Nox2 is responsible for artery dysfunction via production of reactive oxidant species. RNA viruses may activate Nox2, but it is unknown if this occurs in coronavirus 2019(Covid-19). Nox2 activation ...by soluble Nox2-derived peptide(sNox2-dp) was measured in patients hospitalized for Covid-19 (n = 182) and controls (n = 91). sNox2-dp values were higher in Covid-19 patients versus controls and in severe versus non severe Covid-19. Patients with thrombotic events(n = 35,19%) had higher sNox2-dp than thrombotic event-free ones. A logistic regression analysis showed that sNox2 and coronary heart disease predicted thrombotic events. Oxidative stress by Nox2 activation is associated severe disease and thrombotic events in Covid-19 patients.
•Nox2 is responsible for artery dysfunction via production of reactive oxidant species.•sNox2-dp values, markers of Nox2 activation, were high in Covid-19 patients and higher in those with severe disease.•A logistic regression analysis showed that sNox2 predicted thrombotic events.•Oxidative stress by Nox2 activation is associated severe disease and thrombotic events in Covid-19 patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To conduct a multireader validation study to evaluate the interobserver variability and the diagnostic accuracy for the lung involvement by COVID-19 of COVID-19 Reporting and Data System ...(CO-RADS) score.
Methods
This retrospective study included consecutive symptomatic patients who underwent chest CT and reverse transcriptase-polymerase chain reaction (RT-PCR) from March 2020 to May 2020 for suspected COVID-19. Twelve readers with different levels of expertise independently scored each CT using the CO-RADS scheme for detecting pulmonary involvement by COVID-19. Receiver operating characteristic (ROC) curves were computed to investigate diagnostic yield. Fleiss’ kappa statistics was used to evaluate interreader agreement.
Results
A total of 572 patients (mean age, 63 ± 20 standard deviation; 329 men; 142 patients with COVID-19 and 430 patients without COVID-19) were evaluated. There was a moderate agreement for CO-RADS rating among all readers (Fleiss’
K
= 0.43 95% CI 0.42–0.44) with a substantial agreement for CO-RADS 1 category (Fleiss’
K
= 0.61 95% CI 0.60–0.62) and moderate agreement for CO-RADS 5 category (Fleiss’
K
= 0.60 95% CI 0.58–0.61). ROC analysis showed the CO-RADS score ≥ 4 as the optimal threshold, with a cumulative area under the curve of 0.72 (95% CI 66–78%), sensitivity 61% (95% CI 52–69%), and specificity 81% (95% CI 77–84%).
Conclusion
CO-RADS showed high diagnostic accuracy and moderate interrater agreement across readers with different levels of expertise. Specificity is higher than previously thought and that could lead to reconsider the role of CT in this clinical setting.
Key Points
• COVID-19 Reporting and Data System (CO-RADS) demonstrated a good diagnostic accuracy for lung involvement by COVID-19 with an average AUC of 0.72 (95% CI 67
–
75%).
•
When a threshold of ≥ 4 was used, sensitivity and specificity were 61% (95% CI 52
–
69%) and 81% (95% CI 76
–
84%), respectively.
•
There was an overall moderate agreement for CO-RADS rating across readers with different levels of expertise (Fleiss’ K = 0.43 95% CI 0.42
–
0.44).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Emerging evidence argues that monocytes, circulating innate immune cells, are principal players in COVID-19 pneumonia. The study aimed to investigate the role of soluble (s)CD163 and sCD14 plasmatic ...levels in predicting disease severity and characterize peripheral blood monocytes and dendritic cells (DCs), in patients with COVID-19 pneumonia (COVID-19 subjects).
On admission, in COVID-19 subjects sCD163 and sCD14 plasmatic levels, and peripheral blood monocyte and DC subsets were compared to healthy donors (HDs). According to clinical outcome, COVID-19 subjects were divided into ARDS and non-ARDS groups.
Compared to HDs, COVID-19 subjects showed higher sCD163 (p<0.0001) and sCD14 (p<0.0001) plasmatic levels. We observed higher sCD163 plasmatic levels in the ARDS group compared to the non-ARDS one (p=0.002). The cut-off for sCD163 plasmatic level greater than 2032 ng/ml was predictive of disease severity (AUC: 0.6786, p=0.0022; sensitivity 56.7% CI: 44.1-68.4 specificity 73.8% CI: 58.9-84.7). Positive correlation between plasmatic levels of sCD163, LDH and IL-6 and between plasmatic levels of sCD14, D-dimer and ferritin were found. Compared to HDs, COVID-19 subjects showed lower percentages of non-classical (p=0.0012) and intermediate monocytes (p=0.0447), slanDCs (p<0.0001), myeloid DCs (mDCs, p<0.0001), and plasmacytoid DCs (pDCs, p=0.0014). Compared to the non-ARDS group, the ARDS group showed lower percentages of non-classical monocytes (p=0.0006), mDCs (p=0.0346), and pDCs (p=0.0492).
The increase in sCD163 and sCD14 plasmatic levels, observed on hospital admission in COVID-19 subjects, especially in those who developed ARDS, and the correlations of these monocyte/macrophage activation markers with typical inflammatory markers of COVID-19 pneumonia, underline their potential use to assess the risk of progression of the disease. In an early stage of the disease, the assessment of sCD163 plasmatic levels could have clinical utility in predicting the severity of COVID-19 pneumonia.
Abstract
Background
Previous reports highlighted the efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs) against coronavirus disease 2019.
...Methods
We conducted a prospective study on the clinical outcome and antiviral effects of mAbs added to standard of care therapy in SARS-CoV-2-infected patients with primary antibody defects.
Results
Median time of SARS-CoV-2 quantitative polymerase chain reaction (qPCR) positivity was shorter in 8 patients treated with mAbs (22 days) than in 10 patients treated with standard of care therapy only (37 days, P=.026). Median time of SARS-CoV-2 qPCR positivity from mAb administration was 10 days.
Conclusions
The SARS-CoV-2 mAbs treatment was effective and well tolerated in patients with primary antibody defects.
Anti-SARS-CoV-2 monoclonal antibodies are emerging as a potential therapeutic option for high-risk patients. Here we showed that early administration of monoclonal antibodies in patients with primary antibody defects and COVID-19 reduced the time of viral replication and avoid disease evolution.
Increased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10 (CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported in HCV infection. The aim of this study was to ...compare, sCD163 and sCD14 levels in HCV-infected patients undergoing direct acting antiviral (DAA)-containing regimens with or without interferon (IFN).
sCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma samples from 25 HCV-infected patients undergoing IFN-based treatment plus telaprevir or boceprevir and 28 HCV infected subjects treated with DAA IFN-free regimens. Twenty-five healthy donors (HD) were included as controls.
At baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected patients than in HD. CXCL10 and sCD163 levels were significantly decreased in responder (R) patients who achieved sustained virological response (SVR), with both IFN-based and IFN-free regimens, while they were persistently elevated in non-responders (NR) patients who stopped IFN-based treatments because of failure or adverse events. Conversely, sCD14 levels were apparently unchanged during therapy, but at the end of treatment the levels reached normal ranges. Comparing the two regimens, the extent of CXCL10 reduction was more pronounced in patients undergoing DAA IFN-free therapies, whereas sCD163 and sCD14 reduction was similar in the two groups. Interestingly, only in IFN-based regimens baseline sCD163 levels were significantly higher in NR than in R patients, while in the IFN-free treatment group also patients with high sCD163 plasma levels obtained SVR. At the end of therapy, even if the biomarkers were largely decreased, their levels remained significantly higher compared to HD. Only in the early fibrosis stages, sCD163 values tended to normalize.
These results indicate that IFN-free regimens including newer DAA induce an early and marked decrease in circulating inflammatory biomarkers. However, the full normalization of biomarkers was not obtained, especially in patients with advanced fibrosis, thus underlying the need for a treatment in the early stages of HCV infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The risk of developing AIDS is elevated not only among those with a late HIV diagnosis but also among those lost to care (LTC). The aims were to address the risk of becoming LTC and of clinical ...progression in LTC patients who re-enter care. Patients were defined as LTC if they had no visit for ≥ 18 months. Of these, persons with subsequent visits were defined as re-engaged in care (RIC). Factors associated with becoming LTC and RIC were investigated. The risk of disease progression was estimated by comparing RIC with patients continuously followed. Over 11,285 individuals included, 3962 became LTC, and of these, 1062 were RIC. Older age, presentation with AIDS and with higher HIV-RNA were associated with a reduced risk of LTC. In contrast, lower education level, irregular job, being an immigrant and injecting-drug user were associated with an increased LTC probability. Moreover, RIC with HIV-RNA > 200 copies/mL at the re-entry had a higher risk of clinical progression, while those with HIV-RNA ≤ 200 copies/mL had a higher risk of only non-AIDS progression. Patients re-entering care after being LTC appeared to be at higher risk of clinical progression than those continuously in care. Active strategies for re-engagement in care should be promoted.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV). Several studies have shown that HIV infection ...promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In patients with HIV, immune reconstitution after antiretroviral therapy (ART) is often incomplete. We assessed the probability of patients reaching a CD4/CD8 ratio of 1 or more after the start of ...ART and its association with the onset of non-AIDS-defining events and death.
We did an analysis of the ICONA cohort, which recruited treatment-naive patients with HIV in Italy. We included participants in the cohort who started ART, reached an undetectable viral load (≤80 copies per mL), and had a CD4/CD8 ratio of less than 0·8 at the time of an undetectable viral load. We defined ratio normalisation in patients as two consecutive values of 1 or more. We used Kaplan-Meier curves to estimate the cumulative probability of ratio normalisation. We then used Poisson regression models to identify factors independently associated with normalisation and with progression to non-AIDS-defining events or death.
We included 3236 participants, enrolled between Jan 22, 1997, and Feb 25, 2013. At the start of ART, median CD4/CD8 ratio in our population was 0·39 (IQR 0·26-0·55). 458 (14%) patients reached a CD4/CD8 ratio of 1 or more; the estimated probability of normalisation was 4·4% (95% CI 3·7-5·2) by 1 year from baseline, 11·5% (10·2-13·0) by 2 years, and 29·4% (26·7-32·4) by 5 years. Factors associated with normalisation were high pre-ART CD4 cell counts, a high CD4/CD8 ratio at baseline, and negative cytomegalovirus serological findings. The incidence rate of non-AIDS-defining events for patients with a CD4/CD8 ratio of less than 0·30 (4·2 per 100 patient-years, 95% CI 3·4-5·3) was double that for those with a ratio of 0·30-0·45 (2·3, 2·1-2·5) or more than 0·45 (2·2, 1·7-2·9). A ratio of less than 0·30 was independently associated with an increased risk of non-AIDS-defining events or death compared with one of more than 0·45.
Few patients had normalised CD4/CD8 ratios, even though they had viral suppression. Low ratios were associated with increased risk of serious events and deaths. The CD4/CD8 ratio could be used by clinicians to identity patients at risk of non-AIDS-related events.
AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, ViiV Italy.
Objective To evaluate the effectiveness of Tocilizumab (with or without corticosteroids) in a real-life context among moderate-to-severe COVID-19 patients hospitalized at the Infectious Diseases ward ...of two hospitals in Lazio region, Italy, during the first wave of SARS-CoV-2 pandemic. Method We conducted a retrospective cohort study among moderate-to-severe COVID-19 pneumonia to assess the influence of tocilizumab (with or without corticosteroids) on: 1) primary composite outcome: risk for death/invasive mechanical ventilation/ICU-transfer at 14 days from hospital admission; 2) secondary outcome: COVID-related death only. Both outcomes were also assessed at 28 days and restricted to baseline more severe cases. We also evaluated the safety of tocilizumab. Results Overall, 412 patients were recruited, being affected by mild (6.8%), moderate (66.3%) or severe (26.9%) COVID-19 at baseline. The median participant' age was 63 years, 56.5% were men, the sum of comorbidities was 1.34 (±1.44), and the median time from symptom onset to hospital admission was 7 3-10 days. Patients were subdivided in 4 treatment groups: standard of care (SoC) only (n = 172), SoC plus corticosteroid (n = 65), SoC plus tocilizumab (n = 50), SoC plus tocilizumab and corticosteroid (n = 125). Twenty-six (6.3%) patients underwent intubation, and 37 (9%) COVID-related deaths were recorded. After adjusting for several factors, multivariate analysis showed that tocilizumab (with or without corticosteroids) was associated to improved primary and secondary outcomes at 14 days, and at 28-days only when tocilizumab administered without corticosteroid. Among more severe cases the protective effect of tocilizumab (± corticosteroids) was observed at both time-points. No safety concerns were recorded. Conclusion Although contrasting results from randomized clinical trials to date, in our experience tocilizumab was a safe and efficacious therapeutic option for patients with moderate-to-severe COVID-19 pneumonia. Its efficacy was improved by the concomitant administration of corticosteroids in patients affected by severe-COVID-19 pneumonia at baseline.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigated specific humoral and T-cell responses in people living with HIV (PLWH) before (T0), after two (T1) and after six months (T2) from the third dose of the BNT162b2 vaccine. Healthy ...donors (HD) were enrolled. The specific humoral response was present in most PLWH already after the second dose, but the third dose increased both the rate of response and its magnitude. Collectively, no significant differences were found in the percentage of responding T-cells between PLWH and HD. At T0, stratifying PLWH according to CD4 cell count, a lower percentage of responding T-cells in <200 cells/µL subgroup compared to >200 cells/µL one was observed. At T1, this parameter was comparable between the two subgroups, and the same result was found at T2. However, the pattern of co-expression of IFNγ, IL2 and TNFα in PLWH was characterized by a higher expression of TNFα, independently of CD4 cell count, indicating a persistent immunological signature despite successful ART. mRNA vaccination elicited a specific response in most PLWH, although the cellular one seems qualitatively inferior compared to HD. Therefore, an understanding of the T-cell quality dynamic is needed to determine the best vaccination strategy and, in general, the capability of immune response in ART-treated PLWH.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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