Tear lactoferrin concentration in patients with recurrent herpetic stromal keratitis and therapeutic effect of Lacto eyedrops in the multicomponent treatment for this disorder

Authors

  • G.I. Drozhzhyna SI "The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine"
  • N.I Khramenko SI "The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine"
  • K.V. Sereda SI "The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine"
  • L.Iu. Riazanova SI "The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine"
  • L.M. Velychko SI "The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine"

DOI:

https://doi.org/10.31288/oftalmolzh202362027

Keywords:

herpetic keratitis, tear production, corneal sensation, lactoferrin, ELISA, conjunctival bacterial and fungal flora

Abstract

Background: Herpetic stromal keratitis (HSK) is an immunomodulatory disease that develops as a result of herpes simplex virus (HSV)1 or HSV2 reactivation. HSK is the most common form (20-50%) of recurrent herpetic keratitis (HK) that most commonly results in significantly reduced vision. It is well known that changes in biological compound levels in tear fluid can be indicative of the state of the ocular surface and determine whether ocular surface pathology is present, and, therefore, can be used as diagnostic markers of pathological changes in the ocular surface. Lactoferrin (LF) is one of these compounds and has been proven to have innate antibacterial, antifungal, antiviral, antiparasite, anti-inflammatory, immunomodulatory, antioxidative and other properties.
Purpose: To determine tear Lf concentration in patients with recurrent acute HSK, its effect on functional characteristics of the ocular surface, and the therapeutic effect of Lacto eyedrops in the comprehensive treatment for this disorder.
Material and Methods: The study was conducted at the site of Corneal Pathology Department and Immunology Laboratory of the Institute in January to December 2021. Seventeen patients (17 affected eyes and 17 fellow eyes) with recurrent acute HSK were included in the study. Mean patient age plus or minus standard deviation (SD) was 48.7 ± 16.0 years. The ophthalmological examination included biomicroscopy of the bulbar conjunctiva and cornea, fluorescein test, determination of corneal sensation and basal tear production (Schirmer’s II test), and microbiological examination of the conjunctiva. Tear Lf concentration was determined by a human Lf enzyme-linked immunosorbent assay (ELISA) kit (Elabscience Biotechnology, Inc., Wuhan, China). The results were photometrically measured at 450 nm with an ELISA reader (Stat Fax 2100, Awareness Technology Inc, Palm City, FL). Lacto eyedrops were administered two times a day for 30 days. Tear Lf concentrations were determined at baseline and at day 30.
Results: Mean tear LF concentration plus or minus SD in eyes of patients with recurrent HSK was 1.21 ± 0.52 g/l, with no significant difference between the affected eye and fellow eye. However, a subnormal tear LF concentration was more common in the affected eye than in the fellow eye (χ2 = 4.24, р = 0.04). After a 30-day anti-inflammatory treatment with Lacto eyedrops, mean tear LF concentration plus or minus SD increased by 47% to 1.78 ± 0.7 g/l in the affected eyes. A corneal sensation score of 1 to 9 was 12.4 times more common in HSK eyes than in fellow eyes (OR = 12.4; 95% CI, 2.0–76.8), which reflects neurosensory abnormalities in the affected eye. Corneal sensation loss, was, however, more common in HSK eyes with a low tear Lf concentration than in fellow eyes with a low tear Lf concentration. Median basal tear production (as assessed by Schirmer’s II test) was as low as 7-8 mm in eyes with a low tear Lf concentration and as high as 13-16 mm in eyes with a high tear Lf concentration (p < 0.05). There was a direct correlation between the basal tear production and the tear Lf concentration (r=0.45; p < 0.05). Among study patients with recurrent HSK, 24.9% showed baseline microbiological evidence of potentially pathogenic or fungal organisms in the conjunctiva. A course of multicomponent anti-inflammatory treatment with Lacto eyedrops contributed to complete removal of these organisms.
Conclusion: We determined mean tear Lf concentrations in affected and fellow eyes of patients with recurrent HSK, and established certain relationships between functional characteristics of the ocular surface and tear Lf concentrations in these eyes. A disinfecting effect of Lacto eyedrops against any microorganisms present in the conjunctival sac of patients with recurrent HSK was confirmed by the absence of culture growth on completion of the multicomponent anti-inflammatory treatment.

References

Hawthorne KM, Dana R, Chodosh J. Delayed type hypersensitivity in the pathogenesis of recurrent herpes stromal keratitis. Semin Ophthalmol. 2011 Jul-Sep;26(4-5):246-50. doi: 10.3109/08820538.2011.588659.

Dujaili LJ, Clerkin PP, Clement C, McFerrin HE, Bhattacharjee PS, et al. Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated. Future Microbiology. 2011;6(8):877–907. doi: 10.2217/fmb.11.73

Wilhelmus KR. Diagnosis and management of herpes simplex stromal keratitis. Cornea. 1987; 6(4):286-91.

Jenssen H, Sandvik K, Andersen JH, Hancock RE, Gutteberg TJ. Inhibition of HSV cell-to-cell spread by lactoferrin and lactoferricin. Antiviral Res. 2008 Sep;79(3):192-8. doi: 10.1016/j.antiviral.2008.03.004. Epub 2008 Apr 21.

van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. Antiviral activities of lactoferrin. Antiviral Res. 2001 Dec;52(3):225-39. doi: 10.1016/s0166-3542(01)00195-4.

Singh J, Sharma M, Jain N, Aftab I, Vikram Net al. Lactoferrin and its nano-formulations in rare eye diseases. Indian J Ophthalmol. 2022 Jul;70(7):2328-2334. doi: 10.4103/ijo.IJO_303_22.

Wakabayashi H, Oda H, Yamauchi K, Abe F. Lactoferrin for prevention of common viral infections. J Infect Chemother. 2014 Nov;20(11):666-71. doi: 10.1016/j.jiac.2014.08.003. Epub 2014 Aug 30.

Flanagan JL, Willcox MD. Role of lactoferrin in the tear film. Biochimie. 2009 Jan;91(1):35-43. doi: 10.1016/j.biochi.2008.07.007.

Keijser S, Jager MJ, Dogterom-Ballering HC, Schoonderwoerd DT, de Keizer RJ, et al. Lactoferrin Glu561Asp polymorphism is associated with susceptibility to herpes simplex keratitis. Exp Eye Res. 2008 Jan;86(1):105-9. doi: 10.1016/j.exer.2007.09.013.

Fujihara T, Hayashi K. Lactoferrin inhibits herpes simplex virus type-1 (HSV-1) infection to mouse cornea. Arch Virol. 1995;140(8):1469-72. doi: 10.1007/BF01322673.

Marr AK, Jenssen H, Moniri MR, Hancock RE, Panté N. Bovine lactoferrin and lactoferricin interfere with intracellular trafficking of Herpes simplex virus-1. Biochimie. 2009 Jan;91(1):160-4. doi: 10.1016/j.biochi.2008.05.016.

Zinser E, Krawczyk A, Mühl-Zürbes P, Aufderhorst U, Draßner C, et al. A new promising candidate to overcome drug resistant herpes simplex virus infections. Antiviral Res. 2018 Jan;149:202-210. doi: 10.1016/j.antiviral.2017.11.012.

Vagge A, Senni C, Bernabei F, Pellegrini M, Scorcia V, et al.Therapeutic Effects of Lactoferrin in Ocular Diseases: From Dry Eye Disease to Infections. Int J Mol Sci. 2020 Sep 12;21(18):6668. doi: 10.3390/ijms21186668.

Pastori V, Tavazzi S, Lecchi M. Lactoferrin-loaded contact lenses: eye protection against oxidative stress. Cornea. 2015 Jun;34(6):693-7. doi: 10.1097/ICO.0000000000000435.

Wakabayashi H, Kurokawa M, Shin K, Teraguchi S, Tamura Y, et al. Oral lactoferrin prevents body weight loss and increases cytokine responses during herpes simplex virus type 1 infection of mice. Biosci Biotechnol Biochem. 2004 Mar;68(3):537-44. doi: 10.1271/bbb.68.537.

Krzyzowska M, Chodkowski M, Janicka M, Dmowska D, Tomaszewska E, Ranoszek-Soliwoda K, et al. Lactoferrin-Functionalized Noble Metal Nanoparticles as New Antivirals for HSV-2 Infection. Microorganisms. 2022 Jan 5;10(1):110. doi: 10.3390/microorganisms10010110.

Singh J, Sharma M, Jain N, Aftab I, Vikram N, Singh TP, et al. Lactoferrin and its nano-formulations in rare eye diseases. Indian J Ophthalmol. 2022 Jul;70(7):2328-2334. doi: 10.4103/ijo.IJO_303_22.

Marques de Carvalho CA, Matos ADR., Caetano BC, Pedro de Sousa Junior I, Pereira da Costa Campos S, et al. In vitro inhibition of SARS-CoV-2 infection by bovine lactoferrin. Bio Rxiv. 2020 doi: 10.1101/2020.05.13.093781.

Alpogan O, Karakucuk S. Lactoferrin: The Natural Protector of the Eye against Coronavirus-19. Ocul Immunol Inflamm. 2021 May 19;29(4):751-752. doi: 10.1080/09273948.2021.1954202. Epub 2021 Jul 13.

Versura P, Bavelloni A, Grillini M, Fresina M, Campos EC. Diagnostic performance of a tear protein panel in early dry eye. Mol Vis. 2013 Jun 6;19:1247-57.

Ponzini E, Scotti L, Grandori R, Tavazzi S, Zambon A. Lactoferrin Concentration in Human Tears and Ocular Diseases: A Meta-Analysis. Invest Ophthalmol Vis Sci. 2020 Oct 1;61(12):9. doi: 10.1167/iovs.61.12.9.

McDermott A. M. Antimicrobial compounds in tears. Exp Eye Res. 2013;117:53-61.

Weinberg E. D. Human lactoferrin: a novel therapeutic with broad spectrum potential. J Pharm Pharmacol. 2001;53:1303-1310.

Välimaa H, Tenovuo J, Waris M, Hukkanen V. Human lactoferrin but not lysozyme neutralizes HSV-1 and inhibits HSV-1 replication and cell-to-cell spread. Virol J. 2009 May 12;6:53. doi: 10.1186/1743-422X-6-53.

Fujihara T, Nagano T, Endo K, Nakamura M, Nakata K. Lactoferrin protects against UV-B irradiation-induced corneal epithelial damage in rats. Cornea. 2000 Mar;19(2):207-11. doi: 10.1097/00003226-200003000-00015.

Kiratli H, Irkeç M, Orhan M. Tear lactoferrin levels in chronic meibomitis associated with acne rosacea. Eur J Ophthalmol. 2000 Jan-Mar;10(1):11-4.

Keijser S, Jager MJ, Dogterom-Ballering HC, Schoonderwoerd DT, de Keizer RJ, Krose CJ, et al. Lactoferrin Glu561Asp polymorphism is associated with susceptibility to herpes simplex keratitis. Exp Eye Res. 2008 Jan;86(1):105-9. doi: 10.1016/j.exer.2007.09.013. Epub 2007 Oct 7.

Sonobe H, Ogawa Y, Yamada K, Shimizu E, Uchino Y, Kamoi M,et al. A novel and innovative paper-based analytical device for assessing tear lactoferrin of dry eye patients. Ocul Surf. 2019 Jan;17(1):160-166. doi: 10.1016/j.jtos.2018.11.001.

Devendra J, Singh S. Effect of Oral Lactoferrin on Cataract Surgery Induced Dry Eye: A Randomised Controlled Trial. J Clin Diagn Res. 2015;9:NC06–NC09. doi: 10.7860/JCDR/2015/15797.6670.

Leitch EC, Willcox MD. Lactoferrin increases the susceptibility of S. epidermidis biofilms to lysozyme and vancomycin. Curr Eye Res. 1999 Jul;19(1):12-9. doi: 10.1076/ceyr.19.1.12.5342.

Drozhzhyna GI, Riazanova LIu, Khramenko NI, Velychko LM. Lactoferrin concentration in tears of patients with chronic conjunctivitis and effect of Lacto eyedrops in the multicomponent treatment for this disorder. J of Ophthalmology (Ukraine). 2023; 1: 39-46.

Published

2023-12-27

How to Cite

1.
Drozhzhyna G, Khramenko N, Sereda K, Riazanova L, Velychko L. Tear lactoferrin concentration in patients with recurrent herpetic stromal keratitis and therapeutic effect of Lacto eyedrops in the multicomponent treatment for this disorder. J.ophthalmol. (Ukraine) [Internet]. 2023 Dec. 27 [cited 2024 Mar. 5];(6):20-7. Available from: https://ua.ozhurnal.com/index.php/files/article/view/87

Issue

Section

Clinical Ophthalmology