Abstract
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 6/9 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.
Keywords: adenovirus, conjunctivitis, natural history
Introduction
Viral conjunctivitis is estimated to be the cause of up to 80% of cases of infectious conjunctivitis with most viral infections attributed to adenovirus.[1] Adenoviral conjunctivitis (Ad-Cs) is generally self-limiting with signs and symptoms improving over time even without treatment; however, the duration of viral infection has not been well documented. Incubation time has been estimated between 512 days[2,3] until symptom onset.[4] The range of symptoms duration has been estimated to last from 7 to 28 days.[5,6] While the presence or absence of symptoms and signs are often used by clinicians to determine whether to extend or to end quarantine, there is little data in the literature regarding the relationship between the duration of signs/symptoms and adenovirus clearance from the conjunctiva. Signs and symptoms associated with Ad-Cs (conjunctival redness, conjunctival edema, and discharge) involve inflammatory pathways similar to host immune-inflammatory responses seen with other viral infections including herpetic eye disease, pharyngoconjunctival fever, epidemic keratoconjunctivitis, and nonspecific follicular conjunctivitis.[7,8] Infectious and non-infectious etiologies can result in localized inflammatory changes of conjunctival blood vessels including vasodilation, hyperemia, and edema.[8] A previous report has shown that higher Ad-Cs viral titers are correlated with more severe signs and symptoms and longer duration of time for viral clearance.[9] An objective, evidence-based approach to determine appropriate quarantine length is needed as a typical work furlough for Ad-Cs is one to two weeks resulting in loss of 25% to 50% of monthly earning[10] and reduced productivity for small businesses.[10-13]
Quantitative polymerase chain reaction (qPCR), a molecular technique that quantifies the amount of specific nucleic acids present, has become the gold standard for confirming Ad-Cs[14] diagnosis and can detect trace amounts of viral titers (182 DNA copies/ml).[15]
Additionally, qPCR provides an objective measurement of the change in viral titers over time. While the exact threshold level for titers at which a patient is no longer capable of spreading infection is unknown, one can presume that a patient is non-infectious when adenoviral nucleic acids are no longer detectable, as it reflects complete clearance of the virus (live or dead) from the eye.[16, 17] Clinically, it can be difficult to determine when a patient is no longer infectious. However, when there is no longer detectable adenoviral DNA present, clinicians can assume that a patient is no longer infectious.
In this study, data from the control group of the NEI funded Reducing Adenoviral Patient Infected Days (RAPID) pilot study (R-34) which compared the treatment arm (in-office 5% ophthalmic povidone iodine) to the control arm (in-office saline) are reported.[16] The severity of signs and symptoms was correlated to viral clearance over time using longitudinal analyses.[9] This report highlights viral titers in the control group (in-office saline lavage followed by preservative free artificial tears) as assessed by qPCR at baseline and follow up (days 1, 4, 7, 14, and 21) during which time signs and symptoms were also assessed by masked patients and clinicians. The untreated control group provided the unique opportunity to describe the natural history of Ad-Cs. The results from the randomized trial that compared the treatment arm to the control arm have been previously reported. Results from the pilot study by Than et al suggested that a single, in-office administration of 5% PVP-I could not only improve signs and symptoms of Ad-Cs but also reduce viral load.[16] The purpose of this report is to 1) describe the duration of detectable adenoviral titers, as determined by qPCR in ‘untreated’ (receiving only in-office saline lavage) control participants over a 3-week period and 2) investigate the resolution of several clinical signs and symptoms associated with untreated Ad-Cs. By understanding the natural history of the disease and time-course for viral clearance relative to the resolution of clinical signs and symptoms of Ad-Cs, a more evidence-based approach for assessing infectivity would be justified to determine quarantine length and timing for safe return to work or school.
Materials and Methods
Study Participants
Patients with acute onset red eyes and suspected Ad-Cs were recruited for the RAPID study at nine clinical sites including academic centers, tertiary medical centers, and an Army medical center in the United States between March 2015 and July 2018 (Table 1). Institutional review board approval was obtained by each study site and the Coordinating Center at Washington University in St. Louis, Missouri, USA. Written informed consent was obtained from all participants and study procedures followed the ethical standards of the Declaration of Helsinki and Good Clinical practices. The study is registered at https://clinicaltrials.gov/ct2/show/ NCT02472223.
Table 1:
Demographic and baseline clinical characteristics of participants in control group (in-office saline lavage followed by preservative free artificial tears) with Ad-Cs confirmed by immunoassay and qPCR. Symptoms and clinical signs were classified as “present” when symptom grade was greater than “1” on a scale from “0” to “10” and when clinical grade was greater than “0” on a scale from “0” to “4”.
| n | % | ||||||
|---|---|---|---|---|---|---|---|
| Sex | |||||||
| Male | 5 | 41.7 | |||||
| Female | 7 | 58.3 | |||||
| Racial Category | |||||||
| White | 5 | 41.7 | |||||
| African American | 4 | 33.3 | |||||
| Other | 3 | 25.0 | |||||
| Eye infected at screening | |||||||
| Right eye | 4 | 33.3 | |||||
| Left eye | 2 | 16.7 | |||||
| Both eyes | 6 | 50.0 | |||||
| N | Mean | Std | 25th %tile | Median | 75th %tile | ||
| Age at screening (years) | 12 | 40.3 | 14.0 | 29.0 | 37.5 | 52.5 | |
| Onset prior to screening (days) | 12 | 2.7 | 1.3 | 1.5 | 2.5 | 4.0 | |
| Log qPCR | 12 | 6.4 | 1.2 | 5.8 | 6.4 | 7.1 | |
| Baseline days missed | 12 | 0.5 | 1.0 | 0.0 | 0.0 | 0.5 | |
| Baseline days missed anyone in household | 12 | 0.3 | 0.9 | 0.0 | 0.0 | 0.0 | |
| Tearing Symptom 0-10 | 12 | 7.0 | 3.0 | 5.5 | 7.5 | 10.0 | |
| Matting Symptom 0-10 | 12 | 7.0 | 2.9 | 5.5 | 8.0 | 9.0 | |
| Burning Symptom 0-10 | 12 | 4.9 | 3.4 | 2.5 | 4.5 | 8.0 | |
| Itching Symptom 0-10 | 12 | 5.0 | 2.9 | 2.5 | 6.0 | 7.5 | |
| Gritty Symptom 0-10 | 12 | 7.0 | 2.3 | 6.0 | 8.0 | 8.0 | |
| Swelling Symptom 0-10 | 12 | 6.6 | 3.5 | 5.5 | 7.5 | 9.5 | |
| Redness Symptom 0-10 | 12 | 8.9 | 1.4 | 8.0 | 9.5 | 10.0 | |
| Blurred Vision Symptom 0-10 | 12 | 5.9 | 3.4 | 3.5 | 5.5 | 9.5 | |
| Sensitive to light Symptom 0-10 | 12 | 6.6 | 3.1 | 5.0 | 6.0 | 10.0 | |
| Overall Discomfort Symptom 0-10 | 12 | 8.4 | 1.3 | 7.0 | 8.0 | 10.0 | |
| SLE Lid Edema | 12 | 1.8 | 1.3 | 0.8 | 1.9 | 3.0 | |
| SLE Lid Matting | 12 | 1.2 | 1.1 | 0.0 | 1.2 | 1.9 | |
| SLE Mucoid discharge | 12 | 0.9 | 1.0 | 0.0 | 0.5 | 1.6 | |
| SLE Serous Discharge | 12 | 2.4 | 0.8 | 2.0 | 2.0 | 3.0 | |
| SLE bulbar edema | 12 | 2.1 | 1.5 | 1.0 | 1.9 | 3.6 | |
| SLE bulbar redness | 12 | 3.2 | 0.9 | 2.5 | 3.4 | 4.0 | |
| SLE follicular response | 12 | 2.2 | 1.5 | 0.6 | 2.9 | 3.4 | |
| SLE papillary response | 12 | 2.0 | 1.3 | 1.0 | 1.9 | 3.1 | |
Inclusion criteria included age ≥18 years with red eye symptoms of 4 days or less and a positive point-of-care immunoassay test for the adenovirus antigen (AdenoPlus, now named QuickVue Adenoviral conjunctivitis test, Quidel Corp., San Diego, CA). If both eyes were affected, the first eye affected was selected as the study eye. If both eyes became symptomatic on the same day, the study eye was randomly selected. Exclusion criteria included a history of thyroid disease, allergy to iodine or study medications, ocular surgery within the past 3 months, skin vesicles, corneal dendrites, conjunctival membrane or pseudomembrane, subepithelial corneal infiltrates, corneal ulceration, corneal abrasion, corneal foreign body, anterior chamber inflammation, or pregnancy/nursing. Participants with corneal infiltrates and/or a pseudomembrane were excluded as these sequelae typically present later during Ad-Cs infection.
A total of 212 participants were screened, and 186 participants had both AdenoPlus and qPCR results. Seventy percent (130 of 186) of participants tested AdenoPlus negative and were excluded and 30.1% (56 of 186) were AdenoPlus positive and were eligible to participate. 98.5% of participants (128 of 130) who tested AdenoPlus negative also tested negative by qPCR.[16] Of the 56 participants who tested AdenoPlus positive, 50% (28) had detectable adenovirus at baseline by qPCR and were randomized (12 to control group, 16 to 5% PVP-1).[16]
All eligible participants in both the control group and 5% PVP-1 group completed a baseline examination and follow-up visits with a masked clinician on days 1 to 2, 4 (days 3–5), 7 (days 6–10), 14 (days 11–17) and 21 (days 18–21). A 21-day follow up was selected to be conservative. At each visit, participants rated the “bothersomeness” of 10 symptoms: tearing, eyelash matting, burning, itching, gritty/sandy, eyelid swelling, redness, blurred vision, sensitivity to light, and overall discomfort on a scale of 0 (not at all bothersome) to 10 (very bothersome). A scale score of 0 was classified as absent and a scale score of 1 or greater was classified as present. Seven ocular clinical signs were graded by masked clinicians using a standardized grading scale from “0” (absent) to “4” (severe) for serous discharge, bulbar redness, mucoid discharge, eyelid edema, eyelash matting, bulbar edema, and conjunctival follicles. Clinical signs were classified as “present” when the clinical grade was greater than “0” on a scale from “0” to “4”.[18]
The presence of the 8 signs (7 ocular signs plus lymph nodes) stratified by presence or absence of detectable virus for each of the 6 visits is shown in Appendix 2.
Participants were randomized 1:1 to receive in-office saline lavage (control group) or to treatment with 4-5 drops of ophthalmic 5% povidone-iodine (Alcon, Fort Worth, TX). This report includes only participants randomized to the control group to describe the natural history of untreated Ad-Cs. All participants were prescribed preservative-free artificial tears for at-home use in between the follow-up visits.
Ad-Cs Confirmation
Molecular qPCR testing at baseline and follow-up visits was used to confirm the presence of adenovirus. Conjunctival swab samples were collected from the inferior palpebral conjunctiva at each visit. The samples were stored in a −80-degree Celsius freezer within four hours of collection. Samples were shipped on dry ice to Washington University (St. Louis, MO) for DNA extraction and qPCR analysis for adenovirus. After completion of all study visits, qPCR analysis was performed with all samples for a given participant in a single batch. Detailed methods on the qPCR analyses have been previously reported.[15-17] qPCR results were not disclosed to clinicians.
Statistical analysis
For each visit, means and standard deviation (SD) are reported for signs and symptoms as well as the proportion of participants with symptoms or signs classified as “present” or “absent”.
The presence of the 10 symptoms stratified by presence or absence of detectable virus for each of the 6 visits is shown in Appendix 1. Wilcoxon exact test was used to compare age, baseline discomfort, baseline log qPCR and baseline bulbar redness for the participants that completed the day 14 and day 21 visits.
Results
Two hundred and twelve participants who presented with presumed Ad-Cs were consented and screened. Of the 212 participants screened, 28 tested positive at baseline for Ad-Cs using AdenoPlus and qPCR. These 28 participants were randomized, with 12/28 assigned to the saline control group and 16/28 assigned to the 5% PVP-1 group. Baseline demographic and clinical information (participant-reported symptoms and clinician-graded signs) for the 12 participants assigned to the saline control group are reported in Table 1.
At the initial study visit, day 1-2 visit, and day 4-5 visit, all participants (n=12, 9 and 8 respectively) who completed the visits had detectable adenoviral titers. Three participants were lost to follow up. By follow-up day 7, the percentage of participants with detectable virus declined. On day 7, 44% of participants who completed the follow-up visit (4 of 9) had no detectable virus using qPCR testing and at day 14, 67% (6 of 9) had no detectable virus. By day 21, all participants who completed the visit (7) had no detectable viral titers using qPCR analysis.
Participant-Reported Symptoms
All ten symptoms assessed in this study were reported by 67% or more of the participants at baseline, day 1-2 visit and day 4-5 visit (Table 2). On day 7, although no participants reported redness, other symptoms persisted (Table 2). At Day 14, participants with no detectable viral titers (3/8) reported ocular discomfort, blurry vision, and/or light sensitivity. At day 21, symptoms persisted with 5/7 reporting blurry vision (Table 2). Reported blurry vision and/or sensitivity to light could be attributed to the persistence of other signs and symptoms including serous discharge, lid edema, and follicular conjunctivitis.
Table 2:
The number of participants with symptom presence/ number of participants with viral titers detectable or not detectable at each visit.
| Symptom | Baseline (n=12) |
Day 1-2 (n=9) | Day 4-5 (n=8) |
Day 7 (n=9) | Day 14 (n=8) | Day 21 (n=7) |
||
|---|---|---|---|---|---|---|---|---|
| 100% Virus detectable |
100% Virus detectable |
100% Virus Detectable |
Virus Detectable (n=5, 56%) |
Not Detectable (n=4, 44%) |
Virus Detectable (n=3, 33%) |
Not Detectable (n=6, 67%) |
100% Not detectable |
|
| Redness | 12/12 | 9/9 | 8/8 | 5/9 | 0/9 | 0/8 | 2/8 | 1/7 |
| Tearing | 11/12 | 8/9 | 8/8 | 4/9 | 3/9 | 1/8 | 0/8 | 0/7 |
| Discomfort | 12/12 | 9/9 | 8/8 | 4/9 | 3/9 | 1/8 | 3/8 | 2/7 |
| Swelling | 10/12 | 9/9 | 8/8 | 3/9 | 2/9 | 1/8 | 1/8 | 0/7 |
| Burning | 10/12 | 6/9 | 7/8 | 2/9 | 2/9 | 0/8 | 1/8 | 0/7 |
| Blurry Vision | 11/12 | 9/9 | 7/8 | 3/9 | 3/9 | 1/8 | 4/8 | 5/7 |
| Itching | 11/12 | 6/9 | 6/8 | 3/9 | 1/9 | 0/8 | 2/8 | 0/7 |
| Gritty | 12/12 | 8/9 | 6/8 | 4/9 | 1/9 | 1/8 | 2/8 | 1/7 |
| Matting | 11/12 | 9/9 | 8/8 | 4/9 | 3/9 | 1/8 | 0/8 | 0/7 |
| Sensitivity to Light | 11/12 | 7/9 | 7/8 | 2/9 | 3/9 | 0/8 | 3/8 | 2/7 |
The presence of the 10 symptoms stratified by presence or absence of detectable virus for each of the 6 visits is shown in Appendix 1. Wilcoxon exact test was used to compare age (p=0.6828), baseline discomfort (p=0.5051), baseline log qPCR (p=0.5697) and baseline bulbar redness (p=0.7798) for the participants who completed the day 14 visit. Wilcoxon exact test was used to compare age (p=0.7551), baseline discomfort (p=0.1919), baseline log qPCR (p=1.0) and baseline bulbar redness (p=0.7298) for participants who completed the day 21 visit. There were no differences found for baseline demographics, overall patient discomfort and bulbar redness between participants who completed the day 14 and day 21 visits and those who did not.
Masked Clinician-Graded Signs
At baseline, day 1-2, and day 4-5 visits, clinicians noted eight signs of Ad-Cs in 50% or more of these participants (Table 3). On day 7, clinicians noted the presence of redness and follicular conjunctivitis in 3/8 of the participants and lid edema, matting, and bulbar edema in 2/8 of the participants. At the day 14 visit, clinicians noted the presence of follicular conjunctivitis in 5/8, redness in 4/8, bulbar edema in 3/8, and lid edema in 3/8 participants. At the day 21 visit, clinicians noted the presence of redness in 4/7, follicular conjunctivitis in 4/7, and bulbar edema in 3/7 participants (Table 3).
Table 3:
Number of participants with clinician-graded signs present / number of participants with viral titers detectable or not detectable at each visit.
| Sign | Baseline (n=12) |
Day 1-2 (n=9) |
Day 4-5 (n=8) |
Day 7 (n=8) | Day 14 (n=8) | Day 21 (n=7) |
||
|---|---|---|---|---|---|---|---|---|
| 100% Virus detectable |
100% Virus detectable |
100% Virus detectable |
Virus Detectable (n=5, 63%) |
Not Detectable (n=3, 37%) |
Virus Detectable (n=3, 33%) |
Not Detectable (n=6, 67%) |
100% Not detectable |
|
| Redness | 12/12 | 9/9 | 8/8 | 5/8 | 3/8 | 2/8 | 4/8 | 4/7 |
| Follicular Conjunctivitis | 9/12 | 9/9 | 7/8 | 5/8 | 3/8 | 1/8 | 5/8 | 4/7 |
| Serous Discharge | 12/12 | 9/9 | 8/8 | 4/8 | 1/8 | 0/8 | 2/8 | 0/7 |
| Lid Edema | 10/12 | 6/9 | 7/8 | 3/8 | 2/8 | 1/8 | 3/8 | 1/7 |
| Mucoid Discharge | 6/12 | 4/9 | 5/8 | 1/8 | 0/8 | 0/8 | 1/8 | 0/7 |
| Matting | 7/12 | 6/9 | 5/8 | 3/8 | 2/8 | 0/8 | 1/8 | 0/7 |
| Bulbar Edema | 10/12 | 9/9 | 8/8 | 5/8 | 2/8 | 1/8 | 3/8 | 3/7 |
| Palpable Lymph Nodes | 7/12 | 6/9 | 4/8 | 1/8 | 1/8 | 0/8 | 2/8 | 1/7 |
The presence of infiltrates and/or pseudomembranes at the baseline visit excluded participants from this study. Each participant was evaluated at every follow-up visit for the presence/absence of infiltrates and/or pseudomembranes. If a subject developed an infiltrate or pseudomembrane during the follow up period, they were allowed to continue with the study. Depending on symptoms and/or severity of corneal involvement, they were managed with preservative free artificial tears, cool compresses and/or topical corticosteroids based on the clinician’s judgement.
Discussion
In this study, the natural history of Ad-Cs is described using a detailed assessment of viral titers with qPCR performed at baseline and follow up (days 1, 4, 7, 14, and 21). Viral titers were detected in all participants through the day 4-5 visit. By day 7, slightly more than half (56%) of participants had detectable virus reducing to 33% at day 14. On day 21, no participants had detectable virus. Additionally, signs and symptoms of Ad-Cs were assessed using standardized measures by masked patients and masked clinicians. There is no published data on the natural history of resolution of untreated Ad-Cs, specifically viral load in relation to clinical signs and symptoms.
Previous reports have suggested that 13 days after symptom onset, most eyes with Ad-Cs test negative by viral culture.[2,3,19] In this study, a third of patients still had detectable viral titers on day 14; however, none were present on day 21. Of those participants who did not have viral titers on day 14, signs (redness, follicular conjunctivitis, lid and bulbar edema) persisted. At day 21 while there were no viral titers, many participants continued to have signs and symptoms of Ad-Cs (eyelid matting burning, grittiness, eyelid swelling, overall discomfort, bulbar edema, bulbar redness, follicles, and infiltrates). On day 21 no participants had serous or mucus discharge. The presence or absence of palpable lymph nodes was not diagnostic or indicative of viral clearance in this series and therefore palpable lymph nodes should not rule in Ad-Cs, which is a common evaluation in the diagnosis of viral conjunctivitis. The results of this study suggest that symptoms of Ad-Cs are variable and should not be used by clinicians to determine when viral titers are no longer detectable using qPCR. Thus, the data collected from this series of untreated individuals with Ad-Cs indicate that the resolution of signs and symptoms (for example, redness, follicular conjunctivitis, and edema) is a poor indicator of viral clearance.
Saline has been used as an in-office treatment for infectious and non-infectious etiologies of conjunctivitis.[20] The in-office preservative-free buffered saline lavage may have shortened the duration of active virus in this study by lavaging the ocular surface. However, the administration of preservative free artificial tears during the follow up period was provided to both the treatment group and control group.[9] This suggests that artificial tears may provide more symptomatic relief and have little effect on viral load.
Adenoviral conjunctivitis is extremely contagious, and outbreaks often occur in close communities and crowded settings such as school dormitories, healthcare offices, and military housing. Individuals diagnosed with Ad-Cs are typically educated to isolate from others to reduce transmission to others. The absence of symptoms and signs is often used by clinicians to determine the duration of patient quarantine, however, there is little data to support the validity of signs and symptoms as evidence of viral clearance. Signs and symptoms associated with Ad-Cs (conjunctival redness, conjunctival edema, and discharge) involve inflammatory pathways and may persist beyond clearance of adenovirus from the eye.[21] More recently, there has been discussion regarding hyperinflammation due to cytokine storm and uncontrolled viral replication found with COVID-19.[22] The persistence of signs and symptoms due to Ad-Cs could also perhaps be due to a similar inflammatory process as they are both viruses and may have ocular sequelae (viral conjunctivitis).
Conjunctival hyperemia or redness is caused by vasodilation of the microvasculature induced by histamine released from mast cells in the affected tissue in response to inflammation due to a variety of both infectious and non-infectious etiologies.[8] Histamine increases capillary permeability, accumulation of plasma proteins, subsequently resulting in localized edema.[21] In response to pathogen invasion of conjunctival tissue, the vasculature mounts an inflammatory response resulting in dilation and increased permeability of conjunctival vessels, which leads to exacerbation of inflammation and hyperemia. In response, cytokines, vasodilatory mediators, macrophages, and T cells all contribute to conjunctival inflammation and hyperemia.[8] Therefore, while these clinical signs and symptoms are viral infection initiated, these complex processes likely result in sustained clinical findings and patient symptoms after the initiating infection has resolved.
There are several strengths in this study. This report includes multiple regional representation of patients presenting with at nine clinical sites within the United States. Additionally, the study utilized serial qPCR testing, standardized clinical grading scales and clinical assessment by masked patients and masked clinicians. Negative swab samples were replicated, improving confidence that results were not due to sampling variability. qPCR testing may not be practical for the everyday clinician due to cost, time for off-site testing, and time for results. Thus, while it has limitations, point-of-care immunoassay testing may provide an estimate of viral load for the everyday clinician.
Limitations of this study include the small sample size. Viral serotyping was not completed in this study and different subtypes of adenoviral infections have different risks of complications (subepithelial infiltrates and pseudomembranes) and duration of infection.[23] Previous studies have suggested there are regional differences in prevalence of Ad-Cs and distribution of subtypes.[24] Another limitation is that it is unknown as to what extent in-office saline irrigation reduces viral burden from the ocular surface. The control group represented may approximate the natural history of Ad-Cs. Finally, the inclusion criterion consisted of adults and findings may not be applicable to pediatric populations.
For patients with Ad-Cs, it can be challenging for clinicians to determine when to allow a patient to return to work or school. In this study, symptoms and signs persisted after viral titers were no longer detectable by qPCR. As an alternative, previous studies suggest that point of care assay tests may be a better indicator of the presence of viral titers.[15] Using clinical signs and symptoms to set duration of the quarantine period in patients with Ad-Cs could result in patients being furloughed longer than necessary and with a resultant economic impact. A very conservative 21-day quarantine could be recommended but infectivity was not directly studied.
Supplementary Material
Appendix 1: Viral load for each patient at each visit: Baseline/screening, Day 1-2, Day 4-5, Day 7, Day 14, Day 21 ● Participants with symptoms at the visit, and ○ Participants without symptoms at the visit.
Appendix 2: Viral load for each patient at each visit: Baseline/screening, Day 1-2, Day 4-5, Day 7, Day 14, Day 21 ● Participants with clinical signs at the visit, and ○ Participants without clinical signs at the visit.
Disclosure of funding:
This research was supported by: National Institutes of Health (EY023633-01A1, P30EY002687, P30EY001792 and EY01792) and a Research to Prevent Blindness Unrestricted Departmental Grant.
Footnotes
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Conflicts of interest: none
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Associated Data
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Supplementary Materials
Appendix 1: Viral load for each patient at each visit: Baseline/screening, Day 1-2, Day 4-5, Day 7, Day 14, Day 21 ● Participants with symptoms at the visit, and ○ Participants without symptoms at the visit.
Appendix 2: Viral load for each patient at each visit: Baseline/screening, Day 1-2, Day 4-5, Day 7, Day 14, Day 21 ● Participants with clinical signs at the visit, and ○ Participants without clinical signs at the visit.