Efficacy and safety of high doses of inhaled nitric oxide in patients with community-acquired pneumonia: a pilot study

For the first time, the effectiveness and safety of high doses of inhaled nitric oxide (iNO) in patients with community-acquired pneumonia (CAP) has been demonstrated.
The aim of the study was to examine the effectiveness and safety of adding iNO to standard treatment for patients with CAP.
Methods. A pilot, single-center, prospective, randomized, open-label clinical trial was conducted, which included patients (n = 120) hospitalized with CAP. Randomization was carried out using the blind envelope method. Patients in the main group (n = 60) received iNO through nasal cannulas using the Tianox iNO therapy device (AIT-NO-Ol according to TU 32.50. 21-001-07623615-2017) in addition to the therapy according to the standard of care at the study center. Inhalations were carried out with high doses of NO, namely 200 ppm for 15 minutes 3 times a day, regardless of food intake. Patients in the control group (n = 60) received only the therapy recommended by the standard of care at the study center. Clinical and laboratory parameters were assessed and safety of the therapy was monitored during the study.
Results. No significant differences were identified between the main group and the control group in demographic, clinical, laboratory and instrumental data at baseline. Patients receiving iNO as an adjunct to standard therapy had a more significant improvement in clinical symptoms starting from the 3rd day and better oxygenation parameters on the 7th day of therapy. There was a more significant decrease in the level of C-reactive protein on the 5th and 7th days of therapy and a more significant decrease in the level of leukocytes on the 5th day in the main group. The duration of hospitalization in the main group was significantly shorter than that in the control group. NO inhalation was not associated with any side effects and was well tolerated.
Conclusion. The use of high doses of NO has a positive effect on the clinical status, markers of inflammation, reduces the length of hospitalization, and demonstrates good tolerability and safety in patients with CAP.

1. Mónica F.Z., Bian K., Murad F. The endothelium-dependent nitric oxide-cGMP pathway. Adv. Pharmacol. 2016; 77: 1–27. DOI: 10.1016/bs.apha.2016.05.001.

2. Fujikura Y., Kudlackova P., Vokurka M. et al. The effect of nitric oxide on vaccinia virus-encoded ribonucleotide reductase. Nitric Oxide. 2009; 20 (2): 114–121. DOI: 10.1016 /j.niox.2008.09.002.

3. Granger D.L., Lehninger A.L. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J. Cell Biol. 1982; 95 (2, Pt 1): 527–535. DOI: 10.1083 /jcb.95.2.527.

4. Howlin R.P., Cathie K., Hall-Stoodley L. et al. Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis. Mol. Ther. 2017; 25 (9): 2104–2116. DOI: 10.1016 /j.ymthe.2017.06.021.

5. Barraud N., Schleheck D., Klebensberger J. et al. Nitric oxide signaling in Pseudomonas aeruginosa biofilms mediates phosphodiesterase activity, decreased cyclic di-GMP levels, and enhanced dispersal. J. Bacteriol. 2009; 191 (23): 7333–7342. DOI: 10.1128 /JB.00975-09.

6. Keller T.T., Mairuhu A.T., de Kruif M.D. et al. Infections and endothelial cells. Cardiovasc. Res. 2003; 60 (1): 40–48. DOI: 10.1016/s0008-6363(03)00354-7.

7. Varga Z., Flammer A.J., Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020; 395 (10234): 1417–1418. DOI: 10.1016/S0140-6736(20)30937-5.

8. Ahmed S., Zimba O., Gasparyan A.Y. Thrombosis in coronavirus disease 2019 (COVID-19) through the prism of Virchow’s triad. Clin. Rheumatol. 2020; 39 (9): 2529–2543. DOI: 10.1007/s10067-020-05275-1.

9. Goldbart A., Lavie M., Lubetzky R. et al. Inhaled nitric oxide for the treatment of acute bronchiolitis: a multicenter randomized controlled clinical trial to evaluate dose response. Ann. Am. Thorac. Soc. 2023; 20 (2): 236–244. DOI: 10.1513/AnnalsATS.202103-348OC.

10. Kono Y., Shibata H., Adachi K., Tanaka K. Lactate-dependent killing of Escherichia coli by nitrite plus hydrogen peroxide: a possible role of nitrogen dioxide. Arch. Biochem. Biophys. 1994; 311 (1): 153–159. DOI: 10.1006/abbi.1994.1220.

11. De Groote M.A., Granger D., Xu Y. et al. Genetic and redox determinants of nitric oxide cytotoxicity in a Salmonella typhimurium model. Proc. Natl. Acad Sci. USA. 1995; 92 (14): 6399–6403. DOI: 10.1073/pnas.92.14.6399.

12. Pimentel M.A.F., Redfern O.C., Gerry S. et al. A comparison of the ability of the National Early Warning Score and the National Early Warning Score 2 to identify patients at risk of in-hospital mortality: a multi-centre database study. Resuscitation. 2019; 134: 147–156. DOI: 10.1016/j.resuscitation.2018.09.026.

13. Schmidt H.H., Pollock J.S., Nakane M. et al. Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase. Proc. Natl. Acad. Sci. USA. 1991; 88 (2): 365–369. DOI: 10.1073/pnas.88.2.365.

14. Bath P.M., Coleman C.M., Gordon A.L. et al. Nitric oxide for the prevention and treatment of viral, bacterial, protozoal and fungal infections. F1000Res. 2021; 10: 536. DOI: 10.12688/f1000research.51270.2.

15. Kono Y., Shibata H., Adachi K., Tanaka K. Lactate-dependent killing of Escherichia coli by nitrite plus hydrogen peroxide: a possible role of nitrogen dioxide. Arch. Biochem. Biophys. 1994; 311 (1): 153–159. DOI: 10.1006/abbi.1994.1220.

16. Wink D.A., Kasprzak K.S., Maragos C.M. et al. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991; 254 (5034): 1001–1003. DOI: 10.1126/science.1948068.

17. Fujikura Y., Kudlackova P., Vokurka M. et al. The effect of nitric oxide on vaccinia virus-encoded ribonucleotide reductase. Nitric Oxide. 2009; 20 (2): 114–121. DOI: 10.1016 /j.niox.2008.09.002.

18. Granger D.L., Lehninger A.L. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J. Cell Biol. 1982; 95 (2, Pt 1): 527–535. DOI: 10.1083 /jcb.95.2.527.

19. Saura M., Zaragoza C., McMillan A. et al. An antiviral mechanism of nitric oxide: inhibition of a viral protease. Immunity. 1999; 10 (1): 21–28. DOI: 10.1016/s1074-7613(00)80003-5.

20. Mokry R.L., Schumacher M.L., Hogg N., Terhune S.S. Nitric oxide circumvents virus-mediated metabolic regulation during human cytomegalovirus infection. mBio. 2020; 11 (6): e02630-20. DOI: 10.1128/mBio.02630-20.

21. O’Leary V., Solberg M. Effect of sodium nitrite inhibition on intracellular thiol groups and on the activity of certain glycolytic enzymes in Clostridium perfringens. Appl. Environ. Microbiol. 1976; 31 (2): 208–212. DOI: 10.1128/aem.31.2.208-212.1976.

22. Frawley E.R., Karlinsey J.E., Singhal A. et al. Nitric oxide disrupts zinc homeostasis in Salmonella enterica serovar typhimurium. mBio. 2018; 9 (4): e01040–18. DOI: 10.1128/mBio.01040-18.

23. Keyaerts E., Vijgen L., Chen L. et al. Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound. Int. J. Infect Dis. 2004; 8 (4): 223–226. DOI: 10.1016/j.ijid.2004.04.012.

24. Miller C.C., Hergott C.A., Rohan M. et al. Inhaled nitric oxide decreases the bacterial load in a rat model of Pseudomonas aeruginosa pneumonia. J. Cyst. Fibros. 2013; 12 (6): 817–820. DOI: 10.1016/j.jcf.2013.01.008.

25. Bartley B.L., Gardner K.J., Spina S. et al. High-dose inhaled nitric oxide as adjunct therapy in cystic fibrosis targeting Burkholderia multivorans. Case Rep. Pediatr. 2020; 2020: 1536714. DOI: 10.1155/2020/1536714.

26. Howlin R.P., Cathie K., Hall-Stoodley L. et al. Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis. Mol. Ther. 2017; 25 (9): 2104–2116. DOI: 10.1016/j.ymthe.2017.06.021.

27. Deppisch C., Herrmann G., Graepler-Mainka U. et al. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection. 2016; 44 (4): 513–520. DOI: 10.1007/s15010-016-0879-x.

28. Bentur L., Gur M., Ashkenazi M. et al. Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection. J. Cyst. Fibros. 2020; 19 (2): 225–231. DOI: 10.1016/j.jcf.2019.05.002.

29. Efficacy and safety of Inhaled nitric oxide (NO) in cystic fibrosis (CF) patientshttps. ClinicalTrials.gov. 2021; NCT02498535. Available at: https://clinicaltrials.gov/study/NCT02498535