A Review on Prophylactic Regimen by Evaluation of Asymptomatic SARS CoV-II Carriers

Ashwini P. Dhruv*, Nilesh K. Patel, Ashok B. Patel, Amit Kumar J. Vyas, Ajay I. Patel

Pharmaceutical Quality Assurance Department, B.K. Mody Government Pharmacy College,

Rajkot, Gujarat, India.

*Corresponding Author E-mail: a.dhruv9.ad@gmail.com

ABSTRACT:

The coronavirus disease 19(COVID-19) is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-II), which emerged in Wuhan, China and spread around the world. It is considered a relative of Severe Acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), The cause of COVID-19 is a beta coronavirus named SARS-CoV-2 that affects the lower respiratory tract and manifests as pneumonia in humans. The Asymptomatic carriers have become the current focus of global epidemic prevention and control efforts. These carriers of the virus display no clinical symptoms but are known to be contagious. As "silent spreaders", asymptomatic carriers warrant attention as a part of disease prevention and control. The comparable viral load in a group of asymptomatic carriers of COVID-19 was found to be higher than that of the symptomatic carriers. There are numerous micronutrients which are essential for immunocompetence, particularly Vitamin A, C, D, E, B, iron, selenium, and zinc. Immunonutrition refers to the modulation of the immune system through the modification of dietary nutrients. Vitamins A to E highlighted potentially beneficial roles in the fight against COVID-19 via antioxidant effects, immunomodulation, enhancing natural barriers, and local paracrine signaling. The present review provides a brief information on supplementation of Immunonutrients in form of vitamins which ultimately can act as prophylactic regimen for Asymptomatic carriers of SARS CoV-II virus.

KEYWORDS: Asymptomatic carriers, SARS CoV-II, Covid-19, Immunonutrients, Vitamins.

1. INTRODUCTION:

1.1 Introduction to SARS CoV-II virus:

Coronavirus is one of the major pathogens that primarily targets the human respiratory system. The previous outbreaks of coronaviruses include the Severe Acute Respiratory Syndrome¹ and the Middle East Respiratory Syndrome² which have been characterized as agents that are a great public health threat. The COVID-19 epidemic has crossed across the globe in span of months and the World Health Organisation has declared it “Pandemic”³

SARS-CoV-2 is one of seven types of corona virus, including the ones that cause severe diseases like Middle East respiratory syndrome (MERS) and Severe acute respiratory syndrome (SARS). The other corona viruses cause most of the colds that affect us during the year but aren’t a serious threat for otherwise healthy people.⁴

The early transmission studies reported a link between the local fish and wild animal market in China with most of the early infections, indicating the possibility of transmission of virus from animals to humans.⁵ Later, the virus spread new infections which were mainly through human-to-human transmission. Corona viruses constitute the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales, and realm Riboviria.⁶

It has been determined that MERS-CoV was transmitted from dromedary camels to humans and SARS-CoV from civet cats to human. The source of the SARS-CoV-2 (COVID-19) is yet to be determined, but investigations are ongoing to identify the zoonotic source to the outbreak.⁷ SARS-related coronavirus is a single-stranded, enveloped RNA virus with positive senses. The genome of the RNA virus is roughly 30 kb.⁸

In consideration of urgency and to give an identity to current unique symptomatic disease, the World Health Organization (WHO) announced a new name for the epidemic disease: Corona Virus Disease 2019 (COVID-19) on 11 February 2020.

Reproductive number or spread ability factor is a mathematical number that indicates how contagious an infectious disease is. R₀ is dependent on the exponential growth rate of an outbreak, as well as additional factors such as the latent period (the time from infection to infectiousness) and the infectious period.⁹

Subsequently, systemic nomenclature was chosen based on an analysis of the new coronavirus’s evolutionary history and the pathogen that causes severe acute respiratory syndrome (SARS) and thus, new virus has been given the name as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-II) by the International Committee on Taxonomy of Viruses on 11 February 2020.

Fig. 1: Structure of Coronavirus particle, enveloped with non-segmented, positive‐sense single‐stranded RNA virus genomes (26 to 32 kb).¹⁰

1.2 Symptoms of Sars CoV-II Virus:

The symptoms of COVID-19 are mainly for respiratory disorders and similar to severe acute respiratory symptoms. The common signs of infection observed in COVID-19 patients include respiratory symptoms, sneezing, fever, cough, shortness of breath and other breathing difficulties. In case of severely infected patients, infection can cause pneumonia, severe acute respiratory syndrome (SARS), kidney failure and even death in many cases. There are many people who had high viral load but do not develop COVID-19 symptoms like coughing or snizzing.¹¹ Such asymptomatic people serve hidden carriers of virus and may further contribute in enhanced transmission of virus to other peoples.¹²

The most of the patients had a common symptom of fever and cough. Many of the patients often presented without fever, however, developed it in due course of infection. Majority of patients developed fever (43.8% on admission and 88.7% during hospitalization) and nearly two-third of patients had cough (67.8%) as common symptoms. The blood test showed Lymphocytopenia (abnormally low level of lymphocytes in the blood) in majority of the patients (83.2% of the patients) on admission to the hospitals. Diarrhoea was not common in most of the cases as only 3.8% of patients had diarrhoea. The patients developed full symptoms of the COVID-19 in 2 to 7 days20 i.e., the median incubation period of infection development was 4 days with interquartile range of 2 to 7 days in all patients.¹³

1.3 Pathogenesis:

The percentage of death among the reported 2684 cases of COVID-19 was approximately 2.84% as of January 25, 2020 and the median age of the deaths was 75 (range 48–89) years. Patients infected with COVID-19 showed higher leukocyte numbers, abnormal respiratory findings, and increased levels of plasma pro-inflammatory cytokines.⁹ It has been reported in 1 of the patients of COVID-19 with 5 days of fever presented with a cough, coarse breathing sounds of both lungs, and a body temperature of 39.0°C.¹⁴

The laboratory studies showed leukopenia with leukocyte counts of 2.91 × 10^9 cells/L of which 70.0% were neutrophils. Additionally, a value of 16.16 mg/L of blood C-reactive protein was noted which is above the normal range (0–10mg/L). High erythrocyte sedimentation rate and D-dimer were also observed.¹⁵

The main pathogenesis of COVID-19 infection as a respiratory system targeting virus was severe pneumonia, RNA anaemia, combined with the incidence of ground-glass opacities, and acute cardiac injury.

Significantly high blood levels of cytokines and chemokines were noted in patients with COVID-19 infection that included IL1-β, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFNγ, IP10, MCP1, MIP1α, MIP1β, PDGFB, TNFα, and VEGFA.¹⁶

Fig. 2: Current understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced host immune response. SARS-CoV-2 targets cells through the viral structural spike (S) protein that binds to the angiotensin converting enzyme 2 (ACE2) receptor. In the early stage, viral copy numbers can be high in the lower respiratory tract. Inflammatory signaling molecules are released by infected cells and alveolar macrophages in addition to recruited T lymphocytes, monocytes, and neutrophils. In the late stage, pulmonary edema can fill the alveolar spaces with hyaline membrane formation, compatible

with early-phase acute respiratory distress syndrome.¹⁷

1.4 Diagnosis:

Diagnosis of COVID-19 is typically made using polymerase chain reaction testing via nasal swab (Box 2). However, because of false negative test result rates of SARS-CoV-2 PCR testing of nasal swabs, clinical, laboratory, and imaging findings may also be used to make a presumptive diagnosis.

Fig. 3: Collection of Specimens/samples and diagnostics methods for COVID-19: Depiction of various diagnostic methods for COVID-19 infection. CT scans can be utilized to find lung abnormalities in patients with infection, this can be a serious tool to determine severity and track progress.¹⁸

2 Asymptomatic Carriers of Sars CoV-II Virus:

Asymptomatic carriers of the virus display no clinical symptoms but are known to be contagious. Recent evidence reveals that this sub-population, as well as persons with mild and undocumented disease, represent a major contributor in the propagation of this disease.¹⁹ In a report to CNN, the director of the Center for Infectious Disease Research and Policy at the University of aMinnesota confirms that asymptomatic transmission surely can fuel the COVID-19 pandemic and make it very difficult to control.^20,21

The asymptomatic carriers may have been rapidly spreading the virus within, and to, many different countries.

As "silent spreaders", asymptomatic carriers warrant attention as part of disease prevention and control; more efforts should be made to monitor, track, quarantine, and treat asymptomatic carriers.

The comparable viral load in a group of asymptomatic carriers of COVID-19 was higher than that of the symptomatic carriers and increasing level of white blood cell count (12.4×109/L), neutrophil count (7.82×109/L), C-reactive protein level (189.2mg/L), low lymphocyte count (0.84×109/L) and platelet count (88×109/L) was found different than the normal range in asymptomatic patients.²²

2.1 Clinical Evaluation of Asymptomatic Carriers:

Many asymptomatic persons were actually a source of SARS-CoV-2 infection but were considered healthy before they underwent screening. Age was significantly associated with asymptomatic occurrence.

Asymptomatic cases occurred seldom among young people (18–29 years old). A previous study found that people (<15 years old) were prone to be asymptomatic.  It was found that asymptomatic cases of infection occurred seldom in young people (18–29 years old).²³

Nucleic acid testing would therefore be crucial to screen for asymptomatic infections in this population. A previous study indicated that CRP and LDH levels may be predictors of disease severity. CRP levels, LDH levels, and white blood cell counts were elevated occurred in 10, 13 and 1 patient, respectively.²⁴

According to the study, asymptomatic infection was seldom seen in young people; the proportion with severe COVID-19 was low, and the proportion with ordinary COVID-19 was high.

2.3 Evaluation of Asymptomatic and Symptomatic Carriers:

Table-1: Description of general characteristics responsible for evaluation of asymptomatic carriers of Covid-19.

General characteristics	Asymptomatic Carriers	Symptomatic Carriers	Normal range
White blood cell count (× 10⁹ cells per L)	5.65	9.43	4.00–10.00
Neutrophil count (× 10⁹ cells per L)	3.62	8.21	1.80–6.30
Lymphocyte count (× 10⁹ cells per L)	1.55	0.69	1.10–3.20
C-reactive protein (mg/L)	0.69	202.03	0.0–5.0

3 Prophylactic Regimens for Prevention from Sars Cov-II Virus:

This review aims to interrogate the current evidence base, and present the potential immune-mediating, antioxidant, and antimicrobial roles of vitamins A to E in the context of respiratory disease, and to extrapolate this evidence to evaluate the potential roles in the fight against COVID-19.

Diet and nutrition invariably influence the immune system competence and determine the risk and severity of infections. The macro-, micronutrients, and phytonutrients in diet, mainly the fruits and colorful vegetables, generally promote healthy immune responses.

A vitamin is an organic compound required as a vital nutrient in tiny amounts by an organism. In other words, an organic chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet.²⁵

3.1 Immunonutrients:

Immunonutrition refers to the modulation of the immune system through the modification of dietary nutrients. Due to the proinflammatory state in ARDS it has been postulated for many years that increasing the level of antioxidant nutrients within the body will have a beneficial effect.²⁶

Furthermore, improving function of lymphocyte, macrophage, and neutrophil through the addition of nutrients, such as glutamine, has also been described as being beneficial.

The importance of Immunonutrition during the current SARS-CoV-2 pandemic has been found to be beneficial as early nutritional supplementation of those with the disease.

The immune system defends against bacterial infection through frequently interacting innate and adaptive mechanisms and estimates the amino acid sequence space of potential antibodies for identifying attacking pathogens. The adaptive immune system and two components of the innate immune system form the pervasive immune system. The innate system includes extrinsic defenses like serum proteins, nonspecific phagocytic leukocytes, mucous membranes and the skin.²⁷

Phytochemicals in the diet can exert on different targets that can relieve multiple pathological processes, including oxidative damage, epigenetic alterations, chronic inflammation, active stimulators.²⁸

Clinical studies in patients with ADRS have reported that their baseline plasma levels of beta carotene, retinol, alpha tocopherol and total radical antioxidant potential were all lower than normal. This could be normalized after four days of feeding with eicosapentaenoic acid, gamma linolenic acid and antioxidants compared to a control group not receiving supplementation. In many trials of dietary supplementation, the ‘Immunonutrition diet’ is heterogenous, consisting of several vitamins, minerals, and fatty acids administered together, making it difficult to ascertain the potential value of each vitamin as discussed

3.1.1 Vitamin A:

3.1.1.1 Source and physiological role:

Vitamin A is, by structural definition, all-trans-retinol, a retinol in which all four exocyclic double bonds have a trans geometry. Retinoids, compromises both natural and synthetic chemical species that have similar structural appearances with or without biological component/activity, the biological species being those we colloquially refer to as vitamin A.²⁹ The food sources for Vitamin A are Parsley, sweet potatoes, watermelon, nettle leaf, broccoli, carrots, dark leafy greens, eggs, and mangos.³⁰

The carotenoids, generally in the form of alpha/beta/gamma carotene, are more likely to found in fruit and vegetables; β-carotene specifically contributes to the orange color of food and is typically associated with carrots and sweet potatoes.³¹ The liver plays a key role: Retinol is esterified to retinyl esters and stored in the stellate cells.³²

Fig. 4: Chemical structure of vitamin A, retinol³³

3.1.1.2 Mechanism of Action in Disease:

Vitamin A supplementation improved pulmonary function test results in patients with chronic obstructive pulmonary disease (COPD).³⁴

Pediatric asthma studies revealed that Vitamin A deficiency increased serum vitamin A induced good pulmonary function as retinoic acid can reverse airway hyper-responsiveness, in turn conferring protection from asthma by down regulation of oxidative stress.^35,36

3.1.1.3 Relevance in COVID-19:

The pulmonary, immunomodulatory, and antimicrobial roles of vitamin A may enact a crucial element in the fight against viral diseases, including COVID-19. In light of its pulmonary and immunological roles, oral supplementation of vitamin A is currently being investigated in the treatment of COVID-19 alongside a host of other antioxidants.

3.1.2 Vitamins B:

3.1.2.1 Sources and Physiological Role:

B vitamins are a class of water-soluble vitamins (B1, B2, B3, B5, B6, B7, B9, and B12) that play important roles in cell metabolism. They are chemically distinct entities but may coexist in the same foods, including meat and plant-based sources. B12 is found predominantly in meat, such as turkey, tuna, and liver, whereas folate is largely present in plant products, such as legumes (pulses or beans), greens, nuts, whole grains, potatoes, bananas, chili peppers, tempeh, and yeast.

Table 3: Physiological role of B Vitamins

Sr. No	Vitamin B	Chemical Name	Physiological Role
1.	B1	Thiamine	Precursor of coenzyme in sugar and amino acid catabolism
2.	B2	Riboflavin	Precursor of coenzyme needed for flavoproteins enzyme reaction
3.	B3	Niacin	Precursor of coenzyme needed in many metabolic processes
4.	B5	Pantothenic acid	Precursor of coenzyme A
5.	B6	Pyridoxine, Pyridoxal, Pyridoxamine	Precursor of coenzyme in metabolic reactions
6.	B7	Biotin	Coenzyme for carboxylase enzymes needed for gluconeogenesis and fatty acid synthesis
7.	B9	Folate	Precursor needed for DNA synthesis and repair during rapid cell division
8.	B12	Cobolamine	Coenzyme in metabolic reactions affecting DNA, fatty acid and amino acid metabolism

3.1.2.2 Mechanism of action in disease:

Vitamins B6, B12, and folate complementary roles in both innate and adaptive immune responses and have been granted health claims in the European Union for contributing to the normal function of the immune system.^37,38 Deficiencies in these vitamins can impair immune and inhibits cytokine/chemokine release.

Vitamin B9 (folate) deficiency leads to megaloblastic anaemia, failure to thrive, and infections due to combined immunodeficiency with an impaired T-cell proliferation response, and an altered proinflammatory cytokine profile, which are reversed with folate therapy.³⁹

Vitamin B12 (cobalamin) deficiency is particularly common in the elderly due to reduced absorption.⁴⁰

3.1.2.3 Relevance to COVID-19:

The coronavirus polyprotein encodes two proteases, called 3-C-like protease (M-pro) and a papain-like protease (PL-pro), which were previous targets for drug discovery in the SARS and MERS coronavirus. that are predicted to bind tightly to M-pro in SARS-CoV-2 and identified that folate has the potential to form strong hydrogen bonds with active site residues and therefore be a possible therapeutic strategy.⁴¹ These computational screening tools may allow targeted drug testing to be undertaken using cell-based assays and clinical trials, with niacin (B3), folate (B9), and B12 being possible contenders. COVID-19 pandemic, where there is currently no targeted therapeutics and effective treatment options remain very limited.

3.1.3 Vitamin C:

3.1.3.1 Source and Physiological Role:

Vitamin C (Ascorbic acid), is an essential water-soluble nutrient, required as a cofactor for a number of enzymatic reactions required in norepinephrine biosynthesis, carnitine biosynthesis, tyrosine metabolism, and histone demethylation.⁴²

Fig. 5: Chemical structure of Vitamin C, ascorbic acid⁴³

3.1.3.2 Mechanism of action:

It is postulated to exert an antiviral effect through direct virucidal activity and augmenting interferon production whilst also having effector mechanisms in both arms of the innate and adaptive immune system.^44,45 The host response to viruses and bacteria includes the release of reactive oxygen species (ROS) from activated phagocytes.

The relationship between oxidative stress and the induction of genes integral to the systemic inflammatory response, including TNFα, IL-1, IL-8, and ICAM-1, has been shown to be mediated through activation of the nuclear transcription factor NF-κB.^46,47

3.1.3.3 Relevance to COVID-19:

Given the potential role of vitamin C in sepsis and ARDS, there is gathering interest of whether supplementation could be beneficial in COVD-19.^48,49 Despite what we know about the antioxidant properties, antiviral effect, and pleiotropic function of vitamin C, whether or not there are beneficial pathophysiological mechanisms involved in the response to COVID-19 remain to be elucidated.⁵⁰

3.1.4 Vitamin D:

3.1.4.1 Source and Physiological Role:

Vitamin D encompasses a number of fat-soluble secosteroids with a physiological role in mineral homeostasis, primarily calcium, magnesium, and phosphate. Vitamin D in its natural form, cholecalciferol, is acquired through dietary sources, such as oily fish and egg yolks, but is also produced through de novo synthesis.Cholecalciferol is thereafter hydroxylated into its biologically active form 25-hydroxyvitamin D (calcifediol) and 1,25-dihydroxyvitamin D (calcitriol).⁵¹

Fig. 6: Chemical structure of Vitamin D3, cholecalciferol⁵²

3.1.4.2 Mechanism of Action in Disease:

Beyond its role in mineral homeostasis, it has also emerged as an immune system regulator. Supplementation with vitamin D has also been reported previously as reducing the risk of acute upper respiratory tract infections, which has led to speculation that there may be a role for vitamin D in the response to COVID-19.⁵³

3.1.4.3 Relevance to COVID-19:

Binding of the viral S1 spike protein to ACE2 causes both the virus and the enzyme to be translocated into the cell through endocytosis, thereby effectively reducing the surface expression of ACE2 and possibly contributing to the progression of pulmonary disease.

3.1.5 Vitamin E:

3.1.5.1 Source and Physiological Role:

Vitamin E is fat-soluble compound, which consists of eight isoforms, four tocopherols (a-, b-, g-, and d-tocopherols), and four tocotrienols (a-, b-, g-, and d-tocotrienols), and it is a lipid component of biological membranes. The main source in human diet varies depending on the isoform, with a-tocopherol found predominantly in sources, such as nuts like almonds and hazelnuts; legumes, such as peanuts; as well as avocados and sunflower seeds.

Fig. 7: Chemical structure of Vitamin E, (20R, 40R, 80R)-tocopherol.⁵⁴

3.1.5.2 Mechanism of Action in Disease:

Vitamin E is considered a potent antioxidant capable of neutralizing free radicals and ROS by donating a hydrogen ion from its chromanol ring. Free radicals generated from metabolic processes react with polyunsaturated fats within the cell membrane, causing peroxidative decomposition.⁵⁵ Vitamin E deficiency results in greater levels of lipid peroxidation in both in vivo and in vitro models and this is supported clinically by an inverse relationship between plasma lipoperoxidase and vitamin E in ARDS.

Vitamin E enhances T lymphocyte-mediated immune function in response to mitogens and IL-2 but also neutrophil and natural killer function, the decline of which is seen with increasing age.⁵⁶ 

3.1.5.3 Relevance to COVID-19:

Oxidative stress is one of the driving pathological mechanisms that underpins the biology of ARDS as a result of COVID-19. The oxidant-antioxidant balance is severely shifted, resulting in excessive lipid peroxidation and failure of biological membranes. Vitamin E ingestion is known to lower the production of superoxide’s and perhaps tilt the balance back in favour of antioxidants.

4. CONCLUSION:

The number of people with COVID-19 continues to increase. Asymptomatic infections being “silent spreaders” are hidden and easily overlooked. However, their potential to spread the virus cannot be underestimated, as the viral load they carried and their ability to infect close contacts may be like those of symptomatic individuals. In addition, asymptomatic infections can occur in any age and gender, Overall, it is objectively summarized over here regarding the current transmission and clinical characteristics of asymptomatic patients with SARS CoV-2 virus. All asymptomatic patients would be or might be exposed to one or more of the following pathways or protocols: self-isolation, clinical isolation, quarantine, and ambulatory care services. The value of maintaining a diet containing a balance of vitamins seems prudent and applicable to the general population during these unprecedented times Finally, the current review emphasises on control of transmission of SARS CoV-II carriers with the help of prophylactic regimen in form of Immunonutrients.

5. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

6. ACKNOWLEDGMENTS:

There are no acknowledgements.

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Received on 08.06.2021         Modified on 11.01.2022

Accepted on 03.05.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2022; 12(3):217-224.

DOI: 10.52711/2231-5691.2022.00036