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УДК 616.92:616:93:578.834.1 DOI: https://doi.org/10.34680/2076-8052.2020.3(119).10-15
НОВАЯ КОРОНАВИРУСНАЯ ИНФЕКЦИЯ
В.А.Исаков*, Д.В.Исаков*, Е.И.Архипова**, Г.С.Архипов**, Н.Н.Никитина**
NEW CORONAVIRUS DISEASE
V.A.Isakov*, D.V.Isakov*, E.I.Arkhipova**, G.S.Arkhipov**, N.N.Nikitina**
Первый Санкт-Петербургский государственный медицинский университет имени акад. И.П.Павлова, (Санкт-Петербург), Новгородский государственный университет имени Ярослава Мудрого, (Великий Новгород), [email protected]
The new coronavirus infectious disease COVID-19 has caused a pandemic in the world. As of June 23, 2020, 599 705 cases of COVID-19 were detected in Russia, about 8 359 people died, more than 356 thousand recovered. More often the disease is mild, however, in 14—20% of patients, a severe and very severe course is possible. Information on the epidemiology, properties of coronaviruses, and the main clinical manifestations of the infection are given. The therapy and prevention of coronavirus infection using interferon-containing drugs and other dosage forms is briefly described. The possibility of the disease prevention using a topical nasal spray/drops of Grippferon and Meglumine acridоnacetate tablets is shown.
Keywords: coronavirus disease COVID-19, preventive measures, Grippferon, Meglumine acrtdоnacetate
Новая коронавирусная инфекция COVID-19 вызвала пандемию в мире. На 23 июня 2020 г. в России выявлено 599705 случаев заболевания COVID-19, порядка 8359 человек умерли, более 356 тысяч выздоровели. Чаще заболевание протекает легко, однако у 14—20% больных возможно тяжелое и очень тяжелое течение. Даны сведения по эпидемиологии, свойствам коронавирусов, основным клиническим проявлениям инфекции. Кратко изложена терапия и профилактика коронавирусной инфекции с использованием интерферонсодержащих препаратов, других лекарственных форм. Показана возможность профилактики заболевания с использованием местного назального спрея / капель Гриппферона и таблеток Меглюминаакридонацетат.
Ключевые слова: коронавирусная инфекция COVID-19, профилактика, Гриппферон, и Меглюмина акридонацетат
The high incidence of influenza and other acute respiratory viral infections (ARVI) is an important medical and social health problem. Respiratory infections in terms of their social significance, huge damage to the health of the population and the economy of the country, are on the first place among all human diseases. The incidence of influenza and other acute respiratory viral infections exceeds the total incidence of all other infections [1, 2].
Over the past 40 years, more than 30 new previously unknown viruses have been discovered, some of which cause deadly diseases: Marburg virus, Ebola virus, West Nile virus, human immunodeficiency virus (HIV), hepatitis C, D, E, G viruses and others [3, 4]. At the beginning of the 21st century, we faced the emergence of two unusual viruses that caused epidemics: the avian influenza A (H7H9) virus and the new coronavirus (MERS-CoV) — COVID-19 [1, 5].
Respiratory viral infections include influenza, other acute respiratory viral infections that are caused by DNA and RNA viruses: parainfluenza, adenoviruses, respiratory syncytial viruses, metapneumoviruses, bocavi-ruses, herpes viruses, coronaviruses, and others.
It is known that the share of coronavirus infection (CVI) accounts for 4 to 20% of all ARVI cases. Coronaviruses contain a single-stranded RNA molecule. They have a shell with rare thorns or villi, resembling a crown during a solar eclipse. Hence the name — coronavirus. Coronaviruses (CV) are ubiquitous around the globe and
are the etiological factor of acute respiratory viral infections and pneumonia in humans, infectious bronchitis of birds, hepatitis in mice, pneumonia in rats, transmissible gastroenteritis and encephalomyelitis in pigs, diarrhea of calves, which are often deadly for animals. For the first time, CV was isolated in 1936 from chickens with infectious bronchitis. The human CV nucleocapsid contains a single-stranded +RNA with a molecular weight of up to 210,000 daltons, there is an RNA-dependent RNA polymerase enzyme. The CV virion is surrounded by a lipoprotein membrane with fringed villi, its diameter is 80— 220 nm, and multiplies in the cytoplasm of infected cells after 6—36 hours [6-8].
Human coronavirus was first isolated in 1965 from an acute respiratory viral infection patient. Now the family of coronaviruses includes more than 40 types, and it is constantly growing. It is believed that CV (SARS) entered the human population from wild cats (weaver). It is transmitted not only by close contact with a patient through infected sputum, but also by airborne droplets and even by water. The incubation period is from 2 and up to 12 days. These viruses infect people and various animals — cats, horses, swans, camels, dogs, birds, rabbits, bats, snakes, and other animals. In some situations, viruses are able to change, mutate.
Earlier, Russian researchers L.Ya.Zakstelskaya and A.V.Sheboldov (1977) serologically (RTGA or RSK to CV OS43) examined 1 239 hospitalized patients with acute respiratory infections aged from one month to 65
years. The authors revealed a diagnostic increase in specific antiviral (CV) antibodies in 4.2—9.4% of cases, which corresponded to the frequency of detected acute respiratory viral infections of a different etiology during the interepidemic period for influenza [9]. According to our data, among hospitalized adult patients, CV infection (CVI) was recorded in 7—9% of cases, on average, the share of CV in the etiology of ARVI in adults and children in St. Petersburg is 10.8% and 9.7%, respectively [10]. Large outbreaks of CV infection in St. Petersburg happened in 1985, 1986, and 1987, when the incidence of ARVI of CV nature reached 13—28%.
In the 20th century, coronaviruses were known as causative agents of acute respiratory diseases in humans and animals, but they were not among the most dangerous viral infections. The coronavirus family currently includes two types of viruses that cause severe respiratory infections in humans: SARS-Cov (Severe acute respiratory syndrome coronavirus, or SARS coronavirus, causing severe acute respiratory syndrome) and MERS-Cov (Middle East respiratory syndrome coronavirus, or MERS coronavirus, causing Middle East respiratory syndrome). A phyloge-netic analysis of 103 SARS-CoV-2 strains from China identified two different types of SARS-CoV-2, designated type L (accounting for 70 percent of the strains) and type S (accounting for 30 percent) [11].
Currently, it is known about the circulation of four coronaviruses (HCoV-229E, -OC43, -NL63, -HKU1) among the population, which are present year-round in the structure of ARVI, and, as a rule, cause damage to the upper respiratory tract of mild to moderate severity.
A SARS coronavirus caused an epidemic in 2002—2003 [12]. In 33 countries of the world (the largest number of cases was registered in China, Singapore, and Canada), with a total of 7 761 cases, 623 of them died of the disease. On March 11, 2020, WHO announced a pandemic of COVID-19 infection [13].
It is important to note that in addition to the high degree of similarity in genomes, 2019-nCoV, like SARS-CoV [14], infects cells of the respiratory tract through interaction with ectoenzyme angiotensin convertase 2 (ACE2) of horseshoe bats, humans, civets (a mammal from the viverrid family of the carnivorous order) and pigs [6], which may indicate possible intermediate hosts involved in the transmission of the pathogen. It has been shown that in humans the greatest amount of ACE2 is found in type II alveolocytes, and to a lesser extent — in type I alveolo-cytes (alveoli), Clara cells and ciliated epithelium (respiratory tract); fibroblasts, endothelium and macrophages [15], which determines the defeat of the lower respiratory tract and the development of atypical pneumonia (AP).
The source of the new coronavirus in China could be snakes, as local scientists found out — the strain of the virus is most similar to that infecting these amphibians. It is believed that snakes hunt and eat bats. Mice, like snakes, are infected with various variants of CV, a new variant of the virus is formed, which has infected people. The snake meat was sold at the market, where employees and visitors were the first victims. This version has yet to be clarified by taking samples of viral DNA from animals on the market and in the wild, but now new data will improve the prevention and treatment of the disease.
Coronavirus infection is not a serious disease, it is difficult to differentiate from rhinonirus disease, it affects not only adults, but also children, and along with rhinitis, patients may experience mild pharyngitis and even bronchitis [1, 10]. In children, the main difference between this infection is the presence in the overwhelming majority of patients with symptoms of gastrointestinal tract damage, which are observed from the first hours of the disease and often precede catarrhal manifestations. Along with muco-serous rhinitis, inflammation of the laryngeal mucosa and an increase in cervical lymph nodes are often observed. Coronaviruses, like adenoviruses, are frequent causative agents of nosocomial infections [16, 17]. The most common method for identifying the pathogen is the method of fluorescent antibodies. The material is mucus of the oropharynx and nose, sputum. Serological diagnostics is used for retrospective decoding of etiology and is carried out on the basis of an increase in antibody titers in complement-fixation reaction (CFR), indirect hemagglutination reaction (IHR). At the present time, variants of the ELISA test have been developed, PCR methods with the help of which one can quickly clarify the diagnosis.
Severe Acute Respiratory Syndrome (SARS). The disease has many common symptoms and a number of properties in common with influenza, not only at the time of onset, but also at the place of appearance of viruses with increased virulence. It has been proven that SARS-SARS is caused by a new coronavirus, which has been temporarily named SARS-associated coronavirus (SARS-CoV, Severe acute respiratory syndrome coronavirus, or SARS coronavirus, which causes severe acute respiratory syndrome). The severe course of the infection is associated with the development of viral pneumonia, accompanied by acute respiratory distress syndrome (ARDS) and, as a result, acute respiratory failure (ARF). This pathology is characterized by a high death rate (38%), as it is accompanied by acute respiratory failure [16-18].
So, in China, out of 74,500 patients with coronavi-rus infection, 81% were ill easily, 14% were seriously ill: there was a rapid progression of lower respiratory tract disease, pneumonia, ARF, ARDS, sepsis, and shock. In Wuhan, almost all patients with a severe course of the disease develop progressive ARF against the background of pneumonia and ARDS [19].
Against the background of the listed phenomena, the production of proinflammatory cytokines was observed, the intensity of which could increase until the cytokine storm. SARS-CoV is characterized by symptoms of secondary immunosuppression, manifested in the late onset of interferon synthesis and activation of the key inflammatory factor, NLRP3-inflammasome [18]. SARS-CoV-2 infection can primarily affect T lymphocytes, in particular CD4 + and CD8 + T cells, resulting in a decrease in the number and production of IFN-yCD4 + T cells. These potential immunological markers may be important because of their correlation with the severity of COVID-19 disease [20].
According to the WHO, more than 8.7 million people all over the world have been infected with the coronavirus, over 461 thousand have died. In Russia,
592,800 cases of COVID-19 were detected, about 8,200 people died, more than 339,000 recovered.
Clinical features of the new CVI [18].
The incubation period ranges from 2 to 14 days, with an average of 5—7 days.
COVID-19 is characterized by the presence of clinical symptoms of acute respiratory viral infection:
— increased body temperature (> 90%);
— cough (dry or with little phlegm) in 80% of
cases;
— shortness of breath (30%);
— fatigue (40%);
— a feeling of congestion in the chest (> 20%).
There may also be sore throat, runny nose, decreased sense of smell and taste, signs of conjunctivitis, skin lesions.
The most severe shortness of breath develops by 6—8 days from the moment of infection. It was also found that among the first symptoms there can be myalgia (11%), confusion (9%), headaches (8%), hemoptysis (2-3%), diarrhea (3%), nausea, vomiting, palpitations. These symptoms at the onset of infection can be observed in the absence of an increase in body temperature.
Clinical variants and manifestations of COVID-19 [18]:
— Acute respiratory viral infection (affecting only the upper respiratory tract);
— Pneumonia without respiratory distress;
— ARDS (pneumonia with ARF);
— Sepsis, septic (infectious toxic) shock;
— Thrombosis and thromboembolism;
— Hypoxemia (SpO2 < 88%) develops in more than 30% of patients.
Classification of COVID-19 by severity.
Mild course of the disease
— Body temperature < 38°C, cough, weakness, sore throat;
— Lack of criteria for moderate and severe course of disease;
Moderate course of the disease
— Body temperature > 38°C;
— Respiration rate > 22/min;
— Shortness of breath on exertion;
— CT (X-ray) changes are typical of a viral lesion (minimal or moderate lesion volume; CT1-2);
— SpO2 < 95%;
— Blood serum CRP > 10 mg/L;
Severe course of the disease
— Respiration rate > 30/min;
— SpO2 < 93%;
— PaO2 /FiO2 < 300 mm/Hg;
— Decreased level of consciousness, agitation;
— Unstable hemodynamics (systolic blood pressure less than 90 mm Hg or diastolic blood pressure less than 60 mm Hg, diuresis less than 20 ml/hour);
— Changes in the lungs on CT (X-ray), typical for a viral lesion (lesion volume is significant or subtotal; CT3-4);
— Arterial blood lactate > 2 mmol/L;
— qSOFA > 2 points;
Extremely severe course of the disease
— ARF with the need for respiratory support (invasive ventilation);
— Septic shock;
— Multiple organ failure;
— Changes in the lungs on CT (X-ray), typical for a critical viral lesion (the volume of the lesion is significant or subtotal; CT4) or a picture of ARDS.
On average, 50% of those infected are asymptomatic. In 80% of patients with clinical symptoms, the disease is mild ARVI. 20% of confirmed cases reported in the PRC were classified as severe by the PRC health authorities (15% of critically ill patients, 5% in critical condition). The average age of patients in the PRC was 51 years, the most severe forms developed in elderly patients (60 years and more), among sick patients, such concomitant diseases as diabetes mellitus (in 20%), arterial hypertension (in 15%), other cardiovascular diseases (15%).
The details of the clinic, therapy, and prevention of COVID-19 are described in the manual [18] and the Temporary guidelines of the Ministry of Health of the Russian Federation [5].
Principles of prevention and therapy. Treatment of patients with severe respiratory pathology is difficult due to the polyetiology of ARVI, which are caused by DNA and RNA viruses, the presence of mixed infections and complicated forms of diseases, the formation of viral resistance to chemotherapy, the development of secondary immunological insufficiency (SID), aggravating the course and outcome ARVI. The therapeutic effect remains on the background of taking the drug only in relation to respiratory viruses and does not affect immunity, side toxic effects are possible.
In the case of viral infection, the cytokine response develops mainly in the cellular, Thl-type. This is critical in protecting against intracellular pathogens, including viruses. It has been proven that the predominant participation of cytokines produced by Th2 cells is associated with viral persistence and chronicity of the process, and Th1 — with recovery and elimination of the pathogen.
The main purpose of viruses is to suppress the induction of the synthesis and action of interferons (IFN) for unhindered cell infection and spread throughout the body. In this situation, the use of a genetically engineered IFN drug allows the effect of IFN to be manifested in full and at the optimal time to block the spread of the virus. Thus, recombinant IFN introduced from the outside into the respiratory tract, for example, in the form of drops, ointment or aerosol spray, can provide a therapeutic effect at the initial stage of the disease, as well as have a preventive effect during an epidemic.
The advantage of IFN over other antiviral drugs is as follows. First, IFN possesses biological antiviral activity against almost all types of DNA and RNA viruses, launching a program for the synthesis of antiviral proteins in cells. Secondly, at the level of the body, IFNs activate antiviral immunological reactions. As a result, all possible antiviral mechanisms are involved in the organization of a single protective reaction of the body. In this way, IFN compares favorably with most antiviral chemotherapy drugs that have a narrow spectrum of specific activity.
Previous in vitro studies for MERS-CoV infection have shown that IFN type 1 (IFN-a/p) have inhibitory activity. To prevent coronavirus infection 2019-nCoV, the Ministry of Health of the Russian Federation recommends taking individual measures of non-specific prevention: irrigation of the nasal mucosa with isotonic sodium chloride solution, which reduces the number of both viral and bacterial pathogens of infectious diseases.
The use of drugs for local use with barrier functions is a separate measure taken by the Ministry of Health of the Russian Federation to prevent infection with CV. Here, special attention is paid to local forms of interferon-containing drugs.
The Ministry of Health of the Russian Federation recommends the use of interferon alfa 2b preparations (in the form of drops and spray) for the treatment and prevention of children, including from the first days of life, which are used in patients with a therapeutic purpose for seasonal ARVI. The only drug approved for use by pregnant women and children from the first days of life is Grippferon®, nasal drops and spray. Grippferon® is a highly active recombinant interferon alpha-2b preparation for the treatment and prevention of influenza and ARVI. It is developed and manufactured by the biotechnology company FIRN M.
The mechanism of action of Grippferon is based on preventing the multiplication of any viruses that enter the body through the respiratory tract. The safety and effectiveness of the drug Grippferon for the treatment and prevention of respiratory viral infections has been confirmed by numerous studies and many years of experience in use, including in pregnant women and newborns.
Employees of the Research Institute of Influenza of the Russian Academy of Medical Sciences in 2003 proved the effectiveness of the effect of Grippferon on CV. The drug has a direct inhibitory activity against human KV, while the rate of virus replication was significantly reduced. In 2014, the FBSI SSC VB "Vector" of Rospotrebnadzor carried out a research experimental work to assess the antiviral activity of the drug Grip-pferon against CVs that cause SARS and MERS. The authors confirmed that the drug Grippferon inhibits the multiplication of SARS-CoV and MERS-CoV viruses and can be used for the prevention and treatment of diseases caused by these pathogens.
The significant evidence base regarding the efficacy and safety of the drug Grippferon allows us to consider it as one of the promising means of preventing and treating CVI, which is indispensable for pregnant women and children from the first days of life.
In order to prevent CVI, the drug is recommended to be instilled/injected in a single age dose 2 times a day. Another scheme for the prophylactic use of Grippferon is the instillation/injection of the drug at an age-specific dose once in the morning with an interval of 24—48 hours. After instillation/injection of the drug, it is recommended to massage the wings of the nose. More details on the use of Grippferon are described in the Instructions. Preventive courses can be repeated.
Immune-substituting immunomodulatory drugs can be effective in the initial manifestations of the disease. It is known that for the prevention and treatment of patients
with influenza and other acute respiratory viral infections, interferons and their inducers are used, which have bifunc-tional activity — antiviral and immunomodulatory. For example, Viferon, Groprinosin, Likopid, Polyoxidonium, Cycloferon, and others. These drugs block various stages of viral reproduction in the cell, promote the synthesis of endogenous IFN and other cytokines, and increase the antiviral and immune defense of the body.
Among the inducers of IFN, Meglumine acri^nacetate (Cycloferon, OOO NTFP POLISAN) with a proven ability to induce the production of IFN type
1 and to provide pronounced antiviral effects against both DNA and RNA viruses should be distinguished. The domestic drug Meglumine acridonacetate (MA) is a highly effective synthetic inducer of the synthesis of endogenous interferons (ATC code: L03AX). It has been proven that MA can increase the synthesis of IFN I (IFN-a/p) and II type (IFN-y) in human peripheral blood cells in vitro, and the peak of production falls on 4—8 hours from the beginning of incubation [21, 22].
One of the mechanisms of MA action may be its direct binding to DNA and/or interaction with nuclear proteins, possibly participating in the regulation of gene transcription of various cytokines [23]. In particular, through an increase in the synthesis of IL-10, MA is able to limit the production of the pro-inflammatory cytokine IL-1P [24, 25], thereby reducing the severity of protective reactions.
MA is included in the mandatory standard of treatment for conditions accompanied by the development of secondary immunodeficiency syndrome, as well as influenza and ARVI [26, 27]. The high efficiency of MA as a means of treatment and prevention (immunorehabilitation) of respiratory viral infections of various etiologies in adults and children has been shown.
MA drug dosage forms: 12.5% solution for intravenous and intramuscular administration (2 ml ampoule), 150 mg tablets (salt of acridoneacetic acid and N-methyl-glucamine), enteric-coated. The drug is approved for adults and children from 4 years old.
Dosage and Administration of Meglumine acridonacetate (Cycloferon) tablets:
— ingestion (oral administration) 1 time per day, 30 minutes before meals, without chewing.
Age doses for admission:
— children 4—6 years old: 1 tablet (150 mg per dose)*;
— children 7—11 years old: 2 tablets (300 mg per
dose);
— children over 12 years old and adults: up to 4 tablets (600 mg per dose).
Treatment of influenza and other ARVI:
— for uncomplicated influenza and ARVI on the 1st day — 4 tMA (600 mg), on days 2nd, 4th, 6th and 8th —
2 tMA (300 mg) once a day (5 doses);
— for complicated forms of influenza and ARVI — a single dose of 4 tMA on the 1st, 2nd, 4th, 6th, 8th, 11th and 14th, 17th, 20th, 23rd days of treatment against the background of basic therapy (10 doses).
* children from 4 years old in adult dosages.
In the case of a mild course of influenza and ARVI, an adult should take 2 tMA once a day according
to the scheme on days 1st, 2nd, 4th, 6th and 8th of treatment. Against the background of tMA in patients, the duration of fever was 1.8 times, intoxication was 1.4 times shorter than in the group of persons on basic therapy. The catar-rhal syndrome and the duration of the illness turned out to be less prolonged. Complications developed 3.4 times less often [16, 28].
According to WHO recommendations, it is possible to prescribe drugs with alleged etiotropic efficacy offlabel, while their use should comply with the ethical standards recommended by WHO.
As for the drugs recommended for the treatment of CVI, this list includes drugs that should be taken strictly according to indications with an established diagnosis. Experts emphasize that their use should be treated with caution, given the potential for the drug to cause severe side effects. So, ribavirin (tablets) is recommended as an antiviral drug for adults. However, it should be used with caution, as there may be unwanted side effects (primarily anemia and hypoxemia). Other treatment regimens with the inclusion of antiviral agents are possible: ribavirin in combination with lopinavir and ritonavir, used for HIV infection. The priority of treatment of CVI has two directions: the fight to prevent the development of "cytokine storm" and the fight against coagulopathy [5, 18, 29].
Patients with clinical forms of CVI occurring with lesions of the lower respiratory tract (pneumonia) are indicated for the appointment of antimicrobial drugs (amoxicillin / clavulanate, respiratory fluoroquinolones -levofloxacin, moxifloxacin, cephalosporins of the 3rd and 4th generation, carbapenems, etc.). The choice of antibiotics and the method of their administration is based on the severity of the patient's condition, the results of microbiological diagnostics.
If indicated, proteolysis/protease inhibitors are prescribed, detoxification, infusion therapy is carried out:
— Reamberin (Sodium chloride + Potassium chloride + Magnesium chloride + Sodium hydroxide + Me-glumine sodium succinate) — IV drip at a rate of up to 90 drops/min (1—4.5 ml / min) — 400—800 ml / day;
— Remaxol (Succinic acid + Nicotinamide + Inosine + methionine + N-methylglucamine) — IV drip at a rate of 40—60 drops / min (2—3 ml / min) — 400800 ml/day [1, 17, 22].
In conclusion, it should be noted that the clinical characteristics of the main syndromes in patients with severe forms of influenza and other acute respiratory viral infections (coronavirus infection), the isolation of the leading syndrome, as well as the study of the molecular mechanisms of the development of respiratory infections are decisive in the search for new approaches to the treatment of ARVI patients. This strategy is promising, because it will offer effective ways and schemes for the treatment and prevention of ARVI of various etiologies. It should be noted that interferons have long proven to be highly effective for the treatment and prevention of respiratory infections as monotherapy, as well as in combination with other drugs, taking into account the severity of the disease.
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