Adenovirus infection is a significant share in the etiological structure of acute respiratory viral infections (ARVI) in young adults in the newly emerging organized groups [1-4]. The features of acute respiratory diseases adenoviral etiology are the frequent development of bacterial tonsillitis, protracted and recurrent, and associated with adenovirus pneumonia which may be fatal [5, 6]. Therefore, the search for effective means of therapy and prevention of adenovirus infection is one of the objectives of medicine.
Currently, for the treatment of acute respiratory diseases agrippinae etiology, including adenoviral infection, drugs used with direct and indirect antiviral mechanisms of action [7-10]. We have shown that antiviral drugs with a direct action mechanism (ribavirin and umifenovir) significantly reduce the duration of the basic syndromes of peak adenoviral diseases General infectious intoxication, fever and respiratory syndromes, as well as tonsillitis and conjunctivitis .
However, a significant impact on the incidence of virus-associated pneumonia, prolonged and recurrent antiviral drugs with a direct action mechanism is not shown . This is probably due to a primary effect of etiotropic drugs to the stage of replication of adenoviruses, which is accompanied by clinical manifestations of the peak. Protracted and relapsing course of adenovirus infection, as well as “late” pneumonia due to the development of the integrative phase and the long-term persistence of adenoviruses in the organs and tissues, mostly in lymphoid tissue.
It is expected that the combined use of antiviral drugs with direct and indirect (mainly interferon-inducing) effect (interferons and interferons inducers) will significantly reduce the frequency of complications of SARS, including adenoviral etiology . In this context, interesting is the analysis of the influence of immunotropic drugs on the incidence of complications, prolonged and recurrent.
The purpose of this study was to evaluate the clinical effectiveness of antiviral drugs with indirect (immunomodulatory) effect in treatment of acute respiratory diseases adenoviral etiology.
Materials and methods
Analyzed medical records of 292 patients with adenoviral disease of moderate severity were hospitalized. Diagnosed “adenovirus infection” verified virological (warusawithana and/or PCR) and serological (RSK and ELISA IgM and/or IgG) laboratory methods [14-16]. In analysis were included the case histories of patients who were admitted in the first 48 hours from the start of the peak with uncomplicated disease at the time of admission over and destination of the drug (inducer of interferon or interferon). The analysis included case histories of patients with laboratory verified adenoviral infection in the same period only received pathogenetic therapy (control group).
The result was formed five comparison groups: group 1 (control, 96 patients) received for treatment only basic therapy (diet, multivitamins and pathogenetic funds); group 2 (47 patients) in addition to basic therapy received human leukocyte interferon 250,000 IU inhalation aerosol average degree of dispersion of 1 times a day for 3 days; group 3 (58 patients) in addition to basic therapy received the inductor “early” interferon of meglumine acridonacetates tablets 150 mg orally 4 tablets for the 1st and 2nd days, then 2 tablets on the 4th, 6th, 8th day.
The course is 1.5–3 g (10-20 tablets); group 4 (44 patients) in addition to basic therapy received the inductor “early” interferon tilorona 125 mg tablets orally 1 tablet a day for the 1st and 2nd day of treatment, then 1 tablet after 48 hours – on the 4th and 6th day of the appointment; 5 group (47 patients) in addition to basic therapy received the inducer “late” interferon (Kagocel) 12 mg tablets orally 2 tablets 3 times a day for the first two days of treatment 1 tablet 3 times a day for 3-and 4-day of treatment (a course of 4 days).
Criteria of the clinical and therapeutic effectiveness of therapy of acute respiratory diseases adenoviral etiology was: the average duration of the manifestations of the syndrome common infectious intoxication and fever; the average day, which was the maximum temperature of febrile reaction; the average duration of respiratory symptoms and cough, nonrespiratory syndromes (conjunctivitis and tonsillitis), as well as reducing the incidence of protracted, recurrent and complicated pneumonia of the disease.
Results and discussion
At the start of therapy, sex, age, and severity of syndrome common infectious intoxication, and febrile reactions at the date of antiviral therapy in the compared groups were comparable. Since the number of observed cases of adenoviral disease in each comparison group was representative (more than 30), further to identify the differences has been applied to mathematical statistical analysis and the use of parametric and nonparametric statistics.
The average values of the duration of the manifestations of the syndrome common infectious intoxication, and febrile fever, total duration of febrile reactions, the day of the development of the maximum body temperature on the background of therapy, duration of respiratory symptoms, cough and some nonrespiratory syndromes (conjunctivitis and tonsillitis) are presented in the table.
As can be seen from the table, the inductor “early” interferon (meglumine acridonacetates and tilorona) did not significantly affect the duration of common infectious syndromes (intoxication, duration of febrile fever and total duration of the febrile reaction), and respiratory syndromes (rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis), cough and nonrespiratory syndromes (acute conjunctivitis and acute tonsillitis). The dynamics of the individual symptoms that demonstrated significant (p < 0.05) in contrast to the basic treatment, are presented in Fig. 1. The use of the drug interferon showed a significant difference with the reference therapy in terms of duration of febrile fever (1,6 ± 0.88 day versus 3.4 ± 1.98 day, p < 0.05), while the difference between the time development of the maximum temperature and total duration of fever between the groups were observed.
Application of the inducer “late” interferon Kagocel significantly reduced compared with baseline therapy duration of rhinitis (4,1 ± 2.27 day compared with 7.5 ± 2.48 day, p < 0.05) and cough (3,5 ± 1.32 day versus 8.2 ± 3.42 day, p < 0.05).
It is known that acute respiratory viral infections, including adenovirus disease, with uncomplicated purulent tonsillitis, sinusitis and pneumonia, have the property of spontaneous recovery.
In this regard, as well as previously identified clinical characteristics of flow manifested forms of adenovirus infection, the most important indicators of clinical efficacy of antiviral agents in the treatment of SARS patients with adenoviral aetiology are reducing the frequency of complications, prolonged and recurrent course of the disease.
For the evaluation of preventive and curative effectiveness of the interferon and interferon inducers as compared with basic therapy according to the proposed criteria were calculated and statistically compared by χ2-Pearson criterion the frequency of complications (pneumonia) and prolonged and recurrent.
The frequency (%) of pneumonia in patients with adenovirus disease and a protracted and recurrent adenovirus infection in the treatment with the use of inducers of interferons and interferon is shown in Fig. 2.
Comparative statistical analysis of the incidence of complicated, protracted and recurrent have shown that the use of meglumine of acridonacetates inside, tilorone inside and interferon inhalation did not significantly reduced the frequency of complications, prolonged and recurrent. Moreover, as compared with basic therapy application tilorone significantly increased the frequency of pneumonia and recurrent, and interferon – only pneumonia. In the first case, it may be due to the fact that tilorona stimulate significant production of early interferon-alpha, in the second case because the interferon was injected and inhaled with a deep forced breath of patients. The latter is likely to lead to the downward propagation of adenoviruses in lower respiratory tract and lungs.
The use of “late” interferon inducer Kagocel in the treatment of patients with adenoviral disease was significantly reduced, compared with the standard therapy of SARS, the incidence of pneumonia 9.28 times (2.1% vs. 19.5%, p < 0.05), and 7.28 times prolonged (up 2.1% versus 15.3%, p < 0.05) and 2.1 times recurrent (4.2% vs 8,8%; p < 0.05) currents. Also, as was noted above, a significant decrease compared with the baseline therapy, duration of rhinitis (3.4 days, p < 0.05) and cough (4.7 per day, p < 0.05). This positive effect of Kagocel on these indicators can be related to the stimulation of derivatives of polyphenol production of interferons (probably mainly gamma), which led most patients to accelerated elimination of virus-infected epithelial and lymphoid cells . Analysis of treatment showed no adverse reactions. It should be noted that the duration of therapy inducer “late” interferon is 4 days, in contrast to the use tilorona 6 days and meglumine of acridonacetates – 8 days.
Based on the data of previous studies the drugs of choice for relief of clinical syndromes during the height of adenoviral diseases of moderate and severe in the complex therapy remain the antiviral drugs direct action (ribavirin and umifenovir) [11, 12]. To prevent the development of pneumonia, protracted and recurrent adenovirus disease drug of choice, as shown by the results of this work are derivatives of polyphenols, particularly drug Kagocel.
It should be expected that the use of combination antiviral therapy with simultaneous use of direct drugs (ribavirin or umifenovir) and indirect (Kagocel) actions will have a sinergidnyj a medicinal and prophylactic effect . For example, the combination therapy of influenza virus A (H1N1)pdm09 has been shown that the concomitant use of drugs with direct antiviral (oseltamivir and umifenovir) and interferon inducer Kagocel, stimulating the innate immune system of the patient, is more effective than monotherapy with the drug’s direct antiviral action, which was reflected in more rapid relief of symptoms and reducing the frequency of complications .
This inclusion in the scheme of complex therapy of influenza and antiviral drug-mediated mechanism of action (including inductor late interferon) is not limited to a viral etiology, which is important in connection with modern epidemiological situation with simultaneous circulation of different types and strains of viruses, including influenza viruses, as well as detecting mixed infections in one patient, influenza and other respiratory viral infections. Conducted numerous studies of the drug Kagocel confirmed its effectiveness regardless of etiology identified respiratory pathogen .
As studies have shown, the use of the inductor “early” interferon (meglumine of acridonacetates and tilorone) did not significantly affect the duration of common infectious, respiratory and nonrespiratory syndromes in the therapy of adenovirus infection. The use of the drug interferon showed a significant difference with the reference therapy in terms of duration of febrile fever. Application of the inducer “late” interferon Kagocel in the treatment of patients with adenoviral disease was significantly reduced compared with the baseline therapy, duration of rhinitis (3.4 days, p < 0.05) and cough (4.7 per day, p < 0.05), as well as, in contrast to the “early” inductors, was significantly decreased frequency of development of pneumonia 9.28 times (2.1% vs. 19.5%, p < 0.05), 7.28 times prolonged (up 2.1% versus 15.3%, p < 0.05) and 2.1 times recurrent (4.2% vs 8.8%, with p < 0.05) currents. The drug is well combined with the ongoing symptomatic therapy and demonstrated a high safety profile. The obtained results clearly confirm the clinical efficacy of Kagocel in the treatment of SARS, and in line with published studies of other authors .
- Lions N. I., Zhdanov K. V., Lobzin Yu. V. and. Clinical and epidemiological value of adenovirus infection in the military personnel // Military.-med. Sib. 2013. No. 8. S. 19-25.
- Lions N. I. Pisareva M. M., Maltsev O. V. , etc. features of etiological structure of acute respiratory infections in different age and professional groups of the population of St. Petersburg during the epidemic season of 2013-2014 // Journal of Infectology. 2014. Vol. 6, No. 3. S. 62-70.
- N. Lvov, E. Peredelsky, I. Grishin et al. Frequency of isolation of adenovirus in young people from organized groups and the clinical significance of relevant serotypes/3 rd Pan European Congress of Military Medicine: scientific abstracts. Belgrade, 2014. P. 139.
- Zhdanov K. V., Lvov N. I., Maltsev O. V. et al. Main Aetiological Features of Acute Respiratory Viral Diseases in Young People of Draft Age and Conscripts During the 2013-2014 Epidemic Season // the International Review of the Armed Forces Medical Services. 2016. V. 89/2. P. 58-63.
- Ivanov V. V., Kharitonov A. M., Grozovsky, Y. R. Severe virus-associated pneumonia in military personnel // Vestnik of Russian Military medical Academy. 2015. No. 1. P. 146-152.
- Lions N. I., Sominina A. A., Zhdanov K. V., Lobzin Yu. V. peculiarities of clinical course of acute respiratory disease caused by adenovirus serotypes epidemically important // Journal of Infectology. 2014. Vol. 6, No. 2. Pp. 5-11.
- Bulgakov V. A., Poromiv A. A. Grekov, A. I., etc., Pharmaco-epidemiological study of the flow of influenza and other acute respiratory viral infections in high-risk groups // Ter. archive. 2017. T. 89, No. 1. P. 62 to 71.
- Zhdanov K. V., Zakharenko S. M., Lichoborka V. P., Lvov N. I. Diagnosis and treatment of acute respiratory diseases: a methodological guide. SPb: MMA, 2012. 21 C.
- Zhdanov K. V., Zakharenko S. M., Lvov N. I. etc. Flu and acute respiratory infections: diagnosis and choice of etiotropic therapy // VOEN.-med. Sib. 2016, No. 2. P. 48.
- Liutov VV, Blind I. V., Gribov, L. N. etc. the Algorithms of actions of a military doctor upon admission of patients with influenza, acute respiratory infections, pneumonia, generalized form of meningococcal disease: guidance. SPb, 2016. 32 p.
- Lions N. I., Zhdanov K. V., Lobzin Y. V., Maleyev V. V. the Experience of application of antiviral agents in acute respiratory diseases adenoviral etiology // Infectious diseases. 2013. V. 11, No. 4. P. 65-71.
- Lions N. I. Adenoviral infection in military personnel: clinic, diagnostics and treatment. Dis. … MD: 14.01.09. SPb, 2016. 313 p.
- Lobzin Y. V., Lvov N. I. interferon Inducers in therapy of acute respiratory diseases: problems and prospects (literature Review) // VOEN.-med. Sib. 2001. No. 11. P. 41-50.
- Ageeva M. R., Yatsyshina S. B., Lvov N. I. the Advantage of PCR-based studies in the diagnosis of respiratory adenovirus infection // Laboratory service. 2016. No. 5 (3). P. 35-36.
- Amosov V. I., Tomasiceva T. A., M. V. Sverlova , etc. microcultural Using ELISA and the modified method of immunofluorescence for the diagnosis of adenovirus infections // Clinical laboratory diagnostics. 2017. T. 62, No. 4. S. 230-235.
- Janina M. A., Komissarov A. B., Lvov N. I., Osidak L. V. determination of the genotypes of adenovirus in samples obtained from patients with SARS // Molecular diagnosis. 2014. Vol. 1. S. 336-337.
- Popov F. A., Shchelkanov M. Yu., Dmitrenko A. K., Simakova A. I. Сombined therapy of influenza with antiviral drugs with a different mechanism of action in comparison with monotherapy // J. Pharm. Sci. & Res. 2018, V. 10 (2), 357-360.
- Fazylov V. Kh., Sitnikov I. G., Malyshev N. A., Silina E. V., Shevchenko B. S., Yeganyan G. A., Korsantia B. M., Groppa L. G. the Effect of antiviral therapy on the incidence of bacterial complications and the use of antibiotics for systemic use in patients with influenza and SARS (results international cohort observational studies) // Antibiotics and chemotherapy. 2016; 61; 11-12: 39-47.
- Sologub T. V., Tsvetkov V. V. Kagocel in treatment of influenza and acute respiratory viral infections: analysis and systematization of data on the results of preclinical and clinical studies // Therapeutic archive. 2017; 8: 113-119.