Schirmer strip and conjunctival swab for viral detection on the ocular surface of adults: a scoping review

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During the COVID-19 pandemic, one of the biggest challenges is accurate diagnosis, and it is known that, in some cases, ocular manifestations are one of the first symptoms. In this context, this study has the objective of raising scientific evidence that highlights the use of Schirmer strips and conjunctival swabs as a method of sample collection for viral analysis to support future research on this theme. Methods A literature search was conducted in the PubMed, Web of Science and BVS databases, following the Scoping Review protocol defined by Joanna Briggs Institute (JBI) after the guiding question “Is it possible to detect viruses on the ocular surface with Schirmer Test and/or conjunctival swab?”. Results A total of 418 studies were identified, and after discerning analysis, 36 English written studies were selected. Three researchers analyzed studies after virus research, collection methods, and sample analysis. Publications were mainly on adenovirus, herpes simplex virus and SARS-CoV-2, and there is also evidence of ocular detection of more viruses types. Conjuntival swab analyzed through Polymerase Chain Reaction (PCR) or Reverse Transcriptase-PCR (RT-PCR) were the most used methods. Conclusions Studies have generally been conducted to understand viral infection, to develop accurate diagnostic methods and to follow the patients’ response to treatment. Most studies were performed with a small number of patients and lacked clear definitions of collection time and viral persistence since the onset of diseases. Viruses can be detected on the ocular surface through the analysis of Schirmer strips and conjunctival swabs. However, additional studies with larger populations and time permanence are necessary to develop more assertive conclusions on the theme. Ophthalmology virus detection Schirmer strip conjunctival swab ocular surface Figures Figure 1 Figure 1 Figure 2 Figure 3 Figure 4 Figure 4 Introduction Viruses are exclusively intracellular parasites and are also the smallest known infectious agents. Its mechanisms of disease are still not completely clear; however, there are direct factors that contribute to viral tropism: viral receptors in the host cell, specific cell line, and physical barriers that enable and/or inhibit infections. Once inside the cell, the virus may damage or destroy it through direct cytophatic effects, host antiviral immune responses, and/or transformations of the infected cells (1) . It is known that the eye is a site for viral infections that might appear in the intra- or extraocular space without visible systemic reverberation and affect multiple structures with variable manifestations (2, 3) . Red eye, pain and blurred vision are one of the first clinical signs and symptoms of viral ocular impairment. Conjunctivitis is the topmost ocular infection in primary health care, given that 65-90% of cases are caused by adenovirus (AdV) and occasionally herpes simplex virus (HSV) or varicella zoster virus (VZV). Keratitis caused by HSV-1 is also commonly seen, and it is still the main cause of blindness succeeding infection in developed countries, presenting approximately 40 thousand new cases of visual impairment every year worldwide (4) . Viruses that are frequently associated with ocular or systemic complications are Epstein Barr virus (EBV), Measles morbilivirus and Paramyxovirus (5) . Viral diagnosis is made after clinical signs and symptoms and laboratory results that support medical hypotheses. There are a large variety of laboratory tests, but specificity and sensitivity change from one microorganism to another. The doctor in charge, based on clinical information and previous experiences, should decide between available options considering the patient’s singularities. Cell culture and analysis of genetic material with samples collected from blood, mucosa or secretions are the main methods. In the eye, the most commonly used collection method is conjunctival swabs, but Schirmer strips have also shown good results. Current scenario The World Health Organization (WHO) declared COVID-19 a pandemic threat, because of that, the academic community has concentrated all efforts to solve the pandemic and give people’s normal lives back. The Chinese Hero and ophthalmologist Li Wenliang, MD, first reported the possibility of a novel catastrophic virus, SARS-CoV-2, and now, it is already known that, in some cases, ocular manifestations are one of the first symptoms, and consequently, the eye may contribute to the understanding of COVID-19 pathophysiology (6, 7) . Since then, several studies on ocular manifestations of SARS-CoV-2 have been conducted, but virus collection methods and associations with the ocular surface are not clearly stated. Schirmer test The idea of collecting tears as a clinical test was first introduced by the German ophthalmologist Köster in 1900. The test consisted of the placement of filter paper on all extensions of the conjunctival sac while the nasal mucosa was stimulated to produce tearing caused by nasal irritation. The objective was to exhaust tear production to evaluate the function of lacrimal glands. Therefore, this test could take up to 90 minutes, becoming exhaustive and unviable for daily medical practice (8) . In 1903, Otto Schirmer, also a German ophthalmologist, shortened the size of the paper strips and quantified tear production for 5 minutes by three methods, each one analyzed a distinct tearing stimulation pathways: ocular and palpebral mucosa, nasal mucosa, and the retina (8, 9) . Since then, several modifications have been proposed on the Schirmer test; however, this test remains important in the quantification and standardization of tear volume. Currently, it is made with a filter paper strip 60 mm long and 5 mm wide, which is inserted in the temporal side of the conjunctival sac. The patient’s eyes are closed, the strips are removed after 5 minutes, and the wet part is measured. Normal values are considered to be results greater than 15 mm, but they can vary mainly according to medication use, age and the presence of chronic diseases (10, 11) . Conjunctival swab Conjunctival swabs are the most commonly used methods for microbiological analysis because they allow the collection of cells and materials that are spread in the conjunctival sac instead of tears exclusively. The only exception are the in-office rapid antigen tests for AdV, since they are faster and they also present a good sensitivity and specificity, 89% and 94%, respectively (12) . The method of collection is also very fast and simple: a swab with a cotton tip is gently passed in rotational movements on the conjunctival sac (13) . Topic anesthesia can be used to make the procedure more confortable, since there is no significant difference in the final results when samples are analyzed by polymerase chain reaction (PCR) methods (14) . Proxymetacaine 0.5% is recommended for ocular surface anesthesia since it shows fewer bactericidal effects among the commercially available eye drops (15) . It is also recommended to use sterile swabs, since calcium-containing swabs can inhibit polymerase activity (16) . In this context, this study has the objective of raising scientific evidence that highlights the use of Schirmer strips and conjunctival swabs as a method of virus collection on the ocular surface. Methods A literature review was conducted according to what was proposed by The Joanna Briggs Institute (JBI) on Scoping Reviews (17) . All searches and publication access were completed in June 2020, and had no time limit. The guiding question “Is it possible to detect virus on the ocular surface with Schirmer Test and/or conjunctival swab?” was defined for the selection and the search of the studies. This was built through the PCC strategy, which consists of a mnemonic for the words Population, Concept and Context. In this way, “P” was defined as adult patients (older than 18 years old), “C” as Schirmer Test and conjunctival swab, and the last “C” as all viruses. For the literature search, the following descriptors, synonyms and key words were used: “adult patients”, “Schirmer test”, “conjunctival swab” and “virus”. The Boolean operators AND, NOT and OR were used between descriptors. Controlled descriptors were “Adult Patient(s)”, “Schirmer Test”, “Conjunctival Swab(s)” and “Virus”. Not controlled descriptors were “Adult(s)” OR “Patient(s)”, “Schirmer Strip(s)” and “Ocular Virus” OR “Viral Infection”. The search was performed using the databases PubMed, Web of Science, and Blibioteca Virtual em Saúde (BVS). Included articles were only those written in English, published in indexed sources, and with quantitative or qualitative approaches, primary studies and reviews. Insightful reading of the title, abstract and key words was performed to select the articles according to previously established inclusion and exclusion criteria. When the title, abstract and key words were not sufficient, the full text was also analyzed. All articles were called studies, enumerated in chronological order, and evaluated by three different researchers. Recommendations by JBI were adapted for the study singularities and used for data extraction. This article followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guideline and checklist developed under EQUADOR (Enhancing the QUAlity and Transparency Of health Research) network guidance (18) . Results Following the database search, 418 potential studies were identified. After reading the title, abstract and key words, 79 studies were selected, and 27 were excluded because they were also found in different databases. The full texts of the 52 remaining articles were read, and 16 were excluded for not answering the guiding question. Using the described methodology, a literature search found 36 articles that met all criteria. This process is shown in Fig. 1. The three researchers analyzed all studies after virus research, collection methods, and sample analysis. Most of them were experimental or observational studies developed in the United Kingdom (7/36). Studies on the topic started in 1997, but 55,6% were only published in the decade of 2011-2020. Most studies were on AdV (19-31) and HSV (22, 26, 29, 32-40) , followed by SARS-CoV-2 (40-48) . VZV (32-34) , Cytomegalovirus (CMV) (33, 34, 49) , EBV (33, 34) , Ebola (EBO ) (50, 51) , Human papillomavirus (HPV) (52) and Zika virus (53) have also been identified on the ocular surface. The evolution of published articles on AdV, HSV and SARS-CoV-2 is represented in Fig. 2. Enterovirus (EV), Coxsackievirus A24 variant (CA24v), and SARS-CoV were not found positive on the ocular samples by samples collected by conjunctival swab or Schirmer strips (21, 23, 54) . The preferred collection method was conjunctival swab alone, 29 out of 36 articles, while six studies used Schirmer strips, and only one of them compared both collection methods (26) . One of the studies was a narrative review about SARS-CoV-2 (46) . The majority of the samples were analyzed by PCR or Reverse Transcriptase-PCR (RT-PCR) with the exception of the studies number 1 ( 19) and 17 (35) , that used immunochromatography (IC) and enzyme immunoassay (EIA), and immunoblot analysis, respectively. Details of the results are specified in Fig. 3-5. Discussion A literature search found that viruses might be identified on the ocular surface through the analysis of conjunctival swabs or Schirmer strips, but studies mainly focused on AdV, HSV and SARS-CoV-2, while other viruses were still not deeply investigated. Studies that focused on the detection of AdV and HSV were linearly developed over the last 20 years and randomly conducted all over the world. In contrast, in 2020, scientists exponentially published studies on SARS-CoV-2 because the virus was first seen in the last days of 2019; in a few months, the WHO declared its disease as a pandemic, and the world’s research efforts were completely directed to overcoming this pandemic. The evolution of published articles on AdV, HSV and SARS-CoV-2 is represented in Fig. 2. In contrast to SARS-CoV (54) , SARS-CoV-2 RNA was found by RT-PCR in conjunctival swabs (40-48) , although samples were collected from a few patients, and only a low and varying percentage of them presented positive results and/or ocular symptoms (46) . Most of these studies were developed in China (40, 41, 43, 47) , mainly because the country was the first epicenter of the disease. In some cases, ocular manifestations are one of the first symptoms, and because of that, academic societ believes the eye may contribute to the understanding of COVID-19 pathophysiology (6, 7) . Recently, new studies proved the presence of in the conjunctiva, limbus, and cornea, with prominent staining in the superficial epithelium surface, key factors for the infection of SARS-CoV-2 in human cells (55) . Those results collaborate for the necessity of ocular protection in preventing the spread of viruses. Research on viral screening was, most of the time, correlated with external ocular symptoms with the purpose of solving clinical doubts between pathogenic agents and of looking after methods for a fast accurate viral diagnosis. Studies on VZV, CMV and EBV were mostly combined with HSV to determine coinfection and differential diagnosis (32-34) . Only one study correlated viral detection on the ocular surface with intraocular symptoms. This study was published in 2000 and aimed to verify the efficacy of intravenous ganciclovir treatment in immunocompromised AIDS patients with CMV retinitis. The results showed a high clinical relevance for confirming and differentiating the diagnoses of CMV retinitis when ophthalmoscopic findings were associated with PCR methods on conjunctival swab samples (49) . No other studies on the topic were found in this review, probably because the incidence of CMV retinitis in the Acquired Immunodeficiency Syndrome (AIDS) population significantly decreased with the introduction of effective antiretroviral therapy and early accurate diagnosis (56-59) . The most commonly used method for sample collection was conjunctival swabs. This method also collects conjunctival cells, while Schirmer strips allow only the collection of tears, since fluids pass to the filter paper because of gravity, viscosity, and capillary flow dynamics – the same physical processes that explain how liquids impregnate porous materials differently (60, 61) . Consequently, the samples collected represent two different materials: tears, cells and fluids dispersed in the conjunctival sac and tears and substances dissolved in it. Samples were mainly analyzed by PCR or RT-PCR, depending on the viral genetic material, DNA or RNA, respectively. PCR variations are widely used because they allow the replication and detection of low loads of viral DNA/RNA (62) . The point-of-care test was also compared with PCR effectiveness, sensitivity and specificity where high, but this field was only explored in AdV (30) , probably because of epidemiological factors related to uncontrolled and fast spread of AdV conjunctivitis (63) . This review included a large number of articles, 36, from many different countries and time periods, fact that collaborated for a broad comprehension of how the detection of viruses on the ocular surface was worldwide studied in the last decades. The results of this article may contribute for future research by clarifying key concepts that might assist the design of future researches on ocular viruses. In conclusion, viruses can be detected through the analysis of samples collected by Schirmer strips and conjunctival swabs, and studies were generally conducted to understand viral infection, to develop accurate diagnostic methods and to follow patients’ response to treatment. However, this study has some limitations: only three databases were consulted, and new articles on the theme are constantly being published, which might exclude relevant outcomes. Moreover, among the analyzed studies, most were developed on a small number of patients and lacked clear definitions of collection time and viral persistence since the onset of the diseases. Additional studies with larger populations and time permanence are necessary to develop more assertive conclusions on this topic. Declarations Funding Grant #2020/07365-8, São Paulo Research Foundation (FAPESP). 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Sabage","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYBACPgbGBhCdAMSMD0AsA0Ja2JC0MBsQqQUCQFrYJIjTIpHc/IHhj10ef//iY9U8f+4wmEsfIKQlsU2CsS25WOLGs7TbvG3PGCz7EghrAXqHObHhxhmz27wNhxkMzhB0WCLIYfWJ82+c/1bM84c4LQ0SDGyHEzec72Fj5mEjRgvPwzag244XG95gM5ac2/aMx7KHgBZ+9vTHHz78qc6TO3/44Yc3f+7ImfMQ0AIGCSBCAkweIEoDzL4DYC0k6BgFo2AUjIKRAgDV5EP+hqHyJQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-5600-2131","institution":"University of São Paulo, Campus Bauru, Brazil","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Luís","middleName":"Expedito","lastName":"Sabage","suffix":""},{"id":11674546,"identity":"ad601f24-fa39-4030-b389-d3cdee8068b3","order_by":1,"name":"Alessandra Mazzo","email":"","orcid":"https://orcid.org/0000-0001-5074-8939","institution":"University of São Paulo, Campus Bauru, Brazil","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Mazzo","suffix":""},{"id":11674547,"identity":"5879b262-32db-412a-9b39-18dae3c8d571","order_by":2,"name":"Josmar Sabage","email":"","orcid":"https://orcid.org/0000-0001-6125-2111","institution":"Lauro de Souza Lima Institute, Bauru, Brazil","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Josmar","middleName":"","lastName":"Sabage","suffix":""},{"id":11674548,"identity":"05b3de6a-3435-46f4-b4f7-6b393ba11b11","order_by":3,"name":"Taylor Endrigo Toscano Olivo","email":"","orcid":"","institution":"University of São Paulo, Campus Bauru, Brazil","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Taylor","middleName":"Endrigo Toscano","lastName":"Olivo","suffix":""},{"id":11674549,"identity":"0876be38-e6b8-4bb3-bd92-0d005ce274fe","order_by":4,"name":"Carlos Ferreira dos Santos","email":"","orcid":"https://orcid.org/0000-0002-0405-3500","institution":"University of São Paulo, Campus Bauru, Brazil","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"Ferreira dos","lastName":"Santos","suffix":""},{"id":11674550,"identity":"7bbc3bca-60cd-4c23-8e97-b95fea78bddd","order_by":5,"name":"Luiz Fernando Manzoni Lourençone","email":"","orcid":"https://orcid.org/0000-0002-5935-3148","institution":"Hospital of Rehabilitation in Craniofacial Anomalies, University of São Paulo, Bauru, Brazil","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luiz","middleName":"Fernando Manzoni","lastName":"Lourençone","suffix":""}],"badges":[],"createdAt":"2020-11-22 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SARS-CoV-2","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-113899/v4/b6e25abc48b0c01688f740b8.png"},{"id":5905846,"identity":"1311fc28-6f5e-4f48-b8c0-e7073e64ad42","added_by":"auto","created_at":"2021-02-12 16:54:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":412739,"visible":true,"origin":"","legend":"Identification of the included studies ","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-113899/v4/6dd43d8ab9c6dd15910f46b7.png"},{"id":5905718,"identity":"abe70a64-4ae1-45bd-9e65-c5279e37bcf2","added_by":"auto","created_at":"2021-02-12 16:52:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":174394,"visible":true,"origin":"","legend":"Main results of the included studies ","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-113899/v3/2e6a8e16bb55c55328192381.png"},{"id":5905575,"identity":"ddc3f134-4d00-40d2-be93-e45d9758ef2c","added_by":"auto","created_at":"2021-02-12 16:51:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":174394,"visible":true,"origin":"","legend":"Main results of the included studies ","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-113899/v4/8b1c02a3631faab7c59e56f4.png"},{"id":13660733,"identity":"a73a2e63-b708-4c30-95fa-50091b7334b4","added_by":"auto","created_at":"2021-09-17 10:26:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1459905,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-113899/v4/c24c4d40-86d2-473c-9ad0-59026049caea.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eSchirmer strip and conjunctival swab for viral detection on the ocular surface of adults: a scoping review\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eViruses are exclusively intracellular parasites and are also the smallest known infectious agents. Its mechanisms of disease are still not completely clear; however, there are direct factors that contribute to viral tropism: viral receptors in the host cell, specific cell line, and physical barriers that enable and/or inhibit infections. Once inside the cell, the virus may damage or destroy it through direct cytophatic effects, host antiviral immune responses, and/or transformations of the infected cells \u003csup\u003e(1)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; It is known that the eye is a site for viral infections that might appear in the intra- or extraocular space without visible systemic reverberation and affect multiple structures with variable manifestations \u003csup\u003e(2, 3)\u003c/sup\u003e. Red eye, pain and blurred vision are one of the first clinical signs and symptoms of viral ocular impairment. Conjunctivitis is the topmost ocular infection in primary health care, given that 65-90% of cases are caused by adenovirus (AdV) and occasionally herpes simplex virus (HSV) or varicella zoster virus (VZV). Keratitis caused by HSV-1 is also commonly seen, and it is still the main cause of blindness succeeding infection in developed countries, presenting approximately 40 thousand new cases of visual impairment every year worldwide \u003csup\u003e(4)\u003c/sup\u003e. Viruses that are frequently associated with ocular or systemic complications are \u003cem\u003eEpstein \u003c/em\u003e\u003cem\u003eBarr\u003c/em\u003e\u003cem\u003e virus\u003c/em\u003e (EBV), \u003cem\u003eMeasles\u003c/em\u003e \u003cem\u003emorbilivirus\u003c/em\u003e and \u003cem\u003eParamyxovirus\u003c/em\u003e \u003csup\u003e(5)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Viral diagnosis is made after clinical signs and symptoms and laboratory results that support medical hypotheses. There are a large variety of laboratory tests, but specificity and sensitivity change from one microorganism to another. The doctor in charge, based on clinical information and previous experiences, should decide between available options considering the patient\u0026rsquo;s singularities. Cell culture and analysis of genetic material with samples collected from blood, mucosa or secretions are the main methods. In the eye, the most commonly used collection method is conjunctival swabs, but Schirmer strips have also shown good results.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent scenario\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; The World Health Organization (WHO) declared COVID-19 a pandemic threat, because of that, the academic community has concentrated all efforts to solve the pandemic and give people\u0026rsquo;s normal lives back. The Chinese Hero and ophthalmologist Li Wenliang, MD, first reported the possibility of a novel catastrophic virus, SARS-CoV-2, and now, it is already known that, in some cases, ocular manifestations are one of the first symptoms, and consequently, the eye may contribute to the understanding of COVID-19 pathophysiology \u003csup\u003e(6, 7)\u003c/sup\u003e. Since then, several studies on ocular manifestations of SARS-CoV-2 have been conducted, but virus collection methods and associations with the ocular surface are not clearly stated.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSchirmer test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; The idea of collecting tears as a clinical test was first introduced by the German ophthalmologist K\u0026ouml;ster in 1900. The test consisted of the placement of filter paper on all extensions of the conjunctival sac while the nasal mucosa was stimulated to produce tearing caused by nasal irritation. The objective was to exhaust tear production to evaluate the function of lacrimal glands. Therefore, this test could take up to 90 minutes, becoming exhaustive and unviable for daily medical practice \u003csup\u003e(8)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; In 1903, Otto Schirmer, also a German ophthalmologist, shortened the size of the paper strips and quantified tear production for 5 minutes by three methods, each one analyzed a distinct tearing stimulation pathways: ocular and palpebral mucosa, nasal mucosa, and the retina \u003csup\u003e(8, 9)\u003c/sup\u003e. Since then, several modifications have been proposed on the Schirmer test; however, this test remains important in the quantification and standardization of tear volume. Currently, it is made with a filter paper strip 60 mm long and 5 mm wide, which is inserted in the temporal side of the conjunctival sac. The patient\u0026rsquo;s eyes are closed, the strips are removed after 5 minutes, and the wet part is measured. Normal values are considered to be results greater than 15 mm, but they can vary mainly according to medication use, age and the presence of chronic diseases \u003csup\u003e(10, 11)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConjunctival swab\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Conjunctival swabs are the most commonly used methods for microbiological analysis because they allow the collection of cells and materials that are spread in the conjunctival sac instead of tears exclusively. The only exception are the in-office rapid antigen tests for AdV, since they are faster and they also present a good sensitivity and specificity, 89% and 94%, respectively \u003csup\u003e(12)\u003c/sup\u003e. The method of collection is also very fast and simple: a swab with a cotton tip is gently passed in rotational movements on the conjunctival sac \u003csup\u003e(13)\u003c/sup\u003e. Topic anesthesia can be used to make the procedure more confortable, since there is no significant difference in the final results when samples are analyzed by polymerase chain reaction (PCR) methods \u003csup\u003e(14)\u003c/sup\u003e. Proxymetacaine 0.5% is recommended for ocular surface anesthesia since it shows fewer bactericidal effects among the commercially available eye drops \u003csup\u003e(15)\u003c/sup\u003e. It is also recommended to use sterile swabs, since calcium-containing swabs can inhibit polymerase activity \u003csup\u003e(16)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; In this context, this study has the objective of raising scientific evidence that highlights the use of Schirmer strips and conjunctival swabs as a method of virus collection on the ocular surface.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA literature review was conducted according to what was proposed by The Joanna Briggs Institute (JBI) on Scoping Reviews \u003csup\u003e(17)\u003c/sup\u003e. All searches and publication access were completed in June 2020, and had no time limit.\u003c/p\u003e\n\u003cp\u003eThe guiding question \u0026ldquo;Is it possible to detect virus on the ocular surface with Schirmer Test and/or conjunctival swab?\u0026rdquo; was defined for the selection and the search of the studies. This was built through the PCC strategy, which consists of a mnemonic for the words Population, Concept and Context. In this way, \u0026ldquo;P\u0026rdquo; was defined as adult patients (older than 18 years old), \u0026ldquo;C\u0026rdquo; as Schirmer Test and conjunctival swab, and the last \u0026ldquo;C\u0026rdquo; as all viruses.\u003c/p\u003e\n\u003cp\u003eFor the literature search, the following descriptors, synonyms and key words were used: \u0026ldquo;adult patients\u0026rdquo;, \u0026ldquo;Schirmer test\u0026rdquo;, \u0026ldquo;conjunctival swab\u0026rdquo; and \u0026ldquo;virus\u0026rdquo;. The Boolean operators AND, NOT and OR were used between descriptors. Controlled descriptors were \u0026ldquo;Adult Patient(s)\u0026rdquo;, \u0026ldquo;Schirmer Test\u0026rdquo;, \u0026ldquo;Conjunctival Swab(s)\u0026rdquo; and \u0026ldquo;Virus\u0026rdquo;. Not controlled descriptors were \u0026ldquo;Adult(s)\u0026rdquo; OR \u0026ldquo;Patient(s)\u0026rdquo;, \u0026ldquo;Schirmer Strip(s)\u0026rdquo; and \u0026ldquo;Ocular Virus\u0026rdquo; OR \u0026ldquo;Viral Infection\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003eThe search was performed using the databases PubMed, Web of Science, and \u003cem\u003eBlibioteca Virtual em Sa\u0026uacute;de \u003c/em\u003e(BVS). Included articles were only those written in English, published in indexed sources, and with quantitative or qualitative approaches, primary studies and reviews.\u003c/p\u003e\n\u003cp\u003eInsightful reading of the title, abstract and key words was performed to select the articles according to previously established inclusion and exclusion criteria. When the title, abstract and key words were not sufficient, the full text was also analyzed. All articles were called studies, enumerated in chronological order, and evaluated by three different researchers. Recommendations by JBI were adapted for the study singularities and used for data extraction. This article followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guideline and checklist developed under EQUADOR \u0026nbsp;(Enhancing the QUAlity and Transparency Of health Research) network guidance \u003csup\u003e(18)\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFollowing the database search, 418 potential studies were identified. After reading the title, abstract and key words, 79 studies were selected, and 27 were excluded because they were also found in different databases. The full texts of the 52 remaining articles were read, and 16 were excluded for not answering the guiding question. Using the described methodology, a literature search found 36 articles that met all criteria. This process is shown in Fig. 1.\u003c/p\u003e\n\u003cp\u003eThe three researchers analyzed all studies after virus research, collection methods, and sample analysis. Most of them were experimental or observational studies developed in the United Kingdom (7/36). Studies on the topic started in 1997, but 55,6% were only published in the decade of 2011-2020.\u003c/p\u003e\n\u003cp\u003eMost studies were on AdV \u003csup\u003e(19-31)\u003c/sup\u003e and HSV \u003csup\u003e(22, 26, 29, 32-40)\u003c/sup\u003e, followed by SARS-CoV-2 \u003csup\u003e(40-48)\u003c/sup\u003e. VZV \u003csup\u003e(32-34)\u003c/sup\u003e, Cytomegalovirus (CMV) \u003csup\u003e(33, 34, 49)\u003c/sup\u003e, EBV \u003csup\u003e(33, 34)\u003c/sup\u003e, Ebola (EBO\u003csup\u003e) (50, 51)\u003c/sup\u003e, Human papillomavirus (HPV) \u003csup\u003e(52)\u003c/sup\u003e and Zika virus \u003csup\u003e(53)\u003c/sup\u003e have also been identified on the ocular surface. The evolution of published articles on AdV, HSV and SARS-CoV-2 is represented in Fig. 2. Enterovirus (EV), Coxsackievirus A24 variant (CA24v), and SARS-CoV were not found positive on the ocular samples by samples collected by conjunctival swab or Schirmer strips \u003csup\u003e(21, 23, 54)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe preferred collection method was conjunctival swab alone, 29 out of 36 articles, while six studies used Schirmer strips, and only one of them compared both collection methods \u003csup\u003e(26)\u003c/sup\u003e. One of the studies was a narrative review about SARS-CoV-2 \u003csup\u003e(46)\u003c/sup\u003e. \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; The majority of the samples were analyzed by PCR or Reverse Transcriptase-PCR (RT-PCR) with the exception of the studies number 1 \u003csup\u003e(\u003c/sup\u003e\u003csup\u003e19)\u003c/sup\u003e and 17 \u003csup\u003e(35)\u003c/sup\u003e, that used immunochromatography (IC) and enzyme immunoassay (EIA), and immunoblot analysis, respectively. Details of the results are specified in Fig. 3-5.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA literature search found that viruses might be identified on the ocular surface through the analysis of conjunctival swabs or Schirmer strips, but studies mainly focused on AdV, HSV and SARS-CoV-2, while other viruses were still not deeply investigated.\u003c/p\u003e\n\u003cp\u003eStudies that focused on the detection of AdV and HSV were linearly developed over the last 20 years and randomly conducted all over the world. In contrast, in 2020, scientists exponentially published studies on SARS-CoV-2 because the virus was first seen in the last days of 2019; in a few months, the WHO declared its disease as a pandemic, and the world\u0026rsquo;s research efforts were completely directed to overcoming this pandemic. The evolution of published articles on AdV, HSV and SARS-CoV-2 is represented in Fig. 2.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; In contrast to SARS-CoV \u003csup\u003e(54)\u003c/sup\u003e, SARS-CoV-2 RNA was found by RT-PCR in conjunctival swabs \u003csup\u003e(40-48)\u003c/sup\u003e, although samples were collected from a few patients, and only a low and varying percentage of them presented positive results and/or ocular symptoms \u003csup\u003e(46)\u003c/sup\u003e. Most of these studies were developed in China \u003csup\u003e(40, 41, 43, 47)\u003c/sup\u003e, mainly because the country was the first epicenter of the disease. In some cases, ocular manifestations are one of the first symptoms, and because of that, academic societ believes the eye may contribute to the understanding of COVID-19 pathophysiology \u003csup\u003e(6, 7)\u003c/sup\u003e. Recently, new studies proved the presence of in the conjunctiva, limbus, and cornea, with prominent staining in the superficial epithelium surface, key factors for the infection of SARS-CoV-2 in human cells \u003csup\u003e(55)\u003c/sup\u003e. Those results collaborate for the necessity of ocular protection in preventing the spread of viruses.\u003c/p\u003e\n\u003cp\u003eResearch on viral screening was, most of the time, correlated with external ocular symptoms with the purpose of solving clinical doubts between pathogenic agents and of looking after methods for a fast accurate viral diagnosis. Studies on VZV, CMV and EBV were mostly combined with HSV to determine coinfection and differential diagnosis \u003csup\u003e(32-34)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOnly one study correlated viral detection on the ocular surface with intraocular symptoms. This study was published in 2000 and aimed to verify the efficacy of intravenous ganciclovir treatment in immunocompromised AIDS patients with CMV retinitis. The results showed a high clinical relevance for confirming and differentiating the diagnoses of CMV retinitis when ophthalmoscopic findings were associated with PCR methods on conjunctival swab samples \u003csup\u003e(49)\u003c/sup\u003e. No other studies on the topic were found in this review, probably because the incidence of CMV retinitis in the Acquired Immunodeficiency Syndrome (AIDS) population significantly decreased with the introduction of effective antiretroviral therapy and early accurate diagnosis \u003csup\u003e(56-59)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; The most commonly used method for sample collection was conjunctival swabs. This method also collects conjunctival cells, while Schirmer strips allow only the collection of tears, since fluids pass to the filter paper because of gravity, viscosity, and capillary flow dynamics \u0026ndash; the same physical processes that explain how liquids impregnate porous materials differently \u003csup\u003e(60, 61)\u003c/sup\u003e. Consequently, the samples collected represent two different materials: tears, cells and fluids dispersed in the conjunctival sac and tears and substances dissolved in it.\u003c/p\u003e\n\u003cp\u003eSamples were mainly analyzed by PCR or RT-PCR, depending on the viral genetic material, DNA or RNA, respectively. PCR variations are widely used because they allow the replication and detection of low loads of viral DNA/RNA \u003csup\u003e(62)\u003c/sup\u003e. The point-of-care test was also compared with PCR effectiveness, sensitivity and specificity where high, but this field was only explored in AdV \u003csup\u003e(30)\u003c/sup\u003e, probably because of epidemiological factors related to uncontrolled and fast spread of AdV conjunctivitis \u003csup\u003e(63)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThis review included a large number of articles, 36, from many different countries and time periods, fact that collaborated for a broad comprehension of how the detection of viruses on the ocular surface was worldwide studied in the last decades. The results of this article may contribute for future research by clarifying key concepts that might assist the design of future researches on ocular viruses.\u003c/p\u003e\n\u003cp\u003eIn conclusion, viruses can be detected through the analysis of samples collected by Schirmer strips and conjunctival swabs, and studies were generally conducted to understand viral infection, to develop accurate diagnostic methods and to follow patients\u0026rsquo; response to treatment. However, this study has some limitations: only three databases were consulted, and new articles on the theme are constantly being published, which might exclude relevant outcomes. Moreover, among the analyzed studies, most were developed on a small number of patients and lacked clear definitions of collection time and viral persistence since the onset of the diseases. Additional studies with larger populations and time permanence are necessary to develop more assertive conclusions on this topic.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGrant #2020/07365-8, S\u0026atilde;o Paulo Research Foundation (FAPESP).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLES, AM and LFML designed the work, acquired the data, contributed to the analysis and interpretation of data, and drafted the paper. JS, TETO and CFS contributed to the analysis and interpretation of data, and revised the paper. All authors approved the final version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSummers WC. Virus Infection. In: Encyclopedia of Microbiology. Elsevier Inc.; 2009:546-552. doi:10.1016/B978-012373944-5.00323-0\u003c/li\u003e\n\u003cli\u003eNehemy M, Passos E. Oftalmologia na Pr\u0026aacute;tica Cl\u0026iacute;nica. Belo Horizonte: Folium; 2015.\u003c/li\u003e\n\u003cli\u003ePavan-Langston D. Ocular viral infections. Medical Clinics of North America. 1983;67(5):973-970.\u003c/li\u003e\n\u003cli\u003eWatson S, Cabrera-Aguas M, Khoo P. Common eye infections. Aust Prescr. 2018;41(3):67-72.\u003c/li\u003e\n\u003cli\u003eEva PR, Augsburger JJ. Vaughan \u0026amp; Asbury\u0026rsquo;s General Ophthalmology. New York: Lange Medical Books/McGraw-Hill, 2018.\u003c/li\u003e\n\u003cli\u003eParke II DW. COVID-19 and Ophthalmology. 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Cornea. 2001;20:295-300.\u003c/li\u003e\n\u003cli\u003eWeitgasser U, Haller EM, El-Shabrawi Y. Evaluation of polymerase chain reaction for the detection of adenoviruses in conjunctival swab specimens using degenerate primers in comparison with direct immunofluorescence. Ophthalmologica. 2002;216:329-332.\u003c/li\u003e\n\u003cli\u003eMendes RM, Nogueira ML, Marques JT, Pereira MVC, Machado MAS, Cunha AS, Trindade FC, Kroon EG. A rapid polymerase chain reaction protocol to detect adenovirus in eye swabs. Arq Bras Oftalmol 2004;67:423-427.\u003c/li\u003e\n\u003cli\u003eKaye SB, Llyod M, Williams H, Yuen C, Scott JA, O\u0026rsquo;Donnell N, Batterbury M, Hiscott P, Hart CA. Evidence for persistence of adenovirus in the tear film a decade following conjunctivitis. J Med Virol. 2005;77:227-231.\u003c/li\u003e\n\u003cli\u003eMiura-Ochiai R, Shimada Y, Konno T, Yamazaki S, Aoki K, Ohno S, Suzuki E, Ishiko H. Quantitative detection and rapid identification of human adenoviruses. J Clin Microbiol. 2007;45:958-967.\u003c/li\u003e\n\u003cli\u003eWoo PC, Lao SK, Choi GK, Fung HT, Shek KC, Miao J, et al. Resequencing microarray for detection of human adenoviruses in patients with conjunctivitis. J Clin Virol. 2010;47:282-285.\u003c/li\u003e\n\u003cli\u003eMoore C, Gatica L, Jones T, Mathews P, Watkins J, Tyson L, et al. Collect, boil and amplify \u0026ndash; a simple approach for the detection of three common viruses associated with epidemic keratoconjunctivitis, conjunctivitis and dendritic ulcers. J Virol Methods. 2013;189:238-241.\u003c/li\u003e\n\u003cli\u003eKam KY, Ong HS, Bunce C, Ogunbowale L, Verma S. Sensitivity and specificity of the AdenoPlus point-of-care system in detecting adenovirus in conjunctivitis patients at an ophthalmic emergency department: a diagnostic accuracy study. Br J Ophthalmol. 2015;99:1186-1189.\u003c/li\u003e\n\u003cli\u003eGopalkrishna V, Ganorkar NN, Patil PR. 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J Med Virol. 2002;66:506-511.\u003c/li\u003e\n\u003cli\u003eMorishige N, Yamada N, Morita Y, Nakamura Y, Nishida T, Sonoda KH. Detection of ICP0 protein in tear fluid of individuals with active herpetic epithelial keratitis. Jpn J Ophthalmol. 2011;55:591-594.\u003c/li\u003e\n\u003cli\u003eLee SY, Kim MJ, Kim MK, Wee WR. Comparative analysis of polymerase chain reaction assay for herpes simplex virus 1 detection in tear. Korean J Ophthalmol. 2013;27:316-321.\u003c/li\u003e\n\u003cli\u003eBarrado L, Suarez MJ, P\u0026eacute;rez-Bl\u0026aacute;zquez E, Otero JR, Folgueira MD. Could polymerase chain reaction test on conjunctival swabs be useful to diagnose herpetic keratitis?. Enferm Infecc Microbiol Clin. 2014;32:28-30.\u003c/li\u003e\n\u003cli\u003eShoji J, Sakimoto T, Inada N, Kamei Y, Matsubara M, Takamura E, Sawa M. A diagnostic method for herpes simplex keratitis by simultaneous measurement of viral DNA and virus-specific secretory IgA in tears: an evaluation. Jpn J Ophthalmol. 2016;60:294-301.\u003c/li\u003e\n\u003cli\u003eBrunner M, Somerville T, Corless CE, Myneni J, Rajhbeharrysingh T, Tiew S, et al. Use of a corneal impression membrane and PCR for the detection of herpes simplex virus type-1. J Med Microbiol. 2019;68:1324-1329.\u003c/li\u003e\n\u003cli\u003eHu Y, Chen T, Liu M, Zang L, Wang F, et al. Positive detection of SARS-CoV-2 combined HSV1 and HHV6B virus nucleic acid in tear and conjunctival secretions of a non-conjunctivitis COVID-19 patient with obstruction of common lacrimal duct. Acta Ophthalmol. 2020;98(8):859-863.\u003c/li\u003e\n\u003cli\u003eChen L, Liu M, Zhang Z, Qial K, Huang T, Chen M, et al. Ocular manifestations of a hospitalized patient with confirmed 2019 novel coronavirus disease. Br J Ophthalmol. 2020;104:748-751.\u003c/li\u003e\n\u003cli\u003eKumar K, Prakash AA, Gangasagara SB, Rathod S, Kavi K, et al. Presence of viral RNA of SARS-CoV-2 in conjunctival swab specimens of COVID-19 patients. Indian J Ophthalmol. 2020;68:1015-1017.\u003c/li\u003e\n\u003cli\u003eZhang X, Chen X, Chen L, Deng C, Zou X, et al. The evidence of SARS-CoV-2 infection on ocular surface. Ocul Surf. 2020;18:360-362\u003c/li\u003e\n\u003cli\u003eCheema M, Aghazadeh H, Nazarali S, Ting A, Hodges J, et al. Keratoconjunctivitis as the initial medical presentation of the novel coronavirus disease 2019 (COVID-19). Can J Ophthalmol. 2020;55(4):E125-E129.\u003c/li\u003e\n\u003cli\u003eG\u0026uuml;emes-Villahoz N, Burgos-Blasco B, Vilela AA, Arriola-Villalobos P, Rico-Luna CM, Cui\u0026ntilde;a-Sardi\u0026ntilde;a R, et al. Detecting SARS-CoV-2 RNA in conjunctival secretions: is it a valuable diagnostic method of COVID-19?. J Med Virol. 2021;93:383-388.\u003c/li\u003e\n\u003cli\u003eWillcox MD, Walsh K, Nichols JJ, Morgan PB, Jones LW. The ocular surface, coronaviruses and COVID-19. Clin Exp Optom. 2020;103:418-424\u003c/li\u003e\n\u003cli\u003eXie HT, Jiang SY, Xu KK, Liu X, Xu B, Wang L, Zhang MC. SARS-CoV-2 in the ocular surface of COVID-19 patients. Eye Vis (Lond). 2020;7:23.\u003c/li\u003e\n\u003cli\u003eNavel V, Chiambarretta F, Dutheil F (2020) Haemorrhagic conjunctivitis with pseudomembranous related to SARS-CoV-2. Am J Ophthalmol Case Rep. 2020;19:100735.\u003c/li\u003e\n\u003cli\u003eLiu JH, Hsu WM, Wong WW, Wang JJ, Liu WT, Liu CY, Chiou SH. Using conjunctival swab with polymerase chain reaction to aid diagnosis of cytomegalovirus retinitis in AIDS patients. Ophthalmologica. 2000;214:126-130.\u003c/li\u003e\n\u003cli\u003eRodriguez LL, De Roo A, Guimard Y, Trappier SG, Sanchez A, Bressler D, Williams AJ, et al. Persistence and genetic stability of Ebola virus during the outbreak in Kikwit, Democratic Republic of the Congo, 1995. J Infect Dis. 1999;179:S170-S176.\u003c/li\u003e\n\u003cli\u003eGreen E, Hunt L, Ross JC, Nissen NM, Curran T, Badhan A, et al. Viraemia and Ebola virus secretion in survivors of Ebola virus disease in Sierra Leone: a cross-sectional cohort study. Lancet Infect Dis. 2016;16:1052-1056.\u003c/li\u003e\n\u003cli\u003eChalkia AK, Derdas S, Bontzos G, Sourvinos G, Detorakis ET. Non-invasive detection of HPV DNA in exfoliative samples from ophthalmic pterygium: a feasibility study. Graefes Arch Clin Exp Ophthalmol. 2018;256:193-198.\u003c/li\u003e\n\u003cli\u003eTan JJ, Balne PK, Leo YS, Tong L, Ng LFP, Agrawal R. Persistence of Zika virus in conjunctival fluid of convalescence patients. Sci Rep. 2017;7:11194.\u003c/li\u003e\n\u003cli\u003eLeong HN, Chan KP, Khan AS, Oon L, Se-Thoe SY, Bai XL, et al. Virus-specific RNA and antibody from convalescent-phase SARS patients discharged from hospital. Emerg Infect Dis. 2004;10:1745-1750.\u003c/li\u003e\n\u003cli\u003eZhou L, Xu Z, Castiglione GM, Soiberman US, Eberhart CG, Duh EJ. ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. Ocul Surf. 2020;18(4):536-544.\u003c/li\u003e\n\u003cli\u003eTeoh SC, Wang PX, Wong EP. The epidemiology and incidence of cytomegalovirus retinitis in the HIV population in Singapore over 6 years. Invest Ophthalmol Vis Sci. 2012;53:7546-7552.\u003c/li\u003e\n\u003cli\u003eSugar EA, Jabs DA, Ahuja A, Thorne JE, Danis RP, Meinert CL, et al. Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol. 2012;153:1016-1024.\u003c/li\u003e\n\u003cli\u003eAlp NM, Baykam N, Kural G. Immune recovery uveitis associated with highly active antiretroviral therapy in a patient with CMV retinitis and AIDS despite a low CD4+ T cell count: case report and a review of the literature. Int Ophthalmol. 2010;30:183-189.\u003c/li\u003e\n\u003cli\u003eHeiden D, Tun N, Smithuis FN, et al. Active cytomegalovirus retinitis after the start of antiretroviral therapy. \u003cem\u003eBr J Ophthalmol\u003c/em\u003e 2019;103(2):157-60.\u003c/li\u003e\n\u003cli\u003eWashburn EW. The dynamics of capillary flow. Phys Rev. 1921;17:273-283.\u003c/li\u003e\n\u003cli\u003eTelles R, Li W, Dursch TJ, Lin MC, Radke CJ. Human tear-production rate from closed-eye Schirmer-strip capillary dynamics. Colloids Surf A Physicochem Eng Asp. 2017;521:61-68.\u003c/li\u003e\n\u003cli\u003eBachman J. Reverse-transcription PCR (RT-PCR). In: Methods in Enzymology. Vol 530. Academic Press Inc.; 2013:67-74. Doi:10.1016/B978-0-12-420037-1.00002-6.\u003c/li\u003e\n\u003cli\u003eGarcia-Zalisnak D, Rapuano C, Sheppard JD, Davis AR. Adenovirus Ocular Infections: Prevalence, Pathology, Pitfalls, and Practical Pointers. Eye Contact Lens. 2018 Sep;44 Suppl 1:S1-S7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"virus, detection, Schirmer strip, conjunctival swab, ocular surface","lastPublishedDoi":"10.21203/rs.3.rs-113899/v4","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-113899/v4","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u0026nbsp;\u003c/strong\u003eSchirmer Strips and Conjunctival swabs are used in ophthalmology for tears and fluids collection. During the COVID-19 pandemic, one of the biggest challenges is accurate diagnosis, and it is known that, in some cases, ocular manifestations are one of the first symptoms. In this context, this study has the objective of raising scientific evidence that highlights the use of Schirmer strips and conjunctival swabs as a method of sample collection for viral analysis to support future research on this theme. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eA literature search was conducted in the PubMed, Web of Science and BVS databases, following the Scoping Review protocol defined by Joanna Briggs Institute (JBI) after the guiding question “Is it possible to detect viruses on the ocular surface with Schirmer Test and/or conjunctival swab?”.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eA total of\u003cstrong\u003e \u003c/strong\u003e418 studies were identified, and after discerning analysis, 36 English written studies were selected. Three researchers analyzed studies after virus research, collection methods, and sample analysis. Publications were mainly on adenovirus, herpes simplex virus and SARS-CoV-2, and there is also evidence of ocular detection of more viruses types. Conjuntival swab analyzed through Polymerase Chain Reaction (PCR) or Reverse Transcriptase-PCR (RT-PCR) were the most used methods.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eStudies have generally been conducted to understand viral infection, to develop accurate diagnostic methods and to follow the patients’ response to treatment. Most studies were performed with a small number of patients and lacked clear definitions of collection time and viral persistence since the onset of diseases. Viruses can be detected on the ocular surface through the analysis of Schirmer strips and conjunctival swabs. However, additional studies with larger populations and time permanence are necessary to develop more assertive conclusions on the theme.\u003c/p\u003e","manuscriptTitle":"Schirmer strip and conjunctival swab for viral detection on the ocular surface of adults: a scoping review","msid":"","msnumber":"","nonDraftVersions":[{"code":4,"date":"2021-02-12 16:51:29","doi":"10.21203/rs.3.rs-113899/v4","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":3,"date":"2021-02-12 16:49:41","doi":"10.21203/rs.3.rs-113899/v3","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2021-02-09 02:30:03","doi":"10.21203/rs.3.rs-113899/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-11-25 17:57:59","doi":"10.21203/rs.3.rs-113899/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9629db1c-00e1-4567-ae4b-ba03003b4bbd","owner":[],"postedDate":"February 12th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2391888,"name":"Ophthalmology"}],"tags":[],"updatedAt":"2020-11-25T17:57:59+00:00","versionOfRecord":[],"versionCreatedAt":"2021-02-12 16:51:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v4","identity":"rs-113899","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-113899","identity":"rs-113899","version":["v4"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}