RU2600838C1 - Method of enhancing nonspecific protection factors activity in patients with chronic obstructive pulmonary disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to clinical immunology, allergology and pulmonology, and can be used for enhancing the activity of nonspecific protection factors in patients with chronic obstructive pulmonary disease (COPD). For this purpose patients with COPD in a state out of aggravation of the disease are once vaccinated against pneumococcal infection with preparation "Prevenar-13".

EFFECT: method enables enhancing the activity of nonspecific protection factors due to increased phagocytic index of neutrophils, monocytes, indicator of activity of spontaneous NBT test of neutrophils, indicator of activity of induced NBT test of neutrophils, as well as increasing percentage of NBT-positive leukocytes in the spontaneous test at its safety and availability.

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Description

Chronic obstructive pulmonary disease (COPD) is one of the most common human diseases that cause significant economic damage associated with temporary and permanent disability of the most active part of the population [Chuchalin A.G. Chronic obstructive pulmonary disease. Monograph. M.: Atmosphere Publishing House, 2008; 568].

The main place in the development of infectious exacerbations of COPD is occupied by bacterial pathogens (S. pneumoniae, M. catarrhalis, N. influenzae), which are excreted from sputum in 40-50% of patients with signs of exacerbation [Protasov A.D., Zhestkoe A.V., Lavrentieva N.E. et al. The effect of complex vaccination against pneumococcal, hemophilic type b infections and influenza in patients with chronic obstructive pulmonary disease. Journal of Microbiology, Epidemiology and Immunobiology. 2011; 4: 80-84; Protasov A.D. Immunological and clinical effects of the combined use of vaccines against pneumococcal, hemophilic type b infections and influenza in patients with chronic obstructive pulmonary disease. Abstract. diss. Cand. honey. sciences. M., 2012; 26; Sinopalnikov A.I., Romanovskikh A.G. Infectious exacerbation of chronic obstructive pulmonary disease: modern approaches to diagnosis and therapy. Handbook of outpatient physician. 2007; 11: 46-57].

Typically, over the course of a year, a patient with COPD suffers from one to four or more exacerbations. Each subsequent exacerbation in patients with COPD leads to a more rapid progression of the disease and a decrease in the quality of life, increases the cost of treatment [Protasov A.D. Comparative evaluation of the effectiveness of vaccination against pneumococcal infection in patients with chronic obstructive pulmonary disease using 13-valent conjugated and 23-valent polysaccharide vaccines. Russian Allergological Journal. 2014; 4: 12-17; Landyshev Yu.S., Babich M.V. Pharmacoeconomic evaluation of the effectiveness of antibiotic therapy in community-acquired pneumonia associated with chronic obstructive pulmonary disease. Pulmonology. 2010; 3: 97-101]. Severe exacerbation can cause the death of patients with COPD due to the development of acute respiratory failure or decompensation of chronic pulmonary heart disease.

In connection with the foregoing, vaccine prevention of respiratory infections, including pneumococcal, is extremely important for patients with COPD. In our country, for patients with COPD, for prevention of pneumococcal infection, the 23-valent polysaccharide pneumococcal vaccine Pneumo-23 and the 13-valent conjugated pneumococcal vaccine Prevenar-13 are used.

The Pneumo-23 vaccine (Sanofi Pasteur, France) consists of purified capsule polysaccharide pneumococcal antigens of 23 serotypes. When creating this vaccine, each polysaccharide was extracted separately and included in the final product. Each dose of the vaccine contains 25 μg of the S. pneumoniae polysaccharide antigen of each of the 23 serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9V, 9N, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F), preservative - phenol up to 1.25 mg, isotonic buffer solution up to 0.5 ml [World Health Organization. 23-valent pneumococcal polysaccharide vaccine: WHO position paper. Wkly Epidemiol Rec. 2008; 83: 373-384].

The Prevenar-13 vaccine (Pfizer, USA) is a capsular polysaccharide of 13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F), individually conjugated with diphtheria protein CRM ₁₉₇ and adsorbed on aluminum phosphate. The vaccine contains 2.2 μg of polysaccharides of all of the listed serotypes, with the exception of serotype 6B polysaccharide, the amount of which is 4.4 μg. These polysaccharides are conjugated to ~ 32 μg of CRM ₁₉₇ carrier protein. Excipients: aluminum phosphate - 0.5 mg, sodium chloride - 4.25 mg, succinic acid - 0.295 mg, Polysorbate 80 - 0.1 mg, water for injection - up to 0.5 ml. The antigenic composition of the Prevenar-13 vaccine is relevant in the Russian Federation [WHO position paper on pneumococcal vaccines. Wkly Epidemiol. Rec. 2012; 14: 129-144. www.who.wer.int .; Sidorenko S.V., Savinova T.A. The population structure of pneumococci with decreased sensitivity to penicillin and the prospects for anti-pneumococcal vaccination to inhibit the spread of antibacterial resistance. Antibiotics and a chemotherapy. 2011; 56 (5-6): 11-18].

The principal difference between the Prevenar-13 vaccine and the Pneumo-23 preparation is its conjugated nature. Technology polysaccharide conjugation with diphtheria protein CRM ₁₉₇ provides a fundamentally different mechanism of action of such a vaccine. The mechanism of action of the 23-valent pneumococcal polysaccharide vaccine is aimed at the activation of B-lymphocytes with the subsequent formation of plasma cells and the synthesis of specific antibodies, mainly IgM. Polysaccharide vaccines, being T-independent antigens, do not cause the formation of memory cells, so repeated injections of the vaccine do not have the proper booster effect [Park SJ, Seo K.N., Seo MS The immune responses of cationic liposomal polysaccharide against Streptococcus pneumoniae serotype 14. [ Abstract ISPPD-0081]. Pneumonia 2014; 3: 47]. However, a number of authors do not share this point of view, believing that information on lesser antibody production for repeated administration of polysaccharide pneumococcal vaccines is greatly exaggerated and lacks convincing evidence [Fedson D., Guppy M. Pneumococcal vaccination of older adults: conjugate or polysaccharide? Human Vaccines and Immunotherapeutics. 2013; 9 (7): 1382-1384].

Conjugation of a polysaccharide with a protein converts an antigen from T-independent to T-dependent, stimulates the response of T-helpers, provides the formation of memory cells and an immunological response to booster administration, which has been shown in healthy volunteers and in patients with chronic bronchopulmonary pathology [Weinberger B., Herndler-Brandstetter D., Schwanninger A. et al. Biology of immune responses to vaccines in elderly persons. Clin. Infect. Dis. 2008; 46: 1078-1084; Paradiso P.R. Pneumococcal conjugate vaccine for adults: a new paradigm. Vaccines. CID 2012; 55: 259-264; Perova A.L., Ruleva A.A. Vaccination against pneumococcal infection. Treatment and prevention. 2013; 4 (8): 43-53; Shiramoto M., Hanada R., Juergens C. et al. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in Japanese elderly adults who are naive to pneumococcal vaccine. [Abstract ISPPD-0154]. Pneumonia 2014; 3: 199; RF patent for invention No. 2544168 dated 01/17/2014 "Method for the formation of immunological memory for Streptococcus pneumoniae antigens in patients with chronic obstructive pulmonary disease." / Protasov A.D., Zhestkov A.V., Kostinov M.P., Zolotarev P.N., Tezikov Yu.V. // Inventions. Utility Models (Official Bulletin of the Russian Agency for Patents and Trademarks). - 03/10/2015. - No. 7].

For patients with COPD, with a long course of the disease, due to the massive microbial contamination of the bronchial tree, a decrease in nonspecific protection factors is characteristic against the background of their depletion, which can be judged by the phagocytic index of granulocytes and monocytes, as well as by the indicators of spontaneous and induced activity of the HCT test of neutrophils and the percentage of HCT-positive white blood cells in a spontaneous test. This violation is one of the leading in the immunopathogenesis of COPD [Enikeev O.A. Dynamics of immunological parameters of systemic inflammation in chronic obstructive pulmonary disease of various degrees of severity and ways of their correction. Abstract. diss. Cand. honey. sciences. Ufa, 2012; 22; Aflyatunova S.F. Features of immunopathogenesis and clinical and immunological diagnosis of chronic obstructive pulmonary disease. Abstract. diss. Cand. honey. sciences. Ufa, 2011; 22].

The following indicators were used to assess non-specific protection factors:

1. Phagocytic index of granulocytes (%).

2. Phagocytic index of monocytes (%).

3. The activity indicator of the spontaneous HCT test of neutrophils (%).

4. The activity index of the induced HCT test of neutrophils (%).

5. The percentage of HCT-positive white blood cells in a spontaneous test (%).

The phagocytic index was determined in the laboratory of Invitro by a standard method. The functional activity of neutrophils was studied using the HCT test in spontaneous and induced variants [Park V.N., Firkig S.M., Smitwick E.M. Infection and nitroblue tetrazolium reduction by neutrophilis. Lancet 1968; 2: 532-534], as modified by M.E. Wicksman and A.H. Mayansky [Vicksman M.E., Mayansky A.N. A method for evaluating the functional activity of human neutrophils by the reduction reaction of nitro-blue tetrazolium. Kazan; 1979].

A spontaneous HCT test shows that cells have formed aggressive forms of oxygen and have microbicidal activity. The induced HCT test should be larger than spontaneous, it shows the presence of a reserve of cell growth. The norm of the spontaneous HCT test is from 7 to 14% at an intensity equal to 0.2 srvc. units The norm of the induced HCT test is more than 28% at an intensity> 0.36 conventional units.

There is a method of increasing the phagocytic activity of neutrophils in patients with COPD, which uses intravenous administration of a domestic immunomodulator of immunovenine 25-50 ml intravenously, for a course of 2-3 infusions [Abdurakhmanova I.S. Immune mechanisms of inflammation in chronic obstructive pulmonary disease of a severe stage. Abstract. diss. Cand. honey. sciences. Ufa, 2010; twenty].

The disadvantages of this method are the high cost of a course of treatment with Immunovenin, the need for intravenous infusions, which require additional costs (supplies, a qualified nurse, an infusion in a hospital, time costs), the risk of anaphylactic reactions.

There is a method of increasing the phagocytic activity of neutrophils in patients with COPD, which uses immunotropic therapy with topical bacterial lysate IRS-19 or Anaferon (ultra-low doses of antibodies to human gamma-interferon).

According to this method, selected as a prototype, the drug IRS-19 is prescribed to patients with COPD at a dose of 1 dose in each nasal passage 2 times a day for 2 weeks, and after 3 months, a second course is carried out. The smallest doses of antibodies to human interferon (Anaferon) are prescribed 1 tablet 1 time per day sublingually for 3 months [O. V. Polyakova. The effectiveness of immunotropic therapy in patients with chronic obstructive pulmonary disease, depending on the characteristics of the course and immune status. Abstract of the Cand of Medical Sciences. Saratov, 2012; 22].

The disadvantage of this method is the need for long-term treatment, the risk of low patient compliance with the independent use of drugs, low evidence base in relation to the drug Anaferon.

The problem solved by the invention is to increase the activity of factors of nonspecific protection in patients with COPD through the use of conjugated pneumococcal vaccine "Prevenar-13", which provides a good clinical effect. The specified technical result is achieved by the fact that in the method of enhancing the activity of nonspecific protection factors in patients with COPD, a single vaccination of this category of patients in remission against pneumococcal infection with Prevenar-13 is provided. This intervention provides an increase in the values of the phagocytic index of neutrophils, the phagocytic index of monocytes, the activity index of the spontaneous HCT test of neutrophils, the activity index of the induced HCT test of neutrophils, as well as an increase in the percentage of HCT-positive leukocytes in the spontaneous test.

A method of enhancing the activity of non-specific protection factors in patients with COPD is as follows. Patients with COPD who are in remission are vaccinated against pneumococcal infection with Prevenar-13 by intramuscular injection into the deltoid muscle of the shoulder (Registration number LP-000798).

To assess the activity of non-specific protection factors in patients with COPD, we used the determination of the phagocytic index of neutrophils, the phagocytic index of monocytes according to the standard method used in the independent laboratory of Invitro as part of test No. 192 (“Immunological examination expanded”), as well as the determination of the functional activity of neutrophils using HCT -test in spontaneous and induced variants [Park V.N., Firkig SM, Smitwick E.M. Infection and nitroblue tetrazolium reduction by neutrophilis. Lancet 1968; 2: 532-534], as modified by M.E. Wicksman and A.H. Mayansky.

Analysis of the effectiveness of the proposed method for enhancing the activity of non-specific protection factors in patients with COPD was carried out according to the results of the management of 40 patients with this nosology. 20 naive patients with COPD for vaccination against pneumococcal infection were vaccinated with the Prevenar-13 vaccine (average age 62.6 ± 7.4 years), and 20 people received the Pneumo-23 vaccine (average age 59.7 ± 9 ,6 years).

The values of the phagocytic index of neutrophils (reference value 82-90%), the phagocytic index of monocytes (reference value 75-85%), the activity index of the spontaneous HCT test of neutrophils (reference value 7-14%), the activity index of the induced HCT neutrophil test (reference value> 28%), the percentage of HCT-positive white blood cells in the spontaneous test (reference value 2-19%) is initial, as well as in the early post-vaccination period (after 1, 2 and 6 weeks).

Statistical processing of the results was carried out using the software package StatPlus 2009 Professional 5.8.4. Descriptive statistics are presented in the form of a median and interquartile interval, for age - in the form of an average value and standard deviation. The statistical significance of the differences was estimated using the Wilcoxon test, for age - using the Mann-Whitney test.

In patients with COPD from the Prevenar-13 vaccinated group, the phagocytic neutrophil index was initially reduced to 68% [55; 74]. After PCV-13 vaccination in patients with COPD after 2 and 6 weeks, this indicator statistically significantly increased to 84% [75; 89] and 85% [78; 89], respectively (p <0.001), entering the boundaries of reference values. This indicates an increase in the activity of nonspecific protection factors during a single vaccination of PCV-13 in patients with COPD who have an initially reduced phagocytic activity of granulocytes. By the 6th week after PCV-13 vaccination, a statistically significant increase in the phagocytic index of monocytes from 72.1% was observed [70; 78] to 77.2% [75; 90] (p <0.05).

A persistent immunomodulating effect of a single PCV-13 vaccination in patients with COPD was also revealed, aimed at increasing the initially reduced activity indicators of the spontaneous and induced HCT test (neutrophils) and the percentage of HCT-positive white blood cells in the spontaneous test. So, the activity indicator of the spontaneous NBT test of neutrophils after 2 and 6 weeks statistically significantly increased from 5% [2; 11] to 12% [9; 14] and 14% [11; 19], respectively (p <0.01); the activity index of the induced HCT test of neutrophils after 2 and 6 weeks statistically significantly increased from 11% [5; 14] to 22% [15; 30] and 26% [20; 33], respectively (p <0.001); the percentage of HCT-positive white blood cells in the spontaneous test after 2 and 6 weeks also statistically significantly increased from 7% [1; 14] up to 15% [6; 17] and 17% [9; 18], respectively (p <0.01). The revealed changes indicate an increase in oxygen-dependent killing, due to activation of NADPh oxidase, against the background of PCV-13 vaccination in patients with COPD, which is an indicator of increased activity of non-specific defense factors in this group.

In patients with COPD from the Pneumo-23 vaccinated group, the phagocytic neutrophil index was initially reduced to 63% [50; 69]. After vaccination with PPV-23 in patients with COPD after 6 weeks, this indicator did not statistically significantly change, amounting to 67% [53; 70] (p> 0.05). By the 6th week after PPV-23 vaccination, there were no statistically significant differences in the phagocytic index of monocytes: initially 74.8% [73; 80], after 6 weeks - 75.8% [70; 78] (p> 0.05).

Also, at all time points, there were no statistically significant changes in the activity indicators of the spontaneous and induced HCT test (neutrophils) and the percentage of HCT-positive white blood cells in the spontaneous test compared with the initial values for a single vaccination of PPV-23 in patients with COPD. The following results were obtained: the activity indicator of the spontaneous HCT test (neutrophils) was initially 6% [4; 12], after 6 weeks - 7% [3; fourteen]; the activity index of the induced HCT test (neutrophils) was initially 9% [7; 13], after 6 weeks - 12% [9; fourteen]; the percentage of HCT-positive white blood cells in the spontaneous test was initially 6% [4; 14], after 6 weeks - 9% [5; 18] (p> 0.05 for all comparisons).

PPV-23 vaccination in patients with COPD does not affect the phagocytic index of neutrophils, the phagocytic index of monocytes, the activity of spontaneous and induced HCT test (neutrophils) and the percentage of HCT-positive white blood cells in the spontaneous test, which indicates the absence of the effect of the polysaccharide pneumococcal vaccine on the processes occurring with phagocytosis.

Thus, vaccination of patients with COPD against pneumococcal infection using the 13-valent conjugate vaccine “Prevenar-13” leads to increased activity of non-specific defense factors. This effect is not observed with the introduction of the pneumo-23 polysaccharide vaccine. Significant local or general reactions when using this method of enhancing the activity of factors of nonspecific protection in patients with COPD were not noted. The method is safe, available for modern medical institutions.

At the filing date, applicants did not find a way to enhance the activity of non-specific protection factors in patients with COPD with the claimed combination of symptoms, as a result of which it is concluded that the claimed technical solution meets the criteria of the invention of “novelty”.

The use of a single vaccination with the Prevenar-13 drug in patients with COPD with the goal of enhancing the activity of non-specific protection factors is also not known, which indicates the compliance with the criterion of "inventive step".

The inventive method can be carried out in any specialized medical institution, therefore, it meets the criterion of "industrial applicability".

Claims (1)

A method of enhancing the activity of nonspecific protection factors in patients with chronic obstructive pulmonary disease, including a single vaccination of COPD patients who are not exacerbating the disease against pneumococcal infection with Prevenar-13.