Stimulating severe COVID-19: the potential role of GM-CSF antagonism

Leavis, Helen L.; Veerdonk, Frank L. van de; Murthy, Srinivas

doi:10.1016/s2213-2600(21)00539-7

Cited by 13 publications

(5 citation statements)

References 11 publications

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“…Additional ex vivo studies demonstrated that arming and activation of CD56 bright cells occurs especially in severely diseased COVID‐19 patients 13,14 . Other studies demonstrated that the CD56 bright ‐derived IFN‐γ, TNF‐α, GM‐CSF and IL‐13 levels are highly elevated in the serum of severely ill COVID‐19 patients, and may contribute to the disadvantageous immunopathogenesis, leading to a severe course of COVID‐19 15–18 . This supports our data, showing that the rs9916629 polymorphism is highly associated with fatal disease, as the rs9916629 ‐ C allele leads to high CD56 bright frequencies, which potentially exaggerate the release of pro‐inflammatory cytokines.…”

Section: Discussionsupporting

confidence: 89%

The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

Vietzen

Furlano

Traugott³

et al. 2022

Journal of Medical Virology

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The severity of COVID‐19 is associated with individual genetic host factors. Among these, genetic polymorphisms affecting natural killer (NK) cell responses, as variations in the HLA‐E‐ (HLA‐E*0101/0103), FcγRIIIa‐ (FcγRIIIa‐158‐F/V), and NKG2C‐ (KLRC2wt/del) receptor, were associated with severe COVID‐19. Recently, the rs9916629‐C/T genetic polymorphism was identified that indirectly shape the human NK cell repertoire towards highly pro‐inflammatory CD56bright NK cells. We investigated whether the rs9916629‐C/T variants alone and in comparison to the other risk factors are associated with a fatal course of COVID‐19. We included 1042 hospitalized surviving and 159 nonsurviving COVID‐19 patients as well as 1000 healthy controls. rs9916629‐C/T variants were genotyped by TaqMan assays and were compared between the groups. The patients' age, comorbidities, HLA‐E*0101/0103, FcγRIIIa‐158‐F/V, and KLRC2wt/del variants were also determined. The presence of the rs9916629‐C allele was a risk factor for severe and fatal COVID‐19 (p < 0.0001), independent of the patients' age or comorbidities. Fatal COVID‐19 was more frequent in younger patients (<69.85 years) carrying the FcγRIIIa‐158‐V/V (p < 0.006) and in older patients expressing the KLRC2del variant (p < 0.003). Thus, patients with the rs9916629‐C allele have a significantly increased risk for fatal COVID‐19 and identification of the genetic variants may be used as prognostic marker for hospitalized COVID‐19 patients.

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Section: Discussionsupporting

confidence: 89%

The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

Vietzen

Furlano

Traugott³

et al. 2022

Journal of Medical Virology

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“…Serum levels of various inflammatory cytokines, including GM-CSF, tend to be higher in patients with COVID-19 than in healthy controls and are correlated with disease severity ( 9 , 25 ). GM-CSF enhances the production of various inflammatory cytokines ( 26 ) and is a key component of the hyperinflammatory response in COVID-19 ( 8 , 27 , 28 ). A monoclonal antibody against GM-CSF is a candidate for treating COVID-19, and a randomized controlled trial has been conducted with no conclusive results ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Pulmonary Alveolar Proteinosis That Improved after a COVID-19 Episode

et al. 2023

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Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction owing to the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. A 77-year-old man with APAP was referred to our hospital for whole-lung lavage (WLL) due to oxygenation exacerbation and pulmonary shadows. The patient had had coronavirus disease 2019 (COVID-19) during the APAP evaluation before WLL. About three months after COVID-19 resolved, his oxygenation and shadow reflecting APAP had obviously improved, thus avoiding the need for WLL. We suspected that the improvement in APAP was due to various immunological reactions induced by COVID-19.

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“…The COVID-19 pandemic remains an urgent problem around the globe, with the global outbreak still not fully contained and cases rising. Prior research indicates that patients with COVID-19 infection have increased levels of GM-CSF in their blood, especially in the later stages of the disease (Leavis et al 2022 ). Previous studies revealed that GM-CSF can enhance the expression of many pro-inflammatory cytokines and chemokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (Becher et al 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of granulocyte–macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients: a meta-analysis

Luo

Guan

et al. 2022

Inflammopharmacol

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Objective This study aims to determine the efficacy and safety of granulocyte–macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients. Methods We searched Cochrane Library, PubMed, Embase, and ClinicalTrials.gov databases until July 27, 2022. Both randomized control trials (RCTs) and cohort studies were included and analyzed separately. The outcomes included mortality, incidence of invasive mechanical ventilation (IMV), ventilation improvement rate (need oxygen therapy to without oxygen therapy), secondary infection, and adverse events (AEs). The odds ratio (OR) with a 95% confidence interval (CI) was calculated by a random-effects meta-analysis model. Results Five RCTs and 2 cohort studies with 1726 COVID-19 patients were recruited ( n = 866 in the GM-CSF antibody group and n = 891 in the control group). GM-CSF antibodies treatment reduced the incidence of IMV, which was supported by two cohort studies (OR 0.16; 95% CI 0.03, 0.74) and three RCTs (OR 0.62; 95% CI 0.41, 0.94). GM-CSF antibodies resulted in slight but not significant reductions in mortality (based on two cohort studies and five RCTs) and ventilation improvement (based on one cohort study and two RCTs). The sensitive analysis further showed the results of mortality and ventilation improvement rate became statistically significant when one included study was removed. Besides, GM-CSF antibodies did not increase the risks of the second infection (based on one cohort study and five RCTs) and AEs (based on five RCTs). Conclusion GM-CSF antibody treatments may be an efficacious and well-tolerant way for the treatment of COVID-19. Further clinical evidence is still warranted. Supplementary Information The online version contains supplementary material available at 10.1007/s10787-022-01105-9.

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Stimulating severe COVID-19: the potential role of GM-CSF antagonism

Cited by 13 publications

References 11 publications

The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

The natural killer cell‐associated rs9916629‐C allele is a novel genetic risk factor for fatal COVID‐19

Autoimmune Pulmonary Alveolar Proteinosis That Improved after a COVID-19 Episode

Efficacy and safety of granulocyte–macrophage colony-stimulating factor (GM-CSF) antibodies in COVID-19 patients: a meta-analysis

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