{'fraction_non_alphanumeric': 0.02937067589143161, 'fraction_numerical': 0.019890899414582226, 'mean_word_length': 5.590311266988163, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 4, 'lorem ipsum': 0, 'www.': 3, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Epigenetic susceptibility to severe respiratory viral infections and its therapeutic implications: a narrative review

The emergence of highly pathogenic strains of influenza virus and coronavirus (CoV) has been responsible for large epidemic and pandemic outbreaks characterised by severe pulmonary illness associated with high morbidity and mortality. One major challenge for critical care is to stratify and minimise the risk of multi-organ failure during the stay in the intensive care unit (ICU). Epigenetic-sensitive mechanisms, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) methylation, histone modifications, and non-coding RNAs may lead to perturbations of the host immune-related transcriptional programmes by regulating chromatin structure and gene expression patterns. Viruses causing severe pulmonary illness can use epigenetic-regulated mechanisms during host–pathogen interaction to interfere with innate and adaptive immunity, adequacy of inflammatory response, and overall outcome of viral infections. For example, Middle East respiratory syndrome-CoV and H5N1 can affect host antigen presentation through DNA methylation and histone modifications. The same mechanisms would presumably occur in patients with coronavirus disease 2019, in which tocilizumab may epigenetically reduce microvascular damage. Targeting epigenetic pathways by immune modulators (e.g. tocilizumab) or repurposed drugs (e.g. statins) may provide novel therapeutic opportunities to control viral–host interaction during critical illness. In this review, we provide an update on epigenetic-sensitive mechanisms and repurposed drugs interfering with epigenetic pathways which may be clinically suitable for risk stratification and beneficial for treatment of patients affected by severe viral respiratory infections.

influenza, and influenza A virus subtype H5N1 or avian influenza) and coronavirus (CoV) (i.e. severe acute respiratory syndrome [SARS]-CoV, Middle East respiratory syndrome [MERS]-CoV, and SARS-CoV-2) responsible for pandemic infections associated with high morbidity and mortality. 1e5 These viruses may cause a wide spectrum of respiratory manifestations associated with massive inflammatory cell infiltration and proinflammatory cytokine/chemokine release resulting in acute lung injury (ALI); acute respiratory distress syndrome (ARDS); and, ultimately, death from multi-organ failure (MOF). 6e8 Molecular mechanisms regulating virusehost interactions can significantly affect the degree and adequacy of both immune and inflammatory responses influencing clinical outcomes. 9e11 For the critical care physicians, to identify and prevent the occurrence of this exuberant inflammatory response and to stratify the risk of MOF in the intensive care unit (ICU) are still major challenges. 12 Epigenetics may influence host susceptibility to such viral infections. 13 Deoxyribonucleic acid (DNA) methylation, ribonucleic acid (RNA) methylation, histone tail changes, and also non-coding RNAs are heritable and acquired modifications able to alter gene expression at different levels without any changes in the primary DNA sequence. Epigenetic mechanisms, by regulating chromatin structure and gene expression patterns, modulate host immunity and inflammatory response. 14 In critical illness, such epigenetic modifications can promote the release of proinflammatory cytokines and activation of inflammatory cells, responsible for oxidative stress, endothelial dysfunction, apoptosis, and MOF. 15 Epigenetics can also regulate the interaction between host and multidrug-resistant bacteria. 16 The interaction of viruses with host cells can cause perturbations of transcriptional programmes involving such epigenetic mechanisms leading to viral shedding and inadequate immune response. 13 Middle East respiratory syndrome-CoV and H5N1 infections can antagonise the host immune response by modulating antigen presentation through DNA methylation and histone modifications. 17e20 Similar mechanisms would occur during coronavirus disease 2019 . 21,22 Indeed, advanced bioinformatic tools have predicted the possibility of using microRNAs (miRNAs) to inhibit infections caused by COVID-19, SARS-CoV, and MERS-CoV by inhibiting the translation of viral proteins and viral replication. 21 As some epigenetic changes can be reversed by small agents, known as 'epidrugs', or alternatively, epigenetic pathways can be interfered by immune modulators, they might provide useful drug targets to ameliorate the clinical outcome during viral respiratory infections. 23,24 Ongoing trials will answer to this possible clinical application. The goal of the review was to provide an appropriate pathogenic scenario in which epigenetic-sensitive mechanisms and epidrugs may be clinically useful to stratify risk and treatment of patients in ICU affected by severe viral respiratory infections.

Influenza viruses
Influenza viruses are enveloped, single-stranded RNA viruses classified into three major serotypes: A, B, and C. Influenza A viruses, the most extensively studied, are further classified based on the different subtypes of the two surface glycoproteins: haemagglutinin (H1eH18) and neuraminidase (N1eN11) which facilitate virus binding to host respiratory epithelial cells via a sialic acid receptor and virions released from cells, respectively. 25 Avian influenza A virus H5N1 26À28 and swine influenza A H1N1 29À34 infections have caused acute respiratory failure secondary to severe pneumonia and ARDS. The highly pathogenic avian influenza A virus H5N1, first described in 1996, caused severe pneumonia with high mortality (more than 60%), secondary to ARDS and MOF. 26e28 Risks factors for severe influenza A H1N1 infection included pregnancy, Table 1 Clinical and immunological features of viral respiratory infections by influenza viruses. 36e44 COPD, chronic obstructive pulmonary disease; CR, conventional radiograph; CT, computed tomography; GGO, ground glass opacity; HF, heart failure; IFNg, interferon g; IL-1 RA, interleukin-1 receptor antagonist protein; IP-10, interferon-g-inducible protein-10; MCP-1, monocyte chemoattractant protein-1; MIP 1-b, macrophage inflammatory protein 1-B; TLR-3, Toll-like receptor Type 3; TNF-a, tumour necrosis factor-alpha. obesity, asthma, and chronic obstructive pulmonary disease (COPD). 29e34 Mitigation of the pathogenicity of the pandemic virus was probably caused by the presence of a cross-reactive cell response against this virus, which was boosted by seasonal vaccination. 35 In Table 1, we summarised clinical and  immunological features of viral respiratory infections by  influenza viruses. 36e44 Coronaviruses Coronaviruses, named after their crown-like structure, are enveloped, positive-sense RNA viruses, containing the largest known genome amongst RNA viruses. The CoV genome encodes for 16 non-structural proteins, which form the viral replicase transcriptase complex, and four essential structural proteins, involved in the host immune response and virion assembly: the spike (S) protein, responsible for receptor binding and viral entry into the host cell; the membrane (M) and envelope (E) proteins, responsible for virus assembly and release; and the nucleocapsid (N) protein, important for RNA synthesis and its final packaging into the viral particles. 45 The genome sequence of SARS-CoV-2 is about 79% identical to the SARS-CoV and 50% to the MERS-CoV. 46 These viruses cause severe respiratory infections (Table 2). 47e60 Older adults with co-morbidities, especially cardiovascular diseases, diabetes, obesity, renal failure, and COPD, are at higher risk of severe disease. 51,56 ICU admission for organ support occurs in about 20e30%, 5e36%, and 50e89% of patients infected with SARS-CoV, SARS-CoV-2, and MERS-CoV, respectively. 3,51e53,56 Currently, global public health is facing the COVID-19 pandemic as the third CoV crisis in less than 20 yr (https://www.nih.gov/health-information/coronavirus).

Clinical signs and symptoms
Coronaviruses are capable of infecting several other organs, as demonstrated by the presence of SARS-CoV in circulating immune cells, neurones, intestinal mucosa, and epithelium of renal distal tubules. 61 Coronavirusesehost interaction can influence susceptibility to CoV infection and progression to severe disease. 3,11 After entering the body via the respiratory system, a critical step for cell entry and infection is the binding of the envelope S glycoprotein to the epithelial cells through specific receptors. The S protein of the SARS-CoV and SARS-CoV-2 binds to the angiotensinconverting enzyme 2 (ACE2) molecule present on cells through the receptor-binding domain, 62,63 whilst MERS-CoV binds to the host cell protein dipeptidyl peptidase 4. 64 After binding to the host, the S protein needs to be activated by a cellular protease, the transmembrane protease serine 2, which cleaves S in two subunits liberating the fusion peptide that mediates the fusion of the viral envelope with the cellular membrane. Differences in the structural and dynamic state of the receptor-binding domain 65 and S protein priming 66 between SARS-CoV and SARS-CoV-2 cause higher ACE2-binding affinity of the SARS-CoV-2 and favour its evasion of the immune surveillance, 64 suggesting a potential explanation of the higher SARS-CoV-2 infectivity. 63 Angiotensin-converting enzyme 2 can play a protective role in lung injury, 67 and its downregulation by SARS-CoV can contribute to progression to severe lung injury. 68 On the contrary, MERS-CoV regulates dipeptidyl peptidase 4 receptor in the lungs of smokers and COPD, and this could explain their susceptibility to severe disease. 69 To survive in the host cells, the CoVs adopt multiple strategies to evade detection by the host immune system, allowing active virus replication. The virus can downregulate genes involved in the antigen presentation, such as retinoic-acidinducible gene and melanoma differentiation-associated protein 5, and interfere with intracellular signalling pathways through structural (proteins M and N) and non-structural proteins, so delaying interferon (IFN) expression. 3,17,70,71 Ultimately, a delayed but excessive reaction of the immune system with an uncontrolled expression of cytokines and chemokines (the so-called cytokine storm) associated with virus-induced cytopathic effects will result in lung epithelial and endothelial cell apoptosis and activation of the coagulation cascade, leading to vascular leakage; alveolar oedema; microvascular thrombosis; and, later, cell proliferation with pulmonary fibrosis. 3,11,47 Cytokine storm in such patients is associated with more severe lung injury, ICU admission, and worse outcome. 3,51,71 To date, no definitive treatment for

Epigenetic mechanisms and respiratory viral infections
Viruses causing severe pulmonary illness can use three epigenetic-regulated ways during hostepathogen interaction: (i) they can affect host DNA methylation signatures and miR-NAs regulating a cassette of genes underlying innate and adaptive antiviral responses; (ii) they can encode for viral proteins that directly interact with the host modified histones; and (iii) they can manipulate the host miRNA processing nuclear machinery to encode viral non-canonical miRNA-like RNA fragments (v-miRNAs) regulating the viral life cycle and immune response. 73 Here, we focus on epigenetic-sensitive mechanisms by which H5N1 and SARS-CoV-2 may affect susceptibility to pulmonary illness by interfering with both innate and adaptive immune responses in humans 74,75 ( Fig. 1 and Table 3).

Histone modifications
By combining multi-omics data, H5N1 antagonised the early host antiviral response by altering histone methylation at Type I IFN-sensitive genes. 18 In detail, NS1 viral protein was associated with parallel increased H3K27me3 (repressive mark) and decreased H3K4me3 (active mark) levels favouring a heterochromatin state surrounding the SMAD9L, CFHR1, and DDX58 genes in human airway cells. 18 Viral non-canonical miRNA-like RNA fragments induced cytokine storm and high mortality 76 ; however, v-miRNA biogenesis and function remain to be clarified. 81 Overall, the virus skill to produce functional miRNAs can be also exploited to construct delivery systems of miRNAs based on RNA viruses as molecular vectors. 82 Severe acute respiratory syndrome coronavirus 2

DNA methylation
The high transmissibility and asymptomatic infection rates of SARS-CoV-2 may be caused by a more efficient virus replication and reduced IFN production in lung tissues. 83 As both SARS-CoV-2 and MERS can reprogramme the host epigenome, we hypothesise a possible role for epigenetic drivers underlying susceptibility to COVID-19. Sawalha and colleagues 77 have proposed oxidativestress-induced epigenetic pathways linked to ACE2 deregulation to increase susceptibility and severity of COVID-19 in patients affected by systemic lupus erythematosus (SLE). Indeed, the ACE2 gene CpG hypomethylation status characterising SLE patients could be exacerbated upon SARS-CoV-2 infection leading to further ACE2 protein overexpression in T cells, thus promoting viral infections and dissemination. 77 Disease-related epigenetic perturbations might be hotspots favouring viral infection and provide risk biomarkers useful to stratify sensitiveness to infection and disease severity in patients more prone to disseminate SARS-CoV-2 infection. Consistent with this, a bioinformatic analysis focusing on ACE2 gene has supported the hypothesis for which DNA methylation signatures are dependent on host cell type and gender and age, which are risk factors associated with increased susceptibility to COVID-19 and poor prognosis. 84

NETosis
Patients affected by COVID-19 are at higher risk of thromboembolic events and disseminated intravascular coagulation. 85 As evidence of neutrophil lung infiltration, Barnes and colleagues 78 have emphasised the key role of NETosis in contributing to organ damage and mortality of patients affected by COVID-19. Physiologically, NETosis is a form of innate immunity, in which the neutrophil cell death is guided from histone H3 modifications and release of neutrophil extracellular traps (NETs), complexes of DNA fibres, histones, and proteins aimed to provide a scaffold for platelet adhesion and aggregation to entrap pathogens and avoid their diffusion. 86 Moreover, NETs can induce macrophages to secrete IL1B to further sustain the signalling loop between macrophages and neutrophils, leading to progressive inflammatory damage. Previously, NETosis dysregulation was linked to thrombotic events, 86 ARDS, pulmonary inflammation, and extensive lung damage. 87 Interestingly, there is evidence for which heparin can dismantle NETs and prevent histone-induced platelet aggregation. This might represent the molecular basis for which heparin treatment reduces mortality in subjects affected by severe COVID-19, which develop sepsis-induced coagulopathy. 88 Thus, deoxyribonuclease I-mediated degradation of NETs could provide a therapeutic avenue to suppress excess injury in patients severely affected by COVID-19. 89

Epitranscriptome
The epitranscriptome of SARS-CoV-2 was analaysed as a possible strategy to dissect the hidden layer of viral regulation. By using nanopore direct RNA sequencing, almost 41 RNA modification sites, mostly located in the AAGAA motif on viral transcripts with shorter poly(A) tails, have been suggested. 90 As poly(A) tails play a relevant role in RNA turnover and stability, the proposed modifications may represent one of the molecular mechanisms by which SARS-CoV-2 evades the host immune response and indices the cytokine storm. 90 Besides, the authors did not identify what type of RNA modifications occur at these sites and the mechanisms underlying COVID-19 pathogenesis. 90

Epitherapy and immune modulators
Nowadays, the emergence of drug-resistant pathogens continuously increases, thus the discovery of novel drugs or the repositioning of already-approved drugs is needed. 16 Epitherapy may provide further therapeutic opportunities to control viralehost interaction during critical illness. 91 In particular, the current emergence of COVID-19 is guiding researchers towards the possible repurposing of Food and Drug Administration (FDA)-approved epidrugs, 92 including metformin and statins, which may be effective against the novel SARS-CoV-2 infection. Here, we give an update on clinical evidence about the usefulness of novel and FDA-approved drugs interfering with epigenetic pathways, which were applied to ICU patients affected by highly pathogenic strains of influenza virus and CoV, with a particular interest about the novel SARS-CoV-2 (Table 4).
In recent years, a few epidrugs have been introduced into clinic use (e.g. vorinostat and belinostat mainly to treat haematological malignancies), and a wide range of epigeneticbased drugs are undergoing trials, which will clarify whether pharmacological epigenetic modulation is of clinical interest ( Table 5). The road from discovery to clinical approval requires long timelines; thus, the repurposing of old drugs interfering with epigenetic pathways is another goal. In this case, epigenetic effect is inevitably going to be 'off-target' in comparison with the drug action used in the first place. Experimental evidence demonstrated that the effects of epidrugs were achieved at lower doses with prolonged exposure, whereas higher drug concentrations were detrimental. However, when ongoing trials will be completed, we will establish clinically if the dose used for epigenetic modification reversal would be the same as, less than, or more than that used for the original purpose.

De novo epidrugs
Curcumin Curcumin, belonging to the histone deacetylase inhibitor (HDACi) group, is a natural polyphenol extracted from turmeric with a wide range of molecular targets and drug activities, including anti-inflammatory properties. Interestingly, after H1N1 infection, curcumin treatment downregulated the secretion of proinflammatory cytokines and expression of the nuclear factor kappa-light-chain enhancer of activated B cell (NF-kB) gene in human macrophages without affecting cell viability. 93 This evidence suggests that curcumin may confer protection against influenza A virus-induced ALI by counteracting the cytokine signalling without damaging the immune system. 93 Interestingly, curcumin and demetoxycurcumin have been indicated as possible inhibitors of COVID-19 virus main protease, which plays a crucial function in controlling viral replication and transcription of SARS-CoV-2, suggesting a putative useful drugetarget interaction to be validated in clinical trials. 100 Apabetalone An international consortium of scientists has identified 50 proteins as putative drug targets against COVID-19. Amongst these targets, bromodomain (BRD) 2/4 would be relevant during interaction with the (E) envelope proteins of SARS-CoV-2 and viral reproduction. 94 By mimicking the histone structure, the (E) envelope proteins might potentially disrupt BRDhistone complexes. BRD proteins are epigenetic players that bind acetylated groups on histone proteins to aid in the recruitment of transcriptional machinery at promoter genes. Apabetalone can directly inhibit BET2/4 proteineSARS-CoV-2 interaction and may downregulate the expression of ACE2 receptors, which are exploited by the surface S glycoprotein to enter into human cells. 101 Currently, apabetalone is not approved by FDA, but has already shown clinical safety as demonstrated during the Phase 3 trial (BETonMACE) focusing on secondary prevention of cardiovascular dysfunction in diabetics. 102 Overall, this evidence suggests that apabetalone may potentially reduce viral infection and replication. In this way, Resverlogix Corporation (https://bit.ly/2CBaEKB) invites collaborators for further research on apabetalone as a putative therapeutic strategy for COVID-19.

Influenza viruses
Statins are hydroxymethylglutaryl-coenzyme A reductase inhibitors normalising lipid levels with pleiotropic epigeneticoriented effects by acting as HDACi. As statins also show anti-inflammatory effects, 103 they were thought to block the cytokine storm triggered by influenza viruses. 95

Coronaviruses
Clinical evidence about the use of statins in the treatment of viral pneumonia is limited and provided mixed results. Indeed, two trials reported that the anti-inflammatory effects of statins may reduce cardiovascular risk and mortality in ICU patients affected by pneumonia. 109,110 Otherwise, the results of one randomised clinical trial did not support statin use in those patients with ventilator-associated pneumonia. 111 Currently, there is no clinical or experimental evidence supporting the assertion that statins can improve clinical management of COVID-19. As the rates of acute events and mortality associated with COVID-19 infection are extremely high in patients with cardiovascular diseases (10.8%) and diabetics (7.3%), which generally use statins as primary or secondary prevention, these patients should continue the treatment when SARS-CoV-2 infection is suspected or diagnosed (https://www.acc.org/latest-in-cardiology/features/ /media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/2020/ 02/S20028-ACC-Clinical-Bulletin-Coronavirus.pdf). Statins are cleared by the liver metabolism and can increase the level of transaminases in cardio-hepatic patients 112 ; thus, strict evaluation and monitoring of statin therapy should be provided for COVID-19 patients, which commonly show an elevation of the aminotransferases (aspartate transaminase and alanine aminotransferase), with occasional alkaline phosphatase and total bilirubin elevations underlying a high risk for hepatotoxicity. 113,114 Whether a de novo use of statin therapy may play a key role in preventing COVID-19 complications remains to be elucidated. Remarkably, experimental studies supported the hypothesis for which an early and high dose of statins might be a useful strategy for the treatment of MERS-CoV infections by directly affecting the TLReMYD88eNF-kB axis, which plays a pivotal role during CoV infections. 96,115,116 Statins are the most common FDA-approved drugs classified as TLReMYD88 antagonists; moreover, under normal conditions, statins did not strongly alter MYD88 levels, whereas they maintain basal MYD88 levels during stress and hypoxia. 96 This supports that statins might be protective for patients affected by COVID-19. Thus, the putative regulation of MYD88 pathway via statins may be an attractive field of research to explore how to protect innate immune response against novel viral respiratory infections, including SARS-CoV-2.

Influenza viruses
Metformin, belonging to HDACi class, is the first-line antihyperglycaemic drug for type 2 diabetes (T2D) patients, which can indirectly reduce chronic inflammation by normalising glucose levels or directly impact on inflammatory pathways. Recently, Saenwongsa and colleagues 117 have demonstrated that after the trivalent inactivated influenza vaccine (TIV), both the IgG antibody response and IFN-a expression were impaired in T2D patients treated with metformin via repression of rapamycin (mTOR)-mediated pathway and impaired IgG avidity index, leading to increased sensitiveness to H1N1 and H3N2 infection. This suggests that the TIV may not be suitable for T2D patients treated with metformin by emphasising the necessity of developing a more customised strategy for influenza prevention in high-risk groups. Metformin may recover the influenza vaccine responses in T2D patients (treated and non-treated with metformin) by improving the Bcell function via parallel downregulation of inflammation and upregulation of AMPK phosphorylation (active form), a metabolic enzyme involved also in antibody responses. 97 Understanding of the metformin effects on the immune system may guide the repurposing of this drug focused on therapeutic intervention on metabolism in inflammatory diseases.
Immunomodulators and antivirals: could they impact on epigenetic pathways underlying cardiovascular dysfunction in COVID-19?
The repurposing of both immunomodulators and antivirals, including tocilizumab (TCZ), remdesevir, favipiravir, hydroxychloroquine, and chloroquine, could be a fast way to get effective treatments whilst a preventive vaccine will be available (https://www.who.int/emergencies/diseases/novelcoronavirus-2019). In the current COVID-19 pandemic, TCZ is one of the most promising repurposed drugs under clinical investigation for the treatment of severe hospitalised pneumonia patients. Tocilizumab is a humanised monoclonal antibody that can counteract the cytokine storm by blocking the interleukin-6 (IL-6) receptor signalling associated with a high risk of cardiovascular mortality. 118 Immunomodulators can counteract the overactive inflammatory response, which seems to be the driver of increased disease severity. Many old anti-inflammatory drugs are in clinical trials, such as sarilumab (NCT04315298; Phases 2 and 3) and TCZ (NCT04320615; Phase 3). Besides, the efficacy of antivirals inhibiting viral replication, such as favipiravir (NCT04358549; Phase 2) and remdesevir (NCT04292730; Phase 3), is being evaluated in clinical trials compared with standard of care. The impact of COVID-19 on cardiovascular health is an urgent question for physicians. 119 As epigenetics plays an increasing role in cardiovascular diseases and inflammation, 102,120 and also during SARS-CoV-2 infection, 77 we emphasised the need to clarify if these drugs could potentially impact the associated cardiac dysfunction modulating the severity of the disease.
Clinical evidence from rheumatoid arthritis patients demonstrated that TCZ therapy can prevent cardiovascular dysfunction via two main epigenetic-sensitive mechanisms: (i) reduction of NETosis; and (ii) upregulation of miRNA-23, miRNA-146, and miRNA-223 serum levels. 98 Overall, this suggests that TCZ can improve the pro-atherosclerotic status by regulating dyslipidaemias, endothelial dysfunction, inflammation, and oxidative stress. 98 Moreover, TCZ-treated rheumatoid arthritis patients demonstrated a differential expression of 85 lncRNAs in CD14 þ monocytes regulated by IL-6 or tumour necrosis factor-alpha. 99 Preliminary trials have suggested the usefulness of chloroquine or hydroxychloroquine repurposing in the treatment of COVID-19, which is correlated with the ability of these antimalarial agents in interfering with the cellular-mediated viral endocytosis. 121 However, a randomised trial demonstrated that hydroxychloroquine failed in preventing symptomatic infection when taken within 4 days after exposure. 122 At epigenetic level, hydroxychloroquine can exert an inhibitory activity against the polycomb repressive complex 2 (PRC2), responsible of switching chromatin towards a compacted state (inactive gene expression) in blood malignancies. 123 Interestingly, influenza A viruses, MERS-CoV, and SARS-CoV are able to activate the PRC2, which, in turn, increases the levels of H3K27me3 (repressive mark) at the promoters of targeted IFN-stimulated genes to counteract the host antiviral immune response. 124 This let us suggest that also SARS-CoV-2 might use the same mechanisms to inactive IFN-related pathways in infected cells; besides, since polycomb inhibitors have shown a general antiviral activity, 125 it might be useful to investigate whether hydroxychloroquine can directly impact on PRC2 activity in COVID-19. As reported, the clinical effect of i.v. remdesivir seems to be relatively modest; however, a randomised Phase 3 clinical trial (NCT04292899) did not find a significant difference in efficacy between 5-and 10-day courses of this drug. 126 Until now, there is no direct evidence that antivirals, such as remdesevir and favipiravir, would impact epigenetic-sensitive ways during their mechanism of action.

Concluding remarks
Targeted epigenetic-sensitive molecular networks are temporally manipulated during virusehost interactions, providing further risk factors for viral shedding and inadequate immune response also in patients affected by COVID-19, in which ACE2 promoter hypomethylation may be one of the relevant drivers. During the current COVID-19 pandemic, we need to understand why a part of the population becomes critically infected when exposed to low viral load, whilst other subjects are less responsive when exposed to high viral loads. As the influenza virus may also promote acute coronary syndromes (which can be reduced by vaccine), 127 the issue of coinfection (i.e. SARS-CoV-2 and influenza viruses) needs to be further explored both in terms of epigenetic-sensitive tandem events and in critical care. For better risk stratification, it would be needed to clarify the SARS-CoV-2 basic mechanisms of action and how these impact on the individual genetic/ epigenetic background and pre-existent cardio-metabolic diseases highly correlated with mortality rate, especially in the elderly. 128,129 Clinical treatment of mild forms of COVID-19 should not be phobic from fever, which can promote an effective immune response and virus clearance from the body. 130 Ongoing controlled clinical trials would clarify the repositioning of TCZ, whereas curcumin, apabetalone, metformin, and statins could be an effective treatment to protect innate immune response against severe viral respiratory infections. In the era of network medicine, predictive analysis tools are playing a relevant role in addressing the COVID-19 pandemic by providing maps of human proteins interacting with SARS-CoV-2 proteins 101 and a list of candidate repurpose drugs and potential drug combinations targeting SARS-CoV-2. 131 The epigenetic susceptibility to pulmonary viral infections requires further investigation by using the network-oriented analysis to clarify the molecular routes underlying perturbation of the human interactome, 132 in particular in COVID-19 and its impact on cardiovascular health.