433 Pak J Ophthalmol. 2020, Vol. 36 (4): 433-439 ORIGINAL ARTICLE Ocular Manifestations and Viral Prevalence in Conjunctival Secretions of Patients with COVID 19 – A Meta–Analysis Ayisha Shakeel 1 , Sharjeel Sultan 2 , Syed Imtiaz Ali 3 1-3 Al Nafees Medical College and Hospital, Isra University, Islamabad, 2 Dow University of health sciences, Karachi ABSTRACT PubMed was searched using key words “COVID-19”, “coronavirus”, and “SARS CoV-2” in conjunction with “ophthalmology” and “eye” on 17 th May 2020. Total 483 articles were identified. After screening eleven articles were included in the analysis. The frequencies of ocular manifestations and the presence of virus in conjunctiva were analyzed and the final results were compiled. Ten out of eleven articles were analyzed for ocular manifestations. In our analysis a total of 2115 cases had Covid 19, out of which 77 patients developed ocular manifestations (3.64%, 95% CI 2.88 – 4.53). The most common being conjunctival congestion. Twelve patients had SARS – CoV-2 in their ocular secretions confirmed by RT PCR test (2.61%, 95% CI 1.36 – 4.52). This meta- analysis concludes that conjunctiva is neither a preferred site of infection nor a preferred gateway for entry of SARS CoV-2 in the body. As a low risk of infection does exist, eye protective equipment should be used when treating COVID – 19 patients. Key Words: SARS CoV 2, COVID 19, Conjunctiva, Ophthalmology. How to Cite this Article: Ocular Manifestations and Viral Prevalence in Conjunctival Secretions of Patients with COVID 19 – A Meta – Analysis. Pak J Ophthalmol. 2020; 36 (4): 433-439. Doi: https://doi.org/10.36351/pjo.v36i4.1126 INTRODUCTION Human race since its existence has been threatened by many deadly pandemics. The most recent pandemic caused by a corona virus has very quickly spread through the entire world and has affected millions of individuals. 1 Since its beginning earlier this year there have been more than 4.6 million confirmed cases and around 300000 deaths worldwide. 2 Corona viruses are single stranded RNA enveloped viruses. They were first identified in 1960s and were considered to cause mild flu like symptoms in humans until more recently Correspondence: Ayisha Shakeel Al Nafees Medical College and Hospital, Isra University, Islamabad Email: ayishashakeel@gmail.com Received: September 3, 2020 Accepted: September 6, 2020 since the emergence of SARS CoV in 2002 and MERS CoV in 2012. The latter two viruses can cause severe lower respiratory tract infection proceeding to pneumonia and even death. 3 The latest pandemic is caused by a novel corona virus now named as SARS CoV2. Like its predecessors, it can cause a highly infectious pneumonia called corona virus disease or COVID 19. The SARS CoV-2 has a mortality much lower than the mortality of SARS CoV and MERS CoV but it is considered to be more contagious. 4,5 Interest of ophthalmology began in this disease since the first doctor to notice this different kind of flu was an ophthalmologist. Dr Li Wenliang was working in Wuhan, China when he noticed these patients. He unfortunately contracted the disease from one of his patients and died later on. 6 Since then, two more ophthalmologists have died in Wuhan due to occupational exposure and a pulmonologist developed conjunctivitis while treating his patients. The only mailto:ayishashakeel@gmail.com Ocular Manifestations and Viral Prevalence in Conjunctival Secretions of Patients with COVID 19 Pak J Ophthalmol. 2020, Vol. 36 (4): 433-439 434 exposed part of his face were his eyes thus leading to the speculation that ocular entry could be the cause of infection. 5 Due to close proximity to the patients as a job requirement, ophthalmologists are at greater risk of catching or transmitting the disease. 7 Since then many studies and case reports have been published with involvement of eyes of COVID 19 patients. 8,9,10 The most common ocular symptoms were hyperemia, chemosis, lacrimation and increased secretion while none of the patient experienced blurred vision. 11 The SARS CoV-2 spreads through respiratory droplets and by direct contact with virus contaminated fomites. 12 Eye due to exposure to the environment can come in contact with these virus particles. The virus has been sequenced and is found to be 75 – 80% similar to SARS CoV and 40% similar to MERS CoV. 13 It is therefore possible that SARS CoV-2 shares the same mechanism to gain access in the human cells. The virus gains entry into human cells by binding to certain proteins on the cell surface. Two of such key proteins, Angiotensin converting enzyme 2 (ACE 2) and transmembrane serine protease 2 (TMPRSS 2) are the key proteins for entry in host cells. Animal models have shown that in the eye their highest expression is in conjunctiva and cornea. 14 ACE 2 and TMPRSS 2 are found in human conjunctival cells and corneal limbal stem cells. ACE 2 are also present in other parts of the eye like trabecular meshwork, aqueous humor, iris, ciliary body, non- pigmented ciliary epithelium, and retina. 15 Human eye is also connected to the nasopharynx by the constant draining of tears through the nasolacrimal duct. It is therefore, possible that there may be two routes of entry of virus through the eye. One is by binding to the ocular surface cells and the other is by being drained into the nasopharynx with tears. 16 Although the possibility of spread exists, the eyes are rarely involved in COVID 19. 17 This suggests that the eye is neither a preferred organ for human Coronavirus infection nor a preferred gateway of entry that enables human Coronaviruses to infect the respiratory tract. 12 Since the emergence of this disease, a lot of information is coming up on daily basis about COVID 19 and its involvement of the eye. In ophthalmology, the main focus is on two things. Firstly, the ocular manifestations of COVID 19 and secondly how is the eye involved in transmission and infection of this disease. A number of studies have come up in literature to answer these questions with varying opinions. In this paper, we try to sum up the findings of literature by performing a systematic review and meta-analysis with special focus on ocular manifestations and presence of virus in the conjunctiva of patients with possible transmission through the eye. The objective of this analysis was to find out the ocular manifestations of COVID – 19 and presence of virus in the conjunctival secretions of these patients. METHODS This meta-analysis was carried out according to the fundamentals laid in the Preferred Reporting Items for Systematic reviews and Meta‐Analysis (PRISMA) statement. 18 The objective of this analysis was to find out the ocular manifestations of COVID19 and presence of virus in the conjunctival secretions of these patients. In the meta-analysis only comparative studies (both prospective and retrospective observational studies) and Randomized controlled trials since the start of corona virus pandemic till 17 th May 2020 were included. The participants in all these studies were laboratory confirmed COVID – 19 patients. Ocular symptoms of conjunctival hyperemia, discharge, watering, foreign body sensation, itching and chemosis were all included. Reverse transcriptase- polymerase chain reaction test (RT-PCR) was performed on the conjunctival swabs of all patients with ocular symptoms for presence of SARS – CoV-2. PubMed database was searched for relevant articles using the keywords “COVID – 19”, “coronavirus”, and “SARSCoV-2” in conjunction with “ophthalmology” and “eye”. A total of 483 articles were identified through database searching till 17 th May 2020. However, by following the flow diagram of PRISMA guidelines for meta-analysis, 97 articles were identifiedafter removal of duplicates and irrelevant articles. Further screening removed 41 more articles (editorials, communication, case reports, case series) leaving 56 behind to be assessed for eligibility. These full text articles were then assessed for eligibility under the criteria set in the beginning of the article. Thirty-one did not fulfill the criteria and were removed leaving behind 25 articles for qualitative analysis. The results of these articles were assessed and out of these articles, 11 articles were included for meta-analysis. The whole process is shown in Fig. 1. For statistical data analysis, frequencies were calculated in terms of percentages to identify the most Ayisha Shakeel, et al 435 Pak J Ophthalmol. 2020, Vol. 36 (4): 433-439 Fig. 1: Flow Chart. common ocular manifestations and presence of virus in the conjunctiva of patients based upon which, final conclusions were drawn. RESULTS After following the guidelines of PRISMA for meta- analysis a total of 11 articles were finally included in the meta-analysis. Based on the available data ten articles were included to analyze the ocular manifestations in patients with COVID – 19, while eight articles were included to assess the prevalence of virus in ocular secretions in such patients (table 1). The ten studies analyzed for ocular manifestations had a total of 2115 confirmed cases of COVID 19. Out of the total 2115 confirmed cases, 77 patients developed ocular manifestations (3.64%, 95% CI 2.88 – 4.53) of different kind. The most common Ocular Manifestations and Viral Prevalence in Conjunctival Secretions of Patients with COVID 19 Pak J Ophthalmol. 2020, Vol. 36 (4): 433-439 436 ocular manifestations were conjunctival congestion (09 studies) followed by increased secretions (7 studies), itching (4 studies), foreign body sensation (2 studies), dry eyes (2 studies), chemosis, blurred vision and floaters (1 study each). For details see table 2. The eight studies analyzed for prevalence of virus in ocular secretions had a total of 459 confirmed cases of COVID – 19. Out of the total 459 confirmed cases, 12 patients had SARS-CoV 2 in their ocular secretions confirmed by RT PCR test (2.61%, 95% CI 1.36 – 4.52). Table 3 shows the details. Table 1: Studies Included in Meta-analysis. Author Type of Study Sample Size Age Gender (M, F) Patients with Ocular Manifestations Patients with Positive Conjunctival Secretion Yunyun Zhou et al 19 Retrospective 67 35.7 ± 10.6 25, 42 1 3 Nang Hong et al 20 Cross sectional 56 48 ± 21.1 31, 25 15 - Ping Wu et al 11 Retrospective 38 65.8 ± 16.6 25, 13 12 2 Wei-Jie Guan et al 17 Retrospective 1099 47 (35 – 58) 58.1%, 41.9% 9 - Jianhua Xia et al 21 Interventional case series 30 54.5 ± 14.17 27, 3 1 1 Xian Zhang et al 22 Cross sectional 72 58.68 ± 14.81 36, 36 2 1 Yunyun Zhou et al 23 Cross sectional 121 48 53, 68 8 3 Lan Qianqian et al 24 Prospective 81 41.69 ± 18.6 33, 48 3 0 Ivan Yu Jun Seah et al 25 Prospective 17 - - 1 0 Hua-Tao Xie et al 26 Retrospective 33 57.6 ± 14 22, 11 - 2 Liwen Chen et al 27 Cross sectional 534 45 260, 274 25 - Table 2: Studies Included in Analysis of Ocular Manifestations in COVID – 19 Patients. Author Type of Study Sample Size Age Gender (M, F) No of Patients with Ocular Manifestations Percentage of Ocular Symptom 95% CI Yunyun Zhou et al 19 Retrospective 67 35.7 ± 10.6 25,42 1 1.49% 0.04 – 8.04 Nang Hong et al 20 Cross sectional 56 48 ± 21.1 31, 25 15 26.79% 15.83 – 40.3 Ping Wu et al 11 Retrospective 38 65.8 ± 16.6 25, 13 12 31.58% 17.5 – 48.65 Wei-Jie Guan et al 17 Retrospective 1099 47 (35 – 58) 58.1%, 41.9% 9 0.82% 0.38 – 1.55 Jianhua Xia et al 21 Prospective 30 54.5 ± 14.17 27, 3 1 3.33% 0.08 – 17.22 Xian Zhang et al 22 Cross sectional 72 58.68 ± 14.81 36, 36 2 2.78% 0.34 – 9.68 Yunyun Zhou et al 23 Cross sectional 121 48 53, 68 8 6.61% 2.91 – 12.61 Lan Qianqian et al 24 Prospective 81 41.69 ± 18.6 33, 48 3 3.70% 0.77 – 10.4 Ivan Yu Jun Seah et al 25 Prospective 17 1 5.80% 0.15 – 28.65 Liwen Chen et al 27 Cross sectional 534 45 260,274 25 4.68% 3.05 – 6.83 Total Patients 2115 77 3.64 2.88 – 4.53 Table 3: Studies with SARS – CoV-2 in Ocular Secretions. Author Type of Study Sample Size Age Gender M, F No of patients with SARS CoV2 in Conjunctival Secretions % Age of Ocular Symptoms 95% CI Ping Wu et al 11 Retrospective 38 65.8 ± 16.6 25, 13 2 5.26% 0.64 – 1.77 Yunyun Zhou et al 19 Retrospective 67 35.7 ± 10.6 25, 42 3 4.48% 0.093 – 12.5 Jianhua Xia et al 21 Prospective 30 54.5 ± 14.17 27, 3 1 3.33% 0.08 – 17.22 Xian Zhang et al 22 Cross sectional 72 58.68 ± 14.8 36, 36 1 1.39% 0.03 – 7.5 Yunyun Zhou et al 23 Cross sectional 121 48 53, 68 3 2.48% 0.51 – 7.07 Lan Qianqian 24 Prospective 81 41.69 ± 18.6 33, 48 0 0.00% 0 – 4.45 Ivan Yu Jun Seah et al 25 Prospective 17 0 0.00% 0 – 19.5 Hua-Tao Xie et al 26 Retrospective 33 57.6 ± 14 22, 11 2 6.06% 0.74 – 20.23 Total patients 459 12 2.61% 1.36 – 4.52 Ayisha Shakeel, et al 437 Pak J Ophthalmol. 2020, Vol. 36 (4): 433-439 DISCUSSION The results of this meta-analysis shows that overall 3.64% (95% CI 2.88 – 4.53) patients with COVID – 19 presented with ocular manifestations. This is slightly higher than another meta-analysis by Loffredo et al in which 1.1% patients of COVID 19 had ocular manifestations. 28 The reason could be that the number of studies in our meta-analysis were ten as compared to only three in the other meta-analyses. With more and more studies being published the rate and manifestations of the disease will change. Loffredo et al has also mentioned two groups of patients with COVID – 19 and the rate of ocular manifestations in patients with severe disease was 3%. The rate of ocular manifestations in COVID 19 patients has varied among individual studies. Initial studies by Huang, Chan and Chen from Wuhan did not mention any ocular manifestations at all. 29,30,31 Later on multiple studies emerged which mentioned ocular manifestations as symptoms of COVID – 19. A study by Guan et al with a sample size of 1099 patients mentioned ocular manifestations in only 0.82% (95%CI 0.38 – 1.55) of the patients. 17 On the contrary, a retrospective analysis of 38 patients by Wu et al reported ocular manifestationsas high as 31.8% (95% CI 17.5 – 48.65). 11 As COVID – 19 is a new disease and humanity is battling with its effect on the human body, it is not surprising that we will find different features in different reports. The most common ocular manifestation in our analysis was conjunctival congestion, which was present in 82% of our studies. This was followed by increased ocular secretions which was mentioned in 64% of our studies. The next most common manifestations were itching and ocular discomfort or foreign body sensation in around 36% of our studies. Dry eye was another manifestation, which the patients had experienced in 18% of our analyzed studies. The least common ocular manifestations were chemosis, floaters and blurred vision, which were mentioned in only one out of eleven studies (9%). Most of the studies except one did not mention reduced or blurred vision as an ocular manifestation of COVID – 19. These findings were almost similar to the reported literature on ocular manifestations of COVID – 19 in which conjunctival congestion, hyperemia, increased tearing and foreign body sensations were the most common manifestations in the eye. In a case report from France by Navel et al the patient presented with hemorrhagic conjunctivitis with pseudo memebranes. 8 In another case report by Chen et al a patient developed redness, foreign body sensation and tearing during the course of the disease. 9 A case report by Cheema et al from Canada mentioned conjunctivitis as the primary presentation of COVID – 19. 10 Another report by Daruich et al also mentioned ocular redness and foreign body sensation as the primary presentation of the disease. 32 Corona viruses have been reported to cause retinal vasculitis, retinal degeneration and breakdown of blood retinal barriers in animal models in the past. 33 The SARS CoV-2 virus uses ACE2 receptors to get attached to the host cells and ACE 2 receptors have been identified in human retina. Therefore, the possibility of retinal manifestation exists in COVID – 19. A recent case series reported some retinal findings in the patients of COVID 19 possibly due to SARS-CoV-2. 34 As case reports were excluded from this analysis, these diverse retinal findings could not be found in these cross sectional and retrospective studies. Further studies are required to fully understand the spectrum of ocular manifestations in COVID – 19 patients. In this meta-analysis we also looked into the presence of SARS CoV-2 virus in ocular secretions. Out of the eleven studies, eight studies analyzed ocular secretions for the presence of SARS CoV-2 by RT PCR tests. In these studies, a total of 459 patients with confirmed COVID – 19 were analyzed. Out of these, 12 were found to have SARS CoV-2 in their ocular secretions (2.61%, 95% CI 1.36 – 4.52). Two of the studies in this meta-analysis did not show viral shedding in ocular secretions at all. 24,25 The highest rate of viral shedding in ocular secretions was in a study by Xie et al which was 6.06%. 26 As the knowledge about the disease is evolving the varying rates of viral shedding is not surprising. Respiratory- related public health events, such as SARS, were reported to be associated with ophthalmology. 35 Corona virus or Ebola virus had been detected in the tears of patients with SARS and Ebola. 36 A case report by Hu et al detected not only SARS CoV-2 but also HSV1 and HHV6B in ocular secretions 2 weeks after the nasopharyngeal swab became negative. 37 This was not found in the studies under review. Shedding of virus in the ocular secretions of patients who does not have conjunctivitis pose a public health risk of transmission. An article by Liu et al mentioned that ocular route is not the preferred route for virus transmission and respiratory route was the most preferred route. 38 Although it seems, at the Ocular Manifestations and Viral Prevalence in Conjunctival Secretions of Patients with COVID 19 Pak J Ophthalmol. 2020, Vol. 36 (4): 433-439 438 moment, that there is a low risk of coronavirus spreading through tears, it may survive for a long time or replicate in the conjunctiva, even in the absence of conjunctivitis signs, indicating that eye protection (e.g., protective goggles alone or in association with face shield) is advisable to prevent contamination from external droplets and aerosol. CONCLUSION The current analysis indicate that Ocular manifestations are not very common in patients with COVID-19. This meta-analysis concludes that conjunctiva is neither a preferred site of infection nor a preferred gateway for entry of SARS CoV-2 in the body. 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Author’s designation and contribution Ayisha Shakeel; Assistant Professor: Concepts, Design, Literature research, Data acquisition, Data analysis, Statistical analysis, Manuscript preparation, Manuscript editing, Manuscript review Sharjeel Sultan; Assistant Professor: Design, Literature research, Data acquisition, Statistical analysis, Manuscript preparation Syed Imtiaz Ali; Professor: Concepts, Design, Data analysis, Manuscript preparation, Manuscript review. .…  … https://doi.org/10.1101/2020.03.12.20034678