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. 2021 Sep 7;16(9):e0256800. doi: 10.1371/journal.pone.0256800

Interstitial cystitis/bladder pain syndrome patient is associated with subsequent increased risks of outpatient visits and hospitalizations: A population-based study

Kun-Lin Hsieh 1,2, Hung-Yen Chin 3, Tsia-Shu Lo 4,5, Cheng-Yu Long 6,7, Chung-Han Ho 8, Steven Kuan-Hua Huang 1, Yao-Chi Chuang 9, Ming-Ping Wu 10,11,*
Editor: Peter FWM Rosier12
PMCID: PMC8423233  PMID: 34492065

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is not only a chronic urinary bladder pain syndrome but is also associated with multifactorial etiology. Our study aimed to test the hypothesis that IC/BPS is associated with subsequent increased risks of outpatient visits and hospitalizations. Using nationwide database, the diagnoses were based on the International Classification Codes (ICD-9-CM) (595.1) of at least three outpatient services during 2002–2008, (n = 27,990) and cystoscopic finding Hunner type and/or glomerulation with pre-audit criteria. All recruited cases monitored for subsequent outpatient visits and hospitalizations for 2 years, including all-cause and specialty-specific departments, were classified according to medical specialty and age group (<40, 40–60, ≥60 years of age). IC/BPS patients have more overall outpatient department (OPD) visits and an overall adjusted incidence rate ratio (IRR) of 1.64. As for specialty, IRRs were higher in psychiatry (2.75), Chinese medicine (2.01), and emergency medicine (2.00), besides urology and gynecology. The IRRs decreased as age advanced (2.01, 1.71, and 1.44, respectively), except for gynecology (2.42, 2.52, and 2.81). A similar phenomenon happens in hospitalization with IRR of 1.69. Due to claim data characteristics, whether ulcer type IC/BPS findings can be deductive to non-ulcer type remains inclusive. Current results indicate the impacts of healthcare burden in broad spectrum about IC/PBS patients. IC/BPS has been suggested to be associated with lower threshold of healthcare visits and some coexisting disease and is comprised of systemic dysregulation, and is beyond the scope of local bladder-urethra disease. Adequate recognition of associated or comorbid factors and possible recommendation or referral for IC/BPS patients can help provide better healthcare quality.

Introduction

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain syndrome defined by an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder in conjunction with lower urinary tract symptoms (LUTS), including urgency, frequency, and nocturia, of more than 6 weeks’ duration [1]. IC/BPS is associated with a wide variety of clinical phenotypes with diverse etiologies [2]. Some candidate etiologies of IC/BPS have been studied and reported, including inflammatory processes or infection, autoimmunity, mast cell activation, local neuronal dysfunction or mucosal abnormalities, and cross-organ sensitization between visceral organs [3]. However, the real etiology is still inconclusive. IC/BPS was recognized as a local disease before, and treatment was mainly focused on focal symptomatic management. Thereafter, multifactor effects are expounded by most studies.

In addition to the bladder/urethra, IC/BPS is often associated with multiple organ dysfunction. Current hypothesis suggests that IC/BPS is a systemic disorder or a member of a family of hypersensitivity disorders that affects the bladder and other somatic/visceral organs [4]. Keller et al. reported that subjects with IC/BPS had an increased prevalence of multiple comorbidities, such as cardiovascular, neurologic, rheumatological, pulmonary, endocrine, renal gastrointestinal, viral/infectious, hematological, mental illness, oncological, and other diseases [5]. Watkins et al. found that probable current depression and panic attack rates are high, associated with IC/BPS patients with poor quality of life, in a community-based sample [6]. McKernan et al. indicated severe psychological impairment among IC/BPS patients, including anxiety and depression, in a systematic review [7]. Therefore, IC/BPS is possibly associated with subsequent increased risk of medical service, including OPD visits and hospitalizations. Furthermore, higher risk of medical service will lead to larger economic burden to the healthcare system, even though the prevalence of IC/BPS is not so high in the general population [8].

This study hypothesizes that IC/BPS is associated with subsequent increased risk of OPD visits and hospitalizations. Based on a nationwide population-based database among National Health Insurance (NHI) enrollees in Taiwan, this study examines whether IC/BPS is a risk factor of other medical or surgical conditions and the age effect on the healthcare impacts.

Materials and methods

Data source

This study was based on data from National Health Insurance Research Database (NHIRD) in Taiwan. The detailed information of NHIRD was described in our previous report [9]. Briefly, the NHI system was implemented from 1995 and has covered almost all population (98%) in Taiwan by the compulsory and universal health insurance. The diagnostic codes used in the NHIRD are based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM) codes. Except for the ICD-9 CM, the NHIRD provides information of encrypted patient identification numbers, sex, date of birth, dates of OPD visits, inpatient expenditures by hospitalizations, etc. The study was conducted according to the regulations of the NHIRD and obtained exemption from approval by the Institutional Review Board of the Chi Mei Medical Center (IRB10310-E01).

Assembly of study participants

Individuals included in the study group (IC/BPS group, n = 27,900) were identified as those who had at least three outpatient service claims during 2002–2008 with the ICD-9 CM code 595.1. To restrict our study group in more well-defined subjects, only IC/BPS patients who received bladder instillation of sodium hyaluronate were recruited. According to Taiwan’s NHI regulation, the prescription of sodium hyaluronate (Cystistat; Bladder Healthy UK, Birmingham, UK) requires strict pre-audit criteria. Its provision included the presence of glomerulation or Hunner’s lesions under cystoscopy after hydrodistention test, voiding diary, negative urine cytology, and urine analysis. The same methods for the enrollment of IC/BPS patients have already been applied in a previous study of ours and other published studies [9,10].

The control group (non-IC/BPS group matched one-to-one to each IC/BPS patient, n = 27,990) was composed of patients not diagnosed with IC/BPS and randomly selected from the dataset. They were matched by sex, age, index date, and comorbidities, including hypertension (HTN; ICD-9-CM: 401–405), diabetes mellitus (DM; ICD-9-CM: 250), hyperlipidemia (ICD-9-CM: 272), and coronary artery disease (CAD; ICD-9-CM: 410–414). The index date for participants with IC/BPS was the date of their first registration. After the index date, patients would receive survey, assessment, and treatment of sodium hyaluronate instillation. Thus, patients who had outpatient visits with IC/BPS code at least three times after index date into study group have been selected.

All recruited cases of IC/BPS and the non-IC/BPS control group were monitored for subsequent OPD visits and hospitalizations for 2 years after the index date or until the expired day in the follow-up period. Subsequent OPD visits and hospitalizations of healthcare services, including all-cause and specialty-specific OPD visits and hospitalizations, were recorded. The medical services were classified according to medical specialty and age group (<40, 40–60, ≥60 years of age).

Measures and statistical analysis

Demographical information of the patients was obtained from the NHI enrollees, including age, gender, insurance amount, and region. Age was grouped into the following three categories: 18–39, 40–59, and 60 or more years of age. The insurance amounts of the enrollees were classified as follows: less than US$640 (NTD20,000), US$640–US$1280 (NTD 20,000–39,999), and more than US$1,281 (NTD 40,000). The geographic distributions were classified into northern, central, southern, and eastern.

McNemar’s test for paired categorical variables was conducted to compare differences between the IC/BPS and non-IC/BPS groups regarding sociodemographic characteristics and comorbidities. The incidence rate (IR) was calculated as the times of medical services during the follow-up period, divided by the total person years for each group. The subsequent risk of OPD visits and hospitalization were estimated using Poisson regression for the incidence rate ratio (IRR). Poisson regression model was used to estimate the adjusted IRR between the IC/BPS and non-IC/BPS groups using the SAS procedure, after considering the possible overdispersion issue and potential confounders, including age, gender, income, area, HTN, DM, hyperlipidemia, and CAD. Some other potential confounders were not available due to claim data characteristics, including education, marital status, alcohol use, tobacco use, obesity, etc. Subspecialties were categorized under internal medicine or surgery, unless otherwise specified (e.g., neurology and neurosurgery). All analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC, USA). For the descriptive statistical analysis, a p-value of less than 0.05 was considered significant, and a more precise p-value of 0.0025 (0.05/20) with Bonferroni correction (significance level/number of specialty departments) was considered significant because of the multiple hypothesis tests performed.

Results

A total of 27,900 patients were included into each IC/BPS and control group. The participants were matched for age, gender, and underlying disease (DM, HTN, and CAD) in the two groups. The demographic information for IC/BPS and non-IC/BPS individuals is shown in Table 1.

Table 1. Demographic information about interstitial cystitis/bladder pain syndrome (IC/PBS) patients and non-IC/PBS controls.

IC/BPS (N = 27,990) Non-IC/BPS (N = 27,990) p-value*
Age
    <40 8,633 (30.84) 8,633 (30.84) >0.9999
    40–60 11,689 (41.76) 11,689 (41.76)
    >60 7,668 (27.40) 7,668 (27.40)
Gender Female 22,042 (78.75) 22,042 (78.75) >0.9999
Male 5,948 (21.25) 5,948 (21.25)
Area Northern 15,572 (55.63) 14,321 (51.16) <0.0001
Central 4,370 (15.61) 4,932 (17.62)
Southern 7,391 (26.41) 8,116 (29.00)
Eastern 657 (2.35) 621 (2.22)
Income <20,000 13,602 (48.60) 14,263 (50.96) <0.0001
20,000~40,000 10,906 (38.96) 10,249 (36.62)
>40,000 3,482 (12.44) 3,478 (12.43)
Comorbidity
    HTN Yes 5,492 (19.62) 5,492 (19.62) 1.0000
    No 22,498 (80.38) 22,498 (80.38)
    DM Yes 2,379 (8.50) 2,379 (8.50) 1.0000
    No 25,611 (91.50) 25,611 (91.50)
    Hyperlipidemia Yes 2,146 (7.67) 2,146 (7.67) 1.0000
    No 25,844 (92.33) 25,844 (92.33)
    CAD Yes 1,953 (6.98) 1,953 (6.98) 1.0000
    No 26,037 (93.02) 26,037 (93.02)
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*p-value is from McNemar’s test for matched pairs.

OPD visits and hospitalizations of the IC/BPS and control groups were identified. The units of the visits or hospitalizations are expressed as number per one person-year. As expected, patients with IC/BPS had higher OPD visits in gynecology (3.57 for the IC group vs. 1.42 for the control group) (number per one person-year) and urology (1.24 vs. 0.19), with an adjusted IRR of 2.51 (95% confidence interval [CI], 2.43–2.60) and 6.68 (95% CI, 6.22–7.17), respectively. Gender difference was observed in urology visits among IC/BPS patients with an IRR of 1.07 (females) and 2.33 (males), and the adjusted IRR (females to males) was 0.42 (95% CI, 0.40–0.45). The total OPD visit rate (except for gynecology and urology) (number per one person-year) for the IC/BPS and non-IC/BPS groups was 27.74 and 16.96, respectively. After adjusting for age, gender, HTN, DM, hyperlipidemia, and CAD, the adjusted IRR was 1.64 (95% CI, 1.62–1.66). In addition to the IRRs for gynecology and urology, those for other departments were significantly higher as well as in psychiatry (2.75; 95% CI, 2.50–3.01), Chinese medicine (2.01; 95% CI, 1.94–2.08), emergency room (2.00; 95% CI, 1.89–2.11), and others. All p-values were <0.001. Data are shown in detail in Table 2.

Table 2. Incidence rate ratio (IRR) of outpatient visits between IC/BPS and non-IC/BPS individuals.

IC/BPS (N = 27990) Non-IC/BPS (N = 27990) Unadjusted Adjusted
Department Visits Rate* Visits Rate* IRR** (95% CI) p-value IRR***(95% CI) p-value
Gynecology# 156665 3.57 62354 1.42 2.51 (2.42–2.59) <0.01 2.51 (2.43–2.60) <0.01
Urology 69099 1.24 10370 0.19 6.65 (6.14–7.20) <0.01 6.68 (6.22–7.17) <0.01
Internal Medicine 349446 6.27 225426 4.06 1.55 (1.51–1.59) <0.01 1.55 (1.51–1.58) <0.01
GP 130204 2.34 85330 1.54 1.52 (1.45–1.60) <0.01 1.53 (1.46–1.60) <0.01
Chinese Medicine 205928 3.70 103709 1.87 1.98 (1.91–2.05) <0.01 2.01 (1.94–2.08) <0.01
Family Medicine 202042 3.63 138134 2.49 1.46 (1.41–1.51) <0.01 1.46 (1.41–1.51) <0.01
Ophthalmology 84669 1.52 53206 0.96 1.59 (1.53–1.65) <0.01 1.59 (1.54–1.64) <0.01
ENT 105845 1.90 57501 1.03 1.84 (1.77–1.90) <0.01 1.83 (1.76–1.90) <0.01
Surgery 57563 1.03 33353 0.60 1.72 (1.63–1.82) <0.01 1.73 (1.65–1.81) <0.01
Psychiatry 42312 0.76 10370 0.19 2.70 (2.46–2.97) <0.01 2.75 (2.50–3.01) <0.01
ER 18068 0.32 8918 0.16 2.02 (1.90–2.15) <0.01 2.00 (1.89–2.11) <0.01
Others 348780 6.26 220986 3.98 1.57 (1.54–1.61) <0.01 1.58 (1.55–1.61) <0.01
Total 1544857 27.74 942189 16.96 1.64 (1.61–1.66) <0.01 1.64 (1.62–1.66) <0.01
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*per one person-year. The total-person years were 55697.9 in the IC/BPS group (female: 43935.1) and 55563.5 in the non-IC/BPS group (female: 43810.5).

** IRR: Incidence rate ratio of the IC/BPS group vs. the non-IC/BPS group

***adjusted by age, gender, income, area, hypertension(HTN), diabetes mellitus (DM), hyperlipidemia, and coronary artery disease (CAD).

#only women were included in gynecology. GP: General practitioner; ENT: Ear, nose and throat; ER: Emergency room.

Among the three age groups in both the IC/BPS and non-IC/BPS groups, the rate of OPD visits increased with advanced age in urology. The IRRs of OPD visits in urology were the highest in the younger (less than 40 years) group (18.20; 95% CI, 14.8–22.3), followed by the middle-aged (40–60 years) group (8.04; 95% CI, 7.03–9.20), and the older (over 60 years of age) group (4.42; 95% CI, 4.00–4.85). The increasing trend was also found for other departments, except gynecology. In the gynecology group, the highest IRR was found in the older group (2.81; 95% CI, 2.55–3.10), and the lowest in the younger group (2.42; 95% CI, 2.29–2.55). The detailed data are shown in Table 3.

Table 3. Incidence rate ratio (IRR) of outpatient visits between IC/BPS and non-IC/BPS individuals categorized by 3 age groups.

Grouping Age < 40 40≤Age<60 Age≥60
IC/BPS (N = 8633) non-IC/BPS (N = 8633) Adjusted IRR** (95% CI) IC/BPS (N = 11689) Non-IC/BPS (N = 11689) Adjusted IRR** (95% CI) IC/BPS (N = 7668) Non-IC/BPS (N = 7668) Adjusted IRR** (95% CI)
Department Visits Rate* Visits Rate* Visits Rate* Visits Rate* Visits Rate* Visits Rate*
Gynecology# 67981 5.14 27981 2.12 2.42† (2.29–2.55) 70189 3.60 27860 1.43 2.52† (2.40–2.64) 18495 1.65 6513 0.59 2.81† (2.55–3.10)
Urology 15522 0.90 860 0.05 18.20† (14.8–22.3) 25459 1.09 3181 0.14 8.04† (7.03–9.20) 28118 1.86 6329 0.42 4.42† (4.00–4.89)
Internal Medicine 45176 2.62 20225 1.17 2.26† (2.12–2.40) 132354 5.67 79718 3.42 1.67† (1.61–1.73) 171916 11.38 125483 8.37 1.36† (1.31–1.40)
GP 24554 1.42 12788 0.74 1.91† (1.76–2.08) 51335 2.20 32897 1.41 1.57† (1.47–1.68) 54315 3.59 125483 8.37 1.37† (1.26–1.48)
Chinese Medicine 67198 3.89 30507 1.77 2.21† (2.07–2.35) 96337 4.13 47802 2.05 2.05† (1.95–2.16) 42393 2.81 39645 2.64 1.68† (1.55–1.82)
Family Medicine 33304 1.93 16904 0.98 1.97† (1.83–2.13) 77219 3.31 53828 2.31 1.44† (1.37–1.52) 91519 6.06 67402 4.49 1.35† (1.28–1.42)
Ophthalmo-logy 12657 0.73 6647 0.39 1.92† (1.79–2.06) 28126 1.21 15624 0.67 1.81† (1.71–1.93) 43886 2.90 30935 2.06 1.41† (1.34–1.48)
ENT 35175 2.04 18726 1.08 1.88† (1.77–1.99) 48972 2.10 24687 1.06 1.97† (1.86–2.08) 21698 1.44 14088 0.94 1.52† (1.39–1.66)
Surgery 10454 0.61 5238 0.30 2.00† (1.82–2.19) 24049 1.03 13558 0.58 1.78† (1.66–1.91) 23060 1.53 14557 0.97 1.58† (1.44–1.73)
Psychiatry 8663 0.50 3551 0.21 3.62† (3.00–4.37) 13866 0.59 6999 0.30 2.82† (2.45–3.25) 10534 0.70 5076 0.34 2.07† (1.77–2.42)
ER 6059 0.35 2062 0.12 2.91† (2.59–3.26) 5468 0.23 2792 0.12 1.91† (1.77–2.06) 6541 0.43 4064 0.27 1.58† (1.43–1.74)
Others 79055 4.58 46078 2.67 1.72† (1.66–1.79) 135756 5.82 86647 3.72 1.57† (1.52–1.62) 133969 8.87 88261 5.89 1.51† 1.44–1.57)
Total 326309 18.91 162726 9.43 2.01† (1.95–2.07) 618717 26.52 364552 15.64 1.71† (1.67–1.75) 599831 39.70 414911 27.67 1.44† (1.40–1.47)
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*per one person-year. The total person-years for the IC/BPS vs. the non-IC/BPS group were as follows: Age<40 group 17256.5 vs. 17260.7; 40≤age<60 group 23332.7 vs. 23307.2; age≥60 group 15108.8 vs. 14995.7.

**Adjusted IRR: Incidence rate ratio, reference group: Non-IC/BPS, adjusted by age, gender, income, area, HTN, DM, hyperlipidemia and CAD.

#only women were included in gynecology. GP: General practitioner; ENT: Ear, nose, and throat; ER: Emergency room

†p < 0.05. The trend test of each pairwise contrast groups was all p<0.05.

As for hospitalization, rates were higher in gynecology (45.39 in the IC/BPS group vs. 21.30 in the non-IC/BPS group) (number per 1000 person-year) and urology (34.22 vs. 5.80), with an adjusted IRR of 2.14 (95% CI, 1.83–2.49) and 5.95 (95% CI, 5.01–7.08), respectively. Gender difference was observed in urology hospitalization among IC/BPS patients with an IRR of 23.85 (females) and 72.94 (males), and the adjusted IRR (females to males) was 0.34 (95% CI, 0.29–0.40). The total hospitalization rates (except for gynecology and urology) for the IC/BPS and non-IC/BPS groups were 249.37 vs. 148.66 (number per 1000 person years), with an adjusted IRR of 1.69 (95% CI, 1.58–1.80). The adjusted IRRs were also significantly higher in psychiatry (2.66; 95% CI, 1.65–4.29), colorectal surgery (1.90; 95% CI, 1.32–2.73), internal medicine (1.77; 95% CI, 1.63–1.91), neurosurgery (1.68; 95% CI, 1.39–2.04), and others. The details are listed in Table 4.

Table 4. Incidence rate ratio of hospitalizations between IC/BPS and non-IC/BPS individuals.

IC/BPS (N = 27990) Non-IC/BPS (N = 27990) Unadjusted Adjusted
Department No. Rate* No. Rate* IRR** (95% CI) p-value IRR*** (95% CI) p-value
Gynecology# 1994 45.39 933 21.30 2.13 (1.86–2.45) <0.01 2.14 (1.83–2.49) <0.01
Urology 1906 34.22 322 5.80 5.91 (4.93–7.08) <0.01 5.95 (5.01–7.08) <0.01
Internal Medicine 7564 135.80 4291 77.23 1.76 (1.61–1.92) <0.01 1.77 (1.63–1.91) <0.01
Surgery 1758 31.56 1146 20.63 1.53 (1.34–1.74) <0.01 1.54 (1.35–1.76) <0.01
Colorectal 266 4.78 143 2.57 1.86 (1.23–2.79) <0.01 1.90 (1.32–2.73) <0.01
Cardiovascular 88 1.58 83 1.49 1.06 (0.73–1.54) 0.77 1.05 (0.73–1.50) 0.80
Thoracic 92 1.65 56 1.01 1.64 (0.85–3.18) 0.14 1.73 (0.96–3.10) 0.07
Gastrointestinal 66 1.18 51 0.92 1.29 (0.82–2.03) 0.27 1.36 (0.87–2.11) 0.18
Other surgeries 1246 22.37 813 14.63 1.53 (1.32–1.78) <0.01 1.53(1.32–1.78) <0.01
Psychiatry 1107 19.88 433 7.79 2.55 (1.48–4.39) <0.01 2.66 (1.65–4.29) <0.01
Orthopedics 1191 21.38 929 16.72 1.28 (1.15–1.42) <0.01 1.28 (1.15–1.43) <0.01
Neurology 607 10.90 399 7.18 1.52 (1.28–1.80) <0.01 1.53 (1.31–1.78) <0.01
Neurosurgery 469 8.42 281 5.06 1.67 (1.35–2.05) <0.01 1.68 (1.39–2.04) <0.01
Others 1160 20.83 781 14.06 1.48 (1.30–1.69) <0.01 1.48 (1.30–1.69) <0.01
Total 13856 249.37 8260 148.66 1.67 (1.56–1.79) <0.01 1.69 (1.58–1.80) <0.01
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*per 1,000 person-year; The total person years were as follows: 55697.92 in the IC group, 55563.53 in the non-IC group.

**IRR: Incidence rate ratio of the IC group vs. non-IC group.

***adjusted by age, gender, income, area, HTN, DM, hyperlipidemia, and CAD. #only women were included in gynecology.

The IRR of hospitalizations between the IC/BPS and non-IC/BPS groups was also grouped into three categories by age (Table 5). The finding is similar to OPD visits. Significant higher IRR in younger age comparing to older age subgroup in urology department (IRR: 11.33 v.s. 5.55 and 5.38, p-value of age groups was p < 0.0001). This result is similar in most departments, including psychiatry, orthopedics, neurology, and neurosurgery. The IRR of hospitalization in gynecology is higher IRR in the oldest group (less than 40 years: 1.45 v.s. 40 to 60 years: 2.29 v.s. older than 60 years; 5.70, p-value of age group was p < 0.0001).

Table 5. Incidence rate ratio of hospitalizations between IC/BPS and non-IC/BPS individuals by three age groups.

Grouping Age < 40 40≤Age<60 Age≥60
IC/BPS (N = 8633) Non-IC/BPS (N = 8633) Adjusted IRR** (95% CI) IC/BPS (N = 11689) Non-IC/BPS (N = 11689) Adjusted IRR** (95% CI) IC/BPS (N = 7668) Non-IC/BPS (N = 7668) Adjusted IRR** (95% CI)
Department Visits Rate* Visits Rate* Visits Rate* Visits Rate* Visits Rate* Visits Rate*
Gynecology# 909 68.74 629 47.56 1.45* (1.29–1.63) 768 39.34 249 12.77 2.29* (1.61–3.25) 317 28.33 55 4.96 5.70* (2.66–12.22)
Urology 312 18.08 28 1.62 11.33* (6.84–18.78) 681 29.19 123 5.28 5.55* (4.17–7.39) 913 60.43 171 11.40 5.38* (4.20–6.90)
Internal medicine 627 36.33 262 15.18 2.43* (1.83–3.23) 1622 69.52 1000 42.91 1.69* (1.42–2.00) 5315 351.78 3029 201.99 1.73* (1.56–1.92)
Surgery 291 16.86 181 10.49 1.61* (1.19–2.19) 701 30.04 433 18.58 1.67* (1.34–2.06) 766 50.70 532 35.48 1.42* (1.18–1.72)
Psychiatry 525 30.42 161 9.33 3.50* (1.83–6.72) 428 18.34 187 8.02 2.54 (1.33–4.85) 154 10.19 85 5.67 1.79 (0.59–5.47)
Orthopedics 155 8.98 102 5.91 1.54 (1.14–2.08) 365 15.64 278 11.93 1.35* (1.12–1.62) 671 44.41 549 36.61 1.21* (1.05–1.39)
Neurology 56 3.25 17 0.98 3.39* (1.82–6.31) 124 5.31 70 3.00 1.85* (1.30–2.64) 427 28.26 312 20.81 1.36* (1.12–1.64)
Neurosurgery 73 4.23 27 1.56 2.73* (1.61–4.64) 136 5.83 88 3.78 1.58* (1.13–2.21) 260 17.21 166 11.07 1.56* (1.19–2.05)
Other division 320 18.54 180 10.43 1.78* (1.40–2.26) 370 15.86 256 10.98 1.44* (1.14–1.82) 470 31.11 345 23.01 1.34* (1.09–1.66)
Total 2047 118.62 930 53.88 2.25* (1.88–2.68) 3746 160.55 2312 99.20 1.68* (1.48–1.91) 8063 533.66 5018 334.63 1.59* (1.47–1.72)
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*per 1000 person-year. The total person-years for the IC/BPS group vs. the non-IC/BPS group were as follows: Age<40 group 17256.46 vs. 17260.65; 40≤age<60 group 23332.71 vs. 23307.17; age≥60 group, 15108.75 vs. 14995.72

#only women were included in gynecology. The trend test of each pairwise contrast groups was all p<0.05.

Discussion

This population‐based matched‐cohort study using the nationwide insurance database indicated that IC/BPS is associated with subsequent increased risk of outpatient visits and hospitalizations. The risks increase not only in the urology and gynecology departments but also in all other clinical departments. Gender difference was observed in urology OPD visits and hospitalizations. The study also showed that males had higher risk compared to females in IC/BPS group. The age effects for IRRs for OPD visits and hospitalizations decreased as age advanced in all departments, except in the gynecology department. Therefore, the impact of IC/BPS on healthcare services involving broader clinical practice and even public policy can be better understood.

Recently, IC/BPS becomes an interesting topic because of not only its large influence on clinical practice but also its economic burden. Chung et al. reported that IC/BPS patients (350 patients) have significantly higher healthcare-related costs (about 1.5-fold) than 1,750 age-matched controls [11]. Payne et al. reported a twofold increase of hospital OPD visits and a threefold increase in the rate of physician office visits related to IC/BPS between 1992 and 2001 from healthcare system in the United States [8]. The annual costs for IC/BPS increased 1.5-fold. Therefore, although IC/BPS accounts for a small percent of healthcare visits, its economic burden is substantial worldwide. Moreover, the true burden of IC/BPS on the healthcare system is probably even higher due to underdiagnosis. The prevalence of IC/BPS is variable to different definitions [12]. IC/BPS is frequently underdiagnosed due to its wide spectrum of symptoms, and these symptoms are easy to be mistaken with other differential diagnosis, like urinary tract infection, overactive bladder, endometriosis, or prostate-related pain [13]. Our study and other reports may remind physicians to pay attention to patients with IC/BPS in a broader view, in medical, surgical, and mental illness. Adequate recognition of associated or comorbid and possible recommendation or referral for IC/BPS patients can provide not only better healthcare quality but also decrease catastrophic consequences.

It is reasonable that IC/BPS patients have increased risks of OPD visits at the gynecology and urology departments because of typical presentations of IC/BPS as LUTS. After IC/PBS was diagnosed, they will certainly receive treatment and/or follow-ups. Moreover, IC/BPS may be accompanied by other gynecologic symptoms or diseases, e.g., dysmenorrhea [14], endometriosis [15], vulvodynia [16], etc. Tirlapur et al. have reported the prevalence of IC/BPS and endometriosis to be 61% and 70%, respectively, and coexisting IC/BPS and endometriosis was reported to be as high as 48% (16%–78%) among women suffering from chronic pelvic pain in a systemic review (nine studies, 1,016 patients) [17]. The “evil twin syndrome,” which means the coexistence of IC/BPS and endometriosis, is one of the difficult-managed syndromes. This makes IC/BPS patients visit the gynecologic OPD even more frequently. Similarly, Ueda et al. indicated that IC/BPS is a common comorbidity among patients with refractory chronic prostatitis/chronic pelvic pain syndrome [18]. Additionally, a recent study of ours showed that IC/BPS patients are at risk of developing urinary tract cancer at later years [9].

In addition to gynecology and urology mentioned above, the IC/BPS patients also have higher OPD visits and hospitalizations in other specialties. Among them, the psychiatric department is the highest in both OPD visits (IRR, 2.75) and hospitalizations (IRR, 2.66). Many studies reported the association between IC/BPS and psychiatric disorders. Watkins et al. reported that depression and panic are developed on as high as 36% and 52% in IC/BPS patients [6]. Clemens et al. reported that mental health disorders were identified in 23% of IC/BPS patients, when compared to 3% in controls (Odd ratio, 8.2; p < 0.001) [19]. A previous study found that patients with IC/BPS are at risk of developing anxiety, depression, and insomnia with a hazard ratio of 2.4 (95% CI, 2.2–2.7), 2.4 (95% CI, 2.2–2.6), and 2.1 (95% CI, 1.8–2.4), respectively [20]. The IRR is also higher in the Chinese medicine department and emergency room. IC/BPS patients tend easily to visit Chinese medicine, which may be due to culture influence. Some Chinese alternative therapies, including Chinese medicine and acupuncture, focus on holistic healing. Some patients may feel some improvement after this kind of alternative therapies [21]. As for more emergency room visits, this may be because it is easy, available, convenient, and low co-pay system of clinical approach in Taiwan. IC/BPS patients may have lower threshold for healthcare seeking, so they tend to visit the emergency room directly once they feel uncomfortable.

IC/BPS is characterized by chronic pain, frequency and urgency voiding, in which these symptoms do not occur in isolation [22]. Considerable overlapping symptoms exist among these patients. Meanwhile, IC/BPS patients have higher incidence of nocturia and urinary urgency than usual. Urgency and/or nocturia may predispose IC/BPS patients to easily falling down accidents, not only in elderly persons but also in middle-aged woman of more than 40 years old [23,24]. Thus, it can explain the higher IRR of orthopedics and neurosurgery hospitalizations.

The impacts of IC/BPS decrease as age advances, i.e.,., age effect, on healthcare seeking service decreases in urology (IRR of 18.20, 8.04, and 4.42 for age <40, 40 to 60, and >60 years, respectively) and other departments, except in gynecology. Link et al. found that the overall prevalence of symptoms suggestive of IC/BPS is increased in middle-aged adults. As age increases, however, more patients suffered from other symptoms causing from enlarged prostate with bladder outlet obstruction, as in non-IC/BPS controls. This data implied that IC/BPS is more bothersome to younger patients [25]. Our previous study also revealed similar results that younger individuals had increased risks of developing mental illness and insomnia following IC/BPS diagnosis [20]. Similar trends happened in most departments both in OPD visits and hospitalizations, except in gynecology. The age effect on IRR is even higher in older IC/BPS women to seek gynecologic examination. As mentioned above, IC/BPS patients have higher prevalence of some relative gynecologic diseases. In addition to a high coexisting bladder pain syndrome and endometriosis in chronic pelvic pain patients of up to 48% [17], the prevalence of pelvic floor dysfunction in IC/BPS patients ranges from 50% to 85% [26]. Cervigna et al. review showed a close relationship between IC/BPS and pelvic floor dysfunction and vulvodynia. Vulvodynia, most often described as burning pain, occurs in the absence of relevant visible findings. This “burning pain” was reported to be as high as 25% in IC/BPS patients, which is suggestive of a neuropathic pain response [27]. Vulvodynia is estimated to be 11.2-fold (CI 95%, 0.6–203) in IC/PBS patients [28]. This can affect women’s sexual life, sex painful and even impossible [16,27]. These symptoms happen even more commonly in elderly women.

Several explanations for the higher risks of OPD visits and hospitalizations were presented. Firstly, IC/BPS patients may have higher mental need of medical healthcare seeking. Nickel et al. had characterized and compared psychosocial phenotypes in IC/BPS women, in which IC/BPS women have significant cognitive and psychosocial alterations compared to controls, including catastrophizing and stress, and to a lesser extent social support [29]. It is reasonable as regards the higher emergency room visit noted in our study. Moreover, it is also based on easy feasibility and low co-pay health insurance system in Taiwan. However, this reason is hard to explain with the higher risks of hospitalizations, which were decided by medical conditions and doctors, instead of patients.

Secondly, IC/BPS patients may have more comorbidities, as compared with non-IC/BPS controls. Nickel et al., in a population‐based matched‐cohort study, showed that IC/BPS is associated with irritable bowel syndrome, fibromyalgia, and chronic fatigue syndrome [30]. Warren et al. further indicated that IC/BPS patients have more risks of coexisting related non-bladder syndromes, as compared with the control group. Nearly 60% of IC/BPS patients have more than one non-bladder syndromes [28]. Keller et al. reported that up to 32 medical comorbidities are associated with IC/BPS patients [5]. All of these comorbidities may increase subsequent OPD visits and hospitalizations. However, these studies indicated only the cross-sectional correlation between IC/BPS with other diseases; our study further offers a temporal relationship for the subsequent risks of OPD visits and hospitalization in the following two years.

Thirdly, IC/BPS may share some common risk factors; or IC/BPS per se is a precursor (risk factor) for some diseases, as compared with non-IC/BPS controls. Warren et al. reported that several antecedent syndromes are diagnosed more in IC/BPS patients, including migraine, allergies, and sicca syndrome [28]. Many studies implied that IC/BPS is a systemic multi-organ disorder, and the cause may originate from organs outside the bladder. It could induce a systemic inflammation condition and develop into multiple diseases. Thus, IC/BPS may play an important role as a precursor of some systemic diseases [31].

The strength of this study is its large-scale, nationwide, population-based recruitment. The national insurance system is a single-payer system which covers 98% of the population in Taiwan. Many studies have reported the cross-sectional relationship between IC/BPS and other diseases, but this study offers the temporal relationship and age effects on IC/PBS impacts in the clinical practice.

However, this study still has some limitations resulting from the characteristics of the registry of NHIRD database inherent in this study. Firstly, some potential confounders are lacking that could have an impact on the results, including baseline healthy status, habit of alcohol or tobacco use, and education status due to inherent characteristics of claim data. Secondly, the diagnosis of IC/BPS was dependent on the ICD-9 code within the database, which is diagnosed by the physician using the different diagnostic criteria. In this study, only IC/PBS patients with bladder instillation of sodium hyaluronate were recruited, which requires a strict prereview audit system. Third, distinguishing the disease severity and treatment status of IC/BPS is difficult based on this data source. The different clinical status of IC/BPS patients may have different impacts to OPD visits and hospitalizations. Since our IC/BPS cases are only confined to Hunner type and/or glomerulation, whether the difference between symptom-based and cystoscopic-based diagnosis could influence the patient population remains inclusive according to our data setting. This might need case control trial to compare these two diagnostic criteria setting.

In conclusion, IC/PBS patients were found to be associated with subsequent increased risks of outpatient visits and hospitalizations compared to non-IC/PBS controls, not only in the urology and gynecology departments but also in nearly all specialties. The age effects decrease in urology and in most departments, except in gynecology. This study also provides a broader understanding of IC/PBS within multiple and overlapping systems. These findings and explanations emphasized that IC/PBS patients should be paid more attention due to their systemic complex disease and their need for higher medical service. Thus, our findings broaden our understanding about IC/BPS, from organ-centered to multiple system concepts. A better understanding of IC/BPS patients can provide better healthcare quality.

Data Availability

All relevant data are within the manuscript.

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.Hanno PM, Erickson D, Moldwin R, Faraday MM, American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545–53. doi: 10.1016/j.juro.2015.01.086 [DOI] [PubMed] [Google Scholar]
  • 2.Akiyama Y, Hanno P. Phenotyping of interstitial cystitis/bladder pain syndrome. Int J Urol. 2019;26(S1):17–9. doi: 10.1111/iju.13969 [DOI] [PubMed] [Google Scholar]
  • 3.Grundy L, Caldwell A, Brierley SM. Mechanisms underlying overactive bladder and interstitial cystitis/painful bladder syndrome. Front Neurosci. 2018;12:931. doi: 10.3389/fnins.2018.00931 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Warren JW. Bladder pain syndrome/interstitial cystitis as a functional somatic syndrome. J Psychosom Res. 2014;77(6):510–5. doi: 10.1016/j.jpsychores.2014.10.003 [DOI] [PubMed] [Google Scholar]
  • 5.Keller JJ, Chen YK, Lin HC. Comorbidities of bladder pain syndrome/interstitial cystitis: a population-based study. BJU Int. 2012;110(11 Pt C):E903–9. doi: 10.1111/j.1464-410X.2012.11539.x [DOI] [PubMed] [Google Scholar]
  • 6.Watkins KE, Eberhart N, Hilton L, Suttorp MJ, Hepner KA, Clemens JQ, et al. Depressive disorders and panic attacks in women with bladder pain syndrome/interstitial cystitis: a population-based sample. Gen Hosp Psychiatry. 2011;33(2):143–9. doi: 10.1016/j.genhosppsych.2011.01.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.McKernan LC, Walsh CG, Reynolds WS, Crofford LJ, Dmochowski RR, Williams DA. Psychosocial co-morbidities in interstitial cystitis/bladder pain syndrome (ic/bps): a systematic review. Neurourol Urodyn. 2018;37(3):926–41. doi: 10.1002/nau.23421 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Payne CK, Joyce GF, Wise M, Clemens JQ, Urologic Diseases in America Project. Interstitial cystitis and painful bladder syndrome. J Urol. 2007;177(6):2042–9. doi: 10.1016/j.juro.2007.01.124 [DOI] [PubMed] [Google Scholar]
  • 9.Wu MP, Luo HL, Weng SF, Ho CH, Chancellor MB, Chuang YC. Risk of urinary tract carcinoma among subjects with bladder pain syndrome/interstitial cystitis: a nationwide population-based study. Biomed Res Int. 2018;2018:7495081. doi: 10.1155/2018/7495081 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Wen JY, Lo TS, Chuang YC, Ho CH, Long CY, Law KS, et al. Risks of interstitial cystitis among patients with systemic lupus erythematosus: A population‐based cohort study. Int J Urol. 2019;26(9):897–902. doi: 10.1111/iju.14065 [DOI] [PubMed] [Google Scholar]
  • 11.Chung SD, Liu SP, Li HC, Lin HC. Health care service utilization among patients with bladder pain syndrome/interstitial cystitis in a single payer healthcare system. PLoS One. 2014;9(1):e87522. doi: 10.1371/journal.pone.0087522 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Clemens JQ, Meenan RT, Rosetti MC, Gao SY, Calhoun EA. Prevalence and incidence of interstitial cystitis in a managed care population. J Uro. 2005; 173 (1): 98–102. [DOI] [PubMed] [Google Scholar]
  • 13.Cox A, Golda N, Nadeau G, Curtis Nickel J, Carr L, Corcos J, et al. CUA guideline: Diagnosis and treatment of interstitial cystitis/bladder pain syndrome. Can Urol Assoc J. 2016;10(5–6):E136–E55. doi: 10.5489/cuaj.3786 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Chung SD, Liu SP, Lin HC, Kang JH. Association of dysmenorrhea with interstitial cystitis/bladder pain syndrome: a case-control study. Acta Obstet Gynecol Scand. 2014;93(9):921–5. doi: 10.1111/aogs.12437 [DOI] [PubMed] [Google Scholar]
  • 15.Surrey ES, Soliman AM, Johnson SJ, Davis M, Castelli-Haley J, Snabes MC. Risk of developing comorbidities among women with endometriosis: a retrospective matched cohort study. J Womens Health (Larchmt). 2018;27(9):1114–23. doi: 10.1089/jwh.2017.6432 [DOI] [PubMed] [Google Scholar]
  • 16.Cervigni M, Natale F. Gynecological disorders in bladder pain syndrome/interstitial cystitis patients. Int J Urol. 2014;21Suppl 1:85–8. doi: 10.1111/iju.12379 [DOI] [PubMed] [Google Scholar]
  • 17.Tirlapur SA, Kuhrt K, Chaliha C, Ball E, Meads C, Khan KS. The ‘evil twin syndrome’ in chronic pelvic pain: a systematic review of prevalence studies of bladder pain syndrome and endometriosis. Int J Surg. 2013;11(3):233–7. doi: 10.1016/j.ijsu.2013.02.003 [DOI] [PubMed] [Google Scholar]
  • 18.Ueda M, Sengiku A, Kono J, Negoro H, Saito R, Yoshimura N, et al. Low bladder capacity is an important predictor for comorbidity of interstitial cystitis with Hunner’s lesion in patients with refractory chronic prostatitis/chronic pelvic pain syndrome. Int J Urol. 2019;26Suppl 1:53–6. doi: 10.1111/iju.13975 [DOI] [PubMed] [Google Scholar]
  • 19.Clemens JQ, Brown SO, Calhoun EA. Mental health diagnoses in patients with interstitial cystitis/painful bladder syndrome and chronic prostatitis/chronic pelvic pain syndrome: a case/control study. J Urol. 2008;180(4):1378–82. doi: 10.1016/j.juro.2008.06.032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Chuang YC, Weng SF, Hsu YW, Huang CL, Wu MP. Increased risks of healthcare-seeking behaviors of anxiety, depression and insomnia among patients with bladder pain syndrome/interstitial cystitis: a nationwide population-based study. Int Urol Nephrol. 2015;47(2):275–81. doi: 10.1007/s11255-014-0908-6 [DOI] [PubMed] [Google Scholar]
  • 21.Pang R, Ali A. The Chinese approach to complementary and alternative medicine treatment for interstitial cystitis/bladder pain syndrome. Transl Androl Urol. 2015; 4(6): 653–61. doi: 10.3978/j.issn.2223-4683.2015.08.10 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Grundy L, Brierley SM. Cross-organ sensitization between the colon and bladder: to pee or not to pee? Am J Physiol Gastrointest Liver Physiol. 2018;314(3):G301–8. doi: 10.1152/ajpgi.00272.2017 [DOI] [PubMed] [Google Scholar]
  • 23.Moon SJ, Kim YT, Lee TY, Moon H, Kim MJ, Kim SA, et al. The influence of an overactive bladder on falling: a study of females aged 40 and older in the community. Int Neurourol J. 2011; 15(1): 41–7. doi: 10.5213/inj.2011.15.1.41 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kurita N, Yamazaki S, Fukumori N, Otoshi K, Otani K, Sekiguchi M, et al. Overactive bladder symptom severity is associated with falls in community-dwelling adults: LOHAS study. BMJ Open. 2013; 3(5):e002413. doi: 10.1136/bmjopen-2012-002413 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Link CL, Pulliam SJ, Hanno PM, Hall SA, Eggers PW, Kusek JW, et al. Prevalence and psychosocial correlates of symptoms suggestive of painful bladder syndrome: results from the Boston area community health survey. J Urol. 2008;180(2):599–606. doi: 10.1016/j.juro.2008.04.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.De Paepe H, Renson C, Van Laecke E, Raes A, Vande Walle J, Hoebeke P. Pelvic‐floor therapy and toilet training in young children with dysfunctional voiding and obstipation. BJU Int. 2000; 85(7): 889–93. doi: 10.1046/j.1464-410x.2000.00664.x [DOI] [PubMed] [Google Scholar]
  • 27.Peters K, Girdler B, Carrico D, Ibrahim I, Diokno A. Painful bladder syndrome/interstitial cystitis and vulvodynia: a clinical correlation. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(5):665–9. doi: 10.1007/s00192-007-0501-y [DOI] [PubMed] [Google Scholar]
  • 28.Warren JW, Howard FM, Cross RK, Good JL, Weissman MM, Wesselmann U, et al. Antecedent nonbladder syndromes in case-control study of interstitial cystitis/painful bladder syndrome. Urology. 2009;73(1):52–7. doi: 10.1016/j.urology.2008.06.031 [DOI] [PubMed] [Google Scholar]
  • 29.Nickel JC, Tripp DA, International Interstitial Cystitis Study G. Clinical and psychological parameters associated with pain pattern phenotypes in women with interstitial cystitis/bladder pain syndrome. J Urol. 2015;193(1):138–44. doi: 10.1016/j.juro.2014.07.108 [DOI] [PubMed] [Google Scholar]
  • 30.Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr LK, et al. Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J Urol. 2010;184(4):1358–63. doi: 10.1016/j.juro.2010.06.005 [DOI] [PubMed] [Google Scholar]
  • 31.Warren JW, van de Merwe JP, Nickel JC. Interstitial cystitis/bladder pain syndrome and nonbladder syndromes: facts and hypotheses. Urology. 2011;78(4):727–32. doi: 10.1016/j.urology.2011.06.014 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Peter FWM Rosier

17 Mar 2021

PONE-D-21-02197

Interstitial cystitis/ Bladder pain syndrome patients are associated with subsequent increased risks of out-patient visits and hospitalizations: a population-based study

PLOS ONE

Dear Dr. Wu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR:

Based on the comments of the reviewers, I ask that you include your changes very carefully in the revision of the manuscript. Especially the discussion should be more focused and better organized. But also: Make it much clearer how your findings can influence (improve) of the quality of care for people with this syndrome. You also write that the "pathophysiology is unknown." In a large number of people (without Hunner's lesion) the syndrome is not very distinct from overactive bladder syndrome. Can it be determined whether it is excluded in some of the people that specific dysfunction plays a role in the syndrome where the patients refer their signs and symptoms to as pain? And whether you have any information whether the pain has been objectively shown to be related to the lower urinary tract, more specifically, filling (stretching) of the bladder? (are these in local (national) guidelines? as is 'exclusion of other causes', in the international guidelines?)

==============================

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Reviewer #1: The manuscript is well written overall. While the data is clearly presented, and it is clear from the manuscript that patients with IC/BPS have higher rates of outpatient visits and higher rates of hospitalization, some of the discussion is conjecture, not based on the data.

The manuscript would be stronger if it simply focused on the finding of higher visits/costs/resource utilization, and did not stray into physiology such as "cross organ sensitization" between the bladder and rectum. While this may be true (i believe it is), it is neither related to nor supported by the data presented.

Furthermore, the concept of hunner's ulcer as "ic" and non-hunner's ulcer as BPS is interesting, and likely true. The presence of hunner's ulcer is likely a different phenotype and different disease process, but it has virtually nothing to do with the finding of increased utilization, visits, hospitalizations, and should be omitted from the manuscript.

Reviewer #2: This is a study of the rate of out-patient visits and hospitalization in a group of patients with a diagnosis of IC/BPS compared to age matched controls. Patients with IC/BPS had more hospitalizations

1. The review criteria for getting the hyaluronate includes the presence of glomerulations or Hunner’s lesions under cystoscopy after hydrodistension- this criteria for glomerulations is no longer used and was part of the old 1988 NIH guidelines. Current guidelines only use symptoms (ref 1 in the paper). Can you comment on how this difference in diagnosis could influence the patient population being studied?

2. Was there a gender difference in the increase in Urology visits compared to controls? In any of the other non GYN visits?

3. Top of page 26, you cite reference 19 for increased rate of cancer in patients with IC/BPS. This is the incorrect reference – should be Wu MP, Luo HL, Weng SF, Ho CH, Chancellor MB, Chuang YC Risk of Urinary Tract Carcinoma among Subjects with Bladder Pain Syndrome/Interstitial Cystitis: A Nationwide Population-Based Study. BioMed Research International. 2018:7495081, 2018.

4. 4. Bottom of page 27- you postulate that the patients go to orthopedics and neurosurgery more due to risk of falls. You reference two articles that deal with the association of LUTS and specifically urgency in older women and men. However 73% of your cohort is under the age of 60. You did not break out the age in table 4.

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Reviewer #2: Yes: Michel A. Pontari

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PLoS One. 2021 Sep 7;16(9):e0256800. doi: 10.1371/journal.pone.0256800.r002

Author response to Decision Letter 0

30 Apr 2021

Response to academic editor and reviewers:

We would appreciate our deep thanks for the Academic Editor, and Reviewers’ sophisticated reading on our manuscript, and very instructive and important comments and suggestions. Below were our responses in point-to-point pattern. Enclosed please find our response letter, marked version and clean version. We hope our devotion and revision on the manuscript can merit the acceptance and publication in high impact journal, PLOS ONE.

PONE-D-21-02197

Interstitial cystitis/ Bladder pain syndrome patients are associated with subsequent increased risks of out-patient visits and hospitalizations: a population-based study

==============================

ACADEMIC EDITOR:

Q: Based on the comments of the reviewers, I ask that you include your changes very carefully in the revision of the manuscript. Especially the discussion should be more focused and better organized. But also: Make it much clearer how your findings can influence (improve) of the quality of care for people with this syndrome.

Response: Thank you for your comments and suggestions. We have revised accordingly. We have revised and organized our discussion to focus on our findings and delete some paragraphs which were irrelevant to our study.

【p.27, line 260-270】 We deleted the paragraph related to colo-rectal surgery, since many of the relationship between bladder condition and relationship about irritable bowel syndrome, etc are still hypothetic, which is out of the scope of our study. Again, we appreciate the important point of view.

【p.30, line 325-330】【p.27, line 268-270】 We have deleted the paragraph about pathogenesis, e.g. GAG defect and other mechanism, because of irrelevant information, unrelated to our data. We also delete the theory about “ cross sensitization” since our data could not offer evidence to support it.

Also, to follow your instructive suggestions, we tried to make more clear how this study can influence the quality of care. “Our study and other reports may remind physicians to pay attention to patients with IC/BPS in a broader view, in medical, surgical and mental illness. Adequate recognition and possible recommendation or referral for IC/BPS patients not only provide better healthcare quality, even decrease catastrophic consequences”【p.25, line 222-225】. And we emphasized that our findings broaden our understanding about IC/BPS, from organ-centered to multiple system concepts in conclusion “This study also provides a broader understanding of IC/PBS within multiple and overlapping systems. These findings and explanations are emphasized that patient with IC/PBS should be paid more attention due to systemic complex disease and higher medical service.”【p.32, line 365-369】

Q: You also write that the "pathophysiology is unknown." In a large number of people (without Hunner's lesion) the syndrome is not very distinct from overactive bladder syndrome. Can it be determined whether it is excluded in some of the people that specific dysfunction plays a role in the syndrome where the patients refer their signs and symptoms to as pain? And whether you have any information whether the pain has been objectively shown to be related to the lower urinary tract, more specifically, filling (stretching) of the bladder? (are these in local (national) guidelines? as is 'exclusion of other causes', in the international guidelines?)

Response: Thanks for your comments. Since this is a study based on claim data, the inclusion and exclusion criteria of IC/BPS are up to individual physician’s clinical opinions. However, this study included IC/BPS patients who received bladder instillation treatment, which requires a strict pre-review audit system. There are definite rules in payment regulations of National Health Insurance [Ref National Health Insurance]. “Its provision included: the presence of glomerulation or Hunner’s lesions under cystoscopy after hydrodistention test, voiding diary, negative urine cytology and urine analysis “ [p.6 Material and Methods session, Assembly of study participants]. The above guideline is according to the guideline of Taiwan Urology Association, in line with AUA [Ref TUA guideline] [Ref AUA guideline]

Ref: Taiwan National Health Insurance, https://www.nhi.gov.tw/Content_List.aspx?n=197F438368327FE0&topn=5FE8C9FEAE863B46

Ref: TUA guideline, https://online.fliphtml5.com/thpbe/cljw/#p=1

Ref: AUA guideline, https://www.auanet.org/guidelines/interstitial-cystitis-(ic/bps)-guideline

==============================

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Response: Thanks.

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Response: Thanks.

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Response: Thanks.

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Response: After the manuscript revision, we have made substantial English editing.

5. Review Comments to the Author

Reviewer #1: The manuscript is well written overall. While the data is clearly presented, and it is clear from the manuscript that patients with IC/BPS have higher rates of outpatient visits and higher rates of hospitalization, some of the discussion is conjecture, not based on the data.

The manuscript would be stronger if it simply focused on the finding of higher visits/costs/resource utilization, and did not stray into physiology such as "cross organ sensitization" between the bladder and rectum. While this may be true (i believe it is), it is neither related to nor supported by the data presented.

Response to Reviewer 1: We agreed the Reviewer’s comment that some discussion opinions were conjecture, not based on the data. We have revised and organized our discussion to more focus on our findings. Including:

【p.27, line 260-270】 We deleted the paragraph related to colo-rectal surgery, since many of the relationship between bladder condition and relationship about irritable bowel syndrome, etc are still hypothetic, which is out of the scope of our study. Again, we appreciate the important point of view.

【p.30, line 325-330】【p.27, line 268-270】 We have deleted the paragraph about pathogenesis, e.g. GAG defect and other mechanism, because of irrelevant information, unrelated to our data. We also delete the theory about “ cross sensitization” since our data could not offer evidence to support it.

And we also did other revisions.

Besides, we tried to pay more attention to influence of the findings. In 2nd paragraph of discussion 【p.24-25】”Our study and other reports may remind physicians to pay attention to patients with IC/BPS in a broader view, in medical, surgical and mental illness. Adequate recognition and possible recommendation or referral for IC/BPS patients not only provide better healthcare quality, even decrease catastrophic consequences.

Q: Furthermore, the concept of hunner's ulcer as "ic" and non-hunner's ulcer as BPS is interesting, and likely true. The presence of hunner's ulcer is likely a different phenotype and different disease process, but it has virtually nothing to do with the finding of increased utilization, visits, hospitalizations, and should be omitted from the manuscript.

Response: Thanks for your suggestions and comments. In this study, we did not try to discuss on the issue of Hunner-type, or non-Hunner-type, because data inavailability. There are different diagnostic criteria and classifications in IC/BPS. As our response to editor mentioned above, our claim data was collected from NHIRD with inherent claim data characteristics and limitations. We only recruited IC/BPS patients who received bladder instillation treatment after strict pre-review audit system. Therefore our IC/BPS cases only confined to Hunner type (or with glomerulation) due to claim data characteristics. Whether our findings can be deductive to non-Hunner type IC/BPS remains inclusive. It is out of the scope of our study.

Reviewer #2: This is a study of the rate of out-patient visits and hospitalization in a group of patients with a diagnosis of IC/BPS compared to age matched controls. Patients with IC/BPS had more hospitalizations

Q1. The review criteria for getting the hyaluronate includes the presence of glomerulations or Hunner’s lesions under cystoscopy after hydrodistension- this criteria for glomerulations is no longer used and was part of the old 1988 NIH guidelines. Current guidelines only use symptoms (ref 1 in the paper). Can you comment on how this difference in diagnosis could influence the patient population being studied?

Response: We agreed with the Reviewer’s comment that the finding of glomerulations is no longer used in modern clinical practice. However, due to claim data characteristics, we only recruited IC/BPS patients who received bladder instillation treatment, which requires a strict pre-review audit system. “Therefore our IC/BPS cases only confined to Hunner type (or with glomerulation). Whether this difference between symptom-based and cystoscopic-based diagnosis could influence the patient population remain inclusive according to our data setting. This might need case control trial to compare these two diagnostic criteria setting. It is also out of the scope of our study.”【p. 32, line 356-360】Again, we thank for reviewer’s important and instructive comments, we revised it in the limitation.

Q2. Was there a gender difference in the increase in Urology visits compared to controls? In any of the other non GYN visits?

Response: Yes, we found higher risk of male IC/BPS patients than female in Urology visits and also hospitalization. The rate of Urology visit is female (1.07) and male (2.33) (per one person-year) with adjusted IRR were 0.42 (95% CI: 0.40-0.45). The rate of Urology admission is female (23.85) and male (72.94)(no. per 1000 person-year) with adjusted IRR were 0.34 (95% CI: 0.29-0.40).We had added this data to p.12 and p18.

Q3. Top of page 26, you cite reference 19 for increased rate of cancer in patients with IC/BPS. This is the incorrect reference – should be Wu MP, Luo HL, Weng SF, Ho CH, Chancellor MB, Chuang YC Risk of Urinary Tract Carcinoma among Subjects with Bladder Pain Syndrome/Interstitial Cystitis: A Nationwide Population-Based Study. BioMed Research International. 2018:7495081, 2018.

Response: We apologize for the mistake. We have corrected the reference number into our text. We appreciated the Reviewer’s sophisticated reading on the manuscript.

4. 4. Bottom of page 27- you postulate that the patients go to orthopedics and neurosurgery more due to risk of falls. You reference two articles that deal with the association of LUTS and specifically urgency in older women and men. However 73% of your cohort is under the age of 60. You did not break out the age in table 4.

Response: We appreciate the Reviewer’s pointing our mistake. We agreed that the explanation is hypothetic. We further cited a more related reference to explain the possible relationship. Moon SJ et al indicated that higher falling rate in females aged 40 and older due to urgency and LUTS. Also Kurita N et al. found that higher OAB symptoms were associated to high fall risk from 40 year-old and older. [Ref 24 and 25. revision]. These studies showed that high fall risk not only in elderly but also age older than 40.

24 Moon SJ, Kim YT, Lee TY, Moon H, Kim MJ, Kim SA, et al. The influence of an overactive bladder on falling: a study of females aged 40 and older in the community. Int Neurourol J. 2011; 15(1): 41–7.

25 Kurita N, Yamazaki S, Fukumori N, Otoshi K, Otani K, Sekiguchi M, et al. Overactive bladder symptom severity is associated with falls in community-dwelling adults: LOHAS study. BMJ Open. 2013; 3(5):e002413

Attachment

Submitted filename: ICBPS_to_OPD_response_2021.04.14 (finished).docx

Click here for additional data file. (32.6KB, docx)

Decision Letter 1

Peter FWM Rosier

22 Jun 2021

PONE-D-21-02197R1

Interstitial cystitis/ Bladder pain syndrome patients are associated with subsequent increased risks of out-patient visits and hospitalizations: a population-based study

PLOS ONE

Dear Dr. Wu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR:

Can You, with the help of the reviewers comments, make a few changes and additions?

================

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Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

Reviewer #3: Overall this manuscript is strong given the large data set available for analysis and using a matched case: control study sampling method. The selection of IC/BPS cases on ICD9 code in addition to requiring bladder instillation also allows for strong case selection. A few comments that should be addressed:

1) Methods Section, Lines 104-109. IC/BPS cases are followed from “index date of first registration”, not date of diagnosis. It is unclear how long patients are followed prior to date of initial diagnosis, nor how the inclusion of total time followed impacts the analysis. Or if I am mis-reading this, is index date is equivalent to date of diagnosis? Please add more clarity to describe this.

2) Methods, Lines 128-134: In the analysis of impact of gender or age differences, were these calculated as interaction terms in the model?

3) Methods, Lines 131-133: Please indicate how missing data on covariates was handled. Was missing data coded, or were cases excluded with missing data?

4) Table 1: p-values cannot be 1.0. Recommend change to p>0.9999 for the notation.

5) Results: Lines 152-153: Regarding the gender difference in urology rates, please clarify if these are the overall gender rates for Urology. Or are these the specific for just the IC/BPS group? Clarify the description of the IRR rate that this is female to male “...adjusted IRR rate for females to males was 0.42...”

6) Results, Lines 165-166: Regarding the differences observed across ages, if these rates are increasing, please provide the results of the statistical tests with the appropriate p-value for trend. Were each pairwise contrast of Group 1 to 2 and Group 2 to 3 significantly different?

7) Results, Lines 194-199: Please provide p-values to support these statement of significant differences between age groups.

8) The manuscript would benefit from a detailed editing by a native English speaker.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #2: No

Reviewer #3: No

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PLoS One. 2021 Sep 7;16(9):e0256800. doi: 10.1371/journal.pone.0256800.r004

Author response to Decision Letter 1

29 Jul 2021

We would appreciate our deep thanks for the Academic Editor, and Reviewers’ sophisticated reading on our manuscript, and very instructive and important comments and suggestions. Below were our responses in point-to-point pattern. Also we revised out manuscript under reviewers’ suggestions to improve this paper. Enclosed please find our response letter, marked version and clean version. We hope our devotion and revision on the manuscript can merit the acceptance and publication in high impact journal, PLOS ONE.

Thanks for reviewer 2 and here are responses to reviewer 3:

1) Methods Section, Lines 104-109. IC/BPS cases are followed from “index date of first registration”, not date of diagnosis. It is unclear how long patients are followed prior to date of initial diagnosis, nor how the inclusion of total time followed impacts the analysis. Or if I am mis-reading this, is index date is equivalent to date of diagnosis? Please add more clarity to describe this.

Ans: Thanks for your question. We apologize for the lack of clarity. We have tried to define and revise the sentence. The index date is first registration with the diagnostic code of IC/BPS (ICD 9 code 595.1). Later on, the cases who received bladder instillation as mentioned and at least 3 outpatient visits with the same diagnosis at OPD visit were included. .

We add more information in Lines 110-112.

2) Methods, Lines 128-134: In the analysis of impact of gender or age differences, were these calculated as interaction terms in the model?

Ans: Thanks for your comment. Due to the age and gender had been matched, the interaction terms of age and gender did not be included in the model for avoiding the over adjustments.

3) Methods, Lines 131-133: Please indicate how missing data on covariates was handled. Was missing data coded, or were cases excluded with missing data?

Ans: Thanks for your question. We apologize for this mistyped error. We want to tell “Some other potential confounders were NOT available due to claim data characters, such as education…”. We correct it in Line 132. Thanks for your careful reading again.

4) Table 1: p-values cannot be 1.0. Recommend change to p>0.9999 for the notation.

Ans: Thanks for reviewer’s suggestion. The p-value had been modified, accordingly. (We correct in Table 1)

5) Results: Lines 152-153: Regarding the gender difference in urology rates, please clarify if these are the overall gender rates for Urology. Or are these the specific for just the IC/BPS group? Clarify the description of the IRR rate that this is female to male “...adjusted IRR rate for females to males was 0.42...”

Ans: Thanks for review’s question and suggestion. Yes, our description was not so clear. The gender difference in urology rates is specific for patients with IC/PBS. And the adjust IRR is female to male. We will make more clear description of gender difference in Lines 153-155.

6) Results, Lines 165-166: Regarding the differences observed across ages, if these rates are increasing, please provide the results of the statistical tests with the appropriate p-value for trend. Were each pairwise contrast of Group 1 to 2 and Group 2 to 3 significantly different?

Ans: Thanks for the reviewer’s comment. The trend test of outpatient visits rates for patients with IC/PBS following the increased age groups had presented as the below table. The trend test of each pairwise contrast groups was also presented. These p-values was added in the below of Table3 (Line 182)

p-value for trend Overall 40≦ vs. 40-60 40-60 vs. ≧60 40≦ vs. ≧60

Patients with IC/PBS

Outpatient visits <.0001 <.0001 <.0001 <.0001

7) Results, Lines 194-199: Please provide p-values to support these statement of significant differences between age groups.

Ans: Thanks for the reviewer’s comment. The differences between age groups all show p-value<.0001. These p-values were added in the manuscript to explain the statement of differences between age groups. The paragraph was modified as below. (Line 200-207)

“Significant higher IRR in younger age comparing to older age group in urology department (IRR: 11.33 vs. 5.55 and 5.38, p-value of age groups was p<.0001). This result is similar in most departments, including psychiatry,

orthopedics, neurology and neurosurgery. The IRR of hospitalization in gynecology is higher IRR in oldest group (less than 40 years: 1.45 vs. 40 to 60 years: 2.29 vs. older than 60 years: 5.70, p-value of age groups was p<.0001). ”

8) The manuscript would benefit from a detailed editing by a native English speaker.

Ans: Thanks for review’s suggestion. Due to the authors are not native English speakers, we sent the manuscript to international editing company for help. This new version of manuscript had been edited by the editors from Enago.

Attachment

Submitted filename: ICPBS 2021.07.29 (revision2)(answer to reviewer).docx

Click here for additional data file. (287.1KB, docx)

Decision Letter 2

Peter FWM Rosier

17 Aug 2021

Interstitial cystitis/bladder pain syndrome patient is associated with subsequent increased risks of outpatient visits and hospitalizations: a population-based study

PONE-D-21-02197R2

Dear Dr. Wu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Peter F.W.M. Rosier, M.D. PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

Reviewer #3: Very well presented findings. The authors have addressed all concerns raised and the editing has improved the manuscript substantially.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

Acceptance letter

Peter FWM Rosier

27 Aug 2021

PONE-D-21-02197R2

Interstitial cystitis/bladder pain syndrome patient is associated with subsequent increased risks of outpatient visits and hospitalizations: a population-based study

Dear Dr. Wu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

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on behalf of

Dr. Peter F.W.M. Rosier

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PLOS ONE

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