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.

Growth Differentiation Factor 15 (GDF-15) Levels Associate with Lower Survival in Chronic Kidney Disease Patients with COVID-19.

A cytokine storm drives the pathogenesis of severe COVID-19 infection and several biomarkers have been linked to mortality. Chronic kidney disease (CKD) emerged as a risk factor for severe COVID-19. We investigated the association between selected biomarkers and mortality in 77 patients hospitalized for COVID-19, and whether they differ in patients with eGFR higher and lower than 45 mL/min. The association between patients' characteristics, plasma biomarkers and mortality was conducted by univariate logistic regression models and independent predictors of mortality were then used to create a multivariate prediction model through Cox regression. Patients with lower eGFR had a significant increase of GDF-15, CD-25 and RAGE, with higher plasma levels in non-survivors and in patients who needed ventilation. At univariate analysis, low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk. Independent association between GDF-15 quartiles and mortality risk was confirmed in the Cox model and adjusted for eGFR, age, fever and dyspnea (HR 2.28, CI 1.53−3.39, p < 0.0001). The strength of the association between GDF-15 quartiles and mortality risk increased in patients with lower compared to higher eGFR (HR 2.53, CI 1.34−4.79 versus HR 1.99, CI 1.17−3.39). Our findings may suggest a further investigation of the effect of GDF-15 signaling pathway inhibition in CKD.

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.

GDF-15 is a Predictor of Mortality in Chronic Kidney Disease Patients With Covid-19 Infection

BACKGROUND AND AIMS A cytokine storm drives the pathogenesis of severe coronavirus disease (COVID-19) and several biomarkers with different mechanisms of action have been linked to mortality. Chronic kidney disease (CKD) emerged as a very common risk factor for severe COVID-19. Indeed, CKD patients are at increased risk of premature death from many causes, including, but not limited to, cardiovascular disease (CVD) and infections. In this study, we aimed to investigate the associations between the growth differentiation factor 15 (GDF-15), an established cardiovascular and inflammatory biomarker and outcomes in CKD patients hospitalized for COVID-19. METHOD A retrospective study on COVID-19 hospitalized subjects in the acute phase of the disease. A broad range of cytokines (CD25, IL-18, TNF-α, TNF RI, TNF RII, GDF-15, IL-7, LIF, IL-6, CHITINASE3_LIKE1, RAGE and Pentraxin-3) were assessed in plasma (Luminex, ELISA) collected upon hospitalization. A total of 77 subjects were divided into two groups according to their estimated glomerular filtration rate (eGFR, by CKD-EPI formula), ≥45 mL/min (n = 44), or ˂45 mL/min (n = 33). RESULTS We found no statistical differences between the two groups in terms of demographic features. Among comorbidities, we found a higher percentage of patients with diabetes in the eGFR < 45 group. Likewise, the serum tests upon admission showed in the eGFR < 45 group a higher value of neutrophilic count. Upon hospital admission, the patient groups were comparable in terms of symptoms, time from symptom onset to admission and death or discharge, radiological evidence of pneumonia and respiratory parameters and time of hospitalization. Furthermore, there were no statistical differences between medical therapy during hospitalization, need for respiratory support with Continuous Positive Airways Pressure or Non-Invasive Mechanical Ventilation, or death rather than discharge as the clinical outcome. Serum levels of 20 different compounds were measured in COVID-19 patients admitted to the hospital 4–5 days after the onset of symptoms. Interestingly, we found that patients with lower renal function (eGFR < 45 mL/min) had a significant increase of GDF-15, CD-25 and RAGE and, furthermore, higher serum levels of these molecules were detected in non-survivor patients and in those who needed ventilation. Also, TNFα, TNFR I, TNFR II, IL-7 and LIF had a significant increase in patients with eGFR < 45 mL/min with more elevated levels in non-survivor patients. In univariate analysis low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk (Figure 1). Independent association between GDF-15 quartiles and mortality risk was confirmed in Cox model adjusted for eGFR, age, fever, dyspnoea and P/F [hazard ratio (HR) 2.28, 95% confidence interval (CI) 1.53–3.39, P < 0.0001) The strength of association between GDF-15 quartiles and mortality risk was increased in patients with eGFR < 45 mL/min/1.73 m2 (HR 2.53, CI 1.34–4.79) compared with the other eGFR group (HR 1.99, CI 1.17–3.39) (Table 1). CONCLUSION Our results demonstrate that GDF-15 is an independent predictor of COVID-19 mortality in CKD patients. Given the reported increase of this cytokine with age and its possible mechanistic role in various pathological conditions, our findings suggest that GDF-15 signalling pathway inhibitors may be included as possible therapeutic candidates for COVID-19 in CKD.FIGURE 2: Overall likelihood of survival according to quartile of GDF-15. Kaplan–Meier curves for GDF-15 quartiles adjusted for eGFR, age, fever, dyspnoea and P/F. GDF-15: Growth Differentiation Factor 15, eGFR: estimated glomerular filtration rate, P/F: PaO2/FiO2 ratio.

Real World Estimate of Vaccination Protection in Individuals Hospitalized for COVID-19.

Whether vaccination confers a protective effect against progression after hospital admission for COVID-19 remains to be elucidated. Observational study including all the patients admitted to San Paolo Hospital in Milan for COVID-19 in 2021. Previous vaccination was categorized as: none, one dose, full vaccination (two or three doses >14 days before symptoms onset). Data were collected at hospital admission, including demographic and clinical variables, age-unadjusted Charlson Comorbidity index (CCI). The highest intensity of ventilation during hospitalization was registered. The endpoints were in-hospital death (primary) and mechanical ventilation/death (secondary). Survival analysis was conducted by means of Kaplan-Meier curves and Cox regression models. Effect measure modification by age was formally tested. We included 956 patients: 151 (16%) fully vaccinated (18 also third dose), 62 (7%) one dose vaccinated, 743 (78%) unvaccinated. People fully vaccinated were older and suffering from more comorbidities than unvaccinated. By 28 days, the risk of death was of 35.9% (95%CI: 30.1-41.7) in unvaccinated, 41.5% (24.5-58.5) in one dose and 28.4% (18.2-38.5) in fully vaccinated (p = 0.63). After controlling for age, ethnicity, CCI and month of admission, fully vaccinated participants showed a risk reduction of 50% for both in-hospital death, AHR 0.50 (95%CI: 0.30-0.84) and for mechanical ventilation or death, AHR 0.49 (95%CI: 0.35-0.69) compared to unvaccinated, regardless of age (interaction p > 0.56). Fully vaccinated individuals in whom vaccine failed to keep them out of hospital, appeared to be protected against critical disease or death when compared to non-vaccinated. These data support universal COVID-19 vaccination.

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.

Appropriateness for SARS-CoV-2 vaccination for otolaryngologist and head and neck surgeons in case of pregnancy, breastfeeding, or childbearing potential: Yo-IFOS and CEORL-HNS joint clinical consensus statement.

PURPOSE: SARS-CoV-2 vaccines are a key step in fighting the pandemic. Nevertheless, their rapid development did not allow for testing among specific population subgroups such as pregnant and breastfeeding women, or elaborating specific guidelines for healthcare personnel working in high infection risk specialties, such as otolaryngology (ORL). This clinical consensus statement (CCS) aims to offer guidance for SARS-CoV-2 vaccination to this high-risk population based on the best evidence available. METHODS: A multidisciplinary international panel of 33 specialists judged statements through a two-round modified Delphi method survey. Statements were designed to encompass the following topics: risk of SARS-Cov-2 infection and use of protective equipment in ORL; SARS-Cov-2 infection and vaccines and respective risks for the mother/child dyad; and counseling for SARS-CoV-2 vaccination in pregnant, breastfeeding, or fertile healthcare workers (PBFHW). All ORL PBFHW were considered as the target audience. RESULTS: Of the 13 statements, 7 reached consensus or strong consensus, 2 reached no consensus, and 2 reached near-consensus. According to the statements with strong consensus otorhinolaryngologists-head and neck surgeons who are pregnant, breastfeeding, or with childbearing potential should have the opportunity to receive SARS-Cov-2 vaccination. Moreover, personal protective equipment (PPE) should still be used even after the vaccination. CONCLUSION: Until prospective evaluations on these topics are available, ORL-HNS must be considered a high infection risk specialty. While the use of PPE remains pivotal, ORL PBFHW should be allowed access to SARS-CoV-2 vaccination provided they receive up-to-date information.

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.

Heightened Circulating Interferon-Inducible Chemokines, and Activated Pro-Cytolytic Th1-Cell Phenotype Features Covid-19 Aggravation in the Second Week of Illness.

Covid-19 features a delayed onset of critical illness occurring approximately one week from the beginning of symptoms, which corresponds to the bridging of innate and adaptive immunity. We reasoned that the immune events occurring at the turning point of disease might mark the direction toward pathogenic versus protective inflammatory responses. Subjects with either severe (s; PaO2/FiO2 ratio <200) or mild (m; PaO2/FiO2 ratio>300) Covid-19 were enrolled. A range of chemokines and cytokines as well as reactive oxygen species (ROS) were measured in plasma. Dendritic and NK cell frequency, monocyte and B-/T-cell phenotype and SARS-CoV-2-specific T-cell responses were assessed in PBMC. Twenty mCovid-19 and 20 sCovid-19 individuals were studied. sCovid-19 patients displayed higher non-classical monocytes, plasma chemokines (CXCL8, CXCL9, CXCL10), cytokines (IL-6, IL-10), and ROS versus mCovid-19. sCovid-19 also showed significantly increased activated CD38+HLA-DR+ T-lymphocyte, and granzyme-B+/perforin+ pro-cytolytic T-cells. All Covid-19 patients showed SARS-CoV-2 specific-T-cell response with a predominance of Th1 bi- or trifunctional IFN-γ/IL-2/TNF-α-expressing CD4+, while no difference according to disease severity was observed. Severe Covid-19 features heightened circulating IFN-inducible chemokines and activated pro-cytolytic Th1 cell phenotype in the second week of illness, yet SARS-CoV-2-specific responses are similar to that of mild illness. Altogether, our observations suggest Th1 polarization coupled to higher cytolytic profile in sCovid-19 as correlate of disease pathogenesis and as potential targets to be investigated in the roadmap to therapy and vaccine development.