Microbiota of the respiratory tract in children with cystic fibrosis in various subjects of the North Caucasus Federal District

Introduction. The microbial biodiversity of the respiratory tract in children with cystic fibrosis (CF) in various subjects of the North Caucasus Federal District (NCFD) has not yet been sufficiently described. In the NCFD children with CF were previously shown to have specific clinical manifestations of the disease and changes in the frequencies of pathogenic variants of the CFTR gene. In this regard, the topic of the work is relevant.

The aim of the study. To detect changes in the microbiota composition of the respiratory tract in CF children in various subjects of the NCFD.

Materials and methods. There were examined one hundred 48 CF children, who underwent a study of the microbiota of the respiratory tract. The patients were divided into 2 groups: by subject (children of the Chechen, Karachay-Cherkess, Ingush, Kabardino-Balkarian, North Ossetia — Alania and Dagestan Republics) and by age (1 — infants under 12 months, 2 — 1–3 years, 3 — 3–7 years, 4 — 7–17 years).

Results. For the first time, changes in the quantitative and qualitative composition of the respiratory tract microbiota in CF children in various subjects of the NCFD are presented. The quantitative composition of the microbiota of the respiratory tract of CF patients is represented by 45 species of bacteria and mold from the department of ascomycetes. Gram-negative microorganisms (86.3%) occupied a significant place in the composition of the microbiota of the respiratory tract in CF patients. The proportion of Gram-positive bacteria was 13.6%. The leading microbiota in the respiratory tract in CF patients in various subjects of the NCFD were: P. aeruginosa (68.9%), S. aureus (66.8%), of which 37.1% are MRSA, H. influenzae (51.3%), Moraxella catarrhalis and K. pneumoniae (30.4%), respectively. The biodiversity of the microbiota of the respiratory tract in CF children in various subjects of the NCFD differs from other regions of the Russian Federation in the high content of P. aeruginosa and H. influenzae, they are not characterized by the isolation of Achromobacter xylosoxidans. For the first time, a unique frequency distribution of the CFTR gene alleles was revealed in children with CF in various subjects of the NCFD. The most common pathogenic variants of the CFTR gene among all subjects of the NCFD were p.Y515 (150 alleles/51.9%), p.W1282 (48 alleles/16.6%), and p.E92K (26 alleles/8.9%). While the share of these pathogenic variants in the Russian Federation was 2.48%, 1.73%, and 3.67%, respectively.

Conclusion. The established patterns of biodiversity of the microbiota of the respiratory tract in CF children are necessary to optimize their treatment and prevent exacerbations of the disease. Given the high content of hemophilic bacillus in the microbiota in CF children, special attention should be paid to vaccination of children against hemophilic infection type B.

Contribution:
Simonova O.I., Lazareva A.V., Savostyanov K.V. — concept and design of the work;
Lazareva A.V., Simonov M.V., Gorinova Yu.C. — collection and processing of the material, writing the text;
Pushkov A.A., Savostyanov K.V. — conducting molecular genetic research;
Simonova O.I., Pushkov A.A., Smirnov I.E. — editing the text.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: December 26, 2024
Accepted: January 30, 2025
Published: February 28, 2025

1. Riordan J.R., Rommens J.M., Kerem B.S., Alon N.O., Rozmahel R., Grzelczak Z., et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989; 245(4922): 1066–73. https://doi.org/10.1126/science.2475911

2. Høiby N. Cystic fibrosis and the clinical biofilm revolution A survey of the Danish CF Center’s contribution. Biofilm. 2024; 9: 100246. https://doi.org/10.1016/j.bioflm.2024.100246

3. Kondratyeva E.I., Voronkova A.Yu., Kashirskaya N.Yu., Krasovsky S.A., Starinova M.A., Amelina E.L., et al. Russian registry of patients with cystic fibrosis: lessons and perspectives. Pulmonologiya. 2023; 33(2): 171–81. https://doi.org/10.18093/0869-0189-2023-33-2-171-181 https://elibrary.ru/dbhmer (in Russian)

4. Krasovskiy S.A., Adyan T.A., Amelina E.L., Sergienko D.F., Shadrina V.V., Guschin M.Yu., et al. Cystic fibrosis: some issues of epidemiology and genetics. Practicheskaya pulmonologiya. 2019; (4): 45–50. https://elibrary.ru/oaecxd (in Russian)

5. Castellani C., Cuppens H., Macek M. Jr., Cassiman J.J., Kerem E., Durie P., et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J. Cyst. Fibros. 2008; 7(3): 179–96. https://doi.org/10.1016/j.jcf.2008.03.009

6. Fidler M.C., Buckley A., Sullivan J.C., Statia M., Boj S.F., Vries R.G.J., et al. G970R-CFTR mutation (c.2908G>C) results predominantly in a splicing defect. Clin. Transl. Sci. 2021; 14(2): 656–63. https://doi.org/10.1111/cts.12927

7. Oren Y.S., Avizur-Barchad O., Ozeri-Galai E., Elgrabli R., Schirelman M.R., Blinder T., et al. Antisense oligonucleotide splicing modulation as a novel Cystic Fibrosis therapeutic approach for the W1282X nonsense mutation. J. Cyst. Fibros. 2022; 21(4): 630–6. https://doi.org/10.1016/j.jcf.2021.12.012

8. Smirnov I.E., Tarasova O.V., Lukina O.F., Kustova O.V., Sorokina T.E., Simonova O.I. Structural and functional state of the lungs in cystic fibrosis in children. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(2): 11–7. https://elibrary.ru/twinwz (in Russian)

9. Smyth A.R., Bell S.C., Bojcin S., Bryon M., Duff A., Flume P., et al. European cystic fibrosis society standards of care: best practice guidelines. J. Cyst. Fibros. 2014; 13(Suppl. 1): 23–42. https://doi.org/10.1016/j.jcf.2014.03.010

10. Simonova O.I., Voronina O.L., Gorinova Yu.V., Amelina E.L., Burkina N.I., Lazareva A.V. et al. Features of treatment of a patient with cystic fibrosis with mixed microbial infection of the respiratory system, including Pandoraea pnomenusa. Rossiyskiy pediatricheskiy zhurnal. 2016; 19(2): 113–22. https://doi.org/10.18821/1560-9561-2016-19(2)-113-122 https://elibrary.ru/waapdj (in Russian)

11. Kapranov N.I., Kashirskaya N.Yu., Konrdrat’eva E.N., eds. Cystic Fibrosis [Mukovistsidoz]. Moscow: Medpraktika-M; 2021. (in Russian)

12. Harun S.N., Wainwright C.E., Grimwood K., Hennig S. Australasian cystic fibrosis bronchoalveolar lavage (ACFBAL) study group. Aspergillus and progression of lung disease in children with cystic fibrosis. Thorax. 2019; 74(2): 125–31. https://doi.org/10.1136/thoraxjnl-2018-211550

13. Enina E.A., Kondrateva E.I., Vodovozova E.V., Starinova M.A., Pustabaeva M.A., Ledeneva L.N. et al. General characteristics of patients with cystic fibrosis in the North Caucasus Federal District of the Russian Federation. Mezhdunarodnyy nauchno-issledovatelskiy zhurnal. 2024; (2): 37. https://doi.org/10.23670/IRJ.2024.140.64 https://elibrary.ru/wfxblg (in Russian)

14. Simonov M.V., Gorinova Yu.V., Simonova O.I., Pushkov A.A., Zhanin I.S., Alekseeva A.Yu., et al. Geno-phenotypic features of cystic fibrosis in Russian children from the Chechen and Karachay-Cherkess Republics. Nauchnye rezultaty biomeditsinskikh issledovaniy. 2024; 10(3): 389–406. https://doi.org/10.18413/2658-6533-2024-10-3-0-5 (in Russian)

15. Voronkova A.Yu., Amelina E.L., Kashirskaya N.Yu., Kondratieva E.I., Krasovsky S.A., Starinova M.A., et al. The Register of Patients with Cystic Fibrosis in the Russian Federation. 2022. [Registr patsientov s mukoviscidozom v Rossiyskoy Federatsii. 2022 god]. Moscow: Medprktika-M; 2024. https://elibrary.ru/mrzpqv (in Russian)

16. Lyamin A.V., Ismatullin D.D., Zhestkov A.V., Kondratenko O.V. The laboratory diagnostic in patients with mucoviscidosis: a review. Klinicheskaya laboratornaya diagnostika. 2018; 63(5): 315–20. https://doi.org/10.18821/0869-2084-2018-63-5-315-320 https://elibrary.ru/xnjdad (in Russian)

17. Shedko E.D., Lazareva A.V., Zorkin S.N., Novikova I.E., Vershinina M.G., Timoshina O.Yu., et al. Quantitative multiplex real-time PCR as a method for detection of significant bacteriuria in children. Rossiyskiy pediatricheskiy zhurnal. 2020; 23(5): 284–90. http://doi.org/10.18821/1560-9561-2020-23-5-284-290 https://elibrary.ru/pqxwyl (in Russian)

18. Gorinova Yu.V., Savostyanov K.V., Pushkov A.A., Nikitin A.G., Pen’kov E.L., Krasovskiy S.A., et al. Genotype-phenotypic correlations of the course of cystic fibrosis in Russian children. The first description of eleven new mutations. Voprosy sonremennoy pediatrii. 2018; 17(1): 61–9. https://doi.org/10.15690/vsp.v17i1.1856 https://elibrary.ru/yugvsy (in Russian)

19. Savostyanov K.V. Modern algorithms for the genetic diagnosis of rare hereditary diseases in Russian patients: Informational materials. [Sovremennye algoritmy geneticheskoy diagnostiki redkikh nasledstvennykh bolezney u rossiyskikh patsientov: Informatsionnye materialy]. Scientific publication / K.V. Savostyanov. Moscow: Polygraphist and Publisher, LLC, 2022. — ISBN 978-5-6047928-7-2. https://elibrary.ru/rduzgh (in Russian)

20. Langton Hewer S.C., Smith S., Rowbotham N.J., Yule A., Smyth A.R. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst. Rev. 2023; 6(6): CD004197. https://doi.org/0.1002/14651858.CD004197.pub6

21. Mazharov V.N., Klimov L.Ya., Enina E.A., Vodovozova E.V., Shakhgireeva M.R., Mambetova A.M., et al. Registry of Patients with Cystic Fibrosis in the North Caucasus Federal District of the Russian Federation – 2020 [Registr patsientov s mukovistsidozom Severo-Kavkazskogo federal’nogo okruga Rossiyskoy Federatsii –2020 god]. Stavropol’; 2022. (in Russian)

22. Cardines R., Giufre M., Pompilio A., Fiscarelli E., Ricciotti G., Di Bonaventura G., et al. Haemophilus influenzae in children with cystic fibrosis: antimicrobial susceptibility, molecular epidemiology, distribution of adhesins and biofilm formation. Int. J. Med. Microbiol. 2012; 302(1): 45–52. https://doi.org/10.1016/j.ijmm.2011.08.003

23. Blagovidov D.A., Simonova O.I., Kostinov M.P., Smirnov I.E. Pseudomonas infections in patients with chronic nonspecific pulmonary diseases and problems of its vaccine prevention. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(6): 54–60. https://elibrary.ru/vkgoot (in Russian)

24. Yakovlev Ya.Ya., Burnysheva O.V., Gottlieb M.L., Peresadina M.A., Lavrinova O.V., Solovyova A.N. Microbiota of the lower respiratory tract and its sensitivity to antibacterial drugs in children with cystic fibrosis. Mat’ i ditya v Kuzbasse. 2022; (3): 41–7. https://doi.org/10.24412/2686-7338-2022-90-3-41-47 (in Russian)

25. Kondratieva E.I., Kashirskaya N.Yu., Roslavtseva E.A. A review of the national consensus “Cystic fibrosis: determination, diagnostic criteria, therapy” for dietitians and gastroenterologists. Voprosy detskoy dietologii. 2018; 16(1): 58–74. https://elibrary.ru/ywrfoj (in Russian)

26. Gorinova Yu.V., Simonova O.I., Lazareva A.V., Chernevich V.P., Smirnov I.E. Experience of long-term inhalation of tobramycin solution in chronic Pseudomonas aeruginosa infection in children with cystic fibrosis. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(3): 50–3. https://elibrary.ru/uaxnwb (in Russian)

27. Mukhametzyanov A.M., Kaydanek T.V., Latypov A.A., Valeeva D.S., Ponomareva D.N., Ermolenko I.A., et al. Microbial landscape of the respiratory tract of children with cystic fibrosis: monitoring results. Meditsina. 2024; 12(4): 43–59. https://doi.org/10.29234/2308-9113-2024-12-4-43-59 https://elibrary.ru/dnfxkf (in Russian)

28. Chebotar I.V., Bocharova Yu.A. Mysterious Achromobacter. Klinicheskaea mikrobiologiya i antimikrobnaya khimiotherapiya. 2022; 24(1): 4–13. https://doi.org/10.36488/cmac.2022.1.4-13 https://elibrary.ru/uulbio (in Russian)

29. Marsac C., Berdah L., Thouvenin G., Sermet-Gaudelus I., Corvol H. Achromobacter xylosoxidans airway infection is associated with lung disease severity in children with cystic fibrosis. ERJ Open Res. 2021; 7(2): 00076-2021. https://doi.org/10.1183/23120541.00076-2021

30. Simmonds N.J., Southern K.W., De Wachter E., De Boeck K., Bodewes F., Mainz J.G., et al. ECFS standards of care on CFTR-related disorders: Identification and care of the disorders. J. Cyst. Fibros. 2024; 23(4): 590–602. https://doi.org/10.1016/j.jcf.2024.03.008

31. Budzinskiy R.M., Kondratyeva E.I., Odinaeva N.D., Voronkova A.Yu., Sherman V.D., Zhekaite E.K. Experience of allergic bronchopulmonal aspergillosis therapy in children with cystic fibrosis. Meditsinskiy vestnik Severnogo Kavkaza. 2020; 15(2): 220–4. https://doi.org/10.14300/mnnc.2020.15052 https://elibrary.ru/jlitsa (in Russian)

32. Terlizzi V., Motisi M.A., Pellegrino R., Galli L., Taccetti G., Chiappini E. Management of pulmonary aspergillosis in children: a systematic review. Ital. J. Pediatr. 2023; 49(1): 39. https://doi.org/10.1186/s13052-023-01440-9

33.