key: cord-0756765-9igk3ke1
authors: Gasmi, Amin; Noor, Sadaf; Tippairote, Torsak; Dadar, Maryam; Menzel, Alain; Bjørklund, Geir
title: Individual risk management strategy and potential therapeutic options for the COVID-19 pandemic
date: 2020-04-07
journal: Clin Immunol
DOI: 10.1016/j.clim.2020.108409
sha: 1aa7102887a834cf5b833d122ca2eb015b7aeb91
doc_id: 756765
cord_uid: 9igk3ke1

It is an ugly fact that a significant amount of the world's population will contract SARS-CoV infection with the current spreading. While specific treatment is not yet coming soon, individual risk assessment and management strategies are crucial. The individual preventive and protective measures drive the personal risk of getting the disease. Among the virus-contracted hosts, their different metabolic status, as determined by their diet, nutrition, age, sex, medical conditions, lifestyle, and environmental factors, govern the personal fate toward different clinical severity of COVID-19, from asymptomatic, mild, moderate, to death. The careful individual assessment for the possible dietary, nutritional, medical, lifestyle, and environmental risks, together with the proper relevant risk management strategies, is the sensible way to deal with the pandemic of SARS-CoV-II.

In December 2019, several unidentified pneumonia cases occurred in Wuhan, China. On 30 January 2020, this led the World Health Organization (WHO) to declare a public health emergency of international concern. On 12 March 2020, the WHO declared the outbreak of the 2019 novel coronavirus, a global pandemic [1] [2] [3] . The WHO suggested the official name for the disease from this virus as the coronavirus disease 2019 . The Coronaviridae Study Group of the International Committee on Taxonomy of Viruses proposed the name of the virus as 'severe acute respiratory syndrome coronavirus 2 (SARS-CoV-II)', designated by its phylogeny and taxonomy [4] . Up to 4 April 2020, there are registered 1,117,942 confirmed cases and 59,201 deaths worldwide There are connections between age, diet, nutrients, and immunity in the elders [37] . The clinical or subclinical micronutrient deficiency is common in older adults, which contributes to several agerelated diseases and decreased immune functions [38, 39] . This prevalence is probably the consequence of the low appetite and the nature of little diversification of their dietary patterns in the elders. The nutritional assessment and proper management are, therefore, essential to determine the risk of infection, the illness course, and the outcome of COVID-19 in older adults [25] .

The diverse intestinal microbiota shapes the immune system and promotes the host well-being [40, 41] . The respiratory tract microbiota also influences the host immune responses to the virus [42] .

While the immune responses to viral infection determine the efficacy of a vaccine, the disrupted gut microbiota contribute to vaccine failures and other inflammatory conditions [43] . The acute respiratory viral infections disrupt the host-microbiota interactions and create the intestinal dysbiosis with the post-viral immune responses, that contribute to pneumonia development by the secondary bacterial infection [44] . The healthy, diverse intestinal and respiratory tract microbiota is then another critical determinant for the clinical courses of COVID-19 [42, 45] .

Interferons (IFNs) are the first line of immune defense against viral infection, particularly the type I IFNs and the type III IFNs, or IFN-λs [46] . Despite the preliminary understanding of their roles, IFNλs are probably the critical antiviral cytokines in the respiratory epithelial surfaces during the early stages of viral infection. While the type I IFN signaling during acute viral infection increase the proinflammatory responses, their signaling in the persistent infection modulates the counter-regulatory immune responses [47, 48] . Some gut microbiomes mediate the IFN responses to viral infection supplementation needs to start before the onset of respiratory tract infection. However, there is inconclusive evidence regarding the underlying mechanisms of vitamin D deficiency and viral disease development [66] . The potential mechanisms include the antiviral immune induction, the modulation of immunoregulatory defense, induction of autophagy and apoptosis, and genetic or epigenetic regulation [66] . Furthermore, the risk of viral infections can be reduced by vitamin D. The related mechanisms comprised of stimulation of defensins and cathelicidins that can decrease the replication of virus and increase levels of anti-inflammatory cytokines, as well as decreasing concentrations of pro-inflammatory cytokines that induce inflammation-related pneumonia [67] . Supportive data for the effective role of vitamin D in decreasing risk of COVID-19 could be highlighted by increased case-fatality rates with chronic disease comorbidity and age, in which lower concentrations of 25(OH)D have been reported. Vitamin D deficiency is globally prevalent, particularly in the elders [68] . Over half of the hospitalized elders and nursing home residents in the U.S. had vitamin D deficiency [69, 70] . This high prevalence probably contributes to the first outbreak COVID-19 during winter and the high mortality rate in older adults [71] [72] [73] [74] . While the natural source of vitamin D is from sunlight exposure, some dietary sources can provide a certain amount of vitamin D, including the fortified cereals and milk. However, for people at risk of COVID-19, the goal should be to raise the concentrations of 25(OH)D above 40-60 ng/ml (100-150 nmol/l) by considering taking expression, antibody production, and the enhanced functions of neutrophils, natural killer cells, monocytes or macrophages, T cells, and B cells [79, 80] .

Vitamin C deficiency is associated with pneumonia in several pieces of literature in the early days [81, 82] . The immune-modulating effects in respiratory infection of vitamin C are also welldocumented [83] [84] [85] [86] . Nevertheless, the supporting evidence of vitamin C supplementation in the prevention and treatment of acute respiratory diseases are inconclusive [87] [88] [89] [90] . In alignment with the evidence of other micronutrients, the supplementation could benefit the vitamin C deficient individual but not in the healthy subjects [87, 88] . Moreover, it has been reported that megadoses administration of Vitamin C before or after the appearance of flu symptoms could prevent and relieve the flu symptoms in the test population regarding the control group [83, 86, 91, 92] . Based on 31 study comparisons with 9745 common cold episodes, it has been revealed that the regular supplementation of Vitamin C had a modest but consistent effect in decreasing the duration of common cold symptoms [89, 90] . Furthermore, five trials with 598 participants showed that vitamin C decreased the risk of common cold without any adverse effects [93] . Vitamin C supplementation is thus the sensible option to prevent and support the immune responses in the micronutrient-deficit individual at risk for COVID-19.

As the integral part of several selenoproteins, including the glutathione peroxidases and thioredoxin reductases, selenium has a critical role in the defense against viral infection through its antioxidant, redox signaling, and redox homeostatic contributions [94] . Selenium deficiency is associated with increased pathogenicity of several virus infections [95] [96] [97] . In the deficient state, the selenium supplementation is helpful for the prevention and treatment of viral infections [97] [98] [99] [100] . Recently, it has been reported that a mild strain of influenza virus, also shows increased virulence in seleniumdeficient mice. Increased virulence is related to several modifications in the viral genome [95, 101] .

Furthermore, the immune response, such as proinflammatory chemokines, can be increased in J o u r n a l P r e -p r o o f Journal Pre-proof selenium-deficient mice. Moreover, the mRNA expression of macrophage inflammatory protein-1α and -1β, monocyte chemotactic protein-1, and RANTES (regulated upon activation, normal T cell expressed and secreted) were changed in selenium-deficient mice. The mRNA levels of cytokine were also modified in the selenium-deficient mice. IL-4, IL-5, IL-10, and IL-13 were increased, whereas γinterferon and Interleukin (IL)-2 were decreased, which suggests a modification toward a pattern of T-helper-2-like in the Se-deficient mice regarding the pattern of T-helper-1-like in the Se-adequate mice [95] . Therefore, selenium intake differentially affects numerous types of immune responses and related mechanisms, revealing an effective role of selenium-supplementation in viral diseases.

Zinc is an essential micronutrient with the crucial contributions to most enzymatic functions and the transcription regulations in the human body [30, 59] . Zinc is essential for normal function and development of cells regulating nonspecific immunity, including natural killer cells and neutrophils.

Zinc is the main structural component of around 750 zinc-finger transcription factors [102] . The deficiency of zinc also modifies the development of acquired immunity by limiting both the certain and outgrowth functions of T lymphocytes, including the production and activation of Th1 cytokine [103] . The function of macrophage also is adversely affected by the deficiency of zinc through the dysregulation of cytokine production, intracellular killing, and phagocytosis [103] . Zinc deficiency is surprisingly common in modern-day lifestyle [104] . Zinc deficiency impairs the antiviral immunity, particularly to herpes simplex, common cold, herpes simplex virus, hepatitis C, and the human immunodeficiency virus (HIV) [104, 105] . A meta-analysis of oral zinc supplementation studies suggested beneficial effects on the shortened of symptoms and duration of common cold infection [106] [107] [108] . Zinc supplementation was also helpful against hepatitis C virus infection through the induction of metallothionein expressions [109, 110] . Moreover, research has shown that zinc has antiviral effects; it improves immune responses and suppresses viral replication. Therefore, the consumption of up to 50 mg zinc per day may provide a protective role against the COVID-19 pandemic, likely by improving the host's resistance against viral infection [102] . However, these studies did not account for the underlying zinc status in the studied participants. 

There is yet no specific treatment for COVID-19. Therefore, physicians are trying to fight the coronavirus with existing treatments. Patients admitted to the hospitals are administered intravenous antibiotics (57.5% of cases), prescribe oseltamivir, an oral antiviral (35.8% of cases), and corticosteroids (18.6% of cases). This protocol is accompanied by oxygen therapy and non-invasive ventilation for the most severely affected patients [111] . Even with all those preventive and protective measures, there are still the chances of getting the SARS-CoV-II infection. Without the specific treatment for COVID-19, we here explore some potential therapeutic options of some prescribed medications and herbs.

The antiviral medications target several components of the SARS-CoV-II lifecycle. These molecular targets include the viral entry into the host cells, the viral RNA synthesis, and the viral replication [112] . There are high sequence similarities in the genomes of SARS-CoV-II, SARS-CoV, and MERS-CoV. It is possible for the shared effectiveness of the previously approved medications in these conditions for the treatment of COVID-19.

These viral entry blockages include chloroquine, hydroxychloroquine umifenovir, and interferon [112] . A cell line study reported that chloroquine significantly decreased the human coronavirus-229E replication at a lower concentration than the clinical dosage [113] . A systematic review suggested the rationale, pre-clinical supporting evidence of the effectiveness against SARS-CoV-II, and the clinical J o u r n a l P r e -p r o o f Journal Pre-proof safety profiles, that justify future clinical research of chloroquine and hydroxychloroquine in patients with COVID-19 [114] .

There are currently several clinical trials of chloroquine for COVID-19, either as monotherapy or in combination with other medications such as azithromycin [112] . A non-randomized clinical trial reported the reduction of the viral load from the hydroxychloroquine-azithromycin combination in twenty COVID-19 patients but failed to report the critical clinical outcomes, including death [115] .

Chloroquine and hydroxychloroquine are the immunomodulatory drugs with potential antiviral effects. However, there are some long-known clinical side-effects and interactions with other medications. It is still premature to conclude the role of chloroquine and hydroxychloroquine in COVID-19, while several clinical trials are on their ways [116] .

SARS-CoV -II enters the target cells through the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease, serine 2 (TMPRSS2). The TMPRSS2 inhibitors block the cellular entry of the SARS-CoV-II virus through the downregulated priming of the SARS-CoV-II spike protein [117, 118] . There is a known TMPRRSS2 inhibitor in the market, i.e., camostat mesylate. The machine learning algorithms on this entry pathway revealed some other mechanistic possibilities, including the Janus-associated kinase inhibitors through baricitinib, ruiolitinib, and imatinib [119, 120] . Some of these drugs are currently on the clinical trials for COVID-19.

The medications that inhibit viral RNA synthesis include remdesivir, favipiravir, and ribavirin.

Remdesivir is a novel nucleotide analog with the broad-spectrum antiviral activities against the single- [125, 126] . While the proofreading exoribonuclease hampers the effects of most nucleotide-base antiviral treatment, remdesivir inhibits coronavirus with the intact proofreading, thus renders its superior antiviral efficacy [127] . The experimental treatment of intravenous remdesivir in the first COVID-19 patient in the U.S.

showed an impressive response [128] . There is a current randomized, placebo-controlled, doubleblind, multicenter, phase III clinical trial to determine the efficacy and safety of remdesivir in COVID-19 [129] .

Favilavir is a guanine analog with the broad-spectrum antiviral activities through its selective inhibition of viral RNA-dependent RNA polymerase [130] . Favilavir has efficacy against various RNA viruses, including influenza, ebola, yellow fever, chikungunya, norovirus, and enterovirus [131, 132] . A recent cell line study suggested its efficacy against the SARS-CoV-II [133] . While it got the approval for novel influenza treatment, favipiravir is currently on the clinical trials for COVID-19 treatment by the National Infectious Diseases Scientific Science Research Center and the Shenzhen Third People's Hospital [134] . The preliminary results in eighty patients reported the superior efficacy of favipiravir than the lopinavir/ritonavir combination without the significant adverse reactions [135, 136] .

The medications that block the virus replication include lopinavir-ritonavir combination and darunavir-cobicistat combination. The lopinavir-ritonavir combination is a fixed-dose medication for the prevention and treatment of HIV infection [137] . The cytochrome P450 inhibitory effects of ritonavir prolonged the half-life of Lopinavir and extended its protease inhibitory action on the HIV replications. The in-vitro studies suggested that the lopinavir/ritonavir combination can inhibit coronavirus replication.

J o u r n a l P r e -p r o o f 151]. The Chinese herb, cinanserin, is a serotonin receptors antagonist that may inhibit the 3CL pro and inhibit the SARS-CoV replication [152, 153] . Some polyphenol compounds also exhibit the 3CL pro inhibitory effect, such as the antioxidant flavonoids. The in-vitro studies demonstrated that various flavonoids suppress the hepatitis C virus, MERS-CoV, and SARS-CoV, through their 3CL pro inhibitory effects. These flavonoids include herbacetine, isobavachalcone, quercetin, and helichrysetin, rhoifolin, and pectolinarin, [154] [155] [156] . With the upregulated expression of 3CL pro during COVID-19, the 3CL pro inhibitory herbs can be the sensible options in the COVID-19management [157] .

The human convalescent plasma from the recovered patients can be another option for COVID-19 management [158, 159] . The passive immunoglobulin-containing plasma can provide immediate immunity to the susceptible individual. There is a long history of this passive antibody treatment in various infective diseases beyond the era of antimicrobial development [160, 161] . A meta-analysis suggested the beneficial role of early administration of convalescent plasma on the mortality reduction during influenza epidermic in 1918 [159] . There is no report of serious adverse effects of the treatment up to now. The convalescent plasma from the patients who have recovered from the viral infection is thus another rational option for COVID-19 management [160, 161] .

The monoclonal antibodies are the well-recognized passive immunotherapeutic options in many diseases. This human-made antibody can specifically bind to the designated target, thus involves in its molecular mechanisms and provides the desirable effects, which can either inhibit or enhance those molecular pathways [162] . With the updated knowledge of the SARS-CoV-II molecular mechanisms, there are several studies on monoclonal antibody and their trials for COVID-19, conducted by many pharmaceutical companies. Some previously approved drugs for other conditions and several novel J o u r n a l P r e -p r o o f Journal Pre-proof drugs target various molecular targets of SARS-CoV II infection, with the promising therapeutic outcome for COVID-19 management soon [163, 164] . These clinical trials include the monoclonal antibodies that target the pathogenic and pathophysiologic processes of COVID-19. These trials comprise the tocilizumab, which targets the interleukin-6 receptor and possibly mediates the SARS-CoV II-mediated inflammation and modulates the cytokine storms, and several neutralized monoclonal antibodies targeting the SARS-CoV and MERS-CoV molecular mechanism [163, 165] .

Several companies and research groups initiate the development of potential vaccines for COVID-19.

These companies include Pfizer, GlaxoSmithKline, Johnson & Johnson, and many others. However, these trials are still in their early stages and require a certain period until their potential clinical launches. This anticipating option will not come soon [166] [167] [168] .

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