Point-of-care tests for ocular surface disease gaining acceptance as diagnostic tools

Ocular surface disease has various causes, and in-office testing is one means to define those causes. Red eye: There is a test for that. Meibomian gland dysfunction: There is a test for that. Allergy: There is a test for that. Dry eye: There is a test for that — more than one.

Point-of-care testing (POCT) is a growing area in ophthalmology in which clinicians obtain immediate results that enhance the accuracy of a diagnosis or help rule one out during one clinic visit. The most common testing done in an ophthalmologist’s office is for ocular surface disease, which encompasses three primary areas: dry eye, meibomian gland dysfunction and ocular allergy.

The advantages of these in-office tools are speed and simplicity; the disadvantage may be lack of revenue, according to OSN Healio.com/Ophthalmology Board Member William B. Trattler, MD.

“[POCT] is very simple to implement in your office,” Trattler said. “It probably won’t generate a lot of income, but it really helps us hone the diagnosis to better care for our patients.”

“We are just in the beginning of the general acceptance phase,” OSN Cornea/External Disease Board Member Darrell E. White, MD, said.

The accelerator for acceptance, according to White, was the U.S. Food and Drug Administration clearance of the TearLab Osmolarity System (TearLab) in 2009. The slope of the curve of POCT use has steepened, with significant increases seen every 6 months over the past 2 years, he said.

Dry eye

Common tests for dry eye disease include bilateral tear osmolarity, tear film break-up time, corneal staining, conjunctival staining, Schirmer’s test and meibomian gland grading.

“Patients with dry eye often have more concentrated or more salty tears, and their tear osmolarity is higher than normal,” Christopher J. Rapuano, MD, chief of Cornea Service at Wills Eye Hospital, said. “The TearLab test often allows you to better differentiate between dry eye conditions and other conditions such as allergy, for example.”

Another dry eye differentiating test is InflammaDry (Rapid Pathogen Screening, RPS), which tests the tears for an inflammatory mediator, matrix metalloproteinase 9 (MMP-9).

“This is a marker of inflammation that has been shown to be higher in patients with dry eye,” Rapuano said. The test became commercially available earlier this year and received a billing code in April.

“InflammaDry hopefully will also help in the diagnosis of dry eye and differentiating it from other conditions,” he said.

Both the InflammaDry test and the TearLab osmolarity system have received waivers for the Clinical Laboratory Improvement Amendments maintained by the Centers for Medicare and Medicaid Services, and both have 510(k) clearance from the FDA.

According to the TearLab company website, the technician collects nanoliter volumes of tear fluid with a “pen” that contains a single-use test card, or microchip. When the sample is obtained, the pen is docked in the system reader, a tabletop unit, and results are displayed within seconds.

“It is really easy for the technical staff of an ophthalmologist’s office to perform the TearLab test, and it is incredibly easy for the patient,” White said. “If the osmolarity reading is high, the likelihood that the patient has some kind of dry eye is incredibly high, somewhere in the high 90th percentile.”

The test is economically viable, with average insurance reimbursement being greater than the average cost of the microchip, White said.

The test also permits the clinician to follow the degree of dry eye a patient has over time and how the patient is responding to treatment, Trattler said.

Like the TearLab test, the InflammaDry test is also technically simple for the staff and easy for the patient, White said. It takes only a few seconds longer than the TearLab test to obtain the tear sample and then roughly 10 minutes to render a reading on the single-use, self-contained test stick.

“InflammaDry is a very sensitive test for the presence of MMP-9,” White said. “And in some ways, it also allows you to quantify how much MMP-9 activity is present.”

According to the company website, the test is 81% sensitive and 98% specific.

“InflammaDry will be able to diagnose that very specific entity, the inflammatory dry eye,” White said. “This will provide more direction to the ophthalmologist because if you have inflammation then you will use some sort of anti-inflammatory treatment.”

Rapuano said both the TearLab osmolarity and InflammaDry tests need to be performed before any ocular manipulation, including giving drops.

“Sometimes you cannot even do a particular test on the first day because the patient has already had drops and other testing and all kinds of measurements, so the proposed test would be unreliable,” he said. “In these cases, the patient needs to schedule a follow-up appointment and have the desired test performed before their examination.”

Within the next few years, White predicted ophthalmologists will have in their office one or perhaps two tests that, coupled with an exam, will provide “an incredibly specific pinpoint diagnosis and a correspondingly accurate and actionable treatment plan.” He also envisioned two competing platforms — TearLab’s “lab on a chip” and the RPS bioassay platform — each able to perform multiple tests on a single sample.

“It is a race as to which of these two platforms will achieve the broadest number of indications. The platform that demonstrates the greatest clinical relevance may garner a larger share of the market,” White said.

MGD

Meibomian gland dysfunction (MGD) is another contributor to dry eye that can be diagnosed by POCT.

“MGD is caused by the meibomian glands in the posterior lid margin not producing enough oil,” OSN Refractive Surgery Board Member Mitchell A. Jackson, MD, said. The result is evaporative dry eye, which is the most common form of dry eye.

“I see this more often in my practice than aqueous deficiency,” he said. Patients with acne rosacea are particularly prone to MGD.

TearScience offers two non-contact in-office MGD diagnostic devices: the LipiView interferometer and the hand-held Meibomian Gland Evaluator. The former measures the lipid layer of the tear film, and the latter facilitates evaluation of meibomian gland dysfunction at the slit lamp.

The LipiView interferometer helps confirm and quantitate the patient’s evaporative dry eye condition and gives the patient objective evidence of the need for treatment in the form of an interferogram, Jackson said.

“Patients like objective data, especially when making a decision about spending money on a treatment such as the LipiFlow thermal pulsation system,” Jackson said.

The Meibomian Gland Evaluator is used to evaluate meibomian gland obstruction at the slit lamp by mimicking the pressure of a deliberate blink.

No matter what the cause of dry eye, Jackson said he follows up patients with the TearLab osmolarity test to gauge their response to therapy.

“I can show the patient that he/she is improving with an objective number, which self-motivates him/her to maintain compliance with therapy,” Jackson said.

Sjögren’s syndrome

Two of three conditions must be present when diagnosing the autoimmune disorder Sjögren’s syndrome, diagnosed in one out of 10 dry eye patients. One of those conditions is clinically defined dry eye, according to Jackson. The other two are abnormal immunologic titers and/or dry mouth confirmed by parotid gland or lip biopsy.

Sjö (Nicox) is a POCT that addresses the immunology part of the equation with a fingerstick blood sample. With Sjö, a few blood spots are placed on the tester, and the test is mailed to a lab that assesses the four well-known antibody titers associated with Sjögren’s syndrome (rheumatoid factor RF, ANA, SSA and SSB) as well as three new proprietary early immune markers (PSP, CA-6 and SP-1).

“The beauty of the Sjö test is that it tests not only the four traditional titers, but three new titers associated with Sjögren’s,” Jackson said. “This allows the disease to be captured much earlier, so treatment can be initiated that will actually help these patients. Without effective treatment, patients can develop interstitial lung disease and kidney disease, and 5% go on to develop lymphomas.”

Patients with Sjögren’s syndrome are of particular interest for refractive surgery specialists because they are at greater risk than other immune disease-related dry eye patients for suboptimal outcomes after refractive surgery, according to a literature review published in Clinical Ophthalmology. Identifying these patients helps determine non-candidacy for laser vision correction.

“[In the past], we typically ordered our own blood tests or sent the patient to his medical doctor for the blood tests. And if we were highly suspicious, the patient was sent to a rheumatologist,” Rapuano said. “But referring patients to these other doctors is not always very easy or very fast.”

In contrast, the Sjö test can be performed in the office on the same day as the patient’s visit, although lab results take 1 to 2 weeks, Rapuano said. Even though there is no reimbursement for the practice, there is no cost either because the test, provided free by the company, is usually covered by insurance.

“By providing an objective diagnosis of high risk for Sjögren’s syndrome, everyone takes it much more seriously,” Rapuano said.

Red eye

The AdenoPlus test (RPS/Nicox) is used to diagnose adenoviral conjunctivitis.

“Patients with red eye may also have viral conjunctivitis,” Trattler said. “However, in reality, many of these patients do not have adenovirus upon testing. Without testing, some patients might take unnecessary medications or be advised that they are contagious when they are not.”

The simple test involves placing a drop of anesthesia and then touching the inner side of the lower eyelid with the pad of a small tester.

“You press down for about 10 seconds, so that the pad can soak up any viral antigens,” Trattler said. Next, the tester is inserted into a cassette; results are normally displayed in a few minutes.

Trattler said the AdenoPlus test is suitable for both primary care physicians and ophthalmologists, and he does not favor the testing by one office over the other.

“Reimbursement typically covers the cost of testing. It is not going to make money or lose money,” he said.

Trattler co-authored a 128-patient clinical trial on the sensitivity of the test for diagnosing adenoviral conjunctivitis in JAMAOphthalmology. When compared with only viral cell culture with confirmatory immunofluorescence assay, AdenoPlus demonstrated a sensitivity of 90% and specificity of 96%.

“If you are an ophthalmologist who takes care of people with ocular surface disease and dry eye, a staple of your daily diet is people who come into the office with a red eye,” White said. “Therefore, if you can rule in or rule out an adenoviral conjunctivitis, you are able to much more specifically treat something that could be a terrific nuisance in the community. By identifying a contagious patient, you can treat that person dramatically differently and more effectively.”

After ruling out adenoviral conjunctivitis, Trattler said he then considers other conditions, such as allergic conjunctivitis or nonspecific nonviral conjunctivitis.

The Doctor’s Allergy Formula (Doctor’s Allergy Formula) is a POCT for allergy testing.

“For patients with symptoms of allergic conjunctivitis, this test can be performed to identify which allergens patients are actually allergic to,” Trattler said. The test works by dipping a small applicator into a panel of 60 allergens, from dust mites to pollen, and then pressing the applicator onto the skin without puncturing the skin.

“This is different from what is done in an allergist’s office because you are not injecting intradermally the allergens,” he said. The actual test takes about 2 minutes, with 15 minutes of waiting time while test results develop.

“This is a very accurate test,” Trattler said. “If positive, we are able to come up with avoidance and medication strategies to treat a patient’s allergic conjunctivitis.”

Corneal dystrophy test

The Avellino DNA Dual Test for LASIK Safety (Avellino Lab USA) is a saliva swab test that takes seconds to perform. The sample is sent to Avellino’s lab, which looks for the genetic trait of whether the patient is at risk for Avellino corneal dystrophy or granular corneal dystrophy type 1, rare autosomal dominant diseases that may be exacerbated after some refractive surgeries.

LASIK outcomes would be impaired if performed on someone who is genetically positive for this condition, according to Jackson.

“Hence, you do not want to do an elective procedure on someone who is at risk for Avellino granular corneal dystrophy,” he said. “LASIK sometimes can accelerate the presence of the condition sooner than later. The Avellino test might eliminate some of the patient’s fear factor in the decision process.”

Time and training

In a broader sense, POCT takes extra time and training, according to Rapuano, and for many POCTs, there are upfront costs for the equipment and/or tests as well as additional administrative costs to track the supplies and billing.

The reimbursement landscape for POCT has changed over the years.

“Five or 10 years ago, insurance companies would not pay for a visit and a corneal topography on the same day,” Rapuano said. “Therefore, many doctors told their post-corneal transplant patients they would need to return another day for the topography and still another day to have their sutures removed. Today, though, insurance usually allows doctors to test, diagnose and treat the diagnosis the same day.”

Rapuano said that RPS is developing POCT that would eventually allow practitioners to assess multiple indications with a single test, and TearLab said its R&D teams are working on a panel of tests to be performed on its lab on a chip technology.

“Potentially, you could diagnose different bacteria or fungus with one test. That would be great,” Rapuano said.

“POCT will continue to grow,” Trattler said. “Companies are developing newer technologies to help us identify both the presence of different ocular conditions and track the improvement of various ocular indications. And although the tests are already very rapid, they will become even quicker.” – by Bob Kronemyer