection: Retrospective cohort study

Background: The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID-19. Tocilizumab and anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV-2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID-19 patients requiring mechanical ventilation and admitted to intensive care unit. Methods: The association between therapy with tocilizumab or anakinra and in-hospital mortality was assessed in consecutive adult COVID-19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who received to those who did not receive tocilizumab or anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with tocilizumab or anakinra and after patient matching. Results: Sixty-six patients who received immunotherapy (49 tocilizumab, 17 anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in non-treated (OR 0.77, 95% CI 0.56-1.05, p=0.069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0.40, 95% CI 0.19-0.83, p=0.015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission. Conclusions: Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need for mechanical ventilation.

Impact of lockdown restrictions due to covid-19 pandemic on hiv care in italy

Background: It has been observed that lockdown restrictions during COVID-19 pandemic may have had a negative impact on HIV epidemic goals with disruption in care. We aim to analyse the trends in non-viral suppression for PLWH during and after the lockdown for COVID-19 pandemic in Italy compared to 2019. Methods: We included all participants in the ICONA cohort for whom there was ≥1 viral load (VL) in the window Nov 2019-Jan 2020 and with most recent VL≤50 copies/mL (exposed to lockdown), and over Nov 2018-Jan 2019 (not exposed). New enrolments in the study period were excluded. At population level and separately by year, we calculated proportion with VL≤50 copies/mL at each month over March-September and we performed an intermittent time series (ARIMA) model centred in March. In addition, we defined an individual outcome using the first VL over May-September (>50 vs. ≤50 copies/mL), comparing proportion with VL>50 copies/mL between exposed and not exposed by means of logistic regression models. PLWH with missing VL in the outcome window were excluded from the analysis. We also performed an alternative analysis in which censoring bias was minimised using inverse probability of weighting. Sensitivity analyses were performed after restricting to clinical sites with electronic linkage with laboratory data and to the subset of PLWH under follow-up in both years. Results: A total of 3,684 PLWH were included (2019=2,948;2020=736). PLWH exposed to lockdown were significantly older, less frequently MSM, non-Italian, had a higher CD4+ count and more frequently resident in north of Italy. The mean proportion of VL<50 copies/mL was 97% at March 2020 (ref.), 99% before March 2020, 82% at April 2020 (ARIMA estimates -21% 95% CI:-28%;-14%;P=0.01) and 97% after April 2020. In the 2019, the same proportions were 100%, 98%, 95%, and 97% with evidence for a lower drop in April (-6%, 95% CI:-8%;-3%, p=0.02). The results of the logistic regression model are reported in Table 1. When restricting to sites with electronic VL linkage and to those followed-up in both years the IPW OR of 2020 vs. 2019 were 1.23 (0.69-2.18) and 1.03 (0.48-2.19), respectively. Conclusion: We found little evidence for a difference in the proportion of PLWH with a VL>50 copies/mL, following stable suppression, in the period post lockdown due to COVID-19 as compared to the previous year. Although selection bias was minimized, reasons for a missing VL should be further investigated.

Profound CD8 T-cell responses towardsSARS-CoV-2 OFR1ab in COVID-19 patients

While there is accumulating evidence on the antibody response against SARS-CoV-2, we are only beginning toacquire knowledge regarding the SARS-CoV-2 specific CD8 T-cell response. Therefore, it is an urgent matter to gaina deeper insight into the virus specific CD8 T-cell response to both assist vaccine design and provide tools toevaluate the vaccine-induced T-cell responses. To address this issue, we have analyzed samples from 20 COVID-19 patients for CD8 T-cell recognition of 500 predicted SARS-CoV-2-derived epitopes restricted to 10 of the mostcommon HLA-A and HLA-B alleles. For each HLA allele, the top 50 epitopes were selected based on predictedbinding affinity and likelihood of successful proteasomal processing. In addition, SARS-CoV-2 epitope predictionsshared by the science community were considered. To probe for CD8 T-cell recognition of the selected epitopes, wemade use of our in-house technology based on multiplexing of peptide HLA (pHLA) multimers conjugated tofluorescent dyes. Our data demonstrated that CD8 T-cell reactivity against SARS-CoV-2 was common. Remarkably, a substantial fraction of the observed CD8 T-cell responses were directed towards the ORF1ab polyprotein 1ab.These CD8 T-cell responses were frequently of a profound magnitude. In particular, a CD8 T-cell response towardsa potentially immunodominant epitope (TTDPSFLGRY) restricted to the HLA-A∗01:01 allele was found in all patientspositive for this allele. Interestingly, the fraction of SARS-CoV-2 specific CD8 T cells expressing the inhibitoryreceptor NKG2A was higher as compared to bulk CD8 T cells. In conclusion, the fact that a major part of theidentified SARS-CoV-2 specific CD8 T-cell response is directed against a part of the viral genome that is notincluded in the majority of vaccine candidates currently in development may potentially influence their clinical activityand toxicity profile.

Erratum: The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection (Journal of Physical Chemistry DOI: 10.1159/000507914)

In the article by Alfano et al. entitled “The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection” [Blood Purif. DOI: 10.1159/000507914], the affiliations should be indicated as follows:. © 2020 Cambridge University Press. All rights reserved.