The JAK family, particularly JAK3, plays a crucial role in immune signaling and inflammatory responses. Dysregulated JAK3 activation in SARS-CoV-2 infections has been associated with severe inflammation and respiratory complications, making JAK inhibitors a viable therapeutic option. However, their use raises concerns regarding immunosuppression, which could increase susceptibility to secondary infections. While long-term adverse effects are less of a concern in acute COVID-19 treatment, patient selection and monitoring remain critical. Furthermore, adverse effects associated with oral JAK3 inhibitors necessitate the exploration of alternative strategies to optimize therapeutic efficacy while minimizing risks. This review highlights the role of JAK3 in immune and epithelial cells, examines the adverse effects of oral JAK3 inhibitors in COVID-19 and other treatments, and discusses alternative therapeutic strategies for improving patient outcomes.

A challenge that limits our understanding of the underlying pathobiology of pediatric acute respiratory distress syndrome (PARDS) is the lack of a preclinical airway model that can be leveraged for the study of mechanisms and specific molecules for drug testing. We developed a physiologic model system of the small airways for mechanistic application in PARDS using a co-culture of primary human-derived small airway epithelial cells (SAECs) cultured at the air-liquid interface and umbilical vein endothelial cells in a transwell system. The model was validated by exposing the SAECs to a rhinovirus infection, to an inflammatory lung insult using a mixture of cytokines found in ARDS (cytomix), and to airway fluid samples from children with different severity strata of PARDS. We used a combination of transepithelial electrical resistance, immunofluorescence confocal microscopy of tight junctions, targeted gene expression, and cytokine responses to evaluate the model to the aforementioned insults. We then use the model in drug testing and show the reduction in IL-6 expression in conditioned media and STAT3 phosphorylation following co-treatment of SAECs with cytomix and the Janus kinase inhibitor (JAKi) baricitinib. This model enables mechanistic studies of airway pathobiology and may serve as a novel drug testing platform for PARDS.

COVID-19-associated acute respiratory distress syndrome (ARDS) has challenged healthcare systems, initially resembling classical ARDS but later recognized as distinct. Unique features such as endothelial injury, microthrombosis, and dysregulated inflammation influenced treatment efficacy. Understanding its evolution is key to optimizing therapy and improving outcomes.

This review synthesizes current evidence on COVID-19-associated ARDS, covering epidemiology, pathophysiology, clinical phenotypes, and treatments. It explores the shift from L and H phenotypes to a refined disease model and highlights key therapies, including corticosteroids, immunomodulators, prone positioning, ECMO, and vaccination's impact on severity and ARDS incidence.

At the onset of the COVID-19 pandemic in December 2019, uncertainty was overwhelming. Early clinical guidelines relied on case reports and small case series, offering only preliminary insights into disease progression and management. Despite the initial chaos, the scientific community launched an unprecedented research effort, with over 11,000 clinical trials registered on ClinicalTrials.gov investigating COVID-19 treatments. Several evidence-based strategies emerged as gold standards for managing COVID-19-associated acute respiratory distress syndrome, surpassing prior approaches. The pandemic exposed vulnerabilities in global healthcare, reshaped modern medicine, accelerated innovation, and reinforced the essential role of evidence-based practice in critical care and public health policy.

Evidence from randomised clinical trials (RCTs) of Janus kinase (JAK) inhibitors-compared with usual care or placebo-in adults treated in hospital for COVID-19 is conflicting. We aimed to evaluate the benefits and harms of JAK inhibitors compared with placebo or usual care and whether treatment effects differed between prespecified participant subgroups.

For this systematic review and individual participant data meta-analysis (IPDMA), we searched Medline via Ovid, Embase via Elsevier, the Cochrane Central Register of Controlled Trials, the Cochrane COVID-19 Study Register, and the COVID-19 L·OVE Platform, including backward and forward citation searching (last search Nov 28, 2024), for RCTs (unpublished or published in any format and any language) that randomly assigned adults (aged ≥16 years) admitted to a hospital due to COVID-19 to receive either a JAK inhibitor (any type) or no JAK inhibitor (ie, received site-specific standard of care with or without placebo), and requested individual participant data (IPD) from the original trial teams. The primary outcome was all-cause mortality at day 28 after random assignment. We used two-stage meta-analyses adjusting for age and respiratory support, and pooled estimates using random-effects models. The assessment of individual-level effect modifiers was based solely on within-trial information and continuous modifiers were investigated as both linear and non-linear interactions. We used the Instrument for Assessing the Credibility of Effect Modification Analyses to appraise the subgroup analyses and the Grading of Recommendations Assessment, Development, and Evaluation approach to adjudicate the certainty of evidence. Grade 3 or 4 adverse events and serious adverse events by day 28, and adverse events of special interest within 28 days, were assessed among secondary outcomes. This study was registered with PROSPERO (CRD42023431817).

We identified 16 eligible trials. IPD were obtained from 12 trials, corresponding to 12 902 adults admitted to hospital between May, 2020, and March, 2022. These trials represented 12 902 [96·1%] of 13 423 participants from all eligible trials worldwide. Seven trials evaluated baricitinib, three evaluated tofacitinib, and two evaluated ruxolitinib. Overall, 755 (11·7%) of 6465 participants in the JAK inhibitor group died by day 28 compared with 805 (13·2%) of 6108 participants in the no JAK inhibitor group (adjusted odds ratio [aOR] 0·67 [95% CI 0·55-0·82]; high-certainty evidence; 39 fewer per 1000 [95% CI 55 fewer to 21 fewer]). JAK inhibitors decreased the need for new mechanical ventilation or other respiratory support and allowed for faster discharge from hospital by about 1 day. We observed fewer grade 3 and 4 adverse events and serious adverse events in the JAK inhibitor group (14 fewer per 1000 [95% CI 24 fewer to 4 fewer]; moderate-certainty evidence). The rates of adverse events of special interest were similar across both groups. No credible subgroup effect on mortality at day 28 was found for ventilation status, type of JAK inhibitor, presence of comorbidities, timing of treatment initiation after symptom onset, C-reactive protein concentration, or concomitant use of dexamethasone or tocilizumab. We found a moderately credible effect modification by age, with younger participants showing larger relative treatment effects than older participants, but similar absolute treatment effects due to higher baseline risk for older participants.

This IPDMA of RCTs in adults admitted to hospital due to COVID-19 found that JAK inhibitors reduced mortality across all levels of respiratory support, independent of dexamethasone or tocilizumab, and probably decreased serious and severe adverse events compared with no JAK inhibitors.

This project has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 101015736.

In November 2020, the Food and Drug Administration issued an Emergency Use Authorization for baricitinib, a Janus Kinase protein inhibitor, for hospitalized children and adults with COVID-19 requiring supplemental oxygen, but safety data for this pediatric indication is lacking.

This retrospective case series describes patients aged younger than 21 years treated with baricitinib for severe COVID-19 between 2021 and 2022. Patient characteristics, treatments, adverse events, reasons for early discontinuation of baricitinib, durations of oxygen supplementation and hospitalization, and complications were recorded.

There were 37 patients who received baricitinib. Median age was 16 years (range 1-20). All had a comorbidity (59% obesity, 5% malignancy), and 76% were cared for in the intensive care unit. All received remdesivir (median 5 days; range: 2-11), and 34 (92%) received corticosteroids (median 6 days; range: 1-10). Median duration of baricitinib was 6 days (range 3-14). Baricitinib was discontinued early for clinical improvement (2), and adverse events (7; 6 elevated liver enzymes [only 1 meeting discontinuation criteria), 1 thrombocytosis]). One patient had deep vein thrombosis without pulmonary embolism, 5 patients had concurrent infections (4 bacterial, 1 fungal, 2 herpes simplex virus reactivation). All adverse events were resolved. There were no deaths. Median hospitalization was 7 days (range 2-108) and mechanical ventilation was 4.5 days (range 1-86 days). Two patients (5%) were discharged with supplemental oxygen and one with a tracheostomy.

Baricitinib appears safe in children hospitalized for severe COVID-19. Most early baricitinib discontinuation for abnormal laboratory studies was secondary to provider caution.

Background: Current therapies for severe COVID-19, such as steroids and immunomodulators are associated with various side effects. N-acetylcysteine (NAC) has emerged as a potential adjunctive therapy with minimal side effects for patients with cytokine storm due to COVID-19. However, evidence supporting high-dose intravenous NAC in severe COVID-19 pneumonia requiring mechanical ventilation is limited. Methods: We conducted a retrospective analysis of consecutive patients aged ≥ 18 who were admitted for acute respiratory failure (PaO2/FiO2 ratio <300) with SARS-CoV-2 infection to the Intensive Care Unit (ICU) of Queen Elizabeth Hospital from fifth July 2020 to 31st October 2022. Inclusion was limited to patients who required mechanical ventilation. High-dose NAC refers to a dosage of 10 g per day. The primary outcome was all-cause mortality within 28 days. Propensity-score matched analysis using logistic regression was performed. Results: Among the 136 patients analyzed, 42 (40.3%) patients received NAC. The unmatched NAC patients displayed a higher day-28 mortality (12 (28.6%) versus 4 (6.5%), p = 0.005) and fewer ventilator-free days (18.5 (0-23.0) versus 22.0 (18.3-24.0), p = 0.015). No significant differences were observed in ICU and hospital length of stays among survivors. In patients who were not treated with tocilizumab, those receiving NAC exhibited a trend toward a quicker reduction in C-reactive protein compared to those who did not receive NAC.After propensity score matching which included 64 patients with 33 (51.6%) receiving NAC, no significant differences were found in 28-day mortality, ventilator-free days, or ICU and hospital length of stay. After adjusting for potential confounders, logistic regression of the propensity score-matched population did not demonstrate that the use of NAC independently affected 28-day mortality. Conclusions: In patients with COVID-19 pneumonia requiring mechanical ventilation and receiving standard COVID-19 treatment, the addition of high-dose NAC did not lead to improved clinical outcomes.

Meplazumab, a humanized CD147 antibody, showed favorable safety and clinical benefits in phase 1 and phase 2/3 seamless clinical studies. Further evaluation of its therapeutic efficacy in patients with severe COVID-19 is needed. In this phase 3 add-on study, we randomized patients with severe COVID-19 in a 1:1 ratio to receive 0.2 mg/kg meplazumab or placebo via intravenous injection, and evaluated efficacy and safety within 56 days. Between February 2023 and November 2023, 108 patients with severe COVID-19 were randomized to two groups, with their baseline characteristics generally balanced. The primary endpoint, 28-day all-cause mortality was 1.96% in the meplazumab group vs 7.69% in the placebo group (P = 0.1703). Supplementary analysis using composite strategy indicated a significant reduction of 28-day all-cause mortality in meplazumab compared to placebo (3.92% vs 15.38%, P = 0.044). Meplazumab also significantly reduced the mortality in smoking subjects on day 28 (P = 0.047) compared to placebo in supplementary analysis. The secondary endpoint, 56-day all-cause mortality, was 1.96% in the meplazumab group and 11.54% in the placebo group (P = 0.048), which was 3.92% and 15.38%, respectively (P = 0.044) by supplementary analysis. Additional secondary endpoints showed potential benefits, including increased hospital discharge rates, improved clinical outcomes, and improved viral nucleotide conversion rate. Meplazumab demonstrated good safety and tolerability, with no grade ≥ 3 TEAEs observed. These promising results indicate that meplazumab reduces mortality and enhances clinical benefits in severe COVID-19 patients with a good safety profile, providing effective and specific therapeutics for severe COVID-19 (the trial was registered at ClinicalTrials.gov (NCT05679479)).

This review provides a broad overview of lessons learned in the five years since COVID-19 was identified. It is a bimodal disease, starting with an initially virus-driven phase, followed by resolution or ensuing inappropriate immune activation causing severe inflammation that is no longer strictly virus dependent. Humoral immunity is beneficial for preventing or attenuating the early stage, without benefit once the later stage begins. Neutralizing antibodies elicited by natural infection or vaccination are short-lived and highly vulnerable to viral sequence variation. By contrast, cellular immunity, particularly the CD8+ T cell arm, has a role in preventing or attenuating severe disease, is far less susceptible to viral variation, and is longer-lived than antibodies. Finally, an ill-defined phenomenon of prolonged symptoms after acute infection, termed "long COVID," is poorly understood but may involve various immunologic defects that are hyperactivating or immunosuppressive. Remaining issues include needing to better understand the immune dysregulation of severe disease to allow more tailored therapeutic interventions, developing antibody strategies that cope with the viral spike sequence variability, prolonging vaccine efficacy, and unraveling the mechanisms of long COVID to design therapeutic approaches.

ABO blood group has been implicated both in susceptibility to, and severity of, SARS-CoV-2 infection. The aim of this study was to explore a potential association between ABO blood group and severity of COVID-19 infection in critically ill patients and the following biological mechanisms: inflammatory cytokines, endothelial injury, and adipokines.

We conducted a retrospective study of 128 critically ill COVID-19 patients admitted to Vancouver General Hospital from March 2020-March 2021. Outcomes including 28-day mortality, need for mechanical ventilation and length of intensive care unit (ICU) stay were compared between patients with A & AB blood type vs. B & O blood type. Likewise, serum inflammatory markers, markers of endothelial activation, and adipokines were compared.

The association between ABO and severity of disease was confirmed. Patients with A&AB blood group had more frequent ventilation requirements compared to patients with blood group B&O (N(%): 35 (71%) vs 41 (52%), p = 0.041), higher total ICU mortality (14 (29%) vs 9 (11%), p = 0.018), longer median ICU stay (days, median [interquartile range]: 10 [6-19], vs 7 [3-14], p = 0.016) and longer median hospital stay (26 [14-36] vs. 17 [10-30] p = 0.034). No association was found between ABO blood group and serum inflammatory cytokines or their receptors [IL-6, IL-1b, IL-10, TNF, sIL-6R, sgp130] measured within the first 10 days of ICU stay. No association was found between ABO and plasma markers of endothelial injury [Thrombomodulin, ADAMTS13, sP-Selectin, Factor IX, Protein C, Protein S, vWF]. Among the plasma adipokines, there were no differences between lipocalin-2, PAI-1 or resistin. Notably, however, median adipsin was higher in patients with A&AB blood group compared to O&B (16.3 [4.2-38.5] x106 pg/mL vs. 9.61 [3.0-20.8] x 106 pg/mL, p = 0.048).

This retrospective single-center study confirms an association between A and AB blood type with more severe COVID-19. While an underlying mechanism was not identified, the finding of higher adipsin levels in patients with type A/AB blood warrants further investigation in larger prospective studies.

Background: During the COVID-19 pandemic, treatment strategies evolved rapidly. The RECOVERY trial established corticosteroids as the standard care for reducing mortality in COVID-19 patients. However, some critical care clinicians began using doses higher than those recommended in RECOVERY. Objective: To characterize the use of high-dose corticosteroids and IL-6 inhibitors in critically ill COVID-19 patients and examine their association with adverse drug events (ADEs). Methods: A retrospective cohort study of 320 electronic health records (January 1, 2020 - June 30, 2022) was conducted on COVID-19 patients requiring high-flow oxygen or mechanical ventilation. Patients were categorized based on corticosteroid dose: "high dose dexamethasone" (daily dose greater than 12 mg and/or for longer than 10 days), "low dose dexamethasone" (daily dose 12 mg or less for 10 days or less), and "no dexamethasone" (no corticosteroid therapy). Subgroups were created based on IL-6 inhibitor use. Results: High-dose dexamethasone was associated with increased odds of ADEs compared to low dose (OR 2.55, 95% CI 1.45 to 4.49) and no dexamethasone (OR 6.29, 95% CI 2.08 to 19.03). No additional efficacy benefit was observed in patients receiving high dose corticosteroids when compared to low dose corticosteroids. Patients receiving both an IL-6 inhibitor and high-dose dexamethasone had further increased odds of ADEs. High-dose dexamethasone was also associated with increased mortality compared to low dose (OR 3.78, 95% CI 1.97-7.25) and no dexamethasone (OR 15.22, 95% CI 3.27-70.74). Conclusions: Acknowledging the risk for residual confounding, higher doses of dexamethasone were associated with increased ADEs and mortality. These findings highlight the need for careful consideration of the use of high-dose dexamethasone.

This expanded access program (EAP) provided ruxolitinib (oral, selective Janus kinase [JAK]1/JAK2 inhibitor) for emergency treatment of COVID-19-associated cytokine storm in patients eligible for hospitalization (NCT04355793).

Patients received ruxolitinib 5 mg twice daily (preferred regimen when tolerated) or once daily for ≤ 14 days, or until determination of no clinical benefit was made. Outcomes were clinical status, physician-assessed clinical benefit, and serious adverse event (SAE) incidence.

Of 312 patients, 45.5% achieved ≥ 1-point clinical status improvement. Physician-assessed clinical benefit was reported in 42.6% of evaluable patients. SAEs occurred in 42.9%, with 2.6% experiencing an SAE suspected to be ruxolitinib related.

Overall, some hospitalized patients with COVID-19-associated cytokine storm who received ruxolitinib experienced clinical status improvement; ruxolitinib was well tolerated.

ClinicalTrials.gov identifier: NCT04355793.

Immunomodulators tocilizumab and baricitinib have been used for the treatment of severe COVID-19, however, there are only few published studies comparing their efficacy.

All consecutive non-ICU hospitalized severe COVID-19 patients who received baricitinib or tocilizumab, were included retrospectively. Primary outcomes were mortality or intubation on day 14, time to oxygen therapy weaning and duration of hospitalization. Safety was measured as treatment-related adverse events.

321 hospitalized patients with severe COVID-19 were included (mean age 62.4 years ± 14.7); 241 (75.1%) received baricitinib (mean age 64.2 years ± 15.2) and 80 (24.9%) tocilizumab (mean age 57.3 ± 11.7). Patients who received baricitinib presented significantly lower risk of mortality or intubation on day 14, compared to the tocilizumab group after adjusting for age, sex, vaccination, Charlson comorbidity index, body mass index, remdesivir administration and WHO ordinal scale at enrollment (OR: 0.42, 95% CI: 0.20-0.86). In the augmented inverse-probability weighting regression, the protective role of baricitinib remained statistically significant (OR: 0.76, 95% CI: 0.66-0.88). No difference in secondary bacterial infections was detected, but tocilizumab was associated with significant higher rate of liver injury (Odds Ratio, 95%CI, p < 0.001).

Our study suggests survival and safety are significantly better for baricitinib compared to tocilizumab in severe COVID-19. Clinical randomized trials are needed for confirmation.

The COVID-19 pandemic created an unprecedented public health crisis, driven by its rapid global spread and the urgent need for worldwide collaborative interventions to contain it. This urgency spurred the search for therapeutic agents to prevent or manage the infection. Among these, various types of antivirals emerged as a prominent treatment option, supported by a wealth of observational studies and randomized controlled trials. The results from such studies conflict, with some concluding efficacy and others the lack thereof, with variability also occurring depending on the severity of COVID-19 in the studied population. In addition, many agents have been explored using randomized controlled trials-the gold standard in evaluating the efficacy of an intervention-to only a limited degree, with most of the evidence behind their use concluded using observational studies. Thus, the sheer volume of data has made it challenging to resolve inconsistencies and determine true efficacy. Furthermore, there is a paucity in the literature regarding the use of antivirals in the pediatric population infected with COVID-19, with their use being extrapolated from the results of studies done on adult patients. As such, additional trials are needed to solidify the effectiveness of antivirals in managing COVID-19, particularly in the underexplored and especially vulnerable pediatric cardiac patients. Therefore, utilizing the results from randomized controlled trials, this narrative review evaluates the rationale behind the use of antivirals, summarizes the findings from the literature, and concludes with a focused discussion on their application in pediatric cardiac patients.

Baricitinib (Olumiant) is a Janus kinase inhibitor utilized for the management of COVID-19, rheumatoid arthritis, and alopecia areata. It received U.S. Food and Drug Administration approval on May 31, 2018. This work developed a sensitive, rapid, environmentally friendly, and reliable UPLC-MS/MS method for quantifying baricitinib in human liver microsomes, utilized to evaluate the in vitro metabolic stability of baricitinib in HLMs. The StarDrop software, with DEREK and P450 metabolic programs, was employed to detect the structural warnings related to BCB and assess the in silico metabolic lability. The validation of the UPLC-MS/MS approach conformed to U.S. Food and Drug Administration standards for bioanalytical approach validation. The present UPLC-MS/MS method exhibited a wide range of linearity (1.0-3000 ng mL-1) and optimum separation of analytes in an ultra-fast separation time (1 min) and was reproducible and accurate in the absence of human liver microsome matrix effects. Baricitinib and encorafenib (the internal standard) were examined employing an isocratic mobile phase technique on a reversed phase (SB C18) column. This study assessed the accuracy and precision of UPLC-MS/MS methodologies for intra- and inter-day evaluations, which ranged from -1.20% to 8.67% and 0.12% to 11.67%, respectively. The intrinsic clearance of baricitinib was quantified at 27.49 mL min-1 kg-1, while the in vitro half-life was established at 29.50 minutes. In silico analysis proposes that slight structural alterations to the pyrrole ring (88%) and the pyrimidine ring (5%) in drug design may increase safety and metabolic stability related to baricitinib. The evaluation of in silico absorption, distribution, metabolism, excretion, and metabolic stability characteristics for baricitinib is crucial for advancing innovative drug discovery focused on enhancing metabolic stability.

Janus kinase inhibitors (JAKis) represent a relatively new class of immunomodulatory drugs with potent effects on various cytokine signalling pathways. They have revolutionized the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. However, their ability to modulate immune responses presents a dual-edged nature, influencing both protective immunity and pathological inflammation. This review explores the complex role of JAKis in infectious settings, highlighting both beneficial and detrimental effects. On the one hand, experimental models suggest that JAK inhibition can impair host defence mechanisms, increasing susceptibility to certain bacterial and viral infections. For example, tofacitinib-treated mice exhibited more severe joint erosions in Staphylococcus aureus (S. aureus) septic arthritis and showed impaired viral clearance in herpes simplex encephalitis. Additionally, clinical data confirm an increased risk of herpes zoster in patients receiving JAKis, underscoring the need for rigorous monitoring. On the other hand, JAK inhibition has demonstrated protective effects in certain infectious and hyperinflammatory conditions. In sepsis models, including cecal ligation and puncture (CLP) and S. aureus bacteraemia, tofacitinib improved survival by attenuating excessive inflammation. Furthermore, JAKis, particularly baricitinib, have shown substantial efficacy in mitigating cytokine storms during severe COVID-19 infections, leading to improved clinical outcomes and reduced mortality. These observations suggest that JAKis have a role in modulating hyperinflammatory responses in select infectious contexts. In conclusion, JAKis present a complex interplay between immunosuppression and immunomodulation. While they increase the risk of certain infections, they also show potential in managing hyperinflammatory conditions such as cytokine storms. The key challenge is determining which patients and situations benefit most from JAKis while minimizing risks, requiring a careful and personalized treatment approach.

In vitro studies and observational human disease data suggest the complement system contributes to SARS-CoV-2 pathogenesis, although how complement dysregulation develops in severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501YMA30) and a mouse model of COVID-19, we identify significant serologic and pulmonary complement activation post-infection. We observed C3 activation in airway and alveolar epithelia, and pulmonary vascular endothelia. Our evidence suggests the alternative pathway is the primary route of complement activation, however, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia following cytokine and SARS-CoV-2 exposure. This tissue-specific complement response appears to precede lung injury and inflammation. Our results suggest that complement activation is a defining feature of severe COVID-19 in mice, agreeing with previous publications, and provide the basis for further investigation into the role of complement in COVID-19.

COVID-19 poses a significant risk to individuals with haematological malignancies (HM), as they are particularly vulnerable to severe disease progression and hospitalization due to their compromised immune systems. Many clinical decisions regarding the management of COVID-19 in these patients are yet to be fully addressed by existing guidelines, leading to variability in care.

A 28-item Delphi survey was developed to gather expert opinions on key areas of COVID-19 management in patients with HM, including risk stratification for severe COVID-19, diagnostic processes, and treatment decisions.

Twenty-one experts with backgrounds in haematology and infectious diseases were enrolled. Of the 28 questions posed to the experts, consensus was reached on 15 statements.

These Delphi consensus statements offer valuable suggestions with direct implications for clinical practice, addressing critical areas such as risk identification, appropriate diagnostic approaches, and tailored treatment strategies for patients with HM with COVID-19. The findings provide actionable insights that may help fill gaps in current scientific literature, enhancing patient care and decision-making in this high-risk population.

Repurposing of existing drugs for new indications has attracted substantial attention owing to its potential to accelerate drug development and reduce costs. Hundreds of computational resources such as databases and predictive platforms have been developed that can be applied for drug repurposing, making it challenging to select the right resource for a specific drug repurposing project. With the aim of helping to address this challenge, here we overview computational approaches to drug repurposing based on a comprehensive survey of available in silico resources using a purpose-built drug repurposing ontology that classifies the resources into hierarchical categories and provides application-specific information. We also present an expert evaluation of selected resources and three drug repurposing case studies implemented within the Horizon Europe REMEDi4ALL project to demonstrate the practical use of the resources. This comprehensive Review with expert evaluations and case studies provides guidelines and recommendations on the best use of various in silico resources for drug repurposing and establishes a basis for a sustainable and extendable drug repurposing web catalogue.

Immunocompromised patients are at increased risk for severe outcomes from COVID-19 due to their altered immune responses, yet their inflammatory profiles and the interplay between immunosuppression remain poorly understood. We aimed to illustrate the inflammation profile and clinical outcomes of hospitalized immunocompromised patients with COVID-19.

We conducted a retrospective study using a multicenter database and included adult hospitalized patients with Corona virus disease 2019 (COVID-19) in China's late 2022 COVID-19 wave. Crude and adjusted 28- and 60-day mortality was compared between the two groups. Inflammatory phenotypes were evaluated by serum interleukin-6 (IL-6) and C-reactive protein (CRP) level. The interplay between overt inflammation and immunosuppression was analyzed.

Among the 4078 included patients, 348 (8.5%) were immunocompromised. Immunocompromised patients had lower crude mortality but higher adjusted mortality at 28-day (hazard ratio [HR] = 1.55; 95% CI 1.08 to 2.23) and 60-day (HR = 1.47; 95% CI 1.05 to 2.06). Besides, immunocompromised patients had a higher risk of developing hyperinflammation (odd ratio [OR] =1.92; 95% CI 1.47 to 2.50, p <0.001). Moreover, hyperinflammation mediated a major part of the deleterious survival effect of immunosuppression on COVID-19.

Immunodeficiency not only increases short-term mortality risk but also predisposes patients to hyperinflammation. The complex interplay between immunosuppression, hyperinflammation, and COVID-19 outcomes warrants more detailed profiling of inflammation and immunity in this population.

Since the COVID-19 pandemic, it has caused a great threat to the global economy and public health, initiatives have been launched to control the spread of the virus. To explore the efficacy of drugs, a large number of clinical trials have been carried out, with the purpose of providing guidelines based on high-quality evidence for clinicians. We mainly discuss therapeutic agents for COVID-19 and explain the mechanism, including antiviral agents, tocilizumab, Janus kinase (JAK) inhibitors, neutralizing antibody therapies and corticosteroids. In addition, the COVID-19 vaccine has been proven to be efficacious in preventing SARS-CoV-2 infection. We systematically analyzed four mainstream vaccine platforms: messenger RNA (mRNA) vaccines, viral vector vaccines, inactivated vaccines and protein subunit vaccines. We evaluated the therapeutic effects of drugs and vaccines through enumerating the most typical clinical trials. However, the emergence of novel variants has further complicated the interpretation of the available clinical data, especially vaccines and antibody therapies. In the post-epidemic era, therapeutic agents are still the first choice for controlling the progression of disease, whereas the protective effect of vaccines against different strains should be assessed comprehensively.

Treatment guidelines were developed early in the pandemic when much about coronavirus disease 2019 (COVID-19) was unknown. Given the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), real-world data can provide clinicians with updated information. The objective of this analysis was to assess mortality risk in patients hospitalized for COVID-19 during the Omicron period receiving remdesivir + dexamethasone versus dexamethasone alone.

A large, multicenter US hospital database was used to identify adult patients hospitalized with a primary discharge diagnosis of COVID-19 flagged as "present-on-admission" and treated with remdesivir + dexamethasone or dexamethasone alone between December 2021 and April 2023. Patients were matched using 1:1 propensity score matching and stratified by baseline oxygen requirements. Cox proportional hazards model was used to assess time to 14- and 28-day in-hospital all-cause mortality.

A total of 33 037 patients were matched, with most patients ≥65 years old (72%), White (78%), and non-Hispanic (84%). Remdesivir + dexamethasone was associated with lower mortality risk versus dexamethasone alone across all baseline oxygen requirements at 14-days (no supplemental oxygen charges: adjusted hazard ratio [95% confidence interval {CI}]: 0.79 [.72-.87], low flow oxygen: 0.70 [.64-.77], high flow oxygen/non-invasive ventilation: 0.69 [.62-.76], invasive mechanical ventilation/extracorporeal membrane oxygen (IMV/ECMO): 0.78 [.64-.94]), with similar results at 28-days.

Remdesivir + dexamethasone was associated with a significant reduction in 14- and 28-day mortality compared to dexamethasone alone in patients hospitalized for COVID-19 across all levels of baseline respiratory support, including IMV/ECMO. However, the use of remdesivir + dexamethasone still has low clinical practice uptake. In addition, these data suggest a need to update the existing guidelines.

Systemic baricitinib and corticosteroids play important roles in treating severely and critically ill patients with coronavirus disease 2019 (COVID-19). However, the efficacy of the combination of baricitinib and corticosteroids compared to that of corticosteroid monotherapy in severely and critically ill hospitalized patients with COVID-19 remains unclear.

We analyzed severely and critically ill hospitalized patients with COVID-19 aged >18 years between January 1, 2020 and May 31, 2023, using a Japanese multicenter inpatient database. We performed propensity score matching to analyze the effect of the combination of baricitinib and corticosteroids within 2 days of hospital admission (combination group) on the 28-day and in-hospital mortality rates compared with those of corticosteroid monotherapy within 2 days of hospital admission (control group). Sensitivity analysis was performed using inverse probability weighting analysis and the generalized estimating equation method.

The eligible patients (n = 7433) were divided into a combination (n = 679) and a control group (n = 6754). One-to-four propensity score matching analyses included 566 combination and 2264 control group patients. There was no significant difference in 28-day (8.5 % vs. 8.8 %; risk difference, -0.3 % [95 % confidence interval, -2.9 to 2.3]) or in-hospital (11 % vs. 10 %; risk difference, 1.0 [-1.9 to 3.9]) mortality rates between 2 groups. The sensitivity analysis showed similar outcomes.

This observational study, using a Japanese multicenter inpatient database, found that the combination of baricitinib and corticosteroid therapy did not improve the 28-day or in-hospital mortality rates in severely and critically ill patients with COVID-19 compared to corticosteroid monotherapy.

Influenza infections are often complicated by secondary bacterial infections such as MRSA pneumonia, which increase morbidity and mortality. Viral infections lead to an inflammatory response that includes elevated levels of IL-6 and interferons. IL-6 activates the JAK/STAT signaling pathway, amplifying downstream inflammation. Given the clinical efficacy of the JAK inhibitor baricitinib in reducing disease severity in COVID-19, we evaluated its impact in a murine model of influenza, MRSA, and post-influenza MRSA pneumonia. Additionally, because IL-6 inhibitory therapies have improved outcomes during COVID-19, we evaluated the impact of IL-6 deletion on post-influenza MRSA pneumonia. In our studies, baricitinib effectively inhibited the JAK/STAT pathway in the lungs, as demonstrated by decreased interferon-stimulated genes (ISGs) and STAT3 phosphorylation. Despite this inhibition, baricitinib did not cause a global suppression of cytokines. Notably, baricitinib treatment did not impair either antiviral or antibacterial host immunity, inflammatory cell recruitment, or lung tissue injury. IL-6 deficiency did not alter weight loss, inflammatory cell recruitment, or bacterial burden during post-influenza MRSA pneumonia. These findings suggest that both JAK inhibition via baricitinib and IL-6 deletion do not enhance host defense or limit tissue injury in murine models of influenza and post-influenza MRSA pneumonia.

Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear.

We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome.

Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection.

The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.

Baricitinib is a selective inhibitor of Janus kinase (JAK)1 and JAK2, which is associated with clinical improvement in non-severe COVID-19 patients. But in severe COVID-19 patients, the effectiveness of baricitinib is still controversial.

A propensity score-matched and retrospective study was conducted to evaluate the effectiveness of baricitinib in severe COVID-19 patients requiring invasive mechanical ventilation (IMV).

A total number of 48 patients treated with baricitinib were included, and 48 patients were assigned to control group by propensity score matching. The mean ages were high in both group (baricitinib group vs. control group: 78.80 ± 9.04 vs. 82.57 ± 9.27), and most were unvaccinated (62.5% vs. 66.7%. Baricitinib group had a higher proportion of patients with hypertension (73.9% vs. 45.5%, p = 0.006). Control group had higher level of creatine kinase-myocardial band (247.50 vs. 104.50, p = 0.021). Patients in the baricitinib group were more likely to receive nirmatrelvir/ritonavir (39.6% vs. 16.7%, p = 0.017) and intravenous immunoglobin (14.6% vs. 0, p = 0.007). Baricitinib group had significantly lower all-cause 28-days mortality than control group (72.9% vs. 89.6%, p = 0.004).

The present study revealed baricitinib reduced 28-days mortality in severe COVID-19 patients on IMV. The effectiveness of baricitinib in treating patients with severe COVID-19 on IMV needs to be further investigated through future studies.

Using the knowledge from decades of research into RNA-based therapies, the COVID-19 pandemic response saw the rapid design, testing and production of the first ever mRNA vaccines approved for human use in the clinic. This breakthrough has been a significant milestone for RNA therapeutics and vaccines, driving an exponential growth of research into the field. The development of novel RNA therapeutics targeting high-threat pathogens, that pose a substantial risk to global health, could transform the future of health delivery. In this review, we provide a detailed overview of the two RNA interference (RNAi) pathways and how antiviral RNAi therapies can be used to treat acute or chronic diseases caused by the pandemic viruses SARS-CoV-2 and HIV, respectively. We also provide insights into short-interfering RNA (siRNA) delivery systems, with a focus on how lipid nanoparticles can be functionalized to achieve targeted delivery to specific sites of disease. This review will provide the current developments of SARS-CoV-2 and HIV targeted siRNAs, highlighting strategies to advance the progression of antiviral siRNA along the clinical development pathway.

Racial and ethnic minorities have been disproportionally burdened by hospitalization and death due to COVID-19. Participation of individuals of diverse races and ethnicities in clinical trials, according to study-level characteristics of randomized controlled trials (RCTs) that test effectiveness of COVID-19 drugs, could be insightful for future researchers. Our objective for this scoping review was to describe the frequency of race and ethnicity reported as demographic variables and specific reporting of race and ethnicity according to COVID-19 RCT characteristics. We conducted comprehensive searches in PubMed, ProQuest, World Health Organization Database, and Cochrane Central Register of Controlled Trials, and gray literature via preprint servers from January 1, 2020, to May 4, 2022. We included RCTs on emergency- or conditionally approved COVID-19 drug interventions (remdesivir, baricitinib, and molnupiravir) with or without comparators. Self-reported race as American Indian/Pacific Islander, Asian, Black/African American, or White, ethnicity as Hispanic/Latinx, study design characteristics, and participant-relevant data were collected. In total, 17 RCTs with 17 935 participants were included. Most (n = 13; 76%) reported at least 1 race and ethnicity and were US-based, industry-funded RCTs. Asian, Black, Latinx, and White participants were mostly enrolled in RCTs that studied remdesivir. Native American and Hawaiian participants were mostly assessed for progression to high-flow oxygen/noninvasive ventilation. Time to recovery was assessed predominantly in Black and White participants, whereas hospitalization or death was mostly assessed in Asian, Latinx, and multirace participants. Trialists should be aware of RCT-level factors and characteristics that may be associated with low participation of racial and ethnic minorities, which could inform evidence-based interventions to increase minority participation.

Toll-like receptors (TLRs) of human are considered as the most critical immunological mediators of inflammatory pathogenesis of COVID-19. These immunoregulatory glycoproteins are located on the surface and/or intracellular compartment act as innate immune sensors. Upon binding with distinct SARS-CoV-2 ligand(s), TLRs signal activation of different transcription factors that induce expression of the proinflammatory mediators that collectively induce 'cytokine storm'. Similarly, TLR activation is also pivotal in conferring protection to infection and invasion as well as upregulating the tissue repair pathways. This dual role of the human TLRs in deciding the fate of SARS-CoV-2 has made these receptor proteins as the critical mediators of immunoprotective and immunopathogenic consequences associated with COVID-19. Herein, pathbreaking discoveries exploring the immunobiological importance of the TLRs in COVID-19 and developing TLR-directed therapeutic intervention have been reviewed by accessing the up-to-date literatures available in the public domain/databases. In accordance with our knowledge in association with the importance of TLRs' role against viruses and identification of viral particles, they have been recognized as suitable candidates with high potential as vaccine adjuvants. In this regard, the agonists of TLR4 and TLR9 have effective potential in vaccine technology while the others need further investigations. This comprehensive review suggests that basal level expression of TLRs can act as friends to keep our body safe from strangers but act as a foe via overexpression. Therefore, selective inhibition of the overexpressed TLRs appears to be a solution to counteract the cytokine storm while TLR-agonists as vaccine adjuvants could lessen the risk of infection in the naïve population.

The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19.

Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status.

Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs.

This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size.

EU Horizon 2020 (grant number 101015736).