The role of exogenous surfactant in the treatment of respiratory viral infections

Pulmonary surfactant is a complex substance with high surface activity that prevents alveoli collapse at the end of expiration and, therefore, stabilizes the lung volume and the gas exchange. These properties of surfactant opened the way for its investigation in the respiratory distress syndrome of newborn and the acute respiratory distress syndrome (ARDS) in adults including patients with severe virus-associated and bacterial pneumonias. This paper is a review of published laboratory data and clinical findings on the efficacy of surfactant in adults. Several authors demonstrated that exogenous surfactant could improve mortality in patients with ARDS, reduce the need in mechanical ventilation and a length of hospitalization in general. Most clinical trials of surfactant were related to the novel coronavirus infection COVID-19, but several papers included patient with severe pneumonia associated with influenza or respiratory syncytial virus. Moreover, surfactant could be useful for better delivery of pharmacological agents, including antibiotics, in the distal airways and the lung tissue in patients with bacterial pneumonia. Unfortunately, current findings are scarce to certainly detecting a role of exogenous surfactant in the management of such patients. Further studies of clinical efficacy of exogenous surfactant in severe lung injury are required.

1. Frerking I, Günther A, Seeger W, Pison U. Pulmonary surfactant: functions, abnormalities and therapeutic options. Intensive Care Med. 2001;27(11):1699–1717. https://doi.org/10.1007/s00134-001-1121-5.

2. Ji J, Sun L, Luo Z, Zhang Y, Xianzheng W, Liao Y et al. Potential Therapeutic Applications of Pulmonary Surfactant Lipids in the Host Defence Against Respiratory Viral Infections. Front Immunol. 2021;12:730022. https://doi.org/10.3389/fimmu.2021.730022.

3. Woods PS, Doolittle LM, Rosas LE, Joseph LM, Calomeni EP, Davis IC. Lethal H1N1 Influenza A Virus Infection Alters the Murine Alveolar Type II Cell Surfactant Lipidome. Am J Physiol Lung Cell Mol Physiol. 2016;311(6):L1160–L9. https://doi.org/10.1152/ajplung.00339.2016.

4. Han S, Mallampalli RK. The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections. Ann Am Thorac Soc. 2015;12(5):765–774. https://doi.org/10.1513/AnnalsATS.201411-507FR.

5. Gorman EA, O’Kane CM, McAuley DF. Acute respiratory distress syndrome in adults: diagnosis, outcomes, long-term sequelae, and management. Lancet. 2022;400(10358):1157–1170. https://doi.org/10.1016/S0140-6736(22)01439-8.

6. Meng H, Sun Y, Lu J, Fu S, Meng Z, Scott M, Li Q. Exogenous surfactant may improve oxygenation but not mortality in adult patients with acute lung injury/acute respiratory distress syndrome: a meta-analysis of 9 clinical trials. J Cardiothorac Vasc Anesth. 2012;26(5):849–856. https://doi.org/10.1053/j.jvca.2011.11.006.

7. Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents for adults with acute respiratory distress syndrome. Cochrane Database Syst Rev. 2019;7(7):CD004477. https://doi.org/10.1002/14651858.CD004477.pub3.

8. Birkun AA, Kubyshkin AV, Novikov NY, Krivorutchenko YL, Fedosov MI, Postnikova ON, Snitser AA. Joint Intratracheal Surfactant-Antibacterial Therapy in Experimental Pseudomonas-Induced Pneumonia. J Aerosol Med Pulm Drug Deliv. 2015;28(4):299–307. https://doi.org/10.1089/jamp.2014.1161.

9. van’t Veen A, Mouton JW, Gommers D, Lachmann B. Pulmonary surfactant as vehicle for intratracheally instilled tobramycin in mice infected with Klebsiella pneumoniae. Br J Pharmacol. 1996;119(6):1145–1148. https://doi.org/10.1111/j.1476-5381.1996.tb16016.x.

10. Stichtenoth G, Linderholm B, Björkman MH, Walter G, Curstedt T. Herting E. Prophylactic intratracheal polymyxin B/surfactant prevents bacterial growth in neonatal Escherichia coli pneumonia of rabbits. Pediatr Res. 2010;67(4):369–374. https://doi.org/10.1203/PDR.0b013e3181d026f6.

11. Numata M, Voelker DR. Anti-inflammatory and anti-viral actions of anionic pulmonary surfactant phospholipids. Biochim Biophys Acta Mol Cell Biol Lipids. 2022;1867(6):159139. https://doi.org/10.1016/j.bbalip.2022.159139.

12. Numata M, Nagashima Y, Moore ML, Berry KZ, Chan M, Kandasamy P et al. Phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection. J Lipid Res. 2013;54(8):2133–2143. https://doi.org/10.1194/jlr.M037077.

13. Hsieh IN, De Luna X, White MR, Hartshorn KL. The Role and Molecular Mechanism of Action of Surfactant Protein D in Innate Host Defense Against Influenza A Virus. Front Immunol. 2018;9:1368. https://doi.org/10.3389/fimmu.2018.01368.

14. Numata M, Mitchell JR, Tipper JL, Brand JD, Trombley JE, Nagashima Y et al. Pulmonary surfactant lipids inhibit infections with the pandemic H1N1 influenza virus in several animal models. J Biol Chem. 2020;295(6):1704–1715. https://doi.org/10.1074/jbc.RA119.012053.

15. Hillaire ML, Haagsman HP, Osterhaus AD, Rimmelzwaan GF, van Eijk M. Pulmonary surfactant protein D in first-line innate defence against influenza A virus infections. J Innate Immun. 2013;5(3):197–208. https://doi.org/10.1159/000346374.

16. Nishino M, Mizuno D, Kimoto T, Shinahara W, Fukuta A, Takei T et al. Influenza vaccine with Surfacten, a modified pulmonary surfactant, induces systemic and mucosal immune responses without side effects in minipigs. Vaccine. 2009;27(41):5620–5627. https://doi.org/10.1016/j.vaccine.2009.07.024.

17. Donovan BW, Reuter JD, Cao Z, Myc A, Johnson KJ, Baker JR Jr. Prevention of murine influenza A virus pneumonitis by surfactant nano-emulsions. Antivir Chem Chemother. 2000;11(1):41–49. https://doi.org/10.1177/095632020001100104.

18. Busani S, Girardis M, Biagioni E, Pasetto A, Sambri V. Surfactant therapy and intravenous zanamivir in severe respiratory failure due to persistent influenza A/H1N1 2009 virus infection. Am J Respir Crit Care Med. 2010;182(10):1334. https://doi.org/10.1164/ajrccm.182.10.1334.

19. Piva S, DiBlasi RM, Slee AE, Jobe AH, Roccaro AM, Filippini M et al. Surfactant therapy for COVID-19 related ARDS: a retrospective casecontrol pilot study. Respir Res. 2021;22(1):20. https://doi.org/10.1186/s12931-020-01603-w.

20. Avdeev SN, Trushenko NV, Chikina SY, Tsareva NA, Merzhoeva ZM, Yaroshetskiy AI et al. Beneficial effects of inhaled surfactant in patients with COVID-19-associated acute respiratory distress syndrome. Respir Med. 2021;185:106489. https://doi.org/10.1016/j.rmed.2021.106489.

21. Mylavarapu M, Dondapati VVK, Dadana S, Sharma DD, Bollu B. Effect of Surfactant Therapy on Clinical Outcomes of COVID-19 Patients With ARDS: A Systematic Review and Meta-Analysis. Cureus. 2024;16(3):e56238. https://doi.org/10.7759/cureus.56238.