Ocular surface disease and dry eye syndrome can have devastating effects, including constant discomfort, itching, burning, grittiness, and even ocular surface damage and loss of vision. This is a multifactorial disease with many contributing factors, and as a result, has many available treatment options. With the myriad of treatments available, it is important to understand the risks and benefits of each to make the most informed decision about patient care. Appropriate treatment selection should carefully balance the beneficial potential with an understanding of any adverse effects. In this article we will examine the safety of Autologous Serum Eye Drops for use in patients with unresponsive dry eye with an emphasis on toxicity and contamination risks.
Ocular toxicity is a condition in which the environment of the eye is negatively affected by toxic foreign substances, and the damage caused can be irreversible, so it is very important to understand the toxic potential of treatment options.[1] The most common treatment is artificial tears, a solution designed to lubricate the ocular surface by replacing moisture. While these drops can provide some relief, they lack many biological factors found in tears that promote healthy tissue growth and management. Additionally, most commercial artificial tears contain preservatives to inhibit bacterial and fungal contamination. These preservatives are known to cause irritation, and, with frequent use, can cause ocular toxicity and epithelial damage.[2] The negative effects can be hard to identify, as they are often slow to emerge and vary in presentation; however, they are indicative of epithelial damage caused by the preservative solution, and so should not be overlooked.
The most frequently used preservative, Benzalkonium chloride (BAK), has been shown to produce alarming negative effects. Laboratory, clinical and experimental studies have shown that this chemical causes irritation, tear film instability, goblet cell reduction, and corneal and deep tissue damage. The specific cause of this damage is not known, but studies show that several adverse mechanisms are well established, indicating a high risk of toxicity. [3] Thus, preservatives such as BAK should be avoided, especially for patients needing frequent or long-term treatment. For these patients, therefore, it is important to find a safer solution.
Autologous serum eye drops, on the other hand, have no damaging preservatives. Studies on the potential toxicity of ASED support the safety of this alternative treatment. In a laboratory study to determine the toxic effects of several ocular lubricating treatments, ASED was shown to be the least toxic treatment tested. Human corneal epithelial cells were incubated with and without the following lubricating substances: BAK 0.01%, saliva with differing osmolalaties, 50% ASED and 100% ASED. The cells were exposed to various frequencies and concentrations and examined for microvillous density, cell membrane permeability, and intracellular esterase. The results found benzalkonium chloride (BAK) to be the most toxic, followed by saliva, 50% AS, and then 100% AS.[4]
Another in vitro study on conducted on cultured human corneal epithelial cells sought to ascertain the risk of toxicity of autologous serum tears vs unpreserved hypromellose, a popular ocular lubricant commonly used in artificial tears, and found the serum solution produced an improved morphology and reduced toxicity levels as compared with hypromellose.[5] This indicates that the toxicity of preservatives in artificial tears is not the only cause for concern, and ASED could be a safer alternative to even unpreserved artificial tears. Toxicity can also be caused by allergic reactions, so it is important to consider that autologous serum eye drops are non-allergenic, since they are created using a patient’s own blood serum, which further reduces the risk of toxicity.[6]
Since serum eye drops are made without preservatives, there is the potential for biological and fungal growth in the solution; however, several studies have indicated its safety in practical usage. Although contamination does occur, complications from such are rare.[7] A study published in the Journal of the Medical Association of Thailand examined a 20% non-preserved ASED solution. The serum was stored at 4 ℃ and cultured every 3-7 days up to 84 days, and remained free of contaminants, indicating that it can be safely stored for up to 12 weeks.[8] An additional study sampled ASED bottles from 21 patients before and after use. The samples were cultured in standard media, and while positive signs of bacteria and fungi were identified, “neither clinical nor microbiological evidence of infection was demonstrated in any patient during the treatment or follow-up periods,” indicating a minimal risk of clinical infection.[9]
Von Hofsten et al conducted a study to assess the safety of using ASED, and found no negative effects, as well as very few reported cases of complication in the literature. The research included several studies showing a low quantity of positive cultures in stored serum. Even in cases of positive cultures, there were no infections caused in patients. The study cited immunological mechanisms for creating a bacteriostatic environment in the stored serum.[10] Bacteriostatic means that bacteria are inhibited from replicating. In this case, natural components from the blood limit the potential for bacterial growth. Some clinicians opt to include antibiotics with autologous serum use, particularly for high-risk patients, but general handling and storage precautions are typically sufficient.[11]
Autologous serum eye drops present an attractive treatment alternative to traditional artificial tears. The autologous (obtained from the same person) nature of ASED as well as their lack of preservatives make this treatment more favorable to high frequency and long-term patients because of the reduced risk of toxicity. The lack of preservative chemicals raises the question of contamination risk; however, the literature, as well as in vitro and in vivo studies, supports the safety of ASED when handled appropriately. It is important for patients and clinicians to carefully assess each treatment option to determine the best course for each individual, and the benefits of autologous serum eye drops should be carefully considered when creating a treatment plan.
[1] Contributing Ed. Stephenson, M. Systemic Drugs with Ocular Side Effects. Review of Ophthalmol. 2011 Oct 4. Retrieved from https://www.reviewofophthalmology.com/article/systemic-drugs-with-ocular-side-effects
[2] Anitua, E., Muruzabal, F., Tayebba, A., Riestra, A., Perez, V.L., Merayo-Lloves, J., and Orive, G. Autologous serum and plasma rich in growth factors in ophthalmology: preclinical and clinical studies. Acta Ophthalmol. 2015; 93: e605-e614
[3] Baudoin, C., Labbe, A., Liang, H., Pauly, A., and Brignole-Baudouin, F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010 Jul;29(4):312-34. doi: 10.1016/j.preteyeres.2010.03.001. Epub 2010 Mar 17.
[4] Geerling, G., Daniels, T.T., Dart, J.K., Cree, I.A., and Khaw, P.T. Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2001; 42: 948-956.
[5] Poon, A.C., Geerling, G., Dart, J.K., Fraenkel, G.E., and Daniels, J.T. Autologous serum eye drops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol. 2001; 85(10): 1188-1197.
[6] Mangan, R., and Lehman, S. (2012, March 15) How (and Why) to Make Autologous Serum. Review of Optometry. Retrieved from https://www.reviewofoptometry.com/article/how-and-why-to-make-autologous-serum#Dry%20Eye
[7] Jones, L., Downie, L.E., Korb, D., Benitez-del-Castillo, J.M., Dana, R., Deng, S.X., Dong, P.N., Geerling, G., Yudi Hida, R., Liu, Y., Yul Seo, K., Tauber, J., Wakamatsu, T.H., Xu, J., Wolffsohn, J.S., and Craig, J.P. TFOS DEWS II Management and therapy report. Ocul Surf. 2017 July. 15; 3: 575-628.
[8] Prabhasawat, P., Chotikavanich, S., Leelaporn, A. Sterility of non-preservative eye drops. J Med Assoc Thai.2005 Nov; 88 Suppl 9: s6-10.
[9] Thanathanee, O., Phanphruk, W., Anutarapongpan, O., Romphruk, A., and Suwan-Apichon, O. Contamination risk of 100% autologous serum eye drops in management of ocular surface diseases. Cornea. 2013; 32:1116-1119.
[10] Von Hofsten, J., Egardt, M., and Zetterberg, M. The use of autologous serum for the treatment of ocular surface disease at a Swedish tertiary referral center. Int Med Case Rep J. 2016; 9: 47–54. Published online 2016 Mar 2. doi: 10.2147/IMCRJ.S97297
[11] Hasson, M. (2012, Oct.) Autologous serum eye drops reduce ocular surface disease symptoms. Primary Care Optometry News. Retrieved from https://www.healio.com/optometry/cornea-external-disease/news/print/primary-care-optometry-news/%7B3e8ebb26-ec2f-415c-bda7-4a37a3a2f7d8%7D/autologous-serum-eye-drops-reduce-ocular-surface-disease-symptoms
