Aims To investigate the risk of corneal ulcer in patients with atopic keratoconjunctivitis (AKC).
Methods The nationwide, population-based, retrospective, matched cohort study included 171 019 newly diagnosed patients with AKC who were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), code 372.05, and selected from the Taiwan National Health Insurance Research Database. The age-, sex- and potential comorbidities-matched control group included 171 019 patients with non-AKC selected from the Taiwan Longitudinal Health Insurance Database 2000. Patient information was collected between 1 January 2004 and 31 December 2011, and both groups of patients were tracked from the index date until December 2013. The incidence and risk of corneal ulcer (ICD-9-CM code 370.0 except for 370.07) was compared between the groups. A Cox proportional hazard regression analysis was performed to obtain the adjusted HR for corneal ulcer. The cumulative corneal ulcer incidence rate was calculated with the Kaplan-Meier analysis.
Results In total, 2018 patients with AKC and 1481 controls developed a corneal ulcer during the follow-up period. The incidence rate of corneal ulcer was 1.42 times (95% CI1.33 to 1.52; p<0.0001) higher in patients with AKC than in controls. After adjusting for potential confounders, including diabetes mellitus, chronic renal disease, topical steroid ophthalmic agent use, lid margin disease, keratoconjunctivitis sicca, ocular blunt trauma and post-corneal transplantation, patients with AKC were 1.26 times more likely to develop a corneal ulcer than controls (adjusted HR, 1.26; 95% CI 1.14 to 1.39; p<0.05).
Conclusions Patients with AKC had an increased risk of developing a corneal ulcer and should be advised of this risk.
- Ocular surface
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Atopic keratoconjunctivitis (AKC), the most severe form of allergic conjunctival disease, has been regarded as an ocular complication with atopic traits. The disease is a chronic, non-infectious inflammatory ocular surface condition and can affect patients with atopy at any point during the course of their disease. Patients with AKC often suffer from itching, pain, tearing, redness and blurred vision of the eyes.1 2 The characteristics of AKC include tear film dysfunction and instability, corneal scarring and neovascularisation, conjunctiva congestion and thickening, as well as eyelid oedema and thickening.2 3 The pathophysiology of AKC includes T helper (Th)1- and Th2-lymphocyte-derived cytokine-mediated immune mechanisms; eosinophils and other inflammatory cells associated with inflammation; and immunoglobulin E-mediated mast cell degranulation.2 4
Corneal ulcers, a leading cause of visual impairment and blindness worldwide, are caused by infection from pathogens, including bacteria, viruses and fungi.5–7 The most frequent clinical presentation of a corneal ulcer includes redness, photophobia, severe pain, pus formation, watering of the eyes and blurred visual acuity. Predisposing risk factors for corneal ulcers include those that in general compromise the normal ocular surface: contact lens wear, corneal surgery, ocular surface disease, eyelid abnormalities, etc.8–10 Finally, the use of steroid containing eye-drops is also a well-known risk factor in corneal ulcer development.
The ocular inflammatory process and tear film instability of patients with AKC is responsible for many ocular surface disorders including superficial punctate keratitis, macroerosion and a decreased ocular surface barrier function resulting in susceptibility to infectious ulcers.11 12 In addition, chronic eye rubbing is a common manifestation in patients with AKC and regarded as a risk factor for corneal superficial injury, leaving the eye vulnerable to opportunistic infections. Furthermore, topical corticosteroids and immunomodulatory eye-drops that are widely used in patients with AKC could contribute to corneal ulcers.13 14 Therefore, it is clinically relevant to examine whether AKC is a risk factor for corneal ulcers.
A few studies have discussed whether AKC is a contributing factor in corneal ulcers, but their results were limited to case reports and small case series.13 15–18 However, to the best of our knowledge, no large cohort studies have investigated whether AKC is a risk factor for the subsequent development of a corneal ulcer. Therefore, we have designed a nationwide, population-based cohort study to investigate the risk of developing a corneal ulcer following a diagnosis of AKC in Taiwan.
MATERIALS AND METHODS
The data for our study were obtained from the National Health Insurance Research Database (NHIRD), provided by the National Health Research Institute (NHRI) in Taiwan, which records each enrollee’s coded information on their patient demographics such as birthday, sex, residential area and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Regardless of whether the patient was hospitalised or under ambulatory care, the ICD-9-CM records diagnoses, procedures, prescription details and expenditure claims. Because no identifiable personal information was analysed using the public database, the requirements for ethical approval and informed consent were waived by the Institutional Review Board of the Chi-Mei Medical Centre, Tainan.
Selection of patients and variables
We recruited 171 019 newly diagnosed patients with AKC with the ICD-9-CM code 372.05 into our retrospective cohort study. Patient information was collected between 1 January 2004 to 31 December 2011. Patients with an unknown sex or missing demographic data were excluded. We also excluded patients diagnosed with a corneal ulcer prior to AKC. A corneal ulcer was defined as any condition diagnosed under the ICD-9-CM code 370.0, including 370.00 (corneal ulcer, unspecified), 370.01 (marginal corneal ulcer), 370.02 (ring corneal ulcer), 370.03 (central corneal ulcer), 370.04 (hypopyon ulcer), 370.05 (mycotic corneal ulcer) and 370.06 (perforated corneal ulcer), excluding 370.07 (Mooren’s ulcer). The same ICD-9 codes were used to identify patients with corneal ulcers in our previous studies.19 20 Furthermore, the corneal ulcers were subcategorised into normal flora related marginal corneal ulcers (370.01) and pathogen-related infectious corneal ulcers (370.00, 370.02–370.06) in the current study.
For each patient with AKC, one non-AKC control was randomly chosen from the Longitudinal Health Insurance Database 2000 (LHID 2000), a subset of the NHIRD. The NHRI used a systematic sampling method to construct the LHIRD 2000, which contains the overall claim data for 1 000 000 beneficiaries from the year 2000. The 171 019 non-AKC controls were matched with the patients with AKC by age (±30 days), sex, comorbidities including diabetes mellitus and chronic renal disease, as well as the index date. The index date was defined as the first day of AKC diagnosis. Controls were excluded if they were diagnosed with AKC or corneal ulcer before the index date. The database was released by Taiwan NHRI and applied by the public through formal application.21
To determine the incidence of corneal ulcer, each participant in both groups was tracked, and each participant’s demographic data were recorded from the index date until the end of 2013 or death, whichever was earlier. Additionally, data regarding risk factors such as comorbidities including diabetes mellitus19 (ICD-9-CM code 250), chronic renal diseases20 (ICD-9-CM codes 582–588 except unspecified renal sclerosis (code 587) and acute kidney failure (code 584)), the HIV22 (ICD-9-CM code 042 and V08), topical steroid ophthalmic agent use, lid margin disease (ICD-9-CM code 374.0 and 374.1), conjunctival changes (ICD-9-CM code 372.62 and 372.63, keratoconjunctivitis sicca (ICD-9-CM codes 710.2 and 370.33), ocular blunt trauma (ICD-9-CM codes 921.1, 921.2, 921.3, 921.9 and 918.1) and post-corneal transplantation (order codes 85212B, 85213B, 85215B, 85216B and 85217B)8–10 13 were collected. We only included these comorbidities if they appeared in three or more ambulatory care claims, or if the condition occurred in an inpatient setting within 1 year before the index date.
All statistical analyses were performed using SAS 9.4 for Windows (SAS Institute, Cary, NC, USA). The Pearson’s χ2 analysis was performed to calculate the baseline demographics and comorbidities between the AKC and control groups. The incidence of corneal ulcer was measured as the sum of patients with corneal ulcer detected during the follow-up period, divided by the total person-years (PY) for each group by age, sex and selected comorbidities. The incidence rate ratio (IRR), which compared the risk of developing corneal ulcers between the AKC and non-AKC control groups, was obtained with the Poisson regression analysis. We used the Cox proportional hazards regression analysis to calculate the difference in the adjusted HRs and 95% CIs for the risk of developing a corneal ulcer. The Kaplan-Meier method was used to plot the cumulative incidence rate curves and the log-rank test was used to analyse the differences. Statistical significance was defined as p<0.05.
From the beginning of 2004 to the end of 2011, after excluding ineligible subjects, 171 019 patients with AKC and 171 019 controls were recruited. Table 1 shows the baseline demographics and comorbidities of both the patients with AKC and the non-AKC controls. The average age was the same for both the patients with AKC and controls, 30.32 years (SD, 18.50 years). The number of participants <12 years of age at the onset of AKC was 34 958 (20.44%); 12–19 years, 25 470 (14.89%); 20–29 years, 33 397 (19.53%); 30–39 years, 28 620 (16.73%); and ≥40 years, 48 574 (28.40%). Of the 171 019 patients with AKC, 70 942 (41.48%) were men and 100 077 (58.52%) were women. Most patients with AKC resided in a metropolis city (119 482; 69.86%) compared to rural areas (36 978; 21.62%), and satellite cities (14 559; 8.51%), with a significant difference from the controls (p<0.0001). Regarding comorbidities, 1535 (0.90%) of the patients with AKC had diabetes mellitus and 27 (0.02%) had a chronic renal disease. In addition, patients with AKC exhibited a significantly higher prevalence of previously reported risk factors for corneal ulcer development, such as topical steroid ophthalmic agent use, lid margin disease, keratoconjunctivitis sicca, ocular blunt trauma and post-corneal transplantation, than the controls (p<0.0001). HIV and conjunctival changes, including localised and extensive adhesions and strands of conjunctiva, are risk factors for corneal ulcers. However, because patients with AKC and controls do not have these conditions, these two factors could not be evaluated. Of particular note, there was no significant difference in the distribution of corneal ulcer diagnoses among the 2018 corneal ulcer subjects in the AKC group (115 (5.70%) marginal corneal ulcers vs 1903 (94.30%) infectious corneal ulcers), and the 1481 corneal ulcer subjects in the control group (69 (4.66%) marginal corneal ulcers vs 1412 (95.34%) infectious corneal ulcers; p=0.1734).
Corneal ulcer incidence rates
During the follow-up period, there was a higher incidence rate of corneal ulcers in patients with AKC (209.03/100 000 PY) than in the age-matched controls (146.82/100 000 PY) leading to a significant difference in the IRR of corneal ulcers (1.42, 95% CI 1.33 to 1.52, p<0.0001; table 2) between the two groups. Additionally, significant differences were present in the IRRs of marginal corneal ulcers and infectious corneal ulcers (1.74, 95% CI 1.29 to 2.35, p=0.0003; 1.41, 95% CI 1.31 to 1.51, p<0.0001, respectively) between the patients with AKC and the control groups (table 2).
Patients with AKC aged 12–19 years exhibited the highest incidence of corneal ulcers (408.49/100 000 PY), followed by those aged 20–29 years (274.46/100 000 PY), ≥40 years (163.88/100 000 PY), 30–39 years (162.13/100 000 PY) and <12 years (104.13/100 000 PY). The IRR values were significantly higher for patients with AKC than for controls within the same age ranges: 12–19 years, 1.41 (95% CI 1.24 to 1.60; p<0.0001); 20–29 years, 1.36 (95% CI 1.20–1.55; p<0.0001); 30–39 years, 1.46 (95% CI 1.21 to 1.77; p<0.0001); and ≥40 years, 1.72 (95% CI 1.48 to 2.01; p<0.0001). However, there was no significant difference in the incidence rate of corneal ulcers, between patients with AKC aged <12 years and their equivalent controls (table 2).
The incidence rate of corneal ulcers was 163.97/100 000 PY for men with AKC and 108.29/100 000 PY for male controls (IRR =1.51; 95% CI 1.34 to 1.71; p<0.0001). A significant difference was also observed between women with AKC and female controls (IRR =1.37; 95% CI 1.27 to 1.49; p<0.0001; table 2). In addition, significant differences in the incidence rate for corneal ulcers were found between patients residing in a metropolis city (IRR =1.44; 95% CI 1.33 to 1.55; p<0.0001), satellite city (IRR =1.49; 95% CI 1.16 to 1.90; p=0.0017) and a rural area (IRR =1.42; 95% CI 1.20 to 1.69; p<0.0001), and their respective controls (table 2).
In the AKC group, the incidence rate of corneal ulcer was 242.69/100 000 PY in patients with diabetes mellitus and 1492.5/100 000 PY in patients with a chronic renal disease. The IRR for corneal ulcers in patients with AKC who had diabetes mellitus was 2.38 times higher than in controls (IRR=2.38; 95% CI 1.04 to 5.43; p=0.0398). However, the IRR for corneal ulcers associated with patients with AKC with a chronic renal disease could not be determined, because no patients with chronic renal disease developed a corneal ulcer in the control group (table 2). It is worth noting that the IRRs for corneal ulcers in the patients with AKC who had used topical steroid ophthalmic agents or suffered from lid margin disease, keratoconjunctivitis sicca, ocular blunt trauma or post-corneal transplantation did not indicate significantly greater risks than in the corresponding controls (table 2).
Table 3 provides the crude and adjusted HRs for corneal ulcers during the follow-up period. After adjusting for age, sex and the selected comorbidities, AKC remained an independent risk factor for corneal ulcers (adjusted HR, 1.26; 95% CI 1.14 to 1.39; p<0.05). In both the AKC and control groups, the following groups were at a higher risk of developing corneal ulcers compared to others: patients between the ages of 12 and 19 years (adjusted HR, 2.87; 95% CI 2.60 to 3.17; p<0.05); patients between the ages of 20 and 29 years (adjusted HR, 1.87; 95% CI 1.69 to 2.07; p<0.05); females (adjusted HR, 1.47; 95% CI 1.37 to 1.58; p<0.05); patients living in metropolitan cities (adjusted HR, 1.34; 95% CI 1.23 to 1.47; p<0.05); patients with chronic renal disease (adjusted HR, 5.65; 95% CI 1.41 to 22.69; p<0.05); patients who had used a topical steroid ophthalmic agent previously (adjusted HR, 1.16; 95% CI 1.05 to 1.28; p<0.05); patients with lid margin disease (adjusted HR, 1.73; 95% CI 1.13 to 2.67; p<0.05), keratoconjunctivitis sicca (adjusted HR, 2.60; 95% CI 1.71 to 3.97; p<0.05) or ocular blunt trauma (adjusted HR, 3.53; 95% CI 2.20 to 5.67; p<0.05); and patients who had undergone a corneal transplantation (adjusted HR, 33.53; 95% CI 20.47 to 54.93; p<0.05).
Kaplan-Meier analyses revealed higher cumulative incidence rates for corneal ulcers in the AKC group than in the control group, and the log-rank test findings were also significant (p<0.0001; figure 1).
To the best of our knowledge, after a thorough review of the relevant research, our study is the largest-scale population-based study to explore the relationship between AKC and subsequent corneal ulcer. We analysed 171 019 patients with AKC and 171 019 age-, sex- and comorbidities-matched controls and found that the incidence rate of corneal ulcer in patients with AKC was 1.42 times higher than that in controls, and the relative risk of developing a corneal ulcer in patients with AKC was increased 1.26 times in the full cohort after adjusting for age, sex, diabetes mellitus, chronic renal diseases, topical steroid ophthalmic agent use, lid margin disease, keratoconjunctivitis sicca, ocular blunt trauma and post-corneal transplantation.
In the current study, a corneal ulcer was defined as a condition diagnosed under the ICD-9-CM. However, the ICD-9-CM code 370.0 corresponds to many types of corneal ulcers rather than a single type of corneal ulcer. Thus, to exclude non-infectious corneal ulcers, we excluded the ICD-9-CM code 370.07, for Mooren’s ulcer or peripheral ulcerative keratitis, possibly related to an immune reaction. In addition, we have attempted to clarify the ICD-9-CM codes used to identify corneal ulcers in our study and subcategorised them into marginal corneal ulcers and pathogen-related infectious corneal ulcers. The ICD-9-CM code 370.01 relates to a marginal corneal ulcer possibly associated with keratitis, secondary to a normal skin flora such as Staphylococcus aureus. The remaining ICD-9-CM 370 codes imply infectious corneal ulcers secondary to a pathogen including 370.00 (corneal ulcer, unspecified), 370.02 (ring corneal ulcer), 370.03 (central corneal ulcer), 370.04 (hypopyon ulcer), 370.05 (mycotic corneal ulcer) and 370.06 (perforated corneal ulcer). We have shown the distribution of the marginal and infectious corneal ulcers between the AKC group and the control group in table 1, and our results show that AKC is a risk factor for both marginal and infectious corneal ulcers (table 2).
The association between AKC and corneal ulcer has been discussed by a few case reports.13 15–18 Zemba et al reported a case of a 14-year-old male patient with AKC with secondary S. aureus keratitis related to normal flora of the eyelid.18 Inada et al reported the first case of a patient with AKC with Kocuria koreensis keratitis, a part of the resident skin flora.16 Nivenivus et al conducted a case series to show that Candida albicans should be considered when managing keratitis in AKC.15 Nguyen et al first reported a case of microbial keratitis with corneal hydrops in a patient with AKC with keratoglobus.23
Ocular surface inflammation and tear film instability are important in the pathogenesis of a variety of corneal disorders including superficial punctate keratopathy, macroerosions and corneal neovascularisation.11 12 Eosinophils are a major inflammatory cell in the immunoglobulin E-mediated late-phase reaction and are found in the conjunctival tissues and tears of patients with AKC. Eosinophils are not found in the conjunctival epithelium of normal healthy tissue. Eosinophil cationic protein levels significantly correlated with the number of eosinophils in the tears of patients with AKC, as well as the allergic signs and symptoms on the ocular surface. The tear eosinophil cationic protein levels accurately reflect the clinical status of the ocular surface disorder of patients with AKC.24–26 Eosinophils play an important role in the pathogenesis of ocular surface disorders in patients with AKC.24–26 In addition, Dogru et al reported that ocular surface disorders in patients with AKC was characterised by tear film instability, goblet cell loss and a subsequent decrease in ocular mucin.11 12 An ocular surface disorder in a patient with AKC can result in a decreased ocular surface barrier leaving patients with AKC vulnerable to infections, even from opportunistic pathogens that make up the normal flora of the eyelid.16 27
Eye rubbing is a usual physiological response due to a sense of itching, fatigue and discomfort of the eyes in patients with AKC.28 Vigorous and prolonged eye rubbing may result in an ocular surface injury in patients with AKC, making them susceptible to a corneal ulcer. Although topical corticosteroids and immunomodulatory eye-drops have been reported to be effective in the treatment of AKC,14 29 these eye-drops also increase the risk of a corneal ulcer developing in patients with AKC.13–15 Finally, eye rubbing in AKC is reported to be associated with keratoconus.30–32
Contact lens use is one of the major risk factors for the development of a corneal ulcer.33 34 There is a significant association between keratoconus and AKC.21 A large number of keratoconus patients go on to develop the need for rigid gas-permeable and scleral contact lenses, collagen crosslinking and other corneal surgical procedures, all of which increases the risk of corneal ulcer development. One of the limitations of the study is that contact lens use and ectatic disorders may be confounding factors that were not controlled for.
The incidence rate of corneal ulcers was significantly higher in patients with AKC aged 12−19 years and 20−29 years (table 2). Moreover, young patients with AKC remained significantly at risk of developing a corneal ulcer after accounting for sex and comorbidities (table 3). To the best of our knowledge, no previous study has reported the effect of age on the development of corneal ulcers in patients with AKC. The symptoms of AKC typically become apparent during puberty and early adulthood, and can persist into the fourth and fifth decades of life.1 3 Apart from the adolescent- or early adult-onset and -prominent condition of AKC, the lifestyle of adolescents and early adults, including contact lens usage for cosmetic purposes, inappropriate contact lens hygiene and increased outside activities that can lead to corneal foreign body exposure or abrasion, may explain why being between the ages of 12–29 years was a major risk factor for corneal ulcers in patients with AKC. Although contact lens wear is a well-known risk factor for developing a corneal ulcer at a young age,33 34 the effect of this confounder could not be evaluated due to a lack of data on contact lens wear in the NHIRD databank.
We found that the incidence rate of corneal ulcers was higher in women with AKC (table 2). The female sex remained a significant risk factor in the development of a corneal ulcer after accounting for age and comorbidities in both groups (table 3). We propose that more exposure to irrigated materials, such as cosmetic material, artificial cilia and contact lenses to the ocular surface in female patients with AKC, was an aggravating factor that led to eye rubbing and subsequent corneal ulcer formation. This finding, possibly be due to fingernail injury of the cornea, is more common in women. This may be explained by the increased risk of long or artificial nails and the higher prevalence of contact lens usage among women. Our findings were consistent with several other large studies, including the Portsmouth Corneal Ulcer Study and more recently a 15-year retrospective study from Saint Louis University by Hsu et al. These studies found that women had an increased risk of corneal ulcers, which correlated with increased contact lens use.9 10
The incidence rates of corneal ulcers were significantly higher in patients with AKC regardless of whether they lived in a metropolis city, satellite city or a rural area, compared with their respective controls (table 2). Metropolis city residents remained significantly at risk of developing a corneal ulcer after accounting for age, sex and comorbidities in the total cohort (table 3). This finding contradicts the general agreement that corneal ulcers occur more frequently in patients who come from a rural background, than in patients from urban settings. We believe the inconsistency may be as a result of the vague rural–urban divide of residential environments or occupation selection in Taiwan. Furthermore, the higher incidence rate of corneal ulcer diagnoses in metropolis areas may also reflect the availability of low-cost medical care, easy access to ophthalmologists and enhanced access to corneal specialists for diagnosis and management of corneal ulcers, compared with other residential city statuses.
Several studies have reported that there are comorbidities associated with corneal ulcers, such as diabetes mellitus,19 chronic renal disease20 and HIV.22 In this cohort study, we evaluated these comorbidities in patients with AKC and found that the association with HIV could not be determined because of the rare incidence of this comorbidity. In our study, we found that patients with AKC who had diabetes mellitus had a significantly higher IRR for corneal ulcers than in controls (table 2), and chronic renal disease was a significant risk factor for the development of a corneal ulcer in the total cohort (table 3), which is consistent with previous studies.19 20 This consistency could be because of the immunocompromising characteristic of both diabetes mellitus and chronic renal disease in patients, which leave them vulnerable to opportunistic infections.
Use of topical steroid ophthalmic agents as well as characteristics of the eyelid, conjunctiva and tear film in patients with AKC could all be associations that should be considered as risk factors for corneal ulcer development.8–10 13 There are several lid margin diseases commonly seen in patients with AKC including blepharitis, meibomianitis, floppy eyelid disease, trichiasis and ectropion/entropion.2 35 All of these structural conditions are major risk factors for corneal ulcer development.8–10 The conjunctival changes related to AKC, such as subepithelial fibrosis, fornix foreshortening, conjunctival squamous metaplasia and loss of goblet cells, may play a role in corneal ulcer risk.2 35 36 Tear film dysfunction in patients with AKC related to meibomian gland obstruction, lacrimal duct dysfunction, goblet cell loss and tear film instability may contribute to the development of corneal ulcers.2 37 In the current study, we evaluated these confounders and found that use of topical steroid ophthalmic agents, lid margin disease, keratoconjunctivitis sicca, ocular blunt trauma and post-corneal transplantation were independent risk factors for corneal ulcer development in the total cohort (table 3); however, none of these factors led to a significantly higher incidence rate of corneal ulcers between the patients with AKC and controls (table 2).
There are several strengths to our study. First, our population-based cohort study has great statistical power and precision risk appraisal, because there are large numbers of participants, including 171 019 patients with AKC and 171 019 matched controls. In addition, because we control for diabetes mellitus, chronic renal diseases, topical steroid ophthalmic agents, lid margin disease, keratoconjunctivitis sicca, ocular blunt trauma and post-corneal transplantation in our cohort study with longitudinal data of up to 10 years, the potential confounding bias is reduced.
This study also had limitations. Because the medical histories of each participant in the study could only be tracked back to 1996, it could not be confirmed whether the controls had a history of AKC before January 1996. Additionally, HIV infection, an important systemic disorder, could not be assessed as a confounding factor due to its rare incidence. Furthermore, several important confounding factors including occupation, contact lens use, mild ocular trauma, keratoconus, history of ocular refractive surgery, and mud or plant exposure were not evaluated. Finally, because the diagnosis of AKC, corneal ulcer and other comorbidities relied on ICD-9-codes, incorrect classification was a possibility.
In summary, this study showed that the risk of developing a corneal ulcer was significantly higher in patients with AKC. AKC remained an independent risk factor after adjusting for other confounders in the cohort, specifically female patients and those aged 12−29 years. These results suggest that clinicians should inform patients with AKC about the risk of corneal ulcers.
Taiwan Bureau of National Health Insurance and Department of Health provided the National Health Insurance Research Database. The conclusions and interpretations incorporated here do not represent those of the Bureau of National Health Insurance, Department of Health or National Health Research Institutes.
Contributors All authors conceived the study. R-LJ, S-FW, S-HT and Y-SC conducted the study. R-LJ, S-FW and Y-SC analysed the results and wrote the article. J-JW provided materials. All authors reviewed the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information.