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The Association Between Barium Examination and Subsequent Appendicitis: A Nationwide Population-Based Study

      Abstract

      Objective

      The incidence and association between appendicitis and barium examination (BE) remain unclear. Such potential risk may be omitted. We conducted a longitudinal, nationwide, population-based cohort study to investigate the association between BE and appendicitis risk.

      Methods

      From the Taiwan National Health Insurance Research Database, a total of 24,885 patients who underwent BE between January 1, 2000 and December 31, 2010 were enrolled in a BE cohort; an additional 98,384 subjects without BE exposure were selected as a non-BE cohort, matched by age, sex, and index date. The cumulative incidences of subsequent appendicitis in the BE and non-BE cohorts were assessed using the Kaplan-Meier curves and log-rank test. Cox proportional hazards regression analyses were employed to calculate the appendicitis risk between the groups.

      Results

      The cumulative incidence of appendicitis was higher in the BE cohort than in the non-BE cohort (P = .001). The overall incidence rates of appendicitis for the BE and non-BE cohorts were 1.19 and 0.80 per 1000 person-years, respectively. After adjustment for sex, age, and comorbidities, the risk of appendicitis was higher in the BE cohort (adjusted hazard ratio = 1.46, 95% confidence interval = 1.23-1.73) compared with the non-BE cohort, especially in the first 2 months (adjusted hazard ratio = 9.72, 95% confidence interval = 4.65-20.3).

      Conclusions

      BE was associated with an increased, time-dependent appendicitis risk. Clinicians should be aware of this potential risk to avoid delayed diagnoses.

      Keywords

      Clinical Significance
      • Patients who underwent barium examination may have an increased risk of appendicitis; the risk is time dependent, and is highest in the first 2 months.
      • Clinicians should be aware of such potential risk in patients presenting abdominal pain after barium examination.
      Barium sulfate is widely used and considered safe in gastrointestinal (GI) imaging studies. The clinical indications for its use include suspicion of GI tract tumor, unexplained abdominal pain, stricture or obstruction of GI tract, bowel habit change, chronic constipation or diarrhea, and so on. However, some rare complications involving its use, such as appendicitis, have been reported. Since Gubler and Kukral
      • Gubler J.A.
      • Kukral A.J.
      Barium appendicitis.
      reported the first case of barium-related appendicitis in 1954, only case reports of subsequent appendicitis after upper GI series and barium enema studies have been documented, and the clinical courses varied widely from hours to years.
      • Inoue F.
      • Sato R.
      • Takada T.
      Barium appendicitis.
      • Ince V.
      • Işık B.
      • Koç C.
      • Başkıran A.
      • Onur A.
      Barolith as a rare cause of acute appendicitis: a case report.
      • Urade M.
      • Shinbo T.
      Barium appendicitis 1 month after a barium meal.
      • Novotny N.M.
      • Lillemoe K.D.
      • Falimirski M.E.
      Barium appendicitis after upper gastrointestinal imaging.
      • Wu J.M.
      • Liang J.T.
      Education and imaging. Gastrointestinal: barium-induced acute appendicitis.
      • Palder S.B.
      • Dalessandri K.M.
      Barium appendicitis.
      • Nagata H.
      • Ohga S.
      • Hattori S.
      • et al.
      Barium-associated appendicitis in a childhood case with Crohn's disease.
      • Cohen N.
      • Modai D.
      • Rosen A.
      • Golik A.
      • Weissgarten J.
      Barium appendicitis: fact or fancy? Report of a case and review of the literature.
      • Maglinte D.D.
      • Bush M.L.
      • Aruta E.V.
      • Bullington G.E.
      Retained barium n the appendix: diagnostic and clinical significance.
      • Fang Y.J.
      • Wang H.P.
      • Ho C.M.
      • Liu K.L.
      Barium appendicitis.
      The risk and etiology of barium-related appendicitis remain unknown and debatable.
      • Cohen N.
      • Modai D.
      • Rosen A.
      • Golik A.
      • Weissgarten J.
      Barium appendicitis: fact or fancy? Report of a case and review of the literature.
      To ascertain the correlation between barium examination (BE) and appendicitis, a study made up of a relatively large number of BE patients with a high follow-up rate was necessary. We designed a longitudinal, nationwide, population-based cohort study, using data from the Taiwan National Health Insurance Research Database (NHIRD) to determine the subsequent risk of appendicitis in BE patients, and compared the risk with that of a matched non-BE population. We also examined the differences in the appendicitis risk among different entities of BE. There were other examinations reported with subsequent appendicitis, such as colonoscopy.
      • Shaw D.
      • Gallardo G.
      • Basson M.D.
      Post-colonoscopy appendicitis: a case report and systematic review.
      This study preliminarily focused on the relationship between BE and appendicitis.

      Methods

      Data Source

      Since 1995, the National Health Insurance (NHI) program has provided universal health care coverage to 99% of the population of 23.75 million in Taiwan.
      • Chen Y.C.
      • Yeh H.Y.
      • Wu J.C.
      • Haschler I.
      • Chen T.J.
      • Wetter T.
      Taiwan's National Health Insurance Research Database: administrative health care database as study object in bibliometrics.
      The NHIRD consists of comprehensive medical claims data from the Taiwan NHI program. To protect privacy, individual and hospital identifiers were scrambled and encrypted. Data for this study were obtained from a representative NHIRD dataset with one million people, which has been validated by numerous studies.
      • Wei P.L.
      • Chen C.S.
      • Keller J.J.
      • Lin H.C.
      Monthly variation in acute appendicitis incidence: a 10-year nationwide population-based study.
      • Wei P.L.
      • Keller J.J.
      • Liang H.H.
      • Lin H.C.
      Acute appendicitis and adverse pregnancy outcomes: a nationwide population-based study.
      • Chao P.W.
      • Ou S.M.
      • Chen Y.T.
      • et al.
      Acute appendicitis in patients with end-stage renal disease.
      Disease identification was based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). This retrospective cohort study was approved by the Institutional Review Board of China Medical University Hospital (CMUH104-REC2-115).

      Identification and Definition of Study Cohorts

      We identified patients who underwent BE (including upper GI series, small bowel series, single- and double-contrast barium enemas) between January 1, 2000 and December 31, 2010 from the NHIRD as the BE cohort. Those who underwent multiple BEs within 60 days were defined as the “repeated BE subgroup” in the BE cohort. The first date of BE was set as the patient's index date. Patients with a history of appendicitis and other appendiceal diseases (ICD-9-CM codes 540-543) prior to their index date were not enrolled. The ICD-9-CM codes used in this paper for disease definitions and conditions are listed in the Appendix (Supplementary Table 1, available online). To control potential confounders of severe underlying illness, patients with the following comorbidities were excluded: human immunodeficiency virus disease, disorders involving the immune mechanism, end-stage renal disease, inflammatory bowel disease (including Crohn disease and ulcerative colitis), and GI tract malignancy.
      • Chao P.W.
      • Ou S.M.
      • Chen Y.T.
      • et al.
      Acute appendicitis in patients with end-stage renal disease.
      • Sanda R.B.
      Appendicitis as an immunological disease: why it is uncommon in Africans.
      • Crum-Cianflone N.
      • Weekes J.
      • Bavaro M.
      Appendicitis in HIV-infected patients during the era of highly active antiretroviral therapy.
      To avoid surveillance bias and the interaction of other GI examinations, patients who underwent abdominal computed tomography, colonoscopy, or GI imaging studies using water-soluble contrast within 1 year from the index date were also excluded. After applying the same exclusion criteria, randomly selected subjects without BE exposure were propensity score-matched to each patient of the BE cohort on sex, age, and comorbidities of diabetes and intestinal infectious diseases (indicating proven intestinal infections of specific pathogens like cholera, salmonella, shigella, amoeba, protozoa, viruses) as the non-BE cohort. The year and month of index dates were also matched to avoid confounding effects from seasonal variation or endemic outbreak of appendicitis.
      • Wei P.L.
      • Chen C.S.
      • Keller J.J.
      • Lin H.C.
      Monthly variation in acute appendicitis incidence: a 10-year nationwide population-based study.
      • Lamps L.W.
      Infectious causes of appendicitis.
      Figure 1 shows the flow of patients enrolled in this study.
      Figure 1
      Figure 1Flow diagram of the patients enrolled in this study. BE = barium examination; NHIRD = National Health Insurance Research Database.

      Outcome

      The main outcome was appendicitis diagnosed surgically and pathologically during the follow-up period, with a discharge ICD-9-CM code of 540 (acute appendicitis), 541 (appendicitis, unqualified), or 542 (other appendicitis). The term appendicitis in this article not only refers to acute appendicitis (ICD-9-CM codes 540), but also comprises the ICD-9-CM codes of 541 and 542, due to the various presentations of barium-related appendicitis.
      • Gubler J.A.
      • Kukral A.J.
      Barium appendicitis.
      • Inoue F.
      • Sato R.
      • Takada T.
      Barium appendicitis.
      • Ince V.
      • Işık B.
      • Koç C.
      • Başkıran A.
      • Onur A.
      Barolith as a rare cause of acute appendicitis: a case report.
      • Urade M.
      • Shinbo T.
      Barium appendicitis 1 month after a barium meal.
      • Novotny N.M.
      • Lillemoe K.D.
      • Falimirski M.E.
      Barium appendicitis after upper gastrointestinal imaging.
      • Wu J.M.
      • Liang J.T.
      Education and imaging. Gastrointestinal: barium-induced acute appendicitis.
      • Palder S.B.
      • Dalessandri K.M.
      Barium appendicitis.
      • Nagata H.
      • Ohga S.
      • Hattori S.
      • et al.
      Barium-associated appendicitis in a childhood case with Crohn's disease.
      • Cohen N.
      • Modai D.
      • Rosen A.
      • Golik A.
      • Weissgarten J.
      Barium appendicitis: fact or fancy? Report of a case and review of the literature.
      • Maglinte D.D.
      • Bush M.L.
      • Aruta E.V.
      • Bullington G.E.
      Retained barium n the appendix: diagnostic and clinical significance.
      • Fang Y.J.
      • Wang H.P.
      • Ho C.M.
      • Liu K.L.
      Barium appendicitis.
      Perforated appendicitis (ICD-9-CM codes 540.0, 540.1) was also evaluated as a critical issue for clinical management. All patients were followed from their index date until appendicitis diagnosis, death, the date of withdrawal from the NHI program, or the end of 2011.

      Statistical Analysis

      The baseline characteristics of the BE and non-BE cohorts, including sex, age (≤19, 20-39, 40-59, and ≥ 60 years), and comorbidities, were compared using the chi-squared test for categorical variables; a Student's t test was employed for continuous variables. Using the Kaplan-Meier method, we assessed the cumulative incidence of appendicitis between the BE cohort and the non-BE cohort and tested their differences with the log-rank test. We computed the incidence rate (per 1000 person-years) of appendicitis for each cohort. Univariable and multivariable Cox proportional hazards regression analyses were applied to assess the appendicitis risk between both groups with the adjustment of sex, age, and comorbidities; hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. All analyses were performed using the SAS statistical package (Version 9.4; SAS Institute Inc, Cary, NC). A 2-tailed P-value <.05 was considered statistically significant.

      Results

      Baseline Characteristics of the Study Cohorts

      In total, 24,885 patients were enrolled as the BE cohort and 98,384 patients were registered as the non-BE cohort. The baseline characteristics of these 2 cohorts and indications for BE are shown in Table 1. Among the participants in both groups, approximately 51.9% were male and 40.4% were over 60 years of age. The 5 most common indications for BE were disorders of the intestines (such as constipation, diarrhea, and irritable bowel syndrome), disorders of the stomach and duodenum (such as dyspepsia, vomiting, and gastric spasm), hemorrhoids, anemia and unspecified GI hemorrhage, and abdominal pain. No BE was performed under the suspicion of appendicitis. We also scrutinized the medical records of patients with subsequent appendicitis in the BE group, to confirm that their indications for BE were not appendicitis. Detailed characteristics of those appendicitis patients were presented in the supporting material (Appendix: Supplementary Table 2, available online).
      Table 1Baseline Characteristics in BE and Non-BE Patients
      VariableBarium ExaminationP-Value
      Student's t test for continuous variables and chi-squared test for categorical variables.
      NoYes
      n = 98,384n = 24,885
      n (%)n (%)
      Sex.80
       Female51,132 (52.0)12,911 (51.9)
       Male47,252 (48.0)11,974 (48.1)
      Follow-up, years, mean (SD)6.54 (3.23)6.18 (3.43)<.001
      Age, years, mean (SD)53.3 (19.0)53.8 (19.0).001
      Stratify age, years.95
       ≤194440 (4.51)1112 (4.47)
       20-3918,911 (19.2)4764 (19.1)
       40-5935,522 (36.1)8969 (36.0)
       ≥ 6039,511 (40.2)10,040 (40.4)
      Comorbidity
      Diabetes11,390 (11.6)2940 (11.8).30
      Intestinal infectious diseases7522 (7.65)1974 (7.93).13
      Indication for BE
       Disorders of intestines7331 (29.46)
       Disorders of stomach and duodenum5190 (20.86)
       Hemorrhoids3666 (14.73)
       Anemia and unspecified GI hemorrhage1919 (7.71)
       Abdominal pain1179 (4.74)
      BE = barium examination; GI = gastrointestinal; SD = standard deviation.
      Student's t test for continuous variables and chi-squared test for categorical variables.

      Incidences of Appendicitis in the BE and Non-BE Cohorts

      Figure 2 shows that the cumulative incidence of appendicitis was higher in the BE cohort than in the non-BE cohort (P = .001). The incidence rate and adjusted HR (aHR) of appendicitis between the BE and non-BE cohorts are shown in Table 2. The incidence rate of appendicitis was higher in the BE cohort than in the non-BE cohort (1.19 vs 0.80 per 1000 person-years), with an aHR of 1.46 (95% CI 1.23-1.73). The risk of appendicitis was higher for both sexes in the BE cohort compared with the non-BE cohort, especially for men (aHR 1.48; 95% CI, 1.16-1.88). Besides, the age-specific risk of appendicitis was higher for those aged 20-59 years in the BE cohort compared with the non-BE cohort, especially for those aged 40-59 years (aHR 1.80; 95% CI, 1.34-2.41). Table 3 shows the interaction between BE and comorbidity. BE patients without comorbidity had a significantly higher risk of appendicitis (aHR 1.47; 95% CI, 1.22-1.76) compared with the non-BE cohort without comorbidity. Among the BE cohort, patients who underwent double-contrast barium enema accounted for the majority (63.6%). The subgroup of repeated BE within 2 months had the highest risk of appendicitis (aHR 2.52; 95% CI, 1.20-5.31), followed by the subgroup of double-contrast barium enema (aHR 1.62; 95% CI, 1.32-1.98), compared with the non-BE cohort (Table 4).
      Figure 2
      Figure 2Cumulative incidence of appendicitis compared between with and without barium examination cohorts using the Kaplan-Meier method.
      Table 2Comparison of Incidence and HR of Appendicitis Stratified by Sex and Age Between BE and Non-BE Cohorts
      VariableNon-BE CohortsBE CohortsCompared with Non-BE
      EventPYRate
      Rate, incidence rate, per 1000 person-years.
      EventPYRate
      Rate, incidence rate, per 1000 person-years.
      Crude HR (95% CI)Adjusted HR
      Adjusted HR: multivariable analysis including age, sex, comorbidities of diabetes and intestinal infectious diseases.
      (95% CI)
      Appendicitis518643,8460.80183153,7131.191.48 (1.25-1.75)***1.46 (1.23-1.73)***
      Sex
       Female268340,0150.799682,7411.161.47 (1.16-1.86)**1.45 (1.14-1.83)**
       Male250303,8310.828770,9721.231.49 (1.17-1.90)**1.48 (1.16-1.88)**
      Stratify age
       ≤194335,0161.231686391.851.51 (0.85-2.68)1.51 (0.85-2.68)
       20-39152132,3441.155833,2011.751.52 (1.12-2.06)**1.50 (1.11-2.04)**
       40-59149239,5380.626457,6041.111.78 (1.33-2.39)***1.80 (1.34-2.41)***
       ≥ 60174236,9480.734554,2680.831.13 (0.81-1.57)1.10 (0.79-1.53)
      BE = barium examination; CI = confidence interval; HR = hazard ratio; PY = person-years.
      **P <.01; ***P <.001.
      Rate, incidence rate, per 1000 person-years.
      Adjusted HR: multivariable analysis including age, sex, comorbidities of diabetes and intestinal infectious diseases.
      Table 3Risk Analysis of BE-Associated Appendicitis With Interaction of Comorbidity
      VariablenEventRate
      Rate, incidence rate, per 1000 person-years.
      Crude HR (95% CI)Adjusted HR
      Adjusted HR: multivariable analysis including age, sex, comorbidities of diabetes, and intestinal infectious diseases.
      (95% CI)
      BEComorbidity
      Comorbidity: patients with any of the comorbidities of diabetes and intestinal infectious diseases were classified as the comorbidity group.
      NoNo80,2744440.821 (Reference)1 (Reference)
      NoYes18,110740.700.85 (0.66-1.08)0.90 (0.70-1.15)
      YesNo20,0701551.221.47 (1.23-1.77)***1.47 (1.22-1.76)***
      YesYes4815281.061.28 (0.87-1.88)1.36 (0.93-2.00)
      BE = barium examination; CI = confidence interval; HR = hazard ratio.
      ***P <.001.
      Rate, incidence rate, per 1000 person-years.
      Adjusted HR: multivariable analysis including age, sex, comorbidities of diabetes, and intestinal infectious diseases.
      § Comorbidity: patients with any of the comorbidities of diabetes and intestinal infectious diseases were classified as the comorbidity group.
      Table 4Incidence and HR of Appendicitis Between Non-BE and Different Entities of BE
      VariablenEventRate
      Rate, incidence rate, per 1000 person-years.
      Crude HR (95% CI)Adjusted HR
      Adjusted HR: multivariable analysis including age, sex, comorbidities of diabetes, and intestinal infectious diseases.
      (95% CI)
      Non-BE98,3845180.801 (Reference)1 (Reference)
      BE24,8851831.191.48 (1.25-1.75)***1.46 (1.23-1.73)***
       Double-contrast barium enema15,8361181.291.60 (1.31-1.95)***1.62 (1.32-1.98)***
       Single-contrast barium enema1249121.341.67 (0.94-2.95)1.55 (0.87-2.74)
       UGI & Small bowel series7215460.921.14 (0.85-1.55)1.11 (0.82-1.50)
       Repeated BE within 2 mo58572.042.53 (1.20-5.33)*2.52 (1.20-5.31)*
      BE = barium examination; CI = confidence interval; HR = hazard ratio; UGI = upper gastrointestinal.
      *P <.05; ***P <.001.
      Rate, incidence rate, per 1000 person-years.
      Adjusted HR: multivariable analysis including age, sex, comorbidities of diabetes, and intestinal infectious diseases.

      Trends of Appendicitis Risk

      The incidence rate of appendicitis in the BE cohort showed a time-dependent trend during the follow-up period. The risk of appendicitis in the BE cohort was highest in the first 2 months (aHR 9.72; 95% CI, 4.65-20.3) compared with the non-BE cohort (Table 5), and then decreased in the subsequent 3-12 months (aHR 2.11; 95% CI, 1.40-3.18). After 1 year, this risk showed no significant difference in both groups. The risk of perforated appendicitis in the BE cohort had a similar trend, which was highest in the first 2 months (aHR 6.91; 95% CI, 2.72-17.6), then decreased as the time interval increased.
      Table 5Trends of appendicitis & perforated appendicitis risks in BE and non-BE cohorts stratified by follow-up years
      Follow-Up Periods (mo)Non-BE CohortBE CohortCompared with Non-BE
      EventPYRate
      Rate = incidence rate, per 1000 person-years.
      EventPYRate
      Rate = incidence rate, per 1000 person-years.
      Crude HR (95% CI)Adjusted HR
      Adjusted HR = multivariable analysis including age, sex, and comorbidities of diabetes, and intestinal infectious diseases.
      (95% CI)
      Appendicitis
       ≤21016,7000.602541975.969.92 (4.77-20.7)***9.72 (4.65-20.3)***
       3-126780,6280.833619,7931.822.19 (1.46-3.29)***2.11 (1.40-3.18)***
       >12441546,5180.81122129,7230.941.17 (0.95-1.42)1.17 (0.96-1.43)
      Perforated appendicitis
       ≤2716,7000.421241972.866.81 (2.68-17.3)***6.91 (2.72-17.6)***
       3-122280,6280.271219,7920.612.23 (1.10-4.50)*2.25 (1.11-4.54)*
       >12176546,5180.3242129,7230.321.01 (0.72-1.41)1.02 (0.73-1.43)
      BE = barium examination; CI = confidence interval; HR = hazard ratio; PY = person-years.
      *P <.05; ***P <.001.
      Rate = incidence rate, per 1000 person-years.
      Adjusted HR = multivariable analysis including age, sex, and comorbidities of diabetes, and intestinal infectious diseases.

      Discussion

      In the present study, the association between BE and subsequent appendicitis was demonstrated in a large population for the first time. Our data revealed that among the different entities of BE, the subgroup of double-contrast barium enema had a significantly higher risk of appendicitis, and the highest risk was in those patients who had repeated BE within 2 months, indicating a dose-dependent relationship. The risk of developing appendicitis among BE patients was time dependent.
      Although the complications and adverse effects of BE have rarely been observed and are self-limited, some severe and potentially life-threatening conditions have been reported, including anaphylactoid reactions, poisoning from soluble barium ions, barium granuloma, barium impaction, and venous or extraluminal extravasation.
      • Périard M.A.
      Adverse effects and complications related to the use of barium sulphate contrast media for radiological examinations of the gastrointestinal tract: a literature review.
      Abdominal pain after BE was often considered related to gas distention, constipation, or barium impaction. However, over 50 cases of appendicitis following BE have been reported since 1954.
      • Gubler J.A.
      • Kukral A.J.
      Barium appendicitis.
      • Inoue F.
      • Sato R.
      • Takada T.
      Barium appendicitis.
      • Ince V.
      • Işık B.
      • Koç C.
      • Başkıran A.
      • Onur A.
      Barolith as a rare cause of acute appendicitis: a case report.
      • Urade M.
      • Shinbo T.
      Barium appendicitis 1 month after a barium meal.
      • Novotny N.M.
      • Lillemoe K.D.
      • Falimirski M.E.
      Barium appendicitis after upper gastrointestinal imaging.
      • Wu J.M.
      • Liang J.T.
      Education and imaging. Gastrointestinal: barium-induced acute appendicitis.
      • Palder S.B.
      • Dalessandri K.M.
      Barium appendicitis.
      • Nagata H.
      • Ohga S.
      • Hattori S.
      • et al.
      Barium-associated appendicitis in a childhood case with Crohn's disease.
      • Cohen N.
      • Modai D.
      • Rosen A.
      • Golik A.
      • Weissgarten J.
      Barium appendicitis: fact or fancy? Report of a case and review of the literature.
      • Maglinte D.D.
      • Bush M.L.
      • Aruta E.V.
      • Bullington G.E.
      Retained barium n the appendix: diagnostic and clinical significance.
      • Fang Y.J.
      • Wang H.P.
      • Ho C.M.
      • Liu K.L.
      Barium appendicitis.
      The interval between the symptoms onset of appendicitis and BE varied widely, from 6 hours to several years.
      • Inoue F.
      • Sato R.
      • Takada T.
      Barium appendicitis.
      • Nagata H.
      • Ohga S.
      • Hattori S.
      • et al.
      Barium-associated appendicitis in a childhood case with Crohn's disease.
      • Cohen N.
      • Modai D.
      • Rosen A.
      • Golik A.
      • Weissgarten J.
      Barium appendicitis: fact or fancy? Report of a case and review of the literature.
      Thus, no clear association between BE and appendicitis has been determined yet. Gubler and others
      • Gubler J.A.
      • Kukral A.J.
      Barium appendicitis.
      • Inoue F.
      • Sato R.
      • Takada T.
      Barium appendicitis.
      • Ince V.
      • Işık B.
      • Koç C.
      • Başkıran A.
      • Onur A.
      Barolith as a rare cause of acute appendicitis: a case report.
      • Urade M.
      • Shinbo T.
      Barium appendicitis 1 month after a barium meal.
      • Wu J.M.
      • Liang J.T.
      Education and imaging. Gastrointestinal: barium-induced acute appendicitis.
      • Palder S.B.
      • Dalessandri K.M.
      Barium appendicitis.
      • Nagata H.
      • Ohga S.
      • Hattori S.
      • et al.
      Barium-associated appendicitis in a childhood case with Crohn's disease.
      believed that barium retained in the appendix may cause the development of a barolith, causing obstruction and inflammation of the appendix as an appendicolith. However, Cohen et al
      • Cohen N.
      • Modai D.
      • Rosen A.
      • Golik A.
      • Weissgarten J.
      Barium appendicitis: fact or fancy? Report of a case and review of the literature.
      • Maglinte D.D.
      • Bush M.L.
      • Aruta E.V.
      • Bullington G.E.
      Retained barium n the appendix: diagnostic and clinical significance.
      did not believe that retained barium had an etiologic role in subsequent appendicitis, for no appendicitis developed in 31 patients who retained appendiceal barium during a 1-year follow-up.
      In our study, regardless of whether the appendix revealed barium retention, the BE cohort had a significantly higher risk of subsequent appendicitis than the non-BE cohort did, particularly within the first 2 months. The risk of appendicitis in the BE cohort was 9.72 times greater than in the non-BE cohort within the first 2 months and decreased with time from the BE. The result implies that BE may have some acute or subacute effect leading to appendicitis more than the obstruction.
      Increasing evidence suggests that the development of appendicitis is a multifactorial mechanism.
      • Sanda R.B.
      Appendicitis as an immunological disease: why it is uncommon in Africans.
      • Jones R.
      An unexpected increase in adult appendicitis in England (2000/01 to 2012/13): Could cytomegalovirus (CMV) be a risk factor.
      • Singh J.P.
      • Mariadason J.G.
      Role of the faecolith in modern-day appendicitis.
      • Alder A.C.
      • Fomby T.B.
      • Woodward W.A.
      • Haley R.W.
      • Sarosi G.
      • Livingston E.H.
      Association of viral infection and appendicitis.
      • Carr N.J.
      The pathology of acute appendicitis.
      Reduced intestinal mucosal integrity is believed to precipitate appendicitis. Beyond the obstruction theory about barolith (or fecalith) leading to appendicitis, some authors have suggested other possible mechanisms of appendicitis, including increased luminal pressure, which can cause barotrauma and mucosal defects during colonoscopy; mucosal ulceration induced by viral infection or ischemia; type I hypersensitivity or other immune responses to allergens; and constipation, which increases susceptibility to infection.
      • Shaw D.
      • Gallardo G.
      • Basson M.D.
      Post-colonoscopy appendicitis: a case report and systematic review.
      • Singh J.P.
      • Mariadason J.G.
      Role of the faecolith in modern-day appendicitis.
      • Alder A.C.
      • Fomby T.B.
      • Woodward W.A.
      • Haley R.W.
      • Sarosi G.
      • Livingston E.H.
      Association of viral infection and appendicitis.
      • Carr N.J.
      The pathology of acute appendicitis.
      • Sanda R.B.
      Epidemiologic features of appendicitis.
      • Lamps L.W.
      Beyond acute inflammation: a review of appendicitis and infections of the appendix.
      Among the BE group, administration of barium from rectal route showed higher risk of appendicitis than from oral route, especially in the subgroup of double-contrast barium enema (Table 4). Double-contrast barium enema shares a common characteristic with colonoscopy about air inflation during the procedure. The reported perforation rate in double-contrast barium enemas was 0.02%-0.24%.
      • Khan J.
      • Moran B.
      Iatrogenic perforation at colonic imaging.
      Subclinical asymptomatic air leakage is more common and usually not reported. Therefore, the transient increased intraluminal pressure may lead to barotrauma and mucosal defects. Moreover, fine particles of barium sulfate could be deposited in the weakened intestinal wall, forming granulomatous lesions.
      • Périard M.A.
      Adverse effects and complications related to the use of barium sulphate contrast media for radiological examinations of the gastrointestinal tract: a literature review.
      Although barium sulfate is considered safe when the mucosa is intact, the presence of a minor mucosal defect may cause problems. There are also numerous uncertain additives used in barium sulfate solution, including deflocculation agents, suspending agents, and flavoring agents,
      • O'Connor S.D.
      • Summers R.M.
      Revisiting oral barium sulfate contrast agents.
      which may induce hypersensitivity or other immune responses. Barium coating may affect bowel transition and is believed to cause constipation when dehydrated and compacted. All of the above information supports the correlation between BE and appendicitis. However, the exact etiology of barium-related appendicitis requires further investigation.
      The strengths of the current study included a large-scale nationwide cohort, a high follow-up rate over a long period, and a well-matched control group to adjust for age, sex, and other risk factors such as diabetes, intestinal infectious disease, and seasonal variation.
      • Wei P.L.
      • Chen C.S.
      • Keller J.J.
      • Lin H.C.
      Monthly variation in acute appendicitis incidence: a 10-year nationwide population-based study.
      • Lamps L.W.
      Infectious causes of appendicitis.
      • Tsai S.H.
      • Hsu C.W.
      • Chen S.C.
      • Lin Y.Y.
      • Chu S.J.
      Complicated acute appendicitis in diabetic patients.
      To minimize the surveillance bias and confounding effects of severe underlying illness, we excluded patients who underwent abdominal computed tomography, colonoscopy, or GI imaging studies using water-soluble contrast within 1 year from the index date, and who had a history of inflammatory bowel disease, GI tract malignancy, compromised immunity, or end-stage renal disease. This study is the first one to provide epidemiological data of barium-related appendicitis and to demonstrate that the risk of barium-related appendicitis is time dependent.
      Some limitations of this study should be noted. First, information about smoking habits, socioeconomic status, body mass index, race, details of performing BE (such as operators' experience, barium density, inflated air pressure), imaging, or laboratory findings is scarce in the NHIRD. These variables could not be adjusted in the analysis. Second, the exclusion criteria may cause underestimation of the actual incidence rate of barium-related appendicitis in the general population. Third, the interaction of computed tomography colonoscopy was not controlled in this study because computed tomography colonoscopy is rarely used in Taiwan; it is not covered by an NHI program so it is only used in self-paid health examinations. Finally, according to the inherent limitations of administrative data, this study could be susceptible to systematic bias and could not establish a strong causality as well as a randomized controlled trial did. Readers should be careful about interpreting the results of this study. Despite the above limitations, this study still provides important information about the barium-related appendicitis and alerts clinicians to such possibility in patients presenting abdominal pain after BE. These findings may serve as a basis to discover other potential pathogenesis of appendicitis.
      In conclusion, BE patients were more likely to have subsequent appendicitis. The risk was highest in the first 2 months. Clinicians should recognize this potential risk to avoid delayed diagnoses.

      Appendix

      Supplementary Table 1The Corresponding ICD-9-CM Codes for the Diagnoses of Diseases
      DiseaseCorresponding ICD-9-CM Codes
      Abdominal pain789.0
      Anemia and unspecified GI hemorrhage280, 285, 578
      Appendicitis540-542
      Diabetes250
      Disorders involving the immune mechanism279
      Disorders of intestines560, 562, 564, 569, 787.5-787.9
      Disorders of stomach and duodenum531-537, 787.0
      End-stage renal disease585
      GI tract malignancy150-159
      Hemorrhoids455
      Human immunodeficiency virus042-044
      Inflammatory bowel disease555, 556
      Intestinal infectious diseases001-009
      GI = gastrointestinal; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification.
      Supplementary Table 2Characteristics of Appendicitis Patients in BE Group
      CaseAge (y)SexEvent Interval (d)Type of StudyIndication ICD-9-CM Code for BERepeated BE Within 2 MoEvent ICD-9-CM CodePersistent Abdominal Pain Until Event Onset
      119F14DCBE211.3540.9
      261F2855UGI285.8540.9
      365F2923UGI285.9540.9
      450M625UGI285.9540.0
      524F2238DCBE455.0540.9
      649M467DCBE455.0540.9
      778M1424DCBE455.0540.9
      864F2331DCBE455.0540.9
      925F188DCBE455.0540.9
      1049M2053DCBE455.0540.0
      1135M341DCBE455.0540.0
      1273M2155DCBE455.0541
      1377M973DCBE455.6540.9
      1469M2935DCBE455.6541
      1527M2513SCBE455.6540.0
      1664M24DCBE455.6540.0
      1752F760DCBE455.6540.1
      1857F134DCBE455.6540.9
      1966F2912SCBE455.6541
      2052M1380DCBE455.6541
      2154F677DCBE455.6540.9
      2224F2833DCBE455.6540.9
      2347F97DCBE455.6540.9
      2448M1342DCBE455.6540.9
      2524F3324SCBE455.6540.9
      2651M9DCBE455.6540.1
      2765M3226DCBE455.6540.0
      2875M591DCBE455.6540.0
      2968F1241DCBE455.6540.0
      3078F1539DCBE455.6541
      3163F158DCBE455.6540.0
      3242F247DCBE455.8540.0
      3349F238DCBE455.8540.9
      3434F1721DCBE455.8540.9
      3560F240DCBE455.9540.9
      3639M3985UGI531.00540.9
      3745F1750UGI531.30540.0
      386M1810UGI531.40540.9
      3936M1620UGI531.40540.0
      4062F546UGI531.90540.9
      4182M160UGI531.90540.0
      4219M3153UGI531.90540.9
      4370F4143UGI531.90540.9
      4458M1370UGI531.90540.9
      4547M724UGI531.90540.0
      4635F1826UGI532.00540.9
      4728M64UGI532.00540.9
      4853M848UGI532.00540.0
      4917M1048UGI532.30540.9
      5029F4033UGI532.30540.0
      5154M1859UGI532.70540.0
      5259F308UGI532.70540.9
      5350F515UGI532.70540.9
      5431M43UGI532.70540.0
      5548F1654DCBE532.9540.9
      5662F2871UGI533.00540.0
      5737F1556UGI533.00540.9
      5878F354UGI533.50540.9
      5924F1679UGI533.70540.9
      6024M1439DCBE533.90540.0
      6160M1417UGI533.90540.9
      6221M459UGI533.90540.0
      637M2369UGI533.9540.9
      6434M1073UGI533.90540.9
      6544F7UGI533.90540.9
      6640F2511UGI533.90540.0
      6759F1515UGI533.9540.0
      6828M1056UGI533.9542
      6956M936UGI533.9541
      7024F415UGI533.90540.0
      7144F287UGI533.90540.0
      7248F107UGI533.90540.0
      7356M286UGI535.00540.9
      747F3241UGI535.00541
      7535F452UGI535.00540.9
      7618F963UGI536.8540.9
      7759F3646SCBE536.9540.9
      7856M3801UGI536.9540.1
      7941M1510UGI536.9540.1
      8026F46SCBE536.9540.0
      8167M3SCBE537.89UGI540.0
      8251M48DCBE558.9UGI540.0
      833M360SCBE560.0540.1
      842F85SCBE560.0541
      8543M9UGI560.1540.9
      8625F2731DCBE560.1540.9
      8718M2UGI560.1540.9
      8834F282DCBE560.1540.0
      8974M532DCBE560.3540.9
      9058F2767DCBE560.3542
      9135F2674UGI560.39540.9
      9269M230DCBE560.9540.9
      9325F3SCBE562.10540.0
      9450M480DCBE562.10541
      9537F219DCBE562.10541
      9681F336DCBE562.10540.9
      9760F297DCBE562.10540.9
      9880M28DCBE562.10540.9
      9914F276DCBE562.10540.9
      10044M2037DCBE562.10540.1
      1015F1DCBE564.0540.9
      10242M152DCBE564.0540.9
      10349F36DCBE564.0540.0
      10435M1871DCBE564.0540.9
      10532F797DCBE564.0541
      10660M3861DCBE564.0540.1
      10755F892DCBE564.0540.9
      10853F25SCBE564.0540.9
      10945F2701DCBE564.0540.9
      11038F1572DCBE564.0540.9
      11144F2427DCBE564.0540.9
      11225M311DCBE564.0540.9
      11351F1886DCBE564.0540.9
      11474F3SCBE564.0540.9
      11526F2193DCBE564.0540.9
      11632F26DCBE564.0DCBE540.0
      11763F1139DCBE564.0540.9
      11874M8DCBE564.0540.9
      11924M348SCBE564.0541
      12044M1009DCBE564.0540.0
      12145M616SCBE564.1540.9
      12263F2537DCBE564.1540.9
      12343M3880DCBE564.1540.9
      12452M433DCBE564.1540.9
      12534F358SCBE564.1540.9
      12635M2956DCBE564.1540.1
      12721M1181DCBE564.1540.9
      12854F21SCBE564.1540.0
      12933F167DCBE564.1541
      13059M2116DCBE564.1541
      13149F1343DCBE564.1540.0
      13244M343DCBE564.1UGI540.0
      13360M2001SCBE564.8540.9
      13429F1586DCBE564.9540.9
      13529M1311DCBE564.9540.9
      13623M157DCBE564.9540.9
      13779M1302DCBE564.9540.9
      13835M711DCBE564.9540.0
      13975M14DCBE564.9540.0
      14052F3715DCBE564.9541
      14145F1445DCBE569.0540.1
      14223F1968DCBE569.3540.9
      14345F1678SCBE569.42540.9
      14471F1303DCBE569.5UGI540.9
      14537F3390DCBE569.82540.0
      14654F90DCBE569.89540.0
      14752M72DCBE569.9540.9
      14839M1135DCBE569.9540.0
      14964M2159UGI578.0540.9
      15038M2694UGI578.0540.0
      15159F928DCBE578.1541
      15267M4188DCBE578.1540.9
      15339F314SCBE578.1540.9
      15481M480DCBE578.1540.9
      15527M1401DCBE578.1540.0
      15646F903DCBE578.1540.0
      15773M2631DCBE578.9541
      15838M671UGI578.9540.9
      15956M251UGI578.9540.1
      16043F688DCBE578.9540.0
      16134F2159UGI710.0540.0
      1621F5SCBE751.4UGI540.9
      16339M3305SCBE783.2540.1
      16422M347UGI787.1540.0
      16533M303DCBE787.7541
      16648M5DCBE787.91540.9
      16720F7DCBE787.91540.9
      16832M1413DCBE787.91UGI540.0
      16952F1412DCBE787.99540.9
      17078M1504DCBE787.99540.9
      17115F10DCBE787.99540.9
      17282F2182DCBE787.99540.1
      17368F2403DCBE787.99542
      17429F1501DCBE789.0540.0No
      17539F405DCBE789.0540.9No
      1766F2560UGI789.0540.9No
      17759M558DCBE789.0540.0No
      17815M596DCBE789.0540.0No
      17938F3659UGI789.0541No
      18058M1787DCBE789.0541No
      18169M1585DCBE789.9540.0
      18253F41SCBE789.9540.0
      18366F1151DCBE998.11540.9
      DCBE = double-contrast barium enema; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; SCBE = single-contrast barium enema; UGI = upper gastrointestinal study (including small bowel series).

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