IL-6 inhibitors for COVID-19
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Introduction
Clinical significance:
- IL-6 inhibitor data conflicting[1]
- tocilizumab of no benefit in oxygenation, hospital discharge, or mortality[2]
- benefit in shorter duration of vasopressor support (2 vs 5 days)[2]
- may reduce need for mechanical ventilation & reduce mortality[3]
- reduces mortality in COVID-19 patients requiring mechanical ventilation 46% (18% vs 36%)[4]
- may reduce progression to mechanical ventilatiom in hospitalized patients with COVID-19 but does not improve survival[5]
- role of cytokine storm in COVID-19 mortality in question
- plasma IL-6 levels are not elevated & IL-6 blocking Ab tocilizumab noteffective[6]
- in a Chinese clinical trial to reduce inflammatory response, cytokine storm & influx of macrophages[7]
- in-hospital mortality rate diminished by IL-6 inhibitors tocilizumab (28%), sarilumab (22%) vs standard care (36%), all receiving dexamethasone[8]
- of no benefit in clinical status or mortality at 28 days[8]
- IL-6 inhibitors with glucocorticoid diminish 28 day mortality in hospitalized patients with Covid-19 (RR=0.77 for tocilizumab & RR=0.92 for sarilumab) at the expense of increased secondary infections within 28 days 22% vs 18% for placebo[14]
- tocilizumab may confer increased risk for mortality in patients with severe or critical COVID-19[9]
- not enough data to recommend for or against the use of tocilizumab or sarilumab to treat COVID-19 in patients admitted to the ICU[10]
- Infectious Diseases Society of America recommends tocilizumab for COVID-19 SIRS[11] (see page 43 of ref 11)
- tocilizumab FDA emergency use authorization for hospitalized patients receiving glucocorticoid[13]
- anti-CD6 monoclonal antibody itolizumab reduces plasma IL-6
- in combination with other antvirals, itolizumab may reduce disease severity & mortality[12]
- in critically ill patients with Covid-19, IL-6 inhibitors improve 180 day mortality (100% probability)[15]
Additional terms
- COVID-19
- interleukin-6; IL-6; B-cell stimulatory factor 2; BSF-2; CTL differentiation factor; CDF; hybridoma growth factor; interferon beta-2; IFN-beta-2 (IL6, IFNB2)
References
- ↑ Jump up to: 1.0 1.1 Gupta S, Wang W, Hayek SS et al Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med. Published online October 20, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33080002 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772185
Salvarani C, Dolci G, Massari M et al Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia, A Randomized Clinical Trial. JAMA Intern Med. Published online October 20, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33080005 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772186
Hermine O, Mariette X, Tharaux PL et al Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia, A Randomized Clinical Trial. JAMA Intern Med. Published online October 20, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33080017 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772187
Parr JB Time to Reassess Tocilizumab's Role in COVID-19 Pneumonia. JAMA Intern Med. Published online October 20, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33079980 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772184 - ↑ Jump up to: 2.0 2.1 2.2 Kewan T et al Tocilizumab for treatment of patients with severe COVID-19: A retrospective cohort study. EClinicalMedicine from Lancet. Published:June 20, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32766537 Free PMC article. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30162-0/fulltext
- ↑ Jump up to: 3.0 3.1 Guaraldi P, Meschiari M, Cozzi-Lepri A et al Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatology. 2020 Aug;2(8):e474-e484 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32835257 PMCID: PMC7314456 Free PMC article https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30173-9/fulltext
- ↑ Jump up to: 4.0 4.1 Somers EC, Eschenauer GA, Troost JP Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clinical Infectious Diseases, ciaa954, Published: July 11, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32651997 https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa954/5870306
- ↑ Jump up to: 5.0 5.1 Salama C, Han J, Yau L et al Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med 2020, Dec 17 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33332779 https://www.nejm.org/doi/full/10.1056/NEJMoa2030340
- ↑ Jump up to: 6.0 6.1 AMA News. Nov 9, 2020 American Medical Association
Hermine O, Mariette X, Tharaux PL et al Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia. A Randomized Clinical Trial. JAMA Intern Med. Published online October 20, 2020. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33080017 PMCID: PMC7577198 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772187
Gupta A, Wang W, Hayek SS et al Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med. Published online October 20, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33080002 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772185
Stone JH, Frigault MJ, Serling-Boyd NJ et al Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Oct 21 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33085857 https://www.nejm.org/doi/full/10.1056/NEJMoa2028836 - ↑ Jump up to: 7.0 7.1 Ledford H How does COVID-19 kill? Uncertainty is hampering doctors' ability to choose treatments. Nature, NEWS 09 April 2020 https://www.nature.com/articles/d41586-020-01056-7
Xu X, Han M, Li T et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020 Apr 29; PMID: https://www.ncbi.nlm.nih.gov/pubmed/32350134 https://www.pnas.org/content/early/2020/04/27/2005615117 - ↑ Jump up to: 8.0 8.1 8.2 Walker M Mixed Bag for IL-6 Inhibitors in Severe COVID-19 - Two trials, two different outcomes; did other treatments play a role? MedPage Today February 25, 2021 https://www.medpagetoday.com/infectiousdisease/covid19/91369
The REMAP-CAP Investigators. Gordon AC, Mouncey PR, Al-Beidh F et al Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 - Preliminary report. medRxiv. Jan 7, 2021 Not indexed in PubMed https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1
The REMAP-CAP Investigators Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med 2021. Feb 25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33631065 https://www.nejm.org/doi/full/10.1056/NEJMoa2100433
Rosas IO, Brau N, Waters M et al Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med 2021. Feb 25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33631066 https://www.nejm.org/doi/full/10.1056/NEJMoa2028700
Rubin EJ, Longo DL, Baden LR. Interleukin-6 Receptor Inhibition in Covid-19 - Cooling the Inflammatory Soup N Engl J Med 2021. Feb 25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33631064 https://www.nejm.org/doi/full/10.1056/NEJMe2103108 - ↑ Jump up to: 9.0 9.1 Veiga VC Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ 2021;372:n84 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33472855 PMCID: PMC7815251 Free PMC article https://www.bmj.com/content/372/bmj.n84
- ↑ Jump up to: 10.0 10.1 COVID-19 Treatment Guidelines. Last Updated: February 3, 2021 The COVID-19 Treatment Guidelines Panel's Statement on the Use of Tocilizumab (and Other Interleukin-6 Inhibitors) for the Treatment of COVID-19. https://www.covid19treatmentguidelines.nih.gov/statement-on-tocilizumab/
- ↑ Jump up to: 11.0 11.1 Bhimraj A, Morgan RL, Shumaker AH et al Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. https://www.idsociety.org/globalassets/idsa/practice-guidelines/covid-19/treatment/idsa-covid-19-gl-tx-and-mgmt-v4.0.0.pdf
- ↑ Jump up to: 12.0 12.1 Diaz Y, Ramos-Suzarte M, Martin Y et al Use of a Humanized Anti-CD6 Monoclonal Antibody (Itolizumab) in Elderly Patients with Moderate COVID-19 Gerontology. 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33105142 PMCID: PMC7649683 Free PMC article https://www.karger.com/Article/FullText/512210
- ↑ Jump up to: 13.0 13.1 Walker M FDA Authorizes IL-6 Inhibitor for Severe COVID-19 Patients. Tocilizumab received EUA for hospitalized patients receiving steroids. MedPage Today June 25, 2021 https://www.medpagetoday.com/infectiousdisease/covid19/93277
- ↑ Jump up to: 14.0 14.1 The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19A Meta-analysis. JAMA. Published online July 6, 2021 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34228774 https://jamanetwork.com/journals/jama/fullarticle/2781880
Matthay MA, Luetkemeyer AF IL-6 Receptor Antagonist Therapy for Patients Hospitalized for COVID-19. Who, When, and How? JAMA. Published online July 6, 2021 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34228779 https://jamanetwork.com/journals/jama/fullarticle/2781881 - ↑ Jump up to: 15.0 15.1 Writing Committee for the REMAP-CAP Investigators Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial. JAMA. Published online December 16, 2022. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36525245 https://jamanetwork.com/journals/jama/fullarticle/2799870
Barnett ML, Sax PE Long-term Follow-up After Critical COVID-19REMAP-CAP Revisited JAMA. Published online December 16, 2022 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36525259 https://jamanetwork.com/journals/jama/fullarticle/2799872