Carbocysteine Influence on Cough Severity and Local Mucosal Immunity in Acute Respiratory Viral Infections in Children

Aim: To evaluate the effect of carbocysteine on cough and the level of secretory immunoglobulin A (sIgA) in saliva in children with acute respiratory viral infections (ARVI) and the presence of a correlation between the level of sIgA in saliva and the total cough index.

Design: Multicentre observational study.

Materials and methods. 156 children older than 2 years (4.4 ± 1.2 years) with ARVI were included in the study. All patients received carbocysteine at the age dosage. The total cough index and the concentration of sIgA in saliva were measured on days 1–2 and on days 7–10 from the onset of ARVI. Results. The total cough index significantly decreased in 98.7% of patients by the 7–10th day of illness. The level of sIgA in saliva was initially 26.49 (8.94; 56.51) µg/ml, in dynamics — 30.07 (8.52; 60.40) µg/ml (no significant differences were found). An increase in the level of sIgA in dynamics was noted in 43.6% of patients, and in the vast majority of them the increase was significant — 20% or more. A decrease in the concentration of sIgA in dynamics was noted in 55.8% of patients. A significant correlation was found between sIgA concentrations in saliva at the first and second visits (p < 0,001). There was no significant correlation between the total cough index and sIgA levels.

Conclusion. A significant positive dynamic of cough was noted in patients with ARVI during treatment with carbocysteine. The concentration of sIgA in saliva varies within a wide range. A multidirectional change in the level of sIgA in saliva over time was noted in children with ARVI. Further study of the mechanisms of local mucosal immunity can help in the development of new approaches to the treatment and prevention of ARVI.

1. Fokkens W.J., Lund V.J., Hopkins C., Hellings P.W. et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(suppl.S29):1–464. DOI: 10.4193/Rhin20.600

2. Lee S.L., O’Callaghan C., Lau Y.L., Lee C.D. Functional analysis and evaluation of respiratory cilia in healthy Chinese children. Respir. Res. 2020;21(1):259. DOI: 10.1186/s12931-020-01506-w

3. Chilvers M.A., Rutman A., O’Callaghan C. Functional analysis of cilia and ciliated epithelial ultrastructure in healthy children and young adults. Thorax. 2003;58(4):333–8. DOI: 10.1136/thorax.58.4.333

4. Smith C.M., Djakow J., Free R.C., Djakow P. et al. СiliaFA: a research tool for automated, high-throughput measurement of ciliary beat frequency using freely available software. Cilia. 2012;1:14. DOI: 10.1186/2046-2530-1-14

5. Chuchalin A.G., ed. Respiratory medicine: manual: in 3 vol. M.: Litterra; 2017. Vol. 1. 640 p. (in Russian)

6. Deng Y., Herbert J.A., Robinson E., Ren L. et al. Neutrophil-airway epithelial interactions result in increased epithelial damage and viral clearance during respiratory syncytial virus infection. J. Virol. 2020;94(13):e02161–19. DOI: 10.1128/JVI.02161-19

7. Geppe N.A., Oserskaya I.V., Kolosova N.G. New methods of prevention and treatment of acute respiratory viral infections in children. Local protection factors of the respiratory mucosa. Russian Bulletin of Perinatology and Pediatrics. 2019;64(5):14–20. (in Russian). DOI: 10.21508/1027-4065-2019-64-5-14-20

8. Hijano D.R., Siefker D.T., Shrestha B., Jaligama S. et al. Type I interferon potentiates IgA immunity to respiratory syncytial virus infection during infancy. Sci. Rep. 2018;8(1):11034. DOI: 10.1038/s41598-018-29456-w

9. Kok T.W., Izzo A.A., Costabile M. Intracellular immunoglobulin A (icIgA) in protective immunity and vaccines. Scand. J. Immunol. 2023;97(4):e13253. DOI: 10.1111/sji.13253

10. Woof J.M., Kerr M.A. The function of immunoglobulin A in immunity. J. Pathol. 2006;208(2):270–82. DOI: 10.1002/path.1877

11. Moldt B., Saye-Francisco K., Schultz N., Burton D.R. et al. Simplifying the synthesis of sIgA: combination of dIgA and rhSC using affinity chromatography. Methods. 2014;65(1):127–32. DOI: 10.1016/j.ymeth.2013.06.022

12. Uren T.K., Johansen F.E., Wijburg O.L., Koentgen F. et al. Role of the polymeric Ig receptor in mucosal B cell homeostasis. J. Immunol. 2003;170(5):2531–9. DOI: 10.4049/jimmunol.170.5.2531

13. Strugnell R.A. When secretion turns into excretion — the different roles of IgA. Front. Immunol. 2022;13:1076312. DOI: 10.3389/fimmu.2022.1076312

14. Kobatake E., Iwama Y., Arai T., Shioya N. et al. Intake of Lactobacillus paragasseri SBT2055 improves subjective symptoms of common cold during winter season in healthy adults: a randomized, double-blind, placebo-controlled parallel-group comparative study. Front. Nutr. 2022;9:1063584. DOI: 10.3389/fnut.2022.1063584

15. Takeuchi T., Ohno H. IgA in human health and diseases: potential regulator of commensal microbiota. Front. Immunol. 2022;13:1024330. DOI: 10.3389/fimmu.2022.1024330

16. Snoeck V., Peters I.R., Cox E. The IgA system: a comparison of structure and function in different species. Vet. Res. 2006;37(3):455–67. DOI: 10.1051/vetres:2006010

17. Armitage C.W., O’Meara C.P., Harvie M.C., Timms P. et al. Evaluation of intra- and extra-epithelial secretory IgA in chlamydial infections. Immunology. 2014;143(4):520–30. DOI: 10.1111/imm.12317

18. Kugler J., Hess M., Haake D. Secretion of salivary immunoglobulin A in relation to age, saliva flow, mood states, secretion of albumin, cortisol, and catecholamines in saliva. J. Clin. Immunol. 1992;12(1):45–9. DOI: 10.1007/BF00918272

19. Brandtzaeg P. Secretory immunity with special reference to the oral cavity. J. Oral Microbiol. 2013;5. DOI: 10.3402/jom.v5i0.20401

20. Isaacs D., Webster A.D., Valman H.B. Immunoglobulin levels and function in pre-school children with recurrent respiratory infections. Clin. Exp. Immunol. 1984;58(2):335–40.

21. Malakhov A.B., Kolosova N.G., Grebeneva I.V. Cough in children: pediatrician tactics in relation to diagnosis and treatment. Practical Pulmonology. 2021;3:46–52. (in Russian). DOI: 10.24412/2409-6636-2021-12420

22. Mizernitsky Yu.L., Sulaimanov Sh.A., Muratova Zh.K. New approaches to the choice of mucolytic therapy in children with acute and chronic bronchopulmonary diseases. Vestnik KasNMU. 2020;1:779–82. (in Russian)

23. Ermakova I.N., Mizernitskiy Yu.L. Carbocisteine efficacy in the management of flu and other complicated acute respiratory viral infections in children under 6 years of age. Russian Bulletin of Perinatology and Pediatrics. 2020;65(4):299–300. (in Russian). DOI: 10.21508/1027-4065-congress-2018

24. Ikeuchi Y., Kogiso H., Hosogi S., Tanaka S. et al. Carbocisteine stimulated an increase in ciliary bend angle via a decrease in [Cl-] I in mouse airway cilia. Pflugers Arch. 2019;471(2):365–80. DOI: 10.1007/s00424-018-2212-2

25. Inui T.A., Yasuda M., Hirano S., Ikeuchi Y. et al. Enhancement of ciliary beat amplitude by carbocisteine in ciliated human nasal epithelial cells. Laryngoscope. 2020;130(5):E289–97. DOI: 10.1002/lary.28185

26. Pace E., Cerveri I., Lacedonia D., Paone G. et al. Clinical efficacy of carbocysteine in COPD: beyond the mucolytic action. Pharmaceutics. 2022;14(6):1261. DOI: 10.3390/pharmaceutics14061261

27. Mizernitskiy Yu.L., Melnikova I.M. Carbocisteine in outpatient paediatric practice. Lechashi vrach. 2018;9:42–5. (in Russian)

28. Carlevato M.T., Battaglio S., Galeazzi E., Bussi M. Local immunity following treatment with S-carboxymethylcysteine-lysine in tracheotomy patients. Acta Otorhinolaryngol. Ital. 1992;12(2):127–34.

29. Balyasinskaya G.L., Timakov E.Yu. Experience with fluditec used in the treatment of acute obstructive bronchitis in infants. Russian Bulletin of Perinatology and Pediatrics. 2010;55(4):45–9. (in Russian)

30. Scaglione F., Petrini O. Mucoactive agents in the therapy of upper respiratory airways infections: fair to describe them just as mucoactive? Clin. Med. Insights Ear Nose Throat. 2019; 12:1179550618821930. DOI: 10.1177/1179550618821930

31. Chalumeau M., Duijvestijn Y.C.M. Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease. Cochrane Database Syst. Rev. 2013;5:CD003124. DOI: 10.1002/14651858. CD003124.pub4

32. Mallet P., Mourdi N., Dubus J.C., Bavoux F. et al. Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey. PLoS One. 2011;6(7):e22792. DOI: 10.1371/journal.pone.0022792

33. Dilek F., Ozkaya E., Gultepe B., Yazici M. et al. Nasal fluid secretory immunoglobulin A levels in children with allerg44ic rhinitis. Int. J. Pediatr. Otorhinolaryngol. 2016;83:41–6. DOI: 10.1016/j.ijporl.2016.01.018

34. Salvaggio J., Lopez M., Arquembourg P., Waldman R. et al. Salivary, nasal wash, and sputum IgA concentrations in atopic and nonatopic individuals. J. Allergy Clin. Immunol. 1973;51(6):335–43. DOI: 10.1016/0091-6749(73)90072-9

35. Ring B., Hein J., Seyfarth M. Bestimmungen des sekretorischen Immunoglobulin A im Speichel von Kindern mit rezidivierenden und chronischen Atemwegserkrankungen während eines Klimakuraufenthaltes [Determination of secretory immunoglobulin A in the saliva of children with recurrent and chronic respiratory tract diseases during a stay at a health resort]. Kinderarztl Prax. 1991;59(7–8):225–30.

36. Brandtzaeg P. Do salivary antibodies reliably reflect both mucosal and systemic immunity? Ann. N. Y. Acad. Sci. 2007;1098:288–311. DOI: 10.1196/annals.1384.012

37. Wu Z., Gong Y., Wang C., Lin J. et al. Association between salivary s-IgA concentration and dental caries: an updated meta-analysis. Biosci. Rep. 2020;4(12):BSR20203208. DOI: 10.1042/BSR20203208

38. Sonesson M., Hamberg K., Wallengren M.L., Matsson L. et al. Salivary IgA in minor-gland saliva of children, adolescents, and young adults. Eur. J. Oral Sci. 2011;119(1):15–20. DOI: 10.1111/j.1600-0722.2010.00794.x

39. Manzke H., Groh S., Glienicke C. Sekretorisches Immunglobulin A im Speichel von gesunden Kindern und Kindern mit Atemwegserkrankungen [Secretory immunoglobulin A in saliva of healthy children and children with airway diseases]. Klin. Padiatr. 1991;203(3):149–54. DOI: 10.1055/s-2007-1025420

40. Jafarzadeh A., Sadeghi M., Karam G.A., Vazirinejad R. Salivary IgA and IgE levels in healthy subjects: relation to age and gender. Braz. Oral Res. 2010;24(1):21–7. DOI: 10.1590/s1806-83242010000100004

41. Khan S.F., Katti G., Baba I., Khan N. Age-related changes of salivary IgA among healthy subjects. J. Indian Acad. Oral Med. Radiol. 2015;27(2):203–6. DOI: 10.4103/0972-1363.170138

42. Gleeson M., Cripps A.W., Clancy R.L. Modifiers of the human mucosal immune system. Immunol. Cell Biol. 1995;73(5):397–404. DOI: 10.1038/icb.1995.62

43. Booth C.K., Dwyer D.B., Pacque P.F., Ball M.J. Measurement of immunoglobulin A in saliva by particle-enhanced nephelometric immunoassay: sample collection, limits of quantitation, precision, stability and reference range. Ann. Clin. Biochem. 2009;46(5):401– 6. DOI: 10.1258/acb.2009.008248

44. de Farias D.G., Bezerra A.C. Salivary antibodies, amylase and protein from children with early childhood caries. Clin. Oral Investig. 2003;7:154–7. DOI: 10.1007/s00784-003-0222-7

45. Chawda J.G., Chaduvula N., Patel H.R., Jain S.S. et al. Salivary sIgA and dental caries activity. Indian Pediatr. 2011;48:719–21. DOI: 10.1007/s13312-011-0113-y

46. Pandey S., Goel M., Nagpal R., Kar A. et al. Evaluation of total salivary secretory immunoglobulin A and Mi/fans-specific sIgA among children having dissimilar caries status. J. Contemp. Dent. Pract. 2018;19(6):651–5.

47. Doifode D., Damle S. Comparison of salivary IgA levels in caries free and caries active children. Int. J. Clin. Dent. Sci. 2011;2:10–14.

48. Jagadesh Babu B., Venugopal Reddy N., Thimma Reddy B.V., Daneswari V. et al. Comparative evaluation of salivary IgA levels and dental caries in obese and non-obese children. Int. J. Adv. Res. 2017;5:766–72.

49. Lo Giudice G., Nicita F., Militi A., Bertino R. et al. Correlation of s-IgA and IL-6 salivary with caries disease and oral `hygiene parameters in children. Dent. J. (Basel). 2020;8(1):3. DOI: 10.3390/dj8010003

50. Makary C.A., Purnell P.R., O’Brien D., Chaiban R. et al. Antibody deficiencies are more common in adult versus pediatric recurrent acute rhinosinusitis. Am. J. Otolaryngol. 2021;42(5):103004. DOI: 10.1016/j.amjoto.2021.103004

51. Moreira A., Mortatti A.L., Arruda A.F., Freitas C.G. et al. Salivary IgA response and upper respiratory tract infection symptoms during a 21-week competitive season in young soccer players. J. Strength Cond. Res. 2014;28(2):467–73. DOI: 10.1519/JSC.0b013e31829b5512

52. Antualpa K., Aoki M.S., Moreira A. Intensified training period increases salivary IgA responses but does not affect the severity of upper respiratory tract infection symptoms in prepuberal rhythmic gymnasts. Pediatr. Exerc. Sci. 2018;30(2):189–97. DOI: 10.1123/pes.2017-0079

53. Yodfat Y., Silvian I. A prospective study of acute respiratory tract infections among children in a kibbutz: the role of secretory IgA and serum immunoglobulins. J. Infect. Dis. 1977;136(1):26–30. DOI: 10.1093/infdis/136.1.26

54. Lepore L., Longo F., Mascarin M., Toscano C. Salivary IgA in a group of children with recurrent respiratory infections. Minerva Pediatr. 1989;41(4):205–8.

55. Wiersbitzky S., Pester R. Die Kinetik der humoralen und sekretorischen IgA-Produktion im Beginn eines akuten respiratorischen Infektes (A.R.E.) im Säuglings- und Kleinkindesalter [The kinetics of the humoral and secretory IgA-production at the beginning of an acute respiratory disease (A.R.D.) in infants (author’s transl)]. Allerg. Immunol. (Leipz). 1977;23(4):268–72.

56. Del Castillo Aguas G., García Hernández G., Villa Asensi J.R., Ferriz J. et al. Secretory IgA and infantile respiratory pathology. An. Esp. Pediatr. 1988;29(6):428–30.

57. Hofstötter H., Riedler J., Huber E.G. Immunoglobulin A in saliva of children: age dependence and effect of respiratory tract diseases. Wien Klin. Wochenschr. 1996;108(20):640–2.

58. Henocq A., Moreau C., Mallet E., Sauger F. et al. Changes in IgA levels in nasal mucus after upper respiratory tract diseases in infants treated with carbocysteine. Ann. Otolaryngol. Chir. Cervicofac. 1985;102(5):373–5.