COVID-19 (Novel Coronavirus Infection, SARS-CoV-2)

COVID-19 (Novel Coronavirus Infection, SARS-CoV-2).

COVID-19 is an infectious viral disease that predominantly affects lung tissue. Pathognomonic symptoms are respiratory failure, respiratory distress syndrome in a critical course. In addition to these manifestations, patients complain of dry cough, high fever, loss of taste and smell. Diagnostics – detection of the pathogen in biological materials (molecular genetic method), specific antibodies to the pathogen (ELISA). Etiotropic treatment is carried out with known antiviral and other drugs, pathogenetic and symptomatic therapy is used.

Causes
Characteristics of the pathogen
The causative agent of the disease is a new RNA-containing beta coronavirus SARS-CoV2 from the family of the same name. Full genome sequencing, phylogenetic analysis showed that the closest similarity is observed with two types of bat coronaviruses, therefore, they can be a natural reservoir of infection. There is no convincing evidence of transmission of the virus from these mammals, either directly or through an intermediate host.

Several subspecies of coronavirus that have arisen after mutations have been identified:

B.1.1.7 (202012/01 or 20I / 501Y.V1). It was first isolated at the end of 2020 (UK), where it significantly accelerated the growth in the number of cases. This variant contains more than a dozen mutations, several of which are components of the spike protein. According to various estimates, this variant is 50-75% more contagious, 25-40% easier to transmit than the original virus.
B.1.351 (20H / 501Y.V2). This variant has been identified as South African. The virus contains another mutation within the spike protein, E484K, which could potentially affect immunity from previous infection or vaccination. The clinical implications of this decrease in neutralizing activity have not been elucidated, and it is assumed that the immunity induced by the COVID-19 mRNA vaccine will protect against B.1.351 virus.
P.1 (20J / 501Y.V3). The strain was first described by Japanese scientists from four travelers from Brazil. Subsequently, it was identified in many countries, including the United States. This subspecies of coronavirus has several mutations, including three within the spike (spike) S-protein receptor. Mutational changes in the protein of the pathogen can increase transmissibility, affect post-vaccine immunity, and the level of protection after an infection.
B.1.427 and B.1.429 (20C / S452R or CAL.20C). By January 2021, these variants accounted for 35% of viruses sequenced in Southern California. They contain several spike protein mutations, including L452R, which increase cell permeability. In vitro mutations lead to a decrease in the neutralization of the pathogen by the plasma of convalescents and vaccinated persons. These variants colonize and multiply more massively in the nasopharynx than the original virus.
B. 1.617. This variant of the coronavirus consists of several subvariants (B. 1.617.1, B. 1.617.2 and B. 1.617.3). It was first identified in India in October 2020. Data on clinical and epidemiological characteristics are limited. There is no information on the effectiveness of vaccines available for the Indian strain. Limited data from unpublished studies indicate that the serum of vaccinated individuals retains some neutralizing activity against B.1.617 variants.
Transmission mechanism
The source of infection is a sick person or an asymptomatic carrier (with close contact). The route of transmission is airborne, fecal-oral (casuistry). There is evidence of transmission of the virus between humans and animals. Test results for SARS-CoV2 in some animals, such as minks, dogs, domestic cats, lions, tigers and raccoon dogs, have been positive after interacting with infected people.

Risk factors
The main risk factors for COVID-19 are elderly (> 65 years) age, the presence of diabetes mellitus, heart disease, lung disease, and cancer. Other conditions that can lead to a high risk of severe COVID-19 include kidney disease, sickle cell disease, obesity, all immunocompromising conditions. Risk group – transplant recipients, pregnant women, smokers, medical staff, social workers, workers in the service sector.

Pathogenesis
When it enters the upper respiratory tract, the pathogen colonizes the epithelial cells of the nasopharynx and oropharynx, actively multiplies inside, destroying the cells. The nucleocapsid of the virus is found inside the cytoplasm of the epithelial cells of the salivary, lacrimal glands, the digestive system, and the urinary tract. However, the main, rapidly achievable target of coronavirus is the alveolar cells of the lungs of type II, which determines the development of diffuse damage to the alveoli.

Simultaneously with these processes, there is a decrease in the number of T-lymphocytes, an increase in the amount of pro-inflammatory cytokines (for example, IL-6, TNF-alpha) up to the development of a “cytokine storm”. The phenomenon of hypercoagulability is associated with direct damage by the endothelial virus, blood stasis due to forced immobilization, an increase in circulating prothrombotic factors (von Willebrand factor, factor VIII, D-dimer, fibrinogen, etc.).

Classification
COVID-19 is a disease primarily affecting the lower respiratory tract, although antigens of the virus are found in all organs. It is believed that laboratory detection of the pathogen in the peripheral blood correlates with the severity of the pathology. Clinical variants of the course and manifestation of a new coronavirus infection can be divided according to the severity of the course:

Light. It is characterized by a variety of catarrhal symptoms, fever, pneumonia.
Moderately heavy. It is accompanied by prolonged fever> 38 ° C, shortness of breath on exertion, changes on CT.
Heavy. It is characterized by a decrease in the level of consciousness, agitation, and respiratory failure.
Extremely heavy. It is characterized by the identification of signs of ARDS, sepsis, multiple organ failure.
Symptoms of COVID-19
The incubation period is from 2 to 14 days, mainly 5-7 days. Most often, symptoms similar to most acute respiratory viral infections occur: fever of varying severity, dry cough, sore throat. Patients notice a loss of taste, smell, headache. Shortness of breath is noted in a third of patients: it is manifested by an increasing feeling of lack of air, especially in a horizontal position, the need for additional efforts for inhalation and exhalation.

Others may notice the retraction of the intercostal spaces, supraclavicular fossae. Patients are forced to sit, leaning on their hands, quickly get tired, breathing becomes noisy, the skin becomes bluish. In 12-19% of cases, COVID-19 manifests itself with gastrointestinal symptoms: frequent loose watery stools, discomfort and abdominal pain, as well as nausea, vomiting. Shortness of breath in such cases joins in 5-8 days.

Skin rashes during this infection are varied: blisters, spots, bumps and other elements; there may be bubbles, swelling, ulcers, limbs are often affected. Among people over 80 years old, as well as in patients with neurocognitive disorders, the primary symptoms of COVID-19 are delirium: visual hallucinations, delusions, difficulty in orientation in time, the world around them.

Children may develop a multisystem inflammatory syndrome (MIS-C, Kawasaki-like), manifested by an increase in body temperature, rashes of various shapes on the skin, mucous membranes, and enlargement of cervical lymph nodes. Often at the height of the fever, patients complain of redness, discomfort in the eyes, lacrimation, severe pain and limitation of joint mobility, vomiting, nausea, and diarrhea.

Symptoms requiring urgent hospitalization of the patient: increasing shortness of breath, hemoptysis, constant chest pain, sudden confusion in events, memory lapses, inability to wake up or short periods of wakefulness, the appearance of a bluish-purple color of the nasolabial triangle or the entire face, limbs. Also, going to the doctor requires ongoing profuse diarrhea, convulsions, complete absence of urine for more than 12 hours.

Complications
The most common signs of respiratory distress syndrome occur (up to 41% of patients), the likelihood of its development is higher in people 65 years of age and older, with diabetes mellitus, arterial hypertension. Thromboembolic complications in the form of pulmonary embolism, deep vein thrombosis, stroke are observed in 10-40% of patients. Cardiac arrhythmias occur in 17%, symptoms of myocardial damage – in 7%, infectious-toxic shock – in 9%.

Encephalopathy develops in 30% of cases. Rare complications are Guinea-Barré syndrome (about 10%), secondary aspergillosis (8-28%), immune thrombocytopenia (7%), spontaneous pneumothorax (0.56%). After the illness, the postcoid syndrome is noted: fatigue, shortness of breath, chest pain, cough. Patients treated for COVID-19 may have mental (anxiety, depression, PTSD) and cognitive (memory loss, concentration) symptoms.

Diagnostics
Verification of the diagnosis of coronavirus infection, its treatment is carried out by infectious disease doctors, often by resuscitators. Other medical professionals are called on when indicated. It is important to collect an epidemiological history, including data on travel to endemic areas, family, work contacts of the patient. The main clinical, instrumental and laboratory signs of COVID-19:

Physical data. An objective study determines the symptoms of respiratory failure – forced posture, cyanosis of the skin, shortness of breath. There is a dry, less often productive, cough, various rashes and fever. In the lungs, weakening of breathing is heard, rarely – dullness of the percussion sound. Revealed hyperemia of the throat, nasal congestion, moderate abdominal pain on palpation, rumbling. A visual assessment of loose stools, vomiting, if any, is carried out.
Laboratory research. A general clinical blood test usually reveals lymphopenia, thrombocytosis. There is an increase in CRP, creatinine, LDH, transaminases, ferritin in biochemical blood tests, an imbalance in acid-base balance. Hyperglycemia often occurs, as well as hypercoagulation: an increase in PTI, fibrinogen, a decrease in antithrombin. The critical course is associated with high levels of procalcitonin, D-dimer and severe lymphopenia.
Identification of infectious agents. Verification of the diagnosis is carried out using the PCR method (RT PCR SARS-CoV2). The material is a swab from the nasopharynx, nose, saliva, also sputum (it is not recommended to induce its appearance), bronchoalveolar lavage and aspirate from the lower respiratory tract. It is believed that the highest level of virus in a smear is found before symptoms appear; up to 5-40% of smears can be false negative.
Serological screening. ELISA with validated test systems provides an assessment of disease activity by identifying people, among whom COVID-19 has not been diagnosed by PCR, or with asymptomatic or subclinical infection. ELISA also allows the identification of individuals who may be immune to infection; the serological standards for the protective titer of antibodies have not yet been determined.
Other laboratory tests. The practical benefits for routine use of interferon gamma release assays in COVID-19 are being investigated. Isolation of a viral culture in clinical practice is not used due to the biological hazard of the coronavirus.
CT scan of the chest. Typical symptoms of COVID-19: bilateral, mainly lower lobe, opaque-like opacities in 83% of patients with thickening of the pleura, interlobular septum in half of the cases, focal infiltrates located mainly subpleurally along the vascular bundles. Less commonly described are bronchiectasis, pleural, pericardial effusion, lymphadenopathy. Dynamic CT control is required. Radiography of the lungs is not very informative – up to 20% of patients have no changes in the images throughout the entire disease.
Ultrasound of the lungs. It is used when CT is unavailable; there have been no studies of the sensitivity and specificity of the method for COVID-19. Lung ultrasound findings in patients include pleural thickening, discontinuity. Subpleural B lines are described as discrete, multifocal, or confluent. Spotted, banded and nodular consolidations are visualized; there is an effect of air-filled bronchi against the background of an airless lung (symptoms of alveolar edema or pneumonia).
Testing of asymptomatic persons is carried out in case of close contact with a person with COVID-19, or in places of forced gathering of people (long-term care institutions, pre-trial detention centers, prisons, shelters for the homeless, hospitals). It is recommended to carry out PCR testing 5-7 days after the alleged or actual contact with the patient.

Differential diagnosis
Differential diagnosis is carried out with respiratory infections, often the differences can only be laboratory ones. Similar clinical symptoms are observed in the following pathologies:

flu;
respiratory syncytial viral infection;
TORSO;
MERS.
The clinic of respiratory failure can also be given by pneumonia of a bacterial nature, COPD, bronchiectasis. In case of poisoning with gaseous substances, anaphylaxis usually has a clear history.

COVID-19 treatment
The majority of patients with a new coronavirus infection are treated on an outpatient basis, with the exception of a severe course, being in a high-risk group for the development of complications, and the presence of epidemic indications. Bed or semi-bed rest, adequate oxygenation, and replacement of fluid losses are prescribed. One of the monitored conditions of therapy is the appointment of nutritional support for elderly patients, senile patients, as well as those on mechanical ventilation.

Conservative therapy
It is necessary to start treatment in the first week of the disease (as soon as the first symptoms appear). With the progression of respiratory failure, transfer to the intensive care unit is recommended. Usually, patients with a mild form of COVID-19 recover within 2 weeks, while the recovery period among seriously ill patients reaches 2-3 months or more. The following treatment tactics are most often used:

Etiotropic therapy. The drugs of choice, according to the VMR of the Ministry of Health of Russia, are a selective inhibitor of RNA polymerase, an analog of adenosine triphosphate, recombinant interferon alfa, also interferon inducers, antiviral agents, and anticoid plasma. The use of recombinant monoclonal antibodies, human immunoglobulin is recommended.
Pathogenetic treatment. For hospitalized patients, it is carried out with the help of Janus kinase inhibitors, IL-17, IL-6 or blockers of the IL-6 receptor. In severe patients, the use of glucocorticosteroids, an inhibitor of IL1β, is allowed. Antithrombotic therapy (anticoagulants) is carried out, and exogenous surfactant preparations are used for ARDS.
Symptomatic treatment. To relieve the emerging symptoms, the use of antipyretic drugs, nasal decongestants, mucolytics and other drugs is allowed. Patients, especially senile, elderly, in case of delirium can be prescribed tranquilizers. With proven secondary bacterial infection, antibacterial agents are prescribed.
Treatment of respiratory failure is carried out step by step: oxygen therapy through a face mask, nasal cannulas, in case of ineffectiveness – prone position (lying on the stomach; allowed on the side) for at least 12-16 hours daily, or NIV in CPAP mode. Increasing symptoms of respiratory weakness require tracheal intubation and invasive mechanical ventilation. Persistent hypercapnia and oxygen deficiency are indications for the use of extracorporeal membrane oxygenation (ECMO).

Experimental treatment
The interferon beta molecule inhibits SARS-CoV2 replication in vitro, but interim results from a large multinational patient study have not shown clear benefit in severe COVID-19 (when administered subcutaneously or intravenously). But interferon beta, administered by a nebulizer, significantly increased the chance of recovery by day 15 compared with placebo. A number of trials are under way evaluating interferon lambda treatment.

Substances that have been proposed for the treatment of COVID-19 include direct acting antiviral anti-HCV drugs, a selective serotonin receptor inhibitor, an H2 histamine blocker, and zinc. The data obtained are insufficient to confirm their positive role in patients, and for some drugs (homomorphinans, vitamin D) there is evidence of a lack of clinical benefit. Treatment for COVID-19 with these agents is limited to research.

Limited research evidence suggests that for some outpatient COVID-19 patients who have risk factors for severe disease, early treatment with monoclonal antibodies (or high-titer plasma therapy) may slow the progression of infection. These drugs require intravenous administration, their intake is ineffective after the third day of illness, which complicates their widespread use.

Forecast
The prognosis for persons without decompensated somatic pathology with timely access to medical care is favorable. In some patients with initially mild symptoms, the disease may progress within a week. The mortality rate among people suffering from COVID-19 is 2.3%. Unfavorable outcomes are observed predominantly among patients admitted to intensive care units.

Prophylaxis
Non-specific prophylaxis
Non-specific measures to prevent COVID-19 infection are avoiding crowded places, especially enclosed spaces, using masks or respirators, and careful personal hygiene. It is important to observe self-isolation measures by patients and contacts, social distancing, and timely treatment to compensate for chronic diseases. Screening for high-risk groups is a measure to prevent spread.

Vaccination
The first human clinical trials of COVID-19 vaccines began in March 2020. There are various approaches to the creation of drugs for immunization: RNA vaccines, vector, recombinant protein, inactivated vaccines have been developed. None of the early trials identified significant safety concerns, but all vaccines caused systemic side effects (fever, chills, headache, fatigue, myalgia, arthralgia) in a subset of participants. The following vaccines have been registered as of May 2021:

Gam-COVID-Vak (Sputnik V, Gamaleya Institute, Russia). Consists of non-replicated vectors containing a spike glycoprotein. Intramuscularly administered: first a dose of adenovirus vector 26, then a portion of adenovirus vector 5. Efficiency – 91.6%. Clinical trials of the drug (phases I, II, III) took place in June 2020-May 2021. Immunization of the population began in December 2020. Also produced “Gam-COVID-Vac-Lyo” in the form of a lyophilisate.
Sputnik Light (Gamaleya Institute, Russia). The vaccine is a serotype 26 human adenovirus vector (essentially the first component of Sputnik V). The vaccine is administered intramuscularly once, the efficiency is 84.5%. Clinical trials of the drug (phases I, II) took place from June to August 2020. Mass vaccination of the population began in December 2020.
EpiVacCorona (FBSI “Vector” Rospotrebnadzor “, Russia). A vaccine based on synthesized peptide antigens of the S-protein SARS-CoV2 conjugated to a carrier protein. It is administered intramuscularly, twice with an interval of 21 days. Efficiency – 100%. Clinical trials of the drug (phases I, II) took place in July 2020-February 2021. Phase III began in October 2020, the end date is open. Mass vaccination of the population started in January 2021.
KoviVak (FSBSI “FSCIRIP named after MP Chumakov RAS”, Russia). Contains Deactivated Whole Coronavirus. The vaccine is given intramuscularly, twice, after 14 days. Preliminary reports of efficiency – 90%. Clinical trials of the drug (phases I, II) were carried out in December 2020-April 2021, and is currently undergoing phase III studies. Immunization of the population began in March 2021.

Comirnaty (Pfizer-BioNTech COVID-19, USA / Germany). mRNA vaccine in the form of a lipid nanoparticle to represent the full-length S-protein. It is administered intramuscularly, twice, the interval between injections is three weeks. The efficiency is 91.7-95%. Clinical trials of the drug (phases I, II) were carried out in August-December 2020, phase III started in December 2020 and will last until 2023. Vaccination of the population of the United States and some European countries began in December 2020.
mRNA-1273 (Moderna COVID-19, USA). Contains mRNA delivered in a lipid nanoparticle for expression of the full-length S-protein. The vaccine is administered intramuscularly, twice, with a break of 28 days. The efficiency is 86.4-94.1%. Clinical trials (phases I, II) were conducted in August-December 2020, phase III began in July 2020 and will last until 2022. Immunization of citizens of North America, the European Union, Israel is allowed from December 2020.
Ad26.COV2.S (Janssen / Johnson & Johnson COVID-19, USA / Belgium / Netherlands). The vaccine is based on a replication-incompetent adenovirus-26 vector that expresses a stabilized S-protein. It is used intramuscularly in the form of one dose, or two doses with a break of 56 days. The efficiency is 66.9%. Clinical trials (phases I, II, III) were conducted in July-December 2020. Immunization in the EU countries, the USA, the Middle East started in November 2020.
Vaxzevria / Covishield (University of Oxford, AstraZeneca, UK). Includes a chimpanzee adenoviral vector that expresses a spike protein. Two doses of the vaccine are administered intramuscularly, at intervals of 4-12 weeks or more. Efficiency – 76%. Clinical trials (phases I, II) were carried out in July-September 2020, phase III was launched in November 2020, it is planned until September 2021. Vaccination of the population of the EU countries began in November 2020.
Novavax COVID-19 vaccine (Novavax, USA). Recombinant nanoparticle protein vaccine consisting of spike glycoproteins and Matrix-M1 adjuvant. The vaccine is administered intramuscularly twice with an interval of 21 days. Efficiency – 89.3%. Clinical trials (phases I, II) took place in May-September 2020, phase III began in December 2020 with an open end date. Immunization in Canada, UK started in February 2021.
Convidecia. (CanSino Biologics, China). The COVID-19 vaccine, based on non-multiplying adenovirus 5, is administered in a single dose intramuscularly. The data on the effectiveness are not fully published, preliminary it is about 75%. Clinical trials (phases I, II) took place in May-September 2020, phase III was launched in August 2020 with an open end date. Vaccination of the countries of Asia, Europe, South America began in February 2021.
Sinopharm COVID-19 vaccine (Sinopharm, China). Adjuvant inactivated vaccine (aluminum hydroxide). It is injected intramuscularly twice, with an interval of 28 days. The preliminary declared efficiency is 79-86%. Clinical trials (phases I, II) were in April-October 2020, phase III started in July 2020 without an exact end date. Vaccination of the population of Asian and Middle Eastern countries has become available since January 2021.

KoronaVak (Sinovac, China). Inactivated aluminum hydroxide vaccine (adjuvant). It is a two-dose drug, administered after 21 days, intramuscularly. The preliminary declared efficiency is 50-91%. Clinical trials (phases I, II) were conducted in May-July 2020, phase III began in July 2020 with an open completion date. Mass immunization in China, Turkey, and a number of other countries is allowed in January 2021.
Covaxin (Bharat Biotech, India). It is an inactivated vaccine, it also contains an adjuvant (toll-like receptor agonist). It is done intramuscularly twice, after 28 days. It has been reported to be effective up to 81%. Clinical trials (phases I, II) took place in May-November 2020, phase III was launched in November 2020. Mass immunization in India kicks off in January 2021