skip to main content

Knowing When and How to Fight: COVID-19 Between Viral Clearance and Immune Tolerance

Perhimpunan Biologi Medik Indonesia, Indonesia

Received: 12 Jun 2020; Revised: 19 Aug 2020; Accepted: 18 Aug 2020; Available online: 31 Aug 2020; Published: 31 Aug 2020.
Open Access Copyright (c) 2020 Journal of Biomedicine and Translational Research

Citation Format:


COVID-19 is a complex disease involving immunological, vascular, and metabolic pathology caused by and consequences of beta-coronavirus SARS-CoV-2 infection. One may use Sun Tzu analogy of war to fight COVID-19 and to survive infection.  When enemy has not reached the shore, gathering much intelligence is key to know how the enemy moves and who would be the most vulnerable targets of enemy attacks. Physical distancing, massive nucleic acid testing, and identification of comorbidity may prepare for the incoming enemies. Physical distancing has helped to limit transmission of the virus that mainly due to close contacts with droplets coughed off infected individuals. Moreover, aerosolized virus particles may also contribute to spreading. Nucleic acid testing using real time PCR platform has been a diagnostic gold standard to identify infected individuals during early stage of infection. On the other hand, serological test to capture antibody against SARS-CoV-2 may be useful for immunosurveillance.  Discovery of human ACE2 (angiotensin converting enzyme) protein as an obligate partner of SARS-CoV-2 viral entry has provided insights to mechanisms of serious post-infection ramifications to individuals having comorbidities such as hypertension, diabetes or heart conditions.  When the enemy reaches ashore, thorough profiling of biomarkers involved in inflammation and coagulation (IL-6, lymphopenia, ground glass opacity, d-dimers, thrombocytopenia) may help predict disease progression and guide treatment strategy. While estimated 80% of infected individuals may recover on their own, the remaining 20% may require hospitalization and serious therapeutic intervention. Several clinical trials are underway such as repurposing existing drugs and evaluating efficacy of convalescence plasma therapy. Finally, vaccine development using genetic engineering may also help control the global spread if it is proven effective.

Fulltext View|Download
Keywords: COVID-19; SARS-CoV-2; inflammation; coagulation; diagnostic

Article Metrics:

  1. Zhu N, Zhang D, Wang W et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382:727-733
  2. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nature Medicine. 2020;26:450-452
  3. Baden T, Maia Chagas A, Molloy J, Prieto Godino L. Leveraging Open Hardware to Alleviate the Burden of COVID-19 on Global Health Systems. 2020
  4. Ing EB, Xu QA, Salimi A, Torun N. Physician deaths from corona virus (COVID-19) disease. Occup Med (Lond). 2020
  5. Guan WJ, Ni ZY, Hu Y et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382:1708-1720
  6. Zhang L, Zhu F, Xie L et al. Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. Ann Oncol. 2020;31:894-901
  7. Osterhaus AD, Fouchier RA, Kuiken T. The aetiology of SARS: Koch’s postulates fulfilled. Philos Trans R Soc Lond B Biol Sci. 2004;359:1081-1082
  8. Bao L, Deng W, Huang B et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020
  9. Sun SH, Chen Q, Gu HJ et al. A Mouse Model of SARS-CoV-2 Infection and Pathogenesis. Cell Host Microbe. 2020
  10. Hassan AO, Case JB, Winkler ES et al. A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies. Cell. 2020
  11. Lutz C, Maher L, Lee C, Kang W. COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice. Hum Genomics. 2020;14:20
  12. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363-374
  13. Carsana L, Sonzogni A, Nasr A et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis. 2020
  14. Edler C, Schröder AS, Aepfelbacher M et al. Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany. Int J Legal Med. 2020;134:1275-1284
  15. Wichmann D, Sperhake J-P, Lütgehetmann M et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19. Annals of Internal Medicine. 2020
  16. Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. COVID-19 Autopsies, Oklahoma, USA. Am J Clin Pathol. 2020;153:725-733
  17. Ackermann M, Verleden SE, Kuehnel M et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020
  18. Petersen E, Koopmans M, Go U et al. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis. 2020
  19. Shang J, Ye G, Shi K et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581:221-224
  20. Hoffmann M, Kleine-Weber H, Pöhlmann S. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol Cell. 2020;78:779-784.e5
  21. Jaimes JA, Millet JK, Whittaker GR. Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1/S2 Site. iScience. 2020;23:101212
  22. Korber B, Fischer WM, Gnanakaran S et al. Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell. 2020
  23. Grubaugh ND, Hanage WP, Rasmussen AL. Making sense of mutation: what D614G means for the COVID-19 pandemic remains unclear. Cell. 2020
  24. Jayaweera M, Perera H, Gunawardana B, Manatunge J. Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy. Environ Res. 2020;188:109819
  25. Morawska L, Tang JW, Bahnfleth W et al. How can airborne transmission of COVID-19 indoors be minimised[letter]. Environ Int 2020;142:105832
  26. Hamner L, Dubbel P, Capron I et al. High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice - Skagit County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69:606-610
  27. Lau H, Khosrawipour V, Kocbach P et al. The positive impact of lockdown in Wuhan on containing the COVID-19 outbreak in China. J Travel Med. 2020;27
  28. Kwon KT, Ko J-H, Shin H, Sung M, Kim JY. Drive-Through Screening Center for COVID-19: a Safe and Efficient Screening System against Massive Community Outbreak. Journal of Korean Medical Science. 2020;35
  29. Habib H. Has Sweden’s controversial covid-19 strategy been successful. BMJ. 2020;369:m2376
  30. Gémes K, Talbäck M, Modig K et al. Burden and prevalence of prognostic factors for severe COVID-19 in Sweden. Eur J Epidemiol. 2020;35:401-409
  31. Kragholm K, Andersen MP, Gerds TA et al. Association between male sex and outcomes of Coronavirus Disease 2019 (Covid-19) - a Danish nationwide, register-based study. Clin Infect Dis. 2020
  32. Chan JF-W, Yip CC-Y, To KK-W et al. Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens. Journal of Clinical Microbiology. 2020;58
  33. Won J, Lee S, Park M et al. Development of a Laboratory-safe and Low-cost Detection Protocol for SARS-CoV-2 of the Coronavirus Disease 2019 (COVID-19). Exp Neurobiol. 2020;29:107-119
  34. Yu F, Yan L, Wang N et al. Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients. Clinical Infectious Diseases. 2020
  35. Zheng Z, Yao Z, Wu K, Zheng J. Patient Follow‐up after Discharge after COVID‐19 Pneumonia: Considerations for Infectious Control. Journal of Medical Virology. 2020
  36. Tang YW, Schmitz JE, Persing DH, Stratton CW. Laboratory Diagnosis of COVID-19: Current Issues and Challenges. J Clin Microbiol. 2020;58
  37. Feng W, Newbigging AM, Le C et al. Molecular Diagnosis of COVID-19: Challenges and Research Needs. Anal Chem. 2020
  38. Azzi L, Carcano G, Gianfagna F et al. Saliva is a reliable tool to detect SARS-CoV-2. J Infect. 2020;81:e45-e50
  39. Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control Covid-19. [editorial]. N Engl J Med 2020;382(22):2158
  40. Fukumoto T, Iwasaki S, Fujisawa S et al. Efficacy of a novel SARS-CoV-2 detection kit without RNA extraction and purification. Int J Infect Dis. 2020
  41. Deeks JJ, Dinnes J, Takwoingi Y et al. Antibody tests for identification of current and past infection with SARS-CoV-2. Cochrane Database Syst Rev. 2020;6:CD013652
  42. Zhao J, Yuan Q, Wang H et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. 2020
  43. Li D, Zhang J, Li J. Primer design for quantitative real-time PCR for the emerging Coronavirus SARS-CoV-2. Theranostics. 2020;10:7150-7162
  44. Sakurai A, Sasaki T, Kato S et al. Natural History of Asymptomatic SARS-CoV-2 Infection. New England Journal of Medicine. 2020
  45. Kimball A, Hatfield KM, Arons M et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility - King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69:377-381
  46. Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review. Ann Intern Med. 2020
  47. Cheung KS, Hung IFN, Chan PPY et al. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis. Gastroenterology. 2020
  48. Chen C, Gao G, Xu Y et al. SARS-CoV-2-Positive Sputum and Feces After Conversion of Pharyngeal Samples in Patients With COVID-19.[letter]. Ann Intern Med 2020;172(12):832-834
  49. An J, Liao X, Xiao T et al. Clinical characteristics of the recovered COVID-19 patients with re-detectable positive RNA test. 2020
  50. Kang H, Wang Y, Tong Z, Liu X. Retest positive for SARS-CoV-2 RNA of “recovered” patients with COVID-19: Persistence, sampling issues, or re-infection. J Med Virol. 2020
  51. Vabret N, Britton GJ, Gruber C et al. Immunology of COVID-19: Current State of the Science. Immunity. 2020;52:910-941
  52. Long Q-X, Tang X-J, Shi Q-L et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nature Medicine. 2020
  53. Rubino F, Amiel SA, Zimmet P et al. New-Onset Diabetes in Covid-19.[letter]. N Engl J Med 2020
  54. Tao SL, Wang XM, Feng YG et al. Is the presence of lung injury in COVID-19 an independent risk factor for secondary lung cancer. Med Hypotheses. 2020;143:110074
  55. Ciaglia E, Vecchione C, Puca AA. COVID-19 Infection and Circulating ACE2 Levels: Protective Role in Women and Children. Front Pediatr. 2020;8:206
  56. Tikellis C, Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept. 2012;2012:256294
  57. Wu Y, Feng Z, Li P, Yu Q. Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19. Clinica Chimica Acta. 2020;509:220-223
  58. Ellinghaus D, Degenhardt F, Bujanda L et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020
  59. Breiman A, Ruvën-Clouet N, Le Pendu J. Harnessing the natural anti-glycan immune response to limit the transmission of enveloped viruses such as SARS-CoV-2. PLoS Pathog. 2020;16:e1008556
  60. Miyasaka M. Is BCG vaccination causally related to reduced COVID-19 mortality. EMBO Mol Med. 2020;12:e12661
  61. Netea MG, Giamarellos-Bourboulis EJ, Domínguez-Andrés J et al. Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection. Cell. 2020;181:969-977
  62. Riccò M, Gualerzi G, Ranzieri S, Bragazzi NL. Stop playing with data: there is no sound evidence that Bacille Calmette-Guérin may avoid SARS-CoV-2 infection (for now). Acta Biomed. 2020;91:207-213
  63. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect. 2020;80:607-613
  64. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med. 2020
  65. McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. The Lancet Rheumatology. 2020;2:e437-e445
  66. Felsenstein S, Herbert JA, McNamara PS, Hedrich CM. COVID-19: Immunology and treatment options. Clin Immunol. 2020;215:108448
  67. Radzikowska U, Ding M, Tan G et al. Distribution of ACE2, CD147, CD26 and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy. 2020
  68. Ayres JS. A metabolic handbook for the COVID-19 pandemic. Nat Metab. 2020
  69. Gao J, Hu S. Update on use of chloroquine/hydroxychloroquine to treat coronavirus disease 2019 (COVID-19). Biosci Trends. 2020;14:156-158
  70. Salvi R, Patankar P. Emerging pharmacotherapies for COVID-19. Biomed Pharmacother. 2020;128:110267
  71. Esposito S, Noviello S, Pagliano P. Update on treatment of COVID-19: ongoing studies between promising and disappointing results. Infez Med. 2020;28:198-211
  72. 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
  73. Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020;253:117592
  74. Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578
  75. Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020
  76. Bloch EM, Shoham S, Casadevall A et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020;130:2757-2765
  77. Xia X, Li K, Wu L et al. Improved Clinical Symptoms and Mortality on Severe/Critical COVID-19 Patients Utilizing Convalescent Plasma Transfusion. Blood. 2020
  78. Valk SJ, Piechotta V, Chai KL et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a rapid review. Cochrane Database of Systematic Reviews. 2020
  79. Li L, Zhang W, Hu Y et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020
  80. Monteil V, Kwon H, Prado P et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell. 2020;181:905-913.e7
  81. Inal JM. Decoy ACE2-expressing extracellular vesicles that competitively bind SARS-CoV-2 as a possible COVID-19 therapy. Clin Sci (Lond). 2020;134:1301-1304
  82. Sriram K, Insel PA. A hypothesis for pathobiology and treatment of COVID-19: The centrality of ACE1/ACE2 imbalance. Br J Pharmacol. 2020
  83. Alattar R, Ibrahim TBH, Shaar SH et al. Tocilizumab for the treatment of severe coronavirus disease 2019. Journal of Medical Virology. 2020
  84. Roschewski M, Lionakis MS, Sharman JP et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol. 2020;5
  85. Dexamethasone in the management of covid -19. [editorial]. BMJ 2020;370:m2648
  86. Mahase E. Covid-19: Demand for dexamethasone surges as RECOVERY trial publishes preprint. BMJ. 2020m2512
  87. Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2020
  88. Zhang Y, Xiao M, Zhang S et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. New England Journal of Medicine. 2020;382:e38
  89. Magro G. COVID-19: Review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking. Virus Res. 2020;286:198070
  90. Watson RA, Johnson DM, Dharia RN, Merli GJ, Doherty JU. Anti-coagulant and anti-platelet therapy in the COVID-19 patient: a best practices quality initiative across a large health system. Hosp Pract (1995). 20201-11
  91. Guan WJ, Liang WH, Zhao Y et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J. 2020;55
  92. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020;76:14-20
  93. Curfman G. Renin-Angiotensin-Aldosterone Inhibitors and Susceptibility to and Severity of COVID-19. JAMA. 2020
  94. Sukumaran V, Tsuchimochi H, Tatsumi E, Shirai M, Pearson JT. Azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through the modulation of ACE-2/ANG 1-7/Mas receptor cascade. Biochem Pharmacol. 2017;144:90-99
  95. Gao C, Cai Y, Zhang K et al. Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study. Eur Heart J. 2020;41:2058-2066
  96. Zhang P, Zhu L, Cai J et al. Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19. Circ Res. 2020;126:1671-1681
  97. Fosbøl EL, Butt JH, Østergaard L et al. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality. JAMA. 2020
  98. Meng J, Xiao G, Zhang J et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.[letter]. Emerg Microbes Infect 2020;9(1):757-760
  99. Ruilope LM, Tamargo J, Ruiz-Hurtado G. Renin-angiotensin system inhibitors in the COVID-19 pandemic: consequences of antihypertensive drugs. Eur Heart J. 2020;41:2067-2069
  100. Rao S, Lau A, So HC. Exploring Diseases/Traits and Blood Proteins Causally Related to Expression of ACE2, the Putative Receptor of SARS-CoV-2: A Mendelian Randomization Analysis Highlights Tentative Relevance of Diabetes-Related Traits. Diabetes Care. 2020;43:1416-1426
  101. Zhu L, She ZG, Cheng X et al. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020;31:1068-1077.e3
  102. Zhu FC, Li YH, Guan XH et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020;395:1845-1854
  103. Cohen J. Vaccine designers take first shots at COVID-19. Science. 2020;368:14-16
  104. Out of the frying pan and into the fire? Due diligence warranted for ADE in COVID-19. [editorial]. Microbes Infect 2020
  105. Iwasaki A, Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev Immunol. 2020;20:339-341

Last update:

No citation recorded.

Last update:

No citation recorded.