Anaferon for children
Anaferon for children is an immunomodulating drug used in pediatric practice for the treatment of acute respiratory infections in patients up to the age of four. Clinical trials of the drug have confirmed its effectiveness in infections caused by influenza viruses, parainfluenza, HSV-1, HSV-2, chickenpox, monocytic tonsillitis, enterovirus infection, tick-borne encephalitis, rota-, corona-, calice-, and adenovirus infections. The creator of the drug is Russian, its official date of birth is 2001. Anaferon for children is based on antibodies to interferon gamma obtained using affinity purification technology. The drug has undergone the entire legally established cycle of studies, during which its effectiveness, safety, absence of toxicity and negative impact on the immune status were confirmed. Anaferon for children has a dual mechanism of action: it improves functional characteristics and stimulates the body's production of its own interferons and activates gamma-1 receptors for interferon. Clinical and molecular genetic studies have demonstrated the selectivity of the action of Anaferon for children on the production of interferon. Viruses are natural stimulators of the production of these immune proteins. However, often the level of interferon reproduction and the further course of antiviral reactions turns out to be inadequate to the clinical situation.
In turn, Anaferon for children activates the production of alpha and gamma interferons and increases the efficiency of their interaction with target receptors. As a result, during the period of greatest prevalence of viral infection, a larger number of active gamma-interferon molecules appear in the body, which quickly interact with “their” receptors and neutralize the impact of viruses on the body. The effect of the drug on the formation of early and late interferons ensures the effectiveness of pharmacotherapy even if it is not started on time. As viral agents are removed from the body, natural regulatory patterns begin to activate, causing interferon production to decrease. In the absence of the virus, Anaferon for children has virtually no effect on the production of interferons. At the recovery stage, the effect of the drug is expressed in stabilizing at a higher level the properties of cells to produce interferon during the invasion of the virus in the event of re-infection. Anaferon for children is not used in patients under one month of age. When using the drug in recommended doses, the development of any side effects is practically excluded. Taking Anaferon for children does not need to be linked to food intake. No cases of pharmacological interaction with other drugs have been identified to date.
Experience of using Anaferon in pediatric practice
The article reviews clinical studies on the use of the drug Anaferon. Anaferon is an antiviral agent with immunomodulatory activity, many years of experience in the use of which has proven the effectiveness and safety of the drug in the treatment and prevention of a wide range of viral and bacterial infectious diseases in children. The key mechanisms of action of Anaferon are the induction of endogenous type I and II interferons, as well as allosteric modulation of the interferon gamma receptor. The authors note that the high safety of the drug, the possibility of its use in children from 1 month of age, and the lack of addiction allow us to recommend Anaferon as the drug of choice for the treatment and prevention of infectious diseases of various etiologies.
Introduction
Infectious diseases remain the most common in childhood, among which acute respiratory diseases and acute intestinal infections occupy one of the leading places. Every year, more than a billion cases of acute respiratory diseases and the same number of acute intestinal infections are registered worldwide.
Children attending school and preschool institutions most often get sick, which is directly related to the increase in the number of contacts. First of all, we are talking about acute respiratory diseases and influenza, which a child suffers on average 8 times in the first year of visiting, 4–6 times in the second year, and 3–4 times in the third year. In total, in 2012, 28 million 423 thousand 135 people in the country suffered from acute upper respiratory tract infections, of which 67% were children under 14 years of age. The incidence rate was 19,896.3 per 100 thousand people, and in children under 14 years old - 87,391.6 per 100 thousand people. The incidence of acute intestinal infections remains high. If in 2002 635,514 cases of acute intestinal infections were registered in the country, then in 2012 there were 808,585 cases of acute intestinal infections. Among the sick, more than 60% are children, most of them under the age of 3 years.
An undoubted achievement in the field of studying acute respiratory diseases and acute intestinal infections should be considered their etiological decoding. A screening survey showed that about 60% of all diarrheal diseases are caused by viruses, most often by rotaviruses (80%), less often by astro-, calici- and adenoviruses (15%) and in 5% of cases the disease is caused by associations of viruses. About 12% of acute intestinal infections are caused by bacteria, the etiology of 28% remains unspecified.
Acute respiratory viral infections (ARVI) also predominate in the structure of acute respiratory diseases (90–95%). The share of bacterial and other acute respiratory diseases (caused by staphylococci, less commonly streptococci, Moraxella catarrhalis, Haemophilus influenzae, Mycoplasma spp
., mushrooms, etc.) account for 5–10%.
Diagnosis of ARVI
Among the reasons for the total prevalence of ARVI, one can highlight the presence of an extraordinary variety of respiratory pathogens, the formation of type-specific post-infectious immunity and the ease of transmission of pathogens. Nevertheless, the predominant tropism for one or another part of the respiratory tract, formed in the process of evolution, makes it possible to identify characteristic signs, which simplifies the differential diagnosis of the disease and allows timely prescription of etiotropic drugs.
Thus, parainfluenza is characterized by symptoms of damage to the laryngeal mucosa, which in 50% of cases manifests itself as croup syndrome. Adenovirus infection is characterized by damage to the mucous membrane of the nasopharynx with the involvement of lymphoid formations in the process with the formation of pharyngotonsillitis and pharyngitis. With respiratory syncytial infection, the pathological process begins with damage to the mucous membrane of small and medium bronchi, which is clinically manifested by expiratory shortness of breath. The initial symptom of influenza infection is tracheitis, and rhinovirus infection is rhinitis.
Thus, topical diagnosis occupies a central place in the system of clinical guidelines in ARVI. In principle, identifying a symptom pathognomonic for a given infection is a central link in the diagnosis of the disease [1]. For example, a feature of the clinical picture of all calicivirus infections is the presence of a symptom complex of damage to the upper gastrointestinal tract (GIT) in the form of nausea, vomiting and abdominal pain, while shigellosis is characterized by colitis syndrome, which is associated with the tropism of Shigella spp
. to the mucous membrane of the large intestine.
Immunotropic drugs in the treatment of ARVI
The idea of the tropism of the lesion (that is, the initiation of the infectious process only if the pathogen is found, recognized and binds to a specific related receptor in the tropic organ) made it possible to determine the main principle of treating an infectious patient - etiotropic. Currently, treatment regimens have been developed based on the use of etiotropic, pathogenetic and symptomatic agents. Numerous studies have shown that in patients with ARVI, timely administration of Anaferon, Algirem or Arbidol leads to a reduction in clinical manifestations by 1.5–2 times compared to standard therapy.
A promising direction in modern therapy for such infections in children is the use of immunotropic drugs, in particular endogenous interferon inducers (IFN). Interferon inducers have a universally wide range of antiviral activity (etiotropic effect) and a pronounced immunomodulatory effect. Against the background of their use, the synthesis of endogenous interferon is balanced and controlled by the body, which prevents a number of side effects characteristic of exogenously administered interferons. A single administration of classical inducers leads to long-term, and in some cases unreasonably long, circulation of endogenous interferon (up to 120 hours or more) [2].
One of the inducers of endogenous interferons alpha and gamma, widely used in the complex therapy of viral and bacterial infections in children, is the domestic drug Anaferon for children. In the production process of this drug, technological processing of the starting substance is used, which leads to the release of a special physicochemical, biological and pharmacological activity called release activity. Thus, Anaferon for children contains affinity-purified antibodies to IFN-gamma in a release-active form [3].
Release-active antibodies to IFN-gamma have a specific modifying effect on the antigen to which they are produced [3], causing conformational (spatial) changes in the IFN-gamma molecule. In addition, it was found that release-active antibodies to IFN-gamma enhance the interaction of IFN-gamma with its receptor (increase the amount of IFN-gamma bound to the receptor) and change the affinity of the interaction of IFN-gamma with antibodies to IFN-gamma [4, 5].
In a series of preclinical studies, it was shown that when administered prophylactically and/or therapeutically, release-active antibodies to IFN-gamma have an antiviral effect against RNA and DNA viruses and immunotropic activity. The antiviral and immunotropic effect is realized due to the influence on the functional activity of natural factors of immune defense (cellular, humoral immune response, phagocytic activity of neutrophils and macrophages). The wide range of immunotropic effects of the drug is associated with the involvement of the interferon system in the implementation of pharmacological activity, in particular IFN-gamma, the induction of which is a key mechanism of its action [4–8].
Like other interferon inducers, Anaferon for children promotes the production of endogenous interferons. However, unlike classical inducers, Anaferon for children has a selective effect on the production of endogenous IFN alpha and gamma, depending on the presence of the virus in the body. The selectivity of Anaferon's action is manifested in the fact that during the acute period of a viral infection it activates all types of interferon production (spontaneous and stimulated/induced production). This results in an increase in serum concentrations of IFN alpha and gamma to levels sufficient to combat infection. As the virus is eliminated and during the convalescence period, the stimulating effect of Anaferon for children on interferonogenesis decreases. This leads to the fact that by the time the drug is finished (the treatment regimen involves taking the drug for 5–7 days), there is a decrease in the content of interferons in the serum until a normal level is reached without developing a state of hyporeactivity. During this period, the effect of Anaferon for children is manifested by higher (compared to placebo) levels of induced production of IFN alpha and gamma, reflecting the functionality of the IFN system in the event of recurrent infection. Anaferon for children has a similar effect when used prophylactically [3].
Thus, depending on whether there is contact with viruses, Anaferon for children acts differently. During infection, the drug actively stimulates the production of interferons, increases the expression and binding ability of IFN-gamma receptors. Outside of contact with viruses, the drug increases the functional reserves of the interferon system and maintains the child’s body in a state of high readiness to protect against viruses. It should be noted that the ability to influence the reception of IFN-gamma also distinguishes Anaferon for children from other inducers. Optimization of ligand-receptor interactions of IFN-gamma molecules with its receptor may underlie the physiological nature of the action of Anaferon for children. Under conditions of more complete interaction of IFN molecules with receptors, the regulatory effects of IFN-gamma are realized more quickly. On the one hand, this leads to a faster activation of the immune response, and on the other hand, stimulation of the IFN system stops faster through feedback channels [9, 10].
The described properties of Anaferon for children allow its use in repeated therapeutic and prophylactic courses without excessive stimulation of IFN, and therefore, without the risk of depletion of the immune system and the development of a stage of hyporeactivity, which is possible when using other IFN inducers. This also determines the possibility of using Anaferon for children in patients at risk, whose immune system requires a more balanced effect [9]. All of the above indicates the wide therapeutic potential of Anaferon for children, and taking into account the fact that the drug is approved for use in children aged 1 month and older, it can be considered the drug of choice in pediatric practice.
Anaferon for children in the treatment and prevention of influenza and ARVI in children
Currently, a fairly impressive number of studies have been conducted confirming the effectiveness and safety of Anaferon for children in the treatment and prevention of influenza and ARVI in children [11, 12]. Experts note that most studies were comparative, randomized and prospective. A significant part of the work involved the use of placebo control and various masking methods (simple and double blinding) [11].
As part of an expert assessment of 10 years of clinical experience in the use of Anaferon for children, presented at the XX National Congress “Man and Medicine”, Professor E.G. Kondurina noted that over the past decade, clinical studies of Anaferon took place in more than 40 cities of Russia, more than 50 research centers participated in their implementation, and the number of patient participants approached 6,000.
Anaferon for children is most widely used for the treatment and prevention of acute respiratory viral infections. This also determines the predominance of studies devoted to this topic. In the available literature sources you can find information about 27 comparative studies on the use of Anaferon for this pathology in children aged 1 month to 15 years. The vast majority of studies were randomized, and five studies were double-blind placebo-controlled [11, 12].
Thus, according to a two-center randomized placebo-controlled study, the prophylactic use of Anaferon for children in a group of more than 200 people reduced the average number of ARVI episodes by 2.3 times compared with the placebo group (p
The therapeutic effect of Anaferon for children during a multicenter, randomized, double-blind, placebo-controlled clinical trial was manifested in a reduction in the duration of the main symptoms of influenza by 24–43 hours. Thus, the duration of hyperthermia was 54 ± 3.1 hours versus 88.1 ± 2.9 hours in the placebo group (p
It should be noted that Anaferon for children is widely used for the prevention and treatment of viral infections in children at risk for the development of ARVI and complications. These groups include children with secondary immunodeficiency conditions, as well as children with concomitant pathologies that limit the possibility of using pharmacotherapeutic methods for the prevention of ARVI [11]. Research by Professor N.K. Perevoshchikova (Kemerovo) showed the feasibility of including Anaferon for children in the program for the management of frequently ill children with pathology of the lymphopharyngeal ring. It has been proven that the use of preventive courses of Anaferon for children reduces the incidence of ARVI in this category of children by 2.5 times. Moreover, the preventive effect after completion of the 3-month rehabilitation and preventive program remains for another 1.5–2 months (total observation period - 5 months). In addition to clinical effects in frequently ill children receiving Anaferon for children, elimination of microorganisms from the mucous membrane of the nasopharynx is noted. At the same time, the detection of Staphylococcus aureus decreased by 1.5 times, and positive smears for hemolytic streptococcus were detected 6 times less often than in the control group. In nasocytograms of children who received a course of Anaferon for children, there was a significant increase in the number of columnar epithelium, a decrease in sensitization of the nasopharyngeal mucosa, a decrease in the adsorption index of squamous epithelium, which indirectly confirmed a decrease in the content of microorganisms on the mucous membranes of the upper respiratory tract. When using Anaferon for children, a significant increase in lysozyme activity and an increase in the level of IgA and sIgA in nasal secretions were recorded [18–20].
Anaferon for children in the treatment and prevention of acute respiratory viral infections in children suffering from atopic diseases
Pediatricians and allergists have accumulated extensive experience in using Anaferon for children as an antiviral drug and an inducer of interferons, primarily IFN-gamma, in children suffering from atopic diseases. Randomized comparative and placebo-controlled studies were conducted at the Center for Child and Adolescent Health (Moscow), Siberian State Medical University (Tomsk), Novosibirsk State Medical University (Novosibirsk), ChelSMA (Chelyabinsk), as well as in Dnepropetrovsk [21–26]. Prophylactic use of Anaferon for children made it possible to reduce the number of children who suffered acute respiratory infections during the epidemic period by 2–2.5 times, and to reduce the incidence of ARVI by 3.5 times. In addition, under the influence of the drug, the frequency of virus-induced exacerbations of allergic diseases was reduced. For example, the average number of exacerbations of bronchial asthma in the group of children receiving Anaferon was 0.43 ± 0.08 compared to 0.88 ± 0.02 in the placebo group (p
A study of the therapeutic effectiveness of Anaferon for children in acute respiratory viral infections in children with allergic diseases demonstrated the ability of the drug to reduce the severity and duration of intoxication syndrome and catarrhal phenomena, as well as good tolerability of Anaferon. The Influenza Research Institute of the Ministry of Health of the Russian Federation showed that the inclusion of Anaferon for children in the complex therapy of 100 children aged 6 months and older with a history of dermato- and respiratory allergies and combined damage to the respiratory and gastrointestinal tract led to a significant decrease in the proportion of people with elevated body temperature already after 1 day of taking the drug, compared with the group receiving placebo. In addition, after 3 days, the number of children with persistent symptoms of intoxication and gastrointestinal manifestations significantly decreased, and after 4 days - with catarrhal phenomena in the nasopharynx and auscultatory changes in the lungs. In general, signs of acute infection were eliminated on the 5th day in the main group and on the 8th day in the placebo control group. Clinical improvement was accompanied by an increase in serum INF alpha and gamma levels on days 2–3 of illness, as well as in the levels of sIgA, CD3, and CD16. It should be emphasized that by the time of recovery, serum levels of interferons were normalized. The treatment course of Anaferon led to a statistically significant reduction in the release of viral antigens in the nasal passages of these children.
Anaferon for children in the treatment of acute intestinal viral infections
The wide distribution of rotavirus infection in pediatrics is explained by high natural susceptibility, especially in young children. The leading role in antiviral protection, starting from the earliest stage of penetration of rotavirus into the gastrointestinal mucosa, belongs to the interferon system. By inhibiting the processes of transcription and translation of viral templates, they are able to suppress the replication of many RNA and DNA viruses [27, 28]. The effectiveness of including Anaferon for children in the treatment of acute intestinal infections of viral (rotavirus and calicivirus infections), viral-bacterial nature, as well as the prevention and treatment of acute infections with combined damage to the respiratory and intestinal tracts has been studied and confirmed by a number of authoritative experts [12, 27–32 ]. It was shown that the inclusion of Anaferon for children in the treatment regimen for patients with ARVI with gastrointestinal lesions (adeno-, corona-, calici- and rotavirus infections) led to a reduction in fever (1.3 times), intoxication (1.9 times), catarrhal symptoms (2.5 times) and manifestations of gastrointestinal dysfunction (1.4 times), and also shortened the period of isolation of viral antigens from convalescents and led to the discharge of children at an earlier time [27, 32].
Placebo-controlled studies conducted at the Research Institute of Children's Infections of the FMBA, at the Central Research Institute of Epidemiology of Rospotrebnadzor, at the Department of Children's Infectious Diseases of Rostov State Medical University, indicate the advisability of including Anaferon for children in the complex therapy of rotavirus gastroenteritis [32]. A significant reduction in the duration of the main manifestations of the disease was demonstrated in 29 children aged 1 to 8 years. Thus, the symptoms of intoxication were relieved for 24–36 hours, fever – for 48–50 hours, and the restoration of stool character – 2.3 days earlier compared to children receiving standard therapy.
Similar data indicating the cessation of rotavirus isolation in 90% of cases on the 5th day of treatment with Anaferon were obtained by N.Kh. Tkhakushinova and N.G. Soboleva [31]. This fact is apparently due to the activating effect of the drug on antiviral resistance and the immune response, which ensures accelerated sanitation of the body from rotavirus, despite the known tendency of the latter to long-term persistence [27, 28].
The data obtained in a study conducted under the guidance of Professor A.V. deserve special attention. Gorelova [32]. The use of Anaferon for children for the treatment of rotavirus infection made it possible to prevent infection of children during their hospital stay. Thus, among children who received placebo as part of complex therapy for rotavirus infection, by the time of discharge, the number of children in whom the presence of viral-bacterial mixtures in the feces was determined by PCR method increased by 10%, while in the group of children who received Anaferon for children, No such phenomena were noted.
Thus, the interferonogenic activity of Anaferon for children in respiratory and intestinal infections of viral etiology and their combination has a positive effect on various parts of the humoral and cellular antiviral immune response. As a result of the antiviral and immunomodulatory activity of Anaferon for children in the treatment of rotavirus infection, the concentration of the virus in the affected tissues of the gastrointestinal tract decreases and the rate of its elimination increases. This is important both for a specific child and for the pediatric population as a whole, since it prevents prolonged viral shedding by convalescents and helps reduce the level of sporadic and outbreak morbidity.
The prospects for the use of Anaferon in pediatric practice are not limited only to viral infections. In a study conducted by I.V. Babachenko et al. showed that the inclusion of Anaferon for children in the treatment of pertussis infection in children contributed to a reduction in the incidence of intercurrent ARVI by 2–2.5 times compared to the control group, and a reduction in the incidence of pneumonia and bronchitis from 50 to 20% [33].
Use of Anaferon for children in other infections and immunodeficiency conditions
The presence of Anaferon for children not only has an antiviral effect, but also immunomodulatory activity, which makes it possible to effectively use it against the background of secondary immunodeficiency states, chronic infections, which are most difficult to treat due to the high variability of causative viruses and their ability to suppress the immune response. Based on the results of a double-blind, placebo-controlled, randomized clinical trial, conclusions were drawn about the effectiveness and safety of Anaferon for children in the treatment of chickenpox in children [34]. Revealed significant (p
The experience of using Anaferon in children from 4 months to 3 years with HIV infection who had perinatal contact with HIV infection (stages A1–B3) is interesting. According to V.N. Timchenko, against the background of the preventive course of the drug, there was a decrease in the incidence of ARVI, and a quarter of the children in the group did not get sick at all during the observation period, while in the control group the incidence of ARVI was one hundred percent. The proportion of children with repeated ARVI decreased by 2 times. When assessing the therapeutic effectiveness of Anaferon for children in children with HIV infection and contacts of HIV infection (the drug was used according to a standard treatment regimen), it was found that the duration of the main symptoms of ARVI is reduced by 1.5–2.3 times. The safety of using Anaferon for children in HIV-infected young children has also been shown [35].
Currently, there is data on the use of Anaferon for children in infectious mononucleosis, hemorrhagic fever with renal syndrome, pseudotuberculosis and yersiniosis, whooping cough, tubulointerstitial nephritis, enteroviral and meningococcal meningitis, as well as ARVI in children with concomitant cardiac pathology [36–39].
Conclusion
The collected evidence base, which includes registered and published clinical studies with a high level of evidence, allows us to recommend the widespread use of Anaferon for children in practical medicine, including in pediatrics. Anaferon for children occupies a special place in the treatment of influenza and ARVI, which is associated with the physiological effect of the drug on induced interferonogenesis, on the IFN-gamma system. Anaferon for children is not addictive, which allows it to be used to treat children prone to frequent respiratory infections.
A wide range of antiviral activity allows us to classify Anaferon for children as the drug of choice in the treatment of children with viral infections manifested not only by respiratory, but also by other, including gastrointestinal, symptoms. Finally, the combination of effectiveness with a high safety profile plays a special role in the treatment of viral infectious and inflammatory diseases in children with allergic and other underlying pathologies.
