Clinico-Immunological Features of Tuberculin Allergy in Children with Atopic Diseases

The dissertation is devoted to the clinico-immunological features of tuberculin allergy in children with atopic diseases. The relevance of the research is determined by the negative trend in children's health, the increase in allergic pathology, the complication of the tuberculosis problem, and the difficulties in differential diagnosis of post-vaccination and infectious tuberculin allergy under conditions of mass BCG vaccination. The work is aimed at improving the quality of diagnosis of infectious tuberculin allergy in children with atopic diseases.

During the research, a clinico-functional and laboratory characterization of tuberculin allergy was developed, values of total IgE in serum blood under different sensitivity to tuberculin were determined, the effect of antihistamine preparations on the results of tuberculin tests was studied, immunological markers of infectious tuberculin allergy were selected, a mathematical model of post-vaccination and infectious tuberculin allergy was proposed, and a diagnostic algorithm for tuberculosis infection in children with atopic diseases was developed.

Relevance of the problem. Over the past 10 years, a negative trend has been observed in the health of children. The results of the All-Russian pediatric dispensary examination of 2002 confirmed the main trends in children's health that have developed over the past decade. The pediatric population of Russia can be characterized on the basis of distribution into health groups: Group 1 (practically healthy children, in whom no risk factors are noted) - 32.05%; Group 2 (at risk of developing chronic pathology and functional disorders) - 51.7%; Group 3 (with chronic diseases, including also Groups 4 and 5 with pathology in the subcompensation and decompensation stages and disabling manifestations) - 16.24%. The negative trend with respect to Group 3, associated with the accumulation of diseases, is mainly attributable to the impact of ecological and social environmental factors (Baranov A.A., 2001; Sharapova O.V., Tsaregordtsev A.D., Kobrinsky B.A., 2004).

According to WHO data, approximately 5% of the adult population and 15% of children worldwide currently suffer from allergic diseases. The annual universal increase in allergic pathology, the intensification of the severity of the clinical course, and the sharp decline in the quality of life of patients have turned the allergy problem into a global medical and social issue. (Ilina N.N., 1996; Bjorksten B., 1997; Kristal L., Klein R.A., 2000; Rautava S., Kalliomaki M., Isolauri E., 2002; Kemp A., Bjorksten B., 2003).

In the Russian Federation, every fourth citizen suffers from some form of allergy, and in large industrial cities and ecologically unfavorable regions, the level of allergic diseases among the population reaches 30-60%. Over the past 30 years, the prevalence of allergic diseases has doubled every 10 years everywhere. (Khaитов R.M., Bogova A.V., Ilina N.N., 1998; Khaитов R.M., 2002).

• Samara Oblast is a region with a high anthropogenic load, and within the oblast there are territories designated as ecological disasters. As a result of comprehensive examinations, 64% of preschool-age children and 83% of school-age children have chronic pathology, and allergic pathology is increasing (Kotelnikov G.P., 1999; Makovetskaya G.A., Stukolova T.I., Mazur L.I. et al., 2002).

Alongside the worsening of the overall picture of childhood morbidity, the problem of tuberculosis in children and adolescents has become significantly more complicated. An extremely unfavorable epidemiological situation has developed with respect to tuberculosis among children and adolescents not only in Russia but worldwide (Perelman M.I., 2001; Dolin P.J., Raviglione M.S., Kochi A., 1994; Barry R. Bloom, Peter M. Small, 1998; Kochi A., 2001; Raviglione M.C., 2001).

Under the new socio-economic conditions in Russia, a sharp deterioration has been observed with respect to tuberculosis. The incidence of tuberculosis among children in Russia has increased from 7.4 per 100,000 children since 1990 to 20.2 by 2004. From the end of the 20th century to 2004, the beginning of the 21st, infection of children with tuberculosis mycobacteria rose from 6% to 20.7%, and in some districts up to 70%. The number of children newly infected over the past 10 years has increased more than twofold. Each year, 2% of the entire child population becomes infected (Lebedeva L.V. et al., 1995; Mitinskaya L.A. et al., 1997; Korol O.I. et al., 1999; Shilova M.V., 1999; Shevchenko Yu.L., 2000; Aksenova V.A., Meisner A.F., 2002; Perelman M.I., 2001; Aksenova V.A., 2002; Parfenova T.A., Dolgopolov V.B., Zhuravkova O.B., 2003).

In the city of Samara, the incidence of tuberculosis among children has increased from 4-5 per 100,000 children at the beginning of the 1990s to 17 per 100,000 at the beginning of the 21st century, and the number of infected children continues to rise (Borodulin B.E., Baryshnikova L.A., Borodulina E.A., 2004).

The problem of the effectiveness of tuberculin diagnostics as the sole method of mass screening of children for tuberculosis is highly relevant today (Perelman M.I., 2001; Aksenova V.A., 2002; Poddubnaya I.I.V., Kononenko V.G., Tenkovskaya T.G., Dubakova G.F., 2003).

Under conditions of mass BCG vaccination (92-95% of all newborns), it is impossible to reliably establish the level of infection of children with tuberculosis mycobacteria (to distinguish post-vaccination allergy from infectious tuberculin allergy) (Lebedeva L.V., 1996; Aksenova V.A., 2002; Starke J.K., 1988; Migliori G.B., Borghesi V., Rossanigo R. et al., 1992; Menzies D., 1998; Merino J.M., Caspintero I., 1999).

Tuberculin tests, as a method of early detection of tuberculosis infection, have proven insufficiently effective to date. Ways to improve the effectiveness of early tuberculosis detection have not been developed (Firsova V.A., 2001; Aksenova V.A., Baryshnikova I.I.A., 2003; Aleksandrova E.N., Potapova E.N., Chkhetia N.M., 2003).

The literature contains much contradictory data on sensitivity to tuberculin in children with allergic diseases, and problems arise in interpreting the results of routine tuberculin diagnostics (Kozlova O.F., Chugaev Yu.P., Dyachkova G.K. et al., 2003; Kimura M., Converse P.J., 1999; Shirakawa Nago, Enomoto Tadao et al., 1997; Von Mutius E., 1999).

Goal of the research

The goal of this work is to improve the quality of diagnosis of infectious tuberculin allergy in children with atopic diseases.

Tasks of the research

1. To develop a clinico-functional and clinico-laboratory characterization of tuberculin allergy in children with atopic diseases.

2. To determine the values of total IgE in serum blood under different sensitivity to tuberculin in children with atopic diseases.

3. To determine the effect of antihistamine preparations on the results of tuberculin tests in children with atopic diseases.

4. To select, on the basis of comprehensive statistical analysis of the conducted studies, immunological markers of infectious tuberculin allergy in children with atopic diseases.

5. To develop a mathematical model of post-vaccination and infectious tuberculin allergy in children with atopic diseases.

6. To create a diagnostic algorithm for tuberculosis infection ("seroconversion") in children with atopic diseases.

Scientific novelty of the research

For the first time, this work describes and compares the current features of the nature of tuberculin allergy, humoral and cellular immunity indicators in post-vaccination and infectious tuberculin allergy in children with atopic diseases.

As a result of the conducted studies: immunological indicators of post-vaccination and infectious allergy in children with atopic diseases have been established; immunological markers of infectious tuberculin allergy have been identified; values of total IgE in serum blood under different sensitivity to tuberculin have been determined; and a diagnostic method for types of tuberculin allergy based on mathematical modeling in children with atopic diseases has been proposed.

Practical significance of the work

The obtained results have determined the role and significance of humoral and cellular immunity factors and allergic tuberculin tests in the differential diagnosis of post-vaccination and infectious allergy in children with atopic diseases.

The obtained immunological data can be used in the diagnosis of infectious tuberculin allergy in children with atopic diseases.

An accessible set of immunological tests has been proposed for inclusion in the examination plan for children, complementing traditional research methods.

The developed diagnostic algorithm for infectious tuberculin allergy, together with the method for calculating post-vaccination and infectious allergy, will allow differential diagnosis using the proposed immunological tests in children with atopic diseases.

The obtained data can be used in the practical work of pediatric, phthisiatric, and allergological centers and departments, as well as general practitioners.

Provisions for defense:

1. The use of a complex of immunological methods in conducting differential diagnosis of the nature of tuberculin allergy contributes to improving the quality of diagnosis of infectious allergy in children with atopic diseases.

2. The most significant immunological indicators in infectious tuberculin allergy in children with atopic diseases are an increase in the level of IgG in serum blood, a decrease in the initially elevated level of total IgE, an increase in blood cells expressing CD4+, CD8+, CD16+ markers, as well as IL-2.

3. The calculation method based on mathematical modeling of the results of tuberculin tests and immunological indicators allows the diagnosis of post-vaccination and infectious tuberculin allergy in children with atopic diseases with a probability of 98%.

Practical application of the research

Seven scientific papers on the topic of the conducted research have been published, a methodological guide for physicians has been prepared, and two patents for inventions have been obtained. The main provisions of the dissertation have been reported and discussed at the 5th Congress of the Russian Association of Allergologists and Clinical Immunologists (Moscow, 2002), the XI Russian National Congress "Man and Medicine" (Moscow, 2004), and sessions of the scientific-practical societies of phthisiologists, pediatricians, and allergologists-immunologists of Samara Oblast (2001, 2002, 2003, 2004).

Implementation of the research results in practice.

The developed complex of clinico-immunological investigations for differential diagnosis of infectious and post-vaccination tuberculin allergy is applied at the Center for Prevention and Treatment of Allergic Dermatoses of Municipal Clinical Hospital No. 1 of Samara, the Samara Consultation-Diagnostic Center for Children, and has been included in the program of practical classes and lecture courses on phthisiology and pulmonology, and pediatrics for students and physicians at Samara State Medical University.

Scope and structure of the work

The dissertation is presented in 160 pages of typescript, illustrated with 32 tables, 12 figures, 1 scheme, and contains 4 clinical examples. The work consists of an introduction, a literature review, a chapter "Characterization of the studied patient groups and research methods," own observations presented in three chapters, a discussion of the obtained results, a conclusion, findings, and practical recommendations. The reference list contains 321 sources, of which 217 are by domestic authors.