Treatment of acute bronchitis with Derinat in children and adolescents

Introduction Acute bronchitis is the most common disease of the bronchopulmonary apparatus, with an annual incidence rate of approximately 5% in adults and 10% in children. Clinical studies have shown that antibiotics provide limited benefits, and that the early use of immunomodulators improves the clinical course of bronchitis. The present study aimed to determine the therapeutic efficacy of Derinat in children and adolescents with acute bronchitis. Materials and methods


Introduction
Acute bronchitis is the most common disease of the bronchopulmonary apparatus, with an annual incidence rate of approximately 5% in adults and 10% in children [1][2][3] .In most cases, the underlying cause is infection of the respiratory tract, which induces bronchial oedema and mucus overproduction and leads to wheezing and productive cough formation.The bronchial inflammation usually resolves rapidly once the infection is cleared.However, children with recurrent acute bronchitis may be predisposed to the development of asthma.
The current guidelines for the treatment of acute bronchitis recommend antibiotics to clear the infection and symptom management (antitussives, inhalers and expectorants).However, clinical studies have shown that antibiotics provide limited benefits, especially in cases of viral infection 4 .Alternatively, modern medicine is currently exploring the use of immunomodulators for the treatment of infectious and inflammatory processes of diverse aetiology and localisation of the reaction 2,3 , including acute lung infection.For instance, the IgM-based immunotherapeutic, panobacumab, efficiently controlled a murine model of acute lung infection by enhancing innate immune responses 5 .In addition, nasal inoculation of a multivalent liveattenuated vaccine against lipopolysaccharide O antigens induced multifactorial immune responses against acute lung infection in mice.Clinical studies also support the early use of immunomodulators in patients with acute bronchitis 2,[6][7][8] .
Derinat is an agent that stimulates local immunity and is a high molecular-weight polypeptide polyoxidonium that is currently being used for the treatment of patients with acute bronchitis with normal or suppressed immune status [9][10][11] .It is a commercially available preparation of sodium deoxyribonucleate and functions as an immunomodulating agent.It also stimulates haemopoiesis, regeneration and reparation.Derinat has demonstrated high immunological and clinical efficacy in children with chronic adenoiditis 12 and in patients with exacerbation of chronic suppurative otitis media 13 .The immunomodulatory properties of Derinat support immune prophylaxis during surgery 14,15 and are used for the treatment of surgical sepsis.The present study aimed to determine the therapeutic efficacy of Derinat in children and adolescents with acute bronchitis.
Licensee OA Publishing London 2013.Creative Commons Attribution License (CC-BY)

Materials and methods
This work conforms to the values laid down in the Declaration of Helsinki  (1964).The protocol of this study has been approved by the relevant ethical committee related to our institution in which it was performed.All subjects gave full informed consent to participate in this study.

Patient selection and treatment
A randomised trial was conducted at the Kazakh National Medical University to evaluate the therapeutic potential of Derinat for the treatment of acute bronchitis in children and adolescents.A total of 62 children and adolescents diagnosed with acute bronchitis (13.1 ± 0.36 years; range 7-14 years) were recruited in this study.The study's inclusion criteria were as follows: age<15 years and confirmed diagnosis of acute bronchitis (cough, dyspnoea, expectoration, harsh breathing and dry rales).The study's exclusion criteria were as follows: purulent disease located anywhere in the body and bronchopneumonia.The patients were randomly assigned to two groups on the basis of treatment received: control group, which included 32 patients who received conventional therapy, and Derinat group, which included 30 patients who received conventional therapy and Derinat.Derinat (0.25% solution) was intranasally administered at a dosage of 3-4 drops in each nostril 6-10 times a day during the acute phase of the disease.

Assessment of treatment efficacy
Treatment efficacy was determined on the basis of duration and severity of clinical symptoms.The two groups were also compared in terms of serum cellular and humoral immunity indices.In addition to the treatments under evaluation, patients in both groups received symptomatic treatment, including anti-inflammatory drugs, febrifuge drugs, antibechic substances, herbal medicines and multivitamins.

Results
The patients enrolled in this study initially manifested the symptoms of chronic bronchitis, namely cough, dyspnoea, expectoration, harsh breathing and dry rales, as well as fever (37.7°C ± 0.2°C), running nose and intoxication symptoms (malaise, fatigue, headache, loss of appetite and sleep deprivation).The intoxication symptoms lasted for 6-7 days, while the febrile period did not exceed 4-5 days.At the onset of disease, the rise in temperature was accompanied by a dry and regular cough, which became productive on the second and third days and lasted for approximately 11-12 days.In addition, all patients complained of sweating, general weakness and malaise, while five (11.1%) patients experienced moderate dyspnoea on exertion during the first two days.Acute bronchitis was only associated with significant changes in pulmonic sounds around the distal bronchi, where the infection was localised.Over a period of 12-14 days, sounds of vesicular (harsh) breathing increased in intensity.The moist rales varied in intensity depending on the severity of the bronchial lesions.
The baseline characteristics of patients in both groups are presented in Table 1.All patients underwent general blood tests and tests for cellular and humoral immunity.
The treatment efficacy of Derinat was first evaluated on the basis of the intensity of clinical symptoms measured in points 16 before and after the two-week treatment.The conventional treatment significantly decreased all symptoms of the disease (Tables 2 and 3).Cough symptoms disappeared in all patients, except for persistent harsh breathing in three (13.6%).The addition of Derinat to conventional therapy resulted in significantly higher treatment efficacy than that of conventional therapy revealed single dry and moist rales.
The average duration of acute bronchitis in patients who received Derinat was 10 days.The impact of Derinat-conventional therapy on the immune and inflammatory status of patients was determined in terms of leukogram findings as well as cellular and humoral immunity indices.Each treatment group was divided into two age groups: 7-to 14-year-olds and 14-to 18-year-olds.Derinat caused a significant increase in circulating lymphocytes and leukocytes (monocytes) in the children (Table 5) but not in the adolescents (Table 6).With regard to immune correction, blood parameters in the Derinat group recovered in a short period, and some values decreased in comparison with those observed for the control group, indicating positive reactions to Derinat.
Comparison of peripheral blood, cellular and humoral immunity indices before and after Derinat therapy in the adolescents is shown in alone (Table 4).Cough symptoms disappeared in all patients, which presented an overall normalised health status.Only one (4.54%)patient still experienced harsh breathing after 2 weeks.Absolute recovery occurred within an average of 8 or 9 days.
Derinat significantly improved the clinical profile of disease within 2 weeks (Figure 1).It also decreased the average duration of the febrile period.Dry cough, which was noted in the initial stages of the disease, transformed into moist cough by the second or third day and became productive by the seventh or eighth day.Intoxication symptoms, which were observed in all patients (sweating, weakness and malaise), resolved 3 or 4 days after the disease onset and increased the overall health of the patients.Percussion sounds did not change during physical examination of the lungs, but pulmonary auscultation against hard breathing

Discussion
The capacity of Derinat to improve the immune status of the patients is indicated by an increase in systemic immunoglobulins as the primary response.A comparison between parameters measured after treatment and normal values of healthy individuals revealed that the children had recovered normal levels of IgG and IgA, whereas all immunoglobulins We observed a significant decrease in CD8 (p < 0.05), CD16 (p < 0.05) and CD72 (p < 0.01) cells in the Derinat group in comparison with baseline levels.In addition, in the Derinat group, we noted significant increases in the number of eosinophils, monocytes, stab leukocytes and ESR in association with the acute inflammation that occurs during acute bronchitis, whereas in the control group, these values were much lower.In the Derinat group, 23 (51%) patients exhibited leukocytosis, while 19 (42.2%) exhibited a left shift of leukocytes.Consequently, changes in the blood parameters of the patients represented an adequate response of the body to the inflammatory processes in both the children and adolescents.In both age groups with acute bronchitis, there was absolute normalisation of complete blood count and disappearance of clinical symptoms.In the children, a relative increase in the number of leukocytes persisted along with an improvement in their general condition.In children and adolescents of the Derinat group, analysis of immune parameters revealed a significant decrease in CD72 cells, whereas changes in the absolute number of other lymphocyte populations were not established.There was a significant increase in IgM, indicating activation of the primary immune response to infection.We also found a high recovery index [normalisation of increased IgM and increase in the relative value of CD72 cells (14.4 ± 3.7% of the total lymphocyte number in healthy individuals) without a change in their absolute numbers].However, these values remained unchanged in patients without immune correction.An insignificant increase in IgE facilitated the identification of allergic diseases in the examined children, who were then followed up by an allergologist.

Conclusion
This study implies that the use of the immunomodulator Derinat improves blood parameters and strengthens the immune system of children and adolescents with Derinat, resulting in a mild clinical course with reversible cellular and humoral immunity.In four (17.4%) patients, the levels of some immunity indices such as CD3 and CD72 cells remained the same even after immune correction, indicating a lack of lymphopoiesis activation in these patients.It was found that these children had a history of frequent respiratory infections complicated by acute tracheobronchitis and acute bronchitis; in addition, they had a history of allergic reactions such as dermatitis and respiratory allergies.

Figure 1 :
Figure 1: Duration of clinical manifestations in patients with acute bronchitis treated with conventional therapy compared with that in patients treated with a combination of conventional therapy and Derinat.

Table 2 Impact of conventional treatment on the clinical symptoms of acute bronchitis Clinical symptoms Symptom severity points 16
Statistical significance: *p < 0.01; **p < 0.001.