Evaluation of Dry Eyes AHS - G2138

Description of Procedure or Service

Dry eye disease (dysfunctional tear syndrome) is a multifactorial disease of tear production and the ocular surface resulting in discomfort and visual impairment (DEWS, 2007a).

Tears are necessary for maintaining the health of the front surface of the eye and for providing clear vision. The tear film of the eye consists of aqueous, mucous, and lipid components. A healthy tear film is formed by the interaction of the lacrimal glands, eyelids, and ocular surface (Stern et al., 1998), dysfunction of any component can lead to dry eye disease. Dry eye is a common and often chronic problem, particularly in older adults. Schein recently reviewed the prevalence of dry eye stating that “The exact prevalence of dry eye disease is unknown due to the difficulty in defining the disease and the lack of a single diagnostic test to confirm its presence. Based on self-report of dry eyes in the Beaver Dam Offspring cohort, prevalence of dry eye was reported as 14.5 percent (17.9 percent in women and 10.5 percent in men)(Paulsen et al., 2014). Other studies have estimated prevalence at 5 to 30 percent of the population age 50 years and over (DEWS, 2007b; Ezuddin, Alawa, & Galor, 2015; Moss, Klein, & Klein, 2000).” (Shtein, 2017).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

Evaluation of dry eyes is considered investigational for all applications. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Evaluation of Dry Eyes is covered

Not applicable.

When Evaluation of Dry Eyes is not covered

Testing for MMP-9 protein in human tears is considered investigational to aid in the diagnosis of patients suspected of having dry eye disease based on comprehensive eye examination.

Testing of tear osmolarity in patients suspected of having dry eye is investigational to aid in determining the serverity of dry eye disease as well as monitor effectiveness of therapy.

Testing for lactoferrin and/or IgE to aid in the diagnosis of patients suspected of having dry eye disease is considered investigational.

All other testing used in the diagnosis of patients suspected of having dry eye disease is considered investigational. 

Policy Guidelines

Most patients will present with symptoms of chronic eye irritation. However, there is considerable variability in patient-reported symptoms and clinically measurable signs over time, as well as a recognized lack of correlation between these symptoms and signs (Begleyet al., 2003; Lemp, 1995; Nichols, Mitchell, & Zadnik, 2004; Nichols, Nichols, & Mitchell, 2004). Dry eye is classified into two general groups: decreased tear production and increased evaporative loss. In both groups, tear film hyperosmolarity and subsequent ocular surface inflammation lead to the variety of symptoms and signs associated with dry eye (Shtein, 2017). Evaluation should include symptoms of both discomfort and visual disturbance as well as determination of the relative contribution of aqueous production deficiency and evaporative loss of tear volume. Objective parameters of tear film stability, tear osmolarity, degree of lid margin disease, and ocular surface damage should be used to stage severity of dry eye disease to assist in selecting appropriate treatment options (Foulks et al., 2015).

Osmolarity is a measurement of the concentration of dissolved solutes in a solution. Hyperosmolarity of the tear film is a recognized and validated marker of dry eye (Tomlinson, Khanal, Ramaesh, Diaper, & McFadyen, 2006). A point-of-care test for the measurement of the osmolarity of the tear film of patients suspected of having DTS is available (Lemp et al., 2011). The normal tear film osmolarity in patients without DTS ranges from 270 to 308 mOsm/l (mean of 302 mOsm/l). A threshold of 308 mOsm/l has been found to be indicative of early/mild dry eye, whereas a tear film osmolarity of 316 mOsm/l or higher is correlated with moderate-to-severe dry eye. Based on the stability of the tear film in the eyes of normal patients, a difference in the tear film osmolarity of more than 8 mOsm/l between the eyes is suggestive of ocular surface instability and indicative of DED (Bron et al., 2014; Lemp et al., 2011; Tomlinson et al., 2006). The tear film osmolarity assessment has been demonstrated to have an 88% specificity and 78% sensitivity for mild/moderate dry eye and a 95% sensitivity for severe dry eye (Albietz, McLennan, & Lenton, 2003; Lemp et al., 2011; Milner et al., 2017; Tomlinson et al., 2006).

Inflammation is a common factor across the subtypes of DTS. The levels of inflammatory mediators, including cytokines, chemokines, and enzymes, involved in tissue remodeling may be assessed in the tear film. The MMP family of enzymes plays an important role in wound healing and inflammation through the ability to degrade collagen. Elevated levels of MMP-9, a member of the MMP family produced by corneal epithelial cells (Chotikavanich et al., 2009; Honda et al., 2010), have been observed in the tears of patients with dry eye (Sambursky et al., 2013). A point-of-care test for the measurement of the concentration of MMP-9 in the tear film of patients suspected of DTS is available (Sambursky et al., 2013). The normal range of MMP-9 in the tears of patients ranges from 3 to 40 ng/ml. In contrast, the MMP-9 levels in the tears of patients with moderate-to-severe DTS can exceed 40 ng/ml. InflammaDry, a commercial assay of MMP9 in tears, showed sensitivity of 85% (in 121 of 143 patients), specificity of 94% (59 of 63), negative predictive value of 73% (59 of 81), and positive predictive value of 97% (121 of 125)(Milner et al., 2017; Sambursky et al., 2013)

Shtein (2017) noted that tear osmolarity and ocular surface inflammation can be potentially used by the ophthalmologist to determine the severity of dry eye disease and possible etiologies. The author stated that “tear osmolarity testing is a potentially useful measure and is commercially available for use in the clinical setting. Further investigation is needed to determine how best to use for guiding patient care.” The author further stated that “clinical testing for the presence of matrix metalloproteinase 9 as a marker of ocular surface inflammation is available.” A review by Milner et al (2017) assessed the new diagnostic techniques and treatment options for dry eye disease and associated tear film disorders. The authors stated that “members of the DTS Panel have found the assessment of tear osmolarity helpful for diagnosing DTS when used in combination with other clinical assessments and procedures.” The authors also stated that “because of a requirement for MMP-9 levels to be greater than 40 ng/ml to provide a positive assessment using the point-of-care diagnostic, the use of MMP-9 as a diagnostic measure may be valid only for patients with more severe forms of DTS.” They recommended that in the context of an eye exam, tear film osmolarity should be evaluated prior to conducting any additional assessments involving contact with the ocular surface, (Bron et al., 2014; Lemp et al., 2011; Savini etal., 2008; Tomlinson et al., 2006). Next, the level of ocular inflammation can be measured by quantifying the level matrix metalloproteinase (MMP)-9 in the tear film (Chotikavanich et al., 2009; Honda et al., 2010). Finally, relative tear volume and secretion should be measured via a Schirmer strip test (Savini et al., 2008).

Foulks et al (2015) stated that “objective parameters of tear film stability, tear osmolarity, degree of lid margin disease, and ocular surface damage should be used to stage severity of dry eye disease to assist in selecting appropriate treatment options.” The authors noted that “elevated osmolarity of the tear film is a hallmark and defining feature of dry eye disease, but previous methods of measurement have been laborious and time-consuming. Recent availability of an in-office instrument for determination of tear film osmolarity has allowed more clinical application of such technology.” Additionally, tear osmolarity has a positive predictive value in the diagnosis of dry eye disease of 86%, the highest of all the objective measures tested. The authors further stated that “measurement of the levels of inflammatory mediators in the tear film serves to identify the contribution of inflammation and the severity of dry eye disease.” Increased production and activity of matrix metalloproteinase (MMP)-9 has been measured in dry eye.

Messmer et al (2016) conducted a prospective study with 101 patients with dry eye disease and controls. The patients and controls underwent MMP-9 testing of the tear film. Thereafter, they were evaluated for symptoms and signs of DED. The tear film was analyzed for MMP-9 by a commercially available detecting MMP-9 levels of more than 40 ng/ml. In 19 of 47 patients confirmed with dry eye (40.4%) and in 3 of 54 controls (5.6%), the MMP-9 results were positive. The researchers concluded that “MMP-9 testing in DED is a valuable new diagnostic tool. It correlated well with other dry eye tests and identified the presence of ocular surface inflammation in 40% of confirmed dry eye patients. It may be especially helpful to identify patients with ocular surface inflammation and autoimmune disease and may facilitate the decision to institute anti-inflammatory treatment in these patients.”

Sambursky et al (2013) conducted a prospective, masked, multi-center clinical trial to determine the clinical sensitivity, specificity, negative predictive value, and positive predictive value of a rapid point-of-care diagnostic test to detect elevated matrix metalloproteinase 9 levels (InflammaDry). InflammaDry was performed on 143 patients with clinical signs and symptoms of dry eyes disease and 63 healthy individuals serving as controls. InflammaDry showed sensitivity of 85% (in 121 of 143 patients), specificity of 94% (59 of 63), negative predictive value of 73% (59 of 81), and positive predictive value of 97% (121 of 125). The researchers concluded that “matrix metalloproteinase 9 is an inflammatory biomarker that has been shown to be elevated in the tears of patients with dry eyes. The ability to accurately detect elevated matrix metalloproteinase 9 levels may lead to earlier diagnosis, more appropriate treatment, and better management of ocular surface disease.”

Lemp et al (2011) conducted a multi-center prospective, observational case series study consisting of 314 subjects to evaluate the clinical utility of tear osmolarity in the diagnosis of dry eye disease. Bilateral tear osmolarity, tear film break-up time (TBUT), corneal staining, conjunctival staining, Schirmer test, and meibomian gland grading were performed. Of the 6 tests, tear osmolarity was found to have superior diagnostic performance. At a cutoff of 312 mOsms/L, tear hyperosmolarity exhibited 73% sensitivity and 92% specificity. The researchers concluded that “tear osmolarity is the best single metric both to diagnose and classify dry eye disease. Intereye variability is a characteristic of dry eye not seen in normal subjects.” 

Practice Guidelines and Position Statements 

American Academy of Ophthalmology

According to the Dry Eye Syndrome Preferred Practice Pattern guidelines of the American Academy of Ophthalmology (2013), tear osmolarity had not yet demonstrated clinically utility, and Inflammadry testing was not listed as one of the diagnostic testing modalities for this syndrome. AAO stated that “tear osmolarity has been thought to be an indicator of dry eye disease, and a commercial device has recently become available for clinicians’ use. Several studies using this device have demonstrated an increase in tear osmolarity in patients with aqueous tear deficiency or evaporative dry eye, and it has been approved by the FDA for use as a point-of-care laboratory test to diagnose dry eye. However, several studies have failed to correlate tear osmolarity levels with clinical signs or patient symptoms, and it is not clear that the test has great utility in the diagnosis of dry eye syndromes.”

Centers for Medicare and Medicaid Services (CMS) Local Coverage Determination

A CMS LCD on diagnostic evaluation and medical management of moderate-severe dry eye disease noted that “when used in conjunction with other methods of clinical evaluation, measuring the osmolarity of human tears has been shown to aid in the diagnosis of DED in patients suspected of having DED. A commercial device has become available for clinician’s use. Several studies using this device have demonstrated an increase in tear osmolarity in patients with aqueous tear deficiency or evaporative dry eye and it has been approved by the Food and Drug Administration (FDA) for the use as a point-of-care laboratory test to diagnose dry eye.”

It further stated that “elevated MMP-9 levels are highly correlated with clinical exam findings in patients with mild to severe DED. Patients who have elevated MMP-9 in their tears are more likely to respond to anti-inflammatory therapy such as cyclosporine. Patients without elevated MMP-9 are much more likely to benefit from supportive management with artificial tears or punctal occlusion. The MMP-9 test is considered reasonable and necessary because the presence or absence of inflammation related to DED impacts the subsequent treatment.” 

Applicable Federal Regulations

The US Food and Drug Administration (FDA) has approved a rapid in-office test for diagnosis of dry eye disease called InflammaDry, the developer Rapid Pathogen Screening Inc (RPS), of Sarasota, Florida, has announced (Megan Brooks, Dec 02, 2013).

Rapid Pathogen Screening, Inc. (RPS) announced that it has received a Clinical Laboratory Improvement Amendments (CLIA) waiver from the FDA for InflammaDry – a rapid, disposable, in-office test to aid in the diagnosis of dry eye disease, according to a company news release (RPS, Feb 27, 2014).

Obtaining the CLIA waiver, in addition to its FDA 510(k) clearance, enables the InflammaDry test to be used throughout the United States, an expansion from its current use internationally. CLIA waived status is granted to tests that are simple to perform and have an insignificant risk of producing an erroneous result. The InflammaDry test can be administered by any medical office personnel in healthcare facilities with a CLIA Certificate of Waiver.

The InflammaDry test is CE-marked, 510(k) cleared, and commercially available in Europe, Canada, and many countries throughout the rest of the world. Per RPS that InflammaDry inventory is available for sale in the United States from March 2014.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Scientific Background and Reference Sources

AAO. (2013). Dry Eye Syndrome Preferred Practice Patterns - 2013. 

Albietz, J. M., McLennan, S. G., & Lenton, L. M. (2003). Ocular surface management of photorefractive keratectomy and laser in situ keratomileusis. J Refract Surg, 19(6), 636-644.

Begley, C. G., Chalmers, R. L., Abetz, L., Venkataraman, K., Mertzanis, P., Caffery, B. A., . . . Simpson, T. (2003). The relationship between habitual patient-reported symptoms and clinical signs among patients with dry eye of varying severity. Invest Ophthalmol Vis Sci, 44(11), 4753-4761.

Bron, A. J., Tomlinson, A., Foulks, G. N., Pepose, J. S., Baudouin, C., Geerling, G., . . . Lemp, M. A. (2014). Rethinking dry eye disease: a perspective on clinical implications. Ocul Surf, 12(2 Suppl), S1-31. doi:10.1016/j.jtos.2014.02.002

Centers for Medicare and Medicaid Services (2015). Local Coverage Determination: Diagnostic Evaluation and Medical Management of Moderate-Severe Dry Eye Disease.

Chotikavanich, S., de Paiva, C. S., Li de, Q., Chen, J. J., Bian, F., Farley, W. J., & Pflugfelder, S. C. (2009). Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci, 50(7), 3203-3209. doi:10.1167/iovs.08-2476 DEWS. (2007a). The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf, 5(2), 75-92. DEWS. (2007b). The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf, 5(2), 93-107.

Ezuddin, N. S., Alawa, K. A., & Galor, A. (2015). Therapeutic Strategies to Treat Dry Eye in an Aging Population. Drugs Aging, 32(7), 505-513. doi:10.1007/s40266-015-0277-6

Foulks, G. N., Forstot, S. L., Donshik, P. C., Forstot, J. Z., Goldstein, M. H., Lemp, M. A., . . . Jacobs, D. S. (2015). Clinical guidelines for management of dry eye associated with Sjogren disease. Ocul Surf, 13(2), 118-132. doi:10.1016/j.jtos.2014.12.001

Honda, N., Miyai, T., Nejima, R., Miyata, K., Mimura, T., Usui, T., . . . Amano, S. (2010). Effect of latanoprost on the expression of matrix metalloproteinases and tissue inhibitor of metalloproteinase 1 on the ocular surface. Arch Ophthalmol, 128(4), 466-471. doi:10.1001/archophthalmol.2010.40 Lemp, M. A. (1995). Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. Clao j, 21(4), 221-232.

Lemp, M. A., Bron, A. J., Baudouin, C., Benitez Del Castillo, J. M., Geffen, D., Tauber, J., . . . Sullivan, B. D. (2011). Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol, 151(5), 792-798.e791. doi:10.1016/j.ajo.2010.10.032

Messmer, E.M., von Lindelfels, V., Garbe, A., & Kampik, A. (2016). Matrix Metalloproteinase 9 Testing in Dry Eye Disease Using a Commercially Available Point-of-Care Immunoassay. Ophthalmology, 123(11):2300-2308. doi: 10.1016/j.ophtha.2016.07.028.

Milner, M. S., Beckman, K. A., Luchs, J. I., Allen, Q. B., Awdeh, R. M., Berdahl, J., . . . Yeu, E. (2017). Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment. Curr Opin Ophthalmol, 27 Suppl 1, 3-47. doi:10.1097/01.icu.0000512373.81749.b7

Moss, S. E., Klein, R., & Klein, B. E. (2000). Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol, 118(9), 1264-1268.

Nichols, K. K., Mitchell, G. L., & Zadnik, K. (2004). The repeatability of clinical measurements of dry eye. Cornea, 23(3), 272-285.

Nichols, K. K., Nichols, J. J., & Mitchell, G. L. (2004). The lack of association between signs and symptoms in patients with dry eye disease. Cornea, 23(8), 762-770.

Paulsen, A. J., Cruickshanks, K. J., Fischer, M. E., Huang, G. H., Klein, B. E., Klein, R., & Dalton, D. S. (2014). Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol, 157(4), 799-806. doi:10.1016/j.ajo.2013.12.023

Sambursky, R., Davitt, W. F., 3rd, Latkany, R., Tauber, S., Starr, C., Friedberg, M., . . . McDonald, M. (2013). Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA Ophthalmol, 131(1), 24-28. doi:10.1001/jamaophthalmol.2013.561

Savini, G., Prabhawasat, P., Kojima, T., Grueterich, M., Espana, E., & Goto, E. (2008). The challenge of dry eye diagnosis. Clin Ophthalmol, 2(1), 31-55.

Shtein, R. (2017). Dry eyes - UpToDate. In H. Libman (Ed.), UpToDate. Waltham. MA.

Stern, M. E., Beuerman, R. W., Fox, R. I., Gao, J., Mircheff, A. K., & Pflugfelder, S. C. (1998). The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea, 17(6), 584- 589. 

Tomlinson, A., Khanal, S., Ramaesh, K., Diaper, C., & McFadyen, A. (2006). Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci, 47(10), 4309-4315. doi:10.1167/iovs.05-1504

Medical Director review 5/2019

Policy Implementation/Update Information

1/1/2019 New policy developed. Evaluation of dry eyes is considered investigational. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)

5/14/19 Reviewed by Avalon 1st Quarter 2019 CAB. Added additional investigational criteria: Testing for lactoferrin and/or IgE to aid in the diagnosis of patients suspected of having dry eye disease is considered investigational and all other testing used in the diagnosis of patients suspected of having dry eye disease is considered investigational. Added the following CPT codes to “Billing/Coding” section: 82785, 83520, 83861. Medical Director review 5/2019. Policy noticed 5/14/19 for effective date 7/16/19. (lpr)