PURPOSE
To investigate the incidence and ophthalmic complications of pediatric uveitis using the Korean National Health Insurance (NHI) Service database.
DESIGN
Nationwide population-based longitudinal cohort study.
METHODS
This study used the NHI database from 2005 to 2021 and included individuals <18 years of age diagnosed with uveitis on at least three separate visits between 2010 and 2014, with a five-year wash-out period and a seven-year follow-up period. All uveitis cases were classified as either anterior or nonanterior on the basis of the diagnostic code. The occurrence of ophthalmic complications during the follow-up period, and the systemic and socioeconomic associations between pediatric uveitis and its ophthalmic complications were investigated. We obtained the incidence of total, anterior, and nonanterior pediatric uveitis between 2010 and 2014; the percentage of ophthalmic complications during the follow-up period; and hazard ratios for ophthalmic complications of anterior and nonanterior uveitis.
RESULTS
A total of 9495 cases of pediatric uveitis (8734 cases with anterior and 761 with nonanterior uveitis) were identified, with an average annual incidence (per 10 000 children) of total, anterior, and nonanterior uveitis being 2.0, 1.8, and 0.2, respectively. The most common complications were glaucoma or presumed ocular hypertension, macular disease, and amblyopia. Patients with nonanterior uveitis had a significantly higher risk of ophthalmic complications including retinal detachment, cataract, amblyopia, and glaucoma or presumed ocular hypertension than those with anterior uveitis.
CONCLUSIONS
This nationwide analysis of pediatric uveitis in South Korea revealed an average incidence of 2.0 per 10 000 children, highlighting the higher risks of ophthalmic complications associated with nonanterior uveitis.
U veitis is a group of intraocular inflammatory diseases involving the uveal tract of the eye and is recognized as a major cause of vision loss. Uveitis in children is less common than that in adults. While its prevalence varies considerably worldwide and depends on the age range used in the definition, approximately 2% to 14% of all cases of uveitis occur in children below the age range of 16 to 19 years. , However, uveitis in children tends to run a relatively severe disease course and result in higher risk of ocular comorbidities. This is often due to the chronic nature of inflammation and the frequent delay in diagnosis, which is attributable to either the absence of symptoms or a failure to report changes in vision. , Furthermore, these ocular complications have a much greater impact on the patient’s overall quality of life, particularly considering the remaining life span.
Ophthalmic complications of pediatric uveitis include glaucoma, cataract, maculopathy (such as macular edema, epiretinal membrane, and macular choroidal neovascular membrane/scar), retinal detachment, band keratopathy, and amblyopia. , These complications can affect visual development in children, leaving sequelae that can last for a lifetime. Up to one-third of children with uveitis are left with severely impaired vision due to these complications. Ophthalmic complications following uveitis in the general population have been reported in the literature using population-based databases; however, there is a lack of population-based reports on ophthalmic complications in pediatric uveitis. , The National Health Insurance (NHI) database in South Korea provides researchers with population-based epidemiological data on disease occurrence and treatment of the entire South Korean population. Recently, a population-based study in South Korea using the NHI database reported the epidemiology of pediatric noninfectious uveitis. However, ophthalmic complications following pediatric uveitis have not been previously reported using a nationwide population database.
The annual incidence of pediatric uveitis has been reported to be 4 to 7 per 100 000. The majority of the studies reported have used tertiary hospital data, and there are only a few population-based reports on epidemiology of pediatric uveitis and the associated systemic diseases. , , A South Korean epidemiological study on pediatric noninfectious uveitis between 2005 and 2016 reported its incidence to be 4.64 per 100 000 person-years. However, the epidemiology of total pediatric uveitis using population-based database in South Korea has not been reported. Uveitis can be associated with several systemic immune-mediated diseases, including spondylarthritis, inflammatory bowel disease, Adamantiades-Behçet disease, sarcoidosis, systemic lupus erythematosus, multiple sclerosis, and juvenile idiopathic arthritis (JIA). , In pediatric cases, it is more frequently associated with JIA, Kawasaki disease, and tubulointerstitial nephritis and uveitis (TINU), differing from adult associations. , , The most frequently associated disease in South Korea was reported to be JIA using Korean tertiary hospital database. This study aimed to provide a population-based epidemiological report on ophthalmic complications of pediatric uveitis, as well as the epidemiology of pediatric uveitis and associated systemic diseases at the time of uveitis diagnosis.
METHODS
ETHICAL CONSIDERATIONS
This retrospective population-based longitudinal cohort study design was approved by the Institutional Review Board (IRB) of Hanyang University Guri Hospital, Gyunggi-do, South Korea (IRB no. 2023-05-028) and conducted in accordance with the tenets of Declaration of Helsinki. The need for written informed consent was waived by the IRB due to the retrospective nature of the study.
DATABASE
South Korea’s healthcare system includes the NHI and Medical Aid, which covers >97% and the remainder of the population, respectively. The NHI is compulsory health insurance and the sole national insurance provider in South Korea, whereas the Medical Aid program is a public assistance program that provides healthcare to the economically disadvantaged population. Thus, the entire South Korean population is covered by either the NHI or Medical Aid program. The Korean National Health Insurance Service (NHIS) database contains the health records of all NHI and Medical Aid recipients in South Korea, including diagnoses, procedures, prescription records, and sociodemographic characteristics. As patients are identified using a unique identification number in this database, no duplications or omissions can be ensured.
We used the health claims data recorded between 2005 and 2021 from the NHIS database. We initially enrolled all patients with uveitis codes since 2005, then extracted participants with diagnostic codes for uveitis between 2010 and 2014, and then excluded those who also had diagnostic codes for uveitis prior to 2010 (between 2005 and 2009). Since the database does not distinguish between first-time and follow-up diagnoses, we excluded patients with a previous diagnosis of uveitis between 2005 and 2009 and included those newly diagnosed with uveitis since 2010 to identify newly diagnosed cases, based on the assumption that a lack of prior diagnosis indicated a new case. The follow-up period to assess uveitis complications in all patients was fixed at 7 years. Diagnoses were identified according to the Korean Classification of Diseases (KCD), 8th edition, a modified version of the International Classification of Diseases, 10 th edition (ICD-10), as the NHIS database manages claims using the KCD.
COHORT AND CASE DEFINITION
Patients with pediatric uveitis were enrolled if they were under the age of 18 years and had at least three claims of diagnostic codes of uveitis on separate occasions by ophthalmologists between 2010 and 2014. Cases were classified as anterior or nonanterior uveitis based on the KCD and initial diagnostic codes (Supplemental Table 1). Cases initially diagnosed as anterior uveitis were reclassified as nonanterior uveitis if the diagnostic code for nonanterior uveitis appeared afterwards. The exclusion criteria were as follows: (1) intraocular procedure performed during a period of 90 days before the uveitis diagnosis, (2) occurrence of endophthalmitis 30 days before or after the uveitis diagnosis, (3) ocular trauma within 30 days prior to the uveitis diagnosis, or (4) diagnostic or procedure codes with possible relevance to the complications of uveitis before the uveitis diagnosis (Supplemental Table 2). The diagnostic codes used to exclude endophthalmitis and ocular trauma, and the procedure codes used to exclude intraocular procedures are described in Supplemental Table 1. Additionally, we defined the control group among our study population (those with a diagnosis of uveitis) as those under the age of 18 years with one or two claims of diagnostic codes for uveitis during the same inclusion period (2010-2014), and excluded those with diagnostic or procedure codes related to the complications of uveitis prior to the diagnosis of uveitis. Although the criteria did not define a truly healthy population, we considered having less than three diagnoses of uveitis for patients in the control group who did not truly have uveitis ( Figure ).
COMPLICATIONS
Ophthalmic complications including glaucoma or presumed ocular hypertension (OHT), cataract, macular disease (macular edema, epiretinal membrane), retinal detachment, band keratopathy, and amblyopia, and ophthalmic procedures including glaucoma surgery, cataract surgery, and vitreoretinal surgery during the seven-year follow-up period were identified. The diagnostic codes used to identify the ophthalmic complications of pediatric uveitis and the procedure codes used to identify the procedures conducted due to the ophthalmic complications are described in Supplemental Table 3. We categorized the diagnostic codes for glaucoma as “glaucoma or presumed OHT” because the diagnostic codes for glaucoma do not provide distinctions between true glaucoma, OHT, and transient intraocular pressure elevation.
To identify extreme cases of permanent visual impairment following pediatric uveitis, we investigated the number of patients registered as visually impaired during the seven-year follow-up period. In 2019, the grading system for registering visual impairment was reorganized and the previous 6-grade system was replaced with binary severe/not severe classification system. The previous grades of 1 to 3 corresponded to “severe” and 4 to 6 corresponded to “not severe” in the new system. Therefore, we used both classifications to identify the total number of patients with visual impairment.
COVARIATES
Demographic factors collected included age at the time of diagnosis and sex. Socioeconomic factors including residential area and income level were also collected. Residential areas were categorized into three groups: 1) Seoul (the capital of South Korea); 2) Gyeonggi-do, the province surrounding Seoul and metropolitan cities excluding Seoul; and 3) the rest of the country. Household income levels were divided into four groups by quartile.
Associated systemic diseases diagnosed in the five years prior to the diagnosis of uveitis were evaluated (Supplemental Table 4). We assessed associated systemic diseases only if they were diagnosed before the diagnosis of uveitis. Using this approach, we sought to evaluate these comorbidities as factors that may influence the development of the ocular complications of uveitis.
STATISTICAL ANALYSIS
Poisson’s distribution was used to calculate the incidence rate (/10 000) with 95% confidence interval (CIs). The incidence rates were calculated by year, age at the time of diagnosis, and sex. Categorical variables of demographic characteristics were expressed as frequencies and percentages, and group differences were analyzed using the Chi-square and Fisher’s exact tests. Univariate and multivariate logistic regression analyses were used to investigate the risk factors for uveitis. Results were reported as odds ratios (ORs) with corresponding 95% CIs. The Cox proportional hazards model was used to investigate the risk factors for complications. Hazard ratios (HRs) and 95% CIs were expressed. Multivariate analysis included significant variables with P < .05 in the univariate analysis. Statistical significance was defined as a two-sided P value <.05. All statistical analyses were performed using the SAS Enterprise Guide, version 6.1 (SAS Institute Inc, Cary, NC, USA).
RESULTS
PATIENT DEMOGRAPHICS
A total of 12 238 participants aged < 18 years diagnosed with uveitis in at least three separate visits during a five-year period (2010-2014) were included in this study. After applying the exclusion criteria, 9495 patients met the operational definition of uveitis. A total of 19 575 individuals aged < 18 years diagnosed with uveitis less than three times served as controls. Overall, 8734 cases of anterior uveitis and 761 of nonanterior uveitis were identified during the study period ( Figure ). The demographic and clinical characteristics of patients with uveitis and controls are summarized in Table 1 .
| Variable | Total (N = 29 070) | Control (N = 19 575) | Pediatric Uveitis (N = 9495) | P Value a | Anterior Uveitis (N = 8734) | Nonanterior Uveitis (N = 761) | P Value b |
|---|---|---|---|---|---|---|---|
| Age (Years) | <.001 | <.001 | |||||
| 0-6 | 6292 (21.6%) | 5184 (26.5%) | 1108 (11.7%) | 889 (10.2%) | 219 (28.8%) | ||
| 7-12 | 8313 (28.6%) | 5330 (27.2%) | 2983 (31.4%) | 2775 (31.8%) | 208 (27.3%) | ||
| 13-17 | 14 465 (49.8%) | 9061 (46.3%) | 5404 (56.9%) | 5070 (58.1%) | 334 (43.9%) | ||
| Sex | 0.546 | <.001 | |||||
| Male | 18 145 (62.4%) | 12 195 (62.3%) | 5950 (62.7%) | 5546 (63.5%) | 404 (53.1%) | ||
| Female | 10 925 (37.6%) | 7380 (37.7%) | 3545 (37.3%) | 3188 (36.5%) | 357 (46.9%) | ||
| Residence d | <.001 | 0.053 | |||||
| Seoul | 4694 (16.2%) | 3114 (15.9%) | 1580 (16.6%) | 1477 (16.9%) | 103 (13.5%) | ||
| Second Area | 16 015 (55.1%) | 11 007 (56.2%) | 5008 (52.7%) | 4596 (52.6%) | 412 (54.1%) | ||
| Third Area | 8361 (28.8%) | 5454 (27.9%) | 2907 (30.6%) | 2661 (30.5%) | 246 (32.3%) | ||
| Household Income (%) e | <.001 | 0.099 | |||||
| 0-25 | 5119 (17.6%) | 3322 (17.0%) | 1797 (18.9%) | 1668 (19.1%) | 129 (17.0%) | ||
| 25-50 | 4811 (16.6%) | 3249 (16.6%) | 1562 (16.5%) | 1453 (16.6%) | 109 (14.3%) | ||
| 50-75 | 7838 (27.0%) | 5426 (27.7%) | 2412 (25.4%) | 2210 (25.3%) | 202 (26.5%) | ||
| 75-100 | 11 302 (38.9%) | 7578 (38.7%) | 3724 (39.2%) | 3403 (39.0%) | 321 (42.2%) | ||
| Comorbidities f | |||||||
| Behcet’s Disease | 56 (0.2%) | 13 (0.1%) | 43 (0.5%) | <.001 | 33 (0.4%) | 10 (1.3%) | 0.002 c |
| Juvenile Idiopathic Arthritis | 86 (0.3%) | 29 (0.2%) | 57 (0.6%) | <.001 | 54 (0.6%) | 3 (0.4%) | 0.625 c |
| Ankylosing Spondylitis | 17 (0.1%) | 8 (0.0%) | 9 (0.1%) | 0.075 | 9 (0.1%) | – | 1.000 c |
| Systemic Lupus Erythematosus | 22 (0.1%) | 12 (0.1%) | 10 (0.1%) | 0.201 | 9 (0.1%) | 1 (0.1%) | 0.567 c |
| Kawasaki Disease | 283 (1.0%) | 211 (1.1%) | 72 (0.8%) | 0.009 | 68 (0.8%) | 4 (0.5%) | 0.440 |
| Tubulointerstitial Nephritis | 221 (0.8%) | 155 (0.8%) | 66 (0.7%) | 0.373 | 60 (0.7%) | 6 (0.8%) | 0.747 |
| Ulcerative Colitis | 29 (0.1%) | 18 (0.1%) | 11 (0.1%) | 0.545 | 11 (0.1%) | – | 1.000 c |
| Tuberculosis | 102 (0.4%) | 64 (0.3%) | 38 (0.4%) | 0.322 | 32 (0.4%) | 6 (0.8%) | 0.121 c |
| Sarcoidosis | – | – | – | – | – | – | – |
| Crohn’s Disease | 34 (0.1%) | 24 (0.1%) | 10 (0.1%) | 0.686 | 9 (0.1%) | 1 (0.1%) | 0.567 c |
| Multiple Sclerosis | – | – | – | – | – | – | – |
| Reactive Arthritis | 34 (0.1%) | 23 (0.1%) | 11 (0.1%) | 0.969 | 9 (0.1%) | 2 (0.3%) | 0.219 c |
| APS | – | – | – | – | – | – | – |
| Necrotizing Vasculopathy | 1 (0.0%) | 1 (0.0%) | – | 1.000 | – | – | – |
| Ophthalmic Complications | |||||||
| Glaucoma or Presumed Ocular Hypertension | 6633 (22.8%) | 2828 (14.5%) | 3805 (40.1%) | <.001 | 3489 (40.0%) | 316 (41.5%) | 0.395 |
| Cataract | 189 (0.7%) | 62 (0.3%) | 127 (1.3%) | <.001 | 94 (1.1%) | 33 (4.3%) | <.001 |
| Macular Disease | 297 (1.0%) | 64 (0.3%) | 233 (2.5%) | <.001 | 208 (2.4%) | 25 (3.3%) | 0.122 |
| Retinal Detachment | 99 (0.3%) | 44 (0.2%) | 55 (0.6%) | <.001 | 41 (0.5%) | 14 (1.8%) | <.001 c |
| Band Keratopathy | 18 (0.1%) | 8 (0.0%) | 10 (0.1%) | 0.038 | 10 (0.1%) | – | – |
| Amblyopia | 629 (2.2%) | 438 (2.2%) | 191 (2.0%) | 0.214 | 160 (1.8%) | 31 (4.1%) | <.001 |
| Total of Ophthalmic Complications | 7276 (25.0%) | 3257 (16.6%) | 4019 (42.3%) | <.001 | 3674 (42.1%) | 345 (45.3%) | 0.080 |
| Ophthalmic Procedures | |||||||
| Glaucoma Surgery | 28 (0.1%) | 3 (0.0%) | 25 (0.3%) | <.001 | 15 (0.2%) | 10 (1.3%) | <.001 |
| Cataract | 64 (0.2%) | 15 (0.1%) | 49 (0.5%) | <.001 | 27 (0.3%) | 22 (2.9%) | <.001 c |
| Vitreoretinal Surgery | 75 (0.3%) | 30 (0.2%) | 45 (0.5%) | <.001 | 29 (0.3%) | 16 (2.1%) | <.001 c |
| Total of Ophthalmic Procedure | 118 (0.4%) | 37 (0.2%) | 81 (0.9%) | <.001 | 51 (0.6%) | 30 (3.9%) | <.001 |
a Chi-square test (Control vs Uveitis).
b Chi-square test (Anterior vs Nonanterior uveitis).
d Seoul is the capital of South Korea; the second area includes Gyeonggi-do and metropolitan cities, excluding Seoul; and the third includes all other regions.
e A lower percentile indicates a lower household income level.
f Comorbidities diagnosed in the 5 years prior to the diagnosis of uveitis.
INCIDENCE OF PEDIATRIC UVEITIS
The overall annual incidences (per 10 000 children) of total, anterior, and nonanterior uveitis between 2010 and 2014 were 2.0 (95% CI, 1.9-2.0), 1.8 (95% CI, 1.8-1.8), and 0.2 (95% CI, 0.1-0.2), respectively ( Table 2 ). The incidence was lowest in the youngest age group (0-6 years old; 0.7 per 10 000 children) and gradually increased with age (7-12 years old; 1.9 per 10 000 children, 13-17 years old; 3.2 per 10 000 children). The incidence of total (anterior + nonanterior) uveitis was higher in males (2.4, 95% CI, 2.3-2.4) than in females (1.5, 95% CI, 1.5-1.6).
| Number of Patients | Annual Participants | Incidence (/10000) | 95% CI | Number of Patients | Annual Participants | Incidence (/10000) | 95% CI | Number of Patients | Annual Participants | Incidence (/10000) | 95% CI | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Anterior Uveitis | Nonanterior Uveitis | ||||||||||
| Year | ||||||||||||
| 2010 | 1911 | 10 156 455 | 1.9 | 1.8 to 2.0 | 1791 | 10 156 455 | 1.8 | 1.7 to 1.8 | 120 | 10 156 455 | 0.1 | 0.1 to 0.1 |
| 2011 | 1832 | 9 921 012 | 1.8 | 1.8 to 1.9 | 1680 | 9 921 012 | 1.7 | 1.6 to 1.8 | 152 | 9 921 012 | 0.2 | 0.1 to 0.2 |
| 2012 | 2104 | 9 691 876 | 2.2 | 2.1 to 2.3 | 1963 | 9 691 876 | 2.0 | 1.9 to 2.1 | 141 | 9 691 876 | 0.1 | 0.1 to 0.2 |
| 2013 | 1855 | 9 431 699 | 2.0 | 1.9 to 2.1 | 1664 | 9 431 699 | 1.8 | 1.7 to 1.8 | 191 | 9 431 699 | 0.2 | 0.2 to 0.2 |
| 2014 | 1793 | 9 186 841 | 2.0 | 1.9 to 2.0 | 1636 | 9 186 841 | 1.8 | 1.7 to 1.9 | 157 | 9 186 841 | 0.2 | 0.1 to 0.2 |
| Age (Years) | ||||||||||||
| 0-6 | 1108 | 16 161 419 | 0.7 | 0.6 to 0.7 | 889 | 16 161 419 | 0.6 | 0.5 to 0.6 | 219 | 16 161 419 | 0.1 | 0.1 to 0.2 |
| 7-12 | 2983 | 15 585 972 | 1.9 | 1.8 to 2.0 | 2775 | 15 585 972 | 1.8 | 1.7 to 1.8 | 208 | 15 585 972 | 0.1 | 0.1 to 0.2 |
| 13-17 | 5404 | 16 640 492 | 3.2 | 3.2 to 3.3 | 5070 | 16 640 492 | 3.0 | 3.0 to 3.1 | 334 | 16 640 492 | 0.2 | 0.2 to 0.2 |
| Overall | 9495 | 48 387 883 | 2.0 | 1.9 to 2.0 | 8734 | 48 387 883 | 1.8 | 1.8 to 1.8 | 761 | 48 387 883 | 0.2 | 0.1 to 0.2 |
| Male | Female | |||||||||||
| Year | ||||||||||||
| 2010 | 1307 | 5 307 952 | 2.5 | 2.3 to 2.6 | 604 | 4 848 503 | 1.2 | 1.1 to 1.3 | ||||
| 2011 | 1177 | 5 172 000 | 2.3 | 2.1 to 2.4 | 655 | 4 749 012 | 1.4 | 1.3 to 1.5 | ||||
| 2012 | 1341 | 5 039 447 | 2.7 | 2.5 to 2.8 | 763 | 4 652 429 | 1.6 | 1.5 to 1.8 | ||||
| 2013 | 1059 | 4 893 368 | 2.2 | 2.0 to 2.3 | 796 | 4 538 331 | 1.8 | 1.6 to 1.9 | ||||
| 2014 | 1066 | 4 757 780 | 2.2 | 2.1 to 2.4 | 727 | 4 429 061 | 1.6 | 1.5 to 1.8 | ||||
| Age (Years) | ||||||||||||
| 0-6 | 650 | 8 322 991 | 0.8 | 0.7 to 0.8 | 458 | 7 838 428 | 0.6 | 0.5 to 0.6 | ||||
| 7-12 | 2005 | 8 111 457 | 2.5 | 2.4 to 2.6 | 978 | 7 474 515 | 1.3 | 1.2 to 1.4 | ||||
| 13-17 | 3295 | 8 736 099 | 3.8 | 3.6 to 3.9 | 2109 | 7 904 393 | 2.7 | 2.6 to 2.8 | ||||
| Overall | 5950 | 25 170 547 | 2.4 | 2.3 to 2.4 | 3545 | 23 217 336 | 1.5 | 1.5 to 1.6 | ||||
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