Tropical Medicine and International Health doi:10.1111/tmi.

12937

volume 22 no 10 pp 1223–1232 october 2017

Systematic Review

Clostridium difficile infection in low- and middle-human

development index countries: a systematic review
Joseph D. Forrester1, Lawrence Z. Cai1, Chenesa Mbanje2, Tanya N. Rinderknecht1 and Sherry M. Wren1,3

1 Stanford University, Stanford, CA, USA

2 College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe
3 Palo Alto Veterans Affairs Health Care System, Palo Alto, CA, USA

Abstract objective To describe the impact and epidemiology of Clostridium difficile infection (CDI) in low-
and middle-human development index (LMHDI) countries.
method Prospectively registered, systematic literature review of existing literature in the PubMed,
Ovid and Web of Science databases describing the epidemiology and management of C. difficile in
LMHDI countries. Risk factors were compared between studies when available.
results Of the 218 abstracts identified after applying search criteria, 25 studies were reviewed in
detail. The weighted pooled infection rate among symptomatic non-immunosuppressed inpatients was
15.8% (95% CI 12.1–19.5%) and was 10.1% (95% CI 3.0–17.2%) among symptomatic outpatients.
Subgroup analysis of immunosuppressed patient populations revealed pooled infection rates similar to
non-immunosuppressed patient populations. Risk factor analysis was infrequently performed.
conclusions While the percentages of patients with CDI in LMHDI countries among the reviewed
studies are lower than expected, there remains a paucity of epidemiologic data evaluating burden of
C. difficile infection in these settings.

keywords C. difficile infection, low- and middle-income countries, systematic review

settings. Infection with C. difficile could be particularly

Introduction
Clostridium difficile is an anaerobic, toxin-producing,
Gram-positive rod capable of causing infection in health-
care settings and in the community. Initially described in
1935, the association between antibiotic use, pseu-
domembranous colitis and toxigenic C. difficile has been
widely documented [1–3]. The impact and epidemiology
of C. difficile infection (CDI) are now well described as
causing considerable morbidity, mortality and healthcare
expenditure in high human development index (HHDI)
countries [4, 5]. Much less is known about what impact
CDI may have in low- and middle-human development
index (LMHDI) countries.
Prior antibiotic therapy is one of the greatest risk fac-
tors for development of CDI [4]. Antibiotic prescribing
practices are closely regulated in many HHDI countries,
yet infrequently regulated in LMHDI countries. In many
countries, lay-people can purchase antibiotics without
healthcare provider’s prescription [6]. This perfect storm
of unregulated antibiotic use and challenging access to
healthcare could lead to spread of C. difficile in these
devastating as diagnosis of, and therapy for, CDI may
not be widely available. Yet despite what should be a
favourable environment for the proliferation of
C. difficile, in our experience, this infection is infre-
quently reported in LMHDI settings.
We sought to describe the existing research evaluating
CDI in LMHDI countries through a comprehensive and
systematic review of existing literature. Our primary goal
was to describe existing literature describing CDI in
LMHDI countries to establish baseline infection rates,
morbidity and mortality associated with CDI.
Methods
We performed a systematic review of existing literatures
describing the epidemiology and management of toxi-
genic C. difficile infection in LMHDI countries. This
review was prospectively registered with the Prospero
database (Project number 42016036412) in accordance
with PRISMA guidelines. PubMed, Ovid and Web of
Science databases were searched using the terms

© 2017 John Wiley & Sons Ltd 1223

Tropical Medicine and International Health
J. D. Forrester et al. C. difficile infection in LMHDI countries
‘Clostridium difficile’, ‘C. difficile’, ‘antibiotic-associated
colitis’, ‘pseudomembranous colitis’ both alone and in
combination by country listed by name (Appendix S1).
Countries included in the search were those recognised as
LMHDI by United Nations Development Programme
(UNDP) 2015 as LMHDI [7]. LMHDI designation is a
composite index focusing on three dimensions of human
development: life expectancy at birth, mean year of
schooling and expected years of schooling and gross
national income per capita [7]. Inclusion criteria included
any randomised, non-randomised, case–control, cohort or
demographic studies published between January 2000
and March 2016 so as to obtain the most recent and rele-
vant studies. Studies not written in English were trans-
lated using Google Translate and included for further
review.
Initial titles and abstracts from all three databases were
screened for duplicates and then reviewed for relevance
prior to obtaining full-text manuscripts. Eligible articles
were independently assessed by blinded reviewers who
evaluated each study for pre-established variables. These
variables included: study duration, location, type of
study, study size, age, gender, comorbid profile, fre-
quency of CDI, grade of infection, community-acquired
(CA) or healthcare-associated (HA) infection, toxigenic
laboratory diagnosis, strain typing, associated morbidity,
mortality and cost of infection. Manuscripts were cate-
gorised into observational studies, cohort or case–control
studies. Disagreement between reviewers was resolved
through discussion with a third reviewer. Exclusion crite-
ria included case reports or abstracts without available
full-text articles or studies describing only paediatric
patients (defined as patients <18 years of age) or if labo-
ratory confirmation of toxin production was not speci-
fied. If studies included fewer than 30 patients, they were
not included in quantitative analysis in concordance with
the rule of threes sample size based on an assumed infec-
tion rate of 10% in these settings. Manuscripts describing
studies in unique subpopulations such as immunosup-
pressed patients were included in the qualitative synthesis
but underwent independent subgroup analysis to ensure
comparisons between like populations. For studies where
subpopulations of patients were described, subgroups
were split and considered independently. Missing data
were requested from study authors and incorporated
when possible. Additional studies were sought by exam-
ining the bibliographies of all studies identified during the
search process.
Risk factors identified by the Infectious Disease Society
of America were compared between studies where this
information was available [4]. To be included in the risk
factor analysis, a study had to report both the odds ratio
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volume 22 no 10 pp 1223–1232 october 2017
and the 95% confidence interval. Due to heterogeneity
between studies and risk factors and discrepant defini-
tions, odds ratios were not pooled. Statistical analysis
was performed using STATAâ (Version 14.1). This was
determined to be an IRB exempt study as all articles were
publically available.
Results
There were 219 abstracts identified after applying search
criteria (Figure 1). After duplicate records were removed,
150 abstracts remained. Of these abstracts, 108 were
excluded due to non-relevance. Complete manuscripts
were obtained for 42 (19% of total) manuscripts, and 17
were excluded for the following reasons: five did not
evaluate LMHDI country, four evaluated only a paedi-
atric population, four contained no calculable infection
rate or absence of demographic information, three evalu-
ated non-toxin-producing C. difficile and one was an
environmental sampling study.
Twenty-five studies met criteria for qualitative synthesis
(Table 1) [8–32]. Twenty (80%) were observational stud-
ies, three (12%) studies were case–control and two (8%)
were cohort studies. Over half (n = 15, 60%) of the stud-
ies were conducted in India and seven (28%) were per-
formed in sub-Saharan Africa. Only four (16%) studies
were multiinstitution. Most studies (n = 23, 92%) did
not define or distinguish between disease severity. Toxi-
genic status was confirmed solely by enzyme-linked
immunosorbent assay (ELISA) in 10 (40%) studies, by
toxin assay in eight (32%) studies, by a combination of
ELISA and polymerase chain reaction (PCR) in four
(16%) studies, by PCR alone in two (8%) studies and by
a combination of toxin assay and PCR in one (4%)
study. Only one study described the use of surgery as a
potential treatment modality for CDI. Eleven (44%) stud-
ies reported antecedent antibiotic therapy. Only one (4%)
study utilised ribotyping to identify C. difficile strains.
One study evaluated only patients with Entamoeba his-
tolytica colitis and one study had less than 30 patients;
neither of these studies were included in the quantitative
review. No reviewed studies described the financial
impact of CDI.
Seventeen studies were used for the quantitative synthe-
sis in the non-immunosuppressed subgroup analysis.
Among 10 (59%) studies evaluating symptomatic inpa-
tients, the weighted pooled infection rate was 15.8%
(95% confidence interval (CI) 12.1–19.5%). In four
(24%) studies evaluating symptomatic patients presenting
as outpatients, the weighted pooled infection rate was
10.1 (95% CI 3.0–17.2%). The three (18%) studies that
combined inpatients and outpatients had a weighted,
© 2017 John Wiley & Sons Ltd
Tropical Medicine and International Health volume 22 no 10 pp 1223–1232 october 2017

J. D. Forrester et al. C. difficile infection in LMHDI countries

Records identified through Additional records identified

database searching through other sources
(n = 218) (n = 1)

Records after duplicates removed

(n = 149)

Records excluded due

to non-relevance
(n = 108)
Records screened
(n = 150)

Full-text articles
excluded, with reasons:
Full-text articles (n = 17)
assessed for eligibility 5 – Not LMHDI country
(n = 42) 4 – Padiatric
4 – No calculable
infection rate or lack of
demographic data
3 – evaluated non-toxin
producing C. difficile
Studies included in
1 – environmental
qualitative synthesis
sampling study
(n = 25)

Studies included in quantitative Excluded from quantitative synthesis

synthesis 1 – only patients with concurrent
16 – Non-immunosuppressed Entamoeba histolytica
7– Immunosuppressed 1 - Sample size less than 30

Figure 1 PRISMA flowsheet of manuscript selection process.

pooled infection rate of 10.5% (95% CI 0–33.7%). In
the three case–control studies, among controls only five
(5%) had evidence of asymptomatic carriage of toxin-
producing C. difficile. In the five studies where mortality
was reported, there were six fatal cases, which corre-
sponds to a weighted pooled case fatality rate of 18.0%
(95% CI 10.0–26.0%).
Among the seven studies describing immunosuppressed
patient populations, three described human immunodefi-
ciency virus positive (HIV+) patient populations and two
described patients with ulcerative colitis (UC0). One
study described CDI after bone marrow transplant, and
one study described CDI in patients with psoriatic arthri-
tis. The weighted pooled infection rate among HIV+
patients was 7.4% (95% CI 0–22.8%) and among
patients with UC was 15.3% (95% CI 0.0–60.9%). Only
one study reported fatal cases, where six deaths were
reported among nine cases of CDI in patients who had
undergone bone marrow transplant.
Only three (17%) studies described a risk factor analy-
sis (Table 2). Prior antibiotic use, pharmacologic
immunosuppression, prior hospitalisation, intensive care

© 2017 John Wiley & Sons Ltd 1225

1226
Table 1 Manuscripts describing Clostridium difficile infection in low- and middle-human development index countries - Worldwide, 2000-2016

Number with
laboratory confirmed Laboratory method
Source Title Design Country Number C. difficile (%) of toxigenic status

Vaishnavi Clinical and demographic profile of Retrospective India 3044 533 (18) ELISA
et al. 2015 [8] patients reporting for Clostridium observational
difficile infection in a tertiary care
hospital
Rajabally The Clostridium difficile problem: a Prospective South Africa 440 community 32 (7) community- EIA
et al. 2013 [9] South African tertiary institution’s observational 203 hospitalised acquired cases
prospective perspective. in past 90 days 27 (13) hospital
acquired cases
Tropical Medicine and International Health

Chaudhry Changing pattern of Clostridium Retrospective India 524 37 (7) EIA, PCR
et al. 2008 [10] difficile associated diarrhoea in a observational
tertiary care hospital: a 5 year
retrospective study
Vaishnavi Clostridium perfringens type A & Prospective India 285 57 (20) Latex agglutination
et al. 2005 [11] antibiotic associated diarrhoea observational
Simango Detection of Clostridium difficile Prospective Zimbabwe 268 23 (9) EIA
J. D. Forrester et al. C. difficile infection in LMHDI countries

et al. 2014 [12] diarrhoea in Harare, Zimbabwe. observational

Lekalakala Clostridium difficile infections in Prospective South Africa 266 46 (17) EIA
et al. 2010 [13] a tertiary hospital: value of observational
surveillance
Joshy Detection and characterization of Prospective India 214 26 (12) ELISA
et al. 2009 [14] Clostridium difficile from patients observational
with antibiotic-associated
diarrhoea in a tertiary care
hospital in North India.
Warren Clostridium difficile and Entamoeba Prospective Philippines 210 54 (26) ELISA
et al. 2012 [15] histolytica infections in patients observational
with colitis in the Philippines
Ramakrishnan Antibiotic overuse and Clostridium Prospective India 172 7 (4) EIA and PCR
et al. 2015 [16] difficile infections: the Indian observational
paradox and the possible role of
dietary practices
Samie PCR detection of Clostridium Prospective South Africa 167 20 (12) PCR
et al. 2008 [17] difficile triose phosphate isomerase observational
(tpi), toxin A (tcdA), toxin B (tcdB),
binary toxin (cdtA, cdtB),
and tcdC genes in Vhembe
District, South Africa

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volume 22 no 10 pp 1223–1232 october 2017
 Table 1 (Continued)

Number with
laboratory confirmed Laboratory method
Source Title Design Country Number C. difficile (%) of toxigenic status

Oyofo Enteropathogens associated with Prospective Indonesia 154 2 (1) EIA

et al. 2002 [18] acute diarrhea in community and observational

© 2017 John Wiley & Sons Ltd

hospital patients in Jakarta,
Indonesia.
Ingle et al. 2013 [19] Clostridium difficile as a cause of Prospective India 150 12 (8) EIA/ELISA
acute diarrhea: a prospective study observational
in a tertiary care center
Kullin Prevalence of gastrointestinal Prospective South Africa 139 22 (16) PCR
et al. 2015 [20] pathogenic bacteria in patients observational
Tropical Medicine and International Health

with diarrhoea attending Groote

Schuur Hospital, Cape Town,
South Africa
Ingle Prevalence and clinical course of Retrospective India 99 17 (17) ELISA
et al. 2011 [21] Clostridium difficile infection in a observational
tertiary-care hospital: a
retrospective analysis
J. D. Forrester et al. C. difficile infection in LMHDI countries

Sultana Diagnosis of Clostridium difficile Case–control Pakistan Case: 80 Case: 23 (29) ELISA
et al. 2000 [22] antibiotic associated diarrhoea Control: 20 Control: 0 (0)
culture vs. toxin assay
Vaishnavi Preliminary investigation of Prospective India 79 5 (6) Latex agglutination
et al. 2012 [23] environmental prevalence of observational
Clostridium difficile affecting
inpatients in a north Indian
hospital
Kaneria Incidence of Clostridium difficile Case–control India Case: 50 patients Case: 5 (10) EIA
et al. 2012 [24] associated diarrhoea in a tertiary Control: 50 Control: 3 (6)
care hospital. patients
Vishwanath Clostridium difficile infection at Prospective India 25 4 (16) EIA
et al. 2013[25] a tertiary care hospital in south observational
India.
Immunosuppressed
subgroup
Kumar Clostridium difficile infections in Prospective India 237 12 (5) ELISA
et al. 2014 [26] HIV-positive patients with observational
diarrhoea
Onwueme High prevalence of toxinogenic Prospective Nigeria 140 21 (15) ELISA
et al. 2011 [27] Clostridium difficile in Nigerian observational
adult HIV

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1228
Table 1 (Continued)
Tropical Medicine and International Health

Number with
laboratory confirmed Laboratory method
Source Title Design Country Number C. difficile (%) of toxigenic status

Vaishnavi Simultaneous assays for Clostridium Prospective India 94 12 (13) Latex agglutination
et al. 2003 [28] difficile and faecal lactoferrin in observational
ulcerative colitis
Zulu Contrasting incidence of Prospective Zambia 68 0 (0) ELISA
J. D. Forrester et al. C. difficile infection in LMHDI countries

et al. 2000 [29] Clostridium difficile and other observational

enteropathogens in AIDS patients
in London and Lusaka
Kang Etiology of diarrhea in patients Prospective India 65 9 (14) Toxin assay
et al. 2002 [30] undergoing allogeneic bone observational
marrow transplantation in south
India
Kumar Clostridium difficile toxin assay in Cohort India 58 19 (33) ELISA
et al. 2004 [31] psoriatic patients
Balamarugan Estimation of faecal carriage of Case–control India Cases: 37 8 (22) Toxin assay and PCR
et al. 2008 [32] Clostridium difficile in patients Controls: 36 2 (6)
with ulcerative colitis using real
time polymerase chain reaction

© 2017 John Wiley & Sons Ltd

volume 22 no 10 pp 1223–1232 october 2017
Tropical Medicine and International Health volume 22 no 10 pp 1223–1232 october 2017

J. D. Forrester et al. C. difficile infection in LMHDI countries

Table 2 Risk factors for development of C. difficile infection in rates to be as high as 20–30% [4]. These lower rates in
low- and middle-human development index countries, LMHDI settings could be falsely low, and an artefact of
2000–2016 underreporting and underdiagnoses. Alternatively, these
Risk factors for lower rates in LMHDI settings could be a result of yet
development of Adjusted odds undescribed host, environmental, bacterial, microbiome
C. difficile infection Source ratio (95% CI) or even cultural factors. Regardless of underlying aetiol-
ogy, the lower rates of CDI infection among patients in
Age >65 Rajabally et al. 0.7 (0.3–1.8)
LMHDI countries are encouraging. However, more wide-
2013 [9]
Gender Ingle et al. 2011 1.48 (0.44–4.90) spread epidemiologic studies are needed to ensure ade-
[21] (males) quate population sampling, as only three of the 18
Ingle (males) 1.48 (0.44–4.90) studies were multiinstitution studies and none were multi-
et al. 2013 [19] national. To more accurately describe the burden of CDI,
Rajabally et al. 0.9 (0.5–1.6) a more widespread survey of tertiary referral centres
2013 [9] (females) across LMHDI countries could be beneficial.
Antibiotic use Ingle et al. 2013 [30] 3.2 (0.9–11.2)
Less is known about CA-CDI in LMHDI countries.
Rajabally 2.9 (1.6–5.1)
et al. 2013 [9] Given the ability of individuals in many LMHDI coun-
Immunosuppression Ingle et al. 2011 [21] 5.03 (1.42–17.5) tries to purchase antibiotics without a prescription, the
Ingle et al. 2013 [19] 0.3 (0.03–2.5) spread of toxigenic C. difficile could be particularly wide-
Gastrointestinal None reported spread and problematic [6]. An increasing number of
surgery studies are documenting the rise of CA-CDI in HHDI
Gastric acid Ingle et al. 2011 [21] 2.88 (0.8–9.8)
countries, with CA-CDI accounting for up to 32% of
suppression therapy Ingle et al. 2013 [19] 2.3 (0.6–9.2)
Malignancy Ingle et al. 2011 [21] 3.92 (0.96–14.82)
CDI cases in some series [33, 34]. In the four studies
Previous Ingle et al. 2011 [21] 1.43 (0.44–4.74) evaluating symptomatic outpatients, the weighted pooled
hospitalisation Rajabally 1.8 (1–3.1) infection rate was 10.1%. In LMHDI countries where
et al. 2013 [9] non-C. difficile-related diarrhoeal disease is commonplace
Intensive Ingle et al. 2011 [21] 5.04 (1.29–18.6) and is often treated with antibiotics, the importance of
care unit stay Ingle et al. 2013 [19] 4.47 (1.28–15.54) being able to diagnose CDI is critical. Unnecessary antibi-
Tube feeding Ingle et al. 2013 [19] 4.10 (1.10–15.26)
otic therapy would be avoided and antibiotic selective
Bolded odds ratios are statistically significant. pressure could decrease, improving antibiotic stewardship
[4]. Among the reviewed studies, the frequency of asymp-
tomatic carriage was 5% which is consistent with prior
unit admission and tube feeding were associated with studies for both asymptomatic carriage and toxin-nega-
increased odds of developing CDI. tive strains both in HHDICs and LMHDICs [36–38].
Risk factors for development of CDI in LMHDI coun-
tries appear to parallel those found in HHDI countries.
Discussion
Prior antibiotic use – a well-documented risk factor for
Clostridium difficile is widely recognised as the most development of CDI – was found to be associated with
common cause of antibiotic-associated diarrhoea, causes increased odds of developing CDI in one of the two stud-
considerable morbidity and mortality, and is a commonly ies where this association was explored. However, in
encountered pathogen among surgeons in HHDI coun- most of the studies, pre-infection antibiotic use was docu-
tries. Initially described as a healthcare-associated (HA) mented and frequently predated development of CDI.
infection, community-acquired (CA) disease increasingly Only one of two studies evaluating the impact of
contributes to the burden of this pathogen [33, 34]. immunosuppression demonstrated an increased associa-
While the human and financial impacts of CDI have been tion, specifically among patients who were iatrogenically
well documented in HHDI, little is known about the bur- immunosuppressed through medications. Conversely,
den of this infection in LMHDI countries [35]. To among HIV+ patients with diarrhoea the weighted pooled
explore existing data describing the impact of CDI in infection rate was 7.4% which was lower than the rate
LMHDI countries, we performed a comprehensive, struc- observed in the general non-immunosuppressed patient
tured literature review. population. While CDI has been shown to be the most
Among symptomatic inpatients, the weighted pooled common cause of diarrhoea in HIV patients in HHDICs,
infection rate among the reviewed manuscripts was this high frequency of CDI among patients living in
15.8%. Similar studies in HHDI countries have shown LMHDICs appears less pronounced [39, 40]. Similarly,

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Tropical Medicine and International Health
J. D. Forrester et al. C. difficile infection in LMHDI countries
UC patients had a weighted pooled infection rate of
15.3% which was the same as symptomatic inpatients in
LMHDICs. The association between UC and CDI has
been well documented and has been shown to affect
younger patients with less prior antibiotic exposure [41].
Notably, two studies, both by Ingle et al. [19, 21],
demonstrated that intensive care unit admission was asso-
ciated with development of CDI. As both of these two
studies occurred at the same institution, it is unclear if
the observed increased odds were due to greater risk
associated with those authors’ institution or if there is
widespread increased association with ICU stay and CDI
in LMHDI countries. It is also possible that ICU admis-
sion is a marker for patients more likely to receive antibi-
otics or have greater underlying comorbidity.
Few studies described the morbidity and mortality
associated with CDI in LMHDI countries. Two studies
reported no complications, recurrence or need for surgery
among the 249 patients who provided stool samples [19,
21]. The most comprehensive risk factor analysis was
performed by Rajabally et al. [9]. In their prospective
analysis, seven of 59 patients ultimately required colec-
tomy due to severity of disease. The marked difference in
the number of patients requiring surgery for CDI between
the Rajabally and Ingle studies underscores the range of
CDI-attributable morbidity from the reviewed studies.
There were no estimates assessing the financial burden
of CDI in LMHDI countries identified in our review. The
total annual CDI-attributable cost to the US is estimated
to be $6.3 billion USD [42] and in a meta-analysis incor-
porating data from other countries, cost of infection was
estimated between $8911 to $30 049 USD [35]. Clearly,
the opportunity cost of preventing CDI in LMHDI coun-
tries outweighs combating an epidemic. However, no
baseline cost estimate of CDI in LMHDI countries exists
by which to grade prevention interventions.
There are several limitations to this review. First,
results reported by each study are difficult to compare
given variable definitions of diarrhoea and CDI, and
range of utilised laboratory methods. Similarly, the dis-
tinction between HA- and CA-CDI was often blurry;
patients were usually either stratified as presenting to an
outpatient facility or having samples sent from an inpa-
tient facility. Rarely were strict definitions of HA- and
CA-CDI provided or followed. Second, few studies were
designed for risk factor analysis and, due to variable
methods, odds ratios were unable to be pooled limiting
the degree to which CDI risk could be attributed to speci-
fic risk factors. Third, there is likely selection bias, as
only a small number of LMHDI countries were repre-
sented in this review. This may limit generalisability of
the findings. Fourth, publication bias may be present as
1230
volume 22 no 10 pp 1223–1232 october 2017
institutions may be reticent to publish manuscripts
describing patient populations with high rates of CDI
infection. These four limitations underscore the need to
develop larger consortiums in LMHDI countries to create
acceptable case definitions to standardise further
investigation.
Conclusions
Despite the marked increase in the understanding the epi-
demiology of CDI in HHDI countries, there is a paucity
of published literature describing the epidemiology and
burden of CDI in LMHDI countries. The frequency of
CDI among symptomatic inpatients and outpatients
appears to be lower in LMHDI countries than in HHDI
countries, yet risk factors appear to be broadly similar
between these two populations. However, extensive mul-
tiinstitutional or multinational studies have not yet been
performed. Future epidemiologic studies in LMHDI coun-
tries describing basic epidemiology of CDI, risk factors
for development of CDI, patient morbidity and mortality,
as well as financial burden of infection are urgently
needed. Perhaps, the epidemic currently experienced in
many HHDI countries might not be repeated in LMHDI
countries.
Disclaimer
The views expressed in this manuscript are those of the
authors and do not necessarily represent their affiliated
institutions.
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Corresponding Author Joseph D. Forrester, Department of Surgery, 300 Pasteur Drive, H3591, Stanford, CA 94305, USA.
Tel.:+1 720 284 2317; E-mail: jdf1@stanford.edu
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Supporting Information
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Appendix S1: Search Strategy by Database
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