COVID-19: Using the Right Tools at the Right Time
Main Article Content
Abstract
COVID-19, caused by SARS-CoV2, first described in several cases of pneumonia in Wuhan, China in December 2020 has now become a disease that is now present throughout the world. Multiple evidence-based measures and therapeutics are now available for the prevention and treatment of COVID-19. Many therapeutics have been studied and some even continue to be used without compelling evidence to suggest efficacy. Critical to the prevention and successful identification of treatments for COVID-19 has been an appreciation of the multiple stages of this disease. A previous paper published in February 2021 presented a consensus framework of relevant stages of COVID-19 authored by 35 physicians and scientist from multiple disciplines and countries. This framework included: three periods: the period of pre-exposure, the incubation period, the period of detectable viral replication, and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology has served as a framework to guide COVID-19 therapeutics studied or currently in use. We now have a greater understanding of this disease and an update framework with two preclinical periods, the Pre-exposure Period and the Incubation Period, followed by four clinical phases, the Early Viral Upper Respiratory Non-hypoxic Phase, the Early Inflammatory Lower Respiratory Hypoxic Phase, the Secondary Symptomatic Phase and the Late Phase. We also have more evidence regarding the role of improved ventilation, the effectiveness of different masks, several highly effective vaccines, and a few effective antiviral, immunomodulatory, and supportive therapies. As there has been substantial progress made in understanding this disease and the role of various interventions, both nonpharmacological and pharmacological and changes over time in characteristics of SARS-CoV-2 such as a shorter incubation period and different susceptibility to various therapeutics, it is appropriate to put forth this update.
Keywords:
COVID-19, SARS-CoV2, Phases, Cytokine Storm
Article Details
How to Cite
GRIFFIN, Daniel O..
COVID-19: Using the Right Tools at the Right Time.
Medical Research Archives, [S.l.], v. 10, n. 8, aug. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3041>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i8.3041.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. Mar 17 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585
2. A living WHO guideline on drugs for covid-19. Bmj. Apr 25 2022;377:o1045. doi:10.1136/bmj.o1045
3. Group A-TL-CS, Lundgren JD, Grund B, et al. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med. Mar 11 2021;384(10):905-914. doi:10.1056/NEJMoa2033130
4. Consortium WHOST. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. May 21 2022;399(10339):1941-1953. doi:10.1016/S0140-6736(22)00519-0
5. Chu DK, Akl EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet. Jun 27 2020;395(10242):1973-1987. doi:10.1016/S0140-6736(20)31142-9
6. Leung NHL. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol. Aug 2021;19(8):528-545. doi:10.1038/s41579-021-00535-6
7. Bahl P, Doolan C, de Silva C, Chughtai AA, Bourouiba L, MacIntyre CR. Airborne or Droplet Precautions for Health Workers Treating Coronavirus Disease 2019? J Infect Dis. May 4 2022;225(9):1561-1568. doi:10.1093/infdis/jiaa189
8. Chan KH, Yuen KY. COVID-19 epidemic: disentangling the re-emerging controversy about medical facemasks from an epidemiological perspective. Int J Epidemiol. Mar 31 2020;doi:10.1093/ije/dyaa044
9. Schunemann HJ, Akl EA, Chou R, et al. Use of facemasks during the COVID-19 pandemic. Lancet Respir Med. Oct 2020;8(10):954-955. doi:10.1016/S2213-2600(20)30352-0
10. Foster A, Kinzel M. Estimating COVID-19 exposure in a classroom setting: A comparison between mathematical and numerical models. Phys Fluids (1994). Feb 1 2021;33(2):021904. doi:10.1063/5.0040755
11. Kerbert C. Zur Trematodenkenntnis. Zool Anz. 1878;1:271-273.
12. Tsai AC, Harling G, Reynolds Z, Gilbert RF, Siedner MJ. COVID-19 transmission in the U.S. before vs. after relaxation of statewide social distancing measures. Clin Infect Dis. Oct 3 2020;doi:10.1093/cid/ciaa1502
13. de Man P, Paltansing S, Ong DSY, Vaessen N, van Nielen G, Koeleman JGM. Outbreak of COVID-19 in a nursing home associated with aerosol transmission as a result of inadequate ventilation. Clin Infect Dis. Aug 28 2020;doi:10.1093/cid/ciaa1270
14. Dickerman BA, Gerlovin H, Madenci AL, et al. Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans. N Engl J Med. Jan 13 2022;386(2):105-115. doi:10.1056/NEJMoa2115463
15. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. Feb 4 2021;384(5):403-416. doi:10.1056/NEJMoa2035389
16. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. Dec 31 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577
17. Xie J, Feng S, Li X, Gea-Mallorqui E, Prats-Uribe A, Prieto-Alhambra D. Comparative effectiveness of the BNT162b2 and ChAdOx1 vaccines against Covid-19 in people over 50. Nat Commun. Mar 21 2022;13(1):1519. doi:10.1038/s41467-022-29159-x
18. Self WH, Tenforde MW, Rhoads JP, et al. Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions - United States, March-August 2021. MMWR Morb Mortal Wkly Rep. Sep 24 2021;70(38):1337-1343. doi:10.15585/mmwr.mm7038e1
19. DeCuir J, Meng L, Pan Y, et al. COVID-19 Vaccine Provider Availability and Vaccination Coverage Among Children Aged 5-11 Years - United States, November 1, 2021-April 25, 2022. MMWR Morb Mortal Wkly Rep. Jul 1 2022;71(26):847-851. doi:10.15585/mmwr.mm7126a3
20. Montgomery H, Hobbs FDR, Padilla F, et al. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. Jun 7 2022;doi:10.1016/S2213-2600(22)00180-1
21. Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. N Engl J Med. Jun 9 2022;386(23):2188-2200. doi:10.1056/NEJMoa2116620
22. Cai Y, Liu J, Yang H, et al. Association between incubation period and clinical characteristics of patients with COVID-19. J Int Med Res. Sep 2020;48(9):300060520956834. doi:10.1177/0300060520956834
23. Ma T, Ding S, Huang R, et al. The latent period of coronavirus disease 2019 with SARS-CoV-2 B.1.617.2 Delta variant of concern in the postvaccination era. Immun Inflamm Dis. Jul 2022;10(7):e664. doi:10.1002/iid3.664
24. Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. Aug 2020;26(8):1200-1204. doi:10.1038/s41591-020-0965-6
25. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. N Engl J Med. May 28 2020;382(22):2081-2090. doi:10.1056/NEJMoa2008457
26. Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection : A Narrative Review. Ann Intern Med. Sep 1 2020;173(5):362-367. doi:10.7326/M20-3012
27. Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. Mar 2020;25(10)doi:10.2807/1560-7917.ES.2020.25.10.2000180
28. Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open. Jan 4 2021;4(1):e2035057. doi:10.1001/jamanetworkopen.2020.35057
29. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. Apr 30 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032
30. Baj J, Karakula-Juchnowicz H, Teresinski G, et al. COVID-19: Specific and Non-Specific Clinical Manifestations and Symptoms: The Current State of Knowledge. J Clin Med. Jun 5 2020;9(6)doi:10.3390/jcm9061753
31. Sugiyama M, Kinoshita N, Ide S, et al. Serum CCL17 level becomes a predictive marker to distinguish between mild/moderate and severe/critical disease in patients with COVID-19. Gene. Sep 14 2020;766:145145. doi:10.1016/j.gene.2020.145145
32. Agrati C, Sacchi A, Bordoni V, et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ. Nov 2020;27(11):3196-3207. doi:10.1038/s41418-020-0572-6
33. Zhang B, Zhou X, Zhu C, et al. Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19. Front Mol Biosci. 2020;7:157. doi:10.3389/fmolb.2020.00157
34. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. Oct 8 2020;doi:10.1056/NEJMoa2007764
35. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. Oct 28 2020;doi:10.1056/NEJMoa2029849
36. Sun F, Lin Y, Wang X, Gao Y, Ye S. Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection. The Lancet infectious diseases. July 14, 2022 2022;doi:doi.org/10.1016/S1473-3099(22)00430-3
37. Snell LB, Awan AR, Charalampous T, et al. SARS-CoV-2 variants with shortened incubation periods necessitate new definitions for nosocomial acquisition. J Infect. Feb 2022;84(2):248-288. doi:10.1016/j.jinf.2021.08.041
38. Hui KPY, Cheung MC, Perera R, et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med. Jul 2020;8(7):687-695. doi:10.1016/S2213-2600(20)30193-4
39. Shrestha NK, Marco Canosa F, Nowacki AS, et al. Distribution of Transmission Potential during Non-Severe COVID-19 Illness. Clin Infect Dis. Jun 29 2020;doi:10.1093/cid/ciaa886
40. Borremans B, Gamble A, Prager KC, et al. Quantifying antibody kinetics and RNA detection during early-phase SARS-CoV-2 infection by time since symptom onset. Elife. Sep 7 2020;9doi:10.7554/eLife.60122
41. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. May 2020;581(7809):465-469. doi:10.1038/s41586-020-2196-x
42. Kim SE, Jeong HS, Yu Y, et al. Viral kinetics of SARS-CoV-2 in asymptomatic carriers and presymptomatic patients. Int J Infect Dis. Jun 2020;95:441-443. doi:10.1016/j.ijid.2020.04.083
43. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. Apr 14 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542
44. Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. Jan 27 2022;386(4):305-315. doi:10.1056/NEJMoa2116846
45. Wang Q, Guo Y, Iketani S, et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5. Nature. Jul 5 2022;doi:10.1038/s41586-022-05053-w
46. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. Feb 10 2022;386(6):509-520. doi:10.1056/NEJMoa2116044
47. Butler CC, Yu LM, Dorward J, et al. Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet Respir Med. Sep 2021;9(9):1010-1020. doi:10.1016/S2213-2600(21)00310-6
48. Hinks TSC, Cureton L, Knight R, et al. Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet Respir Med. Oct 2021;9(10):1130-1140. doi:10.1016/S2213-2600(21)00263-0
49. Oldenburg CE, Pinsky BA, Brogdon J, et al. Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA. Aug 10 2021;326(6):490-498. doi:10.1001/jama.2021.11517
50. Group PTC. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. Mar 20 2021;397(10279):1063-1074. doi:10.1016/S0140-6736(21)00461-X
51. Sahu AK, Mathew R, Bhat R, et al. Steroids use in non-oxygen requiring COVID-19 patients: a systematic review and meta-analysis. QJM. Nov 5 2021;114(7):455-463. doi:10.1093/qjmed/hcab212
52. Brodin R, Desiree van der Werff S, Hedberg P, et al. The association between pre-exposure to glucocorticoids and other immunosuppressant drugs with severe COVID-19 outcomes. Clin Microbiol Infect. May 26 2022;doi:10.1016/j.cmi.2022.05.014
53. Ng TI, Correia I, Seagal J, et al. Antiviral Drug Discovery for the Treatment of COVID-19 Infections. Viruses. May 4 2022;14(5)doi:10.3390/v14050961
54. Krumm ZA, Lloyd GM, Francis CP, et al. Precision therapeutic targets for COVID-19. Virology journal. Mar 29 2021;18(1):66. doi:10.1186/s12985-021-01526-y
55. van de Leemput J, Han Z. Understanding Individual SARS-CoV-2 Proteins for Targeted Drug Development against COVID-19. Molecular and cellular biology. Aug 24 2021;41(9):e0018521. doi:10.1128/MCB.00185-21
56. V'Kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. Mar 2021;19(3):155-170. doi:10.1038/s41579-020-00468-6
57. Xu T, Chen C, Zhu Z, et al. Clinical features and dynamics of viral load in imported and non-imported patients with COVID-19. Int J Infect Dis. May 2020;94:68-71. doi:10.1016/j.ijid.2020.03.022
58. Fajnzylber J, Regan J, Coxen K, et al. SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nat Commun. Oct 30 2020;11(1):5493. doi:10.1038/s41467-020-19057-5
59. Hu J, Li S, Wu Y, et al. Surveillance and re-positive RNA test in patients recovered from COVID-19. J Med Virol. Sep 29 2020;doi:10.1002/jmv.26568
60. 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. Lancet. Mar 28 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3
61. Vu C, Kawaguchi ES, Torres CH, et al. A More Accurate Measurement of the Burden of COVID-19 Hospitalizations. Open Forum Infectious Diseases. 2022;doi:10.1093/ofid/ofac332
62. Zhen W, Manji R, Smith E, Berry GJ. Comparison of Four Molecular In Vitro Diagnostic Assays for the Detection of SARS-CoV-2 in Nasopharyngeal Specimens. J Clin Microbiol. Jul 23 2020;58(8)doi:10.1128/JCM.00743-20
63. Perera R, Tso E, Tsang OTY, et al. SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease. Emerg Infect Dis. Nov 2020;26(11):2701-2704. doi:10.3201/eid2611.203219
64. Cevik M TM, Lloyd O, Maraolo A, Schafer J, Ho A. SARS-CoV-2, SARS-CoV-1 and MERS-CoV Viral Load Dynamics, Duration of Viral Shedding and Infectiousness: A Living Systematic Review and Meta-Analysis. The Lancet Microbe. 2020;
65. Ke R, Martinez PP, Smith RL, et al. Daily longitudinal sampling of SARS-CoV-2 infection reveals substantial heterogeneity in infectiousness. Nat Microbiol. May 2022;7(5):640-652. doi:10.1038/s41564-022-01105-z
66. Bullard J, Dust K, Funk D, et al. Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect Dis. May 22 2020;doi:10.1093/cid/ciaa638
67. Chu VT, Schwartz NG, Donnelly MAP, et al. Comparison of Home Antigen Testing With RT-PCR and Viral Culture During the Course of SARS-CoV-2 Infection. JAMA Intern Med. Jul 1 2022;182(7):701-709. doi:10.1001/jamainternmed.2022.1827
68. Currie DW, Shah MM, Salvatore PP, et al. Relationship of SARS-CoV-2 Antigen and Reverse Transcription PCR Positivity for Viral Cultures. Emerg Infect Dis. Mar 2022;28(3):717-720. doi:10.3201/eid2803.211747
69. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. Mar 29 2020:105954. doi:10.1016/j.ijantimicag.2020.105954
70. Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: A harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. May 22 2020;doi:10.1016/j.ajem.2020.05.044
71. Kashani KB. Hypoxia in COVID-19: Sign of Severity or Cause for Poor Outcomes. Mayo Clin Proc. Jun 2020;95(6):1094-1096. doi:10.1016/j.mayocp.2020.04.021
72. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol. Mar 27 2020;doi:10.1001/jamacardio.2020.1286
73. Raza A, Estepa A, Chan V, Jafar MS. Acute Renal Failure in Critically Ill COVID-19 Patients With a Focus on the Role of Renal Replacement Therapy: A Review of What We Know So Far. Cureus. Jun 3 2020;12(6):e8429. doi:10.7759/cureus.8429
74. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. Sep 2020;19(9):767-783. doi:10.1016/S1474-4422(20)30221-0
75. Renu K, Prasanna PL, Valsala Gopalakrishnan A. Coronaviruses pathogenesis, comorbidities and multi-organ damage - A review. Life Sci. Aug 15 2020;255:117839. doi:10.1016/j.lfs.2020.117839
76. Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. Jun 2020;8(6):e46-e47. doi:10.1016/S2213-2600(20)30216-2
77. Griffin DO, Jensen A, Khan M, et al. Arterial thromboembolic complications in COVID-19 in low risk patients despite prophylaxis. Br J Haematol. May 6 2020;doi:10.1111/bjh.16792
78. Adam Cuker ET, Robby Nieuwlaat, Panted Angchaisuksiri, Clifton Blair, Kathryn Dane, Jennifer Davila, Maria DeSancho, David Diuguid, Daniel Griffin, Susan Kahn, FA Klok, Alfred Lee, Ignacio Neumann, Ashok Pai, Menaka Pai, Marc Righini, Kristen Sanfilippo, Deborah Siegal, Mike Skara, Kamshad Touri, Elie Akl, Imad Bouakl, Mary Boulos, Romina Brignardello-Petersen, Rana Charide, Matthew Chan, Karen Dearness, Andrea Darzi, Philipp Kolb, Luis Lozano, Razan Mansour, Gian Paolo Morgano, Rami Morsi, Atefeh Noori, Thomas Piggott, Yuan Qiu, Yetiani Roldan, Finn Schünemann, Adrienne Stevens, Karla Solo, Matthew Ventresca, Wojtek Wiercioch, Reem A. Mustafa, and Holger J. Schünemann. ASH 2020 guidelines on the use of anticoagulation in patients with COVID-19: Draft recommendations. Washington, DC: American Society of Hematology. Blood Advances. October 8, 2020 2020;
79. Griffin DO JA, Khan M, Chin J, Chin K, Saad J, Parnell R, Awwad C, and Patel D. Pulmonary embolism and increased levels of d-dimer in patients with coronavirus disease. Emerg Infect Dis. 2020;Augustdoi:https://doi.org/10.3201/eid2608.201477
80. Griffin DO, Jensen A, Khan M, et al. Cytokine storm of a different flavor: the different cytokine signature of SARS-CoV2 the cause of COVID-19 from the original SARS outbreak. J Glob Antimicrob Resist. Nov 23 2020;doi:10.1016/j.jgar.2020.11.005
81. Sinha P, Matthay MA, Calfee CS. Is a "Cytokine Storm" Relevant to COVID-19? JAMA Intern Med. Sep 1 2020;180(9):1152-1154. doi:10.1001/jamainternmed.2020.3313
82. Maude S, Barrett DM. Current status of chimeric antigen receptor therapy for haematological malignancies. Br J Haematol. Jan 2016;172(1):11-22. doi:10.1111/bjh.13792
83. Prozan L, Shusterman E, Ablin J, et al. Prognostic value of neutrophil-to-lymphocyte ratio in COVID-19 compared with Influenza and respiratory syncytial virus infection. Sci Rep. Nov 2 2021;11(1):21519. doi:10.1038/s41598-021-00927-x
84. Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. Feb 25 2021;384(8):693-704. doi:10.1056/NEJMoa2021436
85. Group RC. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. May 1 2021;397(10285):1637-1645. doi:10.1016/S0140-6736(21)00676-0
86. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. Mar 4 2021;384(9):795-807. doi:10.1056/NEJMoa2031994
87. Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. May 23 2022;doi:10.1016/S2213-2600(22)00088-1
88. Moreno Diaz R, Amor Garcia MA, Teigell Munoz FJ, et al. Does timing matter on tocilizumab administration? Clinical, analytical and radiological outcomes in COVID-19. Eur J Hosp Pharm. Feb 24 2021;doi:10.1136/ejhpharm-2020-002669
89. Mahajan A, Moore J, Singh AK, Oks M. Impact of Timing of Tocilizumab Use in Hospitalized Patients With SARS-CoV-2 Infection. Respir Care. May 2022;67(5):629-630. doi:10.4187/respcare.10067
90. Singh AK, Oks M, Husk G, et al. Impact of Timing of Tocilizumab Use in Hospitalized Patients With SARS-CoV-2 Infection. Respir Care. Dec 2021;66(12):1805-1814. doi:10.4187/respcare.08779
91. Mungmunpuntipantip R, Wiwanitkit V. Timing of Tocilizumab Use and COVID-19. Respir Care. Mar 2022;67(3):381-382. doi:10.4187/respcare.09678
92. Abidi E, El Nekidy WS, Alefishat E, et al. Tocilizumab and COVID-19: Timing of Administration and Efficacy. Front Pharmacol. 2022;13:825749. doi:10.3389/fphar.2022.825749
93. Barnette KG, Gordon MS, Rodriguez D, et al. Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis. NEJM Evidence. 0(0):EVIDoa2200145. doi:doi:10.1056/EVIDoa2200145
94. Griffin DO, Jensen A, Khan M, et al. Pulmonary Embolism and Increased Levels of d-Dimer in Patients with Coronavirus Disease. Emerg Infect Dis. Aug 2020;26(8):1941-1943. doi:10.3201/eid2608.201477
95. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. Jul 2020;191:9-14. doi:10.1016/j.thromres.2020.04.024
96. Griffin DO, Jensen A, Khan M, et al. Arterial thromboembolic complications in COVID-19 in low-risk patients despite prophylaxis. Br J Haematol. Jul 2020;190(1):e11-e13. doi:10.1111/bjh.16792
97. Cuker A, Tseng EK, Schunemann HJ, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: March 2022 update on the use of anticoagulation in critically ill patients. Blood Adv. Jun 24 2022;doi:10.1182/bloodadvances.2022007940
98. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis. Blood Adv. Jan 25 2022;6(2):664-671. doi:10.1182/bloodadvances.2021005945
99. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis. Blood Advances. 2022;6(2):664-671. doi:10.1182/bloodadvances.2021005945
100. Chong Y, Nan C, Mu W, Wang C, Zhao M, Yu K. Effects of prone and lateral positioning alternate in high-flow nasal cannula patients with severe COVID-19. Crit Care. Jan 25 2022;26(1):28. doi:10.1186/s13054-022-03897-2
101. Beran A, Srour O, Malhas SE, et al. High-Flow Nasal Cannula Versus Noninvasive Ventilation in Patients With COVID-19. Respir Care. Mar 22 2022;doi:10.4187/respcare.09987
102. Ohl ME, Miller DR, Lund BC, et al. Association of Remdesivir Treatment With Survival and Length of Hospital Stay Among US Veterans Hospitalized With COVID-19. JAMA Netw Open. Jul 1 2021;4(7):e2114741. doi:10.1001/jamanetworkopen.2021.14741
103. Consortium WHOST, Pan H, Peto R, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. Feb 11 2021;384(6):497-511. doi:10.1056/NEJMoa2023184
104. Popp M, Reis S, Schiesser S, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. Jun 21 2022;6:CD015017. doi:10.1002/14651858.CD015017.pub3
105. Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19. Cochrane Database Syst Rev. Feb 12 2021;2:CD013587. doi:10.1002/14651858.CD013587.pub2
106. Mikolajewska A, Fischer AL, Piechotta V, et al. Colchicine for the treatment of COVID-19. Cochrane Database Syst Rev. Oct 18 2021;10:CD015045. doi:10.1002/14651858.CD015045
107. Fu Y, Yang Q, Xu M, et al. Secondary Bacterial Infections in Critical Ill Patients With Coronavirus Disease 2019. Open Forum Infect Dis. Jun 2020;7(6):ofaa220. doi:10.1093/ofid/ofaa220
108. Marklund E, Leach S, Axelsson H, et al. Serum-IgG responses to SARS-CoV-2 after mild and severe COVID-19 infection and analysis of IgG non-responders. PloS one. 2020;15(10):e0241104. doi:10.1371/journal.pone.0241104
109. Halpert G, Shoenfeld Y. SARS-CoV-2, the autoimmune virus. Autoimmun Rev. Dec 2020;19(12):102695. doi:10.1016/j.autrev.2020.102695
110. Gharamti AA, Mei F, Jankousky KC, et al. Diagnostic Utility of a Ferritin-to-Procalcitonin Ratio to Differentiate Patients With COVID-19 From Those With Bacterial Pneumonia: A Multicenter Study. Open Forum Infect Dis. Jun 2021;8(6):ofab124. doi:10.1093/ofid/ofab124
111. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. May 23 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1
112. Morris SB, Schwartz NG, Patel P, et al. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, March-August 2020. MMWR Morb Mortal Wkly Rep. Oct 9 2020;69(40):1450-1456. doi:10.15585/mmwr.mm6940e1
113. Becker RC. COVID-19-associated vasculitis and vasculopathy. J Thromb Thrombolysis. Oct 2020;50(3):499-511. doi:10.1007/s11239-020-02230-4
114. Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barre Syndrome Associated with SARS-CoV-2. N Engl J Med. Jun 25 2020;382(26):2574-2576. doi:10.1056/NEJMc2009191
115. Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol. Jun 2020;99(6):1205-1208. doi:10.1007/s00277-020-04019-0
116. Wise J. Covid-19: Symptoms are common after acute phase of disease, Italian study shows. Bmj. Jul 10 2020;370:m2804. doi:10.1136/bmj.m2804
117. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, Condition WHOCCDWGoP-C-. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. Apr 2022;22(4):e102-e107. doi:10.1016/S1473-3099(21)00703-9
118. Azzolini E, Levi R, Sarti R, et al. Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers. JAMA. Jul 1 2022;doi:10.1001/jama.2022.11691
119. Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. May 25 2022;doi:10.1038/s41591-022-01840-0
120. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis. Jan 2022;22(1):43-55. doi:10.1016/S1473-3099(21)00460-6
2. A living WHO guideline on drugs for covid-19. Bmj. Apr 25 2022;377:o1045. doi:10.1136/bmj.o1045
3. Group A-TL-CS, Lundgren JD, Grund B, et al. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med. Mar 11 2021;384(10):905-914. doi:10.1056/NEJMoa2033130
4. Consortium WHOST. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. May 21 2022;399(10339):1941-1953. doi:10.1016/S0140-6736(22)00519-0
5. Chu DK, Akl EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet. Jun 27 2020;395(10242):1973-1987. doi:10.1016/S0140-6736(20)31142-9
6. Leung NHL. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol. Aug 2021;19(8):528-545. doi:10.1038/s41579-021-00535-6
7. Bahl P, Doolan C, de Silva C, Chughtai AA, Bourouiba L, MacIntyre CR. Airborne or Droplet Precautions for Health Workers Treating Coronavirus Disease 2019? J Infect Dis. May 4 2022;225(9):1561-1568. doi:10.1093/infdis/jiaa189
8. Chan KH, Yuen KY. COVID-19 epidemic: disentangling the re-emerging controversy about medical facemasks from an epidemiological perspective. Int J Epidemiol. Mar 31 2020;doi:10.1093/ije/dyaa044
9. Schunemann HJ, Akl EA, Chou R, et al. Use of facemasks during the COVID-19 pandemic. Lancet Respir Med. Oct 2020;8(10):954-955. doi:10.1016/S2213-2600(20)30352-0
10. Foster A, Kinzel M. Estimating COVID-19 exposure in a classroom setting: A comparison between mathematical and numerical models. Phys Fluids (1994). Feb 1 2021;33(2):021904. doi:10.1063/5.0040755
11. Kerbert C. Zur Trematodenkenntnis. Zool Anz. 1878;1:271-273.
12. Tsai AC, Harling G, Reynolds Z, Gilbert RF, Siedner MJ. COVID-19 transmission in the U.S. before vs. after relaxation of statewide social distancing measures. Clin Infect Dis. Oct 3 2020;doi:10.1093/cid/ciaa1502
13. de Man P, Paltansing S, Ong DSY, Vaessen N, van Nielen G, Koeleman JGM. Outbreak of COVID-19 in a nursing home associated with aerosol transmission as a result of inadequate ventilation. Clin Infect Dis. Aug 28 2020;doi:10.1093/cid/ciaa1270
14. Dickerman BA, Gerlovin H, Madenci AL, et al. Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans. N Engl J Med. Jan 13 2022;386(2):105-115. doi:10.1056/NEJMoa2115463
15. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. Feb 4 2021;384(5):403-416. doi:10.1056/NEJMoa2035389
16. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. Dec 31 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577
17. Xie J, Feng S, Li X, Gea-Mallorqui E, Prats-Uribe A, Prieto-Alhambra D. Comparative effectiveness of the BNT162b2 and ChAdOx1 vaccines against Covid-19 in people over 50. Nat Commun. Mar 21 2022;13(1):1519. doi:10.1038/s41467-022-29159-x
18. Self WH, Tenforde MW, Rhoads JP, et al. Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions - United States, March-August 2021. MMWR Morb Mortal Wkly Rep. Sep 24 2021;70(38):1337-1343. doi:10.15585/mmwr.mm7038e1
19. DeCuir J, Meng L, Pan Y, et al. COVID-19 Vaccine Provider Availability and Vaccination Coverage Among Children Aged 5-11 Years - United States, November 1, 2021-April 25, 2022. MMWR Morb Mortal Wkly Rep. Jul 1 2022;71(26):847-851. doi:10.15585/mmwr.mm7126a3
20. Montgomery H, Hobbs FDR, Padilla F, et al. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. Jun 7 2022;doi:10.1016/S2213-2600(22)00180-1
21. Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. N Engl J Med. Jun 9 2022;386(23):2188-2200. doi:10.1056/NEJMoa2116620
22. Cai Y, Liu J, Yang H, et al. Association between incubation period and clinical characteristics of patients with COVID-19. J Int Med Res. Sep 2020;48(9):300060520956834. doi:10.1177/0300060520956834
23. Ma T, Ding S, Huang R, et al. The latent period of coronavirus disease 2019 with SARS-CoV-2 B.1.617.2 Delta variant of concern in the postvaccination era. Immun Inflamm Dis. Jul 2022;10(7):e664. doi:10.1002/iid3.664
24. Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. Aug 2020;26(8):1200-1204. doi:10.1038/s41591-020-0965-6
25. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. N Engl J Med. May 28 2020;382(22):2081-2090. doi:10.1056/NEJMoa2008457
26. Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection : A Narrative Review. Ann Intern Med. Sep 1 2020;173(5):362-367. doi:10.7326/M20-3012
27. Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. Mar 2020;25(10)doi:10.2807/1560-7917.ES.2020.25.10.2000180
28. Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open. Jan 4 2021;4(1):e2035057. doi:10.1001/jamanetworkopen.2020.35057
29. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. Apr 30 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032
30. Baj J, Karakula-Juchnowicz H, Teresinski G, et al. COVID-19: Specific and Non-Specific Clinical Manifestations and Symptoms: The Current State of Knowledge. J Clin Med. Jun 5 2020;9(6)doi:10.3390/jcm9061753
31. Sugiyama M, Kinoshita N, Ide S, et al. Serum CCL17 level becomes a predictive marker to distinguish between mild/moderate and severe/critical disease in patients with COVID-19. Gene. Sep 14 2020;766:145145. doi:10.1016/j.gene.2020.145145
32. Agrati C, Sacchi A, Bordoni V, et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ. Nov 2020;27(11):3196-3207. doi:10.1038/s41418-020-0572-6
33. Zhang B, Zhou X, Zhu C, et al. Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19. Front Mol Biosci. 2020;7:157. doi:10.3389/fmolb.2020.00157
34. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. Oct 8 2020;doi:10.1056/NEJMoa2007764
35. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. Oct 28 2020;doi:10.1056/NEJMoa2029849
36. Sun F, Lin Y, Wang X, Gao Y, Ye S. Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection. The Lancet infectious diseases. July 14, 2022 2022;doi:doi.org/10.1016/S1473-3099(22)00430-3
37. Snell LB, Awan AR, Charalampous T, et al. SARS-CoV-2 variants with shortened incubation periods necessitate new definitions for nosocomial acquisition. J Infect. Feb 2022;84(2):248-288. doi:10.1016/j.jinf.2021.08.041
38. Hui KPY, Cheung MC, Perera R, et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med. Jul 2020;8(7):687-695. doi:10.1016/S2213-2600(20)30193-4
39. Shrestha NK, Marco Canosa F, Nowacki AS, et al. Distribution of Transmission Potential during Non-Severe COVID-19 Illness. Clin Infect Dis. Jun 29 2020;doi:10.1093/cid/ciaa886
40. Borremans B, Gamble A, Prager KC, et al. Quantifying antibody kinetics and RNA detection during early-phase SARS-CoV-2 infection by time since symptom onset. Elife. Sep 7 2020;9doi:10.7554/eLife.60122
41. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. May 2020;581(7809):465-469. doi:10.1038/s41586-020-2196-x
42. Kim SE, Jeong HS, Yu Y, et al. Viral kinetics of SARS-CoV-2 in asymptomatic carriers and presymptomatic patients. Int J Infect Dis. Jun 2020;95:441-443. doi:10.1016/j.ijid.2020.04.083
43. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. Apr 14 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542
44. Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. Jan 27 2022;386(4):305-315. doi:10.1056/NEJMoa2116846
45. Wang Q, Guo Y, Iketani S, et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, & BA.5. Nature. Jul 5 2022;doi:10.1038/s41586-022-05053-w
46. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. Feb 10 2022;386(6):509-520. doi:10.1056/NEJMoa2116044
47. Butler CC, Yu LM, Dorward J, et al. Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet Respir Med. Sep 2021;9(9):1010-1020. doi:10.1016/S2213-2600(21)00310-6
48. Hinks TSC, Cureton L, Knight R, et al. Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet Respir Med. Oct 2021;9(10):1130-1140. doi:10.1016/S2213-2600(21)00263-0
49. Oldenburg CE, Pinsky BA, Brogdon J, et al. Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA. Aug 10 2021;326(6):490-498. doi:10.1001/jama.2021.11517
50. Group PTC. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. Mar 20 2021;397(10279):1063-1074. doi:10.1016/S0140-6736(21)00461-X
51. Sahu AK, Mathew R, Bhat R, et al. Steroids use in non-oxygen requiring COVID-19 patients: a systematic review and meta-analysis. QJM. Nov 5 2021;114(7):455-463. doi:10.1093/qjmed/hcab212
52. Brodin R, Desiree van der Werff S, Hedberg P, et al. The association between pre-exposure to glucocorticoids and other immunosuppressant drugs with severe COVID-19 outcomes. Clin Microbiol Infect. May 26 2022;doi:10.1016/j.cmi.2022.05.014
53. Ng TI, Correia I, Seagal J, et al. Antiviral Drug Discovery for the Treatment of COVID-19 Infections. Viruses. May 4 2022;14(5)doi:10.3390/v14050961
54. Krumm ZA, Lloyd GM, Francis CP, et al. Precision therapeutic targets for COVID-19. Virology journal. Mar 29 2021;18(1):66. doi:10.1186/s12985-021-01526-y
55. van de Leemput J, Han Z. Understanding Individual SARS-CoV-2 Proteins for Targeted Drug Development against COVID-19. Molecular and cellular biology. Aug 24 2021;41(9):e0018521. doi:10.1128/MCB.00185-21
56. V'Kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. Mar 2021;19(3):155-170. doi:10.1038/s41579-020-00468-6
57. Xu T, Chen C, Zhu Z, et al. Clinical features and dynamics of viral load in imported and non-imported patients with COVID-19. Int J Infect Dis. May 2020;94:68-71. doi:10.1016/j.ijid.2020.03.022
58. Fajnzylber J, Regan J, Coxen K, et al. SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nat Commun. Oct 30 2020;11(1):5493. doi:10.1038/s41467-020-19057-5
59. Hu J, Li S, Wu Y, et al. Surveillance and re-positive RNA test in patients recovered from COVID-19. J Med Virol. Sep 29 2020;doi:10.1002/jmv.26568
60. 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. Lancet. Mar 28 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3
61. Vu C, Kawaguchi ES, Torres CH, et al. A More Accurate Measurement of the Burden of COVID-19 Hospitalizations. Open Forum Infectious Diseases. 2022;doi:10.1093/ofid/ofac332
62. Zhen W, Manji R, Smith E, Berry GJ. Comparison of Four Molecular In Vitro Diagnostic Assays for the Detection of SARS-CoV-2 in Nasopharyngeal Specimens. J Clin Microbiol. Jul 23 2020;58(8)doi:10.1128/JCM.00743-20
63. Perera R, Tso E, Tsang OTY, et al. SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease. Emerg Infect Dis. Nov 2020;26(11):2701-2704. doi:10.3201/eid2611.203219
64. Cevik M TM, Lloyd O, Maraolo A, Schafer J, Ho A. SARS-CoV-2, SARS-CoV-1 and MERS-CoV Viral Load Dynamics, Duration of Viral Shedding and Infectiousness: A Living Systematic Review and Meta-Analysis. The Lancet Microbe. 2020;
65. Ke R, Martinez PP, Smith RL, et al. Daily longitudinal sampling of SARS-CoV-2 infection reveals substantial heterogeneity in infectiousness. Nat Microbiol. May 2022;7(5):640-652. doi:10.1038/s41564-022-01105-z
66. Bullard J, Dust K, Funk D, et al. Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect Dis. May 22 2020;doi:10.1093/cid/ciaa638
67. Chu VT, Schwartz NG, Donnelly MAP, et al. Comparison of Home Antigen Testing With RT-PCR and Viral Culture During the Course of SARS-CoV-2 Infection. JAMA Intern Med. Jul 1 2022;182(7):701-709. doi:10.1001/jamainternmed.2022.1827
68. Currie DW, Shah MM, Salvatore PP, et al. Relationship of SARS-CoV-2 Antigen and Reverse Transcription PCR Positivity for Viral Cultures. Emerg Infect Dis. Mar 2022;28(3):717-720. doi:10.3201/eid2803.211747
69. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. Mar 29 2020:105954. doi:10.1016/j.ijantimicag.2020.105954
70. Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: A harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. May 22 2020;doi:10.1016/j.ajem.2020.05.044
71. Kashani KB. Hypoxia in COVID-19: Sign of Severity or Cause for Poor Outcomes. Mayo Clin Proc. Jun 2020;95(6):1094-1096. doi:10.1016/j.mayocp.2020.04.021
72. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol. Mar 27 2020;doi:10.1001/jamacardio.2020.1286
73. Raza A, Estepa A, Chan V, Jafar MS. Acute Renal Failure in Critically Ill COVID-19 Patients With a Focus on the Role of Renal Replacement Therapy: A Review of What We Know So Far. Cureus. Jun 3 2020;12(6):e8429. doi:10.7759/cureus.8429
74. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. Sep 2020;19(9):767-783. doi:10.1016/S1474-4422(20)30221-0
75. Renu K, Prasanna PL, Valsala Gopalakrishnan A. Coronaviruses pathogenesis, comorbidities and multi-organ damage - A review. Life Sci. Aug 15 2020;255:117839. doi:10.1016/j.lfs.2020.117839
76. Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. Jun 2020;8(6):e46-e47. doi:10.1016/S2213-2600(20)30216-2
77. Griffin DO, Jensen A, Khan M, et al. Arterial thromboembolic complications in COVID-19 in low risk patients despite prophylaxis. Br J Haematol. May 6 2020;doi:10.1111/bjh.16792
78. Adam Cuker ET, Robby Nieuwlaat, Panted Angchaisuksiri, Clifton Blair, Kathryn Dane, Jennifer Davila, Maria DeSancho, David Diuguid, Daniel Griffin, Susan Kahn, FA Klok, Alfred Lee, Ignacio Neumann, Ashok Pai, Menaka Pai, Marc Righini, Kristen Sanfilippo, Deborah Siegal, Mike Skara, Kamshad Touri, Elie Akl, Imad Bouakl, Mary Boulos, Romina Brignardello-Petersen, Rana Charide, Matthew Chan, Karen Dearness, Andrea Darzi, Philipp Kolb, Luis Lozano, Razan Mansour, Gian Paolo Morgano, Rami Morsi, Atefeh Noori, Thomas Piggott, Yuan Qiu, Yetiani Roldan, Finn Schünemann, Adrienne Stevens, Karla Solo, Matthew Ventresca, Wojtek Wiercioch, Reem A. Mustafa, and Holger J. Schünemann. ASH 2020 guidelines on the use of anticoagulation in patients with COVID-19: Draft recommendations. Washington, DC: American Society of Hematology. Blood Advances. October 8, 2020 2020;
79. Griffin DO JA, Khan M, Chin J, Chin K, Saad J, Parnell R, Awwad C, and Patel D. Pulmonary embolism and increased levels of d-dimer in patients with coronavirus disease. Emerg Infect Dis. 2020;Augustdoi:https://doi.org/10.3201/eid2608.201477
80. Griffin DO, Jensen A, Khan M, et al. Cytokine storm of a different flavor: the different cytokine signature of SARS-CoV2 the cause of COVID-19 from the original SARS outbreak. J Glob Antimicrob Resist. Nov 23 2020;doi:10.1016/j.jgar.2020.11.005
81. Sinha P, Matthay MA, Calfee CS. Is a "Cytokine Storm" Relevant to COVID-19? JAMA Intern Med. Sep 1 2020;180(9):1152-1154. doi:10.1001/jamainternmed.2020.3313
82. Maude S, Barrett DM. Current status of chimeric antigen receptor therapy for haematological malignancies. Br J Haematol. Jan 2016;172(1):11-22. doi:10.1111/bjh.13792
83. Prozan L, Shusterman E, Ablin J, et al. Prognostic value of neutrophil-to-lymphocyte ratio in COVID-19 compared with Influenza and respiratory syncytial virus infection. Sci Rep. Nov 2 2021;11(1):21519. doi:10.1038/s41598-021-00927-x
84. Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. Feb 25 2021;384(8):693-704. doi:10.1056/NEJMoa2021436
85. Group RC. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. May 1 2021;397(10285):1637-1645. doi:10.1016/S0140-6736(21)00676-0
86. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. Mar 4 2021;384(9):795-807. doi:10.1056/NEJMoa2031994
87. Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. May 23 2022;doi:10.1016/S2213-2600(22)00088-1
88. Moreno Diaz R, Amor Garcia MA, Teigell Munoz FJ, et al. Does timing matter on tocilizumab administration? Clinical, analytical and radiological outcomes in COVID-19. Eur J Hosp Pharm. Feb 24 2021;doi:10.1136/ejhpharm-2020-002669
89. Mahajan A, Moore J, Singh AK, Oks M. Impact of Timing of Tocilizumab Use in Hospitalized Patients With SARS-CoV-2 Infection. Respir Care. May 2022;67(5):629-630. doi:10.4187/respcare.10067
90. Singh AK, Oks M, Husk G, et al. Impact of Timing of Tocilizumab Use in Hospitalized Patients With SARS-CoV-2 Infection. Respir Care. Dec 2021;66(12):1805-1814. doi:10.4187/respcare.08779
91. Mungmunpuntipantip R, Wiwanitkit V. Timing of Tocilizumab Use and COVID-19. Respir Care. Mar 2022;67(3):381-382. doi:10.4187/respcare.09678
92. Abidi E, El Nekidy WS, Alefishat E, et al. Tocilizumab and COVID-19: Timing of Administration and Efficacy. Front Pharmacol. 2022;13:825749. doi:10.3389/fphar.2022.825749
93. Barnette KG, Gordon MS, Rodriguez D, et al. Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis. NEJM Evidence. 0(0):EVIDoa2200145. doi:doi:10.1056/EVIDoa2200145
94. Griffin DO, Jensen A, Khan M, et al. Pulmonary Embolism and Increased Levels of d-Dimer in Patients with Coronavirus Disease. Emerg Infect Dis. Aug 2020;26(8):1941-1943. doi:10.3201/eid2608.201477
95. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. Jul 2020;191:9-14. doi:10.1016/j.thromres.2020.04.024
96. Griffin DO, Jensen A, Khan M, et al. Arterial thromboembolic complications in COVID-19 in low-risk patients despite prophylaxis. Br J Haematol. Jul 2020;190(1):e11-e13. doi:10.1111/bjh.16792
97. Cuker A, Tseng EK, Schunemann HJ, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: March 2022 update on the use of anticoagulation in critically ill patients. Blood Adv. Jun 24 2022;doi:10.1182/bloodadvances.2022007940
98. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis. Blood Adv. Jan 25 2022;6(2):664-671. doi:10.1182/bloodadvances.2021005945
99. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis. Blood Advances. 2022;6(2):664-671. doi:10.1182/bloodadvances.2021005945
100. Chong Y, Nan C, Mu W, Wang C, Zhao M, Yu K. Effects of prone and lateral positioning alternate in high-flow nasal cannula patients with severe COVID-19. Crit Care. Jan 25 2022;26(1):28. doi:10.1186/s13054-022-03897-2
101. Beran A, Srour O, Malhas SE, et al. High-Flow Nasal Cannula Versus Noninvasive Ventilation in Patients With COVID-19. Respir Care. Mar 22 2022;doi:10.4187/respcare.09987
102. Ohl ME, Miller DR, Lund BC, et al. Association of Remdesivir Treatment With Survival and Length of Hospital Stay Among US Veterans Hospitalized With COVID-19. JAMA Netw Open. Jul 1 2021;4(7):e2114741. doi:10.1001/jamanetworkopen.2021.14741
103. Consortium WHOST, Pan H, Peto R, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. Feb 11 2021;384(6):497-511. doi:10.1056/NEJMoa2023184
104. Popp M, Reis S, Schiesser S, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. Jun 21 2022;6:CD015017. doi:10.1002/14651858.CD015017.pub3
105. Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19. Cochrane Database Syst Rev. Feb 12 2021;2:CD013587. doi:10.1002/14651858.CD013587.pub2
106. Mikolajewska A, Fischer AL, Piechotta V, et al. Colchicine for the treatment of COVID-19. Cochrane Database Syst Rev. Oct 18 2021;10:CD015045. doi:10.1002/14651858.CD015045
107. Fu Y, Yang Q, Xu M, et al. Secondary Bacterial Infections in Critical Ill Patients With Coronavirus Disease 2019. Open Forum Infect Dis. Jun 2020;7(6):ofaa220. doi:10.1093/ofid/ofaa220
108. Marklund E, Leach S, Axelsson H, et al. Serum-IgG responses to SARS-CoV-2 after mild and severe COVID-19 infection and analysis of IgG non-responders. PloS one. 2020;15(10):e0241104. doi:10.1371/journal.pone.0241104
109. Halpert G, Shoenfeld Y. SARS-CoV-2, the autoimmune virus. Autoimmun Rev. Dec 2020;19(12):102695. doi:10.1016/j.autrev.2020.102695
110. Gharamti AA, Mei F, Jankousky KC, et al. Diagnostic Utility of a Ferritin-to-Procalcitonin Ratio to Differentiate Patients With COVID-19 From Those With Bacterial Pneumonia: A Multicenter Study. Open Forum Infect Dis. Jun 2021;8(6):ofab124. doi:10.1093/ofid/ofab124
111. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. May 23 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1
112. Morris SB, Schwartz NG, Patel P, et al. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, March-August 2020. MMWR Morb Mortal Wkly Rep. Oct 9 2020;69(40):1450-1456. doi:10.15585/mmwr.mm6940e1
113. Becker RC. COVID-19-associated vasculitis and vasculopathy. J Thromb Thrombolysis. Oct 2020;50(3):499-511. doi:10.1007/s11239-020-02230-4
114. Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barre Syndrome Associated with SARS-CoV-2. N Engl J Med. Jun 25 2020;382(26):2574-2576. doi:10.1056/NEJMc2009191
115. Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol. Jun 2020;99(6):1205-1208. doi:10.1007/s00277-020-04019-0
116. Wise J. Covid-19: Symptoms are common after acute phase of disease, Italian study shows. Bmj. Jul 10 2020;370:m2804. doi:10.1136/bmj.m2804
117. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, Condition WHOCCDWGoP-C-. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. Apr 2022;22(4):e102-e107. doi:10.1016/S1473-3099(21)00703-9
118. Azzolini E, Levi R, Sarti R, et al. Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers. JAMA. Jul 1 2022;doi:10.1001/jama.2022.11691
119. Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. May 25 2022;doi:10.1038/s41591-022-01840-0
120. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis. Jan 2022;22(1):43-55. doi:10.1016/S1473-3099(21)00460-6