Correlation of Adenoviral Titers with Severity of Adenoviral Conjunctivitis and Time to Viral Clearance for 21 Days.

SIGNIFICANCE: This investigation reports the correlation of conjunctival viral titers in adenoviral conjunctivitis with patient-reported symptoms and clinician-graded signs for 21 days of follow-up. PURPOSE: Adenoviral conjunctivitis is a highly contagious viral eye infection with significant morbidity and economic impact. This study investigates whether severity of signs and symptoms and time to viral clearance are correlated with conjunctival viral titers at baseline and during 21 days of follow-up. METHODS: The Reducing Adenoviral Patient Infected Days study was a pilot study of the efficacy of a single in-office administration of ophthalmic 5% povidone-iodine. This article outlines longitudinal analyses after the primary outcome report. Of 212 participants screened, 28 participants with quantitative polymerase chain reaction-confirmed adenoviral conjunctivitis were randomized and had follow-up visits on days 1, 2, 4, 7, 14, and 21. At each visit, clinician-graded signs, participant-reported symptoms, and a conjunctival swab for quantitative polymerase chain reaction analysis were obtained. The correlation of viral titers with symptoms and signs was calculated: (1) cross-sectionally at each visit and (2) longitudinally for 21 days using a repeated-measures mixed-effects model. RESULTS: Twenty-five of 28 participants had sufficient data for this report. Higher viral titers for 21 days were correlated with greater severity of symptoms (tearing, matting, and redness, r ≥ 0.70; P < .02) and greater severity of clinical signs (bulbar redness and serous discharge, r ≥ 0.60; P < .01). Eyes with highest baseline viral titers required longer time to viral clearance ( r = 0.59, P = .008). Signs and symptoms persisted in approximately half of the eyes even after viral clearance. CONCLUSIONS: Higher conjunctival viral titers across 21 days were strongly correlated with more severe signs and symptoms and longer time to viral clearance. Our results also indicate that symptoms and signs can persist after viral clearance.

Success of Masking 5% Povidone-Iodine Treatment: The Reducing Adenoviral Patient Infected Days Study.

SIGNIFICANCE: The effectiveness of masking is rarely evaluated or reported in single- or double-masked clinical trials. Knowledge of treatment assignment by participants and clinicians can bias the assessment of treatment efficacy. PURPOSE: This study aimed to evaluate the effectiveness of masking in a double-masked trial of 5% povidone-iodine for the treatment of adenoviral conjunctivitis. METHODS: The Reducing Adenoviral Patient Infected Days study is a double-masked, randomized trial comparing a one-time, in-office administration of 5% povidone-iodine with artificial tears for the treatment of adenoviral conjunctivitis. Masking was assessed by asking participants and masked clinicians at designated time points if they believed the treatment administered was povidone-iodine or artificial tears, or if they were unsure. Adequacy of masking was quantified using a modified Bang Blinding Index. RESULTS: Immediately after treatment, 34% of participants who received povidone-iodine and 69% of those who received artificial tears guessed incorrectly or were unsure of their treatment (modified Bang Indices of 0.31 and -0.38, respectively). On day 4, 38% of the povidone-iodine participants and 52% of the artificial tear participants guessed incorrectly or were unsure of their treatment (modified Bang Indices of 0.24 and -0.05, respectively), indicating adequate and ideal masking. On days 1, 4, 7, 14, and 21, masked clinicians guessed incorrectly or were unsure of treatment in 53%, 50%, 40%, 39%, and 42% among povidone-iodine participants compared with 44%, 35%, 38%, 35%, and 39% among artificial tears participants, respectively. The modified Bang Indices for clinician masking in the povidone-iodine group ranged from -0.05 to 0.25 and from 0.13 to 0.29 in the artificial tears group. CONCLUSIONS: Masking of participants and clinicians was adequate. Successful masking increases confidence that subjective measurements are not biased. We recommend quantitative assessment and reporting the effectiveness of masking in ophthalmic clinical trials.

Natural history of adenoviral conjunctivitis in a US-based population: Viral load, signs, and symptoms.

PURPOSE: To report the clinical signs, symptoms, and viral clearance in individuals in the United States with adenoviral conjunctivitis (Ad-Cs). METHODS: Individuals ≥ 18 years presenting within 4 days of symptoms of Ad-Cs who met eligibility criteria and tested positive with both point-of-care immunoassay antigen and quantitative polymerase chain reaction (qPCR) testing were enrolled. Patient-reported symptoms, clinician-graded signs, and qPCR viral titers were collected at baseline, days 1-2, 4 (days 3-5), 7 (days 6-10), 14 (days 11-17) and 21 (days 18-21). RESULTS: There was no detectable viral titers by the day 14 visit in 6/8 patients. By day 21, there was no detectable viral titers in the 7 participants who completed the visit; however, signs and symptoms persisted including: blurry vision (5/7), discomfort (2/7) or redness (1/7). Masked clinicians also noted conjunctival redness (4/7), follicular conjunctivitis (4/7) and bulbar edema (3/7). CONCLUSION: Many patient-reported symptoms and clinical signs persist after viral titers are no longer detectable by qPCR. Using clinical signs and symptoms to determine quarantine duration may result in patients being furloughed longer than the time that the patient is infectious.

Diagnostic accuracy of clinical signs, symptoms and point-of-care testing for early adenoviral conjunctivitis.

CLINICAL RELEVANCE: This study identifies key signs and symptoms of acute conjunctivitis, that when combined with a point-of-care test, can improve clinician accuracy of diagnosing adenoviral conjunctivitis. BACKGROUND: Adenoviral conjunctivitis is a common ocular infection with the potential for high economic impact due to widespread outbreaks and subsequent furloughs from work and school. In this report, we describe clinical signs and participant-reported symptoms that most accurately identify polymerase chain reaction (PCR)-confirmed adenoviral conjunctivitis. METHODS: Adults with 'red eye' symptoms of four days or less were enrolled. Participants rated 10 ocular symptoms from 0 (not bothersome) to 10 (very bothersome), and indicated the presence or absence of systemic flu-like symptoms. Clinicians determined the presence or absence of swollen lymph nodes and rated the severity of eight ocular signs using a 5-point scale. An immunoassay targeting adenovirus antigen was utilised for the point-of-care test, and conjunctival swab samples were obtained for subsequent adenovirus detection by PCR analyses. Univariate and multivariate logistic regression models were used to identify symptoms and signs associated with PCR-confirmed adenoviral conjunctivitis. The diagnostic accuracy of these clinical findings, and the potential benefit of incorporating point-of-care test results, was assessed by calculating areas under the receiver operating characteristic curves (AUC). RESULTS: Clinician-rated bulbar conjunctival redness, participant-rated eyelid swelling and overall ocular discomfort had the best predictive value in the multivariate logistic regression model with an AUC of 0.83. The addition of the point-of-care test results to these three clinical sign/symptom scores improved diagnostic accuracy, increasing the AUC to 0.94. CONCLUSIONS: Conjunctival redness severity and participant-reported eyelid swelling and overall discomfort, along with adenoviral point-of-care test results, were highly predictive in identifying individuals with PCR-confirmed adenoviral conjunctivitis. Improved diagnostic accuracy by clinicians at the initial presenting visit could prevent unnecessary work furloughs and facilitate earlier treatment decisions.

Efficacy of a Single Administration of 5% Povidone-Iodine in the Treatment of Adenoviral Conjunctivitis.

PURPOSE: To evaluate the safety and efficacy of a single, in-office administration of 5% povidone-iodine (PVP-I) compared to artificial tears (AT) for adenoviral conjunctivitis (Ad-Cs). DESIGN: Double-masked pilot randomized trial. METHODS: Patients presenting with presumed adenoviral conjunctivitis were screened at 9 U.S. clinics. INCLUSION CRITERIA: ≥18 years of age, symptoms ≤4 days, and a positive AdenoPlus test. EXCLUSION CRITERIA: thyroid disease, iodine allergy, recent ocular surgery, and ocular findings inconsistent with early-stage Ad-Cs. Randomization was to a single administration of 5% PVP-I or AT in 1 eye and examinations on days 1-2, 4, 7, 14, and 21 with conjunctival swabs taken at each visit for quantitative polymerase chain reaction. Primary outcome was percent reduction from peak viral load. Secondary outcomes were improvement in clinical signs and symptoms. RESULTS: Of 56 patients randomized, 28 had detectable viral titers at baseline. Day 4 posttreatment, viral titers in the 5% PVP-I and AT groups were 2.5% ± 2.7% and 14.4% ± 10.5% of peak, respectively (P = .020). Severity of participant-reported tearing, lid swelling, and redness as well as clinician-graded mucoid discharge, bulbar redness, and bulbar edema were lower in the 5% PVP-I group than AT group on day 4 (P < .05). After day 4, viral titers and severity of signs and symptoms decreased markedly in both groups and no differences between groups were detected. CONCLUSIONS: Pilot data suggest a single, in-office administration of 5% PVP-I could reduce viral load and hasten improvement of clinical signs and symptoms in patients with Ad-Cs.

Predictive Accuracy and Densitometric Analysis of Point-of-Care Immunoassay for Adenoviral Conjunctivitis.

Purpose: Accurate diagnosis of adenoviral conjunctivitis (Ad-Cs) is important for timely and appropriate patient management to reduce disease transmission. This study assessed the diagnostic accuracy of a commercially available point-of-care adenovirus immunoassay and determined whether its predictive accuracy is influenced by signal intensities of test result bands. Methods: Point-of-care immunoassay (AdenoPlus) testing and quantitative polymerase chain reaction (qPCR) testing was performed on conjunctival swab samples obtained from eyes of 186 eligible adult participants with presumed infectious conjunctivitis and symptoms of ≤4 days. Masked observers assessed signal intensities of the immunoassay test and control bands using densitometry. Results: Ad-Cs was confirmed by qPCR in 28 of the 56 eyes that tested positive on the AdenoPlus, a 50% positive predictive value (95% confidence interval [CI] = 36.9, 63.1). No adenovirus was detected by qPCR in 128 of 130 eyes that tested negative on AdenoPlus, a 98.5% negative predictive value (CI = 96.3, 100). Sensitivity and specificity were 93% (CI = 84.4, 100) and 82% (CI = 76.0, 88.1), respectively. Viral titers significantly correlated with ratio of test band signal intensities (R2 = 0.32, P = 0.002). Higher positive predictive value was associated with higher densitometry ratios (receiver operating characteristic [ROC] area = 0.71; 95% CI = 0.59, 0.83). Conclusions: Densitometric analyses suggest that the diagnostic accuracy of AdenoPlus is influenced by the signal intensity of the test result bands. Visual comparison of the test band intensities by clinicians could reduce the false positive rate of point-of-care immunoassays and aid in the diagnosis of viral infections. Translational Relevance: Ratiometric densitometry of point-of-care immunoassays could aid clinicians' decision making in diagnosing infectious diseases, including Ad-Cs.

Safety and tolerability of a one-time, in-office administration of 5% povidone-iodine in the treatment of adenoviral conjunctivitis: The Reducing Adenoviral Patient Infected Days (RAPID) study.

PURPOSE: To report safety and tolerability of a one-time administration of ophthalmic 5% povidone-iodine (5% PVP-I) in a double-masked randomized trial for the treatment of adenoviral conjunctivitis (Ad-Cs). METHODS: Of 212 participants screened, 56 eligible participants with red eye symptoms ≤4 days and a positive adenoviral rapid immunoassay were randomized to a one-time administration of ophthalmic 5% PVP-I or preservative free artificial tears (AT). Safety was assessed by corneal fluorescein staining (baseline, immediate post-administration and Day 1) and visual acuity (VA) (baseline and Day 1). Tolerability was assessed using participant-rated overall ocular discomfort (baseline, immediately post-administration and on Day 1. RESULTS: In the 5% PVP-I group, corneal staining increased immediately post-administration but returned to baseline levels by Day 1. There was no change in VA between baseline and Day 1 in either 5% PVP-I or AT groups (p = 0.87). In the 5% PVP-I group, there was no change in participant-rated overall discomfort immediately post-administration (p = 0.78) or on day 1 (p = 0.10) compared to baseline. In the AT group, participant-rated overall discomfort was lower immediately post-administration but returned to baseline levels by Day 1. One adverse event was reported in the 5% PVP-I group on Day 1-2 that was classified as not related to treatment. CONCLUSION: These results suggest ophthalmic 5% PVP-I used as a one-time treatment is safe and well tolerated by patients with Ad-Cs.

Latanoprost-induced stabilization of central visual function in patients with primary open-angle glaucoma.

PURPOSE: Previous studies have demonstrated that visual function as measured by contrast sensitivity (CS) improves in primary open-angle glaucoma (POAG) patients following beta-blocker therapy and trabeculoplasty. There is evidence that ocular hypotensive agents, such as latanoprost, may provide benefit in terms of improved visual function, despite relatively small differences in the ocular hypotensive effect, when compared to other drugs. The aim of this study was to prospectively compare the effects of latanoprost and timolol maleate in Gelrite on CS. METHODS: Twenty (20) POAG patients on a monotherapy treatment regimen of topical beta blockade and with clinically stable intraocular pressure (IOP) were recruited for this single-masked, randomized, crossover study. Subjects were randomized to begin treatment with latanoprost 0.005% once-daily in the evening or timolol maleate 0.5% in Gelrite once-daily in the morning. At the end of a 3-month treatment period, each subject was crossed over to receive the alternative treatment for 3 months. Blood pressure, heart rate, IOP, and CS were assessed at baseline and after 4, 12, 16, and 24 weeks of treatment. Static central contrast sensitivity was evaluated at four spatial frequencies, 3, 6, 12, and 18 cycles/degree. Visual-field sensitivity was evaluated by using a commercially available program. Static threshold visual-field sensitivity was assessed at baseline and after 12 and 24 weeks of treatment. RESULTS: Subjects who were treated for 3 months with latanoprost, after being switched from timolol, experienced an improvement in CS at 3 cpd (P = 0.03). Conversely, subjects who were treated for 3 months with timolol, after being switched from latanoprost, demonstrated a significant loss in CS at 3 cpd (P = 0.04) and at 18 cpd (P = 0.03). Changes in CS occurred without a corresponding change in IOP, since there were no between-group differences (P > 0.05) at the end of each treatment phase. CONCLUSIONS: Compared with timolol maleate in Gelrite, latanoprost appears to significantly improve, or at least maintain, central visual function, as measured by CS, at different spatial frequencies in patients with POAG.

Aniseikonia testing in an adult population using a new computerized test, "the Aniseikonia Inspector".

PURPOSE: To determine the measurement characteristics of a new computerized test, the Aniseikonia Inspector Version 1, on a sample of clinic patients. METHODS: Aniseikonia was measured in the vertical, horizontal, and oblique meridians on 320 patients (mean 55 years old, range 17-89 years) prior to their optometric exam using the psychometric methods programmed into the Aniseikonia Inspector Version 1. Statistical analyses were performed to determine the distribution of aniseikonia in the sample of patients and the relationships between the amount of aniseikonia and patients' habitual refractive correction, visual acuity, stereopsis and binocular alignment status. The characteristics of the individual measurements were also examined. RESULTS: The means and standard deviations of the measured aniseikonia in the vertical, horizontal, and oblique meridians were -0.5% (2.5%), -0.1% (3.3%) and 0.3% (2.8%) respectively. The means in the vertical and oblique meridians were significantly different from 0.0 (p=0.0001, p=0.0314) while that in the horizontal was not (p=0.61). The distributions of aniseikonia showed that 65.6%, 57.5% and 64.3% had within +/-1.0% aniseikonia in the vertical, horizontal and oblique meridians, respectively. Correspondingly, 16.9%, 25.6% and 25.8% had aniseikonia of +/-3.0% or greater. The discrepancy between these percentages and those expected in a normal distribution indicate that the distributions were significantly more peaked than a normal distribution. This departure from normal is due to a few extreme values in the tails. The magnitude of aniseikonia had no statistically significant relationship with the patients' habitual refractive correction, visual acuity or stereopsis. The effect of phoria on the amount of aniseikonia was significant, more so for measurements in the horizontal meridian. The individual measurements, which are the average of two trials using the method of adjustment, showed no significant bias, no relationship between the means and differences in the two readings, but large differences between the two readings. Measurements in the vertical direction seem to be more stable than those in the other two meridians. CONCLUSION: As measured with the Aniseikonia Inspector 1.0, the majority of the patients sampled in this study exhibited 1.0% or less aniseikonia and were therefore not likely to have symptoms related to aniseikonia. At least 17% of patients had 3.0% or greater aniseikonia measured in the vertical meridian. The Aniseikonia Inspector warrants further evaluation in a clinical setting because of the large limits of agreement between the two settings that are average to determine the magnitude of the aniseikonia. These limits differ considerably from those established by the designers and, therefore, raise questions regarding the actual resolution of the instrument as compared to the nominal resolution.

Comparison of low-abundance biomarker levels in capillary-collected nonstimulated tears and washout tears of aqueous-deficient and normal patients.

PURPOSE: Low tear volume limits the use of nonstimulated (NS) microcapillary tear collection in aqueous-deficient (AD) patients. Adding a small amount of "washout" fluid to the eye prior to tear collection is a potentially viable alternative method for abundant proteins, but is relatively untested for low-abundance biomarkers. This study determined the feasibility of the washout (WO) method as an NS alternative for low-abundance biomarkers. NS and WO biomarker profiles were compared between AD patients and non-AD controls to determine if the two methods identify the same intergroup differences. METHODS: Matching NS and WO tears were collected from 48 patients by micropipette, the WO sample after instillation of 10 µL saline. Tear cytokine levels were measured by 27-Plex Bio-Rad assay. Bland-Altman analyses for each biomarker determined the agreement between tear sample types. Patients were grouped as AD or non-AD based on Schirmer score to determine if NS profile between-group differences were preserved in WO tears. RESULTS: Bland-Altman plots showed good biomarker level agreement between NS and WO tears for most cytokines. Five biomarkers, among those most often cited as differing in AD dry eye, differed significantly between non-AD and AD groups in both tear types. Additional biomarker differences were seen in NS tears only. CONCLUSIONS: The WO tear collection method is a viable alternative to NS tears for many low-abundance biomarkers and is able to replicate major NS tear differences between dry eye groups. More subtle intergroup differences are lost in WO samples because of reduced statistical power.

Idiopathic amblyopia: a diagnosis of exclusion. A report of 3 patients.

PURPOSE: The aim of this study was to report the clinical course for 3 young patients diagnosed with idiopathic amblyopia. CASE REPORTS: The clinical course for 3 young patients with unilateral visual loss initially attributed to idiopathic amblyopia is presented. Extensive evaluations over the years, including optical coherence tomography, were performed in addition to routine clinical testing. In 1 patient, transient anisometropic refractive error during infancy was likely causative for the unilateral visual loss. For the second patient, a subclinical microtropia with varying eccentric fixation was subsequently diagnosed, and for the third patient, a subtle retinal disorder was subsequently diagnosed. CONCLUSION: The diagnosis of idiopathic amblyopia is one of exclusion and should only be made after extensive testing to rule out subclinical binocular vision or pathological anomalies.