key: cord-286683-mettlmhz authors: Ortiz-Prado, Esteban; Simbaña-Rivera, Katherine; Gómez-Barreno, Lenin; Rubio-Neira, Mario; Guaman, Linda P.; Kyriakidis, Nikolaos C; Muslin, Claire; Jaramillo, Ana María Gómez; Barba-Ostria, Carlos; Cevallos-Robalino, Doménica; Sanches-SanMiguel, Hugo; Unigarro, Luis; Zalakeviciute, Rasa; Gadian, Naomi; López-Cortés, Andrés title: Clinical, molecular and epidemiological characterization of the SARS-CoV2 virus and the Coronavirus disease 2019 (COVID-19), a comprehensive literature review date: 2020-05-30 journal: Diagn Microbiol Infect Dis DOI: 10.1016/j.diagmicrobio.2020.115094 sha: doc_id: 286683 cord_uid: mettlmhz Abstract Coronaviruses are an extensive family of viruses that can cause disease in both animals and humans. The current classification of coronaviruses recognizes 39 species in 27 subgenera that belong to the family Coronaviridae. From those, at least seven coronaviruses are known to cause respiratory infections in humans. Four of these viruses can cause common cold-like symptoms. Those that infect animals can evolve and become infectious to humans. Three recent examples of these viral jumps include SARS CoV, MERS-CoV and SARS CoV-2 virus. They are responsible for causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and the most recently discovered coronavirus disease during 2019 (COVID-19). COVID-19, a respiratory disease caused by the SARS-CoV-2 virus, was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. The rapid spread of the disease has taken the scientific and medical community by surprise. Latest figures from 20th May 2020 show more than 5 million people had been infected with the virus, causing more than 330,000 deaths in over 210 countries worldwide. The large amount of information received daily relating to COVID-19 is so abundant and dynamic that medical staff, health authorities, academics and the media are not able to keep up with this new pandemic. In order to offer a clear insight of the extensive literature available, we have conducted a comprehensive literature review of the SARS CoV-2 Virus and the Coronavirus Diseases 2019 (COVID-19). The viral membrane contains the spike (S) glycoprotein that forms the peplomers on the virion surface, giving the virus its 'corona'or crown-like morphology in the electron microscope. The membrane (M) glycoprotein and the envelope (E) protein provide the ring structure. Within the virion interior lies a helical nucleocapsid comprised of the nucleocapsid (N) protein complexed with a single positive-strand RNA genome of about 30 kb in length [16] . The first genome of SARS-CoV-2 named Wuhan-Hu-1 (NCBI reference sequence NC_045512) was isolated and sequenced in China in January 2020 [12, 16] . The SARS-CoV-2 genome has similarities to other viruses: approximately 96% similarity to the bat coronavirus BatCoV RaTH13; an estimated 80% similarity with SARS-CoV [16] , and an estimated 50% identity with MERS-CoV [17, 18] . SARS-CoV-2 has a positive-sense single-stranded RNA genome. It is approximately 30,000 bases in length and comprises of a 5′ terminal cap structure and a 3′ poly A tail. According to Wu et al. [19] , this novel coronavirus (IVDC-HB-01/2019 strain) has 14 open reading frames (ORFs) encoding 29 proteins. The 5' terminus of the genome contains the ORF1ab and ORF1a genes. ORF1ab is the largest gene and encodes the pp1ab protein that contains 15 non-structural proteins named nsps (nsp1-nsp10 and nsp12-nsp16). ORF1a encodes the pp1a protein and also has 10 nsps (nsp1-nsp10) [19] . The 3' terminus of the genome contains four structural proteins: spike (S) glycoprotein; envelope (E) protein; membrane (M) glycoprotein and nucleocapsid (N) phosphoprotein. It also contains 8 accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b and ORF14) [20] (Figure 3b ). The global scientific community from 58 countries have united to study this novel coronavirus by sequencing and submitting 12,059 SARS-CoV-2 genomes to the Global Initiative on Sharing All Influenza Data (GISAID) (https://www.gisaid.org/) between December 2019 and April 2020 [21, 22] . SARS-CoV-2 has accumulated mutations in its RNA genome as the outbreak progresses. As an intracellular obligate microorganism, the coronavirus exploits the host cell machinery for its own replication and spread. Since virus-host interactions form the basis of diseases, knowledge about their interplay is of great importance, particularly when identifying key targets for antivirals. J o u r n a l P r e -p r o o f ACE2 is a type I membrane protein that participates in the maturation of angiotensin, a peptide hormone that controls vasoconstriction and blood pressure [30] . In the respiratory tract, ACE2 is widely expressed on the epithelial cells of alveoli, trachea, bronchi, bronchial serous glands [31] , and alveolar monocytes and macrophages [32] . Xu et al. reported the [33] RNA-seq profiling data of 13 organs with para-carcinoma normal tissues from The Cancer Genome Atlas (TCGA; https://www.cancer.gov/tcga) and 14 organs with normal tissue from FANTOM5 CAGE (https://fantom.gsc.riken.jp/). These were used to validate the expression of the human cell receptor ACE2 in the virus and may indicate the potential infection routes of SARS-CoV-2 [34] . Interestingly, the ACE2 receptor is expressed more in oral cavity than lung. This potentially could indicate that susceptibility and infectivity of SARS-CoV-2 is greater from oral mucosa surfaces [33] . Following the binding of the RBD in the S1 subunit to the receptor ACE2, SARS-CoV-2 S protein is cleaved by the cell surface-associated transmembrane protease serine 2 TMPRSS2, which activates S2 domain for membrane fusion between the viral and cell membrane [35] . A functional polybasic (furin) cleavage site was found at the S1-S2 boundary through the insertion of 12 nucleotides [13, 29, 36] . The S673, T678 and S686 residues of O-linked glycans flank the cleavage site and are unique in SARS-CoV-2 [29] . In addition to the S glycoprotein -ACE2 receptor complex, Wang Following the release and uncoating of viral RNA to the cytoplasm, coronavirus replication starts with the translation of ORF1a and ORF1b into polyproteins pp1a and pp1ab via a frameshifting mechanism (Figure 4 ) [38] . Subsequently, polyproteins pp1a and pp1ab are processed by internal viral proteases, including the main protease M pro , a potential drug target whose crystal structure was recently determined for SARS-CoV-2 [15] . Polyprotein cleavage yields 15 mature replicase proteins, which assemble into a replicationtranscription complex that engages in negative-strand RNA synthesis. Both full-length and multiple subgenomic negative-strand RNAs are produced. The former serves as template for new full-length genomic RNAs and the latter template the synthesis of the subgenomic mRNAs required to express the structural and accessory protein genes residing in the 3′proximal quarter of the genome [37] . Coronavirus RNA replication occurs on a virusinduced reticulovesicular network of modified endoplasmic reticulum (ER) membranes [39] . The assembly of virions is quickly ensued with the accumulation of new genomic RNA and structural components. The N protein complexes with genome RNA, forming helical structures. Then, the transmembrane M protein, localized to the intracellular membranes of the ER -Golgi intermediate compartment (ERGIC) , interacts with the other viral structural proteins (S, E and N proteins) to allow the budding of virions [40, 41] . Following assembly and budding, virions are transported in vesicles and eventually released by exocytosis. Normal immune responses against the majority of viruses involve a rapid containment phase mediated by innate immunity components and -if necessary-a delayed, yet more sophisticated adaptive immunity phase that should be able to eradicate the pathogen andhopefully-generate long-lasting immunological memory. The former includes antiviral Type I Interferons (IFNs), macrophage and neutrophil activation that leads to proinflammatory cytokine production and NK cells On the other hand, anti-viral adaptive immune responses involve a virus-tailored coordinated attack by antigen specific CD8+ cytotoxic T cells (CTLs), the Th1 subset of CD4+ T helper cells that orchestrates the J o u r n a l P r e -p r o o f immune response against viruses and other intracellular pathogens, specific antibody producing plasma cells, and finally the production of memory T and B cell subsets. Immune responses following SARS-CoV-2 infection can be a double-edged sword. A rapid and robust Type I IFN orchestrated response can lead to virus clearance and -given that antiviral lymphocytes are activated and expanded-immune memory. Conversely, a late activation of innate immunity, possibly owing to is usually associated with severe pathology that can lead to pneumonia, ARDS, septic shock, multi-organ failure and, eventually, death. In this line, a delayed Type I IFN response and inefficient SARS-CoV-2 clearance by alveolar macrophages can promote excessive viral replication that can lead to severe pathology accompanied by increased viral shedding and, thus, viral transmissibility. Accordingly, in patients whose immune system is weakened or otherwise dysregulated, such as older men with comorbidities, severe COVID-19 is clearly more likely to occur [42] [43] [44] . A recent study has demonstrated that the average duration of SARS-CoV-2 viral shedding was 20 days after COVID-19 onset, raising a debate as to the optimal time of patient isolation [45] . However, in terms of transmission viral shedding seems to be more relevant in the early phases of the infection as it can precede COVID-19 symptoms by 2-3 days whilst up to 50% of infections are associated with viral shedding by asymptomatic cases [46] [47] [48] Therefore, individuals that mount efficient containment-phase immune responses accompanied by decreased inflammatory responses will not experience infection-or immune response-mediated overt manifestations, but may be important silent spreaders of SARS-CoV-2. Type I IFNs are mainly produced by plasmacytoid dendritic cells (pDCs) and have a plethora of antiviral effects such as blocking cell entry and trafficking of viral particles, inducing RNase and DNase expression to degrade virus genetic material, enhancing presentation of viral antigens by MHC-I, inhibiting protein synthesis, inducing apoptosis of J o u r n a l P r e -p r o o f infected cells and activating anti-viral subsets such as macrophages and cytotoxic NK cells and T lymphocytes [49] . Pathogen recognition receptors like cytosolic RIG-I and MDA-5 [50, 51] or endosomal Toll like receptors (TLRs) 7 and 8 that recognize viral RNA [52] are responsible for the activation of signaling cascades that activate the transcription factors NF-kB, interferon regulatory factor (IRF) 3 and IRF7 that translocate to the nucleus and induce proinflammatory cytokines and Type I interferon (IFN) production. In turn, Type I IFNs activate the downstream JAK-STAT signal pathway resulting in expression of IFNstimulated genes (ISGs) [53, 54] . Our experience from SARS-CoV and MERS-CoV infection has shown that delayed type I IFN production and excessive recruitment and activation of infiltrating proinflammatory cells (neutrophils and monocytes-macrophages) are possible mediators of lung dysfunction and bad prognostic factors for the outcome of the infection. Delayed type I IFN production allows for highly efficient viral replication that, in turn, results in recruitment of hyperinflammatory neutrophils and monocytes. Therefore, the pathogen recognition receptors (PRRs) of these proinflammatory cells recognize high numbers of their ligands and subsequently secrete excessive amounts of proinflammatory cytokines that lead to septic shock, lung pathology, pneumonia or acute respiratory distress syndrome. It has been shown that in severe cases both SARS-CoV and MERS-CoV fruitfully employ an immune evasion mechanism whereby early type I IFN responses to viral infection are dampened [54] . This can be achieved by blocking signaling both upstream, as well as downstream of type I IFN expression. SARS-CoV can inhibit IRF3 nuclear translocation, whereas MERS-CoV can impede histone modification [56] . Additionally, both viruses can inhibit IFN signaling by decreasing STAT1 phosphorylation [57] . Due to the many sequence similarities of SARS-CoV-2 with SARS-CoV and MERS-CoV it would be enticing to speculate that similar mechanisms are also present, however further studies are needed to shed light to this hypothesis. Hyperactivated neutrophils and monocytes-macrophages are the usual source of the cytokine storm. In this aspect, absolute neutrophil counts and neutrophil to lymphocyte J o u r n a l P r e -p r o o f ratio (NLR) were strongly associated with disease severity in a large cohort of COVID-19 patients and were proposed as markers of adverse disease prognosis [58] . Interestingly, the increased amounts of proinflammatory cytokines in serum associated with pulmonary inflammation and extensive lung damage described both in SARS [59] and MERS diseases [60] were also reported in the early study of 41 patients with COVID-19 in Wuhan [41] . Evidence shows that the leading cause of COVID-19 mortality is respiratory failure caused by acute respiratory distress syndrome (ARDS). There is an association with a cytokine storm mediated by high-levels of proinflammatory cytokines including IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1A and TNF-α. ARDS was associated with increased fatality and subsequent studies confirmed IL-6 and C-reactive protein are significantly upregulated in patients that died compared to convalescent patients [56] Moreover, a recent study of 452 patients in Wuhan identified that severe cases showed significantly higher cytokines and chemokines such as tumor necrosis factor-α (TNF-α), IL-2, IL-6, IL-8 and IL-10 expressed [58] . In accordance with these findings, therapeutic strategies are being tested. A phase 3 randomized controlled trial of IL-1 blockade (anakinra) in sepsis has shown significant survival benefit in patients with hyperinflammation, without apparent increased adverse events [61] . Currently, a multicenter, randomized controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome), is being trialed in patients with COVID-19 pneumonia presenting with high levels of IL-6 in China (ChiCTR2000029765) [62] . Moreover, several clinical trials are exploring if the well-established antiviral [63] and anti-inflammatory effects of hydroxychloroquine will be effective in treating patients with COVID-19 as has previously been suggested for SARS-CoV infection [64] . This has also been demonstrated in vitro for SARS-CoV-2 [65] . In contrast, Janus kinase (JAK) inhibition has been proposed as a potential treatment in order to reduce both inflammation and cellular viral entry in COVID-19 [66] . Thus, it comes as no surprise that in a recent correspondence, Lancet authors have identified the following potential therapeutic options for cytokine storm syndrome including ARDS the use of corticosteroids, selective cytokine blockade (eg, anakinra or tocilizumab) and JAK inhibition [67] . J o u r n a l P r e -p r o o f Virus presentation to the different T cell subsets stands on the crossroads between innate and adaptive immune responses. Studies on SARS-CoV and MERS-CoV [72] presentation have identified several susceptibility and protection conferring HLA alleles. The dearth of similar data regarding SARS-CoV-2 antigen presentation to T cells and possible virus evasion mechanisms of this process suggests it is a virgin investigation field to be explored. Apart from the sustained inflammation and cytokine storm, lymphopenia has been implicated as a major risk factor for ARDS and mortality in the context of COVID-19 [73] . Similar findings were described for SARS-CoV infected patients who had considerable decreases of CD4+ T and CD8+ T cells [69] . However, in convalescent patients specific Tcell memory responses to SARS-CoV were still found six years post infection [74] . showed no reactivity with viral antigens. However, the small number of sera used (n=4) implies that further investigation is needed to corroborate these results [78] . Nonetheless, since we are currently in early stages of SARS-CoV-2 pandemic more studies need to be carried out to shed light on antibody persistence (both IgM and IgG) and protective effects. Recently, macaques re-challenged with SARS-CoV-2 after a primary infection did not show signs of re-infection, suggesting that protective immunity and memory responses were fruitfully mounted. This finding can also impact vaccine production strategies [79] . Importantly, COVID-19 convalescent sera was shown to hold promise as a passive immune therapy alternative to facilitate disease containment [80] . To the best of our knowledge, at J o u r n a l P r e -p r o o f least one pharmaceutical company, Takeda, is preparing to purify antibody preparations from COVID-19 convalescent sera against SARS-CoV-2 [81] . A recently published case report of a patient with mild-to-moderate COVID-19 revealed the presence of an increased activated CD4+ T cells and CD8+ T cells, antibody-secreting cells (ASCs), follicular helper T cells (TFH cells), and anti-SARS-CoV-2 IgM and IgG antibodies, suggesting that both cellular and humoral responses are important in containing the virus and inhibiting severe pathology [82] . Antibody dependent enhancement (ADE) is a mechanism whereby non-protective antibodies produced during an infection with an agent either mediate increased uptake of this agent into target cells or cross-recognize a different pathogen and facilitate its entrance to target cells [83] . Evidence emerging over the past two decades suggests that antibodies against different coronavirus can cross-react to some extent and mediate ADE [84] . ADE in the context of SARS-CoV was thought to be mediated by antibodies produced against 229E-CoV [85] and was contemplated as contributing to high mortality rates in China [86] . The described mechanism suggests that low affinity or low title anti-Spike protein antibodies rather than neutralizing the virus result in Fc receptor mediated infection of immune cells, further aggravating the dysregulation of anti-SARS-CoV immune responses [87] . Indeed, in vitro as well as in vivo experimental models have shown that ADE hinders the ability to manage inflammation in the lung and elsewhere. This may lead to ARDS and other hyperinflammation-induced clinical manifestations also observed in several of the documented cases of severe COVID-19 [88, 89] . While the molecular and immunological host response to SARS-CoV-2 infection has not yet been fully elucidated to confirm ADE is occurring, anti-SARS-CoV-2 antibodies have been shown to partially cross-react with SARS-CoV, suggesting enhancement is a possibility. With this in mind, ADE in populations previously exposed to other coronavirus can partially explain the geographic discrepancies observed in COVID-19 pathogenesis and severity. Finally, ADE can have several implications in vaccine development as low-affinity or low-titer antibody producing vaccines can increment susceptibility rather than confer protection against the pathogen as has previously been described for a Dengue vaccine [90] [91] [92] . J o u r n a l P r e -p r o o f Detection methods based on nucleic amplification are often used in the case of SARS-CoV, MERS-CoV and other viruses, because have high sensitivity and specificity, particularly in the acute phase of infection [93] . Case identification and surveillance of COVID-19 spread Although RT-qPCR assay is considered the gold-standard method to detect viruses such as SARS-CoV and MERS-CoV [94, 95] , currently available RT-qPCR assays targeting SARS-CoV-2 have important considerations. Firstly, due to the genome similarity of J o u r n a l P r e -p r o o f SARS-CoV-2 to SARS-CoV (82% of nucleotide identity [96] ), some of the primer-probe sets described by different groups and listed in the WHO Coronavirus disease (COVID- 19) technical guidance [97] , have cross-reaction with SARS-CoV and other bat-associated SARS-related viruses, therefore, it is important to run confirmatory tests. Loop-mediated isothermal amplification (LAMP) is a one-step isothermal amplification reaction that couples amplification of a target sequence with four to six primers, to ensure high sensitivity and specificity, under isothermal conditions (63-65°C), using a polymerase with high strand displacement activity [129] . In the case of an RNA sample, LAMP, is preceded by the reverse transcription of the sample RNA. RT-LAMP has been used before for the detection of various pathogens [130] . including SARS-CoV-2 and other respiratory viruses [131, 132] . Recently, it received emergency use authorization (EUA) from the U.S. J o u r n a l P r e -p r o o f Serological tests also, called immunoassays, are rapid and simple alternatives for screening of individuals that have been exposed to SARS-CoV-2 based on the qualitative or quantitative detection of SARS-CoV-2 antigens and/or anti-SARS-CoV-2 antibodies. There are several types of serological tests available, including ELISA (enzyme-linked immunosorbent assay), IIFT (indirect immunofluorescence test), lateral flow immunoassays and neutralization tests. Immunoassays assays are very useful because they allow to study the immune response(s) to SARS-CoV-2 in a qualitative and quantitative manner. In addition, help to determine the precise rate of the infection [78, 133] , and to determine more precisely the fatality rate of the infection [78] . Several SARS-CoV-2 targeted serological tests are commercially available or in development [134] . A recently developed kit, reported a sensitivity of 88.66% and specificity of 90.63% [135] using SARS-CoV-2 IgG-IgM combined antibody rapid (within 15 minutes) test [135] . Despite their simple and fast readout and their potential for being used outside laboratory environments (bedside, small clinics, airports, train stations, etc.), serological tests have a critical disadvantage; given the fact that antibodies specifically targeting the virus would normally appear after 6 days or longer [136] after the illness onset [137] , tests based on this principle have a lag period of approximately 4 to 7 days post-infection. During this lag period, infected and non-infected individuals will both result in a negative output. In addition, it is important to highlight that because serological tests depend on the ability to produce antibodies, intrinsic immunological differences and/or responses between individuals, can significantly affect the outcome of these tests. Recently, some commercially available immunoassays received CE Mark for professional use [138, 139] , and therefore are registered as in vitro diagnostic devices. Currently, there are a plethora of antibody tests for COVID-19 with variable performance (sensitivity varying from 45 to 100%, specificity from 96 to 100%, reviewed in (Foundation for Innovative New Diagnostics) [134] . Different manufacturers of serological assays declare that their assays have no cross reactivity to other human coronaviruses and other respiratory viruses. However, despite the data provided by manufacturers, recent studies highlighted that several of the commercially available tests have sensitivity and/or specificity issues that should be considered for using and analyzing results of many of these tests [140] [141] [142] [143] [144] . J o u r n a l P r e -p r o o f As mentioned before, immunoassays -particularly tests detecting anti-SARS-CoV-2 IgM and/or IgG-indicate that the person has been exposed to the virus. In the case of other viral infections, having antibodies targeting a pathogen has often been considered an indication of having immunity against that pathogen [145] . Based on this idea, some governments have suggested using serological tests, to determine who has developed immunity against SARS-CoV-2 and provide positive individuals a "risk-free certificate" or "immunity passports", which would enable them to travel or to return to work, assuming that they are protected against re-infection [146]. However, based on the limited knowledge of how immunity to this virus works [147] , there is not enough evidence to declare a person immune, or to confirm that people who have anti-SARS-CoV-2 antibodies are protected from a re-infection. Even though COVID-19 can be diagnosed using qPCR as the gold standard, inadequate access to reagents and equipment has slowed disease detection even in developed countries such as the US. Several low cost and rapid tests using different approaches have been described. UnLOCKing) technique for the detection of COVID-19 and the DETECTR (developed by Mammoth Biosciences) prototype rapid detection diagnosis kit using CRISPR to detect the SARS-COV-2 in human samples have been described [148] . The use of RNA aptamers, have recently emerged as a powerful background-free technology for live-cell RNA imaging due to their fluorogenic properties upon ligand binding, a technology that could be of use to diagnose SARS-CoV-2 infection [149] . Finally the use of next generation sequence (Explify®) might be used to detect and identify bacterial, viral, fungal, and parasitic pathogens by their unique genome sequences [107] . In COVID-19 symptomatic infection, the clinical presentation can range from mild to ventilation assistance [151] . The spectrum of symptoms of COVID19 infection are characteristic of a mild disease in most of the cases, however, it is important to point that the progression could lead to a severe respiratory distress. Asymptomatic infection (while incubation occurs) was described both in the first cases in Wuhan and in other cohorts. A group of isolated patients were screened for SARS-CoV-2, where 17% (629 cases) were positive for the test, and half of these cases had no symptoms. On the other hand, there are reports of cases without overt symptoms in which there were ground glass images in the chest tomography in up to 50% of patients [152] . Of the asymptomatic cases studied in Wuhan city, the 2.5% of people exposed developed specific symptoms in 2.2 days, and the remaining 97.5% were symptomatic in the following 11.5 days (CI, 8.2 to 15.6 days). The median estimated incubation period was 5.1 days (95% CI, 4.5 to 5.8 days) [153] . Some patients with initially mild symptoms had symptom progression over the course of one week [154] . The descriptive studies available so far have concluded that the majority of cases are mild infections (more than 80% of cases); with up to 15% of patients being sever J o u r n a l P r e -p r o o f in most cohorts, and less than 5% have been considered as critical cases with high vital risk [155] . In a study describing 138 patients with COVID-19 pneumonia in Wuhan, the most common clinical characteristics at the onset of the disease were described. This is consistent with other international cohorts (Table 3 ) [150] . It is important to note that fever is not always present and up to 20% of patients could had a low grade temperature between 37.5 to 38 degrees Celsius or normal temperature [156] . If these patients required hospitalization, 89% developed a fever during the course of the illness. Rarer accompanying symptoms included headache without warning signs, odynophagia and rhinorrhea. Gastrointestinal symptoms such as nausea and watery diarrhea were relatively rare [151] . Dyspnea develops after a median of 5 to 8 days from the onset of symptoms. It is important to notice that, if dyspnea is an important clinical finding, not all the patients with this J o u r n a l P r e -p r o o f symptom will develop severe respiratory distress or require oxygen supplementation [150] . According to World Health Organization (WHO) guidelines, COVID-19 infection can present as pneumonia without signs of severity, and could be managed in the outpatient setting. This is applicable to those patients who do not need supplemental oxygen [157] . As previously mentioned, the most serious manifestation of COVID 19 infection is pneumonia, characterized by cough, dyspnea, and infiltrates on chest images; the latter is indistinguishable from other viral lung infections. Acute respiratory distress syndrome (ARDS) is a major complication of COVID pneumonia in patients with severe disease. This develops in 20% after a median of eight days. Mechanical ventilation is implemented in 12.3% of cases [158] . In different case reports, the need for supplemental oxygen via the nasal cannula was required in approximately 50% of hospitalized patients. 30% required non-invasive mechanical ventilation, and less than 3% required invasive mechanical ventilation with or without Extracorporeal Membrane Oxygenation (ECMO) [159] . It is important to mention that the proportion of severe cases is highly dependent on the study population and may be related to the epidemiological behavior of the infection in each country. Additionally, the number of people tested will influence the denominator. In Italy, the average age of people infected with COVID-19 is between 60 and 65 years, and 16% of those hospitalized require admission to the intensive care unit (ICU) [160]. The WHO recommendations had established that severe COVID-19 disease could be defined by the following parameters in Table 4 [157] . [162] . Among the established risk factors for the development of ARDS is age greater than 65 years, diabetes mellitus and hypertension, in at least 40% of patients [151] . It should be clarified that, although advanced age is identified as a risk factor for a severe infection, those of any age may suffer from severe illness from COVID-19. The descriptions made so far of the patients from China have determined that almost 90% of the patients were between the ages of 30 and 79 years (cohort of 44,500 cases) [155] . In other population settings, such as in the United States, more than 60% of confirmed The clinical characteristics of symptomatic cases and their severity has been described. In addition to the symptoms reported by the patients, the findings on physical examination may be absent during mild COIVD-19 infection. Those with moderate to severe COVID-19 infection have various signs during pulmonary auscultation, however the most common findings include: wet rales; global decrease in respiratory sounds and increased thrill [164] . Early recognition is essential to classify cases as potential cases and initiate one of the most important measures to contain the pandemic, isolation. 2. Anyone who has resided or been traveling in areas where widespread community transmission has been reported. 3. Any patient who has had potential exposure through attending events or has spent time in specific settings where cases of COVID-19 have been reported. The scenarios described respond to the context of a high suspicion of COVID-19 infection. The world health authorities (CDC, WHO) continually update these contexts. There have been multiple case definitions and clarifications regarding when to perform a COVID-19 test: • They have pointed out the importance of fever, cough and dyspnea as sentinel symptoms, since these should form part of the clinical judgment that guides doctors. This allows to expand the group of suspicious patients. • In cases of severe respiratory distress of undetermined etiology and that do not meet the previously indicated criteria, a screening for COVID-19 would be indicated. • In areas of limited resources, the suggestion is to prioritize cases that require hospital care, and in this way guide the epidemiological fence to order isolation and protect the most vulnerable people (chronically ill and over 65 years of age), as well as test those with the greatest possibility of exposure (travelers and health personnel). Currently, there is no laboratory data profile that is framed in COVID 19 infection. From a cohort of 43 patients confirmed with COVID 19, these findings were classified as mild, moderate and severe disease [165] . High levels of D-dimer and more severe lymphopenia have been associated with mortality due to a prothrombotic state that determines multi-organ failure. In general, leukopenia and / or leukocytosis can be found in the interpretation of blood biometry, however, the most widely described finding is lymphopenia [166] . It should be considered that in the context of viral pneumonia biomarkers such as Procalcitonin and PCR are not useful, as often these biomarkers are in the normal range for patients with COVID-19. Among other findings, descriptive studies have reported considerable elevations of lactate dehydrogenase and ferritin as well as alteration in aminotransferases; although elevation ranges for these parameters have not been established [167] . About the imaging findings, COVID 19 viral pneumonia has similar features on imaging to other viral infections. Although computed tomography (CT) is the test of choice, it is not useful for a definitive diagnosis due to the wide variety of images that can be found in patients with COVID 19 infection. This statement is derived from a large cohort of more than 1000 Wuhan patients, where RT-PCR confirmation of COVID 19 and chest CT images of these patients were correspondingly analyzed. CT images were determined to have a sensitivity of 98%; however, the specificity was only 25% [168] . In general, the majority of descriptive studies concur that the finding of ground glass opacifications is most common. It is typically basal and bilateral, and rarely associated with underlying consolidation. A multicenter Chinese study that retrospectively reviewed the CT scans of 101 patients found that 87% had typical ground-glass images and up to 53% had this finding along with consolidations. These findings were more frequent in the most J o u r n a l P r e -p r o o f severe and older age groups of patients [169] . pleural effusion (4%), and lymphadenopathy (2.7%) [170] . The emergence and outbreak of SARS-CoV-2, the causative agent of COVID-19, has rapidly become a global concern that highlights the need for fast, sensitive, and specific tools to monitor the spread of this infectious agent. Diagnostic protocols to detect SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR) were listed on the World Health Organization (WHO) website as guidance, however, various institutions and governments have chosen to establish their own protocols that might not be publicly available or listed by WHO. There are important challenges associated with close surveillance of the current SARS-CoV-2 outbreak. Firstly, the rapid increase of cases has overwhelmed diagnostic testing capacity in many countries, highlighting the need for a high-throughput, scalable pipelines for sample processing [171, 172] . Secondly, given that SARS-CoV-2 is closely related to other coronaviruses [96] , some of the currently available nucleic acid detection assays can result in false positives [173] . Thirdly, critical concern for molecular detection is the low sensitivity reported for RT-qPCR assays [168] and serological tests [135] , particularly in the early stages of infection. Additionally, most of the available RT-qPCR assays require sample processing and equipment only available in diagnostic and/or research laboratories. It is important to mention that coinfection is a possibility, as some reports from Italy and In Spain, less than 1% of cases in a cohort correspond to PLWH, which have had a satisfactory evolution and less than half required an intensive care unit [177] . In the US, of the 5,700 hospitalized patients in the New York area, only 47 patients had HIV, while in San Francisco, data was published on 1,233 people who had diagnosed with SARS-CoV-2 infection, of which less than 3% had HIV and none of them developed severe COVID-19 [178] . Despite the existence of in vitro studies on the efficacy of the use of lopinavir / ritonavir, it is currently known that its effect in cases of moderate and severe COVID-19 is null, and therefore at the moment no recommendation can be given nor how treatment, much less as prophylaxis [179] . This clarification is important given that there is a belief that PLWHs could be protected if they take antiretroviral therapy. Therefore, current recommendations for PLWHs are to maintain antiretroviral therapy with the goal of controlling HIV as well as following the same standards of care as the general population to avoid acquiring a SARS-CoV-2 infection [180] . Regarding SARS-nCoV infection in pregnant women, there is currently limited evidence about the effect of the virus on the mother or fetus. However, due to the physiological changes typical of pregnancy, especially on the immune system (immunosuppression) and the cardiopulmonary system, pregnant women are thought to be more susceptible to developing severe symptoms when they acquire the viral respiratory disease. In 2009, when Influenza A H1N1 infection occurred, only 1% of the infected population were pregnant, yet they accounted for 5% of infection-related deaths [181] . pregnancy (25%) [182] . In another study of 11 pregnant patients infected with MERS-CoV, 9 presented adverse results (91%), 6 neonates were admitted to the neonatal intensive care unit (55%) and three of them died (27%) [183] . However, it is important to note the small sample size which could increase the risk of bias and low power of the study. With information obtained so far from the Wuhan SARS-CoV-2 outbreak, the infection appears to be less severe for pregnant women, compared to previous SARS-CoV and MERS-CoV outbreaks [181] . However, it is important to take into account that the data from COVID-19 infection should be monitored with a Doppler ultrasound every two weeks, due to the risk of developing intrauterine growth restriction [187, 188] . The time of termination of the pregnancy, as well as the method, also depend on several factors, including gestational age, maternal condition in relation to SARS-CoV-2 infection, presence of maternal comorbidities, and fetal condition. Decisions must be made collaboratively during multidisciplinary team discussions, with individualized management plans established for each patient [189] . A diagnosis of COVID-19 alone is not an indication for the termination of pregnancy, rather it should be made in combination with consideration of morbidity and mortality of both the fetus and mother. After delivery, the use of corticosteroids is recommended for antenatal fetal lung maturation, with betamethasone or dexamethasone [190] ; taking special care in critically nursing patients, as this may worsen their condition, and may delay delivery, which is necessary for the management of these patients [187, 191] . The symptoms children present with are similar to adults, as is the incubation period ranging from 1 to 14 days (mean of 5.2). A cough is the most frequent presenting symptom (65%) followed by fever (60%). There is a higher occurrence of gastrointestinal symptoms including diarrhea (15%), nausea, vomiting (10 %) and abdominal pain. These gastrointestinal symptoms are usually more variable in children than adults and are sometimes the only clinical manifestation in associations with fevers. [192, 193] . The clinical progression and disease severity in pediatric patients is markedly different from that of adults. Over 90% of affected children are asymptomatic or have mild to moderate disease [192] . The majority of serious cases in children are related to those with significant comorbidities such as heart disease, immunosuppression, etc. To date of this review, only a few cases of children without underlying comorbidities have died as a result of COVID 19 have been reported. This difference of severity of illness between adults and J o u r n a l P r e -p r o o f children has not been clarified, however, several theories have been postulated. These include that children express more ACE2 receptors in their lungs which confer some protection to severe injuries such as those caused by RSV and which would decrease dramatically with age [194, 195] . Immunological factors may also influence outcomes, as in childhood we are most exposed to frequent challenges including recent seasonal viruses such as RSV in the winter months. Most likely, it is multifactorial and depends on factors from both the host and the virus itself [195] . Abnormal radiological (CT) findings are found in asymptomatic children and consist of bilateral lung lesions (50%). Elevated CRP (Creactive protein), Procalcitonin PCT (80%), and liver enzymes are present in most affected children, unlike adults in whom PCT is not a reliable marker. Virus elimination via the stool even after the negativity in the nasopharyngeal mucosa and the disappearance of symptoms makes them a potential source of contagion through the fecal-oral route [196] . Patients with cancer are generally more susceptible to infections than healthy people, because they have a state of systemic immunosuppression that is exacerbated during chemotherapy or radiotherapy [197] . In China, according to national surveillance data, coronavirus infection occurs in 1.3% of patients with malignant tumors. This is a much higher proportion than the general incidence of 0.3% [198] . p<0.0001) even after adjusting for age [197] . Further research, completed in a tertiary hospital in Wuhuan -China similarly found that 25% of patients with cancer and SARS-COV-2 infection died, most of them over 60 years of age [199] . Due to these findings, it has been proposed by many international entities that during the pandemic, for prevention, an individualized plan based on the patient's specific conditions is required, with the aim to minimize the number of visits to health institutions.  For early-stage patients with need of post-surgical adjuvant chemotherapy, especially those whose clinical, pathologic, and molecular biologic staging suggest a better prognosis, the start time of adjuvant chemotherapy may be delayed up to 90 days after surgery without affecting the overall effect of treatment [200] .  For patients with advanced cancer, the main approach should be to minimize hospitalization in COVID-19 positive installations. Replacing the existing intravenous treatment regimen with oral chemotherapy during this special period may be considered, to ensure that treatment is not interrupted for a long time during the pandemic [201] . However, if there is a suspicion of COVID-19 infection in this population group, the same updated diagnostic guidelines and the corresponding management should be followed depending on their severity of illness. Moreover, an individualized follow-up plan should be outlined due to higher likelihood of complications in this group of population [202] . It should be noted that patients attending out-patient appointments for cancer have higher levels of anxiety, depression and other mental health problems than the general population. Studies have shown that approximately 50% of malignant tumor survivors have a moderate to severe fear of tumor recurrence [203] . For this reason, psychologist surveillance of outpatients in quarantine or during hospitalization should be considered. Reported complications derived from COVID-19 describe a severe disease that requires management in an intensive care unit (ICU) in approximately 5% of proven infections. J o u r n a l P r e -p r o o f appear to be most susceptible to the life-threatening complications. The risk of patient-topatient transmission in the ICU is currently unknown, therefore adherence to infection control precautions is paramount [204, 205] . Progressive deterioration of respiratory function is undoubtedly the most common and lifethreatening complication of the infection. The prevalence of hypoxic respiratory failure in COVID-19 patients is 19%, and it can progress to acute respiratory distress syndrome (ARDS), with the need of mechanical ventilation support at 10.5 days on average. One study found that between 10 and 32% of hospitalized patients require admission to the ICU due to respiratory deterioration [205] . As respiratory complications are the most common cause of severe deterioration, early identification of them will undoubtedly help in timely support. Support provided should be adapted to take into account risk factors such as advanced age, neutrophilia and organic dysfunction for the development of ARDS. The diagnostic support of pulmonary tomography is undoubtedly a valid tool; images in patients with different clinical types of COVID-19 have characteristic manifestations, but it can become an operational problem due to the difficulty in performing imaging on critically ill patients. On the contrary, lung ultrasound at the bed-side could provide an alternative to radiographs and tomography during the diagnosis of COVID-19 [206, 207] . Since more than 70% of hospitalized patients will require supplemental oxygen, it is recommended that oxygen should be started when pulse oximetry values fall below 90%. An upper-limit of 96% saturation should be established, since higher values have been shown to be harmful [208, 209] . Hemodynamic deterioration has a variability of presentation, this depends on the study population and the definition [223] , the presence of shock in the intensive care unit may be present between 25 to 35% [204, 224] . Cardiomyopathy related to viral infection is one of J o u r n a l P r e -p r o o f the main causes of hemodynamic detriment, occurring in up to 23% of patients with COVID-19 [43] . Hemodynamic failure is one of the main causes of death in these patients, with percentages of up to 40%, inconclusive risk factors are associated to date such as diabetes, hypertension, lymphopenia, and elevation of D-dimer [225] . Acute kidney injury (AKI) is present in up to 12% of critically ill patients, podocytes and proximal tubule cells are potential host cells for SARS-CoV-2, caused by the virus induced cytopathic effect. The diagnosis is based on markers of early kidney injury and urinary output [210] . Initial management of shock is based on fluid resuscitation, based on the application of dynamic parameters to predict response to fluids, such as variation in stroke volume (SVV), variation in pulse pressure volume (PPV) and change in stroke volume with passive leg elevation or fluid challenge above static parameters [225] . Variables such as skin temperature, capillary refill time and/or serum lactate measurement are currently valid tools to assess shock. The volume of liquids used in resuscitation should be restricted and administered in relation to dynamic assessment. A liberal water resuscitation strategy is not recommended, rather a balance of crystalloids over colloids as resuscitation liquids should be encouraged and avoiding the use of hydroxyethyl starches, albumin, dextrans or gelatins [226, 227] . Indirect evidence suggests that the target mean arterial pressure (TAM) for patients with septic shock is 65 mmHg using vasoactive support [228] . The recommendation of norepinephrine use as the first agent is maintained. If norepinephrine is unavailable, vasopressin or epinephrine could be used, avoiding the use of dopamine as the initial vasopressor due to the potential development of arrhythmias [229, 230] . In patients with COVID-19 and shock with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and norepinephrine use, dobutamine as inotropic is recommended. Given the development of refractory septic shock, the suggestion of the use of hydrocortisone in continuous infusion is maintained, as indirect evidence, this in favor of reducing the length of stay in the ICU and the resolution time of the shock [229] . According to the investigative mission of the WHO in China, the case-fatality rate ranged Other reports from China have coincided with this clinical risk profile, for example, a study that included 41 confirmed cases, 12 patients who had ARDS had as main underlying diseases: diabetes and high blood pressure. Of these cases, 6 patients died [156] . According to WHO, the recovery time is estimated to be two weeks for patients with mild infections and three to six weeks for those with serious illnesses. On the other hand, CDC established that people who had symptoms in the mild to moderate spectrum and maintained home isolation have a resolution of 3 days after the fever decrease, and there was a substantial improvement in respiratory symptoms, even without use of medications. Isolation may be limited to 7 days from resolution of symptoms, however, it must be adapted to the population circumstances of the epidemic [158] . The evolution of the epidemiological curve in COVID-19 outbreak makes consider containment strategies in China primarily, and other countries based on nonpharmaceutical interventions (NPIs). According to the WHO, the most effective measure is hands washing [231] . combination as public health measures reduced contact rates in the population and therefore reduce virus transmission (Table 6 ) [232] . Table 6 Non -pharmacological measures. Increasing the level of hand cleanliness to 60% in places with a high concentration of people, like all airports in the world would have a reduction of 69% in the impact of a potential disease spreading [233] . The epidemiological evolution of the COVID-19 pandemic through phases has required the application of specific measures according to the time or phase in which the virus is found in each country. The evolution in the non-pharmacological measures has been as variable as the pharmacological ones, in such a way, since January to March, it was ensured that the use of face masks was limited only to people who had contact with epidemiological foci, not to healthy people [234] . This concept was also reinforced by CDC, in order to optimize the use of masks for health workforce. Definitely the course of the pandemic was changing rapidly, which also demanded the change from containment measures to mitigation. The recommendations in the current context remain regarding the use of a facial mask in the community, but its optimization is important for health professionals. The use of the mask is not a substitute for handwashing and social distancing measures, as these ones together allow avoiding viral particles in aerosols or drops, as a low cost and accessible measure for general population [235, 236] . There is still non-specific information for the recommendation of masks, in general, having in several studies claims that surgical or cotton cloth masks do not prevent the spread of the SARS-CoV-2 virus [237] . The evidence about the transmission of the virus in the asymptomatic period also changed the containment measures, suggesting the community use of masks. It is from this that the recommendations for the rational use of masks arise since in some J o u r n a l P r e -p r o o f countries the massive use of N95 masks was reported, masks indicated for the use of medical personnel [238] . Regarding to this non pharmaceutical recommendations, the studies suggest to priories the resources on vulnerable population, in endemic areas, older people, adult with comorbidities and health workforce. Studies are still needed on the duration of the protective effect of the masks and above all the possibility of their reuse for resource optimization. Meanwhile the most important recommendation continues to be its use in addition to hand hygiene and social distancing [238] . Therapeutic J o u r n a l P r e -p r o o f This effect is reinforced by Azithromycin. There were the best results in terms of viral load reduction, even though is mentioned some limitations in the study like small sample size, a short long-term outcome follow-up, and dropout of six patients from the study [246] . Concerning to mortality rates, a study was conducted in New York with 1376 patients (0.63-1.85). Thus, it concludes that the use of HCQ is not associated with either a decreased or increased clinical impairment, intubation or death [247] Results reinforced by other study in 1438 hospitalized patients with COVID-19 diagnosis in New York city, whom received treatment with hydroxychloroquine, azithromycin, or both drugs was not associated with significantly reduction in mortality [248] . Relating to safety of this drug, in a study carried out in 200 patients in which the theoretical complications of the use of HCQ and its combination with macrolides (azithromycin) were assessed by serial electrocardiograms, the following results were obtained. In 5% of patients (10) received chloroquine, 95% (191) received HCQ, and 59% (119) [252] . Supportive therapies in immune regulation, together with the use of antivirals, are important to take into account, especially in those patients in a serious and critical state, in which they could improve the clinical response and perhaps avoid residual lung injuries. The convalescent plasma is extracted from recovered individuals from an infection, being an antibody transfer medium to provide passive immunity (neutralizing antibodies and globulin). The goal is to provide a rapid immune response until the patient can develop their own active immune response in the hope that there will be clinical improvement [253] . improvement in most individuals, as well as viral suppression 7 days after treatment [255] . In the same country, at the Shenzhen Hospital, 5 cases of patients with severe COVID-19 were reported who met criteria for acute respiratory distress syndrome (ARDS), who were administered convalescent plasma (titration greater than 1: 1000 and neutralizing antibodies greater than 40). It was found that clinical recovery occurred approximately 12 days after the transfusion (4 patients) and 3 of the 5 patients were discharged 55 days after admission. It is important to mention that this group of patients also received antivirals, methylprednisolone and all the necessary support measures in intensive care [256] . Other drugs like ivermectin, nitazoxanide, and others have been studied in the context of COVID-19 treatment, but the results are inconsistent. All of the clinical trials evidence, supporting or against the use of mentioned drugs are detailed in (Supplementary Table 2 ). This review summarized some drug repurposing agents previously known to has efficacy against other virus like SARS-CoV, MERS-CoV, influenza. Actually, exist some new drugs with high potential action on targets for Covid-19 therapeutics. It is important to notice that there is no specific treatment for the coronavirus approach. In context of the scientific evidence exposed and the particular clinical features of each patient, the reader will be able to make the best clinical and therapeutic decisions. When it comes to vaccine design and manufacturing, the main objectives are to ensure its safety, its efficacy in activating specific adaptive immune responses and the production ofideally-long term memory. Thus, eliciting protective immune responses including neutralization antibodies and/or CTL generation is of paramount importance. Huge challenges need to be tackled in order to minimize the long and cumbersome process of vaccine generation. Among them, candidate antigen targets need to be identified, immunization routes and delivery systems investigated, animal models set, adjuvants optimized, scalability and production facility considered, target population selected, and vaccine safety and long-term efficiency evaluated. Currently there are no approved vaccines against any human coronavirus, suggesting that their generation is quite novel. Several candidate vaccines against SARS-CoV had shown promise reaching Phase I or Phase II clinical trials [258, 259] , but the rapid containment of SARS-CoV expansion rendered them redundant, did not allow for a test population for Phase III trials and, therefore, put their further assessment to a halt. CTL memory could last up to 11 years after infection [260] . These data suggest that vaccine strategies employing viral structural proteins that can elicit effective, long-term memory T cell responses could yield fruitful results. On the other hand, the S1 spike protein region containing the ACE receptor binding domain (RDB) is the obvious option when neutralizing antibody responses are considered [261] [262] [263] . Indeed, a candidate SARS vaccine antigen consisting of the RBD of SARS-CoV Spike protein was created and found it could elicit robust neutralizing antibody responses and long-term protection in vaccinated animals [264] . The fact that COVID-19 convalescent sera shows potential as a therapeutic approach [80] aligns with the theory that efficient B cell responses are mounted and lead to production of protective antibodies. Two different groups, using an immunoinformatic approach mapped several CTL and B cell epitopes on different proteins of the virus [265, 266] . Moreover, various CTL epitopes were found to be binding MHC class I peptide-binding grooves via multiple contacts, illustrating their probable capacity to elicit immune responses [265, 266] . Consequently, these identified B and T cell epitopes could be potential targets for therapeutic vaccines. However, important safety considerations should be taken into account before releasing a new vaccine in the market. Previous studies on macaque models have shown that a vaccineinduced anti-Spike protein antibody at the acute stage of SARS-CoV infection can provoke severe acute lung injury [267] . Similar observations of SARS-CoV vaccine-induced pulmonary injury have also been described in multiple several murine and monkey animal models [268] . An additional factor that needs to be checked in phase II and III trials is that the vaccine does not cause ADE of the pathogen, as has previously been described. Such concerns have risen in the context of a Dengue vaccine [269] . The pharmaceutical companies that are currently on a race to produce a vaccine for COVID-19 along with the vaccine developing strategies they are using are summarized in Table 8 and Figure 7 . As can be easily deduced from Table 8 hospitalization and admission to already heavily charged ICUs due to these pathologies that could prove critical for weaker health systems that would struggle to carry the burden of combined outbreaks. Moreover, vaccinating health care workers is crucial for reducing the risk of absence due to disease, thereby strengthening the healthcare workforce and minimizing the risk to infect COVID-19 hospitalized patients with additional pneumoniacausing pathogens. Lastly, COVID-19 patients vaccinated for influenza and Streptococcus pneumoniae allow their immune system to focus on one pathogen and, therefore, give it a better fighting chance against SARS-CoV-2 infection [276] . High risk groups prioritized for vaccination for these two pathogens include pregnant women, persons with immunocompromised immune systems (either due to congenital or acquired immunodeficiencies), children, adults ≥ 65 years and health care professionals. J o u r n a l P r e -p r o o f heat or chemical treatment inactivation. F) Attenuated live pathogen vaccine strategies consist in administering a live pathogen that due to cell culture passaging has lost its virulence. They usually elicit robust and long-term memory immune responses without the need to administer an adjuvant. G) In DNA vaccines the DNA codifying a highly immunogenic antigen is administered and captured by professional antigen presenting cells (APCs) leading to antigen production and presentation by these cells. H) Moderna's vaccine candidate already in Phase I clinical trials uses an mRNA vaccine approach whereby the genetic information codifying for the S protein of SARS-CoV-2 is delivered in LNPs to enhance absorption by APCs. Once uptaken by APCs the mRNA induces the expression of S antigen that is subsequently mounted on and presented by MHC molecules to elicit adaptive immune response. Numerous studies confirm that climate has an impact on virus (i.e., influenza, coronavirus, etc.) spread through manipulating the conditions of i) its diffusion, ii) the virus survival outside the host, and iii) the immunity of host population [277] . Meteorological conditions, such as temperature, humidity, wind speed and direction, atmospheric pressure, solar radiation (including ultraviolet (UV) spectrum) and precipitation amount and intensity depend on the latitude and the elevation of the location, thus creating distinct climatic zones in the planet. While in some regions, such as temperate climate zones, human influenza peaks have clear seasonal cycles, in others it is not as predictable [276] [277] [278] [279] [280] . An array of studies, investigating the relationship between climatic factors and the activity of influenza all over the world, concluded that at the high latitudes of the world the peaks of influenza correlate with cold and dry weather conditions (i.e., winter season), while around the equatorial zone, it is more common during the months of high humidity and precipitation [282] [283] [284] [285] [286] [287] [288] . Essentially, it depends on explicit threshold conditions based on monthly averages of specific humidity and temperature. 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