Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in vitro toxicity studies

Alexander C Poon; Gerd Geerling; John K G Dart; Graham E Fraenkel; Julie T Daniels

doi:10.1136/bjo.85.10.1188

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Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in vitro toxicity studies

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Autologous serum in epithelial defects: Authors' reply
John Dart
Published on: 22 March 2016
Role of autologous serum in persistent epithelial defects
Rasik B Vajpayee
Published on: 22 March 2016

Published on: 22 March 2016
Autologous serum in epithelial defects: Authors' reply
- John Dart, MA DM FRCS
- Other Contributors:
  A Poon
Dear Editor
Vajpayee and colleagues have criticised several aspects of our study and justified their views with unrepresentative quotations from the literature.
Choice of time period before an epithelial defect can be described as "persistent".
There is no accepted definition of persistent epithelial defect (PED) that includes a time period. We favour the definition given in one text"......
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Dear Editor
Vajpayee and colleagues have criticised several aspects of our study and justified their views with unrepresentative quotations from the literature.
Choice of time period before an epithelial defect can be described as "persistent".
There is no accepted definition of persistent epithelial defect (PED) that includes a time period. We favour the definition given in one text"... when the epithelium fails to regrow over a defect within the expected time course".[1] For the purpose of a study the time course must be specified. Vajpayee et al. Prefer 2 weeks [2] whereas in another recent paper 10 days was chosen with the proviso that the study treatment could start earlier if there was progression to perforation.[3] The penalty for patients at high risk of corneal melt, in the presence of a persistent defect, is substantial. In our study 2/13 patients had an epithelial defect for less than 2 weeks before inclusion in the study; Vajpayee et al. can ignore the data from these patients if they wish.
Wash-out period with preservative-free artificial tears
No "wash-out period" was used in this study, as we were trying to identify whether serum would have an additional effect on epithelial healing over preservative-free artificial tears and conventional therapy in patients with severe ocular surface disease. We were not trying to compare the efficacy of serum against preservative-free lubricants in healing PEDs. Conventional therapy was continued as serum alone could not fully address all the ocular surface problems, including aqueous tear deficiency and eyelid trauma, so that giving serum without continuing the other modalities may have caused harm to some of the patients. Other studies have adopted similar protocols with a PED defined as a defect that persisted "...despite conventional treatment such as artificial tears or extended wear contact lenses" with no wash out period [2] or that allowed a reduction in the 10 day wash out period if corneal ulceration progressed.[3] In a clinical study some ethical committees may not condone the treatment of persistent defects without non-preserved antibiotic prophylaxis against bacterial keratitis.
Keratoplasty patients being treated without waiting for the corneal epithelial defect to heal by itself
These patients had both failed previous grafts because of corneal perforation resulting from PEDs and one patient had recurrent epithelial breakdown, responding to the re-introduction of serum drops, after their initial withdrawal. We thought that, for some readers, this might be useful data to add to this descriptive study.
The rationale behind the use of 100 % serum when previous studies have proved the efficacy of a 20 % solution
The previous study Vajpayee et al. quote is, like ours and all the other studies on this subject, a descriptive study and no more proves that serum drops at 20 % work than does our own with 50% and 100%. Other studies, all uncontrolled, have used from 20% to 30% serum [2,4] for both persistent defect and dry eye. All these studies use empirical regimens for serum concentration and dosing frequency. Unlike Vajpayee et al., we have some patients (one reported in the study) who prefer 100 % serum to 50 %. Vajpayee et al. are probably also unaware of our study demonstrating that 100 % serum is less toxic that 50 % serum to cultured corneal epithelial cells;[5] this provides some laboratory data to support the use of 100 % serum. Lastly, the manufacture of 100 % serum requires less handling, reducing the risk of contamination.
The use of the slit lamp micrometer
Vajpayee et al. have missed the point that the treatment end point was closure of the defect, for which their proposed technique is inappropriate, rather than rate of closure, for which it would be ideal. The deficiencies in our study are not the points that Vajpayee et al. have made but the fact that it was uncontrolled. The study was planned as a randomised controlled trial but could not be carried out as such for the reasons alluded to in the last paragraph. These regulatory problems are being overcome in the UK. We should all hope to see randomised treatment trials carried out in this area as well as the laboratory studies necessary to support the clinical application of serum.
John Dart
Alex Poon
References
(1) Macaluso DC, Feldman ST. Persistent epithelial defects and sterile ulceration. Pathogenesis of sterile corneal erosions and ulcerations. In Vol 1, Chapter 10; 204 of Krachmer J, Mannis M, Holland E, (Eds) Cornea; fundamentals of cornea and external disease. St Louis 1007: Mosby.
(2) Tsubota K, Goto E, Simmer S, Shimazaki J. Treatment of persistent epithelial defect by autologous serum application. Ophthalmology 1999;106:1984-9.
(3) Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 2000;107:1347-51.
(4) Fox RI, Chan R, Michelson J, Belmont J, Michelson P. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum 1984;29:577-83.
(5) Geerling G, Daniels JT, Dart JK, Cree IA, Khaw PT. Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Investigative Ophthalmology & Visual Science 2001;42(5):948-56.
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Conflict of Interest:
None declared.
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Published on: 22 March 2016
Role of autologous serum in persistent epithelial defects
- Rasik B Vajpayee
- Other Contributors:
  Nitin Mukerji, and Rajesh Sinha
Dear Editor
Poon et al.[1] in their excellent article have reiterated the efficacy of autologous serum in the treatment of persistent epithelial defects (PEDs) of the cornea. We would like to invite the attention of the authors to certain aspects of the study. The authors have considered a period of one week for labeling an epithelial defect to be persistent. However, most studies on a similar subject have tak...
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Dear Editor
Poon et al.[1] in their excellent article have reiterated the efficacy of autologous serum in the treatment of persistent epithelial defects (PEDs) of the cornea. We would like to invite the attention of the authors to certain aspects of the study. The authors have considered a period of one week for labeling an epithelial defect to be persistent. However, most studies on a similar subject have taken the criterion to be two weeks.[2] It is generally recommended that a 'wash out' period of a least two weeks be given with preservative free artificial tears3 and only those epithelial defects that remain either static or demonstrate an increase in size in this period be included in the study. The authors have not mentioned such a 'wash out' period being included in the protocol. When using autologous serum drops most investigators have not used any other therapeutic modality at the same time to enhance epithelialization apart from preservative free lubricants. The use of therapeutic contact lenses in five cases by the authors makes it difficult to evaluate the actual contribution of serum drops in the healing of the epithelial defect in these cases. Further, the use of serum drops in the immediate post operative period in two patients with poor ocular surface undergoing keratoplasty without waiting for the corneal epithelial defect to heal by itself cannot be extrapolated to making a comment on the beneficial effect of autologous serum. Also the rationale behind the use of 100 % serum when previous studies have proved the efficacy of a 20 % solution[2] is not clear. The 100 % concentration of serum can cause stickiness, which would be inconvenient to the patients and may reduce compliance. The use of the slit lamp micrometer by the authors for measuring the epithelial defects may not be accurate because of its inherent inter-observer and intra-observer variations. A better method would be measuring the area of the defect instead of the greatest dimensions by the use of digital photographs and area measuring software such as Image Pro PlusTM available from Media Cybernetics.
References
(1) Poon AC, Geerling G, Dart JKG, et al. Autologous Serum eye drops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol 2001;85:1188-97.
(2) Tsubota K, Goto E, Shimmura S, et al. Treatment of persistent epithelial defect by autologous serum application. Ophthalmology 1999;106:1984-9. (3) Gordon JF, Johnson P, Musch DC. Topical fibronectin ophthalmic solution in the treatment of persistent defects of the corneal epithelium. Am J Ophthalmol 1995;119:281-7.
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Conflict of Interest:
None declared.
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