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Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

ABSTRACT: Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.

SUBMITTER: Agresti N

PROVIDER: S-EPMC7823045 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

Agresti Nicholas N Lalezari Jacob P JP Amodeo Phillip P PP Mody Kabir K Mosher Steven F SF Seethamraju Harish H Kelly Scott A SA Pourhassan Nader Z NZ Sudduth C David CD Bovinet Christopher C ElSharkawi Ahmed E AE Patterson Bruce K BK Stephen Reejis R Sacha Jonah B JB Wu Helen L HL Gross Seth A SA Dhody Kush K

Journal of translational autoimmunity 20210106

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options a ...[more]

PMID: 33521616

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Project description:The number of confirmed cases of infection with SARS-CoV-2, the virus causing Coronavirus disease 2019 (COVID-19), continues to increase and is associated with substantial morbidity and mortality in virtually every country in the world. Although in the long-term mass vaccinations remains the most promising approach to control the pandemic, evidence suggests that new variants of the virus have emerged that may be able to evade the immune responses triggered by current vaccines. Therefore despite the recent approval of a number of SARS-CoV-2 vaccines there remains considerable urgency for effective treatments for COVID-19. Severe-to-critical COVID-19 has been shown to be associated with a dysregulated host immune response to SARS-CoV-2 with elevated levels of C-C chemokine receptor type 5 (CCR5) ligands including chemokine C-C ligands 3, 4, 5, as well as interleukins 6 and 10. Leronlimab, a CCR5-specific humanised IgG4 monoclonal antibody originally developed for the treatment of HIV has been studied for the treatment of COVID-19. In the TEMPEST trial which compared leronlimab to placebo in subjects with mild-to-moderate COVID-19, a post hoc analysis showed that leronlimab led to improvements from baseline in National Early Warning Score 2 (NEWS2) at Day 14 in the sub-set of people with more severe disease. Data has also been released on a further ongoing, randomized, placebo-controlled phase 3 registrational trial of leronlimab in 394 people with severe-to-critical COVID-19. The results show that Day 28 mortality was reduced (P = 0.0319) in the subset of participants receiving leronlimab plus other pre-specified commonly used COVID-19 treatments including dexamethasone administered as part of their standard of care (SOC) compared to participants receiving placebo plus other pre-specified commonly used COVID-19 treatments including dexamethasone as part of their SOC. Several cases have recently been reported demonstrated that treatment with leronlimab restores immune function and achieves clinical improvement in people with critical COVID-19. Here we report on a further case of a critically ill person who was treated with leronlimab. This person had been on extracorporeal membrane oxygenation (ECMO) for an extended period of time before receiving 4 doses of leronlimab. The male subject received his first dose of leronlimab on Day 79 of hospitalization he was weaned off ECMO by Day 84 and discharged from the ECMO intensive care unit on Day 91.

Project description:CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.

Project description:IntroductionMortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality.MethodsWe performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients.ResultsThe mean patient age was 65.6 years (range, 29-92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25th to 75th percentile: 6-18), while the median total number of hospital stay was 18 (25th to 75th percentile: 12-28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis.ConclusionIn the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.

Project description:ImportanceThyroid storm is the most severe form of thyrotoxicosis, with high mortality, and is treated with propylthiouracil and methimazole. Some guidelines recommend propylthiouracil over methimazole, although the difference in outcomes associated with each treatment is unclear.ObjectiveTo compare outcomes associated with use of propylthiouracil vs methimazole for the treatment of thyroid storm.Design, setting, and participantsThis comparative effectiveness study comprised a large, multicenter, US-based cohort from the Premier Healthcare Database between January 1, 2016, and December 31, 2020. It included 1383 adult patients admitted to intensive or intermediate care units with a diagnosis of thyroid storm per International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and treated with either propylthiouracil or methimazole. Analyses were conducted from July 2022 to February 2023.ExposurePatients received either propylthiouracil or methimazole for treatment of thyroid storm. Exposure was assigned based on the initial thionamide administered.Main outcomes and measuresThe primary outcome was the adjusted risk difference of in-hospital death or discharge to hospice between patients treated with propylthiouracil and those treated with methimazole, assessed by targeted maximum likelihood estimation.ResultsA total of 1383 patients (656 [47.4%] treated with propylthiouracil; mean [SD] age, 45 [16] years; 473 women [72.1%]; and 727 [52.6%] treated with methimazole; mean [SD] age, 45 [16] years; 520 women [71.5%]) were included in the study. The standardized mean difference for age was 0.056, and the standardized mean difference for sex was 0.013. The primary composite outcome occurred in 7.4% of of patients (102 of 1383; 95% CI, 6.0%-8.8%). A total of 8.5% (56 of 656; 95% CI, 6.4%-10.7%) of patients who initiated propylthiouracil and 6.3% (46 of 727; 95% CI, 4.6%-8.1%) who initiated methimazole died in the hospital (adjusted risk difference, 0.6% [95% CI, -1.8% to 3.0%]; P = .64). There were no significant differences in duration of organ support, total hospitalization costs, or rates of adverse events between the 2 treatment groups.Conclusion and relevanceIn this comparative effectiveness study of a multicenter cohort of adult patients with thyroid storm, no significant differences were found in mortality or adverse events in patients who were treated with propylthiouracil or methimazole. Thus, current guidelines recommending propylthiouracil over methimazole for treatment of thyroid storm may merit reevaluation.

Project description:Systemic inflammation is a key characteristic of sepsis but also also in non-infectious conditions such as post-cardiac arrest syndrome. Cytokine adsorption and extracorporeal membrane oxygenation are emerging therapies applied in these critically ill patients, but the experience with their concurrent use is limited. We evaluated cytokine adsorption in critically ill patients requiring support with either veno-venous (vv) or veno-arterial (va) extracorporeal membrane oxygenation (ECMO) support and hypothesized that adsorber incorporation into the ECMO circuit was technically feasible and not associated with imminent risk. We analyzed data from the first six cases of a prospective single-center registry of patients undergoing veno-venous (vv) or veno-arterial (va) ECMO therapy. While in most published cases cytokine adsorbers were inserted into a hemofiltration circuit, we directly incorporated the adsorber into the ECMO circuit without interruption of continuous ECMO support. We observed no relevant side effects attributable to cytokine adsorption. Thirty-day mortality was 83% (predicted mortality 87%), indicating that the decision for adding cytokine adsorption may have been considered as an ultima ratio decision in severe cases with poor prognosis. Vasopressor or inotrope use, lactate level, and fluid balance did not change significantly when comparing pre- vs. post-cytokine adsorption values. Interestingly, the real-time course of the mentioned three surrogate parameters remained unaltered in all but two cases, regardless of cytokine removal. Beneficial effects of cytokine adsorption are plausible in two va-ECMO-treated patient, where increasing lactate began to drop after initiation of cytokine adsorption. Taken together, these data suggest that incorporation of cytokine adsorption into the management of critically ill patients requiring continued ECMO support is feasible and easy to handle. Whether cytokine removal improves clinical outcome in ECMO-treated patients should now be investigated in randomized controlled trials.

Dataset Information

Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

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Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

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