Abstract
Purpose
We aimed to compare the tear film stability of individuals who had recovered from coronavirus disease (COVID-19), that of individuals vaccinated against COVID-19 and that of healthy individuals in a control group.
Methods
This study included 61 eyes of 61 post-COVID-19 patients, 63 eyes of 63 participants who had received at least two doses of the SARS-CoV-2 mRNA BNT162b2 (Pfizer–BioNTech) vaccine, and 57 eyes of healthy individuals in a control group. We compared the groups’ tear film stability.
Results
The mean non-invasive first tear break-up time (NIF-BUT) value was 4.1±2.7 seconds in the post-COVID-19 group, 4.7±2.9 seconds in the vaccinated group, and 5.8±2.8 seconds in the control group. This value was statistically significantly lower in the post-COVID-19 and vaccinated groups than in the control group (p= 0.007). The rate of superotemporal (ST) quadrant breakup, statistically significantly higher in the vaccinated group than in the other two groups (p=0.001). According to a qualitative examination of the results, at least one breakup occurred in 47 (77%) of the post-COVID-19 participants’ eyes, 50 (79.4%) of the vaccinated group's eyes, and 33 (57.9%) of the control group's eyes. In terms of this qualitative value, the post-COVID-19 and vaccinated groups had significantly higher breakup rates than the control group (p=0.018).
Conclusions
Destabilization in the tear film was more common in both the post covid group and the vaccinated group. In addition to individuals who have post-Covid, we think that post-vaccination individuals should be followed closely in terms of ocular surface diseases.
Keywords: Coronavirus disease, Coronavirus vaccine, Noninvasive breakup time test, Tear film impairment, Ocular surface in coronavirus
1. INTRODUCTION
The World Health Organization (WHO) declared coronavirus disease (COVID-19) to be a pandemic approximately 3 months after the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case was diagnosed and recorded in December 2019 in China [1]. Although respiratory symptoms are prominent in this disease, COVID-19 infects ocular tissues and may produce symptoms associated with them [2], [3], [4], [5], [6], [7]. In a study by Kelvin et al. it was found that meibomian gland dysfunction was higher and the tear film was more unstable in post-COVID-19 patients. They also showed that these ocular surface problems increased with increasing viral load as found by the cycle threshold in PCR at diagnosis of the disease [8]. In a study by Kase et al. it was found that Inflammatory cell infiltration and glandular damage in the lacrimal gland was observed after Covid-19. Expression of angiotensin converting enzyme 2 was measured in the lacrimal gland indicating that this gland could be the target for Covid-19 infection [9]. According to these two studies, the eye may be the site of primary viral infection, which can affect two important structures that contribute to the tear film, the lacrimal glands and the Meibomian glands [8,9]. COVID-19’s ocular symptoms and signs have been revealed in many retrospective and prospective studies [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Hong et al. found that the Ocular Surface Disease Index (OSDI) score was higher in post-COVID-19 patients [5]. A study by Gambini et al. revealed that the rate of dry eye disease increased in a post-COVID-19 group [4]. Acet et al. evaluated tear film in a non-invasive way and found that tear film demonstrated more instability in post-COVID-19 patients than in healthy individuals [7].
The high transmission of COVID-19 has led to an increased predisposition in vaccine studies at the national and international levels [14,15]. At the end of 2020, many national and international organizations have approved the emergency use of vaccines developed against COVID-19 [16], [17], [18], [19], [20], [21]. With the introduction of vaccines in 2021, studies on vaccines’ effects and side effects have been conducted [22], [23], [24], [25].
Tear film stability and patterns vary depending on infectious and inflammatory factors [26], [27], [28]. This variability is explained by various mechanisms: (a) immune system reaction, (b) opportunistic infections, and (c) the destruction of the ocular surface due to direct microbial infection effect [26], [27], [28], [29]. In this study, we used the non-invasive tear film break-up time (NI-BUT) to compare the tear film patterns of participants who had been infected with COVID-19 disease, participants who had received COVID-19 vaccines, and healthy participants who did not have COVID-19 disease. To the best of our knowledge, this is the first prospective study to compare post vaccination ocular surface parameters.
2. MATERIALS AND METHODS
We conducted this prospective case–control study in accordance with the principles outlined in the Declaration of Helsinki. We obtained the required ethical approval. Additionally, we obtained approval from the Provincial Health Directorate as well as written informed consent forms from all participants. We conducted the study at Mardin Training and Research Hospital (Mardin, Turkey) between October 2021 and January 2022. To eliminate the effects of long-term mask use on tear film, we examined the three groups of participants included in this study during the same period of the pandemic, including the conditions for mask use. To eliminate the effects of short-term mask use, we isolated all participants in the test room and ensured that their masks were removed 15 minutes before the procedure. All participants took the NI-BUT test between 8:30 a.m. and 10:00 a.m. Thus, we minimized issues that could affect tear film stability [30,31]. We selected all participants from among patients who visited the ophthalmologist for routine eye examinations. The post-COVID-19 group included patients who had positive PCR test results, were diagnosed with COVID-19 and treated and had completed their quarantine processes at least a month before the start of the study. The vaccinated group included patients who had not previously detected PCR positivity, had no COVID-19 symptoms, had no positive COVID-19 tests (which we determined by examining their medical records), and had received their second dose of the SARS-CoV-2 mRNA BNT162b2 (Pfizer–BioNTech) vaccine over 15 days before the start of the study. The control group included patients who had not demonstrated positive PCR test results, had no COVID-19 symptoms and had no positive COVID-19 tests in their medical records, had not received any SARS-CoV-2 vaccines, and had not volunteered in any vaccine studies. We did not take into account whether patients had previous diagnoses of dry eye in any of the three groups. However, we excluded patients who had used cyclosporine, steroids, or artificial tears for the treatment of dry eye in the past month. We also excluded patients with previous diagnoses of glaucoma and/or history of using glaucoma medication. We included volunteers with a history of cataracts and/or refractive surgery, those with a history of contact lens use, those with no autoimmune diseases causing dry eye, and those with no apparent ptosis in the study. Tear film stability was evaluated by non- invasive break-up time test (NI-BUT). For each of the three groups, we conducted the NI-BUT test on only one of each participant's eyes and planned to record the NI-BUT values of only one eye in the study results. We informed the participants regarding the test's application and process immediately before the test. We asked them to close and open their eyes twice and then to keep their eyes open for as long as they could. We conducted the NI-BUT test using the Sirius™ (Costruzione Strumenti Oftalmici [CSO] S.R.L., Italy) corneal topography device. This device uses a combination of Scheimpflug and Placido disks, analyses 25 film frames per second for a total of approximately 400 film frames, and provides quantitative values, such as the first break-up time(NIF-BUT) and the average value of all breakup (NIAvg-BUT) for each participants . We compared these values between the groups. The device software also provides qualitative values, such as each breakup's localization [7,32,33]. After taking the participants’ NI-BUT measurements, we performed detailed slit-lamp and funduscopic examinations of all participants. These examinations included best-corrected visual acuity and intraocular pressure measurements. After eliminating eyes with blepharitis, conjunctivitis, keratopathy, eyelid deformity, and concretion from all three groups, we included 61 eyes of 61 participants in the post-COVID-19 group, 63 eyes of 63 participants in the post-vaccine group, and 57 eyes of 57 participants in the control group. We compared the results obtained from these three groups.
2.1. Values and Abbreviations
NIF-BUT: The time, in seconds, at which the first breakup occur
Avg-BUT: This is the average value of all breakups (NIAvg-BUT) for each volunteer.
Damaged (DMGD): This qualitative value indicates a situation in which at least one breakup occurred in the tear film during the measurement.
F5:This qualitative value indicates a case in which the first break-uptime (NIF-BUT) value was less than or equal to 5 seconds.
F5–7:This qualitative value indicates a case in which the first breakup value (NIF-BUT) was 5.1 to 7 seconds.
F7–10:This qualitative value indicates a case in which the first breakup value (NIF-BUT) was 7.1 to 10 seconds.
F10:This qualitative value indicates a case in which the first breakup value (NIF-BUT) was greater than 10seconds.
A5:This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was less than or equal to 5 seconds.
A5–7:This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was 5.1 to 7 seconds.
A7–10:This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was 7.1 to 10 seconds (Fig. 1).
Fig. 1.
NI-BUT output of a participant in the vaccinated group; the first breakup (NIF-BUT) occurred after 3.6 seconds. The mean average value of all breakup (NIAvg-BUT) for each volunteer was 7.6 seconds. The first two breakup occurred in the inferotemporal region, and common breakup occurred in all quadrants and across the surface.
A10:This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was greater than 10seconds.
S:This qualitative value indicates that a breakup occurred in the ocular surface's superior quadrant.
I:This qualitative value indicates that a breakup occurred in the ocular surface's inferior quadrant.
T:This qualitative value indicates that a breakup occurred in the ocular surface's temporal quadrant.
N:This qualitative value indicates that a breakup occurred in the ocular surface's nasal quadrant.
ST:This qualitative value indicates that a breakup occurred in the ocular surface's superotemporal quadrant.
SN:This qualitative value indicates that a breakup occurred in the ocular surface's superonasal quadrant.
IT:This qualitative value indicates that a breakup occurred in the ocular surface's inferotemporal quadrant.
IN:This qualitative value indicates that a breakup occurred in the ocular surface's inferonasal quadrant.
2.2. Statistical method
We used averages, standard deviations, medians, minimum and maximum values, frequencies, and ratios in the data's descriptive statistics. We measured the variables’ distributions using the Kolmogorov–Smirnov test. We used analysis of variance (ANOVA;Tukey's test), the Kruskal–Wallis test, and the Mann–Whitney U test in the analysis of the quantitative data. We used a chi-squared test to analyse the qualitative data, and we used Fisher's exact test when chi-squared test conditions were not met. We used SPSS 22.0 software for the analysis. Table 1
Table 1.
Demographic, Qualitative, and Quantitative NI-BUT Values for All Participants.
| Min–Max | Median | Mean ± SD/n-% | ||||||
|---|---|---|---|---|---|---|---|---|
| Age(years) | 18.0–66.0 | 42.0 | 40.9 ± 11.5 | |||||
| Gender | Female | 95 | 52.5% | |||||
| Male | 86 | 47.5% | ||||||
| NIF-BUT(sec) | 1.2–14.6 | 4.0 | 4.8 ± 2.9 | |||||
| Avg-BUT(sec) | 1.2–14.8 | 7.4 | 7.4 ± 3.1 | |||||
| DMGD | (−) | 51 | 28.2% | |||||
| (+) | 130 | 71.8% | ||||||
| F5 | 84 | 64.6% | ||||||
| F5–7 | 24 | 18.5% | ||||||
| F7–10 | 14 | 10.8% | ||||||
| F10–17 | 10 | 7.7% | ||||||
| A5 | 31 | 23.8% | ||||||
| A5–7 | 32 | 24.6% | ||||||
| A7–10 | 37 | 28.5% | ||||||
| A10–17 | 30 | 23.1% | ||||||
| S | 51 | 39.2% | ||||||
| I | 76 | 58.5% | ||||||
| T | 63 | 48.5% | ||||||
| N | 73 | 56.2% | ||||||
| SN | 61 | 46.9% | ||||||
| ST | 67 | 51.5% | ||||||
| IT | 85 | 65.4% | ||||||
| IN | 92 | 70.8% | ||||||
NIF-BUT: The time, in seconds, at which the first breakup occurs. Avg-BUT: average value of all breakup (NIAvg-BUT) for each volunteer during the measurement. Damaged (DMGD): This qualitative value indicates a case in which at least one breakup occurred in the tear film during the measurement. F5: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was less than or equal to 5 seconds. F5–7: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was 5.1 to 7 seconds. F7–10: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was 7.1 to 10 seconds. F10: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was greater than 10 seconds. A5: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was less than or equal to 5 seconds. A5–7: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was 5.1 to 7 seconds. A7–10: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was 7.1 to 10 seconds. A10: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was greater than 10 seconds. S: This qualitative value indicates that a breakup occurred in the ocular surface's superior quadrant. I: This qualitative value indicates that a breakup occurred in the ocular surface's inferior quadrant. T: This qualitative value indicates that a breakup occurred in the ocular surface's temporal quadrant. N: This qualitative value indicates that a breakup occurred in the ocular surface's nasal quadrant. ST: This qualitative value indicates that a breakup occurred in the ocular surface's superotemporal quadrant. SN: This qualitative value indicates that a breakup occurred in the ocular surface's superonasal quadrant. IT: This qualitative value indicates that a breakup occurred in the ocular surface's inferotemporal quadrant. IN: This qualitative value indicates that a breakup occurred in the ocular surface's inferonasal quadrant.
3. RESULTS
The youngest participant included in the study was 18 years old, and the oldest participant was 66 years old. The participants’ mean age was 40.9 ±11.5 years. Of the participants, 95 were women, and 86 were men. Among all participants, the shortest NIF-BUT value was 1.2 seconds, the longest NIF-BUT value was 14.6 seconds, and the mean NIF-BUT value was 4.8 ±2.9 seconds. The lowest Avg-BUT value was 1.2 seconds, and the highest Avg-BUT value was 14.8 seconds. The mean Avg-BUT value was 7.4±3.1 seconds. The percentage of eyes with at least one breakup during the test, which are referred to as damaged (DMGD) by the device, was 71.8%. Among all participants, the inferonasal quadrant was the quadrant with the most breakups (70.8%), and the superior quadrant was the quadrant with the least breakups(39.2%). In 84 (64.6%) of the study participants, the NIF-BUT value was 5 seconds or less (F5), making this interval the most frequently detected interval of NIF-BUT values. In contrast, the NIF-BUT interval was 10.1–17 seconds (F10–17) in only 10 (7.7%) of the participants. In the vast majority of the patients, breakups occurred in the inferior hemisphere.
3.1. Subgroup Analysis
We found no significant differences among the post-COVID-19, vaccinated and control groups in terms of demographic characteristics such as the patients’ age and gender distributions (p> 005; Table 2 ).
Table 2.
Comparison of Groups’ Demographic Data, NIF-BUT, Avg-BUT, and Damaged Values.
| Post-COVID-19 group | Post-vaccine group | Control group | p | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age(years) | Mean ± SD | 42.1 | ± | 11.7 | 38.3 | ± | 10.4 | 42.4 | ± | 12.1 | 0.108 | K | |||
| Median | 42.0 | 42.0 | 45.0 | ||||||||||||
| Gender | Female | n-% | 30 | 49.2% | 34 | 54.0% | 31 | 54.4% | 0.817 | X² | |||||
| Male | n-% | 31 | 50.8% | 29 | 46.0% | 26 | 45.6% | ||||||||
| NIF-BUT(sec) | Mean ± SD | 4.1 | ± | 2.7 | 4.7 | ± | 2.9 | 5.8 | ± | 2.8 | 0.007 | K | |||
| Median | 3.6 | 4.2 | 4.8 | ||||||||||||
| Avg-BUT(sec) | Mean ± SD | 6.7 | ± | 3.2 | 7.6 | ± | 3.1 | 8.3 | ± | 2.8 | 0.063 | A | |||
| Median | 6.3 | 7.8 | 8.4 | ||||||||||||
| DMGD | (−) | n-% | 14 | 23.0% | 13 | 20.6% | 24 | 42.1% | 0.018 | X² | |||||
| (+) | n-% | 47 | 77.0% | 50 | 79.4% | 33 | 57.9% | ||||||||
| A ANOVA / K Kruskal–Wallis (Mann–Whitney U test) / X² chi-squared test | |||||||||||||||
NIF-BUT: The time, in seconds, at which the first breakup occurs. Avg-BUT: average value of all breakup (NIAvg-BUT) for each volunteer during the measurement. Damaged (DMGD): This qualitative value refers to a situation in which at least one breakup occurred in the tear film during the measurement.
The mean NIF-BUT value was 4.1±2.7 seconds in the post-COVID-19 group, 4.7±2.9 seconds in the vaccinated group, and 5.8±2.8 seconds in the control group. The mean NIF-BUT values was statistically significantly lower in the post-COVID-19 and vaccinated groups than in the control group (p= 0.007). There was no statistically significant difference between the post-COVID-19 and vaccinated groups in terms of mean NIF-BUT value (p> 0.05). The mean NIAvg-BUT values were 6.7±3.2 seconds in the post-COVID-19 group, 7.6±3.1 seconds in the vaccinated group, and 8.3±2.8 seconds in the control group. This difference among the groups was statistically insignificant (p> 0.05), and there was no significant difference in binary group comparisons in terms of NIAvg-BUT value (p> 0.05). Examining the results qualitatively, at least one breakup occurred in 47 (77%) of the post-COVID-19group's eyes, 50 (79.4%) of the post-vaccine group's eyes, and 33 (57.9%) of the control group's eyes. In terms of this qualitative value, the post-COVID-19 and post-vaccine groups had significantly higher incidences of breakup than the control group (p=0.018). In contrast, there was no significant difference between the post-COVID-19 group and the vaccinated group in terms of the rate of eyes with at least one breakup (p > 0.05),which the device referred to as damaged (DMGD;Table 2).
There was no significant difference among the three groups in terms of rates of NIF-BUT values of less than or equal to 5 seconds (F5), NIF-BUT values of 5.1–7 seconds (F5–7), or NIF-BUT values of 7.1–10 seconds(F7–10; p> 005; Table 3 ).
Table 3.
Comparisons of the Groups in Terms of Breakup Values.
| Post-COVID group | Post-vaccine group | Control group | p | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | % | n | % | n | % | ||||||||||
| F5 | 33 | 70.2% | 33 | 66.0% | 18 | 54.5% | 0.341 | X² | |||||||
| F5-7 | 9 | 19.1% | 8 | 16.0% | 7 | 21.2% | 0.826 | X² | |||||||
| F7-10 | 5 | 10.6% | 4 | 8.0% | 5 | 15.2% | 0.589 | X² | |||||||
| F10-17 | 3 | 6.4% | 5 | 10.0% | 2 | 6.1% | 0.736 | X² | |||||||
| A5 | 15 | 31.9% | 13 | 26.0% | 3 | 9.1% | 0.056 | X² | |||||||
| A5-7 | 13 | 27.7% | 9 | 18.0% | 10 | 30.3% | 0.370 | X² | |||||||
| A7-10 | 11 | 23.4% | 13 | 26.0% | 13 | 39.4% | 0.262 | X² | |||||||
| A10-17 | 8 | 17.0% | 15 | 30.0% | 7 | 21.2% | 0.303 | X² | |||||||
| X² Chi-Square test | |||||||||||||||
F5: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was less than or equal to 5 seconds.
F5–7: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was 5.1 to 7 seconds.
F7–10: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was 7.1 to 10 seconds.
F10: This qualitative value indicates a case in which the first breakup value (NIF-BUT) was greater than 10 seconds.
A5: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was less than or equal to 5 seconds.
A5–7: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was 5.1 to 7 seconds.
A7–10: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was 7.1 to 10 seconds.
A10: This qualitative value indicates a case in which the mean breakup value (Avg-BUT) was greater than 10 seconds.
Considering the distribution rates of the breakup on the ocular surface, the rate of breakup formation in the nasal quadrant (N) was significantly lower in the post-vaccine group than in the post-COVID-19 group (p=0.011). However, there was no significant difference between the post-vaccine group and the control group in terms of nasal quadrant involvement (p>005). The rates of breakup in the superotemporal quadrant (ST) were 72% in the post-vaccine group, 40.4% in the post-COVID-19 group, and 36.4% in the control group. The incidence of ST quadrant breakup after vaccination was statistically significantly higher in the post-vaccine group than in the other two groups (p=0.001). There was no significant difference between the post-COVID-19 group and the control group in terms of ST quadrant involvement. (p> 005). Additionally, the rates of breakup in the inferotemporal quadrant were 80% in the post-vaccine group, 63.8% in the post-COVID-19 group, and 45.5% in the control group. Although the rate of breakup formation in the inferotemporal quadrant indicated a significant difference between the post-vaccine group and the control group (p=0.005), there was no significant difference between the post-vaccine group and the post-COVID-19 group (p>005). We found no significant difference among the groups or between pairs of groups in terms of the other quadrant distributions (p> 005; Table 4 ).
Table 4.
Comparisons of the Groups in Terms of Breakup Values.
| Post-COVID-19 group | Post-vaccine group | Control group | p | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | % | n | % | n | % | ||||||||||
| S | 19 | 40.4% | 19 | 38.0% | 13 | 39.4% | 0.970 | X² | |||||||
| I | 31 | 66.0% | 28 | 56.0% | 17 | 51.5% | 0.393 | X² | |||||||
| T | 26 | 55.3% | 26 | 52.0% | 11 | 33.3% | 0.125 | X² | |||||||
| N | 34 | 72.3% | 21 | 42.0% | 18 | 54.5% | 0.011 | X² | |||||||
| SN | 19 | 40.4% | 25 | 50.0% | 17 | 51.5% | 0.531 | X² | |||||||
| ST | 19 | 40.4% | 36 | 72.0% | 12 | 36.4% | 0.001 | X² | |||||||
| IT | 30 | 63.8% | 40 | 80.0% | 15 | 45.5% | 0.005 | X² | |||||||
| IN | 35 | 74.5% | 35 | 70.0% | 22 | 66.7% | 0.743 | X² | |||||||
| X² Chi-Square test | |||||||||||||||
S: This qualitative value indicates that a breakup occurred in the ocular surface's superior quadrant.
I: This qualitative value indicates that a breakup occurred in the ocular surface's inferior quadrant.
T: This qualitative value indicates that a breakup occurred in the ocular surface's temporal quadrant.
N: This qualitative value indicatesthat a breakup occurred in the ocular surface's nasal quadrant.
ST: This qualitative value indicatesthat a breakup occurred in the ocular surface's superotemporal quadrant.
SN: This qualitative value indicatesthat a breakup occurred in the ocular surface's superonasal quadrant.
IT: This qualitative value indicatesthat a breakup occurred in the ocular surface's inferotemporal quadrant.
IN: This qualitative value indicatesthat a breakup occurred in the ocular surface's inferonasal quadrant.
4. DISCUSSION
In this study, we detected increased tear film destabilization in both the post-COVID-19 group and the vaccinated group compared to the control group. In a different study, we detected increased tear film destabilization in post-COVID-19 patients compared to the control group [7]. Because COVID-19 vaccines had not yet been administered at the time of previous study, we compared only post-COVID-19 patients and a control group in that study [7]. At that time, it was thought that the increased destabilization in post-COVID-19 patients could be a direct effect of the virus or result of an immune reaction [8,9,[26], [27], [28]]. In the present study, we found the NIF-BUT values to be 4.1 seconds in the post-COVID-19 group, 4.7 seconds in the vaccinated group, and 5.8 seconds in the control group. Although there was no significant difference between the post-COVID-19 group and the vaccinated group in terms of NIF-BUT value, we found that the values of both the post-COVID-19 group and the vaccinated group were significantly lower than those of the control group, and the post-COVID-19 and vaccinated groups had more unstable tear film. Additionally, when we examined the rates of eyes in which at least one breakup occurred, these rates were 77.0% in the post-COVID-19 group, 79.4% in the vaccinated group, and 57.9% in the control group. We found that tear film stability was lower in both the post-COVID-19 and vaccinated groups than in the control group, and we did not detect a significant difference between the post-COVID-19 and vaccinated groups in terms of this qualitative value. Based on these results, we found that the post-COVID-19 group had the worst tear film health of the three groups, but the tear film stability values of the vaccinated group were similar to those of the post-COVID-19 group. Although the study's design has prevented us from determining causality our observational results may indicate that COVID-19 could cause tear film destabilization because of an immune effect rather than an infectious effect. However, this result must be further investigated and supported by clinical trials that include inflammation parameters.
Ocular surface inflammation causes tear film instability, and tear film instability and loss of homeostasis are accepted as two multifactorial etiological factors for dry eye [34]. Baudouin et al. suggested that a “vicious cycle of inflammation” is the leading risk factor for dry eye [35]. According to this “vicious cycle of inflammation”, autoimmunity in intrinsic factors and conjunctivitis in extrinsic factors [[33], [36]] were evaluated as etiological factors. These etiological factors can be adapted as immunity (an intrinsic factor), which is the only effect caused by the vaccine in our study, and conditions that arise from the virus's binary effects on the ocular surface. These effects include (a) an extrinsic factor with a direct effect of conjunctivitis and (b) an intrinsic factor (immunity) caused by an immune reaction caused by the virus's immune-system-stimulating effect. This provides us with information regarding why the post-COVID-19 group had the most unstable tear film.
In a study conducted by telephone in the form of questionnaire questions in the early stages of the pandemic, dry eye symptoms were detected in approximately 20% of patients who had contracted and overcome COVID-19 [6]. In the pandemic's later stages, further studies involving additional dry eye tests revealed that dry eye symptoms were significantly more prevalent in post-COVID-19 patients than in control groups [3,4,7]. Unlike those proving the increased occurrence of ocular surface defects in post-COVID-19 patients [2], [3], [4], [5], [6], [7], [8], [9], there is no study to the best of our knowledge on ocular surface defects after vaccination or on COVID-19 vaccines’ side effects on ocular tissues.
Case reports of eyelid lesions and superficial mild dermatitis post-vaccination have been reported [37,38]. Cases of corneal graft rejection (which is the most frequently reported anterior segment finding after vaccination) also reported [39], [40], [41], [42], [43], [44]. The possible mechanism of graft rejection is thought to be increased vascular permeability and induction of a strong antibody response by COVID-19 vaccines with CD4+ and Th1 cells [41,45]. Some case reports are available on disorders such as Vogt–Koyanagi–Harada syndrome [46], uveitis [47], [48], [49], central serous chorioretinopathy [50], retinal vascular occlusions [51,52], arteritis anterior ischemic optic neuropathy [53] and abducens nerve palsy [54]. The US Vaccine Adverse Events Reporting System (VAERS) has received reports of similar adverse effects. However, it has been concluded that some of these adverse effects may be real effects related to the vaccine, or they may be considered random events unrelated to the vaccine [55]. Adverse ocular effects are associated with not only COVID-19 vaccines but also some vaccines that have been applied for a long time; the reported cases include uveitis and choroid after yellow fever vaccines [56,57]; multiple evanescent white dot syndrome after influenza vaccination [58]; unilateral acute idiopathic maculopathy [59], acute macular neuroretinopathy [60] and Vogt–Koyanagi–Harada disease [[61], [62]] after hepatitis B vaccination. This study reveals deteriorations in the tear film in both the post-COVID-19 and vaccinated groups.
In our study, we did not examine the antibody titers showing the immune response in the vaccinated and post-COVID-19 groups; this could be evaluated as a limitation of this study.
5. Conclusion
We detected impaired tear film in the post-COVID-19 and vaccinated groups. We found that the post-COVID-19 and post-vaccine groups were similar in terms of tear film impairment. We think that both post-COVID-19 patients and vaccinated individuals should be followed closely in terms of dry eye.
CRediT authorship contribution statement
Yaşar DAĞ: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Yakup ACET: Writing – review & editing, Software, Resources, Methodology, Formal analysis.
Declaration of Competing Interest
No Conflicts of Interest
Acknowledgments
Ethics approval
No funding was received for this research
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Bioethics Committee of the Medical University of Harran (HRU/21.05.27).
Informed consent
Informed consent was obtained from all individual participants included in the study.
Editor: Ron R. Allison
Footnotes
Data and materials are Available upon reguest :dryasardag@gmail.com
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