Anterior Segment, Corneal and External Disorders, Ocular Surface Disease
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Biomarkers In Dry Eye Disease

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Published Online: May 22nd 2012 European Ophthalmic Review, 2012;6(3):157-163 DOI:
Authors: Michael A Lemp, Benjamin D Sullivan, Leslie A Crews
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Dry eye disease is a multifactorial chronic disorder of the ocular surface that affects up to 100 million people worldwide. During the pathogenesis of dry eye, impaired function of the lacrimal and meibomian glands results in hyposecretion of aqueous tear fluid, coupled with increased evaporation and instability of the tear film, which becomes increasingly hyperosmolar in character at more severe stages of disease. One critical issue in the field is that the commonly used clinical signs and symptoms for the diagnosis or classification of dry eye often do not correlate with one another. This underscores the need to systematically evaluate current tests and highlights the importance of developing new markers of disease progression for use as endpoints in clinical trials of diagnostic devices and potential therapeutics. In this review, we examine the utility and limitations of commonly used signs and symptoms of dry eye disease and comment on newer biomarkers and analytical devices that show promise for future diagnostic and therapeutic use.


Dry eye disease, biomarkers, tear film, hyperosmolarity, symptoms, objective, subjective


Dry eye disease (DED) is thought to affect upwards of 30–40 million people within the US.1 Officially, the definition and classification of dry eye was updated in 2007 during the Tear Film and Ocular Surface (TFOS) Dry Eye WorkShop (DEWS).2

‘Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.’

Whether initiated by ageing, androgen deficiency, contact lens wear, refractive surgery or an autoimmune disease,1,3 dysfunctions of the lacrimal and meibomian glands result in hyposecretion and increased evaporation of tear fluid, which promote instability of the tear film.2,4 This leads to significant fluctuations in vision, loss of lubrication, inflammation, an increase in wear (epitheliopathy) and varying levels of neuropathy and corneal sensitisation. Thus, while diagnosis of DED may be thought to be straightforward in more severe examples of disease, determining the severity of the disease – especially at early stages, requires a deeper understanding of the potential aetiologies and clinical presentation of the disease to reconcile both the statistical and subjective aspects of severity.

Biomarkers – surrogates or substitutes for variables of clinical disease – are often used in the assessment of disease states, particularly in clinical trials of therapeutics and diagnostic devices.5

The terms (bio)markers, surrogates, endpoints, outcomes and others ave been used to describe a metric that is either objective or subjective, which accurately reflects the characteristics of disease. In medicine, common examples of this are the use of serum cholesterol or blood pressure for cardiovascular disease,6 or in ophthalmology intraocular pressure for glaucoma.7 A surrogate outcome has been defined as a “laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives”.8 The value of such a metric lies in how accurately it can capture important aspects of the disease. Such measures are typically used clinically in diagnosis, assessment of disease severity and response to therapy.

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Article Information:

This study was supported by TearLab Corporation (San Diego, CA). The authors wish to indicate the following financial interests in TearLab Corporation: Consultant (MAL, LAC), Equity (MAL, BDS), Patents (BDS), Employee (BDS).


Michael A Lemp, TearLab Corporation, 7360 Carroll Road Suite 200, San Diego CA, 92121, US. E:




  1. Tomlinson A, Epidemiology of dry eye disease. In: Asbell PA, Lemp MA, Dry Eye Disease: The Clinician's Guide to Diagnosis and Treatment, New York, NY: Thieme Medical Publishers, Inc., 2006;1–15.
  2. International Dry Eye WorkShop, Ocul Surf, 2007;5:65–204.
  3. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop, Ocul Surf, 2007;5:93–107.
  4. Bron AJ, Diagnosis of dry eye, Surv Ophthalmol, 2001;45 (Suppl. 2):S221–6.
  5. Ellenberg S, Hamilton JM, Surrogate endpoints in clinical trials: cancer, Stat Med, 1989;8:405–13.
  6. Tatasciore A, Renda G, Zimarino M, et al., Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects, Hypertension, 2007;50:325–32.
  7. Fogagnolo P, Sangermani C, Oddone F, et al., Long-term perimetric fluctuation in patients with different stages of glaucoma, Br J Ophthalmol, 2011;95:189–93.
  8. Lassere MN, Johnson KR, Boers M, et al., Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema, J Rheumatol, 2007;34:607–15.
  9. Sullivan BD, Crews LA, Sönmez B, et al., Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management, Cornea, 2012; [Epub ahead of print].
  10. Sullivan BD, Whitmer D, Nichols KK, et al., An objective approach to dry eye disease severity, Invest Ophthalmol Vis Sci, 2010;51:6125–30.
  11. Sullivan BD, Crews LA, Messmer EM, et al., Evaluation of the relationship among common clinical tests for the management of dry eye disease, Arch Ophthalmol, 2011 [Submitted].
  12. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop, Ocul Surf, 2007;5:75–92.
  13. Gilbard JP, Rossi SR, Changes in tear ion concentrations in dry-eye disorders, Adv Exp Med Biol, 1994;350:529–33.
  14. Lemp MA, Bron AJ, Baudouin C, et al., Tear osmolarity in the diagnosis and management of dry eye disease, Am J Ophthalmol, 2011;151:792–8 e1.
  15. Liu H, Begley C, Chen M, et al., A link between tear instability and hyperosmolarity in dry eye, Invest Ophthalmol Vis Sci, 2009;50:3671–9.
  16. Johnson ME, Murphy PJ, Changes in the tear film and ocular surface from dry eye syndrome, Prog Retin Eye Res, 2004;23:449–74.
  17. Acera A, Rocha G, Vecino E, et al., Inflammatory markers in the tears of patients with ocular surface disease, Ophthalmic Res, 2008;40:315–21.
  18. Luo L, Li DQ, Corrales RM, Pflugfelder SC, Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface, Eye Contact Lens, 2005;31:186–93.
  19. Luo L, Li DQ, Doshi A, et al., Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface, Invest Ophthalmol Vis Sci, 2004;45:4293–301.
  20. Sullivan DA, Immunology of the lacrimal gland and tear film, Dev Ophthalmol, 1999;30:39–53.
  21. Nichols KK, Foulks GN, Bron AJ, et al., The international workshop on meibomian gland dysfunction: executive summary, Invest Ophthalmol Vis Sci, 2011;52:1922–9.
  22. Lemp MA, Crews LA, Bron AJ, et al., Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study, Cornea, 2012;31(5):472–8.
  23. Kallarackal GU, Ansari EA, Amos N, et al., A comparative study to assess the clinical use of Fluorescein Meniscus Time (FMT) with Tear Break up Time (TBUT) and Schirmer’s tests (ST) in the diagnosis of dry eyes, Eye (Lond), 2002;16:594–600.
  24. Moore JE, Graham JE, Goodall EA, et al., Concordance between common dry eye diagnostic tests, Br J Ophthalmol, 2009;93:66–72.
  25. Fuentes-Páez G, Herreras JM, Cordero Y, et al., [Lack of concordance between dry eye syndrome questionnaires and diagnostic tests], Arch Soc Esp Oftalmol, 2011;86:3–7.
  26. Tuisku IS, Konttinen YT, Konttinen LM, Tervo TM, Alterations in corneal sensitivity and nerve morphology in patients with primary Sjogren's syndrome, Exp Eye Res, 2008;86:879–85.
  27. Nichols KK, Nichols JJ, Mitchell GL, The lack of association between signs and symptoms in patients with dry eye disease, Cornea, 2004;23:762–70.
  28. Foulks GN, Challenges and pitfalls in clinical trials of treatments for dry eye, Ocul Surf, 2003;1:20–30.
  29. Gipson IK, Spurr-Michaud SJ, Senchyna M, et al., Comparison of mucin levels at the ocular surface of postmenopausal women with and without a history of dry eye, Cornea, 2011;30:1346–52.
  30. Mathers WD, Daley TE, Tear flow and evaporation in patients with and without dry eye, Ophthalmology 1996;103:664–9.
  31. Tsubota K, Yamada M, Tear evaporation from the ocular surface, Invest Ophthalmol Vis Sci, 1992;33:2942–50.
  32. Yamada M, Tsubota K, [Measurement of tear evaporation from ocular surface], Nihon Ganka Gakkai Zasshi, 1990;94:1061–70.
  33. Rolando M, Refojo MF, Kenyon KR, Increased tear evaporation in eyes with keratoconjunctivitis sicca, Arch Ophthalmol, 1983;101:557–8.
  34. Craig JP, Tomlinson A, Importance of the lipid layer in human tear film stability and evaporation, Optom Vis Sci, 1997;74:8–13.
  35. Goto E, Ishida R, Kaido M, et al., Optical aberrations and visual disturbances associated with dry eye, Ocul Surf, 2006;4:207–13.
  36. Craig JP, Singh I, Tomlinson A, et al., The role of tear physiology in ocular surface temperature, Eye (Lond), 2000;14 (Pt 4):635–41.
  37. Walker PM, Lane KJ, Ousler GW 3rd, et al., Diurnal variation of visual function and the signs and symptoms of dry eye, Cornea, 2010;29:607–12.
  38. Cho P, Yap M, Schirmer test. II. A clinical study of its repeatability, Optom Vis Sci, 1993;70:157–9.
  39. Johnson ME, Murphy PJ, The Effect of instilled fluorescein solution volume on the values and repeatability of TBUT measurements, Cornea, 2005;24:811–7.
  40. Alonso-Caneiro D, Turuwhenua J, Iskander DR, Collins MJ, Diagnosing dry eye with dynamic-area high-speed videokeratoscopy, J Biomed Opt, 2011;16:076012.
  41. Yokoi N, Komuro A, Non-invasive methods of assessing the tear film, Exp Eye Res, 2004;78:399–407.
  42. Blackie CA, Solomon JD, Scaffidi RC, et al., The relationship between dry eye symptoms and lipid layer thickness, Cornea, 2009;28:789–94.
  43. Wang Y, Xu J, Sun X, et al., Dynamic wavefront aberrations and visual acuity in normal and dry eyes, Clin Exp Optom, 2009;92:267–73.
  44. Montés-Micó R, Cerviño A, Ferrer-Blasco T, et al., The tear film and the optical quality of the eye, Ocul Surf, 2010;8:185–92.
  45. Liu H, Thibos L, Begley CG, Bradley A, Measurement of the time course of optical quality and visual deterioration during tear break-up, Invest Ophthalmol Vis Sci, 2010;51:3318–26.
  46. Pflugfelder SC, de Paiva CS, Tong L, et al., Stress-activated protein kinase signaling pathways in dry eye and ocular surface disease, Ocul Surf, 2005;3:S154–7.
  47. Smith VA, Rishmawi H, Hussein H, Easty DL, Tear film MMP accumulation and corneal disease, Br J Ophthalmol, 2001;85:147–53.
  48. Tong L, Zhou L, Beuerman RW, et al., Association of tear proteins with Meibomian gland disease and dry eye symptoms, Br J Ophthalmol, 2011;95(6):848–52.
  49. Tsai PS, Evans JE, Green KM, et al., Proteomic analysis of human meibomian gland secretions, Br J Ophthalmol, 2006;90:372–7.
  50. Chotikavanich S, de Paiva CS, Li de Q, et al., Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome, Invest Ophthalmol Vis Sci, 2009;50:3203–9.
  51. Lam H, Bleiden L, de Paiva CS, et al., Tear cytokine profiles in dysfunctional tear syndrome, Am J Ophthalmol, 2009;147:198–205 e1.
  52. Yoon KC, Park CS, You IC, et al., Expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome, Invest Ophthalmol Vis Sci, 2010;51:643–50.
  53. Massingale ML, Li X, Vallabhajosyula M, et al., Analysis of inflammatory cytokines in the tears of dry eye patients, Cornea, 2009;28:1023–7.
  54. Enriquez-de-Salamanca A, Castellanos E, Stern ME, et al., Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease, Mol Vis 2010;16:862–73.
  55. Narayanan S, Miller WL, McDermott AM, Conjunctival cytokine expression in symptomatic moderate dry eye subjects, Invest Ophthalmol Vis Sci, 2006;47:2445–50.
  56. Li S, Sack R, Vijmasi T, et al., Antibody protein array analysis of the tear film cytokines, Optom Vis Sci, 2008;85:653–60.
  57. VanDerMeid KR, Su SP, Krenzer KL, et al., A method to extract cytokines and matrix metalloproteinases from Schirmer strips and analyze using Luminex, Mol Vis 2011;17:1056–63.
  58. Carreno E, Enriquez-de-Salamanca A, Teson M, et al., Cytokine and chemokine levels in tears from healthy subjects, Acta Ophthalmol, 2010;88:e250–8.
  59. Eliason JA, Maurice DM, Staining of the conjunctiva and conjunctival tear film, Br J Ophthalmol, 1990;74:519–22.
  60. Korb DR, Survey of preferred tests for diagnosis of the tear film and dry eye, Cornea, 2000;19:483–6.
  61. Argüeso P, Tisdale A, Spurr-Michaud S, et al., Mucin characteristics of human corneal-limbal epithelial cells that exclude the rose bengal anionic dye, Invest Ophthalmol Vis Sci, 2006;47:113–9.
  62. van Bijsterveld OP, Diagnostic tests in the Sicca syndrome, Arch Ophthalmol, 1969;82:10–4.
  63. Foulks GN, Bron AJ, Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading, Ocul Surf, 2003;1:107–26.
  64. The Report of the TFOS Workshop on Meibomian Gland Dysfunction, Invest Ophthalmol Vis Sci, 2011;52(4):1917–2085.
  65. Luo L, Li DQ, Pflugfelder SC, Hyperosmolarity-induced apoptosis in human corneal epithelial cells is mediated by cytochrome c and MAPK pathways, Cornea, 2007;26:452–60.
  66. Gilbard JP, Carter JB, Sang DN, et al., Morphologic effect of hyperosmolarity on rabbit corneal epithelium, Ophthalmology, 1984;91:1205–12.
  67. Pisella PJ, Habay T, Nochez Y, Evaluation of tear film quality with a double-pass scattering index, Presented at: 6th International Conference on the Tear Film and Ocular Surface, Florence, Italy, 22–25 September, 2010.
  68. Arita R, Itoh K, Inoue K, et al., Contact lens wear is associated with decrease of meibomian glands, Ophthalmology, 2009;116:379–84.
  69. Korb DR, Herman JP, Blackie CA, et al., Prevalence of lid wiper epitheliopathy in subjects with dry eye signs and symptoms, Cornea, 2010;29:377–83.
  70. Samsom ML, Sullivan BD, Schmidt TA, Effect of hyperosmolarity on PRG4’s ocular surface boundary lubricating ability at a human cornea-eyelid biointerface, Presented at: Association for Research in Vision and Ophthalmology (ARVO) meeting, Florida, US, 6 May 2012.
  71. Preferred Practice Pattern Guidelines: Dry Eye Syndrome – Limited Revision, American Academy of Ophthalmology, San Francisco, CA, US, 2011.
  72. Khanal S, Millar TJ, Barriers to clinical uptake of tear osmolarity measurements, Br J Ophthalmol, 2012;96(3):341–4.
  73. Fortes MB, Diment BC, Di Felice U, et al., Tear fluid osmolarity as a potential marker of hydration status, Med Sci Sports Exerc, 2011;43(8):1590–7.
  74. TearLab, OcuSense, Inc., TearLab Osmolarity System, 510(k). Available at: K083184.pdf (accessed 10 August 2012).
  75. Sullivan BD, Crews LA, Messmer EM, et al., Correlation between commonly used clinical tests in the management of dry eye disease, IOVS, 2012;53:ARVO E-Abstract 550.
  76. Behrens A, Doyle JJ, Stern L, et al., Dysfunctional tear syndrome: a Delphi approach to treatment recommendations, Cornea, 2006;25:900–7.
  77. Schiffman RM, Christianson MD, Jacobsen G, et al., Reliability and validity of the Ocular Surface Disease Index, Arch Ophthalmol, 2000;118:615–21.

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