norepinephrine, and milrinone infusions and improved over 2 weeks. 11 Inciardi et al 12 treated a healthy 53-year-old woman with COVID-19infection and myocarditis. She too had elevated troponin and BNP levels as well as decreased systolic function. She was treated with steroids, antiviral medications, chloroquine, and a dobutamine infusion. She also improved with time. 12 Data from the National Health Commission of the People ’ s Republic of China revealed that of those who died of COVID-19, 11.8% who did not previously have underlying cardiac disease had substantial cardiac damage deﬁned as elevated troponin levels or cardiac arrest during hospitalization. 4
Initially it was suggested that the mechanisms of the cardiac events may be related to interactions of the SARS-CoV-2 virus with the angiotensin-converting enzyme-2 (ACE2) receptor, since both this virus and the SARS virus, and influenza before that, were documented to use the ACE2 receptor as a functional receptor; furthermore, smoking and hypertension (for which ACE inhibitors and ACE2 receptor blockers are commonly used as treatment) have previously been documented as underlying comorbid risk factors for COVID-19infection and both have been shown to increase expression of the ACE2 receptor. [14,24,25]
The infection of Covid-19, recently declared pandemic by WHO, represents perhaps one of the most serious worldwide emergencies, potentially able to destroy social order and economies and to deeply change our lifestyle in the near future. Since the first appearance of this new Coronavirus (SARS-CoV-2) (Worldometers, 2020), however, the Covid-19infection has been treated with very mixed feelings: from just a disease a little more serious than a seasonal flu, to a very severe and troubling infection. The epidemics was firstly detected in China, in the city of Wuhan, at the end of December 2019. After some interlocutory days, the government of China showed serious concern and implemented very severe measures in the Hubei province, the centre of the epidemics, to contain the epidemic spreading of the infection. About 45 days after the first detection (mid- February 2020), the epidemics started to seriously affect several other countries (South Korea among the firsts, being a rather natural candidate that borders with China). Since the end of February, it flared up in Italy and Iran for less clear reasons and, since mid-March 2020, the epidemics has spread all over Europe, in the USA, and many other countries (Worldometers, 2020). Here we want to focus on the Covid-19 epidemic in Italy that shows some peculiar features, distinguishing its evolution from the one observed in other countries. The epidemic appears very aggressive, both in terms of spread rate and mortality, which are however very uncertain parameters for this new virus. In Italy, the infection is mainly focused in the Lombardia Region and the area around the Po river. The most affected regions are Lombardia, Emilia-Romagna and Veneto, which also represent the richest and more productive parts of Italy. In Italy the infection grew very fast, overcoming South Korea in the number of infected people as early as 30 March 2020 reaching 101.739 total infections. Moreover, it showed an average Case Fatality Ratio (CFR) over 11%, well above any other country and more than double with respect to the Hubei Region in China, where the new virus first appeared, and where CFR was significantly higher than in other parts of the China and higher than several countries in the world.
In this brief communication, we propose the concept that capillary regression may represent a primary pathogenic process underlying COVID-19infection, particularly in the serious and life-threatening manifestations of the disease. We suggest that the marked elevations of pro-inflammatory mediators that are observed in these seriously ill patients may directly induce capillary regression and endothelial cell (EC) loss. Recent autopsy studies are demonstrating EC loss leading to widespread microthrombi and associated tissue damage. Recent work has indicated that interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNFα), and thrombin, individually and in combination, can potently cause capillary tube regression in experimental models in vitro and in vivo. Other pro-inflammatory mediators including interferon gamma (IFNγ), interleukin-4 (IL- 4), and interleukin-13 (IL-13) were also shown to be pro-regressive and could be
The progression of the recent COVID-19 pandemic surprised political authorities as well as scientists. The possibility to design powerful strategies for health care and preserving economic and social activities strongly relies on the capacity to monitor correctly the virus spreading and the immune response in the symptomatic and asymptomatic population. The available data relative to the first pandemic months indicate that the test reliability was progressively improved but also that the extremely variable methodologies used in the diagnostic studies generated data that are often not comparable. This condition prevents a simple metadata analysis for the identification of reliable diagnostics guidelines. Nevertheless, there are converging evidences that combinations of complementary approaches may enable more precise identification of virus infection. Furthermore, it appears that the similarities between SARS-CoV2 and the related types SARS-CoV1 and MERS that caused outbreaks in the last 20 years can be exploited to infer some information for which no direct evidence is still available
Vitamin D has diverse immunomodulatory effects to reduce viral infections. These include strengthening of epithelial cell junction integrity, up-regulatory effect on the anti-microbial cathelicid in family of peptides, recruitment of immune cells to the site of infection, and reducing the cytokine storm induced by the innate immune system as well as adaptive immune response 2 . The entry of SARS-CoV-2 into the human cells is via ACE 2, a membrane exopeptidase that converts Angiotensin I to the nonapeptide angiotensin. ACE2 negatively regulated the RAS by converting Ang II to Ang-(1–7). It is expressed in human airway epithelia. The RAS, which includes ACE and ACE2, is a complex network that has a major role in various biological functions 31 . Chronic vitamin D deficiency may induce RAS activation lung fibrosis through activation of the RAS 35 ; therefore, increasing evidence indicates that 1,25(OH)2D3 may also be a negative endocrine regulator of the RAS. Inducing the expression of renin, ACE, Ang II and AT1R, and inhibiting ACE2 expression could result in acute lung injury. Vitamin D inhibits renin, ACE and Ang II expression, and induces ACE2 levels in ALI. Therefore, vitamin D may attenuate ALI by inducing ACE2/Ang-(1–7) axis and inhibiting renin and the ACE/Ang II/AT1R cascade 8,14 .
correlate with increased inflammation in multiple systems (100-102), while IL-6 has been shown to inhibit the cleavage of ultra-large VWF strings by ADAMTS13 under flowing conditions (79, 103). The authors could find only five studies evaluating both VWF and ADAMTS13 levels in COVID-19 patients in literature (104-108) (Table 3). Majority of these studies reported lower ADAMTS13 activity concurrent with higher VWF in COVID-19 patients (104-107). In one of these studies, Bazzan et al. (104) reported lower ADAMTS13 levels in 88 COVID-19 patients compared to healthy controls (48.71 ± 18.7% vs HC, 108 ± 9.1%; normal value 60–130%). Within patient cohort, lower ADAMTS13 and higher VWF levels were found non-survivors (9/88) compared to survivors. Further, lower than 30% ADAMTS13 activity were significantly associated with mortality in survivor analysis. Huisman et al. (105), observed low ADAMTS13 activity levels (0.48±0.14 IU/mL against a reference range of 0.61-1.31) in parallel with elevated VWF antigen and activity (~4 fold) in 12 ICU-admitted patients. A similar reduction in
ACE2 the target receptor, which plays a crucial role in the entry of virus into the cell, has been the focus for the Infection-genomics of COVID-19infection and disease progress. Several groups have analyzed human genome and single-cell RNA-seq databases for ACE2 variants, allele frequency and expression in various tissues to understand the susceptibility and mechanism of pathophysiology of COVID-19infection [21, 56, 57, 58]. In a recent study, Asian male (55 y) was reported to have an extremely large number of ACE2-expressing cell clusters, including type II alveolar cells (AT2), in the lung compared to five African American and two white individuals . Single cell RNA-seq data with significant depth could be used evaluate ACE2 and CD147 expression along with relevant proteases and other accessory proteins in specific cell types of major organs will help us clarify details . Analyses of coding-region variants in ACE2 and the expression quantitative trait loci (eQTL) variants among different populations show that none of the ACE2 mutants are resistant to binding to the virus . Variations in allele frequencies in the eQTL variants along with varied ACE2 expression may suggest distinct susceptibility from different populations . The deletion/insertion (D/I) polymorphism in intron 16 of ACE1 shows geographical and ethnic variations  and the D allele is associated with a reduced ACE2 expression. D-allele frequency is inversely proportional to COVID-19 infections . Viruses will reach heart, kidney and ileum through blood, most likely at later stages, which is the leading cause of death through comorbidities. Patients with preexisting hypertension and cardiovascular diseases, particularly who are taking ACE inhibitors or angiotensin II receptor antagonists and have increased ACE2 expression [60, 61], have an increased risk of severe disease and death [62, 63]. Thus, ACE2 is critical for initial infection followed by disease progression.
The role of health care workers (HCWs) who are at the frontline of containing the pandemic cannot be over-emphasised. HCWs are exposed to high risk of COVID-19infection in the course of treatment of patients 4 . HCWs are likely to have close contact with COVID-19 patients in the course of examination and management. The risk of exposure of HCWs is further compounded by several factors mostly beyond their control. Some patients present with symptoms not previously recorded whilst some are completely asymptomatic. In many cases, the needed personal protective equipment (PPEs) are not readily available for HCWs.
laboratory diagnosis, liver function tests and COVID19, SARS-COV-2 and coronavirus. Reference lists of selected articles were also searched to identify missed studies. Time of publications was not restricted, however, only studies published in English were included. Studies were also included if they were primary research articles, assessed the association between serum levels of liver biochemical outcome from COVID19infection and reported in mean (SD) or median (IQR). Review articles, expert opinions, books, newsletters, commentaries, theses, editorials were all excluded. Patients were grouped as mild or severe cases. All patients in an intensive care unit (ICU) and non-survival cases were classified as severe cases whereas patients who are not in ICU and those that are survivors as seen in some studies were grouped as mild cases. All publications were retrieved online while data extraction was carried out for each paper highlighting the following: name of first author and year of publication, study design, study location, laboratory parameter, serum levels of the analytes, sample size, age, gender, and disease severity criteria. The search strategy and results are provided in Figure 1.
The emergence of the Novel Coronavirus otherwise known as COVID-19, which broke out in the Hubei Province of China in December 2019, has no doubt hurt the socio-economic growth of the World. According to the World Health Organization (WHO), most people infected with the Novel Coronavirus will experience mild to moderate respiratory illness and recover without requiring special treatment. It is also evident that older people, and those with underlying medical problems like cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness . The reward of the successful effort in containing the COVID-19infection in Asia came about in WHO pronouncing Europe as the focal point of the illness on the 13th of March, 2020. Although the mortality rate of the Novel Coronavirus is put at 3.4% by the WHO as of the 3rd of March, 2020 , the rate at which it spreads is alarming. Currently, COVID-19 is said to have affected all the Continents of the World with Europe being one of the hardest-hit continents. According to Our World in Data (OWD) report on the 4th of April, 2020, Italy sits comfortably at the top of the chart of the death rate with more than 15,000 deaths recorded and many others infected while the United States of America (USA) is currently the highest hit with more than 50,000 deaths recorded as at the 26th of April, 2020 . Many nations of the world are currently experiencing partial lockdown while, others are experiencing a total lockdown. In this regard, we discuss briefly a few misconceptions circulating around and as well report the recent manifestation of the transmission of the disease from humans to animals. We also highlight the roles Mathematical Epidemiologists could play in reducing the spread of the Pandemic and make recommendations for policymakers.
In light of perceptions in the USA, Spain, Italy, France and, the UK, and from postmortem of lungs implicated in Covid-19, all uncovered pulmonary thrombosis which isn’t a case of ARDS(Acute respiratory distress syndrome), however all the more disturbing that it shows restraint hypoxemia that isn’t reacting to PEEP (positive end-expiratory pressure) but high oxygen stream. Like methemoglobin, the Covid-19infection basic protein sticks to heme - dislodges oxygen which discharge free-iron, that prompts toxicity and causes swelling of alveolar macrophages that outcomes in respective CT scan changes as it is a systemic response. There is no advantage of invasive ventilation, however patients may require recurrent blood transfusions or plasmapheresis. The Covid-19 virus assaults beta chain, separates heme, displace iron, and converting to porphyrin. The infection can separate oxy- Hb, carboxy-Hb, and glycosylated Hb. Lung inflammation occurred from both oxygen and CO 2 exchange, prompting the ground glass on x-rays, it reflects CO 2 toxicity as an
In the end of April nearly 100 cases of children aged between 6 month and 9 years with Kawasaki like disease were reported (mostly in Europe) probably linked to COVID-19. With the increasing awareness of this condition the number of cases reported is increasing worldwide. We aim to sum up the known data about this new entity based on published data (in a case report, a series of 8 cases and in newspapers and society statement) and using our knowledge of classical Kawasaki disease. It seems to be a post infectious disease with an onset between 2- 4 weeks after the infection, probably in genetically predisposed children aged between 6 month to 17 years. A very rough estimation of incidence based on current data from Bergamo, Italy, and New York State and a lot assumption is between 0.016% (95% CI:0.013-0.02%) - 0.31% (95% CI: 0.2-0.47%) of infected children. Clinical signs overlaps with Kawasaki disease in some children, but another feature is prominent gastrointestinal manifestations. For the 9 detailed patients most had incomplete presentation for Kawasaki disease (with a mean 1.7 (+/- 1.2) criteria per patient for the 5 non fever criterion) and only one had a classical form. In some cases, presentation is closer to toxic shock syndrome or isolated myocarditis. Persistent fever seems to be constant and biological exploration are consistent with inflammation (elevated CRP, ferritin and D-Dimers). Management is described as supportive and children seem to improve rapidly, but can require cardiac or respiratory support. In date of 11 may 2020 there is 4 deaths confirmed linked to these new entities (1 in UK and 3 in New York). Paediatricians and general practitioners need to be aware of these possible evolution following COVID-19infection. However it seems to be rare and children are probably still spared from most morbidities and mortality linked to COVID-19infection .There are need of published detailed cohorts to better delineate these entities.
‘isolation’, ‘travel bans’, and ‘social distancing’ is troublesome for the authority because the transmission of COVID-19infection from human to human or from any other source to human could be either without any symptoms or with very mild symptomatic cases taking 5 to 14 days of incubation. In fact, it is very significant to measure the severity and the rate of transmission of the infection: mild, very mild and without any symptom cases, prior to take the decision to impose lockdown and/or curfew to make ‘quarantine’, ‘isolation’, ‘travel bans’, and ‘social distancing’ a successful. The nature of infection- mild, very mild and asymptomatic of COVID-19infection determine the containment and restraint strategies formulation. [48-50]. In addition, temporary and emergency hospitals could be established, obviously apart from locality, to provide treatment and take care in pandemic like COVID- 19 . List of quarantinable diseases is declared by the legal authorities of Centers for Disease Control and Prevention (CDC): cholera, diphtheria, infectious tuberculosis, plague, smallpox, yellow fever, viral hemorrhagic fevers, severe acute respiratory syndrome, influenza that can cause a pandemic; COVID- 19 belongs to the quarantinable diseases as it has severe acute respiratory syndrome .
In December 2019 a pandemic of acute respiratory distress syndromes occurred in Wuhan, China, the early evidence suggests this may be due to exposure to local sea foods in China  The pathogen was isolated from Chinese patients and designated as severe acute respiratory syndrome corona virus 2 (SARS- COV-2) .WHO announces this as global pandemic on March 11; 2020. COVID-19 mainly affects lungs by producing respiratory predominant symptoms like fever, cough, flu and dyspnea . The virus primarily attacks the angiotensin converting enzyme-2 receptor (Ace2) of the lung. However recent reports suggested that COVID-19infection is not confined only to lungs.As ACE2 receptor is the binding site of (SARS-COV-2) and there are abundance of this receptor on different body organs such as in alveolar epithelial type II cells of lung tissues, as well as extrapulmonary tissues such as the heart, endothelium, kidneys, and intestines [3, 4, 5, 6]. In addition to respiratory disease there are a lot of complications associated with COVID-19. The pandemic
wild animal market and most cases of infection, indicating possible animal-to-human transmission, and studies have increasingly demonstrated human-to-human transmission of SARS-CoV-2 through droplets or direct contact 2,8-10 . Moreover, according to one study, presumed hospital-related transmission of SARS-CoV-2 was suspected in 41% of patients 8 . Based on the evidence of a rapidly increasing incidence of infections 11 and the possibility of transmission by asymptomatic carriers 12 , SARS-CoV-2 can be transmitted effectively among humans and exhibits high potential for a pandemic 5,10,13 . In addition to the high transmission efficiency of SARS-CoV-2, the advancement and convenience of global travel could further enhance its worldwide spread 12 . On 30 th January 2020, the WHO declared the COVID- 19 outbreak as the sixth public health emergency of international concern, following H1N1 (2009), polio (2014), Ebola in West Africa (2014), Zika (2016) and Ebola in the Democratic Republic of Congo (2019). Therefore, health workers, governments and the public needs to co-operate globally to prevent its spread 14 .
Since December 2019, many unexplained cases of pneumonia with cough, dyspnea, fatigue, and fever as the main symptoms have occurred in Wuhan, China in a short period of time [1,2]. China’s health authorities and CDC quickly identified the pathogen of such cases as a new type of coronavirus, which the World Health Organi- zation (WHO) named COVID-19 on January 10, 2020 .On January 22, 2020, the Information Office of the State Council of the People’s Republic of China held a press conference introduced the relevant situation of pneumonia prevention and control of new coronavirus infection. On the same day, the People’s Republic of China’s CDC re- leased a plan for the prevention and control of pneumonitis of new coronavirus infection, including the COVID-19 epidemic Research, specimen collection and testing, tracking and management of close contacts, and propaganda, education and risk communication to the public .Wuhan, China is the origin of COVID-19 and one of the cities most affected by it. The Mayor of Wuhan stated at a press con- ference on January 31, 2020 that Wuhan is urgently building Vulcan Mountain Hospital and Thunder Mountain Hospital patients will be officially admitted on February 3 and February 6 . By 24:00 on February 6, 2020, a total of 31,161 confirmed cases, including 636 deaths, were reported in the Chinese mainland, 22,112 confirmed cases, including 618 deaths, were reported in Hubei province, and 11,618 confirmed cases, including 478 deaths, were reported in Wuhan city. The spread of COVID-19 and various interventions have had an incalculable negative impact on People’s daily lives and the normal functioning of society. Cities in China’s Hubei province have issued varying degrees of closures and traffic restrictions . In fact, there are many imminent questions about the spread of COVID-19. How many people will be infected tomorrow? When will the inflection point of the infection rate appear? How many people will be infected during the peak period? Can existing interventions effectively control the COVID-19? What mathematical models are available to help us answer these questions? The COVID-19 is a novel coronavirus that was only discovered in December 2019, so data on the outbreak is still insufficient, and medical means such as clinical trials are still in a difficult exploratory stage . So far, epidemic data have been difficult to apply directly to existing mathematical models, and questions need to be addressed as to how effective the existing emergency response has been and how to invest medical resources more scientifically in the future and so on. Based on this, this article aims to study the gaps in this part.
CoV-2 infection. In COVID-19 patients, IgM antibodies appeared within a week post disease onset, and gradually decreased, whereas IgG antibodies were produced 10 days after infection and lasted for a longer time . Neutralizing antibodies block SARS- CoV-2 infection, and macrophages recognize neutralized viruses and clear them by phagocytosis . However, neutralizing antibodies titres varied in recovered COVID- 19 patients, ranging from below detection (<30) to 1936, and virus neutralization deficiency occurred in some patients . In our study, plasma SARS-CoV-2-specific IgM was close to normal (Figure. 2C). Although all patients generated plasma SARS- CoV-2-specific IgG at a relatively high level, neutralizing antibodies titres were mild, with 22.72% (5/22) patients not presenting any neutralizing activity (Figure. 2C). The low neutralizing antibodies had no correlation to B cells and CD4+ T cells (Figure. 2E, 2F). Taken together, these findings suggested that SARS-CoV-2-specific antibodies had low or even no virus neutralizing activity in COVID-19 patients with long-term SARS-CoV-2 infection. The reason nevertheless needs further investigation.
Another way to reduce the false negativity in nucleic acid based testing is to perform CT scans. As discussed in Section 3.1, it can be more sensitive to diagnose COVID-19 using CT scans. The caveat for the CT scan is its relatively low specificity (false positive results), which may be tolerated at the initial stage of an outbreak. However, positive CT scans only show for patients at the later stage of their COVID-19 infections, which limits its use for early stage screening. The method is still valuable to quickly screen serious cases from mild ones. Due to limited testing kits and over-burdened clinical resources, many patients with mild symptoms have been self-isolated first. When their conditions deteriorate, it becomes important to
COVID-19 is the newly emerged outbreak, the understanding of its nature, also the prevention and control of this disease is limited. Since there are very few studies on this new coronavirus, some knowledge and assumption were drawn from the lesson learnt from the outbreak of SARs and MERs (both are also RNA coronavirus) in the past. Therefore, the recommendation, as stated in this manuscript, needs to be updated accordingly to the current situation. The medical practitioners need to cling on the new status of COVID-19 constantly. In case that anyone who has any relevant information and want to bring to our attention, please email to firstname.lastname@example.org. With no legal effect, this guidance should contemporarily conform to the occurrence (current situation or incident), character (internal factors of the patient), and circumstances (external factors of the patient, e.g. hospital resources, equipment, and capacity).