On January 12, 2020, the World Health Organization (WHO) received the sequenced genome[42]​ of the new virus that causes the disease and temporarily named it 2019-nCoV, from the English 2019-novel coronavirus (new coronavirus), while the disease was called "2019-nCoV infection" in medical documents,[43]​[44]​ and Wuhan SARS or Wu Flu (Wu flu) on the Internet.[45]​[46]​ On January 30, the WHO recommended that the provisional name of the disease be "2019-nCoV acute respiratory disease", until the International Classification of Diseases gave an official name.[47]​ Despite this recommendation, the media and news agencies continued to use the name Wuhan pneumonia to refer to the disease.[48][49][50]​.

The WHO announced on February 11, 2020 that COVID-19 would be the official name of the disease.[51] The name is an acronym for coronavirus disease 2019 (coronavirus disease 2019, in Spanish). It was ensured that the name did not contain names of people or references to any place, animal species, type of food, industry, culture or group of people, in line with international recommendations, to avoid stigmatization against any group.[52]​[53]​.

In Spanish, the gender of the disease name can be both feminine and masculine; However, the feminine was from the beginning the one preferred by the Fundéu BBVA and, later, by the Royal Spanish Academy (RAE): The COVID-19, because "COVID-19" is the English acronym for disease due to coronavirus 2019, where disease (word represented by the letter D, the main element of the acronym) can only be feminine in the Spanish language.[6]​ Although the feminine is the that the WHO uses in all its writings, the use of the masculine is more standardized in public discourse, according to the RAE, due to the influence of the gender of coronavirus and other viral diseases: *dengue, *MERS, *SARS, *Zika, and others.[54]​ The Fundéu BBVA also points out that the name of the disease can be lexicalized in general texts, writing everything in lowercase (covid-19) because it is a noun, instead of the initial capital letter (Covid-19), as used in some writings;[6]​ and that it is not uncommon or incorrect to use only the first lexeme of this compound word (COVID instead of COVID-19). This simplification would be explained by the phenomenon of linguistic economy, especially in the informal register and spoken discourse.

When it is written with digits ("COVID-19" instead of "COVID"), the use of the hyphen "Hyphen (spelling sign)") is mandatory in Spanish (it is incorrect "COVID19" - all together - or "COVID 19" - with a space), since it is present in the official name, and, furthermore, the Spanish language has the habit of separating words that are made up of letters and numbers. The latter is carried out with a script.[55]​.

Regarding its accentuation, both institutions indicate that the majority use of the first lexeme of the word is acute /ko'βið/ (COVID-19) —and that the voice is, in fact, acute in Spanish—, so only a minority population of Spanish speakers accentuate it as flat /'ko.βið/, due to the influence of English, the language of origin of the term (COVID-19).[56][57]​

The full name of the disease should preferably be read as: [ko'βið.dje.si'nwe.βe] in non-sessing areas, and as: [ko'βið.dje.θi'nwe.βe] in non-sessing areas.

Discovery

In December 2019, there was an epidemic outbreak of pneumonia of unknown cause in Wuhan, Hubei Province, China; which, as Reporters Without Borders later stated, affected more than 60 people on the 20th of that month.[58]​.

According to the Chinese Center for Disease Control and Prevention (CCDC), on December 29, a hospital in Wuhan (Provincial Hospital of Integrated Traditional Chinese and Western Medicine, also known as Xinhua Hospital,) admitted 4 individuals with pneumonia, who worked in a market in that city. The hospital reported this to CCDC, whose city team launched an investigation. The team found more cases related to the market and on December 30, Wuhan health authorities reported the cases to the CCDC, which sent experts to Wuhan to support the investigation. Samples were obtained from these patients for laboratory analysis.[59]​.

On December 31, the Wuhan Municipal Health Committee reported to the World Health Organization (WHO) that 27 people had been diagnosed with pneumonia of unknown cause, with 7 in critical condition; The majority of these cases were workers at the aforementioned market.[60]​ By January 1, 2020, the market had been closed and the cause of the pneumonia had been ruled out as SARS, MERS, influenza, avian flu or other common respiratory diseases caused by viruses.[43]​.

On January 7, 2020, Chinese scientists had isolated the virus that causes the disease and performed genome sequencing. This sequencing was available to the WHO on January 12, 2020, allowing laboratories in different countries to produce specific diagnoses via PCR tests.[43]​.

On January 12, 2020, the Chinese authorities had confirmed the existence of 41 people infected with the new virus, who began to feel symptoms between December 8, 2019 and January 2, 2020, which included: fever, malaise, dry cough, difficulty breathing and respiratory failure;[43] invasive pneumonic infiltrates were also observed in both lungs observable in the thorax.[44]​.

Spread of the disease

Following the first outbreak of COVID-19 in Wuhan in December 2019, where Chinese authorities confirmed 41 cases detected between December 8 and January 2, 2020,[44] the city stopped reporting cases until January 19, when 17 more cases were confirmed. By then, the first cases of COVID-19 outside China had already been reported: two in Thailand and one in Japan.[61]​.

The rapid spread of the disease caused the World Health Organization, on January 30, 2020, to declare it a health emergency of international concern, based on the impact that the virus could have in underdeveloped countries with fewer health infrastructures.[62]​ On that date, the disease had been detected in all provinces of mainland China,[63]​ and cases were diagnosed in 15 other countries.

On March 11, the disease was already in more than 100 territories worldwide, and was recognized as a pandemic by the WHO.[64]​ The number of confirmed cases continued to grow until reaching 500,000 cases worldwide on March 26, 2020.[65]​.

To prevent the spread of the virus, governments imposed travel restrictions, quarantines, lockdowns, social isolation, cancellation of events, and closure of non-essential establishments. The pandemic had a disruptive socioeconomic effect,[66]​ and fear of supply shortages led to panic buying. There was misinformation and conspiracy theories spread online about the virus,[67][68]​ and incidents of xenophobia and racism against citizens of China and other East and Southeast Asian countries.[69]​.

It has been proven that the quarantines, restrictions on human traffic and isolation that occurred due to the pandemic had negative psychological effects.[70]​ At the end of January, the National Health Commission of China published a guide for the management of psychological crises, in which it advocated the intervention of affected people, close contacts, those locked in their homes, relatives and friends of the patients, health personnel and the general public who required it.[71]​[72]​ According to studies carried out. In 2020, it was confirmed that it has affected the mental health of women to a greater extent than that of men. Among the reasons is the increase in gender violence and their more precarious socioeconomic situation. A good part of the women work in the restaurant and tourism sectors, one of the most affected by the pandemic, in addition to being the main caregivers of sick people, children and the elderly.[73][74]​.

Isolation has meant that many patients were unable to continue with their treatments, aggravating their health problems. In these scenarios, women, whether family members or caregivers, usually play a fundamental role.[75]​.

Contenido

En esta enfermedad se describe un "triángulo epidemiológico causal" que está formado por: el medio ambiente, el agente etiológico (el virus SARS-CoV-2) y el huésped "Huésped (biología)").

Transmission

Person-to-person transmission routes of the SARS-CoV-2 etiological agent include direct transmission by inhalation of droplets and aerosols released through coughing, sneezing, breathing, speaking, shouting or singing,[23]​[76][77]​ or by hand contact with contaminated surfaces, which then touch oral, nasal or ocular mucous membranes.[78]​ It can also be transmitted through saliva, and possibly by the fecal-oral route.[26]​.

A study of 2,143 children suggests that this population group may be a critical factor in the rapid spread of the disease.[79]​.

Vaccinated people can still transmit COVID, although it is more difficult.[80]​ So those vaccinated must still make preventive measures (washing hands with soap, wearing a mask, maintaining social distance, etc.) so that the disease does not spread, especially to vulnerable people.

According to studies published in the scientific journals New England Journal of Medicine (March 17, 2020) and The Lancet Microbe (April 2), the persistence on different surfaces is as follows:[81]​.

• - Paper and tissues: 3 hours.

• - Copper: 4 hours.

• - Cardboard: 24 hours.

• - Wood: 2 days.

• - Fabric: 2 days.

• - Stainless steel: 2 - 3 days.

• - Polypropylene plastic: 3 days.

• - Crystal: 4 days.

• - Tickets: 4 days.

• - The outside of a mask: 7 days.

• - From 21° to 23° and 40% relative humidity.

• - At 71° and 65% relative humidity.

The World Health Organization recommends for this reason that surfaces be disinfected, especially in the healthcare environment. Outside of this, the role that fomite transmission may have is unknown, but less important than when it occurs through close contact with an infected person.[82]​.

Currently, there are many studies that focus on evaluating possible vertical transmission.[83]​ So far, the tests that have been carried out rule out the presence of SARS-CoV-2 in amniotic fluid, umbilical cord blood and breast milk.[83]​.

However, it is still too early to know with certainty whether vertical transmission can occur or not, since there are cases in which the presence of antibodies has been demonstrated in neonates born to mothers carrying the virus.[83]​ Therefore, although it is true that this evidence comes from a small number of cases, this further demonstrates the possibility of vertical transmission.[83]​.

Regarding breastfeeding, the presence of SARS-CoV-2 in the breast milk of infected patients has not been demonstrated.[83]​ Therefore, as there is no risk of contagion through breast milk, breastfeeding is not contraindicated in infected patients as long as the necessary hygiene measures are taken, including hand washing and the correct use of the mask.[83]​.

Reproductive rate R0

The reproductive number R is the average number of new infections that an infected person can generate; The higher this is, the greater the pandemic potential of a disease. The Chinese Academy of Sciences estimated a reproductive number or R=4 for COVID-19 in February 2020, although there is uncertainty about many of the factors taken into consideration to calculate the R. Imperial College London calculated R=1.5 to 3.5.[84]​.

Patient zero

The index case or "patient zero" is the case that gives rise to the attention of the researcher and causes actions to identify a focus of infection; It corresponds to the first case confirmed by the health authority and leads (indicates) towards a localized outbreak.[85]​[86]​[87]​.

Patient one

Sometimes the first case of COVID-19 identified by the health system (index case or patient 0) does not coincide with the case that gave rise to the epidemic. The "authentic index case" or "primary case" would be the first one that initiates the epidemic outbreak.[88]​.

The causal agent of COVID-19 is the virus (SARS-CoV-2),[11]​[89]​ which is a type of Orthocoronavirinae.[6]​[11]​ It was first discovered and isolated in Wuhan, China, after causing the 2019-2020 coronavirus disease epidemic. It appears to have a zoonotic origin, that is, it passed from an animal host (a bat) to a human host.[90] The virus genome is made up of a single strand of RNA, and is classified as a positive single-stranded RNA virus. Its genetic sequence has been isolated from a sample obtained from a patient affected by pneumonia in the Chinese city of Wuhan.[91][92][93][94][95]​.

The RNA of the SARS-CoV-2 virus encodes 4 structural proteins: protein S (spike protein), protein E (envelope), protein M (membrane) and protein N (nucleocapsid). The N protein is inside the virion associated with the viral RNA, and the other four proteins are associated with the viral envelope. The S protein assembles into homotrimers, forming structures that protrude from the virus envelope. The S protein contains the binding domain to the cellular receptor and is therefore the protein that determines the tropism of the virus and is also the protein that has the fusion activity of the viral membrane with the cellular one and in this way allows the release of the viral genome inside the cell that is going to infect.[97]​.

SARS-CoV-2 penetrates the cell using angiotensin-converting enzyme 2 (ACE-2) as a receptor, a membrane exopeptidase present mainly in the kidney, lungs and heart.[98] It has been observed that severe cases of COVID-19 present very high levels of Angiotensin II. And the level of angiotensin II has been correlated with SARS-CoV-2 viral load and lung damage. This imbalance of the renin-angiotensin-aldosterone system could be related to the inhibition of the angiotensin-2 converting enzyme by the virus. This same mechanism was observed in the outbreak caused by severe acute respiratory syndrome in 2003.[97]​.

The S glycoprotein of the virus envelope interacts with the cellular receptor ACE2 (angiotensin-converting enzyme 2), a cell membrane protein that catalyzes the conversion of angiotensin I to the nonapeptide angiotensin 1-9 or of angiotensin II to angiotensin 1-7. The virus enters by endocytosis. Once in the endosome, a lysosome-mediated drop in pH occurs, which promotes the fusion of the endosome membrane with the virus envelope, which releases the nucleocapsid into the cytoplasm. Cellular proteases degrade the capsid and the virus genome is free in the cytoplasm. Next, since it is a positive sense RNA genome, the cellular machinery directly translates it into polyproteins that are processed and the replication and transcription complex is formed. The complementary strand of negative sense pre-genomic RNA is then synthesized that will serve as a template to replicate the positive sense viral genome. Additionally, the replication and transcription complex will synthesize a series of smaller, positive sense subgenomic RNAs. These are the ones that will be translated into viral proteins. This entire process will occur in the cytoplasm of the cell. The structural proteins that will be expressed in the membrane of the endoplasmic reticulum will be synthesized. There, in the reticle, is where the assembly will occur. In fact, the envelope of the virus comes from the membrane of the endoplasmic reticulum. The viral particle will travel, through the cellular vesicle transport system in which the Golgi apparatus intervenes, to the surface. The viral particle will leave the cell by exocytosis. After a final maturation phase, in which viral proteases intervene, all the components of the virus will fit together, the particle will be infectious and a new cell cycle can begin.[99]​.

The virus can pass through the mucous membranes, especially the nasal and laryngeal mucosa, then enters the lungs through the respiratory tract. The virus would then attack the target organs that express ACE2, such as the lungs, heart, kidney system and gastrointestinal tract. The virus begins a second attack, causing the patient's condition to worsen around 7 to 14 days after the onset. Depletion of B lymphocytes can occur early in the disease, which can affect antibody production in the patient. Furthermore, inflammatory factors associated with mainly IL-6-containing diseases were significantly increased, which also contributed to the aggravation of the disease around 2 to 10 days after onset. The clinical spectrum of COVID-19 varies from asymptomatic forms[100]​ to clinical conditions characterized by severe respiratory failure requiring mechanical ventilation and support in an intensive care unit (ICU), to manifestations in various organs "Organ (biology)") and systems producing sepsis, septic shock and multiple organ dysfunction syndrome.[97]​.

The incubation period, that is, the time that passes from when a person is infected by the virus until they present symptoms, generally ranges between 4 and 7 days, in 95% of cases it is less than 12.5 days. The extreme limits have been established between 2 and 14 days after infection.[101]​.

At the immunological level, elevated levels of IL-6 and other proinflammatory cytokines have been shown in patients with severe COVID-19. This observation, together with other clinical parameters associated with severe cases such as lymphopenia (decrease in lymphocytes in the blood) and hyperferritinemia, has led to the hypothesis that a subgroup of COVID-19 patients may suffer from a cytokine release syndrome. Cytokine release syndrome (CRS), also called cytokine storm, is a syndrome caused by a systemic cytokine-mediated inflammatory response that can be triggered by a variety of factors such as infections and some medications. Cytokines are soluble proteins that act on cells of the immune system and regulate cell activation, proliferation and recruitment. Cytokine release syndrome occurs when large numbers of leukocytes (neutrophils, macrophages, and mast cells) are activated and release large amounts of proinflammatory cytokines. CRS was initially described as an adverse effect of monoclonal antibody therapies, and is also common in CART cell (chimeric antigen receptor T cell) therapies. The main cytokines involved in the pathogenesis of CRS include interleukin (IL)-6, IL-10, interferon (IFN), monocyte chemotactic protein 1 (MCP1), and granulocyte-macrophage colony-stimulating factor (GM-CSF); Other cytokines such as tumor necrosis factor (TNF), IL-1, IL-2, IL-2-receptor, and IL-8 have also been described during CRS. The pathogenesis of CRS in patients with COVID-19 is still unknown. However, clinical observations suggest that when the immune response is not able to effectively control the virus, such as in older people with a weakened immune system, the virus would spread more effectively, causing damage to the lung tissue, which would activate macrophages and granulocytes and lead to the massive release of proinflammatory cytokines. This increased lung inflammation would be associated with acute respiratory distress syndrome (ARDS), which has been described as the main cause of mortality from COVID-19.[97]​.

Response in pregnancy.

Today, there are many unknowns about the situation of pregnant women during the COVID-19 pandemic. Because they are prone to serious complications and infections from other types of coronavirus, they have been considered a risk group and advised to take a series of additional preventive measures.[102]​.

Some of the responses during pregnancy may be:

• Immunological: As with other viruses, the immune response to COVID-19 will depend on whether you have a healthy immune system. This adapts during pregnancy to allow the development of a fetus whose genetic makeup only half shares with its mother, which leads to a different immune reaction to infections during the pregnancy stage.[102]​.

• Respiratory: There are numerous factors that increase the vulnerability of pregnant women to serious respiratory infections. Two examples of this may be decreased lung capacity and the inability to eliminate secretions.[103]​.

• Coagulation: During pregnancy, coagulation levels in the circulatory system are high, and the pathogenesis of SARS-CoV-2 may be related to this. Thromboembolic events with associated mortality are a risk for pregnant women.[102]​.

However, based on current evidence, it is difficult to draw definitive conclusions about whether pregnant women are at increased risk of serious consequences from this virus.[102]​.

In addition, other clinical trials have shown that SARS-CoV-2 can affect the pregnancy period in different ways. On the one hand, there is not much evidence about its impact during the first 12 weeks of gestation. On the other hand, COVID-19 infection can cause negative consequences during the pregnancy period. Some examples of this may be fetal growth restriction, premature birth and perinatal mortality, that is, the death of the fetus after 22 or 28 completed weeks of pregnancy, as well as the death of newborn children at 7 days old.[103]​.

Infected people may be asymptomatic or present a series of symptoms that range from mild to very severe, including fever, dyspnea[104]​[105]​[106]​ and dry cough.[13]​ COVID-19 affects each person in different ways. Most people who become infected have mild or moderate symptoms and recover without the need for hospitalization. Diarrhea and other symptoms of the nasopharynx, such as sneezing, rhinorrhea and sore throat, are less common.[107]​ Although older people are more vulnerable to the disease, in mid-March 2020, the WHO recalled that young people can also have complications and even death from the virus.[108]​.

The symptoms of COVID-19 are non-specific and its presentation, according to the WHO, may even lack symptoms (asymptomatic). Based on a statistical sample of 55,924 laboratory-confirmed cases, the frequency of symptom presentation in the Chinese population was as shown in the attached table.[1]​.

*(As of February 20, 2020 and based on 55,924 laboratory confirmed cases).[1]​.

Complete loss of smell (anosmia) has been reported in 80% of those diagnosed, reaching 88% of those who present some degree of alteration in taste.[111] Others have recorded the sudden loss of smell and taste on a less frequent basis (without mucus being the cause).[112]​[113]​.

Symptoms were initially reported to include fever in 90% of cases, malaise and dry cough in 80% of cases, and breathing difficulties in 20% of cases.[43][114][115][116]​.

On January 24, 2020, The Lancet published a study of the first 41 cases of patients admitted (in a Wuhan hospital) with a confirmed diagnosis, from December 16, 2019 to January 2, 2020.[107] Of them, less than half had underlying diseases, including diabetes, hypertension, and cardiovascular disease. Common symptoms at the onset of the disease were fever, dry cough, and myalgia or fatigue; the least common symptoms were sputum production, headache, hemoptysis, and diarrhea. Dyspnea developed in 22 of 40 patients (55%), with a median "Median (statistical)") time from illness onset to dyspnea of ​​eight days. Lymphopenia occurred in 26 of 41 patients (63%). All patients had pneumonia with abnormal findings on chest CT.[117]​.

Some of those infected may be asymptomatic and show test results confirming infection, but do not show clinical symptoms, so researchers have issued advice that people with close contact with confirmed infected patients should be closely monitored and examined to rule out infection.[118] Skin changes associated with COVID-19 have been described.[119]​.

Complications included acute respiratory distress syndrome (real-time RT-PCR positive result on plasma sample), acute cardiac injury, and secondary infection. In a case series study published in January 2020, of 41 patients admitted to a hospital in Wuhan for COVID-19, 13 were admitted to an ICU (32%) and six died (15%). In a clinical commentary in the same journal, a comparison of the 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 notably infrequent (for example, no patient had a sore throat).[117]​.

It should be mentioned that COVID-19 has had more serious consequences in men than in women due to biological differences: women's immune system is more powerful, some chronic diseases are more common in men, etc.[73]​ The most frequent complications are pneumonia and multiple organ failure that sometimes cause death.[43][120]​ In the case of pregnant women, it is important to note that, according to the Centers for Disease Control and Prevention, pregnant women are at greater risk. of becoming seriously ill from COVID-19.[83]​ This is because pregnant women who have COVID-19 appear to be more likely to develop respiratory and obstetric complications that can lead to miscarriage, preterm birth, and intrauterine growth restriction (IUGR).[83]​.

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.[121]​.

Additionally, COVID-19 may predispose to arterial and venous thromboembolic disease due to excessive inflammation, hypoxia, immobilization, and disseminated intravascular coagulation (DIC). Surprisingly, thrombotic complications have barely been described. Accurate knowledge of the occurrence of thrombotic complications in patients with COVID-19 is important for decision-making regarding the intensity of thromboprophylaxis, especially in patients admitted to the intensive care unit (ICU) who have a higher thrombotic risk. In a study published on April 11, 2020, it was shown that there were 31% of thrombotic complications in patients with COVID-19 hospitalized in the ICU.[122]​ Sequelae in the form of physical, cognitive and psychological deterioration frequently occur in COVID-19 patients who have been in the ICU, who often receive rehabilitative treatment.[123]​.

It predisposes to complications in patients with atrial fibrillation[124]​.

De entre los 41 primeros casos de COVID-19 que fueron tratados en hospitales de Wuhan, trece (32 %) necesitaron cuidados intensivos y seis (15 %) murieron.[107]​ Muchos de los que fallecieron presentaban patologías previas como hipertensión arterial, diabetes o enfermedad cardiovascular que debilitaban sus sistemas inmunológicos.[125]​.

En estos casos tempranos que acabaron en fallecimiento, la mediana "Mediana (estadística)") de la duración de la enfermedad fue de catorce días y el rango total fue de 6 a 41 días.[126]​ De los casos confirmados, 80,9 % fueron clasificados como casos leves.[127]​[94]​.

Case fatality rate

According to a study of COVID-19 deaths in China's Hubei Province, out of a total of 72,314 patient records, 44,672 (61.8%) were confirmed as COVID-19 cases. Among them, 1,023 deaths were recorded, which represents a mortality rate of 2.3%.[127] This data, however, may be an underestimate of the real mortality because many people may have been infected, but do not present symptoms, and therefore have not been counted. Other studies indicate that apparent mortality was highest in the early stages of the outbreak (17.3% for symptomatic cases between January 1 and 10), and that it decreased over time to 0.7% for patients with symptom onset after February 1, 2020.[1]​.

South Korea, which is the only country in the world where systematic analyzes of large population groups were carried out since the beginning of the pandemic (about 10,000 per day, with 210,000 counted until March 10), found a much lower mortality rate.[128]​.

As of March 3, 2020 globally, 3,110 of the 90,892 reported cases of COVID-19 had died (3.4%), according to figures indicated by the director of the WHO.[129][130]​.

According to global data, in most countries, mortality rates from COVID-19 are higher in men than women. However, in some countries such as India, Nepal, Vietnam and Slovenia they are higher in women (even reaching 3.5% in some countries).[131]​.

For example, in the first country mentioned (where a total of 6.4 million cases had been registered as of September 30, 2020), the fatality rate is higher in women (3.3% of women compared to 2.9% of men), since there is a certain gender inequality in access to healthcare. However, the data are ambiguous and there are other aspects that must be taken into account, namely: the lower degree of aging of the female population makes women less likely to die, but the small number of tests does not provide definitive data (it is estimated that the mortality range is high, especially in women between 40 and 49 years old). Ignorance regarding COVID-19 is still present in many areas. It is essential that studies be carried out regarding the age, socioeconomic level and race of each person in order to take forceful and effective measures to definitively differentiate biological aspects from environmental aspects.[131]​.

Effect according to age and previous pathologies

In Italy as of March 31, 2020, it was found that the "Median (statistical)" median age of those who died from COVID-19 was 79 years. 69% of those who died were men and only 2% were in good health (that is, absence of previous pathologies) before infection.[132]​.

In China, mortality was also observed to increase with age and is higher among men than women (4.7% vs. 2.8%). While patients without previous pathologies had a mortality rate of 1.4%, those who did die at much higher rates: 13.2% for cardiovascular diseases, 9.2% for diabetes, 8.4% for hypertension, 8.0% for chronic respiratory disease and 7.6% for cancer.[1]​.

In a study published online in the journal Pediatrics, researchers analyzed 2,143 cases of children under the age of 18 who were reported to the CCDC through February 8, 2020. About half of the children had mild symptoms, such as fever, fatigue, dry cough, congestion, and possibly nausea or diarrhea. About 39% became moderately ill, with additional symptoms including pneumonia or lung problems revealed by the CT scan, but no obvious respiratory distress. About 4% had no symptoms at all. But 125 children, almost 6%, developed very severe illness and a 14-year-old boy with confirmed coronavirus infection died. Thirteen of them were considered "critical", on the verge of respiratory or organ failure. The others were classified as "serious" because they had severe breathing problems. More than 60% of the 125 children who became seriously ill or critically ill were 5 years old or younger. Forty of them were infants, younger than 12 months.[79]​ However, a systematic review on COVID-19 in pediatric patients suggests that males are more affected by the disease and that lung alterations observed in imaging studies are more frequent than clinical signs, such as cough and fever.[133]​.

It should be noted that, although the greatest risk of developing severe disease from COVID-19 falls on older people, according to studies published in the journal Nature, the probability of developing critical COVID as a consequence of genetic susceptibility is greater in individuals under 60 years of age.[134]​.

Therefore, the effects of the pandemic have a greater impact on older groups of people and especially on women, with the infection rate being higher among women, although the virus is more lethal in men. Likewise, persistent COVID is more common in women[135]​.

One of the factors may be that care usually falls on women, and, therefore, their exposure to the virus is greater than in the case of men. Furthermore, within the family, caring for dependent people also usually falls to women. Among health workers, the percentage of infections is also higher in women (66%).

According to the WHO, in similar situations with other viruses, women have also reached a higher rate of infection. In the case of men, the WHO also suggests that they have a greater risk of exposure in the workplace, while women are more likely to become infected in daily activities, as indicated above.

Socioeconomic effect

It is worth highlighting the analysis of the socioeconomic consequences of the coronavirus pandemic from a gender perspective. Women are the most affected at the work level and, as a consequence, at the social level.[137]​ It can be stated that during the first almost global confinement, household tasks increased greatly, with these falling mainly on women; 78.7% of European women carry out household tasks, while only 33.7% of men are in charge of this.[138]​ To this we add that due to teleworking and the demand for part-time jobs, it has increased. and it is more requested by women who have to take care of their children and do housework at the same time. Thus, women face a triple burden of work that can aggravate pre-existing inequalities.[137]​.

The service sector, as well as jobs facing the public or on the front line against the fight against coronavirus, are the most affected in this crisis, sectors made up of a greater number of women than men, which is why these are the ones who have to face more job losses.[137]​ Adding to the fact that part-time jobs earn less than full-time jobs, one of the most serious consequences on a socioeconomic level is the increase in the wage gap, which in global terms constitutes 23% between men and women. women.[139]​[137]​.

The situation of structural vulnerability of the LGTBI community has also increased as a result of the pandemic. The measures in the economy have especially affected this group because a high number of LGTBI people work in sectors in which virus containment restrictions have led to the loss of numerous jobs, and in many cases they depend on informal sources of income.[140]​.

On the other hand, the pandemic has affected the mental, social and sexual health of LGTBI people for several reasons. The closure of venues and leisure spaces aimed at the group has caused a significant loss of safe socialization spaces for LGTBI people. Furthermore, isolation measures have caused many people in the group to have had to be locked up in hostile situations, with family members or other cohabitants who do not accept their sexual condition and identity,[141]​ thus generating situations of psychological and even physical violence,[141]​ with evident emotional and mental health consequences, among which are an increase or worsening of anxiety and depression disorders. Furthermore, these types of measures have aggravated the situation of loneliness in members of the community, particularly in older LGTBI people, since they frequently live alone and do not have positive relationships with their families.[142]​.

Furthermore, several human rights defense organizations (Human Rights Watch, Amnesty International, IESOGI) appeal to the fact that several governments have made use of the pandemic context to criminalize and demonize members of minorities such as the LGTBI community.[140]​ These people have suffered the consequences of the promulgation of hate speeches that point to them as the source of transmission of the disease, and even, in more extreme cases, as responsible for it.[140]​ Likewise, the pandemic has caused the entry into force of rights for the LGTBI population to be postponed or in some cases stopped.[140]​.

Immunity

Humans' natural immune response to the SARS-CoV-2 virus occurs as a combination of cell-mediated immunity and antibody production, as with almost all other infections. B cells interact with T cells and begin dividing before selection into the plasma cell, partly based on their affinity for the antigen. The presence of neutralizing antibodies in the blood is considered evidence of immunity against infection, but the level of neutralizing antibodies decreases over time, disappearing after three months in 1% of patients and after six months in 12%.[144] However, the absence of antibodies in the blood does not mean that the immune system cannot quickly produce new antibodies in the event of re-exposure to SARS-CoV-2. Memory B cells specific for SARS-CoV-2 nucleocapsid and spike proteins last at least 6 months after symptom onset.

Since SARS-CoV-2 has only been in the human population since December 2019, it was unknown early in the pandemic whether immunity was long-lasting in people who recover from the disease. Cases of reinfection were reported in patients who had already had the disease and it was feared that SARS-CoV-2 behaved like some other coronaviruses, which are capable of reinfecting after approximately a year.[145]​.

A January 2021 study found that most patients infected with the SARS-CoV-2 virus remain immunized for at least five months, with a much lower probability (83%) of becoming infected again than those who had not previously been exposed to the virus. Furthermore, in the case of reinfection, those previously infected usually did not present symptoms (78% of cases) while the absence of symptoms only occurred in 34% of those not previously infected.[146]​[147]​ In a March 2021 study, it was observed that only 0.65% of patients infected with SARS-CoV-2 tested positive in PCR again at least three months later and that none were infected a third time. It is estimated that having been infected reduces, on average, 80% the probability of being infected a second time and that protection lasts at least six months.[148]​[149]​ In another study published in May 2021, it was concluded that natural immunity against SARS-CoV-2 lasts for years, probably a lifetime, even in people who had mild symptoms of covid or did not have it when they were infected. infected.[150]​[151]​[152]​[153]​ This is due to the action of both B cells and long-lived bone marrow plasma cells.

In total, it is estimated that having contracted the virus provides 94% natural immunization against COVID-19 symptoms. This figure is comparable to what was initially announced for the best vaccines. However, like vaccines, having passed the virus does not guarantee that a person cannot contract it and spread it again, which is why health authorities recommend that all previously infected people continue to apply the usual prevention methods.[154]​.

An Israeli study published in August 2021 shows that natural immunity is actually more robust and longer lasting than that obtained through vaccination.[155]​.

Symptomatic diagnosis

Chest radiology (either x-ray, computed tomography, or ultrasound) can help diagnose COVID-19 and identify or rule out pulmonary complications.[172]​.

Outbreak management

A key part of actions in an infectious disease outbreak is trying to reduce the epidemic peak, known as flattening the epidemic curve. This helps reduce the risk of health services being overwhelmed and provides more time to develop a vaccine and treatment. Social distancing and isolation of infected populations can contain the epidemic.[175]​.

Preventive measures

Some international organizations, such as the WHO, have published preventive measures to reduce the transmission of the virus. They are similar to those that have been recommended to prevent infection by other coronaviruses and include:.

• - Wash your hands frequently with soap and water.

• - When coughing or sneezing, cover your mouth and nose with the indentation or cubital fossa (the concavity that forms the inside of the arm when it is flexed at the elbow).

• - Maintain at least one meter distance from other people, "particularly those who cough, sneeze and have a fever."

• - Use facial masks.[176]​.

• - Avoid touching your eyes, nose and mouth.

• - Go to the doctor in case of fever, cough and difficulty breathing, calling in advance if you are in areas where the virus is spreading or if you have visited them in the last 14 days.

• - Stay at home if you start to feel unwell, even if the symptoms are mild such as headache and mild rhinorrhea, until you recover if you are in areas where the virus is spreading or if you have visited each other in the last 14 days.[30]​.

To reduce your chances of becoming infected, health organizations recommend avoiding close contact with sick people; wash your hands frequently with soap and water; do not touch your eyes, nose or mouth with unwashed hands; and practice good respiratory hygiene.[177]​[30]​.

People who are already infected are recommended to stay home except to receive medical care, call ahead before visiting a health care provider, wear a face mask (especially in public), cover coughs and sneezes with a tissue, wash hands regularly with soap and water, and avoid sharing personal household items.[178] Depending on the laws of each country, intentional transmission of the virus is punishable according to the legal system where the infection occurs. fact.[179]​.

The Hong Kong government warned anyone traveling outside the city not to touch animals; do not eat game meat; and avoid visiting wet markets, live bird markets, and farms.[180]​ There is no evidence that pets, such as dogs and cats, can become infected.[181]​ The Chinese government has banned the trade and consumption of wild animals.[182]​.

For healthcare providers caring for someone who may be infected, standard precautions, contact precautions, and precautions against airborne viruses are recommended, as well as wearing eye protection.[183]​.

Hand washing is recommended to prevent the spread of coronavirus. The CDC recommends:[177]​.

• - Wash your hands often with soap and water for at least 20 seconds, especially after going to the bathroom; before eating; and after blowing your nose, coughing or sneezing.

• - If soap and water are not available, use an alcohol-based hand sanitizer with at least 60% concentration. Always wash your hands with soap and water if your hands are visibly dirty.

People should avoid touching their eyes, nose, or mouth with unwashed hands.[30]​.

SARS-CoV-2 can survive and remain contagious on inanimate surfaces such as metal, glass or plastic for several days. Methods to eliminate the virus from surfaces include chlorine-based disinfectants, 75% ethanol, peracetic acid, and chloroform.[181]​.

Health organizations recommend covering your mouth and nose with a bent elbow when coughing or sneezing or covering your mouth and nose with a disposable tissue (which should then be discarded immediately) and then washing your hands with an alcohol-based hand sanitizer or soap and water.[30]​[184]​.

Governments have ordered the general use of masks to contain the pandemic. Masks benefit public health by reducing infections.

Those who suspect they are infected should call a doctor for advice and wear a mask (especially when around other people).[180]​[185]​ Masks limit the volume and travel distance of respiratory droplets dispersed by talking, sneezing, and coughing. However, several studies have concluded that because masks are designed according to prototypical male features, they tend not to fit well on women's faces, leaving them more exposed to the virus.[186]​.

If a mask is not available, anyone experiencing respiratory symptoms should cover their cough or sneeze with a tissue, promptly dispose of it in the trash, and wash their hands. If tissue is not available, people can cover their mouth or nose with a flexed elbow.[30]​.

Masks are also recommended for those caring for someone who may have the disease.[185]​ Rinsing the nose, gargling with mouthwash, and eating garlic are not effective methods.[181]​ Some studies have shown the effectiveness of mouthwashes in reducing SARS Cov-2.[187]​.

The WHO advises using masks like this:[185]​.

• - Carefully position the mask to cover the mouth and nose and tie securely to minimize any gaps between the face and the mask; While in use, avoid touching the mask;

• - Remove the mask using appropriate technique (i.e. do not touch the front but rather remove the lace from the back);.

• - After removing it or any time you inadvertently touch a used mask, clean your hands with an alcohol-based hand sanitizer or soap and water if visibly dirty;

• - Replace the masks with a new clean, dry mask as soon as they become wet;

• - Do not reuse single-use masks; Throw away single-use masks after each use and throw them away immediately after removal.

Normal masks primarily seek to reduce the spread of the disease by avoiding infecting others, so they can give a false sense of security to those who wear them. On the other hand, certified respirators also provide great protection to their wearer.

Healthcare professionals who interact directly with people who have the disease are recommended to use respirators with protection as high as NIOSH-certified grade N95, or EU grade FFP2, or equivalent, in addition to other possible personal protective equipment.[185]​[188]​.

There are masks that have an exhalation valve (that is, outlet), which expels unfiltered breathing air. If its wearer is infected (and they may be without knowing it), they would transmit the virus through the valve, even if the mask is certified. So masks with an outlet valve are not recommended to control the pandemic.

(Normal) surgical masks have long been used by healthy people in Hong Kong,[189]​ Japan,[190]​ Singapore[191]​[192]​ and Malaysia.[193]​.

In addition to the guidance mentioned above on handwashing and respiratory hygiene, public health agencies advise that sick people who suspect they may have COVID-19 should restrict activities outside the home, except to obtain medical care:[178]​[194][195]​.

• - Do not go to work, school or public areas. Avoid using public transportation, rideshares or taxis.

• - Call ahead before visiting a doctor.

• - Separate from other people and animals in the home; do not share personal items; use a separate bathroom if available.

• - Use a household cleaner to clean all frequently touched surfaces (counters, toilets, doorknobs, etc.) every day.

Prevention measures recommended by the WHO include regular hand washing with soap and water, covering the mouth and nose with a bent elbow when coughing or sneezing, and avoiding direct contact with people who show symptoms of respiratory illness without adequate protective measures. other infectious diseases, only eat meat or eggs if they are well roasted or cooked.[196]​.

Social distancing includes infection control actions intended to slow the spread of the disease by minimizing close contact between people. Methods include quarantines, travel restrictions and closures of schools, workplaces, stadiums, theaters or shopping malls. People can also apply social distancing methods by limiting travel, avoiding crowded areas, and physically distancing themselves from sick people.[30][198] Many governments now require or recommend social distancing in regions affected by the outbreak.[199][200][201]​.

Older adults and those with serious chronic conditions face a higher risk of serious illness and complications from COVID-19 and the US CDC has advised them to avoid crowds and stay home as much as possible in community outbreak areas.[202]​.

Some countries, such as Canada and the United States, have issued guidelines against shaking hands, hugging, or kissing.[203] Some countries, such as India, have advised their citizens to avoid spitting in public places.[204] The World Health Organization (WHO) now recommends that the general population maintain "at least 1 meter (3 feet) distance between yourself and other people, particularly those who cough, sneeze, and have a fever."[30]

The Harvard T.H. The Chan School of Public Health recommends a healthy diet, being physically active,[205]​ managing psychological stress, and getting enough sleep.[206]​.

There is no strong evidence that vitamin D status has any relationship with COVID-19 health outcomes.[207] Recently (December 2021), a systematic review has been published in which observational studies involving almost two million adults suggest that vitamin D deficiency/insufficiency increases susceptibility to COVID-19 and severe COVID-19. There is a high risk of heterogeneity, so the meta-analysis could not be done.[208][209]​.

Multiple studies affirm that obesity is one of the most important factors that lead to hospitalization, the development of the most severe form of the disease and admission to the ICU; in addition to the development of serious, life-threatening complications from COVID-19.[210]​.

When someone has been vaccinated against COVID (they have received all the necessary doses of the vaccine, and a set time has passed), it is still possible to transmit the disease, although the chances are greatly reduced (according to some research).[80]​[234]​ In addition, the vaccines fail in a small proportion of vaccinated people.

Therefore, it is recommended that the population continue to carry out preventive measures (wash hands with soap, wear a mask, maintain social distance, etc.) to avoid contagion, especially to vulnerable people. The precautions would end when the dangers of the pandemic are officially over.

Regarding pregnancy, although insufficient testing has been done, 23 women became pregnant during the clinical trial of the Pfizer vaccine and none of them showed any adverse effects. However, the Food and Drug Administration (FDA) recommends that pregnant or nursing women consult with their doctors when deciding whether they should get vaccinated. It is important to emphasize that, if a woman is in the process of trying to get pregnant, the vaccine will not affect her fertility in any case.[235]​.

Currently (August 2021), there is a recommendation to vaccinate all pregnant women.[236]​.

Varios tratamientos experimentales contra el covid-19 están actualmente en desarrollo o han sido aprobados en al menos un país:.

• - la fluvoxamina, un antidepresivo barato y abundante;[237]​.

• - antivirales como el remdesivir (de Gilead),[238]​ el molnupiravir (desarrollado por Merck),[239]​ y el PF-07321332") (desarrollado por Pfizer).[240]​[241]​.

• - la transfusión de plasma sanguíneo de donantes que ya han pasado la enfermedad.[242]​.

Otros tratamientos que se consideraron prometedores durante los primeros meses de la pandemia, como la hidroxicloroquina y el lopinavir/ritonavir, resultaron después ser inefectivos o incluso perjudiciales.[243]​ La colchicina, un antiinflamatorio, ha dado resultados inciertos.[244]​.

Treatments in development

Research to find an effective treatment began in January 2020.[245]​ The Chinese Center for Disease Control and Prevention began testing, in late January, the effectiveness of some pre-existing effective treatments against pneumonia in patients with COVID-19.[246]​ Tests have also been done with drugs such as Remdesivir, an RNA polymerase inhibitor,[247]​[248][249][250]​ and with interferon beta").[250]​.

Recent studies have revealed intercellular adhesion molecules (such as E-Selectin) involved in the recruitment of immune cells in critical COVID, so they are being studied as possible therapeutic targets.[251]​.

On January 23, 2020, Gilead Sciences was in communication with researchers and physicians in the United States and China regarding the ongoing Wuhan coronavirus outbreak and the potential use of Remdesivir as an investigational treatment.[252]​.

In 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.[253]​ Nitazoxanide has been recommended for further in vivo studies after demonstrating low-concentration inhibition of SARS-CoV-2.[254]​ On February 2, 2020, Doctors in Thailand claimed to have successfully treated a patient with a combination of lopinavir/ritonavir and the anti-influenza drug oseltamivir.[255][256] On February 5, China began patenting the use of remdesivir against the disease.[257][258][259][260][258][257] Phase 2 clinical trials are underway in March. 3 in the United States, China, and Italy with remdesivir.[261][262][263] In April, it was announced that ivermectin inhibits SARS-CoV-2 replication in vitro[264] Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large and statistically significant reductions in mortality, time to clinical recovery, and time to clearance viral.[265]​.

In late January, Russia's Health Ministry identified three drugs for adults that could help treat the disease. They are ribavirin, lopinavir/ritonavir and interferon beta-1b. These drugs are commonly used to treat hepatitis C, HIV infection and multiple sclerosis, respectively. The ministry provided Russian hospitals with descriptions and guides on the treatment's mechanism of action and recommended doses.[266] In February, China began using triazavirin), a 2014 drug developed in Russia, with the aim of testing whether it is effective in controlling the disease. This drug was created at the Ural Federal University in Yekaterinburg to treat H5N1 influenza (bird flu). It has been used against COVID-19 due to the similarity between the two diseases. The drug also appears to be effective against Rift Valley fever and West Nile virus, among others.[267]​.

On March 18, an article reports that treatment with lopinavir/ritonavir is negative in clinical trials with 199 patients in China. There are no benefits.[268]​.

Chinese researchers discovered that Arbidol, an antiviral drug used to treat influenza, could be combined with Darunavir, a drug used in the treatment of HIV, to treat coronavirus patients.[269][270]​.

Chloroquine phosphate has demonstrated apparent efficacy in the treatment of COVID-19-associated pneumonia. In clinical trials with 100 patients it was found to be superior to control treatment in inhibiting pneumonia exacerbation, improving lung imaging findings, promoting negative conversion to the virus, and shortening the illness. Research results showed that SARS-CoV-2 protein ORF8 and surface glycoprotein could bind to porphyrin, respectively, while SARS-CoV-2 proteins orf1ab, ORF10, and ORF3a could coordinately attack heme to dissociate iron to form porphyrin. The mechanism seriously interfered with the normal anabolic heme pathway in the human body and this produces a human disease. According to the validation analysis of these findings, chloroquine could prevent orf1ab, ORF3a and ORF10 from attacking heme to form porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent.[271]​[272][273]​.

Researchers at the Norwegian University of Science and Technology (NTNU) have created a database of 120 broad-spectrum antiviral agents safe for people and identified 31 drug candidates for the treatment of SARS-CoV-2.[274]​.

China's National Biotechnology Development Center stated on March 17 that the antiviral Favipiravir, an RNA polymerase inhibitor,[275] showed positive results in a case-control study of 80 patients at Shenzhen No. 3 People's Hospital; 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 the treatment.[276]​[277]​.

Recent studies have shown that the initial priming of the spike protein by 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.[278][279] These findings suggest that the TMPRSS2 inhibitor Camostat") approved for clinical use in Japan to inhibit fibrosis in liver and kidney disease, postoperative reflux") and pancreatitis could constitute an effective off-label treatment option.

Hydroxychloroquine, a less toxic derivative of chloroquine, would be more potent in inhibiting SARS-CoV-2 infection in vitro.[280][281] 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-Méditerranée infection) in Marseille (Bouches-du-Rhône, Provence-Alpes-Côte d'Azur), announced that a trial with 24 patients from southeastern France had shown that chloroquine is an effective treatment for COVID-19.[282][283]​ 600 mg of hydroxychloroquine (brand name Plaquenil) was administered to these patients 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."[282] While chloroquine has a long safety record, 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 [infected] patients who had not yet received treatment... We were able to determine that 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. Paterson announced his intention to conduct a major clinical investigation. trial of the effectiveness of chloroquine and remedesivir as treatments for COVID-19.[284]​ The trial would compare one drug, against the other drug, against the combination of the two drugs. Professor Paterson hoped to begin enrolling patients at the end of March 2020.[284]​.

A limited French study shows that hydroxychloroquine combined with azithromycin is faster than hydroxychloroquine alone in transforming COVID-19 patients to negative.[285]​ This combination is not indicated for the treatment of COVID-19 and has been shown to have serious side effects.[286]​.

Nafamostat mesylate (brand name: Fusan), a medication used to treat acute pancreatitis, can effectively block the required viral entry process that the novel coronavirus (SARS-CoV-2) uses to spread and cause disease (COVID-19). The University of Tokyo plans to launch clinical trials in April 2020 to evaluate the effectiveness of these two drugs in treating COVID-19.[287]​.

Fujifilm announces the initiation of a Phase III clinical trial of the influenza antiviral drug "Avigan Tablet" (generic name: favipiravir).[288]​.

Tocilizumab (a monoclonal antibody) has been included in treatment guidelines by the National Health Commission of China after a small study was completed.[289][290]​ It is undergoing a nationwide non-randomized phase 2 trial in Italy after showing positive results in people with severe disease.[291][292]​ In combination with a serum ferritin blood test to identify cytokine storms, it is intended to counteract such developments, which are believed to be the cause of death in some affected people.[293]​[294]​ The interleukin-6 receptor antagonist was approved by the FDA for treatment against cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017.[295]​.

Northwell Health's Feinstein Institute announced a study in March on "a human antibody that may prevent the activity" of IL-6. Called sarilumab developed jointly by Regeneron Pharmaceuticals") and Sanofi.[296]​.

The NIH has guidelines on the use of tocilizumab in the treatment of COVID-19:[297]​.

In March 2021, the Cochrane Library published a systematic review on tocilizumad in the treatment of COVID19[298].

lung transplant

In patients with severe acute respiratory syndrome, who do not respond to treatment and with criteria for lung involvement with fibrosis, results on lung transplantation have already been published[299]. The findings of this report show that lung transplantation is the only option for survival in some patients with ARDS associated with severe COVID-19 that does not resolve, and that the procedure can be performed successfully, with good early results after transplantation, in carefully selected patients.

The use of blood plasma donations ('Plasma (blood)') from people who have already recovered from COVID-19 is being investigated,[300]​ a strategy that was successfully applied against the 1918 flu and has been tested for SARS, an earlier cousin of COVID-19[300]​ and other diseases such as Argentine hemorrhagic fever. The mechanism of action is that naturally produced antibodies ("convalescent serum") in the immune system of those who have already recovered are transferred directly to people who need them.[300]​ This provides a non-vaccine-based form of immunization. This therapy was authorized by the US FDA in August 2020 as an emergency treatment against COVID-19.[301]​ The first complete clinical trial, published in January 2021, concluded that the application of plasma transfusions during the initial phase of mild symptoms reduced the severity of the disease in 60% of cases.[302][242]​.

A more complex version of this therapy consists of synthesizing COVID-19 antibodies, called "monoclonals," in the laboratory and then injecting them into patients.[300]​[303]​ Several pharmaceutical companies, such as Vir Biotechnology, have evaluated the effectiveness against the SARS-Cov-2 virus of monoclonal antibodies previously identified against other viruses.[304]​ In March 2020, a human monoclonal antibody was found that blocks the SARS-CoV-2 infection.[305]​[306]​ While plasma transfusions are very cheap and easy to perform, treatment with monoclonal antibodies would cost tens of thousands of euros per patient.[307]​.

NIH position on the use of monoclonal antibodies in the treatment of SARS-CoV-2 infection[308]​.

• - COVID-19 pandemic.

• - Severe acute respiratory syndrome (SARS).

• - Middle East respiratory syndrome (MERS).

• - Orthocoronavirinae.

• - Database in Clinical Trials.

• - SAR-COV-2 data.

• - COVID-19 Pubmed (118,397 articles as of 03-31-2021).

• - News in treatment.

• - Therapeutic management of adults with COVID-19.

• - US NIH database on treatments in development against COVID-19.

• - Immunological knowledge timeline.

• - COVI-19 resources at Cochrane.

• - Wiktionary has definitions and other information about COVID-19.

• - Coronavirus disease (COVID-19) outbreak on the World Health Organization website.

• - New coronavirus disease, COVID-19 on the website of the Spanish Ministry of Health.

On January 12, 2020, the World Health Organization (WHO) received the sequenced genome[42]​ of the new virus that causes the disease and temporarily named it 2019-nCoV, from the English 2019-novel coronavirus (new coronavirus), while the disease was called "2019-nCoV infection" in medical documents,[43]​[44]​ and Wuhan SARS or Wu Flu (Wu flu) on the Internet.[45]​[46]​ On January 30, the WHO recommended that the provisional name of the disease be "2019-nCoV acute respiratory disease", until the International Classification of Diseases gave an official name.[47]​ Despite this recommendation, the media and news agencies continued to use the name Wuhan pneumonia to refer to the disease.[48][49][50]​.

The WHO announced on February 11, 2020 that COVID-19 would be the official name of the disease.[51] The name is an acronym for coronavirus disease 2019 (coronavirus disease 2019, in Spanish). It was ensured that the name did not contain names of people or references to any place, animal species, type of food, industry, culture or group of people, in line with international recommendations, to avoid stigmatization against any group.[52]​[53]​.

In Spanish, the gender of the disease name can be both feminine and masculine; However, the feminine was from the beginning the one preferred by the Fundéu BBVA and, later, by the Royal Spanish Academy (RAE): The COVID-19, because "COVID-19" is the English acronym for disease due to coronavirus 2019, where disease (word represented by the letter D, the main element of the acronym) can only be feminine in the Spanish language.[6]​ Although the feminine is the that the WHO uses in all its writings, the use of the masculine is more standardized in public discourse, according to the RAE, due to the influence of the gender of coronavirus and other viral diseases: *dengue, *MERS, *SARS, *Zika, and others.[54]​ The Fundéu BBVA also points out that the name of the disease can be lexicalized in general texts, writing everything in lowercase (covid-19) because it is a noun, instead of the initial capital letter (Covid-19), as used in some writings;[6]​ and that it is not uncommon or incorrect to use only the first lexeme of this compound word (COVID instead of COVID-19). This simplification would be explained by the phenomenon of linguistic economy, especially in the informal register and spoken discourse.

When it is written with digits ("COVID-19" instead of "COVID"), the use of the hyphen "Hyphen (spelling sign)") is mandatory in Spanish (it is incorrect "COVID19" - all together - or "COVID 19" - with a space), since it is present in the official name, and, furthermore, the Spanish language has the habit of separating words that are made up of letters and numbers. The latter is carried out with a script.[55]​.

Regarding its accentuation, both institutions indicate that the majority use of the first lexeme of the word is acute /ko'βið/ (COVID-19) —and that the voice is, in fact, acute in Spanish—, so only a minority population of Spanish speakers accentuate it as flat /'ko.βið/, due to the influence of English, the language of origin of the term (COVID-19).[56][57]​

The full name of the disease should preferably be read as: [ko'βið.dje.si'nwe.βe] in non-sessing areas, and as: [ko'βið.dje.θi'nwe.βe] in non-sessing areas.

Discovery

In December 2019, there was an epidemic outbreak of pneumonia of unknown cause in Wuhan, Hubei Province, China; which, as Reporters Without Borders later stated, affected more than 60 people on the 20th of that month.[58]​.

According to the Chinese Center for Disease Control and Prevention (CCDC), on December 29, a hospital in Wuhan (Provincial Hospital of Integrated Traditional Chinese and Western Medicine, also known as Xinhua Hospital,) admitted 4 individuals with pneumonia, who worked in a market in that city. The hospital reported this to CCDC, whose city team launched an investigation. The team found more cases related to the market and on December 30, Wuhan health authorities reported the cases to the CCDC, which sent experts to Wuhan to support the investigation. Samples were obtained from these patients for laboratory analysis.[59]​.

On December 31, the Wuhan Municipal Health Committee reported to the World Health Organization (WHO) that 27 people had been diagnosed with pneumonia of unknown cause, with 7 in critical condition; The majority of these cases were workers at the aforementioned market.[60]​ By January 1, 2020, the market had been closed and the cause of the pneumonia had been ruled out as SARS, MERS, influenza, avian flu or other common respiratory diseases caused by viruses.[43]​.

On January 7, 2020, Chinese scientists had isolated the virus that causes the disease and performed genome sequencing. This sequencing was available to the WHO on January 12, 2020, allowing laboratories in different countries to produce specific diagnoses via PCR tests.[43]​.

On January 12, 2020, the Chinese authorities had confirmed the existence of 41 people infected with the new virus, who began to feel symptoms between December 8, 2019 and January 2, 2020, which included: fever, malaise, dry cough, difficulty breathing and respiratory failure;[43] invasive pneumonic infiltrates were also observed in both lungs observable in the thorax.[44]​.

Spread of the disease

Following the first outbreak of COVID-19 in Wuhan in December 2019, where Chinese authorities confirmed 41 cases detected between December 8 and January 2, 2020,[44] the city stopped reporting cases until January 19, when 17 more cases were confirmed. By then, the first cases of COVID-19 outside China had already been reported: two in Thailand and one in Japan.[61]​.

The rapid spread of the disease caused the World Health Organization, on January 30, 2020, to declare it a health emergency of international concern, based on the impact that the virus could have in underdeveloped countries with fewer health infrastructures.[62]​ On that date, the disease had been detected in all provinces of mainland China,[63]​ and cases were diagnosed in 15 other countries.

On March 11, the disease was already in more than 100 territories worldwide, and was recognized as a pandemic by the WHO.[64]​ The number of confirmed cases continued to grow until reaching 500,000 cases worldwide on March 26, 2020.[65]​.

To prevent the spread of the virus, governments imposed travel restrictions, quarantines, lockdowns, social isolation, cancellation of events, and closure of non-essential establishments. The pandemic had a disruptive socioeconomic effect,[66]​ and fear of supply shortages led to panic buying. There was misinformation and conspiracy theories spread online about the virus,[67][68]​ and incidents of xenophobia and racism against citizens of China and other East and Southeast Asian countries.[69]​.

It has been proven that the quarantines, restrictions on human traffic and isolation that occurred due to the pandemic had negative psychological effects.[70]​ At the end of January, the National Health Commission of China published a guide for the management of psychological crises, in which it advocated the intervention of affected people, close contacts, those locked in their homes, relatives and friends of the patients, health personnel and the general public who required it.[71]​[72]​ According to studies carried out. In 2020, it was confirmed that it has affected the mental health of women to a greater extent than that of men. Among the reasons is the increase in gender violence and their more precarious socioeconomic situation. A good part of the women work in the restaurant and tourism sectors, one of the most affected by the pandemic, in addition to being the main caregivers of sick people, children and the elderly.[73][74]​.

Isolation has meant that many patients were unable to continue with their treatments, aggravating their health problems. In these scenarios, women, whether family members or caregivers, usually play a fundamental role.[75]​.

Contenido

En esta enfermedad se describe un "triángulo epidemiológico causal" que está formado por: el medio ambiente, el agente etiológico (el virus SARS-CoV-2) y el huésped "Huésped (biología)").

Transmission

Person-to-person transmission routes of the SARS-CoV-2 etiological agent include direct transmission by inhalation of droplets and aerosols released through coughing, sneezing, breathing, speaking, shouting or singing,[23]​[76][77]​ or by hand contact with contaminated surfaces, which then touch oral, nasal or ocular mucous membranes.[78]​ It can also be transmitted through saliva, and possibly by the fecal-oral route.[26]​.

A study of 2,143 children suggests that this population group may be a critical factor in the rapid spread of the disease.[79]​.

Vaccinated people can still transmit COVID, although it is more difficult.[80]​ So those vaccinated must still make preventive measures (washing hands with soap, wearing a mask, maintaining social distance, etc.) so that the disease does not spread, especially to vulnerable people.

According to studies published in the scientific journals New England Journal of Medicine (March 17, 2020) and The Lancet Microbe (April 2), the persistence on different surfaces is as follows:[81]​.

• - Paper and tissues: 3 hours.

• - Copper: 4 hours.

• - Cardboard: 24 hours.

• - Wood: 2 days.

• - Fabric: 2 days.

• - Stainless steel: 2 - 3 days.

• - Polypropylene plastic: 3 days.

• - Crystal: 4 days.

• - Tickets: 4 days.

• - The outside of a mask: 7 days.

• - From 21° to 23° and 40% relative humidity.

• - At 71° and 65% relative humidity.

The World Health Organization recommends for this reason that surfaces be disinfected, especially in the healthcare environment. Outside of this, the role that fomite transmission may have is unknown, but less important than when it occurs through close contact with an infected person.[82]​.

Currently, there are many studies that focus on evaluating possible vertical transmission.[83]​ So far, the tests that have been carried out rule out the presence of SARS-CoV-2 in amniotic fluid, umbilical cord blood and breast milk.[83]​.

However, it is still too early to know with certainty whether vertical transmission can occur or not, since there are cases in which the presence of antibodies has been demonstrated in neonates born to mothers carrying the virus.[83]​ Therefore, although it is true that this evidence comes from a small number of cases, this further demonstrates the possibility of vertical transmission.[83]​.

Regarding breastfeeding, the presence of SARS-CoV-2 in the breast milk of infected patients has not been demonstrated.[83]​ Therefore, as there is no risk of contagion through breast milk, breastfeeding is not contraindicated in infected patients as long as the necessary hygiene measures are taken, including hand washing and the correct use of the mask.[83]​.

Reproductive rate R0

The reproductive number R is the average number of new infections that an infected person can generate; The higher this is, the greater the pandemic potential of a disease. The Chinese Academy of Sciences estimated a reproductive number or R=4 for COVID-19 in February 2020, although there is uncertainty about many of the factors taken into consideration to calculate the R. Imperial College London calculated R=1.5 to 3.5.[84]​.

Patient zero

The index case or "patient zero" is the case that gives rise to the attention of the researcher and causes actions to identify a focus of infection; It corresponds to the first case confirmed by the health authority and leads (indicates) towards a localized outbreak.[85]​[86]​[87]​.

Patient one

Sometimes the first case of COVID-19 identified by the health system (index case or patient 0) does not coincide with the case that gave rise to the epidemic. The "authentic index case" or "primary case" would be the first one that initiates the epidemic outbreak.[88]​.

The causal agent of COVID-19 is the virus (SARS-CoV-2),[11]​[89]​ which is a type of Orthocoronavirinae.[6]​[11]​ It was first discovered and isolated in Wuhan, China, after causing the 2019-2020 coronavirus disease epidemic. It appears to have a zoonotic origin, that is, it passed from an animal host (a bat) to a human host.[90] The virus genome is made up of a single strand of RNA, and is classified as a positive single-stranded RNA virus. Its genetic sequence has been isolated from a sample obtained from a patient affected by pneumonia in the Chinese city of Wuhan.[91][92][93][94][95]​.

The RNA of the SARS-CoV-2 virus encodes 4 structural proteins: protein S (spike protein), protein E (envelope), protein M (membrane) and protein N (nucleocapsid). The N protein is inside the virion associated with the viral RNA, and the other four proteins are associated with the viral envelope. The S protein assembles into homotrimers, forming structures that protrude from the virus envelope. The S protein contains the binding domain to the cellular receptor and is therefore the protein that determines the tropism of the virus and is also the protein that has the fusion activity of the viral membrane with the cellular one and in this way allows the release of the viral genome inside the cell that is going to infect.[97]​.

SARS-CoV-2 penetrates the cell using angiotensin-converting enzyme 2 (ACE-2) as a receptor, a membrane exopeptidase present mainly in the kidney, lungs and heart.[98] It has been observed that severe cases of COVID-19 present very high levels of Angiotensin II. And the level of angiotensin II has been correlated with SARS-CoV-2 viral load and lung damage. This imbalance of the renin-angiotensin-aldosterone system could be related to the inhibition of the angiotensin-2 converting enzyme by the virus. This same mechanism was observed in the outbreak caused by severe acute respiratory syndrome in 2003.[97]​.

The S glycoprotein of the virus envelope interacts with the cellular receptor ACE2 (angiotensin-converting enzyme 2), a cell membrane protein that catalyzes the conversion of angiotensin I to the nonapeptide angiotensin 1-9 or of angiotensin II to angiotensin 1-7. The virus enters by endocytosis. Once in the endosome, a lysosome-mediated drop in pH occurs, which promotes the fusion of the endosome membrane with the virus envelope, which releases the nucleocapsid into the cytoplasm. Cellular proteases degrade the capsid and the virus genome is free in the cytoplasm. Next, since it is a positive sense RNA genome, the cellular machinery directly translates it into polyproteins that are processed and the replication and transcription complex is formed. The complementary strand of negative sense pre-genomic RNA is then synthesized that will serve as a template to replicate the positive sense viral genome. Additionally, the replication and transcription complex will synthesize a series of smaller, positive sense subgenomic RNAs. These are the ones that will be translated into viral proteins. This entire process will occur in the cytoplasm of the cell. The structural proteins that will be expressed in the membrane of the endoplasmic reticulum will be synthesized. There, in the reticle, is where the assembly will occur. In fact, the envelope of the virus comes from the membrane of the endoplasmic reticulum. The viral particle will travel, through the cellular vesicle transport system in which the Golgi apparatus intervenes, to the surface. The viral particle will leave the cell by exocytosis. After a final maturation phase, in which viral proteases intervene, all the components of the virus will fit together, the particle will be infectious and a new cell cycle can begin.[99]​.

The virus can pass through the mucous membranes, especially the nasal and laryngeal mucosa, then enters the lungs through the respiratory tract. The virus would then attack the target organs that express ACE2, such as the lungs, heart, kidney system and gastrointestinal tract. The virus begins a second attack, causing the patient's condition to worsen around 7 to 14 days after the onset. Depletion of B lymphocytes can occur early in the disease, which can affect antibody production in the patient. Furthermore, inflammatory factors associated with mainly IL-6-containing diseases were significantly increased, which also contributed to the aggravation of the disease around 2 to 10 days after onset. The clinical spectrum of COVID-19 varies from asymptomatic forms[100]​ to clinical conditions characterized by severe respiratory failure requiring mechanical ventilation and support in an intensive care unit (ICU), to manifestations in various organs "Organ (biology)") and systems producing sepsis, septic shock and multiple organ dysfunction syndrome.[97]​.

The incubation period, that is, the time that passes from when a person is infected by the virus until they present symptoms, generally ranges between 4 and 7 days, in 95% of cases it is less than 12.5 days. The extreme limits have been established between 2 and 14 days after infection.[101]​.

At the immunological level, elevated levels of IL-6 and other proinflammatory cytokines have been shown in patients with severe COVID-19. This observation, together with other clinical parameters associated with severe cases such as lymphopenia (decrease in lymphocytes in the blood) and hyperferritinemia, has led to the hypothesis that a subgroup of COVID-19 patients may suffer from a cytokine release syndrome. Cytokine release syndrome (CRS), also called cytokine storm, is a syndrome caused by a systemic cytokine-mediated inflammatory response that can be triggered by a variety of factors such as infections and some medications. Cytokines are soluble proteins that act on cells of the immune system and regulate cell activation, proliferation and recruitment. Cytokine release syndrome occurs when large numbers of leukocytes (neutrophils, macrophages, and mast cells) are activated and release large amounts of proinflammatory cytokines. CRS was initially described as an adverse effect of monoclonal antibody therapies, and is also common in CART cell (chimeric antigen receptor T cell) therapies. The main cytokines involved in the pathogenesis of CRS include interleukin (IL)-6, IL-10, interferon (IFN), monocyte chemotactic protein 1 (MCP1), and granulocyte-macrophage colony-stimulating factor (GM-CSF); Other cytokines such as tumor necrosis factor (TNF), IL-1, IL-2, IL-2-receptor, and IL-8 have also been described during CRS. The pathogenesis of CRS in patients with COVID-19 is still unknown. However, clinical observations suggest that when the immune response is not able to effectively control the virus, such as in older people with a weakened immune system, the virus would spread more effectively, causing damage to the lung tissue, which would activate macrophages and granulocytes and lead to the massive release of proinflammatory cytokines. This increased lung inflammation would be associated with acute respiratory distress syndrome (ARDS), which has been described as the main cause of mortality from COVID-19.[97]​.

Response in pregnancy.

Today, there are many unknowns about the situation of pregnant women during the COVID-19 pandemic. Because they are prone to serious complications and infections from other types of coronavirus, they have been considered a risk group and advised to take a series of additional preventive measures.[102]​.

Some of the responses during pregnancy may be:

• Immunological: As with other viruses, the immune response to COVID-19 will depend on whether you have a healthy immune system. This adapts during pregnancy to allow the development of a fetus whose genetic makeup only half shares with its mother, which leads to a different immune reaction to infections during the pregnancy stage.[102]​.

• Respiratory: There are numerous factors that increase the vulnerability of pregnant women to serious respiratory infections. Two examples of this may be decreased lung capacity and the inability to eliminate secretions.[103]​.

• Coagulation: During pregnancy, coagulation levels in the circulatory system are high, and the pathogenesis of SARS-CoV-2 may be related to this. Thromboembolic events with associated mortality are a risk for pregnant women.[102]​.

However, based on current evidence, it is difficult to draw definitive conclusions about whether pregnant women are at increased risk of serious consequences from this virus.[102]​.

In addition, other clinical trials have shown that SARS-CoV-2 can affect the pregnancy period in different ways. On the one hand, there is not much evidence about its impact during the first 12 weeks of gestation. On the other hand, COVID-19 infection can cause negative consequences during the pregnancy period. Some examples of this may be fetal growth restriction, premature birth and perinatal mortality, that is, the death of the fetus after 22 or 28 completed weeks of pregnancy, as well as the death of newborn children at 7 days old.[103]​.

Infected people may be asymptomatic or present a series of symptoms that range from mild to very severe, including fever, dyspnea[104]​[105]​[106]​ and dry cough.[13]​ COVID-19 affects each person in different ways. Most people who become infected have mild or moderate symptoms and recover without the need for hospitalization. Diarrhea and other symptoms of the nasopharynx, such as sneezing, rhinorrhea and sore throat, are less common.[107]​ Although older people are more vulnerable to the disease, in mid-March 2020, the WHO recalled that young people can also have complications and even death from the virus.[108]​.

The symptoms of COVID-19 are non-specific and its presentation, according to the WHO, may even lack symptoms (asymptomatic). Based on a statistical sample of 55,924 laboratory-confirmed cases, the frequency of symptom presentation in the Chinese population was as shown in the attached table.[1]​.

*(As of February 20, 2020 and based on 55,924 laboratory confirmed cases).[1]​.

Complete loss of smell (anosmia) has been reported in 80% of those diagnosed, reaching 88% of those who present some degree of alteration in taste.[111] Others have recorded the sudden loss of smell and taste on a less frequent basis (without mucus being the cause).[112]​[113]​.

Symptoms were initially reported to include fever in 90% of cases, malaise and dry cough in 80% of cases, and breathing difficulties in 20% of cases.[43][114][115][116]​.

On January 24, 2020, The Lancet published a study of the first 41 cases of patients admitted (in a Wuhan hospital) with a confirmed diagnosis, from December 16, 2019 to January 2, 2020.[107] Of them, less than half had underlying diseases, including diabetes, hypertension, and cardiovascular disease. Common symptoms at the onset of the disease were fever, dry cough, and myalgia or fatigue; the least common symptoms were sputum production, headache, hemoptysis, and diarrhea. Dyspnea developed in 22 of 40 patients (55%), with a median "Median (statistical)") time from illness onset to dyspnea of ​​eight days. Lymphopenia occurred in 26 of 41 patients (63%). All patients had pneumonia with abnormal findings on chest CT.[117]​.

Some of those infected may be asymptomatic and show test results confirming infection, but do not show clinical symptoms, so researchers have issued advice that people with close contact with confirmed infected patients should be closely monitored and examined to rule out infection.[118] Skin changes associated with COVID-19 have been described.[119]​.

Complications included acute respiratory distress syndrome (real-time RT-PCR positive result on plasma sample), acute cardiac injury, and secondary infection. In a case series study published in January 2020, of 41 patients admitted to a hospital in Wuhan for COVID-19, 13 were admitted to an ICU (32%) and six died (15%). In a clinical commentary in the same journal, a comparison of the 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 notably infrequent (for example, no patient had a sore throat).[117]​.

It should be mentioned that COVID-19 has had more serious consequences in men than in women due to biological differences: women's immune system is more powerful, some chronic diseases are more common in men, etc.[73]​ The most frequent complications are pneumonia and multiple organ failure that sometimes cause death.[43][120]​ In the case of pregnant women, it is important to note that, according to the Centers for Disease Control and Prevention, pregnant women are at greater risk. of becoming seriously ill from COVID-19.[83]​ This is because pregnant women who have COVID-19 appear to be more likely to develop respiratory and obstetric complications that can lead to miscarriage, preterm birth, and intrauterine growth restriction (IUGR).[83]​.

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.[121]​.

Additionally, COVID-19 may predispose to arterial and venous thromboembolic disease due to excessive inflammation, hypoxia, immobilization, and disseminated intravascular coagulation (DIC). Surprisingly, thrombotic complications have barely been described. Accurate knowledge of the occurrence of thrombotic complications in patients with COVID-19 is important for decision-making regarding the intensity of thromboprophylaxis, especially in patients admitted to the intensive care unit (ICU) who have a higher thrombotic risk. In a study published on April 11, 2020, it was shown that there were 31% of thrombotic complications in patients with COVID-19 hospitalized in the ICU.[122]​ Sequelae in the form of physical, cognitive and psychological deterioration frequently occur in COVID-19 patients who have been in the ICU, who often receive rehabilitative treatment.[123]​.

It predisposes to complications in patients with atrial fibrillation[124]​.

De entre los 41 primeros casos de COVID-19 que fueron tratados en hospitales de Wuhan, trece (32 %) necesitaron cuidados intensivos y seis (15 %) murieron.[107]​ Muchos de los que fallecieron presentaban patologías previas como hipertensión arterial, diabetes o enfermedad cardiovascular que debilitaban sus sistemas inmunológicos.[125]​.

En estos casos tempranos que acabaron en fallecimiento, la mediana "Mediana (estadística)") de la duración de la enfermedad fue de catorce días y el rango total fue de 6 a 41 días.[126]​ De los casos confirmados, 80,9 % fueron clasificados como casos leves.[127]​[94]​.

Case fatality rate

According to a study of COVID-19 deaths in China's Hubei Province, out of a total of 72,314 patient records, 44,672 (61.8%) were confirmed as COVID-19 cases. Among them, 1,023 deaths were recorded, which represents a mortality rate of 2.3%.[127] This data, however, may be an underestimate of the real mortality because many people may have been infected, but do not present symptoms, and therefore have not been counted. Other studies indicate that apparent mortality was highest in the early stages of the outbreak (17.3% for symptomatic cases between January 1 and 10), and that it decreased over time to 0.7% for patients with symptom onset after February 1, 2020.[1]​.

South Korea, which is the only country in the world where systematic analyzes of large population groups were carried out since the beginning of the pandemic (about 10,000 per day, with 210,000 counted until March 10), found a much lower mortality rate.[128]​.

As of March 3, 2020 globally, 3,110 of the 90,892 reported cases of COVID-19 had died (3.4%), according to figures indicated by the director of the WHO.[129][130]​.

According to global data, in most countries, mortality rates from COVID-19 are higher in men than women. However, in some countries such as India, Nepal, Vietnam and Slovenia they are higher in women (even reaching 3.5% in some countries).[131]​.

For example, in the first country mentioned (where a total of 6.4 million cases had been registered as of September 30, 2020), the fatality rate is higher in women (3.3% of women compared to 2.9% of men), since there is a certain gender inequality in access to healthcare. However, the data are ambiguous and there are other aspects that must be taken into account, namely: the lower degree of aging of the female population makes women less likely to die, but the small number of tests does not provide definitive data (it is estimated that the mortality range is high, especially in women between 40 and 49 years old). Ignorance regarding COVID-19 is still present in many areas. It is essential that studies be carried out regarding the age, socioeconomic level and race of each person in order to take forceful and effective measures to definitively differentiate biological aspects from environmental aspects.[131]​.

Effect according to age and previous pathologies

In Italy as of March 31, 2020, it was found that the "Median (statistical)" median age of those who died from COVID-19 was 79 years. 69% of those who died were men and only 2% were in good health (that is, absence of previous pathologies) before infection.[132]​.

In China, mortality was also observed to increase with age and is higher among men than women (4.7% vs. 2.8%). While patients without previous pathologies had a mortality rate of 1.4%, those who did die at much higher rates: 13.2% for cardiovascular diseases, 9.2% for diabetes, 8.4% for hypertension, 8.0% for chronic respiratory disease and 7.6% for cancer.[1]​.

In a study published online in the journal Pediatrics, researchers analyzed 2,143 cases of children under the age of 18 who were reported to the CCDC through February 8, 2020. About half of the children had mild symptoms, such as fever, fatigue, dry cough, congestion, and possibly nausea or diarrhea. About 39% became moderately ill, with additional symptoms including pneumonia or lung problems revealed by the CT scan, but no obvious respiratory distress. About 4% had no symptoms at all. But 125 children, almost 6%, developed very severe illness and a 14-year-old boy with confirmed coronavirus infection died. Thirteen of them were considered "critical", on the verge of respiratory or organ failure. The others were classified as "serious" because they had severe breathing problems. More than 60% of the 125 children who became seriously ill or critically ill were 5 years old or younger. Forty of them were infants, younger than 12 months.[79]​ However, a systematic review on COVID-19 in pediatric patients suggests that males are more affected by the disease and that lung alterations observed in imaging studies are more frequent than clinical signs, such as cough and fever.[133]​.

It should be noted that, although the greatest risk of developing severe disease from COVID-19 falls on older people, according to studies published in the journal Nature, the probability of developing critical COVID as a consequence of genetic susceptibility is greater in individuals under 60 years of age.[134]​.

Therefore, the effects of the pandemic have a greater impact on older groups of people and especially on women, with the infection rate being higher among women, although the virus is more lethal in men. Likewise, persistent COVID is more common in women[135]​.

One of the factors may be that care usually falls on women, and, therefore, their exposure to the virus is greater than in the case of men. Furthermore, within the family, caring for dependent people also usually falls to women. Among health workers, the percentage of infections is also higher in women (66%).

According to the WHO, in similar situations with other viruses, women have also reached a higher rate of infection. In the case of men, the WHO also suggests that they have a greater risk of exposure in the workplace, while women are more likely to become infected in daily activities, as indicated above.

Socioeconomic effect

It is worth highlighting the analysis of the socioeconomic consequences of the coronavirus pandemic from a gender perspective. Women are the most affected at the work level and, as a consequence, at the social level.[137]​ It can be stated that during the first almost global confinement, household tasks increased greatly, with these falling mainly on women; 78.7% of European women carry out household tasks, while only 33.7% of men are in charge of this.[138]​ To this we add that due to teleworking and the demand for part-time jobs, it has increased. and it is more requested by women who have to take care of their children and do housework at the same time. Thus, women face a triple burden of work that can aggravate pre-existing inequalities.[137]​.

The service sector, as well as jobs facing the public or on the front line against the fight against coronavirus, are the most affected in this crisis, sectors made up of a greater number of women than men, which is why these are the ones who have to face more job losses.[137]​ Adding to the fact that part-time jobs earn less than full-time jobs, one of the most serious consequences on a socioeconomic level is the increase in the wage gap, which in global terms constitutes 23% between men and women. women.[139]​[137]​.

The situation of structural vulnerability of the LGTBI community has also increased as a result of the pandemic. The measures in the economy have especially affected this group because a high number of LGTBI people work in sectors in which virus containment restrictions have led to the loss of numerous jobs, and in many cases they depend on informal sources of income.[140]​.

On the other hand, the pandemic has affected the mental, social and sexual health of LGTBI people for several reasons. The closure of venues and leisure spaces aimed at the group has caused a significant loss of safe socialization spaces for LGTBI people. Furthermore, isolation measures have caused many people in the group to have had to be locked up in hostile situations, with family members or other cohabitants who do not accept their sexual condition and identity,[141]​ thus generating situations of psychological and even physical violence,[141]​ with evident emotional and mental health consequences, among which are an increase or worsening of anxiety and depression disorders. Furthermore, these types of measures have aggravated the situation of loneliness in members of the community, particularly in older LGTBI people, since they frequently live alone and do not have positive relationships with their families.[142]​.

Furthermore, several human rights defense organizations (Human Rights Watch, Amnesty International, IESOGI) appeal to the fact that several governments have made use of the pandemic context to criminalize and demonize members of minorities such as the LGTBI community.[140]​ These people have suffered the consequences of the promulgation of hate speeches that point to them as the source of transmission of the disease, and even, in more extreme cases, as responsible for it.[140]​ Likewise, the pandemic has caused the entry into force of rights for the LGTBI population to be postponed or in some cases stopped.[140]​.

Immunity

Humans' natural immune response to the SARS-CoV-2 virus occurs as a combination of cell-mediated immunity and antibody production, as with almost all other infections. B cells interact with T cells and begin dividing before selection into the plasma cell, partly based on their affinity for the antigen. The presence of neutralizing antibodies in the blood is considered evidence of immunity against infection, but the level of neutralizing antibodies decreases over time, disappearing after three months in 1% of patients and after six months in 12%.[144] However, the absence of antibodies in the blood does not mean that the immune system cannot quickly produce new antibodies in the event of re-exposure to SARS-CoV-2. Memory B cells specific for SARS-CoV-2 nucleocapsid and spike proteins last at least 6 months after symptom onset.

Since SARS-CoV-2 has only been in the human population since December 2019, it was unknown early in the pandemic whether immunity was long-lasting in people who recover from the disease. Cases of reinfection were reported in patients who had already had the disease and it was feared that SARS-CoV-2 behaved like some other coronaviruses, which are capable of reinfecting after approximately a year.[145]​.

A January 2021 study found that most patients infected with the SARS-CoV-2 virus remain immunized for at least five months, with a much lower probability (83%) of becoming infected again than those who had not previously been exposed to the virus. Furthermore, in the case of reinfection, those previously infected usually did not present symptoms (78% of cases) while the absence of symptoms only occurred in 34% of those not previously infected.[146]​[147]​ In a March 2021 study, it was observed that only 0.65% of patients infected with SARS-CoV-2 tested positive in PCR again at least three months later and that none were infected a third time. It is estimated that having been infected reduces, on average, 80% the probability of being infected a second time and that protection lasts at least six months.[148]​[149]​ In another study published in May 2021, it was concluded that natural immunity against SARS-CoV-2 lasts for years, probably a lifetime, even in people who had mild symptoms of covid or did not have it when they were infected. infected.[150]​[151]​[152]​[153]​ This is due to the action of both B cells and long-lived bone marrow plasma cells.

In total, it is estimated that having contracted the virus provides 94% natural immunization against COVID-19 symptoms. This figure is comparable to what was initially announced for the best vaccines. However, like vaccines, having passed the virus does not guarantee that a person cannot contract it and spread it again, which is why health authorities recommend that all previously infected people continue to apply the usual prevention methods.[154]​.

An Israeli study published in August 2021 shows that natural immunity is actually more robust and longer lasting than that obtained through vaccination.[155]​.

Symptomatic diagnosis

Chest radiology (either x-ray, computed tomography, or ultrasound) can help diagnose COVID-19 and identify or rule out pulmonary complications.[172]​.

Outbreak management

A key part of actions in an infectious disease outbreak is trying to reduce the epidemic peak, known as flattening the epidemic curve. This helps reduce the risk of health services being overwhelmed and provides more time to develop a vaccine and treatment. Social distancing and isolation of infected populations can contain the epidemic.[175]​.

Preventive measures

Some international organizations, such as the WHO, have published preventive measures to reduce the transmission of the virus. They are similar to those that have been recommended to prevent infection by other coronaviruses and include:.

• - Wash your hands frequently with soap and water.

• - When coughing or sneezing, cover your mouth and nose with the indentation or cubital fossa (the concavity that forms the inside of the arm when it is flexed at the elbow).

• - Maintain at least one meter distance from other people, "particularly those who cough, sneeze and have a fever."

• - Use facial masks.[176]​.

• - Avoid touching your eyes, nose and mouth.

• - Go to the doctor in case of fever, cough and difficulty breathing, calling in advance if you are in areas where the virus is spreading or if you have visited them in the last 14 days.

• - Stay at home if you start to feel unwell, even if the symptoms are mild such as headache and mild rhinorrhea, until you recover if you are in areas where the virus is spreading or if you have visited each other in the last 14 days.[30]​.

To reduce your chances of becoming infected, health organizations recommend avoiding close contact with sick people; wash your hands frequently with soap and water; do not touch your eyes, nose or mouth with unwashed hands; and practice good respiratory hygiene.[177]​[30]​.

People who are already infected are recommended to stay home except to receive medical care, call ahead before visiting a health care provider, wear a face mask (especially in public), cover coughs and sneezes with a tissue, wash hands regularly with soap and water, and avoid sharing personal household items.[178] Depending on the laws of each country, intentional transmission of the virus is punishable according to the legal system where the infection occurs. fact.[179]​.

The Hong Kong government warned anyone traveling outside the city not to touch animals; do not eat game meat; and avoid visiting wet markets, live bird markets, and farms.[180]​ There is no evidence that pets, such as dogs and cats, can become infected.[181]​ The Chinese government has banned the trade and consumption of wild animals.[182]​.

For healthcare providers caring for someone who may be infected, standard precautions, contact precautions, and precautions against airborne viruses are recommended, as well as wearing eye protection.[183]​.

Hand washing is recommended to prevent the spread of coronavirus. The CDC recommends:[177]​.

• - Wash your hands often with soap and water for at least 20 seconds, especially after going to the bathroom; before eating; and after blowing your nose, coughing or sneezing.

• - If soap and water are not available, use an alcohol-based hand sanitizer with at least 60% concentration. Always wash your hands with soap and water if your hands are visibly dirty.

People should avoid touching their eyes, nose, or mouth with unwashed hands.[30]​.

SARS-CoV-2 can survive and remain contagious on inanimate surfaces such as metal, glass or plastic for several days. Methods to eliminate the virus from surfaces include chlorine-based disinfectants, 75% ethanol, peracetic acid, and chloroform.[181]​.

Health organizations recommend covering your mouth and nose with a bent elbow when coughing or sneezing or covering your mouth and nose with a disposable tissue (which should then be discarded immediately) and then washing your hands with an alcohol-based hand sanitizer or soap and water.[30]​[184]​.

Governments have ordered the general use of masks to contain the pandemic. Masks benefit public health by reducing infections.

Those who suspect they are infected should call a doctor for advice and wear a mask (especially when around other people).[180]​[185]​ Masks limit the volume and travel distance of respiratory droplets dispersed by talking, sneezing, and coughing. However, several studies have concluded that because masks are designed according to prototypical male features, they tend not to fit well on women's faces, leaving them more exposed to the virus.[186]​.

If a mask is not available, anyone experiencing respiratory symptoms should cover their cough or sneeze with a tissue, promptly dispose of it in the trash, and wash their hands. If tissue is not available, people can cover their mouth or nose with a flexed elbow.[30]​.

Masks are also recommended for those caring for someone who may have the disease.[185]​ Rinsing the nose, gargling with mouthwash, and eating garlic are not effective methods.[181]​ Some studies have shown the effectiveness of mouthwashes in reducing SARS Cov-2.[187]​.

The WHO advises using masks like this:[185]​.

• - Carefully position the mask to cover the mouth and nose and tie securely to minimize any gaps between the face and the mask; While in use, avoid touching the mask;

• - Remove the mask using appropriate technique (i.e. do not touch the front but rather remove the lace from the back);.

• - After removing it or any time you inadvertently touch a used mask, clean your hands with an alcohol-based hand sanitizer or soap and water if visibly dirty;

• - Replace the masks with a new clean, dry mask as soon as they become wet;

• - Do not reuse single-use masks; Throw away single-use masks after each use and throw them away immediately after removal.

Normal masks primarily seek to reduce the spread of the disease by avoiding infecting others, so they can give a false sense of security to those who wear them. On the other hand, certified respirators also provide great protection to their wearer.

Healthcare professionals who interact directly with people who have the disease are recommended to use respirators with protection as high as NIOSH-certified grade N95, or EU grade FFP2, or equivalent, in addition to other possible personal protective equipment.[185]​[188]​.

There are masks that have an exhalation valve (that is, outlet), which expels unfiltered breathing air. If its wearer is infected (and they may be without knowing it), they would transmit the virus through the valve, even if the mask is certified. So masks with an outlet valve are not recommended to control the pandemic.

(Normal) surgical masks have long been used by healthy people in Hong Kong,[189]​ Japan,[190]​ Singapore[191]​[192]​ and Malaysia.[193]​.

In addition to the guidance mentioned above on handwashing and respiratory hygiene, public health agencies advise that sick people who suspect they may have COVID-19 should restrict activities outside the home, except to obtain medical care:[178]​[194][195]​.

• - Do not go to work, school or public areas. Avoid using public transportation, rideshares or taxis.

• - Call ahead before visiting a doctor.

• - Separate from other people and animals in the home; do not share personal items; use a separate bathroom if available.

• - Use a household cleaner to clean all frequently touched surfaces (counters, toilets, doorknobs, etc.) every day.

Prevention measures recommended by the WHO include regular hand washing with soap and water, covering the mouth and nose with a bent elbow when coughing or sneezing, and avoiding direct contact with people who show symptoms of respiratory illness without adequate protective measures. other infectious diseases, only eat meat or eggs if they are well roasted or cooked.[196]​.

Social distancing includes infection control actions intended to slow the spread of the disease by minimizing close contact between people. Methods include quarantines, travel restrictions and closures of schools, workplaces, stadiums, theaters or shopping malls. People can also apply social distancing methods by limiting travel, avoiding crowded areas, and physically distancing themselves from sick people.[30][198] Many governments now require or recommend social distancing in regions affected by the outbreak.[199][200][201]​.

Older adults and those with serious chronic conditions face a higher risk of serious illness and complications from COVID-19 and the US CDC has advised them to avoid crowds and stay home as much as possible in community outbreak areas.[202]​.

Some countries, such as Canada and the United States, have issued guidelines against shaking hands, hugging, or kissing.[203] Some countries, such as India, have advised their citizens to avoid spitting in public places.[204] The World Health Organization (WHO) now recommends that the general population maintain "at least 1 meter (3 feet) distance between yourself and other people, particularly those who cough, sneeze, and have a fever."[30]

The Harvard T.H. The Chan School of Public Health recommends a healthy diet, being physically active,[205]​ managing psychological stress, and getting enough sleep.[206]​.

There is no strong evidence that vitamin D status has any relationship with COVID-19 health outcomes.[207] Recently (December 2021), a systematic review has been published in which observational studies involving almost two million adults suggest that vitamin D deficiency/insufficiency increases susceptibility to COVID-19 and severe COVID-19. There is a high risk of heterogeneity, so the meta-analysis could not be done.[208][209]​.

Multiple studies affirm that obesity is one of the most important factors that lead to hospitalization, the development of the most severe form of the disease and admission to the ICU; in addition to the development of serious, life-threatening complications from COVID-19.[210]​.

When someone has been vaccinated against COVID (they have received all the necessary doses of the vaccine, and a set time has passed), it is still possible to transmit the disease, although the chances are greatly reduced (according to some research).[80]​[234]​ In addition, the vaccines fail in a small proportion of vaccinated people.

Therefore, it is recommended that the population continue to carry out preventive measures (wash hands with soap, wear a mask, maintain social distance, etc.) to avoid contagion, especially to vulnerable people. The precautions would end when the dangers of the pandemic are officially over.

Regarding pregnancy, although insufficient testing has been done, 23 women became pregnant during the clinical trial of the Pfizer vaccine and none of them showed any adverse effects. However, the Food and Drug Administration (FDA) recommends that pregnant or nursing women consult with their doctors when deciding whether they should get vaccinated. It is important to emphasize that, if a woman is in the process of trying to get pregnant, the vaccine will not affect her fertility in any case.[235]​.

Currently (August 2021), there is a recommendation to vaccinate all pregnant women.[236]​.

Varios tratamientos experimentales contra el covid-19 están actualmente en desarrollo o han sido aprobados en al menos un país:.

• - la fluvoxamina, un antidepresivo barato y abundante;[237]​.

• - antivirales como el remdesivir (de Gilead),[238]​ el molnupiravir (desarrollado por Merck),[239]​ y el PF-07321332") (desarrollado por Pfizer).[240]​[241]​.

• - la transfusión de plasma sanguíneo de donantes que ya han pasado la enfermedad.[242]​.

Otros tratamientos que se consideraron prometedores durante los primeros meses de la pandemia, como la hidroxicloroquina y el lopinavir/ritonavir, resultaron después ser inefectivos o incluso perjudiciales.[243]​ La colchicina, un antiinflamatorio, ha dado resultados inciertos.[244]​.

Treatments in development

Research to find an effective treatment began in January 2020.[245]​ The Chinese Center for Disease Control and Prevention began testing, in late January, the effectiveness of some pre-existing effective treatments against pneumonia in patients with COVID-19.[246]​ Tests have also been done with drugs such as Remdesivir, an RNA polymerase inhibitor,[247]​[248][249][250]​ and with interferon beta").[250]​.

Recent studies have revealed intercellular adhesion molecules (such as E-Selectin) involved in the recruitment of immune cells in critical COVID, so they are being studied as possible therapeutic targets.[251]​.

On January 23, 2020, Gilead Sciences was in communication with researchers and physicians in the United States and China regarding the ongoing Wuhan coronavirus outbreak and the potential use of Remdesivir as an investigational treatment.[252]​.

In 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.[253]​ Nitazoxanide has been recommended for further in vivo studies after demonstrating low-concentration inhibition of SARS-CoV-2.[254]​ On February 2, 2020, Doctors in Thailand claimed to have successfully treated a patient with a combination of lopinavir/ritonavir and the anti-influenza drug oseltamivir.[255][256] On February 5, China began patenting the use of remdesivir against the disease.[257][258][259][260][258][257] Phase 2 clinical trials are underway in March. 3 in the United States, China, and Italy with remdesivir.[261][262][263] In April, it was announced that ivermectin inhibits SARS-CoV-2 replication in vitro[264] Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large and statistically significant reductions in mortality, time to clinical recovery, and time to clearance viral.[265]​.

In late January, Russia's Health Ministry identified three drugs for adults that could help treat the disease. They are ribavirin, lopinavir/ritonavir and interferon beta-1b. These drugs are commonly used to treat hepatitis C, HIV infection and multiple sclerosis, respectively. The ministry provided Russian hospitals with descriptions and guides on the treatment's mechanism of action and recommended doses.[266] In February, China began using triazavirin), a 2014 drug developed in Russia, with the aim of testing whether it is effective in controlling the disease. This drug was created at the Ural Federal University in Yekaterinburg to treat H5N1 influenza (bird flu). It has been used against COVID-19 due to the similarity between the two diseases. The drug also appears to be effective against Rift Valley fever and West Nile virus, among others.[267]​.

On March 18, an article reports that treatment with lopinavir/ritonavir is negative in clinical trials with 199 patients in China. There are no benefits.[268]​.

Chinese researchers discovered that Arbidol, an antiviral drug used to treat influenza, could be combined with Darunavir, a drug used in the treatment of HIV, to treat coronavirus patients.[269][270]​.

Chloroquine phosphate has demonstrated apparent efficacy in the treatment of COVID-19-associated pneumonia. In clinical trials with 100 patients it was found to be superior to control treatment in inhibiting pneumonia exacerbation, improving lung imaging findings, promoting negative conversion to the virus, and shortening the illness. Research results showed that SARS-CoV-2 protein ORF8 and surface glycoprotein could bind to porphyrin, respectively, while SARS-CoV-2 proteins orf1ab, ORF10, and ORF3a could coordinately attack heme to dissociate iron to form porphyrin. The mechanism seriously interfered with the normal anabolic heme pathway in the human body and this produces a human disease. According to the validation analysis of these findings, chloroquine could prevent orf1ab, ORF3a and ORF10 from attacking heme to form porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent.[271]​[272][273]​.

Researchers at the Norwegian University of Science and Technology (NTNU) have created a database of 120 broad-spectrum antiviral agents safe for people and identified 31 drug candidates for the treatment of SARS-CoV-2.[274]​.

China's National Biotechnology Development Center stated on March 17 that the antiviral Favipiravir, an RNA polymerase inhibitor,[275] showed positive results in a case-control study of 80 patients at Shenzhen No. 3 People's Hospital; 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 the treatment.[276]​[277]​.

Recent studies have shown that the initial priming of the spike protein by 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.[278][279] These findings suggest that the TMPRSS2 inhibitor Camostat") approved for clinical use in Japan to inhibit fibrosis in liver and kidney disease, postoperative reflux") and pancreatitis could constitute an effective off-label treatment option.

Hydroxychloroquine, a less toxic derivative of chloroquine, would be more potent in inhibiting SARS-CoV-2 infection in vitro.[280][281] 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-Méditerranée infection) in Marseille (Bouches-du-Rhône, Provence-Alpes-Côte d'Azur), announced that a trial with 24 patients from southeastern France had shown that chloroquine is an effective treatment for COVID-19.[282][283]​ 600 mg of hydroxychloroquine (brand name Plaquenil) was administered to these patients 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."[282] While chloroquine has a long safety record, 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 [infected] patients who had not yet received treatment... We were able to determine that 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. Paterson announced his intention to conduct a major clinical investigation. trial of the effectiveness of chloroquine and remedesivir as treatments for COVID-19.[284]​ The trial would compare one drug, against the other drug, against the combination of the two drugs. Professor Paterson hoped to begin enrolling patients at the end of March 2020.[284]​.

A limited French study shows that hydroxychloroquine combined with azithromycin is faster than hydroxychloroquine alone in transforming COVID-19 patients to negative.[285]​ This combination is not indicated for the treatment of COVID-19 and has been shown to have serious side effects.[286]​.

Nafamostat mesylate (brand name: Fusan), a medication used to treat acute pancreatitis, can effectively block the required viral entry process that the novel coronavirus (SARS-CoV-2) uses to spread and cause disease (COVID-19). The University of Tokyo plans to launch clinical trials in April 2020 to evaluate the effectiveness of these two drugs in treating COVID-19.[287]​.

Fujifilm announces the initiation of a Phase III clinical trial of the influenza antiviral drug "Avigan Tablet" (generic name: favipiravir).[288]​.

Tocilizumab (a monoclonal antibody) has been included in treatment guidelines by the National Health Commission of China after a small study was completed.[289][290]​ It is undergoing a nationwide non-randomized phase 2 trial in Italy after showing positive results in people with severe disease.[291][292]​ In combination with a serum ferritin blood test to identify cytokine storms, it is intended to counteract such developments, which are believed to be the cause of death in some affected people.[293]​[294]​ The interleukin-6 receptor antagonist was approved by the FDA for treatment against cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017.[295]​.

Northwell Health's Feinstein Institute announced a study in March on "a human antibody that may prevent the activity" of IL-6. Called sarilumab developed jointly by Regeneron Pharmaceuticals") and Sanofi.[296]​.

The NIH has guidelines on the use of tocilizumab in the treatment of COVID-19:[297]​.

In March 2021, the Cochrane Library published a systematic review on tocilizumad in the treatment of COVID19[298].

lung transplant

In patients with severe acute respiratory syndrome, who do not respond to treatment and with criteria for lung involvement with fibrosis, results on lung transplantation have already been published[299]. The findings of this report show that lung transplantation is the only option for survival in some patients with ARDS associated with severe COVID-19 that does not resolve, and that the procedure can be performed successfully, with good early results after transplantation, in carefully selected patients.

The use of blood plasma donations ('Plasma (blood)') from people who have already recovered from COVID-19 is being investigated,[300]​ a strategy that was successfully applied against the 1918 flu and has been tested for SARS, an earlier cousin of COVID-19[300]​ and other diseases such as Argentine hemorrhagic fever. The mechanism of action is that naturally produced antibodies ("convalescent serum") in the immune system of those who have already recovered are transferred directly to people who need them.[300]​ This provides a non-vaccine-based form of immunization. This therapy was authorized by the US FDA in August 2020 as an emergency treatment against COVID-19.[301]​ The first complete clinical trial, published in January 2021, concluded that the application of plasma transfusions during the initial phase of mild symptoms reduced the severity of the disease in 60% of cases.[302][242]​.

A more complex version of this therapy consists of synthesizing COVID-19 antibodies, called "monoclonals," in the laboratory and then injecting them into patients.[300]​[303]​ Several pharmaceutical companies, such as Vir Biotechnology, have evaluated the effectiveness against the SARS-Cov-2 virus of monoclonal antibodies previously identified against other viruses.[304]​ In March 2020, a human monoclonal antibody was found that blocks the SARS-CoV-2 infection.[305]​[306]​ While plasma transfusions are very cheap and easy to perform, treatment with monoclonal antibodies would cost tens of thousands of euros per patient.[307]​.

NIH position on the use of monoclonal antibodies in the treatment of SARS-CoV-2 infection[308]​.

• - COVID-19 pandemic.

• - Severe acute respiratory syndrome (SARS).

• - Middle East respiratory syndrome (MERS).

• - Orthocoronavirinae.

• - Database in Clinical Trials.

• - SAR-COV-2 data.

• - COVID-19 Pubmed (118,397 articles as of 03-31-2021).

• - News in treatment.

• - Therapeutic management of adults with COVID-19.

• - US NIH database on treatments in development against COVID-19.

• - Immunological knowledge timeline.

• - COVI-19 resources at Cochrane.

• - Wiktionary has definitions and other information about COVID-19.

• - Coronavirus disease (COVID-19) outbreak on the World Health Organization website.

• - New coronavirus disease, COVID-19 on the website of the Spanish Ministry of Health.