COVID-19 is an infectious viral disease that mainly affects the lung tissue. Pathognomonic symptoms are respiratory failure, respiratory distress syndrome in critical course. In addition to these manifestations, patients complain of dry cough, high fever, loss of taste and sense of 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 are used.
COVID-19 (new coronavirus infection) is a respiratory infection. It was first recorded in December 2019 in Wuhan (China), from where it subsequently spread to Southeast Asia, Europe, South and North America, Russia and the CIS. In March 2020, WHO declared a pandemic, in October 2020 – the second wave of the disease. As of April 2021, more than 150 million cases of COVID-19 have been confirmed worldwide, more than 3 million people have died. The most susceptible to pathology are older people with chronic diseases, as well as blacks, Latinos and Asians. Men are predisposed to the most severe course of infection.
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. Sequencing of the complete genome and phylogenetic analysis have shown that the closest similarity is observed with two types of bat coronaviruses, therefore, they may be a natural reservoir of infection. There is no convincing evidence of transmission of the virus from these mammals, either directly or with the help of an intermediate host.
Several subspecies of coronavirus that arose after mutations have been identified:
- B.1.1.7 (202012/01 or 20I/501Y.V1). It was first isolated at the end of 2020 (Great Britain), where it significantly accelerated the increase in the number of cases. This variant contains more than a dozen mutations, several of them are components of the spike protein. According to various estimates, this variant is 50-75% more contagious, 25-40% more easily transmitted than the original virus.
- B.1.351 (20H/501Y.V2). This variant has been identified as South African. The virus contains another mutation inside the spike protein – E484K, which can potentially affect immunity from previous infection or vaccination. The clinical consequences of this decrease in neutralizing activity have not been clarified, it is assumed that the immunity induced by the COVID-19 mRNA vaccine will protect against the B.1.351 virus.
- P.1 (20J/501Y.V3). The strain was first described by Japanese scientists in four travelers from Brazil. Subsequently, it was identified in many countries, including the USA. This subspecies of coronavirus has several mutations, including three inside the spike (spike) S-protein receptor. Mutational changes in the pathogen protein can increase transmissivity, affect post-vaccination immunity, and the level of protection after 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 increases cell permeability. In vitro mutations lead to a decrease in the neutralization of the pathogen by the plasma of convalescents and vaccinated. 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 about the effectiveness of the vaccines available for the Indian strain. Limited data from unpublished studies so far indicate that the blood serum of vaccinated individuals retains some neutralizing activity against variants B.1.617.
The source of infection is a sick person or an asymptomatic carrier (with close contact). The way of transmission is airborne, fecal-oral (casuistry). There is evidence of transmission of the virus between humans and animals. The results of testing for SARS-CoV2 of some animals, such as minks, dogs, domestic cats, lions, tigers and raccoon dogs, after interacting with infected people were positive.
The main risk factors for COVID-19 are elderly (> 65 years old) age, the presence of diabetes mellitus, heart disease, lung disease, oncopathology. Other conditions that can lead to a high risk of severe COVID-19 include kidney disease, sickle cell anemia, obesity, all immunocompromising conditions. The risk group is transplant recipients, pregnant women, smokers, medical staff, social workers, workers in the service sector.
When it enters the upper respiratory tract, the pathogen colonizes the epithelial cells of the nasopharynx and oropharynx, actively multiply inside, destroying cells. The nucleocapsid of the virus is found inside the cytoplasm of epithelial cells of the salivary, lacrimal glands, digestive system, urinary tract. However, the main, quickly achievable target of the coronavirus is alveolar lung cells 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 number of pro-inflammatory cytokines (for example, IL-6, TNF-alpha) up to the development of a “cytokine storm”. The phenomenon of hypercoagulation is associated with direct endothelial virus damage, blood stasis due to forced immobilization, an increase in circulating prothrombotic factors (von Willebrand factor, factor VIII, D-dimer, fibrinogen, etc.).
COVID-19 is a disease that mainly damages the lower respiratory tract, although the virus antigens are detected in all organs. It is believed that laboratory detection of the pathogen in peripheral blood correlates with the severity of the pathology. Clinical variants of the course and manifestations of a new coronavirus infection can be divided according to the severity of the course:
- Light. It is characterized by various catarrhal phenomena, fever < 38 ° C, rarely pneumonia.
- Medium-heavy. Accompanied by prolonged fever >38 ° C, shortness of breath during exercise, changes in CT.
- Heavy. It is characterized by a decrease in the level of consciousness, agitation, respiratory failure.
- Extremely heavy. It is characterized by the detection 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 there are symptoms similar to most acute respiratory infections: fever of varying severity, dry cough, sore throat. Patients note loss of taste, smell, headache. Shortness of breath is noted in a third of patients: it is manifested by a growing feeling of lack of air, especially in a horizontal position, the need for additional efforts to inhale and exhale.
Others may notice the retraction of intercostal spaces, supraclavicular pits. Patients are forced to sit leaning on their hands, get tired quickly, breathing becomes noisy, the skin acquires a bluish hue. In 12-19% of cases, COVID-19 manifests gastrointestinal symptoms: frequent liquid watery stools, discomfort and abdominal pain, as well as nausea, vomiting. Shortness of breath in such cases joins after 5-8 days.
Skin rashes during this infection are diverse: blisters, spots, bumps and other elements; there may be bubbles, swelling, ulcers, limbs are often affected. Among people over 80 years of age, as well as in patients with neurocognitive disorders, the primary symptoms of COVID-19 are delirium: visual hallucinations, delirium, difficult orientation in time, the surrounding world.
Children may have 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 an increase in cervical lymph nodes. Often at fever altitude, patients complain of redness, discomfort in the eyes, watery eyes, severe pain and limited joint mobility, vomiting, nausea, 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 brief periods of wakefulness, the appearance of bluish-purple coloration of the nasolabial triangle or the entire face, limbs. Also, going to the doctor requires continued copious diarrhea, convulsions, complete absence of urine for more than 12 hours.
Most often there are signs of respiratory distress syndrome (up to 41% of patients), the probability of its development is higher in people 65 years and older, with diabetes mellitus, arterial hypertension. Thromboembolic complications in the form of pulmonary embolism, deep vein thrombosis, stroke are noted in 10-40% of patients. Cardiac arrhythmias occur in 17%, symptoms of myocardial damage – in 7%, infectious and toxic shock – 9%.
Encephalopathy develops in 30% of cases. Rare complications are Giain-Barre syndrome (about 10%), secondary aspergillosis (8-28%), immune thrombocytopenia (7%), spontaneous pneumothorax (0.56%). After the disease, there is a postcovid syndrome: fatigue, shortness of breath, chest pain, cough. Patients treated with COVID-19 may have mental (anxiety, depression, PTSD) and cognitive (decreased memory, concentration) symptoms.
Verification of the diagnosis of coronavirus infection, its treatment is carried out by infectious diseases doctors, often by resuscitators. Other medical specialists are involved according to indications. It is important to collect an epidemiological history, including data on travel to endemic areas, family and work contacts of the patient. The main clinical, instrumental and laboratory signs of COVID-19:
- Physical data. Objective examination determines the symptoms of respiratory failure – forced posture, cyanosis of the skin, shortness of breath. There is a dry, rarely productive, cough, a variety of rash and fever. In the lungs, a weakening of breathing is heard, rarely a dulling of the percussion sound. Hyperemia of the pharynx, nasal congestion, moderate abdominal pain during palpation, rumbling are detected. A visual assessment of liquid stool, vomiting, if any, is carried out.
- Laboratory tests. 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 of 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 smear 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 the virus in the smear is detected before symptoms appear; up to 5-40% of smears may be false negative.
- Serological screening. ELISA with validated test systems provides 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 makes it possible to identify individuals who may be immune to infection; serological norms of the protective titer of antibodies have not yet been determined.
- Other laboratory tests. The practical use of gamma interferon release analysis for routine use in COVID-19 is being studied. Isolation of viral culture is not used in clinical practice due to the biological danger of coronavirus.
- CT of the chest organs. Typical symptoms of COVID-19: bilateral, mainly lower lobe, opaque glass-type darkening in 83% of patients with thickening of the pleura, interlobular septum in half of cases, focal infiltrates located mainly subpleurally along the vascular bundles. Bronchiectasis, pleural, pericardial effusion, lymphadenopathy are less often described. Dynamic CT control is required. Lung radiography is not informative – up to 20% of patients have no changes in the images throughout the 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 in COVID-19. The results of ultrasound examination of the lungs in patients include thickening, discontinuity of the pleural line. Subpleural B-lines are described as discrete, multifocal, or merging. Spotted, striped 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 congestion of people (long-term care institutions, pre-trial detention centers, prisons, homeless shelters, hospitals). It is recommended to conduct PCR testing 5-7 days after the intended or actual contact with the patient.
Differential diagnosis is carried out with respiratory infections, often the differences can only be laboratory. Similar clinical symptoms are observed in the following pathologies:
- respiratory syncytial viral infection;
Respiratory failure clinic can also be given bacterial pneumonia, COPD, bronchiectatic disease. When poisoning with gaseous substances, anaphylaxis usually has a clear history.
Treatment of the majority of patients with a new coronavirus infection is carried out on an outpatient basis, with the exception of severe course, being in a high-risk group for the development of complications, and the presence of epidemic indications. Bed or semi-bed rest is prescribed, adequate oxygenation, replenishment of fluid losses. One of the monitored conditions of therapy is the appointment of nutritional support for elderly, senile patients, as well as those on a ventilator.
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, a transfer to the intensive care unit is recommended. Usually, patients with a mild form of COVID-19 recover within 2 weeks, while the period of convalescence among seriously ill patients reaches 2-3 months or more. The following therapeutic tactics are most often used:
- Etiotropic therapy. The drugs of choice, according to the VMR of the Ministry of Health of the Russian Federation, are a selective RNA polymerase inhibitor, an adenosine triphosphate analog, recombinant interferon alpha, also interferon inducers, antiviral agents, and antikovid 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 IL-6 receptor blockers. In severe patients, the use of glucocorticosteroids, an IL1ß inhibitor, is allowed. Antithrombotic therapy (anticoagulants) is carried out, exogenous surfactant preparations are used for ARDS.
- Symptomatic treatment. For the relief of emerging symptoms, the use of antipyretic drugs, nasal decongestants, mucolytics and other medicines is allowed. Tranquilizers may be prescribed to patients, especially senile, elderly, in case of delirium. With proven secondary bacterial infection, antibacterial agents are prescribed.
Treatment of respiratory insufficiency is carried out step by step: oxygen therapy through a facial mask, nasal cannulas, if ineffective, a pron position (lying on your stomach; allowed on your side) for at least 12-16 hours daily, or NIVL in CPAP mode. The increasing symptoms of respiratory weakness require tracheal intubation and invasive ventilation. Persistent hypercapnia and oxygen deficiency are indications for the use of extracorporeal membrane oxygenation (ECMO).
The interferon beta molecule inhibits the replication of SARS-CoV2 in vitro, but the interim results of a large multinational study of patients did not show a clear benefit in severe COVID-19 (with subcutaneous or intravenous administration). But the drug interferon beta, administered by a nebulizer, significantly increases the likelihood of recovery by the 15th day compared to placebo. There are a number of tests evaluating the treatment with interferon lambda.
Substances that have been proposed for COVID-19 therapy include direct-acting antiviral anti-HCV drugs, selective serotonin receptor inhibitor, 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 of COVID-19 with these drugs is limited to research.
Limited research data indicate that for some outpatient COVID-19 patients with severe risk factors, early treatment with monoclonal antibodies (or plasma therapy with a high antibody titer) it can slow down the progression of infection. These drugs require intravenous administration, their reception is ineffective after the third day of the disease, which complicates their widespread use.
The prognosis in persons without decompensated somatic pathology with timely medical treatment is favorable. In some patients with initially mild symptoms, the disease can progress within a week. The mortality rate among people suffering from COVID-19 is 2.3%. Adverse outcomes are observed mainly among patients placed in intensive care units.
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 also important to observe self-isolation measures by patients and contact persons, social distancing, timely treatment to compensate for chronic diseases. Screening of high-risk groups is a measure to prevent the spread.
The first clinical trials of COVID-19 vaccines in humans 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 revealed serious safety problems, but all vaccinations caused systemic side effects (fever, chills, headache, fatigue, myalgia, arthralgia) in some of the participants. As of May 2021 , the following vaccines have been registered:
- Comirnaty (Pfizer-BioNTech COVID-19, USA/Germany). mRNA vaccine in the form of a lipid nanoparticle to represent a full-sized 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 (phase I, II) were conducted 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). It contains mRNA delivered in a lipid nanoparticle for the expression of a full-sized S-protein. The vaccine is administered intramuscularly, twice, 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 an adenovirus-26 vector incapable of replication, which expresses a stabilized S-protein. It is applied intramuscularly in the form of one dose, or two doses with a break of 56 days. Efficiency ‒ 66.9%. Clinical trials (phases I, II, III) were conducted in July-December 2020. Immunization in the EU, USA, and the Middle East started in November 2020.
- Vaxzevria/Covishield (Oxford University, AstraZeneca, UK). Includes a chimpanzee adenovirus 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 conducted in July-September 2020, Phase III was launched in November 2020, planned until September 2021. Vaccination of the population of the EU countries began in November 2020.
- Novavax COVID-19 vaccine (Novavax, USA). Recombinant protein vaccine with nanoparticles 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 and the 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. Data on the effectiveness has not been fully published, previously 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 deadline. Vaccination in Asia, Europe, and South America began in February 2021.
- Sinopharm COVID Sinopharm COVID-19 vaccine (Sinopharm, China). Inactivated vaccine with adjuvant (aluminum hydroxide). It is administered intramuscularly twice, with an interval of 28 days. The preliminary declared efficiency is 79-86%. Clinical trials (phases I, II) were held 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.
- CoronaVac (Sinovac, China). Inactivated vaccine with aluminum hydroxide (adjuvant). It is a two-dose drug, administered after 21 days, intramuscularly. The pre-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.
- Kovaxin (Bharat Biotech, India). It is an inactivated vaccine, also contains an adjuvant (agonist of toll-like receptors). It is done intramuscularly twice, after 28 days. Efficiency of up to 81% is reported. Clinical trials (phases I, II) took place in May-November 2020, Phase III was launched in November 2020. Mass immunization in India started in January 2021.