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Epidemiology and Etiology of Diarrhea in UK military personnel serving on the United
Nations Mission in South Sudan in 2017: A prospective cohort study.
Jason S. Biswasa,b,*, Julian Lentaigneb, Neil E. Hillb, James J. Harrisonb, Hector Mackenziea,
Ernest Akorlia, Daniel S. Burnsb, Emma J. Hutleya, Patrick Connorb, David R. Woodsb
Author Affiliations: aCentre of Defence Pathology, Royal Centre of Defence Medicine,
Birmingham, U.K. bAcademic Department of Military Medicine, Medical Directorate,
Defence Medical Services, Birmingham, U.K.
*Corresponding author: Major J.S. Biswas RAMC, Centre of Defence Pathology, ICT Park,
Vincent Drive, Birmingham, B15 2SQ, UK. Telephone: +44 7970 741435. E-mail:
Running title: Diarrhea in UK troops in South Sudan
Keywords: Gastrointestinal Disorder, Wilderness Medicine, Long Term Traveler
Abstract word count: 200
Manuscript word count: 3389
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Abstract
Background
Diarrhea is a well-established problem in travellers, with military personnel at especially high
risk. This study aimed to characterise the spectrum of pathogens causing diarrhea in UK
military personnel in South Sudan, and assess the utility of culture-independent testing for
etiology and antimicrobial resistance in a logistically challenging and austere environment.
Methods
All military personnel presenting with diarrhea were admitted to the UK Level 2 Medical
Treatment Facility in Bentiu, South Sudan. Samples were tested for etiology utilising
multiplex PCR-based diagnostics (BioFire FilmArray). In addition, the presence of
carbapenemase resistance genes was determined using the geneXpert Carba-R platform.
Results
Over 5 months, 127 samples were tested. The vast majority of pathogens detected were
diarrheagenic Escherichia coli. The presence of either enterotoxigenic (ETEC) or
enteropathogenic (EPEC) E. coli was a significant predictor of the other being present. In this
study patients presenting with vomiting were 32 times more likely to have norovirus than not
(p<0.001). No carbapenem resistance was detected.
Conclusions
Diarrhea in UK military personnel in South Sudan was determined to be predominantly
bacterial, with norovirus presenting a distinct clinical and epidemiological pattern. Multiplex
PCR and molecular resistance point of care testing were robust and effective in this
environment.
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1. Introduction
Travellers’ diarrhea (TD), initially described half a century ago [1], affects up to half of
global travellers, with large variation depending on intrinsic traveller characteristics as well
as extrinsic factors such as location [2, 3]. Effects may range from discomfort and
inconvenience, to hospitalisation, medical evacuation and significant post-diarrhea
symptoms. Worldwide the incidence of TD has been thought to be falling with rates of 65%
over twenty years ago [4] now dropping, with varying figures of 10-50% [5, 6].
In the case of military personnel on operations, diarrhea may significantly impact on the
ability to perform the mission, and an outbreak may rapidly compromise operational
effectiveness. Military personnel are particularly at risk due to their geographical exposure,
the nature of the tasks undertaken [7] and the challenge of providing adequate sanitary
conditions in an often austere environment. Although for many years acute military diarrhea
has been classed alongside TD, these epidemiological factors potentially make it a distinct
entity, whilst remaining sentinel for the pathological causes of TD [8].
Recent expert opinion suggests a change in the severity grading of TD from a traditional
frequency-based to an effects-based definition [9] and this has in turn had an effect on
studying TD [10]. On military operations in frequently adverse conditions, diarrhea rating as
moderate severity will almost certainly prevent some planned activities [7]. Studies have
demonstrated that antibiotic treatment reduces duration and severity of TD [11] and that
loperamide together with antibiotic is superior to antibiotics alone [12], though a recent
systematic review suggested a lack of evidence of superiority of antibiotics over loperamide
in mild/moderate TD [13]. Obtaining data on the epidemiology and etiology of diarrhea in
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these challenging environments is extremely difficult due to the logistic challenges of being
able to perform microbiological tests and accurately record data [14]. In addition, the
logistical, legal and bureaucratic challenges in moving specimens out of country for more
advanced methods of pathogen detection and characterisation dictates the requirement for
portable, robust and effective systems. However, currently few portable molecular (culture-
independent) systems exist to be able to assess etiology in austere environments, and these
multiplex PCR systems are in the main qualitative. Systems exist to detect carbapenemase
genes, but no deployable system for detecting extended spectrum β-lactamase (ESBL) genes
exists.
This study (the Enteric Disease and Resistance in South Sudan study (EDRISS)) aimed to
characterise the etiology of diarrhea in military personnel on the United Nations Mission in
South Sudan (UNMISS), the presence or absence of carbapenem resistance and assess the
utility and robustness of culture-independent molecular diagnostic techniques deployed as far
forward as possible.
2. Methods
2.1. Study population
This study took place at the UK Level 1 (deployed General Practitioner) and Level 2 (a tented
light field hospital with surgical and medical capabilities) Medical Treatment Facilities
(MTF) in Bentiu, South Sudan, during the entry operation for UK forces operating in support
of UNMISS. In this entry operation military personnel were accommodated in
Weatherhaven-style tents and ate in an open-sided dining tent, whilst hard standing facilities
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were being constructed. Troops were issued with bottled water for drinking and ablutions
such as brushing teeth, with water from a borehole used as ‘grey water’ for showering and
handwashing. Flush latrines were constructed by the Royal Engineers, which were plumbed
from the borehole. Alcohol hand-sanitizer was available at all communal facilities, as well as
outside medical facilities. UK field kitchens and chefs provided food, utilising UN supplied
fresh produce, with a few locally employed contractors as kitchen porters, and Operational
Ration Packs were not utilised except if a loss of supply occurred (which did not occur during
this study).
The study took place between May and September 2017. All UK forces had been vaccinated
with Dukoral® for the prevention of cholera, as well as routine travel vaccinations including
against typhoid.
2.2. Sample acquisition
All military personnel presenting with diarrhea were admitted to isolation areas either within
the Level 1 ‘bedding-down’ facility or the Level 2 MTF, under the care of either the General
Practitioner or the hospital Internal Medicine specialist. Given the deployment environment
and military necessity, troops were encouraged to present to medical providers after two or
more episodes of ‘loose stool’ (Bristol Stool Chart type 6 or 7 [15]) over a 24-hour period, in
order to perform early assessment and determine need for further management. All patients
were isolated before discharge for 48 hours from their last loose stool (meaning a minimum
stay of 2 days if no further loose stool occurred after admission) to reduce potential
transmission within the camp. At the time the study took place, treatment was heterogenous
and at the discretion of the treating clinician.
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2.3. Laboratory analysis
Diarrhea samples were tested on the FilmArray Gastrointestinal Panel (GIP) (BioFire
Diagnostics, Salt Lake City, UT) according to manufacturer’s instructions. This platform has
been established as having high sensitivity for pathogenic organisms [16, 17].
Latter samples were additionally tested with the geneXpert Carba-R cartridge (Cepheid,
Sunnyvale, CA) for the presence of carbapenemase genes (KPC, VIM, NDM-1, IMP-1,
OXA-48) in the stool. This platform, deployed initially for diagnosis of tuberculosis, arrived
in country midway through the study period, and provided an opportunity to look for
specified antibiotic resistance. Stool was homogenised (with the addition of sterile water if
required) using gentle agitation, and 100 microliters of the sample were pipetted directly in to
the Carba-R sample reagent, ensuring no solid debris or mucous was transferred. The sample
reagent was mixed gently for 60 seconds and then loaded onto the analyser as per the
manufacture’s standard protocols. Utilising a Klebsiella pneumoniae strain NCTC 13443,
which possesses a class B NDM gene, we were able to demonstrate by spiking previously
negative (by geneXpert and conventional growth on CLED) stool samples [18, 19] that this
technique detected carbapenemase genes from organisms at a concentration as low as 7.5
CFU/ml of stool.
2.4. Clinical assessment
Whilst not the primary aim of the study, clinical data were collected. Length of stay (LOS),
number of days of preceding symptoms and the number of days a patient had been in South
Sudan were collected as continuous variables. All other data (presence of different pathogens,
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presence of symptoms (fever, muscle aches, headaches, joint pain, nausea and vomiting))
were collected as dichotomous, categorical variables.
2.5 Data analysis and ethical approval
These were analysed using SPSS 17.0 (IBM) through a mixture of chi-squared, general linear
model and t-tests, as described below.
This work received ethical approval from the Ministry of Defence Research Ethics
Committee (808/MoDREC/17, 10 April 2017), and written, informed consent to take part in
the study was obtained from all participants. All study data were securely stored in military
facilities in accordance with UK data protection standards.
3. Results
Pooled data were obtained from 127 participants over a five-month period. The UK
population at risk in this location numbered around 200 during this study, consisting of
engineers, medical staff and some force protection elements. Table 1 shows the
epidemiological characteristics of participants.
The mean number of pathogens present in a single sample was 2.45 (s.d. = 1.19), with the
distribution shown in Figure 1. Enterotoxigenic E. coli (ETEC) was present in 68.3% of all
samples, enteropathogenic E. coli (EPEC) in 62.5% and enteroaggregative E. coli (EAEC) in
50.1%. Salmonella species were present in 2.2% and Campylobacter was present in 0.8% of
samples. Norovirus was present in 23.6% of samples. Samples with just one pathogenic
organism present totalled 20/127 (15.8%), and 100/127 (78.7%) had two or more pathogens
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present. Only seven samples (5.5% of total) had a negative result (no organism detected). In
total there were 44 different combinations of pathogen carriage (Figure 2), with the three
most common being ETEC, EPEC and EAEC co-occurring (14.96% of sample), ETEC and
EPEC co-occurring (12.60% of sample) and EAEC as a single pathogen (6.30% of sample).
The most common pathogens (nine or greater cases) of ETEC, EPEC, EAEC, norovirus and
Giardia were cross tabulated using Chi-Squared tests to ascertain whether they occurred
independently of each other. This resulted in 10 comparisons, and as such a Bonferroni-
corrected alpha level of 0.005 was used. The majority of pathogens appeared to be present
independently of one another, with the exception of ETEC and EPEC, where the presence of
one was a significant predictor of the presence of the other (positive φ-coefficient 0.31,
p = 0.001, χ2 = 12.04).
We postulated that those who had spent longer in region would carry more pathogens when
presenting with diarrhea. However, a linear regression analysis revealed that number of days
in theatre was not predictive of the absolute number of pathogens carried (F(1,125) = 0.02, p
= 0.894, R2 = 0.01) (Figure 3). A multiple regression analysis was then performed to test
whether the presence or absence of individual pathogens was related to the number of days in
theatre. As per previous analysis, pathogens present in nine or more cases were entered into
the model. A significant model was calculated (F(5,121) = 4.64, p = 0.001, R2 = 0.13).
Carriage of EAEC was related to a longer stay in theatre (t = 2.66, p = 0.009), such that
carriage of EAEC was associated with individuals who were in theatre 13 days longer. The
presence of norovirus was a significant predictor of a shorter time in theatre, such that those
who were carrying norovirus had spent on average 15 days less in theatre than those who did
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not carry it (t = -2.61, p = 0.010). (Figure 4). ETEC, EPEC and Giardia were not significant
predictors of length of time in theatre.
Given previous data suggesting an interaction between E. coli and norovirus [20-22], we
performed a post hoc analysis to isolate the effects of individual pathogens, using our only
outcome marker of LOS (discussed below). The effect of carriage of different pathogens on
LOS was analysed using a Univariate ANOVA, with the only significant interaction being a
three-way interaction between ETEC × EPEC × norovirus (F(1,94) = 10.67, p = 0.002, η2 =
0.10). In order to ascertain the direction of this interaction, post-hoc independent samples t-
tests were carried out, and a Bonferroni-Corrected Alpha level of 0.0125 was taken in order
to guard against inflated error (Figure 5). It was revealed that when ETEC and EPEC are
both present, norovirus is related to a significantly longer LOS (t(61) = -2.63, p = 0.011, r =
0.32). This effect was not seen when only EPEC was present (t(21) = -0.25, p = 0.81), when
only ETEC was present (t(15) = 0.17, p = 0.87) or when neither EPEC nor ETEC were
present (t(22) = -2.49, p = 0.021). (Note that the effect of norovirus seen when neither EPEC
nor ETEC were present approached, but did not reach, significance – sample size for this
comparison was small.)
To develop a predictive model for the presence of norovirus, a logistic regression was
performed with symptoms as predictor variables, and presence of norovirus as the dependent
variable. The overall model was found to be significant (χ2 = 54.56, p < 0.001, R2 = 0.53),
where the model predicted 88% of cases correctly. It was found that, in our cohort, headaches
and vomiting were significant predictors of norovirus (headaches: Wald statistic = 6.06, p =
0.014; vomiting: Wald statistic = 30.92, p < 0.001). An individual presenting with vomiting
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was 32.8 times more likely to have norovirus than not, and an individual presenting with
headaches was 4.2 times more likely to have norovirus than not.
Testing for carbapenem resistance (detection of relevant genes by geneXpert) was technically
successful in 65/67 samples; no carbapenemase production genes were detected.
4. Discussion
This work was performed in an austere environment under challenging circumstances. During
this study numerous environmental challenges were faced- constructing and manning the
field hospital, a solitary bore hole for water which frequently failed, field kitchens including
eating in open-sided tents, and a transition from dry to wet season with deterioration in the
environment (standing pools of water, flooding) and associated increases in insect numbers.
Many of these challenges have equivalent civilian difficulties. Despite this, from an area
where no recent data on TD exist, we present results which add to the evolving body of work
on the presence of diarrheagenic pathogens in travellers’ and military diarrhea.
The significant novel findings of this culture-independent study were the presence of
pathogens in 95% of diarrhea samples, most commonly ETEC, EPEC, EAEC or a
combination of these. The presence of norovirus was a significant predictor of having been in
country for a shorter period of time and the presence of vomiting indicated a 32x greater
chance of having symptoms due to norovirus in the context of an outbreak. In addition, no
carbapenem resistance was discovered.
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The etiology of TD has been variously reviewed in the civilian and military populations [23-
27]. Previous data encompassing Africa as a whole have suggested ETEC as the most
common etiology for around a third of TD cases, EAEC for between 5 and 20%, norovirus
for around 15-25%, with other organisms around 10% or less. No bacterial pathogen was
detected in up to 50% of samples. This most likely reflects the difficulties in the use of
conventional microbiological techniques in establishing the etiology of TD, as well as
limitations related to the delay between the sample being obtained and microbiological
testing, together with separation in time between the diarrheal episode and the traveller’s
return and post-hoc testing in some studies.
Our data support this hierarchy with ETEC proven to be the commonest detected organism,
followed by EPEC and then EAEC. Our results show that EPEC may be more common than
previous literature has reported. Norovirus was present in 23% of our samples (all of whom
had consistent symptoms) in accordance with that previously reported.
Only 7/127 (5.5%) of samples failed to return a positive result on the GIP, as compared to up
to 50% of cases reported in most studies (and 42% in the most recent military study [28]).
Although the limitations of ascribing causality from a qualitative multiplex system are well
known [29], it is clear that in 95% of samples there was at least one and often multiple
organisms present that are known to cause TD. Given that the majority of these were
combinations of different variations of E. coli (ETEC +/- EPEC +/- EAEC) we are confident
that our data strongly demonstrate that the use of an appropriate (as defined by geographical)
antibiotic would cover the vast majority of travellers with TD, certainly in Eastern Africa.
Recent military studies [28] and guidelines [30] reinforce this approach, to allow completion
of the mission.
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Military personnel are as much at risk of acquiring antibiotic resistances as the civilian global
traveller [31], and the lack of carbapenem resistance seen in our study confirms assumptions,
and is welcome. Recent data from East Africa [32, 33] suggest that increasing antibiotic
resistance is being seen in Gram-negative organisms, particularly with respect to beta
lactams. A recent systematic review suggests that in Africa resistance to ciprofloxacin
appears relatively low, and further confirms that carbapenem resistance in Enterobacteriaceae
in the region is extremely low [34]. However given the increasing nature of this problem
globally, and the exposures that military personnel are subjected to, we suspect it will not be
long before carbapenem resistance makes it way to this region to join the other resistances
seen [35]. Perhaps as important, if not more so, is the acquisition and carriage of ESBL
pathogens. Data has shown rates of acquisition both in treated and untreated cases of TD, as
well as controls [36, 37]. Development of a deployable culture-independent system for
detection of ESBL genes will be of vital importance in understanding, monitoring and
ultimately combatting this threat. Data also suggests that pathogens are still detected after
treatment of TD with antibiotics [38], which may be due to either intrinsic resistance or re-
colonisation by resistant organisms, and this may have implications on guidelines the use of
antibiotics in the future.
Our data show that the presence of vomiting and/or headaches is statistically related to the
presence of norovirus, and that the norovirus cases appeared in two distinct clusters. This is
an important finding as the effects of a norovirus outbreak on a military deployment cannot
be underestimated [39, 40]. Our evidence that norovirus occurred more often in those who
had more recently arrived in the country suggests that introduction of the virus into the camp
was potentially due to carriage from the UK. Planners (both military and civilian) must be
prepared for the influx of fresh staff and their potential risks. All norovirus cases presented in
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two separate outbreaks (both before and after the changeover of personnel), within hours of
other cases, and with a distinct clinical presentation. Patients presenting this way therefore,
were treated as norovirus, and did not receive antibiotic treatment.
LOS is a subjective and weak outcome measure, and as such is generally not used in TD
research. Militarily however, LOS is important as it uses critical resources and effects
military planning in a way one might not appreciate from a civilian viewpoint. The need to
keep someone in an isolation facility is far more important in a military setting and could be
compared to a ‘cruise ship’ scenario. Accepting its limitations, our data regarding the
interaction between norovirus, ETEC and EPEC are interesting. Previous work has suggested
that interactions and co-infection between enteric pathogens and norovirus may be significant
[20-22], and this is worthy of further investigation.
Although a previous report has suggested that oral cholera vaccines may offer some
protection against ETEC [41], our data suggest that this is not the case, in agreement with a
recent systematic review [42].
There are constraints to this study. Concurrent standard microbiological media plates were
not available to compare standard and advanced microbiological data. However, the UK
military aim of ‘freedom from fridges and freezers’ dictates this as the direction of travel for
deployable diagnostics. Current deployable multiplex PCR systems provide qualitative rather
than quantitative data, so attributing causality to single pathogens was not possible. Future
studies will aim to address this [43]. Utilising stool cards to allow future quantitative analysis
would improve security of causality and maintain the ‘freedom from fridges and freezers’
direction. For deployable PCR systems to be fully appreciated in this setting, industry needs
to drive the development of robust, sensitive yet specific semi-quantitative platforms.
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We were unable to perform disc sensitivity testing, and did not have a portable platform to
perform antibiotic resistance gene detection beyond carbapenemases. Future studies may be
able to incorporate these aspects, although significant logistical challenges in getting this
testing to the theatre of operations (or the samples back out) remain, and deployable ESBL
gene detection platforms are yet to be commercially available.
Military personnel are generally fit, mainly young and predominantly male. However, as has
been shown previously, TD data is generalizable to the general civilian population and whilst
tourist travel is not yet possible in this area, this data should be of use to humanitarian and
other NGO organisations providing such valuable contributions in the region.
5. Conclusion
Within its limitations, the EDRISS study demonstrates that contemporaneous research using
molecular technologies can take place in the most austere of environments.
Our data lend further evidence to support the predominant bacterial etiology of TD, and
demonstrate that the prevalence of E. coli in the stools of those with diarrhea may be much
higher than previously reported. Multiplex PCR provides valuable evidence in understanding
the etiology and potential treatment of TD, is robust and performs well with, we believe,
results consistent with current expectations for this region. However the presence of multiple
pathogens in many clinical samples from patients with disease means that technology in
isolation still requires expertise to interpret the results generated and is yet to function as a
standalone solution.
Given the global risk of antibiotic resistance, the ability to conduct antibiotic resistance
testing in this environment is a significant asset, particularly in regions with much higher
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resistance levels, and encouragement to industry to develop deployable rugged systems in
this regard is essential.
Acknowledgements
We thank the patients and staff of the UK Medical Group in South Sudan during the period of
the study. We are indebted to the work of the Centre of Defence Pathology, Birmingham, UK
for facilitating and enabling the technical aspects of this study.
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Conflicts of Interest
There are no conflicts of interest reported by any author.
Funding
This work was supported by the Ministry of Defence, United Kingdom. The study sponsor
was not involved in the design of this study, data handling and interpretation, writing up of
the manuscript, and decision to submit.
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Number (n=127) % totalGender Male 100 78.7
Female 27 21.3Career group Medical 66 52
Engineering 41 32.2Force Protection and others 20 15.8
Age 18-24 25 19.725-29 38 29.930-34 24 18.935-39 15 11.840-44 11 8.745+ 14 11
Duration of symptoms (days) 1 87 68.5
2 32 25.2≥3 8 6.3
Days in theatre ≤28 42 33.1>28 85 66.91
Antibiotic used Ciprofloxacin single dose 62 48.8Ciprofloxacin 3-day course 10 7.9Azithromycin single dose 6 4.7Azithromycin 3-day course 6 4.7Metronidazole (any course) 9 7.1Combination (metronidazole and one other) 9 7.1
Nil 25 19.7
Table 1. Demographics of participants in the EDRISS study. Total number of participants was 127.
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Figure 1. Frequency distribution of number of pathogens present in individual samples
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Figure 2. Distribution and co-occurrence of pathogens. Individual data are represented by vertical columns, and detection of pathogens by the
presence of a grey block. Note the majority of cases presented with a mix of pathogens. (Crypto= Cryptosporidium species, Campy=
Campylobacter species, C Diff= Clostridium difficile, Ples= Plesiomonas shigelloides).
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Figure 3. Scatter plot of numbers of pathogens carried in a sample against time that patient
had spent in South Sudan. Average number of pathogens carried was 2.45. Dotted line shows
the least-squares line of best fit (r = -0.01).
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Figure 4. Presence of norovirus was a significant predictor of an individual being in theatre
for a shorter period of time. Presence of EAEC was a significant predictor of an individual
being in theatre for a longer period of time. Error bars show ±1 × Standard Deviation.
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Figure 5. Effect of norovirus on LOS. When ETEC and EPEC are present, presence of
norovirus is related to significantly longer LOS; however this effect is not seen if only ETEC,
only EPEC or neither ETEC nor EPEC are present. Error bars show ±1 × Standard Deviation.
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