Effect of IL-6R Blockade on Plasma Lipids and Clinical Outcomes Among Hospitalized Patients with COVID-19 Infection

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2024 May 25

PMID 38795859

Authors

Kusha Mohammadi

Mark W Sleeman

Anita Boyapati

Parnian Bigdelou

Gregory P Geba

Sergio Fazio

Affiliations

Soon will be listed here.

Abstract

Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6-mediated inflammation.

References

Catapano A, Pirillo A, Bonacina F, Norata G . HDL in innate and adaptive immunity. Cardiovasc Res. 2014; 103(3):372-83. DOI: 10.1093/cvr/cvu150. View

Eltahan N, Elsawy N, Abdelaaty K, Elhamaky A, Hassan A, Emara M . Atorvastatin for reduction of 28-day mortality in severe and critical COVID-19 patients: a randomized controlled trial. Respir Res. 2024; 25(1):97. PMC: 10885389. DOI: 10.1186/s12931-024-02732-2. View

Navarese E, Podhajski P, Gurbel P, Grzelakowska K, Ruscio E, Tantry U . PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection. J Am Coll Cardiol. 2023; 81(3):224-234. PMC: 9842071. DOI: 10.1016/j.jacc.2022.10.030. View

Aparisi A, Martin-Fernandez M, Ybarra-Falcon C, Gil J, Carrasco-Moraleja M, Martinez-Paz P . Dyslipidemia and Inflammation as Hallmarks of Oxidative Stress in COVID-19: A Follow-Up Study. Int J Mol Sci. 2022; 23(23). PMC: 9736368. DOI: 10.3390/ijms232315350. View

Bonacina F, Pirillo A, Catapano A, Norata G . HDL in Immune-Inflammatory Responses: Implications beyond Cardiovascular Diseases. Cells. 2021; 10(5). PMC: 8146776. DOI: 10.3390/cells10051061. View

Feingold K . The bidirectional interaction of COVID-19 infections and lipoproteins. Best Pract Res Clin Endocrinol Metab. 2023; 37(4):101751. PMC: 9951034. DOI: 10.1016/j.beem.2023.101751. View

Li G, Li Y, Yamate M, Li S, Ikuta K . Lipid rafts play an important role in the early stage of severe acute respiratory syndrome-coronavirus life cycle. Microbes Infect. 2006; 9(1):96-102. PMC: 7110773. DOI: 10.1016/j.micinf.2006.10.015. View

Hu X, Chen D, Wu L, He G, Ye W . Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection. Clin Chim Acta. 2020; 510:105-110. PMC: 7350883. DOI: 10.1016/j.cca.2020.07.015. View

Wu Z, McGoogan J . Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323(13):1239-1242. DOI: 10.1001/jama.2020.2648. View

10.

Marcello A, Civra A, Milan Bonotto R, Nascimento Alves L, Rajasekharan S, Giacobone C . The cholesterol metabolite 27-hydroxycholesterol inhibits SARS-CoV-2 and is markedly decreased in COVID-19 patients. Redox Biol. 2020; 36:101682. PMC: 7416714. DOI: 10.1016/j.redox.2020.101682. View

11.

Zhang X, Qin J, Cheng X, Shen L, Zhao Y, Yuan Y . In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020; 32(2):176-187.e4. PMC: 7311917. DOI: 10.1016/j.cmet.2020.06.015. View

12.

Hills T, Lorenzi E, Berry L, Shyamsundar M, Al-Beidh F, Annane D . Simvastatin in Critically Ill Patients with Covid-19. N Engl J Med. 2023; 389(25):2341-2354. PMC: 10755839. DOI: 10.1056/NEJMoa2309995. View

13.

Khalaji A, Behnoush A, Alilou S, Rezaee M, Peiman S, Sahebkar A . Adjunctive therapy with lipid-lowering agents in COVID-19: a systematic review and meta-analysis of randomized controlled trials. Lipids Health Dis. 2023; 22(1):61. PMC: 10165571. DOI: 10.1186/s12944-023-01828-w. View

14.

Uchiyama Y, Yoshida H, Koike N, Hayakawa N, Sugita A, Nishimura T . Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production. Int Immunopharmacol. 2008; 8(11):1595-601. DOI: 10.1016/j.intimp.2008.07.002. View

15.

von Eckardstein A, Nordestgaard B, Remaley A, Catapano A . High-density lipoprotein revisited: biological functions and clinical relevance. Eur Heart J. 2022; 44(16):1394-1407. PMC: 10119031. DOI: 10.1093/eurheartj/ehac605. View

16.

Wei X, Zeng W, Su J, Wan H, Yu X, Cao X . Hypolipidemia is associated with the severity of COVID-19. J Clin Lipidol. 2020; 14(3):297-304. PMC: 7192140. DOI: 10.1016/j.jacl.2020.04.008. View

17.

Agouridis A, Pagkali A, Zintzaras E, Rizos E, Ntzani E . High-density lipoprotein cholesterol: A marker of COVID-19 infection severity?. Atheroscler Plus. 2021; 44:1-9. PMC: 8383482. DOI: 10.1016/j.athplu.2021.08.007. View

18.

Talasaz A, Sadeghipour P, Aghakouchakzadeh M, Dreyfus I, Kakavand H, Ariannejad H . Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021; 78(16):1635-1654. PMC: 8504484. DOI: 10.1016/j.jacc.2021.08.021. View

19.

Chacko S, DeJoy 3rd R, Lo K, Albano J, Peterson E, Bhargav R . Association of Pre-Admission Statin Use With Reduced In-Hospital Mortality in COVID-19. Am J Med Sci. 2021; 361(6):725-730. PMC: 7923853. DOI: 10.1016/j.amjms.2021.03.001. View

20.

Sahin F, Yildiz P . Distinctive biochemical changes in pulmonary tuberculosis and pneumonia. Arch Med Sci. 2013; 9(4):656-61. PMC: 3776170. DOI: 10.5114/aoms.2013.34403. View