IMPORTANCEConvalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. OBJECTIVE To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg were eligible. INTERVENTIONS Patients in the experimental group received intravenous high-titer CP (Ն1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. MAIN OUTCOMES AND MEASURESThe primary outcome was a composite of worsening respiratory failure (PaO 2 /FiO 2 ratio <150 mm Hg) or death within 30 days from randomization. RESULTSOf the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P = .54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P = .04). CONCLUSIONS AND RELEVANCEIn patients with moderate to severe COVID-19 pneumonia, hightiter anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. (continued) Key Points Question Is convalescent plasma useful in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia? Findings In this randomized clinical trial of 487 patients with COVID-19 pneumonia and a partial pressure of arterial oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg at enrollment, the rate of the primary clinical end point (need for mechanical ventilation, defined as PaO 2 /FiO 2 ratio <150 mm Hg, or death) was not significantly different between the convalescent plasma group and the control group. Meaning In this trial, convalescent plasma did not reduce the progression to severe respiratory failure or death within 30 days.

Introduction Different antivirals are available for the treatment of outpatients with COVID-19. Our aim was to describe a real-world experience of outpatient management of COVID-19 subjects at high risk of progression. Methods This prospective observational study conducted in the University Hospital of Pisa (January 2022–July 2022) included consecutive COVID-19 outpatients with at least one risk factor for disease progression. Patients received nirmatrelvir/ritonavir, molnupiravir, or 3-day remdesivir, according to the Italian Medicines Agency (AIFA) indications. All patients were followed up until 30 days from the first positive nasopharyngeal swab. The primary endpoint was a composite of death or hospitalization. Secondary endpoints were occurrence of adverse events and a negative test within 10 days from the first positive test. Multivariable analysis was performed to identify factors associated with death or hospitalization. Results Overall, 562 outpatients were included: 114 (20.3%) received molnupiravir, 252 (44.8%) nirmatrelvir/ritonavir, and 196 (34.9%) 3-day remdesivir. The composite endpoint occurred in 2.5% of patients and was more frequent in patients treated with remdesivir (5.1%) compared with molnupiravir (1.8%) or nirmatrelvir/ritonavir (0.8%, ANOVA among groups p = 0.012). On multivariable Cox regression analysis, presence of ≥ 3 comorbidities, hematological disease, gastrointestinal symptoms, and each-day increment from symptoms onset were factors associated with death or hospitalization, while antiviral treatment was not a predictor. Adverse events occurred more frequently in the nirmatrelvir/ritonavir group (49.2%). Nirmatrelvir/ritonavir compared with remdesivir was associated with a higher probability of having a negative test within 10 days from the first positive one. Conclusion Death or hospitalization did not differ among high-risk COVID-19 outpatients treated with currently available antivirals. Safety and time to a negative test differed among the three drugs. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-022-00729-2.

Purpose Preliminary data suggest that remdesivir may influence the course of COVID-19 according to the duration of pre-admission symptoms. We aim to evaluate whether an early use of remdesivir is associated with a reduced COVID-19 progression in a homogeneous cohort of patients with mild-to-moderate COVID-19. Methods This prospective observational study included patients withCOVID-19 pneumonia treated with remdesivir at the University Hospital of Pisa (Italy) fromSeptember 2020 to January 2021. According to the national recommendations remdesivir was prescribed in patients with pneumonia who required oxygen supplementation by nasal cannula or mask but without the need for high-flow nasal cannula (HFNC),non-invasiveventilation (NIV) or invasive mechanical ventilation (MV) and had symptoms from no more than 10 days. Patients who received early (<5 days from onset of symptoms) and late (>5 days from onset of symptoms) remdesivir were compared. The primary outcome was a composite of HFNC, NIV, invasiveMV or death. A multivariate logistic regression analysis was performed to identify factors independently associated with the composite endpoint. Findings Among 312 consecutive patients with COVID-19 pneumonia who received remdesivir, 90 (28.8%) patients received early remdesivir, while 222 (71.2%) late remdesivir. Twenty-nine (32.2%) patients in the early-remdesivir group versus 104 (46.8%) patients in the late-remdesivir group met the primary endpoint (p=0.018). On multivariate analysis, a history of dyspnea at home (OR 2.53, 95% CI 1.55-4.12, p<0.001) was the strongest factor independently associated with the progression to severe COVID-19, while early-remdesivir use was a protective factor (OR 0.49, 95% CI 0.27-0.87, p=0.015). The delayed admission to the hospital was associated with a delayed administration of remdesivir. Implications The early use of remdesivir (<5 days from symptoms onset) may reduce the COVID-19 progression. The identification of patients who need early hospitalization and early remdesivir may provide clinical benefit in patients with COVID-19.

Background. Although preclinical studies highlighted the potential role of NADPH oxidase (NOX) in sepsis, only few studies evaluated the oxidative stress in patients with sepsis and septic shock. The objective of the study is to appraise the oxidative stress status and platelet function in patients with sepsis and septic shock compared to healthy controls. Methods and Results. Patients with sepsis or septic shock admitted to the hospital Policlinico Umberto I (Sapienza University, Rome) underwent a blood sample collection within 1 hour from admission. Platelet aggregation, serum thromboxane B2 (TxB2), soluble NOX2-derived peptides (sNox2-dp), and hydrogen peroxide breakdown activity (HBA) were measured and compared to those of healthy volunteers. Overall, 33 patients were enrolled; of these, 20 (60.6%) had sepsis and 13 (39.4%) septic shock. Compared to healthy controls ( n = 10 , age 67.8 ± 3.2 , male 50%), patients with sepsis and septic shock had higher platelet aggregation (49% (IQR 45-55), 60% (55.75-67.25), and 73% (IQR 69-80), respectively, p < 0.001 ), higher serum TxB2 (77.5 (56.5-86.25), 122.5 (114-131.5), and 210 (195-230) pmol/L, respectively, p < 0.001 ), higher sNox2-dp (10 (7.75-12), 19.5 (17.25-21), and 33 (29.5-39) pg/mL, respectively, p < 0.001 ), and lower HBA (75% (67.25-81.5), 50% (45-54.75), and 27% (21.5-32.5), respectively, p < 0.001 ). Although not statistically significant, a trend in higher levels of serum TxB2 and sNox2-dp in patients who died was observed. Conclusions. Patients with septic shock exhibit higher Nox2 activity and platelet activation than patients with sepsis. These insights joined to better knowledge of these mechanisms could guide the identification of future prognostic biomarkers and new therapeutic strategies in the scenario of septic shock.