Evolution of SARS-CoV-2 variants of concern over a period of Delta and Omicron cocirculation, among patients hospitalized for COVID-19 in an Italian reference hospital: Impact on clinical outcomes.

Despite the higher transmissibility of Omicron Variant of Concern (VOC), several reports have suggested lower risk for hospitalization and severe outcomes compared to previous variants of SARS-CoV-2. This study, enrolling all COVID-19 adults admitted to a reference hospital who underwent both the S-gene-target-failure test and VOC identification by Sanger sequencing, aimed to describe the evolving prevalence of Delta and Omicron variants and to compare the main in-hospital outcomes of severity, during a trimester (December 2021 to March 2022) of VOCs' cocirculation. Factors associated with clinical progression to noninvasive ventilation (NIV)/mechanical ventilation (MV)/death within 10 days and to MV/admission to intensive care unit (ICU)/death within 28 days, were investigated through multivariable logistic regressions. Overall, VOCs were: Delta n = 130/428, Omicron n = 298/428 (sublineages BA.1 n = 275 and BA.2 n = 23). Until mid-February, Delta predominance shifted to BA.1, which was gradually displaced by BA.2 until mid-March. Participants with Omicron VOC were more likely to be older, fully vaccinated, with multiple comorbidities and to have a shorter time from symptoms' onset, and less likely to have systemic symptoms and respiratory complications. Although the need of NIV within 10 days and MV within 28 days from hospitalization and the admission to ICU were less frequent for patients with Omicron compared to those with Delta infections, mortality was similar between the two VOCs. In the adjusted analysis, multiple comorbidities and a longer time from symptoms' onset predicted 10-day clinical progression, while complete vaccination halved the risk. Multimorbidity was the only risk factor associated with 28-day clinical progression. In our population, in the first trimester of 2022, Omicron rapidly displaced Delta in COVID-19 hospitalized adults. Clinical profile and presentation differed between the two VOCs and, although Omicron infections showed a less severe clinical picture, no substantial differences for clinical progression were found. This finding suggests that any hospitalization, especially in more vulnerable individuals, may be at risk for severe progression, which is more related to the underlying frailty of patients than to the intrinsic severity of the viral variant.

Evaluation of the immunomodulatory effects of interleukin-10 on peripheral blood immune cells of COVID-19 patients: Implication for COVID-19 therapy.

Objective: Several therapies with immune-modulatory functions have been proposed to reduce the overwhelmed inflammation associated with COVID-19. Here we investigated the impact of IL-10 in COVID-19, through the ex-vivo assessment of the effects of exogenous IL-10 on SARS-CoV-2-specific-response using a whole-blood platform. Methods: Two cohorts were evaluated: in "study population A", plasma levels of 27 immune factors were measured by a multiplex (Luminex) assay in 39 hospitalized "COVID-19 patients" and 29 "NO COVID-19 controls" all unvaccinated. In "study population B", 29 COVID-19 patients and 30 NO COVID-19-Vaccinated Controls (NO COVID-19-VCs) were prospectively enrolled for the IL-10 study. Whole-blood was stimulated overnight with SARS-COV-2 antigens and then treated with IL-10. Plasma was collected and used for ELISA and multiplex assay. In parallel, whole-blood was stimulated and used for flow cytometry analysis. Results: Baseline levels of several immune factors, including IL-10, were significantly elevated in COVID-19 patients compared with NO COVID-19 subjects in "study population A". Among them, IL-2, FGF, IFN-γ, and MCP-1 reached their highest levels within the second week of infection and then decreased. To note that, MCP-1 levels remained significantly elevated compared with controls. IL-10, GM-CSF, and IL-6 increased later and showed an increasing trend over time. Moreover, exogenous addition of IL-10 significantly downregulated IFN-γ response and several other immune factors in both COVID-19 patients and NO COVID-19-VCs evaluated by ELISA and a multiplex analysis (Luminex) in "study population B". Importantly, IL-10 did not affect cell survival, but decreased the frequencies of T-cells producing IFN-γ, TNF-α, and IL-2 (p<0.05) and down-modulated HLA-DR expression on CD8+ and NK cells. Conclusion: This study provides important insights into immune modulating effects of IL-10 in COVID-19 and may provide valuable information regarding the further in vivo investigations.

Recovery from Triple Infection with SARS-CoV-2, RSV and Influenza virus: A case report.

The overall probability of infection with RSV, influenza virus, or SARS-CoV-2 in the general population is assessed as high by the ECDC. A high level of respiratory virus circulation increases hospitalizations and places significant pressure on healthcare systems. Here we describe the case of a 52-year-old woman who recovered from pneumonia with a triple infection with SARS-CoV-2, RSV, and Influenza virus. We suggest searching for antigenic or molecular detection of VSR and influenza viruses, together with SARS-CoV-2, in patients with respiratory symptoms during this epidemic period, whereas all three viruses are present right now.

Characterization of the immune impairment of patients with tuberculosis and COVID-19 coinfection.

OBJECTIVES: To characterize the plasma immune profile of patients with tuberculosis (TB)-COVID-19 compared with COVID-19, TB, or healthy controls and to evaluate in vitro the specific responses to SARS-CoV-2 and Mycobacterium tuberculosis (Mtb)-antigens. METHODS: We enrolled 119 subjects: 14 TB-COVID-19, 47 COVID-19, 38 TB, and 20 controls. The plasmatic levels of 27 immune factors were measured at baseline using a multiplex assay. The specific response to SARS-CoV-2 and Mtb antigens was evaluated using a home-made whole blood platform and QuantiFERON-Plus tubes, respectively. RESULTS: We found an immune signature (tumor necrosis factor [TNF]-α, macrophage inflammatory protein-1ß, and interleukin [IL]-9) associated with TB-COVID-19 coinfection compared with COVID-19 (P <0.05), and TNF-α showed the highest discriminant power. We also found another signature (TNF-α, IL-1ß, IL-17A, IL-5, fibroblast growth factor-basic, and granulocyte macrophage colony-stimulating factor [GM-CSF]) in coinfected patients compared with patients with TB (P <0.05), and among them, TNF-α and granulocyte macrophage colony-stimulating factor showed a non-negligible discriminating ability. Moreover, coinfected patients showed a significantly reduced SARS-CoV-2-specific response compared with COVID-19 for several pro-inflammatory cytokines/chemokines, anti-inflammatory cytokines, and growth factors (P ≤0.05). Furthermore, coinfection negatively affected the Mtb-specific response (P ≤0.05). CONCLUSION: We found immune signatures associated with TB-COVID-19 coinfection and observed a major impairment of SARS-CoV-2-specific and, to a lesser extent, the Mtb-specific immune responses. These findings further advance our knowledge of the immunopathology of TB-COVID-19 coinfection.

Sarilumab plus standard of care vs standard of care for the treatment of severe COVID-19: a phase 3, randomized, open-labeled, multi-center study (ESCAPE study).

Background: Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19. Methods: In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Findings: Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.07 [0.8-1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p = 0.049) and in the strata with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7]; log-rank p = 0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p = 0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p = 0.244). There were no treatment-related deaths. Interpretation: The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results. Funding: This study was supported by INMI "Lazzaro Spallanzani" Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.

Coordinated innate and T-cell immune responses in mild COVID-19 patients from household contacts of COVID-19 cases during the first pandemic wave.

Objective: To better define the immunopathogenesis of COVID-19, the present study aims to characterize the early immune responses to SARS-CoV-2 infection in household contacts of COVID-19 cases. In particular, innate, T- and B-cell specific responses were evaluated over time. Methods: Household contacts of COVID-19 cases screened for SARS-CoV-2 infection by nasopharyngeal swab for surveillance purposes were enrolled (T0, n=42). Of these, 28 subjects returned for a follow-up test (T1). The innate response was assessed by detecting a panel of soluble factors by multiplex-technology in plasma samples. Cell-mediated response was evaluated by measuring interferon (IFN)-γ levels by ELISA in plasma harvested from whole-blood stimulated with SARS-CoV-2 peptide pools, including spike (S), nucleocapsid (N) and membrane (M) proteins. The serological response was assessed by quantifying anti-Receptor-Binding-Domain (RBD), anti-Nucleocapsid (N), whole virus indirect immunofluorescence, and neutralizing antibodies. Results: At T0, higher levels of plasmatic IFN-α, IL-1ra, MCP-1 and IP-10, and lower levels of IL-1ß, IL-9, MIP-1ß and RANTES were observed in subjects with positive swab compared to individuals with a negative one (p<0.05). Plasmatic IFN-α was the only cytokine detectable in subjects with positive SARS-CoV-2 swabs with high accuracy for swab score positivity (0.93, p<0.0001). Among subjects with positive swabs, significant negative correlations were found among the RT-PCR cycle threshold values reported for genes S and N and IFN-α or IP-10 levels. At T0, the IFN-γ T-cell specific response was detected in 50% (5/10) of subjects with positive swab, while anti-RBD/anti-N antibodies showed a positivity rate of 10% (1/10). At T1, the IFN-γ T-cell specific response was detected in most of the confirmed-infection subjects (77.8%, 7/9), whereas the serological response was still observed in a minority of them (44.4%, 4/9). Overall, the swab test showed a moderate concordance with the T-cell response (78.6%, k=0.467), and a scarce concordance with the serological one (72.9%, k=0.194). Conclusions: Plasmatic IFN-α and the IFN-γ T-cell specific response appear early even in the absence of seroconversion, and show a greater positivity rate than the serological response in household contacts with positive swab.

Proteomic analysis identifies a signature of disease severity in the plasma of COVID-19 pneumonia patients associated to neutrophil, platelet and complement activation.

Most patients infected with SARS-CoV-2 display mild symptoms with good prognosis, while 20% of patients suffer from severe viral pneumonia and up to 5% may require intensive care unit (ICU) admission due to severe acute respiratory syndrome, which could be accompanied by multiorgan failure.Plasma proteomics provide valuable and unbiased information about disease progression and therapeutic candidates. Recent proteomic studies have identified molecular changes in plasma of COVID-19 patients that implied significant dysregulation of several aspects of the inflammatory response accompanied by a general metabolic suppression. However, which of these plasma alterations are associated with disease severity remains only partly characterized.A known limitation of proteomic studies of plasma samples is the large difference in the macromolecule abundance, with concentration spanning at least 10 orders of magnitude. To improve the coverage of plasma contents, we performed a deep proteomic analysis of plasma from 10 COVID-19 patients with severe/fatal pneumonia compared to 10 COVID-19 patients with pneumonia who did not require ICU admission (non-ICU). To this aim, plasma samples were first depleted of the most abundant proteins, trypsin digested and peptides subjected to a high pH reversed-phase peptide fractionation before LC-MS analysis.These results highlighted an increase of proteins involved in neutrophil and platelet activity and acute phase response, which is significantly higher in severe/fatal COVID-19 patients when compared to non-ICU ones. Importantly, these changes are associated with a selective induction of complement cascade factors in severe/fatal COVID-19 patients. Data are available via ProteomeXchange with identifier PXD036491. Among these alterations, we confirmed by ELISA that higher levels of the neutrophil granule proteins DEFA3 and LCN2 are present in COVID-19 patients requiring ICU admission when compared to non-ICU and healthy donors.Altogether, our study provided an in-depth view of plasma proteome changes that occur in COVID-19 patients in relation to disease severity, which can be helpful to identify therapeutic strategies to improve the disease outcome.

Evaluation of the immunomodulatory effects of interleukin-10 on peripheral blood immune cells of COVID-19 patients: Implication for COVID-19 therapy

Objective Several therapies with immune-modulatory functions have been proposed to reduce the overwhelmed inflammation associated with COVID-19. Here we investigated the impact of IL-10 in COVID-19, through the ex-vivo assessment of the effects of exogenous IL-10 on SARS-CoV-2-specific-response using a whole-blood platform. Methods Two cohorts were evaluated: in “study population A”, plasma levels of 27 immune factors were measured by a multiplex (Luminex) assay in 39 hospitalized “COVID-19 patients” and 29 “NO COVID-19 controls” all unvaccinated. In “study population B”, 29 COVID-19 patients and 30 NO COVID-19-Vaccinated Controls (NO COVID-19-VCs) were prospectively enrolled for the IL-10 study. Whole-blood was stimulated overnight with SARS-COV-2 antigens and then treated with IL-10. Plasma was collected and used for ELISA and multiplex assay. In parallel, whole-blood was stimulated and used for flow cytometry analysis. Results Baseline levels of several immune factors, including IL-10, were significantly elevated in COVID-19 patients compared with NO COVID-19 subjects in “study population A”. Among them, IL-2, FGF, IFN-γ, and MCP-1 reached their highest levels within the second week of infection and then decreased. To note that, MCP-1 levels remained significantly elevated compared with controls. IL-10, GM-CSF, and IL-6 increased later and showed an increasing trend over time. Moreover, exogenous addition of IL-10 significantly downregulated IFN-γ response and several other immune factors in both COVID-19 patients and NO COVID-19-VCs evaluated by ELISA and a multiplex analysis (Luminex) in “study population B”. Importantly, IL-10 did not affect cell survival, but decreased the frequencies of T-cells producing IFN-γ, TNF-α, and IL-2 (p<0.05) and down-modulated HLA-DR expression on CD8+ and NK cells. Conclusion This study provides important insights into immune modulating effects of IL-10 in COVID-19 and may provide valuable information regarding the further in vivo investigations.

Accuracy of QuantiFERON SARS-CoV-2 research use only assay and characterization of the CD4+ and CD8+ T cell-SARS-CoV-2 response: comparison with a homemade interferon-γ release assay.

OBJECTIVES: In this study, we aimed to characterize the SARS-CoV-2-specific T cell response detected by the QuantiFERON SARS-CoV-2 research use only assay in terms of accuracy and T cell subsets involved compared with a homemade interferon (IFN)-γ release assay (IGRA). METHODS: We evaluated T cell response by the standardized QuantiFERON SARS-CoV-2 tubes (antigen [Ag]1 and Ag2) and a homemade IGRA quantifying IFN-γ response to SARS-CoV-2 spike peptides (homemade-IGRA-SPIKE test). We evaluated the T cell subsets mediating the specific response using flow cytometry. RESULTS: We prospectively enrolled 66 individuals: COVID-19 or post-COVID-19 subjects and NO-COVID-19-vaccinated subjects, including healthy donors and immunocompromised subjects. The standardized kit detected 62.1% (41/66) of T cell responders. Ag2 tube showed a higher IFN-γ quantitative and qualitative response. Ag1 tube response was mainly mediated by CD4+ T cells; Ag2 tube response was mediated by CD4+ and CD8+ T cells. The homemade-IGRA-SPIKE test detected a higher number of responders (52/66, 78.8%) than the QuantiFERON SARS-CoV-2 assay (P = 0.056). The response was found in both T cell subsets, although a higher magnitude and response rate was observed in the CD4+ T cell subset. CONCLUSION: The QuantiFERON SARS-CoV-2 response is mediated by CD4+ and CD8+ T cells. A lower number of responders is found compared with the homemade-IGRA-SPIKE test, likely because of the different peptide composition.

Epidemiology of ventilator-associated pneumonia in ICU COVID-19 patients: an alarming high rate of multidrug-resistant bacteria

Background COVID‑19 is a novel cause of acute respiratory distress syndrome (ARDS) that leads patients to intensive care unit (ICU) admission requiring invasive ventilation, who consequently are at risk of developing of ventilator‑associated pneumonia (VAP). The aim of this study was to assess the incidence, antimicrobial resistance, risk factors, and outcome of VAP in ICU COVID-19 patients in invasive mechanical ventilation (MV). Methods Observational prospective study including adult ICU admissions between January 1, 2021, and June 31, 2021, with confirmed COVID-19 diagnosis were recorded daily, including demographics, medical history, ICU clinical data, etiology of VAPs, and the outcome. The diagnosis of VAP was based on multi-criteria decision analysis which included a combination of radiological, clinical, and microbiological criteria in ICU patients in MV for at least 48 h. Results Two hundred eighty-four COVID-19 patients in MV were admitted in ICU. Ninety-four patients (33%) had VAP during the ICU stay, of which 85 had a single episode of VAP and 9 multiple episodes. The median time of onset of VAP from intubation were 8 days (IQR, 5–13). The overall incidence of VAP was of 13.48 episodes per 1000 days in MV. The main etiological agent was Pseudomonas aeruginosa (39.8% of all VAPs) followed by Klebsiella spp. (16.5%);of them, 41.4% and 17.6% were carbapenem resistant, respectively. Patients during the mechanical ventilation in orotracheal intubation (OTI) had a higher incidence than those in tracheostomy, 16.46 and 9.8 episodes per 1000-MV day, respectively. An increased risk of VAP was reported in patients receiving blood transfusion (OR 2.13, 95% CI 1.26–3.59, p = 0.005) or therapy with Tocilizumab/Sarilumab (OR 2.08, 95% CI 1.12–3.84, p = 0.02). The pronation and PaO2/FiO2 ratio at ICU admission were not significantly associated with the development of VAPs. Furthermore, VAP episodes did not increase the risk of death in ICU COVID-19 patients. Conclusions COVID-19 patients have a higher incidence of VAP compared to the general ICU population, but it is similar to that of ICU ARDS patients in the pre-COVID-19 period. Interleukin-6 inhibitors and blood transfusions may increase the risk of VAP. The widespread use of empirical antibiotics in these patients should be avoided to reduce the selecting pressure on the growth of multidrug-resistant bacteria by implementing infection control measures and antimicrobial stewardship programs even before ICU admission. Supplementary Information The online version contains supplementary material available at 10.1186/s44158-022-00065-4.

Coordinated innate and T-cell immune responses in mild COVID-19 patients from household contacts of COVID-19 cases during the first pandemic wave

Objective To better define the immunopathogenesis of COVID-19, the present study aims to characterize the early immune responses to SARS-CoV-2 infection in household contacts of COVID-19 cases. In particular, innate, T- and B-cell specific responses were evaluated over time. Methods Household contacts of COVID-19 cases screened for SARS−CoV−2 infection by nasopharyngeal swab for surveillance purposes were enrolled (T0, n=42). Of these, 28 subjects returned for a follow-up test (T1). The innate response was assessed by detecting a panel of soluble factors by multiplex-technology in plasma samples. Cell-mediated response was evaluated by measuring interferon (IFN)-γ levels by ELISA in plasma harvested from whole-blood stimulated with SARS−CoV−2 peptide pools, including spike (S), nucleocapsid (N) and membrane (M) proteins. The serological response was assessed by quantifying anti-Receptor-Binding-Domain (RBD), anti-Nucleocapsid (N), whole virus indirect immunofluorescence, and neutralizing antibodies. Results At T0, higher levels of plasmatic IFN-α, IL-1ra, MCP-1 and IP-10, and lower levels of IL-1β, IL-9, MIP-1β and RANTES were observed in subjects with positive swab compared to individuals with a negative one (p<0.05). Plasmatic IFN-α was the only cytokine detectable in subjects with positive SARS-CoV-2 swabs with high accuracy for swab score positivity (0.93, p<0.0001). Among subjects with positive swabs, significant negative correlations were found among the RT-PCR cycle threshold values reported for genes S and N and IFN-α or IP-10 levels. At T0, the IFN-γ T-cell specific response was detected in 50% (5/10) of subjects with positive swab, while anti-RBD/anti-N antibodies showed a positivity rate of 10% (1/10). At T1, the IFN-γ T-cell specific response was detected in most of the confirmed-infection subjects (77.8%, 7/9), whereas the serological response was still observed in a minority of them (44.4%, 4/9). Overall, the swab test showed a moderate concordance with the T-cell response (78.6%, k=0.467), and a scarce concordance with the serological one (72.9%, k=0.194). Conclusions Plasmatic IFN-α and the IFN-γ T-cell specific response appear early even in the absence of seroconversion, and show a greater positivity rate than the serological response in household contacts with positive swab.

Timing and Outcomes of Noninvasive Ventilation in 307 ARDS COVID-19 Patients: An Observational Study in an Italian Third Level COVID-19 Hospital.

Background and Objectives: Background: Coronavirus disease 2019 (COVID-19) is a novel cause of Acute Respiratory Distress Syndrome (ARDS). Noninvasive ventilation (NIV) is widely used in patients with ARDS across several etiologies. Indeed, with the increase of ARDS cases due to the COVID-19 pandemic, its use has grown significantly in hospital wards. However, there is a lack of evidence to support the efficacy of NIV in patients with COVID-19 ARDS. Materials and Methods: We conducted an observational cohort study including adult ARDS COVID-19 patients admitted in a third level COVID-center in Rome, Italy. The study analyzed the rate of NIV failure defined by the occurrence of orotracheal intubation and/or death within 28 days from starting NIV, its effectiveness, and the associated relative risk of death. The factors associated with the outcomes were identified through logistic regression analysis. Results: During the study period, a total of 942 COVID-19 patients were admitted to our hospital, of which 307 (32.5%) presented with ARDS at hospitalization. During hospitalization 224 (23.8%) were treated with NIV. NIV failure occurred in 84 (37.5%) patients. At 28 days from starting NIV, moderate and severe ARDS had five-fold and twenty-fold independent increased risk of NIV failure (adjusted odds ratio, aOR = 5.01, 95% CI 2.08-12.09, and 19.95, 95% CI 5.31-74.94), respectively, compared to patients with mild ARDS. A total of 128 patients (13.5%) were admitted to the Intensive Care Unit (ICU). At 28-day from ICU admission, intubated COVID-19 patients treated with early NIV had 40% lower mortality (aOR 0.60, 95% CI 0.25-1.46, p = 0.010) compared with patients that underwent orotracheal intubation without prior NIV. Conclusions: These findings show that NIV failure was independently correlated with the severity category of COVID-19 ARDS. The start of NIV in COVID-19 patients with mild ARDS (P/F > 200 mmHg) appears to increase NIV effectiveness and reduce the risk of orotracheal intubation and/or death. Moreover, early NIV (P/F > 200 mmHg) treatment seems to reduce the risk of ICU mortality at 28 days from ICU admission.

Antibiotics and Infectious Respiratory Diseases.

Respiratory infectious diseases (rIDs) remain among the most significant causes of morbidity and mortality worldwide, and, in the era of COVID-19, they have come into major focus in the scientific world and global health approaches [...].

Humoral and Cellular Response to Spike of Delta SARS-CoV-2 Variant in Vaccinated Patients With Multiple Sclerosis.

Objectives: We assessed vaccination-induced antibody and cellular response against spike from the ancestral strain and from the Delta Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) variant in patients with Multiple Sclerosis (MS) treated with disease modifying treatments. Methods: We enrolled 47 patients with MS and nine controls ("no MS") having completed the vaccination schedule within 4-6 months from the first dose. The Interferon (IFN)-γ-response to spike peptides derived from the ancestral and the Delta SARS-CoV-2 was measured by enzyme-linked immunoassay (ELISA). Anti-Receptor Binding Domain (RBD) IgG were also evaluated. Results: No significant differences were found comparing the IFN-γ-specific immune response between MS and "no MS" subjects to the ancestral (P = 0.62) or Delta peptide pools (P = 0.68). Nevertheless, a reduced IFN-γ-specific response to the ancestral or to the Delta pools was observed in subjects taking fingolimod or cladribine compared to subjects treated with ocrelizumab or IFN-ß. The antibody response was significantly reduced in patients with MS compared to "no MS" subjects (P = 0.0452) mainly in patients taking ocrelizumab or fingolimod. Conclusions: Cellular responses to Delta SARS-CoV-2 variant remain largely intact in patients with MS. However, the magnitude of these responses depends on the specific therapy.

Epidemiology, Clinical Presentation and Treatment of Non-Hepatic Hyperammonemia in ICU COVID-19 Patients.

(1) Background: Although COVID-19 is largely a respiratory disease, it is actually a systemic disease that has a wide range of effects that are not yet fully known. The aim of this study was to determine the incidence, predictors and outcome of non-hepatic hyperammonemia (NHH) in COVID-19 in intensive care unit (ICU); (2) Methods: This is a 3-month prospective observational study in a third-level COVID-19 hospital. The authors collected demographic, clinical, severity score and outcome data. Logistic regression analyses were performed to identify predictors of NHH; (3) Results: 156 COVID-19 patients were admitted to the ICU. The incidence of NHH was 12.2% (19 patients). The univariate analysis showed that invasive mechanical ventilation had a 6.6-fold higher risk (OR 6.66, 95% CI 0.86-51.6, p = 0.039) for NHH, while in the multiple regression analysis, there was a 7-fold higher risk for NHH-but it was not statistically significant (OR 7.1, 95% CI 0.90-56.4, p = 0.062). Demographics, clinical characteristics and mortality in the ICU at 28 days did not show a significant association with NHH. (4) Conclusions: The incidence of NHH in ICU COVID-19 patients was not low. NHH did not appear to significantly increase mortality, and all patients with non-hepatic hyperammonemia were successfully treated without further complications. However, the pathogenesis of NHH in ICU patients with COVID-19 remains a topic to be explored with further research.

Characteristics and Outcomes of COVID-19-Related Hospitalization among PLWH.

BACKGROUND: There is conflicting evidence for how HIV influences COVID-19 infection. The aim of this study was to compare characteristics at presentation and the clinical outcomes of people living with HIV (PLWH) versus HIV-negative patients (non-PLWH) hospitalized with COVID-19. METHODS: Primary endpoint: time until invasive ventilation/death. Secondary endpoints: time until ventilation/death, time until symptoms resolution. RESULTS: A total of 1647 hospitalized patients were included (43 (2.6%) PLWH, 1604 non-PLWH). PLWH were younger (55 vs. 61 years) and less likely to be with PaO2/FiO2 < 300 mmHg compared with non-PLWH. Among PLWH, nadir of CD4 was 185 (75-322) cells/µL; CD4 at COVID-19 diagnosis was 272 cells/µL (127-468) and 77% of these were virologically suppressed. The cumulative probability of invasive mechanical ventilation/death at day 15 was 4.7% (95%CI 1.2-17.3) in PLWH versus 18.9% (16.9-21.1) in non-PLWH (p = 0.023). The cumulative probability of non-invasive/invasive ventilation/death at day 15 was 20.9% (11.5-36.4) in PLWH versus 37.6% (35.1-40.2) in non-PLWH (p = 0.044). The adjusted hazard ratio (aHR) of invasive mechanical ventilation/death of PLWH was 0.49 (95% CI 0.12-1.96, p = 0.310) versus non-PLWH; similarly, aHR of non-invasive/invasive ventilation/death of PLWH was 1.03 (95% CI 0.53-2.00, p = 0.926). CONCLUSION: A less-severe presentation of COVID-19 at hospitalization was observed in PLWH compared to non-PLWH; no difference in clinical outcomes could be detected.

Increased Association of Pulmonary Thromboembolism and Tuberculosis during COVID-19 Pandemic: Data from an Italian Infectious Disease Referral Hospital.

Pulmonary thromboembolism (PTE) has been associated with tuberculosis (TB), but the true incidence is unknown. The aim of our study was to retrospectively evaluate the PTE prevalence in TB patients hospitalized at the National Institute for Infectious Diseases L. Spallanzani during the January 2016-December 2021 period. Retrospective data collection and evaluation were conducted. Among 1801 TB patients, 29 (1.61%) exhibited PTE. Twenty (69%) had comorbidities; eleven (37.9%) had predisposing factors for PTE. Nineteen (65.5%) had extensive TB disease. The commonest respiratory symptoms were cough (37.9%), dyspnea (31%), chest pain (10.3%), and hemoptysis (6.9%). Twenty-five (86.2%) had elevated serum D-dimer levels. An increased prevalence of PTE from 0.6% in the pre-COVID-19 pandemic period to 4.6% in the pandemic period was found. Acute respiratory failure and extensive TB disease increased significantly in the pandemic period. The increase in PTE could be explained by the increased severity of TB in patients in the pandemic period and by increased clinical suspicion and, consequently, increased requests for D-dimer testing, including in patients with non-COVID-19 pneumonia. Patients with extensive pulmonary disease are at high risk of developing PTE. Clinicians should be aware of this potentially life-threatening complication of TB, and patients should receive a thromboembolism risk assessment.

Coinfection of tuberculosis and COVID-19 limits the ability to in vitro respond to SARS-CoV-2.

OBJECTIVES: The interaction of COVID-19 and tuberculosis (TB) are still poor characterized. Here we evaluated the immune response specific for Micobacterium tuberculosis (Mtb) and SARS-CoV-2 using a whole-blood-based assay-platform in COVID-19 patients either with TB or latent TB infection (LTBI). METHODS: We evaluated IFN-γ level in plasma from whole-blood stimulated with Mtb antigens in the Quantiferon-Plus format or with peptides derived from SARS-CoV-2 spike protein, Wuhan-Hu-1 isolate (CD4-S). RESULTS: We consecutively enrolled 63 COVID-19, 10 TB-COVID-19 and 11 LTBI-COVID-19 patients. IFN-γ response to Mtb-antigens was significantly associated to TB status and therefore it was higher in TB-COVID-19 and LTBI-COVID-19 patients compared to COVID-19 patients (p ≤ 0.0007). Positive responses against CD4-S were found in 35/63 COVID-19 patients, 7/11 LTBI-COVID-19 and only 2/10 TB-COVID-19 patients. Interestingly, the responders in the TB-COVID-19 group were less compared to COVID-19 and LTBI-COVID-19 groups (p = 0.037 and 0.044, respectively). Moreover, TB-COVID-19 patients showed the lowest quantitative IFN-γ response to CD4-S compared to COVID-19-patients (p = 0.0336) and LTBI-COVID-19 patients (p = 0.0178). CONCLUSIONS: Our data demonstrate that COVID-19 patients either TB or LTBI have a low ability to build an immune response to SARS-CoV-2 while retaining the ability to respond to Mtb-specific antigens.

Incidence of Pneumothorax and Pneumomediastinum in 497 COVID-19 Patients with Moderate-Severe ARDS over a Year of the Pandemic: An Observational Study in an Italian Third Level COVID-19 Hospital.

(1) Background: COVID-19 is a novel cause of acute respiratory distress syndrome (ARDS). Indeed, with the increase of ARDS cases due to the COVID-19 pandemic, there has also been an increase in the incidence of cases with pneumothorax (PNX) and pneumomediastinum (PNM). However, the incidence and the predictors of PNX/PMN in these patients are currently unclear and even conflicting. (2) Methods: The present observational study analyzed the incidence of barotrauma (PNX/PNM) in COVID-19 patients with moderate-severe ARDS hospitalized in a year of the pandemic, also focusing on the three waves occurring during the year, and treated with positive-pressure ventilation (PPV). We collected demographic and clinical data. (3) Results: During this period, 40 patients developed PNX/PNM. The overall incidence of barotrauma in all COVID-19 patients hospitalized in a year was 1.6%, and in those with moderate-severe ARDS in PPV was 7.2% and 3.8 events per 1000 positive-pressure ventilator days. The incidence of barotrauma in moderate-severe ARDS COVID-19 patients during the three waves was 7.8%, 7.4%, and 8.7%, respectively. Treatment with noninvasive respiratory support alone was associated with an incidence of barotrauma of 9.1% and 2.6 events per 1000 noninvasive ventilator days, of which 95% were admitted to the ICU after the event, due to a worsening of respiratory parameters. The incidence of barotrauma of ICU COVID-19 patients in invasive ventilation over a year was 5.8% and 2.7 events per 1000 invasive ventilator days. There was no significant difference in demographics and clinical features between the barotrauma and non-barotrauma group. The mortality was higher in the barotrauma group (17 patients died, 47.2%) than in the non-barotrauma group (170 patients died, 37%), although this difference was not statistically significant (p = 0.429). (4) Conclusions: The incidence of PNX/PNM in moderate-severe ARDS COVID-19 patients did not differ significantly between the three waves over a year, and does not appear to be very different from that in ARDS patients in the pre-COVID era. The barotrauma does not appear to significantly increase mortality in COVID-19 patients with moderate-severe ARDS if protective ventilation strategies are applied. Attention should be paid to the risk of barotrauma in COVID-19 patients in noninvasive ventilation because the event increases the probability of admission to the intensive care unit (ICU) and intubation.