Latent tuberculosis infection in the pediatric population without contact: a prospective controlled study

Background

Latent tuberculosis infection (LTBI) is a major public health problem affecting approximately 25% of the world’s population. According to the latest data from the World Health Organization, approximately 1.2 million cases of tuberculosis (TB) are registered annually in children under 15 years of age, with mortality reaching 200,000 cases. The pediatric population is characterized by an increased risk of LTBI progression to active TB due to the peculiarities of the immune response to Mycobacterium tuberculosis (MBT) [1, 2, 3]. Modern studies show that the risk of LTBI progression to localized tuberculosis is 5-10% during life, with the highest risk observed in the first 2-5 years after infection [4, 5]. In children, this risk is higher due to the immaturity of the immune system, but a significant proportion of patients with LTBI do not have obvious epidemiological links. Latent tuberculosis infection is a state of immune response to MBT antigens indicating their proliferation in the body, in the absence of clinical and radiological signs of active TB [6, 7]. To reduce the global incidence of tuberculosis, it is necessary to pay attention not only to the prevention but also to the prognosis, prevention and treatment of LTBI in children.

Latent tuberculosis infection in children with no documented contact with tuberculosis patients is a unique clinical and immunological problem. These children rarely develop active TB but have specific somatic and immunological features that require a special approach to dispensary observation and prevention. The literature does not describe the specifics of managing this group of children by a pediatrician at the outpatient stage, so this study has important scientific and practical significance.

Objective

To determine the characteristics of the somatic status in children with LTBI without identified contacts with tuberculosis patients.

Materials and methods

A prospective controlled study was conducted involving 40 children (June 2024) who were observed in children’s clinics in Yaroslavl. The main group consisted of 20 patients with verified LTBI without confirmed contacts with tuberculosis patients, and the control group consisted of 20 children without LTBI. The age range was 8-17 years (median 15 years). The diagnosis of "latent tuberculosis infection" was made on the basis of approved clinical guidelines in the presence of a positive test with a recombinant tuberculosis allergen (Diaskintest®), in the absence of changes in the multispiral computed tomography (MSCT) of the chest and other local manifestations of tuberculosis. The children were examined using the clinical and anamnestic method, immunological tests in the form of assessing the phagocytic activity of leukocytes, and serological diagnostics (determination of IgG to T. canis, A. lumbricoides, total antibodies to G. lamblia).

Statistical data processing was performed using Stattech (Kazan) programs using parametric and nonparametric statistics methods. Differences were considered statistically significant at p <0.05. 

The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Informed consent for the participation of children in the study was obtained from all parents/legal representatives. The confidentiality of the personal data of the study participants was maintained. The study was approved by the local ethics committee of the Yaroslavl State Medical University of the Ministry of Health of the Russian Federation (protocol No. 70 dated September 16, 2024).

Results and discussion

All patients from the main group with LTBI were under the observation of a phthisiatrician for 4-5 years and received anti-tuberculosis chemotherapy according to the current clinical recommendations for 3-6 months. Despite the treatment, only half of the children with LTBI had the sizes of reactions to the test with the recombinant tuberculosis allergen (RTA) after preventive chemotherapy decreased by 2 mm or more. At the same time, only 10% of those treated had a reaction to Diaskintest® change from positive to negative. During the observation by the phthisiatrician, these children did not have any local forms of tuberculosis. This may indirectly indicate that the occurrence of positive reactions to the RTA test in the absence of active TB can be influenced by many specific and non-specific factors. The observations obtained in the form of preservation of positive samples with RTA for several years can be explained by the formation of resident memory T cells reacting to CFP-10/ESAT-6 antigens even in the absence of active replication of M. tuberculosis, chronic antigen stimulation due to persistent degraded mycobacterial particles in the lymphoid tissue, and dysfunction of phagocytes leading to incomplete clearance of the pathogen and maintenance of a latent reservoir. The phagocytic activity of leukocytes was studied in 30 children, 15 children with LTBI from the main group and 15 children from the control group. All results are reflected in the table.

As can be seen from the table, the phagocytic activity in children with LTBI was 30% lower than that in children in the control group.

When studying non-specific factors, it was found that children from the main group can be classified as "children with recurrent respiratory diseases" (more than 8 episodes of acute respiratory viral infection per year) in 89% of cases, which is also associated with impaired phagocytic activity of leukocytes (p=0.05). Comorbid disorders were found as markers of immune dysregulation: 60% of children with LTBI were found to have combined somatic pathologies. Grade 2 obesity in children of the main group (50% of cases versus 10% in the control group) was accompanied by the hyperproduction of leptin, which inhibits the differentiation of Th1 lymphocytes, which are critical for the control of MBT (p=0.04). The presence of obesity correlates with the size of the reaction to the test with the recombinant tuberculosis allergen (r=0.72). The data are shown in the figure.

Fig. Relationship between obesity and the reaction to a test with a recombinant tuberculosis allergen in children with latent tuberculosis infection

Connective tissue dysplasia (myopia, flat feet) is associated with defects of type IV collagen, disrupting the barrier function of the alveolar-capillary membrane and phagocyte migration, and occurred in 40% of children with LTBI versus 10% in the control group (p=0.05). Caries and aphthous stomatitis (34% of cases versus 8.5%) in the group of children with LTBI indicated chronic calcium and vitamin D deficiency, which reduces the expression of cathelicidin, a key peptide of antimicrobial protection (p=0.003). Allergic diseases in 60% of children with LTBI (2 times more often than in the control) were accompanied by a Th2 shift, limiting the effectiveness of anti-tuberculosis immunity (p=0.05). Parasitic coinfections can act as modulators of the immune response. High titers of antibodies to Giardia (3.2 times higher than the control) induced IL-10-dependent suppression of the Th1 response, creating a microenvironment for the persistence of MBT (p=0.004). At the same time, helminthiasis reduces the effectiveness of BCG vaccination by suppressing CD40L-mediated antigen presentation, which is confirmed by the data obtained in the study of specific risk factors for LTBI.

Ineffective vaccination against tuberculosis (absence of a scar after BCG-M) was observed in 10% of children in the LTBI group, which was 2 times higher than the same indicator in the control group (p=0.001). Primary infection with MBT in children with LTBI in 60% of cases occurred at the age of up to 3 years, whereas in the control group, only 10% of children were infected at an early age (p=0.01).

The obtained results indicate that early primary MBT infection and ineffective BCG-M vaccination are significant risk factors for the development of LTBI in children. Obesity, frequent respiratory infections, eye diseases, and musculoskeletal diseases may increase the risk of LTBI. The presence of a high titer of antibodies to Giardia and a decrease in the phagocytic activity of leukocytes may indicate a violation of the immune response in children with LTBI.

Children with LTBI without obvious contacts represent a group with a unique immuno-metabolic profile, where the persistence of mycobacterial antigens is combined with comorbid disorders. Based on the obtained results, it can be assumed that the persistence of positive RTA tests in children without established contacts with TB patients reflects the characteristics of immunological reactions, rather than active infection. This requires a transition from standardized monitoring schemes for children with LTBI to a personalized approach. 

Based on the data obtained, it can be concluded that children with LTBI require an individual extended vaccination schedule: pneumococcal conjugate vaccine (PCV13) to increase the phagocytic index by 30% 6 months after administration. Inactivated polio vaccine is mandatory in cases of concomitant helminthiasis to prevent vaccine-associated paralysis. The influenza vaccine is recommended annually to reduce the incidence of respiratory infections. The dispensary observation of children with LTBI should continue for at least 5 years and include an interdisciplinary approach. The child should be observed by a phthisiatrician quarterly during the first 2 years, then annually up to 5 years if the reaction to the test with RTA ≥6 mm is maintained. The pediatrician should assess the anthropometric parameters (body mass index, growth rate) and correct the vitamin and mineral status monthly.

Conclusion

The obtained results expand the existing understanding of the risk factors for developing LTBI in children. The identified patterns can be used to develop individual prognostic models and optimize preventive measures.