Contextual Background

Coronaviruses (CoVs) are associated with the extended family of positive, encased, extensively diverse, and single-stranded RNA viruses.^1,2 Coronaviruses were first perceived in the mid-1930s, and the first human coronavirus was notified in 1960, causing common cold-like symptoms.^3–5 In 2003, a beta (β) – coronavirus emerged from bats and disseminated through the palm civet (mediator host). It was transmitted to humans in China’s Guangdong territory, where it was designated as the SARS (Severe Acute Respiratory Syndrome) virus, affecting approximately 8422 people, 916 of whom died. ^4,6 In the middle of 2012, the initial instance of MERS (Middle East Respiratory Syndrome) was identified in Jeddah, Saudi Arabia. It emerged from bats, but the mediator host was a camel, and it affected 2994 individuals, 858 of whom died.^4,7 Wuhan, China was the initial location to identify instances of the COVID-19 obtained from patients with pneumonia. Later, it spread globally to almost every country, creating a nationwide lockdown.^4,8,9

The WHO (World Health Organization) designated the outbreak as COVID-19 (Novel Coronavirus Disease 2019), which is caused by the SARS CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), on February 11, 2020. The assumed method of spreading COVID-19 is from one person to another through droplets expelled by infected individuals when they cough or sneeze nearby.^1,10,11 The primary signs of COVID-19 include are pyrexia (fever), tussis (cough), emesis (vomiting), and diarrhea.^1,12 The major health issues caused by SARS CoV-2 include and multiple organ failure, sepsis, ARDS (acute respiratory distress syndrome), septic shock, which are associated with co-morbidities (cancer, immunodeficiency, immunosuppressive disorders, cardiovascular diseases, diabetes, and asthma) (Table 1).^13–16 The geriatric section and patients with co-morbidities or chronic diseases are specifically vulnerable populations.^1,17 Nearly five years have passed since the first COVID-19 cases were reported in Wuhan, China. Over the past few challenging years, we’ve explored a variety of treatment approaches, implemented preventative measures, embraced social distancing, and fueled groundbreaking vaccine research. Unfortunately, in spite of these initiatives, especially concerning pharmacotherapy and patient management, over 775 million people worldwide have contracted SARS-CoV-2, and more than 7 million of those cases have resulted in death from COVID-19 infection. Furthermore, based on epidemiological mortality rate assessment research, the death rate has surpassed 18.2 million so far, and this deadly epidemic will claim many lives.¹⁸

Table 1: Symptoms, Disease Pathogenesis and Clinical Manifestations Observed in Different Stages of COVID-19.

Materials and Methods 

A comprehensive review was conducted to evaluate the progression of the SARS-CoV-2 virus (COVID-19), its impact on public health, associated neurological complications, and the available treatments and vaccination approaches. The review was based on an extensive search of peer-reviewed literature published on the COVID-19. The following methods were employed:

Literature Search Strategy

A systematic search was performed across multiple electronic databases including PubMed, ResearchGate, Scopus, Semantic Scholar, and Google Scholar. The search strategy incorporated a broad set of keywords related to COVID-19, such as: “COVID-19”; “SARS-COV-2”; “Coronavirus”; “SARS-COV-2 Variants”; “SARS-COV-2 Taxonomy”; “COVID-19 Pathology”; “COVID-19 Diagnosis”; “COVID-19 Comorbidities”; “COVID-19 Cardio-Vascular Disorder”; “COVID-19 Hypertension”; “COVID-19 Diabetes”; “COVID-19 Neurological Disorders”; “COVID-19 Encephalopathy”; “COVID-19 Guillain-Barré Syndrome”; “COVID-19 Stroke”; “COVID-19 Treatments”; “COVID-19 Immunomodulatory Treatment”; “COVID-19 Antiviral Drugs”; and “COVID-19 Vaccines”. Studies were selected based on relevance, quality, and inclusion of information on the virology, pathology, comorbidities, neurological impact, and vaccine development significantly centred on the topic “COVID-19”.

Selection Criteria

This review article included original research articles, reviews and studies that provided information on the structure and taxonomy, as well as the immuno-pathophysiology of SARS-CoV-2. Additionally, it incorporated studies exploring the relationship between comorbidities and COVID-19, investigations into the neurological effects of COVID-19, and articles highlighting COVID-19 management as well as examining the development, efficacy, and safety of COVID-19 vaccines. 

Results

Eligible studies, including full-text reviews and original research articles focused specifically on COVID-19, were critically reviewed to extract data on viral taxonomy, structural virology, immuno-pathogenesis, neurological complications, treatments, and vaccine development. The extracted data was then categorized into the following areas:

Taxonomy and Structural Virology

Information on the classification of SARS-CoV-2 within the coronavirus family and its structural composition and units.

Immuno-Pathophysiology of SARS-CoV-2

Insights into the mechanisms of SARS-CoV-2 viral entry and developing a disease severity.

Neurological Complications

Information on the incidence and types of neurological complications associated with COVID-19

Rapid Detection of COVID-19

Methods and technologies for the swift identification of COVID-19, including rRT-PCR tests, lateral flow immunoassay, and emerging diagnostic tools for early detection.

Impact of Comorbidities on COVID-19 Severity

Insights into how underlying conditions like diabetes, hypertension, and cardiovascular disease exacerbate the severity of COVID-19.

Treatment Strategies

An overview of antiviral agents, immunomodulatory treatments, neutralizing antibodies, convalescent plasma therapy, and antithrombotic therapy, along with their application in managing mild to severe COVID-19 cases.

Comprehensive List of COVID-19 Vaccines

An overview of available COVID-19 vaccines, highlighting their adverse effects, effectiveness, and efficacy against various SARS-CoV-2 variants.

By following this systematic approach, this review article offers a comprehensive summary of viral taxonomy, structural virology, immuno-pathogenesis, neurological complications, treatment strategies, and vaccine development , all focused specifically on COVID-19. 

Discussion

Taxonomy, Structural Virology and Circulating Sars-Cov-2 Variants

The International Committee on Taxonomy of Viruses (ICTV) classified coronaviruses under the order Nidovirales and the family Coronaviridae and subfamily Orthocoronavirinae (Figure 1A).²¹ The ‘Coronavirus’ is named since the outer surface of the virus contains crown-like spike projections. ² Based on serological evidence, the subfamily Orthocoronavirinae is divided into four genera: α-CoVs (alpha-coronavirus), β-CoVs (beta-coronavirus), ϒ-CoVs (gamma-coronavirus), and δ-CoVs (delta-coronavirus) (Figure 1A).^4,22,23 Coronaviruses are generally nurtured in mammals (bats, camels, cattle, cats, etc.) and birds. Alpha and beta-coronaviruses infect mostly mammals, whereas gamma-coronaviruses primarily infect birds and a few mammals. However, delta-coronaviruses infect both. Animal coronaviruses largely infect domestic birds and animals, affecting productivity along with economic loss. ^22,23 These animal coronaviruses include Porcine Epidemic Diarrhoea Virus (PEDV), Avian Infectious Bronchitis Virus (IBV), Transmissible Gastroenteritis Virus (TGEV), and Swine Acute Diarrhoea Syndrome Coronavirus (SADS‐CoV). Coronaviruses are unusually potent human infectors and could spread through from one person to another. The initial coronaviruses identified were IBV, which caused respiratory illness in chickens, and Human Coronavirus 229E and OC43 (HCoV OC43 and HCoV 229E), which caused common cold-like symptoms in humans. Several other human coronaviruses were identified, such as in 2002 [Severe Acute Respiratory Syndrome Coronavirus (SARS‐CoV)], in 2004 [Human Coronavirus (HCoV)-NL63], in 2005 [Human Coronavirus (HCoV)- HKU1], in 2012 [Middle East Respiratory Syndrome-Coronavirus (MERS‐CoV)], and the recent global pandemic [Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2)]. ^9,22,24–27

Coronaviruses are observed under an electron microscope as minute, spherical, enveloped particles 60 to 140 nm in diameter, made up of single-stranded RNA (26 to 32 kbs in length). ^2,4,28 The coronavirus mRNA encodes the four structural proteins: Spike (S) protein, Nucleocapsid (N) protein, Membrane (M) protein, and Envelope (E) protein (Figure 1B). The spike glycoprotein (S-protein) projections are a vital characteristic feature of coronaviruses. ⁴ It forms the bulky glycosylated peplomers embedded in the lipid bilayer, mediates attachment to the Angiotensin-Converting Enzyme 2 (ACE2) receptor, and facilitates membrane fusion to initiate viral pathogenicity in the host cell. The embedded hemagglutinin-esterase (HE) dimer designs the minute spikes on the viral outer surface. The positive-sense viral RNA is integrated with the viral nucleotide N-protein to form the nucleocapsid, which plays an important role in viral replication and transcription. The hydrophobic trans-membrane protein (M-protein) is the most prominent viral surface glycoprotein and is assumed to be the central organiser for assembling the coronaviruses. The trans-membrane envelope glycoprotein (E-protein) is the minor component of the coronaviruses and plays a prominent role in virus assembly, host cell membrane permeability, and also virus-host cell interaction.^2,4,22,28,29

Eventually, researchers discovered a worldwide dominant variant, D614G, which was associated with increased transmissibility but not the potential to cause severe illness.³⁰ Several SARS-CoV-2 variations have been reported since then, some of which are regarded as variants of concern (VOCs) because they may result in increased transmissibility or pathogenicity. A categorization method for differentiating the new SARS-CoV-2 variations into variants of interest (VOIs) and variants of concern (VOCs) has been separately developed by the World Health Organisation (WHO) and the United States Centres for Disease Control and Prevention (CDC) (Table 2). ³¹ Fortunately, no SARSCoV-2 variant that satisfies the VOC requirements is currently in circulation. Certain Omicron lineages, such as EG.5, XBB.1.5, and XBB.1.16, are considered to be VOIs that are currently in circulation (Table 2).¹⁸ A number of Omicron lineages have been identified as presently circulating variants under monitoring (VUMs), such as XBB, XBB.1.9.1, and XBB.2.3. Information about the immunological escape, growth rate, and transmissibility of these new Omicron lineages is limited. These lineages have been associated with the following primary spike mutations: I332V, D339H, R403K, V445H, G446S, K444T, L452R, N450D, L452W, E180V, T478R, F486P, N481K, 483del, and E484K. More research and observation are necessary because the epidemiological and phenotypic effects of these mutations and associated lineages are still uncertain.¹⁸ 

Figure 1: Illustrating the taxonomical and schematic structure of SARS CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Click here to view Figure

Schematically representing the taxonomical classification of coronaviruses. Constructed using the following references: ^{2,4,9,21–27,32}

Schematic structure of SARS CoV-2. Constructed using the following references: ^2,4,22,28,29 and this figure was partially made using Servier Medical Art ³³

Table 2:  System of Classification for Differentiating the Emerging SARS-CoV-2 Variants. 

Immuno-Pathophysiology of SARS-COV-2

The genome of a coronavirus consists of about 30,000 nucleotides, and its structural proteins are encoded by its mRNA.^1,28 Earlier research shows that the main targets of SARS-CoV are the host’s pulmonary system, especially the macrophages, alveolar epithelial cells, vascular endothelial cells, and airway epithelial cells, which have Angiotensin-Converting Enzyme 2 (ACE2) receptors. In a similar manner, SARS-CoV-2 utilizes the ACE2 receptor on the host cell to facilitate entry (Figure 2). When the virus attaches to the ACE2 receptor, it reduces its expression and causes the lung cells to down-regulate, which results in acute lung damage.^37–46

The two subunits that make up the spike (S) glycoprotein are S1 and S2. An ATD (Amino-Terminal Domain) and a RBD (Receptor-Binding Domain) make up the subunit S1. ^43,47–49 The RBD starts the viral infection phase by attaching itself to the host cellular target ACE2. RBD connects to the cellular receptor ACE2, which triggers the endocytosis of SARS CoV-2 virion and exposes it to the host endosomal proteases furin and trypsin. HR1 and HR2, the Heptad Repeat Regions, and the FP (Fusion Peptide) region make up subunit S2. After the subunit S1 is broken down within the endosome, FP emerges and enters the host membrane. The viral payload is subsequently released into the host cell’s cytoplasm when the subunit S2 coincides on itself to connect the two heptad repeat sections in proximity, triggering the membrane fusion (Figure 2). ^43,50–52 Biophysical tests and computer modelling show that the RBD of SARS CoV-2 attaches to ACE2 with greater proximity than that of SARS-CoV. Like MERS-CoV and HC-OC43, the spike glycoprotein of SARS-CoV-2 forms a furin-like cleavage site, increasing the pathogenicity in comparison to SARS-CoV. TMPRSS2 (Transmembrane Protease Serine 2) is necessary for the recognition of the SARS CoV-2 spike glycoprotein and for facilitating the viral entrance into the host cell. ^43,53,54 After the virus enters the host cell’s cytoplasm by endocytosis, the SARS CoV-2 RNA gets released and processed into two polyproteins and structural proteins that eventually replicate the virus’s genome. ^1,28 The replicating viral component mediates viral genome replication and is composed of an exonuclease N, a helicase, an RdRp (RNA-dependent RNA polymerase), and other related proteins.⁵⁵ The mechanism by which N protein encapsidates duplicated genomes in the cytoplasm results in nucleocapsids, which then consolidate within the membrane to self-assemble into new virions. The ER (Endoplasmic Reticulum) and Golgi Apparatus membranes both include the recently synthesised structural glycoproteins in the cytoplasm, which are then transferred to the ERGIC (Endoplasmic Reticulum-Golgi Intermediate Compartment). ^1,28,56 Finally, the novel virions are fused with the plasma membrane via exocytosis, and the virus is released (Figure 2).^1,28

The released virus instigates the host cell to initiate pyroptosis and release ATP, ASC oligomers, Interleukin-1 (IL-1), and nucleic acids, which constitute the Damage-Associated Molecular Patterns (DAMPs). Adjacent epithelial cells, alveolar macrophages, and endothelial cells recognise the released danger signals (DAMPs), which trigger pro-inflammatory cytokines (such as TNF [Tumor Necrosis Factor-alpha]–α; TGF [Transforming Growth Factor-beta]–β; IFN [Interferon-alpha]–α,γ; Interleukin [IL]–1β, 6, 12, 18, 33, 281) and chemokines (such as CCL [C‑C motif chemokine ligand]–2, 3, 5, and CXCL [C-X-C motif chemokine]–8, 9, 10).^{1,13,43,57–59} T cells, macrophages, and monocytes are drawn to the infection site by pro-inflammatory chemokines and cytokines, which also promote further inflammation through the production of interferon-gamma (IFN-γ) by T cells and a pro-inflammatory feedback looping mechanism. When the spike glycoprotein of SARS CoV-2 binds to the ACE2 receptor, it affects the RAS and causes vascular permeability. This can result in a faulty immunological response where immune system cells build up in the lungs, producing excessive pro-inflammatory cytokines and adversely impacting the lung (Figure 2). ^{1,28,37–39,43,56} The subsequent cytokine storm spreads to neighboring organs, leading to malfunction or failure of several organs. Moreover, through Antibody-Dependent Enhancement (ADE), non-neutralizing antibodies produced by B lymphocyte cells (B cells) increase the SARS CoV-2 disease and exacerbate organ dysfunction or injury. In favorable immune responses, virus-specific CD⁴⁺ and CD⁸⁺ T cells draw in and destroy the virus at the onset of inflammation, preventing it from spreading. The alveolar macrophages recognizes the viral cells and neutralized them. They phagocytose the apoptotic cells to eliminate the virus and maintain minimal lung damage with resultant recovery.^{1,13,43,57–59}

Figure 2: The plausible immunopathogenesis mechanism of SARS-CoV-2. Click here to view Figure

Constructed using the following references:^{1,13,28,37–40,42–54,56–60} and this figure was partially made using Servier Medical Art³³

Rapid Detection of COVID-19

Rapid diagnosis or detection is a predominant health care function since it imparts details about the health issues of a patient and provides consecutive decisions.⁶¹ The vital advantages of rapid diagnostic techniques are the prospect of rapid intervention and a focused solution to potential problems. Similarly, COVID-19 can be detected using rapid diagnostic techniques like RT-PCR (real-time polymerase chain reaction), primary screening through an immunodiagnostic test (rapid antibody test), and finally by Artificial Intelligence (AI)-based image processing techniques such as chest X-ray and CT (Computed Tomography) scan (Figure 3A).^4,61,62

The most recent technique for qualitatively and quantitatively identifying the SARS-CoV-2 nucleic acid in both upper and lower respiratory swab samples in the intense period of illness is real-time reverse transcription-polymerase chain reaction, or rRT-PCR.^4,61,62 One of the best and most efficient scientific techniques for tracking, treating, and analyzing the COVID-19 is rRT-PCR. By using particular primers for the COVID-19 viral genes, cDNA is produced using this technique from the COVID-19 virus’s retrieved RNA. Specific areas of cDNA (target genes) are amplified and identified using various fluorescent dyes (Figure 3B). The use of rRT-PCR assays has several important advantages, but the main one is that the amplification and analysis would take place in a contained system, reducing the likelihood of false-positive findings.^63–66

After contracting SARS-CoV-2, the patient produces IgM or IgG antibodies which are specific for the viral antigens to the receptor binding domain (RBD), the spike glycoprotein (S1, S2 subunits), or the nucleocapsid (N) protein.^67,68 IgM first appears after infection and remains detectable for a couple of days and then IgG follows. All current quick SARS-CoV-2 antibody assessments rely on the ability of the N, S1, S2, or RBD domain of the SARS-CoV-2 spike protein to associate with IgM or IgG antibodies in the patient’s blood.^68–70 Time-dependent detection of IgM or IgG isotypes only reaches high sensitivity around three weeks after symptoms start.^68,71 Lateral flow detection [Lateral Flow Immunoassay (LFIA)] is used in rapid SARS-CoV-2 antibody testing (Figure 3C).^68,72 The blood sample taken from the person who has a suspected COVID-19 infection is used for LFIA. In lateral flow testing, an absorbent pad attached to the leading edge of the strip allows an antigen or antigen-antibody complex to flow across it. The polymeric strip’s different zones are travelled by a liquid sample that contains the analyte. As a sponge, the sample pad allows fluid to go to the next conjugate pad after it has been moistened. A chemical reaction between an antigen and an antibody can be carried out using the chemicals included on the conjugate pad. The antigen passes through the pad, leaving a mark behind. The antigen continues to flow via the test and control lines. Following its passage through these lines, the fluid enters a porous material that serves as a disposal storage.⁷² Observations are made based on the state of the patient and can be classified into the following categories: negative (just the control sign formed), IgM positive (both the IgM mark and control markings formed), IgG positive (both the IgG mark and control markings formed), or just both IgG and IgM positive (both the IgM and IgG markings developed along with the control line) (Figure 3C).^72,73

Figure 3: Quick methods for identifying or diagnosing COVID-19. Click here to view Figure

Rapid detection or diagnostic methods for detecting COVID-19. Constructed using the following references: ^4,61,62,74 and this figure was partially made using Servier Medical Art³³

The classic rRT-PCR (real-time reverse transcription-polymerase chain reaction) procedure is demonstrated, in which viral RNA is isolated and transformed into cDNA. By using rRT-PCR, specific regions of cDNA (target genes) are amplified and identified. Constructed using the following references: ^63–66 and this figure was partially made using Servier Medical Art³³

Steps representing LFIA (lateral flow immunoassay)-based COVID-19 diagnosis. Constructed using the following references:^67–72,74 and this figure was partially made using Servier Medical Art³³

Comorbidities of Cardiovascular Disease, Diabetes, and Hypertension in the Context of COVID-19

Patients with COVID-19 are more likely to have acute cases and greater fatality rates if they have underlying comorbidities and are older than 70. The prominent comorbidities that are associated with COVID-19 are cardiovascular diseases, diabetes mellitus, and hypertension.^16,75–78 This can be suggested by a study conducted by Li et al.,¹⁷ among 1527 COVID-19 patients admitted; 17.1% had hypertension, 16.4% had cardiovascular disease, and 9.7% had diabetes mellitus. ¹⁷ The survey by Huang et al.,¹³ comprised 41 hospitalized patients with a confirmed COVID-19 infection; 32% of these patients had concomitant conditions such as cardiovascular illnesses (15%), diabetes (20%), and hypertension (15%).¹³ Similarly, the study of Wang et al.,⁷⁹ suggests the prevalence of one or more comorbidities (likely 31% of patients with hypertension, 14.5% with cardiovascular diseases, and diabetes 10.0%) in 64 individuals from 138 hospitalized COVID-19 patients.⁷⁹ In general, COVID-19 infects both sexes; however, men have a 3.6% case fatality rate compared to women’s 1.6%.⁸⁰ Patients with cardiovascular diseases who contracted COVID-19 were three times more likely to experience an acute illness or require admission to the intensive care unit (ICU) than those with diabetes mellitus or hypertension.^17,76,80 According to a Chinese Centre for Disease Control and Prevention⁸¹ study, 44,672 patients out of 72,314 distinct records had COVID-19 confirmed in them; 1,023 of these patients died, resulting in a crude case fatality rate of 2.3% (number of confirmed mortality divided by the overall number of confirmed infections). Additionally, a greater fatality frequency was noted for individuals with underlying comorbidities: 10.5% of patients having cardiovascular disorders, 7.3% of patients with diabetes, and 6.0% of patients with hypertension.⁸¹

A survey by Chen et al.,⁸² involving 99 patients confirmed with COVID-19 revealed that 51% of the admitted patients were detected with chronic medical illness (40% with cerebrovascular or cardiovascular disease). ⁸² A retrospective multi-centre study by Ruan et al.,⁸³ included 150 patients with confirmed COVID-19 and found that people with cardiovascular diseases have a much higher risk of dying from SARS-CoV-2 infection.⁸³ Secondary infections were seen in 1% (1/82) and 16% (11/68) of the patients in the discharge group and death groups, respectively. According to laboratory results, white blood cell counts, platelets, absolute values of lymphocytes, total bilirubin, albumin, blood creatinine, blood urea nitrogen, cardiac troponin, CRP (C-reactive protein), IL-6 (interleukin-6), myoglobin, and all were significantly different between the two groups.⁸³ According to reports, SARS-CoV-2 is thought to infect the myocardium and cause myocarditis because of the myocardial infiltration by the interstitial mononuclear inflammatory cells that were found there during the post-mortem biopsy.^45,80 In some instances, acute myocarditis with reduced systolic function is observed post-COVID-19. ^80,84,85 Research on cardiac biomarkers suggested that hospitalized COVID-19 patients had a significant probability of cardiac injury. ^45,80,86,87 Myocardial injury is probably accompanied by myocarditis and/or ischemia and is a vital predictive aspect of COVID-19.⁸⁰ A single-centre observational study by Shi et al.,⁸⁷ revealed the significance of cardiac injury in 416 admitted COVID-19 patients, of whom 82 (19.7%) died of cardiac injury. Admitted older patients with more underlying comorbidities and high levels of leukocytes are reported to have cardiac injury due to greater hs-cTnI (high sensitive cardiac troponin I).⁸⁷ A retrospective single-centre case series by Guo et al., ⁸⁶ where 187 patients with confirmed COVID-19 were admitted to the hospital; 66 (35.3%) of these patients had preexisting cardiovascular conditions (cardiomyopathy, hypertension, and coronary heart disease), and 52 (27.8%) had myocardial damage, which suggests elevated cTnT (cardiac troponin T) readings.⁸⁶

Diabetes is one of the vital co-factors of morbidity and fatality throughout the world and is accompanied by various microvascular and macrovascular problems that eventually affect the overall patient’s survival. ⁷⁶ The prevalence of diabetes was found to be 35% (mean age, 79.5 years) in an analysis of a randomly chosen sample of fatal SARS-CoV-2 patients in Italy. ^88,89 A comprehensive retrospective study of 1591 SARS-CoV-2 patients admitted in ICUs in Lombardy, Italy, over the course of four weeks revealed an occurrence of T2DM (Type 2 Diabetes Mellitus) of 17%. ^88,90 In T2DM, apart from the pro-inflammatory storm of cytokines, a disproportion between coagulation and fibrinolysis occurs, with an inflated proportion of clotting factors and relative fibrinolytic system inhibition.⁷⁶ Both T2DM and insulin resistance are accompanied by endothelial malfunction and inflated platelet accumulation and activation, which instigate the progression of a hypercoagulable pro-thrombotic state.^76,91 Older people with COVID-19 are noted to have impaired T-cell and B-cell functions and an inflammatory cytokine storm. Consequently, T2DM by itself or in conjunction with advanced age and other comorbidities may encourage unchecked SARS CoV-2 proliferation, increasing the disease’s lethality.^76,92 Since the elderly population is most impacted by COVID-19 and hypertension is particularly widespread in older people, the prevalence of hypertension in these patients is not wholly uncommon.^77,93 Recent studies indicate that a high death rate was detected in COVID-19 individuals who had underlying comorbidities, most notably diabetes, hypertension, and cardiovascular disorders.^76,77,93,94

COVID-19 and Pathophysiological Aspects of Neurological Complications

Neurological problems are prevalent in COVID-19 patients, especially in hospitalized patients, who exhibit greater rates than in patients with less severe disease. ^95,96 Smell and taste problems, intracranial haemorrhage, ischemic stroke, encephalopathy, encephalomyelitis, and neuromuscular illnesses are among the most frequent neurological consequences.^97,98 A variety of factors, such as SARS-CoV-2 neurotropism, endothelial dysfunction, hypercoagulability, hypoxia, systemic illness, and response, may cause the development of neurological manifestation signs.⁹⁷

Neurological problems can result from the SARS-CoV-2 virus’s ability to enter the central neuronal system and affect both neurons and glial cells. Various patho-mechanisms give rise to neurological diseases. Findings indicate that the initial mechanism by which SARS-CoV-2 enters host cells is the ACE2 (angiotensin-converting enzyme type 2), which is found on the cell periphery of many tissues. ^97,99–104 By adhering to ACE2 in a variety of organs, including as the neurological system, skeletal muscle, and vascular endothelium, SARS-CoV-2 can enter the central neuronal system and impair blood vessels. ^97,103,104 Massive intracerebral haemorrhage can emerge from ruptured blood vessels triggered by disruption to the cerebral endothelium and a rise in cerebral blood pressure. ^97,103 However, concomitant COVID-19 infection, hypercoagulability, and thromboembolic circumstances may result in an ischemic stroke. ^97,105 The brainstem—which comprises the paraventricular nuclei and the nucleus of the solitary tract—is where ACE2 is mostly expressed in the brain and is responsible for cardiac and vascular function. ^97,101,102 Additionally, it has been demonstrated that an infection can spread via synaptic connections from peripheral neuronal to the central neuronal system. ^106,107 The dissemination of SARS-CoV-2 through the olfactory nerve may be an example of how disease proceeds along a neural route because of the peculiar structure of the olfactory nerve including associated olfactory fibres inside the nasal canal. Through the olfactory nerve and bulb routes, coronaviruses can colonize the nasal passages before entering the brain and cerebrospinal fluid, resulting in an inflammatory and demyelinating reaction. ^100,101 Another source of negative consequences is the development of an extremely wide systemic inflammatory response (SIRS), which results in an excess of interleukin (IL-6,12,15) and TNF-α (tumour necrosis factor-alpha). This inflammation triggers glial cell activation and a strong proinflammatory phase in the central nervous system, which in turn causes severe hypoxia, leading to cerebral oedema, cerebral vasodilation, and ischemia.^97,106,107

The most prevalent neurological side effects are problems related to taste and smell. Anosmia and taste abnormalities were identified as preliminary markers of COVID-19 in one study, affecting more than 80% of patients.¹⁰⁸ Smell dysfunction impacted 48% of patients, according to a meta-analysis of 83 research involving over 27,000 participants (95% CI 41.2–54.5).¹⁰⁹ Anosmia is reported by younger patients more frequently than by older ones. Additionally, women experience it more frequently than men do. ¹¹⁰ The majority of patients have either significant improvement or overall regression in 2-3 weeks, indicating a typically good prognosis for smell and taste impairments linked to COVID-19. As a result, the prognosis is probably more favorable than it would be for other aetiologies of smell disorders. However, in 10% to 20% of cases, severe and persistent deficiencies persist.⁹⁸ Fortunately, most COVID-19 patients experience a natural recovery of their taste and smell problems, indicating that no special management is needed. However, smell training approaches could be helpful as a treatment if smell abnormalities last longer than four weeks.^97,111

In most cases, patients in critical condition acquire encephalopathy. Delirium associated with encephalopathy is extremely uncommon and may manifest early or even without symptoms. In a cohort investigation involving 2088 COVID-19 individuals admitted to intensive care units, 55% of patients experienced delirium.¹¹² Shah et al.,¹¹³ found that out of 12,601 hospitalized patients, 1092 (8.7%) had acute encephalopathy.¹¹³ In an alternate study, 509 hospitalized COVID-19 patients were found to have encephalopathy in 31.8% of them.⁹⁵ It usually has a multifaceted etiology. Older male patients who have previous instances such as neurological ailments, cancer, cerebral vasculitis, diabetes, renal diseases, dyslipidemia, cardiovascular disease, hypertension, or smoking are primarily affected. ^95,97 Indications of encephalopathy and encephalitis include neuropsychological issues, agitation, delirium, motor impairments linked to extrapyramidal manifestations, abnormal coordination, seizures, diminished consciousness, and specific neurological impairments.^97,98

In COVID-19, stroke appears to be slightly less prevalent.^114–117 Among hospitalized patients, the proportions of intracranial haemorrhage were 0.2–0.9%, and the rates of ischemic stroke associated with COVID-19 were 0.4–2.7%.^118,119 Additionally, there are reported cases of cerebral venous thrombosis (CVT) in COVID-19 individuals. ^120,121 In a retrospective analysis involving more than 13,000 patients, twelve people with CVT were found within three months, indicating 8.8 cases per 10,000 patients. ¹²² A comprehensive evaluation of 34,331 hospitalized patients infected with SARS-CoV-2 estimated the prevalence of CVT to be 0.08% (95% CI 0.01–0.5).¹²³ The majority of the time, a stroke occurs one to three weeks after COVID-19 symptoms initially manifest.^{122,124–126}

In both the moderate and severe COVID-19 variations, myalgia is frequently experienced.⁹⁷ It has been reported in 22–63% of patients,⁹⁸ and in more extreme instances (19 vs. 5%), it is accompanied by elevated creatinine kinase (CK) levels; myopathy, or muscle injury, is also suspected.¹¹⁰ A rare and infrequent repercussion of COVID-19 is severe rhabdomyolysis.¹²⁷ In 0.2% of patients, it was noticed, and in 13.7% of cases, elevated CK levels were found. Within five to seven days of the SARS-CoV-2 infection-induced fever, three Italian patients experienced prevalent myasthenia including positive acetylcholine receptor antibodies.¹²⁸ While it is hypothesized that myasthenia may be caused by the immune system’s reaction to SARS-CoV-2, another possibility is that the infection just catalysis the onset of symptoms in individuals who already have myasthenia. Amyotrophic lateral sclerosis (ALS) cases have also been shown to involve an exacerbation of a pre-existing neuromuscular condition. It indicates that people with neuromuscular disorders do not have a significantly higher risk of contracting SARS-CoV-2 disease.⁹⁸ Peripheral nerve abnormalities, inflammatory/autoimmune muscle disorders, and neuromuscular junction issues should all be managed according to the current guidelines. Immunoglobulin therapy and plasmapheresis are advised. It is recommended to postpone the use of rituximab or long-term oral immunosuppressive medicine in accordance with the patient’s clinical status and medical background. ^97,98

About 0.4% of COVID-19 patients experience Guillain-Barré syndrome (GBS), which usually appears five to ten days after the viral infection.¹²⁹ It implies that GBS is a parainfectious condition based on the appearance of the initial COVID-19 manifestations.¹³⁰ It has been observed in specific studies that the symptoms are more intense and might manifest prematurely than those reported in conventional GBS. ¹³¹ In one study, mechanical ventilation was necessary for three out of five patients.¹³¹ In a span of one month, three hospitals in Italy’s northern region admitted almost 1200 individuals with COVID-19, but only five cases of GBS were found.¹²⁹ Within one to four days, the majority of COVID-19 and GBS patients manifest progressive limb weakness.¹³² For GBS management in COVID-19, lacks particular recommendations. Patients should receive the same treatment as other individuals with GBS.⁹⁷

Therapeutic Options for the Treatment of COVID-19

Since the pandemic outbreak, COVID-19 treatment has shifted rapidly, and it currently consists mainly of antiviral and immunomodulatory medications. Remdesivir and nirmatrelvir-ritonavir are two varieties of antivirals that have been reported to be most effective when used early in an illness (like outpatient treatment) and in cases of less acute illness. Janus kinase inhibitors Interleukin-6, and Dexamethasone, are examples of immunomodulatory therapies that work best when used in cases of extreme illness or critical condition. Due to the appearance of viral variations that are not expected to respond to these treatments, the significance of anti-SARS-CoV-2 monoclonal antibodies has decreased, and opinions regarding the use of convalescent plasma are still divided. The following sections cover the wide spectrum of available treatments, categorized by the classification of agent: antiviral medications, immunomodulators, neutralizing antibodies and convalescent plasma, and antithrombotic treatment. Patients undergoing various treatments have been explored with varying degrees of disease severity: mild to adequate COVID-19 in non-hospitalized patients; serious COVID-19 in hospitalized patients who need additional oxygen; and severe conditions in patients who need non-invasive or mechanical ventilation.¹⁹ The discussion mostly centres on randomized trials, which have contributed significantly to the current treatment paradigms. Every therapeutic section ends with a reference to the National Institutes of Health (NIH) COVID-19 Treatment Guidelines, which offer insight into the recommended usage of each therapy (Table 3).^19,133

Primary Antiviral Agents utilized in the Management of COVID-19

Individuals with mild COVID-19 disease typically exhibit indications including myalgia, a high temperature, cough, and sore throat; on the other hand, patients with moderate disease show signs of lower respiratory tract involvement on radiographic or clinical examinations while still maintaining an oxygen saturation level of at least 94%. ^134,135 The majority of these individuals can be safely treated in outpatient settings, such as emergency rooms, clinics, and telemedicine consultations.^136,137 One of the first medications to show efficacy in a randomized controlled trial (RCT) during the early phases of the global outbreak was Remdesivir, a drug that inhibits viral RNA-dependent RNA polymerase. ¹⁹ The effectiveness of two oral anti-SARS-CoV-2 antiviral medications, molnupiravir and nirmatrelvir-ritonavir, provided to outpatients was assessed in two seminal phase 3 randomised trials, the EPIC-HR and MOVe-OUT trials. Molnupiravir and nirmatrelvir-ritonavir decreased hospitalization or mortality by 30 and 89%, respectively, when administered to unvaccinated people with COVID-19 disease (mild to adequate) within five days of apparition of symptoms and who were at risk of disease development.^138,139 Hospitalization for symptomatic COVID-19 disease or non-COVID-related reasons may also be necessary for patients with mild-to- adequate illness. Compared to patients treated as outpatients, these patients had a higher chance of developing a severe clinical manifestation and a faster rate of disease development. ¹³⁵ The clinical efficacy of molnupiravir and nirmatrelvir-ritonavir in patients hospitalized having mild-to-moderate COVID-19 disease was evaluate in three real-world studies conducted in Hong Kong and Japan. The majority of the patients involved in the research were older than sixty years, and their recommended immunization rates ranged from 10 to 80%.^140–142 In comparison to controls that were matched, molnupiravir and nirmatrelvir-ritonavir were consistently linked to a 40–55% decreased risk of clinical deterioration. Additionally, it was found that nirmatrelvir-ritonavir and molnupiravir were linked to 66–90% and 52–69% decreased risk of death, respectively.^140–142 An overview of the primary antiviral medications used to treat COVID-19 is discussed in (Table 3).

Primary Immunomodulatory Agents utilized in the Management of COVID-19

Severe and serious COVID-19 disease is treated with immunomodulatory substances, which include Janus kinase inhibitors (like baricitinib), interleukin-6 inhibitors (like tocilizumab), and corticosteroids.^135,143 Corticosteroids were the first medications to improve survival in the treatment of COVID-19.¹⁴⁴ It is advised to add interleukin-6 or Janus kinase inhibitors to corticosteroids in individuals whose condition progresses quickly and they show signs of systemic inflammation, such as increasing C-reaction protein. In summary, current research supports the application of remdesivir for the whole range of pulmonary assistance in hospitalized patients with serious and potentially fatal illnesses. Patients using low-flow supplemental oxygen should have their use of oral antivirals carefully assessed. In their clinical care, corticosteroids and other immunomodulatory therapies are indispensable.¹³⁵ The primary immunomodulatory medications used to treat COVID-19 are summarized in (Table 3).

Neutralizing Antibodies and Convalescent Plasma Therapy

During the early stages of the global outbreak, antibody therapy proved to be a powerful treatment and prevention strategy for COVID-19. Convalescent plasma (CP) from recovered COVID-19 sufferers and monoclonal antibodies (mAbs) that aimed the S1 region of the SARS-CoV-2 spike protein were the two types of antibody products used. Pre-exposure prophylactic for immunocompromised individuals with the anti-SARS-CoV-2 monoclonal antibodies tixagevimab and cilgavimab (Evusheld^TM) was authorized by the FDA. Many anti-SARS-CoV-2 treatments with monoclonal antibodies were approved, encompassing bamlanivimab plus etesevimab, bebtelovimab, sotrovimab, and casirivimab plus imdevimab. As the prevalence of various variants of concern (VOCs) increased, the pseudo-viral and in vitro viral neutralization activities of the monoclonal antibodies were utilized to forecast medical efficacy. In 2020, VOCs dominated the strains; however, numerous mAbs continued to have a neutralizing effect against B.1.1.7 (Alpha).¹⁹ But only bebtelovimab and sotrovimab retained relevance after Omicron (B.1.1.529) was fixed at the end of 2021, and not any of the approved mAbs sustained cross-neutralizing activity after Omicron subvariants continued to evolve in 2022.¹⁴⁵ Consequently, the anti-SARS-CoV-2 monoclonal antibodies (mAbs) are not anymore used for pre-exposure prophylaxis, prophylaxis, or for the COVID-19 treatment.^19,133

Antithrombotic Therapy

In the initial pandemic phase, hospitalized COVID-19 suffers experienced a higher prevalence of venous thromboembolism (VTE) episodes, which were most likely attributed to thromboinflammation. ¹⁴⁶ It is difficult to establish the precise rate when compared to historical controls, although it has been estimated to be as high as three times the adult hospitalization baseline rate.¹⁴⁷ The effectiveness of empiric anticoagulation and VTE prophylaxis has been assessed in numerous trials in addressing the elevated load of VTE (venous thromboembolism). The OVID and ETHIC randomized controlled trials (RCTs) examined individuals who were not hospitalized and contrasted enoxaparin or the conventional treatment. None of the two trials demonstrated effectiveness in lowering hospitalization or mortality, and both terminated prematurely.^148,149 Unless there is a contraindication, prophylactic-dose heparin is advised for anticoagulation in hospitalized patients. Relying on the outcomes of randomized controlled trials assessing the application of anticoagulant therapy in non-critically condition and severely diseased hospitalized patients, the NIH (National Institutes of Health) COVID-19 Treatment Guidelines suggested therapeutic-dose heparin for adults who need traditional oxygen but not critical care, but only in cases where the D-dimer concentration is raised and there aren’t any circumstances which boost the likelihood of blood loss.. Moreover, prophylactic-dose heparin should be administered to individuals needing intensive care or high-flow oxygen rather than therapeutic-dose heparin (except when there are restrictions, such as confirmed thromboembolic disease).^{19,133,150,151}

Table 3: An Overview of the Primary Antiviral Medications and Immunomodulatory Therapy Used to Treat COVID-19.

Vaccines Available for the Prevention of COVID-19

The development of treatment options and preventative vaccinations against SARS-CoV-2 has garnered international attention since the pandemic’s onset and the disease’s effects. Prophylactic vaccinations were intended to produce protective immunity in opposition to SARS-CoV-2, whereas the treatment goals were whereas the treatment goals were centred around measures that might reduce hospitalization time and improve the survival rate of infected patients. The development of effective preventive vaccinations in opposition to SARS-CoV-2 was crucial because of the urgent global outbreak situation and its related repercussions, including limited hospital capacity and ventilators.^166–168 The process of developing vaccines is lengthy and intricate, and it might take years or even decades to generate a vaccine that proves effective. On the other hand, the COVID-19 vaccine development effort took a year and was an international triumph. ^169,170 Developing a COVID-19 vaccine within the allotted 12-to 24-month timeframe posed an immense challenge for the researchers.^170,171 A number of factors contributed to the immediate development of the COVID-19 vaccine, including the timely release of the viral genome sequence, technological advancements and innovation, active participation from the international scientific community, a strong regulatory framework, sufficient government funding, and high market demand. Researchers from all around the world reported outstanding progress in the development of vaccines by the beginning of December 2020. On December 2, 2020, a vaccine developed by Pfizer in partnership with BioNTech, a German biotech company became the first completely tested vaccine to be authorized for use in an emergency. ¹⁷⁰ Global vaccination campaigns have primarily employed five types of COVID-19 vaccines: protein subunit, replicating and non-replicating viral vector, nucleic acid (DNA and RNA), inactivated complete virus, and virus-like particles (VLPs) vaccines. In (Table 4), the most recent COVID-19 vaccines updates are presented with adverse effects as well as their efficacy and coverage versus various SARS-Cov-2 variants.^166,167,170

Table 4: The Comprehensive List of Vaccines for COVID-19 are presented with their Adverse Effects, Effectiveness, and Efficacy against several SARS-Cov-2 variants. Click here to view Figure

Conclusion

Five years have passed since Wuhan, China, reported the initial COVID-19 occurrences. Worldwide, more than 775 million people have been infected with SARS-CoV-2, while more than 7 million of those cases have led to COVID-19 infection-related deaths. Every aspect of the socioeconomic framework has been significantly impacted by the COVID-19 outbreak, but it has especially highlighted inadequacies in the healthcare system. It demonstrated the futile struggle the world was in against the biggest threat of the twenty-first century. Infection with COVID-19 has been associated with complications in several organs, including cardiovascular, respiratory, the renal system, and gastrointestinal tract, haematological, cognitive, and dermatological issues. The comorbidities have a strong relationship with the mortality rate of COVID-19 patients. Acute instances and higher death rates are linked to COVID-19 individuals, and they are more common in people over 70 who also have underlying comorbidities. Individuals with cardiovascular illnesses had a threefold greater risk of developing an acute illness or requiring an intensive care unit (ICU) admission, compared to patients with hypertension or diabetes mellitus. Additionally, SARS-CoV-2 is recognized to have exceptional neurotropic potential. Numerous neurotoxins that cause neurological symptoms are released during the cytokine storm, which affects both the lungs and the central nervous system. In an effort to control COVID-19-related death rates and pathologies during these difficult years, a number of treatment alternatives and preventative measures, such as the COVID-19 vaccine, were considered. Since the pandemic began, there has been a tremendous evolution in the field of scientific study on COVID-19 disease treatment. Even those who have received the SARS-CoV-2 vaccination are susceptible of contracting a mild-to-moderate illness; nevertheless, effective antiviral therapy is currently available for early administration. The frequent emergence of variations resistant to existing products limits the usage of monoclonal antibodies. The management of severe and critical diseases requires the combination of immunomodulatory therapy and antiviral therapy. It is anticipated that future developments may benefit difficult-to-treat populations that are immunocompromised or have coexisting comorbidity conditions that limit the use of currently available choices. These patients may need individualized care in terms of the selection, combination, and duration of antiviral medications.

Acknowledgement

I gratefully acknowledge Servier Medical Art (https://smart.servier.com/) for providing free access to their high-quality professional images [licensed under CC BY 4.0 (https://creativecommons.org/ licenses/by/ 4.0/)], which greatly contributed to the visual clarity and quality of this publication. Servier Medical Art’s generous support is instrumental in enhancing the advancement of scientific communication. 

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The authors do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Clinical Trial Registration

This research does not involve any clinical trials.

Permission to reproduce material from other sources

Not Applicable

Author Contributions

The sole author was responsible for the conceptualization, methodology, data collection, analysis, writing, and final approval of the manuscript.

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