Long-term symptoms after SARS-CoV-2 infection in a cohort of people living with HIV (PLWH): a real-life study (preprint)

Background Our Hospital in Northern Italy assists 3817 people living with HIV (PLWH) and has faced the impact of COVID-19. Little is known about the impact of HIV infection on the risk of post-COVID-19 conditions (PCCs) onset. We aim to assess the incidence of PCC in PLWH and the factors associated with its occurrence.Methods We performed a retrospective, observational study including all PLWH > 18 years registered in the Brescia Health Protection Agency database, assessing SARS-CoV-2 burden, vaccination status, socio-demographic, and viro-immunological parameters from February 2020 until May 2022. Persistence of self-reported symptoms (clustered into gastrointestinal, respiratory, osteo-muscular, and neuro-behavioral symptoms) was evaluated after 3 months by a telephone-administered questionnaire. We estimated the associations between all variables and outcomes through univariate and multivariable logistic models.Results In the study period, 653 PLWH were diagnosed with SARS-CoV-2 infection (17.1%). We observed 19 (2.9%) reinfections, 71 (10.9%) hospitalizations, and 3 (0.5%) deaths. We interviewed 510/653 PLWH (78%), and 178 (PCCs prevalence 34.9%; CI95% 30.7–39.2) reported persistent symptoms. Asthenia/fatigue was the most reported symptom (60/178), followed by muscular pain (54/178). In the multivariate regression model, male sex was protective (adjusted OR = 0.64; CI95% 0.99–3.66), while hospitalization during acute infection was associated with an increased the risk of PCCs (adjusted OR = 1.9; CI95% 0.99–3.66). Notably, no viro-immunological variable modified the PCCs risk onset.Conclusions Our study highlights a substantial prevalence of PCCs among PLWH, three months post-SARS-CoV-2 infection, independent of viro-immunological features or vaccination status.

Potential Benefit of Early Treatment with Sotrovimab in Patients With High Risk for Severe COVID-19 Carrying BA.2 Infection (preprint)

Coronavirus disease 19 (COVID-19) continues to spread worldwide as a severe pandemic. The Omicron BA.2 became the predominant variant and the protagonist of the ongoing surge. As the virus continues to mutate, using of approved drugs or developing new therapeutic or prophylactic therapies against COVID-19 could be more complex. Sotrovimab is a monoclonal antibody (mAb) targeting the conserved epitope on the spike protein receptor; the most recent studies observed that it has substantially decreased in vitro activity against the Omicron BA.2 subvariant, but real-life data are still scarce. We describe the outcome of a case series of outpatients with BA.1 or BA.2 infection treated with sotrovimab. We conducted a retrospective observational study including all non-hospitalized adult patients treated with sotrovimab, for which a Sanger sequencing of SARS-CoV-2 was performed within a regional genomic surveillance program. Eleven (50%) patients with BA.1 infection and eleven (50%) with BA.2 infection were considered. Most patients were immunocompromised. During the follow-up period, no patient died and only one with BA.1 infection was hospitalized for severe COVID-19 pneumonia onset. One month after treatment, 90.9% of patients were completely asymptomatic in each group. We demonstrated that patients carrying the BA.2 variant treated with sotrovimab did not evolve to severe COVID-19, showing a similar outcome to BA.1 infected patients. Further studies are needed to prove that vaccination or the presumably high doses of mAbs used can protect this group of patients at high risk of progression.

Psychological and Emotional Impact Of COVID-19 Pandemic on People Living with Chronic Disease: HIV and Cancer (preprint)

People living with chronic disease (PLWCD) are the frailest category, both for the risk of severe COVID-19 illness and for the impact on the care continuum. Aim of this study was to analyze coping strategies and resilience in people living with HIV (PLWH) compared to people living with oncological diseases (PLWOD) during COVID-19 pandemic. We administrated an anonymous questionnaire, which explored the emotional experience, the demographic factors linked to a COVID-19-related stress syndrome, the patient’s perception about the adequacy of clinical undertaking from the hospital and the resilience. We analyzed 324 questionnaires. There were no significant differences in prevalence of psychological distress among the whole cohort; however, PLWOD were calmer, less troubled, and more serene than PLWH. Moreover, PLWH smoked more, ate more and gained more weight than PLWOD. Most patients didn’t feel lonely and continued to take pleasure from their activities. No differences in resilience were found between the groups. In the whole cohort lower levels of resilience were found in patients that were unemployed, with history of psychological disorders and in those who experienced more feelings of anger, anxiety and concern. PLWCD had high level of resilience, preserved their well-being, and activated adaptive coping during the pandemic.

Explorative Study Regarding Influenza Vaccine Hesitancy Among HIV-infected Patients (preprint)

There are scarce data regarding flu vaccination among people with HIV infection (PWHIV). The goal of this explorative study is to assess hesitancy toward influenza vaccination in a group of PWHIV during the pandemic. A questionnaire was administered to 219 patients vaccinated at our clinic during the 2020-2021 campaign. It evaluated subjects’ adherence over the last 3 seasonal vaccination campaigns, vaccine confidence, complacency and convenience, and the effect of the pandemic on the choice to vaccinate. The population was divided into two groups: fully adherent (all 3 campaigns, 117 patients) and non-fully adherent (1 or 2 campaigns, 102 patients). Adherence increased in non-fully adherent group in 2020-2021, but the pandemic did not affect the choice. Misbelieves emerged: influenza vaccine was considered protective SARS-CoV-2 (22.8% of total population); almost half of all patients thought influenza vaccine could improve their CD4+ cell level (57.3% in fully adherent, 40.2% in non-fully adherent, p<0.05). A quarter of the non-fully adherent group would not have vaccinated in a location other than our clinic (24.5% vs 11.9% in fully adherent group, p<0.05). Conclusively, offering a secure and private space for vaccination seems to encourage vaccination; healthcare professionals should improve counselling to increase adherence and correct misbeliefs.

Sex differences in a cohort of COVID-19 Italian patients hospitalized during the first and second pandemic waves. (preprint)

Background: Coronavirus Disease 2019 (COVID-19) severity seems to be influenced by genetic background, sex, age, and presence of specific comorbidities. So far, little attention has been paid to sex-specific variations of demographic, clinical and laboratory features of COVID-19 patients referred to the same hospital in the two consecutive pandemic waves.Methods: Demographic, clinical and laboratory data were collected in 1,000 COVID-19 patients (367 females and 633 males), 500 hospitalized in the first wave and 500 in the second one, at the ASST Spedali Civili of Brescia from March to December 2020. Statistical analyses have been employed to compare data obtained in females and males, taking into account their age, and during the first and second COVID-19 waves. Results: The mean age at the time of hospitalization was similar in females and males but was significantly higher for both in the second wave; the time elapsed from symptoms onset to hospital admission did not differ between sexes in the two waves and no correlation was observed between delayed hospital admission and length of hospitalization. The number of multi-symptomatic males was higher than that of females and patients with a higher number of comorbidities were more frequently admitted to intensive care unit (ICU) and more frequently died. Older males remained in ICU longer than females and showed a longer disease duration, mainly the first wave. The highest levels of white blood cells, neutrophils, C-reactive protein and fibrinogen were significantly higher in males and in the first, and along with higher levels of D-dimer, ferritin, lactate dehydrogenase and procalcitonin which were preferentially documented in patients requiring ICU or died. While the ICU death rate was higher in males, the overall death rate did not differ between the sexes; however, the deceased women were older.Conclusions: These data indicate that once patients were hospitalized, the risk of dying was similar between females and males. Therefore, future studies should aim at understanding the reasons why, for a given number of SARS-CoV-2 infection, less females develop the disease requiring hospitalization.

Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males (preprint)

Background: COVID-19 clinical presentation ranges from asymptomatic to fatal outcome. This variability is due in part to host genome specific mutations. Recently, two families in which COVID-19 segregates like an X-linked recessive monogenic disorder environmentally conditioned by SARS-CoV-2 have been reported leading to identification of loss-of-function variants in TLR7. Objective: We sought to determine whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: We compared male subjects with extreme phenotype selected from the Italian GEN-COVID cohort of 1178 SARS-CoV-2-infected subjects (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on the young male subset, picking up TLR7 as the most important susceptibility gene. Results: Rare TLR7 missense variants were predicted to impact on protein function in severely affected males and in none of the asymptomatic subjects. We then investigated a similar white European cohort in Spain, confirming the impact of TRL7 variants. A gene expression profile analysis in peripheral blood mononuclear cells after stimulation with TLR7 agonist demonstrated a reduction of mRNA level of TLR7, IRF7, ISG15, IFN-[a] and IFN-{gamma} in COVID-19 patients compared with unaffected controls demonstrating an impairment in type I and II INF responses. Conclusion: Young males with TLR7 loss-of-function mutations and severe COVID-19 in the two reported families represent only a fraction of a broader and complex host genome situation. Specifically, missense mutations in the X-linked recessive TLR7 disorder may significantly contribute to disease susceptibility in up to 4% of severe COVID-19.

Consequences of the COVID-19 pandemic on the continuum of the care in a cohort of people living with HIV followed in a single center of Northern Italy (preprint)

Introduction: During the COVID-19 pandemic, hospitals faced increasing pressure, where people living with HIV risked to either acquire SARS-CoV-2 and to interrupt the HIV continuum of care. Methods: this is a retrospective, observational study. We compared the numbers of medical visits performed, antiretroviral drugs dispensed and the number of new HIV diagnosis and of hospitalizations in a cohort of people living with HIV (PLWH) followed by the Spedali Civili of Brescia between the bimester of the COVID-19 pandemic peak and the bimester of October-November 2019. Data were retrieved from administrative files and from paper and electronic clinical charts. Categorical variables were described using frequencies and percentages, while continuous variables were described using mean, median, and interquartile range (IQR) values. Means for continuous variables were compared using Student’s t-tests and the Mann-Whitney test. Proportions for categorical variables were compared using the χ2 test. Results: : As of December 31st, 2019, a total of 3875 PLWH were followed in our clinic. Mean age was 51,4 ±13 years old, where 28% were females and 18.8% non-Italian. Overall, 98.9% were on ART (n=3834), 93% were viro-suppressed. A total of 1217 and 1162 patients had their visit scheduled at our out-patient HIV clinic during the two bimesters of 2019 and 2020, respectively. Comparing the two periods, we observed a raise of missed visits from 5% to 8% (p<0.01), a reduction in the number of new HIV diagnosis from 6.4 in 2019 to 2.5 per month in 2020 (p=0.01), a drop in ART dispensation and an increase of hospitalized HIV patients due to COVID-19 . ART regimens including protease inhibitors (PIs) had a smaller average drop than ART not including PIs (16,6% vs 21,6%, p<0.05). Whether this may be due to the perception of a possible efficacy of PIs on COVID19 is not known. Conclusions: : Our experience highlights the importance of a resilient healthcare system and the need to implement new strategies in order to guarantee the continuum of HIV care even in the context of emergency.

Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels (preprint)

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4]; Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.