Results of an open observational multicenter study of the effectiveness and tolerability of levodropropizine in comparison with standard antitussive therapy (real practice) in the treatment of patients with COVID-19

Cough is one of the most common symptoms of COVID-19 (COronaVIrus Disease-2019), occurring in more than 70% of cases. The cough associated with the new coronavirus infection tends to be non-productive and requires symptomatic antitussive therapy. However, at present, there is insufficient data on the effectiveness of various antitussive agents in COVID-19.

The aim. Analysis of the clinical and economic efficiency and safety of the use of levodropropizin in comparison with standard symptomatic therapy of patients with a new coronavirus infection COVID-19 in the real-life clinical setting.

Methods. An open observational multicenter study was conducted in Moscow, Krasnodar, Kazan, Voronezh, and Rostov-on-Don. The study enrolled 250 inpatient COVID 19 patients (1 875 years) with complaints of dry unproductive cough which required symptomatic treatment. The main group included 150 people who received levodropropizine according to the label. The comparison group received other antitussive drugs. Each patient was examined on days 1, 4 and 8. The examination included collection of the current complaints and medical history, physical examination and assessment of the intensity of cough using day and night cough assessment scale using a 6-point scale for assessing daytime and nighttime cough and a visual analog scale (VAS).

Results. In the main group, significant differences were revealed between the baseline and Day 4 in the form of a significant decrease in the severity of daytime cough (р = 0.002); significant differences were found between Day 4 and Day 8 for both daytime (р = 0.002) and nocturnal cough (р = 0.0001). The comparison group showed positive dynamics, but significant differences were seen only between the baseline and Day 8 at night (р = 0.001). The severity of cough on VAS scale in the main group differed significantly on Day 8 as compared to baseline (р = 0.001), as well as between Day 4 and Day 8 (р = 0.002). No significant differences were seen in the comparison group. No adverse effects were observed during treatment with levodropropizine.

Conclusion. Levodropropizine has shown high efficacy and safety in the treatment of dry unproductive cough in comparison with standard symptomatic therapy in the form of a significant decrease in cough intensity according to both scales, starting from the 4^th day.

1. Morice А.H., Millqvist Е., Bieksiene K. et al. [European Respiratory Society guidelines on the diagnosis and treatment of chronic cough in adults and children]. Pul’monologiya. 2021; 31 (4): 418–438. DOI: 10.18093/0869-0189-2021-31-4-418-438 (in Russian).

2. Zaytsev A.A., Okovityy S.V., Miroshnichenko N.A., Kryukov E.V. [Cough: guidelines]. Moscow: Burdenko General Clinical Hospital; 2021. Available at: https://cough-conf.ru/wp-content/uploads/kashel-2021.pdf?ysclid=l5kkhz6irs73862917 (in Russian).

3. Ortiz-Prado E., Simbaña-Rivera K., Gómez-Barreno L. et al. Clinical, molecular, and epidemiological characterization of the SARS-CoV-2 virus and the Coronavirus disease 2019 (COVID-19), a comprehensive literature review. Diagn. Microbiol. Infect. Dis. 2020; 98 (1): 115094. DOI: 10.1016/j.diagmicrobio.2020.115094.

4. Okovityy S.V., Sukhanov D.S., Zaytsev A.A. [Cough associated with the new coronavirus infection (COVID-19): rational approaches to pharmacotherapy]. Pul’monologiya. 2022; 32 (2): 232–238. DOI: 10.18093/0869-0189-2022-32-2-232-238 (in Russian).

5. Okovityy S.V., Sukhanov D.S., Zaytsev A.A. et al. [Efficacy of methylprednisolone pulse therapy in patients with COVID-19]. Klinicheskaya mikrobiologiya i antimikrobnaya terapiya. 2020; 22 (2): 88–91. DOI: 10.36488/cmac.2020.2.8891 (in Russian).

6. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. BMJ. 2020; 369: m1461. DOI: 10.1136/bmj.m1461.

7. Lovato A., de Filippis C. Clinical resentation of COVID-19: a systematic review focusing on upper airway symptoms. Ear Nose Throat J. 2020; 99 (9): 569–575. DOI: 10.1177/0145561320920762.

8. Goërtz Y.M.J., Van Herck M., Delbressine J.M. et al. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome? ERJ Open Res. 2020; 26; 6 (4): 00542–2020. DOI: 10.1183/23120541.00542-2020.

9. Zaccone E.J., Lieu T., Muroi Y. et al. Parainfluenza 3-induced cough hypersensitivity in the guinea pig airways. PLoS One. 2016; 11 (5): e0155526. DOI: 10.1371/journal.pone.0155526.

10. Deng Z., Zhou W., Sun J. et al IFN-γ enhances the cough reflex sensitivity via calcium influx in vagal sensory neurons. Am. J. Respir. Crit. Care Med. 2018; 198 (7): 868–879. DOI: 10.1164/rccm.201709-1813OC.

11. Patil M.J., Ru F., Sun H. et al. Acute activation of bronchopulmonary vagal nociceptors by type I interferons. J. Physiol. 2020; 598 (23): 5541–5554. DOI: 10.1113/JP280276.

12. West P.W., Canning B.J., Merlo-Pich E. et al. Morphologic characterization of nerves in whole-mount airway biopsies. Am. J. Respir. Crit. Care Med. 2015; 192 (1): 30–39. DOI: 10.1164/rccm.201412-2293OC.

13. Zaytsev A.A. [Cough: problems and solutions]. Prakticheskaya pul’monologiya. 2020; (2): 78–86. Available at: http://www.atmosphere-ph.ru/modules/Magazines/articles//pulmo/pp_2_2020_78.pdf (in Russian).

14. Nalbandian A., Sehgal K., Gupta A. et al. Post-acute COVID-19 syndrome. Nat. Med. 2021; 27 (4): 601–615 DOI: 10.1038/s41591-021-01283-z.

15. Funke-Chambour M., Bridevaux P.O., Clarenbach C.F. Swiss recommendation for the follow-up and treatment of pulmonary long COVID guidelines. Respiration. 2021; 100 (8): 826–841. DOI: 10.1159/000517255.

16. Savushkina O.I., Chernyak A.V., Kryukov E.V. et al. [Follow-up pulmonary function of COVID-19 patients 4 months after hospital discharge]. Pul’monologiya. 2021; 31 (5): 580–586. DOI: 10.18093/0869-0189-2021-31-5-580-587 (in Russian).

17. Zanasi A., Lanata L., Fontana G. et al. Levodropropizine for treating cough in adult and children: a meta-analysis of published studies. Multidiscip. Respir. Med. 2015; 10 (1): 19. DOI: 10.1186/s40248-015-0014-3.

18. Marseglia G.L., Manti S., Chiappini E. et al. Acute cough in children and adolescents: A systematic review and a practical algorithm by the Italian Society of Pediatric Allergy and Immunology. Allergol. Immunopathol. (Madr.). 2021; 49 (2): 155–169. DOI: 10.15586/aei.v49i2.45.

19. Gunella G., Zanasi A., Massimo Vanasia C.B. [Efficacy and safety of the use of levodropropizine in patients with chronic interstitial lungdiseases]. Clin. Ter. 1991; 136 (4): 261–266. Available at: https://pubmed.ncbi.nlm.nih.gov/1827388 (in Italian).

20. Birring S., de Blasio F., Dicpinigaitis P.V. et al. Antitussive therapy: A role for levodropropizine. Pulm. Pharmacol. Ther. 2019; 56: 79–85. DOI: 10.1016/j.pupt.2019.03.003.

21. Catena E., Daffonchio L. Efficacy and tolerability of levodropropizine in adult patients with non-productive cough. Comparison with dextromethorphan. Pulm. Pharmacol. Ther. 1997; 10 (2): 89–96. DOI: 10.1006/pupt.1997.0083.

22. Luo Y.L., Li P.B., Zhang C.C. et al. Effects of four antitussives on airway neurogenic inflammation in a guinea pig model of chronic cough induced by cigarette smoke exposure. Inflamm. Res. 2013; 62 (12): 1053–1061. DOI: 10.1007/s00011-013-0664-6.

23. Zanasi A., Lanata, Saibene F. et al. Prospective study of the efficacy of antibiotics versus antitussive drugs for the management of URTI-re-lated acute cough in children. Multidiscip. Respir. Med. 2016; 11: 29. DOI: 10.1186/s40248-016-0059-y.

24. Schildmann E.K., Rémi C., Bausewein C. Levodropropizine in the management of cough associated with cancer or nonmalignant chronic disease – a systematic review. J. Pain Palliat. Care Pharmacother. 2011; 25 (3): 209–218. DOI: 10.3109/15360288.2011.583979.

25. De Blasio F., Virchow J.C., Polverino M. et al. Cough management: a practical approach. Cough. 2012; 7 (1): 7. DOI: 10.1186/1745-9974-7-7.

26. Zanasi L., de Blasio S. Observational study on effectiveness of the combination of antitussives and NASAIDs in patients with URTI related cough. Eur. Respir. J. 2015; 46 (Suppl. 59): PA3852. DOI: 10.1183/13993003.congress-2015.PA3852.

27. Mannini C., Lavorini F., Zanasi A. et al. Randomized clinical trial comparing the effects of antitussive agents on respiratory center output in patients with chronic cough. Chest. 2017; 151 (6): 1288–1294. DOI: 10.1016/j.chest.2017.02.001.

28. Ciprandi G., Licari A., Tosca M.A., Marseglia G.L. Levodropropizine in children: over thirty years of clinical experience. J. Biol. Regul. Homeost. Agents. 2021; 35 (4): 1377–1388. DOI: 10.23812/21-176-L.

29. Budnevskiy A.V., Ovsyannikov E.S., Feygel’man S.N. [Study of the efficacy of levopront in the treatment of non-productive cough]. Prakticheskaya pul’monologiya. 2021; (2): 65–74. DOI: 10.24412/2409-6636-2021-12693 (in Russian).