DTIC ADA591292: A Case Control Study of Incident Rheumatological Conditions Following Acute Gastroenteritis During Military Deployment

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by  Defense Technical Information Center

Open Access Research
–
A case control study of incident
rheumatological conditions following
acute gastroenteritis during military
deployment
Kathryn H DeYoung,1,2 Mark S Riddle,3 Larissa May,2,4 Chad K Porter3
Tocite:DeYoungKH, ABSTRACT
Strengths and limitations of this study
RiddleMS,MayL,etal. Objectives:Theaimofthisstudywastoassessthe
Acase–controlstudyof
riskofincidentrheumatologicaldiagnoses(RD) ▪ Use of self-reported gastroenteritis instead of
incidentrheumatological
conditionsfollowingacute associatedwithself-reporteddiarrhoeaandvomiting medical encounter data or culture-confirmed
gastroenteritisduringmilitary duringafirst-timedeploymenttoIraqorAfghanistan. infectious gastroenteritis enabled inclusion of a
deployment.BMJOpen SuchanassociationwouldprovideevidencethatRDin larger portion of personnel potentially exposed
2013;3:e003801. thispopulationmayincludeindividualswithreactive topathogensofinterest.
doi:10.1136/bmjopen-2013- arthritis(ReA)fromdeployment-relatedinfectious ▪ Extraction of data from a health assessment
003801 gastroenteritis. completed by all military personnel returning
Design:Thiscase–controlepidemiologicalstudyused from deployment allowed access to a large pool
▸ Prepublicationhistoryfor univariateandmultivariatelogisticregressiontocompare ofrespondents.
thispaperisavailableonline. theoddsofself-reporteddiarrhoea/vomitingamong ▪ Broadly defining reactive arthritis by the specific
Toviewthesefilesplease deployedUSmilitarypersonnelwithincidentRDtothe and non-specific International Classification of
visitthejournalonline oddsofdiarrhoea/vomitingamongacontrolpopulation. Diseases, Ninth Revision, Clinical Modification
(http://dx.doi.org/10.1136/ Setting:Weanalysedhealthrecordsofpersonnel codesincreasedthesensitivity.
bmjopen-2013-003801). deployedtoIraqorAfghanistan,includingresponseson ▪ Each of these study design decisions introduced
apostdeploymenthealthassessmentandmedicalfollow- the possibility of non-differential biases, includ-
Received15August2013
uppostdeployment. ing exposure misclassification, recall bias and
Revised23October2013
Accepted6November2013 Participants:Anonymousdatawereobtainedfrom891 outcome misclassification. This would likely bias
USmilitarypersonnelwithatleast6monthsofmedical theassociationstowardsthenull.
follow-upfollowingafirst-timedeploymenttoIraqor
Afghanistanin2008–2009.Casesweredefinedusing
InternationalClassificationofDiseases,NinthRevision, Conclusions:Incidentrheumatologicalconditions,
ClinicalModification(ICD-9-CM)diagnosiscodes; eventhoseclassifiedas‘non-specific,’aresignificantly
controlshadanunrelatedmedicalencounterandwere associatedwithpriorseverediarrhoeainpreviously
representativeofthestudypopulation. deployedmilitarypersonnel,potentiallyindicatingReA
Mainoutcomemeasures:Theprimarymeasurewas andneedforpreventivemeasurestoreduce
anassociationbetweenincidentRDandself-reported diarrhoeagenicbacterialexposuresinmilitarypersonnel
diarrhoea/vomitingduringdeployment.Asecondary andothertravellerstothedevelopingregions.
1DenverPublicHealth,
measurewastheoverallincidenceofRDinthis
Denver,Colorado,USA
population.
2DepartmentofEpidemiology
Results:Weidentified98casesofnewonsetRD,witha
andBiostatistics,Schoolof
PublicHealthandHealth totalincidenceof161/100000persons.Ofthose,two
INTRODUCTION
Services,GeorgeWashington participantshadbeendiagnosedwithReiter’sdiseasei
Travellers’ diarrhoea (TD) is common
University,WashingtonDC, (3.3/100000persons)andtheremainderwithnon-
USA specificarthritis/arthralgia(157.5/100000persons).The among those travelling from the developed
3EntericDiseases ORforacutediarrhoeawas2.67(p=0.03)afteradjusting to the developing regions of the world.
Department,NavalMedical forimportantcovariates. Incidence is broadly estimated at 20–40% of
ResearchCenter,Silver
travellers per month but varies by country
Spring,Maryland,USA
4DepartmentofEmergency or region visited, duration of travel and
Medicine,George sociodemographic factors.1–3 The aetiology
iThe terms Reiter’s disease and Reiter’s syndrome are
WashingtonUniversity, of TD is predominantly bacterial, commonly
beingreplacedwiththemoreappropriatetermReactive
WashingtonDC,USA Arthritis. Usage in this article strictly refers to their caused by diarrhoeagenic Escherichia coli,
useintheInternationalClassificationofDiseases,Ninth Campylobacter spp., Shigella spp. and non-
Correspondenceto Revision, Clinical ModificationICD-9-CM diagnostic
DrChadKPorter; codes (099.3 and 711.1) and is not an endorsement of typhoidal Salmonella spp., although viral and
[email protected] theterms. parasitic infections also occur.3–5 While the
DeYoungKH,RiddleMS,MayL,etal.BMJOpen2013;3:e003801.doi:10.1136/bmjopen-2013-003801 1
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4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER
A case control study of incident rheumatological conditions following
5b. GRANT NUMBER
acute gastroenteritis during military deployment
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Open Access
acute symptoms associated with TD are predominately regions, we sought to assess the risk of incident rheum-
self-limited and may be shortened in duration by anti- atological diagnoses (RD) associated with self-reported
biotic therapy, sequelae associated with infection by diarrhoea and vomiting during a first-time deployment
pathogens of TD can cause long-term gastrointestinal, to Iraq or Afghanistan.15 16
neurological and rheumatological health outcomes.6–8
Reactive arthritis (ReA) is a sterile asymmetric arthritis
of one or more joints that can include inflammation of METHODS
the tendons, eyes, genitourinary tract and skin.9 Joint A case–control study of military personnel was designed
inflammation is most common in the large joints of the to comparethe odds ofself-reported diarrhoea or vomit-
lower limbs.9 10 The most stronglyassociated enteric bac- ing during deployment among personnel with incident
teria are Campylobacter jejuni and coli, non-typhoidal RD (cases) to the odds among those without such diag-
Salmonella spp, Shigella spp and Yersinia enterocolitica.9–13 noses (controls). All participants were active duty US
Reports of ReA following bacterial gastroenteritis are military personnel on initial deployment between 2008
most common following large-scale outbreaks, and esti- and 2009 with at least 6 months of postdeployment
mates of incident ReA outcomes range from 0% to 30% medical follow-up (figure 1). Cases were identified using
depending on the infecting pathogen, host characteris- International Classification of Diseases, Ninth Revision,
tics, outcome definitions and other factors.10 14 Clinical Modification (ICD-9-CM) codes for Reiter’s
Deployed military personnel represent a young, pre- diseasei (099.3 and 711.1), postdysenteric arthropathy
dominately healthy subset of the general travel popula- (711.3) and, due to the confounding factors underlying
tion at high risk of TD and, potentially, of related Reiter’s diseasei diagnoses, a category of non-specific
sequelae. Given the prior reports of an increased risk of arthritis/arthralgia (NAA) was included (716.4-.6,
functional gastrointestinal disorders following infectious 716.8-.9).10 16 17 The ICD-9-CM codes for postdysenteric
gastroenteritis during military deployment and atwofold arthropathy and non-specific arthritis/arthropathy
increased risk of Reiter’s diseasei and postdysenteric include a fifth digit subclassification indicating the body
arthropathy among personnel deployed to high-risk area affected (figure 2). Cases required a minimum of
Figure1 Schemaofselectionforanalysis.
2 DeYoungKH,RiddleMS,MayL,etal.BMJOpen2013;3:e003801.doi:10.1136/bmjopen-2013-003801
Open Access
Figure2 Fifthdigit
subclassificationofbodyarea
affected.
two separate outcome-specific medical encounters for and/or had been ordered to remain in their quarters
within 365days with no concurrent diagnoses of (bed rest) or placed on medically restricted duty status
Chlamydia trachomatis, Neisseria gonorrhoeae or Ureaplasma (light/limited duty) for diarrhoea or vomiting. Personnel
urealyticum. Controls were of a similar age, deployment who consistently did not respond to the exposure ques-
location (Iraq or Afghanistan), had an unrelated tions were excluded from the case–control analysis; for
medical encounter and were representative of the study those who answered at least one exposure question, we
population. consideredmissingresponsesas‘no’responses.
All data were obtained from the Defense Medical The incidence of RD was calculated based on the
Surveillance System (DMSS), a repository for medical number of active duty US military personnel eligible for
surveillance data on US military personnel.18 inclusion into this study. Multivariate logistic regression
Demographic variables, including age, gender, race, models were developed utilising a backward elimination
rank and marital status were analysed to assess their approach in which all covariates were initially included.
association with incident RD. Because acute enteric The final adjusted model was developed iteratively for
infections are under-reported through electronic the outcome of any diarrhoea or vomiting during
medical records, exposure data were obtained from deployment, and only variables with α≤0.15 were
postdeployment health assessments (PDHAs), a self- retained. The final model was then applied to each
administered survey completed by all US military person- exposure strata. Reference groups were chosen based on
nel returning from deployment. Of specific interest for prior epidemiological studies as well as distribution of
this study were questions about diarrhoea and vomiting our data. Statistical analyses were conducted using SAS
during deployment. Respondents indicated whether V.9 for Windows (SAS Institute, Cary, North Carolina,
during deployment, they had seen a healthcare provider USA) and interpretedusing α=0.05.
DeYoungKH,RiddleMS,MayL,etal.BMJOpen2013;3:e003801.doi:10.1136/bmjopen-2013-003801 3
Open Access
The study protocol was approved by the Naval Medical Compared with controls, cases were more predominately
Research Center Institutional Review Board in compli- male (94% vs 70%; p<0.001) and tended to be married
ance with all applicable Federal regulations governing (60% vs 48%; p=0.06). The prevalence of self-reported
the protection of human participants. gastroenteritis was relatively low across deployments
(19.4%; table 2). However, personnel deployed to
Afghanistan reported diarrhoea and/or vomiting more
RESULTS oftenthanthosedeployedtoIraq(37%vs17%,p=0.01).
We identified 98 cases of new onset RD among active Univariate logistic regression showed that male
duty military personnel with an initial deployment to gender (p<0.001) and rank (p=0.01) were associated
Iraq and/or Afghanistan between 2008 and 2009 for a with increased incidence of rheumatological outcomes
total incidence of 161/100000 persons (figure 1). Two (table 3). A greater per cent of cases than controls
cases were diagnosed with Reiter’s diseasei (3.3/100000 reported care-seeking (23.5% vs 15.2%; p=0.07) and
persons) and the rest with NAA (157.5/100000 being assigned light/limited duty (10.3% vs 5.0%
persons). Of the nine possible subclassifications, the p=0.07) for diarrhoea. Black or white race (p=0.15),
most frequently specified body areas affected were lower junior officer rank (p=0.11) and being married
leg (27%), shoulder (21%) and ankle/foot (21%); 18% (p=0.06) were also more common among those with
of diagnoses did not specify a body area (figure 2). The RD. Afteradjusting forcovariates, the prevalence ofdiar-
remaining 13% were composed of pelvic region/thigh rhoea and vomiting was consistently higher among cases
(4.5%), forearm (2.4%), hand (0.9%), upper arm than among controls (table 4). In personnel reporting
(0.6%), and other (2.4%) or multiple (2.1%) sites. more severe diarrhoea (eg, being sick-in-quarters or
Excluding primary exposure non-respondents (ie, placed on light/limited duty), there was an approxi-
those who did not answer gastroenteritis questions) mately 2.5-fold increased odds of RD compared with
yielded 891 participants: 68 cases and 823 controls those who did not (aOR 2.67; p=0.03). Although the
(figure 1). Overall, 28% of original participants were association with milder diarrhoea was not statistically sig-
non-respondents: 31% of cases and 28% of controls. As nificant, there was a trend suggestive of a dose–response
intended, there was no difference in the average age of effect. Self-reported vomiting was not a significant pre-
cases or controls (mean 27.6years; SD 6.8; table 1). dictorof incident RD.
Table1 DemographicandexposurecharacteristicsofUSmilitaryservicemembersaftertheirfirstdeploymenttoIraqor
Afghanistanbetween2008and2009
Variable Cases*(n=68) Controls(n=823) pValue
Meanage(SD) 28.5(6.8) 27.5(7.6) 0.26
Gender
Female 4(6%) 244(30%) <0.001
Male 64(94%) 579(70%)
Race
Black 15(22%) 167(20%) 0.72
White 45(66%) 500(61%)
Other 8(12%) 156(19%)
Rank
Enlisted 60(88%) 702(85%) 0.50
Officer/warrantofficer 8(12%) 121(15%)
Maritalstatus
Single/other 27(40%) 426(52%) 0.06
Married 41(60%) 397(48%)
Deploymentregion†
Afghanistan 7(10%) 97(12%)
Iraq 60(90%) 721(88%) 0.73
Gastroenteritis
Anydiarrhoea/vomiting 19(27.9%) 154(18.7%) 0.07
Anydiarrhoea 16(23.5%) 131(15.9%) 0.11
Soughtcarefordiarrhoea 16(23.5%) 125(15.2%) 0.07
Limiteddutystatus—diarrhoea 7(10.3%) 41(5.0%) 0.07
Anyvomiting 9(13.2%) 71(8.6%0 0.21
Soughtcareforvomiting 8(11.8%) 66(8.0%) 0.29
Limiteddutystatus—vomiting 4(5.9%) 39(4.7%) 0.67
*DiagnosedatleasttwicewithICD-9-CMcodesmeetingstudycriteriaforincidentRDwithin365days.
†Excludessixpersonnelwhodeployedtobothregions.Casen=67,controln=818.
4 DeYoungKH,RiddleMS,MayL,etal.BMJOpen2013;3:e003801.doi:10.1136/bmjopen-2013-003801
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Table2 Frequency(n(%))ofself-reported,deployment-relatedexposuresbydeploymentregion(excludingsixpersonnel
deployedtobothregions)
Variable Afghanistan(n=104) Iraq(n=781) pValue
Anygastroenteritis 40(38) 132(17) 0.01
Anydiarrhoea 33(32) 114(15) 0.28
Soughtcarefordiarrhoea 32(31) 109(14) 0.39
Bedrest/lightorlimiteddutystatus—diarrhoea 9(9) 39(5) 0.92
Anyvomiting 17(16) 62(8) 0.29
Soughtcareforvomiting 15(14) 58(7) 0.19
Bedrest/lightorlimiteddutystatus—vomiting 8(8) 34(4) 0.59
DISCUSSION post-deployment surveys to identify diarrheal cases.
We found that 16% of deployed service members sought However, this could also indicate a true decrease in inci-
care for diarrhoea, 38% of whom required a change in dence due to decreased risk in theatre, which has been
duty as a result of the acute illness. This is much lower reported in apreviouspublication.21
than prior estimates of gastroenteritis in deployed mili- We identified an overall incidence of RD of 161/
tary personnel.19 20 Specifically, Sanders et al19 found in 100000 (Reiter’s diseasei: 3.1/100000 and NAA: 157.5/
2004 that 77% of US personnel who served in Iraq and 100000), similar to estimates reported by Curry et al.16
54% ofthose deployed toAfghanistan reported any diar- These estimates are greater than those from population-
rheal illness; nearly half of those with diarrheal illness based studies within the USA, likely due to differences
had sought care. Differences in study methods may have in study populations and methods utilised to classify
contributed to this difference. Use of a post-deployment exposures and outcomes.11 In addition, exposure to spe-
questionnaire in our study is likely to have resulted in cific bacterial pathogens in deployed populations is
under-reporting of exposure, while Sanders et al utilised likely more common than in the developed countries,
active case-surveillance through mid-deployment and where viruses are the dominant cause of acute
Table3 UnadjustedconditionalORs(95%CIs)forexposurevariablesandcovariatesfromunivariateanalysisevaluating
RDafterfirstdeploymenttoIraqorAfghanistanbetween2008and2009
Variable OR 95%CI pValue
Gender
Female 1.0
Male 6.74 2.48to18.71 <0.001
Race
Other 1.0
Black/white 1.75 0.82to3.74 0.15
Rank
Enlisted 1.0
Juniorofficer 0.43 0.15to1.22 0.11
Seniorofficer 11.70 1.62to84.54 0.01
Warrantofficer 2.13 0.46to9.82 0.33
Maritalstatus
Single/other 1.0
Married 1.63 0.98to2.70 0.06
Deployment*
Afghanistan 1.0
Iraq 1.15 0.512to2.595 0.73
Gastroenteritis
Anydiarrhoea/vomiting 1.68 0.96to2.94 0.07
Anydiarrhoea 1.68 0.96to2.94 0.11
Soughtcarefordiarrhoea 1.72 0.95to3.11 0.07
Limiteddutystatus—diarrhoea 2.19 0.94to5.09 0.07
Anyvomiting 1.62 0.77to3.39 0.21
Soughtcareforvomiting 1.53 0.70to3.33 0.29
Limiteddutystatus—vomiting 1.26 0.44to3.63 0.67
*ExcludessixparticipantsdeployedtobothIraqandAfghanistan.
RD,rheumatologicaldiagnoses.
DeYoungKH,RiddleMS,MayL,etal.BMJOpen2013;3:e003801.doi:10.1136/bmjopen-2013-003801 5
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Table4 Adjusted*ORs(95%CIs)forexposurevariablesfrommultivariateanalysisevaluatingincidentRDafterfirst
deploymenttoIraqorAfghanistanbetween2008and2009
N(%)
Variable Cases Controls aOR* 95%CI pValue
Anydiarrhoea/vomiting 19(28) 154(19) 1.65 0.92to2.96 0.09
Anydiarrhoea 16(24) 131(16) 1.49 0.80to2.77 0.21
Soughtcarefordiarrhoea 16(24) 125(15) 1.56 0.83to2.91 0.17
Quarters/lightorlimiteddutystatusfordiarrhoea 7(10) 41(5) 2.67 1.11to6.47 0.03
Anyvomiting 9(13) 71(9) 1.91 0.89to4.11 0.10
Soughtcareforvomiting 8(12) 66(8) 1.83 0.82to4.08 0.14
Quarters/lightorlimiteddutystatusforvomiting 4(6) 39(5) 1.76 0.59to5.29 0.31
*ORadjustedforgender,race,rankandmaritalstatus.
aOR,adjustedOR;N,number.
RD,rheumatologicaldiagnoses.
gastroenteritis.3 22 23 Importantly, the body areas infectiousgastroenteritis,wewereabletoincludealarger
affected, primarily the lower leg, are consistent with portion of personnel potentially exposed to the patho-
other reports of ReA.10 14 ReA is known to commonly gens of interest. This is especially important because
occur in multiple joints at once, but clinicians may have medical encounter data in the deployment setting are
chosen to specify only one body area because it was the not routinely recorded in electronic medical records
body area worst affected or because it was the body area capable of being linked with ambulatory and inpatient
in which the condition had persisted until that medical medicalencounters.However,byusingthisexposuredef-
encounter.14 inition, we may have included an undefined number of
We found a nearly threefold increased risk (aOR 2.67, non-bacterial gastroenteritis episodes resulting in expos-
95% CI 1.11 to 6.47) of exposure to severe diarrhoea ure misclassification—likely non-differential and thus
during deployment for RD, elaborating on the findings biasing towards the null. In addition, utilising data col-
by Curry et al16 of associations between prior infectious lectedattheendofdeployment,potentiallymonthsafter
gastroenteritis and/or deployment to high-risk regions the gastroenteritis episode, opened the study to non-
and Reiter’s disease or NAA. Using the same outcome differential recall bias. Similarly,broadly defining ReA by
definitions, Curry et al reported an adjusted OR (aOR) the specific and non-specific ICD-9-CM codes increased
of 1.76 (95% CI 1.49 to 2.07) for NAA risk in those with sensitivity, but likely increased outcome misclassification.
documented infectious gastroenteritis compared with ICD-9-CM codes are useful for health surveillance but
thosewithout. have several known sources of error and variance which
The incidence of RD in this study was higher than in impact data reliability.24 25 Using the surveillance data
population-based studies, but possibly lower than the available from the DMSS expanded our access to poten-
incidence in all deployed personnel due to our relatively tial research participants and their records. However,
young study population. Our sample was limited to per- response rates, particularly to the questions of interest in
sonnel on first-time deployment, yielding a mean age of this study,werepoor.Only69%ofcasesand75%ofcon-
27.6years (SD 6.8); this is lower than the average age of trols answered the gastroenteritis questions and the rest
ReA diagnosis in the general population (30–40years).10 could not be included in case–control analyses. This
Curry16 observed that the rates of NAA and ReA design allowed us to examine the risk of ReA in active
increased significantly with age. In a prospective studyof duty military personnel, a group of people who have a
culture-confirmed Campylobacter, E coli O157, Salmonella, high rate of gastroenteritis and whose risk for ReA has
Shigella and Yersinia infections among patients >1year, notbeenwellstudied.
Townes et al14 observed a median age of 41years among Further research is needed to define the incidence,
individuals with confirmed ReA. If younger persons are risk factors,durationand costsofReAinactivedutymili-
less likely to develop ReA, our incidence estimate may tary personnel and other travel populations. Improved
be lower than the incidence of ReA among all deployed characterisation of incidence and risk factors can be
service membersand the broader travel population. accomplished with study designs targeting more well-
Although these data may not be directly generalisable refined diagnoses of ReA and postdysenteric arthropa-
to every travel population, our findings highlight ReA as thy, case-finding that does not depend on ICD-9-CM
an important TD sequela among travellers who stay for codes and more specific measures of bacterial gastro-
long periods in the developing regions of the world enteritis during travel than are available through the
wherebacillarydiarrhoeaiscommon.However,thisstudy PDHA. In a US military population, a longitudinal study
should be interpreted with a full appreciation of the could utilise duration and cost of illness data extracted
inherentlimitations.Inusingself-reportedgastroenteritis from the DMSS. Our study suggests that a significant
instead of medical encounter data or culture-confirmed proportion of individuals with ReA may currently be
6 DeYoungKH,RiddleMS,MayL,etal.BMJOpen2013;3:e003801.doi:10.1136/bmjopen-2013-003801
Open Access
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andrelationtoplaceofexposureamongillreturnedtravelers.NEngl
investigated by clinically examining patients in a variety
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Contributors CKPandMSRdesignedthestudyandacquiredthedata.KHDY 16. CurryJA,RiddleMS,GormleyRP,etal.Theepidemiologyof
andCKPconductedthedataanalysisandinterpretation.KHDPandCKPare infectiousgastroenteritisrelatedreactivearthritisinUSmilitary
personnel:acase-controlstudy.BMCInfectDis2010;10:266.
guarantorsofthismanuscript.KHDP,CKP,MSRandLMcollaboratedinthe
17. SinghJA,HolmgrenAR,KrugH,etal.Accuracyofthediagnosesof
interpretationofresultsandwritingofthemanuscript.Allauthorsrevisedit
spondylarthritidesinveteransaffairsmedicalcenterdatabases.
criticallyforintellectualcontentandhavegivenfinalapprovaloftheversionof ArthritisRheum2007;57:648–55.
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