Predictors of Mortality in Severe and Critical COVID-19 Patients Receiving High Dose Intravenous Anakinra

Abstract

Objective: In this study, we aim to evaluate the predictive factors associated with mortality in patients with severe and critical COVID-19 receiving high dose intravenous anakinra. Methods: This is an observational retrospective study was conducted at a tertiary referral center between 01.09.2021 and 01.02.2022 in Turkey. COVID-19 disease severity was evaluated according to National Institute of Health (NIH) severity scale. Inflammatory state of the patients was calculated according to COVID hyperinflammatory syndrome (cHIS) score. Clinical (patients characteristics, disease severity, inflammatory state) and laboratory parameters such as lymphocyte count, CRP, LDH, ferritin and d-dimer levels were compared in patients had mortality and those had not. Results: Data of 148 patients (n=78; 53% male) were analyzed. Mean±standard deviation (SD) patient age was 66.8±17 years and median (interquartile of range; IQR) duration of hospitalization was 11 (12) days. In this cohort, 57 patients (38.5%) severe, 91 patients (61.5%) had critical disease and mean±SD cHIS score was 3.4±1.2. Overall, 56 patients (37.8%) died during the follow-up and ICU admission was in 60 patients (40.5%) and intubation was in 54 patients (36.5%). Conclusion: In our study mortality was developed in third of anakinra receiving severe and critical ill COVID-19 patients. Mortality was independently associated with advanced age, critical illness and higher cHIS score reflecting higher inflammatory burden. Furthermore, highest levels of CRP, LDH, ferritin, D-dimer and higher cHIS score predict higher mortality in patients with COVID-19 receiving anakinra.

Keywords

• COVID 19
• Anakinra
• Cytokine Storm
• Hyperinflammation
• Predictors

Project Number

Yok

Yüksek Doz İntravenöz Anakinra Alan Ciddi ve Kritik COVİD-19 Hastalarında Mortalite Öngördürücüleri

Abstract

Amaç: Bu çalışmada, yüksek doz intravenöz anakinra alan ciddi ve kritik COVID-19 hastalarında mortalite ile ilişkili öngörücü faktörleri değerlendirmeyi amaçladık. Yöntem: Bu çalışma, 01.09.2021 ile 01.02.2022 tarihleri arasında üçüncü basamak referans merkezinde gerçekleştirilmiştir. Çalışmamız geriye dönük gözlemsel bir çalışmadır. COVID-19 hastalık şiddeti NIH şiddet ölçeğine göre değerlendirildi. COVID hiperinflamatuar sendrom (cHIS) skoru hastaların inflamatuvar durumlarını değerlendirmek için hesaplandı. Klinik (hasta özellikleri, hastalık şiddeti, inflamatuvar durum) ve laboratuvar parametreleri (lenfosit sayısı, CRP, LDH, ferritin ve d-dimer düzeyleri) mortalite gerçekleşen ve gerçekleşmeyen hastalarda karşılaştırıldı. Bulgular: 148 hastanın (n=78; %53 erkek) verileri analiz edildi. Ortalama±standart sapma (SS) hasta yaşı 66.8±17 yıl ve ortanca (çeyrekler arası aralık; IQR) hastanede kalış süresi 11 (12) gündü. Bu kohortta 57 hasta (%38.5) şiddetli, 91 hasta (%61.5) kritik hastalığa sahipti ve hastaların ortalama±SD cHIS skoru 3.4±1.2 idi. Toplamda 56 hastada (%37.8) takip sırasında mortalite gerçekleşti ve 60 hastada (%40.5) yoğun bakım ünitesine yatış ve 54 hastada (%36.5) entübasyon ihtiyacı oluştu. Sonuç: Çalışmamızda ciddi ve kritik seyirli COVİD-19 hastalarının yaklaşık üçte birinde mortalite gerçekleşmiştir. Mortalite hızı ileri hasta yaşı, kritik hastalık şiddeti ve inflamatuvar yükü yansıtan cHIS skoru ile ilişkili bulundu. Dahası, yüksek CRP, LDH, ferritin, d-dimer seviyeleri ve cHIS skoru anakinra alan COVİD-19 hastalarında yüksek mortaliteyi öngördürmekteydi

Keywords

• COVİD-19
• Anakinra
• Sitokin Fırtınası
• Hiperinflamasyon
• Öngördürücüler

Supporting Institution

Yok

Project Number

Yok

References

1. WHO WHOJIg. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. 2020;13.
2. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. International journal of antimicrobial agents. 2020;55(3):105924.
3. Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Frontiers in immunology. 2020;11:1446.
4. Vardhana SA, Wolchok JDJJoEM. The many faces of the anti-COVID immune response. 2020;217(6).
5. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (London, England). 2020;395(10223):507-13.
6. Webb BJ, Peltan ID, Jensen P, Hoda D, Hunter B, Silver A, et al. Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study. The Lancet Rheumatology. 2020;2(12):e754-e63.
7. Caricchio R, Gallucci M, Dass C, Zhang X, Gallucci S, Fleece D, et al. Preliminary predictive criteria for COVID-19 cytokine storm. Annals of the rheumatic diseases. 2021;80(1):88-95.
8. Cappanera S, Palumbo M, Kwan SH, Priante G, Martella LA, Saraca LM, et al. When Does the Cytokine Storm Begin in COVID-19 Patients? A Quick Score to Recognize It. Journal of clinical medicine. 2021;10(2).

9. Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nature reviews Rheumatology. 2016;12(5):259-68.
10. Bami S, Vagrecha A, Soberman D, Badawi M, Cannone D, Lipton JM, et al. The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis. Pediatric blood & cancer. 2020;67(11):e28581.
11. Gallo Marin B, Aghagoli G, Lavine K, Yang L, Siff EJ, Chiang SS, et al. Predictors of COVID-19 severity: A literature review. Reviews in medical virology. 2021;31(1):1-10.
12. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. The European respiratory journal. 2020;55(5).
13. O’Driscoll M, Ribeiro Dos Santos G, Wang L, Cummings DAT, Azman AS, Paireau J, et al. Age specific mortality and immunity patterns of SARS-CoV-2. Nature. 2021;590(7844):140-5.
14. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674-8.
15. Heneka MT. Inflammasome activation and innate immunity in Alzheimer’s disease. Brain pathology (Zurich, Switzerland). 2017;27(2):220-2.
16. Sipilä PN, Heikkilä N, Lindbohm JV, Hakulinen C, Vahtera J, Elovainio M, et al. Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort. The Lancet Infectious Diseases. 2021;21(11):1557-67.
17. Chu CS, Liang CS, Tsai SJ, Bai YM, Su TP, Chen TJ, et al. Bacterial pneumonia and subsequent dementia risk: A nationwide cohort study. Brain, behavior, and immunity. 2022;103:12-8.
18. Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature medicine. 2020;26(5):681-7.
19. Koyama S, Ishii KJ, Coban C, Akira S. Innate immune response to viral infection. Cytokine. 2008;43(3):336-41.
20. Chau AS, Weber AG, Maria NI, Narain S, Liu A, Hajizadeh N, et al. The Longitudinal Immune Response to Coronavirus Disease 2019: Chasing the Cytokine Storm. Arthritis & rheumatology (Hoboken, NJ). 2021;73(1):23-35.
21. López-Reyes A, Martinez-Armenta C, Espinosa-Velázquez R, Vázquez-Cárdenas P, Cruz-Ramos M, Palacios-Gonzalez B, et al. NLRP3 Inflammasome: The Stormy Link Between Obesity and COVID-19. Frontiers in immunology. 2020;11:570251.
22. Brisse E, Wouters CH, Matthys P. Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders. Cytokine & growth factor reviews. 2015;26(3):263-80.
23. Davì S, Consolaro A, Guseinova D, Pistorio A, Ruperto N, Martini A, et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. The Journal of rheumatology. 2011;38(4):764-8.
24. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiology and molecular biology reviews : MMBR. 2012;76(1):16-32.
25. Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018;104:8-13.
26. Manson JJ, Crooks C, Naja M, Ledlie A, Goulden B, Liddle T, et al. COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study. The Lancet Rheumatology. 2020;2(10):e594-e602.
27. Evlice O, Kuş F, Arık Ö, Bektaş M. Redıctıve Relevance Of Dıfferent Clınıcal And Laboratory Fındıngs For Hıgher Mortalıty In Patıents Wıth Covıd-19 In A Sıngle Center Cohort: Neutrophıl/ Lymphocyte Ratıo, Hıgh Crp, Ggt And Creatınıne Levels Are Assocıated Wıth Hıgh Mortalıty. Journal Of Istanbul Faculty Of Medicine / İstanbul Tıp Fakültesi Dergisi. 2022;0(0):0-.
28. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England). 2020;395(10223):497-506.
29. Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, et al. Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. JAMA Intern Med. 2020;180(10):1345-55.
30. 30. Rodriguez-Nava G, Yanez-Bello MA, Trelles Garcia DP, Chung CW, Friedman HJ, Hines DW. Performance of the quick COVID-19 severity index and the Brescia-COVID respiratory severity scale in hospitalized patients with COVID-19 in a community hospital setting. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2021;102:571-6.
31. Cavalli G, Larcher A, Tomelleri A, Campochiaro C, Della-Torre E, De Luca G, et al. Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study. Lancet Rheumatol. 2021;3(4):e253-e61.
32. Ong SWX, Chiew CJ, Ang LW, Mak TM, Cui L, Toh M, et al. Clinical and virological features of SARS-CoV-2 variants of concern: a retrospective cohort study comparing B.1.1.7 (Alpha), B.1.315 (Beta), and B.1.617.2 (Delta). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021.
33. Loconsole D, Centrone F, Morcavallo C, Campanella S, Accogli M, Sallustio A, et al. Changing Features of COVID-19: Characteristics of Infections with the SARS-CoV-2 Delta (B.1.617.2) and Alpha (B.1.1.7) Variants in Southern Italy. Vaccines. 2021;9(11).
34. Balkhair A, Al-Zakwani I, Al Busaidi M, Al Khirbash A, Al Mubaihsi S, BaTaher H, et al. Anakinra in hospitalized patients with severe COVID-19 pneumonia requiring oxygen therapy: Results of a prospective, open-label, interventional study. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2021;103:288-96.
35. Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, Adamis G, Tsiakos K, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nature medicine. 2021;27(10):1752-60.
36. Mehta P, Cron RQ, Hartwell J, Manson JJ, Tattersall RS. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. The Lancet Rheumatology. 2020;2(6):e358-e67.
37. Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis and rheumatism. 2011;63(2):545-55.
38. Phadke O, Rouster-Stevens K, Giannopoulos H, Chandrakasan S, Prahalad S. Intravenous administration of anakinra in children with macrophage activation syndrome. Pediatric rheumatology online journal. 2021;19(1):98.
39. Cavalli G, De Luca G, Campochiaro C, Della Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325-e31.
40. Karakike E, Dalekos GN, Koutsodimitropoulos I, Saridaki M, Pourzitaki C, Papathanakos G, et al. ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients. Journal of innate immunity. 2021;71:1-11.
41. Pontali E, Volpi S, Signori A, Antonucci G, Castellaneta M, Buzzi D, et al. Efficacy of early anti-inflammatory treatment with high doses of intravenous anakinra with or without glucocorticoids in patients with severe COVID-19 pneumonia. The Journal of allergy and clinical immunology. 2021;147(4):1217-25