In-office lab testing provides diagnostic information

May 19, 2017
Damon Dierker, OD, FAAO

Dr. Dierker has helped to create a comprehensive ocular surface disease service within his practice that incorporates the latest diagnostic and therapeutic advances to serve his patients. He is active in developing innovative strategies to help colleagues

Similar to the benefits that the primary care and pediatrics fields have enjoyed following years of rapid strep and flu testing, the uptake of rapid, single-use, point-of-care (POC) testing in optometry helps to guide clinical management and therapeutic decisions.

Similar to the benefits that the primary care and pediatrics fields have enjoyed following years of rapid strep and flu testing, the uptake of rapid, single-use, point-of-care (POC) testing in optometry helps to guide clinical management and therapeutic decisions.

One of the pioneers of POC testing for eye care professionals is RPS Diagnostics, which developed a suite of cost-effective POC diagnostic test kits based on a patented immunodiagnostic technology platform. These tests include InflammaDry to detect elevated levels of MMP-9, a nonspecific inflammatory marker that has consistently been shown to be elevated in the tears of patients with dry eye disease, and AdenoPlus, a rapid test for detecting adenoviral conjunctivitis. These POC tests enable eyecare providers to more accurately diagnose ocular disease, provide appropriate and timely treatment, and reduce the costs associated with spread of disease, unnecessary treatment methods, and patient dissatisfaction.

InflammaDry and AdenoPlus were acquired by Quidel Corporation from RPS Diagnostics in May 2017.

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

Testing for MMP-9

The InflammaDry test identifies patients with elevated MMP-9, which represents clinically significant ocular surface inflammation. Matrix metalloproteinases are proteolytic enzymes that are produced by stressed epithelial cells on the ocular surface.1

MMP-9 destabilizes the tear film and directly contributes to corneal barrier dysfunction by breaking down tight junctions and facilitating inflammatory cell migration. This ultimately leads to corneal staining, rapid tear break-up times (TBUT), ocular discomfort, and fluctuating vision.1 MMP-9 is the ideal biomarker for ocular surface inflammation because it elevates early, catalyzes the development of IL-1 and TNF-α, and accumulates as part of the persistent cycle of inflammation.

Unfortunately, traditional dry eye testing methods (TBUT, Schirmer’s, osmolarity) cannot determine which patients have clinically significant inflammation.2 Sambursky and colleagues showed that MMP-9 was positive (≥40 ng/ml) only 53 percent of the time in symptomatic dry eye patients.3 Lanza and others measured TBUT, Schirmer’s, osmolarity, and MMP-9 in 110 patients with dry eye symptoms and determined that 39 percent were positive for elevated MMP-9. No statistical difference was found in the profile of dry eye patients that tested positive or negative for elevated MMP-9 based on symptoms and signs.3 Furthermore, Tong  and colleagues showed that tear inflammatory mediators including MMP-9 did not improve after punctal occlusion.4

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

The presence or absence of ocular surface inflammation helps to guide therapeutic decision-making in patients with symptoms of dry eye.3 Artificial tears provide palliative relief of eye irritation in patients with aqueous tear deficiency but do not reduce MMP-9 levels or reduce inflammation in chronic dry eye.5 Patients with confirmed inflammation benefit from chronic anti-inflammatory therapy.5,6

Repeated InflammaDry testing after initiation of therapy can confirm an adequate therapeutic response or suggest that additional and/or more aggressive anti-inflammatory regimens are required. Punctal occlusion should be reserved for patients without inflammation or performed after the inflammation is controlled.4

 

Testing for adenovirus

Adenovirus is the most frequent cause of acute conjunctivitis, responsible for approximately 25 percent of cases in the United States.7 Adenoviral conjunctivitis is considered to be highly contagious and frequently can lead to localized epidemics. Less than 5 percent of the population has antibodies effective against any serotype of adenoviral conjunctivitis. Adenovirus is remarkably robust and can resist heat and chemical disinfectants while remaining viable for up to five weeks.8


 

A confident diagnosis of adenovirus infection avoids the unnecessary use of antibiotics, which is important in reducing the risk of adverse events and multidrug resistance. Adenovirus infections can mimic preseptal and orbital cellulitis, especially in children, and this often leads to unnecessary hospital admissions, CT scans, and IV antibiotics. In one study, Ruttum et al revealed that 16 percent of patients with signs of preseptal or orbital infection were culture positive for adenovirus.9

Studies repeatedly show that skilled clinicians have difficulty reliably distinguishing between viral and bacterial conjunctivitis, especially during the first week after onset of symptoms.10 Rietveld examined a cohort of 184 adults with an acute red eye associated with symptoms of their eye being stuck shut in the morning and/or mucopurulent discharge. Of the 57 patients with confirmed bacterial conjunctivitis, 53 percent reported a history of one eye being stuck shut in the morning, while 39 percent reported bilateral involvement.11 Among 120 patients without bacterial conjunctivitis, 62 percent had one eye stuck shut, and 11 percent had bilateral involvement. Additionally, a clinical trial at 16 academic centers to evaluate cidofovir treatment showed that experts had a clinical accuracy of about 48 percent in correctly diagnosing the etiology of acute conjunctivitis.12

Related: Clinical laboratory testing in optometry: Next frontier

The AdenoPlus test has 90 percent sensitivity and 96 percent specificity when testing in the first seven days as compared to cell culture.7 After seven days, when the disease process typically transitions from infectious to inflammatory, approximately 25 percent of patients remain contagious at 10 days and 5 percent at two weeks.13

It is important to identify these patients through a positive AdenoPlus test result because they require more time away from work, school, or daycare. Conversely, a negative AdenoPlus test result supports the empirical diagnosis of bacterial conjunctivitis (after excluding allergic and fungal conjunctivitis). This supports the prescription of an appropriate antibiotic, as well as the patient’s return to work, school, or daycare after 24 to 48 hours.

An effective antiviral can significantly shorten adenoviral conjunctivitis, which may cause significant morbidity, protracted courses, and vision-compromising complications. Associated subepithelial infiltrates can impair visual acuity for months and significantly exacerbate chronic dry eye disease.12

Off-label use of ganciclovir ophthalmic gel 0.15%, which is FDA approved for treatment of herpes simplex epithelial keratitis (dendritic ulcers), has shown efficacy against adenoviral conjunctivitis in early clinical use.14 Evidence of ophthalmic efficacy came in a prospective study with 18 patients with adenoviral keratoconjunctivitis. Reported symptoms in the ganciclovir arm were less than half than in controls who received preservative-free tears (7.7 days vs. 18.5 days). Significantly fewer patients in the treatment group developed subepithelial opacities (two of nine vs seven of nine).

 

POC protocols

As part of implementing a dry eye or red eye office protocol, a technician, prior to the clinician seeing the patient, can easily perform a POC test. For InflammaDry and AdenoPlus tests, collecting the sample and activating the test takes less than two minutes.

Tears from the palpebral conjunctiva are collected on the sterile sampling fleece located on the sample collector. The sample collector is then assembled to the test cassette, bringing the antigen in direct contact with an immunoassay strip, which is then dipped into a buffer solution to activate the test.

Within 10 minutes, either one blue control line or one blue control and one red result line appear in a readout area (much like a pregnancy test). A single blue control line indicates a negative result, and two lines (a blue control and red result line) indicate a positive result: either elevated MMP-9 or the presence of adenovirus. The more intense the red line, the more antigen is present.

POC testing allows healthcare providers to administer and receive prompt results from laboratory-quality tests in a single healthcare setting, leading to time and cost efficiencies and savings.

Related: Incorporating lactoferrin and immunoglobin testing

References

1. Chotikavanich S, de Paiva CS, Li de Q, Chen JJ, Bian F, Farley WJ, Pflugfelder SC. Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3203-3209.

2. Lanza NL, McClellan AL, Batawi H, Felix ER, Sarantopoulos KD, Levitt RC, Galor A. Dry Eye Profiles in Patients with a Positive Elevated Surface Matrix Metalloproteinase 9 Point-of-Care Test Versus Negative Patients. Ocul Surf. 2016 Apr;14(2):216-23.

3. Sambursky R, Davitt WF 3rd, Friedberg M, Tauber S. Prospective, multicenter, clinical evaluation of point-of-care matrix metalloproteinase-9 test for confirming dry eye disease. Cornea. 2014 Aug;33(8):812-818.

4. Tong L, Beuerman R, Simonyi S, Hollander DA, Stern ME. Effects of Punctal Occlusion on Clinical Signs and Symptoms and on Tear Cytokine Levels in Patients with Dry Eye. Ocul Surf. 2016;14(2):233-241.

5. Aragona P, Aguennouz M, Rania L, Postorino E, Sommario MS, Roszkowska AM, De Pasquale MG, Pisani A, Puzzolo D. Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease. Ophthalmology. 2015 Jan;122(1):62-71

6. Gürdal C, Genç I, Saraç O, Gönül I, Takmaz T, Can I. Topical cyclosporine in thyroid orbitopathy-related dry eye: clinical findings, conjunctival epithelial apoptosis, and MMP-9 expression. Curr Eye Res. 2010 Sep;35(9):771-7.

7. Sambursky R, Trattler W, Tauber S, Starr C, Friedberg M, Boland T, McDonald M, DellaVecchia M, Luchs J. Sensitivity and specificity of the AdenoPlus test for diagnosing adenoviral conjunctivitis. JAMA Ophthalmol. 2013 Jan;131(1):17-22.

8. Russell KL, Broderick MP, Franklin SE, Blyn LB, Freed NE, Moradi E, Ecker DJ, Kammerer PE, Osuna MA, Kajon AE, Morn CB, Ryan MA. Transmission dynamics and prospective environmental sampling of adenovirus in a military recruit setting. J Infect Dis. 2006 Oct 1;194(7):877-85.

9. Ruttum MS, Ogawa G. Adenovirus conjunctivitis mimics preseptal and orbital cellulitis in young children. Pediatr Infect Dis J. 1996 Mar;15(3):266-7.

10. Cheung D, Bremner J, Chan JT. Epidemic kerato-conjunctivitis--do outbreaks have to be epidemic? Eye (Lond). 2003 Apr;17(3):356-363.

11. Rietveld RP, van Weert HC, ter Riet G, Bindels PJ. Diagnostic impact of signs and symptoms in acute infectious conjunctivitis: systematic literature search. BMJ. 2003 Oct 4;327(7418):789.

12. O'Brien TP, Jeng BH, McDonald M, Raizman MB. Acute conjunctivitis: truth and misconceptions. Curr Med Res Opin. 2009 Aug;25(8):1953-1961.

13. Roba LA, Kowalski RP, Gordon AT, Romanowski EG, Gordon YJ. Adenovirus ocular isolates demonstrate serotype-dependent differences in in vitro infectivity titers and clinical course. Cornea. 1995 Jul;14(4):388-93.

14. Tabbara KF. Ganciclovir effects in adenoviral keratoconjunctivitis. Poster presented at 2001 Association of Research and Vision in Ophthalmology (ARVO) Conference; Poster B253:Fort Lauderdale, FL.

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