Vitamin D Role in Chronic Dacryocystitis

Introduction: Vitamin D deciency has been associated with dry eye disease or Sjogren's syndrome. Due to the anti-inammatory role of vitamin D in eye diseases, it has been proposed to study the role of this vitamin in chronic dacryocystitis, which is an infectious and inammatory process affecting the nasolacrimal system. Objective: Determine the association between vitamin D levels with the presence of chronic dacryocystititis. Materials and Methods: A cross-sectional descriptive observational study analyzed a sample of 40 individuals, of whom had been diagnosed with chronic dacryocystitis. Biochemical tests for serum 25-hydroxyvitamin D (vitamin D) were subjected to the entire sample. The difference in the means was calculated using the T-test for associated data. The reference signicance value was 0.05. Results: Chronic dacryocystitis commonly occurs in the age group of 51 to 67 years. Women were more vulnerable to infection than men. No association was found between the presence of chronic dacriocystitis and vitamin D levels (p-0.755). It is recommended to use larger cohorts as well as multicenter studies evaluating this association, such as supplemental use of vitamin D on a large scale. Conclusions: Low vitamin D levels are not associated with the presence of chronic dacriocystitis.


Introduction
Obstruction of the nasolacrimal duct leads to the excess over ow of tears called epiphora, a common complaint among ophthalmic patients. Physiologically, the mucosa of the lacrimal sac is very resistant to infection, occasionally distal obstruction of the nasolacrimal duct may occur, which can trigger in ammatory and infectious processes 1 .
Pathologies of tear duct drainage account for about 3% of eye consultations, of which dacryocystitis is by far the most common cause of epiphora. Dacryocystitis is in ammation of the tear sac, and is classi ed according to the time of evolution in acute and chronic 2 . Of these two varieties, chronic dacryocystitis is the most common, and is associated with nasolacrimal duct obstruction. Chronic dacryocystitis usually affects both children and adults more often women ≥ 40 years old. 3 .
The prevalence of chronic dacryocystitis exceeds acute infection, this is related to the microbiological pathogenesis of dacryocystitis, as well as the patterns of geographic variation of the etiological agents in these infections. Another in uencing factor is the co-occurrence of nasal pathologies with the presence of chronic dacryocystitis 1,4 .
Causes of chronic dacryocystitis range from idiopathic causes to secondary causes to infectious processes, local or systemic in ammations, nasal trauma, nasal polyps, nasal septum deviation, hypertrophic rhinitis, lower corneal hypertrophy, congenital disorder or neoplasms, which triggers a buildup of tears in the sac, mucoid secretions and aky cells, which cannot be drained to the nose, but usually over ow to the outside of the eye 5 . The accumulation of cell debris, mucus and tears leads to the arrival of bacteria and with it the origin of dacriocystitis 6 .
Chronic dacryocystitis associated with bacterial infections represents around 61-95% of all dacryocystitis 6,7 . The causative agents of the infection colonize and multiply in the nasolacrimal duct and produce relevant symptoms such as epiphora, pyorrhea, ophthalmodynia and conjunctival hyperemia, among others, which affect the quality of life of patients. Delayed treatment can trigger infection extension to other tissues, such as orbital cellulitis, abscesses, meningitis, cavernous sinus thrombosis, and sepsis 7 .
Symptoms associated with chronic dacryocystitis include continuous epiphoria, regurgitation of mucoid or mucopurulent secretions to digitopression in the tear sac or by infusing uids into the tear drainage system 2 .
Vitamin D is a known steroid hormone which can be endogenously synthesized or ingested in the diet. An improvement in cornea epithelial bore has been reported in patients with vitamin D supplementation, because it regulates narrow joints between cells 10 . In addition, vitamin D immunomodulatory mechanisms have been proposed in in ammatory eye processes, expressed in inhibition of in ammatory cell migration (Th1 and Th2 cells), increased interleucine synthesis (IL) 10, reduction of in ammatory cytokines such as IL6, C-reactive protein and tumor necrosis factor (TNF) alpha 11,12 . Other described functions of this vitamin is act as a stabilizer of the eye surface, through the reduction of the osmolarity of tears 12 . So vitamin D can in uence the functions of the tear system 10 .

Normal levels of vitamin D in adults according to the Center for Disease Control and Prevention (CDC)
range from 20-80 ng/ml, described as vitamin D de ciency at levels below 20 ng/ml and severe vitamin D de ciency for levels below 10 ng/ml). Tests to evaluate vitamin D may be total levels of 25 (OH) D (diagnosis and monitoring of vitamin D de ciency) and measurement of the 25 (OH) D2 and 25 (OH) D3 (treatment follow-up) 13 .
Human studies have determined a link between elevated serum vitamin D levels with improved symptoms in dry eye syndrome 14 , and highlighting that 25-hydroxyvitamin D de ciency linked to lack of sun exposure are associated with dry eye syndrome 10 . That is, adequate levels of vitamin D have a positive impact on dry eye syndrome.
According to the review, this is the rst study to evaluate the association between vitamin D levels in the presence of chronic dacryocystitis.
H0: There is no association between chronic dacriocystitis and vitamin D levels.
H1: Chronic dacriocystitis is associated with vitamin D levels.
Based on the background described, it is proposed to determine the association between vitamin 25-OHhydroxyvitamin D levels in patients with chronic dacryocystitis.

Material And Methods
This study was a descriptive, retrospective and cross-sectional observational study, where vitamin D de ciency is to be checked as a predictive factor in the onset of chronic dacryocystitis. Consecutive patients with and without patent lacrimal drainage system were recruited prospectively from the Clinical University Hospital of Valladolid for a period of 12 weeks, from September 1, 2020 to November 30, 2020.
This study was approved by the ethics committee of the University Hospital of Valladolid and was carried out in accordance with the principles of the Helsinki Declaration.

Participants
Consecutive patients with and without permeable tear drainage were prospectively recruited at the Clinical University Hospital of Valladolid, from 1 September 2020 to 30 November 2020. Twenty patients with permeable tear drainage system and 20 patients without permeable tear drainage system. All patients with con rmed or minimally suspected vitamin D supplementation and paediatric patients were excluded.
Patients were diagnosed as chronic dacryocystitis based on their history of persistent epiphoria and regurgitation of mucoid or mucopurulent material at pressure over the sac area or tear duct test irrigation.

Data collection
Basal serum levels of 25-hydroxy vitamin D were measured by high-resolution liquid chromatography. All patients included were given a total serum level of 25-hydroxy vitamin D. Vitamin D de ciency was de ned as 25(OH)D concentrations below 20 ng/mL, a level between 20-30 was considered a vitamin D insu ciency and a vitamin D level of 31 ng/mL or higher was adequate for good health, according to our laboratory guidelines. Serum levels of 25-hydroxy vitamin D were compared between patients with and without a permeable tear system.
The main result measure included the association between vitamin D levels and chronic dacriocystitis.

Statistical Analysis
All statistical analyses were performed by the SPSS version 25 statistical program. The mean was calculated for the age with standard deviation.
Pearson's correlation test was used to analyze the association between categorical variables (Healthy_sick and vitamin D levels).
Statistical signi cance was de ned as a value of p <0.05. Table 1 presents the demographic characteristics of including chronic dacryocystitis cases and healthy controls (with permeable tear system). A total of 20 cases of chronic dacryocystitis (3 men and 17 women) and 20 unmatched controls (6 men and 14 women) were included. The average age was 69.33 ± years between the two groups, and ages ranged from 51 to 87 years, with differences in the female gender. The number of women was higher than that of men in both groups, with 31 (77.5%) women and 9 (22.5%) men. Furthermore, Table 1 re ects Pearson correlation data between categorical variables.
In the current study, we categorized subjects according to their vitamin D status in three groups: less than or equal to 10 ng/ml as insu cient levels, range between 11 to 20 ng/ml as low vitamin D levels, and more than 20 ng/ml as normal vitamin D levels to better understand the association between vitamin D status and chronic dacryocystitis.
The data from the healthy group were not signi cantly different from those of the patient group. In the group of patients with chronic dacryocystitis, low or insu cient levels of vitamin D were reported in 9 patients (45% of cases), while the group with tear sac permeability recorded a total of 10 people with low vitamin D levels (50%) ( Table 2). There is a 75.2% chance of error between chronic dacryocystitis and vitamin D levels. So, the study hypothesis is rejected, and the null hypothesis is accepted.

Discussion
This study consisted of associating the presence of chronic dacryocystitis with vitamin D levels, compared with a control group of healthy patients, recruited in the same time period. There were not signi cant differences between the two groups for vitamin D levels.
Pearson's bivariate correlation with R showed an R-index of Pearson (0.050), re ecting a moderate correlation, however, the bilateral asymptotic signi cance data re ected a value of p-0.755 which, being a value greater than 5% of the signi cance posed for this work (margin of error of 5%) the independence of the variables studied was considered.
That is, vitamin D levels are not accepted to be associated with chronic dacryocystitis. Non-parametric tests with similar results were applied. This may be due to the low sample collected, vitamin D measurements, or that the variables have no signi cance in the in ammatory and infectious process of the tear sac, however, for this it is necessary to use larger study cohorts, as well as multicenter studies in order to generalize this data to the general population.
Other variables that accompany vitamin D values that complement these tests may also be analyzed.
No clinical trials were found in animals or humans to assess the association between vitamin D levels with chronic dacryocystitis, so this is considered a line of research to be expanded, to describe the possible association between this vitamin with diseases related to tear drainage.
Similarly, it is recommended to perform immunological tests associated with chronic dacryocystitis and correlate with vitamin D levels, to describe the immunomodulatory role found in other studies 10,14 .
Although association of vitamin D levels has been reported in patients with dry eye syndrome, due to the immunodulating role of vitamin D at the level of innate and acquired immunological responses 13,15 . Still not studying the correlation of vitamin D levels with other eye disorders, in vitro studies indicate that vitamin D inhibits the release of pro-in ammatory cytokines from CD4 + T cells, and that it is able to induce a regulatory T-cell phenotype 16 . Other studies indicate the involvement of vitamin D in the release of cytokines from circulating monocytes 13,15 .
The importance of studying this association between this disease and large-scale vitamin D levels is because of the prophylactic ability that can be achieved by using vitamin D as a supplemental for prophylaxis for the development of nasolacrimal duct obstruction.
The limitations of this study should be taken into account when interpreting their results. First, the entire sample was very low, and the selection of cases should be random in order to give greater objectivity to the results obtained. Second, measurements of vitamin D levels were total, no vitamin D2 and D3 measurements were used in either of the participants in both groups. And thirdly and nally, some variables that may have confused the results, such as socioeconomic level, caffeine intake, occupation, and exposure to sunlight, were not evaluated.
Despite these limitations, no association was found between study variables. Lower levels of vitamin D were present in both groups (healthy and sick), result probably biased due to lower sun exposure caused by motility limitations established in the Covid-19 pandemic.

Conclusions
Chronic dacryocystitis is an in ammatory and infectious disease of the tear sac, the causes of which range from infections to autoimmune diseases. This is the rst study that raised the association between vitamin D levels with the presence of chronic dacryocystitis compared to a healthy control group. However, no association was established between these variables, due to external factors such as the total sample recruited, the evaluation of chronic in ammation variables along with serum vitamin D measurements is recommended, because a higher degree of in ammation can be associated with alterations in levels of vitamins and other substances, the behavior of vitamin D and the role in diseases by blockage of the nasolacrimal duct can be evaluated.

Con icts of Interest
The author declares no con icts of interest. Figure 1 Frequency of vitamin D levels depending on healthy and sick patients.