LitCovid-sentences  

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Id Subject Object Predicate Lexical cue
T20 0-126 Sentence denotes Coronaviruses are separated into four types: alphacoronaviruses, betacoronaviruses, gammacoronaviruses and deltacoronaviruses.
T21 127-257 Sentence denotes Alphacoronaviruses and betacoronaviruses infect mammals, and gammacoronaviruses and deltacoronaviruses predominantly infect birds.
T22 258-572 Sentence denotes 1 The greatest diversity of coronaviruses have been found in bats and birds, suggesting that these are the primary reservoirs of these viruses, 1 with bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.
T23 573-574 Sentence denotes 2
T24 575-858 Sentence denotes Of the coronaviruses that are known to infect humans, human coronavirus (hCoV) 229E and NL63 are alphacoronaviruses and OC43, HKU1, severe acute respiratory syndrome coronavirus (SARS‐CoV), Middle East respiratory syndrome coronavirus (MERS‐CoV) and SARS‐CoV‐2 are betacoronaviruses.
T25 859-1019 Sentence denotes All coronaviruses are termed ‘enveloped’ viruses due to the lipid membrane that surrounds their capsid (protein), which in turn contains RNA (genetic material).
T26 1020-1177 Sentence denotes Proteins protrude from their lipid envelope (Figure 1) and these can be imaged with electron microscopy as a corona surrounding the virus – hence their name.
T27 1178-1289 Sentence denotes Coronaviruses contain four major structural proteins, the spike, nucleocapsid, membrane, and envelope proteins.
T28 1290-1465 Sentence denotes The nucleocapsid, membrane and envelope proteins are mainly involved in forming and structuring the virus, whereas the spike protein is also involved in binding to host cells.
T29 1466-1467 Sentence denotes 3
T30 1468-1734 Sentence denotes Figure 1 Representation of SARS‐CoV‐2 viral particles (drawn by Dr Chau‐Minh Phan, Centre for Ocular Research & Education, School of Optometry and Vision Science, University of Waterloo, Canada) The coronavirus SARS‐CoV‐2 causes coronavirus disease 2019 (COVID‐19).
T31 1735-1943 Sentence denotes COVID‐19 was declared a pandemic by the World Health Organization (WHO) on 11 March 2020 4 and at the time of writing, cases have been reported by nearly all countries and territories in the world (n = 212).
T32 1944-2080 Sentence denotes 5 COVID‐19 has resulted in a large number of deaths, causing changes to the daily lives of many people and significant economic losses.
T33 2081-2210 Sentence denotes As of 5 May 2020, COVID‐19 has been confirmed in nearly three and a half million people and resulted in just over 230,000 deaths.
T34 2211-2430 Sentence denotes 6 One of the first widely reported deaths due to SARS‐CoV‐2 was an ophthalmologist working at Wuhan Central Hospital in early January 2020, who reported he had contracted COVID‐19 from an asymptomatic glaucoma patient.
T35 2431-2475 Sentence denotes He succumbed to the disease one month later.
T36 2476-2650 Sentence denotes 7 Subsequently, there has been a great deal of interest in the scientific literature as well as in the lay press about the association of SARS‐CoV‐2 with the ocular surface.
T37 2651-2915 Sentence denotes This has resulted in speculation regarding the safety of contact lenses,8, 9 as well as the potential for transmission of the virus to and from the ocular surface, with implications for transmission among the general population and specifically in ophthalmic care.
T38 2916-3112 Sentence denotes The authors conducted a recent review of the literature which indicates that contact lens wear is still a safe form of vision correction, as long as wearers continue to use good hygiene practices.
T39 3113-3306 Sentence denotes 8 However, it is clear that much of the speculation regarding the potential to transmit SARS‐CoV‐2 to and from the ocular surface has not been based on an analysis of the available literature.
T40 3307-3663 Sentence denotes Hence, the authors have conducted a thorough literature search in this area, and an assessment of this literature is presented in this review, particularly focusing on what is known about the ability of coronaviruses to adhere to ocular surface cells, the presence of coronaviruses at the ocular surface and the association of conjunctivitis with COVID‐19.
T41 3665-3691 Sentence denotes Literature search strategy
T42 3692-3972 Sentence denotes A literature search was conducted on 15 April 2020 in the Scopus database using the search terms ‘coronavirus’ AND ‘conjunctiv*’ OR ‘cornea’ OR ‘ocular surface’, which yielded 91 documents; and ‘SARS’ AND ‘conjunctiv*’ OR ‘cornea’ OR ‘ocular surface’, which yielded 189 documents.
T43 3973-4237 Sentence denotes Further references were obtained by searching for keywords ‘ACE2’ AND ‘conjunctiv*’ OR ‘cornea’ OR ‘ocular surface’, which yielded two documents; and ‘Angiotensin converting enzyme‐2’ AND ‘conjunctiv*’ OR ‘cornea’ OR ‘ocular surface’, which yielded five documents.
T44 4238-4403 Sentence denotes The abstracts of all these documents were read, and those dealing with any coronavirus and the ocular surface tissues or conjunctivitis were downloaded and reviewed.
T45 4404-4557 Sentence denotes In addition, the references contained in these downloaded documents were examined for other sources of information that would be pertinent to the review.
T46 4558-4878 Sentence denotes In cases where documents were available with abstracts only in English but the full paper only in Chinese, if the abstract was thought to be pertinent, the paper was translated initially by Google Translate (https://translate.google.com.au) and then by Dr Renxun Chen, (University of New South Wales) for further review.
T47 4880-4893 Sentence denotes Coronaviruses
T48 4894-5000 Sentence denotes Coronaviruses are a relatively large group of viruses that can cause diseases in humans and other animals.
T49 5001-5166 Sentence denotes Human coronaviruses hCoV‐229E, OC43, NL63, and HKU1 typically cause mild respiratory diseases, are seasonal (peaking in the winter) and have been around for decades.
T50 5167-5333 Sentence denotes More recently, coronaviruses which can cause fatal infections in humans – SARS‐CoV in 2002–2003, MERS‐CoV in 2012 10 and of course SARS‐CoV‐2 in 2019 – have emerged.
T51 5334-5636 Sentence denotes Coronaviruses also cause large economic losses as they can cause severe diseases in farm animals such as cows 11 and chickens12, 13 as well as domestic animals such as cats.14, 15 All viruses need to bind (adhere) to host cells, as the first step in their invasion of cells and subsequent replication.
T52 5637-5760 Sentence denotes Coronaviruses use the spike protein that protrudes through their lipid envelope to bind to various receptors on host cells.
T53 5761-5762 Sentence denotes 3
T54 5764-5854 Sentence denotes Binding of coronaviruses to host cells, and presence of receptors in ocular surface tissue
T55 5855-5984 Sentence denotes SARS‐CoV‐2 uses angiotensin converting enzyme‐2 (ACE2) as its receptor on human cells, and binding to this facilitates infection.
T56 5985-6284 Sentence denotes 16 The mammalian serine protease TMPRSS2 or the protease Furin (also known as Paired basic Amino acid Cleaving Enzyme) appear to prime the spike protein for interaction with ACE2.17, 18 SARS‐CoV also binds to the cell‐surface protein ACE2 and this binding is required for the virus to infect cells.
T57 6285-6450 Sentence denotes 19 The binding of SARS‐CoV‐2 to ACE2 is enhanced compared to that of SARS‐CoV due to several changes in the gene and hence amino acid sequence of the spike protein.
T58 6451-6731 Sentence denotes 20 SARS‐CoV also binds to CD209 (dendritic cell [DC]‐specific intercellular adhesion molecule [ICAM‐3] grabbing non‐integrin; DC‐SIGN) and CD209L (L‐SIGN).21, 22, 23 MERS‐CoV binds to the cell‐surface molecule CD26 (DPP‐4) and this is facilitated by the cofactor CD66e (CEACAM5).
T59 6732-6734 Sentence denotes 24
T60 6735-6928 Sentence denotes For the less pathogenic human coronaviruses, hCoV‐229E uses CD13 to infect cells, 25 OC43 and HKU1 bind to 9‐O‐acetylated sialic acid (Neu5,9Ac2), 26 and NL63 uses ACE2 to bind to host cells.
T61 6929-7121 Sentence denotes 27 NL63 and SARS‐CoV first anchor to cells via heparan sulfate proteoglycans before interacting with the ACE2 entry receptor,19, 27, 28 but this binding alone is not sufficient for infection.
T62 7122-7233 Sentence denotes 19 In fact many viruses, not just coronaviruses, utilise heparan sulfate on cell surfaces for initial binding.
T63 7234-7338 Sentence denotes 29 Feline infectious peritonitis virus uses CD13 (aminopeptidase N) or CD209 to bind to its host cells.
T64 7339-7416 Sentence denotes 15 Bovine coronavirus binds to 9‐O‐acetylated sialic acid on its host cells.
T65 7417-7419 Sentence denotes 30
T66 7420-7568 Sentence denotes Table 1 presents a comparison of receptors for SARS‐CoV‐2, SARS‐CoV and MERS‐CoV on ocular surface and lung cells.31, 32, 33, 34, 35, 36, 37, 38, 39
T67 7569-7662 Sentence denotes Table 1 Comparison of SARS‐CoV‐2, SARS‐CoV and MERS‐CoV receptors on ocular surface and lung
T68 7663-7748 Sentence denotes Coronaviruses Receptor Role in human CoV disease Ocular surface (cell types) Lung
T69 7749-7757 Sentence denotes SARS‐CoV
T70 7758-7918 Sentence denotes SARS‐CoV‐2 ACE2 Host cell receptor and essential for infection + (conjunctival epithelium and fibroblasts; corneal epithelium) 31 + (airway epithelia)32, 33
T71 7919-7997 Sentence denotes TMPRSS2 Primes spike protein for binding to ACE2 – + (airway epithelium) 34
T72 7998-8092 Sentence denotes CD209 Cell‐to‐cell viral transfer + (corneal dendritic cells) 35 + (alveola macrophages) 36
T73 8093-8237 Sentence denotes MERS‐CoV CD26 Host cell receptor and essential for infection +/− (conjunctival vascular endothelium) 37 + (lung epithelia and endothelia) 38
T74 8238-8330 Sentence denotes CD66e Co‐receptor +/− (palpebral conjunctiva) 39 + (bronchial and alveolar epithelium) 32
T75 8331-8496 Sentence denotes +: the receptor has been found, −: there are no reports of the receptor on the ocular surface, +/−: found in tissue but only on non‐virally‐mediated inflamed tissue.
T76 8497-8694 Sentence denotes Expression of the gene for ACE2 has been shown in corneal and conjunctival epithelial cells, and preliminary evidence has been presented for the presence of the protein associated with these cells.
T77 8695-8950 Sentence denotes 40 The isolated surface protein S240 of SARS‐CoV can bind to conjunctival epithelial and fibroblast cells and corneal epithelial cells, with this binding inhibited by soluble ACE2, indicating that the binding was being mediated through cell‐surface ACE2.
T78 8951-9186 Sentence denotes 31 However, the authors did note that ‘the amount of ACE2 expressed in conjunctival and corneal cells and tissues (was) less than that in heart, lung tissues and Vero E6 cells’, and was approximately 50 per cent that of Vero E6 cells.
T79 9187-9331 Sentence denotes 31 Another paper provided evidence of expression of mRNA for ACE2 in corneal epithelium with no evidence provided of mRNA from the conjunctiva.
T80 9332-9556 Sentence denotes 41 The normalised expression of ACE2 in the corneal epithelial mRNA was only 20‐28 units, compared to > 400 units in the testes, > 200 units in the small intestine terminal ileum and > 100 units in the heart left ventricle.
T81 9557-9728 Sentence denotes 41 The previously mentioned serine protease TMPRSS2 or Furin, which appear to prime the spike protein, had not been reported in tears or on corneal or conjunctival cells.
T82 9729-10030 Sentence denotes However, 15 per cent of superficial conjunctival cells have been shown to have “greater‐than‐zero expression” of the gene for TMPRSS2, three per cent of cells in superficial conjunctiva and one per cent of limbal superficial cells have “greater‐than‐zero expression” of genes of both TMPRSS2 and ACE2.
T83 10031-10301 Sentence denotes The mean level of expression of mRNA for ACE2 or TMPRSS2 in any ocular tissue was approximately 0.6 per cent, whereas the mean level of expression was greater (1.2–1.4 per cent) in most other tissues (such as nasal cavity, lung parenchyma, ileum, colon, heart) examined.
T84 10302-10304 Sentence denotes 42
T85 10305-10357 Sentence denotes CD209 can be found on human corneal dendritic cells.
T86 10358-10573 Sentence denotes 35 CD26 is not expressed in normal conjunctival tissue, and has only been found, and then only weakly expressed, in vascular endothelial cells of conjunctival tissue from biopsies of vernal conjunctivitis patients.
T87 10574-10715 Sentence denotes 37 The only report of CD66e in the conjunctiva was from patients with trachoma who had gene expression in their upper palpebral conjunctiva.
T88 10716-10777 Sentence denotes 39 There are no reports of CD26 or CD66e in cornea or tears.
T89 10778-10898 Sentence denotes CD13 has not been reported on conjunctival or corneal epithelial cells, but has been found on human corneal keratocytes.
T90 10899-10987 Sentence denotes 43 9‐O‐acetylated sialic acid has been found in human tears and on human corneal mucin.
T91 10988-11067 Sentence denotes 44 Heparan sulfate has been found on human cornea and conjunctiva cells.45, 46
T92 11068-11205 Sentence denotes In summary, the ocular surface does possess the ubiquitous viral receptor heparan sulfate, which can facilitate initial viral attachment.
T93 11206-11264 Sentence denotes However, this is not sufficient for coronavirus infection.
T94 11265-11397 Sentence denotes Furthermore, lactoferrin that is present in high concentrations in tears (2 mg/ml) 47 prevents viral attachment to heparan sulfate.
T95 11398-11609 Sentence denotes 19 The ocular surface appears to possess the SARS‐CoV‐2, SAR‐CoV and NL63 receptor ACE2, but may not possess the TMPRSS2 or Furin proteins, which is required for the spike protein of SARS‐CoV‐2 to bind to ACE2.
T96 11610-11913 Sentence denotes Furthermore, apart from 9‐O‐acetylated sialic acid, the other co‐receptors for coronaviruses (CD209, CD26, CD13, CD66e), have been found either in fibroblasts and dendritic cells that lie in tissue under the surface corneal and conjunctival epithelial cells, or have not been reported in ocular tissues.
T97 11914-12125 Sentence denotes It is possible that the 9‐O‐acetylated sialic acid associated with proteins in tears can act as a decoy receptor, binding to the viruses and preventing them binding to cell‐associated 9‐O‐acetylated sialic acid.
T98 12126-12257 Sentence denotes 44 Therefore, the evidence to date suggests that coronaviruses are unlikely to bind to ocular surface cells to initiate infection.
T99 12259-12304 Sentence denotes Animal studies of human coronavirus infection
T100 12305-12443 Sentence denotes Using animal models can help to determine whether the eye can become infected and the consequence of application of live virus to the eye.
T101 12444-12562 Sentence denotes Unfortunately, most studies have not been designed specifically to examine the role of the eye in the disease process.
T102 12563-12870 Sentence denotes Some studies have inoculated monkeys with SARS‐CoV intranasally and by topical application to the conjunctiva, and often also via their trachea.48, 49, 50 While the monkeys developed pneumonia, the role of the conjunctival inoculation cannot be analysed separately from the inoculation via the other routes.
T103 12871-13055 Sentence denotes However, an as yet non‐peer‐reviewed paper has been made available that directly compares inoculation of SARS‐CoV‐2 of rhesus macaque monkeys via their conjunctiva, trachea or stomach.
T104 13056-13219 Sentence denotes 51 While the one monkey that received SARS‐CoV‐2 via their trachea had weight loss, the two monkeys that were inoculated via their conjunctiva had no weight loss.
T105 13220-13337 Sentence denotes SARS‐CoV‐2 RNA was transiently found in the conjunctiva after one day only, and only in conjunctiva‐infected monkeys.
T106 13338-13478 Sentence denotes For the conjunctiva‐infected and trachea‐infected animals, viral RNA could be found in nasal and throat swabs over the course of seven days.
T107 13479-13582 Sentence denotes Interestingly, the conjunctiva‐infected animal on day 14 had the highest antibody levels to SARS‐CoV‐2.
T108 13583-13705 Sentence denotes The authors concluded that conjunctival inoculation resulted in a mild lung infection compared to the trachea inoculation.
T109 13706-13913 Sentence denotes 51 Unfortunately, no histology was performed on the eye during the infection, and given the very transient level of virus found in the conjunctival samples, infection or inflammation probably did not occur.
T110 13914-14056 Sentence denotes If there was infection of the ocular surface, then conjunctivitis and perhaps keratitis would be expected to be manifestations of the disease.
T111 14057-14393 Sentence denotes This study does suggest, at least for relatively large inocula (the authors used 1 × 106 50 per cent tissue‐culture infectious doses), that viral particles on the eye can travel to the lung but that they are either reduced in their virulence or the numbers that reach the lung are very low, and so the resulting infection was very mild.
T112 14395-14443 Sentence denotes Association of coronaviruses with conjunctivitis
T113 14444-14691 Sentence denotes There has been one report of a woman who presented with rhinorrhoea, cough, nasal congestion, unilateral conjunctivitis, but no fever (although the subject had taken over‐the‐counter antipyretic medication) as the initial presentation of COVID‐19.
T114 14692-14852 Sentence denotes 52 The case history indicates that the patient had returned from a vacation in the Philippines and had transited through San Francisco on her return to Canada.
T115 14853-14971 Sentence denotes She had swum in the sea and hotel swimming pools on vacation, and a public swimming pool once on her return to Canada.
T116 14972-15242 Sentence denotes Upon presentation to an ophthalmology clinic she was initially diagnosed with presumed herpetic keratoconjunctivitis, which was subsequently changed to presumed epidemic keratoconjunctivitis after initial antiviral medications did not appear to be affecting the disease.
T117 15243-15325 Sentence denotes The conjunctivitis remained unilateral during the seven days of the investigation.
T118 15326-15501 Sentence denotes Seven days after the initial symptoms the patient was tested for SARS‐CoV‐2 after changes to screening recommendations occurred for new arrivals into Canada, and was positive.
T119 15502-15697 Sentence denotes A retest of a conjunctival swab (which had been negative for chlamydia, gonorrhoea, and bacterial culture) taken five days after initial symptoms was reported to be weakly positive for viral RNA.
T120 15698-15700 Sentence denotes 52
T121 15701-15893 Sentence denotes In a separate case report, 53 a 65‐year‐old woman who had returned to Italy from Wuhan in China was admitted to hospital one day after noticing symptoms and six days after returning to Italy.
T122 15894-15984 Sentence denotes She presented with non‐productive cough, sore throat, coryza and bilateral conjunctivitis.
T123 15985-16130 Sentence denotes Conjunctivitis persisted until day 16 after symptom onset and ocular swabs were positive for viral RNA up until 21 days after hospital admission.
T124 16131-16341 Sentence denotes Interestingly, five days after it became undetectable in ocular swabs, RNA for SARS‐CoV‐2 was again present upon polymerase chain reaction (PCR), but only for this one day after which it was again undetectable.
T125 16342-16462 Sentence denotes SARS‐CoV‐2 was able to be grown in cell culture from the first swab but no other swabs were submitted for viral culture.
T126 16463-16598 Sentence denotes 52 A 65‐year‐old Iranian diabetic male presented with symptoms of a burning eye and discharge, with no fever, cough or other symptoms.
T127 16599-16634 Sentence denotes He had no recent history of travel.
T128 16635-16689 Sentence denotes An initial diagnosis of viral conjunctivitis was made.
T129 16690-16831 Sentence denotes 54 Two days after initial presentation he reported with sudden‐onset fever and a swab of his nasopharynx was positive for SARS‐CoV‐2 by PCR.
T130 16832-16834 Sentence denotes 54
T131 16835-17038 Sentence denotes In reports of 99 55 or 140 56 patients with SARS‐CoV‐2 from Wuhan China – the initial site of infection that resulted in the pandemic – conjunctivitis was not noted as a sign or symptom of the disease.
T132 17039-17164 Sentence denotes Also, conjunctivitis was not noted as a sign or symptom in 32 confirmed COVID‐19 patients examined outside of Wuhan in China.
T133 17165-17425 Sentence denotes 57 Of 17 COVID‐19 patients recruited in a prospective study in Singapore, none demonstrated ocular signs or symptoms of conjunctivitis at initial recruitment into the study, 58 but one developed conjunctival infection and chemosis during their hospital stay.
T134 17426-17569 Sentence denotes 58 Only two patients of 72 confirmed COVID‐19 cases examined at Tongji Hospital in Shanghai were diagnosed with conjunctivitis (2.8 per cent).
T135 17570-17739 Sentence denotes 59 A report of the WHO‐China Joint Mission which summarised 55,924 cases of COVID‐19 reported that only 0.8 per cent of patients had signs of conjunctival ‘congestion’.
T136 17740-17742 Sentence denotes 60
T137 17743-17869 Sentence denotes Three patients out of 30 diagnosed with COVID‐19 pneumonia in Wuhan have been reported as having conjunctivitis (10 per cent).
T138 17870-17999 Sentence denotes 61 One of these patients reported having red eyes, itching and blurred vision three days prior to being diagnosed with COVID‐19.
T139 18000-18236 Sentence denotes Another of these patients, who had uveitis five years prior to COVID‐19, had a mild dry cough and fatigue two days prior to noticing binocular redness with foreign body sensation, with conjunctivitis confirmed by slitlamp biomicroscopy.
T140 18237-18338 Sentence denotes The third patient developed conjunctivitis three days after being admitted to hospital with COVID‐19.
T141 18339-18341 Sentence denotes 61
T142 18342-18576 Sentence denotes Thirty‐eight patients at Yichang Central People's Hospital China who were diagnosed with COVID‐19 had ocular examinations which resulted in 12 of these being diagnosed with epiphora, conjunctival congestion, or chemosis (32 per cent).
T143 18577-18787 Sentence denotes 62 All of these patients were diagnosed with either moderate (4/12) or severe to critical (8/12) COVID‐19, and only one of the patients reported ocular symptoms (epiphora) as a first sign of possible COVID‐19.
T144 18788-18790 Sentence denotes 62
T145 18791-19033 Sentence denotes A member of the national expert panel on pneumonia reported that he believed he had become infected with SARS‐CoV‐2 during an inspection of a hospital in Wuhan via his eyes, which had become red ‘several days’ prior to the onset of pneumonia.
T146 19034-19415 Sentence denotes 63 However, the statement that the conjunctivitis occurred ‘several days’ before the onset of pneumonia has been refuted by Peng and Zhou 64 who refer to the original report as stating that conjunctivitis was noticed just two to three hours before development of fever and catarrhal symptoms, and that conjunctivitis probably occurred after COVID‐19 had developed into pneumonia.
T147 19416-19857 Sentence denotes In the case of infection with SARS‐CoV or MERS‐CoV, reports and reviews have not identified conjunctivitis as a sign or symptom, even in cases diagnosed early in their disease.65, 66, 67, 68 For disease caused by NL63, in a review of 15 studies which had a combined number of cases of over 7,500, 69 only a single study from France reported the appearance of conjunctivitis, and then conjunctivitis was seen in 17 per cent of the 300 cases.
T148 19858-20049 Sentence denotes 70 NL63 was initially isolated from a child with both bronchiolitis and conjunctivitis, but the other seven cases in that first report did not have conjunctivitis as a noted sign or symptom.
T149 20050-20334 Sentence denotes 71 Infections with HKU1 have not produced any associated conjunctivitis,72, 73 and while there is a report showing that a patient with Kawasaki disease infected with OC43/HKU1 had conjunctival injection, 74 this conjunctivitis was most likely due to the underlying Kawasaki disease.
T150 20335-20633 Sentence denotes It appears that (kerato)conjunctivitis is a rare manifestation of human coronavirus disease, and this was also the conclusion of Sun et al., who stated ‘The eye is rarely involved in human CoVs infection, conjunctivitis is quite rare in patients with SARS‐CoV and 2019‐nCoV (SARS‐CoV‐2) infection’.
T151 20634-20819 Sentence denotes 75 However, all cases of (kerato)conjunctivitis, especially those with any associated upper respiratory tract symptoms (however mild), should be considered as potential COVID‐19 cases.
T152 20820-21016 Sentence denotes In most cases that have reported conjunctivitis associated with coronavirus infection, the studies have been of patients in hospitals who would likely have presented with severe forms of COVID‐19.
T153 21017-21278 Sentence denotes However, as COVID‐19 patients have been reported to have viral RNA detected in their plasma, and the case of keratoconjunctivitis 52 had a weak positive test for SARS‐CoV‐2 in a conjunctival swab, it is possible that the virus can appear at the ocular surface.
T154 21280-21326 Sentence denotes Detection of coronavirus at the ocular surface
T155 21327-21668 Sentence denotes SARS‐CoV‐2, SARS‐CoV and other coronaviruses may be able to appear at the ocular surface as the result of: (1) the conjunctiva being the direct inoculation site of virus from infected droplets; (2) migration via the nasolacrimal duct during upper respiratory tract infection; or (3) exudation through conjunctival vessels during the disease.
T156 21669-21829 Sentence denotes The present authors have dealt with (1) in the section of adhesion of these viruses to ocular surface tissue, and concluded that this is an unlikely occurrence.
T157 21830-21946 Sentence denotes In this section, the question as to whether the viruses can be found at the ocular surface and in tears is examined.
T158 21947-22078 Sentence denotes A patient with keratoconjunctivitis who was later confirmed to have COVID‐19 had SARS‐CoV‐2 RNA in a two‐day‐old conjunctival swab.
T159 22079-22281 Sentence denotes 52 Also, a patient in Italy who had bilateral conjunctivitis as part of their first symptoms was reported to have RNA in ocular swabs for 21 days after onset of symptoms, which included conjunctivitis.
T160 22282-22369 Sentence denotes 53 SARS‐CoV‐2 was grown from the ocular swab taken three days after onset of symptoms.
T161 22370-22535 Sentence denotes 53 However, another report shows that another patient who developed conjunctival infection and chemosis during their stay in the hospital had no viral RNA in tears.
T162 22536-22538 Sentence denotes 58
T163 22539-22650 Sentence denotes Most other studies have examined COVID‐19 patients who have not been reported to have ocular signs or symptoms.
T164 22651-22799 Sentence denotes One study collected 64 tear samples using a Schirmer strip from 17 confirmed COVID‐19 patients and analysed the tears using PCR to detect viral RNA.
T165 22800-22883 Sentence denotes 58 The samples were collected during three weeks of the infection in the patients.
T166 22884-23100 Sentence denotes While viral RNA could be detected in all nasopharyngeal swabs, no virus was grown from the tear samples and no viral RNA could be detected, even from those patients with symptoms of upper respiratory tract infection.
T167 23101-23200 Sentence denotes 58 The authors concluded ‘the hypothesis of the lacrimal duct as a viral conduit may not be true’.
T168 23201-23344 Sentence denotes A patient who presented with conjunctivitis that was later diagnosed with COVID‐19 had viral RNA detected in two subsequent conjunctival swabs.
T169 23345-23347 Sentence denotes 58
T170 23348-23439 Sentence denotes Another study collected tears and conjunctival secretions using a swab of the lower fornix.
T171 23440-23540 Sentence denotes 76 The study included 21 patients with ‘common‐type’ and nine patients with ‘severe‐type’ COVID‐19.
T172 23541-23656 Sentence denotes Fifty‐eight conjunctival swab samples from 20 common‐type patients and nine severe‐type patients were all negative.
T173 23657-23751 Sentence denotes Two conjunctival swabs of one common‐type patient yielded viral RNA upon PCR (three per cent).
T174 23752-23826 Sentence denotes In contrast, 55 of 60 sputum samples were positive upon PCR (92 per cent).
T175 23827-23956 Sentence denotes 76 A third study examined 63 confirmed COVID‐19 patients and four suspected patients by PCR for viral RNA of conjunctival swabs.
T176 23957-24075 Sentence denotes 77 Only one conjunctival sample was confirmed positive by PCR, and the only patient with conjunctivitis was negative.
T177 24076-24078 Sentence denotes 77
T178 24079-24155 Sentence denotes Ocular surfaces have also been sampled from patients infected with SARS‐CoV.
T179 24156-24350 Sentence denotes One study used both PCR and viral culture of tears collected from the deep lower fornix using a swab and conjunctival scrapings of the lower palpebral conjunctiva of 17 confirmed SARS‐CoV cases.
T180 24351-24442 Sentence denotes 78 That study was unable to detect virus using PCR and no virus was grown from any sample.
T181 24443-24445 Sentence denotes 78
T182 24446-24716 Sentence denotes A second study used PCR to detect SARS‐CoV RNA in 36 tear samples from probable (serology confirmed) or suspect cases of SARS, collected by everting the eyelids and sweeping the inferior fornixes of both eyes with sterile cotton tipped swabs without topical anaesthesia.
T183 24717-24850 Sentence denotes 79 Three of the eight probable cases were positive for viral RNA in their samples, while none of the 28 suspect cases were positive.
T184 24851-25043 Sentence denotes 79 The three positive cases had tears collected within nine days of onset of their illness, whereas the five negative cases had samples collected on average 19.4 days after onset of symptoms.
T185 25044-25385 Sentence denotes Examining all of the studies that have attempted to isolate live virus or analysed ocular samples for viral RNA demonstrates that, at any stage of disease, viral RNA was detected in only five per cent of ocular surface swabs (9/178); in other words, 95 per cent of samples did not yield viral RNA, and, where attempted, no sample grew virus.
T186 25386-25576 Sentence denotes As is acknowledged by Xia et al., 76 PCR can yield false positive and false negative data: false positive data due to sample contamination and false negative data due to sample degradation.
T187 25577-25813 Sentence denotes Given the low number of positive samples and the high number of negative samples, the present authors feel that the data demonstrate that it is very unlikely that SARS‐CoV‐2 is present at the ocular surface during coronavirus infection.
T188 25814-25964 Sentence denotes Thus, the hypotheses that the virus could travel from the nasopharynx or through the conjunctival capillaries during infection are probably incorrect.
T189 25966-25973 Sentence denotes Summary
T190 25974-26035 Sentence denotes Human coronaviruses bind to specific receptors on host cells.
T191 26036-26119 Sentence denotes Binding of SARS‐CoV‐2 and SARS‐CoV to ACE2 is required for initiation of infection.
T192 26120-26405 Sentence denotes There is some preliminary evidence for ACE2 expression on corneal and conjunctival cells, but most of the other receptors known to bind to coronaviruses appear to be found only on fibroblasts and dendritic cells that are found under the surface epithelial layers of the ocular surface.
T193 26406-26540 Sentence denotes Lactoferrin in tears can inhibit coronavirus binding, as may decoy receptors such as 9‐O‐acetylated sialic acid on tear glycoproteins.
T194 26541-26834 Sentence denotes Animal studies on human coronaviruses have not focused on the role of ocular surface binding in the infection process, apart from one study that showed conjunctival infection could lead to mild signs and symptoms of pneumonia, but only transient association of SARS‐CoV‐2 with the conjunctiva.
T195 26835-26990 Sentence denotes While coronavirus infection is rarely associated with conjunctivitis, there have been occasional findings of conjunctivitis in confirmed COVID‐19 patients.
T196 26991-27075 Sentence denotes Similarly, coronaviruses have been rarely isolated from tears or conjunctival swabs.
T197 27077-27093 Sentence denotes Further research
T198 27094-27199 Sentence denotes The expression of coronavirus receptors on ocular surface cells needs further confirmatory investigation.
T199 27200-27377 Sentence denotes It would also be of interest to examine whether contact lens wear or ocular surface diseases such as dry eye disease are associated with increased expression of these receptors.
T200 27378-27488 Sentence denotes The ability of tears to inhibit binding of coronaviruses to ocular surface cells is another area for research.
T201 27489-27630 Sentence denotes This may identify substances that can be translated into new prophylaxis treatments to reduce the spread of coronaviruses in the environment.
T202 27631-27770 Sentence denotes Further studies, using animal models, on the role of contamination of the ocular surface on progression of the disease are urgently needed.
T203 27771-27914 Sentence denotes These studies, as well as further studies with human cases of disease, will also help to definitively identify the virus at the ocular surface.
T204 27915-28206 Sentence denotes As only one study has been able to grow SARS‐CoV‐2 from ocular swabs and then only reported growth early in the disease and did not attempt to grow viruses from subsequent ocular surface swabs, 53 studies should also then examine whether any ocular surface‐associated viruses are infective.
T205 28207-28325 Sentence denotes Epidemiological studies and case reports should include analysis of ocular complications during coronavirus infection.
T206 28327-28345 Sentence denotes Clinical relevance
T207 28346-28501 Sentence denotes The conclusions from this review are clinically relevant both in terms of their implications for clinical practice, and in the wider education of patients.
T208 28502-28624 Sentence denotes The nature of ocular examination demands that the eye‐care practitioner and patient are in close proximity to one another.
T209 28625-28905 Sentence denotes Given the main mode of transmission of the virus is thought to be via person‐to‐person contact through respiratory droplets transmission (airborne or through direct contact), 80 it is unsurprising that ophthalmic practice has been significantly affected by the COVID‐19 pandemic.
T210 28906-29055 Sentence denotes Many countries have temporarily stopped all routine appointments, moving to a service offering only emergency care during the height of the pandemic.
T211 29056-29258 Sentence denotes Even with this precaution, in the case of a presumed ocular emergency, following initial remote consultation by phone or other electronic means, a face‐to‐face examination may still be deemed necessary.
T212 29259-29429 Sentence denotes For these situations, eye‐care practitioners have been advised to take significant precautions to protect themselves and their patients from potential viral transmission.
T213 29430-29768 Sentence denotes Five steps were recently summarised in relation to contact lens practice in particular,9, 81 including ensuring the patient is well, wearing personal protective equipment (PPE),81, 82, 83, 84, 85 installation of a protective shield on the slitlamp biomicroscope, 7 and thorough sanitisation of hands and all surfaces pre‐ and post‐visit.
T214 29769-30011 Sentence denotes The precautions listed above are necessary to limit exposure of both the patient and eye‐care practitioner to the virus, and should remain in place until such time that the pandemic has been declared over or other measures can be implemented.
T215 30012-30350 Sentence denotes The conclusions shared in this review provide evidence and reassurance that the eye itself is unlikely to be a route for transmission, although this does not change the level of care required in clinical situations at present, given the potential to transmit the virus through airborne droplets and direct contact from the mouth and nose.
T216 30351-30530 Sentence denotes One area that should be remembered, and already covered in this review, is that of the potential, albeit rare, for (kerato)conjunctivitis to present as the first sign of COVID‐19.
T217 30531-30703 Sentence denotes All eye‐care practitioners must bear this in mind when triaging patients and considering how best to review, and potentially examine, or refer, a patient in this situation.
T218 30704-31006 Sentence denotes Given the need for contact lens wearers to touch their face and eyes on application and removal of their contact lenses, it is understandable that questions have been raised about the safety of continuing with contact lens use during the pandemic, as discussed in a recent paper by the present authors.
T219 31007-31270 Sentence denotes 8 Despite the current review indicating that the eye is an unlikely site for SARS‐CoV‐2 infection, scrupulous contact lens hygiene practices should continue to be advocated, along with use of correct wear, care, cleaning and replacement of lenses and lens cases.
T220 31271-31438 Sentence denotes This advice is true for all contact lens wearers in normal times, but especially relevant during the current pandemic, where access to routine eye care may be limited.
T221 31439-31680 Sentence denotes Further, and in accordance with WHO and Centers for Disease Control recommendations,86, 87 it is important to remind all patients, regardless of their use of vision correction, to avoid touching their nose, mouth or eyes with unwashed hands.
T222 31682-31692 Sentence denotes Conclusion
T223 31693-31864 Sentence denotes Precautions employed by both eye‐care practitioners and patients during the COVID‐19 pandemic remain necessary to minimise viral transmission via person‐to‐person contact.
T224 31865-32191 Sentence denotes It is reassuring to recognise that current evidence suggests the virus is unlikely to bind to the ocular surface to initiate infection, and that the ocular manifestations such as conjunctivitis and presence of SARS‐CoV‐2 in tears have so far only been found rarely and primarily in people with confirmed, symptomatic COVID‐19.