Table of Contents  
EDITORIAL
Year : 2020  |  Volume : 12  |  Issue : 2  |  Page : 65-68

Update on SARS-CoV-2: Pathogenesis, Immunity, Treatment Protocol and Vaccines in Perspective


Department of Oral Pathology, Sathyabama Dental College and Hospital, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India

Date of Submission25-Nov-2020
Date of Acceptance28-Nov-2020
Date of Web Publication16-Feb-2021

Correspondence Address:
Dr. K M Vidya
Department of Oral Pathology, Sathyabama Dental College and Hospital, Sathyabama Institute of Science and Technology, Jeppiar Nagar, Rajiv Gandhi Salai, Chennai-600119, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jofs.jofs_279_20

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How to cite this article:
Vidya K M. Update on SARS-CoV-2: Pathogenesis, Immunity, Treatment Protocol and Vaccines in Perspective. J Orofac Sci 2020;12:65-8

How to cite this URL:
Vidya K M. Update on SARS-CoV-2: Pathogenesis, Immunity, Treatment Protocol and Vaccines in Perspective. J Orofac Sci [serial online] 2020 [cited 2021 Aug 3];12:65-8. Available from: https://www.jofs.in/text.asp?2020/12/2/65/309587



The SARS-CoV-2 infection has affected 58,712,326 human beings worldwide. The WHO has reported 1,388,528 SARS-COV-2 deaths till date. India ranks second next to USA, with a cumulative total of 9,177,840 confirmed cases.[1] The median incubation period is 4 to 5 days with the clinical presentation ranging from asymptomatic or mild illness to severe acute respiratory distress and death. The primary route of transmission of SARS-CoV-2, remains through respiratory secretions.[2]

Though the symptoms are similar to the normal flu-like illness, SARS-CoV-2 popularly dubbed COVID-19, has threatened the entire human race. The virus, after entering the upper respiratory tract, binds to the angiotensin-converting enzyme 2 (ACE2) receptors of the respiratory epithelial cells via its spike proteins. This entry into the epithelial cell is further facilitated by type II transmembrane protease (TMPRSS2) expressed by the epithelial cells.[3] The virus is sensed by host cell membrane toll-like like receptors and cytosolic receptors. The host cell, thus injured by the viral entry, produces damaged molecular patterns which contain viral single stranded RNA. The host-virus interaction activates the innate immune system of the nearby lymphatic system, whereby, macrophages and plasmacytoid dendritic cells come to the site of infection. They produce type I and III interferons that in turn activate mediators of both innate immunity (neutrophils, Natural Killer cells) and adaptive immunity (naïve CD8+ T lymphocytes). Activated inflammatory cells produce a profusion of cytokines such as C-reactive protein, ferritin, fibrinogen, lactate dehydrogenase, D-dimer, etc. These are the mainstay laboratory biomarkers of SARS-CoV-2 infection determining the disease severity in the present times.[4],[5]

From the time of emergence of this disease in December 2019, scientists all over the world have focussed primarily on the innate immune system to explain its etiopathogenesis. Presently, the focus has shifted to the adaptive T cell immunity. Characterization of SARS-CoV-2 specific T cells has gained prominence, as it is differentially expressed in the clinical presentation of the disease. Quantification and immune-profiling studies from China, Iran, and US have found that, the CD4+ and CD8+ subsets specific to SARS-CoV-2 reduced in number in severe disease.[6],[7],[8]Alternately, they were expressed robustly, exhibited lymph node homing properties and in addition persisted for 2 months postinfection in convalescing patients. The lymph node homing/memory property is emphasized here, as this induces B cell maturation and production of neutralising antibodies. Such SARS-CoV-2 specific T cells expressed CD127, which proliferated in response to interleukin-7 (IL-7), one of the cytokines expressed in SARS-CoV-2 immune response. This has paved the way for using IL-7 in hospitalized lymphopenic patients in a clinical trial to stimulate the production of SAR-CoV-2 specific T cells.[8]

In the context of asymptomatic and mild disease patients, it has been hypothesized that they may have been exposed to SARS-CoV-1 or Middle Eastern respiratory syndrome (MERS) virus that could have primed their T cells to recognize SARS-CoV2. Additionally, memory CD4 T cells that reacts to SARS-CoV-2 epitope, can also cross-react with similar sequences from common cold corona viruses.[6]

The morbidity associated with SARS-CoV-2 is not only because of the involvement of respiratory system, but also because the viral spike protein binds to ACE2 receptors, which are expressed almost ubiquitously by all organ systems in the human body namely, type II alveolar cells of lungs, the myocardial cells, urothelial cells, cells of gastrointestinal tract, cholangiocytes of liver, and the vascular endothelium. It follows that, the population with systemic/noncommunicable illnesses such as diabetes, hypertension, cardiovascular diseases, chronic liver disease, and compromised kidneys is at a higher risk of progressing to severe SARS-CoV-2 manifestations. Morbidity in these cases is attributed to the direct cytopathic effects of the virus and a compromised immune response.[9],[10]

The cytokine storm which results due to an imbalance in the pro- and anti-inflammatory cytokines homeostasis leads to acute respiratory distress syndrome and immune-thrombosis. This imbalance is characterized by numerous cellular events such as exuberant immune response, delayed neutrophil response, delayed T cell activation, and aberrant CD4+ T cell response after the exposure to the virus.[4]

Treatment in SARS-CoV-2 is based on targeting the virus, immune-based therapy, adjunctive therapy and supportive therapy to assist ventilation. Severity of the disease dictates the use of a single or a combination drug therapy.[2] Antiviral drugs include pharmacologic agents that have been approved for other diseases but may be effective in reducing the severity and duration of SARS-CoV-2 infection. This is popularly phrased “drug repurposing” because, to date, there is no single approved antiviral drug for SARS-CoV-2. The treatment is symptomatic. Remdesivir (used for Ebola infection), Favipiravir (used for influenza), and Ribavarin (used in the treatment of hepatitis C and respiratory syncytial virus infections) inhibit a vital enzyme required for viral RNA transcription.[11] Efficacy trials are still in progress in various parts of the world and both CDC in the US and the Ministry of Health and Family Welfare, Government of India have strictly recommended Remdesivir use in hospital settings and for severe cases.[2],[12] Protease inhibitors, Lopinavir, Ritonavir, and Darunavir, used in HIV treatment, inhibit virus replication and were found to be effective in SARS-CoV-1 outbreak in the 2000s. These are undergoing efficacy trials. Umifenovir, a viral entry inhibitor drug, earlier used to combat influenza, prevents the binding of the viral protein to host cell receptors. Umifenovir is undergoing human trial research in Russia and China.[11]

In the early 2020s, quinoline derivatives, chloroquine, and hydroxychloroquine (HCQ) were used in the treatment of severe SARS-CoV-2. These are termed “disease modifying’ drugs used in rheumatoid arthritis to combat the inflammatory cascade and the associated cytokine-induced damage to joints. Efficacy trials for repurposing HCQ in SARS-CoV-2, revealed that the adverse events, mainly, cardiovascular complications outweighed the clinical benefits. HCQ use in SARS-COV-2 remains uncertain as the trial results are ambiguous.[11]

Immune-based therapies are targeted at the mediators of inflammation, which inhibit cytokines such as ILs, the complement cascade, T and B cell inhibitors, chemokine inhibitors, etc. Tocilizumab, Infliximab, Eculizumab, Rituximab, Tacrolimus, and Cyclosporine are some of the immune modifiers undergoing clinical trials worldwide. [4],[13]

Ivermectin is an antiparasitic drug, which has been repurposed for SARS-CoV-2. This drug acts by inhibiting the host proteins that are hijacked by the virus for suppressing the host response. Its usage is restricted to hospitalized SARS-COV-2 patients. Efficacy trials have not been conclusive in Ivermectin use.[2]

Corticosteroids are recommended for use in severely ill patients requiring oxygen support. They are broad immunosuppressive agents, they combat the profuse inflammatory response in SARS-CoV-2. Mortality rate has reduced in trials on patients requiring mechanical ventilation.[11] Though, their use shows promising improvement, judicious usage is advised especially in diabetics, as corticosteroids can cause hyperglycaemia when given intravenously. The present recommendation for hospitalizehospitalized diabetic SARS-CoV-2 patients are: Substitution of oral antidiabetics with Insulin, diligent monitoring of blood glucose levels to prevent deterioration of the diabetic state and SARS-CoV-2 infection.[14]

Plasma from convalescent SARS-CoV-2 patients contains immunoglobulins produced in response to the infection. This therapy is again repurposed in the present context, as it has a precedence of successful use in Ebola and MERS infections. Convalescent plasma therapy is recommended for moderately ill patients in whom the oxygen requirement increases despite corticosteroid use. ABO and crossmatching should be done prior to plasma therapy. These patients should be closely monitored for transfusion-related adverse events.[12]

The Ministry of Health and Family Welfare, Government of India has also formulated revised treatment protocol with due consideration given to the severity of the disease on clinical presentation. Some of the therapeutic agents are termed “Off label’ therapies.[12]

Mesenchymal stem cells are being tried in clinical trials as they most importantly lack ACE2 receptors and therefore are resistant to viral entry. They are self-renewing and can differentiate into many types of tissues. They may be used to reduce lung injury.[2]

Adjunctive therapy includes the use of routine therapeutic doses of vitamin C, D, and zinc. Though they are essential for maintenance of overall well-being, research related to the efficacy of these vitamins in preventing the SARS-CoV-2 infection is ambiguous. Extracorporeal membrane oxygenation (ECMO) is the advanced life support system recommended in critically ill SARS-CoV-2 patients.[2]

Testing strategy recommended by Indian Council of Medical Research (ICMR) are the rapid antigen test, RT-PCR test, Cartridge-based nucleic acid amplification test (CBNAAT), and TrueNAT. CBNAAT and TrueNAT (portable version of CBNAAT) produce faster results compared to RT-PCR. Nasal or throat swabs are used in these tests. Saliva-based Rapid Antigen Test kits are also being validated.[15]

Numerous vaccine trials have been instituted around the world. ICMR has presently approved different vaccine trials, which are being evaluated at various medical institutions in Indian states. The participants in these trials are healthy human volunteers.[15]


  Future Perspectives Top


Though the panel of inflammatory biomarkers are used in prognostication, it is difficult to predict which patient is going to suffer from severe disease in SARS-CoV-2 infection. Presently, the Government of India has initiated the SARS-CoV-2 vaccination program in phases, healthcare professionals followed by other frontline service personnel are being innoculated. Vaccine is provided free of cost. Vaccination program for the general public, has also started at various government hospitals. Other factors to be seriously considered in the vaccination context, irrespective of whether it is a DNA or RNA vaccine, are: duration of the effect, requirement of booster dose, side effects such as allergies, effects in individuals with systemic illnesses and immunocompromise, cross-reactions in individuals taking drugs for systemic illnesses, whether the vaccine will be effective in future mutated strains of the virus and so on. Social distancing, hand hygiene, and mask protocols must be mandatorily in place, at least till the mass vaccination program begins and even afterward. Humans to animals and back to humans transmission with newer, mutated, and resistant virus strains have been reported, which is worrisome.[16] Indigenous Indian ayurvedic and siddha medicines, which have set a precedence in the treatment of chikungunya need to explored further.[17] Many recovered SARS-CoV-2 patients are suffering from persistent symptoms like fatigue, myalgia, breathlessness, headaches, etc., even after 3 months of recovery, they are called “long haulers”.[18] Long-term effects of SARS-CoV-2 infection on the human body, remains to be seen. A hopeful note in this update is that our Indian government is one of the global partners of International Vaccine Institute based in Seoul, South Korea, which is into developing cutting edge technology in vaccine discovery, production, and implementation of various vaccine programs all over the world.[19],[20],[21]

A mutated variant belonging to 20B/GR clade of SARS-CoV-2 (lineage B1.1.7) has emerged in December of 2020 in the United Kingdom and has spread to 60 countries. This variant is spreading rapidly and may be associated with increased hospitalization and higher mortality.[20],[21]

Acknowledgements

I express my heartfelt gratitude to Dr.Meera Govindarajan, MD (General Pathology) and Dr.T.S.Kannan (Internal Medicine) for selflessly sharing their professional expertise in this writeup.

Financial Support

Nil.

Conflict of interest

There are no conflicts of interest.

Note: MeSH terms used in pubmed to retrieve articles for this editorial were “SARS-CoV-2” and “India”,“COVID 19” AND “T lymphocytes” “Covid 19” and “Immunity”. The best yield of 112 articles were screened. Back references from the articles wherever pertinent, were hand searched and appraised.



 
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Tan AS, Nerurkar SN, Tan WCC, Goh D, Lai CPT, Poh Sheng YJ. The virological, immunological and imaging approaches for COVID-19 diagnosis and research. SLAS Technol 2020;18:2472630320950248. https://doi.org/ 10.1177/2472630320950248.  Back to cited text no. 3
    
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Chau AS, Weber AG, Maria NI et al. The longitudinal immune response to Coronavirus Disease 2019: Chasing the Cytokine Storm. Arthritis Rheumatol 2020; Epub ahead of print. https://doi.org/10.1002/ART.41526.  Back to cited text no. 4
    
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Sánchez-Cerrillo I, Landete P, Aldave B et al. REINMUN-COVID and EDEPIMIC groups. COVID-19 severity associates with pulmonary redistribution of CD1c+ DCs and inflammatory transitional and nonclassical monocytes. J Clin Invest 2020; 26140335. https://doi.org/10.1172/J CI140335.  Back to cited text no. 5
    
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Han H, Xu Z, Cheng X et al. Descriptive, retrospective study of the clinical characteristics of asymptomatic COVID-19 patients. mSphere 2020;5:e00922-20. https://doi.org/ 10.1128/mSphere.00922-20.  Back to cited text no. 6
    
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Fathi F, Sami R, Mozafarpoor S et al. Immune system changes during COVID-19 recovery play key role indetermining disease severity. Int J Immunopathol Pharmacol 2020;34:2058738420966497. https://doi.org/ 10.1177/2058738420966497.  Back to cited text no. 7
    
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Neidleman J, Luo X, Frouard J et al. SARS-CoV-2-specific T cells exhibit unique features characterized by robust helperfunction, lack of terminal differentiation, and high proliferative potential. bioRxiv [Preprint]. 2020 :2020.06.08.138826. https://doi.org/ 10.1101/2020.06.08.138826.  Back to cited text no. 8
    
9.
Zou X, Chen K, Zou J et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020;14:185-92. https://doi.org/10.1007/s11684-020-0754-0.  Back to cited text no. 9
    
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Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M. COVID-19 and the liver. J Hepatol 2020;73:1231-40  Back to cited text no. 10
    
11.
Ahsan W, Alhazmi HA, Patel KS et al. Recentadvancements in the diagnosis, prevention, and prospective drug therapy of COVID-19. Front Public Health 2020;8:384.  Back to cited text no. 11
    
12.
https://doi.org/10.3389/fpubh.2020.00384.www.mohfw.gov.in/pdf/Clinical Management Protocol for COVID19.pdf  Back to cited text no. 12
    
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14.
Deng F, Gao D, Ma X et al. Corticosteroids in diabetes patients infected with COVID-19. Ir J of Med Sci 1971. −https://doi.org/10.1007/s11845-020-02287-3.  Back to cited text no. 14
    
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16.
COVID mink analysis shows mutations are not dangerous-Yet, News, 13 November 2020, nature.com  Back to cited text no. 16
    
17.
Girija PLT, Sivan N. Ayurvedic treatment of COVID-19/SARS-CoV-2: A case report. J Ayurveda Integr Med 2020. https:// doi.org/10.1016/j.jaim.2020.06.00.  Back to cited text no. 17
    
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Rubin R. As their numbers grow, COVID-19 ‘Long haulers’ stump experts. JAMA 2020;324:1381-1383.  Back to cited text no. 18
    
19.
www.ivi.int; IVI-International vaccine Institute, Seoul, South Korea.  Back to cited text no. 19
    
20.
Tang JW, Tambyah PA, Hui DS. Emergence of a new SARS-CoV-2 variant in the UK. DOI: https://doi.org/10.1016/j.jinf.2020.12.024.  Back to cited text no. 20
    
21.
“Some Evidence” UK Coronavirus Strain More Deadly: Boris Johnson. https://www.ndtv.com/world-news/2356764.  Back to cited text no. 21
    




 

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