Influenza: Diagnosis, Treatment, and Prevention - V.D. Moskaliuk 2010

Influenza
Therapeutic Measures for ARVI
Interferon Therapy

The Use of interferons (IFs) shows great promise in the Treatment of Influenza and other acute respiratory viral infections (ARVIs). Attention to IFs has increased significantly in recent years (V.M. Gagarinova, G.S. Ignatyeva, A.V. Turyeva et al., 1990; K. Takei, P. McPherson, S. Schmid, P. De Camilli, 1995; S.G. Aleksina et al., 1999; V.F. Popov, 2002). At the very dawn of virology as a science, researchers noted the ability of animals to develop resistance or Immunity to infection by Viruses of one type following prior infection by viruses of another type. This phenomenon became known as viral Interference. Subsequently, the substances isolated from the leukocytes of such resistant animals in the late 1950s were named interferons (Yu.V. Lobzin, N.I. Lvov, A.A. Kolokoltsov, 2004).

Interferons—low-molecular-weight Polypeptides (18,000–25,000 daltons)—are genetically determined Components of the body's universal defense system against foreign Genetic information or its expression products. These products enter the human or animal Organism in the form of microorganisms or various natural and synthetic substances (polyphosphates, polycarbonates, etc.). Within The Human Body, they interact with the immune and interferon-induced defense systems. The interferon defense system serves as a rapid-response mechanism against infection within an infected organism (D.K. Novikov, 2002).

The antiviral mechanism of alpha-IF involves inhibiting the synthesis of virus-specific Proteins by blocking viral mRNA Translation. Interferons exhibit multiple biological effects that extend far beyond their antiviral activity (Y. Guun, K. Shortage, S. Krauss et al., 1996; J. Banchereau, R.-M. Steinman, 1998; V.M. Kozko, D.V. Katsapov, 2000; G.J. Demmler, 2000; M.M. Kozlovsky et al., 2002).

These effects are conventionally divided into three groups: antimicrobial, immunomodulatory, and antiproliferative. While controlling The rate of mitosis, they do not disrupt normal Cell Division rates, yet they inhibit high proliferation rates, such as those seen in malignant tumors.

Interferons are divided into two main categories. The first category comprises natural interferons, specifically human leukocyte interferon, which is synthesized by leukocytes. Its synonyms include alpha-IF, etipheron, and wellferon. Next is human fibroblast interferon, also known as beta-IF or feron, which is synthesized by human fibroblasts. The third type of natural interferon is human immune interferon, synthesized by T-lymphocytes and commonly known as gamma-IF (Y. Guan, K.F. Shortage, S. Krauss, R.G. Webster, 1999).

The second major category of interferon preparations consists of recombinant interferons, or second-generation IFs. These include alpha-IF-2a (reaferon, roferon), alpha-IF-2b (intron, inrek), and alpha-IF-2c (berophor). Recombinant gamma-IF (betaferon) and gamma-IF (gammaferon) have also been developed (K. Hartshorn, K. Sastry, D. Brown et al., 1993).

Numerous studies have demonstrated positive outcomes from the clinical use of interferons in acute and chronic Viral Hepatitis, as well as a range of viral respiratory diseases, including influenza and influenza-like infections (L.R. Goading, 1992; E.E. Pokrovskaya, L.V. Osidak, V.P. Drinevsky et al., 1995; E.V. Markelova, E.V. Prosekov, O.V. Nedobylsky, 2000).

It has been established that both natural and microbiologically synthesized interferons possess significant therapeutic potential, capable of protecting Cells and the human body as a whole from a variety of common viral infections. The interferon system mounts a response that significantly outpaces that of The Immune System.

The Functions of interferons are highly diverse. One of the most crucial is their antiviral activity, which is exerted by stimulating The production of antiviral proteins in intact cells, thereby establishing an antiviral state within them. Interferons also exhibit immunomodulatory properties (I.S. Markov, 1999; E. Sotomayor, L. Borrello, E. Tubb et al., 1999; P. Stordeur, L. Poulin, L. Cracium et al., 2002; G.I. Yupatov, E.A. Dotsenko, A.A. Chirkin, 2003).

The interferon system comprises more than 20 distinct protein variants. Functioning as a component of nonspecific defense—taking into account the effects induced by various classes of interferons and their producer cells—interferons are divided into type I and type II. Type I includes alpha-IF and beta-IF, while type II comprises gamma-IF. Type I interferons act as primary natural barriers against infection; alpha-IF exerts a systemic effect, whereas beta-IF, when produced by fibroblasts, acts predominantly locally (S.M. Mikheev, 2000; J. Robertson, C. Nicolson, J. Boatman et al., 1991). Alpha-IF stimulates the phagocytosis of macrophages (MFs) and neutrophils (NFs), activates the production of reactive oxygen species within them (thereby enhancing cellular cytotoxicity), and increases the synthesis of IL-1 and TNF in phagocytes (K. Jakeman, H. Smith, C. Sweet, 1989; S. Velichko, C. Wagner, J. Turkson et al., 2002).

The bactericidal functions of neutrophils are regulated by various cytokines. Proinflammatory cytokines—such as TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, IL-8, and gamma-IF—activate neutrophils and enhance their functional activity, which primarily manifests as an increased capacity to destroy microorganisms. Neutrophils are capable not only of killing microorganisms but also of destroying foreign somatic cells (cytotoxic function) and suppressing their proliferation (cytostatic function). METABOLISM/18.html">The Influence of cytokines on these neutrophil functions remains insufficiently studied (J.M. Katz, M.I. Wang, R.G. Webster, 1990).

It has been established that virtually all body cells are capable of producing interferons to varying degrees. The most potent interferon producers are immunocompetent cells (E.N. Chuyan, I.A. Temuryants, O.B. Moskovchuk et al., 2003; W. Tan, X. Xiang, D. Qiu et al., 2003; D.S. Fedson, 2003). The interferon system lacks specialized cells or Organs, as any cell can potentially be infected by a virus and therefore must possess a system for recognizing and eliminating foreign genetic information.

The primary producers of alpha-IF are B-lymphocytes, macrophages, and monocytes, whereas beta-IF is mainly produced by fibroblasts and epithelioid cells. The synthesis of type I interferons is stimulated by viruses, Bacteria, and their respective Antigens (T. Luft, K. Pang, E. Thomas et al., 1998; D.L. Suarez, M.L. Perdue, N.J. Cox et al., 1998; K. Subbarao, A. Klimov, J. Katz et al., 1998).

Initially, it was believed that the primary Biological Significance of interferons was restricted to their ability to induce resistance to viral infection. However, in the late 1970s, it was experimentally proven that the in vivo protective effect of interferons during viral infection is realized primarily through the activation of the immune system (N.J. Cox, K.A. Fukuda, 1998). It was demonstrated that interferons elicit diverse effects manifested at both the cellular and systemic levels (N.J. Cox, K.A. Fukuda, 1998; M.C. Steinhoff, N.A. Halsey, N.H. Wilson et al., 1990).

A distinctive feature of gamma-IF is its broad spectrum of immunotropic activity. It activates T-lymphocytes, including T-helper cells that stimulate antibody production, T-helper cells that promote the maturation of natural killer (NK) cells, and specific B-cell subpopulations (J. Hsia, T. Tang, M. Paroff et al., 1994; T.A. Fehniger, M.A. Caligiuri, 2001).

The multitude of described interferon effects—immunomodulatory, antiviral, antimicrobial, antiproliferative, and others—points to the broad Regulatory Functions of these factors aimed at maintaining Homeostasis (S.G. Aleksina, N.F. Dorokhova, Z.A. Izvolskaya et al., 1999; L. Kaiser, R.B. Couch, G.J. Galasso et al., 1999). Interferons also stimulate cellular resistance to viruses.

Research has established that close feedforward and feedback loops exist between the immune and interferon systems. Nevertheless, recent years have also highlighted key differences in the directional actions of these systems (R. Whitely, F. Hayden et al., 2000; E. Kilbourne, 2006; V.D. Moskalyuk, 2006).

While The primary function of the immune system is to monitor protein constancy within multicellular populations, the interferon system plays a leading role in overseeing the genetic Stability of the organism (R.J. Whitley, F.G. Hayden, K.S. Reisinger, 2001).

F.I. Ershov and colleagues distinguish three normal ranges of leukocyte interferon activity: high (>128 IU/mL), moderate (32–64 IU/mL), and low (<16 IU/mL). Most healthy individuals exhibit a high or moderate capacity for interferon production. Furthermore, serum interferon is undetectable in 75% of healthy people, while in the remainder, levels do not exceed 4–8 IU/mL (F.I. Ershov et al., 2003).

It has been established (F.I. Ershov, A.N. Narovlyansky, M.M. Mezentseva, 2004) that acute viral infections are accompanied in most cases by a significant surge in circulating interferon levels from the very first hours of the illness. Concurrently, interferon-dependent intracellular antiviral mechanisms and immune responses are activated. In two-thirds of acute viral cases, an antiviral state of the cells develops within the first 1 to 4 days of illness. At the same time, the production of alpha, beta, and gamma-IF decreases upon corresponding lymphocyte induction.

Overall, the clinical course and outcome of a disease depend on how quickly the interferon system is engaged in the body's antiviral defense. Delayed or insufficient endogenous interferon production can lead to chronic disease progression or malignant worsening of a viral infection, potentially resulting in fatal outcomes (J.M. Katz, M.I. Wang, R.G. Webster, 1990; F.I. Ershov, N.V. Kasyanova, V.O. Polonsky, 2003; F.I. Ershov, A.N. Narovlyansky, M.M. Mezentseva, 2004).

The findings obtained by F.I. Ershov et al. (D. Wraith, 1987; F.I. Ershov, A.N. Narovlyansky, M.M. Mezentseva, 2004; V.D. Moskalyuk, 2006) indicate that high serum interferon titers are detected in influenza, whereas respiratory syncytial (RS) virus infection shows no elevation in circulating interferon levels, consequently failing to induce an antiviral state in lymphocytes. In the authors' view, this is linked to the weak ability of these viruses to induce interferon production. Another reason may be the reduced susceptibility of certain viruses to interferon action, which is particularly characteristic of Adenoviruses. As a result, the necessary level of cellular antiviral defense is not established (W.S. Yeow, C.M. Lawson, M.W. Beilharz, 1998; S.Ya. Gad, A.A. Protopopov, T.I. Subbotina, 2000).

Overall, a situation where interferon parameters fail to reach normal levels objectively reflects a decline in the body's physiological resistance (D.K. Lvov, A.N. Slepushkin, S.S. Yamnikova, E.I. Burtseva, 1998).

Interferons present in high concentrations within secretions enhance cellular resistance to viruses (R.B. Belche, R.M. Mendelman, J. Treanor et al., 1998; A.M. Nikolaev, 2003; R.C. Welliver, 2003).

A potent specific mucosal defense factor against viral penetration consists of secretory IgM and IgA Antibodies. By binding to viruses, these antibodies block viral receptors and inhibit their ability to adsorb onto cells. However, such antibodies appear either following prior immunization or after a resolved infection—that is, when immunological memory to the antigens of the given virus has already been established (R.B. Belche, R.M. Mendelman, J. Treanor et al., 1998; I.G. Gryzhak, B.M. Dykyl, 2001; V.P. Divocha, M.T. Mikelashvili, V.N. Mikhalchuk, 2001; V.M. Kozko, G.I. Hradil, D.V. Katsapov, 2001).

It is well established that the aerosol route is the most effective method for administering medications in acute respiratory viral infections (ARVI) (L.A. Vishnyakova, N.V. Putov, 1990; N.G. Orazayev, 2004).

The most accessible and cost-effective option is the domestic IFN – laferon. The human recombinant alpha-2b IFN formulation is a protein with a Molecular Weight of 18 kD, synthesized by Escherichia coli cells based on a Gene encoding a product identical to human alpha-2b IFN, utilizing phage-dependent Introduction/32.html">Genetic Engineering BIOTECHNOLOGY (A. Rudenko, M. Spivak, L. Ganova et al., 2001; V.D. Moskalyuk, 2006). It exhibits a pronounced antiviral and immunomodulatory effect. No contraindications to its use have been established.

The most optimal way to exert the virucidal effect of laferon is through inhalation administration.

The advantages of this method are as follows:

✵ rapid and intensive absorption of laferon due to an increased active surface area;

✵ deposition of laferon in the submucosal layer, which is rich in Blood and Lymphatic vessels;

✵ creation of high concentrations of laferon directly at the lesion site;

✵ delivery of the drug directly to the affected Cells of the target organ (this circumstance prevents the dissemination of the drug throughout the body or its redistribution to other organs and Tissues, such as accumulation in the Liver or concentration in the Kidneys);

✵ a dramatic reduction in in vivo drug loss caused by metabolic conversion, as is observed with remantadine during standard oral administration;

✵ In addition to the therapeutic effect of laferon, concurrent breathing exercises exert a positive effect on the body (deep inhalation and maximal exhalation improve BLOOD AND Lymph Circulation, and consequently intensify tissue metabolism).

According to Zh.I. Vozianova (2001), short-term use of IFN for 2–3 days eases the course of influenza and other ARVI, but by no means via injections, as IFN itself can trigger a flu-like syndrome.

Reaferon-EC-Lipint has also proven effective in influenza patients (I.G. Marinich, M.S. Paramonova, M.K. Yerofeyeva et al., 1997).

In recent years, recombinant a2ß-IFN suppositories (viferon), which possess pronounced antiviral and immunomodulatory effects, have been widely used in the treatment of viral pathologies (hepatitis, herpetic and cytomegalovirus infections) (A.A. Yarilin, 2003). There are isolated studies indicating that viferon combined with antioxidants is effective for ARVI in children. Its use has been associated with higher levels of serum IFN, an increased number of activated cells and enhanced phagocytic activity, as well as elevated production of IgA and IgG compared to patients receiving standard therapy. However, literature sources lack studies on its use for ARVI in adults.

Human leukocyte IFN is effective against any serological variant of influenza and other ARVI. However, its high cost and A number of adverse reactions (it is produced using donor blood, which may harbor infectious agents not always detected by control laboratories) limit its application.