Utilization of Therapeutic Interventions for Coronavirus Disease-2019 (COVID-19) Hospitalized Patients and Emerging Treatment Possibilities from Clinical Trials: A Systematic Review and Meta-Analysis
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Background and Objective: Few small observational studies have described various therapeutic interventions utilized in coronavirus disease 2019 (COVID-19) patients based on single/multi-center experiences across the globe. Understanding the utilization of available and possible treatments to curb the COVID-19 pandemic is paramount. We aimed to identify the prevalence and disease-associated utilization of specific therapeutic reagents in hospitalized COVID-19 patients as a function of severity status.
Methods: In systematic review and meta-analysis, extracted data on treatments utilized and severity of COVID-19 hospitalized patients from observational studies using PRISMA guidelines from December 1, 2019 to August 20, 2020. The pooled prevalence and odds of treatment utilization were obtained, and created forest plots using random‐effects models.
Results: 29 studies with 8570 COVID-19-positive patients were included. Higher odds of the utilization of steroids (pooled OR:4.47; 95%CI:3.18–6.28; p<0.00001), antibiotics (3.1;1.81–5.30; p<0.0001), and IV Immunoglobulin (IVIG) (3.76;2.11–6.72; p<0.00001) was observed in patients with severe disease. No association of remdesivir (initially administered via clinical trials and subsequently FDA-approved during this study period), lopinavir/ritonavir, or hydroxychloroquine (HCQ) treatment with the severity of disease was observed.
Conclusion: Higher utilization of steroids, lopinavir/ritonavir, antibiotics, hydroxychloroquine (HCQ), and IV Immunoglobulin (IVIG) was observed in severe COVID-19 patients. Due to limited studies on remdesivir, its accurate utilization could not be delineated. Currently, no Level A evidence favoring single-drug treatment for COVID-19 exists, and trials are needed of combination therapy to evaluate efficacy on the survival outcome.
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2. COVID-19 CORONAVIRUS PANDEMIC, https://www.worldometers.info/coronavirus/#countries (2020, accessed March 20 2021).
3. Guan W-j, Liang W-h, Zhao Y, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J 2020; 55: 2000547. DOI: 10.1183/13993003.00547-2020.
4. Hong KS, Lee KH, Chung JH, et al. Clinical Features and Outcomes of 98 Patients Hospitalized with SARS-CoV-2 Infection in Daegu, South Korea: A Brief Descriptive Study. Yonsei Med J 2020; 61: 431-437. 2020/05/12. DOI: 10.3349/ymj.2020.61.5.431.
5. Wang Y, Liao B, Guo Y, et al. Clinical Characteristics of Patients Infected With the Novel 2019 Coronavirus (SARS-Cov-2) in Guangzhou, China. Open Forum Infectious Diseases 2020; 7. DOI: 10.1093/ofid/ofaa187.
6. Zhao D, Yao F, Wang L, et al. A comparative study on the clinical features of COVID-19 pneumonia to other pneumonias. Clin Infect Dis 2020. DOI: 10.1093/cid/ciaa247.
7. Huang R, Zhu L, Xue L, et al. Clinical findings of patients with coronavirus disease 2019 in Jiangsu province, China: A retrospective, multi-center study. PLoS Negl Trop Dis 2020; 14: e0008280. 2020/05/10. DOI: 10.1371/journal.pntd.0008280.
8. Mikami T, Miyashita H, Yamada T, et al. Risk Factors for Mortality in Patients with COVID-19 in New York City. J Gen Intern Med 2020. DOI: 10.1007/s11606-020-05983-z.
9. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical Characteristics of Covid-19 in New York City. N Engl J Med 2020; 382: 2372-2374. DOI: 10.1056/NEJMc2010419.
10. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097. 2009/07/22. DOI: 10.1371/journal.pmed.1000097.
11. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008-2012. 2000/05/02. DOI: 10.1001/jama.283.15.2008.
12. GA Wells, B Shea, D O’Connell, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (2020).
13. Prescott HC and Rice TW. Corticosteroids in COVID-19 ARDS: Evidence and Hope During the Pandemic. JAMA 2020; 324: 1292-1295. DOI: 10.1001/jama.2020.16747.
14. Fang F, Zhang Y, Tang J, et al. Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis. JAMA Internal Medicine 2019; 179: 213-223. DOI: 10.1001/jamainternmed.2018.5849.
15. Group TWREAfC-TW. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA 2020; 324: 1330-1341. DOI: 10.1001/jama.2020.17023.
16. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J 2003; 9: 399-406. 2003/12/09.
17. Yao T-T, Qian J-D, Zhu W-Y, et al. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus—A possible reference for coronavirus disease-19 treatment option. J Med Virol 2020; 92: 556-563. DOI: https://doi.org/10.1002/jmv.25729.
18. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; 382: 1787-1799. DOI: 10.1056/NEJMoa2001282.
19. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet 2020; 395: 1569-1578. DOI: 10.1016/S0140-6736(20)31022-9.
20. (FDA) FaDA. Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment., https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment (2020, accessed October 30 2020).
21. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020; 383: 1813-1826. DOI: 10.1056/NEJMoa2007764.
22. Savarino A, Di Trani L, Donatelli I, et al. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 2006; 6: 67-69. 2006/01/28. DOI: 10.1016/s1473-3099(06)70361-9.
23. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005; 2: 69. DOI: 10.1186/1743-422X-2-69.
24. Self WH, Semler MW, Leither LM, et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA 2020; 324: 2165-2176. DOI: 10.1001/jama.2020.22240.
25. Owji H, Negahdaripour M and Hajighahramani N. Immunotherapeutic approaches to curtail COVID-19. Int Immunopharmacol 2020; 88: 106924. 2020/09/03. DOI: 10.1016/j.intimp.2020.106924.
26. Liu X, Cao W and Li T. High-Dose Intravenous Immunoglobulins in the Treatment of Severe Acute Viral Pneumonia: The Known Mechanisms and Clinical Effects. Front Immunol 2020; 11: 1660. 2020/08/08. DOI: 10.3389/fimmu.2020.01660.
27. Cao W, Liu X, Bai T, et al. High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease 2019. Open Forum Infectious Diseases 2020; 7. DOI: 10.1093/ofid/ofaa102.
28. Guo Y, Tian X, Wang X, et al. Adverse Effects of Immunoglobulin Therapy. Front Immunol 2018; 9: 1299. 2018/06/29. DOI: 10.3389/fimmu.2018.01299.
29. McCullough PA, Alexander PE, Armstrong R, et al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Rev Cardiovasc Med 2020; 21: 517-530. 2021/01/04. DOI: 10.31083/j.rcm.2020.04.264.
30. Derwand R, Scholz M and Zelenko V. COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study. Int J Antimicrob Agents 2020; 56: 106214-106214. 2020/10/26. DOI: 10.1016/j.ijantimicag.2020.106214.
31. Procter MDBC, Aprn FNPCCRMSN, Pa-C MVP, et al. Early Ambulatory Multidrug Therapy Reduces Hospitalization and Death in High-Risk Patients with SARS-CoV-2 (COVID-19). International Journal of Innovative Research in Medical Science 2021; 6: 219 - 221. DOI: 10.23958/ijirms/vol06-i03/1100.
32. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506. 2020/01/28. DOI: 10.1016/s0140-6736(20)30183-5.
33. Guan W-j, Ni Z-y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020. DOI: 10.1056/NEJMoa2002032.
34. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020; 323: 1061-1069. DOI: 10.1001/jama.2020.1585.
35. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020 2020/02/28. DOI: 10.1016/s2213-2600(20)30079-5.
36. Mo P, Xing Y, Xiao Y, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis 2020 2020/03/17. DOI: 10.1093/cid/ciaa270.
37. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; 46: 846-848. 2020/03/04. DOI: 10.1007/s00134-020-05991-x.
38. Wang Z, Yang B, Li Q, et al. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis 2020 2020/03/17. DOI: 10.1093/cid/ciaa272.
39. Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med 2020 2020/03/14. DOI: 10.1001/jamainternmed.2020.0994.
40. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 2020; 395: 1054-1062. DOI: https://doi.org/10.1016/S0140-6736(20)30566-3.
41. Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of Clinical Investigation 2020; 130: 2620-2629. DOI: 10.1172/JCI137244.
42. Colaneri M, Sacchi P, Zuccaro V, et al. Clinical characteristics of coronavirus disease (COVID-19) early findings from a teaching hospital in Pavia, North Italy, 21 to 28 February 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020; 25: 2000460. DOI: 10.2807/1560-7917.ES.2020.25.16.2000460.
43. Zhao X-Y, Xu X-X, Yin H-S, et al. Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study. BMC Infect Dis 2020; 20: 311. DOI: 10.1186/s12879-020-05010-w.
44. Wan S, Xiang Y, Fang W, et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol 2020; 92: 797-806. 2020/03/22. DOI: 10.1002/jmv.25783.
45. Zheng Y, Sun L-J, Xu M, et al. Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China. Journal of Zhejiang University Science B 2020; 21: 378-387. DOI: 10.1631/jzus.B2000174.
46. Cao Z, Li T, Liang L, et al. Clinical characteristics of Coronavirus Disease 2019 patients in Beijing, China. PLoS One 2020; 15: e0234764. 2020/06/20. DOI: 10.1371/journal.pone.0234764.
47. Deng M, Qi Y, Deng L, et al. Obesity as a Potential Predictor of Disease Severity in Young COVID-19 Patients: A Retrospective Study. Obesity (Silver Spring, Md) 2020 2020/07/01. DOI: 10.1002/oby.22943.
48. Shahriarirad R, Khodamoradi Z, Erfani A, et al. Epidemiological and clinical features of 2019 novel coronavirus diseases (COVID-19) in the South of Iran. BMC Infect Dis 2020; 20: 427. DOI: 10.1186/s12879-020-05128-x.
49. Zhang G, Hu C, Luo L, et al. Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China. J Clin Virol 2020; 127: 104364. 2020/04/21. DOI: 10.1016/j.jcv.2020.104364.
50. Gregoriano C, Koch D, Haubitz S, et al. Characteristics, predictors and outcomes among 99 patients hospitalised with COVID-19 in a tertiary care centre in Switzerland: an observational analysis. Swiss Med Wkly 2020; 150: w20316. 2020/07/16. DOI: 10.4414/smw.2020.20316.
51. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 2020; 146: 110-118. 2020/04/16. DOI: 10.1016/j.jaci.2020.04.006.
52. Xu J, Yang X, Yang L, et al. Clinical course and predictors of 60-day mortality in 239 critically ill patients with COVID-19: a multi-center retrospective study from Wuhan, China. Crit Care 2020; 24: 394. 2020/07/08. DOI: 10.1186/s13054-020-03098-9.
53. Zhang SY, Lian JS, Hu JH, et al. Clinical characteristics of different subtypes and risk factors for the severity of illness in patients with COVID-19 in Zhejiang, China. Infectious diseases of poverty 2020; 9: 85. 2020/07/10. DOI: 10.1186/s40249-020-00710-6.
54. Ferguson J, Rosser JI, Quintero O, et al. Characteristics and Outcomes of Coronavirus Disease Patients under Nonsurge Conditions, Northern California, USA, March-April 2020. Emerg Infect Dis 2020; 26: 1679-1685. 2020/05/15. DOI: 10.3201/eid2608.201776.
55. Yang Q, Xie L, Zhang W, et al. Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019. J Clin Pharm Ther 2020; 45: 609-616. 2020/05/26. DOI: 10.1111/jcpt.13170.