D. Focosi et al.

Monoclonal antibody therapies against SARS-CoV-2

The Lancet Infectious Diseases, July 2022;  doi.org/10.1016/S1473-3099(22)00311-5

Abstract

Monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV-2 have been widely used in the ongoing COVID-19 pandemic. In this paper, we review the properties of mAbs and their effect as therapeutics in the pandemic, including structural classification, outcomes in clinical trials that led to the authorisation of mAbs, and baseline and treatment-emergent immune escape. We show how the omicron (B.1.1.529) variant of concern has reset treatment strategies so far, discuss future developments that could lead to improved outcomes, and report the intrinsic limitations of using mAbs as therapeutic agents.

S.E. Greasley et al.

Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants

J. Biol. Chem., April 2022; doi.org/10.1016/j.jbc.2022.101972

Abstract

The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). However, the efficacy of nirmatrelvir is underdetermined against evolving SARS-CoV-2 variants. Here, we evaluated the in vitro catalytic activity and potency of nirmatrelvir against the Mpro of prevalent variants of concern (VOCs) or variants of interest (VOIs): Alpha (α, B.1.1.7), Beta (β, B.1.351), Delta (δ, B1.617.2), Gamma (γ, P.1), Lambda (λ, B.1.1.1.37/C37), Omicron (ο, B.1.1.529), as well as the original Washington or wildtype strain. These VOCs/VOIs carry prevalent mutations at varying frequencies in the Mpro specifically for α, β, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant Mpro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933 nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the ο, λ, and β Mpro at 1.63 to 2.09 Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARSCoV-2 VOC/VOI, including Omicron, from replicating in cells.

D. Iaconis et al.

Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants

Nature, Cell Death and Disease, May 2022; doi.org/10.1038/s41419-022-04961-z

Abstract

The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug’s ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication.

H. Montgomery et al.

Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind,placebo-controlled trial

Lancet, Respir. Med., June 2022; doi.org/10.1016/ S2213-2600(22)00180-1

Abstract

Background Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab–cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab–cilgavimab in preventing progression to severe COVID-19 or death.

Methods TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab–cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394.

Findings      Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab–cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6–71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1–8·0; p<0·0001). Adverse events occurred in 132 (29%) of 452 participants in the tixagevimab–cilgavimab group and 163 (36%) of 451 participants in the placebo group, and were mostly of mild or moderate severity. There were three COVID-19-reported deaths in the tixagevimab–cilgavimab group and six in the placebo group.

Interpretation     A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.

M.G. Johnson et al.

Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19: A Randomized, Placebo-Controlled Trial

Annals of Internal Medicine, June 2022;  doi.org/10.7326/M22-0729

Abstract

In the MOVe-OUT trial, molnupiravir showed a clinically meaningful reduction in the risk for hospitalization or death in adults with mild to moderate COVID-19 and risk factors for progression to severe disease.

Objective:

To identify other potential clinical benefits of molnupiravir versus placebo.

Design:

Secondary analysis of the randomized, double-blind, placebo-controlled phase 3 component of MOVe-OUT. (ClinicalTrials.gov: NCT04575597)

Setting:

107 sites globally.

Participants:

1433 nonhospitalized adults aged 18 years or older with mild to moderate COVID-19.

Intervention:

Molnupiravir, 800 mg, or placebo every 12 hours for 5 days.

Measurements:

Changes from baseline in C-reactive protein (CRP) concentration and oxygen saturation (Spo2), need for respiratory interventions (including invasive mechanical ventilation), and need for medical services in all randomly assigned participants through day 29, and need for respiratory interventions and time to discharge in the subgroup of participants who were hospitalized after randomization.

Results:

Participants receiving molnupiravir showed faster normalization of CRP and Spo2, with improvements observed on day 3 of therapy, compared with placebo. Molnupiravir-treated participants had a decreased need for respiratory interventions versus placebo-treated participants (relative risk reduction [RRR], 34.3% [95% CI, 4.3% to 54.9%]), with similar findings in participants who were hospitalized after randomization (RRR, 21.3% [CI, 0.2% to 38.0%]). Hospitalized participants who received molnupiravir were discharged a median of 3 days before those who received placebo. Acute care visits (7.2% vs. 10.6%; RRR, 32.1% [CI, 4.4% to 51.7%]) and COVID-19–related acute care visits (6.6% vs. 10.0%; RRR, 33.8% [CI, 5.6% to 53.6%]) were less frequent in molnupiravir- versus placebo-treated participants.

Limitations:

Some analyses were performed post hoc. Longer-term benefits of molnupiravir therapy were not evaluated. Participants were not immunized against SARS-CoV-2.

Conclusion:

The findings suggest there are additional important clinical benefits of molnupiravir beyond reduction in hospitalization or death.

S. Miersch et al.

Ultrapotent and broad neutralization of SARS-CoV-2 variants by modular, tetravalent, bi-paratopic antibodies

Cell Reports, May 2022; doi.org/10.1016/j.celrep.2022.110905

Abstract

Neutralizing antibodies (nAbs) that target the SARS-CoV-2 spike protein have received emergency use approval for treatment of COVID-19. However, with the emergence of variants of concern, there is a need for new treatment options. We report a format that enables modular assembly of bi-paratopic tetravalent nAbs with antigen-binding sites from two distinct nAbs. The tetravalent nAb purifies in high yield and exhibits biophysical characteristics that are comparable to those of clinically used therapeutic antibodies. The tetravalent nAb binds to the spike protein trimer at least 100-fold more tightly than bivalent IgGs (apparent KD < 1 pM) and neutralizes a broad array of SARS-CoV-2 pseudoviruses, chimeric viruses, and authentic viral variants with high potency. Together, these results establish the tetravalent diabody-Fc-Fab as a robust, modular platform for rapid production of drug-grade nAbs with potencies and breadth of coverage that greatly exceed those of conventional bivalent IgGs.

T.  Cheuk-Fung Yip et al.

Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalisation in Community COVID-19 Patients

The Lancet, May 2022; doi.org/10.2139/ssrn.4112160

Abstract

Background We examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalisation and deaths in a real-world cohort of non-hospitalised COVID-19 patients.
Methods This was a territory-wide retrospective cohort study in Hong Kong. Non-hospitalised COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2021 were identified. Patients who were hospitalised on the day of the first appointment at clinic or used both oral antivirals were excluded. The primary endpoint was hospitalisation. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death. Patients’ clinical characteristics were balanced using propensity score weighting.

Findings Of 93,883 patients, 83,154 (88·6%), 5,808 (6·2%), and 4,921 (5·2%) were oral antiviral non-users, molnupiravir users, and nirmatrelvir/ritonavir users respectively. Compared to non-users, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalisations in the previous year. Molnupiravir users were older, and had more comorbidities, lower complete vaccination rate, and more hospitalisations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1,931 (2·1%) patients were admitted to hospital and 225 (0·2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0·79, 95% CI 0·65-0·95, P =0·011) but not molnupiravir use (weighted hazard ratio 1·17, 95% CI 0·99-1·39, P =0·062) was associated with a reduced risk of hospitalisation than non-users. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared to non-users. In the subgroup of patients aged ≥60 years or aged <60 years with comorbidities, nirmatrelvir/ritonavir use but not molnupiravir use was associated with a reduced risk of hospitalisation than non-users.

Interpretation The use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalisation in real-world non-hospitalised COVID-19 patients.

Benedetti et al.

Can Cytokine Blocking Prevent Depression in COVID-19 Survivors?

J Neuroimmune Pharmacol., January 2021; doi: 10.1007/s11481-020-09966-z

Abstract

Current insight on inflammation in psychiatry suggests that infection-triggered perturbation of immune homeostasis could foster psychopathology (Miller and Raison 2016). High rates of psychiatric disorders have been reported during and after coronavirus infection (Rogers et al. 2020). We also observed a psychopathological impact of COVID-19, with emergent depression and post-traumatic stress disorder (PTSD) after COVID-19 associated to systemic inflammation index (SII) during the acute illness (Mazza et al. 2020): 31% of patients self-rated in the psychopathological range for depression and 28% for PTSD, one month after hospital discharge, complete viral clearance and clinical recovery.

Studies revealed persistent low-grade inflammation in mood disorders, and pointed at interleukin (IL)-1β and IL-6 as inflammatory cytokines implicated in major depression and its detrimental outcomes(Arteaga-Henríquez et al. 2019). Severe COVID-19 induces a ‘cytokine storm’ involving massive release of IL-1β and IL-6. Pharmacological blockade of both cytokines was explored and we reported benefits on hyper-inflammation and progression to respiratory failure with high-dose anakinra (Cavalli et al. 2020), a recombinant version of the human IL-1β receptor antagonist, and less clear effects with tocilizumab (Campochiaro et al. 2020), a monoclonal antibody targeting the IL-6 receptor. Given the central role of IL-1 and IL-6 in depression, we hypothesize that depressive symptoms should be lower in COVID-19 survivors treated with cytokine-blocking agents.

K. Gupta et al.

Rapid Relapse of Symptomatic SARS-CoV-2 Infection Following Early Suppression with

Nirmatrelvir/Ritonavir

Research Square, April 2022; doi.org/10.21203/rs.3.rs-1588371/v1

Abstract

Initiation of NM/R treatment on Day 0 in a 71-year-old vaccinated and boosted male resulted in rapid resolution of COVID-19 symptoms followed one week later by the development of typical cold symptoms. SARS-CoV-2 viral load fluctuated in parallel with symptoms, with two distinct peaks on Day 1 and Day 9 of illness. No other respiratory pathogens were identified. Viral samples demonstrated sequence identity for the omicron subvariant BA.1 on Days 1, 7, and 11. Our findings suggest that viral replication and COVID-19 symptoms may recur after very early treatment with NM/R before natural immunity is sufficient to fully clear SARS-CoV-2.

WHO Solidarity Trial Consortium

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses

The Lancet, May 2022; doi.org/10.1016/S0140-6736(22)00519-0

Abstract

Background

The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date.

Methods

Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.govNCT04315948.

Findings

Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82–1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89–1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76–0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46–1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76–0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77–1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75–0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.

Interpretation

Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

K. Westendorf et al.

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

BioRxiv, March 2022;  doi: 10.1101/2021.04.30.442182

Abstract

SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization when administered early during COVID-19 disease. However, the emergence of variants of concern has negatively impacted the therapeutic use of some authorized mAbs. Using a high throughput B-cell screening pipeline, we isolated a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody called LY-CoV1404 (also known as bebtelovimab). LY-CoV1404 potently neutralizes authentic SARS-CoV-2 virus, including the prototype, B.1.1.7, B.1.351 and B.1.617.2). In pseudovirus neutralization studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant and retains binding to spike proteins with a variety of underlying RBD mutations including K417N, L452R, E484K, and N501Y. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved with the exception of N439 and N501. Notably, the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of reactivity to amino acid substitutions present among current VOC together with broad and potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants causing COVID-19.

In brief: LY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated.

Highlights: LY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and known variants of concern including the B.1.1.529 (Omicron), the BA.2 Omicron subvariant, and B.1.617.2 (Delta) variantsNo loss of potency against currently circulating variantsBinding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID databaseBreadth of neutralizing activity and potency supports clinical development.

R. Libster et al.

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

N Engl J Med. February 2021; doi: 10.1056/NEJMoa2033700

Abstract

BACKGROUND

Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

RESULTS

A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

CONCLUSIONS

Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19.

Therapeutics and COVID-19 – Living guideline April 2022

WHO, April 2022; www.who.int/publications

The WHO Therapeutics and COVID-19: living guideline contains the Organization’s most up-to-date recommendations for the use of therapeutics in the treatment of COVID-19. The latest version of this living guideline is available in pdf format (via the ‘Download’ button) and via an online platform, and is updated regularly as new evidence emerges.

This tenth version of the WHO living guideline now contains 17 recommendations, including two new recommendations regarding nirmatrelvir-ritonavir. No further updates to the previous existing recommendations were made in this latest version.

C. L. Todd et al.

Fluvoxamine for Outpatient Management of COVID-19 to Prevent HospitalizationA Systematic Review and Meta-analysis

JAMA Netw. Open, April 2022; doi:10.1001/jamanetworkopen.2022.6269

Abstract

Importance  Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization.

Objective  To perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19.

Data Sources  World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov.

Study Selection  Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included.

Data Extraction and Synthesis  The PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool and a bayesian random effects meta-analysis with different estimates of prior probability was conducted: a weakly neutral prior (50% chance of efficacy with 95% CI for risk ratio [RR] between 0.5 and 2.0) and a moderately optimistic prior (85% chance of efficacy). A frequentist random-effects meta-analysis was conducted as a senstivity analysis, and the results were contextualized by estimating the probability of any association (RR ≤ 1) and moderate association (RR ≤ 0.9) with reduced hospitalization.

Main Outcomes and Measures  All-cause hospitalization.

Results  This systematic review and meta-analysis of 3 randomized clinical trials and included 2196 participants. The RRs for hospitalization were 0.78 (95% CI, 0.58-1.08) for the bayesian weakly neutral prior, 0.73 (95% CI, 0.53-1.01) for the bayesian moderately optimistic prior, and 0.75 (95% CI, 0.58-0.97) for the frequentist analysis. Depending on the scenario, the probability of any association with reduced hospitalization ranged from 94.1% to 98.6%, and the probability of moderate association ranged from 81.6% to 91.8%.

Conclusions and Relevance  In this systematic review and meta-analysis of data from 3 trials, under a variety of assumptions, fluvoxamine showed a high probability of being associated with reduced hospitalization in outpatients with COVID-19. Ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates. Meanwhile, fluvoxamine could be recommended as a management option, particularly in resource-limited settings or for individuals without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals.

M. Cosentino et al.

Early outpatient treatment of Covid-19: a retrospective analysis of 392 cases in Italy

MedRxiv, April 2022; doi.org/10.1101/2022.04.04.22273356

Abstract

Introduction: The pandemic of severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) disease 2019 (COVID-19) was declared in march 2020. Knowledge of COVID-19 pathophysiology soon provided a strong rationale for the early use of anti-inflammatory, antiplatelet and anticoagulant drugs, however the evidence was only slowly and partially incorporated into institutional guidelines. Unmet needs of COVID-19 outpatients were soon taken care of by networks of physicians and researchers, using pharmacotherapeutic approaches based on the best available experiences.

Methods: Observational retrospective study investigating characteristics, management and outcomes in COVID-19 patients taken care of in Italy by physicians volunteering within the IppocrateOrg Association, one of the main international assistance networks, between 1st november 2020 and 31st march 2021.

Results: Ten doctors took part in the study and provided data about 392 consecutive COVID-19 patients. Patients’ mean age was 48,5 years (range: 0,5-97). They were 51,3% females and were taken care of when in COVID-19 stage 0 (15,6%), 1 (50,0%), 2a (28,8%), 2b (5,6%). Many patients were overweight (26%) or obese (11,5%), with chronic comorbidities (34,9%), mainly cardiovascular (23%) and metabolic (13,3%). Drugs most frequently prescribed included: vitamins and supplements (98,7%), aspirin (66,1%), antibiotics (62%), glucocorticoids (41,8%), hydroxychloroquine (29,6%), enoxaparin (28,6%), colchicine (8,9%), oxygen therapy (6,9%), ivermectin (2,8%). Hospitalization occurred in 5,8% of total cases, mainly in patients taken care of when in stage 2b (27,3%). Altogether, 390 patients (99,6%) recovered, one patient (0,2%) was lost at follow up, and one patient (0,2%) died after hospitalization. One doctor reported one grade 1 adverse drug reaction (ADR) (transient or mild discomfort), and 3 doctors reported in total 8 grade 2 ADR (mild to moderate limitation in activity).

Conclusions: This is the first study describing attitudes and behaviors of physicians caring for COVID-19 outpatients, and the effectiveness and safety of COVID-19 early treatment in the real world. COVID-19 lethality in our cohort was 0,2%, while the overall COVID-19 lethality in Italy in the same period was between 3% and 3,8%. The use of individual drugs and drug combinations described in this study appears therefore effective and safe, as indicated by the few and mild ADR reported. Present evidence should be carefully considered by physicians caring for COVID-19 patients as well as by political decision makers managing the current global crisis.

Alfano G. et al.

Awaiting a cure for COVID-19: therapeutic approach in patients with different severity levels of COVID-19

Le Infezioni in Medicina, 2022; doi: 10.53854/liim-3001-2

Abstract

COVID-19 is an unpredictable infectious disease caused by SARS-CoV-2. The development of effective anti-COVID-19 vaccines has enormously minimized the risk of severe illness in most immunocompetent patients. However, unvaccinated patients and non-responders to the COVID-19 vaccine are at risk of shortand long-term consequences. In these patients, the outcome of COVID-19 relies on an interplay of multiple factors including age, immunocompetence, comorbidities, inflammatory response triggered by the virus as well as the virulence of SARS-CoV-2 variants. Generally, COVID-19 is asymptomatic or mildly symptomatic in young people, but it may manifest with respiratory insufficiency requiring mechanical ventilation in certain susceptible groups of patients. Furthermore, severe SARS-CoV-2 infection induces multiorgan failure syndrome by affecting liver, kidney heart and nervous system. Since December 2019, multiple drugs have been tested to treat COVID-19, but only a few have been proven effective to mitigate the course of the disease that continues to cause death and comorbidity worldwide. Current treatment of COVID-19 patients is essentialSUMMARY ly based on the administration of supportive oxygen therapy and the use of specific drugs such as steroids, anticoagulants, antivirals, anti-SARS-CoV-2 antibodies and immunomodulators. However, the rapid spread of new  variants and the release of new data coming from the numerous ongoing clinical  trials have created the conditions for maintaining a continuous updating  of the therapeutic management of COVID-19 patients. Furthermore, we believe that a well-established therapeutic strategy along with the continuum of medical care for all patients with COVID-19 is pivotal to improving disease outcomes and restoring healthcare care fragmentation caused by the pandemic. This narrative review, focusing on the therapeutic management of COVID-19 patients, aimed to provide an overview of current therapies for (i) asymptomatic or mildly/moderate symptomatic patients, (ii) hospitalized patients requiring low-flow oxygen, (iii) highflow oxygen and (iv) mechanical ventilation. Keywords: COVID-19, SARS-CoV-2, therapy, ventilation, steroid, anticoagulant, tocilizumab, convalescent-plasma, monoclonal antibody, antiviral.

A. Jayk Bernal et al.

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

New England J of Medicine, February 2022;  doi: 10.1056/NEJMoa2116044

Abstract

Background: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29.

Results: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.

Conclusions: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).

V. Belleudi et al.

Drug Prescriptions in the Outpatient Management of COVID-19: Evidence-Based Recommendations Versus Real Practice

Front. Pharmacol., March 2022; https://doi.org/10.3389/fphar.2022.825479

Abstract

Background: Evidence-based recommendations for outpatient management of COVID-19 were published by the Italian Medicines Agency (AIFA) to limit the use of off-label treatments. The aim of this study is to measure the use of outpatient drug treatments in a COVID-19-positive population, taking into account the Italian regulatory agency’s advices.

Methods: A descriptive observational study was conducted. All patients testing positive for COVID-19 residing in Lazio region, Italy, with diagnosis date between March 2020 and May 2021 were selected, and outpatient medicine prescription patterns were identified.

Results: Independent of AIFA recommendations, the use of drug therapy in the management of outpatient COVID-19 cases was frequent (about one-third of the cases). The most used drug therapy was antibiotics, specifically azithromycin, despite the negative recommendation of AIFA, while the use of corticosteroids increased after the positive recommendation of regulatory agency for the use in subjects with severe COVID-19 disease. The use of hydroxychloroquine was limited to the early pandemic period where evidence on its potential benefit was controversial. Antithrombotics were widely used in outpatient settings, even if their use was recommended for hospitalized patients.

Conclusion: In this study, we show a frequent use of drug therapy in the management of outpatient cases of COVID-19, mainly attributable to antibiotics use. Our research highlights the discrepancy between recommendations for care and clinical practice and the need for strategies to bridge gaps in evidence-informed decision-making.

D. J. Sullivan et al.

Early Outpatient Treatment for Covid-19 with Convalescent Plasma

The New England J of Medicine, March 2022; doi: 10.1056/NEJMoa2119657

Abstract

BACKGROUND

Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.

METHODS

In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19–related hospitalization within 28 days after transfusion.

RESULTS

Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P=0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.

CONCLUSIONS

In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460. opens in new tab.)

Franck Touret et al.

In vitro evaluation of therapeutic antibodies against a SARSCoV2 Omicron B.1.1.529 isolate

Nature, https://www.nature.com/articles/s41598-022-08559-5.pdf

CONTENUTO E COMMENTO: In questo studio è stato analizzato il potere neutralizzante di otto anticorpi monoclonali attualmente utilizzati contro la variante Omicron. E’ stato osservato che sei di questi anticorpi hanno perso la loro capacità di neutralizzazione. Degli anticorpi che mantengono attività neutralizzante, Sotrovimab/Vir-7831 mostra una lieve riduzione, Cilgavimab/AZD1061 da solo mostra una notevole riduzione nell'efficacia, con conseguente perdita significativa di attività di Evusheld (Tixagevimab-Cilgavimab ) in cui Tixagevimab non conserva attività significativa contro Omicron.

Duvignaud A et al

Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE)

CMI, https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00108-2/fulltext

CONTENUTO E COMMENTO : Trial clinico randomizzato open-label su 217 pazienti con COVID-19 non ospedalizzati, trattati con ciclesonide (steroide) per via inalatoria con endpoint primario il peggioramento clinico entro il giorno 14 dalla diagnosi. Si conclude per una insufficiente evidenza di beneficio degli steroidi inalatori in COVID-19.

Puskarich MA et al

Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury A Randomized Clinical Trial

JAMA, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2790162 

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato con placebo eseguito in 13 centri degli USA nel periodo aprile 2020 – febbraio 2021 su 205 pazienti ospedalizzati con polmonite da SARS-CoV-2 e trattati con il sartano losartan o con placebo in aggiunta alla terapia standard per COVID-19 : non si osserva un miglioramento degli scambi gassosi (paO2/FiO2) a 7 giorni nei trattati con losartan, che dunque non appare utile nel trattamento di COVID-19.

Sydney B. Ross et al.

COVID-SAFER: Deprescribing Guidance for Nirmatrelvir-ritonavir Drug Interactions in Older Adults

Medrxiv.org, https://www.medrxiv.org/content/10.1101/2022.03.01.22271254v1.full.pdf

CONTENUTO E COMMENTO : Questo studio analizza le interazioni farmacologiche tra nirmatrelvir-ritonavir, potente CYP3A4 inibitore, e i farmaci potenzialmente inappropriati (PIM) assunti dalla popolazione anziana, ad alto rischio di gravi complicanze da COVID-19.

Di 5698 partecipanti, il 68% stava assumendo un farmaco che potenzialmente avrebbe interagito con nirmatrelvir-ritonavir, e di questi il 21% assumevano almeno un PIM. Con questa analisi viene sottolineata l’importanza di effettuare azioni di deprescribing negli anziani che assumono numerosi farmaci, per aumentare la proporzione di paziente che possono, in caso di  infezione da Sars-CoV2, assumere nirmatrelvir-ritonavir senza interazioni.

Rebecca Rockett et al.

Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use

NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMc2120219?articleTools=true

CONTENUTO E COMMENTO: Tra i primi 100 pazienti che hanno ricevuto sotrovimab, un anticorpo monoclonale diretto contro SARS-CoV-2, in un centro in Australia, in 8 pazienti il tampone molecolare rimaneva persistentemente positivo. Gli isolati ottenuti da 4 pazienti hanno mostrato una mutazione associata alla resistenza a sotrovimab nel dominio del recettore e le colture sono risultate positive a 2-3 settimane dopo il trattamento.

Nicola K Wills et al.

Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

Medrxiv.org, https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1.full.pdf

CONTENUTO E COMMENTO: Metanalisi su 11 trial clinic randomizzati per un totale di 5873 pazienti con COVID19 trattati con terapia anticoagulante a dosaggio profilattico o aumentato (intermedio o terapeutico): la terapia anticoagulante a dosaggio aumentato non ha dimostrato alcun effetto significativo sulla mortalità a breve termine ed era invece associata ad un aumento del rischio di sanguinamento. La riduzione del rischio di tromboembolia venosa osservata e la possibile tendenza alla riduzione della mortalità nei pazienti ospedalizzati non in ICU richiedono ulteriori studi.

Emi Takashita et al.

Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2

NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMc2201933?articleTools=true

CONTENUTO E COMMNENTO: Valutazione dell'attività in vitro degli anticorpi monoclonali e degli antivirali nei confronti della variante Omicron/BA.2.

Le suscettibilità di Omicron/BA.2 a remdesivir, molnupiravir e nirmatrelvir è confermata, mentre è stata osservata un'attività variabile degli anticorpi monoclonali, in particolare S309 (precursore di sotrovimab) ha dimostrato una ridotta attività neutralizzante nei confronti di Omicron/BA.2.

Shytaj I L et al

The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters

Virology, https://journals.asm.org/doi/full/10.1128/mbio.03705-21

CONTENUTO E COMMENTO: Secondo lo studio, il cobicistat  (questo e' il nome del farmaco) potrebbe inibire la moltiplicazione del virus SARS-CoV-2 con un meccanismo diverso da quello dei farmaci ad ora utilizzati, ovvero bloccandone la fusione alle cellule bersaglio. Inoltre, lo studio dimostra che il cobicistat puó attenuare la progressione della malattia nel modello animale di criceto, potenziando in tal senso anche l´effetto di un altro farmaco anti-COVID, ovvero il remdesivir.

Finora i tentativi di usare farmaci antiretrovirali contro il SARS-CoV-2 non avevano portato risultati significativi. Come spiegano gli autori dello studio, uno dei motivi principali sono i dosaggi necessari per ottenere un effetto inibitorio contro la replicazione del virus. Lo studio infatti dimostra che il cobicistat inibisce efficacemente la moltiplicazione del virus SARS-CoV-2 a livelli circa quattro volte superiori a quelli somministrati nelle sperimentazioni cliniche iniziali.

L´aspetto più importante dello studio è la dimostrazione che un composto che coadiuva l´azione di altri farmaci possa anche avere un effetto antivirale in vivo. Questo doppio effetto consente di testare una vasta gamma di combinazioni farmacologiche per arrivare ad un cocktail ottimale che possa inibire completamente la replicazione del virus.

Albuquerque AM et al

Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and CorticosteroidsA Bayesian Reanalysis of a Previous Meta-analysis

JAMA Network Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789444

CONTENUTO E COMMENTO : Re-analisi di una metanalisi su 15 trial clinic randomizzati, per un totale di 5339 pazienti ospedalizzati e trattati con tocilizumab e steroidi per COVID-19: il beneficio del tocilizumab sulla mortalità, già dimostrato in una metanalisi precedente, sarebbe confermato per i pazienti trattati con ossigenoterapia convenzionale o ventilazione non invasiva, ma non per i pazienti sottoposti a ventilazione meccanica invasiva. Il ruolo di tocilizumab nel trattamento di COVID-19 merita ulteriore studio.

Broman N et al

Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM – A prospective, randomized, single center, open label study

Clinical Microbiology and Infection, https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00104-5/fulltext

CONTENUTO E COMMENTO : Studio prospettico randomizzato monocentrico open-label su soli 57 pazienti, in cui sono stati inclusi adulti ospedalizzati per ipossiemia e COVID-19, con almeno due marker infiammatori elevati fra PCR, ferritina, D-dimero e interleukina-6: l’aggiunta di tocilizumab alla terapia standard è associata in questa casistica a una migliore condizione clinica (scala WHO) a 28 giorni e a una minore durata di ospedalizzazione.

Lim SCL et al

Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities The I-TECH Randomized Clinical Trial

JAMA, https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2789362

CONTENUTO E COMMENTO : Trial clinico su 490 pazienti adulti di età superiore a 50 anni condotto in Malesia, in cui si somministrava l’antiparassitario ivermectina oppure un placebo, oltre alle terapie standard, nella prima settimana dall’esordio di COVID-19 lieve-moderata : l’ivermectina non riduce significativamente il rischio di progressione verso la malattia grave e dunque non appare indicata come trattamento nelle fasi precoci di COVID-19.

Komagamine J et al

Evaluation of Antimicrobial Drug Use and Concurrent Infections During Hospitalization of Patients With COVID-19 in Japan

JAMA, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789175

CONTENUTO E COMMENTO : Studio retrospettivo cross-sectional condotto in Giappone su oltre 1000 pazienti ricoverati per COVID-19 in un centro privo di Rianimazione. La metà dei pazienti aveva polmonite, solo 1.7% ha ricevuto antibiotici durante l’ospedalizzazione. Le sovrainfezioni batteriche sono state solo 7, in meno dell’1% dei ricoverati in questo gruppo di pazienti.

Steven Chee Loon Lim et al.

Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities The I-TECH Randomized Clinical Trial

JAMA Intern Med, https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2789362

CONTENUTO E COMMENTO: Trial clinico randomizzato condotto su pazienti affetti da COVID19 ad alto rischio di progressione verso la malattia severa trattati con l’aggiunta di ivermectina per 5 giorni somministrata per via orale durante la prima settimana di malattia.

I risultati hanno mostrato che l’aggiunta di ivermectina allo standard of care non era associata a unariduzione del rischio di sviluppare una malattia grave.

Pertanto i risultati dello studio non supportanol'utilizzo di ivermectina per i pazienti con COVID-19.

Jennifer Hammond et al.

Oral Nirmatrelvir for High-Risk,Nonhospitalized Adults with Covid-19

The New England Journal of Medicine, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2118542?articleTools=true

CONTENUTO E COMMENTO: Trial di fase 2-3 in doppio cieco, randomizzato e controllato in cui adulti sintomatici, non vaccinati e non ospedalizzati, ad alto rischio di progressione verso una forma grave di Covid-19 sono stati assegnati in rapporto 1:1 a ricevere 300 mg di nirmatrelvir per via orale (inibitore della proteasi principale Mpro con una potente attività in vitro contro i coronavirus umani), più 100 mg di ritonavir o placebo.

I risultati hanno mostrato che il trattamento di adulti con COVID-19 sintomatici con nirmatrelvirpiù ritonavir è associato ad unariduzione del rischio di progressione a COVID-19 severo dell’89% rispetto al gruppotrattato con placebo, con un buonprofilo di sicurezza.

RECOVERY Collaborative group

Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

The Lancet,

 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00163-5/fulltext

CONTENUTO E COMMENTO : Studio randomizzato, controllato, open-label condotto sulla piattaforma RECOVERY, in 127 ospedali in UK su pazienti ospedalizzati per COVID-19 tra settembre 2020 e maggio 2021. L’obiettivo dello studio era quello di valutare l’efficacia di casirivimab e imdevimab, due anticorpi monoclonali che legano due differenti siti del receptor binding domain della proteina spike di SARS-CoV-2, nel ridurre la mortalità a 28 giorni.

I ridultati dimostrano che l’utilizzo di anticorpi monoclonali casirivimab e imdevimab nei pazienti ospedalizzati con COVID-19 riduce la mortalità a 28 giorni solo nei pazienti sieronegativi ma non in quelli sieropositivi, ovvero soltanto in coloro che non avevano precedentemente montato una propria risposta immunitaria.

Cairns DM et al

Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients With Mild to Moderate COVID-19A Phase 2 Randomized Clinical Trial

JAMA Netw Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788857

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato con placebo condotto su pazienti con COVID-19 lieve-moderato con l’obiettivo di valutare se l’utilizzo di niclosamide (un antielmintico orale con potente attività anti-SARS-CoV-2 in vitro) sia efficace nel ridurre lo shedding virale e la durata dei sintomi. Il trial è stato interrotto precocemente ad aprile 2021 per la drammatica riduzione dei casi di COVID-19 in Massachusetts, arruolando soltanto 73 partecipanti. Non è stata dimostrata nessuna differenza statisticamente significativa tra i due gruppi nella clearance virale a livello orofaringeo a 3 giorni né nella durata dei sintomi COVID-19 relati.

Behr CR et al

Anti–SARS-CoV-2 Monoclonal Antibody Distribution to High-risk Medicare Beneficiaries, 2020-2021

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2788904?widget=personalizedcontent&previousarticle=2788849

CONTENUTO E COMMENTO : Studio della allocazione delle terapia con anticorpi monoclonali contro SARS-CoV-2 in quasi 2 milioni di adulti con COVID-19 negli USA. Si osserva che per lo più le terapie erano destinate a pazienti a minor rischio, possibilmente a causa della difficoltà per i pazienti a rischio maggiore di malattia grave di ricevere diagnosi e prescrizione nei tempi adeguati.

Frank L. van de Veerdonk et al.

A guide to immunotherapy for COVID-19

Nature Medicine, https://www.nature.com/articles/s41591-021-01643-9.pdf

CONTENUTO E COMMENTO: La disfunzione immunitaria è una componente importante della fisiopatologia del COVID-19. Una vasta letteratura ha riportato l'effetto di terapie immunitarie in pazienti con COVID-19, con alcuni notevoli successi come l'uso di steroidi o le terapie anti-citochine.

Attraverso questa revisione delle strategie di immunoterapia nei pazienti con COVID-19, viene fornita una panoramica delle evidenze finora pubblicate, viene discussa una stratificazione del paziente e proposto un algoritmo per guidare l'utilizzo dell’immunoterapia nella pratica clinica.

The ITAC (INSIGHT 013) Study Group

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2822%2900101-5

CONTENUTO E COMMENTO: Trial clinico randomizzato di fase 3, doppio cieco, controllato con placebo, in cui i pazienti ricoverati con COVID-19, sintomatici per un massimo di 12 giorni e senza end-organ failure, sono stati assegnati in modo casuale (1:1) a ricevere immunoglobuline iperimmuni per via endovenosa (hIVIG) o placebo, oltre al remdesivir. Lo studio non ha evidenziato efficacia nel trattamento con hIVIG per i pazienti ricoverati con COVID-19 senza end-organ failure.

O’Brien MP et al

Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection A Randomized Clinical Trial

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2788256

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato in doppio-cieco di fase 3 con l’biettivo di valutare l’effetto della somministrazione sottocutanea della combinazione di anticorpi monoclonali casirivimab e imdevimab nel prevenire la progressione dell’infezione da SARS-CoV-2 dalla forma asintomatica alla malattia sintomatica. Studio condotto in USA, Romania e Moldavia tra luglio 2020 e marzo 2021.

Lo studio dimostra che la somministrazione sottocutanea di  casirivimab e imdevimab nei pazienti asintomatici con infezione da SARS-CoV-2 riduce significativamente il rischio di sviluppare malattia sintomatica e la durata dei sintomi sviluppati.

Questo studio ha il vantaggio di indagare la somministrazione di anticorpi monoclonali per via sottocutanea, di più facile applicabilità rispetto all’infusione endovenosa, facilità che ne consentirebbe una maggiore diffusione anche a livello territoriale. D’altro canto lo studio è stato condotto in un arco temporale in cui non era ancora diffusa la variante omicron, contro cui casirivimab e imdevimab sembrano aver perso potere neutralizzante ed efficacia, come emerso da recenti studi di laboratorio.

Jayk Bernal A et al

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2116044?query=featured_coronavirus

CONTENUTO E COMMENTO:  Trial clinico di fase 3 su 1433 pazienti con infezione da SARS-CoV-2, non ospedalizzati ma sintomatici, trattati con l’antivirale molnupiravir contro placebo per 5 giorni, iniziando il trattamento entro 5 giorni dall’esordio dei sintomi : si osserva una riduzione del rischio di ospedalizzazione. Esclusi i vaccinati e le persone con storia di infezione pregressa da SARS-CoV-2. Pur tenendo conto del fatto che si tratti di uno studio condotto sui non vaccinati, ridurre l’ospedalizzazione significa ridurre la pressione sui sistemi sanitari, il che rende i trattamenti domiciliari come molnupiravir molto promettenti.

Gottlieb RL et al

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2116846?query=featured_coronavirus

CONTENUTO E COMMENTO : Trial clinico su 562 pazienti con infezione da SARS-CoV-2, sintomatici e non ospedalizzati ma con almeno un fattore di rischio di progressione a malattia grave, randomizzati a ricevere o placebo o l’antivirale Remdesivir per 3 giorni, entro 7 giorni dall’esordio dei sintomi : riduzione dell’87% del rischio di ospedalizzazione nel gruppo trattato con 3 dosi di farmaco. Esclusi i pazienti vaccinati o con storia di precedente infezione da SARS-CoV-2, per cui la popolazione studiata riflette solo parzialmente le caratteristiche dei pazienti di oggi.

Ospina-Tascon GA et al

Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19 A Randomized Clinical Trial

JAMA, https://jamanetwork.com/journals/jama/article-abstract/2786830

CONTENUTO : Trial clinico randomizzato open-label in cui sono stati inclusi 220 pazienti con distress respiratorio da COVID-19 con un rapporto tra pressione parziale di ossigeno arterioso e frazione di ossigeno inalato (P/F) <200, con l’obiettivo di valutare l’effetto dell’ossigenoterapia con cannule nasali ad alti flussi vs ossigenoterapia convenzionale in termini di necessità di intubazione e risposta clinica.

Nello studio viene dimostrato che l’utilizzo di ossigeno ad alti flussi tramite cannule nasali riduce significativamente la necessità di ventilazione meccanica e il tempo di guarigione clinica se confrontato con l’ossigenoterapia convenzionale.

COMMENTO: Prima di questo studio, a nostra conoscenza, non era stato ancora ben stabilito l’effetto della ossigeno-terapia ad alti flussi (HFNC) rispetto a quella convenzionale nel setting di pazienti affetti da COVID-19. Dal punto di vista fisiopatologico risulta necessario fornire in questa categoria di pazienti con P/F<200 supporto ventilatorio adeguato, dal momento che il distress respiratorio su un parenchima danneggiato potrebbe determinare importanti fluttuazioni di pressione transpolmonare nonchè danno polmonare autoinflitto durante respirazione spontanea, per via del drive respiratorio elevato. Pertanto, il supporto con ossigeno-terapia HFNC oltre a favorire un incremento della pressione parziale di ossigeno, contribuirebbe miglioranedo il supporto ventilatorio, lo sforzo inspiratorio, il volume corrente e la frequenza respiratoria. Inoltre, il minimo effetto PEEP garantito, associato eventualmente alla pronazione durante la veglia, consente di migliorare la compliance polmonare dinamica, la pressione transpolmonare e l’omogeneità del parenchima. Pertanto, limitare il danno polmonare, sia autoinflitto che da evoluzione ARDS e migliorare la meccanica respiratoria potrebbero ridurre i tempi di recupero clinico.

In altre circostanze cliniche non COVID-19, la terapia con HFNC non è associata a maggiori tassi di mortalità o tempi di recupero più lunghi in caso di eventuale ritardo nell’intubazione oro-tracheale. Rispetto all’ossigeno terapia convenzionale, la terapia con HFNC ha effetti positivi e migliora il tempo di recupero, riducendo l’entità e il periodo di esposizione a FiO2 elevata, poiché l'iperossia correla con danno polmonare aggravato.

Lo studio in esame valuta l’effetto della HFNC rispetto la ossigeno terapia convenzionale sul ricorso alla ventilazione meccanica invasiva e il recupero clinico nei pazienti con COVID-19 severo. Si tratta di un trial clinico, open-label, randomizzato, condotto nelle unità di terapia intensiva e di emergenza-urgenza in 3 ospedali in Colombia. Sono stati selezionati 220 pazienti con ARDS e un rapporto P/F<200. I pazienti sono stati assegnati casualmente al gruppo alti flussi o ossigeno convenzionale con un rapporto 1:1. L’outcome primario è stato la necessità di intubazione e il tempo di recupero clinico valutato su una scala a 7 categorie (valori maggiori indicavano una peggiore condizione).

Dei 220 pazienti ne sono stati arruolati 199; l’età media era 60 anni, prevalentemente di sesso maschile (67%). È stato intubato il 34% dei pazienti assegnati al gruppo alti flussi e il 51% dei pazienti assegnati al gruppo ossigeno-terapia convenzionale. Nel 13% dei pazienti sottoposti ad alti flussi si è manifestata polmonite batterica sospetta, e nel 17% nei pazienti sottoposti ad ossigeno-terapia convenzionale, mentre la batteriemia è stata riscontrata nel 7% e 11%, rispettivamente.

In conclusione tra i pazienti con forme severe di COVID-19, l’utilizzo di ossigeno-terapia ad alti flussi attraverso cannule nasali riduce significativamente la necessità di supporto e il tempo di recupero clinico comparato con l’ossigeno-terapia convenzionale a bassi flussi. Tale evidenza assegna formalmente alla HFNC un ruolo importante nel trattamento dei pazienti affetti da COVID-19.

Gupta A et al.

Effect of the Neutralizing SARS-CoV-2 Antibody Sotrovimab in Preventing Progression of COVID-19: A Randomized Clinical Trial

MedRxiv, https://www.medrxiv.org/content/10.1101/2021.11.03.21265533v1.full.pdf

CONTENUTO: Studio randomizzato, in doppio cieco, multicentrico, controllato con placebo, di fase 3 volto a valutare l’efficacia di sotrovimab, un anticorpo neutralizzante anti-SARS-CoV-2, nel prevenire la progressione delle forme lievi-moderate di COVID-19 verso la malattia severa. Pazienti non ospedalizzati con COVID-19 sintomatico lieve-moderato ed almeno un fattore di rischio di progressione sono stati randomizzati con un rapporto 1:1 a ricevere sotrovimab 500 mg in infusione endovenosa o placebo. lo studio ha dimostrato che l’utilizzo di sotrovimab in questa categoria di pazienti riduce significativamente il rischio di ospedalizzazione, di supporto di ossigeno e di progressione verso forme di insufficienza respiratoria severa.

COMMENTO: Negli Stati Uniti, le attuali linee guida per il trattamento dei pazienti non ospedalizzati con forma lieve-moderata di COVID-19 che sono a elevato rischio di progressione clinica della malattia raccomandanocasirivimab/indevimab o sotrovimab indipendentemente dalla regione di provenienza e contesto epidemiologico. A differenza degli altri anticorpi monoclonali,sotrovimab ha come obiettivo un epitopo altamente conservato nella proteina spike del virus in una regione che non compete con il legame dell’ACE-II. In aggiunta, ha dimostrato in vitro un potente effetto di clearance del virus. Un fattore importante è anche la dimostrata efficacia (in test preclinici) di sotrovimab verso le singole mutazioni osservate nella variante omicron, anche se sono necessari ulteriori analisi che valutino l’efficacia di tale farmaco verso l’effetto del virus con le mutazioni nel suo complesso (https://www.gsk.com/en-gb/media/press-releases/preclinical-data-demonstrate-sotrovimab-retains-activity-against-key-omicron-mutations-new-sars-cov-2-variant/).

Il trial COMET-ICE ha valutato l’efficacia e la sicurezza di sotrovimab somministrato per via endovenosa nei pazienti ad alto rischio con forme lievi-moderate di COVID-19. L’arruolamento dei pazienti è stato interrotto prematuramente in quanto le ospedalizzazioni o morti nei  pazienti trattati si sono dimostrate precocemente e significativamente inferiori  rispetto a quanto osservato nei pazienti del braccio di controllo.

Sono stati arruolati 1057 pazienti e assegnati casualmente al gruppo sotrovimab (n=528) o placebo (n=529). L’età media dei pazienti era 53 anni, con 20% di pazienti di età superiore a 65 anni. I fattori di rischio o comorbidità più comuni erano l’obesità, età >55 aa, diabete mellito in trattamento farmacologico, asma moderata/severa.

 La percentuale di pazienti che hanno effettuato accesso presso il PS, l’ospedalizzazione di qualsiasi durata o la morte, erano ridotte del 66% con sotrovimab rispetto al placebo. Similmente, sotrovimab ha ridotto significativamente la progressione verso forme severe/critiche di COVID-19 rispetto al placebo. Inoltre, nessun paziente che aveva ricevuto sotrovimab ha avuto necessità di degenza in ambiente intensivo o di supporto con ventilazione meccanica rispetto ai 10 (2%) e 6 (1%) pazienti che avevano ricevuto placebo, rispettivamente.

Nonostante questi promettenti risultati, si evidenziano alcuni punti importanti: il primo risulta essere rappresentato dalla via di somministrazione del farmaco che lo rende poco maneggevole e non rapidamente accessibile all’utenza (sarebbe infatti auspicabile quantomeno una somministrazione intramuscolare che faciliterebbe il sistema sanitario alla gestione e all’accesso alle cure); il secondo è rappresentato dal timing di somministrazione delfarmaco, che richiede una identificazione precoce dello stato di malattia, nonché un corrispondente e rapido accesso ai trattamenti, che necessita a sua volta di una organizzazione virtuosa solamente auspicabile ma non sempre globalmente rappresentata; il terzo è rappresentato dal costo del farmaco che impone di condurre più studi farmaco-economici e predittivi dell’utilità clinica allo scopo di ottimizzare la selezione dei pazienti, individuando coloro che siano in effetti realmente più a rischio di progressione e ai quali, quindi, valga maggiormente la pena prescrivere il farmaco stesso.

Tesmesgen Z et al

Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial

The Lancet Respiratory Medicine,

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00494-X/fulltext

CONTENUTO: Trial di fase 3, randomizzato, in doppio cieco, controllato con placebo, volto a valutare l’efficacia e la sicurezza di lenzilumab, un anticorpo monoclonale neutralizzante anti GM-CSF somministrato in tre infusioni endovenose da 600 mg ciascuna a distanza di 8 ore, nel trattamento dei pazienti ospedalizzati con polmonite COVID-19 che non necessitano di ventilazione meccanica. Lenzilumab si è dimostrato efficace nel migliorare la sopravvivenza senza ventilazione meccanica in pazienti ospedalizzati con polmonite COVID-19. Il valore aggiunto di lenzilumab rispetto ad altri immunomodulatori in aggiunta al trattamento con steroidi rimane da determinare.

COMMENTO: Il fattore stimolante le colonie granulocito-macrofagiche(GM-CSF) è un’interleuchina prodotta dai linfociti T nella fase precoce di COVID-19 che partecipa alla cosiddetta “tempesta citochinica” che spesso caratterizza la malattia grave. Questo studio di fase tre, multicentrico, in doppio cieco e contro placebo, studia la capacità di lenzilumab, un anticorpo monoclonale diretto contro GM-CSF, nel determinare un’aumentata sopravvivenza libera da ventilazione meccanica a 28 giorni dalla randomizzazione. I pazienti ricoverati per COVID-19 in aria ambiente o che necessitano di sistemi di erogazione di ossigeno a bassi o alti flussi sono stati trattati con tre dosi di 600 mg di lenzilumab o destinati a ricevere il placebo.

Gli elementi di forza dello studio sono rappresentati dall’omogeneità dei gruppi e dal profilo di sicurezza di lenzilumab che dimostra un tasso di eventi avversi sovrapponibile al placebo. L’endpoint primario viene raggiunto, tuttavia con un livello di significatività statistica molto limitato (p: 0,04). Lo studio presenta inoltre i seguenti due limiti:

  • La maggior parte dei pazienti inclusi nello studio (circa il 60%) era in aria ambiente o in ossigenoterapia a bassi flussi: questo rappresenta un possibile bias per cui è possibile che il beneficio osservato dipenda dalla precocità del trattamento (non a caso il gruppo nel quale si osserva il vantaggio maggiore nelle analisi per sottogruppi è quello trattato solo con remdesivir, che è più spesso somministrato ai soggetti che necessitano di ossigenoterapia a bassi flussi).
  • Lo studio non è costruito per dimostrare formalmente un vantaggio in termini di mortalità.

L’impiego di lenzilumab ha un razionale interessante avendo il GM-CSF dimostrato in un precedente studio di predire l’evoluzione verso una forma grave di COVID-19 già al quarto giorno dall’esordio sintomatologico, ma sono necessari ulteriori studi per definire se e come il lenzilumab può essere impiegato nella pratica clinica per il trattamento di COVID-19.

Menichetti F et al

JAMA Network Open

Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 Pneumonia: A Randomized Clinical Trial

JAMA Network Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2786680

CONTENUTO: Trial clinico randomizzato, prospettico, open-label volto a valutare l’efficacia del plasma convalescente in aggiunta a terapia standard rispetto alla sola terapia standard nel prevenire il peggioramento respiratorio o la morte in pazienti ospedalizzati con polmonite COVID-19 e un rapporto Pao2/Fio2 tra 200 e 350. I pazienti nel gruppo sperimentale hanno ricevuto plasma convalescente ad alto titolo (≥1:160 al test in microdiluizione) per via endovenosa in aggiunta alla terapia standard, rappresentata da remdesivir, corticosteroidi ed eparina a basso peso molecolare. Lo studio non ha dimostrato un’efficacia del plasma convalescente anti-SARS-CoV-2 ad alto titolo nel ridurre la progressione delle forme moderato-severe dipolmonite verso l’insufficienza respiratoria grave o il decesso.

COMMENTO: Questo trial clinico randomizzato, prospettico, open-label ha valutato l’efficacia del plasma convalescente in aggiunta a terapia standard rispetto alla sola terapia standard (rappresentata daremdesivir, corticosteroidi ed eparina a basso peso molecolare) nel prevenire il peggioramentorespiratorio o la morte in pazienti ospedalizzati con polmonite COVID-19 da moderata a grave (rapporto PaO2 /FiO2 tra 200 e 350). I pazienti nel gruppo sperimentale ricevevano infusioni di plasma convalescente ad alto titolo (≥1:160 al test in microdiluizione) in aggiunta alla terapia standard. Lo studio non ha dimostrato un’efficacia del plasma convalescente anti-SARS-CoV-2 ad alto titolo nel ridurre la progressione delle forme moderato-severe di polmonite verso l’insufficienza respiratoria grave o il decesso (outcome primario dello studio) né si è evidenziato un benefico effetto sulla riduzione della necessità di supporto respiratorio medianteventilazione meccanica, sulla guarigione virologica e sulla riduzione del tempo tra ricovero e dimissioni dei pazienti (outcome secondari).

Nonostante tale studio censuri fermamente l’utilizzo del plasma da convalescente nel trattamento dei pazienti con infezione da SARS-CoV-2, lo stesso ci permette di fare alcune importanti considerazioni:

  • La presenza di anticorpi IgG anti-SARS-CoV-2 nei riceventi prima della ricezione della terapia con plasma da convalescente veniva citato da alcuni studi come possibile motivo della mancanza di un effetto benefico di tale trattamento, infatti i dati dello studio RECOVERY dimostravano un esito migliore nei riceventi la terapia con plasma quando era presente una sierologia negativa al momento della trasfusione (OR, 0,90; 95% CI, 0,82-0,97). In questo studio, oggetto del presente commento, il dato sulla presenza degli anticorpi IgG anti-spike al basale era disponibile solo per 252 pazienti (53,3%) e la sierologia risultava positiva in 28 su 112 pazienti (25,0%) del gruppo sperimentale.
  • Come suggerito da alcuni studi è probabile che le terapie a base di anticorpi siano più efficaci nelle prime fasi di COVID-19 quando è maggiormente intensa la replicazione virale (come già si è ampiamente verificato nel caso di trattamenti con gli anticorpi monoclonali). In questo trial, il tempo mediano dall'inizio della malattia alla somministrazione del trattamento con plasma era di 7,7 giorni, quindi avveniva tardivamente. Infatti, nello studio di Libster e collaboratori (https://www.nejm.org/doi/full/10.1056/NEJMoa2033700), plasma ad alto titolo somministrato entro 72 ore dall'insorgenza della malattia riduceva in maniera marcata la progressione della stessa in una popolazione anche più anziana rispetto allo studio oggetto della nostra osservazione, inoltre in quel caso i pazienti erano affetti da una forma lieve di polmonite.
  • Sempre lo studio di Libster et al. suggeriva la presenza di un effetto IgG dose-dipendente nelle infusioni di plasma convalescente. In quel trial infatti il plasma con titolo di IgG pari a 1:3200 o superiore riduceva del 73% il rischio di progredire verso forme di insufficienza respiratoria grave. Invece, in questo studio, il titolo di anticorpi mediano (IQR) era 226,3 (160-320) e 149 pazienti (64,2%) ricevevano unità di plasma con titolo inferiore a 320, mentre solo 83 pazienti (35,8%) ricevevano unità di plasma con titolo di almeno 320.

In conclusione, nonostante i risultati di tale trial, si ritiene opportuno attuare ulteriori studi ben disegnati per valutare il ruolo della terapia con plasma da convalescente ad alto titolo in dei sottogruppi specifici di pazienti con COVID-19 che come già detto potrebbero beneficiare di tale trattamento, ovvero i pazienti con polmonite lieve, esordio precoce della malattia (<72 ore) e sierologia negativa.

Axfors C et al

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

BMC InfectiousDiseases

CONTENUTO: Revisione sistematica della letteratura e metanalisi di 33 trial clinici (per un totale di oltre 16000 pazienti inclusi, quasi tutti ricoverati) che confrontano la mortalità per COVID-19 nei trattati con plasma di soggetti guariti rispetto ai non trattati con questa terapia: non si osserva una differenza significativa, per cui non appare raccomandato l’utilizzo del plasma se non nell’ambito di ulteriori trial clinici.

COMMENTO: Ulteriore studio che conferma la non efficacia del plasma iperimmune da pazienti convalescenti dal COVID 19. La raccomandazione, pur deludente, di evitare questo approccio terapeutico consente di evitare soverchie illusioni, comporta un risparmio ed è dettata come sempre deve essere dal rigore scientifico.

Tom J et al

Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial

Critical Care Medicine,

https://journals.lww.com/ccmjournal/Abstract/9000/Prognostic_and_Predictive_Biomarkers_in_Patients.95049.aspx

CONTENUTO : Sulla base dei dati del trial clinico COVACTA su 295 pazienti con COVID-19 grave trattati con tocilizumab (8 mg/Kg) contro 142 trattati con placebo vengono ricercati biomarcatori in grado di prédire il miglioramento clinico, la mortalità, la durata di degenza e la necessità di ventilazione meccanica al giorno 28: la ferritina sierica elevata è associata a migliori outcome (mortalità, ventilazione e miglioramento clinico) nei trattati con tocilizumab rispetto al placebo.

COMMENTO : Lo studio si propone  di ricercare degli indicatori di outcome nei pazienti COVID 19 che ricevono un trattamento con il Tocilizumab, un antagonista recettoriale dell’interleukina 6 che ha lo scopo di mitigare la grave reazione infiammatoria che accompagna il COVID.

L’identificazione precoce di biomarcatori consente di essere più preparati ad eventuali complicanze per quei pazienti identificati a maggior rischio.

Clemency BM et al

Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19

A Randomized Clinical Trial

JAMA Internal Medicine,

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2786012

CONTENUTO :  Mentre i corticosteroidi per via sistemica sono comunemente utilizzati nel trattamento delle forme severe di COVID-19, il ruolo dei corticosteroidi per via inalatoria nei pazienti con infezione lieve-moderata è dibattuto.

In questo studio randomizzato, in doppio-cieco, multicentrico, di fase 3 è stata valutata l’efficacia e la sicurezza dell’utilizzo di ciclesonide per via inalatoria nel trattamento di pazienti non ospedalizzati con COVID-19 sintomatico. I pazienti sono stati randomizzati a ricevere ciclesonide per via inalatoria due volte al giorno (640 μg al giorno) o placebo per 30 giorni.

Lo studio non ha dimostrato una differenza significativa tra i due gruppi in termini di tempo di miglioramento dei sintomi COVID-relati né del tasso di risoluzione dei sintomi a 30 giorni. I pazienti in trattamento con ciclosenide hanno avuto però meno accessi in Pronto Soccorso o ricoveri ospedalieri per motivi legati a COVID-19.

COMMENTO: In questo trial randomizzato, in doppio-cieco, multicentrico, di fase 3 si valuta l’efficacia e la sicurezza dell’utilizzo di ciclesonide per via inalatoria nel trattamento di pazienti non ospedalizzati con COVID-19 sintomatico. I pazienti venivano randomizzati a ricevere ciclesonide per via inalatoria due volte al giorno (640 μg al giorno) o placebo per 30 giorni. Lo studio non evidenzia una differenza statisticamente significativa tra i due gruppi in termini di tempo di miglioramento dei sintomi COVID-19 né del tasso di risoluzione dei sintomi a 30 giorni (outcome primario dello studio) .

Tuttavia, analizzando il trial più attentamente si può evidenziare come i pazienti in trattamento con ciclosenide siano andati incontro a meno accessi in Pronto Soccorso o ricoveri ospedalieri per motivi legati a COVID-19 (1.0% vs 5.4%; P = .03; numberneeded to treat=23). Gli autori rimarcano molto come questo risultato possa essere più rilevante per i pazienti e i sistemi sanitari rispetto all’outcome inizialmente prefissato come primario dello studio, poichè gli steroidi per via inalatoria potrebbero rappresentare un intervento relativamente a basso costo atto a ridurre gli accessi in pronto soccorso o i ricoveri ospedalieri conseguenti all’infezione da SARS-CoV-2.

Il trial non è scevro da limitazioni:

  • Non c’è omogeneità tra i due gruppi in osservazione riguardo alle patologie concomitanti al baseline: ad esempio, i pazienti del gruppo sperimentale erano maggiormente affetti da asma e diabete mellito di tipo 2 rispetto al gruppo di controllo.
  • L’uso di steroidi per via inalatoria o sistemica faceva parte dei criteri di esclusione dallo studio. Ciò potrebbe aver escluso potenziali partecipanti con comorbidità, come asma da moderata a grave o malattia polmonare cronica ostruttiva che avrebbero potuto avere beneficio dall'aggiunta di uno steroide per via inalatoria.
  • Non c’era standardizzazione riguardo ai trattamenti concomitanti attuati dai vari partecipanti allo studio e, inoltre, gli stessi potevano ottenere cure mediche al di fuori del protocollo del trial senza supervisione da parte degli investigatori.
  • L’età media dei partecipanti è stata di 44 anni: il trial escludeva quindi dall’osservazione fasce di età come quella geriatrica che è noto essere più a rischio di evolvere verso forme moderate/severe di malattia.

In conclusione, nonostante i risultati di tale studio sconsiglino l’aggiunta di un corticosteroide inalatorio come ciclesonide nel trattamento di pazienti non ospedalizzati con COVID-19 sintomatico, è auspicabile che si conducano trial meglio strutturati con una ottimale standardizzazione riguardo ai trattamenti farmacologici concomitanti ed alle comorbidità preesistenti, per meglio chiarire i potenziali effetti dei corticosteroidi inalatori, in particolare in pazienti ad alto rischio di progredire verso forme severe di COVID-19 come ad esempio quelli geriatrici.

Aljuhani O et al

Association between tocilizumab and emerging multidrug-resistant organisms in critically ill patients with COVID-19: A multicenter, retrospective cohort study

BMC Infectious Diseases, https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06813-1

CONTENUTO : Studio di coorte retrospettivo su 738 pazienti ricoverati in Rianimazione per COVID-19, di cui 262 trattati con l’immunomodulatore tocilizumab (anti interleukina-6): non si osserva una associazione indipendente fra l’uso del farmaco e l’isolamento di batteri dagli esami colturali dei pazienti, né in particolare di batteri resistenti agli antibiotici.

COMMENTO: l’utilizzo di molecole con capacità immunomodulante potrebbe esporre il malato a sviluppare più facilmente infezioni serie durante il ricovero ospedaliero, specie quelle sostenute da germi resistenti agli antibiotici.

Questo studio, che ha il limite di essere retrospettico e non randomizzato e controllato, non pone in relazione l’uso del Tocilizumab e la comparsa più frequente di complicanze infettive e l’emergenza di germi resistenti.

Medicines and Healthcare products Regulatory Agency, UK

Regulatory approval of Lagevrio (molnupiravir)

https://www.gov.uk/government/publications/regulatory-approval-of-lagevrio-molnupiravir

CONTENUTO: La MHRA, agenzia regolatoria in UK, ha rilasciato un’autorizzazione condizionale all’immissione in commercio di molnupiravir, farmaco antivirale indicato nel trattamento della COVID-19 da lieve a moderata, nei pazienti con un test diagnostico positivo per SARS-CoV-2 e che hanno almeno un fattore di rischio per malattia grave. Molnupiravir deve essere somministrato il prima possibile e comunque entro 5 giorni dall’insorgenza dei sintomi. La dose raccomandata è di 800 mg (4 capsule da 200 mg) ogni 12 ore per 5 giorni.

COMMENTO: La Gran Bretagna sarà il primo Paese ad approvare molnupiravir per l’impiego clinco sulla base dei risultati di uno studio che è stato addirittura interrotto in quanto proseguire avrebbe voluto dire penalizzare chi stesse ricevendo il placebo. Il farmaco appare adeguato per l’impiego domiciliare non solo per ragioni di efficacia ma anche per facilità di somministrazione (per via orale) e modalità di conservazione senza particolari restrizioni. Il farmaco è riservato a pazienti non ospedalizzati con fattori di rischio di progressione della malattia COVID-19 o in una fase intermedia della malattia. L'Italia sta rendendo il farmaco disponibile in emergenza poichè si attende ancora l'approvazione dall’Agenzia Regolatoria Europea (EMA).

Il meccanismo del farmaco consiste nell’indurre la mutagenesi del virus, cioè promuoverne la variazione genetica al punto tale che il materiale genetico “impazzito” non riesce più a sostenere la formazione di virus vitali, completi e infettanti. E’ stato tuttavia sollevato il dubbio che la mutagenesi indotta dal farmaco possa agire anche sul genoma umano del paziente inducendo pericolose variazioni.

E’ anche da considerare come il farmaco sia efficace solo a patto che sia iniziato molto precocemente, condizione che è difficilmente ottenibile nella pratica clinica e che richiede una organizzazione “ad hoc” del Sistema Sanitario. Nel caso in cui la precocità e l’appropriatezza non fossero assicurate vi è il rischio che il virus, sottoposto alla pressione selettiva del farmaco, possa selezionare mutazioni di resistenza che possono condizionare la mancata risposta al farmaco stesso, mentre i pazienti non riceverebbero alcun beneficio significativo a fronte di possibili effetti collaterali inutili.

Anche l’obiettivo di impego del farmaco precoce per ridurre la trasmissione virale potrebbe essere più facilmente ottenibile in contesti assistenziali specifici (ad esempio anziani istituzionalizzati in Residenze Socio Assistenziali, anche se asintomatici) piuttosto che, realisticamente, nella popolazione generale di pazienti non ricoverati. 

Un’arma importante dunque, ma che dobbiamo imparare a utilizzare al meglio e monitorare nei suoi effetti su più ampi numeri di pazienti nella fase d’impiego post-marketing.

Pfizer Press Release

PFIZER’S NOVEL COVID-19 ORAL ANTIVIRAL TREATMENT CANDIDATE REDUCED RISK OF HOSPITALIZATION OR DEATH BY 89% IN INTERIM ANALYSIS OF PHASE 2/3 EPIC-HR STUDY

https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate

 CONTENUTO : L'azienda farmaceutica Pfizer, in un comunicato stampa del 5 novembre 2021, ha annunciato che, in base a quanto emerso da un’analisi ad interim dello studio randomizzato in doppio cieco di fase 2/3 EPIC-HR condotto su pazienti adulti non ospedalizzati con COVID-19 ad alto rischio di progressione verso la forma grave, il nuovo farmaco candidato come antivirale orale PAXLOVIDTM riduce significativamente il rischio di ospedalizzazione o morte (riduzione del rischio dell’89% nei pazienti trattati entro 3 giorni dall’insorgenza dei sintomi, risultato simile nei pazienti trattati entro 5 giorni). Pfizer ha quindi sospeso l’arruolamento nello studio per l’evidente efficacia dimostrata da questi risultati e ha in programma di sottomettere questi dati all’FDA statunitense per l’Autorizzazione all’uso in emergenza del farmaco.

COMMENTO: In data 05.11.2021 è stato annunciato che il nuovo farmaco antivirale orale ha ridotto significativamente le ospedalizzazione e le morti, sulla base di una analisi ad interim di uno studio randomizzato, doppio cieco EPIC-HR (valutazione degli inibitori delle proteasi nei pazienti ad alto rischio affetti da COVID-19), di pazienti adulti non ospedalizzati con COVID-19, che sono ad alto rischio di progressione verso malattia severa.

È un farmaco antivirale inibitore delle proteasi di SARS-CoV-2, appositamente progettato per essere assunto per via orale affinchè possa essere prescritto ai primi segni di infezione o in seguito a contatto stretto con paziente positivo. Questo farmaco è stato disegnato per inibire l’azione della proteasi 3CL del SARS-CoV-2, un enzima necessario affinchè il virus possa replicarsi, in una fase nota come proteolisi, che si verifica prima della replicazione dell’RNA virale. La co-somministrazione con un basso dosaggio di ritonavir aiuta il rallentamento del metabolismo, o la degradazione, in modo che rimanga attivo per periodi di tempo più lunghi a concentrazioni più elevate per favorire la clearance del virus. Negli studi preclinici, non ha mostrato evidenza di indurre alterazioni mutageniche del DNA.

Un fattore rilevante è il potenziale facile impiego a domicilio per la prevenzione della progressione di malattia, nonché le ospedalizzazioni e la morte correlata a COVID-19. Inoltre potrebbe ridurre il rischio di infezione post-esposizione. Ha dimostrato efficacia in vitro contro le varianti più preoccupanti del virus e di altri coronavirus; considerando anche la possibilità di trattamento di multiple infezioni da più coronavirus. Le analisi sull’utilizzo di questo farmaco in pazienti a rischio standard e in profilassi post-esposizione non sono incluse in questa analisi ad interim e sono tutt’ora in corso.

La significatività statistica dei risultati di efficacia in termini di riduzione di ospedalizzazioni o morte è molto alta.

La revisione dei dati di sicurezza include una coorte più ampia di 1881 nell’EPIC-HR, tali dati erano disponibili al momento dell’analisi. Gli eventi avversi emergenti dal trattamento erano comparabili tra PAXLOVID (19%) e placebo (21%), la maggior parte dei quali di lieve intensità. Tra i pazienti valutabili per eventi avversi emergenti dal trattamento, sono stati osservati meno eventi avversi gravi (1,7% vs. 6,6%) e interruzione del farmaco in studio a causa di eventi avversi (2,1% vs. 4,1%) nei pazienti trattati con PAXLOVID™ rispetto a placebo, rispettivamente.

Al momento questi risultati riguardano tuttavia solo una sottopopolazione di pazienti considerati ad alto rischio di evoluzione della malattia. Valgono ovviamente anche in questo caso alcuni dei caveat sollevati nel commento precedente relativo a molnupiravir per quanto concerne la difficoltà di applicazione nelle fasi precocissime, la richiesta di un modello organizzativo prescrittivo e di monitoraggio e la necessità di proseguire studi osservazionali post-marketing clinici e virologici.

Nature Communications

Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets

Cox RM et al, https://www.nature.com/articles/s41467-021-26760-4.pdf

CONTENUTO : L’utilizzo del remdesivir, farmaco antivirale approvato per il trattamento di COVID-19 in fase precoce, è limitato dal suo uso per via endovenosa, che ne ostacola la somministrazione in pazienti non ospedalizzati nei primi giorni di malattia. Gli autori hanno quindi condotto questo studio su modello animale (furetto) volto a dimostrare l’efficacia anti-SARS-CoV-2 di GS-621763, un profarmaco orale di GS-441524, parente del remdesivir. GS-621763 somministrato per via orale due volte al giorno si è dimostrato efficace nel ridurre i livelli di SARS-CoV-2, bloccare la replicazione virale e prevenire la trasmissione agli animali non trattati.

COMMENTO: In questo studio condotto su modello animale (furetto) gli autori evidenziano l’efficacia anti-SARS-CoV-2 di GS-621763, un profarmaco orale di GS-441524, parente del remdesivir:

  • La somministrazione orale due volte al giorno di 10 mg/kg di GS-621763 (dosaggio terapeutico) riduceva la carica di SARS-CoV-2 a livelli quasi non rilevabili negli animali in studio.
  • Gli autori testavano il farmaco contro la VOC (variants of concern) P.1 gamma γ, dimostrando che, quando GS-621763 veniva somministrato per via orale al dosaggio terapeutico prima descritto, esso era in grado di bloccare la replicazione virale e di impedire la trasmissione ai furetti non trattati (i quali venivano lasciati in contatto con gli animali infetti e trattati).
  • Gli autori rimarcano l’efficacia in coltura cellulare di GS-621763 e del suo metabolita GS-441524 contro le VOC α, β, e γ la quale risultava comparabile a quella che il farmaco mostrava contro la variante virale originaria WA1/2020.

Analizzando criticamente lo studio si evidenzia però una limitazione importante:

  • Il farmaco veniva testato in particolare contro le VOC α, β, e γ non tenendo conto che ad oggi la variante prevalente è la variante Delta la quale, secondo l’ultimo report integrale del monitoraggio settimanale dell'andamento dell'epidemia da Covid-19 dell'Istituto superiore di Sanità (ISS), ridurrebbe l'efficacia vaccinale nel prevenire qualsiasi diagnosi sintomatica o asintomatica di Covid-19 nelle persone completamente vaccinate (si passa infatti dall'89%" registrato "durante la fase epidemica con variante Alfa prevalente", al "75% durante la fase epidemica con variante Delta prevalente"). È noto inoltre che la variante Delta risulta essere contagiosa 2 volte in più rispetto alle varianti precedenti (fonte: CDC).

In conclusione, dallo studio emergono sicuramente risultati confortanti che devono portare tutta la comunità scientifica a promuovere ulteriori studi clinici su questa nuova generazione di farmaci antivirali orali che potenzialmente potrebbero essere utili nell’inizio di un trattamento precoce a domicilio, riducendo così il carico di lavoro ospedaliero e soprattutto evitando la progressione verso forme severe di malattia, interrompendo inoltre la diffusione del virus in comunità. Tuttavia si parla appunto di risultati ottenuti su modello animale che necessitano una conferma di efficacia, da ottenere nel più breve tempo possibile con studi sull’uomo, tenendo conto delle varianti a oggi prevalenti e di quelle emergenti (vedasi notizie dell’ultima ora sull’emergenza di una variante “Delta plus” probabilmente ancora più contagiosa dell’originaria).

Rosas IO et al

Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial

Intensive Care Medicine

https://link.springer.com/article/10.1007%2Fs00134-021-06507-x

CONTENUTO : Trial clinico multicentrico randomizzato, controllato con placebo, che confronta il trattamento della polmonite grave da SARS-CoV-2 con remdesivir (antivirale) con o senza aggiunta di tocilizumab (immunomodulatore) in 649 pazienti ricoverati in rianimazione: non si dimostra un beneficio dell’aggiunta di tocilizumab in termini di dimissibilità dei pazienti al giorno 28.

COMMENTO: Ulteriore studio che delinea luci ed ombre su alcune associazioni terapeutiche attualmente proposte per il COVID-19.Le conclusioni non vanno lette negativamente nei confronti dell’inibitore del recettore per l’interleukina 6 (il tocilizimab), ma piuttosto con la perdurante necessità di identificare precocemente e al meglio i pazienti per un trattamento efficace.

The Lancet Global Health

Reis G et al

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial

Reis G et al, https://www.thelancet.com/action/showPdf?pii=S2214-109X%2821%2900448-4

CONTENUTO: Studio adattativo, randomizzato, controllato con placebo su pazienti con infezione acuta da SARS-CoV-2 sintomatici ad alto rischio di progressione verso la forma grave di COVID-19. I pazienti sono stati randomizzati con un rapporto 1:1 a ricevere fluvoxamina 100 mg due volte al giorno per 10 giorni o placebo, con l’obiettivo di indagare l’efficacia di fluvoxamina nel prevenire l’ospedalizzazione per COVID-19. Dai risultati emerge che l’utilizzo di fluvoxamina in pazienti con infezione precoce da SARS-CoV-2 ad alto rischio di progressione riduce la necessità di ospedalizzazione per COVID-19.

COMMENTO: Il TOGETHER trial è un piccolo trial clinico randomizzato, adattativo con placebo per indagare l’efficacia di farmaci riproposti per la malattia da COVID-19 in pazienti ad alto rischio non ricoverati. Tra i farmaci in studio è stato valutato come la fluvoxamina (SSRI con possibile effetto antiinfiammatorio e antivirale) possa ridurre il peggioramento clinico e quindi la necessità di ospedalizzazione dei pazienti a domicilio affetti da COVID-19 comparandola con il placebo.

Il meccanismo d’azione della fluvoxamina in corso di malattia da COVID-19 rimane incerto. Uno tra i meccanismi è l’effetto antinfiammatorio tramite l’attivazione di una proteina di membrana del reticolo endoplasmatico coinvolta nella regolazione della produzione di citochine in risposta agli stimoli infiammatori. In uno studio del 2019 di Rosen e collaboratori, fluvoxamina ha mostrato un beneficio nei modelli preclinici di infiammazione e sepsi attraverso questo meccanismo. Un secondo meccanismo può essere l’attività antiaggregante, in quanto gli SSRIs possono prevenire il caricamento della serotonina nelle piastrine e prevenirne la loro attivazione, riducendo il rischio di trombosi con possibili effetti cardioprotettivi. Infine, un altro meccanismo di azione può essere correlato all’effetto della fluvoxamina nell’incrementare i livelli plasmatici di melatonina.

Questo studio è stato condotto in Brasile e Minas Gerais reclutando i pazienti dalle strutture di comunità (pronto soccorso, centri di riferimento o centri di cura primari).

Sono stati inclusi tutti i pazienti con test antigenico rapido positivo al momento dello screening; test diagnostico per COVID-19 positivo entro i 7 giorni dall’insorgenza dei sintomi; comparsa dei sintomi entro 7 giorni dalla data dello screening; pazienti che si recavano in setting ambulatoriale con una condizione clinica acuta compatibile con COVID-19. Sono stati considerati eleggibili i pazienti con comorbidità e non vaccinati.

Tutti i pazienti venivano sottoposti al trattamento standard per COVID-19 ed in seguito assegnati casualmente con un rapporto 1:1 al gruppo fluvoxamina al dosaggio di 100 mg x 2/die per 10 giorni e al gruppo placebo. È stata evidenziato un beneficio della fluvoxamina nella riduzione dell’endpoint primario composito di ospedalizzazione definito come qualsiasi accesso presso setting di accettazione/emergenza COVID-19 o il trasferimento in ospedale di terzo livello.

Data la sicurezza, la tollerabilità, la maneggevolezza, il basso costo, la disponibilità di fluvoxamina, questi risultati potrebbero influenzare le linee guida nazionali e internazionali sulla gestione clinica di COVID-19. Questi risultati sono in linea con i precedenti e più piccoli trial condotti negli USA. Un più grande studio osservazionale dalla Francia ha coinvolto una differente popolazione (7230 pazienti ospedalizzati con COVID-19) riportando una riduzione dell’intubazione o la morte con l’utilizzo degli SSRIs.

Le limitazioni maggiori di questo trial sono:

  • Scarsa conoscenza delle caratteristiche della malattia poichè non è ancora ben defnito chi siano effettivamente i pazienti ad alto rischio di progressione di malattia e quindi le caratteristiche della popolazione possono essere eterogenee.
  • Non è stato applicato uno standard uniforme di cure per i trattamenti precoci di COVID-19.
  • La popolazione di questo studio ha un alto tasso di eventi di ospedalizzazione, rispetto a quanto osservato nella maggior parte degli studi clinici; pertanto potrebbero esserci state interferenze nel condizionare l’apparente effetto del trattamento in studio.
  • Al momento in cui è iniziato il trial, i vaccini non erano disponibili in Brasile, per cui questo studio valuta gli effetti della fluvoxamina su una popolazione non vaccinata. Sarebbe pertanto auspicabile e opportuno valutare l’efficacia anche nella popolazione vaccinata.

Gupta A et al

Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab

The New England Journal of Medicine, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2107934?articleTools=true

CONTENUTO: In questo trial clinico di fase 3 multicentrico in doppio cieco, pazienti non ospedalizzati con COVID-19 sintomatico (entro 5 giorni dall’insorgenza dei sintomi) e con almeno un fattore di rischio per progressione di malattia, sono stati randomizzati a ricevere una singola infusione di sotrovimab (anticorpo monoclonale pan-sarbecovirus) alla dose di 500 mg o placebo. Lo studio è ancora in corso ed i risultati di riferiscono ad un’analisi ad interim. Dai risultati emerge che la somministrazione precoce di sotrovimab riduce il rischio di ospedalizzazione o morte dell’85%, senza significative differenze in termini di eventi avversi.

COMMENTO: In questo trial clinico di fase 3 multicentrico in doppio cieco, pazienti non ospedalizzati con COVID-19 sintomatico (entro 5 giorni dall’insorgenza dei sintomi) e con almeno un fattore di rischio per progressione di malattia, venivano randomizzati a ricevere una singola infusione di sotrovimab (anticorpo monoclonale pan-sarbecovirus) alla dose di 500 mg o placebo. Dai risultati di un’analisi ad interim (lo studio è ancora in corso) si evidenziava come la somministrazione precoce di sotrovimab riduceva il rischio di ospedalizzazione (di durata maggiore di 24 ore) per qualsiasi causa o morte dell’85% (3 pazienti [1%] nel gruppo sperimentale vs. 21 pazienti [7%] nel gruppo placebo andavano incontro ad ospedalizzazione o morte).

Anche dagli outcome secondari si evidenziava un vantaggio derivante dall’utilizzo di sotrovimab. Infatti emergeva una riduzione delle visite al pronto soccorso nel gruppo sperimentale rispetto al controllo e inoltre dato da evidenziare è che nessuno dei pazienti del gruppo trattato con l’anticorpo monoclonale accedeva in unità di terapia intensiva durante il ricovero mentre dei 21 pazienti del gruppo di controllo in cui la malattia si aggravava, 5 venivano ricoverati in terapia intensiva.

Non si evidenziavano significative differenze in termini di eventi avversi tra i due gruppi.

Lo studio è tuttavia limitato da alcuni fattori che riducono la trasferibilità dei risultati:

  • La popolazione in studio era relativamente giovane infatti l’età mediana era di circa 53 anni e solo il 22% dei pazienti aveva un’età maggiore di 65 anni.
  • E’ vero che circa il 63% dei pazienti aveva come fattore di rischio un BMI maggiore di 30 e che circa il 23% era affetto da diabete mellito, ma i pazienti con BPCO, scompenso cardiaco e malattia renale cronica rappresentavano una percentuale del campione poco numerosa in particolare nel gruppo sperimentale (5%, <1% e <1%, rispettivamente)
  • Lo studio considerava tra i criteri di inclusione l’avere almeno un fattore di rischio di progressione verso forme severe di COVID-19 e tra questi fattori di rischio era inclusa un’età maggiore o uguale di 55 anni che probabilmente però rappresenta un valore soglia troppo basso.
  • Con solo tre casi del gruppo sotrovimab che andavano incontro ad ospedalizzazione, non è possibile determinare quali caratteristiche del paziente o della malattia potrebbero essere associati al fallimento del trattamento con sotrovimab, per questo sarà utile avere i risultati relativi all’analisi conclusiva dello studio.
  • Il trial veniva condotto in 4 Paesi ovvero USA, Canada, Brasile e Spagna, pertanto non è noto se tali risultati siano riproducibili su scala globale.

In conclusione, dal trial emergono sicuramente risultati vantaggiosi che però dovranno essere confermati da quelli dell’analisi conclusiva. Tuttavia, appare ancora una volta auspicabile che si focalizzi l’attenzione su fasce di popolazione ancora più a rischio di sviluppare forme severe di COVID-19 in particolare i grandi anziani, pazienti affetti da patologie oncologiche, quelli con malattie autoimmuni, trapiantati in terapia immunosoppressiva ecc. Inoltre è sempre auspicabile che tali studi siano quanto più rappresentativi possibili di tutta la popolazione mondiale.

Dougan M et al

A randomized, placebo-controlled clinical trial of bamlanivimab and etesevimab together in high-risk ambulatory patients with COVID-19 and validation of the prognostic value of persistently high viral load 

Clinical Infectious Diseases, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab912/6413724

CONTENUTO : In questa porzione di fase 3 del trial BLAZE-1 viene indagato l’effetto di bamlanivimab ed etesevimab sullo status clinico complessivo e sugli outcome virologici in pazienti ambulatoriali >12 anni con COVID-19 lieve o moderato e con almeno un fattore di rischio di progressione e/o di ospedalizzazione. I pazienti sono stati randomizzati a ricevere bamlanivimab ed etesevimab insieme (700mg/1400mg) o placebo in singola infusione entro 3 giorni dal primo test positivo per COVID-19. I pazienti che hanno ricevuto il trattamento con anticorpi avevano una maggiore riduzione della carica virale al giorno 7 e un minor tasso di ospedalizzazione o morte da COVID-19. Questi dati supportano l’utilizzo di bamlanivimab ed etesevimab nei pazienti ambulatoriali ad alto rischio di COVID-19 grave.

COMMENTO: Questo studio conferma l’ormai comprovata efficacia degli anticorpi monoclonali anti-SARS-CoV-2 balmanivimab/etesivimab al dosaggio di 700/1400 mg nell’evitare il ricovero dei pazienti infettati dal virus e ad alto rischio di sviluppare COVID-19, in particolare a 29 giorni la probabilità di ospedalizzazione viene ridotta dell’87% in chi si è sottoposto a infusione di anticorpi rispetto al placebo. Inoltre solo l’1.2% dei pazienti trattati è stato ricoverato o si è presentato al pronto soccorso entro i 29 giorni dalla somministrazione, nessuno è deceduto. Si conferma altresì la sicurezza dell’infusione non essendo stati osservati effetti collaterali gravi attribuibili al trattamento. Un ulteriore elemento rilevante che emerge dallo studio è il valore prognostico della carica virale, in grado di predire sia l’ospedalizzazione per COVID-19 che la mortalità per tutte le cause: il 68% dei pazienti che andava in contro ad uno di questi outcome sfavorevoli aveva un valore di Ct all’analisi molecolare inferiore a 27.5, corrispondente a cariche virali più elevate.

Il limite principale di questo studio è paradossalmente il tempismo del trattamento (a tre giorni dalla positività al tampone naso-faringeo per ricerca di SARS-CoV-2 RNA) cosa non sempre facilmente riproducibile nella pratica clinica. Inoltre, la carica virale persistentemente elevata che si osserva a sette giorni dall’infusione in alcuni soggetti refrattari, almeno in parte, al trattamento con anticorpi monoclonali potrebbe essere un endpoint surrogato sfavorevole da corroborare attraverso altri studi allo scopo di candidare questi pazienti a terapie alternative o all’impiego di diversi regimi di anticorpi monoclonali per un approccio sempre più personalizzato. In particolare andrà valutata l’efficacia di questa combinazione di anticorpi monoclonali nei confronti delle nuove varianti virali.

The COVID STEROID 2 Trial Group

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia

JAMA,

https://jamanetwork.com/journals/jama/fullarticle/2785529?utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=olf&utm_term=102121

CONTENUTO : Trial clinico randomizzato multicentrico condotto su 971 adulti ricoverati per polmonite da SARS-CoV-2 (escluse donne in gravidanza, persone già trattate con alte dosi di steroidi e con infezioni gravi di altra natura) sottoposti a ventilazione meccanica, ventilazione non invasiva o con fabbisogno di ossigeno molto elevato (> 10 litri/minuto). Si osserva che la somministrazione di 12 mg/die di desametasone (il doppio della dose di 6 mg indicata attualmente in base alle evidenze a nostra disposizione) non è correlata a una maggiore sopravvivenza senza necessità di cure intensive a 28 giorni.

COMMENTO : Lo studio rigoroso cerca di risolvere una domanda che aleggia sin dall’inizio della pandemia : usare precocemente nei malati critici colpiti dal COVID-19 dosi di steroide più alte o inferiori modifica l’outcome? Questo studio multicentrico dimostra che tra i due dosaggi non esiste differenza in termini di esito finale. L’incidenza di complicanze è stata simile nei 2 gruppi. Legittimo quindi poter scegliere individualmente e forse preferire i 6 mg al giorno invece che i 12. Tuttavia gli autori riconoscono la possibilità che il campione di popolazione, sebbene ragguardevole potrebbe esser stata non pienamente sufficiente per una conclusione al 100% sicura.

RECOVERY Collaborative Group

Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

The Lancet Respiratory Medicine, https://www.thelancet.com/action/showPdf?pii=S2213-2600%2821%2900435-5

CONTENUTO : In questo trial clinico randomizzato controllato open-label condotto da novembre 2020 a marzo 2021 in 177 centri in UK, 2 in Indonesia e 2 in Nepal, pazienti ricoverati con diagnosi di COVID-19 sono stati assegnati con un rapporto 1:1 a ricevere terapia standard oppure terapia standard più colchicina. I risultati hanno mostrato che non ci sono differenze significative tra i due gruppi in termini di mortalità a 28 giorni (outcome primario), durata di ricovero, percentuale di pazienti dimessi entro 28 giorni e rischio di progressione di malattie verso ventilazione meccanica o morte (outcome secondari).

COMMENTO: Lo studio RECOVERY ha dimostrato come l’utilizzo di colchicina in pazienti ospedalizzati con COVID-19 non si associ a un significativo effetto sulla mortalità, durata di ospedalizzazione, rischio di progressione verso la ventilazione meccanica invasiva e morte.

Risulta essere, ad oggi, lo studio con la maggiore dimensione campionaria, considerando che sono stati condotti solo tre trial clinici randomizzati ma che non dispongono della potenza statistica, dato l’esiguo campione disponibile. Inoltre, i primi due trial hanno dimostrato una riduzione di due giorni di ospedalizzazione e un miglioramento del quadro polmonare ma i pazienti erano sottoposti a trattamento con idrossiclorochina in associazione a desametasone e, pertanto, non sono comparabili con i risultati ottenuti dallo studio RECOVERY oltre che non affidabili nel valutare gli effetti della colchicina sulla mortalità. Lo studio RECOVERY invece, con più di 11000 partecipanti e più di 2000 decessi, ha un eccellente potere statistico per identificare modesti benefici del trattamento.

E’ però importante considerare come il protocollo abbia definito un massimo di 10 giorni di trattamento con colchicina per cui non possiamo escludere un possibile beneficio derivante da una durata maggiore di terapia. Peraltro, la maggior parte dei partecipanti ha terminato colchicina prima dei 10 giorni o per morte o per dimissione dall’ospedale o a discrezione del clinico e la maggior parte dei pazienti assumeva terapia corticosteroidea concomitante.

Riteniamo ancora oggetto di interesse condurre valutazioni sulla efficacia e sicurezza della colchicina nella prevenzione dell’ospedalizzazione, progressione di malattia e morte nei pazienti affetti da COVID-19 non ospedalizzati, dal momento che uno dei pochi studi disponibili (COLCORONA) è stato interrotto prematuramente. Infatti, se nei pazienti ospedalizzati e con malattia moderata-severa da COVID-19 la colchicina non si è dimostrata efficace nella riduzione della mortalità e della durata dell’ospedalizzazione, dai pochi studi emergenti è stato dimostrato un effetto di riduzione della necessità di ospedalizzazione e del rischio di morte nei pazienti non ospedalizzati, facendo presupporre che l’effetto anti-infiammatorio di colchicina possa essere sufficiente a interferire positivamente con i pathway di infiammazione, almeno nelle forme lievi-moderate di COVID-19.

Izadi Z et al

Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19

JAMA Network Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2785080

CONTENUTO:  Studio di coorte volto a valutare l’associazione tra monoterapia con inibitori del tumor-necrosis factor (TNF) e rischio di ospedalizzazione o morte per COVID-19 in pazienti adulti affetti da malattia infiammatoria immuno-mediata (IMID). In particolare sono stati inclusi pazienti affetti da artriti infiammatorie, malattie infiammatorie croniche intestinali e psoriasi presenti su 3 registri internazionali dal 12 marzo 2020 al 1 febbraio 2021. I pazienti in terapia con inibitori del TNF sono stati posti a confronto con pazienti che ricevevano altri trattamenti immunomodulatori, quali metotrexate, azatioprina e inibitori di Jak. Lo studio ha dimostrato che i pazienti in monoterapia con farmaci anti-TNF avevano un rischio significativamente più basso di ospedalizzazione o morte per COVID-19 in confronto a pazienti che ricevevano altri trattamenti immunomodulatori.

COMMENTO: COVID-19 è in grado di provocare una aberrante risposta infiammatoria nota come tempesta citochinica peggiorando la gravità di malattia del paziente che ne è affetto. Gli inibitori del fattore di necrosi tumorale (TNF) vengono utilizzati nei pazienti con malattie infiammatorie (reumatiche, IBD, psoriasiche) diminuendo i livelli della tale citochina ad attività pro-infiammatoria.

Questo studio ha cercato di chiarire se l'uso di inibitori del TNF in questa tipologia di pazienti con concomitante infezione da SARS-CoV-2 potesse ridurre o associarsi ad aumentato rischio di decesso o ospedalizzazione (outcome dello studio). Gli autori hanno quindi raccolto i dati di 6077 pazienti affetti da malattie infiammatorie da tre registri internazionali che raccoglievano i dati di pazienti con IBD, malattia reumatica e psoriasica ed erano altresì COVID-19 positivi.

Gli inibitori del TNF che venivano analizzati nello studio includevano adalimumab, certolizumab pegol, etanercept, golimumab e infliximab; questi venivano comparati in monoterapia rispetto alla combinazione degli stessi con metotrexato o azatioprina/6-mercaptopurina. Inoltre anche il metotrexato e l'azatioprina/6-mercaptopurina venivano valutati come monoterapia, così come gli inibitori della Janus chinasi (Jak) come tofacitinib, baricitinib e upadacitinib.

Dai risultati di tale studio si evince come:

  • Il trattamento in monoterapia utilizzando gli inibitori del TNF sia associato ad un rischio inferiore di decesso o di ospedalizzazione rispetto al trattamento di combinazione anti-TNF con azatioprina/6-mercaptopurina.
  • Il trattamento in monoterapia utilizzando gli inibitori del TNF sia associato ad un rischio inferiore di decesso o di ospedalizzazione rispetto al trattamento con le altre classi di farmaci utilizzati in monoterapia (metotrexato, azatioprina/6-mercaptopurina, inibitore di Jak).
  • Il trattamento in monoterapia utilizzando gli inibitori del TNF non sia associato ad un rischio aumentato di decesso o di ospedalizzazione rispetto al trattamento di combinazione anti-TNF con metotrexato.

Tale studio sembra quindi suggerire un vantaggio in termini di riduzione del rischio di decesso e ospedalizzazione nei pazienti COVID-19 positivi e affetti da malattia infiammatoria nell’utilizzo della sola monoterapia con anti-TNF.

Valutando attentamente il disegno del trial ed i criteri di selezione del campione si possono osservare punti di forza ma anche alcune limitazioni dello stesso:

  • Tra i punti di forza si evidenzia la elevata numerosità del campione e la specifica nella compilazione di tali registri sull’attività o meno della malattia infiammatoria intestinale dei pazienti inclusi nella valutazione.
  • Tra le limitazioni osserviamo:
    • l’età media dei pazienti molto giovane (circa 50 anni);
    • la non uniformità nella diagnosi di COVID-19 dei pazienti inclusi nello studio (gli autori specificano come in alcuni casi la diagnosi si basava su test molecolari, in altri sia su test sierologici piuttosto che indagini radiologiche ed in alcuni casi solo sulla presenza di sintomi sospetti per COVID-19;
    • non vi è una specifica sulla tipologia dei trattamenti precedentemente utilizzati dai pazienti per la patologia infiammatoria di base né sulla loro durata;
    • i criteri di ospedalizzazione non sono ovviamente standardizzati dato che i dati dei pazienti in analisi derivava da registri internazionali;
    • i pazienti inclusi nella analisi non sono stati stratificati per gravità di malattia COVID-19 relata.

In conclusione, i risultati dello studio in oggetto possono costituire il punto di partenza per trial che siano randomizzati e controllati, che si basino su criteri diagnostici per COVID-19 uniformi e che utilizzino standardizzati criteri di ospedalizzazione dei pazienti con infezione da SARS-CoV-2.

Maisonnasse P et al

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

Nature Communications , https://www.nature.com/articles/s41467-021-26354-0.pdf

CONTENUTO : Studio pre-clinico in vivo su 3 modelli animali (topo, criceto e macaco) sull’effetto profilattico e terapeutico di COVA1-18, anticorpo monoclonale neutralizzante altamente efficace contro la variante B.1.1.7 di SARS-CoV-2. COVA1-18 si è dimostrato efficace su tutti e 3 i modelli animali nel ridurre di più del 95% l’infettività virale nelle alte vie respiratorie e nel prevenire l’insorgenza di linfopenia e di danno polmonare grave. La dimostrazione in questo studio preclinico della sua potente attività antivirale, rende COVA1-18 un buon candidato per successivi studi clinici.

COMMENTO: Nonostante lo sviluppo di vaccini efficaci, l’insorgenza di nuove varianti virali e la possibilità che alcuni soggetti risultino non responsivi all’immunizzazione rende centrale il ruolo degli anticorpi monoclonali neutralizzanti anti-SARS-CoV-2 nella cura della malattia e nel controllo tempestivo dei focolai epidemici, questo studio sperimentale si inquadra in questo contesto.

Si dimostra l’efficacia del nuovo anticorpo COVA1-18:

  • in vitro COVA1-18 inibisce fortemente la replicazione e l’efficacia non è inficiata da alcuni polimorfismi a singolo nucleotide del virus. Il risultato è reso più robusto dalla collaborazione tra più laboratori;
  • nel topo, sia che l’infezione venga indotta il giorno prima o quello dopo la somministrazione di COVA1-18, non si osservano segni di replicazione virale nel polmone;
  • nel criceto il siero acquisisce potere neutralizzante nei confronti del virus già a tre giorni dall’infezione nella maggior parte dei roditori trattati 24 ore dopo l’inoculo virale e la carica virale polmonare è significativamente inferiore rispetto al gruppo di controllo;
  • nel macaco risulta efficace in profilassi pre-esposizione e mostra delle caratteristiche farmacocinetiche interessanti in quanto si distribuisce in tutti gli organi (tranne nel cervello nel quale le concentrazioni potrebbero non essere adeguate a garantire un effettivo potere neutralizzante). Gli animali trattati sviluppano blande alterazioni obiettivabili con la tomografia computerizzata (TC) del polmone. La presenza del virus viene ridotta del 95-99% sia a livello nasofaringeo che tracheale ciò lascia sperare in una ridotta infettività degli animali trattati.

Non è tuttavia possibile, purtroppo, delineare un profilo di sicurezza dell’anticorpo nemmeno nel modello animale dato il numero esiguo degli animali trattati. Inoltre, l’utilizzo della variante inglese per testare l’efficacia del farmaco, in un momento storico nel quale la variante Delta risulta essere la principale causa di COVID-19, rappresenta un’importante limitazione dello studio. Infine, in tutti i modelli sperimentali nel quale l’anticorpo è impiegato a scopo terapeutico, il trattamento è talmente precoce (24 ore) da essere impraticabile in un contesto clinico quotidiano.

Questo nuovo anticorpo monoclonale potrebbe essere un candidato per gli studi clinici, ma è opportuno che ne venga meglio chiarita la sicurezza in vivo prima di proporlo per la sperimentazione umana.

Memel ZN et al

Association of Statins and 28-Day Mortality in Patients Hospitalized with SARS CoV-2 Infection

The Journal of Infectious Diseases, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab539/6402971

CONTENUTO: Studio di coorte su 1179 pazienti ospedalizzati per infezione da SARS-CoV-2 con l’obiettivo di valutare l’associazione tra l’utilizzo intra-ospedaliero di statine e la mortalità a 28 giorni o il ricovero in Terapia Intensiva. I pazienti sono stati stratificati in 4 gruppi: quelli che assumevano statine prima del ricovero (continuate o sospese al momento dell’ospedalizzazione) e quelli che non le assumevano (che le hanno iniziate de novo al momento del ricovero o che non le hanno mai assunte). Dall’analisi statistica è emerso che l’utilizzo di statine durante il ricovero per infezione da SARS-CoV-2 (sia come prosecuzione di una terapia domiciliare che come nuova prescrizione) era associato ad un ridotto rischio di mortalità a 28 giorni.

COMMENTO: Questo studio conferma i risultati di una serie di osservazioni e di una recente meta-analisi (https://www.ijidonline.com/article/S1201-9712(21)00636-6/fulltext).

L’originalità e l’importanza di questo studio deriva dal fatto che mentre negli studi precedenti la prescrizione di statine veniva analizzata in modo piuttosto approssimativo (cioè come farmaco in atto o meno al momento del ricovero), Memel e Collaboratori hanno diviso la popolazione in studio in modo da valutare separatamente coloro che hanno iniziato o sospeso le statine successivamente al ricovero, rispetto ai pazienti che già assumevano tali farmaci prima del ricovero. Questa distinzione è importante in quanto l’assunzione di statine già prima del ricovero potrebbe avere arrecato negli studi precedenti un errore sistematico (bias) dovuto al fatto che i pazienti già in terapia potrebbero essere stati quelli meglio seguiti e, quindi, il beneficio di questi farmaci potrebbe essere stato solo apparente, cioè da riferirsi a un migliore stato di salute generale, piuttosto che essere dovuto a un effetto farmacologico diretto.

Vi sono altresì motivi di plausibilità biologica che suggeriscono come la somministrazione di statine possa realmente arrecare benefici clinici ai pazienti: (i) le statine agiscono sull’enzima HMG-CoA reduttasi e con questo meccanismo riducono il rischio di morte nei pazienti con malattia aterosclerotica; (ii) si tratta di farmaci anti-infiammatori che stabilizzano e migliorano la funzione endoteliale compromessa dall’infezione da SARS-CoV-2; (iii) possono interagire in modo potenzialmente utile con Mpro (una proteasi di SARS-CoV-2) o con meccanismi di adesione del virus alla cellula bersaglio.

Anche questo studio, tuttavia, è gravato da alcuni limiti:

  • Il farmaco veniva somministrato dopo il ricovero non solo per compensare a una mancata somministrazione prima del ricovero nonostante chiare indicazioni pre-esistenti, ma anche a giudizio clinico. Per questa ragione è possibile che, anche in questo studio, coloro che hanno ricevuto il farmaco siano stati meglio seguiti e, quindi, lo studio in oggetto potrebbe soffrire del bias insito anche nei precedenti studi.
  • Gli stessi autori ammettono che anche nel loro studio, in quanto osservazionale e nonostante approfonditi controlli, i dati potrebbero non essere completamente affidabili. In particolare, gli autori non sono stati in grado di valutare adeguatamente eventuali sospensioni temporanee delle statine in corso di ricovero.
  • I pazienti che hanno interrotto le statine durante il ricovero erano pazienti differenti dagli altri per valori di PCR, troponina, CPK e d-dimero più elevati. Pertanto, questa categoria di pazienti non appare confrontabile con gli altri e merita ulteriori indagini più approfondite.
  • I pazienti inviati a cure palliative venivano considerati come decessi scondo quanto pattuito nel disegno dello studio.
  • Lo studio offre una finestra di osservazione limitata a 28 giorni e, quindi, nulla si può dire su quanto sia avvenuto nel medio-lungo termine a questi pazienti.
  • I risultati non tengono in considerazione l’effetto terapeutico di farmaci importanti come i cortisonici.

In conclusione, sebbene questo studio offra a considerare importanti risultati e obblighi il clinico a valutare attentamente la prescrizione di statine almeno nei pazienti in cui vi sia indicazione per rischi cardio-metabolici in atto, anche in questo caso solo gli studi randomizzati in corso potranno confermare o smentire un reale effetto terapeutico delle statine per COVID-19 (Clinicaltrials.gov Identifiers: NCT04407273, NCT04390074, NCT04348695, NCT04426084, NCT04333407, NCT04380402, NCT04486508).

Spyropoulos AC et al

Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19

The HEP-COVID Randomized Clinical Trial

JAMA Internal Medicine, https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2785004

CONTENUTO : HEP-COVID, trial clinico multicentrico in cui pazienti adulti ospedalizzati per COVID-19 ed evidenza di coagulopatia (definita come un valore di D-dimero >4 volte il limite superiore della norma o un sepsis-induced coagulopathy score>=4) sono stati randomizzati a ricevere eparina a dosaggio profilattico o intermedio (1) oppure eparina a dosaggio terapeutico (2). Gli autori hanno dimostrato che gli outcome di efficacia primaria, ovvero tromboembolismo venoso, tromboembolismo arterioso e mortalità, erano significativamente ridotti nei pazienti non in terapia intensiva che ricevevano eparina a dosaggio terapeutico, anche se questo beneficio non è stato dimostrato per i pazienti in terapia intensiva. Non sono state dimostrate differenze significative nei due gruppi per quanto riguarda il rischio di sanguinamento.

COMMENTO: Questo trial clinico considera un argomento ancora molto controverso: quale sia il dosaggio di eparina adeguato ed in quale popolazione, nel trattamento dei pazienti affetti da COVID-19.

Infatti ad oggi, anche come mostrato da alcune meta-analisi, non vi è una chiara indicazione su quale sia il dosaggio più sicuro e più efficace di eparina e in quale sottogruppo di pazienti, anche perché gli studi attualmente disponibili a riguardo sono di scarsa qualità o con diversi bias (ridotti numeri di pazienti, non omogeneità nella popolazione del dosaggio di eparina, diverse strategie terapeutiche, eterogeneità nella selezione della popolazione e nella gravità della malattia) che rendono difficilmente intellegibili le interpretazioni e per cui risulta difficilmente estrapolabile una indicazione definitiva.

Per tale motivo, questo studio ha valutato l’efficacia e la sicurezza di un dosaggio di eparina a dose terapeutica in una popolazione selezionata di pazienti ricoverati con COVID-19 in stadio non critico ma ad alto rischio di sviluppo di complicanze o critico comparandola con la dose profilattica o intermedia di eparina.

Di 11.649 pazienti ne sono stati arruolati solamente un gruppo di 257 (130 sono stati sottoposti a dose terapeutica e 127 a dose profilattica), quasi tutti (98,4%) con valori di d-dimero di almeno 4 volte superiori ai valori normali, mentre solo il 33% erano pazienti critici. Lo studio ha evidenziato un vantaggio significativo di dosi più elevate di eparina solamente nella popolazione non critica ad alto rischio. Questo potrebbe essere dovuto ad una serie di fattori:

  1. La popolazione non critica ad alto rischio è stata selezionata secondo il criterio di valori di d-dimero molto elevati, presupponendo un effetto sul decorso di malattia.
  2. Gli effetti del trattamento dell’eparina sono efficaci nella fase precoce di malattia come forma di prevenzione degli stati di trombosi micro-vascolare, prima che si verifichi uno stato di iper-infiammazione irreversibile e una tempesta citochinica che causa trombo-infiammazione.

Anche se il numero di pazienti ad alto rischio da trattare per prevenire un singolo evento trombo embolico è piccolo (8 nella popolazione generale e 5 nei pazienti non critici), suggerendo un effetto benefico del regime a dosaggio terapeutico, le evidenze dello studio dovranno venire rivalutate su una popolazione maggiore di pazienti con caratteristiche più eterogenee, così da consentire una maggiore generalizzazione dei risultati (in questo caso la popolazione era prevalentemente affetta da malattie cardiovascolari, pertanto l’effetto dell’eparina ha influito sull’outcome anche interagendo con i meccanismi fisiopatologici delle comorbidità del paziente).

Infine, sebbene questo studio non abbia evidenziato differenze statisticamente significative nel rischio di sanguinamenti maggiori, in altri studi (oggetto di commento nelle settimane precedenti) tale rischio è apparso non trascurabile nei pazienti trattati con dosaggi rinforzati di eparina, soprattutto nei pazienti più critici.

Sorge quindi il sospetto che il basso numero di pazienti critici in questo studio abbia condizionato l’impossibilità di mettere in luce differenze statisticamente significative tra i bracci sia per l’outcome dell’efficacia che per quello della sicurezza.

Dougan M et al

Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19

New England Journal of Medicine, https://www.nejm.org/doi/full/10.1056/NEJMoa2102685

CONTENUTO : Trial clinico di fase 3 in cui pazienti ambulatoriali con COVID-19 lieve o moderato ad alto rischio di progressione venivano randomizzati a ricevere una singola infusione di una combinazione di anticorpi monoclonali neutralizzanti (2800 mg di bamlanivimab e 2800 mg di etesevimab) oppure placebo entro 3 giorni dalla diagnosi laboratoristica di infezione da SARS-CoV-2. I pazienti che ricevevano la combinazione di bamlanivimab ed etesevimab avevano un’incidenza di ospedalizzazione COVID-19-relata e di morte significativamente minore rispetto ai pazienti che ricevevano placebo, oltre ad una riduzione molto più rapida della carica virale di SARS-CoV-2.

COMMENTO: In questo studio randomizzato di fase 3 in pazienti con COVID-19 lieve o moderato trattati in ambiente extraospedaliero si evidenzia come pazienti trattati con la combinazione di anticorpi monoclonali Bamlanivimab- Etesevimab avevano un rischio del 4.8% in meno rispetto al gruppo placebo di essere ospedalizzati o di andare incontro al decesso (per qualsiasi causa occorsa) al 29° giorno di osservazione e in aggiunta nessun decesso occorreva nel gruppo sperimentale mentre 9 decessi correlabili a COVID-19  venivano registrati nel gruppo placebo. Inoltre, analizzando gli outcomes secondari dello studio si può evidenziare come i pazienti inclusi nel gruppo sperimentale avessero impiegato un tempo significativamente minore per raggiungere la riduzione della carica virale di SARS-CoV-2 su tampone (nel gruppo sperimentale si aveva una riduzione della carica virale di circa 16 volte superiore a quella registrata nel gruppo placebo al 7° giorno di osservazione), mentre non c’era una significativa differenza tra i due gruppi in osservazione sulla risoluzione dei sintomi della malattia (nel gruppo sperimentale si registrava una durata dei sintomi di 1 solo giorno inferiore a quella osservata nel gruppo placebo).

 Tra i risultati non propriamente esplicitati come outcomes primari o secondari dagli autori dello studio vi è anche l’evidenza di come la combinazione di anticorpi monoclonali possa ridurre sia il rischio di ospedalizzazione (2.1% gruppo sperimentale vs 6.4% gruppo placebo), che la durata dell’ospedalizzazione (7.3 giorni gruppo sperimentale vs 11.2 giorni gruppo placebo).

E’ importante rimarcare come la randomizzazione dei pazienti fosse avvenuta con una mediana che cadeva al 4° giorno dall’insorgenza dei sintomi e come solo circa il 5% dei pazienti avessero riportato sintomi per più di 8 giorni prima di ricevere l'infusione. Questi risultati sono quindi ottenibili solo a patto che il trattamento venga iniziato tanto precocemente.

Volendo analizzare in maniera critica i risultati del trial possiamo evidenziare anche alcuni altri aspetti:  (a) la popolazione studiata aveva nella maggior parte dei casi una malattia lieve e non moderata (i pazienti con COVID-19 lieve nel gruppo sperimentale erano il 76.6% e nel gruppo placebo erano il 77.9 %); (b) solo il 30% circa dei pazienti aveva un’età maggiore o uguale a 65 anni; (c) lo studio non teneva conto dell’emergenza delle varianti di SARS-CoV-2 che come noto da studi in vitro riducono l’efficacia della combinazione Bamlanivimab-Etesevimab; (d) i pazienti con condizioni cliniche patologiche pre-esistenti (insufficienza renale cronica, malattie cardiovascolari, BPCO, immunosoppressi o in terapia immunosoppressiva) hanno rappresentato una parte molto minoritaria del campione studiato; (e) lo studio è stato condotto solo negli Stati Uniti per cui non è certo se i risultati dello stesso siano riproducibili in contesti demografici e socio-sanitari diversi.

In conclusione, i risultati del trial sono sicuramente importanti e costituiscono un punto di partenza per ulteriori studi magari focalizzati su categorie di pazienti definibili più a rischio di progredire verso forme severe di COVID-19, ovvero quelli di età più avanzata e con condizioni patologiche pre-esistenti che li rendono appunto più fragili e i pazienti con malattia non lieve. Sarebbe altresì opportuno avviare studi su scala globale in modo da rendere i risultati riproducibili in popolazioni diverse per differenti caratteristiche demografiche e socio-sanitarie, tenendo contemporaneamente in debita considerazione l’emergenza di varianti virali che possono ridurre l’efficacia degli anticorpi monoclonali.

Al Sulaiman K et al

Ascorbic acid as an adjunctive therapy in critically ill patients with COVID19: a propensity score matched study

Scientific Reports, https://www.nature.com/articles/s41598-021-96703-y.pdf

CONTENUTO E COMMENTO : Studio di coorte retrospettivo condotto in Arabia Saudita su 296 pazienti con infezione critica da SARS-CoV-2 : l’utilizzo di acido ascorbico (vitamina C, 1 g/die per una mediana di 11 giorni a partire dal ricovero in Rianimazione) in aggiunta alle terapie standard non sembra conferire un beneficio in termini di mortalità, ma sembra associato a minore incidenza di trombosi venosa e arteriosa.

Christie MJ, et al.

Of bats and men: Immunomodulatory treatment options for COVID-19 guided by the immunopathology of SARS-CoV-2 infection

Science Immunology, https://www.science.org/doi/10.1126/sciimmunol.abd0205#T2

CONTENUTO : Review narrativa sulle tipologie di risposte immuni innescate dall’infezione da SARS CoV2 e sulle strategie messe in atto dal virus in atto per evaderle. Dopo aver offerto una panoramica sulle dinamiche immunologiche delle tre fasi di malattia (infezione preclinica, moderata e severa), e aver approfondito le possibili cause dell’immunotolleranza dei pipistrelli al virus, la review si concentra sulle diverse strategie terapeutiche disponibili e in corso di studio.

COMMENTO: Questa review fornisce una panoramica dei fondamenti scientifici da cui è possibile trarre indicazioni sul trattamento del COVID-19. Alla luce degli studi sui pipistrelli capaci di contenere l’infezione da coronavirus (CoV) e sulle strategie di evasione immunitaria della famiglia dei CoV, vengono presi in esame promettenti approcci terapeutici o profilattici. Un esempio è l’uso di una piccola molecola (chiamata diABZI) agonista di STING, un importante messaggero intracellulare che promuove la produzione degli interferoni, che hanno a loro volta potente attività antivirale e immunostimolante: una singola dose intranasale di diABZI ha protetto fortemente i topi non solo dagli effetti deleteri dell'infezione da SARS-CoV-2, ma anche da altri COV e da altri virus respiratori come la parainfluenza e il rinovirus. Promettenti per le fasi iniziali dell’infezione, sono alcuni studi pilota che domostrerebbero che alcune nuove molecole che incrementano le risposte immunitarie permetterebbero resistenza all’infezione, come farmaci che aumentano produzione di citochine pro-infiammatorie comeGM-CSF (Sargramostim) or G-CSF (Filgrastim); oppure agonisti dei toll-like receptors (TL)2/6/9 (come PUL-042). Viceversa nelle fasi avanzate della malattia, approcci terapeutici indirizzati a limitare le eccessive risposte infiammatorie sembrano essere più idonei e con più successo: per esempio, molteplici farmaci (come baricitinib, ruxolitinib, tofacitinib, fedratinib,  acalabrutinib, nintedanib and imatinib) agiscono come  inibitori delle tirosinchinasi resposabili dell’attivazione di diverse citochine pro-infiammatorie, e sembrano ridurre l’insufficienza respiratoria, le infezioni secondarie, e i fenomeni tromboembolici, che sono tipici del COVID-19 grave. Infine, sono stati presi in esame gli anticorpi monoclonali (mAb) generati con l'obiettivo di bloccare l'ingresso cellulare di SARS-CoV-2 legandosi alla proteina spike, che rappresenta la chiave con cui il virus entra nelle cellule per infettarle. Tali mAb hanno mostrato efficacia preclinica e rappresentano opzioni per la profilassi e il trattamento di COVID-19. L’FDA (l’agenzia ameircana per il farmaco) ha già dato il permensso per alcuni di essi (sotrovimab e REGEN-CoV) in pazienti ambulatoriali adulti e pediatrici ad alto rischio (da 12 a 17 anni) nel trattamento e profilassi post-esposizione, poiché questi anticorpi hanno ridotto il rischio di ospedalizzazione e morte. Tuttavia, le mutazioni virali hanno già iniziato a minare l'efficacia di alcuni di questi mAbs, ad esempio bamlanivimab + etesevimab, ed è probabile che molti diventino obsoleti.

Ulteriori strategie terapeutiche nel campo del COVID-19 includono indagini dettagliate sulla biologia molecolare di SARS-CoV-2 (ad esempio, delucidazione funzionale delle sue proteine ​​ e delle sue capacità di evadere il sistema immunitario), e sulla 'affidabilità dei biomarcatori per la stadiazione della malattia. Inoltre sono molto importanti gli studi sulle potenziali interazioni tra virus e microbioma dei pazienti: l'interazione tra la difesa dell'ospite, SARS-CoV-2 e i microbiomi intestinali e polmonari può almeno in parte spiegare l'influenza dell'età e delle comorbilità sulla gravità del COVID-19, allo scopo di sfruttare l'asse intestino-polmone per effetti terapeutici.

In conclusione, questa review fornisce un utile contributo all'importante lavoro svolto dai ricercatori in questo campo, dai medici che curano i pazienti con COVID-19 e dai dipendenti pubblici che prendono decisioni in questo spazio in rapida evoluzione. L’obiettivo prinicipale è quindi sostenere gli sforzi globali per arginare questa pandemia mortale e le sue devastanti conseguenze economiche, psicosociali e mediche.

O’Brien MP et al.

Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2109682

CONTENUTO : Trial controllato randomizzato esplorante l’efficacia della somministrazione degli anticorpi monoclonali casirivimab/imdevimab nei soggetti esposti a SARS-CoV2 prima che si manifestino i sintomi (profilassi post-esposizione). In questo studio, i pazienti trattati hanno presentato un rischio significativamente più basso di sviluppare una infezione sintomatica e, anche tra quelli che hanno manifestato dei sintomi, questi sono stati più lievi e di più breve durata.

COMMENTO : Questo importante lavoro descrive i risultati di un trial clinico sull’uso del REGEN-COV, somministrato per via sottocutanea in 753 pazienti  (al di sopra degli 11 anni di età) , entro 96 ore dalla  diagnosi di COVID -19 dovuta ad esposizione domestica al  SARS-CoV-2, confrontati con 752 pazienti analoghi a cui era stato somministrato placebo.  REGEN-COV è la combinazione di due anticorpi monoclonali (casirivimab/imdevimab), i quali bloccano l'ingresso cellulare di SARS-CoV-2 legandosi a due siti diversi della proteina spike, e più precisamente della regione di spike che che lega il recettore ACE-2, attraverso cui il virus entra nelle cellule per infettarle: bloccando due siti sulla stessa proteina spike,  in precedenti lavori, REGEN-COV si era mostrato più efficiente nel bloccare il virus anche quando mutato.

REGEN-COV sottocutaneo ha ridotto significativamente la progressione dell'infezione sintomatica (che si manifestava nell’1.5% dei trattati contro il 7.8% dei non-trattati con  REGEN-COV ), il tempo di risoluzione (2 volte più corta nel trattati che nei non-trattati), e la durata dell’alta carica virale, senza procurare effetti collaterali. Questi risultati sono molto incoraggianti per il trattamento nelle fasi iniziali del COVID-19, nonchè per il suo uso nella profilassi di persone a rischio, soprattutto immunocompromessi (con tumori, sottoposti a chmioterapici, anziani fragili ecc), in cui la risposta al vaccino può non essere efficace.

Studi ulteriori sono necessari sia per verificare se REGEN-COV sottocutaneo prevenga l'infezione da sindrome respiratoria acuta grave da SARS-CoV-2, nello stesso tipo di pazienti, sia per verificare se esso sarà efficace contro varianti future.

Peng J et al

Efficacy and secondary infection risk of tocilizumab, sarilumab and anakinra in COVID-19 patients: A systematic review and meta-analysis

Reviews in Medical virology, https://onlinelibrary.wiley.com/doi/epdf/10.1002/rmv.2295

CONTENUTO: Meta-analisi sull’efficacia e la sicurezza clinica di farmaci immunosoppressivi (tocilizumab, sarilumab e anakinra) nel trattamento di pazienti con COVID-19. Gli autori concludono che la terapia immunosoppressiva riduce significativamente il rischio di mortalità, senza aumentare il rischio di infezioni secondarie. I pazienti trattati con tocilizumab hanno però mostrato un rischio significativamente aumentato di co-infezione fungina.

COMMENTO: Questi risultati giungono a supporto delle recenti indicazioni dell’Agenzia Italiana del Farmaco (AIFA) che autorizza l’impiego di anakinra, baricitinib, sarilumab e tocilizumab in pazienti con polmonite da SARS-CoV-2 da moderata a severa o in condizioni cliniche rapidamente ingravescenti. Questi farmaci agiscono, infatti, contrastando la “tempesta citochinica”, riducendo il danno indotto dalla infiammazione innescata dall’infezione e questo si traduce in una apparente riduzione del rischio di morte.

Tuttavia, è importante considerare come gli studi analizzati riguardino prevalentemente tocilizumab per il quale è stato rilevato un incrementato rischio di infezioni fungine, rendendo l’impiego del farmaco non completamente sicuro. Sebbene è possibile che questo effetto collaterale possa essere facilitato dalla concomitante terapia con cortisone e dalla stessa immuno-compromissione indotta dall’infezione da SARS-CoV-2, il dato indica cautela nella somministrazione del farmaco che deve avvenire sotto stretto monitoraggio clinico, attuando una diagnosi precoce e una terapia tempestiva di eventuali infezioni sovrapposte. E’ importante altresì implementare azioni di farmaco-vigilanza allo scopo di meglio chiarire sia l’entità di questo rischio che i possibili fattori associati o predittori per una migliore individualizzazione dell’uso terapeutico (non solo per tocilizumab ma anche per gli altri immuno-modulatori proposti per l’impiego).

Mentre oggi questi farmaci si usano in pazienti già gravi o con progressione di malattia in atto e con elevati livelli di flogosi come anche indicato da AIFA (PCR almeno pari a 75 mg/L per baricitinib, sarilumab e tocilizumab; suPAR almeno pari a 6 ng/ml per anakinra), l’individuazione di fattori di rischio per l’innesco della “cascata citochinica” potrà forse condurre a un impiego preventivo di questi farmaci in coloro che sono maggiormente a rischio, prima che le condizioni immunologiche e cliniche risultino più compromesse, cioè  prima di un eventuale “punto di non ritorno” con l’obiettivo di aumentare l’effetto terapeutico. L’impiego precoce in pazienti meno fragili potrebbe altresì ridurre il rischio di effetti collaterali e di infezioni sovrapposte. Purtroppo, al momento, nemmeno i risultati di questa importante meta-analisi ci possono guidare verso un impiego più intelligente e mirato di questi farmaci.

Rosa L et al

Journal of Clinical Medicine

Ambulatory COVID-19 Patients Treated with Lactoferrin as a Supplementary Antiviral Agent: A Preliminary Study

Journal of Clinical Medicine, https://www.mdpi.com/2077-0383/10/18/4276/htm

CONTENUTO:  Studio retrospettivo sull’utilizzo di lattoferrina in pazienti con COVID-19 asintomatico, paucisintomatico o moderatamente sintomatico. I pazienti trattati con lattoferrina hanno impiegato un tempo significativamente minore per raggiungere la negativizzazione dell’RNA di SARS-CoV-2 su tampone nasale se confrontati con i pazienti non trattati con lattoferrina. Gli autori concludono che la lattoferrina potrebbe rappresentare un’importante terapia supplementare nell’infezione da SARS-CoV-2.

COMMENTO: In questo studio si evidenzia come pazienti trattati con lattoferrina abbiano impiegato un tempo significativamente ridotto (37.5% in meno) per raggiungere la negativizzazione dell’RNA di SARS-CoV-2 da tampone oro-naso-faringeo.

Questo beneficio si riscontra solo nei pazienti sintomatici/paucisintomatici mentre non lo si riscontra nei pazienti asintomatici (probabilmente perché l’asintomatico di per sé ha carica virale più bassa nelle vie respiratorie).

Una criticità da evidenziare è insita nel disegno retrospettivo dello studio per cui la lattoferrina potrebbe essere stata impiegata preferenzialmente in pazienti con infezione contratta da più giorni (e quindi apparentemente più gravi), i quali, quindi, hanno richiesto un periodo più breve per raggiungere la negativizzazione. Peraltro, oltre al trattamento con lattoferrina, venivano altresì impiegati paracetamolo, ibuprofene, cortisone o azitromicina e, quindi, non possiamo essere certi che il vantaggio sia stato riconducibile all’utilizzo della sola lattoferrina o, forse, sia stato maggiormente dovuto al contributo degli altri trattamenti impiegati.

Una ulteriore criticità che dobbiamo evidenziare è inoltre la mancata evidenza del beneficio di questo trattamento sulla riduzione dei sintomi della malattia nonostante gli autori rimarchino i benefici sul rischio di ospedalizzazione che però non sembra essere un dato così forte (solo un paziente del gruppo controllo veniva ospedalizzato e nessuno del gruppo sperimentale veniva ospedalizzato).

Dato interessante che invece emerge dallo studio è che c'è un effetto protettivo di lattoferrina nel ridurre il tempo di risoluzione dei sintomi direttamente proporzionale all'avanzare dell'età.

In conclusione, in un momento pandemico come quello attuale in cui ancora manca un trattamento efficace e poco costoso nonché versatile,  da utilizzare in ambito extraospedaliero (anche se notizie dell’ultim’ora ci forniscono dati confortanti sul farmaco antivirale molnupiravir utilizzabile per via orale), alcuni dati di questo studio possono costituire un buon punto di partenza a favore dell’impiego di lattoferrina. In effetti, il possibile ruolo della lattoferrina merita di venire approfondito mediante studi randomizzati-controllati e con un campione di pazienti più ampio, sia allo scopo di confermarne l’efficacia, che per valutare se particolari sottogruppi di pazienti possano trarre un maggiore beneficio dall’impiego di lattoferrina (in particolare i pazienti di età più avanzata).

Weinreich DM et al

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19

The New England Journal of Medicine,

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2108163?articleTools=true

CONTENUTO:  Trial adattativo randomizzato di fase 3 su pazienti con COVID-19 e fattori di rischio per malattia grave trattati a domicilio. I pazienti venivano assegnati in maniera casuale a ricevere REGEN-COV (una combinazione degli anticorpi monoclonali casirivimab e imdevimab) per via endovenosa a vari dosaggi o placebo. REGEN-COV si è dimostrato efficace nel ridurre il rischio di ospedalizzazione per COVID-19 o di morte e nel ridurre i tempi di risoluzione dei sintomi e la carica virale di SARS-CoV-2.

COMMENTO: La sicurezza e l’efficacia della combinazione di anticorpi neutralizzanti anti-SARS-CoV-2 casirivimab/imdevimab (REGEN-COV), sia al dosaggio di 1200 mg che di 2400 mg, viene confermata in questo studio di fase tre, multicentrico, in doppio cieco, randomizzato contro placebo. Il trial include pazienti non ospedalizzati ma sintomatici ad elevato rischio di progressione per COVID-19 che sono reclutati a meno di 72 ore dalla positività al tampone naso-faringeo per ricerca di SARS-CoV-2 RNA. In particolare, i pazienti trattati con REGEN-COV, indipendentemente dalla posologia, dimostrano una carica virale significativamente ridotta, hanno una risoluzione della sintomatologia più precoce (dieci giorni) rispetto a quelli trattati con placebo (14 giorni), rimangono degenti per un periodo più breve ed hanno un rischio sensibilmente ridotto di trasferimento in area critica. Non è stato tuttavia dimostrato formalmente un beneficio del trattamento in termini di mortalità, ma, verosimilmente, solo per la quantità esigua di decessi registrati nei tre bracci sperimentali (placebo, REGEN-COV 1200 mg, REGEN-COV 2400 mg).

La novità di questa fase dello studio è sostanzialmente che la co-somministrazione di casirivimab e imdevimab è efficace nel prevenire la malattia grave già alla posologia più bassa (1200 mg) nei pazienti ad alto rischio.

Il ruolo dell’associazione casirivimab/imdevimab è centrale per il suo ampio spettro di efficacia contro diverse varianti e in particolare contro le VOCs (variants of concern) attualmente circolanti (beta, gamma e delta). L’utilizzo di questi, come di altri anticorpi monoclonali neutralizzanti anti-SARS-CoV-2, è diventato ormai uno standard di cura consolidato anche in Italia, nello specifico l’associazione casirivimab/imdevimab è attualmente raccomandata da AIFA per il trattamento dei soggetti non ospedalizzati ma ad alto rischio di progressione di malattia al dosaggio di 2400 mg. Questo studio suggerisce di utilizzare dosi dimezzate di farmaco offrendo così virtualmente l’opportunità di accedere al trattamento al doppio dei pazienti a parità di dosi disponibili. Sarebbe interessante a questo punto definire la posologia minima efficace anche nei pazienti già in ossigenoterapia a bassi flussi per COVID-19 (attualmente AIFA indica 8000 mg e solo se non è ancora avvenuta la sieroconversione). Inoltre, non essendo sempre il tipo e l’entità del supporto ventilatorio associato strettamente allo stadio della malattia, resta da provare se anche pazienti che necessitano di ossigenoterapia ad alti flussi o sistemi di ventilazione meccanica non invasiva possano in alcuni casi selezionati beneficiare dell’infusione di anticorpi monoclonali. A questo scopo è auspicabile l’implementazione di biomarcatori predittivi di risposta al trattamento anche per l’infezione da SARS-CoV-2. Un altro punto da dirimere resta il ruolo del REGEN-COV in profilassi post-esposizione che è già supportato dalla letteratura scientifica e contemplato dall’ultimo aggiornamento delle linee guida dell’Infectious Disease Society of America (IDSA), ma che ancora non rappresenta un’opportunità che si può offrire nel nostro Paese.

Arpan Acharya et al.

Discovery and evaluation of entry inhibitors for SARS-CoV-2 and its emerging variants.

J Virol., https://journals.asm.org/doi/10.1128/JVI.01437-21

CONTENUTO: L o studio mira a ricercare dei possibili inibitori dell’ingresso di SARS-CoV-2 nella cellula dell’ospite mediante un modello « computer-aided drug design ». Gli autori hanno rilevato cinque potenziali inibitori dell’ingresso di SARS-CoV-2, due dei quali esprimono attività antivirale sia per il ceppo classico che per le VOC emergenti sudafricana e scozzese ; inoltre, uno di tali inibitori possiede attività sinergica con il remdesivir.

COMMENTO: Esistono diverse situazioni logistiche e cliniche che non consentono la somministrazione del vaccino. Per questa ragione la ricerca didi nuovi farmaci antivirali contro la replicazione di SARS-COV-2 deve andare avanti. In questo ambito si colloca la ricerca pubblicata su J. Virology, la rivista più prestigiosa nell’ambito della virologia di base.  Si tratta di osservazioni importanti sulla identificazione di inibitori della replicazione virale a livello dell’adsorbimento. I dati tuttavia necessitano di consolidamento soprattutto in relazione al loro utilizzo in vivo.

Ader F et al

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

The Lancet Infectious Diseases, https://www.thelancet.com/action/showPdf?pii=S1473-3099%2821%2900485-0

CONTENUTO: Trial randomizzato controllato multicentrico adattativo open-label di fase 3, condotto in 48 centri europei su pazienti >18 anni ricoverati in ospedale con diagnosi di infezione da SARS-CoV-2 confermata laboratoristicamente e polmonite ipossiemica o necessità di ossigenoterapia. I pazienti che ricevevano remdesivir in aggiunta alla terapia standard, confrontati con i pazienti che ricevevano esclusivamente terapia standard, non hanno avuto un significativo miglioramento dello stato clinico (misurato secondo la scala ordinale a 7 punti della WHO) al giorno 15.

COMMENTO: In una recente revisione dei dati di letteratura (DOI: 10.1002/14651858.CD014962), il gruppo Cochrane, analizzando i dati di 7452 pazienti di cui 3886 trattati con remdesivir in 5 trialsrandomizzati e controllati, ha concluso come vi sia un rilevante grado di incertezza sul reale beneficio clinico del farmaco. I risultati dello studio DisCoVeRy vanno ad aggiungersi a quelli già inclusi nella review di Cochrane e puntano nella stessa direzione, suggerendo l’assenza di beneficio clinico significativo nel complesso dei pazienti trattati. Tuttavia, analizzando i risultati dello studio più approfonditamente possiamo notare che: (i) nel sottogruppo di pazienti che non avevano necessità di ventilazione meccanica o ECMO il remdesivir ha ritardato significativamente la necessità di ricorrere alla ventilazione meccanica o ECMO; (ii) il farmaco è stato somministrato in almeno il 50% dei pazienti solo dopo almeno 9 giorni dalla comparsa dei sintomi, cioè probabilmente in ritardo rispetto alla finestra temporale in cui avrebbe potuto produrre i maggiori benefici.  In conclusione, nonostante il valore di remdesivir come primo antivirale nella cura di COVID-19, è innegabile come il suo beneficio clinico sia marginale nel complesso dei pazienti trattati. Ulteriori studi sono necessari per meglio comprendere se e come impiegare questo farmaco allo scopo di ottenere benefici più consistenti in sottopopolazioni di pazienti selezionati, cioè probabilmente in coloro in cui la malattia è meno severa e in fase precoce rispetto al momento della diagnosi di infezione. E’ altresì importante valutarel’impiego del farmaco nel contesto di terapie di combinazione ad esempio con anticorpi monoclonali. Infine, auspichiamo di potere al più presto disporre di antivirali diretti a maggiore potenza, somministrabili per via orale in modo da integrali nei protocolli di terapia domiciliare.

Giossi R et al

A Systematic Review and a Meta-Analysis Comparing Prophylactic and Therapeutic Low Molecular Weight Heparins for Mortality Reduction in 32,688 COVID-19 Patients

Frontiers in Pharmacology ,https://www.frontiersin.org/articles/10.3389/fphar.2021.698008/full

CONTENUTO: Revisione sistematica e meta-analisi che include trial randomizzati controllati e studi osservazionali di coorte sull’efficacia dell’eparina nel trattamento di pazienti con COVID-19, per un totale di 32,688 pazienti. L’eparina, sia a dosaggio profilattico che terapeutico, si dimostra efficace nel ridurre la mortalità nei pazienti ospedalizzati con COVID-19. Tuttavia l’eparina a dosaggio terapeutico pieno è associata ad un maggior rischio di sanguinamento.

COMMENTO: Questo studio ha confermato come, complessivamente, l’utilizzo di eparina riduca significativamente la mortalità ospedaliera dei pazienti affetti da COVID-19.  Sia la dose profilattica che la dose terapeutica sono state infatti associate ad una ridotta mortalità, con il vantaggio però che nel gruppo in cui è stata somministrata la dose profilattica vi è stato anche un minor rischio di sanguinamento. Per questo motivo, alla luce dei dati disponibili, l’utilizzo di una dose profilattica, specialmente nei soggetti con maggior rischio di sanguinamento, appare essere definito come lo standard terapeutico. Tale raccomandazione è già stata peraltro riportata nelle attuali linee guida CHEST, NIH e WHO. Tuttavia, sebbene non siano disponibili evidenze sufficienti che ne supportino l’indicazione, riteniamo come un dosaggio aumentato o terapeutico di eparina non sia da proscrivere in senso assoluto per la prevenzione delle complicanze trombo-emboliche. Infatti, lo studio in oggetto è inficiato da una serie di limitazioni: (i) scarsa qualità degli studi analizzati; (ii) eterogeneità nel dosaggio di eparina; (iii) elevata variabilità nella gravità della malattia; (iv) eterogeneità  tra i vari studi nell’assegnazione dei regimi terapeutici in base alla gravità di COVID-19, livelli di d-dimero e discrezionalità del clinico prescrittore. E’ interessante notare come i risultati pubblicati dai gruppi ATTACC, ACTIV-4a e REMAP-CAP suggeriscano un effetto differente in pazienti in condizioni non critiche (DOI: 10.1056/NEJMoa2105911) rispetto a pazienti in condizioni di malattiacritiche (DOI: 10.1056/NEJMoa2103417). Infatti, solo nei pazienti non critici, il dosaggio terapeutico ha consentito di ottenere un aumento della sopravvivenza alla dimissione con un uso più limitato del supporto di ossigeno. In entrambi i gruppi di pazienti, tuttavia, si è riscontrato un incremento del rischio di sanguinamento in coloro che avevano ricevuto il dosaggio terapeutico (1,9% vs. 0,9% in pazienti non critici e 3,8% vs. 2,3% in pazienti critici). E’ ragionevole quindi ipotizzare come l’impego di dosaggi terapeutici debba essere considerato solo per specifiche categorie di pazienti sulla base delle loro condizioni cliniche, del rischio tromboembolico, del rischio emorragico stimato e anche avvalendosi del risultato di possibili bio-marcatori come il d-dimero. Fino a quando non esisteranno validati algoritmi basati su risultati di studi in pazienti con COVID-19, l’impiego tailored di differenti dosaggi dovrà unicamente basarsi sulla esperienza e decisione del clinico.

Vellas C et al

Clinical Microbiology and Infection

Influence of treatment with neutralizing monoclonal antibodies on the SARS-CoV-2 nasopharyngeal load and quasispecies

Clinical Microbiology and Infection, https://www.clinicalmicrobiologyandinfection.com/action/showPdf?pii=S1198-743X%2821%2900498-5

CONTENUTO: Studio retrospettivo su un totale di 32 pazienti immunosoppressi, >80 anni o a rischio di COVID-19 grave per comorbidità, trattati con anticorpi monoclonali (Bamlanivimab, Bamlanivimab/Etesevimab o Casirivimab/Imdevimab), con l’obiettivo di valutare se la pressione selettiva indotta dalla terapia con anticorpi monoclonali (mAbs) possa facilitare la proliferazione di varianti virali meno responsive alla terapia con mAbs. In 5 pazienti immunosoppressi trattati con Bamlanivimab/Etesevimab sono state individuate mutazioni della proteina spike in grado di ridurre l’attività degli mAbs. I pazienti trattati con mAbs, specialmente se immunosoppressi, dovrebbero essere attentamente monitorizzati e le misure per contenere la diffusione del virus rinforzate.

COMMENTO: Questa evidenza si aggiunge a numerose altre prove a favore delle possibilità evolutive di SARS-CoV-2 che appaiono ben superiori a quelle che si potevano inizialmente immaginare e che trovano la loro massima espressione nella persistenza della pandemia e nell’emergenza e diffusione delle varianti virali. Gli studi in vitro di Andreano et al. (https://doi.org/10.1073/pnas.2103154118) hanno per esempio dimostrato come, sotto pressione selettiva, il virus possa rendersi resistente all’azione di >70% degli anticorpi neutralizzanti analizzati, grazie all’emergenza e accumulo di sole tre mutazioni. Inoltre, Van Egeren et al. (https://doi.org/10.1371/journal.pone.0250780) hanno sviluppato un modello che suggerisce come un ridotto numero di mutazioni che determinano un vantaggio evolutivo sotto pressione selettiva sono presenti in una notevole quota di popolazione virale infettante (quasispecie) senza pregiudizio della fitness del virus, creando il presupposto per l’escape virale e la trasmissione di varianti resistenti che possono condurre al fallimento delle strategie di eliminazione. Tali strategie dovrebbero quindi venire diversificate con l’impiego di presidi terapeutici in grado di colpire più bersagli molecolari diversi in combinazione. Lo studio in oggetto suggerisce come il rischio di escape virale possa essere anche maggiore in pazienti immuno-compromessi per un ridotto controllo da parte della risposta immunitaria dell’ospite.  Andrà valutato se l’impiego di anticorpi monoclonali diversi in grado di colpire uno o più bersagli molecolari più conservati del virus ovvero capaci di sollecitare una più vigorosa risposta immunitaria tramite meccanismi opsonizzanti possano condurre a un controllo più efficace dell’emergenza di varianti resistenti. Infine, particolarmente in pazienti immuno-compromessi, potrebbe essere indicato l’impiego di terapie di combinazione con anticorpi neutralizzanti in associazione ad antivirali ad azione diretta allo scopo di ulteriormente restringere le possibilità evolutive di SARS-CoV-2.

Hinks TSC et al

Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial

The Lancet, July 2021;  DOI: 10.1016/S2213-2600(21)00263-0

COMMENTO: Background

The antibacterial, anti-inflammatory, and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-to-moderate disease are not available. We assessed whether azithromycin is effective in reducing hospital admission in patients with mild-to-moderate COVID-19.

Methods

This prospective, open-label, randomised superiority trial was done at 19 hospitals in the UK. We enrolled adults aged at least 18 years presenting to hospitals with clinically diagnosed, highly probable or confirmed COVID-19 infection, with fewer than 14 days of symptoms, who were considered suitable for initial ambulatory management. Patients were randomly assigned (1:1) to azithromycin (500 mg once daily orally for 14 days) plus standard care or to standard care alone. The primary outcome was death or hospital admission from any cause over the 28 days from randomisation. The primary and safety outcomes were assessed according to the intention-to-treat principle. This trial is registered at ClinicalTrials.gov (NCT04381962) and recruitment is closed.

Findings

298 participants were enrolled from June 3, 2020, to Jan 29, 2021. Three participants withdrew consent and requested removal of all data, and three further participants withdrew consent after randomisation, thus, the primary outcome was assessed in 292 participants (145 in the azithromycin group and 147 in the standard care group). The mean age of the participants was 45·9 years (SD 14·9). 15 (10%) participants in the azithromycin group and 17 (12%) in the standard care group were admitted to hospital or died during the study (adjusted OR 0·91 [95% CI 0·43–1·92], p=0·80). No serious adverse events were reported.

Interpretation

In patients with mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death. Our findings do not support the use of azithromycin in patients with mild-to-moderate COVID-19.

Gupta T et al

Hydroxychloroquine in the treatment of coronavirus disease 2019: Rapid updated systematic review and meta-analysis

Rev Med Virol, July 2021 ; DOI: 10.1002/rmv.2276

COMMENTO: Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 continues to grow and spread throughout the world since being declared a pandemic. Despite extensive scientific research globally including repurposing of several existing drugs, there is no effective or proven therapy for this enigmatic disease which is still largely managed empirically This systematic review evaluated the role of hydroxychloroquine (HCQ) in the treatment of COVID-19 infection and was conducted using Cochrane methodology for systematic reviews of interventional studies including risk of bias assessment and grading of the quality of evidence. Only prospective clinical trials randomly assigning COVID-19 patients to HCQ plus standard of care therapy (test arm) versus placebo/standard of care (control arm) were included. Data were pooled using the random-effects model and expressed as risk ratio (RR) with 95% confidence interval (CI). A total of 10,492 patients from 19 randomised controlled trials were included. The use of HCQ was not associated with higher rates of clinical improvement (RR = 1.00, 95% CI: 0.96-1.03, p = 0.79) or reduction in all-cause mortality by Day14 (RR = 1.07, 95% CI: 0.97-1.19, p = 0.19) or Day28 (RR = 1.08, 95% CI: 0.99-1.19, p = 0.09) compared to placebo/standard of care. There was no significant difference in serious adverse events between the two arms (RR = 1.01, 95% CI: 0.85-1.19, p = 0.95).

There is low-to-moderate certainty evidence that HCQ therapy is generally safe but does not reduce mortality or enhance recovery in patients with COVID-19 infection.

Dougan M et al

Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19

NEJM, July 2021; DOI: 10.1056/NEJMoa2102685

COMMENTO: BACKGROUND

Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications.

METHODS

In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19–related hospitalization or death from any cause by day 29.

RESULTS

A total of 1035 patients underwent randomization and received an infusion of bamlanivimab–etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab–etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19–related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, −1.20; 95% CI, −1.46 to −0.94; P<0.001).

CONCLUSIONS

Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load.

Wang L et al

Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

Science, July 2021 ; DOI: 10.1126/science.abh1766

COMMENTO : The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526 and B.1.617 VOCs. Two antibodies are ultrapotent, with sub-nanomolar neutralization titers (IC50 0.3 to 11.1 ng/mL; IC80 1.5 to 34.5 ng/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.

Tacquard C et al

Impact of High-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19 Pneumonia

Chest, June 2021 ; doi: 10.1016/j.chest.2021.01.017.

COMMENTO: Background

Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent.

Research Question

What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC?

Study Design and Methods

All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight.

Results

Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75).

Interpretation

High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results.

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis

JAMA, July 2021;  DOI: 10.1001/jama.2021.11330

COMMENTO: Importance  Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

Objective  To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

Data Sources  Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

Study Selection  Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

Data Extraction and Synthesis  In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

Main Outcomes and Measures  The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

Results  A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

Conclusions and Relevance  In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Tummino TA et al

Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2

Science, June 2021; DOI: 10.1126/science.abi4708

COMMENTO : Repurposing drugs as treatments for COVID-19 has drawn much attention. Beginning with sigma receptor ligands, and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs, and does not reflect specific target-based activities, rather it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.

Di Castelnuovo A et al

Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Front Med, June 2021; DOI: 10.3389/fmed.2021.639970

COMMENTO: Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.

Di Castelnuovo A et al

Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering

Journal of Helathcare Engineering, January 2021; doi.org/10.1101/2021.01.27.21250238

COMMENTO: The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

Bennett-Guerrero E et al

Severe Acute Respiratory Syndrome Coronavirus 2 Convalescent Plasma Versus Standard Plasma in Coronavirus Disease 2019 Infected Hospitalized Patients in New York: A Double-Blind Randomized Trial

Critical Care Med, July 2021;  DOI: 10.1097/CCM.0000000000005066

COMMENTO: OBJECTIVES:

Four peer-reviewed publications have reported results from randomized controlled trials of convalescent plasma for coronavirus disease 2019 infection; none were conducted in the United States nor used standard plasma as a comparator. To determine if administration of convalescent plasma to patients with coronavirus disease 2019 increases antibodies to severe acute respiratory syndrome coronavirus 2 and improves outcome.

DESIGN:

Double-blind randomized controlled trial.

SETTING:

Hospital in New York.

PATIENTS:

Patients with polymerase chain reaction documented coronavirus disease 2019 infection.

INTERVENTIONS:

Patients were randomized (4:1) to receive 2 U of convalescent plasma versus standard plasma. Antibodies to severe acute respiratory syndrome coronavirus 2 were measured in plasma units and in trial recipients.

MEASUREMENTS AND MAIN RESULTS:

Enrollment was terminated after emergency use authorization was granted for convalescent plasma. Seventy-four patients were randomized. At baseline, mean (sd) Acute Physiology and Chronic Health Evaluation II score (23.4 [5.6] and 22.5 [6.6]), percent of patients intubated (19% and 20%), and median (interquartile range) days from symptom onset to randomization of 9 (6–18) and 9 (6–15), were similar in the convalescent plasma versus standard plasma arms, respectively. Convalescent plasma had high neutralizing activity (median [interquartile range] titer 1:526 [1:359–1:786]) and its administration increased antibodies to severe acute respiratory syndrome coronavirus 2 by 14.4%, whereas standard plasma administration led to an 8.6% decrease (p = 0.005). No difference was observed for ventilator-free days through 28 days (primary study endpoint): median (interquartile range) of 28 (2–28) versus 28 (0–28; p = 0.86) for the convalescent plasma and standard plasma groups, respectively. A greater than or equal to 2 point improvement in the World Health Organization scale was achieved by 20% of subjects in both arms (p = 0.99). All-cause mortality through 90 days was numerically lower in the convalescent plasma versus standard plasma groups (27% vs 33%; p = 0.63) but did not achieve statistical significance. A key prespecified subgroup analysis of time to death in patients who were intubated at baseline was statistically significant; however, sample size numbers were small.

CONCLUSIONS:

Administration of convalescent plasma to hospitalized patients with coronavirus disease 2019 infection increased antibodies to severe acute respiratory syndrome coronavirus disease 2 but was not associated with improved outcome.

 Di Castelnuovo A et al

Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials

Pathogens and Global Health, June 2021; DOI: 10.1080/20477724.2021.1936818

COMMENTO : Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19, but its association with mortality is unclear. We reviewed published literature for evidence of an association between HCQ (with or without azithromycin (AZM)) and total mortality in COVID-19 patients.

Methods: Articles were retrieved until April 29th, 2021 by searching in seven databases. Data were combined using the general-variance-based method.

Results: A total of 25 cohort studies (N=41,339 patients) and 11 randomized clinical trials (RCTs; N=8,709) were found. The use of HCQ was not associated with mortality in meta-analysis of RCTs (pooled risk ratio (PRR): 1.08, 95%CI: 0.97-1.20; I2=0%), but it was associated with 20% lower mortality risk (PRR=0.80, 95%CI: 0.69-0.93; I2=80%) in pooling of cohort studies. The negative association with mortality was mainly apparent by pooling cohort studies that used lower doses of HCQ (≤400 mg/day; PRR=0.69, 95%CI: 0.57-0.87). Use of HCQ+AZM (11 studies) was associated with 25% non-statistically significant lower mortality risk (PPR=0.75; 0.51-1.10; P=0.15). Use of HCQ was not associated with severe adverse events (PRR=1.12, 95%CI: 0.88-1.44; I2=0%).

Conclusions: HCQ use was not associated with mortality in COVID-19 patients in pooling results from RCTs (high level of certainty of evidence), but it was associated with 20% mortality reduction when findings from observational studies were combined (low level of certainty of evidence). The reduction of mortality was mainly apparent in observational studies where lower doses of HCQ were used. These findings might help disentangling the debate on HCQ use in COVID-19.

Guimaraes PO et al

Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia

NEJM, June 2021; DOI: 10.1056/NEJMoa2101643

COMMENTO: BACKGROUND : The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear.

METHODS : We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed.

RESULTS : A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P=0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group.

CONCLUSIONS : Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo.

Copin R et al

The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies

Cell, June 2021; doi.org/10.1016/j.cell.2021.06.002

COMMENTO : Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.

Rubin R et al

Could Statins Do More Than Lower Cholesterol in Patients With COVID-19?

JAMA, June 2021; doi:10.1001/jama.2021.8201

COMMENTO: Preclinical studies indicate that statins could worsen COVID-19 or at least increase the chances of infection, Italian researchers pointed out in a recent JAMA Internal Medicine article. That’s because statins, along with several other classes of drugs used to treat atherosclerotic heart disease and its risk factors, upregulate angiotensin-converting enzyme 2 (ACE2) receptors, which happen to be SARS-CoV-2’s gateway into cells. Yet theoretically, the authors noted, the same drugs may improve the clinical course of COVID-19 by reducing vasoconstriction, inflammation, and oxidation.

Di Castelnuovo A et al

Research Article Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering

https://www.researchgate.net/publication/352002163_Research_Article_Disentangling_the_Association_of_Hydroxychloroquine_Treatment_with_Mortality_in_Covid-19_Hospitalized_Patients_through_Hierarchical_Clustering

COMMENTO: The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification  of  effect  by  treatment with  HCQ.  We  identified  two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, andone of 483 generally older and  more comorbid subjects, more prevalently men and smokers. The latter group was  at  increased  death  risk  adjusted  by  HCQ  (HR[CI95%] = 3.80[3.08-4.67]),  while  HCQ  showed  an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p<0.001). This is was driven by a differential association of HCQ with  mortality between the high  (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medicationsin  use and  were concordant  with  associations with  disease  severity and  outcome.  These findings  suggest aparticularly  beneficial  effect of  HCQ within  low risk  Covid-19 patients and may  contribute to  clarifying thecurrent controversy on HCQ efficacy in Covid-19 treatment

Corti D et al

Tackling COVID-19 with neutralizing monoclonal antibodies

Cell, June 2021;  DOI: 10.1016/j.cell.2021.05.005

COMMENTO: Monoclonal antibodies (mAbs) have revolutionized the treatment of several human diseases, including cancer and autoimmunity and inflammatory conditions, and represent a new frontier for the treatment of infectious diseases. In the last 20 years, innovative methods have allowed the rapid isolation of mAbs from convalescent subjects, humanized mice, or libraries assembled in vitro and have proven that mAbs can be effective countermeasures against emerging pathogens. During the past year, an unprecedentedly large number of mAbs have been developed to fight coronavirus disease 2019 (COVID-19). Lessons learned from this pandemic will pave the way for the development of more mAb-based therapeutics for other infectious diseases. Here, we provide an overview of SARS-CoV-2-neutralizing mAbs, including their origin, specificity, structure, antiviral and immunological mechanisms of action, and resistance to circulating variants, as well as a snapshot of the clinical trials of approved or late-stage mAb therapeutics.

 Lambermont B et al

Outcome Improvement Between the First Two Waves of the Coronavirus Disease 2019 Pandemic in a Single Tertiary-Care Hospital in Belgium

Critical Care Explorations, May 2021; DOI: 10.1097/CCE.0000000000000438

COMMENTO : Objectives: To compare patient management and outcome during the first and second waves of the coronavirus 2019 pandemic.

Design: Single-center prospective cohort study.

Setting: Tertiary-care University Hospital.

Patients: All adult patients admitted in either the first (from March 15 to May 15, 2020) or second (from October 1 to November 30, 2020) wave of coronavirus disease 2019.

Interventions: None.

Measurements and Main Results: Primary outcome was 30-day mortality. During the second wave of the coronavirus disease 2019 pandemic, 33 patients (4.8%) were transferred due to overcrowding and excluded from analysis. There were 341 (first wave of the coronavirus disease 2019 pandemic) and 695 (second wave of the coronavirus disease 2019 pandemic) coronavirus disease 2019 patients admitted to the hospital, with median age first wave of the coronavirus disease 2019 pandemic as 68 (57–80) and second wave of the coronavirus disease 2019 pandemic as 71 (60–80) (p = 0.15), and similar admission severity. For the first wave of the coronavirus disease 2019 pandemic versus second wave of the coronavirus disease 2019 pandemic, 30-day mortality was 74/341 (22%) and 98/662 (15%) (p = 0.007). In the ward, 11/341 (3.2%) and 404/662 (61%) received dexamethasone (p < 0.001); 6/341 (2%) and 79/662 (12%) received high-flow nasal oxygen (p < 0.0001); 2/341 (0.6%) and 88/662 (13.3%) received remdesivir (p < 0.0001); 249/341 (73%) and 0/662 (0%) received hydroxychloroquine (p < 0.0001); and 87/341 (26%) and 128/662 (19%) (p = 0.024) patients were transferred to ICU. On ICU admission, median Sequential Organ Failure Assessment was 6 (3–7) and 4 (3–6) (p = 0.02). High-flow nasal oxygen was given to 16/87 (18%) and 102/128 (80%) (p < 0.001); 69/87 (79%) and 56/128 (44%) received mechanical ventilation (p < 0.001) with durations 17 days (10–26 d) and 10 days (5–17 d) (p = 0.01). Median ICU length of stay was 14 days (5–27 d) and 6 days (3–11 d) (p < 0.001). Finally, 16/87 (18%) and 8/128 (6%) received renal replacement therapy (p = 0.0055); and 64/87 (74%) and 51/128 (40%) needed vasopressor support (p < 0.001).

Conclusions: The main therapeutic changes between the first wave of the coronavirus disease 2019 pandemic and the second wave of the coronavirus disease 2019 pandemic were use of steroids, unrestrictive use of high-flow nasal oxygen for hypoxemic patients, and transfer of patients to other geographic areas in the case of ICU overcrowding. These changes were associated with a decreasein 30-day mortality, ICU admission, and organ support.

Ranjbar K et al

Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial

BMC Infectious Diseases, April 2021; doi.org/10.1186/s12879-021-06045-3

COMMENTO : Background : Although almost a year has passed since the Coronavirus disease 2019 (COVID-19) outbreak and promising reports of vaccines have been presented, we still have a long way until these measures are available for all. Furthermore, the most appropriate corticosteroid and dose in the treatment of COVID-19 have remained uncertain. We conducted a study to assess the effectiveness of methylprednisolone treatment versus dexamethasone for hospitalized COVID-19 patients.

Methods : In this prospective triple-blinded randomized controlled trial, we enrolled 86 hospitalized COVID-19 patients from August to November 2020, in Shiraz, Iran. The patients were randomly allocated into two groups to receive either methylprednisolone (2 mg/kg/day; intervention group) or dexamethasone (6 mg/kg/day; control group). Data were assessed based on a 9-point WHO ordinal scale extending from uninfected (point 0) to death (point 8).

Results : There were no significant differences between the groups on admission. However, the intervention group demonstrated significantly better clinical status compared to the control group at day 5 (4.02 vs. 5.21, p = 0.002) and day 10 (2.90 vs. 4.71, p = 0.001) of admission. There wasalso a significant difference in the over all mean score between the intervention group and the control group, (3.909 vs. 4.873 respectively, p = 0.004). The meanlength of hospitalstaywas 7.43 ± 3.64 and 10.52 ± 5.47 days in the intervention and control groups, respectively (p = 0.015). The need for a ventilator was significantly lower in the intervention group than in the control group (18.2% vs 38.1% p = 0.040).

Conclusion : In hospitalized hypoxic COVID-19 patients, methylprednisolone demonstrated better results compared to dexamethasone.

Mariette X et al

Effectiveness of Tocilizumab in Patients Hospitalized With COVID-19. A Follow-up of the CORIMUNO-TOCI-1 Randomized Clinical Trial

JAMA, May 2021;  doi:10.1001/jamainternmed.2021.2209

COMMENTO: We previously published a trial of tocilizumab in hospitalized patients who were receiving oxygen (rate, ≥3 L/min) but did not require high-flow or mechanical ventilation.3 The study met its primary composite end point, which was the proportion of patients who required noninvasive ventilation or intubation or who died at day 14, but found no survival difference at day 28. In this follow-up article, we extended follow-up to 90 days and examined whether survival varied with baseline CRP levels.

Ader F et l

An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19

Clinical Microbiology and Infection, May 2021; DOI: 10.1016/j.cmi.2021.05.020

COMMENTO: Objectives

We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support.

Methods

We conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely.

Results

The intention-to-treat population included 583 participants (lopinavir/ritonavir, n=145; lopinavir/ritonavir-IFN-β-1a, n=145; hydroxychloroquine, n=145; control, n=148), among whom 418 (71.7%) were male, the median age was 63 years (IQR, 54-71) and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval [CI] 0.55-1.26, P=0.39); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, P=0.08); hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, P=0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.

Conclusion

In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

Medeiros IG et al

A small interfering RNA (siRNA) database for SARS-CoV-2

Scientific Reports, April 2021; doi.org/10.1038/s41598-021-88310-8

COMMENTO : Coronavirus disease 2019 (COVID-19) rapidly transformed into a global pandemic, for which a demand for developing antivirals capable of targeting the SARS-CoV-2 RNA genome and blocking the activity of its genes has emerged. In this work, we presented a database of SARS-CoV-2 targets for small interference RNA (siRNA) based approaches, aiming to speed the design process by providing a broad set of possible targets and siRNA sequences. The siRNAs sequences are characterized and evaluated by more than 170 features, including thermodynamic information, base context, target genes and alignment information of sequences against the human genome, and diverse SARS-CoV-2 strains, to assess possible bindings to off-target sequences. This dataset is available as a set of four tables, available in a spreadsheet and CSV (Comma-Separated Values) formats, each one corresponding to sequences of 18, 19, 20, and 21 nucleotides length, aiming to meet the diversity of technology and expertise among laboratories around the world. A metadata table (Supplementary Table S1), which describes each feature, is also provided in the aforementioned formats. We hope that this database helps to speed up the development of new target antivirals for SARS-CoV-2, contributing to a possible strategy for a faster and effective response to the COVID-19 pandemic.

Ministero della Salute

GESTIONE DOMICILIARE DEI PAZIENTI CON INFEZIONE DA SARS-CoV-2

https://www.trovanorme.salute.gov.it/norme/renderNormsanPdf?anno=2021&codLeg=80056&parte=1%20&serie=null

COMMENTO : […] non utilizzare routinariamente corticosteroidi. L’uso dei corticosteroidi è raccomandato esclusivamente nei soggetti con malattia COVID-19 grave che necessitano di supplementazione di ossigeno. L’impiego di tali farmaci a domicilio può essere considerato solo in pazienti con fattori di rischio di progressione di malattia verso forme severe, in presenza di un peggioramento dei parametri pulsossimetrici che richieda l’ossigenoterapia ove non sia possibile nell’immediato il ricovero per sovraccarico delle strutture ospedaliere. L’utilizzo della terapia precoce con steroidi si è rivelata inutile se non dannosa in quanto in grado di inficiare lo sviluppo di un’adeguata risposta immunitaria […].

Leentjens J et al

COVID-19-associated coagulopathy and antithrombotic agents—lessons after 1 year

The Lancet, April 2021; doi.org/10.1016/S2352-3026(21)00105-8

COMMENTO : COVID-19 isassociatedwith a high incidence of thrombotic complications, which can beexplained by the complex and unique interplaybetweencoronaviruses and endothelialcells, the local and systemic inflammatory response, and the coagulation system. Empirically, an intensified dose of thrombosis prophylaxisisbeingused in patients admitted to hospitalwith COVID-19 and several guidelines on this topic have been published, although the insufficiency of high quality and direct evidence has led to weakrecommendations. In thisViewpointwesummarise the pathophysiology of COVID-19 coagulopathy in the context of patients who are ambulant, admitted to hospital, and criticallyill or non-criticallyill, and those post-dischargefromhospital. We also review data from random ised controlled trials in the pastyear of antithrombotictherapy in patients who are critically ill. These data provide the first high-qualityevidence on optimal use of antithrombotic therapy in patients with COVID-19. Pharmacologicalthromboprophylaxisis not routinely recommended for patients who are ambulant and post-discharge. A first ever trial in non-criticallyill patients who were admitted to hospital has shownthat a therapeutic dose of low-molecular-weightheparinmightimproveclinicaloutcomes in this population. In criticallyill patients, this same treatment does not improve outcomes and prophylactic dose anticoagulant thromboprophylaxis is recommended. In the upcoming months we expect numerous data from the on going antithrombotic COVID-19 studies to guide clinicians at different stages of the disease.

Tleyjeh IM et al

Efficacy and safety of tocilizumab in COVID-19 patients: A living systematic Review and meta-analysis: first update

Clinical Microbiology and Infection, April 2021; doi.org/10.1016/j.cmi.2021.04.019

COMMENTO : Background : Cytokine release syndrome withelevated interleukin-6 (IL-6) levelsisassociatedwithmultiorgan damage and death in severe coronavirus disease 2019 (COVID-19).

Objectives : To update data a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist, tocilizumab, in COVID-19 patients.

Data sources : Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google from October 8, 2020 till February 24, 2021.

Studyeligibilitycriteria : Randomizedcontrolled trials (RCTs) and observationalstudies at low or moderaterisk of bias.

Participants : Hospitalized COVID-19 patients.

Interventions : Tocilizumab versus placebo or standard of care.

Methods : Wepooledcruderisk ratios (RRs) of RCTswithrandomeffects model and evaluatedinconsistencybetweenstudieswith I2. Weassessed the certainty of evidenceusing the GRADE approach.

Results : Of 1600 citations, 8 RCTs and 28 cohorts were eligible. The 8 RCTs, at low risk of bias, with 6311 patients examined the effect of tocilizumab on short-term mortality; pooled RR was 0.91 (95%CI 0.78, 1.07, I2 = 25%). Only the REMAP-CAP and RECOVERY trials with the majority of their patients on concomitant corticosteroids, showed lower 30-day mortality with tocilizumab use, RR 0.74 (95%CI 0.59, 0.93) and 0.89 (95%CI 0.81, 0.97), respectively. Seven RCTs, with 5391 patients examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.84 (95% CI 0.76, 0.93), I2 = 0%, with a corresponding number needed to treat of 20 (95%CI 14.3–33.3). Eight RCTs, with 5,340 patients, examined the effect of tocilizumab on a composite of poor outcome; pooled RR was 0.82 (95% CI 0.76, 0.90, I2 = 3%). Data from the RCTs showed a lower risk of infections and no higher risk of serious adverse events with tocilizumab; pooled RR 0.67 (95%CI 0.45, 0.99, eight RCTs) and 0.85 (95%CI 0.63, 1.16, seven RCTs), respectively. Among 28 cohortswith 15484 patients, the pooledadjusted RR for mortalitywas 0.53 (95%CI 0.43, 0.67, I2 = 76%).

Conclusions : Cumulative high certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized patients withsevere COVID-19. Moderatecertaintyevidence shows that tocilizumab reduces the risk of pooroutcome and the risk of secondary infections in hospitalized COVID-19 patients. This review will continuous lye valuate the role of tocilizumab in COVID-19 treatment.

Bafna K et al

Hepatitis C Virus Drugs That Inhibit the SARS-CoV-2 Papain-Like Protease Synergize with Remdesivir to Suppress Viral Replication in Cell Culture

Cell Reports, April 2021; doi.org/10.1016/j.celrep.2021.109133

COMMENTO : Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessedt en hepatitis C virus (HCV) protease-inhibitordrugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (Mpro) and HCV NS3/4A protease. Virtual dockingexperiments show that these HCV drugs can potentially bind into the Mpro binding cleft. We show thatseven HCV drugs inhibit both SARS-CoV-2 Mproprotease activity and SARS-CoV-2 virus replication in Vero and/or humancells. However, their Mpro inhibiting activities did not correlate with their antiviral activities. This conundrumwasresolved by demonstratingthat four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazo previrinhibit the SARS CoV-2 papain-like protease (PLpro). HCV drugs that inhibitPLprosynergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir’s antiviral activity as much as 10-fold, while those that only inhibit Mpro do not synergize with remdesivir.

Focosi D et al

Patient-blood management for COVID19 convalescent plasma therapy: should donor-recipient differences in concentration and affinity of neutralizing antibodies drive use?

Clinical Microbiology and Infection, April 2021; doi.org/10.1016/j.cmi.2021.04.003

COMMENTO : Background : COVID19 convalescent plasma (CCP) is being extensively investigated as a treatment, with mixed results to date. Overall, there has been a generalized lack of appropriateness in prescriptions, which is termed patient-blood management in the field of transfusion medicine.

Objectives : Weaimed at dissectingstudy design variables which could affect clinical outcome after CCP therapy. We focus here on variables such as pre transfusion antibody testing in recipients, dose adjustements, and antibody affinity measurements.

Sources : Wesearched PubMed and preprint servers for relevant preclinical and clinical studies discussing each of these variables in the field of CCP therapy.

Content : We show evidences on how neglecting those variables has affected the outcomes of the vast majority of CCP clinical trials to date.

Implications : A better understanding of such variables will improve the design of the nex tgeneration of CCP clinical trials. This will likely lead to bette rclinical outcomes and minimize risks from subneutralizing neutralizing antibody doses.

Adarsh B et al

Infectious Diseases Society of America Guidelines on the Treatment and Management ofPatients with COVID-19

InfectiousDiseases Society of America, April 2021 ; DOI: 10.1093/cid/ciaa478

COMMENTO : Background: There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19). There is a need for frequently updated practice guidelines on their use, based on criticalevaluation of rapidlyemergingliterature.

Objective: There are many pharmacologic therapies that are being used or considered for treatment of COVID-19. There is a need for frequently updated practice guidelines on their use,based on critical evaluation of rapidly emerging literature.

Methods: In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise. The process followed a rapidrecommendation

checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer reviewed and grey literature was conducted. The Grading of Recommendations Assessment,

Development and Evaluation (GRADE) approachwasused to assess the certainty of evidence and make recommendations.

Results: On April 11, 2020, IDSA released online initial treatment recommendations and narrative summaries of other treatments under evaluation. Sincethat time, the guideline paneland methodologists have continued to monitor the literature and issue updates andaddendums to these guidelines in response to evolvingresearch.

Conclusions: Since the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the

efficacy and safety of various therapies for COVID-19, given that we could not make a determination whether the benefits outweigh harms for most treatments.

Ramakrishnan S et al

Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial

The Lancet, April 2021; doi.org/10.1016/S2213-2600(21)00160-0

COMMENTO: Background : Multiple early reports of patients admitted to hospital with COVID-19 showed that patients with chronic respiratory disease were significantly under-represented in these cohorts. We hypothesised that the widespread use of inhaled glucocorticoids among these patients was responsible for this finding, and tested if inhaled glucocorticoids would be an effective treatment for early COVID-19.

Methods : We performed an open-label, parallel-group, phase 2, randomised controlled trial (Steroids in COVID-19; STOIC) of inhaled budesonide, compared with usual care, in adults within 7 days of the onset of mild COVID-19 symptoms. The trial was done in the community in Oxfordshire, UK. Participants were randomly assigned to inhaled budsonide or usual care stratified for age (≤40 years or >40 years), sex (male or female), and number of comorbidities (≤1 and ≥2). Randomisation was done using random sequence generation in block randomisation in a 1:1 ratio. Budesonide dry powder was delivered using a turbohaler at a dose of 800 μg per actuation. Participants were asked to take two inhalations twice a day until symptom resolution. The primary endpoint was COVID-19-related urgent care visit, including emergency department assessment or hospitalisation, analysed for both the per-protocol and intention-to-treat (ITT) populations. The secondary outcomes were self-reported clinical recovery (symptom resolution), viral symptoms measured using the Common Cold Questionnare (CCQ) and the InFLUenza Patient Reported Outcome Questionnaire (FLUPro), body temperature, blood oxygen saturations, and SARS-CoV-2 viral load. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. This trial is registered with ClinicalTrials.gov, NCT04416399.

Findings : From July 16 to Dec 9, 2020, 167 participants were recruited and assessed for eligibility. 21 did not meet eligibility criteria and were excluded. 146 participants were randomly assigned—73 to usual care and 73 to budesonide. For the per-protocol population (n=139), the primary outcome occurred in ten (14%) of 70 participants in the budesonide group and one (1%) of 69 participant in the usual care group (difference in proportions 0·131, 95% CI 0·043 to 0·218; p=0·004). For the ITT population, the primary outcome occurred in 11 (15%) participants in the usual care group and two (3%) participants in the budesonide group (difference in proportions 0·123, 95% CI 0·033 to 0·213; p=0·009). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was eight. Clinical recovery was 1 day shorter in the budesonide group compared with the usual care group (median 7 days [95% CI 6 to 9] in the budesonide group vs 8 days [7 to 11] in the usual care group; log-rank test p=0·007). The mean proportion of days with a fever in the first 14 days was lower in the budesonide group (2%, SD 6) than the usual care group (8%, SD 18; Wilcoxon test p=0·051) and the proportion of participants with at least 1 day of fever was lower in the budesonide group when compared with the usual care group. As-needed antipyretic medication was required for fewer proportion of days in the budesonide group compared with the usual care group (27% [IQR 0–50] vs 50% [15–71]; p=0·025) Fewer participants randomly assigned to budesonide had persistent symptoms at days 14 and 28 compared with participants receiving usual care (difference in proportions 0·204, 95% CI 0·075 to 0·334; p=0·003). The mean total score change in the CCQ and FLUPro over 14 days was significantly better in the budesonide group compared with the usual care group (CCQ mean difference −0·12, 95% CI −0·21 to −0·02 [p=0·016]; FLUPro mean difference −0·10, 95% CI −0·21 to −0·00 [p=0·044]). Blood oxygen saturations and SARS-CoV-2 load, measured by cycle threshold, were not different between the groups. Budesonide was safe, with only five (7%) participants reporting self-limiting adverse events.

Interpretation : Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19.

Schjørring OL et al

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure

NEJM, April 2021; DOI: 10.1056/NEJMoa2032510

COMMENTO: BACKGROUND : Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target.

METHODS : In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days.

RESULTS : At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P=0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P=0.24).

CONCLUSIONS : Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days.

Kumar RN et al

Real-World Experience of Bamlanivimab for COVID-19: A Case-Control Study

Clinical Infectious Diseases, April 2021; doi.org/10.1093/cid/ciab305

COMMENTO : Background : COVID-19 has strained healthcare systems with patient hospitalizations and deaths. Anti-spike monoclonal antibodies, including bamlanivimab, have demonstrated reduction in hospitalization rates in clinical trials, yet real-world evidence is lacking.

Methods : We conducted a retrospective case-control study across a single healthcare system of non-hospitalized patients, age 18 years or older, with documented positive SARS-CoV-2 testing, risk factors for severe COVID-19, and referrals for bamlanivimab via emergency use authorization. Cases were defined as patients who received bamlanivimab; contemporary controls had a referral order placed but did not receive bamlanivimab. The primary outcome was 30-day hospitalization rate from initial positive SARS-CoV-2 PCR. Descriptive statistics, including Chi-square and Mann-Whitney U test, were performed. Multivariable logistic regression was used for adjusted analysis to evaluate independent associations with 30-day hospitalization.

Results : Between November 20, 2020 and January 19, 2021, 218 patients received bamlanivimab (cases) and 185 were referred but did not receive drug (controls). Thirty-day hospitalization rate was significantly lower among patients who received bamlanivimab (7.3% v 20.0%, RR 0.37, 95% CI 0.21-0.64, p<0.001), and the number needed to treat was 8. On logistic regression, odds of hospitalization were increased in patients not receiving bamlanivimab and with a higher number of pre-specified comorbidities (OR 4.19 CI: 1.31-2.16, p<0.001; OR 1.68, CI: 2.12-8.30, p<0.001, respectively).

Conclusion : Ambulatory patients with COVID-19 who received bamlanivimab had a lower 30-day hospitalization than control patients in real-world experience. We identified receipt of bamlanivimab and fewer comorbidities as protective factors against hospitalization.

Ufficio Registri di Monitoraggio AIFA

Monitoraggio Anticorpi Monoclonali per COVID-1

https://www.aifa.gov.it/documents/20142/1475526/report_n.1_monitoraggio_monoclonali_09.04.2021.pdf

COMMENTO : Dati relativi alla settimana 2 – 8 aprile 2021

(estrazione dati 9 aprile 2021)

Gallay L et al

14-Day survival among older adults with severe SARS-Cov2 infection treated with corticosteroid: a cohort study

Clinical Microbiology and Infection, April 2021; doi.org/10.1016/j.cmi.2021.03.021

COMMENTO : Objective : To assess the effectiveness of corticosteroids among older adults with COVID-19 pneumonia requiring oxygen.

Methods : We used routine care data from 36 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.4 mg/kg/day eq. prednisone (treatment group) versus standard of care (control group) among adults ≥ 80 years old with PCR-confirmed SARS-CoV-2 infection or CT-scan images typical of COVID-19 pneumonia, requiring oxygen ≥ 3 L/min, and with an inflammatory syndrome (C-reactive protein ≥ 40 mg/L). The primaryoutcomewasoverallsurvival at day 14. In our main analysis, characteristics of patients at baseline (i.e., time when patients met all inclusion criteria) werebalanced by usingpropensity-score inverse probability of treatmentweighting.

Results : Among the 267 patients included in the analysis, 98 wereassigned to the treatment group. Theirmedianagewas 86 years (interquartile range 83 to 90), and 95% had a SARS-CoV-2 PCR-confirmeddiagnosis. In total, 43/98 (43.9%) patients in the treatment group and 84/166 (50.6%) in the control group diedbeforeday 14 (weightedhazard ratio [wHR] 0.67, 95% CI 0.46 to 0.99). The treatment and control groups did not differsignificantly for the proportion of patients discharged to home/rehabilitation at day 14 (wRR 1.12, 95% CI 0.68 to 1.82). Twenty-two (16.7%) patients receivingcorticosteroidsdeveloped adverse events, but only 11 (6.4%) from the control group.

Conclusions : Corticosteroidswereassociatedwith a significantincrease in the overallsurvival at day 14 of patients aged 80 years and olderhospitalised for severe COVID-19.

Suter F et al

A SIMPLE, HOME-THERAPY ALGORYTHM TO PREVENT HOSPITALIZATION OF COVID-19 PATIENTS: A RETROSPECTIVE OBSERVATIONAL MATCHED-COHORT STUDY

medRXiv – preprint, not peer reviewed, March 2021; doi.org/10.1101/2021.03.25.21254296

COMMENTO : Background Effective simple, home-treatment algorithms implemented on the basis of a pathophysiologic and pharmacologic rationale to accelerate recovery and prevent hospitalization of patients with early coronavirus disease 2019 (COVID-19) would have major implications for patients and health care providers.

Methods This academic, matched-cohort study compared outcomes of 90 consecutive consenting patients with mild COVID-19 treated at home by their family physicians from October 2020 to January 2021 according to the proposed recommendation algorithm with those of 90 age-, sex-, and comorbidities-matched patients who received other therapeutic regimens. Primary outcome was time to resolution of major symptoms. Secondary outcomes included prevention of hospitalization. Analyses were by intention-to-treat.

Findings All patients achieved complete remission. The median [IQR] time to resolution of major symptoms was 18 [14-23] days in the ‘recommended’ schedule cohort and 14 [7-30] days in the matched ‘control’ cohort (p=0·033). Minor symptoms persisted in a lower percentage of patients in the ‘recommended’ than in the ‘control’ cohort (23·3% versus 73·3%, respectively, p<0·0001) and for a shorter period (p=0·0107). Two patients in the ‘recommended’ cohort were hospitalized compared to 13 (14·4%) controls (Log-rank test, p=0·0038). Prevention algorithm abated the days and cumulative costs of hospitalization by >90% (from 481 to 44 days and from 296 to 28 thousand Euros, respectively. 1·2 patients had to be treated to save one hospitalization event.

Interpretation Implementation of an early, home-treatment algorithm failed to accelerate recovery from major symptoms of COVID-19, but almost blunted the risk of hospitalization and related treatment costs.

Evidence before this study We searched PubMed and the Cochrane Library for peer-reviewed articles published in any language up to March 19, 2021, using the search terms (“2019-nCoV” or “SARS-CoV-2” or “COVID-19”) and (“early” or “outpatient” or “treatment” or “home”). Our search did not identify any randomised clinical trials or observational studies that assessed the effectiveness of treatment regimens targeting early mild symptoms of COVID-19 in the outpatient setting.

Added value of this study In this fully academic, observational matched-cohort study, we found that early home-treatment of 90 consecutive patients with mild COVID-19 by their family physicians according to the proposed recommendation algorithm, designed on the basis of a pathophysiologic and pharmacologic rationale, significantly reduced the risk of hospitalisation compared to 90 age-, sex-, and comorbidities-matched patients who received other therapeutic regimens. Days of hospitalization and related treatment costs were reduced by more than 90%. Just 1.2 patients needed to be treated to save one hospitalization event. The ‘recommended’ schedule cohort required a few more days to achieve resolution of major symptoms, including fever, dyspnea, musculoskeletal pain, headache and cough compared to the ‘control’ cohort. Symptoms, such as anosmia and ageusia/dysgeusia, persisted less commonly and for a shorter period in the ‘recommendation’ than in the ‘control’ cohort.

Implications of the available evidence The finding that the implementation of the proposed simple treatment algorithm during the initial, mild phase of COVID-19 has the potential to prevent disease progression, eventually limiting the need of hospital admission may have major implications for patients and health care providers. Indeed, preventing hospitalisations due to worsening of COVID-19 will not only save lives, but will also contribute to remarkably reduce treatment costs and to reshape health care systems that are overburdened because of the pandemic effects.

European Medicines Agency

EMA advises against use of ivermectin for the prevention or treatment of COVID-19 outside randomised clinical trials

https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-19-outside-randomised-clinical-trials

COMMENTO : EMA has reviewed the latest evidence on the use of ivermectin for the prevention and treatment of COVID-19 and concluded that the available data do not support its use for COVID-19 outside well-designed clinical trials.

In the EU, ivermectin tablets are approved for treating some parasitic worm infestations while ivermectin skin preparations are approved for treating skin conditions such as rosacea. Ivermectin is also authorised for veterinary use for a wide range of animal species for internal and external parasites.

Ivermectin medicines are not authorised for use in COVID-19 in the EU, and EMA has not received any application for such use.

Janiaud P et al

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19 A Systematic Review and Meta-analysis

JAMA, March 2021 ; DOI: 10.1001/jama.2021.2747

COMMENTO : Importance  Convalescent plasma is a proposed treatment for COVID-19.

Objective  To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).

Data Sources  PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021.

Study Selection  The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting.

Data Extraction and Synthesis  Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance–weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.

Main Outcomes and Measures  All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events.

Results  A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was −1.21% (95% CI, −5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was −2.56% [95% CI, −13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences.

Conclusions and Relevance  Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

Garibaldi BT et al

Comparison of Time to Clinical Improvement With vs Without Remdesivir Treatment in Hospitalized Patients With COVID-19

JAMA, March 2021;  doi:10.1001/jamanetworkopen.2021.3071

COMMENTO : Importance : Clinical effectiveness data on remdesivir are urgently needed, especially among diverse populations and in combination with other therapies.

Objective : To examine whether remdesivir administered with or without corticosteroids for treatment of coronavirus disease 2019 (COVID-19) is associated with more rapid clinical improvement in a racially/ethnically diverse population.

Design, Setting, and Participants :  This retrospective comparative effectiveness research study was conducted from March 4 to August 29, 2020, in a 5-hospital health system in the Baltimore, Maryland, and Washington, DC, area. Of 2483 individuals with confirmed severe acute respiratory syndrome coronavirus 2 infection assessed by polymerase chain reaction, those who received remdesivir were matched to infected individuals who did not receive remdesivir using time-invariant covariates (age, sex, race/ethnicity, Charlson Comorbidity Index, body mass index, and do-not-resuscitate or do-not-intubate orders) and time-dependent covariates (ratio of peripheral blood oxygen saturation to fraction of inspired oxygen, blood pressure, pulse, temperature, respiratory rate, C-reactive protein level, complete white blood cell count, lymphocyte count, albumin level, alanine aminotransferase level, glomerular filtration rate, dimerized plasmin fragment D [D-dimer] level, and oxygen device). An individual in the remdesivir group with k days of treatment was matched to a control patient who stayed in the hospital at least k days (5 days maximum) beyond the matching day.

Exposures : Remdesivir treatment with or without corticosteroid administration.

Main Outcomes and Measures : The primary outcome was rate of clinical improvement (hospital discharge or decrease of 2 points on the World Health Organization severity score), and the secondary outcome, mortality at 28 days. An additional outcome was clinical improvement and time to death associated with combined remdesivir and corticosteroid treatment.

Results : Of 2483 consecutive admissions, 342 individuals received remdesivir, 184 of whom also received corticosteroids and 158 of whom received remdesivir alone. For these 342 patients, the median age was 60 years (interquartile range, 46-69 years), 189 (55.3%) were men, and 276 (80.7%) self-identified as non-White race/ethnicity. Remdesivir recipients had a shorter time to clinical improvement than matched controls without remdesivir treatment (median, 5.0 days [interquartile range, 4.0-8.0 days] vs 7.0 days [interquartile range, 4.0-10.0 days]; adjusted hazard ratio, 1.47 [95% CI, 1.22-1.79]). Remdesivir recipients had a 28-day mortality rate of 7.7% (22 deaths) compared with 14.0% (40 deaths) among matched controls, but this difference was not statistically significant in the time-to-death analysis (adjusted hazard ratio, 0.70; 95% CI, 0.38-1.28). The addition of corticosteroids to remdesivir was not associated with a reduced hazard of death at 28 days (adjusted hazard ratio, 1.94; 95% CI, 0.67-5.57).

Conclusions and Relevance : In this comparative effectiveness research study of adults hospitalized with COVID-19, receipt of remdesivir was associated with faster clinical improvement in a cohort of predominantly non-White patients. Remdesivir plus corticosteroid administration did not reduce the time to death compared with remdesivir administered alone.

Olimpieri PP et al

Mortality after remdesivir treatment of pneumonia in hospitalised patients with laboratory confirmed COVID-19: national data in the Italian real-world practice collected by the AIFA

https://europepmc.org/article/PPR/PPR300812

COMMENTO : Background. The Italian Medicines Agency (AIFA) granted reimbursement for remdesivir (Veklury®) exclusively to COVID-19 patients with pneumonia and requiring supplemental low-flow oxygen therapy and instituted a monitoring registry to control use appropriateness and to manage vials delivery. The aim of this work is to provide a picture on mortality in a large cohort of patients having these characteristics. Methods: The Remdesivir Registry (RR) collected very few and essential healthcare data necessary to manage the distribution of vials across Italian hospitals. Mortality by day 15 and 29 was estimated using the Kaplan-Meier estimator and the Cox proportional-hazards (PH) model was applied to analyse the risks connected to patient’s background features relative to all-cause mortality by day 29. Findings. 16396 SARS-CoV-2 positive patients were included in the registry with a mean age of 66·3 years and a male/female ratio of 2·0/1. 2226 deaths were registered. The Kaplan–Meier estimate of national mortality by day 15 was 6·9% (95% CI: 6·5%-7·3%) while mortality by day 29 was 11·5% (95% CI: 11·0%-11·9%). Cox-adjusted estimates by day 29 shown 18·4% (IC 95% 16·9% -19·9%) mortality in the class 65 years or older. Interpretation. To the best of our knowledge, this study provided the largest figure on mortality after the remdesivir treatment of SARS-Cov2 pneumonia in the real-world context showing a dramatic effect of the age on mortality.

Grieco DL et al

Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure The HENIVOT Randomized Clinical Trial

JAMA, March 2021; doi:10.1001/jama.2021.4682

COMMENTO : Importance  High-flow nasal oxygen is recommended as initial treatment for acute hypoxemic respiratory failure and is widely applied in patients with COVID-19.

Objective To assess whether helmet noninvasive ventilation can increase the days free of respiratory support in patients with COVID-19 compared with high-flow nasal oxygen alone.

Design, Setting, and Participants  Multicenter randomized clinical trial in 4 intensive care units (ICUs) in Italy between October and December 2020, end of follow-up February 11, 2021, including 109 patients with COVID-19 and moderate to severe hypoxemic respiratory failure (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤200).

Interventions  Participants were randomly assigned to receive continuous treatment with helmet noninvasive ventilation (positive end-expiratory pressure, 10-12 cm H2O; pressure support, 10-12 cm H2O) for at least 48 hours eventually followed by high-flow nasal oxygen (n = 54) or high-flow oxygen alone (60 L/min) (n = 55).

Main Outcomes and Measures  The primary outcome was the number of days free of respiratory support within 28 days after enrollment. Secondary outcomes included the proportion of patients who required endotracheal intubation within 28 days from study enrollment, the number of days free of invasive mechanical ventilation at day 28, the number of days free of invasive mechanical ventilation at day 60, in-ICU mortality, in-hospital mortality, 28-day mortality, 60-day mortality, ICU length of stay, and hospital length of stay.

Results  Among 110 patients who were randomized, 109 (99%) completed the trial (median age, 65 years [interquartile range {IQR}, 55-70]; 21 women [19%]). The median days free of respiratory support within 28 days after randomization were 20 (IQR, 0-25) in the helmet group and 18 (IQR, 0-22) in the high-flow nasal oxygen group, a difference that was not statistically significant (mean difference, 2 days [95% CI, −2 to 6]; P = .26). Of 9 prespecified secondary outcomes reported, 7 showed no significant difference. The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow nasal oxygen group (30% vs 51%; difference, −21% [95% CI, −38% to −3%]; P = .03). The median number of days free of invasive mechanical ventilation within 28 days was significantly higher in the helmet group than in the high-flow nasal oxygen group (28 [IQR, 13-28] vs 25 [IQR 4-28]; mean difference, 3 days [95% CI, 0-7]; P = .04). The rate of in-hospital mortality was 24% in the helmet group and 25% in the high-flow nasal oxygen group (absolute difference, −1% [95% CI, −17% to 15%]; P > .99).

Conclusions and Relevance Among patients with COVID-19 and moderate to severe hypoxemia, treatment with helmet noninvasive ventilation, compared with high-flow nasal oxygen, resulted in no significant difference in the number of days free of respiratory support within 28 days. Further research is warranted to determine effects on other outcomes, including the need for endotracheal intubation.

Jimenez-Soto R et al

The impact of different prophylactic anticoagulation doses on the outcomes of patients with COVID-19

Thrombosis Research, November 2020 ; doi.org/10.1182/blood-2020-142594

COMMENTO: We conducted a study to determine if intermediate and formal anticoagulation were associated with a lower risk of death. From March 12th to July 15th, 2020 we collected information on clinical, biochemical and imaging variables from patients admitted at the ABC Medical Center, a private hospital in Mexico City, as part of the ARMII cohort. We included patients who were 18 years or older and had a diagnosis of COVID-19, defined as a positive PCR for SARS-CoV2 and/or a chest CT scan with characteristic findings and who received thromboprophylaxis with enoxaparin since admission. We excluded patients receiving anticoagulation prior to admission and those who received other anticoagulants. The study was approved by local scientific and ethics committees.

Yuan S et al

Clofazimine broadly inhibits coronaviruses including SARS-CoV-2

Nature, March 2021; doi.org/10.1038/s41586-021-03431-4

COMMENTO: COVID-19 pandemic is the third zoonotic coronavirus (CoV) outbreak of the century after severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) since 2012. Treatment options for CoVs are largely lacking. Here we show that clofazimine, an anti-leprosy drug with a favourable safety profile, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 and MERS-CoV replication in multiple in vitro systems. The FDA-approved molecule was found to inhibit viral spike-mediated cell fusion and viral helicase activity. In a hamster model of SARS-CoV-2 pathogenesis, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and faecal viral shedding, and also mitigated inflammation associated with viral infection. Combinatorial application of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted upper respiratory tract viral shedding. Since clofazimine is orally bioavailable and has a comparatively low manufacturing cost, it is an attractive clinical candidate for outpatient treatment and remdesivir-based combinatorial therapy for hospitalized COVID-19 patients, particularly in developing countries. Taken together, our data provide evidence that clofazimine may have a role in the control of the current pandemic SARS-CoV-2, and, possibly most importantly, emerging CoVs of the future.

INSPIRATION Investigators

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit The INSPIRATION Randomized Clinical Trial

JAMA, March 2021; doi:10.1001/jama.2021.4152

COMMENTO: Importance  Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis.

Objective  To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU).

Design, Setting, and Participants  Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020.

Interventions  Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up.

Main Outcomes and Measures  The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated.

Results  Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, −6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, −∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01).

Conclusions and Relevance  Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19.

Al-Samkari H et al

Finding the Optimal Thromboprophylaxis Dose in Patients With COVID-19

JAMA, March 2021; doi:10.1001/jama.2021.4295

COMMENTO: Therefore, with an important contribution from the trial performed by Sadeghipour and colleagues, the preponderance of high-quality evidence at this time supports use of standard-dose thromboprophylaxis, not dose escalation, in critically ill patients with COVID-19. However, pending the publication of final results from the ATTACC, REMAP-CAP, and ACTIV-4a multiplatform trial confirming the interim report, escalated thromboprophylaxis could be appropriate in moderately ill hospitalized patients with COVID-19 while balancing known comorbidities and bleeding risks. Additional important questions pertaining to thromboprophylaxis in COVID-19 remain under active investigation, including the utility of postdischarge thromboprophylaxis and the effect of outpatient thromboprophylaxis for patients with mild COVID-19 not requiring hospital admission.

Geurts MH et al

The Organoid Platform: Promises and Challenges as Tools in the Fight against COVID-19

Stem Cell Reports, March 2021; doi.org/10.1016/j.stemcr.2020.11.009

COMMENTO: Many pathogenic viruses that affect man display species specificity, limiting the use of animal models. Studying viral biology and identifying potential treatments therefore benefits from the development of in vitro cell systems that closely mimic human physiology. In the current COVID-19 pandemic, rapid scientific insights are of the utmost importance to limit its impact on public health and society. Organoids are emerging as versatile tools to progress the understanding of SARS-CoV-2 biology and to aid in the quest for novel treatments.

Kyriazopoulou E et al

An open label trial of anakinra to prevent respiratory failure in COVID-19

eLife ; March 2021 ; DOI: 10.7554/eLife.66125

COMMENTO: Background It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19.

Methods 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied.

Results 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata.

Conclusions Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance.

Ramakrishnan S et al

Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial

medRXiv – not peer reviewed, February 2021; https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3777194

COMMENTO: Background Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness.

Methods We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment.

Results 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care.

Conclusion Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.

ACTIV-3/TICO LY-CoV555 Study Group

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

NEJM, December 2020; DOI: 10.1056/NEJMoa2033130

COMMENTO: BACKGROUND : LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.

METHODS : In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.

RESULTS : On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P=0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P=0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).

CONCLUSIONS : Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure.

Touafchia A et al

Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns

Clinical Microbiology and Infection, February 2021; doi.org/10.1016/j.cmi.2021.02.013

COMMENTO : Objectives : In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia.

Methods : Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23th of September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% Confident Intervals (95% CI).

Results : We found 302 cardiac effects including 94 bradycardia (31%) among the 2,603 reports with remdesivir prescribed in COVID-19 patients. Most of reports were serious (75, 80%) and in 16 reports (17%) evolution was fatal. Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65; 95% CI 1.23, 2.22). Consistent results were observed in other sensitivity analyses.

Conclusions : This post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. This result is in line with pharmacodynamic properties of the remdesivir.

Kalil AC et al

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

NEJM, March 2021 ; DOI: 10.1056/NEJMoa2031994

COMMENTO : BACKGROUND : Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.

METHODS : We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.

RESULTS : A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P=0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3; P=0.03), as were new infections (5.9% vs. 11.2%; difference, −5.3 percentage points; 95% CI, −8.7 to −1.9; P=0.003).

CONCLUSIONS : Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events.

López-Medina E et al

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial

JAMA, March 2021;  doi:10.1001/jama.2021.3071

COMMENTO : Importance  Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit.

Objective  To determine whether ivermectin is an efficacious treatment for mild COVID-19.

Design, Setting, and Participants  Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state’s health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020.

Intervention  Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200).

Main Outcomes and Measures  Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected.

Results  Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group).

Conclusion and Relevance  Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

Hill A et al

Preliminary meta-analysis of randomized trials of ivermectin to treat SARSCoV-2 infection

ResearchSquare – not peer reviewed, January; DOI:10.21203/rs.3.rs-148845/v1

COMMENTO : Introduction: Ivermectin is a well-established antiparasitic drug licensed since 1981, more recently approved for its anti- inflammatory effects against rosacea. It is being investigated for repurposing against SARS-CoV-2. In-vitro, ivermectin showed some antiviral activity but at higher concentrations than achieved in human plasma after normal oral dosing. An animal model demonstrated pathological benefits in COVID19 but no effect on viral RNA. We aimed to assess the available global data from randomized controlled trials (RCTs) of ivermectin in COVID-19. Methods: We conducted a systematic search of PUBMED, EMBASE, MedRxiv and trial registries. We excluded prevention studies and non-randomized or casecontrolled studies. We identified and included 18 RCTs. Data were combined from 2282 patients into a systematic review and meta-analysis.

Results: Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. Ivermectin showed significantly shorter duration of hospitalization compared to control. In six RCTs of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12- 0.52]; p=0.0002); 14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in controls) with favorable clinical recovery and reduced hospitalization.

Discussion: Many studies that were included were not yet published or peerreviewed and meta-analyses are prone to confounding issues. Furthermore, there was a wide variation in standards of care across trials, and ivermectin dose and duration of treatment was heterogeneous. Ivermectin should be validated in larger, appropriately controlled randomized trials before the results are sufficient for review by regulatory authorities.

Ma S et al

Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials

Nature, February 2021;  DOI: 10.1038/s41392-021-00521-7

COMMENTO : The benefits and harms of corticosteroids for patients with severe coronavirus disease 2019 (COVID-19) remain unclear. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from December 31, 2019 to October 1, 2020 to identify randomized controlled trials (RCTs) that evaluated corticosteroids in severe COVID-19 patients. The primary outcome was all-cause mortality at the longest follow-up. Secondary outcomes included a composite disease progression (progression to intubation, ventilation, extracorporeal membrane oxygenation, ICU transfer, or death among those not ventilated at enrollment) and incidence of serious adverse events. A random-effects model was applied to calculate risk ratio (RR) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation approach to evaluate the certainty of the evidence. Seven RCTs involving 6250 patients were included, of which the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial comprised nearly 78% of all included subjects. Results showed that corticosteroids were associated with a decreased all-cause mortality (27.3 vs. 31.1%; RR: 0.85; 95% CI: 0.73–0.99; P = 0.04; low-certainty evidence). Trial sequential analysis suggested that more trials were still required to confirm the results. However, such survival benefit was absent if RECOVERY trial was excluded (RR: 0.83; 95% CI: 0.65–1.06; P = 0.13). Furthermore, corticosteroids decreased the occurrence of composite disease progression (30.6 vs. 33.3%; RR: 0.77; 95% CI: 0.64–0.92; P = 0.005), but not increased the incidence of serious adverse events (3.5 vs. 3.4%; RR: 1.16; 95% CI: 0.39–3.43; P = 0.79).

Khan F et al

Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19

Thorax, February 2021; doi: 10.1136/thoraxjnl-2020-215266

COMMENTO : BACKGROUND: There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19. METHODS: Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality. RESULTS: 71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I(2)=0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I(2)=98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I(2)=76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI -0.07 to 0.80, I(2)=93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent. CONCLUSION: Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings.

Al- Samkari H et al

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

Annals of Internal Medicine, January 2021; DOI: 10.7326/m20-6739 

COMMENTO : Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19).

Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival.

Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used.

Setting: 67 hospitals in the United States.

Participants: Adults with COVID-19 admitted to a participating ICU.

Measurements: Time to death, censored at hospital discharge, or date of last follow-up.

Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]).

Limitation: Observational design.

Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation.

Patell R et al

Pharmacologic Thromboprophylaxis and Thrombosis in Hospitalized Patients with COVID-19: A Pooled Analysis

Thrombosis and Haemosthasis, December 2020;  DOI: 10.1055/s-0040-1721664

COMMENTO : Background Coronavirus disease 2019 (COVID-19) increases thrombosis in hospitalized patients prompting adoption of different thromboprophylaxis strategies. Safety and efficacy of escalated-dose pharmacologic thromboprophylaxis are not established.

Objectives To determine the pooled incidence of thrombosis/bleeding in hospitalized patients with COVID-19 for standard-dose, intermediate-dose, therapeutic anticoagulation, and no pharmacologic thromboprophylaxis.

Methods MEDLINE, EMBASE, and Cochrane CENTRAL were searched up to August 29, 2020 for studies reporting pharmacologic thromboprophylaxis and thrombosis or bleeding. Pooled event rates were calculated using a random-effects model.

Results Thirty-five observational studies were included. The pooled incidence rates of total venous thromboembolism (N = 4,685) were: no prophylaxis 41.9% (95% confidence interval [CI]: 28.1–57.2, I 2 = 76%), standard-dose prophylaxis 19.8% (95% CI: 13.2–28.6, I 2 = 95%), intermediate-dose prophylaxis 11.9% (95% CI: 4.3–28.6, I 2 = 91%), and therapeutic-dose anticoagulants 10.5% (95% CI: 4.2–23.8, I 2 = 82%, p = 0.003). The pooled incidence rates of arterial thrombosis (N = 1,464) were: no prophylaxis 11.3% (95% CI: 5.2–23.0, I 2 = 0%), standard-dose prophylaxis 2.5% (95% CI: 1.4–4.3, I 2 = 45%), intermediate-dose prophylaxis 2.1% (95% CI: 0.5–7.7, I 2 = 45%), and therapeutic-dose anticoagulants 1.3% (95% CI: 0.2–8.8, I 2 = 0, p = 0.009). The pooled bleeding event rates (N = 6,393) were nonsignificantly higher in therapeutic-dose anticoagulants compared with standard-dose prophylaxis, (6.3 vs. 1.7%, p = 0.083).

Conclusion Thrombosis rates were lower in hospitalized COVID-19 patients who received pharmacologic thromboprophylaxis. Thrombosis and bleeding rates for patients receiving intermediate-dose thromboprophylaxis or therapeutic anticoagulation were similar to those who received standard-dose pharmacologic thromboprophylaxis.

Rentsch CT et al

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study

The BMJ, February 2021; doi.org/10.1136/bmj.n311 

COMMENTO : Objective : To evaluate whethere arly initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of deathamong patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States.

Design :Observational cohort study.

Setting Nationwidecohort of patients receiving care in the Department of VeteransAffairs, a large integrated national healthcare system.

Participants : All 4297 patients admitted to hospitalfrom 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation.

Main outcome measures : The main outcome was 30 day mortality. Secondary outcomes were in patient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding tha trequired transfusion.

Results :  Of 4297 patients admitted to hospitalwith covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients receivedsubcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurredduring hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 dayswas 14.3% (95% confidence interval 13.1% to 15.5%) amongthosewhoreceivedprophylactic anticoagulation and 18.7% (15.1% to 22.9%) amongthosewhodid not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 daymortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations werefound for inpatientmortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative biasanalysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 daymortality). Results persisted in several sensitivity analyses.

Conclusions :Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospitalwith covid-19 wasassociated with a decreased risk of 30 daymortality and no increasedrisk of seriousbleedingevents. Thesefindingsprovidestrong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.

Libster R et al

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

NEJM, February 2021; DOI: 10.1056/NEJMoa2033700

COMMENTO : BACKGROUND : Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Amongthem, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodie sshould be administered earlier in the course of illness.

METHODS : We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in olderadult patients within 72 hoursafter the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient wasbreathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

RESULTS : A total of 160 patients underwent randomization. In the intention-to-treat population, severerespiratorydiseasedevelopedin 13 of 80 patients (16%) whoreceived convalescent plasma and 25 of 80 patients (31%) whoreceived placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative riskreduction of 48%. A modified intention-to-treatanalysisthatexcluded 6 patients whohad a primary end-point eventbefore infusion of convalescent plasma or placebo showed a largereffect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse eventswereobserved.

CONCLUSIONS : Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildlyillinfectedolderadultsreduced the progression of Covid-19.

Simonovich VA et al

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia

NEJM, February 2021; DOI: 10.1056/NEJMoa2031304

COMMENTO : BACKGROUND : Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials.

METHODS : We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primaryoutcomewas the patient’sclinicalstatus 30 daysafter the intervention, as measured on a six-point ordinal scalerangingfrom total recovery to death.

RESULTS : A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients werelost to follow-up. At day 30 day, no significantdifferencewasnotedbetween the convalescent plasma group and the placebo group in the distribution of clinicaloutcomesaccording to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P=0.46). Overallmortalitywas 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Total SARS-CoV-2 antibodytiterstended to behigher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse eventsweresimilar in the two groups.

CONCLUSIONS : No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo.

Alhazzani W et al

Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update

Critical Care Medicine, February 2021; doi: 10.1097/CCM.0000000000004899

COMMENTO : BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidlygrowingevidence base, weimplemented a living guideline model to provide guidance on the management of patients withsevere or critical coronavirus disease 2019 in the ICU.

METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update,the panel addressednine questions relevant to managingsevere or critical coronavirus disease 2019 in the ICU. Weused the World Health Organization’s definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effectsmeta-analysis to summarize treatment effects. We assessed the quality of the evidenceusing the Grading of Recommendations, Assessment,Development, and Evaluation approach, thenused the evidence-to-decisionframework to generat erecommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility.

RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outsideclinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in non ventilated patients withsevere coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning.

CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

Feld JJ et al

Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial

The Lancet, February 2021; doi.org/10.1016/S2213-2600(20)30566-X

COMMENTO : Background

To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19.

Methods

In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259.

Findings

Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15–16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49–31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported.

Interpretation

Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding.

Prud’homme E et al

Effect of Prone Positioning on the respiratory support of non-intubated patients with COVID-19 and acute hypoxemic respiratory failure: A retrospective matching cohortstudy

Chest, January 2021 ; DOI: 10.1016/j.chest.2021.01.048

COMMENTO: Coronavirus disease 2019 (COVID-19) associated respiratory illness may lead to acute respiratory distress syndrome (ARDS). In intubated patients with severe ARDS, early, prolonged and repeated sessions of prone positioning (PP) decrease mortality. Awake PP is feasible, improves oxygenation in some patients and may prevent respiratory worsening. The main objective of the present study was to evaluate the effect of PP on the outcome of spontaneously breathing COVID-19 patients with acute respiratory failure.

Chapman J et al

CNS Complications in Adult Patients Treated With Extracorporeal Membrane Oxygenation

Critical Care Medicine, February 2021 ; DOI: 10.1097/CCM.0000000000004789

COMMENTO: Objectives: To describe the incidence and outcomes of radiologically confirmed acute CNS complications in extracorporeal membrane oxygenation patients at an Australian extracorporeal membrane oxygenation referral center and identify associated patient characteristics.

Design: Retrospective cohort study.

Setting: Single-center tertiary institution.

Patients: Four-hundred twelve consecutive adult patients supported with extracorporeal membrane oxygenation from 2009 to 2017.

Results: Fifty-five patients (13.3%) had a CNS complication confirmed by CT or MRI, including ischemic stroke (7.0%), intracerebral hemorrhage (3.4%), hypoxic ischemic encephalopathy (3.6%), and spinal cord injury (1.2%). CNS complication rates in the venoarterial, venovenous, and veno-pulmonary artery extracorporeal membrane oxygenation subgroups were 18.0%, 4.6%, and 13.6%, respectively. Neurologic complications were independently associated with the use of venoarterial extracorporeal membrane oxygenation (p = 0.002) and renal replacement therapy (p = 0.04). Sixty-five percent of patients with a neurologic complication died during their hospital admission compared with 32% of patients without this complication (p < 0.001). Venoarterial extracorporeal membrane oxygenation, renal replacement therapy, and days of extracorporeal membrane oxygenation support were also associated with hospital mortality and remained so after adjustment in a multivariable regression model (p = 0.01, p < 0.001, and p = 0.003, respectively).

Conclusions: CNS complications appear to occur more frequently in patients requiring circulatory as opposed to respiratory support on extracorporeal membrane oxygenation and are independently associated with mortality. It remains unclear if these complications are causative of a poor outcome or a marker of severity of the underlying condition. Further research is required to better elucidate modifiable or preventable aspects through better patient selection and change in ongoing care.

Kaka AS et al

Major Update: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points

Annals of Internal Medicine, February 2021; doi.org/10.7326/M20-5752

COMMENTO: Background: Remdesivir is being studied and used for treatment of coronavirus disease 2019 (COVID-19).

Purpose: To update a previous review of remdesivir for adults with COVID-19, including new meta-analyses of patients with COVID-19 of any severity compared with control.

Data Sources: Several sources from 1 January 2020 through 7 December 2020.

Study Selection: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. New evidence is incorporated by using living review methods.

Data Extraction: 1 reviewer abstracted data; a second reviewer verified the data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used.

Data Synthesis: The update includes 5 RCTs, incorporating data from a new large RCT and the final results of a previous RCT. Compared with control, a 10-day course of remdesivir probably results in little to no reduction in mortality (risk ratio [RR], 0.93 [95% CI, 0.82 to 1.06]; 4 RCTs) but may result in a small reduction in the proportion of patients receiving mechanical ventilation (RR, 0.71 [CI, 0.56 to 0.90]; 3 RCTs). Remdesivir probably results in a moderate increase in the percentage of patients who recovered and a moderate decrease in serious adverse events and may result in a large reduction in time to recovery. Effect on hospital length of stay or percentage remaining hospitalized is mixed. Compared with a 10-day course for those not requiring ventilation at baseline, a 5-day course may reduce mortality, the need for ventilation, and serious adverse events while increasing the percentage of patients who recovered or clinically improved.

Limitation: Summarizing findings was challenging because of varying disease severity definitions and outcomes.

Conclusion: In hospitalized adults with COVID-19, remdesivir probably results in little to no mortality difference but probably improves the percentage recovered and reduces serious harms and may result in a small reduction in the proportion receiving ventilation. For patients not receiving ventilation, a 5-day course may provide greater benefits and fewer harms with lower drug costs than a 10-day course.

Ammassari A et al

Comparison of Demand for Drugs Used for COVID-19 Treatment and Other Drugs

During the Early Phase of the COVID-19 Pandemic in Italy

JAMA Open, Febraury 2021; doi:10.1001/jamanetworkopen.2020.37060

COMMENTO: In February 2020, Italy was the first European country to detect coronavirus disease 2019 (COVID-19) in individuals and rapidly turned into one of the most-affected regions of the world. The National Health Service (NHS), which provides universal coverage to citizens, was challenged as never before in the history of the institution. Because no approved drug was available, patients received potentially effective drugs, participated in clinical trials, accessed compassionate drug use programs, or self-medicated. The aim of this study was to evaluate changes in drug demand during the early phase of the COVID-19 outbreak in Italy compared with the period before the outbreak.

WHO Solidarity Trial Consortium

Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results

NEJM,  Febraury 2021; DOI: 10.1056/NEJMoa2023184

COMMENTO: BACKGROUND : World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19).

METHODS : We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.

RESULTS : At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.

CONCLUSIONS : These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.

Lacout A et al

Hydroxychloroquine in Hospitalized Patients with Covid-19

NEJM , February 2021 ; DOI: 10.1056/NEJMc2035374

COMMENTO: In vitro studies show that the effect of hydroxychloroquine is mainly mediated by alkalinization of the phagolysosomes,  where it can

concentrate about 1500 times more than in plasma. This effect can be obtained with low doses of hydroxychloroquine because of its long elimination half-life.

Fiolet T et al

Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis

Clinical Microbiology and Infection, 1 January 2021 ; doi.org/10.1016/j.cmi.2020.08.022

COMMENTO: Background : Hydroxychloroquine or chloroquine with or without azithromycin have been widely promoted to treat coronavirus disease 2019 (COVID-19) following early in vitro antiviral effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Objective : The aim of this systematic review and meta-analysis was to assess whether chloroquine or hydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared with the standard of care.

Data sources : PubMed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv were searched up to 25 July 2020.

Study eligibility criteria : We included published and unpublished studies comparing the mortality rate between patients treated with chloroquine or hydroxychloroquine with or without azithromycin and patients managed with standard of care.

Participants : Patients ≥18 years old with confirmed COVID-19.

Interventions : Chloroquine or hydroxychloroquine with or without azithromycin.

Methods : Effect sizes were pooled using a random-effects model. Multiple subgroup analyses were conducted to assess drug safety.

Results : The initial search yielded 839 articles, of which 29 met our inclusion criteria. All studies except one were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin. Among the 29 articles, three were randomized controlled trials, one was a non-randomized trial and 25 were observational studies, including 11 with a critical risk of bias and 14 with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysis included 11 932 participants for the hydroxychloroquine group, 8081 for the hydroxychloroquine with azithromycin group and 12 930 for the control group. Hydroxychloroquine was not significantly associated with mortality: pooled relative risk (RR) 0.83 (95% CI 0.65–1.06, n = 17 studies) for all studies and RR = 1.09 (95% CI 0.97–1.24, n = 3 studies) for randomized controlled trials. Hydroxychloroquine with azithromycin was associated with an increased mortality (RR = 1.27; 95% CI 1.04–1.54, n = 7 studies). We found similar results with a Bayesian meta-analysis.

Conclusion : Hydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19 patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.

Paul M et al

Has the door closed on hydroxychloroquine for SARS-COV-2?

Clinical Microbiology and Infection, 19 October 2020; doi.org/10.1016/j.cmi.2020.10.011

COMMENTO: Shortly following the onset of the SARS-COV-2 pandemic, Raoult's group from Marseille published a study describing improved virological cure with hydroxychloroquine (HCQ), especially in combination with azithromycin. Beyond being “non-randomized” this was a small, unadjusted comparison including 36 patients in total, reporting only on virological cure and excluding from the analysis the most severely ill patients. It was probably meant as an alert for a potentially useful treatment and reported as responsible sharing of the local experience given the urgent situation (as the authors noted “we believe that our results should be shared with the scientific community”). Yet this publication launched a heated debate of HCQ believers and non-believers, moving far beyond the realm of science, with politicians expressing views, countries stockpiling the drug and people taking it prophylactically. This also led to a flurry of studies, resulting now in more than 25 systematic reviews and/or meta-analyses summarizing specifically the efficacy of HCQ for COVID-19 from these studies on PubMed and 12 unpublished on medRxiv. A systematic review of observational studies and randomized controlled (RCTs) published recently in Clinical Microbiology and Infection concluded no benefit for HCQ and increased mortality with HCQ and azithromycin. Is this the last word on HCQ for corona?

Raoult D et al

Rational for meta-analysis and randomized treatment: the COVID-19 example

Clinical Microbiology and Infection, 21 October 2020; doi.org/10.1016/j.cmi.2020.10.012

COMMENTO: All in all, there is no indisputable science of therapeutic trials and their evaluation. It cannot be said that significant progress has been made in the practice of care by randomized trials in infectious diseases. They have generated a new specialty, particularly in the medical world, which is that of methodologists and analysts who, by definition, are convinced that their method is the best. In principle, over the history of hydroxychloroquine, depending on the studies that one decides to exclude, one is likely to retain one hypothesis or another.

Leibovici L

Difficult editorial decisions

Clinical Microbiology and Infection, 27 January 2021; DOI: 10.1016/j.cmi.2020.10.013

COMMENTO: In the present issue of CMI we publish a systematic review and meta-analysis on hydroxychloroquine with and without azithromycin for treating COVID-19; two accompanying commentaries; and letters to the editor addressing the systematic review, including the authors' response. Almost all involved difficult editorial decisions, although of different kinds. This is a partial explanation on how we made these decisions.

Zheng R et al

COVID-19-associated coagulopathy: thromboembolism prophylaxis and poor prognosis in ICU

BMCExperimental Hematology & Oncology, 01 Febrary 2021; doi.org/10.1186/s40164-021-00202-9

COMMENTO: Background : Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities which are indicators of higher mortality especially in severe cases.

Methods : We studied patients with proven COVID-19 disease in the intensive care unit of Jinyintan Hospital, Wuhan, China from 30 to 2019 to 31 March 2020.

Results : Of 180 patients, 89 (49.44 %) had died, 85 (47.22 %) had been discharged alive, and 6 (3.33 %) were still hospitalised by the end of data collection. A D-dimer concentration of > 0.5 mg/L on admission was significantly associated with 30 day mortality, and a D-dimer concentration of > 5 mg/L was found in a much higher proportion of non-survivors than survivors. Sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC) scoring systems were dichotomised as < 4 or ≥ 4 and < 5 or ≥ 5, respectively, and the mortality rate was significantly different between the two stratifications in both scoring systems. Enoxaparin was administered to 68 (37.78 %) patients for thromboembolic prophylaxis, and stratification by the D-dimer concentration and DIC score confirmed lower mortality in patients who received enoxaparin when the D-dimer concentration was > 2 than < 2 mg/L or DIC score was ≥ 5 than < 5. A low platelet count and low serum calcium concentration were also related to mortality.

Conclusions : A D-dimer concentration of > 0.5 mg/L on admission is a risk factor for severe disease. A SIC score of > 4 and DIC score of > 5 may be used to predict mortality. Thromboembolic prophylaxis can reduce mortality only in patients with a D-dimer concentration of > 2 mg/L or DIC score of ≥ 5.

Mitjà O et al

A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19

NEJM, 4 Febrary 2021; DOI: 10.1056/NEJMoa2021801

COMMENTO: BACKGROUND : Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking.

METHODS : We conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)–confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days.

RESULTS : The analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported.

CONCLUSIONS : Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient.

Starr TN et al

Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Science, 1 December 2020; doi.org/10.1101/2020.11.30.405472

COMMENTO : Antibodies are a potentialtherapy for SARS-CoV-2, but the risk of the virus evolving to escape themremainsunclear. Herewemap how all mutations to SARS-CoV-2’s receptor-binding domain (RBD) affect binding by the antibodies in the REGN-COV2 cocktail and the antibody LY-CoV016. Thesecompletemapsuncover a single amino-acid mutation thatfully escapes the REGN-COV2 cocktail, whichconsists of twoantibodiestargeting distinct structural epitopes. The mapsalsoidentify viral mutations that are selected in a persistentlyinfected patient treatedwith REGN-COV2, as well as during in vitro viral escape selections. Finally, the mapsrevealthat mutations escaping the individualantibodies are alreadypresent in circulating SARS-CoV-2 strains. Overall, thesecomplete escape maps enable interpretation of the consequences of mutations observedduring viral surveillance.

Thomson EC et al

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

Cell, 22 January 2021; doi: 10.1016/j.cell.2021.01.037

COMMENTO : SARS-CoV-2 can mutate and evadeimmunity, withconsequences for efficacy of emerging vaccines and antibodytherapeutics. Hereinwedemonstratethat the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S, and provideepidemiological, clinical, and molecularcharacterization of a prevalent, sentinel RBM mutation, N439K. Wedemonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections withsimilarclinicaloutcomes as compared to wild-type. We show the N439K mutation confersresistanceagainstseveralneutralizing monoclonal antibodies, including one authorized for emergency use by the FDA, and reduces the activity of some polyclonal sera frompersonsrecoveredfrom infection. Immune evasion mutations thatmaintain virulence and fitness such as N439K can emergewithin SARS-CoV-2 S, highlighting the need for ongoingmolecular surveillance to guide development and usage of vaccines and therapeutics.

Chaccour C et al

The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial

EClinicalMedicine, 19 January 2021 ; doi.org/10.1016/j.eclinm.2020.100720

COMMENTO: Background : Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset.

Methods : Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022.

Findings : All patients recruited completed the trial (median age, 26 [IQR 19–36 in the ivermectin and 21–44 in the controls] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77–1·09, p = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) and day 7 (p = 0·16 for gene E; p = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment (p = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001).

Interpretation : Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials.

Schjorring OL et al

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure

NEJM, 20 January 2021; DOI: 10.1056/NEJMoa2032510

COMMENTO: BACKGROUND : Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target.

METHODS : In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days.

RESULTS : At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P=0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P=0.24).

CONCLUSIONS : Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days.

Weinreich DM et al

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

NEJM, 21 January 2021 ; DOI: 10.1056/NEJMoa2035002

COMMENTO: BACKGROUND : Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.

METHODS : In this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients.

RESULTS : Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.

CONCLUSIONS : In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629. opens in new tab.)

Morgan C et al

Almitrine Infusion in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Acute Respiratory Distress Syndrome: A Single-Center Observational Study

Critacl Care medicine, February 2021 - Volume 49 - Issue 2 - p e191-e198; doi: 10.1097/CCM.0000000000004711

COMMENTO: Objectives: Treating acute respiratory failure in patients with coronavirus disease 2019 is challenging due to the lack of knowledge of the underlying pathophysiology. Hypoxemia may be explained in part by the loss of hypoxic pulmonary vasoconstriction. The present study assessed the effect of almitrine, a selective pulmonary vasoconstrictor, on arterial oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome.

Design: Single-center retrospective observational study.

Setting: ICU of Lille Teaching Hospital, France, from February 27, 2020, to April 14, 2020.

Patients: Patients with coronavirus disease 2019 pneumonia confirmed by positive reverse transcriptase-polymerase chain reaction for severe acute respiratory syndrome-coronavirus 2 and acute respiratory distress syndrome according to Berlin definition. Data focused on clinicobiological features, ventilator settings, therapeutics, outcomes, and almitrine-related adverse events.

Interventions: Almitrine was considered in patients with severe hypoxemia (Pao2/Fio2 ratio < 150 mm Hg) in addition to the recommended therapies, at an hourly IV delivery of 10 μg/kg/min. Comparative bloodgasesweredonebeforestartingalmitrine trial and immediatelyafter the end of the infusion. A positive response to almitrine was defined by an increase of Pao2/Fio2 ratio greater than or equal to 20% at the end of the infusion.

Measurements and Main Results: A total of 169 patients were enrolled. Thirty-two patients with acute respiratory distress syndrome received an almitrine infusion trial. In most cases, almitrine was infused in combination with inhaled nitric oxide (75%). Twenty-one patients (66%) were responders. The median Pao2/Fio2 ratio improvement was 39% (9–93%) and differs significantly between the responders and nonresponders (67% [39–131%] vs 6% [9–16%], respectively; p < 0.0001). The 28-day mortality rates were 47.6% and 63.6% (p = 0.39) for the responders and nonresponders, respectively. Hemodynamic parameters remained similar before and after the trial, not suggesting acute cor pulmonale.

Conclusions: Almitrine infusion improved oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome without adverse effects. In a multistep clinical approach to manage severe hypoxemia in this population, almitrine could be an interesting therapeutic option to counteract the loss of hypoxic pulmonary vasoconstriction and redistribute blood flow away from shunting zones.

Joyner MJ et al

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19

NEJM, 13 January 2021 ; DOI: 10.1056/NEJMoa2031893

COMMENTO : BACKGROUND : Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown.

METHODS : In a retrospective study based on a U.S. national registry, we determined the anti–SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti–SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis.

RESULTS : Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti–SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32).

CONCLUSIONS : Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti–SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels.

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