Generally reserved for more severe, recalcitrant dry eye syndrome (DES), autologous serum (AS) can play an important role in treatment for certain patients. According to the International Dry Eye Workshop, AS is most suitable for severity level 3 dry eye patients with TBUT ≤5 seconds, Schirmer tear test ≤ 5mm in five minutes, moderate to marked staining, and severe symptoms that do not respond to simpler treatments.1,2 

Though AS eye drops have been used to manage dry eye for more than 30 years, researchers are still looking for the “best” concentration. In the last 18 months, several new studies evaluating AS in the management of DES and other corneal diseases have been published.3 Their findings are summarized below with emphasis on the clinical significance of their conclusions.


How Does it Work?
Certain components in AS—epidermal growth factor, nerve growth factor, insulin-like growth factor 1, neurotrophic factors (substance P), bacteriostatic factors (lysozyme, immunoglobulins), fibronectin and vitamin A—may preserve and even restore ocular surface integrity by exerting epitheliotropic effects. This composition makes AS suitable to treat dry eye, neurotrophic keratitis, persistent corneal epithelial defects, recurrent corneal erosions, superior limbic keratoconjunctivitis, acute corneal burns and post-op dry eye after refractive surgery.4, 5 

AS eye drops are compounded using whole venous blood obtained from the patient via venipuncture, which is left to stand at room temperature for two hours to allow for clotting to occur. The serum is then separated from the clot by centrifugation for 10 minutes at 4,000 RPM (or at a speed not so high as to cause hemolysis). In a laminar flow cabinet under sterile environment, the supernatant liquid is drawn off and diluted (typically using isotonic (0.9%) preservative-free saline) to the desired concentration. The resulting eye drops are placed in opaque containers to prevent UV degradation of vitamin A. 

In the US, the FDA and the American Association of Blood Banks typically require autologous blood donors to have a minimum hemoglobin concentration of 11 g/dL (33% hematocrit) and be free of conditions that may result in bacteremia. Patients should also be well enough to undergo venipuncture several times a year and be able to tolerate blood loss. Because other family members may unintentionally use these serum drops, it is recommended that the donor be tested for blood-transmitted diseases such as HIV and hepatitis C.5 

AS eye drops diluted in saline are typically instilled four to eight times daily.5 AS vials should be refrigerated between use and discarded on a regular basis at least every month (though some prefer to have patients replace vials weekly). Extra AS drops can be kept in the freezer for up to three months. There is no need for the drops to contain an antibiotic, due to the bacteriostatic nature of serum imparted by immunoglobulins and lysozyme. Also, as the inclusion of a preservative has the potential for additional corneal toxicity, AS eye drops are typically preservative free.

AS eye drops are generally well tolerated by patients, but rare complications do exist, including deposition of immune complexes in the cornea and peripheral corneal infiltrates.3  Higher concentrations of AS eye drops also require more blood, raising the risk of anemia. 

A Serum Six-Pack
The following six studies help us to understand the clinical viability of AS as a treatment modality, particularly in severe DES.

AS beats AT. Celebi et al. evaluated 20% AS (saline diluent) compared to preservative-free (PF) artificial tears (AT) in patients with severe DES who had failed to respond to conventional dry eye therapies. Following a two-week washout period using PF isotonic saline, subjects were randomized to either AS or artificial tears dosed every six hours. After one month of therapy and a second two-week washout period, the treatments were switched. 

Compared to baseline, both therapies resulted in slightly increased Schirmer and slightly less ocular surface staining. Symptoms also improved in both groups, but statistically and clinically significantly more so when subjects were treated with AS. TBUT increased from two seconds at baseline to four seconds following one month of therapy with AS, but only to three seconds with PF AT. Overall, AS was more effective in improving comfort and stabilizing the tear film. In this study, 100% of patients had relief of severe dry eye symptoms.3 

Healing response seen. In a study by Jirsova et al., a small group of patients (n=17) with severe DES instilled 20% AS (saline diluent) drops 15 minutes after artificial tear use up to 12 times a day for three months. Patient symptoms improved and remained better than baseline three months after cessation of AS treatment. There was also improvement in ocular surface dryness (via Schirmer) and goblet cell density of the bulbar conjunctiva. Epithelial cell density increased significantly, signaling a reduction in the degree of squamous metaplasia. The authors concluded that a three-month treatment with AS led to an improvement in ocular surface dryness and epithelium health.7

Good for corneal pathology. A single-site prospective study evaluated AS in patients with corneal pathologies such as recurrent corneal erosion, neurotrophic keratopathy, KCS and corneal burns. Patient signs and symptoms improved irrespective of corneal pathology.4

Thwarted by cytokines. Hwang et al. studied AS in DES patients with primary and secondary Sjögren’s syndrome (SS). Characterized by chronic inflammation affecting salivary and lacrimal glands, SS is classified as secondary when associated with diseases such as rheumatoid arthritis or systemic lupus erythematosus and has been linked to an increased level of serum proinflammatory cytokine levels—a connection some believe may inhibit the abilities of AS. 

This group reported proinflammatory cytokine levels to be higher in patients with secondary SS vs. primary after evaluating patients before and after four weeks of AS (50%; diluted with 0.1% sodium hyaluronate) used eight times a day. The authors concluded that AS might not be helpful with managing severe DES in secondary SS due to the elevated serum level of detrimental cytokines.8

SH allows sustained release. Another study of SS patients (n=26) compared AS 20% diluted in either saline or sodium hyaluronate (SH)—one in each eye—over two months. Drops were instilled every eight hours and vials were discarded every seven days. López-Garcia et al. reported AS with SH exhibited excellent stability for one month in both fresh and defrosted samples, as well as improvement over AS with saline in tear film stability, staining, TBUT and patient symptoms. The study concluded SH allows for a sustained release of various growth factors, thereby making it an excellent diluent for AS.9 

Alternative to AS? Watson et al. evaluated therapeutic ocular surface medium (TOSM), a preservative- and antibiotic-free serum substitute manufactured to allow culturing of epithelial cells in a lab setting, for persistent epithelial defects (PED). Containing similar components, TOSM is more available and easier to prepare than AS, making it a possible alternative for various corneal pathologies. In this study, the majority of patients showed PED improvement and tolerance of TOSM. The authors concluded that TOSM might be a potential therapy for PED without some of the supply concerns noted with AS.10 

The Take-Home Message
With respect to these studies, AS at concentrations of 20% to 50% diluted in SH appears to be the most effective formulation and so should be considered in advanced DES unresponsive to more traditional therapies. No more than 50% of AS should be considered due to the risk of pathogen incubation. Additionally, if SS patients present with an underlying systemic connective tissue disease, caution should be used in determining treatment. Lastly, TOSM might have the nutrient benefits of AS without the difficulty of production, but more research is needed to confirm.  

1. Management and therapy of dry eye disease: report of the management and therapy subcommittee of the international dry eye workshop (2007). Ocul Surf. 2007;5(2):163-178.
2. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye workshop (2007). Ocul Surf. 2007;5(2):75-92.
3. Celebi ARC, Ulusoy C, Mirza GE. The efficacy of autologous serum eye drops for severe dry eye syndrome: a randomized double-blind crossover study. Graefes Arch Clin Exp Ophthalmol. 2014;252:619-626.
4. Semeraro F, Forbice E, Braga O, et al. Evaluation of the efficacy of 50% autologous serum eye drops in different ocular surface pathologies. Biomed Res Int. 2014; Published online Jul 22.
5. Pan Q, Angelina A, Zambrano A, et al. Autologous serum eye drops for dry eye. Cochrane Database Syst Rev. 2013 Published online Aug 23.
6. Cho YK, Huang W, Kim GY, Lim BS. Comparison of autologous serum eye drops with different diluents. Current Eye Research. 2013;38(1):9-17.
7. Jirsova K, Brejchova K, Krabcova I, et al. The application of autologous serum eye drop in severe dry eye patients; subjective and objective parameters before and after treatment. Current Eye Research. 2014;39(1):21-30.
8. Hwang J, Chung SH, Jeon S, et al. Comparison of clinical efficacies of autologous serum eye drops in patients with primary and secondary sjogren syndrome. Cornea. 2014;33(7):663-667.
9. López-Garcia JS, Garcia-Lozano I, Rivas L, et al. Autologous serum eye drops diluted with sodium hyaluraonte; clinical and experimental comparative study. Acta Ophthalmol. 2014;92(1):e22-29.
10. Watson SL, Geerling G, Dart JKG. Clinical therapy of therapeutic ocular surface medium for persistent epithelial defect. Ophthalmic Res. 2014;51(2):82-87.