Incorporating lactoferrin and immunoglobin testing

May 5, 2017

While ophthalmic diagnostic lab tests-specifically those targeting ocular surface disorders-have been around for over 20 years, it is only within the past five years that they have begun to gain measurable use.

While ophthalmic diagnostic lab tests-specifically those targeting ocular surface disorders-have been around for over 20 years, it is only within the past five years that they have begun to gain measurable use.

Still, the number of clinicians who have adopted these diagnostic tools remains quite small-fewer than five percent in the U.S.1

Let’s review the collection of ophthalmic diagnostic lab tests that have received clearance from the FDA for clinical and commercial use, in the order of their release.

Advanced Tear Diagnostic (ATD) Lactoferrin (LF) Diagnostic Test Kit. Cleared in 1995, ATD’s test for lactoferrin (LF) was the first point-of-care diagnostic test specifically designed for ophthalmic diagnostics.2

It requires a small 0.5 µL tear sample (1/100 of a drop) collected via metered micropipette, is a Clinical Laboratory Improvement Amendment (CLIA) Class II moderate complexity lab test, and takes about three to four minutes to produce a result. It provides an accurate assessment of the secretory function of the lacrimal gland as it relates to keratoconjunctivitis sicca (dry eye), is quantitative (provides a number), and is differential.3

Clinically, if the LF concentration is low, as judged against an established range, the patient has aqueous deficient dry eye.

ATD Total Immunoglobulin E (IgE) Diagnostic Test Kit. Cleared in 1999, ATD’s test for total IgE (not allergen specific) is a quantitative test designed to confirm allergic conjunctivitis.4 It also requires a 0.5 µL tear sample.

Related: How point-of-care diagnostic lab tests help clinical decisions

Clinically, if the concentration of IgE antibodies exceeds the established clinical cutoff, the patient is confirmed to have an active ocular allergen in need of some level of intervention.

TearLab Osmolarity System. Cleared in 2009, TearLab’s osmolarity test requires a 0.05 µL tear sample collected via integrated microcapillary tube.5 It is a CLIA Class I (waived) test and provides a result in approximately 10 seconds.

Clinically, the accurate measurement of ocular osmolarity is useful in confirming dry eye. If the osmolarity reading is over an established clinical cutoff value, the patient has dry eye. It is confirmatory only-it does not provide data that could differentiate aqueous-deficient dry eye, evaporative dry eye, or a possible allergic component to the presenting condition.

Rapid Pathogen Screening (RPS) AdenoPlus. Cleared in 2011, AdenoPlus is a qualitative (yes/no) tear test for confirming adenoviral conjunctivitis.6

RPS InflammaDry. Cleared in 2014, RPS’s qualitative test for matrix metalloproteinase-9 (MMP9) is a clinically relevant nonspecific inflammatory marker often associated with dry eye and conjunctochalasis.7

Note that LF and IgE tests together make up ATD’s TearScan MicroAssay System. It is the only POC measurement that incorporates two tests.

The above tests are important clinical tools, and each provides a level of clinical efficiency and precision not available prior to their introduction. Each is approved for reimbursement, and all require a CLIA certificate before clinical use.

 

Adding POC testing

I have been in practice for 17 years and see about 30 patients per day with a staff of five. Such a schedule requires focused attention on clinical efficiency.

It is not uncommon for our clinic to carefully study potential challenges that could slow down patient flow. Considering this, we were initially concerned how the adoption of point-of-care lab testing would affect operations. With thought, and a bit of trial and error, we have made this transition in a way that enhances our practice.

We began with the TearLab Osmolarity system and soon added the Advanced Tear Diagnostic’s MicroAssay system for both IgE and lactoferrin. I find that the two tests greatly aid my diagnostic accuracy.

Performing lab testing requires additional time, so it comes down to making a clinical decision: Does the testing data provide sufficient value to justify the time spent on data collection?

Based on our experience, I would say absolutely yes. It’s all about the difference between thinking you are making the correct diagnosis and treatment decisions and knowing you are.

Clinically, this decision was driven by the reproducible differential diagnostic data provided by the ATD system and the correlation between the test data and specific ocular surface disorders that are treatable. For example, patients with early dry eye demonstrated a significant reduction in tear proteins, including lactoferrin.8 There is very little benefit in diagnosing a condition that lacks an effective treatment.

In my practice, we use a modified form of the Ocular Surface Disease Index (OSDI) questionnaire to start the process of evaluating dry eye patients. Depending on those results, I determine if the patient should undergo further dry eye testing.

Related: Clinical laboratory testing in optometry: Next frontier

Surprisingly, I am discovering dry eye in more and more children. Two school districts in my area are completely paperless-the students use digital devices all day. These students, between school and home tablet usage, are on tablets more than 12 hours per day. I am finding an large number of students with dry eye.

Each initial dry eye workup includes testing for osmolarity, lactoferrin, and IgE. Based on the lab results, there is a far greater level of certainty that we are making the proper diagnosis and, importantly, initiating proper treatment leading to better outcomes.

While having a test that confirms dry eye was a move in the right direction, LF and IgE tests provided the ability to differentiate among the underlying etiologies, namely separating out aqueous deficient from evaporative or allergy-related causes. Tear assay testing does not confirm the presence of evaporative tear disorder, but it does confirm the presence, or lack, of lacrimal gland dysfunction and/or an active allergen.

If, for example, you suspect a patient should be diagnosed with dry eye and the LF test is within a normal range, you may have a high confidence that the patient is not aqueous deficient, resulting in less chair time and a more precise diagnosis and targeted treatment.

ATD’s IgE test is a surprisingly powerful tool in confirming an active allergic reaction. The information has been valuable in our initial workup of dry eye patients and surprising to see how often the presenting condition may be tied to an underlying low- to medium-grade allergic reaction.

Another revelation was the number of patients with elevated IgE whose symptoms did not include itching.

Further, there is a growing recognition that ophthalmic surgery has been associated with increased anterior surface inflammatory processes that include dry eye syndromes and ocular allergy.9 In addition, poorer outcomes of LASIK procedures, for example, have been reported in patients with moderate to severe ocular allergies and chronic forms of allergic conjunctivitis, which is an absolute contraindication to the LASIK procedure.10

Both LF and IgE tests are designed to be performed by technicians following an in-office training session. Training covered CLIA requirements for the lab director (me) as well as focused technician training on collecting and processing samples.

 

Finances of POC testing

Reimbursement is always a concern with adding new data-gathering tests. While all of the tests have been approved for reimbursement, I recommend for any new technology under consideration to contact your top five or six payer representatives directly to verify local policies relative to indications, number of tests allowed per year, and reimbursement levels.

My practice experienced a rapid payback on the initial cost of the system-I easily paid off the system in the first year of use. Based on our patient population, I estimate we are testing 10 to 15 percent of our patients using the two systems, and I anticipate this number will increase over time.

Point-of-care diagnostic lab testing is not for all optometrists. If your practice leans toward primary medical eye care, consider adding one or more POC tests to your practice flow. You’ll appreciate having hard data on which to base your clinical decisions, and your patients will appreciate good care.  

Related: A new player in point-of-care allergy testing

References

1. TearLab. 2016 Investor Deck. Available at: https://www.tearlab.com/pdfs/Investor_Deck_April_12_2016.pdf. Accessed 4/1/2017.

2. U.S. Food and Drug Administration. 510(k) Premarket Notification. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K934473. Accessed 4/18/2017.

3. McCollum CJ, Foulks GN, Bodner B, Shepard J, Daniels K, Gross V, Kelly L, Cavanagh HD. Rapid assay of lactoferrin in keratoconjunctivitis sicca. Cornea. 1994 Nov;13(6):505-8. Accessed 4/18/2017.

4. U.S. Food and Drug Administration. 510(k) Premarket Notification. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K991316. Accessed 4/18/17.

5. U.S. Food and Drug Administration. 510(k) Premarket Notification. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K083184. Accessed 4/18/2917.

6. U.S. Food and Drug Administration. 510(k) Premarket Notification. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf11/K110722.pdf. Accessed 4/18/2017.

7. U.S. Food and Drug Administration. 510(k) Premarket Notification. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/K132066.pdf. Accessed 4/18/17.

8. Versura P, Bavelloni A, Grillini M, Fresina M, Campos EC. Diagnostic performance of a tear protein panel in early dry eye. Mol Vis. 2013 Jun 6;19:1247-57.

9. Gao S, Li S, Liu L, Wang Y, Ding H, Li L, Zhong X. Early changes in ocular surface and tear inflammatory mediators after small incision lenticule extraction and femtosecond laser-assisted laser in-situ keratomileusis. PLoS One. 2014 Sep 11;9(9):e107370

10. Bielory BP, O’Brien TP. Allergic complications with laser-assisted in-situ keratomileusis. Curr Opin Allergy Clin Immunol. 2011 Oct;11(5):483-491.