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Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.

Background The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery. Methods In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery. Results Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2–5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1–0.7) or in OT (HR = 0.1, 95% CI = 0.0–0.8) treated with tocilizumab. Conclusion To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.

This Mini Review of the literature aimed to assess the role of tocilizumab for the treatment of severe coronavirus disease 2019 (COVID-19). Based on the available scientific evidence, it is not clear to date what is the best therapeutic strategy for the treatment of COVID-19. Since SARS-CoV-2 infection stimulates a vigorous proinflammatory response and may cause the so-called “cytokine storm”, immunomodulator drugs have been investigated as potential treatment for severe COVID-19 pneumonia. Among immunomodulators, tocilizumab, a recombinant humanized monoclonal antibody directed against IL-6 receptor, seems to be promising. An increasing number of clinical trials are exploring the role of tocilizumab in COVID-19, focusing on outcomes like mortality, risk of intensive care unit admission and the need for mechanical ventilation. At the moment, there is no conclusive evidence that tocilizumab would be proper outright in all patients with COVID-19 pneumonia, but some studies suggest that its use may be beneficial in selected categories of patients., Highlights • SARS-CoV-2 infection stimulates a proinflammatory response called cytokine storm. • Immunomodulatory drugs like Tocilizumab are under investigation for use in COVID-19. • Tocilizumab is likely to maximize its positive effects in selected patients.

The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p > .05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c, p = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.

Aims The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia. Methods This was an observational prospective study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients’ medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO2/FiO2 ratio Results A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth “boosted mixed model” included 20 variables was selected from the model 3, achieved the best predictive performance (AUC = 0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example. Conclusion This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.

The expression and activity of main inflammasome components in monocytes from successfully treated human immunodeficiency virus (HIV)-positive patients are poorly studied. Thus, we enrolled 18 patients with a low and 17 with a normal ratio of CD4+ T cells to CD8+ T cells and 11 healthy donors. We found that patients with a low ratio had decreased CCR2 expression among classical and intermediate monocytes and increased CCR5 expression among classical monocytes, compared with patients with a normal ratio. Patients with a low ratio also had higher NAIP and PYCARD messenger RNA levels after lipopolysaccharide stimulation, suggesting an altered ability to control immune activation that could affect their immune reconstitution.

Background Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

Introduction: Aim of the study is to evaluate the prevalence of HBV, HIV, HCV, tuberculosis and syphilis infection among immigrants assigned to the immigrant centre of the province of Modena. Methods: At the time of arrival all immigrant were tested for: HBsAg, HBsAb, HBcAb, Ag p24/HIVAb, HCVAb, RPR, TPPA, Mantoux test (>10 mm diameter of induration was considered to be positive), Chest X-rays. In case of positive samples, second level tests were performed (HbeAg, HBeAb, HDVAb, and baseline management and treatment of the infection detected). Results: A total of 304 immigrant people were enrolled in the study. HBsAg positivity was 12.2%, HCVAb 3.3%, HIVAb 1.6%, TPPA + RPR positivity in the 0.7%; 10.2% had a positive Mantoux test; 5.6% had Chest X-rays positive for signs of infection and 6 patients had an active tuberculosis. 83.8% HBsAg were HBeAb positive/HBeAg negative. HDVAb resulted positive in 1 patient (2.7%). Previous HBV infection was detected in 28.6% of cases, isolated HBcAb in 2.3%; 5.6% of patients resulted to be positive to HbsAb alone (probable vaccinated). Conclusion: Our study confirms the high prevalence of HBsAg positivity and latent tuberculosis among immigrants, underlying the importance of screening for infections in this special population. Keywords: Immigrant population, Sexually transmitted infections, Tuberculosis, Screening

Combined antiretroviral therapy (cART) blocks different steps of HIV replication and maintains plasma viral RNA at undetectable levels. The virus can remain in long-living cells and create a reservoir where HIV can restart replicating after cART discontinuation. A persistent viral production triggers and maintains a persistent immune activation, which is a well-known feature of chronic HIV infection, and contributes either to precocious aging, or to the increased incidence of morbidity and mortality of HIV positive patients. The new frontier of the treatment of HIV infection is nowadays eradication of the virus from all host cells and tissues. For this reason, it is crucial to have a clear and precise idea of where the virus hides, and which are the cells that keep it silent. Important efforts have been made to improve the detection of viral reservoirs, and new techniques are now giving the opportunity to characterize viral reservoirs. Among these techniques, a strategic approach based upon cell sorting and droplet digital PCR (ddPCR) is opening new horizons and opportunities of research. This review provides an overview of the methods that combine cell sorting and ddPCR for the quantification of HIV DNA in different cell types, and for the detection of its maintenance.

Background Little is known about the applicability of dual treatments based on integrase inhibitors. We explored the combination of lamivudine + dolutegravir as an option when switching from standard cART in virologically suppressed patients. Methods In this prospective cohort we enrolled patients previously switched to 3TC + DTG who were 18 years or older, with no previous resistance mutations to the used drugs, having a HIV-RNA 6 months) cART. Results Ninety-four individuals were included. They were mostly men (77.7%) with a mean age of 53 years. They presented 159 co-morbidities including cardiovascular, bone, hepatic, kidney, and CNS diseases. Because of these pathologies, they took 207 non-ARV drugs (mean 2.2 per patient). Median duration of viral suppression was 77.5 months (IQR 61). All subjects were prospectively followed up to week 24 and all remained on dual therapy during the whole period. Neither virological failure, nor viral blip was detected. The median CD4 count rose from 658 cells/mcl (IQR 403) to 724 cells/mcl (IQR 401) (P = 0.006) without a significant (P = 0.44) change in the CD4/CD8 ratio. A significant (P

Microbial translocation has been suggested as a major driver of chronic immune activation HIV infection. Thus, we compared the extent of microbial translocation in patients with acute HIV infection and patients followed after CD4-guided structured treatment interruption (STI) by measuring different circulating markers: (1) lipopolysaccharide (LPS)-binding protein (LBP), (2) bacterial DNA, (3) soluble CD14 (sCD14), and (4) mitochondrial DNA (mtDNA). Bacterial DNA and sCD14 levels were similar in all groups. Patients in acute phase showed higher levels of LBP and mtDNA. In STI, we found a positive correlation between the percentage of CD8+ T cells and bacterial DNA levels. Considering all patients, LBP was positively correlated with the percentage and the absolute count of CD8+ T cells, and with mtDNA stressing the importance of mitochondrial products in sustaining chronic immune activation.