COVID-19 and Mixed Cryoglobulinemia Syndrome: Long-Term Survey Study on the Prevalence and Outcome, Vaccine Safety, and Immunogenicity.

PURPOSE: Mixed cryoglobulinemia syndrome (MCs) is a rare immunoproliferative systemic disorder with cutaneous and multiple organ involvement. Our multicenter survey study aimed to investigate the prevalence and outcome of COVID-19 and the safety and immunogenicity of COVID-19 vaccines in a large MCs series. METHODS: The survey included 430 unselected MCs patients (130 M, 300 F; mean age 70 ± 10.96 years) consecutively collected at 11 Italian referral centers. Disease classification, clinico-serological assessment, COVID-19 tests, and vaccination immunogenicity were carried out according to current methodologies. RESULTS: A significantly higher prevalence of COVID-19 was found in MCs patients compared to Italian general population (11.9% vs 8.0%, p < 0.005), and the use of immunomodulators was associated to a higher risk to get infected (p = 0.0166). Moreover, higher mortality rate was recorded in MCs with COVID-19 compared to those without (p < 0.01). Patients' older age (≥ 60 years) correlated with worse COVID-19 outcomes. The 87% of patients underwent vaccination and 50% a booster dose. Of note, vaccine-related disease flares/worsening were significantly less frequent than those associated to COVID-19 (p = 0.0012). Impaired vaccination immunogenicity was observed in MCs patients compared to controls either after the first vaccination (p = 0.0039) and also after the booster dose (p = 0.05). Finally, some immunomodulators, namely, rituximab and glucocorticoids, hampered the vaccine-induced immunogenicity (p = 0.029). CONCLUSIONS: The present survey revealed an increased prevalence and morbidity of COVID-19 in MCs patients, as well an impaired immunogenicity even after booster vaccination with high rate of no response. Therefore, MCs can be included among frail populations at high risk of infection and severe COVID-19 manifestations, suggesting the need of a close monitoring and specific preventive/therapeutical measures during the ongoing pandemic.

Distinct platelet crosstalk with adaptive and innate immune cells after adenoviral and mRNA vaccination against SARS-CoV-2.

BACKGROUND: Genetic-based COVID-19 vaccines have proved to be highly effective in reducing the risk of hospitalization and death. Because they were first distributed in a large-scale population, the adenoviral-based vaccines were linked to a very rare thrombosis with thrombocytopenia syndrome, and the interplay between platelets and vaccinations increasingly gained attention. OBJECTIVES: The objective of this article was to study the crosstalk between platelets and the vaccine-induced immune response. METHODS: We prospectively enrolled young healthy volunteers who received the mRNA-based vaccine, BNT162b2 (n = 15), or the adenovirus-based vaccine, AZD1222 (n = 25) and studied their short-term platelet and immune response before and after vaccine injections. In a separate cohort, we retrospectively analyzed the effect of aspirin on the antibody response 1 and 5 months after BNT162b2 vaccination. RESULTS: Here, we show that a faster antibody response to either vaccine is associated with the formation of platelet aggregates with marginal zone-like B cells, a subset geared to bridge the temporal gap between innate and adaptive immunities. However, although the mRNA-based vaccine is associated with a more gradual and tolerogenic response that fosters the crosstalk between platelets and adaptive immunity, the adenovirus-based vaccine, the less immunogenic of the 2, evokes an antiviral-like response during which the platelets are cleared and less likely to cooperate with B cells. Moreover, subjects taking aspirin (n = 56) display lower antibody levels after BNT162b2 vaccination compared with matched individuals. CONCLUSION: Platelets are a component of the innate immune pathways that promote the B-cell response after vaccination. Future studies on the platelet-immune crosstalk post-immunization will improve the safety, efficacy, and strategic administration of next-generation vaccines.

Opposite Effects of mRNA-Based and Adenovirus-Vectored SARS-CoV-2 Vaccines on Regulatory T Cells: A Pilot Study.

New-generation mRNA and adenovirus vectored vaccines against SARS-CoV-2 spike protein are endowed with immunogenic, inflammatory and immunomodulatory properties. Recently, BioNTech developed a noninflammatory tolerogenic mRNA vaccine (MOGm1Ψ) that induces in mice robust expansion of antigen-specific regulatory T (Treg) cells. The Pfizer/BioNTech BNT162b2 mRNA vaccine against SARS-CoV-2 is identical to MOGm1Ψ except for the lipid carrier, which differs for containing lipid nanoparticles rather than lipoplex. Here we report that vaccination with BNT162b2 led to an increase in the frequency and absolute count of CD4posCD25highCD127low putative Treg cells; in sharp contrast, vaccination with the adenovirus-vectored ChAdOx1 nCoV-19 vaccine led to a significant decrease of CD4posCD25high cells. This pilot study is very preliminary, suffers from important limitations and, frustratingly, very hardly can be refined in Italy because of the >90% vaccination coverage. Thus, the provocative perspective that BNT162b2 and MOGm1Ψ may share the capacity to promote expansion of Treg cells deserves confirmatory studies in other settings.

Serological Response and Relationship with Gender-Sensitive Variables among Healthcare Workers after SARS-CoV-2 Vaccination.

Vaccine-induced immunity is a key strategy in the long-term control of the COVID-19 pandemic. The aim of our study was to explore the relationship between mRNA vaccine-induced antibodies and gender-sensitive variables among healthcare workers. Two thousand-sixty-five volunteers who received the BNT162b2 vaccine were enrolled in the study and followed up. Demographic, clinical, and social variables (educational level, marital status, occupation, childcare) were evaluated through a self-administered questionnaire. Anti-Spike (S) IgG were measured at 1 month (T1) and at 5 months (T2) after the second vaccine dose. At T1, median anti-S IgG values were 693 [394->800] AU/mL (1 AU = 2.6 BAU). Values > 800 AU/mL (2080 BAU/mL) were directly associated with a previous COVID-19 (p < 0.001) infection and inversely with age (p < 0.001), smoking habit (p < 0.001), and autoimmune diseases (p < 0.001). At T2, a significant decreasing in anti-S IgG values was observed (187 [81-262] AU/mL), with a median decrease of 72 [60-82]%. On multivariate data analysis, a reduction of more than 82% was directly associated with male sex (p < 0.021), age (p < 0.001), smoking (p = 0.038), hypertension (p = 0.042), and, inversely, with previous COVID-19 infection (p < 0.001) and being "cohabiting" (p = 0.005). Our findings suggest that demographic, clinical, and social variables play a role in anti-S IgG values decreasing in long-term follow up and should be considered to find personalized vaccine schedules.

Prevalence of New-Onset Atrial Fibrillation and Associated Outcomes in Patients with Sepsis: A Systematic Review and Meta-Analysis.

BACKGROUND: New-onset atrial fibrillation (NOAF) is a common complication in patients with sepsis, although its prevalence and impact on outcomes are still unclear. We aim to provide a systematic review and meta-analysis on the prevalence of NOAF in patients with sepsis, and its impact on in-hospital mortality and intensive care unit (ICU) mortality. METHODS: PubMed and EMBASE were systematically searched on 26 December 2021. Studies reporting on the prevalence of NOAF and/or its impact on in-hospital mortality or ICU mortality in patients with sepsis or septic shock were included. The pooled prevalence and 95% confidence intervals (CI) were calculated, as well as the risk ratios (RR), 95%CI and 95% prediction intervals (PI) for outcomes. Subgroup analyses and meta-regressions were performed to account for heterogeneity. RESULTS: Among 4988 records retrieved from the literature search, 22 articles were included. Across 207,847 patients with sepsis, NOAF was found in 13.5% (95%CI: 8.9-20.1%), with high heterogeneity between studies; significant subgroup differences were observed, according to the geographical location, study design and sample size of the included studies. A multivariable meta-regression model showed that sample size and geographical location account for most of the heterogeneity. NOAF patients showed an increased risk of both in-hospital mortality (RR: 1.69, 95%CI: 1.47-1.96, 95%PI: 1.15-2.50) and ICU mortality (RR: 2.12, 95%CI: 1.86-2.43, 95%PI: 1.71-2.63), with moderate to no heterogeneity between the included studies. CONCLUSIONS: NOAF is a common complication during sepsis, being present in one out of seven individuals. Patients with NOAF are at a higher risk of adverse events during sepsis, and may need specific therapeutical interventions.

Platelet and immune signature associated with a rapid response to the BNT162b2 mRNA COVID-19 vaccine.

BACKGROUND: A rapid immune response is critical to ensure effective protection against COVID-19. Platelets are first-line sentinels of the vascular system able to rapidly alert and stimulate the immune system. However, their role in the immune response to vaccines is not known. OBJECTIVE: To identify features of the platelet-immune crosstalk that would provide an early readout of vaccine efficacy in adults who received the mRNA-based COVID-19 vaccine (BNT162b2). METHODS: We prospectively enrolled 11 young healthy volunteers (54% females, median age: 28 years) who received two doses of BNT162b2, 21 days apart, and we studied their platelet and immune response before and after each dose of the vaccine (3 and 10 ± 2 days post-injection), in relation to the kinetics of the humoral response. RESULTS: Participants achieving an effective level of neutralizing antibodies before the second dose of the vaccine (fast responders) had a higher leukocyte count, mounted a rapid cytokine response that incremented further after the second dose, and an elevated platelet turnover that ensured platelet count stability. Their circulating platelets were not more reactive but expressed lower surface levels of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-coupled receptor CD31 (PECAM-1) compared to slow responders, and formed specific platelet-leukocyte aggregates, with B cells, just 3 days after the first dose, and with non-classical monocytes and eosinophils. CONCLUSION: We identified features of the platelet-immune crosstalk that are associated with the development of a rapid humoral response to an mRNA-based vaccine (BNT162b2) and that could be exploited as early biomarkers of vaccine efficacy.

A SWOT analysis of Italian medical curricular adaptations to the COVID-19 pandemic: A nationwide survey of medical school leaders.

BACKGROUND: There is a growing literature on how medical education adapts to the COVID-19 pandemic. However, there is a need to examine the facilitators and barriers of these adaptations. This study explores the strengths, weaknesses, opportunities, and threats (SWOT) of how Italian medical schools adapted their curricula to the COVID -19 pandemic. METHODS: The authors conducted an online survey of directors of medical curricula in Italy. Free-text responses to open-ended questions about curricular adaptations and reflections on these adaptations were analysed using qualitative thematic analysis. RESULTS: Twenty out of 60 Italian medical school directors completed the survey. Strengths identified were rapid responses and a spirit of cooperation. Weaknesses included dependency on clinical facilities, teachers' limited skills to use technology, and lack of mental health support for staff. Opportunities highlighted were clear government rules, new ways of teaching and a renewed focus on underrepresented topics. Threats expressed included impaired relationships, difficulties related to online assessment, lack of IT access, and legal and insurance issues. CONCLUSIONS: This study, in documenting the curricular adaptations of Italian medical schools during an active global pandemic, and recording the perspectives of medical education leaders, offers important lessons for the future.

Cutaneous adverse reactions after COVID-19 vaccines in a cohort of 2740 Italian subjects: An observational study.

An in-depth characterization of the incidence, morphology, and onset of COVID-19-vaccines cutaneous adverse reactions is currently lacking. The existing literature on COVID-19 vaccination-related cutaneous adverse reactions largely focused on messenger RNA vaccines and mainly included type 1 hypersensitivity reactions, such as urticaria and angioedema. Other cutaneous manifestations are still poorly characterized and have been classified as delayed hypersensitivity rash. Our prospective observational study on a sample of 2740 subjects who underwent the COVID-19 vaccination aimed at defining the prevalence of cutaneous adverse reactions and at identifying their timing of onset and their correlation with the administered dose. Vaccine-related cutaneous adverse reactions occurred in 50 subjects. Patients were asked to complete a questionnaire on the type of COVID-19 vaccine received, the time of onset of cutaneous reactions, and the dates of administration. Out of 2740 individuals who received the COVID-19 vaccination, 50 were diagnosed with cutaneous adverse reactions to vaccine, after the first dose in 28 patients, after the second in 20, and after both in two. We reported localized injection site erythema in 12 patients and generalized cutaneous reactions in 38 patients. Our study shows that cutaneous adverse reactions to COVID-19 vaccination are not common and most often occur after the first dose, recurring infrequently after the second dose. These reactions are usually easily manageable and, even in severe generalized cases, oral antihistamines and corticosteroids were sufficient for resolution. Therefore, except for immediate hypersensitivity reactions, cutaneous adverse reactions do not represent a contraindication to the completion of the vaccination cycle.

Prevalence of right ventricular dysfunction and impact on all-cause death in hospitalized patients with COVID-19: a systematic review and meta-analysis.

The Coronavirus Disease (COVID-19) pandemic imposed a high burden of morbidity and mortality. In COVID-19, direct lung parenchymal involvement and pulmonary microcirculation dysfunction may entail pulmonary hypertension (PH). PH and direct cardiac injury beget right ventricular dysfunction (RVD) occurrence, which has been frequently reported in COVID-19 patients; however, the prevalence of RVD and its impact on outcomes during COVID-19 are still unclear. This study aims to evaluate the prevalence of RVD and associated outcomes in patients with COVID-19, through a Systematic Review and Meta-Analysis. MEDLINE and EMBASE were systematically searched from inception to 15th July 2021. All studies reporting either the prevalence of RVD in COVID-19 patients or all-cause death according to RVD status were included. The pooled prevalence of RVD and Odds Ratio (OR) for all-cause death according to RVD status were computed and reported. Subgroup analysis and meta-regression were also performed. Among 29 studies (3813 patients) included, pooled prevalence of RVD was 20.4% (95% CI 17.1-24.3%; 95% PI 7.8-43.9%), with a high grade of heterogeneity. No significant differences were found across geographical locations, or according to the risk of bias. Severity of COVID-19 was associated with increased prevalence of RVD at meta-regression. The presence of RVD was found associated with an increased likelihood of all-cause death (OR 3.32, 95% CI 1.94-5.70). RVD was found in 1 out of 5 COVID-19 patients, and was associated with all-cause mortality. RVD may represent one crucial marker for prognostic stratification in COVID-19; further prospective and larger are needed to investigate specific management and therapeutic approach for these patients.

Rethinking of osteoporosis through a sex- and gender-informed approach in the COVID-19 era.

Standards and models of reference for osteoporosis (OP) have been developed for female individuals as they are more likely to be affected by the disease. Nonetheless, OP is also responsible for one-third of hip fractures in male individuals suggesting that a sex-blinded approach to OP may lead to miss opportunities for equity in bone health. OP-related fractures, especially hip fractures, are a matter of immediate concern as they are associated with limited mobility, chronic disability, loss of independence, and reduced quality of life in both sexes. When it comes to sociocultural gender, the effect of gender domains (i.e., identity, roles, relations, and institutionalized gender) on development and management of OP is largely overlooked despite risk factors or protective conditions are gendered. Clinical trials testing the efficacy and safety of anti-OP drugs as well as non-pharmacological interventions have been conducted mainly in female participants, limiting the generalizability of the findings. The present narrative review deals with the sex and gender-based challenges and drawbacks in OP knowledge and translation to clinical practice, also considering the impact of coronavirus disease 2019 pandemic.