Epidemiology of Clostridium difficile Infection–Associated Reactive Arthritis in Children: An Underdiagnosed, Potentially Morbid Condition | Gastroenterology | JAMA Pediatrics | JAMA Network
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Figure.  Patient Selection for Clostridium Difficile Infection–Associated Reactive Arthritis and C Difficile Infection
Patient Selection for Clostridium Difficile Infection–Associated Reactive Arthritis and C Difficile Infection

aInternational Classification of Diseases, Ninth Revision, Clinical Modification(ICD-9-CM) Current Procedural Terminology codes suggesting arthritis.

bICD-9-CM code 008.45 and/or positive C difficile testing.

cNot mutually exclusive.

dCases were matched to up to 4 controls by network and time of C difficile infection within 3 months; 2 cases had only 2 to 3 matched controls.

Table 1.  Incidence of C difficile Infection and C difficile Infection–Associated Reactive Arthritis Over Time
Incidence of C difficile Infection and C difficile Infection–Associated Reactive Arthritis Over Time
Table 2.  Characteristics of C Difficile Infection–Associated Reactive Arthritis in 26 Cases
Characteristics of C Difficile Infection–Associated Reactive Arthritis in 26 Cases
Table 3.  Characteristics of Children With Clostridium Difficile Infection–Associated Reactive Arthritis Clinically Concerning for Septic Arthritis
Characteristics of Children With Clostridium Difficile Infection–Associated Reactive Arthritis Clinically Concerning for Septic Arthritis
Table 4.  Characteristics of Children With C Difficile Infection With (Cases) and Without (Controls) Reactive Arthritis
Characteristics of Children With C Difficile Infection With (Cases) and Without (Controls) Reactive Arthritis
1.
Bartlett  JG.  Clinical practice. Antibiotic-associated diarrhea.  N Engl J Med. 2002;346(5):334-339.PubMedGoogle ScholarCrossref
2.
Khanna  S, Baddour  LM, Huskins  WC,  et al.  The epidemiology of Clostridium difficile infection in children: a population-based study.  Clin Infect Dis. 2013;56(10):1401-1406.PubMedGoogle ScholarCrossref
3.
Zilberberg  MD, Tillotson  GS, McDonald  C.  Clostridium difficile infections among hospitalized children, United States, 1997-2006.  Emerg Infect Dis. 2010;16(4):604-609.PubMedGoogle ScholarCrossref
4.
Nylund  CM, Goudie  A, Garza  JM, Fairbrother  G, Cohen  MB.  Clostridium difficile infection in hospitalized children in the United States.  Arch Pediatr Adolesc Med. 2011;165(5):451-457.PubMedGoogle ScholarCrossref
5.
Sammons  JS, Localio  R, Xiao  R, Coffin  SE, Zaoutis  T.  Clostridium difficile infection is associated with increased risk of death and prolonged hospitalization in children.  Clin Infect Dis. 2013;57(1):1-8.PubMedGoogle ScholarCrossref
6.
Birnbaum  J, Bartlett  JG, Gelber  AC.  Clostridium difficile: an under-recognized cause of reactive arthritis?  Clin Rheumatol. 2008;27(2):253-255.PubMedGoogle ScholarCrossref
7.
Hayward  RS, Wensel  RH, Kibsey  P.  Relapsing Clostridium difficile colitis and Reiter’s syndrome.  Am J Gastroenterol. 1990;85(6):752-756.PubMedGoogle Scholar
8.
Jacobs  A, Barnard  K, Fishel  R, Gradon  JD.  Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature.  Medicine (Baltimore). 2001;80(2):88-101.PubMedGoogle ScholarCrossref
9.
Koçar  IH, Calişkaner  Z, Pay  S, Turan  M.  Clostridium difficile infection in patients with reactive arthritis of undetermined etiology.  Scand J Rheumatol. 1998;27(5):357-362.PubMedGoogle ScholarCrossref
10.
Prati  C, Bertolini  E, Toussirot  E, Wendling  D.  Reactive arthritis due to Clostridium difficile.  Joint Bone Spine. 2010;77(2):190-192.PubMedGoogle ScholarCrossref
11.
Wright  TW, Linscheid  RL, O’Duffy  JD.  Acute flexor tenosynovitis in association with Clostridium difficile infection: a case report.  J Hand Surg Am. 1996;21(2):304-306.PubMedGoogle ScholarCrossref
12.
Delègue  P, Dhote  R, Permal  S, Boissonnas  A, Christoforov  B.  [Clostridium difficile reactive arthritis].  Gastroenterol Clin Biol. 2001;25(8-9):830-831.PubMedGoogle Scholar
13.
Keating  RM, Vyas  AS.  Reactive arthritis following Clostridium difficile colitis.  West J Med. 1995;162(1):61-63.PubMedGoogle Scholar
14.
Razavi  B.  Reactive arthritis after Helicobacter pylori eradication.  Lancet. 2000;355(9205):720.PubMedGoogle ScholarCrossref
15.
Cron  RQ, Gordon  PV.  Reactive arthritis to Clostridium difficile in a child.  West J Med. 1997;166(6):419-421.PubMedGoogle Scholar
16.
Dacheux  C, Pruvost  I, Herbaux  B, Nectoux  E.  [Clostridium difficile reactive arthritis in a 7-year-old child].  Arch Pediatr. 2012;19(6):607-611.PubMedGoogle ScholarCrossref
17.
Durand  CL, Miller  PF.  Severe Clostridium difficile colitis and reactive arthritis in a ten-year-old child.  Pediatr Infect Dis J. 2009;28(8):750-751.PubMedGoogle ScholarCrossref
18.
Finger  DR, Neubauer  JV.  Reactive arthritis following Clostridium difficile colitis in a 3-year-old patient.  J Clin Rheumatol. 1997;3(2):102-104.PubMedGoogle ScholarCrossref
19.
Löffler  HA, Pron  B, Mouy  R, Wulffraat  NM, Prieur  A-M.  Clostridium difficile-associated reactive arthritis in two children.  Joint Bone Spine. 2004;71(1):60-62.PubMedGoogle ScholarCrossref
20.
Shaklee  J, Zerr  DM, Elward  A,  et al.  Improving surveillance for pediatric Clostridium difficile infection: derivation and validation of an accurate case-finding tool.  Pediatr Infect Dis J. 2011;30(3):e38-e40.PubMedGoogle ScholarCrossref
21.
Cohen  SH, Gerding  DN, Johnson  S,  et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America.  Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA).  Infect Control Hosp Epidemiol. 2010;31(5):431-455.PubMedGoogle ScholarCrossref
22.
Centers for Disease Control and Prevention (CDC).  Vital signs: preventing Clostridium difficile infections.  MMWR Morb Mortal Wkly Rep. 2012;61(9):157-162.PubMedGoogle Scholar
23.
Harris  PA, Taylor  R, Thielke  R, Payne  J, Gonzalez  N, Conde  JG.  Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.  J Biomed Inform. 2009;42(2):377-381.Google ScholarCrossref
24.
Feemster  KA, Li  Y, Grundmeier  R, Localio  AR, Metlay  JP.  Validation of a pediatric primary care network in a US metropolitan region as a community-based infectious disease surveillance system.  Interdiscip Perspect Infect Dis. 2011;2011:219859.PubMedGoogle Scholar
25.
Putterman  C, Rubinow  A.  Reactive arthritis associated with Clostridium difficile pseudomembranous colitis.  Semin Arthritis Rheum. 1993;22(6):420-426.PubMedGoogle ScholarCrossref
26.
Kuuliala  K, Orpana  A, Leirisalo-Repo  M, Repo  H.  Neutrophils of healthy subjects with a history of reactive arthritis show enhanced responsiveness, as defined by CD11b expression in adherent and non-adherent whole blood cultures.  Rheumatology (Oxford). 2007;46(6):934-937.PubMedGoogle ScholarCrossref
27.
Rihl  M, Barthel  C, Klos  A,  et al.  Identification of candidate genes for susceptibility to reactive arthritis.  Rheumatol Int. 2009;29(12):1519-1522.PubMedGoogle ScholarCrossref
28.
Baillet  AC, Rehaume  LM, Benham  H,  et al.  High chlamydia burden promotes tumor necrosis factor-dependent reactive arthritis in SKG mice.  Arthritis Rheumatol. 2015;67(6):1535-1547.PubMedGoogle ScholarCrossref
29.
Ng  J, Hirota  SA, Gross  O,  et al.  Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome.  Gastroenterology. 2010;139(2):542-552, 552.e1-552.e3.PubMedGoogle ScholarCrossref
30.
Xu  H, Yang  J, Gao  W,  et al.  Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome.  Nature. 2014;513(7517):237-241.PubMedGoogle ScholarCrossref
31.
Jafari  NV, Kuehne  SA, Bryant  CE,  et al.  Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s).  PLoS One. 2013;8(7):e69846.PubMedGoogle ScholarCrossref
32.
Cowardin  CA, Kuehne  SA, Buonomo  EL, Marie  CS, Minton  NP, Petri  WA  Jr.  Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile.  MBio. 2015;6(1):e02386-14.PubMedGoogle ScholarCrossref
33.
Lubberts  E.  The IL-23-IL-17 axis in inflammatory arthritis.  Nat Rev Rheumatol. 2015;11(7):415-429.PubMedGoogle ScholarCrossref
34.
Rath  HC, Herfarth  HH, Ikeda  JS,  et al.  Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats.  J Clin Invest. 1996;98(4):945-953.PubMedGoogle ScholarCrossref
35.
Schiellerup  P, Krogfelt  KA, Locht  H.  A comparison of self-reported joint symptoms following infection with different enteric pathogens: effect of HLA-B27.  J Rheumatol. 2008;35(3):480-487.PubMedGoogle Scholar
36.
Lin  P, Bach  M, Asquith  M,  et al.  HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats.  PLoS One. 2014;9(8):e105684.PubMedGoogle ScholarCrossref
Original Investigation
July 5, 2016

Epidemiology of Clostridium difficile Infection–Associated Reactive Arthritis in Children: An Underdiagnosed, Potentially Morbid Condition

Author Affiliations
  • 1Rutgers Biomedical and Health Sciences, New Brunswick, New Jersey
  • 2 Division of Pediatric Rheumatology, Department of Pediatrics, Nemours A.I. duPont Hospital for Children, Wilmington, Delaware
  • 3Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 4Division of Pediatric Rheumatology, Department of Pediatrics, Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia
  • 5Division of Infectious Diseases, Department of Pediatrics, Infection Prevention and Control, Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia
JAMA Pediatr. 2016;170(7):e160217. doi:10.1001/jamapediatrics.2016.0217
Abstract

Importance  The incidence of Clostridium difficile infection has increased among children. The epidemiology of pediatric C difficile infection–associated reactive arthritis is poorly understood.

Objective  To characterize the incidence, recognition, and distinguishing clinical features of pediatric C difficile infection–associated reactive arthritis among children with C difficile infection.

Design, Setting, and Participants  In this cohort and nested case-control study using electronic health records from January 1, 2004, to December 31, 2013, across 3 geographically diverse pediatric health care networks, we screened for reactive arthritis among 148 children between ages 2 and 21 years with diagnostic or procedural codes suggesting musculoskeletal disease associated with C difficile diagnosis or positive testing. We identified 26 cases with acute arthritis or tenosynovitis within 4 weeks before to 12 weeks after confirmed C difficile infection with (1) no alternative explanation for arthritis and (2) negative synovial cultures (if obtained). Network-matched C difficile–infected controls without arthritis were randomly selected at the time of cohort member C difficile infections.

Main Outcomes and Measures  Incidence of C difficile infection–associated reactive arthritis was calculated based on (1) pediatric source population and (2) children with C difficile infection. Characteristics of cases and controls were compared using conditional logistic regression.

Results  Based on the cases identified within the source population of the 3 hospital networks, we estimated that C difficile infection–associated reactive arthritis incidence was 5.0 cases per million person-years (95% CI, 3.0-7.8). Reactive arthritis affected 1.4% of children with C difficile infection yearly (95% CI 0.8%-2.3%). Joint symptoms began a median of 10.5 days after initial gastrointestinal symptoms, often accompanied by fever (n = 15 [58%]) or rash (n = 14 [54%]). Only 35% of cases of C difficile infection–associated reactive arthritis were correctly diagnosed by treating health care professionals (range across centers, 0%-64%). Five affected children (19%) were treated for presumed culture-negative septic hip arthritis despite having prior postantibiotic diarrhea and/or other involved joints. Compared with controls, cases of C difficile infection–associated reactive arthritis were less likely to have underlying chronic conditions (odds ratio [OR], 0.3; 95% CI, 0.1-0.8). Although all cases had community-onset C difficile infection and fewer comorbidities, they were more likely to be treated in emergency departments and/or hospitalized (OR, 7.1; 95% CI, 1.6-31.7).

Conclusions and Relevance  C difficile infection–associated reactive arthritis is an underdiagnosed, potentially morbid reactive arthritis associated with C difficile infection occasionally misdiagnosed as septic arthritis. Given the rising incidence of pediatric C difficile infections, better recognition of its associated reactive arthritis is needed.

Introduction

Clostridium difficile infection (CDI) is an important cause of morbidity and mortality caused by a toxin-releasing anaerobic bacterium, typically following antibiotic exposure.1 The incidence of pediatric CDI has increased dramatically over the last 2 decades, with a 12.5-fold increase in overall incidence and 80% rise in CDI-related hospitalizations.2,3 Hospitalized children with CDI have more infectious complications and medical comorbidities, longer lengths of stay, higher hospital costs, and greater mortality compared with hospitalized children without CDI.4,5

Aside from its well-known gastrointestinal manifestations, CDI is also associated with inflammatory reactive arthritis. Most published information about CDI-associated reactive arthritis (CDIAReA; pronounced “see diarrhea”) comes from case reports, series, and reviews, mostly in adults.6-10 This condition presents acutely in multiple joints recruited asymmetrically, usually beginning soon after the start of antibiotic-associated diarrhea. Clostridum difficile-associated tenosynovitis has also been described.11 The HLA-B27 gene has been identified in 70% of adult cases10 and may be a risk factor for prolonged or recurrent arthritis.6,7,12-14 The few published cases of CDIAReA in children demonstrated similar clinical features as adults.15-19 In 2 children, CDIAReA resembled septic arthritis.16,17

While the condition is documented in the published literature, the epidemiology of CDIAReA is poorly understood, both in adult and pediatric populations. Our study aims to objectively characterize the incidence, recognition, and distinguishing clinical features of CDIAReA in children infected with C difficile.

Box Section Ref ID

Key Points

  • Question What are the incidence, recognition, and distinguishing clinical features of pediatric Clostridium difficile infection–associated reactive arthritis?

  • Findings In this multicenter cohort and nested case-control study, children with reactive arthritis generally had higher rates of emergency care and/or hospitalization than other children with C difficile infection despite having fewer comorbidities and more community-onset infections. Only one-third of cases of C difficile infection–associated reactive arthritis were correctly diagnosed, and occasionally this condition was misdiagnosed and treated as a septic arthritis.

  • Meaning Better recognition of C difficile infection–associated reactive arthritis is needed.

Methods
Study Design and Setting

We performed a retrospective cohort and nested case-control study using the electronic health records (EHRs) of 3 large pediatric care networks encompassing 3 free-standing children’s hospitals—the Children's Hospital of Philadelphia (Philadelphia, Pennsylvania), Nemours A. I. duPont Hospital for Children (Wilmington, Deleware), and Nemours Children’s Hospital (Orlando, Florida)—and their affiliated clinics across 4 states. This study was approved by the corresponding institutional review boards and by the institutional review board of Rutgers Biomedical and Health Sciences.

Study Population

Eligible participants for the cohort were between ages 2 and 21 years and diagnosed with symptomatic, laboratory-confirmed CDI between January 1, 2004, and December 31, 2013. We screened for children with CDI using the International Classification of Diseases, Ninth Revision (ICD-9) code 008.4520 (previously validated for CDI in hospitalized children) and/or positive test results for C difficile. We confirmed CDI by record review as having diarrhea (≥3 loose stools/d) and either a positive C difficile stool test (toxin assay or polymerase chain reaction [PCR] test, the latter used more routinely in study centers since 2011) or gross pseudomembranous colitis, per Society for Healthcare Epidemiology of America surveillance criteria.21

We screened for cases of CDIAReA among children in the cohort with ICD-9-CM codes or Current Procedural Terminology (CPT) codes suggesting musculoskeletal disease (eTable 1 in the Supplement) within 4 weeks before to 12 weeks after either CDI code or positive C difficile testing. Record review was performed to confirm cases using the following definition: presence of confirmed CDI plus acute arthritis and/or tenosynovitis documented by a physician, physician-level professional, or imaging study within 4 weeks before to 12 weeks after CDI plus (1) no other apparent cause for arthritis and (2) negative synovial fluid cultures (if obtained). While we anticipated that gastrointestinal and musculoskeletal symptoms would usually occur within several weeks after CDI, the long window was designed to maximize sensitivity using the EHR. We defined arthritis as the presence of joint effusion, swelling, or 2 other signs of joint inflammation (warmth, tenderness, restricted or painful range of motion). Children meeting the above criteria were classified as having CDIAReA, irrespective of diagnoses of treating clinicians.

For comparison, we identified controls among cohort participants with confirmed CDI but no concomitant joint pain, arthritis, or history of CDIAReA, as confirmed by medical record review. We matched each case to up to 4 controls by date of CDI diagnosis within 3 months of diagnosis and hospital network. Matching was occasionally incomplete at Nemours from 2004 to 2010, when C difficile laboratory test results were not reliably captured in discrete fields of the EHRs, limiting the pool of eligible controls.

Study Variables

We described cases and controls by demographics; comorbidities; clinical features of CDI and (for cases) arthritis; treatments used for CDI and, where applicable, arthritis; health care usage; and outcomes. We defined community-onset CDI as having diarrhea beginning outside the hospital or before hospital day 3.22 We classified CDI severity as complicated (causing hypotension, shock, ileus, megacolon, or surgical intervention), severe (acute kidney injury), or mild to moderate (anything else).21 We did not use white blood cell count greater than 15 000/μL (to convert to ×109/L, multiply by 0.001) to define severe CDI21 because leukocytosis may occur with CDIAReA despite mild gastrointestinal involvement. Study data were collected by record review and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at Nemours.23

Data Analysis

For the pediatric source population, we calculated the yearly incidence of CDIAReA and CDI and used these results to determine the incidence of CDIAReA among children diagnosed with CDI. We excluded from incidence calculations children from Nemours in 2004 to 2010 due to unreliable recording of C difficile tests. The source population consisted of children ages 2 to 21 years with 1 or more encounter in the hospital network in a given year who also had a prior outpatient visit (primary or subspecialty care) in the same network within the past 24 months. This definition enabled tabulation of cases among children receiving ongoing care within the respective care network to derive population-representative incidence estimates. A similar approach was validated in surveillance of another infectious disease.24 We tallied cases of CDI via EHR query, counting children in the source population with both ICD-9-CM code 008.45 and positive C difficile testing in the same year. This definition has greater specificity for CDI than using diagnostic codes or test results alone.20 Cases of CDIAReA included in incidence calculations were confirmed by record review to be in the source population and have both CDI diagnosis code and positive test results. We examined trends in CDIAReA incidence using linear regression and adjusted for changes in CDI incidence.

We calculated descriptive statistics for cases of CDIAReA and matched controls. We evaluated risk factors and other clinical features associated with CDIAReA using conditional logistic regression to account for matching. All analyses assumed a 2-sided type I error rate of 0.05. Results were expressed with 95% confidence intervals (CI). We used Stata/IC version 12.1 (StataCorp) for all analyses.

Results
Incidence and Clinical Features of C difficile Infection–Associated Reactive Arthritis

The overall incidence of CDIAREA was 5.0 cases (95% CI, 3.2-7.8) per million children per year (19 children with CDIAREA detected among 3.8 million person-years of follow-up). The yearly incidence of CDIAReA rose throughout the study period by 0.8 additional cases (95% CI, 0.3-1.3) per million person-years (Table 1). Among children with CDI, the incidence of CDIAReA was 1.4 cases (95% CI, 0.8-2.3) per 100 children with C difficile infections yearly.

We identified 26 children with CDI who met the predefined definition of CDIAReA (Figure). There were 17 additional possible cases (excluded from analyses) with CDI-associated arthritis with other possible etiologies or arthralgias without documented arthritis. Children with presumed CDIAReA generally developed pain, swelling, limited movement, and sometimes redness in multiple joints (median, 4.5 joints; interquartile range [IQR], 3-8 joints) (Table 2). The pattern of arthritis was most often migratory (n = 20 [77%]), whereby inflammation would resolve in 1 or several joints as new joints became inflamed. CDIAReA involved large and small joints, most commonly the hip (n = 16 [62%]) and knee (n = 18 [69%]), as well as tendons (eTable 2 in the Supplement). About half of affected children had concurrent fever (n = 15 [58%]) and/or a rash (n = 14 [54%]), often consisting of blanching red macules and/or urticarial papules. Seven children underwent HLA-B27 testing, and results were negative (normal) for all. When performed, imaging revealed articular as well as periarticular inflammation affecting the soft tissues, fasciae, muscles, and/or bone (Table 2).

The onset of musculoskeletal symptoms typically followed diarrheal onset by 1 to 2 weeks (median [IQR], 10.5 [7-15] days). The median (IQR) time from onset of musculoskeletal symptoms to presentation for clinical care was 1 (0-3) day(s), underscoring the disruptive nature of CDIAReA. In half of children (n = 13), arthritis symptoms resolved within 2 weeks (IQR, 6-22.5 days) of CDI treatment initiation, although a majority (n = 15 [58%]) also received concurrent anti-inflammatories (mostly nonsteroidal). Over median follow-up of 2.5 years (IQR, 0.9-5.0 years), 4 children with CDIAReA developed recurrent joint pains (15%), only 1 with a confirmed new CDI. None was diagnosed with chronic arthritis or inflammatory bowel disease.

Underdiagnosis and Morbidity of CDIAReA

Clinicians providing treatment specifically attributed the arthritis to CDI in only 9 cases (35% overall; 0%, 15%, and 64% at participating centers, with overlapping confidence intervals). Alternative diagnoses included reactive arthritis from unknown causes or toxic and/or transient synovitis (n = 10 [38%]), septic arthritis (n = 5 [19%]), serum sickness (n = 3 [12%]), acute rheumatic fever (n = 1 [4%]), and bursitis and/or cellulitis (n = 1 [4%]). Nonsurgical pediatric subspecialists were involved in the care of all children diagnosed with CDIAReA, but over half of children who saw such subspecialists (n = 10 [53%]) were not diagnosed with CDIAReA by any physician.

Nearly half of cases (n = 12 [46%]) raised clinician concerns for septic arthritis during their clinical course. These children were more likely to have hip involvement than other cases (83% vs 43%; P = .03). In addition to having fever, severe joint pain, and difficulty bearing weight, many of these children also had laboratory findings consistent with increased inflammation: elevated inflammatory markers and elevated white blood cell counts both in the blood and synovial fluid (median [IQR] 56 375 [50 000-103 000] cells/mL; median [IQR] 91.5% [90%-93%] neutrophils) (Table 3; eTable 3 in the Supplement). The 5 children diagnosed with culture-negative septic arthritis (all affecting the hip) underwent surgical drainage procedures and completed full courses of antibiotics in addition to treatment specifically for CDI. Notably, all children whose condition resembled septic arthritis had antecedent postantibiotic diarrhea and/or prior musculoskeletal symptoms affecting other joints.

Comparison of C difficile–Infected Children With and Without Reactive Arthritis

Among children with CDI, cases and controls had similar demographic characteristics (Table 4). Compared with controls, children with CDIAReA were less likely to have a chronic underlying condition (odds ratio [OR], 0.3; 95% CI, 0.1-0.8; P = .01) and had significantly fewer medical comorbidities (OR, 0.5; 95% CI, 0.3-0.8; P = .009). Cases did not differ from controls in their history of autoimmune comorbidities or arthritis. With regard to the CDI itself, cases were more likely to have community-onset CDI (100% cases vs 75% controls; P = .005). Otherwise, there were no differences between cases and controls in their history of preceding infections or antibiotic exposures, CDI severity, or CDI treatment.

Despite having fewer comorbidities and exclusively community-onset CDI, children with CDIAReA had notably higher rates of health care usage compared with controls (Table 4). Nearly all cases (n = 24 [92%]) were seen in emergency departments and/or hospitalized for their acute CDI-related illness. Two-thirds (n = 17 [65%]) were hospitalized specifically for arthritis. Children with CDIAReA saw various pediatric generalists and specialists other than their primary care physicians for their acute illness (eTable 4 in the Supplement).

Discussion

To our knowledge, this is the first systematic evaluation of the clinical epidemiology of CDIAReA. CDIAReA is an underdiagnosed and often morbid condition affecting 1% to 2% of children with CDI. CDIAReA was sometimes identified as a reactive process (reactive arthritis, transient synovitis, or serum sickness) by clinicians, but it was attributed to CDI in a minority of cases. Complicating this issue further, CDIAReA was occasionally misdiagnosed as a septic arthritis owing to severe, isolated joint (usually hip) pain and systemic inflammation (eg, fever, marked laboratory abnormalities). Some children with CDIAReA were treated for presumed culture-negative septic arthritis despite clinical clues suggestive of an alternative diagnosis, namely preceding postantibiotic diarrhea and other transiently symptomatic joints. Furthermore, nearly all affected children were seen in emergency departments and/or were hospitalized acutely even though they had fewer medical comorbidities and presented more frequently with community-onset CDI than matched C difficile–infected comparators. These findings, along with the rising incidence of CDIAReA, suggest that better recognition of this condition is needed to treat C difficile promptly, while avoiding unnecessary, potentially harmful interventions.

Clostridium difficile is considered an uncommon cause of reactive arthritis compared with other enteric pathogens.6 More than 50 cases of CDIAReA have been published in the medical literature since 1976, predominantly in adults.6-10 Case reports reviewing other published cases have highlighted common features of CDIAReA: onset of arthritis within 1 to 3 weeks of gastrointestinal symptoms; frequent presence of fever; migratory involvement of multiple large and small joints (most commonly wrists, knees, and ankles in adults); and symptomatic resolution for most patients within 2 months of treatment for C difficile.8,10,25 While disparate reported cases cannot be considered a representative sample, these clinical features are compatible with the few reported pediatric cases15-19 and our own study’s findings. In contrast with adults, children appear to have more frequent hip involvement and, associated with this, more dramatic clinical presentations that sometimes raise concerns for septic arthritis.16,17

Several children with CDIAReA in our cohort were diagnosed with serum sickness. Generally, this immune complex-mediated disease presents within 1 to 2 weeks after antibiotic exposure as a symmetric arthritis of multiple joints accompanied by urticarial-like rash and angioedema. In contrast, in our cohort, CDIAReA usually presented over 2 weeks after the most recent antibiotic course with asymmetric, migratory joint inflammation and sometimes rash without angioedema.

The passing resemblance of some cases of CDIAReA to septic arthritis can pose greater challenges in management because of the potential morbidity of joint infections as well as their treatment. In some children, it can be difficult to discern whether the joint is infected, so treatment likely should be aggressive. Drainage procedures, even when performed outside the operating room, may provide symptomatic relief as well as fluid for analysis and culture.16,17 However, for those with preceding (postantibiotic) diarrhea and migratory or multiple-site arthritis, CDIAReA can be presumed and closely monitored. In our study, CDIAReA was self-limited, usually resolving within 1 to 3 weeks after treatment for CDI. Use of oral anti-inflammatories (nonsteroidal, occasionally glucocorticoids) was a helpful adjunct for children with more severe or persistent symptoms. Whether prompt recognition and treatment of CDI could prevent this rheumatic complication is unclear.

We did not detect clinical risk factors for CDIAReA among those with preexisting CDI; cases and controls had similar demographics, overall rates of antecedent infection and antibiotic exposure, and treatment of CDI upon diagnosis. While there were some group differences in specific infections and antibiotics before CDI, these differences more likely reflected the better baseline health of cases. The co-occurrence of arthritis with C difficile infection may relate to other genetic, immunologic, and microbiologic factors, as reported with other infectious triggers.26-28 Interestingly, some children with C difficile–associated arthralgias were neutropenic with their illness, which may have prevented frank arthritis from manifesting. In contrast, those with CDIAReA resembling septic arthritis had robust neutrophilic immune responses in the blood and synovial fluid. These observations highlight the potential importance of the innate immune system in the severity of CDIAReA. Notably, C difficile toxin is a potent activator of innate immunity.29,30 Moreover, C difficile can also stimulate cytokines important for the activity of Th17 cells,31,32 adaptive immune cells important in the pathophysiology of chronic arthritis.33

Our study has several strengths. We used a systematic approach to identify cases of CDIAReA along with matched controls in the EHR of several large pediatric hospital networks across 4 states. This approach allowed us to study the incidence and risk factors for this disease within a large pediatric population, yielding novel epidemiologic data on this poorly understood disease. Of note, rates of pediatric CDI in our study were compatible with rates reported elsewhere2 during the same period. In addition, our case-finding method allowed us to evaluate children with CDIAReA whose diagnosis was not recognized by treating clinicians, as well as study a wider spectrum of clinical disease than might otherwise have been possible based on referral alone.

This study also has limitations. Our case-finding algorithm relied on documentation of both CDI and musculoskeletal problems within a limited window of time. It is possible that we missed cases either because of mild symptoms or incomplete documentation. We identified other children with CDI and arthralgias and/or arthritis suggestive of CDIAReA who did not meet our study definition because of alternative possible etiologies or the lack of documented arthritis. For this reason, we may have underestimated CDIAReA incidence, and we may have focused on children with more severe musculoskeletal disease and thus overestimated CDIAReA severity. On the other hand, because reactive arthritis is a diagnosis of exclusion, we cannot be certain that CDI triggered arthritis in all cases. Testing for alternative bacterial pathogens was not comprehensive, and 1 child also tested positive for rotavirus (not generally considered a cause of reactive arthritis). Furthermore, the apparent rise in CDIAReA incidence during the study period may have reflected other secular trends, such as improving EHR documentation or the introduction of sensitive PCR-based techniques to detect C difficile. Additionally, although we studied CDIAReA within large pediatric populations across several states, our findings may still reflect local patterns of CDI, genetic susceptibility, and practice patterns that may not generalize to other regions. In our study, few patients were tested for HLA-B27, and those that were had negative (normal) results, limiting more systematic examination of a genetic risk factor linked to joint inflammation in response to gut microbiota imbalance.34-36 Finally, though this is the largest epidemiologic study of CDIAReA to date, we may have been limited in statistical power to identify all clinical factors associated with this disease.

Conclusions

CDIAReA is an underdiagnosed, potentially morbid reactive arthritis associated with CDI that can occasionally present similarly to septic arthritis. A history of migratory or multiple joint pains and concurrent postantibiotic diarrhea may be important diagnostic clues in children presenting with fever and severe joint pain. CDIAReA leads to high rates of health care usage even though many affected children are otherwise healthy and have community-associated CDIs. As the incidence of CDIs and CDIAReA increases in children, better recognition of CDIAReA is needed to initiate prompt treatment while avoiding unnecessary intervention.

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Article Information

Corresponding Author: Daniel B. Horton, MD, MSCE, Child Health Institute of New Jersey, 89 French St, Room 4102, New Brunswick, NJ 08901 (daniel.horton@rutgers.edu).

Accepted for Publication: January 14, 2016.

Published Online: May 16, 2016. doi:10.1001/jamapediatrics.2016.0217.

Author Contributions: Dr Horton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Horton, Putt, Rose, Sherry, Sammons.

Acquisition, analysis, or interpretation of data: Horton, Strom, Rose, Sammons.

Drafting of the manuscript: Horton.

Critical revision of the manuscript for important intellectual content: Strom, Putt, Rose, Sherry, Sammons.

Statistical analysis: Horton.

Obtained funding: Horton.

Administrative, technical, or material support: Rose, Sammons.

Study supervision: Strom, Putt, Rose, Sammons.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by the National Institute of General Medical Sciences (grant T32 GM075766) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant F32 AR066461).

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Jenna Tress, CCRP, provided valuable research coordination and regulatory assistance. Janille Diaz, BA, Elizabeth Kaufman, BA, and Bernadette Lewcun, BA, assisted with data collection. Molly E. Collins, MD, gave critical feedback on the manuscript. No one received compensation for their additional contributions.

References
1.
Bartlett  JG.  Clinical practice. Antibiotic-associated diarrhea.  N Engl J Med. 2002;346(5):334-339.PubMedGoogle ScholarCrossref
2.
Khanna  S, Baddour  LM, Huskins  WC,  et al.  The epidemiology of Clostridium difficile infection in children: a population-based study.  Clin Infect Dis. 2013;56(10):1401-1406.PubMedGoogle ScholarCrossref
3.
Zilberberg  MD, Tillotson  GS, McDonald  C.  Clostridium difficile infections among hospitalized children, United States, 1997-2006.  Emerg Infect Dis. 2010;16(4):604-609.PubMedGoogle ScholarCrossref
4.
Nylund  CM, Goudie  A, Garza  JM, Fairbrother  G, Cohen  MB.  Clostridium difficile infection in hospitalized children in the United States.  Arch Pediatr Adolesc Med. 2011;165(5):451-457.PubMedGoogle ScholarCrossref
5.
Sammons  JS, Localio  R, Xiao  R, Coffin  SE, Zaoutis  T.  Clostridium difficile infection is associated with increased risk of death and prolonged hospitalization in children.  Clin Infect Dis. 2013;57(1):1-8.PubMedGoogle ScholarCrossref
6.
Birnbaum  J, Bartlett  JG, Gelber  AC.  Clostridium difficile: an under-recognized cause of reactive arthritis?  Clin Rheumatol. 2008;27(2):253-255.PubMedGoogle ScholarCrossref
7.
Hayward  RS, Wensel  RH, Kibsey  P.  Relapsing Clostridium difficile colitis and Reiter’s syndrome.  Am J Gastroenterol. 1990;85(6):752-756.PubMedGoogle Scholar
8.
Jacobs  A, Barnard  K, Fishel  R, Gradon  JD.  Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature.  Medicine (Baltimore). 2001;80(2):88-101.PubMedGoogle ScholarCrossref
9.
Koçar  IH, Calişkaner  Z, Pay  S, Turan  M.  Clostridium difficile infection in patients with reactive arthritis of undetermined etiology.  Scand J Rheumatol. 1998;27(5):357-362.PubMedGoogle ScholarCrossref
10.
Prati  C, Bertolini  E, Toussirot  E, Wendling  D.  Reactive arthritis due to Clostridium difficile.  Joint Bone Spine. 2010;77(2):190-192.PubMedGoogle ScholarCrossref
11.
Wright  TW, Linscheid  RL, O’Duffy  JD.  Acute flexor tenosynovitis in association with Clostridium difficile infection: a case report.  J Hand Surg Am. 1996;21(2):304-306.PubMedGoogle ScholarCrossref
12.
Delègue  P, Dhote  R, Permal  S, Boissonnas  A, Christoforov  B.  [Clostridium difficile reactive arthritis].  Gastroenterol Clin Biol. 2001;25(8-9):830-831.PubMedGoogle Scholar
13.
Keating  RM, Vyas  AS.  Reactive arthritis following Clostridium difficile colitis.  West J Med. 1995;162(1):61-63.PubMedGoogle Scholar
14.
Razavi  B.  Reactive arthritis after Helicobacter pylori eradication.  Lancet. 2000;355(9205):720.PubMedGoogle ScholarCrossref
15.
Cron  RQ, Gordon  PV.  Reactive arthritis to Clostridium difficile in a child.  West J Med. 1997;166(6):419-421.PubMedGoogle Scholar
16.
Dacheux  C, Pruvost  I, Herbaux  B, Nectoux  E.  [Clostridium difficile reactive arthritis in a 7-year-old child].  Arch Pediatr. 2012;19(6):607-611.PubMedGoogle ScholarCrossref
17.
Durand  CL, Miller  PF.  Severe Clostridium difficile colitis and reactive arthritis in a ten-year-old child.  Pediatr Infect Dis J. 2009;28(8):750-751.PubMedGoogle ScholarCrossref
18.
Finger  DR, Neubauer  JV.  Reactive arthritis following Clostridium difficile colitis in a 3-year-old patient.  J Clin Rheumatol. 1997;3(2):102-104.PubMedGoogle ScholarCrossref
19.
Löffler  HA, Pron  B, Mouy  R, Wulffraat  NM, Prieur  A-M.  Clostridium difficile-associated reactive arthritis in two children.  Joint Bone Spine. 2004;71(1):60-62.PubMedGoogle ScholarCrossref
20.
Shaklee  J, Zerr  DM, Elward  A,  et al.  Improving surveillance for pediatric Clostridium difficile infection: derivation and validation of an accurate case-finding tool.  Pediatr Infect Dis J. 2011;30(3):e38-e40.PubMedGoogle ScholarCrossref
21.
Cohen  SH, Gerding  DN, Johnson  S,  et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America.  Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA).  Infect Control Hosp Epidemiol. 2010;31(5):431-455.PubMedGoogle ScholarCrossref
22.
Centers for Disease Control and Prevention (CDC).  Vital signs: preventing Clostridium difficile infections.  MMWR Morb Mortal Wkly Rep. 2012;61(9):157-162.PubMedGoogle Scholar
23.
Harris  PA, Taylor  R, Thielke  R, Payne  J, Gonzalez  N, Conde  JG.  Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.  J Biomed Inform. 2009;42(2):377-381.Google ScholarCrossref
24.
Feemster  KA, Li  Y, Grundmeier  R, Localio  AR, Metlay  JP.  Validation of a pediatric primary care network in a US metropolitan region as a community-based infectious disease surveillance system.  Interdiscip Perspect Infect Dis. 2011;2011:219859.PubMedGoogle Scholar
25.
Putterman  C, Rubinow  A.  Reactive arthritis associated with Clostridium difficile pseudomembranous colitis.  Semin Arthritis Rheum. 1993;22(6):420-426.PubMedGoogle ScholarCrossref
26.
Kuuliala  K, Orpana  A, Leirisalo-Repo  M, Repo  H.  Neutrophils of healthy subjects with a history of reactive arthritis show enhanced responsiveness, as defined by CD11b expression in adherent and non-adherent whole blood cultures.  Rheumatology (Oxford). 2007;46(6):934-937.PubMedGoogle ScholarCrossref
27.
Rihl  M, Barthel  C, Klos  A,  et al.  Identification of candidate genes for susceptibility to reactive arthritis.  Rheumatol Int. 2009;29(12):1519-1522.PubMedGoogle ScholarCrossref
28.
Baillet  AC, Rehaume  LM, Benham  H,  et al.  High chlamydia burden promotes tumor necrosis factor-dependent reactive arthritis in SKG mice.  Arthritis Rheumatol. 2015;67(6):1535-1547.PubMedGoogle ScholarCrossref
29.
Ng  J, Hirota  SA, Gross  O,  et al.  Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome.  Gastroenterology. 2010;139(2):542-552, 552.e1-552.e3.PubMedGoogle ScholarCrossref
30.
Xu  H, Yang  J, Gao  W,  et al.  Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome.  Nature. 2014;513(7517):237-241.PubMedGoogle ScholarCrossref
31.
Jafari  NV, Kuehne  SA, Bryant  CE,  et al.  Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s).  PLoS One. 2013;8(7):e69846.PubMedGoogle ScholarCrossref
32.
Cowardin  CA, Kuehne  SA, Buonomo  EL, Marie  CS, Minton  NP, Petri  WA  Jr.  Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile.  MBio. 2015;6(1):e02386-14.PubMedGoogle ScholarCrossref
33.
Lubberts  E.  The IL-23-IL-17 axis in inflammatory arthritis.  Nat Rev Rheumatol. 2015;11(7):415-429.PubMedGoogle ScholarCrossref
34.
Rath  HC, Herfarth  HH, Ikeda  JS,  et al.  Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats.  J Clin Invest. 1996;98(4):945-953.PubMedGoogle ScholarCrossref
35.
Schiellerup  P, Krogfelt  KA, Locht  H.  A comparison of self-reported joint symptoms following infection with different enteric pathogens: effect of HLA-B27.  J Rheumatol. 2008;35(3):480-487.PubMedGoogle Scholar
36.
Lin  P, Bach  M, Asquith  M,  et al.  HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats.  PLoS One. 2014;9(8):e105684.PubMedGoogle ScholarCrossref
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