Epidemiology and Clinical Features of Anterior Uveitis: a Prospective Study

Purpose: To report the pattern, epidemiology, and clinical features of anterior uveitis (AU) in southern Taiwan Methods: A prospective case series was performed to recruit patients with AU at two medical centers (Kaohsiung Chang Gung Memorial Hospital and Kaohsiung Veterans General Hospital) in southern Taiwan from December 1, 2018 to March 31, 2020. These patients enrolled were reviewed for clinical diagnoses, ocular presentations, and laboratory data, including aqueous polymerase chain reaction tests. Results: A total of 112 patients were included. The most common clinical diagnoses were idiopathic AU (37.5%), HLA-B27-associated acute AU (25.0%), and herpetic AU (18.8%); among herpetic etiology, cytomegalovirus (CMV) was the most common pathogen. Hypertensive AU was associated with older age, more males, and greater numbers of corneal edema, and fewer iris posterior synechiae. Compared with HLA-B27-associated acute AU, CMV AU was associated with older age, high intraocular pressure, more keratic precipitates, greater iris atrophy, more pseudophakia, and fewer pupil posterior synechiae. Conclusion: This prospective study identi�ed the epidemiological and clinical features of AU in southern Taiwan. The most common etiologies were idiopathic AU, HLA-B27-associated acute AU, and herpetic (most CMV) AU.


Introduction
Uveitis, also referred to as intraocular in ammation, is a complex in ammatory process, primarily involving the uveal tract, with or without the involvement of the adjacent intraocular structures.Uveitis is a major cause of ocular morbidity, contributing to 5-10% of visual impairment worldwide [1].
Approximately 35% of patients with uveitis suffer from signi cant vision loss due to legal blindness [2].Moreover, most affected individuals are at their working age (20-65 years), resulting in signi cant socioeconomic impacts [3].The differential diagnosis of uveitis varies and is in uenced by several factors, such as genetic, ethnic, geographic, environmental, nutritional, and socioeconomic factors [4].Infections are a leading cause of uveitis in developing countries, whereas idiopathic uveitis is the leading cause in developed countries [5].Determining the proper underlying etiology is challenging [5,6].
In Eastern Asia, few prospective studies have clari ed the etiology of AU.This study aimed to investigate the current etiologies and clinical features of AU in Taiwan using a prospective method.

Patients
This prospective study was conducted in Kaohsiung city in southern Taiwan from December 2018 to March 2020.Patients were enrolled from two medical centers (Kaohsiung Chang Gung Memorial Hospital and Kaohsiung Veterans General Hospital) by four uveitis specialists (Dr.Shwu-Jiuan Sheu, Dr. Hsi-Kung Kuo, Dr. Shih-Chou Chen, and Dr. Wei-Yu Chiang).The inclusion criteria were patients with the clinical manifestations of AU, which was diagnosed based on history, ocular examination, laboratory data, and image data.However, patients with uveitis other than AU were excluded.The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of the Chang Gung Memorial Hospital (study reference number: 201702154A3).Informed consent was obtained from all participants.

Protocol
The protocol included a 2-step examination; the rst step included collecting demographics, clinical presentations, and laboratory tests; the second step included an aqueous humor polymerase chain reaction (PCR) test.The detailed collected items included age, sex, history of rst episode or not, symptom duration, and acute course, ocular examination of one or both affected eyes, intraocular pressure (IOP), keratic precipitates (KP), corneal edema, hypopyon, iris atrophy, posterior synechiae (PS), and intraocular lens (IOL).The acute course was de ned as a sudden onset and limited duration of ≤ 3 months.Laboratory tests included complete blood count, HLA-B27, C-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, rheumatoid factor, rapid plasma regain, Treponema pallidum hemagglutination, and chest and sacroiliac X-ray.An aqueous PCR test was designed for CMV, HSV, VZV, and EBV.If the rst step con rmed the diagnosis of HLA-B27-associated acute AU with HLA-B27 positivity and its corresponding presentations, the PCR test could be neglected.If HLA-B27-associated acute AU was absent, the patient would undergo an aqueous PCR examination.

Aqueous humor PCR
If clinically indicated, patients with AU underwent PCR for aqueous humor DNA extraction and ampli cation.Anterior chamber paracentesis with a 27#-gauge needle was performed using an aseptic technique with the aid of a microscope.The details of the sample processing and primer information are described in our previous study [17].

Statistics
In the descriptive analysis, categorical data were shown as numbers and percentages and continuous variables were expressed as mean ± standard deviations (SDs).Comparisons were performed using Student's t-test for continuous variables and Chi-square test for categorical factors.In the multivariate analyses, stepwise logistic regression analysis was used to identify significant independent predictors for differentiating HLA-B27-associated and CMV AU.Statistical significance was defined as a two-tailed pvalue of <0.05.

Results
A total of 112 patients were enrolled in this study.The nal diagnoses are shown in Table 1.The etiologies were idiopathic acute and chronic AU (37.5%),HLA-B27-associated acute AU (25.0%), herpetic AU (18.8%),PSS (11.6%),FHI (3.6%), JIA (2.7%), and Behcet's disease (0.9%).The diagnoses were based on the physicians' clinical impressions.The clinical manifestations of PSS included recurrent unilateral, mild, acute non-granulomatous anterior uveitis with markedly elevated IOP, corneal edema, KPs, lowgrade cell, and vague symptoms.The clinical manifestations of FHI included recurrent unilateral anterior uveitis with small KPs, presence of heterochromia, lack of synechiae, and lack of symptoms.All patients with suspected PSS and FHI underwent aqueous PCR.If PCR was positive, then these cases were classi ed as herpetic AU; otherwise, they were classi ed as initial PSS or FHI diagnoses.The demographics and clinical manifestations of all the participants are listed in Table 2.

Table 1. The clinical diagnosis of anterior uveitis
The most common etiologies were idiopathic AU, HLA-B27-associated AU, and herpetic AU.
Most AU patients had unilateral disease (83.7%), and initial bilateral presentations were more often seen in intermediate uveitis, posterior uveitis, and panuveitis in a Taiwanese report [7].Our study demonstrated similar results, with 87.7% of AU patients presenting with unilateral eye disease.
HLA-B27 is the best-known immune biomarker of AU.The seropositivity rate, different in several ethnicities, was reported to be 7.7% in a healthy Taiwanese population [25].HLA-B27-associated acute AU has distinct characteristics in AU.Approximately 50%-75% of patients with HLA-B27-associated acute AU have seronegative spondyloarthropathy, with ankylosing spondylitis (AS) being the most common diagnosis [26].A Chinese report indicated that the prevalence of AAU in AS was 15.8%, and the presence of AAU in AS patients may be associated with higher disease activity, poor functional ability, and advanced physical impairment [27].Conversely, acute AU is the most common ocular manifestation in HLA-B27 positive seronegative spondyloarthropathies [28].HLA-B27-associated AU classically presents as an acute AU with symptomatic, unilateral, sudden-onset, and limited-duration anterior segment in ammation [29].The rst attack of HLA-B27-associated acute AU occurs between 20 and 40 years of age in the majority of cases, approximately 10 years younger than that observed in patients with HLA-B27-negative AU [30].Male preponderance was noted, with men affected 1.5-2.5 times more frequently than females [31,32].In this study, 28 patients with HLA-B27-associated acute AU exhibited a mean age of 38.8 years, an acute course of 96.4% with a mean symptom duration of only 9.6 days, but only 46.4% of occurrences in males (Table 3).
Ocular hypertension is a speci c sign of active uveitis, especially in non-HLA-B27-associated acute AU.Increased availability of PCR enhances the diagnosis of hypertensive AU to detect herpetic etiologies and even connect herpetic AU to previously presumed PSS or FHI.For example, both CMV and the Rubella virus have been implicated as etiologies of PSS or FHI [21][22][23]33].In the current study, ocular hypertension accounted for 26.8% (30/112, Table 2) of all cases.Approximately 30.0%(9/30) of ocular hypertension demonstrated positive in PCR test and all were CMV.A Thailand study de ned ocular hypertension as IOP > 25mmHg and demonstrated 32% positivity in herpesviridae PCR, including 19% for CMV, 10% for HSV, and 3% for VZV [34].In our study, 27 cases had IOP > 25mmHg and 25.9% (7/27) were positive for herpesviridae PCR with all CMV infections.A high percentage of CMV AU was found in our retrospective review and con rmed in this prospective study [17].CMV seroprevalence tended to be the highest in South America, Africa and Asia and lowest in Western Europe and the United States [35].This may re ect the high CMV carrier rate in Asia.3).
In addition to an idiopathic etiology, HLA-B27-associated acute AU and CMV AU were the two most popular speci c diseases.The comparison between these two etiologies of AU was clari ed in this study (Table 3).If patients with AU present with younger age, lower IOP than the fellow eye, rst episode, acute course, shorter symptom duration, more PS, less iris atrophy, HLA-B27-associated acute AU is a preferred etiology compared to CMV.For AU patients with ocular hypertension, PCR analysis of the anterior chamber uid is important to detect herpetic etiology.
Our previous study retrospectively collected the aqueous PCR data of HLA-B27 negative AU patients with increased IOP or corneal edema [17].In that retrospective study, 41.1% of the enrolled patients were herpesviridae-positive.Compared with the current prospective study, 29.6% of the patients were herpesviridae-positive, and all of them were CMV.The CMV-AU group (Table 3) showed older age, more iris atrophy, and more pseudophakia.Both studies indicated that a signi cant proportion of patients with herpesviridae or CMV-positive AU had undergone intraocular lens implantation.
This study had three major limitations.First, the number of patients was small.Second, some patients received rst aid at local clinics or other facilities, which may have affected ocular presentation.The treatment details, such as corticosteroids, IOP-controlling agents, and mydriatics, were not recorded.Third, this study only enrolled patients from tertiary referral centers, which could not represent the overall epidemiology.However, this study provides readers with guidelines for the care of patients with AU.First, the protocol mentioned in the Methods section can be used in clinical practice.Among several clinical parameters, IOP has exhibited strong evidence for differential diagnoses.Second, PCR is a useful tool for identifying herpetic etiology, especially in cases of ocular hypertension.
In conclusion, this prospective study identi ed the epidemiological and clinical features of anterior uveitis in southern Taiwan.The leading etiologies of AU were idiopathic acute, HLA-B27-associated, and CMV AU.The PCR test is an important adjunct.

Table 2 .
Demographics and clinical manifestations of all participants and the comparison between ocular hypertension (IOP>21) and non-ocular hypertension (IOP≦21) with p valuesThe ocular hypertension group demonstrated older age, more males, longer duration, more corneal edema, less iris PS and less HLA-B27 positivity.