Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)-study protocol for a phase 2, randomized, placebo controlled trial.

BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.

Dysfunctional purinergic signaling correlates with disease severity in COVID-19 patients.

Ectonucleotidases modulate inflammatory responses by balancing extracellular ATP and adenosine (ADO) and might be involved in COVID-19 immunopathogenesis. Here, we explored the contribution of extracellular nucleotide metabolism to COVID-19 severity in mild and severe cases of the disease. We verified that the gene expression of ectonucleotidases is reduced in the whole blood of patients with COVID-19 and is negatively correlated to levels of CRP, an inflammatory marker of disease severity. In line with these findings, COVID-19 patients present higher ATP levels in plasma and reduced levels of ADO when compared to healthy controls. Cell type-specific analysis revealed higher frequencies of CD39+ T cells in severely ill patients, while CD4+ and CD8+ expressing CD73 are reduced in this same group. The frequency of B cells CD39+CD73+ is also decreased during acute COVID-19. Interestingly, B cells from COVID-19 patients showed a reduced capacity to hydrolyze ATP into ADP and ADO. Furthermore, impaired expression of ADO receptors and a compromised activation of its signaling pathway is observed in COVID-19 patients. The presence of ADO in vitro, however, suppressed inflammatory responses triggered in patients' cells. In summary, our findings support the idea that alterations in the metabolism of extracellular purines contribute to immune dysregulation during COVID-19, possibly favoring disease severity, and suggest that ADO may be a therapeutic approach for the disease.

FDA approved drugs with antiviral activity against SARS-CoV-2: From structure-based repurposing to host-specific mechanisms.

The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.

In adults hospitalized with COVID-19, adding baricitinib vs. dexamethasone to remdesivir did not differ for MV-free survival.

SOURCE CITATION: Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022;10:888-99. 35617986.

Synthesis and Anticancer and Antiviral Activities of C-2'-Branched Arabinonucleosides.

d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were prepared from the corresponding 3',5'-O-silylene acetal-protected nucleoside 2'-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2'-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl ß-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2' substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2'-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.

Suppressed renoprotective purines in COVID-19 patients with acute kidney injury.

Acute kidney injury (AKI) is common in patients hospitalized for COVID-19, complicating their clinical course and contributing to worse outcomes. Animal studies show that adenosine, inosine and guanosine protect the kidney against some types of AKI. However, until now there was no evidence in patients supporting the possibility that abnormally low kidney levels of adenosine, inosine and guanosine contribute to AKI. Here, we addressed the question as to whether these renoprotective purines are altered in the urine of COVID-19 patients with AKI. Purines were measured by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with stable-isotope-labeled internal standards for each purine of interest. Compared with COVID-19 patients without AKI (n = 23), COVID-19 patients with AKI (n = 20) had significantly lower urine levels of adenosine (P < 0.0001), inosine (P = 0.0008), and guanosine (P = 0.0008) (medians reduced by 85%, 48% and 61%, respectively) and lower levels (P = 0.0003; median reduced by 67%) of the 2nd messenger for A2A and A2B adenosine receptors, i.e., 3',5'-cAMP. Moreover, in COVID-19 patients with AKI, urine levels of 8-aminoguanine (endogenous inhibitor of inosine and guanosine metabolism) were nearly abolished (P < 0.0001). In contrast, the "upstream" precursors of renoprotective purines, namely 5'-AMP and 5'-GMP, were not significantly altered in COVID-19 patients with AKI, suggesting defective conversion of these precursors by CD73 (converts 5'-AMP to adenosine and 5'-GMP to guanosine). These findings imply that an imbalance in renoprotective purines may contribute to AKI in COVID-19 patients and that pharmacotherapy targeted to restore levels of renoprotective purines may attenuate the risk of AKI in susceptible patients with COVID-19.

Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.

BACKGROUND: We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1-2 inhibitor, for the treatment of patients admitted to hospital with COVID-19. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing. FINDINGS: Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45-0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72-0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. INTERPRETATION: In patients hospitalised with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Does baricitinib reduce mortality and disease progression in SARS-CoV-2 virus infected patients? A systematic review and meta analysis.

BACKGROUND: There are conflicting reports on the results of several of the latest clinical trials related to the use of baricitinib in the management of COVID-19 patients. The aim of the current systematic review and meta-analysis was to evaluate the efficacy of baricitinib in COVID-19 patients. METHODS: Databases like ScienceDirect, PubMed/Medline, Publons, Google Scholar and other sources like ClinicalTrials.gov, Cochrane, medRxiv, Research Square and reference lists were thoroughly searched. RESULTS: Fifteen (15) articles which met the inclusion criteria were qualitatively and quantitatively analysed. Based on Cochrane and Newcastle-Ottawa Scale (NOS) risk of bias (RoB) analyses, 14/15 articles are grouped as high-quality. Meta-analyses revealed that randomised control trials (RCTs) and non-randomised control trials (nRCTs) statistically significantly reduced the mortality rate in COVID-19 patients, with a risk ratio (RR) in the fixed-effect model was RR = 0.64 [95% CI: 0.51 to 0.79; p < 0.0001] and RR = 0.58 [95% CI: 0.45 to 0.73; p < 0.00001], respectively, with insignificant heterogeneity and no publication bias found. For block/reduce disease progression (BDP), baricitinib did not statistically significantly reduce disease progression for RCTs. The RR in the random effect model was RR = 0.80 [95% CI: 0.58 to 1.10: p = 0.17], with significant heterogeneity, where I2 was 60%. On the other hand, baricitinib statistically significantly reduced disease progression in nRCTs, as the RR of the fixed effect model was RR = 0.54 [95% CI: 0.37 to 0.78; p = 0.001] with insignificant heterogeneity. CONCLUSION: The current meta-analyses revealed that baricitinib statistically significantly reduced mortality rate and disease progression in COVID-19 patients. PROSPERO REGISTRATION NUMBER: CRD42021281556.

Acute femoral artery occlusion in a male with Duhring disease and COVID-19 pneumonia treated with baricitinib.

Arterial thromboembolic events (ATE) in COVID-19, similarly as venous thromboembolism (VTE), are observed mainly in severely ill patients. ATE include brain, heart, aortic, and peripheral ischemic complications which usually aggravate a course of the disease leading to lifethreatening conditions. A CASE REPORT: The authors describe a case of a 53-year-old male with Duhring disease in the remission period admitted due to severe COVID-19 pneumonia. The patient was treated with ceftriaxone (2000 mg once daily), dexamethasone (8 mg once daily), enoxaparin (60 mg twice daily), baricitinib (4 mg once daily), and remdesivir (200 mg on the first day, followed by 100 mg within 4 consecutive days); he required high flow oxygen therapy. On day 5 of hospitalization, he began to suffer from pain of the right lower extremity; in physical examination the limb was cold with absent femoral, popliteal, and pedal pulses. Urgent computed tomography angiography revealed total occlusion of the right superficial femoral artery (SFA) in the absence of any atherosclerotic plaques in the aorta. The patient was intubated and transferred to department of vascular surgery, where a giant clot was removed from SFA. Unfortunately, the patient outcome was unfavorable due to respiratory failure progression. The authors underline that ATE may occur even in anticoagulated patients and that association of some therapeutic options of COVID-19, like janus kinase (JAK) inhibitors use with an increased risk of ATE, should not be excluded.

A Review of Safety Outcomes from Clinical Trials of Baricitinib in Rheumatology, Dermatology and COVID-19.

Baricitinib is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 that transiently and reversibly inhibits many proinflammatory cytokines. This mechanism is a key mediator in a number of chronic inflammatory diseases; accordingly, baricitinib has been studied and approved for the treatment of several rheumatological and dermatological disorders, as well as COVID-19. This narrative review summarises and discusses the safety profile of baricitinib across these diseases, with special focus on adverse events of special interest (AESI) for JAK inhibitors, using integrated safety data sets of clinical trial data, and puts findings into context with the underlying risk in the respective disease populations, using supporting literature. We show that rates of infection with baricitinib generally reflected the inherent risk of the disease populations being treated, with serious infections and herpes zoster being more frequent in rheumatic diseases than in dermatological disorders, and herpes simplex being reported particularly in atopic dermatitis. Similarly, rates of major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and malignancies were generally within or below the ranges reported for the respective disease populations, thereby reflecting the underlying risk; these events were therefore more frequent in patients with rheumatic diseases than in those with dermatological disorders, the latter of whom generally had low absolute risk. AESI were usually more common in patients with risk factors specific for each event. When a population similar to that of ORAL Surveillance was considered, the incidence rate of MACE with baricitinib was numerically lower than that reported with tofacitinib and similar to that of tumour necrosis factor inhibitors. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Identifying the patterns and likelihoods of AEs that occur during treatment in large groups of patients with different diseases can help the physician and patient better contextualise the benefit-to-risk ratio for the individual patient.

The oral selective inhibitor of Janus kinase (JAK)1/JAK2 baricitinib transiently and reversibly inhibits elements of the inflammatory pathway, which are key mechanisms for several chronic, inflammatory rheumatological and dermatological diseases but, as with all drugs, it can be associated with unwanted effects. This narrative review summarises adverse events of special interest (AESI) for baricitinib, considered as such either because of characteristics of patients with the disease being treated (rheumatological and dermatological disorders and COVID-19) or the mechanism of action of the drug. The risk of these events is considered in light of the inherent risk of each event in populations with the respective diseases. We show that serious infections and herpes zoster during baricitinib therapy were most common in patients with rheumatological disorders, and herpes simplex was reported particularly in patients with atopic dermatitis, likely because of disease-related risk factors. MACE, VTE and malignancies generally occurred in baricitinib-treated patients with a frequency within or below the ranges reported for the respective disease populations. Rates generally reflected the underlying risk of the disease populations, being higher in patients with rheumatological diseases than in those with dermatological disorders, and mostly occurring in patients with underlying risk factors for the AESI. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Characterising patterns and likelihoods of unwanted events that occur during treatment in large groups of patients with different diseases can help put the actual risk to an individual patient into perspective.

Tocilizumab, netakimab, and baricitinib in patients with mild-to-moderate COVID-19: An observational study.

OBJECTIVE: The aim of the study was to assess inflammatory markers and clinical outcomes in adult patients admitted to hospital with mild-to-moderate COVID-19 and treated with a combination of standard-of-care (SOC) and targeted immunosuppressive therapy including anti-IL-17A (netakimab), anti-IL-6R (tocilizumab), or JAK1/JAK2 inhibitor (baricitinib) or with a standard-of-care therapy alone. METHODS: The observational cohort study included 154 adults hospitalized between February and August, 2020 with RT-PCR-confirmed SARS-CoV-2 with National Early Warning Score2 (NEWS2) < 7 and C-reactive protein (CRP) levels ≤ 140 mg/L on the day of the start of the therapy or observation. Patients were divided into the following groups: I) 4 mg baricitinib, 1 or 2 times a day for an average of 5 days (n = 38); II) 120 mg netakimab, one dose (n = 48); III) 400 mg tocilizumab, one dose (n = 34), IV) SOC only: hydroxychloroquine, antiviral, antibacterial, anticoagulant, and dexamethasone (n = 34). RESULTS: CRP levels significantly decreased after 72 h in the tocilizumab (p = 1 x 10-5) and netakimab (p = 8 x 10-4) groups and remained low after 120 h. The effect was stronger with tocilizumab compared to other groups (p = 0.028). A significant decrease in lactate dehydrogenase (LDH) levels was observed 72 h after netakimab therapy (p = 0.029). NEWS2 scores significantly improved 72 h after tocilizumab (p = 6.8 x 10-5) and netakimab (p = 0.01) therapy, and 120 h after the start of tocilizumab (p = 8.6 x 10-5), netakimab (p = 0.001), or baricitinib (p = 4.6 x 10-4) therapy, but not in the SOC group. Blood neutrophil counts (p = 6.4 x 10-4) and neutrophil-to-lymphocyte ratios (p = 0.006) significantly increased 72 h after netakimab therapy and remained high after 120 h. The percentage of patients discharged 5-7 days after the start of therapy was higher in the tocilizumab (44.1%) and netakimab (41.7%) groups than in the baricitinib (31.6%) and SOC (23.5%) groups. Compared to SOC (3 of the 34; 8.8%), mortality was lower in netakimab (0 of the 48; 0%, RR = 0.1 (95% CI: 0.0054 to 1.91)), tocilizumab (0 of the 34; 0%, RR = 0.14 (95% CI: 0.0077 to 2.67)), and baricitinib (1 of the 38; 2.6%, RR = 0.3 (95% CI: 0.033 to 2.73)) groups. CONCLUSION: In hospitalized patients with mild-to-moderate COVID-19, the combination of SOC with anti-IL-17A or anti-IL-6R therapy were superior or comparable to the combination with JAK1/JAK2 inhibitor, and all three were superior to SOC alone. Whereas previous studies did not demonstrate significant benefit of anti-IL-17A therapy for severe COVID-19, our data suggest that such therapy could be a rational choice for mild-to-moderate disease, considering the generally high safety profile of IL-17A blockers. The significant increase in blood neutrophil count in the netakimab group may reflect efflux of neutrophils from inflamed tissues. We therefore hypothesize that neutrophil count and neutrophil-to-lymphocyte ratio could serve as markers of therapeutic efficiency for IL-17A-blocking antibodies in the context of active inflammation.

Combination therapy with remdesivir and immunomodulators improves respiratory status in COVID-19: A retrospective study.

Immunomodulators (tocilizumab/baricitinib) improve outcomes of coronavirus disease 2019 (COVID-19) patients, but the synergistic effect of remdesivir is unknown. The effect of combination therapy with remdesivir, immunomodulators, and standard treatment in COVID-19 patients was investigated. This retrospective, single-center study included COVID-19 patients who were treated with tocilizumab or baricitinib. The severity of respiratory status in the two groups on Days 14 and 28 and the duration to respiratory recovery in both groups were compared, and the effect of remdesivir use on respiratory status was examined in a multivariate analysis. Ninety-eight patients received tocilizumab or baricitinib; among them, 72 used remdesivir (remdesivir group) and 26 did not (control group). The remdesivir group achieved faster respiratory recovery than the control group (median 11 vs. 21 days, p = 0.033), faster weaning from supplemental oxygen (hazard ratio [HR]: 2.54, 95% confidence interval [CI]: 1.14-5.66, p = 0.021). Age, body mass index, diabetes mellitus, and time from onset to oxygen administration were independent prognostic factors. The remdesivir group achieved better severity level at Days 14 and 28 (p = 0.033 and 0.003, respectively) and greater improvement from baseline severity (p = 0.047 and 0.018, respectively). Remdesivir combination therapy did not prolong survival (HR: 0.31, 95% CI: 0.04-2.16, p = 0.23). Among severely ill COVID-19 patients who received immunomodulator, remdesivir contributed to a shorter respiratory recovery time and better respiratory status at Days 14 and 28. Concomitant remdesivir with immunomodulators and standard treatment may provide additional benefit in improving respiratory status of COVID-19 patients.

Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and Evaluation of Their Antiviral Activity.

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by 1H, 19F, and 13C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus.

Raman Fingerprints of the SARS-CoV-2 Delta Variant and Mechanisms of Its Instantaneous Inactivation by Silicon Nitride Bioceramics.

Raman spectroscopy uncovered molecular scale markers of the viral structure of the SARS-CoV-2 Delta variant and related viral inactivation mechanisms at the biological interface with silicon nitride (Si3N4) bioceramics. A comparison of Raman spectra collected on the TY11-927 variant (lineage B.1.617.2; simply referred to as the Delta variant henceforth) with those of the JPN/TY/WK-521 variant (lineage B.1.617.1; referred to as the Kappa variant or simply as the Japanese isolate henceforth) revealed the occurrence of key mutations of the spike receptor together with profound structural differences in the molecular structure/symmetry of sulfur-containing amino acid and altered hydrophobic interactions of the tyrosine residue. Additionally, different vibrational fractions of RNA purines and pyrimidines and dissimilar protein secondary structures were also recorded. Despite mutations, hydrolytic reactions at the surface of silicon nitride (Si3N4) bioceramics induced instantaneous inactivation of the Delta variant at the same rate as that of the Kappa variant. Contact between virions and micrometric Si3N4 particles yielded post-translational deimination of arginine spike residues, methionine sulfoxidation, tyrosine nitration, and oxidation of RNA purines to form formamidopyrimidines. Si3N4 bioceramics proved to be a safe and effective inorganic compound for instantaneous environmental sanitation.

In patients with COVID-19 receiving IMV or ECMO, adding baricitinib to usual care reduced all-cause mortality.

SOURCE CITATION: Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022;10:327-36. 35123660.

Baricitinib attenuates the proinflammatory phase of COVID-19 driven by lung-infiltrating monocytes.

SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation, whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression, and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of proneutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target.