ABSTRACT
BACKGROUND: The vast majority of COVID-19 disease occurs in outpatients where treatment is limited to anti-virals for high-risk subgroups. Acebilustat, a leukotriene B4 (LTB4) inhibitor, has potential to reduce inflammation and symptom duration. METHODS: In a single-center trial spanning Delta and Omicron variants, outpatients were randomized to 100 mg of oral acebilustat or placebo for 28 days. Patients reported daily symptoms via electronic query through Day 28 with phone follow-up on Day 120 and collected nasal swabs on Days 1-10. The primary outcome was sustained symptom resolution to Day 28. Secondary 28-day outcomes included time to first symptom resolution, area under the curve (AUC) of longitudinal daily symptom scores; duration of viral shedding through Day 10; and symptoms on Day 120. RESULTS: Sixty participants were randomized to each study arm. At enrollment, median duration and number of symptoms were 4 (IQR 3-5) days and 9 (IQR 7-11) symptoms. Most patients (90%) were vaccinated with 73% having neutralizing antibodies. A minority (44%) of participants (35% in the acebilustat arm and 53% in placebo) had sustained symptom resolution at Day 28 (HR 0.6, 95% CI 0.34-1.04, p = 0.07 favoring placebo). There was no difference in mean AUC of symptom scores over 28 days (difference in mean of AUC 9.4, 95% CI -42.1-60.9, p=0.72). Acebilustat did not impact viral shedding or symptoms at Day 120. CONCLUSIONS: Sustained symptoms through Day 28 were common in this low-risk population. Despite this, LTB4 antagonism with acebilustat did not shorten symptom duration in outpatients with COVID-19.
ABSTRACT
Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment.
Subject(s)
COVID-19 , Iron , Humans , Iron/metabolism , Lipocalin-2 , Post-Acute COVID-19 Syndrome , Arachidonate 5-Lipoxygenase/metabolism , Proteomics , BiomarkersABSTRACT
Background: Monocytes and macrophages drive the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) and they are a major source of eicosanoids in airway inflammation. Method: We used RNA sequencing and LC-MS/ MS analysis to determine transcriptional and lipid mediator profiles of monocyte-derived macrophages from convalescent COVID-19 patients 3-5 months post-SARS- CoV- 2 infection. Results: We found that monocyte-derived macrophages (MDM) from SARS-CoV- 2- infected individuals with mild disease show an inflammatory transcriptional and metabolic imprint several (3-5) months after SARS-CoV- 2 infection. MDM from convalescent SARS-CoV- 2- infected individuals showed higher expression of fatty acid-metabolic enzymes and increased production of pro-inflammatory eicosanoids, particularly neutrophil chemotactic leukotriene B4 (LTB4) and LTD4 a driver of airway remodeling. MDM from previously SARS-CoV- 2- infected subjects showed an exaggerated induction of inflammatory chemokines as well as T-cell suppressive enzymes and receptors following stimulation with spike protein or LPS. Corticosteroids reduced inflammatory cytokine-, but increased leukotriene production in macrophages. Conclusion: Thus, SARS-CoV- 2 infection leaves an inflammatory imprint in the monocyte/macrophage compartment that drives aberrant effector functions and eicosanoid metabolism, possibly explaining long-term effects in patients recovering from mild COVID-19.
ABSTRACT
COVID-19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical acute respiratory distress syndrome (ARDS) seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical hemolytic uremic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID-19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5, respectively. C5a is a potent cell signalling protein that activates a cytokine storm-a hyper-inflammatory phenomenon-within hours of infection and the innate immune response. However, excess C5a can result in a pro-inflammatory environment orchestrated through a plethora of mechanisms that propagate lung injury, lymphocyte exhaustion, and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro-coagulant state in the microvasculature of critical organs. Fatal COVID-19 has been associated with a systemic inflammatory response accompanied by a pro-coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID-19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19.