Conjunctival Histopathological Changes and Clinical Tear Film in Children with Atopic Dermatitis

Abstract

Purpose Evaluation of changes in the ocular surfaces in children with a diagnosis of atopic dermatitis (AD).

Methods Thirty-six children with a diagnosis of AD (Eye-AD group) and 40 healthy subjects (Eye-HS group) were enrolled in this prospective case-control study. Tear film break-up time (T-BUT), Schirmer tear test (STT), conjunctival impression cytology (CIC), tear meniscus height (TMH), tear meniscus area (TMA), and ocular surface disease index (OSDI) were measured.

Results The participants were similar in terms of demographic characteristics, such as mean age and gender (p > 0.05). The mean T-BUT was 9.3 ± 2.22 s (5 – 16) in the Eye-AD group and 11.83 ± 2.03 s (7 – 16) in the Eye-HS group. The mean STT was 11.12 ± 3.28 mm (5 – 21) in the Eye-AD group and 15.44 ± 3.8 mm (8 – 20) in the Eye-HS group (p < 0.001, p < 0.001, respectively). The mean OSDI scores were 13.12 ± 1.41 (10 – 15) in the Eye-AD group and 13.97 ± 2.93 (8 – 20) in the Eye-HS group (p = 0.052). Mean TMH and TMA were 306.48 ± 7.29 µm and 0.22 ± 0.004 mm², respectively, in the Eye-AD group, and 312.94 ± 5.31 µm and 0.027 ± 0.005 mm², respectively, in the Eye-HS group. In the CIC analyses, 22 of the samples in the Eye-AD group and 35 in the Eye-HS group had a classification of grade 0, 10 in the Eye-AD group and 5 in the Eye-HS group had a classification of grade 1, and 4 in the Eye-AD group and none in the Eye-HS group had a classification of grade 2 (p = 0.015).

Conclusion Pediatric patients with AD may have significant changes in conjunctival histopathology. These changes can be manifested in the tests used to measure the tear film. Dry eye was shown to be present in the majority of children with AD.

Zusammenfassung

Zweck Die Beurteilung von Veränderungen der Augenoberfläche bei Kindern mit der Diagnose atopische Dermatitis (AD).

Methoden In dieser prospektiven Fall-Kontroll-Studie wurden die Augen von 36 Kindern mit der Diagnose AD (Augen-AD-Gruppe) und 40 gesunden Probanden (Augen-HS-Gruppe) aufgenommen. Die Werte für die Aufreißzeit des Tränenfilms (T-BUT), den Schirmer-Tränentest (STT), die konjunktivale Impressionszytologie (CIC), die Tränenmeniskushöhe (TMH), die Tränenmeniskusfläche (TMA) und den Augenoberflächenkrankheitsindex (OSDI) wurden ermittelt und gesammelt.

Ergebnisse Die Teilnehmer waren hinsichtlich demografischer Merkmale wie Durchschnittsalter und Geschlecht ähnlich (p > 0,05). Die mittlere T-BUT betrug 9,3 ± 2,22 s (5 – 16) in der Eye-AD-Gruppe, 11,83 ± 2,03 s (7 – 16) in der Eye-HS-Gruppe, STT 11,12 ± 3,28 mm (5 – 21) in der Eye-AD-Gruppe und 15,44 ± 3,8 mm (8 – 20) in der Eye-HS-Gruppe (p < 0,001 bzw. p < 0,001). Die mittleren OSDI-Werte betrugen 13,12 ± 1,41 (10 – 15) in der Eye-AD-Gruppe und 13,97 ± 2,93 (8 – 20) in der Eye-HS-Gruppe (p = 0,052). Die mittleren TMH- und TMA-Werte betrugen 306,48 ± 7,29 µm und 0,22 ± 0,004 mm² in der Eye-AD-Gruppe und 312,94 ± 5,31 µm und 0,027 ± 0,005 mm² in der Eye-HS-Gruppe. In den CIC-Analysen hatten von den Proben 22 in der Eye-AD-Gruppe und 35 in der Eye-HS-Gruppe eine Klassifizierung mit Grad 0, 10 in der Eye-AD-Gruppe und 5 in der Eye-HS-Gruppe eine Klassifizierung mit der Grad 1 und 4 in der Eye-AD-Gruppe und keiner in der Eye-HS-Gruppe hatte eine Klassifizierung von Grad 2 (p = 0,015).

Schlussfolgerung Pädiatrische Patienten mit AD können erhebliche histopathologische Veränderungen der Bindehaut aufweisen. Diese Veränderungen können sich in den Tests zur Messung des Tränenfilms manifestieren. Es wurde gezeigt, dass bei der Mehrzahl der Kinder mit AD ein trockenes Auge vorliegt.

Keywords

cornea - paediatric ophthalmology - atopic dermatitis - dry eye

Schlüsselwörter

Kinderophthalmologie - Kornea - atopische Dermatitis - trockenes Auge

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsing eczema with intractable itching. It affects 20% of children and 3% of adults in the population [1], [2]. The reason why AD is more common in children is that although the disease begins in childhood, approximately 70% of patients go into remission before adolescence [1]. It has been shown that AD is associated with diseases like allergic asthma, rhinitis, and conjunctivitis [2]. Recently, ocular pathologies due to AD have been reported. Specifically, eye diseases such as cataract, detached retina, eyelid inflammation (blepharitis), glaucoma, keratoconus, and keratoconjunctivitis have all been linked to AD [3], [4], [5], [6]. Atopic keratoconjunctivitis (AKC) is the most commonly reported ocular comorbidity of AD, with a frequency from 25 to 40% [2]. Despite this fact, the ocular disorders that patients with a diagnosis of AD have are not generally a concern for most doctors other than ophthalmologists, especially if the patient does not have any complaints about associated symptoms. Moreover, children with a diagnosis of dry eye (DrE) might not show as many symptoms as adults with a diagnosis of similar DrE conditions. It might be that children do not experience as much discomfort and/or pain, and therefore, they may describe the discomfort caused by the ocular surface disorder less [7]. Because of this, examining pediatric patients with a diagnosis of AD is important to prevent further complications of the ocular surface.

The aim, therefore, of this current research, was investigating the presence of DrE in children with AD with both clinical tests and histopathological tests.

Methods

Ethical Approval

This was a case-control as well as prospective study that was done at the Department of Ophthalmology of a tertiary university hospital. Practices related to this conducted research adhered to the Declaration of Helsinki. The institutional board for the local ethics committee approved the study (protocol with number E-10840098-772.02-1593). All study participants, and the participantsʼ parents, submitted informed consent in writing before they were accepted into the study groups.

Study Participants

The study group was made up of 36 eyes of the 36 children with AD (Eye-AD group). The Eye-AD group patients had atopic disease that required treatment with systemic steroids at least once during their lifetime. None of the patients with atopy had a history of Stevens-Johnson syndrome, chemical or thermal injury, or any other systemic disorder. None of the patients were treated with cytotoxic immunosuppressants, topical prostaglandin inhibitors, or topical corticosteroids at the time of impression cytology. The inclusion criteria for the healthy subject controls (Eye-HS group; n = 40) were age- and sex-matched healthy subject, no history of ocular or systemic diseases, refractive spherical or cylindrical error < 1 D, with BCVA of ≥ 20/20. Data collection was done using just the participantsʼ right eye. Participants under the age of 6, above the age of 18, and those with various systemic diseases such as hypertension (HT), autoimmune disease (AID), thyroid disease (THD), or coronary heart disease (CHD), history of ocular surgery, corneal pathology, choroidal and optic nerve disease, refractive error above ± 1 D, axial length exceeding 24 mm, or eye pressure above 21 mmHg were excluded from the study.

Ocular examination

A routine eye exam was done for all patients, which comprised visual acuity testing (Snellen), intraocular pressure testing with pneumotonometry, and anterior segment (AS) and fundus exams via slit lamp biomicroscopy.

Tear film break-up time test

Tear film break-up time (T-BUT) and Schirmer tear test (STT) were performed 30 minutes after the routine ophthalmological exam without anesthesia. When doing the T-BUT test, the subjects were given instructions that they should blink following the fluorescent staining (ERC Medical Products, Ankara, Turkey). Examination of the tear film (TF) was done via the cobalt blue filter that was part of the slit lamp biomicroscope. The time from the moment the eyelids were opened, after the subject blinked, to the first appearance of a random dryness spot was recorded. The mean of three consecutively taken measurements was deemed to be the T-BUT.

Schirmer tear test

For the STT, a standardized strip of Whatman #41 filter paper (ERC Medical Products, Ankara, Turkey) was set in place at one-third of the lateral tarsal conjunctiva, without coming into contact with the cornea. The wetness seen on the filter paper was measured after 5 minutes and the result of the STT was determined.

Ocular Surface Disease Index score

A standard questionnaire, the ocular surface disease index (OSDI), was used for assessing the tear function, eye irritation symptoms, and visual function related to DrE. The questionnaire questions were reviewed with the study participants by an experienced ophthalmologist. The participants were instructed to rate each of the questions, with 0 indicating never, up to 4, indicating always. The OSDI scores were then calculated via the following formula: the sum of the scores/the total number of questions that were answered × 25 [8]. When OSDI scores are evaluated, there are 2 possible outcomes; first, values between 0 and 25 are normal; second, values > 25 are considered in favor of DrED ([Table 1]).

Table 1 Ocular surface disease index questionnaire.

	All of the time	Most of the time	Half of the time	Some of the time	None of the time
Eyes that are sensitive to light?	4	3	2	1	0
Eyes that feel gritty?	4	3	2	1	0
Painful or sore eyes?	4	3	2	1	0
Blurred vision?	4	3	2	1	0
Poor vision?	4	3	2	1	0
Have problems with your eyes limited you in performing any of the following during last week?
	All of the time	Most of the time	Half of the time	Some of the time	None of the time
Reading?	4	3	2	1	0
Driving at night?	4	3	2	1	0
Working with a computer or bank machine (ATM)?	4	3	2	1	0
Watching TV?	4	3	2	1	0
Have your eyes felt uncomfortable in any of the following situations during the last week?
	All of the time	Most of the time	Half of the time	Some of the time	None of the time
Windy conditions?	4	3	2	1	0
Places or areas with low humidity (very dry)?	4	3	2	1	0
Areas that are air conditioned?	4	3	2	1	0

Tear meniscus height and tear meniscus area

Optical coherence tomography (OCT) measurements were done via the AS module on a Spectralis Cirrus HD-OCT 5000/500 OCT system (Carl Zeiss Meditec, Inc., Dublin, CA, USA). Images were taken of the area between the lower part of the eyelid and the cornea. Measuring of the tear meniscus height (TMH) and tear meniscus area (TMA) was done with a caliper ([Fig. 1]).

Fig. 1 Tear meniscus height measurement with AS-OCT.

Conjunctival impression cytology

Following topical 0.5% proparacaine application with Alcaine (Alcon Laboratories, Fort Worth, TX, USA), a 4 × 5-mm piece of a cellulose nitrate filter (Whatman; GE Healthcare, Chicago, IL, USA) was set in place on the lower bulbar conjunctiva area for conjunctival impression cytology (CIC). The filter was removed using forceps after 5 seconds and then the filter was put in a solution of 95% ethanol. Afterwards, the staining of the samples was done manually via a periodic acid Schiff (PAS) stain. The sample examinations were done by a very experienced pathologist with a light microscope by following the method designed by Nelson [9]. Samples were graded from 0 to 3 according to Nelsonʼs classification [9]. Following evaluation, the interobserver and intra-observer reliabilities for these measurements were each 95%. This was done with intraclass correlation coefficients (ICCs) with a confidence interval (CI) of 95%. An ICC value above 0.75 was acceptable, while a value above 0.90 was considered excellent. When using this method, the detection of changes on the surface of the eye, like squamous metaplasia or goblet cell loss, is possible at early stages [10], [11]. When the samples are examined according to the Nelson classification, grades 0 and 1 represent normality, while grades 2 and 3 represent abnormal cytology [9].

Statistical analysis

The program IBM SPSS Statistical Statistics Program for Windows, version 25.0, was used to do all statistical analyses. Only the right eye of the participants was used in the analyses. The Kolmogorov-Smirnov test and Shapiro-Wilk test were used when testing the normality of the data. The mean and standard deviation (SD) were used for descriptive analyses. The independent t-test was used when comparing two normally distributed groups The chi-square test was used when comparing the categorical variables. P < 0.05 was deemed to be statistically significant.

Results

The mean age of the participants was 12.86 ± 2.36 years old in the Eye-AD group and 12.58 ± 3.56 years old in the Eye-HS group The participants were similar in terms of demographic characteristics such as the mean age and gender (p > 0.05).

The mean T-BUT and STT measurements were 9.3 ± 2.22 s (5 – 16) and 11.12 ± 3.28 mm (5 – 21) in the Eye-AD group and 11.83 ± 2.03 s (7 – 16) and 15.44 ± 3.8 mm (8 – 20) in the Eye-HS group (p < 0.001 and p < 0.001, respectively; [Fig. 2] and [Fig. 3]). In the Eye-AD group, 21 patients (58%) had a T-BUT below 10 s and 20 patients (50%) had STT results below 10 mm, while the Eye-HS group, which only had 4 patients (10%), had a T-BUT below 10 s and STT below 10 mm (for both of them: p < 0.001).

Fig. 2 Comparison of the T-BUT between the groups.

Fig. 3 Comparison of the STT results between the groups.

The mean OSDI scores were 13.12 ± 1.41 (10 – 15) in the Eye-AD group and 13.97 ± 2.93 (8 – 20) in Eye-HS group (p = 0.052).

The mean TMH and TMA were 306.48 ± 7.29 µm and 0.22 ± 0.004 mm² in Eye-AD group, and 312.94 ± 5.31 µm and 0.027 ± 0.005 mm² in the Eye-HS group ([Fig. 4] and [Fig. 5]).

Fig. 4 Comparison of the TMH between the groups.

Fig. 5 Comparison of the TMA between the groups.

In the CIC analyses, of the samples, 22 in the Eye-AD group and 35 in the Eye-HS group had a classification of grade 0, 10 in the Eye-AD group and 5 in the Eye-HS group had a classification of grade 1, and 4 in the Eye-AD group and none in the Eye-HS group had a classification of grade 2 (p = 0.015). Samples of conjunctival impression cytology were shown in [Fig. 6].

Fig. 6 Samples of conjunctival impression cytology (grading as per the Nelson scoring system). a Grade 0, basaloid squamous surface cells with abundant goblet cells. Note the prominent mucin globules within the goblet cells. b Grade 1, conjunctival surface epithelial cells with a nucleus; the cytoplasm ratio of 1 : 2 to 3 with a decreased number of goblet cells. c Grade 2 is characterized by the presence of intermediate-like squamous cells (i.e., the cells with a nucleus, cytoplasm ratio of 1 : 4 to 5) and only a few goblet cells.

Discussion

DrE is a disease involving multiple factors that affect the surface of the eye. It is accompanied by ocular symptoms, loss of TF homeostasis, ocular surface damage, and inflammation, which play an etiological role [10]. In ophthalmology, histopathological studies for diagnostic purposes in ocular surface-related diseases have been increasing in recent years. The findings identified in this study may provide important information about the pathogenetic effects of AD on the ocular surface in pediatric patients.

In the present literature, parameters evaluating tear function have been studied in a limited number of AD cases. In the current study, an evaluation of the OSDI questionnaire, T-BUT, STT, CIC, TMH, and TMA was done to investigate if it is possible for ocular surface changes to develop in children with a diagnosis of AD, and compare the obtained results with those for healthy children. Morphological, cytological, and immunocytological changes associated with DrE can be analyzed with CIC by taking samples from the conjunctival surface [12], [13]. One of strengths of the present research was the examination of the cytological changes in children with a diagnosis of AD by CIC, which has been recommended by some researchers as the gold standard for DrE disease (DrED). The findings determined herein might be able to provide important information about the pathophysiological effects that AD has on the TF in children [10].

Based on the results we obtained, 4 patients had abnormal cytology, such as grade 2 in the Eye-AD group. A decrease, with statistical significance, was seen in goblet cell density in the Eye-AD group in comparison with the Eye-HS group. Some patients in the Eye-AD group had a cytology classification of grade 1. Dogru et al. [14] studied 44 active AD patients and found the loss of goblet cells and conjunctival squamous metaplasia. Goblet cell loss found in our study could be supported by their study, but we did find abnormal cytology in only four patients. Dogru et al. stated that that squamous metaplasia is related to a recurrence of AD instead of how long the patient had the disease, and it is also related to facial atopy and allergic keratoconjunctivitis. Squamous metaplasia may not have been detected in most patients because our patients were children, were not in the active period, and had low recurrence rates.

Abnormal conjunctival histopathological changes (CHCs) in children with a diagnosis of AD were also supported by clinical findings related to tear function, such as low T-BUT and STT measurements. Allergic conjunctivitis, which results from several immunological and inflammatory pathways, is a common finding in those patients [15]. The presence of both eosinophils, which is an inflammatory cell in IgE-related reactions, and leucocytes were shown in AD. In the literature, immune-mediated or inflammatory DrE was documented in adult patients with AD [16], [17]. The histopathological abnormalities and decreased goblet count observed in the CIC in this study can be considered as the cause of AD causing inflammatory pathways that could have important involvement in the changes seen in clinical manifestations related to tear function in children. This is the first study of conjunctival changes in pediatric AD patients – comparable to the one done in adults [17].

Mucin, water, and lipid are the main properties making up the TF [18]. Pediatric patients with AD are at risk of adverse effects on these components. The low STT values in our study may be related to the main lacrimal gland not functioning properly, because it has an effect on the secretion of the watery parts of the TF. It is believed that goblet cell secretion is the primary source of tear mucin [19]. It is also believed that mucins on the surface of the eye form a barrier that prevents pathogens and matter particulates from getting into the ocular surface epithelium, and because of the heavy O-linked glycosylation that they possess, they help to maintain ocular surface hydration and tear stability [20]. In a recently conducted study by Niederkorn [21], they were able to demonstrate, using an allergic conjunctivitis mouse model, that in the conjunctiva of mice, repeated applications of allergens caused the goblet cell count to reduce. The T-BUT test shows TF instability. This test is not just for the absence of the TFʼs aqueous layer, it is also for the deficiency of the mucin and/or lipid component of the TF that is produced via the meibomian glands and the conjunctival goblet cells. Decreased goblet cell counts in our study can also explain why the STT results and T-BUT scores were low in the Eye-AD group.

Recently, AS-OCT was used to do this via an evaluation of the tear meniscus, both upper and lower, in the determination of DrED [22], [23]. It has been reported that the TMH and TMA values show a decrease in patients with DrED in comparison with healthy individuals [23]. In this current study, the TMA and TMH values were not as high in the children with a diagnosis of AD. OCT can be a useful and easy tool for use in diagnosing DrE in children due to its noninvasive nature.

Meibomian gland dysfunction should be considered as a potential mechanism for these changes in the ocular surface associated with pediatric AD patients and DrE. However, the validity of this hypothesis should be tested with further investigations such as meibography, with further studies investigating the association with pediatric AD patients and DrE at longer follow-up.

According to the consensus in both the literature and ophthalmology practice, the detection of a T-BUT less than 10 seconds and STT less than 5 mm is considered to be in favor of DrE [24], [25]. Based on the results we obtained, some patients who have AD also have DrED. Evaluating and treating DrED in early life is important to prevent further complications.

The OSDI questionnaire is a clinicianʼs quantitative measure of the effects of DrE-related ocular irritation symptoms, consisting of the subjective assessments of patients to assess the severity of DrE. Schiffman et al. [26] reported a specificity of 79% and a sensitivity of 60% for the OSDI questionnaire. Although some patients had DrE, the OSDI values obtained for both groups were well within normal range. In this study, the OSDI values and objective (STT and T-BUT) test results, which were not as good in the children with AD, were not combined. There could be several reasons for this situation. The first reason may be that the Eye-AD group consisted of children. In a study reported by Han et al. [7], they showed that children with a diagnosis of DrE may not show the same number or type of symptoms as adults that have similar DrE conditions, which could be because children may not experience the same level of discomfort or pain, and, therefore, they may describe the discomfort caused by ocular surface disorder less. Second, it might have something to do with the OSDI scoring methodʼs subjective nature. In previous studies, some researchers have also reported a discrepancy like this between the OSDI score and objective (STT and T-BUT) tests [26].

Compared to the literature, the patient population was pediatric and there is little information on this topic in children with AD. This study broadens the horizon and makes an important contribution to the literature. DrE is seen in children with AD; DrE may start in the pediatric period. Patients with AD may have DrE, not just adults but children as well. With this information in mind, possible DrE findings should be considered. When treating children with AD, clinicians should consider that children may have DrE and that DrE may affect the childrenʼs quality of life.

A major limitation of the research we conducted is that it lacked meibography, in vivo corneal confocal microscopy, and TF osmolarity testing. In addition, the effects that acute and chronic events have on tear function are not the same. As best as we were able to determine, this is the first research that has evaluated tear function parameters in pediatric patients who have AD. The examination of tear function by subjective (OSDI questionnaire), objective (STT and T-BUT), and clinical/laboratory investigations (CIC), and then reporting these obtained results were seen as the important strengths of this work.

Conclusion

Already know: AD may show eye symptoms such as keratoconjunctivitis, cataract, and retinal detachment. It is also known to cause DrE in adult patients.

Newly described: There are significant CHCs that occur in children with a diagnosis of AD. These changes impact some clinical signs that are associated with tear function, like the STT and T-BUT values.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publikationsverlauf

Eingereicht: 02. Oktober 2023

Angenommen: 28. Juli 2024

Accepted Manuscript online:
30. Juli 2024

Artikel online veröffentlicht:
27. August 2024