COVID-19 HASTALARINDA KORTİKOSTEROİD TEDAVİSİ: NE ZAMAN VE NASIL?

Öz

Çin’in Wuhan şehrinde ilk vakanın görülmesinden bu yana COVID-19 dünyada 2,7 milyondan fazla insanın hayatını kaybetmesine neden olmuştur. COVID-19’a bağlı ölümün başlıca nedenleri ARDS, sepsis ve/veya septik şoktur. Hastalığın etkinliği kanıtlanmış bir tedavisi henüz mevcut değildir. COVID-19’a bağlı oluşan hiperinflamasyon ve sitokin fırtınasının kontrolünde sentetik kortikosteroidlerin etkili olabileceği düşünülmüş ve klinik çalışmalar bu grup ilaçların mortaliteyi ve mekanik ventilasyon ihtiyacını azaltmada etkili olduklarını göstermiştir. Dünya Sağlık Örgütü, ciddi ve kritik hastalarda kortikosteroidlerin kullanımını güçlü öneri ile desteklerken ciddi olmayan hastalıkta kullanımdan kaçınılmasına koşullu öneri getirmiştir. Bu öneriler, sekiz randomize kontrollü çalışmanın sonuçlarına dayanmaktadır. Şu ana kadar yapılan çalışmalarda, tedavide en sık tercih edilen kortikosteroid molekülü metilprednizolon olmakla birlikte, deksametazon, hidrokortizon ve diğer sentetik glukokortikoidler de kullanılmaktadır. Kortikosteroidlerin mortalite üzerine etkilerinin ortaya konulduğu çalışmalarda genellikle düşük-orta dozda ilaç kullanılmış olup doz karşılaştırmalarının yapıldığı prospektif çalışmalar literatürde henüz mevcut değildir. Kortikosteroid tedavisi ile ilgili çekincelerden biri, tedavinin viral klirens üzerine etkisidir. Düşük dozda kortikosteroidlerin viral klirens üzerine az etkileri olduğu ya da etkilerinin olmadığı bildirilmekle birlikte, yüksek doz uygulamaların viral klirens üzerine etkisi ve yine gecikmiş viral klirensin klinik önemi net değildir. Kortikosteroidlerin en sık yan etkileri olan hiperglisemi ve sekonder bakteriyel infeksiyonlar yönünden hastaların yakın takip edilmeleri ve ciddi-kritik COVID-19 hastalarında, kritik-hastalıkla ilişkili kortikosteroid yetmezliği de bulunabileceğinden, tedavinin dikkatlice kesilmesi büyük önem taşımaktadır. COVID-19 tedavisinde kullanılacak kortikosteroidlerin türü, ideal zamanlaması, dozu, diğer ilaçlarla birlikte kullanımı konularında ve oluşabilecek muhtemel yan etkiler açısından daha fazla araştırmaya gerek vardır.

Anahtar Kelimeler

• COVID-19
• Tedavi
• Kortikosteroidler
• Deksametazon
• Metilprednizolon

CORTICOSTEROID TREATMENT OF COVID-19 PATIENTS: WHEN AND HOW?

Öz

COVID-19 caused death of more than 2,7 million people all over the world since the first case seen in the Wuhan city of China. The primary causes of death due to COVID-19 are ARDS, sepsis and/or septic shock. There is no proven effective therapy for COVID-19 yet. It was considered that synthetic corticosteroids may be effective in the control of hyperinflammation and cytokine storm due to COVID-19 and clinical trials have shown that this group of drugs are effective in reducing mortality and need of mechanical ventilation. World Health Organisation made a strong recommendation for sistemic corticosteroid therapy in patients with severe and critical COVID-19 and a conditional recommendation not to use corticosteroid therapy in patients with non-severe COVID-19. These recommendations are based on the results of eight randomised controlled trials. Although the most widely preferred corticosteroid molecule in the trials till now was methylprednisolone; dexamethasone, hydrocortisone and other synthetic glucocorticoids are also used. In studies revealing the effect of these drugs on mortality, generally low to moderate doses are used and comparative prospective studies of dosing do not exist in literature yet. One of the drawbacks of corticosteroid treatment is the effect of treatment on viral clearance. Although low-dose steroids are reported to have little or no effect on viral clearance, the effect of applying high doses on viral clearance as well as the clinical importance of delayed viral clearance are not clear. Follow-up of patients for the most frequent side effects such as hyperglycemia and secondary bacterial infections and a cautious dose tapering, since critical illness related corticosteroid insufficiency may exist in patients with severe-critical COVID-19, are of paramount importance. More investigations are needed about the type, optimal timing and dosing of steroid preparations for COVID-19 treatment as well as usage of them with other drugs and potential side-effects.

Anahtar Kelimeler

• COVID-19
• Treatment
• Corticosteroids
• Dexamethasone
• Methylprednisolone

Kaynakça

1. 1. WHO. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
2. 2. Recovery Collaborative Group. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2020; 396 (24): 1345-1352.
3. 3. WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. N Engl J Med 2021; 384 (6): 497-511.
4. 4. Wu Z, McGoogan JM. 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.
5. 5. Esmailzadeh A, Elahi R. Immunobiology and immunotherapy of COVID-19: A clinically updated overview. J Cell Physiol 2020 Oct 6: 10.1002/jcp.30076.
6. 6. Lee C, Choi WJ. Overview of COVID-19 inflammatory pathogenesis from the therapeutic perspective. Arch Pharm Res 2021 Jan 4: 1–18.
7. 7. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 - Preliminary report. N Engl J Med 2020 Jul 17; NEJMoa2021436.
8. 8. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA 2020 Oct 6; 324(13): 1-13.

9. 9. Oster H, Challet E, Ott V, Arvat E, de Kloet ER, Dijk DJ, et al. The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr Rev 2017; 38 (1): 3-45.
10. 10. Kim P, Oster H, Lehnert H, Schmid SM, Salamat N, Barclay JL, et al. Coupling the circadian clock to homeostasis: the role of period in timing physiology. Endocr Rev 2019; 40 (1): 66-95.
11. 11. Lightman SL, Birnie MT, Conway-Campbell BL. Dynamics of ACTH and cortisol secretion and implications for disease. Endocr Rev 2020; 41 (3): 470-490.
12. 12. Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2020; 16(1): 61-71.
13. 13. Meduri GU, Annane D, Confalonieri M, Chrousos GP, Rochwerg B, Busby A, et al. Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med 2020; 46(12): 2284-2296.
14. 14. Cain DW, Cidlowski JA. After 62 years of regulating immunity, dexamethasone meets Covid-19. Nat Rev Immunol 2020; 20(10): 587-588.
15. 15. Quatrini L, Ugolini S. New insights into the cell- and tissue-specificity of glucocorticoid actions. Cell Mol Immunol 2021; 18(2): 269-278.
16. 16. Panettieri RA, Schaafsma D, Amrani Y, Koziol-White C, Ostrom R, Tliba O. Non-genomic effects of glucocorticoids: an updated view. Trends Pharmacol Sci 2019; 40(1): 38-49.
17. 17. Ferraù F, Ceccato F, Cannavò S, Scaroni C. What we have to know about corticosteroid use during Sars-Cov-2 infection. J Endocrinol Invest 2021; 44(4): 693-701.
18. 18. Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part 1): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM). Crit Care Med 2017; 45(12): 2078-2088.
19. 19. Teng D, Pang QF, Yan WJ, Zhao Xin W, Xu CY. The harmful effect of prolonged high-dose methylprednisolone in acute lung injury. Int Immunopharmacol 2013; 15(2): 223-226.
20. 20. Takaki M, Ichikado K, Kawamura K, Gushima Y, Suga M. The negative effect of initial high-dose methylprednisolone and tapering regimen for acute respiratory distress syndrome: a retrospective propensity matched cohort study. Crit Care 2017; 21(1): 135-141.
21. 21. Kido T, Muramatsu K, Asakawa T, Otsubo H, Ogoshi T, Oda K, et al. The relationship between high-dose corticosteroid treatment and mortality in acute respiratory distress syndrome: a retrospective and observational study using a nationwide administrative database in Japan. BMC Pulmonary Med 2018; 18(1): 28-34.
22. 22. Bartko J, Stiebellehner L, Derhaschnig U, Schoergenhofer C, Schwameis M, Prosch H, et al. Dissociation between systemic and pulmonary anti‐inflammatory effects of dexamethasone in humans. Br J Clin Pharmacol 2016; 81(5): 865-877.
23. 23. Croxtall JD, Van Hal PTW, Choudhury Q, Gilroy DW, Flower RJ. Different glucocorticoids vary in their genomic and non‐genomic mechanism of action in A549 cells. Br J Pharmacol 2002; 135(2): 511-519.
24. 24. Buttgereit F, Brand MD,Burmester GR. Equivalent doses and relative drug potencies for nongenomic glucocorticoid effects: a novel glucocorticoid hierarchy. Biochem Pharmacol 1999; 58(2): 363-368.
25. 25. Alexaki VI, Henneicke H. The role of glucocorticoids in the management of COVID-19. Horm Metab Res 2021; 53(1): 9-15.
26. 26. Franco LM, Gadkari M, Howe KN, Sun J, Kardava L, Kumar P, et al. Immune regulation by glucocorticoids can be linked to cell-type dependent transcriptional responses. J Exp Med 2019; 216(2): 384-406.
27. 27. Liu L, Wang YX, Zhou J, Long F, Sun HW, Liu Y, et al. Rapid non-genomic inhibitory effects of glucocorticoids on human neutrophil degranulation. Inflamm Res 2005; 54(1): 37-41.
28. 28. Ghosh R, Chakraborty A, Biswas A, Chowdhuri S. Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study.J Biomol Struct Dyn 2020 Oct 23: 1-14.
29. 29. Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19. The REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA 2020; 324(13): 1317- 1329.
30. 30. Dequin P-F, Heming N, Meziani F, Plantegѐve F, Voiriot G, Badié J, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19. JAMA 2020; 324(13): 1298-1306.
31. 31. Tomazini, BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial. JAMA 2020; 324(13): 1307-1316.
32. 32. Li H, Chen C, Hu F, Wang J, Zhao Q, Gale RP, Liang Y. Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis. Leukemia 2020; 34(6): 1502-1511.
33. 33. Yang Z, Liu J, Zhou Y, Zhao X, Zhao Q, Liu J. The effect of corticosteroid treatment on patients with coronavirus infection: A systematic review and metaanalysis. J Infect 2020; 81(1): e13-e20.
34. 34. Veronese N, Demurtas J, Yang L, Tonelli R, Barbagallo M, Lopalco P, et al. Use of corticosteroids in coronavirus disease 2019 pneumonia: A systematic review of the literature. Front Med (Lausanne) 2020 Apr 24; 7: 170.
35. 35. Lu S, Zhou Q, Huang L, Shi Q, Zhao S, Wang Z, et al. Effectiveness and safety of glucocorticoids to treat COVID-19: A rapid review and meta-analysis. Ann Transl Med 2020; 8(10): 627.
36. 36. Singh AK, Majumdar S, Singh R, Misra A. Role of corticosteroids in the management of COVID-19: A systemic review and a clinician’s perspective. Diabetes Metab Syndr 2020; 14(5): 971-978.
37. 37. Hasan SS, Capstick T, Ahmed R, Kow SC, Mazhar F, Merchant Ha, et al. Mortality in COVID-19 patients with ARDS and corticosteroids use: A systematic review and metaanalysis. Exp Rev Respir Med 2020; 14(11): 1149-1163.
38. 38. Yousefifard M, Mohamed Ali K, Aghaei A, Zali A, Madani Neishaboori A, Zarghi A, et al. Corticosteroids in the management of COVID-19: A systemic review and metaanalysis. Iran J Public Health 2020; 49(8): 1411-1421.
39. 39. Sarkar S, Khanna P, Soni KD. Are the steroids a blanket solution for COVID‐19? A systematic review and meta‐analysis. J Med Virol 2021; 93(3): 1538–1547.
40. 40. Cheng W, Li Y, Cui L, Chen Y, Shan S, Xiaou D, et al. Efficacy and safety of corticosteroid treatment in patients with COVID-19: A systematic review and metaanalysis. Front Pharmacol 2020 Sep 9; 11: 571156.
41. 41. Tlayjeh H, Mhish OH, Enani MA, Alruwaili A, Tleyjeh R, Thalib L, et al. Association of corticosteroids use and outcome in COVID-19 patients: A systematic review and metaanalysis. J Infect Public Health 2020; 13(11): 1652-1663.
42. 42. Budhathoki P, Shrestha DB, Rawal E, Khadka S. Corticosteroids in COVID-19: Is it rational? A systematic review and metaanalysis. SN Compr Clin Med 2020 Oct 19; 1-21.
43. 43. Cano EJ, Fuentes XF, Campioli CC, O’Horo JC, Saleh OA, Odeyemi Y, et al. Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and metaanalysis. Chest 2021;159(3):1019-1040. (Epub 2020 Oct 28.)
44. 44. Van Paassen J, Vos JS, Hoekstra EM, Neumann KMI, Boot PC, Arbous SM. Corticosteroid use in COVID 19 patients: A systematic review and metaanalysis on clinical outcomes. Critical Care 2020 Dec 14; 24(1): 696.
45. 45. WHO. Clinical management of COVID-19 interim guidance. 27 May 2020. www. euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/publications-and-technical-guidance/2020/clinical-management-of-covid-19-interim-guidance,-27-may-2020.
46. 46. WHO. Corticosteroids for COVID-19. WHO/2019-nCoV/Corticosteroids/2020.1.
47. 47. WHO. COVID-19 Clinical management: living guidance. https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1
48. 48. Alhazzani W, Evans L, Alshamsi F, Møller MH, Ostermann M, Prescott HC, et al. Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update. Crit Care Med 2021 Mar 1; 49(3): e219-e234.
49. 49. T.C. Sağlık Bakanlığı Halk Sağlığı Genel Müdürlüğü. COVID-19 (SARS-CoV-2 Enfeksiyonu) Erişkin Hasta Tedavisi. 12 Ekim 2020. https://covid19.saglik.gov.tr/Eklenti/39061/0/covid-19rehberieriskinhastatedavisipdf.pdf
50. 50. T.C. Sağlık Bakanlığı Halk Sağlığı Genel Müdürlüğü. COVID-19 (SARS-CoV-2 Enfeksiyonu) Ağır pnömoni, ARDS, sepsis ve septik şok yönetimi. 7 Kasım 2020. https://covid19.saglik.gov.tr/Eklenti/39297/0/covid-19rehberiagirpnomoniardssepsisveseptiksokyontemipdf.pdf
51. 51. Pasin L, Navalesi P, Zangrillo A, Kuzovlev A, Likhvantsev V, Ludhmila AJ, et al. Corticosteroids for patients with coronavirus disease 2019 with different disease severity: A meta-analysis of randomized clinical trials. J Cardiothorac Vasc Anesth 2021; 35(2): 578-584.
52. 52. Shuto H, Komiya K, Yamasue M, Uchida S, Ogura T, Mukae H, et al. A systematic review of corticosteroid treatment for noncritically ill patients with COVID-19. Sci Rep 2020 Dec 1; 10(1): 20935.
53. 53. Ruiz-Irastorza G, Pijoan JI, Bereciartua E, Dunder S, Dominguez J, Garcia-Escudero P, et al. Second week methyl-prednisolone pulses improve prognosis in patients with severe coronavirus disease 2019 pneumonia: An observational comparative study using routine care data. PLoS One 2020 Sep 22; 15(9): e0239401.
54. 54. Li Y, Zhou X, Li T, Chan S, Yu Y, Ai J-W, et al. Corticosterid prevents COVID-19 progression within its therapetic window: a multicentre, proof-of-concept, observational study. Emerg Microbes Infect 2000; 9(1): 1869-1877.
55. 55. Berton AM, Prencipe N, Giordano R, Ghigo E, Grottoli S. Systemic steroids in patients with COVID-19: pros and contras, an endocrinological point of view. Endonrinol Invest 2021 Apr; 44(4): 873-875. (Epub 2020 Jun 8)
56. 56. Draghici S, Nguyen TM, Sonna LA, Ziraldo C, Vanciu R, Fadel R, et al. COVID-19: disease pathways and gene expression changes predict methylprednisolone can improve outcome in severe cases. Bioinformatics 2021 Mar 9; btab163.
57. 57. Rana MA, Hashmi M, Qayyum A, Pervaiz R, Saleem M, Munir MF, et al. Comparison of efficacy of dexamethasone and methylprednisolone in improving PaO2/FiO2 ratio among COVID-19 patients. Cureus 2020; 12(10): e10918.
58. 58. Fatima SA, Asif M, Khan KA, Siddique N, Khan AZ. Comparison of efficacy of dexamethasone and methylprednisolone in moderate to severe covid 19 disease. Ann Med Surg 2020 Dec; 60: 413–416.
59. 59. So C, Ro S, Murakami M, Imai R, Jinta T. High dose, short-term corticosteroids for ARDS caused by COVID-19: a case series. Respirol Case Rep 2020 Jun 4; 8(6): e00596.
60. 60. Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J 2020 Dec 24; 56(6): 2002808.
61. 61. Chalmers JD. Pandemic trials: evidence-based medicine on steroids. Eur Respir J 2020 Dec 24; 56(6): 2004116.
62. 62. Monreal E, Sainz de la Maza S, Natera-Villalba E, Beltrán-Corbellini Á, Rodríguez-Jorge F, Fernández-Velasco JI, et al. High versus standard doses of corticosteroids in severe COVID-19: a retrospective cohort study. Eur J Clin Microbiol Infect Dis 2021 Apr; 40(4): 761-769. (Epub 2020 Oct 20)
63. 63. Gogali A, Kyriakopoulos C, Kostikas K. Corticosteroids in COVID-19: One size does not fit all. Eur Respir J 2021 Feb 11; 2100224.
64. 64. Mishra GP, Mulani J. Corticosteroids for COVID-19: the search for an optimum duration of therapy. Lancet 2021 Jan 9: e8.
65. 65. Mattos-Silva P, Felix NS, Silva PL, Robba C, Battaglini D, Pelosi P, et al. Pros and cons of corticosteroid therapy for COVID-19 patients. Respir Physiol Neurobiol 2020 Sep; 280: 103492.