key: cord-0736789-yr5i03a7 authors: Chen, Yu-Yen; Yen, Yung-Feng; Huang, Li-Ying; Chou, Pesus title: Manifestations and Virus Detection in the Ocular Surface of Adult COVID-19 Patients: A Meta-Analysis date: 2021-06-19 journal: J Ophthalmol DOI: 10.1155/2021/9997631 sha: 49683426fbd21965fe9ab20d817cb2867709de08 doc_id: 736789 cord_uid: yr5i03a7 PURPOSE: This study aims to examine the prevalence rate of ocular manifestations and the positive rate for the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in conjunctival/tear swabs among adult patients with coronavirus disease 2019 (COVID-19). METHODS: PubMed and EMBASE were reviewed between December 1, 2019, and January 31, 2021, and only peer-reviewed clinical studies in our pooled analyses were included. Details regarding the patient numbers, demographics, ocular manifestations, positivity of ocular surface RT-PCR, and severity of pneumonia were recorded from each study. Primary outcomes were the occurrence of ocular manifestations and virus detection on the ocular surface. Meanwhile, secondary outcomes included frequencies of various ocular symptoms/signs (s/s), the proportion of patients with ocular manifestation as the initial symptom, and the relationship between the severity of pneumonia and the presentation of ocular manifestations. RESULTS: In total, 35 studies with 4,432 adult COVID-19 patients were included in this analysis. The overall prevalence rate of ocular manifestations was found to be 11.3%, and the positive rate of SARS-CoV-2 in the ocular surface was 7.4%. The four most common ocular s/s were follicular conjunctivitis, redness, watering, and discharge. A proportion of 3.3% presented with ocular s/s preceding other findings. Besides, patients with higher severity of pneumonia were more likely to have ocular manifestations (odds ratio = 2.25; 95% confidence interval (CI): 1.45–3.50). CONCLUSION: As per our findings, it was determined that ocular transmission of SARS-CoV-2 might be possible, highlighting the importance of eye protective equipment among healthcare personnel. erefore, the conjunctiva may be an infection route of SARS-CoV-2 [3, 4] . Some COVID-19 patients present with conjunctivitis as symptoms of redness, watering, discharge, foreign body sensation, chemosis, etc. However, the prevalence rate of ocular manifestations was found to differ a lot among different studies [5, 6] . Except for the findings of ocular s/s, the direct evidence of ocular involvement by SARS-CoV-2 is the detection of the virus RNA in the ocular surface. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays are currently the standard for COVID-19 diagnosis. Data published on the topic of ocular surface involvement presented as the results of RT-PCR in conjunctival swabs or tear samples remain to be inconsistent [5] . ese studies have been conducted in a hospital setting, mostly with small case numbers. To better identify the ocular surface manifestations and analyze the positive rate for the SARS-CoV-2 RT-PCR in the ocular surface among adult COVID-19 patients, a meta-analysis of relevant studies was conducted. Whether COVID-19 patients with more severe pneumonia would have a higher prevalence of ocular manifestations was also examined. is study was conducted in accordance with the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and EMBASE were reviewed for studies published from December 2019 to February 2021, using the keywords "(SARS-CoV-2 or COVID-19 or 2019-nCoV) and (conjunctiva or conjunctivitis or ocular manifestations or conjunctival swab or ocular symptoms)." e titles and abstracts of the studies were first screened. Candidate papers were further scrutinized in their full texts to see if they have fulfilled the inclusion criteria. Bibliographies were also manually searched for relevant literature. Only peer-reviewed journal articles written in English were included in this analysis. e confirmation of COVID-19 cases should be based on the clinical criteria or positive RT-PCR for virus RNA from nasopharyngeal swabs. ese studies should be cross-sectional, prospective, or retrospective clinical cohort studies or case series. Studies or case reports with case numbers not larger than five were excluded. Reviews, metaanalyses, conference abstracts, or letters to editors were also excluded due to possible repeated cases. Two researchers (Chen and Yen) independently assessed the eligibility of these articles. A third researcher (Huang) reassessed and determined the eligibility if discrepancies occurred. Evaluation of the quality of included studies was independently performed by three researchers (Chen, Yen, and Huang) using Hoy's checklist [7] . Consensus should be reached. If not, the supervisor (Chou) would make the final decision. e checklist assesses the risk of bias on 9 domains, including representativeness of the target population, random selection, likelihood of nonresponse bias, data collection, use of case definitions, reliability and validity of measuring tools, and appropriate use of numerator and denominator for the ocular symptoms. Each domain contains a question (criteria). e domain was rated as "Yes" and scored 0 if the criteria were satisfied. On the contrary, the domain was rated as "No" and scored 1 if the criteria were not fulfilled. en, the total score was obtained by summation of the 9 numbers to decide the risk of bias. e risk of bias was classified as low if the total score was 0-3, moderate if the total score was 4-6, and high if the total score was more than 6. e following data were recorded from each included article: the first author, date of publication, mean age of participants, total number of patients, clinical features of ocular s/s, and the number of patients who had ocular s/s, who had positive conjunctival RT-PCR, and who had ocular s/s as the first presentation of the disease. Additionally, proportions of patients who had ocular s/s among those with severe pneumonia and mild-tomoderate pneumonia were also collected. e Comprehensive Meta-Analysis software, version 3 (Biostat, Englewood, NJ, USA), was used to perform the meta-analysis. e primary outcomes are as follows: (1) the proportion of patients with ocular s/s among COVID-19 cases and (2) the positive rate of RT-PCR from conjunctival/tear samples among COVID-19 cases. e secondary outcomes included the following: (1) clinical features of ocular manifestations, (2) subgroup analysis regarding proportions of the four most common ocular s/s, (3) the proportion of patients whose first s/s appeared as ocular manifestations, and (4) the odds ratio (OR) for ocular s/s among patients with severe pneumonia relative to mildto-moderate pneumonia. Besides, between-trial heterogeneity of the primary outcomes was calculated using I 2 statistics. I 2 statistics of ≥75% represents considerable heterogeneity. Publication bias was determined using funnel plots and Egger's test. Figure 1 illustrates the PRISMA flowchart of study screening and selection. An initial search yielded 695 citations. Of them, 260 were removed because of duplication. Subsequently, 135 nonrelevant studies were excluded after screening titles and abstracts. Following fulltext examination, 241 studies categorized as reviews, metaanalyses, or case reports with case numbers not larger than five were also excluded. Furthermore, another 24 papers not written in English were excluded. Finally, 35 studies with a total of 4,432 patients were included in our meta-analysis. e risk of bias of each study is presented in Table 1 . Most of them had a moderate risk of bias and none of them had a high risk of bias. Figure 2 demonstrates that 11.3% (95% confidence interval (CI): 7.2-17.2%) of COVID-19 patients had ocular s/s using random-effects model from pooling of the 30 studies. Figure 3 illustrates that using the same model, the overall positive rate of RT-PCR for the virus in the ocular surface from the 21 studies was 7.4% (95% CI: 4.1-12.8%). Bias. Considerable heterogeneity in studies was found in evaluating the proportions of patients having ocular s/s and the positive rate of ocular surface RT-PCR (I 2 � 94.4% and 80.3%, respectively). e funnel plots for calculating publication bias are presented in Figures 4 and 5. e results of Egger's test revealed p � 0.12 and p < 0.0001, respectively. e study conducted by Tostmann et al. had different inclusion criteria from other studies because it included healthcare workers only. When the study was removed from the analysis, the remaining studies yielded an overall proportion of ocular manifestations to be 10.7% (95% CI: 6.7-16.7%). Considerable heterogeneity still existed (I 2 � 94.5%). Table 3 shows the clinical features of the ocular manifestations. Classification of ocular manifestations included redness, follicular conjunctivitis, watering, discharge, dryness, and itching. Proportions of patients whose first s/s were ocular manifestations varied a lot from 0% to 31.3%. Figure 6 displays the subgroup analysis according to the four most prevalent ocular s/s, which were follicular conjunctivitis, redness, watering, and discharge. Using randomeffects models, the overall prevalence rates were calculated as 10.6%, 10.5%, 8.6%, and 7.6%, respectively (all p < 0.001). Figure 7 reveals the proportion of patients whose first s/s were ocular manifestations. e overall proportion was 3.3% (1.3-7.8%). Figure 8 explores the relationship between odds of ocular manifestations and severity of COVID-19. Patients with severe pneumonia had significantly higher pooled odds for ocular s/s than those with mild-to-moderate pneumonia (OR � 2.25; 95% CI: 1.45-3.50). is meta-analysis focused on the ocular manifestations and positive rate of conjunctiva/tear RT-PCR in adult patients with COVID-19. In total, 4,432 patients in 35 studies were included in our analyses. e overall prevalence rate of ocular manifestations was 11.3% (95% CI: 7.2-17.2%), with considerable heterogeneity between studies. Moreover, the overall positive rate of ocular surface RT-PCR was 7.4% (95% CI: 4.1-12.8%) with considerable heterogeneity. e four most prevalent ocular manifestations were follicular conjunctivitis (10.6%), redness (10.5%), watering (8.6%), and discharge (7.6%). A proportion of 3.3% of COVID-19 patients presented with ocular manifestations as their first s/s. Moreover, patients with higher severity of pneumonia had a significantly higher possibility of ocular manifestations. Our study found an overall proportion of ocular manifestations among COVID-19 patients to be 11.3%, which was compatible with previous meta-analyses performed by Aggarwal et al. [5] and Inomata et al. [6] . Conjunctivitis, presented as redness, watering, discharge, foreign body sensation, etc., can occur in COVID-19 but may go unnoticed due to several reasons. First, doctors may pay more attention to the damage of vital organs (e.g., lung, heart, and kidney) and ignore the ocular findings. Second, detailed ophthalmic examinations, with a short working distance, are not safe to be performed in the acute stage of COVID-19. ird, patients under ventilators frequently have ocular complications, including dryness, chemosis, and subconjunctival hemorrhage. Whether these manifestations are directly caused by SARS-CoV-2 is hard to tell. Fourth, some ocular symptoms are related to previous long-term disorders (e.g., dry eye syndrome, chronic inflammation, or allergy). To address these difficulties regarding data retrieval, most studies used questionnaires and focused on the new-onset s/ s during the infection of SARS-CoV-2. Information bias might occur because of differences in subjective perception. erefore, some studies required a simplified ocular examination (torch, ophthalmoscopy, and photography) in a long distance. However, the carefulness of inspection might influence the sensitivity and specificity. It may explain the considerable heterogeneity between studies, reaching 94.4% in our analysis, which is a limitation of our study. Further studies with a standardized method to record ocular s/s are warranted. A more straightforward method to indicate virus infection in the ocular surface is RT-PCR analysis of conjunctival secretions/tears. e conjunctiva is easily exposed to the pathogens in the environment and is also connected to the respiratory tract through the nasolacrimal duct. Whether the virus travels from the conjunctiva to the lung or spreads retrogradely from the lung to the conjunctiva remains a concern under discussion. Another issue worth exploring is the inconsistent results of the ocular surface RT-PCR among different studies. Four studies conducted by Seah, Meduri, Pirraglia, and Shemer revealed zero positive rates [8, 31, 34, 38] . However, 21 (55.3%) out of 38 COVID-19 patients in Hanege's study had positive RT-PCT results in conjunctival swabs [33] . e considerable heterogeneity, as high as 80.3%, may be due to variations in techniques and time of collecting samples, the severity of diseases, and testing regimen among different studies. e positivity of RT-PCR in conjunctiva or tears was found to be high when sampled from the 4th to 9th day of symptoms in Arora et al.'s study [40] and then decreased from the second week [43, 44] . erefore, performing RT-PCR in conjunctival/tear swabs at multiple stages (early and late) of infection would be better to reduce the falsenegative rate. Besides, the conjunctiva may have a lower viral concentration and a different genome composition compared to the nasopharyngeal specimen [13, 45] , highlighting the importance of accurate sampling and appropriate PCR primers. Furthermore, the drainage of the tear film may decrease the virus load on the ocular surface. Immune activation with an increase in lactoferrin and secretory IgA levels in tears may also contribute to the low RT-PCR positive rate of the conjunctiva/tear samples in our study [46] . e most prevalent s/s of the ocular manifestations in our study are follicular conjunctivitis, redness, watering, and discharge. is finding is similar to the meta-analysis conducted by Aggarwal et al. [5] , which revealed that the most common ocular manifestations are pain, discharge, and watering. Our study also revealed that 3.3% of the COVID-19 patients had ocular s/s as the prodromal manifestations. Although the proportion is low, doctors and Follicular conjunctivitis (9); watering (9); itching (8); photophobia (4); burning sensation (5); blurred vision (2) 0 (0%) NR NR Meduri 29 Foreign body sensation (3); ocular pain (3); dryness (2); watering (5); hyperemia (7) Figure 6 : Subgroup analysis regarding the four most prevalent ocular symptoms/signs. D represents discharge. F represents follicular conjunctivitis, R represents redness, and W represents watering. s/s and the severity of COVID-19. Wu et al. found that the patients with ocular s/s were more likely to have higher levels of neutrophil, procalcitonin, C-reactive protein, and lactate dehydrogenase than those patients without ocular s/s [12] . ey also found that patients with ocular manifestations had a higher severity of pneumonia. Our study further calculated the pooled odds for ocular manifestations to be significantly higher in patients with severe pneumonia than those with mild-to-moderate pneumonia (OR � 2.25). e limitation of our analyses was the heterogeneity among the included studies. ere is no standardized procedure regarding ocular examination or ocular surface testing for patients with COVID-19. erefore, interstudy or intrastudy variation may occur. Moreover, some studies acquired data of symptoms using questionnaires or telephone interviews, which might increase the information bias. Globally accepted protocols of data collection and ocular PCR should be applied in upcoming studies. In conclusion, this meta-analysis has demonstrated the possibility of ocular manifestations and virus detection in the ocular surface of COVID-19 patients. It also reminds us that the ocular manifestations might occur as a prodromal finding of COVID-19. Furthermore, our study highlights that severity of pneumonia may be significantly associated with ocular manifestations. Further experimental and clinical research should be conducted to derive more data regarding the COVID-19 infection through the ocular surface route. At present, our study provides evidence implying ocular transmission. us, doctors should be aware of the ocular manifestations in patients possibly infected with COVID-19. In addition, wearing protective equipment, including eye goggles, by ophthalmologists is imperative to minimize the risk of infection. Angiotensin-converting enzyme 2 s/s: Symptoms/signs RT-PCR: Reverse transcriptase-polymerase chain reaction PRISMA: Preferred Items for Systematic Reviews and Meta-Analyses OR: Odds ratio CI: Confidence interval. e data used to support the findings of this study are available from the corresponding author upon request. None of the authors have any conflicts of interest to disclose. Chen, Yen, and Chou were involved in research design. Chen and Yen were involved in data collection. Chen, Yen, and Huang were involved in analysis and interpretation. Chen was responsible for manuscript preparation. 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TCVGH-1106901B).