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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 3  |  Page : 127-133

Elucidating the pathogenicity, diagnosis, treatment, and prevention of COVID-19: Part I


Department of Conservative Dentistry and Endodontics, SRM Dental College, SRM Institute of Science and Technology, Chennai, Tamil Nadu, India

Date of Submission07-Jul-2022
Date of Decision25-Jul-2022
Date of Acceptance26-Jul-2022
Date of Web Publication09-Sep-2022

Correspondence Address:
Dr. Monisha Parshotam Khatri
A-501 Gitanjali Apartments 15 Medavakkam Tank Road, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/srmjrds.srmjrds_91_22

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  Abstract 

Background: From the beginning of 2020, much and more has been spoken about the coronavirus and coronavirus disease-19 (COVID-19). The concepts in terms of the infection, its transmission, the treatment, and its prevention are ever changing as well as unclear. Aim: The Part I of this review article strived to provide a clear picture on the pathogenesis, diagnosis, and treatment of COVID-19. Methods: An electronic search was performed in PubMed and Google Scholar database with the keywords “Corona Virus, COVID 19, World Health Organization, Severe Acute Respiratory Syndrome (SARS), SARS-CoV-2, Pathogenesis, Diagnosis, Treatment, Plasma Convalescent Therapy, Immune system” from January 2017 to December 2021. Results: A total of 65 articles were included in the current review and analyzed to simplify the complicated information available in the literature. Conclusion: COVID-19 as said to originate from bats and transmitted through intermediatory hosts like pangolins, can be diagnosed symptomatically and with tests such as blood investigation, reverse transcription–polymerase chain reaction, computed tomography scan, saliva, or gingival crevicular fluid. Various treatment options include use of drugs such as antivirals, antimalarial, immune enhancers, nonsteroidal anti-inflammatory drugs, corticosteroids, anticoagulant therapy, and antibodies.

Keywords: Coronavirus, plasma convalescent therapy, severe acute respiratory syndrome, severe acute respiratory syndrome-CoV-2, World Health Organization


How to cite this article:
Khatri MP, Mahalaxmi S. Elucidating the pathogenicity, diagnosis, treatment, and prevention of COVID-19: Part I. SRM J Res Dent Sci 2022;13:127-33

How to cite this URL:
Khatri MP, Mahalaxmi S. Elucidating the pathogenicity, diagnosis, treatment, and prevention of COVID-19: Part I. SRM J Res Dent Sci [serial online] 2022 [cited 2022 Oct 6];13:127-33. Available from: https://www.srmjrds.in/text.asp?2022/13/3/127/355833


  Introduction Top


A Dictionary of Epidemiology defines pandemic as “an epidemic occurring worldwide, or over a very wide area, crossing international boundaries and usually affecting a large number of people.”[1] The other features associated with a pandemic disease are high attack rates with explosiveness, minimal population immunity, novelty, infectiousness, contagiousness, and severity. History has witnessed many pandemic diseases such as smallpox, cholera, plague, dengue, AIDS, influenza, severe acute respiratory syndrome (SARS), tuberculosis, and now COVID-19 caused by coronavirus.[2] The coronavirus belongs to a subfamily Orthocoronavirinae in the family of a large class of viruses known as Coronaviridae in the order Nidovirales that are prevalent in nature.[3] This novel virus has been officially named as SARS-CoV-2 by the International Committee on Taxonomy of Viruses and the disease caused by it is named as coronavirus disease-2019 (COVID-19) by the World Health Organization (WHO). The first case of COVID-19 was identified in December 2019 in Wuhan, China, with the disease being declared a pandemic by the WHO on March 11, 2020.[4]

As we eagerly await a cure for this pandemic, it is justifiable to understand the activity of this virus and the steps as well as the theories suggested so far to combat it. With no claim as to the current viral infection, this article is an attempt to simplify and understand the various aspects of COVID-19 pandemic. This review article strived to discuss about the pathogenesis, diagnosis, and treatment of COVID-19.


  Methods Top


An electronic search was performed in PubMed and Google Scholar database with the keywords “Corona Virus, COVID 19, World Health Organization, Severe Acute Respiratory Syndrome, SARS-CoV-2, Pathogenesis, Diagnosis, Treatment, Plasma Convalescent Therapy, Immune system” from January 2017 to December 2021.


  Results Top


A total of 65 articles were included in the current review and were analyzed to simplify the complicated information available in the literature and to provide a clear picture on the pathogenesis, diagnosis, and varied treatment options for COVID-19.


  Discussion Top


COVID-19 and its pathogenicity

Coronaviruses are single-stranded RNA viruses with diameter ranging from 65 to 125 nm. Similar to SARS, SARS-CoV-2 has a genomic organization consisting of 5'-untranslated region (UTR), a replicase complex (orf1ab) encoding nonstructural proteins, a spike protein (S) gene, envelope protein (E) gene, a membrane protein (M) gene, a nucleocapsid protein (N) gene, 3'-UTR, and several unidentified nonstructural open reading frames.[3] The spike surface glycoprotein plays an important role in binding to receptors on host cells and once attached are split by human airway trypsin-like protease, cathepsins and transmembrane protease serine 2 (TMPRSS2) that help in further penetration.[3]

The spike proteins of SARS-CoV-2 are reported to bind with cellular receptors of angiotensin-converting enzyme 2 (ACE2) in the host cells similar to that of SARS. Once bound, the spike protein undergoes a conformation change that expedites viral envelope fusion with the cell membrane through the endosomal pathway. Following this fusion, the replication process begins wherein the viral RNA of SARS-CoV-2 is released into the host cell and translated into viral replicase polyproteins pp1a and 1ab. These polyproteins are further cleaved by viral proteinases that produce a series of subgenomic mRNAs by discontinuous transcription and finally translated into relevant small viral proteins. These viral proteins and genome RNA makeup for the virions assembled in the endoplasmic reticulum and Golgi bodies that are transported via vesicles and released out of the cell.[3]

Owing to its genomic sequence, the novel coronavirus (nCOV) is said to be 96% identical to human SARS-CoV, both said to have originated from bats with an intermediary host such as pangolins.[5] Although the theory of an intermediate host is unclear, various studies suggest that the recombinant virus of bat, snake, turtle, Bovidae, or Cricetidae may have formed the 2019-nCOV.[6]

Diagnosis of COVID-19

The infected patient apart from being asymptomatic may show varied symptoms ranging from fever or chills, dry cough, sore throat, congestion or runny nose, fatigue, headache, myalgia, diarrhea, nausea, vomiting, and breathlessness to acute kidney injury, acute respiratory distress syndrome (ARDS), acute myocardial injury, and chronic cardiovascular damage, sometimes causing multiple organ dysfunction in patients with severe comorbidities.[7],[8] Cytokine storm is one of the important mechanisms of ARDS, in which the release of large amount of proinflammatory cytokines and chemokines leads to deadly uncontrolled systemic inflammatory response.[9] Moreover, reports correlating presence of a healing oral ulcer; viral conjunctivitis; cutaneous manifestations such as erythematous rash, discolored fingers and toes, widespread urticaria, chickenpox-like vesicles; olfactory and gustatory dysfunction such as anosmia and ageusia have also been documented.[10],[11],[12]

Diagnosis of SARS-CoV-2 is majorly dependent on demonstration of the virus in respiratory secretions by a special molecular testing. Specimen collection is done from upper respiratory secretions such as nasopharyngeal and oropharyngeal swab or wash in ambulatory patients, lower respiratory secretions sputum and/or endotracheal aspirate or bronchoalveolar lavage in patients with more severe respiratory disease. Blood, saliva, urine, and stool may be additional clinical specimens for the collection of SARS-CoV-2.[13],[14] Molecular testing included nucleic acid amplification tests, where unique sequence of viral RNA is detected by real-time reverse transcription–polymerase chain reaction (RT-PCR), transcribed to complementary DNA strands and amplified with the help of primers and fluorescently labeled hydrolysis probes.[15],[16] However, false negative results with RT-PCR tests are common and may be attributed to early stage of infection, poor quality and quantity, mishandling or late collection of the specimen, and technical reasons inherent in the tests used.[14],[17]

To potentially rule out these false negative results, a two target system is introduced in which primers detect two different targets on the COVID-19 virus genome, of which at least one target is specific for SARS CoV-2.[14] In addition to the laboratory testing, 350 conventional RT-PCR COVID-19 testing kits are commercially available, out of which 29 kits have been approved by the United States Food and Drug Administration.[16] Common blood investigations for the detection of coronavirus include normal or low white cell count, lymphopenia, elevated C-reactive protein, and erythrocyte sedimentation rate, while severe infections may also show elevated levels of alanine transaminase, aspartate transaminase, prothrombin time, creatinine, D-dimer, creatine phosphokinase, and lactate dehydrogenase.[7],[18]

ACE2 is the main binding site for SARS-CoV-2 and is abundantly present in alveolar cells of the lung; upper and stratified epithelial cells of the esophagus; absorptive enterocytes from the ileum and colon; cholangiocytes, myocardial cells, and proximal tubule cells of the kidney; and bladder urothelial cells.[19] A study done by Xu et al. confirmed the presence of ACE2 in the oral tissues with a higher expression in the tongue when compared to the buccal or gingival tissues.[19]

Therefore, a noninvasive platform such as collection of saliva or GCF from the oval cavity may intensify disease detection and help rapidly differentiate the biomarkers.[9],[20] Studies have shown saline mouth rinse/gargle samples to be a better alternative to swabs, as it would improve the recovery of viral RNA from oropharynx, this can be done at home without the need of trained manpower, personal protective equipment, swabs or transport media also ensuring utmost comfort to the patients.[21],[22]

Treatment

The main difficulty in treating viral infections lie in the fact that viruses cannot survive without a host and can reproduce only by attaching to the human cells. Therefore, any treatment done to eradicate the virus will have a negative effect on the normal human cells as well. As such, there is no effective drug available till date to treat the disease, but an approved list of the WHO drugs are being tested as an experimental treatment for COVID-19, few of which are discussed as follows [Figure 1].[23]
Figure 1: Available treatment options for COVID-19

Click here to view


Antivirals

Blocking the virus with antivirals can be done by the following ways, ACE2 receptors present in the lungs and gastrointestinal tissues can be saturated by particles similar to the receptor-binding domain (RBD) present on the spike protein of the coronavirus or by antibodies and also by directly targeting the RBD with help of ACE2 receptors. Inhibition of viral replication can be done by preventing endocytosis, inhibiting maturation of endosomes, release of viral genome, transcription, and translation of viral proteins.[24]

Lopinavir–ritonavir

Lopinavir is a 3-chymotrypsin-like protease inhibitor, and ritonavir in addition also inhibits cytochrome P450 and glycoprotein and acts mainly by increasing the serum concentration of lopinavir. This combination impedes the formation of viral protein and thus hinders the replication process of the virus.[25] An early case report by Lim et al. showed decreased viral load with no or little coronavirus titers in a patient infected with SARS-CoV-2 during the early phase of the infection when treated with this antiviral combination.[26] However, a randomized controlled trial (RCT) on 244 patients did not show any significant clinical improvement in seriously ill hospitalized COVID-19 patients when treated with the same combination of drugs. The study concluded by stating that this combination may not be of any clinical benefit in patients with mild or severe disease.[27] The most commonly studied dosing for lopinavir/ritonavir is 400 mg/100 mg twice daily for up to 14 days.[28],[29] The use of this drug is not recommended anymore due to adverse effects of this combination such as diarrhea, nausea, stomatitis, fever, anemia, leukopenia, and prolonged QT interval.[27],[29]

Remdesivir

It is a nucleotide analog that disrupts the virus's ability to reproduce by inhibiting viral replication through premature termination of its RNA transcription.[30] A study by Wang et al. is the first known in vitro study done on African green monkey kidney Vero E6 cells that showed inhibition on SARS-CoV-2 when subjected to remdesivir.[30],[31] In vivo studies done on transgenic mice and rhesus macaques on MERS-COV and SARS-COV showed a strong antiviral effect of remdesivir along with reduced severity of respiratory signs and improved survival.[30]

Among reported use on humans, the first patient to present with COVID-19 in the U.S. was treated with intravenous remdesivir within 2 days after developing severe pneumonia, following which the male patient's condition improved with no reported side effects. Although the use of remdesivir was shown to be effective in a small number of patients with severe symptoms, its effectiveness is difficult to interpret due to the lack of randomization and a control group.[32] A randomized multicenter trial by Wang et al. concluded that although not statistically significant, patients receiving remdesivir had faster clinical improvement than those receiving placebo. The study also stated that an early cessation of the drug was required in confirmed SARS-CoV-2-infected patients due to the associated adverse effects.[33] Many studies reported the adverse effects to be anorexia, nausea, vomiting, increased aminotransferase or bilirubin levels, and worsened kidney and cardiopulmonary status.[33],[34],[35] Remdesivir cannot be used in conjunction with hydroxychloroquine as it leads to increased risk of QT prolongation and fatal dysrhythmias. Currently, remdesivir is the drug of choice for most of the COVID patients worldwide administered intravenously at a dose of 200 mg over 30–120 min on the 1st day followed by maintenance dose of 100 mg over 30–120 min administered once a day for 9 days in severely ill COVID patients on ventilator and for 4 days in patients not dependent on ventilator.[34] Although currently used widely, the adverse effects associated with remdesivir should not be neglected and thus this drug should be used with caution.

Antimalarial drugs

Chloroquine and hydroxychloroquine

Both chloroquine (CQ) and hydroxychloroquine (HCQ) belong to the same molecular family with only difference of a hydroxyl group on the side chain end of HCQ. They generate immunomodulatory effects on host cells by reducing cytokine production and inhibiting lysosomal and autophagy activity. In addition to this, they also inhibit viral entry by blocking glycosylation of host receptors, proteolytic processing, and endosomal acidification.[28],[36] HCQ is said to be more potent with better safety profile due to lower tissue accumulation when compared to CQ, with its half-maximal effective concentration of HCQ lesser than that of CQ.[37] An open-label, nonrandomized clinical trial showed similar results when HCQ was given along with azithromycin in comparison to giving HCQ alone. Azithromycin causes increased level of interferons (IFNs) and IFN-stimulated proteins in the epithelial cells, which in turn inhibits viral replication.[38] This was, however, questioned by another open-label RCT by Cavalcanti et al., which showed increased QTc interval prolongation and liver enzyme level elevation with no improvement in the clinical status of COVID-19 patients with mild-to-moderate symptoms when treated with HCQ alone or in combination with azithromycin.[39] Moreover, the side effects associated with the use of HCQ and CQ include hypoglycemia, neuropsychiatric effects, retinopathy, QT interval prolongation, and an increased risk of torsades de pointes. A recently published Cochrane systematic review concluded that HCQ is of no use in averting death in COVID-19 affected individuals and that its use should be prohibited.[40]

Nonspecific antivirals (immunoenhancers)

Interferons

IFN-α and IFN-β which are known as type I IFNs are potent antiviral agents and are one among the earliest cytokines to get activated during a viral infection. They activate the IFN-stimulated gene, which impedes viral replication as well as activates the adaptive immunity by promoting cytokine production.[40],[41] A study by Mantlo et al. showed sensitivity of SARS-CoV-2 when treated with 50 IU/ml concentration of IFNα or IFN-β, with the latter showing a slightly higher efficacy than the former.[42] IFN-β upregulates other type I IFNs, which in turn activates the innate immunity that mediates protective and antiviral response.[41],[42] This may be the reason we find that 80% of patients with mild symptoms recover during the early stage of infection.[42] Another RCT, COVIFERON, by Alavi Darazam et al. compared the time taken for clinical improvement when treated with control of HCQ along with lopinavir/ritonavir or in combination of IFN-β1a and IFN-β1b and concluded that control with IFN-β1a showed better results than the other two groups.[43] On the contrary to the above, an interim WHO Solidarity trial result stated that the use of IFNs did not decrease the chances of mortality, mechanical ventilation, or hospitalization duration in moderate-to-severe cases of COVID-19.[44] Therefore, the use of IFNs can be justified based on the severity of the disease and the stage of infection.

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in pain relief and are potent antipyretic drugs that act by inhibiting cyclooxygenase 1 and 2, which in turn blocks the prostaglandin synthesis.[32] According to Jamerson and Haryadi, the fever in the infected patients should let run its course to alert the immune system against the infection and allow easy unloading of oxygen from hemoglobin in case of increased temperature.[45] In such situations, acetaminophen is said to be a better substitute compared to ibuprofen due to its mild antipyretic action.[46] Another use of ibuprofen may be in cases of COVID-19 patients with cytokine storm; however, there has been speculation against its use as it causes upregulation of ACE-2 receptors, which are the entry point of SARS-CoV-2.[47]

A study by Amici et al. showed the effectiveness of indomethacin against SARS-CoV and concluded that it blocks viral RNA synthesis. However, the use of indomethacin in the current scenario is yet to be evaluated.[48],[49] Aspirin, a potent NSAID, is used at low doses (75–81 mg/day) for its anticoagulant property and at intermediate doses (650 mg to 4 g/day) for its analgesic, anti-inflammatory, and antipyretic properties.[50] Further, its role in inhibiting excessive type I IFN production, C-reactive protein, and prohibiting prostaglandin E2 synthesis in macrophages confirms its potent antiviral activity. Due to its multivariate potency, the use of aspirin in COVID-19 patients at an early stage may protect them from severe infection and further reduce the complication associated with coagulation and cardiovascular disease at a later stage. The prophylactic use of aspirin should be continued further in COVID-19 patients with cardiovascular disease, as it may prevent thrombus formation and pulmonary neutrophil recruitment.[47] On the other hand, the associated risk with the use of aspirin prevails as it irreversibly inhibits platelet cyclooxygenase and thus increases the risk of bleeding in severely ill SARS-CoV-2 patients.[50],[51] NSAIDs are associated with complications such as bronchoconstriction, increased risk of bleeding, and renal injury.[18] Therefore, its role to treat COVID patients is inconclusive as there are not many studies supporting its effectiveness in the current situation.

Corticosteroids

The use of corticosteroids is suggested in severe cases of COVID-19 patients to prevent lung injury and progression to ARDS. A retrospective cohort study of 201 patients done by Wu et al. showed that patients with ARDS who received a dosage of 1–2 mg/kg daily IV of methylprednisolone for 5–7 days had higher survival rate that those who did not receive it.[52]

Although the use of corticosteroids is always associated with adverse effects such as delayed virus clearance, psychosis, diabetes, and avascular necrosis, these side effects in the current scenario seemed to be less harmful.[53],[54]

The WHO in their living guidance has advised to limit the use of corticosteroids to patients with severe and critical COVID-19, with further studies required to evaluate the long-term effects in these patients as well as the clinical effects of corticosteroids in patients with nonsevere COVID-19.[55]

Anticoagulant therapy

Heparin

Low-molecular-weight heparin (LMWH) has shown to inhibit viral adhesion as well as exhibit anti-inflammatory action by inhibiting neutrophil chemotaxis and leukocyte migration. A report by Lindahl and Li stated that low-affinity chain heparin binds weakly to the antithrombin pentasaccharide structure when compared to high-affinity chain and thus have reduced anticoagulant property.[56] However, due to the distinct unavailability of pure low-affinity chain heparin, LMWH with both low- and high-affinity chains can be used with adequate measures to eliminate its anticoagulant property. Studies conducted recently have shown a decreased mortality rate in severely ill COVID-19 patients with sepsis-induced hypercoagulation receiving LMWH, thereby justifying its use as a prophylactic anticoagulant.[56],[57] In contrast to the above, a study has shown that therapeutic LMWH did not improve the condition of such patients when compared to the routine pharmacologic thromboprophylaxis.[58] However, other independent properties of LMWH such as its effective dosage, anti-inflammatory effect, inhibition of viral replication, and endothelial protection also need to be explored.

Antibodies

Monoclonal or polyclonal antibodies may help prove beneficial to fight SARS-CoV-2. Monoclonal antibodies (Mab) act against specific viral protein such as the spike glycoprotein present on the surface of SARS-CoV-2. They target the specific site and inhibit their activity either by neutralization or with help of Fc effector functions. It is target specific and can be engineered for specific purpose. An array of Mabs such as levilimab, itolizumab, ravulizumab, olokizumab, and sotrovimab are being used to treat patients with COVID-19 and have shown to be beneficial.[59],[60]

Cytokine storm is seen in severe cases of COVID-19 due to various inflammatory responses, one among them being activation of interleukin-6 (IL-6). A monoclonal antibody known as tocilizumab is a recombinant humanized antihuman IL-6 receptor antibody that binds to IL-6 receptor, thereby preventing immune damage and inhibiting inflammatory response caused by it. In addition, sarilumab and siltuximab are fully human IGg1 Mab that act against IL-6.[61] A systematic review by Solis-García Del Pozo et al. stated that though individual case reports show success in treating COVID-19 patients with the above-mentioned Mab, the data to thoroughly prove the same are questionable. Moreover, these drugs are associated with adverse effects such as neutropenia, liver enzyme elevation, and lipidic alterations and should not be administered in patients with severe liver or kidney failure.[62]

Polyclonal antibodies/plasma convalescent therapy

Convalescent plasma in simple terms means plasma obtained from the blood of a recovered patient after resolution of infection and development of antibodies. The passive infusion of these antibodies in susceptible individuals can, thereby, reduce the viral load and improve the chances of survival. Studies that evaluated the effect of plasma convalescent therapy (PCT) for the treatment of SARS concluded that PCT effectively decreased the viral load and significantly reduced the mortality rate specially when administered after early onset of symptoms.[63]

With regard to COVID-19 infections, in an open-label RCT that included 103 severe and life-threatening COVID-19 patients, plasma of approximately 4–13 mL/kg of the recipient's body weight was transfused after matching the ABO blood type of the donor and the recipient. The primary outcome of the study evaluated the time of clinical improvement within a period of 28 days. The study showed increased antiviral activity in patients treated with PCT, but no significant difference in the time to clinical improvement when compared to those who were treated with symptom-based standard care alone. The adverse effects associated with this therapy include transfusion-associated febrile and allergic reactions, dyspnea, hypotensive, hemolytic and septic reactions, acute lung injury, and circulatory overload.[64] A systematic review and quantitative analysis by Peng et al. individually summarized the outcomes of various clinical studies, commentary articles, review, protocol, guidelines, and in vitro studies, all of which highlighted the need of an in detail evaluation and standardized protocol to evaluate the treatment outcome in patients treated with PCT.[65] Although there are studies showing favorable improvement as well as no improvement after PCT, structured RCTs are further required to investigate its efficacy and safety in the current situation.[60],[65]

Although a promising treatment option, PCT comes with a lot of challenges such as safety of plasma donation by recovering patients, formulation of standard protocols to identify and screen recovered COVID-19 patients, and selection of a standard antibody titer.[61],[63] In addition, structured approach in increasing the blood banking facilities, motivating recovered patients for plasma donation, and maintaining a registry for future donations is a herculean task for a highly populous country like India.


  Conclusion Top


To curb the adverse effects of coronavirus, it is important to understand its origin, transmission, as well as the methods available to diagnose it. This article gives an insight into the nature of the virus and enumerates the various options available to diagnose and treat the disease available at the time of writing this article. How can COVID-19 be prevented and is dealt with worldwide will be discussed in detail in part II.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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