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Introduction This study’s purpose was to investigate the relationship between laboratory blood parameters and ocular findings in patients hospitalized with moderate or severe COVID-19. Methods Ophthalmologic examination of 215 patients who were hospitalized with the diagnosis of COVID-19 was performed in their hospital beds and their ocular findings were noted. Blood parameters were compared in patients with and without conjunctivitis-like symptoms. Results Conjunctivitis-like inflammatory findings were detected in 15 (7.44%) of 215 moderate or severe COVID-19 patients. There was no difference between the patients with and without ocular findings in terms of laboratory findings such as white blood cells count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, procalcitonin, D-dimer, C-reactive protein, and ferritin. Conclusions There was a significant relationship between COVID-19 and an acute conjunctival inflammatory response. Blood parameters that determined progression in patients with COVID-19 were not significant in terms of ocular findings.
The COVID-19 pandemic started with the reporting of pneumonia cases of unknown etiology, continued with the identification of a novel coronavirus (2019-nCoV), and this new virus spread rapidly and became a global problem. The new virus was named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to its close similarity to SARS-CoV, and the disease caused by the virus was named coronavirus disease-2019 (COVID-19). In the clinical presentation of COVID-19, fever, dry cough, and respiratory distress are considered as major findings.1,2 Although patients mostly present with an asymptomatic or mild clinical picture, it may progress to pneumonia or acute respiratory distress syndrome in patients with additional diseases and those aged over 65 years.3 Infection is transmitted from person to person by droplet inhalation or, hypothetically, by contact with the eyes, nose, and mouth after touching surfaces contaminated by the virus.4
Some respiratory system viruses such as adenovirus and H7 influenza virus can strongly stimulate the immune response in the cornea and conjunctiva, causing the inflammatory pathway to be activated and to consequently form conjunctivitis or keratoconjunctivitis.5
Certain coronaviruses have also been reported to cause conjunctivitis in humans. For example, human coronavirus NL63 (HCoV-NL63) was first identified in an infant with bronchiolitis and conjunctivitis. Then, conjunctivitis was reported in 17% of 18 in pediatric patients with HCoV-NL63.6 No ocular involvement was reported in Middle East respiratory syndrome-related coronavirus (MERS-CoV) or SARS-CoV infections.6 However, in animal studies, ocular infection was observed as a result of direct inoculation of SARS-CoV in the mouth, nose or eye.7 A tear film mostly covers the eye surface and prevents bacteria and viruses from adhering to the cornea and conjunctiva with antimicrobial agents and the immunoglobulins it contains.8
It has been shown that SARS-CoV-2 infects host cells via angiotensin-converting enzyme 2 (ACE2) just like SARS-CoV and has similar receptor binding sites.9 The ACE2 receptor has been detected in the retina,10 choroid11 and conjunctival epithelium12in the human eye. In previous studies, findings such as acute follicular conjunctivitis, conjunctival hyperemia, chemosis, epiphora, and increased secretion have been described in patients with COVID-19.13 As with other viral infections, it is assumed that the ocular symptoms of COVID-19 are self-limited and can be managed with symptomatic treatment.
It is known that SARS-CoV-2 can be found in tears and it adheres to the ocular surface. Conjunctivitis in patients with COVID-19 has been reported at different rates in various studies. It is not clear whether it causes different findings or subclinical conditions on the ocular surface.
The aim of this study was to evaluate the frequency of ocular involvement in hospitalized patients with COVID-19 and to compare the demographic findings and various blood parameters of patients with and without ocular findings.
A total of 215 patients who were diagnosed as having COVID-19 with clinical findings or with polymerase chain reaction (PCR) test positivity and who were hospitalized at Prof. Dr. Feriha Öz Emergency Hospital in Istanbul, Turkey between July 2020 and August 2020 were included in the study. Patients who had ground-glass opacities, bilateral involvement, peripheral distribution and multilobar involvement in lung computed tomography (CT) findings, and these were supported by clinical findings such as cough, weakness, and fever, were diagnosed with PCR-negative COVID-19 disease.
This is a cros-sectional study that required one eye examination for each patient included. The hospitalized patients were seen individually during their hospital admission, and the lower eyelid conjunctiva and ocular surface were macroscopically examined with penlight by inspection. The eyes of the patients were examined in terms of conjunctival follicle in the lower eyelid, congestion on the ocular surface, hyperemia or chemosis. The patients were questioned as to whether there was burning, foreign body sensation, itching, epiphora or blurred vision. Patients with any symptoms were asked when they started, whether their symptoms increased or not, and whether they had had similar symptoms before COVID-19. Patients who were hospitalized in the intensive care unit due to COVİD-19, had previously diagnosed ocular surface disease, had undergone any eye surgery or used regular eye drops were not included in the study. Nasopharyngeal SARS-CoV-2 real-time (RT)-PCR results, lung CT imaging findings, lactate dehydrogenase (LDH), white blood cells (WBC), neutrophil counts, lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), procalcitonin, C-reactive protein (CRP), and ferritin values were recorded. Blood parameters were collected at the time of the ophthalmologic examination.
Ethics approval was obtained from the Medeniyet University Göztepe Training and Research Hospital Ethics Board before the start of the study. Verbal informed consent was obtained, and only willing participants were ultimately included in the study. The study followed the tenets of the Declaration of Helsinki.
Statistical analysis
Statistical analysis was performed using the SPSS 16.0 (SPSS Inc., USA) software. The Shapiro-Wilk test was used to test the normality of data distribution. The independent sample t-test was used for data with normal distribution; data are shown as mean ± standard deviation in the table. Numerical data without normal distribution were analyzed using the Mann-Witney U test and are shown as median (and the IQR: 25th-75thpercentile) values. Categorical data were analyzed using the Chi-square and Fischer's exact tests and shown as percentage (%). Statistical significance was assessed as p-value <0.05.
Of the 215 patients hospitalized with COVID-19, 113 (53%) were male (mean age: 54.27 years) and 102 (47%) were female (mean age: 58.71 years). One hundred forty-five (67%) patients were found to be positive on nasopharyngeal SARS-CoV-2 RT-PCR test and they were defined as laboratory-confirmed patients. In 176 (82%) patients, CT findings of COVID-19 were present.
During the examination, there were 16 patients (7.44%) who had at least two findings of conjunctivitis-related findings such as conjunctival congestion, conjunctival hyperemia, conjunctival follicle, chemosis and epiphora, who were considered as having conjunctivitis. The ocular findings recorded during the ophthalmological consultation are given in Table 1.
Table 1. Ocular findings of patients with COVID-19
It was observed that the most common ocular findings in patients with COVID-19 were epiphora and hyperemia. Patients with chronic dry eye or allergic conjunctivitis who had had such symptoms before were not included in the study. When the patients with and without ocular findings were evaluated in terms of age, sex, CT findings, and nasopharyngeal PCR positivity, no significant difference was found (Table 2).
In addition, there was no difference between the patients with and without ocular findings in terms of laboratory findings such as WBCs, neutrophil counts, lymphocyte counts, NLR, LDH, procalcitonin, D-dimer, CRP, and ferritin (Table 1).
There is the hypothesis and certain evidence that SARS-CoV-2 could infect ocular surfaces, through potential mechanisms that may include: direct conjunctival contact with infected droplets, hematogenous dissemination to the lacrimal gland or viral migration from the upper respiratory system.14The incidence of conjunctivitis in patients with COVID-19 has been reported as 0.8 and 4.76 percent.15,16
In the study conducted by Ping Wu et al., the ocular symptoms of 38 patients who were clinically diagnosed as having COVID-19 and treated as inpatients were assessed, and RT-PCR was performed by taking nasopharyngeal and conjunctival samples. Although SARS-CoV-2 was detected in nasopharyngeal samples in 28 (73.7%) patients, it was shown in conjunctival samples in only 2 (5.2%) patients. However, in 12 of 38 patients (31.6%), symptoms related to conjunctivitis such as conjunctival hyperemia, chemosis, and epiphora were observed. Ocular symptoms were mostly observed in patients with severe pneumonia and the middle stage of the disease.13
In an epidemiologic study conducted in China on 534 patients who were SARS-CoV-2–positive, 25 (4.68%) patients had conjunctival congestion, dry eye (112, 20.97%), blurred vision (68, 12.73%), and sensation of foreign body (63, 11.80%) were reported as the most common symptoms associated with COVID-19.17 In another epidemiologic study conducted in a total of 30 hospitals in China, conjunctivitis was found in 9 (0.8%) of 1099 patients who had a positive SARS-CoV-2 test and were hospitalized.18
In a study from Wuhan, China, conducted by Deng et al., SARS-CoV-2 was detected using RT-
PCR in nasopharyngeal samples in 90 (76%) of 114 patients followed up in hospital due to COVID-19 pneumonia, and the virus was not detected in any of the conjunctival samples. In addition, none of the 114 patients had ocular symptoms such as red eye or pain.19 In another study, five patients with COVID-19 presenting only with symptoms and signs of conjunctivitis were described.20
In our study, there were 16 (7.44%) patients showing conjunctival inflammatory response who had foreign body sensation, epiphora, and conjunctival congestion symptoms, which were not present prior to COVID-19. Although more comprehensive studies are needed, our study seems to be compatible with the existing literature. The rate of conjunctivitis or conjunctival inflammatory response has been shown in a wide spectrum in these studies. These spectra were explained by the fact that no biomicroscopy examination was performed on patients in any studies in the literature, and that the data in most studies were based on patients' subjective symptoms obtained through teleconferences. During our study, the fact that the patients were seen by an ophthalmologist in person and evaluated with a penlight, although a biomicroscopic examination was not performed, was a strength of our data.
In a meta-analysis evaluating laboratory findings, 5350 patients from 25 studies were included and high levels of CRP, procalcitonin, D-dimer, and ferritin were associated with poor outcomes.21In another study, it was shown that patients with COVID-19 with ocular symptoms had higher WNC counts, neutrophil counts, and CRP, LDH, and procalcitonin valuescompared with patients without ocular symptoms.13 In another study, no significant difference was found between patients with and without SARS-CoV-2 virus isolated from the conjunctiva in terms of laboratory findings.22In our study, when the laboratory data of 215 patients were compared, no significant difference was found between patients with and without ocular symptoms. Our patients had moderate or severe symptoms and were hospitalized patients. Patients with very severe disease in the intensive care unit (ICU) or asymptomatic patients followed up at home were excluded from the study. As far as we know, no other comprehensive studies have investigated the relationship between conjunctivitis and laboratory data in patients with COVID-19.
It was suggested that the ocular surface might be an entry point for SARS-CoV-2, and ocular involvement was less common thanks to the antiviral defense system in the conjunctiva and cornea, as well as lactoferrin and secretory immunoglobulin (Ig)-A.23
Viruses trigger the immune system, leading to an increase in immunoglobulin, chemokine and antibody production, and cause tissue damage, apoptosis, and inflammation.24
Ocular findings associated with COVID-19 may be due to viral effects or to dry eye that develops in these patients. There may be several reasons why dry eye occurs in these patients. The first is the prolongation of the time of watching screens following restrictions of social activities in patients. Another reason is that with the use of a mask, the airflow from the mask to the ocular surface evaporates the tears earlier. Indeed, there are some viruses associated with dry eye disease.25 Taking this into consideration, it can be hypothesized that SARS-CoV-2 could affect the conjunctival goblet cells or the lacrimal gland hematogenously, disrupting the tear structure and thus leading to development of dry eye or conjunctival inflammatory response.
Symptomatic approaches and anti-inflammatory eye drops used in other types of viral conjunctivitis are recommended for patients with conjunctivitis due to COVID-19.
Our study had some limitations. The sample size was relatively small, patients with severe clinical findings in the ICU were not included, and SARS-CoV-2 RT-PCR examinations were not performed on conjunctival samples.
As a result, there was an important relationship between COVID-19 and an acute conjunctival inflammatory response. Blood parameters that determined progression in patients with COVID-19 were not significantly associated with ocular findings.
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