Hyperinflammatory Immune Response and COVID-19: A Double Edged Sword

Tan, Li Yin; Komarasamy, Thamil Vaani; Balasubramaniam, Vinod

doi:10.3389/fimmu.2021.742941

Cited by 107 publications

(102 citation statements)

References 121 publications

(185 reference statements)

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“…IL-1, IL-6, TNF-α, and TGF-β are important pro-inflammatory cytokines that contribute to the pathophysiology of the cytokine release syndrome (CRS), ARDS and multi-organ failure in critically sick adult COVID-19 patients with viral sepsis [13][14][15][16][17][18][19][20][21][22][23] as well as children and adolescents with COVID-19 who develop a multi-system inflammatory syndrome (MIS-C) [59][60][61][62]. Recently, we demonstrated that RJX prevents in the LPS-GalN mouse model of sepsis the marked increase of each of these cytokines in the serum as well as lungs and liver [26].…”

Section: Discussionmentioning

confidence: 99%

“…Several monoclonal antibodies that serve as inhibitors of the receptors and/or signaling pathways activated by specific pro-inflammatory cytokines are being developed and evaluated as anti-inflammatory drug candidates for prevention of CRS-related complications of severe COVID-19, including but not limited to the IL-1 receptor antagonist Anakinra (Kineret), IL-6 receptor antagonist tocilizumab (Actemra), TNF-α inhibitor infliximab (Remicade) [14,15,22,42,[49][50][51][52]. A major potential advantage of RJX versus biotherapeutic agents such as monoclonal antibodies that inhibit specific cytokine pathways is its ability to inhibit multiple pathways combined with its low cost of production which should make it readily available in low-to middle-income countries and therefore its further development and assessment as a potential COVID-19 drug candidate has potential global relevance.…”

Section: Discussionmentioning

confidence: 99%

“…Several pro-inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β), contribute to the development of a potentially fatal severe systemic inflammation in high-risk COVD-19 patients, which is known as cytokine release syndrome (CRS) and is often associated with acute lung injury (ALI) leading to ARDS and potentially multi-organ dysfunction (MOD) in rapid progression [13][14][15][16][17][18][19][20][21][22][23]. A ~40% likelihood of progression to severe-critical disease and ARDS within 10 days after symptom onset has been reported for high-risk COVID-19 patients [24][25][26] The identification of effective strategies capable of preventing the development of potentially fatal viral sepsis, cytokine release syndrome (CRS) and ARDS in high-risk COVID-19 patients, is an urgent and unmet medical need.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and Non-clinical Proof of Concept Supporting the Development of RJX As an Adjunct to Standard of Care Against Severe COVID-19

Uckun¹,

Saeed²,

Awili³

et al. 2022

Preprint

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Background. The identification of effective strategies capable of reducing the case mortality rate of high-risk COVID-19 is an urgent and unmet medical need. We recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). Here we report data from a pilot clinical study (RPI-015) which examined the safety, tolerability, and feasibility of using RJX in combination with clinical standard of care (SOC) in hospitalized COVID-19 patients with pneumonia (ClinicalTrials.gov Identifier: NCT04708340). In addition to our early clinical proof of concept (POC) data, we also present non-clinical POC from a mouse model of CRS and ARDS that informed the design of the reported clinical study. Methods. 13 patients, who were hospitalized with COVID-19 pneumonia and abnormally elevated serum inflammatory biomarkers markers ≥3 months prior to the identification of the first confirmed U.S case of the Omicron variant, were treated with IV RJX (daily x 7 days) plus SOC. Non-clinical POC study examined the ability of RJX plus dexamethasone (DEX) to improve the survival outcome in the lipopolysaccharide (LPS)-Galactosamine (GalN) mouse model of fatal cytokine release syndrome (CRS), sepsis and acute respiratory distress syndrome (ARDS). Findings. In the Phase 1 clinical study, none of the 13 patients developed a treatment-related DLT, SAE, or Grade 3-5 AEs. Nine (9) of the 12 evaluable patients, including 3 patients with hypoxemic respiratory failure, showed rapid clinical recovery. In the non-clinical POC study in LPS-GalN challenged mice, the combination of RJX plus DEX was more effective than RJX alone or DEX alone, reversed the CRS as well as inflammatory tissue damage in the lungs and liver, and improved the survival outcome. Taken together, these findings provide the early clinical and non-clinical POC for the development of RJX as an adjunct to the SOC in the multi-modality management of high-risk COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical and Non-clinical Proof of Concept Supporting the Development of RJX As an Adjunct to Standard of Care Against Severe COVID-19

Uckun¹,

Saeed²,

Awili³

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…[6,7] These factors might be linked to a hyperinflammatory syndrome, which favors an exaggerated immune response and organ failure when facing a viral infection. [8,9] Some ecological studies have evaluated COVID-19 mortality in high-altitude places, but the results are contradictory. Some authors reported higher mortality in men younger than 65 years old living in the USA and Mexico at >2,000 m elevation than in those located <1,500 m. [10] Other studies developed in an Andean population (Colombia and Perú) showed a negative correlation between high altitude and COVID-19 mortality and lower mortality excess.…”

Section: Introductionmentioning

confidence: 99%

The interaction effect between hemoglobin and hypoxemia on COVID-19 mortality in a sample from Bogotá, Colombia: An exploratory study

Patiño-Aldana

Ruiz-Sternberg

Pinzón-Rondón

et al. 2022

Preprint

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Purpose: We aimed to assess the effect of hemoglobin (Hb) concentration and oxygenation index on COVID-19 patients' mortality risk.Patients and methods: We retrospectively reviewed sociodemographic and clinical characteristics, laboratory findings, and clinical outcomes from patients admitted to a tertiary care hospital in Bogotá, Colombia. We assessed exploratory associations between oxygenation index and Hb concentration at admission and clinical outcomes. We used a generalized additive model (GAM) to evaluate the nonlinear relations observed and the classification and regression trees (CART) algorithm to assess the interaction effects found.Results: From March to July 2020, 643 patients were admitted, of which 52% were male. The median age was 60 years old, and the most frequent comorbidity was hypertension (35.76%). The median value of SpO2/FiO2 was 419, and the median Hb concentration was 14.8 g/dL. The mortality was 19.1% (123 patients). Age, sex, and history of hypertension were independently associated with mortality. We described a nonlinear relationship between SpO2/FiO2, Hb concentration and neutrophil-to-lymphocyte ratio with mortality and an interaction effect between SpO2/FiO2 and Hb concentration. Patients with a similar oxygenation index had different mortality likelihoods based upon their Hb at admission. CART showed that patients with SpO2/FiO2 < 324, who were older than 62 years, and had an Hb of >= 16 g/dl had the highest mortality risk (96%). Additionally, patients with SpO2/FiO2 > 324 but Hb of < 12 and neutrophil-to-lymphocyte ratio of > 4 had a higher mortality likelihood (57%). In contrast, patients with SpO2/FiO2 > 324 and Hb of > 12 g/dl had the lowest mortality risk (10%).Conclusion: We found that a decreased SpO2/FiO2 increased mortality risk. Extreme values of Hb, either low or high, showed an increase in likelihood of mortality. However, Hb concentration modified the SpO2/FiO2 effect on mortality; the likelihood of death in patients with low SpO2/FiO2 increased as Hb increased.

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“…In principle, the inflammatory responses incurred by SARS-CoV-2 involve diversified upstream stimuli, multiple signaling pathways, and numerous downstream effectors. 3 Therefore, targeting any particular cytokine or even signaling pathway may not be sufficient in alleviating the systemic overreaction of immune system in severe COVID-19, namely cytokine storm. It is urgent and pivotal to develop means which can systemically tuning down the exaggerated immune responses via a relative central node in the inflammation signaling cascades.…”

mentioning

confidence: 99%