We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1⁺ and FCN1⁺SPP1⁺ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48^hiS100A12⁺ and CD48⁺SPP1⁺ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4⁺ predominant in healthy lung was transcriptionally related to STM cluster TREM2⁺ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post–COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1⁺ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14⁺ monocytes and development of PD-L1⁺ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post–COVID-19 pathology.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, responsible for Coronavirus Disease 2019 (COVID-19), exhibits a spectrum of clinical manifestations, ranging from asymptomatic to severe pulmonary dysfunction or death. The variability in COVID-19 severity has largely been attributed to the host’s genetic characteristics, suggesting a polygenic genetic architecture, without significant strong evidence of sex-related genetic differences. In this Italian retrospective case–control study, we investigated the association between COVID-19 severity (severe vs. asymptomatic/oligosymptomatic healed individuals) and HLA gene variants, analyzed by next-generation sequencing (NGS). We identified significant HLA alleles (according to the conventional nomenclature), SNPs and haplotypes in the HLA-B, -C, -F, -DQA1, -DRB1, and -DRB5 genes associated with COVID-19 severity. Interestingly, these variants showed biological sex-related effects. Also, we identified specific haplotypes associated with COVID-19 severity that are shared by different conventional HLA alleles, indicated here as “super-haplotypes”. These haplotypes had a biological sex-specific impact on disease severity and markedly increased the risk of severe COVID-19 compared to the conventional HLA alleles (odds ratio of up to 15). Our data suggest that the revision of the current HLA nomenclature may help to identify variants with a stronger effect on disease susceptibility and that association studies could benefit from the stratification of patients by biological sex. If replicated in other disease models, these findings could help to define the functional diversity in immune response between sexes, also based on the HLA system. Finally, due to the global pandemic’s mortality rate, we hypothesize here that SARS-CoV-2 may have acted as a natural selection trigger, leading to a drift in HLA allelic frequencies in the general population.

Importance: Interleukin-6 signal blockade has shown preliminary beneficial effects in treating aberrant host inflammatory response against SARS-CoV-2 leading to severe respiratory distress. Objective: to describe the effect of off-label intravenous use of Sarilumab in patients with severe SARS-CoV-2-related pneumonia. Design: Observational clinical cohort study. Setting: Fondazione Policlinico Universitario A. Gemelli IRCCS as Italian Covid reference center. Participants: Patients with laboratory-confirmed SARS-CoV-2 infection and respiratory distress with PaO ₂ /FiO ₂ ratio<300 treated with Sarilumab between March 23rd − April 4th, 2020. Date of final follow-up was April 18, 2020. Main outcomes and measures: We describe the clinical outcomes of 53 patients with SARS−CoV−2 severe pneumonia treated with intravenous Sarilumab in terms of pulmonary function improvement or Intensive Care Unit (ICU) admission rate in medical wards setting and of live discharge rate in ICU treated patients as well as in terms of safety. Each patient received Sarilumab 400 mg administered intravenously on day 1, with eventual additional infusion based on clinical judgement, and was followed for at least 14 days, unless previously discharged or dead. No gluco-corticosteroids were used at baseline. Results: Of the 53 SARS−CoV−2pos patients receiving Sarilumab, 39 (73.6%) were treated in medical wards (66.7% with a single infusion) while 14 (26.4%) in ICU (92.6% with a second infusion). The median PaO ₂ /FiO ₂ of patients in the Medical Ward was 146(IQR:120−212) while the median PaO ₂ /FiO ₂ of patients in ICU was 112(IQR:100−141.5), respectively. Within the medical wards, 7(17.9%) required ICU admission, 4 of whom were re−admitted to the ward within 5-8 days. At 19 days median follow−up, 89.7% of medical inpatients significantly improved (46.1% after 24 hours, 61.5% after 3 days), 70.6% were discharged from the hospital and 85.7% no longer needed oxygen therapy. Within patients receiving Sarilumab in ICU, 64.2% were discharged from ICU to the ward and 35.8% were still alive at the last follow-up. Overall mortality rate was 5.7% after Sarilumab administration: 1(2.5%) patient died in the Medical Ward whilst 2(14.2%) patients died in ICU, respectively. Conclusions and relevance: IL6−R inhibition appears to be a potential treatment strategy for severe SARS−CoV−2 pneumonia and intravenous Sarilumab seems a promising treatment approach showing, in the short term, an important clinical benefit and good safety.

Increased rates of anxiety and depression have been reported for older adults during the COVID-19 pandemic. However, little is known regarding the onset of mental health morbidity during the acute phase of the disease and the role of age as potential independent risk factor for psychiatric symptoms. The cross-sectional association between older age and psychiatric symptoms has been estimated in a sample of 130 patients hospitalized for COVID-19 during the first and second wave of the pandemic. Compared to younger patients, those who were 70 years of age or older resulted at a higher risk of psychiatric symptoms measured on the Brief Psychiatric Symptoms Rating Scale (BPRS) (adjusted (adj.) odds ratio (OR) 2.36, 95% confidence interval (CI) 1.05–5.30) and delirium (adj. OR 5.24, 95% CI 1.63–16.8)). No association was found between older age and depressive symptoms or anxiety. Age was associated with psychiatric symptoms independently of gender, marital status, history of psychiatric illness, severity of disease and cardiovascular morbidity. Older adults appear at high risk of developing psychiatric symptoms related to COVID-19 disease during hospital stay. Multidisciplinary preventive and therapeutic interventions should be implemented to reduce the risk of psychiatric morbidity and related adverse health care outcomes among older hospital inpatients with COVID-19.

Background and Objectives: The management of HIV patients presenting with fever in the Emergency Department (ED) remains a challenging clinical scenario. Accurate risk stratification and prognostic indicators are crucial for timely intervention and improved patient outcomes. Procalcitonin (PCT) has emerged as a promising biomarker for assessing the severity and prognosis of various infectious diseases. The study aimed to evaluate the prognostic value of procalcitonin (PCT) in HIV patients admitted to the Emergency Department for clinical suspicion of infection and assess its association with in-hospital mortality. Methods: A retrospective analysis was conducted on febrile HIV-positive patients admitted to the Emergency Department. Clinical data were collected from 2018 to 2022. Patients were categorized based on PCT levels (>0.5 ng/dL), clinical findings, comorbidities, and viro-immunological status. Results: We investigated data from 289 HIV-positive patients (74% male). The median age of the sample was 54 years [IQR: 42–62], 100 (35%) patients presented detectable viremia, and the median value of CD4+ T lymphocytes was 358 [IQR: 104–531]. Elevated PCT levels (≥0.5 ng/dL) were detected in 69 (23.8%) patients. A significant association was observed between elevated PCT and increased mortality risk (p < 0.05). The mortality rate among patients with detectable HIV viremia was higher compared to those with undetectable viremia (p = 0.02). Moreover, deceased patients had statistically lower CD4+ values compared to survivors (61 [IQR: 14–186] vs. 370 [IQR: 136–548], p < 0.001). Conclusions: In febrile HIV patients admitted to the Emergency Department, elevated procalcitonin levels, low CD4+, and detectable viremia are associated with an increased risk of in-hospital mortality.

Objective. We aimed to report the real-world use and outcomes over time in immunocompromised individuals receiving tixagevimab/cilgavimab (T/C) pre-exposure prophylaxis (PrEP). Methods. This observational study included participants who received T/C PrEP, categorized into three groups: (i) No COVID-19 (NoC), i.e., participants who never had COVID-19; (ii) Hybrids (H), i.e., participants who had COVID-19 before PrEP; and (iii) Break-through Infections (BTIs), i.e., participants who had COVID-19 after PrEP. The study measured several immune markers at the administration of T/C (T0) at 3 (T1), 6 (T2), and 9 (T3) months afterward. These markers included: anti-receptor-binding domain (RBD) IgG antibodies; BA.5-neutralizing antibodies (nAbs); mucosal IgG; and T cell immunity. The incidence rate ratios for BTIs were analyzed using a Poisson regression model. Results. A total of 231 participants with a median age of 63 years (IQR 54.0–73.0). were included. Among these, 84% had hematological diseases and received a median of three vaccine doses. N = 72 participants belonged to the NoC group, N = 103 to the H group, and n = 56 to the BTI group (24%), with most BTIs being mild/moderate. The incidence rate (IR) of BTIs was 4.2 per 100 patient-months (95% CI 3.2–5.4), with no associated risk factors identified. There was a significant increase in anti-RBD IgG levels 3 months after the T/C administration in all groups, followed by a decline at 6 months, whereas at the same time points, geometric mean titers (GMTs) of anti-BA.5 nAbs were low for all groups and were around or below the detection threshold. No significant changes were observed in IFN-γ levels. The mucosal immune response was observed only 3 months after the PrEP administration. Conclusion. We provided a real-world experience model on the clinical efficacy of T/C PrEP in preventing severe COVID-19 during the Omicron wave through a comprehensive virological and immunological study. While waiting for the arrival of new monoclonal antibodies that can effectively neutralize the most recent variants, T/C PrEP remains the only viable strategy in the available armamentarium today to prevent COVID-19 complications in an extremely fragile population with suboptimal immune responses to COVID-19 vaccines.