HOSPITAL IN ITALY WHERE A CORONAVIRUS PATIENT IS TREATED IN APRIL 2020<\/figcaption><\/figure>\nThe routes of person-to-person transmission of SARS-CoV-2 include direct transmission, such as coughing, sneezing, droplet transmission, and contact transmission, such as contact with oral, nasal, and ocular mucous membranes. [20]\u200b<\/sup><\/p>\nSymptoms appear between (2) two and (14) fourteen days, with an average of (5) five days after exposure to the virus. 21]<\/sup>[22<\/sup>][23<\/sup>][24<\/sup>] Transmission can be prevented by hand washing, use of masks, coughing up bleeding (sunken part of the arm opposite the elbow), and early diagnosis of the disease. [25<\/sup>]\u200b[15<\/sup>]\u200b<\/p>\nCoronavirus Name<\/span><\/h2>\nThe World Health Organization announced on 11 February 2020 that COVID-19 would be the official name of the disease. The name is an acronym for coronavirus disease 2019<\/i>. Care was taken to ensure that the name did not contain references to any place, animal species or group of people in line with international recommendations, to avoid any stigmatization against any group. [26]<\/sup>\u200b<\/p>\n<\/span>Epidemiology Of The Coronavirus<\/span><\/h2>\nCovid-19 was first identified on December 1, 2019, in the city of Wuhan, capital of Hubei Province, in central China, when a group of people were reported to have pneumonia of unknown cause, linked mainly to workers at Wuhan’s southern Chinese wholesale seafood market. 27]<\/sup> The number of cases increased rapidly in the rest of Hubei and spread to other territories.<\/p>\nThe rapid spread of the disease led the World Health Organization to declare it a health emergency of international concern on 30 January 2020, based on the impact the virus could have on underdeveloped countries with less health infrastructure, [28]<\/sup> and to recognize it as a pandemic on 11 March. 13]<\/sup> Cases have been declared in Western countries (including Italy, Spain and the United States, in terms of the number of patients[29]<\/sup>), in the Asia-Pacific region and in almost all parts of the world. [30]<\/sup>\u200b<\/p>\nTo prevent the spread of the virus, governments have imposed travel restrictions, quarantines, confinements, social isolation, cancellation of events, and closure of establishments. The pandemic is having a disruptive socio-economic effect,[33]<\/sup> and fears of supply shortages have led to panic buying. There has been misinformation and conspiracy theories spread online about the virus,[34<\/sup>][35<\/sup>] and incidents of xenophobia and racism against citizens of China and other East and Southeast Asian countries. [36<\/sup>]\u200b<\/p>\n<\/span>Coronavirus Etiology: Origin of COVID-19<\/span><\/h2>\nThe cause of covid-19 is infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [9]<\/sup>[37]<\/sup> which is a type of Orthocoronavirinae<\/i>. 3]<\/sup>[9<\/sup>] Initially, the virus was named 2019-nCoV<\/i>[38<\/sup>]. It was first discovered and isolated in Wuhan, China, after causing the 2019-2020 coronavirus disease epidemic. It appears to be of zoonotic origin, i.e., it passed from an animal host (a bat) to a human host. [39]\u200b<\/sup><\/p>\nThe virus genome consists of a single strand of RNA, so it is classified as a single-stranded RNA-positive virus. Its genetic sequence has been isolated from a sample obtained from a patient affected by pneumonia in the Chinese city of Wuhan. [40]<\/sup>\u200b[41<\/sup>]\u200b[42<\/sup>]\u200b[43<\/sup>]\u200b[44<\/sup>]\u200b[45<\/sup>]\u200b<\/p>\nIt was suggested that interpersonal transmission of the virus could occur through saliva droplets expelled through coughing and sneezing. 14]<\/sup> It can cause acute respiratory disease and severe pneumonia in humans.<\/p>\n<\/span>Clinical picture of the Coronavirus<\/span><\/h2>\n<\/span>Onset of Coronavirus Infection<\/span><\/h3>\nIt all starts inside the human body, when the coronavirus comes into contact with the mucous membranes of the nose, eyes or mouth from respiratory secretions of an infected person or from contact with hands contaminated by the virus. It is there, mainly in the cells of the mucosa of the upper respiratory tract, that the virus has the opportunity to enter as if it were a Trojan horse. The microscopic infiltration occurs because this virus has developed specific “keys” (proteins) that serve to open the “locks” of these human cells and have a free way to infiltrate them. One of the keys it uses, the S-protein, fits very well with a lock, the ACE2 protein, which is present on the surface of a wide variety of cells in the human body. [46]\u200b<\/sup><\/p>\n<\/span>Hatching of Coronavirus<\/span><\/h3>\nOnce the coronavirus has managed to enter the cells, it takes over the cellular machinery to use it for its own benefit. It forces the human body’s own cells to make millions and millions of copies of the virus by synthesizing its RNA (its genetic material) and its proteins which are then assembled to create new viruses. These new viruses leave the cells, destroying them, and go to neighbouring cells to repeat the cycle indefinitely.<\/p>\n
The SARS-CoV-2 virus is able to spread and multiply in the cells of the respiratory tract (also in other types of cells to a lesser extent, such as intestinal cells), without our body sending out alarm signals for several days. This is what we call the incubation period, the time that passes from the moment of infection until the development of symptoms; the calm before the storm.<\/p>\n
The WHO estimates that the incubation period (the time between infection and the onset of symptoms), lasts between two and ten days,[47]<\/sup> while for the US Centers for Disease Control and Prevention it lasts between two and fourteen,[48]<\/sup> although it is generally 4-6 days. 49]<\/sup>[50<\/sup>] A study published in February by Chinese researchers found that the period can be extended to 24 days. 51<\/sup>] One case is reported to have had an incubation period of 27 days. [52<\/sup>]\u200b<\/p>\n<\/span>Coronavirus Symptoms<\/span><\/h2>\nInfected people may be asymptomatic or have a flurry of symptoms ranging from mild to very severe, including fever, cough and shortness of breath. 53]<\/sup>[54<\/sup>][55<\/sup>] Diarrhea and other rhinopharyngeal symptoms, such as sneezing, runny nose, and sore throat, are less common. [56<\/sup>]\u200b<\/p>\nThe symptoms of covid-19 are non-specific and its presentation, according to WHO\/WHO, may even be symptomless (asymptomatic). Based on a statistical sample of 55 924 laboratory-confirmed cases, the frequency of presentation of the symptoms in the Chinese population was as shown in the attached table. [57]\u200b<\/sup><\/p>\n\n\n\nSymptom present:<\/th>\n | Frequency *<\/p>\n (%)<\/th>\n<\/tr>\n |
\nFever<\/td>\n | 87,9 %<\/td>\n<\/tr>\n |
\nDry cough<\/td>\n | 67,7 %<\/td>\n<\/tr>\n |
\nFatigue<\/td>\n | 38,1 %<\/td>\n<\/tr>\n |
\nSputum production<\/td>\n | 33,4 %<\/td>\n<\/tr>\n |
\nDyspnea<\/td>\n | 18,6 %<\/td>\n<\/tr>\n |
\nMuscle pain or joint pain<\/td>\n | 14,8 %<\/td>\n<\/tr>\n |
\nSore Throat<\/td>\n | 13,9 %<\/td>\n<\/tr>\n |
\nHeadache<\/td>\n | 13,6 %<\/td>\n<\/tr>\n |
\nChills<\/td>\n | 11,4 %<\/td>\n<\/tr>\n |
\nNausea or vomiting<\/td>\n | 0 5,0 %<\/td>\n<\/tr>\n |
\nNasal congestion<\/td>\n | 0 4,8 %<\/td>\n<\/tr>\n |
\nDiarrhoea<\/td>\n | 0 3,7 %<\/td>\n<\/tr>\n |
\nHemoptysis<\/td>\n | 0 0,9 %<\/td>\n<\/tr>\n |
\nConjunctival congestion<\/td>\n | 0 0,8 %<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n *(Until 1 May 2020 and based on 55,924 confirmed cases per laboratory). [57]\u200b<\/sup><\/p>\nSymptoms were reported to include fever in 90% of cases, fatigue and dry cough in 80% of cases, and breathing difficulties in 20% of cases. 58]<\/sup>[59<\/sup>][60<\/sup>][61<\/sup>] Chest x-rays have revealed signs of pneumonia in both lungs. Vital signs are generally stable during the time of hospitalization. Blood tests have shown a low number of white blood cells in the blood.<\/p>\nOn 20th January The Lancet<\/i> published a study of the first 41 cases of patients admitted with a confirmed diagnosis from 16th December 2019 to 2nd January 2020. 62]<\/sup> Of these, less than half had underlying diseases, including diabetes, hypertension, and cardiovascular disease. Common symptoms at the onset of the disease were fever, cough, and myalgia or fatigue; less common symptoms were sputum production, headache, hemoptysis, and diarrhea. Dyspnea developed in 22 out of 40 patients (55 %), with a median time from disease onset to dyspnea of 8 days. Lymphopenia was present in 26 out of 41 patients (63 %). All patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (positive for real-time RT-PCR in the plasma sample), acute cardiac injury and secondary infection. Thirteen patients (32%) were admitted to an ICU and six died (15%). In a clinical commentary in the same journal, a comparison of clinical presentation against other emerging coronaviruses (SARS and MERS) is presented; among other clinical data in the cases studied so far, it should be noted that upper respiratory tract symptoms are remarkably uncommon (e.g. no patient had a sore throat). [63]<\/sup>\u200b<\/p>\nSome of those infected may be asymptomatic and show test results that confirm the infection but do not show clinical symptoms, so researchers have issued advice that people in close contact with confirmed infected patients should be monitored and examined closely to rule out infection. [64]\u200b<\/sup><\/p>\n<\/span>Clinical Phase<\/span><\/h3>\nThe spread of the coronavirus throughout the body alerts the immune system, which responds through multiple and complex mechanisms to stop its proliferation and attack the infected cells. It is the beginning of the clinical phase of the disease, where the symptoms and signs that a person suffers are caused not only by the action of the coronavirus, but also by the human body’s defense systems against it, through mechanisms such as inflammation. The symptoms usually begin in the upper airways and progressively move down through the bronchi until, in some people, they reach the lungs.<\/p>\n The disease that causes the new coronavirus, COVID-19, can present clinically with very varied signs and symptoms depending on the characteristics of the person. However, dry cough (68% of affected patients), fever (88%) and respiratory distress (19%) are three key signs of suspected new disease. Other very common symptoms, as recorded by the World Health Organization (WHO), are general fatigue (38%), expectoration (33%), sore throat (14%), headache (14%), muscle or joint pain (15%), chills (11%), nausea or vomiting (5%), nasal congestion (5%), diarrhea (4%) or coughing up blood. In addition, many health professionals have also observed that some affected people lose their sense of smell and taste for several days. It is during the clinical phase that the maximum release of virus from the respiratory mucosa occurs, although this may also occur, to a lesser extent, in an asymptomatic stage or in the recovery process.<\/p>\n In reality, symptoms such as fever or headache are not caused by the virus, but by the immune response of the human body to fight the virus. Something similar occurs with death, it is not only the coronavirus that causes death (parasites are not usually interested in killing their hosts), but in some cases it is also caused by an uncontrolled immune response (called “cytokine storm”) that can lead to multiorgan failure. Although it is not yet known how, the coronavirus can trigger a disproportionate inflammation that causes more harm than good to the patient.<\/p>\n The most common complications are pneumonia and multiorgan failure, which sometimes result in death. [11]<\/sup>\u200b[65<\/sup>]\u200b<\/p>\nWhen the virus manages to travel to the lungs and the immune system responds, viral pneumonia occurs, the main nightmare for health professionals in this pandemic. This pneumonia can cause anything from mild respiratory distress to outright suffocation due to the inability of the lungs to deliver oxygen to the blood. The virus interferes with this process by damaging the cells of the lungs and causing severe inflammation that clogs these organs, interfering with their gas exchange function.<\/p>\n Fortunately, in 80% of the cases of COVID-19 the disease is mild, to the point of being confused with colds or flu. However, 15% of patients show severe symptoms that require hospitalization and 5% develop very serious symptoms that must be treated in intensive care units.<\/p>\n Clinical research found that a high concentration of cytokines is detected in the plasma of critically ill patients infected with SARS-CoV-2, suggesting that the cytokine storm was associated with the severity of the disease. [66]\u200b<\/sup><\/p>\n<\/span>Coronavirus Diagnosis<\/span><\/h2>\n\n \n <\/p>\n \n Laboratory equipment needed to perform real-time PCR, a technique for the diagnosis of infection.<\/p>\n<\/div>\n<\/div>\n<\/div>\n Guidelines published on February 6 by the Zhongnan Hospital of Wuhan University recommended methods based on epidemiological risk and clinical characteristics for diagnosis. This included identifying patients who had recently traveled to Wuhan or had had contact with someone infected, as well as two or more of the following symptoms: fever, radiological signs of pneumonia, normal or low white blood cell count (leukopenia) and lymphopenia. [67]<\/sup>\u200b<\/p>\nWHO published several protocols for the diagnosis of the disease for Japan. 68]<\/sup>[69<\/sup>] The test of choice was real-time RT-PCR (or retrotranscription followed by quantitative polymerase chain reaction). 70<\/sup>] It was performed on respiratory or blood samples. 71]<\/sup> Results were available, as of January 30, within a few hours or days. 72]<\/sup>[73<\/sup>] The PCR test can be performed because Chinese scientists have isolated and published a genetic sequence of the coronavirus. [11<\/sup>]\u200b[74<\/sup>]\u200b[75<\/sup>]\u200b[76<\/sup>]\u200b[77<\/sup>]\u200b<\/p>\nChinese scientists succeeded in isolating a strain of the coronavirus and publishing the genetic sequence so that laboratories around the world could independently develop PCR tests to detect infection by the virus. [78]<\/sup>\u200b[79<\/sup>]\u200b[80<\/sup>]\u200b[81<\/sup>]\u200b<\/p>\nTreatment of Coronavirus<\/span><\/h2>\n\n \n Preventing an acute peak of infections, known as flattening the epidemic curve, helps prevent health systems from collapsing, and also provides more time for treatment\/vaccine development. Spreading infections over a longer time frame allows health services to better manage patient volumes. [82]\u200b[<\/sup>83<\/sup>]\u200b<\/p>\n<\/div>\n<\/div>\nThere is no known effective treatment for the disease. The WHO recommends that randomised controlled trials be conducted with volunteers to test the effectiveness and safety of some potential treatments. [84]\u200b<\/sup><\/p>\nResearch to find an effective treatment began in January 2020, but results are not likely to be available until 2021. [85<\/sup>]<\/sup><\/sup><\/sup> The Chinese Center for Disease Control and Prevention began testing the effectiveness of some pre-existing effective treatments for pneumonia in patients with COVID-19 in late January.<\/sup> [90]\u200b<\/p>\n<\/span>Investigational treatments<\/span><\/h3>\nVaccines<\/span><\/h4>\nThree vaccination strategies are being investigated. First, researchers aim to build a whole virus vaccine<\/i>. The use of such a virus, either inactive or killed, aims at a rapid immune response of the human body to a new infection with COVID-19. A second strategy, subunit vaccines<\/i>, aims to create a vaccine that sensitizes the immune system to certain subunits of the virus. In the case of SARS-CoV-2, this research focuses on the S-spike protein that helps the virus introduce the enzyme ACE2. A third strategy is nucleic acid<\/i> vaccines (DNA or RNA vaccines, a novel technique for creating a vaccine). Experimental vaccines of any of these strategies would have to be tested for safety and efficacy. [91]\u200b<\/sup><\/p>\nSeveral organizations in different countries are in the process of developing a vaccine. The U.S. National Institutes of Health hopes to conduct human trials of a vaccine by April 2020. [92]<\/sup> The Chinese Center for Disease Control and Prevention (CCDC) has begun developing vaccines against the new coronavirus and is testing the effectiveness of existing drugs for pneumonia. 93]<\/sup>[94<\/sup>] The Military Academy of Medical Sciences of the People’s Republic of China claimed to have “successfully” developed the recombinant coronavirus vaccine, and said it is preparing for “large-scale” production, according to a statement issued by the Chinese Ministry of Defense. 95]<\/sup> The Coalition for Innovations in Epidemic Preparedness (CEPI) is funding three vaccine projects[96]<\/sup> and hopes to have a vaccine in trials by June 2020 and approved and ready in one year. The University of Queensland in Australia received US$10.6 million in funding from CEPI to develop a “molecular clamp” vaccine platform. 97]<\/sup>[98<\/sup>][99<\/sup>] Moderna Inc. is developing an mRNA vaccine with funding from ECCE. 100]<\/sup>[101<\/sup>] Inovio Pharmaceuticals received a grant from CEPI and designed a vaccine within two hours of receiving the gene sequence. 102]<\/sup> The vaccine is being manufactured so that it can first be tested on animals. [102<\/sup>]\u200b<\/p>\nIsraeli scientists hope to have an oral vaccine ready in 90 days, after going through the safety testing phase. [103]\u200b<\/sup><\/p>\nBy early March 2020, some 30 vaccine candidates were in development, with Gilead Sciences and Ascletis Pharma products in Phase III clinical trials. [104]\u200b[<\/sup>105<\/sup>]\u200b<\/p>\nAntivirals<\/span><\/h4>\nOn Jan. 23, Gilead Sciences was in communication with researchers and physicians in the United States and China about the ongoing outbreak of Wuhan coronavirus and the potential use of Remdesivir as an investigational treatment. [106]\u200b<\/sup><\/p>\nIn late January 2020, Chinese medical researchers expressed their intention to begin clinical trials with remdesivir, chloroquine and lopinavir\/ritonavir, which appeared to have inhibitory effects on SARS-CoV-2 at the cellular level in exploratory in vitro experiments. 107]<\/sup> Nitazoxanide has been recommended for further in vivo studies after demonstrating low-concentration inhibition of SARS-CoV-2. [108]<\/sup> On February 2, 2020, physicians in Thailand claimed to have successfully treated a patient with a combination of lopinavir\/ritonavir and the influenza drug oseltamivir. 109]<\/sup>[110<\/sup>] On February 5, China began patenting the use of remdesivir against the disease. 111<\/sup>][112<\/sup>][113<\/sup>][114<\/sup>][115<\/sup>][116<\/sup>] Phase 3 clinical trials with remdesivir are under way in March in the United States, China, and Italy. [117]<\/sup>\u200b[118<\/sup>]\u200b[119<\/sup>]\u200b<\/p>\nIn late January, the Russian Ministry of Health identified three adult medications that could help treat the disease. They are ribavirin, lopinavir\/ritonavir and beta-1b interferon. These drugs are commonly used to treat hepatitis C, HIV infection and multiple sclerosis, respectively. The ministry provided Russian hospitals with descriptions and guidelines on the mechanism of action of treatment and recommended doses. 120]<\/sup> In February, China began using triazavirin, a 2014 drug developed in Russia, to test its effectiveness in controlling the disease. This drug was created at Ural Federal University in Ekaterinburg to treat H5N1 (bird) flu. It has been used against COVID-19 because of the similarity between the two diseases. The drug also appears to be effective against Rift Valley Fever and West Nile virus, among others. [121]\u200b[<\/sup>122<\/sup>]\u200b<\/p>\nOn March 18 an article reports that lopinavir\/ritonavir treatment is negative in clinical trials with 199 patients in China. There are no benefits. [123]\u200b<\/sup><\/p>\nChinese researchers discovered that Arbidol, an antiviral drug used to treat the flu, could be combined with Darunavir, a drug used in the treatment of HIV, to treat patients with coronaviruses. [124]\u200b[<\/sup>125<\/sup>]\u200b<\/p>\nChloroquine phosphate has shown apparent efficacy in the treatment of VID-19-associated pneumonia. In clinical trials with 100 patients it was found to be superior to control treatment in inhibiting exacerbation of pneumonia, improving pulmonary imaging findings, promoting negative conversion to the virus, and shortening disease. Research results showed that the SARS-CoV-2 protein ORF8 and the surface glycoprotein could bind to porphyrin, respectively, while the SARS-CoV-2 proteins orf1ab, ORF10 and ORF3a could coordinate with heme to dissociate iron to form porphyrin. The mechanism seriously interfered with the normal anabolic pathway of heme in the human body and this results in human disease. Based on validation analysis of these findings, chloroquine may prevent orf1ab, ORF3a and ORF10 from attacking heme to form porphyrin, and inhibit ORF8 and surface glycoprotein binding to porphyrins to some extent. [126]<\/sup>\u200b[127<\/sup>]\u200b[128<\/sup>]\u200b<\/p>\nResearchers at the Norwegian University of Science and Technology (NTNU) have created a database with 120 broad-spectrum antiviral agents that are safe for humans and identified 31 drug candidates for the treatment of SARS-CoV-2<\/sup><\/p>\nChina’s National Center for Biotechnology Development said March 17 that the antiviral Favipiravir, an RNA polymerase inhibitor,[130]<\/sup> showed positive results in a case-control study of 80 patients at Shenzhen People’s Hospital No. 3, those treated with Favipiravir tested negative within a shorter period of time compared to those in the control group, and recommended that it be included in treatment. [131]\u200b[<\/sup>132<\/sup>]\u200b<\/p>\nRecent studies have shown that initial priming of the peak protein by the transmembrane protease serine 2 (TMPRSS2) is essential for the entry of SARS-CoV-2, SARS-CoV and MERS-CoV through interaction with the ACE2 receptor.133][<\/sup>134<\/sup>] These findings suggest that the TMPRSS2 inhibitor Camostat, approved for clinical use in Japan to inhibit fibrosis in liver and kidney disease, postoperative reflux esophagitis, and pancreatitis, may be an effective off-label treatment option.<\/p>\nHydroxychloroquine, a less toxic chloroquine derivative, would be more potent in inhibiting SARS-CoV-2 infection in vitro. 135][<\/sup>136<\/sup>] On March 16, 2020, a leading French authority and advisor to the French government on COVID-19, Professor Didier Raoult of the University Hospital Institute of Infectious Diseases (IHU-M\u00e9diterran\u00e9e infection) in Marseille (Bouches-du-Rh\u00f4ne, Provence-Alpes-C\u00f4te d ‘Azur), announced that a trial involving 24 patients in southeastern France had shown chloroquine to be an effective treatment for COVID-19.137][<\/sup>138<\/sup>] These patients were given 600 mg of hydroxychloroquine (brand name Plaquenil) every day for 10 days. This led to a “rapid and effective acceleration of their healing process, and a sharp decrease in the amount of time they remained contagious. 139]<\/sup> Although chloroquine has a long history of safety, patients were closely monitored for drug interactions and possible serious side effects. Professor Raoult said, “We included everyone who agreed [to be treated], which was almost everyone. Two cities in the protocol, Nice and Avignon, gave us patients [infected] who had not yet received treatment … We were able to determine that the patients who had not received Plaquenil [the drug containing hydroxychloroquine] were still contagious after six days, but of those who had received Plaquenil, after six days, only 25% were still contagious. 140<\/sup>]<\/sup> In Australia, the Director of the Clinical Research Centre at the University of Queensland, Professor David Paterson, announced his intention to conduct a major clinical research trial on the efficacy of chloroquine and remedesivir as treatments for COVID-19. Professor Paterson hoped to begin enrolling patients by the end of March 2020. [142]\u200b<\/sup><\/p>\nA limited French study shows that hydroxychloroquine combined with azithromycin is faster than hydroxychloroquine alone in transforming VOC-19 patients to negative. [143]\u200b[<\/sup>144<\/sup>]\u200b<\/p>\nAgainst the cytokine storm<\/span><\/h4>\nTocilizumab has been included in treatment guidelines by the National Health Commission of China after a small study was completed. 145][<\/sup>146<\/sup>] It is undergoing national phase 2 nonrandomized testing in Italy after showing positive results in people with severe disease. 147<\/sup>][ |