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1.
Cancer Immunol Res ; 10(4): 384-402, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1775028

ABSTRACT

Vaccination has been a game changer in our efforts to address the coronavirus disease 2019 (COVID-19) pandemic. However, the disease might still represent a clinical crisis for several more years, in part because of the inevitable emergence of variants capable of evading the preexisting immunity. Drugs affecting viral spread will help curtail transmission, but therapeutics are needed to treat the more severe cases requiring hospitalization. A deep analysis of the evolving immune landscape of COVID-19 suggests that understanding the molecular bases of the distinct clinical stages is paramount if we are to limit the burden of inflammation, which can lead to death in frail individuals, according to age, sex, and comorbidities. Different phases can be defined using immune biomarkers and need specific therapeutic approaches, tailored to the underlying immune contexture.


Subject(s)
COVID-19 , Hospitalization , Humans , Pandemics , SARS-CoV-2 , Vaccination
2.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388432

ABSTRACT

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.


Subject(s)
Antiviral Agents/pharmacology , Azetidines/pharmacology , COVID-19/mortality , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Liver/virology , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/pathogenicity , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Profiling , Humans , Interferon alpha-2/metabolism , Italy , Janus Kinases/metabolism , Liver/drug effects , Male , Middle Aged , Patient Safety , Platelet Activation , Proportional Hazards Models , RNA-Seq , Spain , Virus Internalization/drug effects
4.
J Infect ; 82(4): 58-66, 2021 04.
Article in English | MEDLINE | ID: covidwho-1101375

ABSTRACT

OBJECTIVE: Baricitinib seems a promising therapy for COVID-19. To fully-investigate its effects, we in-vitro evaluated the impact of baricitinib on the SARS-CoV-2-specific-response using the whole-blood platform. METHODS: We evaluated baricitinib effect on the IFN-γ-release and on a panel of soluble factors by multiplex-technology after stimulating whole-blood from 39 COVID-19 patients with SARS-CoV-2 antigens. Staphylococcal Enterotoxin B (SEB) antigen was used as a positive control. RESULTS: In-vitro exogenous addition of baricitinib significantly decreased IFN-γ response to spike- (median: 0.21, IQR: 0.01-1; spike+baricitinib 1000 nM median: 0.05, IQR: 0-0.18; p < 0.0001) and to the remainder-antigens (median: 0.08 IQR: 0-0.55; remainder-antigens+baricitinib 1000 nM median: 0.03, IQR: 0-0.14; p = 0.0013). Moreover, baricitinib significantly decreased SEB-induced response (median: 12.52, IQR: 9.7-15.2; SEB+baricitinib 1000 nM median: 8, IQR: 1.44-12.16; p < 0.0001). Baricitinib did modulate other soluble factors besides IFN-γ, significantly decreasing the spike-specific-response mediated by IL-17, IL-1ß, IL-6, TNF-α, IL-4, IL-13, IL-1ra, IL-10, GM-CSF, FGF, IP-10, MCP-1, MIP-1ß (p ≤ 0.0156). The baricitinib-decreased SARS-CoV-2-specific-response was observed mainly in mild/moderate COVID-19 and in those with lymphocyte count ≥1 × 103/µl. CONCLUSIONS: Exogenous addition of baricitinib decreases the in-vitro SARS-CoV-2-specific response in COVID-19 patients using a whole-blood platform. These results are the first to show the effects of this therapy on the immune-specific viral response.


Subject(s)
COVID-19 , Azetidines , COVID-19/drug therapy , Cytokines , Humans , Purines , Pyrazoles , SARS-CoV-2 , Sulfonamides
6.
Drugs ; 80(18): 1929-1946, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-871600

ABSTRACT

BACKGROUND: Based on current evidence, recent guidelines of the National Institute of Health, USA indicated the use of remdesivir and dexamethasone for the treatment of COVID-19 patients with mild-moderate disease, not requiring high-flow oxygen. No therapeutic agent directed against the immunologic pathogenic mechanisms related to the cytokine release syndrome complicating the disease was indicated. OBJECTIVES: The purpose of this review was to assess the clinical impact of different therapies for COVID-19; thus, helping to identify the optimal management of the disease. To explain the rationale for the different therapeutic approaches, the characteristics of SARS-CoV-2, the pathogenesis of COVID-19, and the immune response triggered by SARS-CoV-2 infection were reported. METHODS: The efficacy assessment of the different treatments was performed by a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Available English language published articles including randomised controlled trials, open-label trials of antivirals and immune therapies extracted from Medline, Google Scholar, and MedRxiv databases were analysed. For inclusion, the primary end point of the trials had to be the efficacy as measured by the improvement of clinical features, or mortality, or the Intensive Care Unit Admission rate, or the discharge number. Case reports, paediatric studies, and studies without control group were excluded. The literature search was extended up to August 15, 2020. RESULTS: After the removal of duplicate articles, and the exclusion of studies not meeting the eligibility criteria, 2 trials of lopinavir/ritonavir, 1 of favipiravir, 3 of remdesivir, 1 of dexamethasone, 3 of hydroxychloroquine, 2 of colchicine, 6 of tocilizumab, 1 of sarilumab, 1 of siltuximab, 2 of anakinra, 3 of baricitinib, 1 of ruxolitinib, 1 of mavrilimumab, and 1 of itolizumab were suitable for the review. Among antivirals, only remdesivir significantly reduced the time to recovery, and mortality. Data for chloroquine and hydroxychloroquine were largely inconclusive. In a large trial, dexamethasone 6 mg/day reduced mortality by one-third. Trials of tocilizumab and sarilumab did not definitively demonstrate efficacy. Anakinra significantly reduced the mortality in 2 trials. Three retrospective trials on a cumulative number of 145 patients, reported the efficacy of baricitinib, with significant reduction of intensive care unit admission, and deaths. These results were recently confirmed by the ACTT-2 trial. Due to paucity of studies and to the small size clinical series, the results of other immune therapies were not conclusive. CONCLUSIONS: Beyond the supportive therapy, up to now the best therapeutic approach for COVID-19 may be a three-step combination therapy, including remdesivir 100 mg/day (200 mg loading dose on first day) in the first stage of the disease, and combined dexamethasone 6 mg/day plus baricitinib 4 mg/day to target the immune dysregulation triggered by the SARS-CoV-2 infection. The promising results of anakinra should be confirmed by the ongoing RCTs.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , COVID-19/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Anti-Inflammatory Agents/administration & dosage , Antibodies, Monoclonal, Humanized , Antiviral Agents/administration & dosage , Biological Products/administration & dosage , COVID-19/therapy , Cytokines/drug effects , Cytokines/metabolism , Dexamethasone/therapeutic use , Drug Therapy, Combination , Humans , Inflammation Mediators/metabolism , Intensive Care Units , Pandemics , Retrospective Studies , SARS-CoV-2
7.
Clin Microbiol Infect ; 27(2): 286.e7-286.e13, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-845619

ABSTRACT

OBJECTIVES: To examine whether specific T-cell-responses to SARS-CoV-2 peptides can be detected in COVID-19 using a whole-blood experimental setting, which may be further explored as a potential diagnostic tool. METHODS: We evaluated interferon (IFN)-γ levels after stimulating whole-blood with spike and remainder-antigens peptides megapools (MP) derived from SARS-CoV-2 sequences; interleukin (IL)-1ß, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, eotaxin, basic fibroblast growth factor (FGF), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ, Interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß, Platelet-derived growth factor (PDGF), RANTES (regulated on activation, normal T cell expressed and secreted), tumour necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF) were also evaluated. RESULTS: IFN-γ-response to spike and remainder-antigens MPs was significantly increased in 35 COVID-19 patients compared with 29 'no COVID-19' individuals (medians spike-MP: 0.26 vs 0, p = 0.0002; medians remainder-antigens-MP: 0.07 vs 0.02; p = 0.02). This response was detected independently of patients' clinical parameters. IFN-γ-response to SARS-CoV-2-unrelated antigens cytomegalovirus (CMV) and Staphylococcal Enterotoxin B (SEB) was similar in COVID-19 compared with 'no COVID-19' individuals (median CMV: 3.46 vs 5.28, p = 0.16; median SEB: 12.68 vs 15.05; p = 0.1). In response to spike-MPs in COVID-19- compared with 'no COVID-19' -individuals, we found significant higher median of IL-2 (50.08 vs 0, p = 0.0018), IFN-γ (90.16 vs 0, p = 0.01), IL-4 (0.52 vs 0, p = 0.03), IL-13 (0.84 vs 0, p = 0.007) and MCP-1 (4602 vs 359.2, p = 0.05). CONCLUSIONS: Immune response to SARS-CoV-2 peptides in a whole-blood assay is associated with COVID-19 and it is characterized by both Th1 and Th2 profile. This experimental approach may be useful for developing new T-cell based diagnostic tests for disease and vaccine settings.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , Antigens, Viral/immunology , COVID-19/blood , Cytokines/blood , Cytokines/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Interferon-gamma/blood , Interferon-gamma/immunology , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Th2 Cells/immunology
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