Six-month immune responses to mRNA-1273 vaccine in combination antiretroviral therapy treated late presenter people with HIV according to previous SARS-CoV-2 infection.

OBJECTIVE: Immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in people with HIV (PWH) with a history of late presentation (LP) and their durability have not been fully characterized. DESIGN: In this prospective, longitudinal study, we sought to assess T-cell and humoral responses to SARS-CoV-2 mRNA vaccination up to 6 months in LP-PWH on effective combination antiretroviral therapy (cART) as compared to HIV-negative healthcare workers (HCWs), and to evaluate whether previous SARS-CoV-2 infection modulates immune responses to vaccine. METHODS: SARS-CoV-2 spike (S)-specific T-cell responses were determined by two complementary flow cytometry methodologies, namely activation-induced marker (AIM) assay and intracellular cytokine staining (ICS), whereas humoral responses were measured by ELISA [anti-receptor binding domain (RBD) antibodies) and receptor-binding inhibition assay (spike-ACE2 binding inhibition activity), before vaccination (T0), 1 month (T1) and 5 months (T2) after the second dose. RESULTS: LP-PWH showed at T1 and T2 significant increase of: S-specific memory and circulating T follicular helper (cTfh) CD4 + T cells; polyfunctional Th1-cytokine (IFN-γ, TNF-α, IL-2)- and Th2-cytokine (IL-4)-producing S-specific CD4 + T cells; anti-RBD antibodies and spike-ACE2 binding inhibition activity. Immune responses to vaccine in LP-PWH were not inferior to HCWs overall, yet S-specific CD8 + T cells and spike-ACE2 binding inhibition activity correlated negatively with markers of immune recovery on cART. Interestingly, natural SARS-CoV-2 infection, while able to sustain S-specific antibody response, seems less efficacious in inducing a T-cell memory and in boosting immune responses to vaccine, possibly reflecting an enduring partial immunodeficiency. CONCLUSIONS: Altogether, these findings support the need for additional vaccine doses in PWH with a history of advanced immune depression and poor immune recovery on effective cART.

Immunologic Interplay Between HIV/AIDS and COVID-19: Adding Fuel to the Flames?

PURPOSE OF REVIEW: HIV/AIDS and COVID-19 have been the major pandemics overwhelming our times. Given the enduring immune disfunction featuring people living with HIV (PLWH) despite combination antiretroviral therapy (cART), concerns for higher incidence and severity of SARS-CoV-2 infection as well as for suboptimal responses to the newly developed vaccines in this population arose early during the pandemics. Herein, we discuss the complex interplay between HIV and SARS-CoV-2, with a special focus on the immune responses to SARS-CoV-2 natural infection and vaccination in PLWH. RECENT FINDINGS: Overall, current literature shows that COVID-19 severity and outcomes may be worse and immune responses to infection or vaccination lower in PLWH with poor CD4 + T-cell counts and/or uncontrolled HIV viremia. Data regarding the risk of post-acute sequelae of SARS-CoV-2 infection (PASC) among PLWH are extremely scarce, yet they seem to suggest a higher incidence of such condition. Scarce immunovirological control appears to be the major driver of weak immune responses to SARS-CoV-2 infection/vaccination and worse COVID-19 outcomes in PLWH. Therefore, such individuals should be prioritized for vaccination and should receive additional vaccine doses. Furthermore, given the potentially higher risk of developing long-term sequelae, PLWH who experienced COVID-19 should be ensured a more careful and prolonged follow-up.

Association between SARS-CoV-2 RNAemia and dysregulated immune response in acutely ill hospitalized COVID-19 patients.

Severe/critical COVID-19 is associated with immune dysregulation and plasmatic SARS-CoV-2 detection (i.e. RNAemia). We detailed the association of SARS-CoV-2 RNAemia with immune responses in COVID-19 patients at the end of the first week of disease. We enrolled patients hospitalized in acute phase of ascertained SARS-CoV-2 pneumonia, and evaluated SARS-CoV-2 RNAemia, plasmatic cytokines, activated/pro-cytolytic T-cells phenotypes, SARS-CoV-2-specific cytokine-producing T-cells (IL-2, IFN-γ, TNF-α, IL-4, IL-17A), simultaneous Th1-cytokines production (polyfunctionality) and amount (iMFI). The humoral responses were assessed with anti-S1/S2 IgG, anti-RBD total-Ig, IgM, IgA, IgG1 and IgG3, neutralization and antibody-dependent cellular cytotoxicity (ADCC). Out of 54 patients, 27 had detectable viremia (viremic). Albeit comparable age and co-morbidities, viremic more frequently required ventilatory support, with a trend to higher death. Viremic displayed higher pro-inflammatory cytokines (IFN-α, IL-6), lower activated T-cells (HLA-DR+CD38+), lower functional SARS-CoV-2-specific T-cells (IFN-γ+CD4+, TNF-α+CD8+, IL-4+CD8+, IL-2+TNF-α+CD4+, and IL-2+TNF-α+CD4+ iMFI) and SARS-CoV-2-specific Abs (anti-S IgG, anti-RBD total-Ig, IgM, IgG1, IgG3; ID50, %ADCC). These data suggest a link between SARS-CoV-2 RNAemia at the end of the first stage of disease and immune dysregulation. Whether high ab initium viral burden and/or intrinsic host factors contribute to immune dysregulation in severe COVID-19 remains to be elucidated, to further inform strategies of targeted therapeutic interventions.

Hallmarks of Severe COVID-19 Pathogenesis: A Pas de Deux Between Viral and Host Factors.

Two years into Coronavirus Disease 2019 (COVID-19) pandemic, a comprehensive characterization of the pathogenesis of severe and critical forms of COVID-19 is still missing. While a deep dysregulation of both the magnitude and functionality of innate and adaptive immune responses have been described in severe COVID-19, the mechanisms underlying such dysregulations are still a matter of scientific debate, in turn hampering the identification of new therapies and of subgroups of patients that would most benefit from individual clinical interventions. Here we review the current understanding of viral and host factors that contribute to immune dysregulation associated with COVID-19 severity in the attempt to unfold and broaden the comprehension of COVID-19 pathogenesis and to define correlates of protection to further inform strategies of targeted therapeutic interventions.

Female gender is associated with long COVID syndrome: a prospective cohort study.

OBJECTIVE: We explored the association between female gender and long COVID syndrome, defined as persistence of physical and/or psychological symptoms for more than 4 weeks after recovery from acute COVID-19 disease. The secondary aim was to identify predictors of long COVID syndrome by multivariable logistic regression analysis. METHODS: This was a single-centre prospective cohort study conducted at San Paolo Hospital in Milan, Italy. We enrolled adult patients who were evaluated at the post-COVID outpatient service of our Infectious Diseases Unit between 15 April 2020 and 15 December 2020. Participants were individuals who had clinically recovered from COVID-19 and in whom virological clearance had occurred. Previous infection by SARS-CoV-2 was microbiologically documented by positivity using a reverse-transcriptase polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab. All enrolled patients underwent blood tests and a comprehensive medical examination at follow-up. Individuals were interviewed about resolved and persisting symptoms and were asked to fill in two questionnaires to allow assessment of the Hospital Anxiety and Depression symptoms (HADS) score and of the Impact of Event Scale-Revised (IES-R) score. RESULTS: A total of 377 patients were enrolled in the study. The median time from symtpom onset to virological clerance was 44 (37-53) days. A diagnosis of long COVID syndrome was made in 260/377 (69%) patients. The most common reported symptoms were fatigue (149/377, 39.5%), exertional dyspnoea (109/377, 28.9%), musculoskeletal pain (80/377, 21.2%) and "brain fog" (76/377, 20.2%). Anxiety symptoms were ascertained in 71/377 (18.8%) individuals, whereas 40/377 (10.6%) patients presented symptoms of depression. Post-traumatic stress disorder (defined by a pathological IES-R score) was diagnosed in one-third of patients (85/275, 31%). Female gender was independently associated with long COVID syndrome at multivariable analysis (AOR 3.3 vs. males, 95% CI 1.8-6.2, p < 0.0001). Advanced age (adjusted (A)OR 1.03 for 10 years older, 95% CI 1.01-1.05, p 0.01) and active smoking (AOR 0.19 for former smokers vs. active smokers, 95% CI 0.06-0.62, p 0.002) were also associated with a higher risk of long COVID, while no association was found between severity of disease and long COVID (AOR 0.67 for continuous positive airway pressure (CPAP)/non-invasive mechanical ventilation (NIMV)/orotracheal intubation (OTI) vs. no 02 therapy, 95% CI 0.29-1.55, p 0.85). DISCUSSION: Factors that were found to be associated with a higher risk of developing "long COVID" syndrome were female gender, older age and active smoking, but not severity of the acute disease. Individuals affected by SARS-CoV-2 infection with the aforementioned features should be early identified and involved in follow-up programmes.

Declining Mortality Rate of Hospitalised Patients in the Second Wave of the COVID-19 Epidemics in Italy: Risk Factors and the Age-Specific Patterns.

BACKGROUND: Mortality rate from COVID-19 in Italy is among the world's highest. We aimed to ascertain whether there was any reduction of in-hospital mortality in patients hospitalised for COVID-19 in the second-wave period (October 2020-January 2021) compared to the first one (February-May 2020); further, we verified whether there were clusters of hospitalised patients who particularly benefitted from reduced mortality rate. METHODS: Data collected related to in-patients' demographics, clinical, laboratory, therapies and outcome. Primary end-point was time to in-hospital death. Factors associated were evaluated by uni- and multivariable analyses. A flow diagram was created to determine the rate of in-hospital death according to individual and disease characteristics. RESULTS: A total of 1561 patients were included. The 14-day cumulative incidence of in-hospital death by competing risk regression was of 24.8% (95% CI: 21.3-28.5) and 15.9% (95% CI: 13.7-18.2) in the first and second wave. We observed that the highest relative reduction of death from first to second wave (more than 47%) occurred mainly in the clusters of patients younger than 70 years. CONCLUSIONS: Progress in care and supporting therapies did affect population over 70 years to a lesser extent. Preventive and vaccination campaigns should focus on individuals whose risk of death from COVID-19 remains high.

A Quantitative Estimate of the Expected Shortening of the Median Isolation Period of Patients With COVID-19 After the Adoption of a Symptom-Based Strategy.

A long period of isolation was observed in patients hospitalized for COVID-19 in Milan over March-September 2020 (45; IQR: 37-54 days). A significantly shorter period would have been observed by the application of May-WHO (22, IQR: 17-30 days, P < 0.001) and October-Italian (26, IQR: 21-34 days, P < 0.001) Guidelines. The adoption of the new symptom-based criteria is likely to lead to a significant reduction in the length of the isolation period with potential social, economic and psychological benefits, particularly in the younger population with mild/moderate disease and no comorbidities. In our opinion, the release from isolation after 21 days from symptoms onset, even without a PCR diagnostic test, in most cases seems the most adequate strategy that could balance precautions to prevent SARS CoV-2 transmission and unnecessary prolonged isolation or overuse of diagnostic testing.

The importance of patients' case-mix for the correct interpretation of the hospital fatality rate in COVID-19 disease.

OBJECTIVE: We aimed to document data on the epidemiology and factors associated with clinical course leading to death of patients hospitalised with COVID-19. METHODS: Prospective observational cohort study on patients hospitalised with COVID-19 disease in February-24th/May-17th 2020 in Milan, Italy. Uni-multivariable Cox regression analyses were performed. Death's percentage by two-weeks' intervals according to age and disease severity was analysed. RESULTS: A total of 174/539 (32.3%) patients died in hospital over 8228 person-day follow-up; the 14-day Kaplan-Meier probability of death was 29.5% (95%CI: 25.5-34.0). Older age, burden of comorbidities, COVID-19 disease severity, inflammatory markers at admission were independent predictors of increased risk, while several drug-combinations were predictors of reduced risk of in-hospital death. The highest fatality rate, 36.5%, occurred during the 2nd-3rd week of March, when 55.4% of patients presented with severe disease, while a second peak, by the end of April, was related to the admission of older patients (55% ≥80 years) with less severe disease, 30% coming from long-term care facilities. CONCLUSIONS: The unusual fatality rate in our setting is likely to be related to age and the clinical conditions of our patients. These findings may be useful to better allocate resources of the national healthcare system, in case of re-intensification of COVID-19 epidemics.