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Global Causes of Diarrheal Disease Mortality in Children <5 Years of Age: A Systematic Review

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  • Instituto de Investigacion Nutricional, Lima, Peru

Abstract and Figures

Estimation of pathogen-specific causes of child diarrhea deaths is needed to guide vaccine development and other prevention strategies. We did a systematic review of articles published between 1990 and 2011 reporting at least one of 13 pathogens in children <5 years of age hospitalized with diarrhea. We included 2011 rotavirus data from the Rotavirus Surveillance Network coordinated by WHO. We excluded studies conducted during diarrhea outbreaks that did not discriminate between inpatient and outpatient cases, reporting nosocomial infections, those conducted in special populations, not done with adequate methods, and rotavirus studies in countries where the rotavirus vaccine was used. Age-adjusted median proportions for each pathogen were calculated and applied to 712 000 deaths due to diarrhea in children under 5 years for 2011, assuming that those observed among children hospitalized for diarrhea represent those causing child diarrhea deaths. 163 articles and WHO studies done in 31 countries were selected representing 286 inpatient studies. Studies seeking only one pathogen found higher proportions for some pathogens than studies seeking multiple pathogens (e.g. 39% rotavirus in 180 single-pathogen studies vs. 20% in 24 studies with 5-13 pathogens, p<0·0001). The percentage of episodes for which no pathogen could be identified was estimated to be 34%; the total of all age-adjusted percentages for pathogens and no-pathogen cases was 138%. Adjusting all proportions, including unknowns, to add to 100%, we estimated that rotavirus caused 197 000 [Uncertainty range (UR) 110 000-295 000], enteropathogenic E. coli 79 000 (UR 31 000-146 000), calicivirus 71 000 (UR 39 000-113 000), and enterotoxigenic E. coli 42 000 (UR 20 000-76 000) deaths. Rotavirus, calicivirus, enteropathogenic and enterotoxigenic E. coli cause more than half of all diarrheal deaths in children <5 years in the world.
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Global Causes of Diarrheal Disease Mortality in Children
,
5 Years of Age: A Systematic Review
Claudio F. Lanata
1,2,3
*, Christa L. Fischer-Walker
4
, Ana C. Olascoaga
1
, Carla X. Torres
1
, Martin J. Aryee
5
,
Robert E. Black
4
for the Child Health Epidemiology Reference Group of the World Health Organization
and UNICEF
1Instituto de Investigacion Nutricional, Lima, Peru, 2US Navy Medical Research Unit 6, Callao, Peru, 3School of Medicine, Universidad Peruana de Ciencias Aplicadas,
Lima, Peru, 4Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America, 5Division of
Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
Abstract
Estimation of pathogen-specific causes of child diarrhea deaths is needed to guide vaccine development and other
prevention strategies. We did a systematic review of articles published between 1990 and 2011 reporting at least one of 13
pathogens in children ,5 years of age hospitalized with diarrhea. We included 2011 rotavirus data from the Rotavirus
Surveillance Network coordinated by WHO. We excluded studies conducted during diarrhea outbreaks that did not
discriminate between inpatient and outpatient cases, reporting nosocomial infections, those conducted in special
populations, not done with adequate methods, and rotavirus studies in countries where the rotavirus vaccine was used.
Age-adjusted median proportions for each pathogen were calculated and applied to 712 000 deaths due to diarrhea in
children under 5 years for 2011, assuming that those observed among children hospitalized for diarrhea represent those
causing child diarrhea deaths. 163 articles and WHO studies done in 31 countries were selected representing 286 inpatient
studies. Studies seeking only one pathogen found higher proportions for some pathogens than studies seeking multiple
pathogens (e.g. 39% rotavirus in 180 single-pathogen studies vs. 20% in 24 studies with 5–13 pathogens, p,0?0001). The
percentage of episodes for which no pathogen could be identified was estimated to be 34%; the total of all age-adjusted
percentages for pathogens and no-pathogen cases was 138%. Adjusting all proportions, including unknowns, to add to
100%, we estimated that rotavirus caused 197 000 [Uncertainty range (UR) 110 000–295 000], enteropathogenic E. coli 79
000 (UR 31 000–146 000), calicivirus 71 000 (UR 39 000–113 000), and enterotoxigenic E. coli 42 000 (UR 20 000–76 000)
deaths. Rotavirus, calicivirus, enteropathogenic and enterotoxigenic E. coli cause more than half of all diarrheal deaths in
children ,5 years in the world.
Citation: Lanata CF, Fischer-Walker CL, Olascoaga AC, Torres CX, Aryee MJ, et al. (2013) Global Causes of Diarrheal Disease Mortality in Children ,5 Years of Age:
A Systematic Review. PLoS ONE 8(9): e72788. doi:10.1371/journal.pone.0072788
Editor: Karol Sestak, Tulane University, United States of America
Received May 10, 2013; Accepted July 12, 2013; Published September 4, 2013
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: The work was supported by a grant to the US Fund for United Nations Children’s Fund (UNICEF) from the Bill & Melinda Gates Foundation for the Child
Health Epidemiology Reference Group of World Health Organization and UNICEF and by Prof. Lanatas Institutional Research Funds. The funders had no role in
study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: clanata@iin.sld.pe
Introduction
Despite global success in the reduction of all cause and diarrhea-
specific mortality in the past 30 years, diarrhea remains the second
leading cause of death due to infections among children under five
years of age worldwide [1,2]. It is estimated that diarrhea
accounted for 9?9% of the 6?9 million deaths among children
under 5 in 2011 [2,3]. Several organisms have been implicated as
important causes of these deaths [4,5], yet there has not been a
review using standardized methods to determine the importance of
all of the common pathogens. The Child Health Epidemiology
Reference Group (CHERG) has estimated the causes of child
deaths from major causes since 2001. We have undertaken this
review to develop estimates of pathogen-specific diarrhea mortality
among children under 5 years of age. We present the results of a
systematic literature review of studies of diarrhea etiology in
hospitalized children and use these results to estimate the global
burden of diarrhea mortality by pathogen for children under
5 years of age for 2011.
Methods
Search strategy and selection criteria
We searched Medline, Lilacs, and MedScape for studies
published between 1990 and 2011. We used the terms ‘‘diarrhea’’
(or ‘‘diarrhoea’’), ‘‘gastroenteritis’’, ‘‘rotavirus’’, ‘‘E.coli’’ (or
‘‘Escherichia coli’’), ‘‘Salmonella’’ (not ‘‘typhi’’), ‘‘Shigella’’,
‘‘Campylobacter’’, ‘‘Giardia lamblia’’, ‘‘Vibrio’’, ‘‘Cryptosporidi-
um’’, ‘‘Entamoeba’’, ‘‘norovirus’’, ‘‘calicivirus’’, ‘‘Norwalk agent’’,
using ‘‘AND children’’ as a search restriction. An example of one
of the search instructions in Medline-PubMed is: ‘‘diarrhea’’[-
mesh] OR ‘‘diarrhea’’[all fields] or ‘‘diarrhoea’’[all fields] OR
‘‘gastroenteritis’’[mesh] OR ‘‘gastroenteritis’’[all fields] OR ‘‘ro-
tavirus’’[mesh] OR ‘‘rotavirus’’[all fields] OR ‘‘E.coli’’[all fields]
or ‘‘Escherichia coli’’[mesh] OR ‘‘Escherichia coli’’[all fields] OR
‘‘Salmonella’’[mesh] OR ‘‘Salmonella’’[all fields] OR ‘‘Shigella’’[-
mesh] OR ‘‘Shigella’’[all fields] OR ‘‘Campylobacter’’[mesh] OR
‘‘Campylobacter’’[all fields] OR ‘‘Giardia lamblia’’[mesh] OR
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‘‘Giardia lamblia’’[all fields] OR ‘‘Vibrio’’[mesh] OR ‘‘Vibrio’’[all
fields] OR ‘‘Cryptosporidium’’[mesh] OR ‘‘Cryptosporidium’’[all
fields] OR ‘‘Entamoeba’’[mesh] OR ‘‘Entamoeba’’[all fields] OR
‘‘norovirus’’[mesh] OR ‘‘norovirus’’[all fields] OR ‘‘caliciviru-
s’’[all fields] OR ‘‘Norwalk agent’’[all fields] AND ‘‘children’’[all
fields]. Limited to publication dates January 1, 1990 – December
31, 2011. We also included data from the WHO Rotavirus
Surveillance Network for 2011 provided to us by WHO only from
countries that had not introduced rotavirus vaccine as of
December 2011 and had data covering the 12-month period.
These studies used a standard protocol across the network [6]. We
included studies that sought at least one of the above listed
pathogens and conducted 12 or more months of surveillance
among children less than 5 years of age hospitalized with diarrhea.
Studies must have included all diarrhea patients at the selected
study site or a systematic sampling of cases for the duration of the
study. We did not require a minimal number of children evaluated
to be included. Laboratory tests were performed on rectal swabs or
stools samples. We excluded studies conducted during reported
diarrhea outbreaks, those that did not discriminate between
inpatient and outpatient cases, those that included patients with
nosocomial infections, and those conduced in special populations,
such as HIV-positive patients. We also excluded studies that did
not describe adequate surveillance methods or standard laboratory
methods, according to the following criteria: a) salmonella and
shigella isolation in salmonella/shigella agar, xylose-lysine-deoxy-
cholate agar, Hektoen enteric agar, and selenite enrichment for
salmonella [7]; b) campylobacter isolation by use of transport
media with antibiotics (Skirrow’s supplement or similar) and
inoculation into 5% sheep blood with antibiotics (Butzlers
supplement or similar), cultivated at 42uC in micro-aerobic
atmosphere [7]; c) Vibrio cholerae isolation by alkaline peptone
water enrichment and subculture at 8 hrs into thiosulfate-citrate-
bile salts – sucrose agar (TCBS) [7]; d) E. coli isolation from
MacConkey agar and identification of ETEC by DNA probes or
polymerase chain reaction (PCR) for heat-labile (LT) or heat-
stable (ST) toxins, cell cultures (Y1, CHO cells), ileal loop or
mouse models [7]; e) EPEC isolation by the use of Hep 2 cell
cultures or the presence of the plasmid for adherence (BFP) and
the intimin gene (eae) identify in DNA probes or by PCR [7]; f)
rotavirus, calicivirus (or norovirus), astrovirus and enteric adeno-
virus identification with the use of enzyme-linked immunoassays
(ELISA), electronic microscopy, or PCR [7]; g) Giardia lamblia
identification by direct microscopic examination, or zinc-sulfate
concentration from direct stools or by ELISA [7]; h) Cryptosporidium
spp. identification by ELISA, or the modified Ziehl-Neelsen stain
for microscopy [7]; i) Entamoeba histolytica identification by direct
microscopic examination [7]. We did not include studies in areas
or countries where the rotavirus vaccine was used but included
data from the placebo arm of rotavirus vaccine trials. Articles
published in languages other than English, Spanish, Portuguese,
Italian, German and French were not included.
The following enteropathogens were considered: Rotavirus,
enteropathogenic Escherichia coli (EPEC), enterotoxigenic Escherichia
coli (ETEC), Salmonella spp. (excluding Salmonella typhi), Shigella spp.,
Campylobacter spp., Vibrio cholerae O1 and O139, Giardia lamblia,
Cryptosporidium spp., Entamoeba hystolitica, human Caliciviruses
(genogroup I and II norovirus and sapovirus) or astrovirus,
coronavirus, and enteric adenovirus. We extracted data for all
children less than five years of age for each pathogen. Data from
more than one hospital in a country were treated as separate
studies if the presentation of data permitted. Papers that published
different etiological data from the same study site were grouped
into one study. If co-infections were reported, they were not
treated separately so each pathogen was counted as present if
isolated alone or in combination. Three reviewers (CO, CXT, and
CFL) did the primary extraction and all selected papers were
reviewed by CFL and CFW independently. Disagreements were
resolved by CFL and/or REB.
Statistical analysis
We calculated overall median proportions of positive diarrheal
stool samples for each pathogen for children 0–59 months of age
using the overall proportion for all children included in the study;
39 studies enrolled children from a narrower age range so we
calculated for these studies an age-adjusted proportion for the 0–
59 months of age group by calculating a conversion factor for age
group X as the median of 0–59 prevalence over age group X
prevalence (median (prev
0–59
/prev
X
)) using studies that reported
both 0–59 and the age group X for a given pathogen. To use this
method we required at least 3 studies, where each study reported
both 0–59 months and age group X. In situations where less than
3 studies were available we employed an alternative method where
the conversion factor for age group X was taken as the ratio of the
median prev
0–59
to median prev
X
(median (prev
0–59
)/median
(prev
X
)). For this approach we required that 3 or more studies
contribute to each of the two medians, but dropped the Method 1
requirement that individual studies report both age groups. If
neither of these sets of conditions were met, we borrowed the
conversion factor for the age group X from a similar age group
within the same pathogen (for instance, used the conversion factor
calculated for studies including infants 0–11 months of age for
studies that included infants 0–5 months of age) or from a similar
pathogen (conversion factor for age group X for a study on EPEC
borrowed from studies on ETEC). The 0–59 months prevalence
proportion for each pathogen was estimated using the median
individual study 0–59 months pathogen prevalence.
We stratified studies by the number of pathogens sought and
calculated the unadjusted and age-adjusted medians, as described
above, separately for single pathogen studies and for studies that
sought 5 to 13 pathogens. For estimating the proportion of
diarrheal stools due to unknown pathogens, we included 12 studies
that sought 8 or more pathogens.
For the numbers of diarrheal deaths attributable to each
pathogen, we assume that the distribution of pathogens observed
among children hospitalized for diarrhea represents the pathogen
prevalence among child diarrhea deaths. We applied the age-
adjusted median proportion for each pathogen and for unknowns
to the overall number of diarrhea deaths of 712 000 estimated for
the world in 2011 [3], adjusting all proportions equally to be
constrained to add to 100%. We explored alternative estimates
using all studies selected or only those that sought 5 to 13
pathogens, constraining or not all proportions to add to 100%.
The uncertainty around each estimate was calculated using
Bootstrap confidence intervals [8]. ‘Pseudo-data sets’ were created
by sampling studies with replacement from the real dataset. Each
of the 1000 pseudo-datasets was used in the estimation procedure
described above to generate a corresponding 1 000 prevalence
proportions. The 2?5
th
and 97?5
th
percentile of these proportions
gave the 95% confidence interval (CI). To estimate the uncertainty
of the number of deaths for each pathogen, we paired each of the 1
000 pseudo-datasets with random draws from the under 5 total
mortality envelope, the proportion of total deaths attributable to
diarrhea [2,3], and the proportion of diarrhea deaths due to
unknown pathogens. The under 5 year global total mortality
envelope estimate and standard deviation were calculated by
sampling and combining 100 000 random draws from each of the
194 countries in the world [2,9]. For each country, a normal mean
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and standard deviation was estimated from the point estimate and
associated confidence interval.
Results
From 22 643 citations identified in the electronic search, 1 003
articles were selected for further evaluation (Fig. 1); 840 articles
were excluded because they had one or more of the exclusion
criteria (About 35% because they were not longitudinal studies or
inappropriate laboratory methods were used, 31% because no
data was given for children ,5 years of age, 23% for studies that
lasted less than 12 months of duration, and the rest because data
were reported after rotavirus vaccine introduction, duplicate
publications or reporting results on a pathogen not included in
our list). A total 163 articles and 31 WHO Rotavirus Surveillance
Network sites were selected representing 286 inpatient studies with
data for at least one pathogen [list of the 163 references can be
found at www.cherg.org]. The geographical localization of the
study sites is shown in Figure 2.
The median and age-adjusted median proportions (with 95%
CI) of isolation of each enteropathogen in hospitalized diarrhea
cases are shown in Table 1. Rotavirus, EPEC, calicivirus, and
ETEC were the most frequently identified organisms. The sum of
these age-adjusted median proportions, including unknowns was
138%, indicating a problem with many articles reporting mixed
infections as separate causes. Different isolation rates were
observed in studies in which only one, versus at least 5
enteropathogens were sought (Table 2). Rotavirus was more
frequently isolated in 180 single-pathogen inpatient studies in
comparison with 24 multiple-pathogen studies (39% vs. 20%,
respectively, p,0?0001). The same trend was observed between
single- and multiple-pathogen studies for most pathogens, but
mainly for Giardia lamblia (16% vs. 3%, p,0?001), shigella (24% vs.
7%, p,0?001) and V. cholerae (10% vs. 0.2%, p,0?001). Very few
studies sought a substantial number of pathogens. From the 286
inpatient studies, only 12 (4%) sought 8 or more pathogens (1
study with 13, 2 studies with 10, 5 studies with 9, and 4 studies
with 8 pathogens). In these studies, 33?7% of cases had no
pathogen identified.
Adjusting all proportions, including unknowns, to add to 100%,
we estimated that rotavirus caused 197 000 (Uncertainty range
UR 110 000–295 000), enteropathogenic E. coli 79 000 (UR 31
000–146 000), calicivirus 71 000 (UR 39 000–113 000), and
enterotoxigenic E. coli 42 000 (UR 20 000–76 000) deaths. These
four pathogens were associated with 55% of all diarrhea deaths
(Table 3). These estimates varied substantially depending on the
methods used. If the proportions were not made to add to 100%,
rotavirus would be said to cause 272 000 deaths or if only studies
that sought .4 pathogens were selected and the proportions were
adjusted to 100% rotavirus would be said to cause 126 000 deaths
(Table 4).
Figure 1. PRISMA Flow Diagram of studies included.
doi:10.1371/journal.pone.0072788.g001
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When classifying studies by WHO region, most studies were
done in the Western Pacific Region (78 studies) and less in the
Eastern Mediterranean Region (19 studies) (Table 5). Rotavirus
was more frequently isolated in the Western Pacific Region (33%)
and less in the American Region (23%). Other comparisons were
limited by few or no studies in some regions (Table 5).
Discussion
In this review, we showed that more than half of the severe
diarrhea episodes, most likely to result in death among children
under the age of 5 years in 2011, could be attributed to rotavirus,
EPEC, calicivirus, and ETEC. Our estimates have been adjusted
for age in studies that did not cover all children ,5 years old, and
Figure 2. Location of the 286 inpatient etiologic studies included in the analysis.
doi:10.1371/journal.pone.0072788.g002
Table 1. Age-adjusted median proportions of diarrheal episodes requiring hospitalizations associated with each enteropathogen
in children 0–59 m of age in the world.
Pathogen Inpatients (n = 286 studies)
N studies N samples positive N samples examined Median % Age adjusted median % (95%CI)
Viruses
Rotavirus 242 77 392 228 277 38?2% 38?3% (35?5–40?2)
Calicivirus 36 4 468 52 179 13?6% 13?8 % (11?8–17?6)
Astrovirus 26 883 49 993 2?9% 3?0% (2?0–4?2)
Adenovirus 30 1 675 52 734 4?7% 4?3% (3?1–5?8)
Bacteria
EPEC 11 708 4 461 15?3% 15?3% (7?8–27?6)
ETEC 21 1 032 18 989 6?9% 8?2% (4?8–12?2)
Shigella spp 36 946 66 502 4?7% 5?4% (2?9–7?9)
Campylobacter spp 32 951 54 580 4?3% 4?3% (3?0–8?8)
Salmonella spp 34 2 184 69 340 3?5% 3?5% (2?9–5?2)
Vibrio cholerae O1 19 1 024 51 043 1?8% 1?8% (0?0–6?1)
Parasites
Cryptosporidum spp 25 517 46 254 2?7% 2?7% (0?6–5?6)
Giardia lamblia 17 536 40 444 3?1% 3?1% (0?0–14?2)
Entamoeba histolytica 15 175 55 365 0?3% 0?3% (0?0–3?5)
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Table 2. Median proportions of pathogens isolated in stool samples from diarrheal episodes seen in inpatient services, in 208 studies that sought one or 27 studies that sought 5–
13 pathogens in children 0–59 m of age in the world, by type of pathogen.
Pathogen Single pathogen (n = 208 studies) Studies that sought 5–13 pathogens (n = 27 studies)
N studies
N samples
positive
N samples
examined Median %
Age adjusted
median %
(95%CI)
*
N studies
N samples
positive
N samples
examined Median %
Age adjusted
median %
(95%CI)
Viruses
Rotavirus 180 59 226 161 126 39?4% 39?4% (37?1–43?1) 24 8 384 43 719 19?7% 20?2% (15?7–26?3)
Calicivirus 12 639 4 412 15?6% 15?6% (10?5–21?2) 7 2 681 39 195 8?2% 8?2% (4?8–12?7)
Astrovirus 1 28 708 4?0% 4?0% (NA) 10 577 39 597 2?3% 2.3% (1?1–3?5)
Adenovirus 1 17 866 2?0% 2?0% (NA) 10 942 39 615 3?6% 3?6% (1?7–5?8)
Bacteria
EPEC 0 - - - - 9 605 2 961 15?8% 15?8% (7?9–29?2)
ETEC 1 43 314 13?7% 13?7% (NA) 16 355 5 461 8?1% 8?2% (5?1–11?9)
Shigella spp 2 118 668 17?1% 24?5% (NA) 24 520 43 947 6?0% 7?2% (3?2–7?9)
Campylobacter spp 164 2163 3?0% 3?0% (NA) 23 596 43 882 4?8% 4?8% (3?1–9?3)
Salmonella spp 0 - - - - 24 853 44 060 3?2% 3?2% (2?7–3?5)
Vibrio cholerae O1 2 134 1 441 10?5% 10?5% (NA) 11 227 36 025 0?2% 0?2% (0?0–6?1)
Parasites
Cryptosporidium spp 7 192 5 451 2?8% 2?8% (2?0–6?1) 17 290 40 493 2?6% 2?6% (0?4–7?0)
Giardia lamblia 146 291 15?8% 15?8% (NA) 14 425 39 762 2?8% 2?8% (0?4–10?5)
Entamoeba histolytica 0 - - - - 12 150 39 067 0?3% 0?3% (0?0–3?8)
*CI = confidence interval.
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to add to 100%, including a fraction of episodes with unknown
etiology. Such adjustments have not been done in previously
published estimates for single diarrhea etiologies [4,5,10–12].
We identified a potential selection bias among studies that focus
on a single pathogen. For example, the median proportion of
diarrheal episodes with rotavirus identified varied from 39% in
single-pathogen studies to 20% in studies that sought more than 4
pathogens. It is possible that studies looking for a particular
pathogen are more likely to be conducted in a study site with a
high prevalence of that pathogen and/or a low prevalence of other
pathogens. An urban hospital that treats children of higher
socioeconomic status and living in more hygienic conditions than
children in rural areas may find a higher proportion of cases with
rotavirus. A study of cholera done in a hospital in an endemic area
may not be representative of national or regional populations.
Because of the low number of studies that sought multiple
pathogens, we have not restricted our analysis to only those
studies, in an attempt to include as much global data as possible,
but it should be recognized that the inclusion of single-etiology
studies may result in a biased higher estimate for some pathogens.
By including 13 pathogens in this review we are able to address
the problem of mixed infections, an important factor ignored in
previously published single-pathogen estimates of deaths. No
methodology has been developed to identify the true cause of an
episode when more than one pathogen is identified in the stool.
Our adjustment of all percentages to fit 100% is done to correct
for this problem, assuming that each pathogen is equally likely to
cause the illness. This is probably not correct because some
organisms are carried in the feces for a relatively long time after
infection-causing illness, like norovirus [13], or may not cause
illness, especially in older children who have acquired immunity
that protects against disease, but not carriage of the organism, like
some protozoa [14]. This method of including all equally in the
constraint to 100% of diarrhea deaths may result in an
underestimate of the importance of some pathogens, such as
rotavirus in young children, and overestimate the importance of
others, such as Giardia. We do not have data on the presence of
these pathogens in the stools of asymptomatic children in the
studies selected in this review so we cannot determine the
attributable fraction related to each pathogen as done in other
studies [15]. However, controlling for pathogens found in non-ill
children does not necessarily eliminate the problem because some
pathogens with long excretion periods after illness, like norovirus,
may be wrongly classified as not causing diarrhea. Carefully
conducted longitudinal studies are needed to separate long-term
excretors after illness from asymptomatic infections, to reveal the
true pathogenic role of these different organisms in developing
countries.
We estimated that the number of diarrhea episodes for which no
pathogen can be identified is 34%, which is based on studies that
sought at least 8 pathogens, not necessarily all 13 and thus may be
an overestimate. These ‘‘unknowns’’ could be due either to the
same pathogens not detected because insensitive methods were
used to identify them (either the method itself or to using a rectal
swab instead of a stool sample) [16], to the use of antibiotics prior
to obtaining the stool sample, to other yet undiscovered infections,
or to non-infectious causes of diarrhea. The proportion of samples
with unknown causes was based on a selected group of 12 studies
that searched for 8 or more pathogens. These studies do not
represent the world as the rest of the studies did. The recently
conducted studies called The Global Enterics Multicenter Study
(GEMS) in 7 countries in Africa and Asia were designed to fill this
gap [15,17,18]. However, they studied cases with moderate and
severe diarrhea seen in health services (hospitals, emergency rooms
and community clinics), not separating those being hospitalized
from milder outpatient cases, therefore, those studies would not
Table 3. Number of diarrheal deaths estimated for each pathogen in children 0–59 m of age in the world for the year 2011, using
constrained median proportions to fit 100%.
Pathogen Medians restricted to add 100%
Median No. Deaths (61000) 95% CI (61000)
Viruses
Rotavirus 27?8% 197 110–295
Calicivirus 9?9% 71 39–113
Astrovirus 2?1% 15 9–26
Adenovirus 3?1% 22 12–37
Bacteria
EPEC 11?1% 79 31–146
ETEC 6?0% 42 20–76
Shigella spp 3?9% 28 12–53
Campylobacter spp 3?2% 22 11–50
Salmonella spp 2?5% 18 10–30
Vibrio cholerae O1 1?3% 9 0–37
Parasites
Cryptosporidum spp 2?0% 14 3–31
Giardia lamblia 2?3% 16 0–66
Entamoeba histolytica 0?2% 1 0–19
Episodes with unknown etiology 24?5% 176 56–304
Total 100?0% 712 491–1 049
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Table 4. Number of diarrheal deaths estimated for each pathogen in children 0–59 m of age in the world for the year 2011, estimated using un-constrained or constrained
median proportions to fit 100% obtained from all 286 inpatient studies or from 27 studies that searched for 5 to 13 pathogens.
Using all 286 studies Using 27 studies that searched for 5 to 13 pathogens
Pathogen Un-restricted medians Un-restricted medians Medians restricted to 100% including unknowns
Median
No. Deaths
(61000) 95% CI (61000) Median
No. Deaths
(61000) 95% CI (61000) Median
No. Deaths
(61000) 95% CI (61000)
Viruses
Rotavirus 38?3% 272 163–374 20?2% 144 82–206 17?8% 126 70–200
Calicivirus 13?7% 98 57–153 8?2% 59 28–115 7?3% 52 22–95
Astrovirus 3?0% 21 11–35 2?3% 17 7–27 2?1% 15 6–25
Adenovirus 4?3% 31 16–49 3?6% 26 10–44 3?2% 23 8–39
Bacteria
EPEC 15?3% 109 43–213 15?8% 112 57–242 14?0% 99 51–196
ETEC 8?2% 59 28–102 8?2% 59 29–102 7?3% 52 24–92
Shigella spp 5?4% 38 17–71 7?2% 51 20–74 6?4% 45 17–69
Campylobacter spp 4?3% 31 16–71 4?8% 34 19–80 4?2% 30 15–73
Salmonella spp 3?5% 25 15–40 3?2% 22 13–32 2?8% 20 10–31
Vibrio cholerae O1 1?8% 13 0–49 0?2% 1 0–42 0?2% 1 0–36
Parasites
Cryptosporidum spp 2?7% 19 4–45 2?6% 19 3–50 2?3% 16 2–43
Giardia lamblia 3?1% 22 0–97 2?8% 20 2–79 2?5% 18 2–66
Entamoeba histolytica 0?3% 2 0–29 0?3% 2 0–28 0?3% 2 0–24
Episodes with unknown etiology 33?7% 243 68–500 33?7% 243 68–500 29?8% 214 71–362
Total 137?6% 983 582–1 475 112?8% 808 491–1 244 100?0% 712 491–1 049
doi:10.1371/journal.pone.0072788.t004
Causes of Diarrheal Deaths in Children ,5
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meet our inclusion criteria. Given that we cannot distinguish
among the reasons no pathogen was found during the episode, our
estimates may represent an under-estimate, at least for some
causes. We could not include some pathogens known to cause
diarrhea in our review, such as organisms that cause food-borne
outbreaks (i.e. Clostridium perfringens [19], or Staphylococcus aureus
producing enterotoxins [20]), because there are very little data on
their importance in developing countries.
Table 5. Median age-adjusted proportions of causes of diarrhea, constrained to fit 100%, in 286 inpatients studies of children
,5 years of age published between 1990–2011, by WHO region.
Pathogen AFRO (n = 22) AMRO (n = 53) EMRO (n = 19) EURO (n= 50) SEARO (n = 64) WPRO (n = 78)
N Median N Median N Median N Median N Median N Median
Viruses
Rotavirus 18 26?84723?41631?34425?94225?57532?6
Calicivirus 1 15?9613?6110?2119?868?41110?3
Astrovirus 1 6?653?10– 70?932?1102?8
Adenovirus 1 3?742?40– 102?745?1113?4
Bacteria
EPEC 1 10?3610?8213?00– 28?90
ETEC 1 5?0107?435?00– 74?30
Shigella spp 24?1155?7211?950?1103?520?2
Campylobacter spp 22?396?117?962?193?551?9
Salmonella spp 23?2122?126?065?282?643?2
Vibrio cholerae O1 2 0?440?010?00– 114?510?04
Parasites
Cryptosporidium spp 22?5123?10– 10?092?110?3
Giardia lamblia 11?8104?70– 10?045?210?5
Entamoeba histolytica 10?380?02 0– 10?041?710?2
doi:10.1371/journal.pone.0072788.t005
Figure 3. Median proportion of stool samples with rotavirus by mid study period.
doi:10.1371/journal.pone.0072788.g003
Causes of Diarrheal Deaths in Children ,5
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A recent review of rotavirus studies estimated that rotavirus
caused 453 000 deaths in children ,5 in 2008 [4]. If we would
apply the median proportion of 38% rotavirus isolation found in
the 242 inpatient studies that sought it in our review, without any
adjustment, to the 1 236 million U5 diarrheal deaths in 2008, we
would estimate 472 000 rotavirus deaths in 2008. In 2011 it is
estimated that diarrhea deaths have been reduced to 712 000 [3].
Our estimate of 197 000 deaths due to rotavirus, using our
improved methods, still represents an important global public
health problem, with 23 children dying due to this condition every
hour. This estimate does not account for any recent reduction in
rotavirus-specific proportionate mortality due to the introduction
of rotavirus vaccine, as seen in some Latin America countries [21],
but these countries account for a very small fraction of global
diarrhea mortality. Wide scale use of the rotavirus vaccine in high
mortality countries will allow a more precise estimate of the true
proportion of diarrhea deaths caused by rotavirus.
Our estimate of 28 000 deaths for shigella is much lower than a
previous estimate of 667 695 deaths due to shigellosis in children
under 5 years in the world in 1995 published by Kotloff et al [5].
This initial estimate was not based on a systematic review of the
literature; rather, it used a single study in Latin America to
estimate the proportion of shigella cases that were hospitalized and
a Bangladeshi study to estimate the case-fatality rate of children
hospitalized with shigellosis to estimate the global burden due to
this organism. Using the same methodology of Kotloff et al but
with an updated review of the literature and current case fatality
rates observed in Bangladesh, Bardhan P et al [22] estimated that
only 14 000 children younger than 5 years of age died due to
shigellosis in Asia in 2005. Our estimates are compatible with this
Asian estimate.
The total number of deaths due to calicivirus of 71 000 deaths
has indicated to be the third most common cause of death due to
diarrhea in children under 5 years of age. Few studies differen-
tiated between GI and GII norovirus and other types of human
caliciviruses, but in those few that did, most of calicivirus isolated
in children with severe diarrhea have been due to norovirus GII
[23,24]. Patel et al [25] estimated 218 000 deaths due to norovirus
among children under 5, but this was calculated using very
different methods and assumptions: they used an attributable
fraction due to norovirus when data on asymptomatic children was
available, and applied their mean isolation rate of 12.1% from
inpatient studies (not much different from our median isolation
rate of 13.8%) to 1.8 million deaths due to diarrhea in the world;
they did not adjust for mixed infections or unknowns.
The 79 000 deaths estimated to be caused by EPEC represent
different sub-types of this type of pathogenic E. coli, a group that
requires further epidemiological studies in different parts of the
world to further characterize them since some sub-types are
isolated with the same frequency in diarrhea and control children
[26], new ‘‘typical’’ and ‘‘atypical’’ EPEC strains have been
identified [27], and in some regions have been identified to cause
more persistent than acute diarrhea [28].
These estimates have several limitations. The studies included in
this review were conducted in selected sites and in some cases in
populations with increased risk of diarrheal diseases. Thus, they
may not be representative of the countries where they were
conducted, nor of the world. For several regions, such as Russia
and the former Soviet states or Sub-Saharan Africa we have
limited or no data (fig. 2, Table 4). The gap of information from
Africa, for pathogens other than rotavirus, is most acute because of
the number of diarrhea deaths in this region is very high [1–3]. No
study has been conducted to identify pathogens in children who
died due to diarrheal diseases, so we assume that children in need
of hospitalization are the best proxy of diarrhea deaths in low to
middle income countries, but this may not be true for some
pathogens. Another limitation is the combination of laboratory
methods with different sensitivities to identify a pathogen: from the
culture-based identification of salmonella or shigella to the highly
sensitive real-time PCR method for norovirus. This may have
affected the relative importance of one vs another pathogen in our
estimates. We excluded studies on nosocomial infections, on
displaced populations and on diarrhea outbreaks, which may have
caused us to under-represent deaths due to some pathogens like V.
cholerae.
We included in our estimates a total of 13 pathogens (4 viruses,
6 bacteria and 3 parasites) that have been incriminated as causes of
severe diarrheal diseases. Some viruses, like adenovirus, and
parasites, like G. lamblia, have not been completely documented as
a cause of severe diarrhea in developing countries [14,29,30]. The
subject of causality of diarrheal diseases is still not completely
understood in settings where children are heavily exposed to many
Table 6. Comparison between Global Burden of Diseases (for 2010) and the Child Epidemiology Reference Group (for 2011)
estimates of the number of diarrhea deaths (61000), by cause and age, in children ,5 years of age in the world.
Global Burden of Disease Estimate for 2010 CHERG estimate for 2011
Causes 0–6 d 7–27 d 28–364 d 1–4 yr 0–5 yr
Total diarrheal deaths 25 52 353 235 666 712
V. cholerae O1 2 3 21 17 42 10
Salmonella spp 1 2 15 12 30 18
Shigella spp 2 3 22 17 44 28
EPEC 3 6 45 19 73 79
ETEC 1 3 20 14 39 43
Campylobacter spp 2 5 36 20 64 22
Entamoeba histolytica 0?314 492
Cryptosporidium spp. 4 7 47 25 83 14
Rotavirus 6 13 90 64 173 198
Other causes/unknown 4 8 54 44 109 176
doi:10.1371/journal.pone.0072788.t006
Causes of Diarrheal Deaths in Children ,5
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pathogens early in life. Young infants may be protected by breast
milk and trans-placental maternal immunity and very low doses of
ingested pathogens early in life may result in subclinical infections
and development of immunity. This immunity may not preclude,
however, the excretion of these pathogens in the child’s feces.
Practically all studies done in children who were studied when they
were healthy as well as when they developed an acute diarrheal
episode have found the same pathogens, although usually with
lower frequency, in healthy states. Thus, the assumption that any
pathogen identified in a child with diarrhea is the cause of the
episode is naive and additional methods are needed to determine
the pathogenicity of microbes. With a better understanding of the
pathogenicity of key organisms our estimates could be further
adjusted. Also, some studies suggest that children ill with a
pathogen, as with EPEC, may excrete higher amounts in the stool,
as compared with asymptomatic infections [31], so future studies
may consider quantifying the amount of each pathogen in the stool
to help identifying those ill with it. Finally, the review period
covering studies published between 1990 and 2011 (studies were
conducted with a median mid-study period of 2005, only 24 (8%)
studies were done prior to 1990). We have not identified a
significant change of the proportions assigned to each pathogen
over time, so this does not seem to affect our estimates, as shown in
Fig. 3 for rotavirus.
The Global Burden of Disease Study recently published cause of
death estimates for 187 countries in 2010 [32]. For children
,5 years of age, GBD estimated a total of 666 000 deaths due to
diarrheal diseases in 2010 while CHERG estimated 712 000
deaths for 2011. GBD also estimated deaths due to 9 etiologies and
produced estimates for 0–6, 7–27, and 28–364 days and 1–4 years
of age. CHERG estimates for 2011 in children ,5 years of age are
slightly higher than GBD estimates for rotavirus (198 000 vs 173
000 rotavirus deaths, respectively), similar for EPEC and ETEC
deaths (79 000 vs 73 000, and 43 000 vs 39 000, respectively), and
lower for cholera, salmonella, shigella, campylobacter, Entamoeba
histolytica, and Cryptosporidium spp. (Table 6). GBD did not estimate
deaths due to norovirus, which was the third leading cause of
death in our review. GBD used rates reported in diarrhea studies
published between 1975 and 2010 done in outpatients, case-
control, and community-based studies as a reference category to
adjust the proportions seen in inpatient studies. CHERG only used
data from inpatient studies published between 1990 and 2011.
Both GBD and CHERG used modeling to obtain the total
number of diarrheal deaths for children ,5, but unlike GBD,
CHERG has not used models for etiology-specific causes of deaths
for each age group and for each country to produce its global
estimate. Age specific data and modeling may produce spurious
results, more so if there are no data. For example, very few studies
have been done describing causes of diarrhea in neonates in
developing countries, but GBD has estimated deaths caused by
each of the 9 pathogens in neonates 0–6 and 7–27 days of age
(Table 6). GBD only produced estimates for 9 etiologies of
diarrhea and by subtracting the total of these estimates from the
total of diarrheal deaths; they estimated the proportion of other
causes of diarrheal deaths. CHERG estimated the proportion due
to unknowns from studies that searched for 9–13 pathogens, which
we feel realistically addresses the fact that a causative agent is not
identified in every illness. This also explains why we estimated a
higher number of deaths in this category (176 000) than GBD for
‘‘other causes’’ which should include unknowns (109 000). GBD
and CHERG recognized the problem of mixed infections, but the
methods used to adjust for it was different: GBD only used
proportions for each etiology from inpatient studies that searched
for 2–8 etiologies and used that information to produce weights to
adjust their estimates in the models. We choose to constrain all
proportions, including unknowns, to 100% to correct for mixed
infections, which we feel it is more appropriate until better data
and analytical tools are available. We have done an extensive
search of the literature to include the 286 inpatient studies used in
our estimates. GBD has not published the studies included, their
search strategy, or modeling methods. Until these are published
we will not be able to completely compare these estimates.
This is the first systematic review attempting to estimate the
cause of deaths for these 13 enteric pathogens. Rotavirus,
calicivirus, enteropathogenic and enterotoxigenic E. coli cause
more than half of all diarrheal deaths in children ,5 in the world.
We have identified a potential selection bias in studies searching
for only one enteropathogen, and the problem when mixed
infections (more than one enteropathogen is identified in a stool
sample taken from a child with severe diarrhea) are not taken into
consideration when estimating causes of diarrheal deaths, factors
that has affected previous published estimates. Future studies
should be done in hospital services dealing with all types of severe
diarrhea, searching for all known enteropathogens, removing the
effect of asymptomatic excretes, and establishing a mechanism to
attribute to one enteropathogen the cause of a diarrheal episode in
cases of mixed infections.
Supporting Information
Checklist S1 PRISMA Checklist
(DOC)
Acknowledgments
Cynthia Boschi-Pinto of WHO and Theresa Diaz of UNICEF
provided coordination of the involvement in CHERG of their
respective institutions. Carolyn Weidemann served as coordinator
of the grant in support of CHERG from the Bill and Melinda
Gates Foundation. CHERG provided advice on methods and
interpretation of results. We thank Walter Mendoza for his initial
literature review, Cynthia Boschi-Pinto and Laura Lamberti for
their support in searching for articles, and Edda Franco for
editorial assistance. We thank the countries who provided data
through the WHO-coordinated Global Rotavirus Surveillance
Network of participating ministries of health, sentinel hospital sites,
and the rotavirus laboratory network. We also thank John Sanders
and Theresa J. Ochoa for providing useful comments on early
drafts of the manuscript. Preliminary results of this study has been
presented at CHERG and Food Borne Epidemiology Reference
Group (FERG) meetings at WHO and at the Infectious Disease
Society Association annual meeting in Vancouver, British Ontario,
Canada on Oct 20
th
, 2010. Disclaimer: The views expressed in
this article are those of the authors and do not necessarily reflect
the official policy or position of the Department of the Navy,
Department of Defense, nor the U.S. Government. Author
Claudio F. Lanata is a contractor of the U.S. Government. This
work was prepared as part of his official duties. Title 17 U.S.C. 1
105 provides that ‘Copyright protection under this title is not
available for any work of the United States Government’. Title 17
U.S.C. 1101 defines a U.S. Government work as a work prepared
by a military service members or employees of the U.S.
Government as part of those persons’ official duties.
Author Contributions
Conceived and designed the experiments: CFL CLF REB. Performed the
experiments: CFL ACO CXT CLF REB. Analyzed the data: CFL CLF
MJA. Contributed reagents/materials/analysis tools: MJA. Wrote the
paper: CFL CLF MJA REB.
Causes of Diarrheal Deaths in Children ,5
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Escherichia coli is a gram-negative commensal bacterium living in human and animal intestines. Its pathogenic strains lead to high morbidity and mortality, which can adversely affect people by causing urinary tract infections, food poisoning, septic shock, or meningitis. Humans can contract E. coli by eating contaminated food—such as raw or undercooked raw milk, meat products, and fresh produce sold in open markets—as well as by coming into contact with contaminated settings like wastewater, municipal water, soil, and faeces. Some pathogenic strains identified in Nigeria, include Enterohemorrhagic (Verotoxigenic), Enterotoxigenic, Enteropathogenic, Enteroinvasive, and Enteroaggregative E. coli. This causes acute watery or bloody diarrhoea, stomach cramps, and vomiting. Apart from the virulence profile of E. coli, antibiotic resistance mechanisms such as the presence of blaCTX-M found in humans, animals, and environmental isolates are of great importance and require surveillance and monitoring for emerging threats in resource-limited countries. This review is aimed at understanding the underlying mechanisms of evolution and antibiotic resistance in E. coli in Nigeria and highlights the use of improving One Health approaches to combat the problem of emerging infectious diseases.
... Introduction Exposure to enteric pathogens during childhood is associated with substantial disease burden. Enteric infections and diarrheal diseases are the fifth leading cause of death in children under age five globally [1][2][3][4][5]. Persistent exposure to enteric pathogens during childhood can result in recurrent infections and lifelong consequences, such as deficits in growth and cognitive development [6][7][8][9][10][11][12]. ...
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Exposure to animal feces and associated enteric pathogens poses significant risks to child health. However, public health strategies to mitigate enteric infections among children largely aim to reduce exposure to human feces, overlooking transmission pathways related to animal feces. In this study we examine if and how children are exposed to enteric pathogens in animal feces in northwestern coastal Ecuador. We conducted qualitative interviews with mothers of children aged 10–18 months that owned (n = 32) and did not own (n = 26) animals in urban and rural communities. Using thematic analysis, we identified community, household, and child behavioral factors that influence exposure. We also compared child exposure by household animal ownership. Our findings revealed myriad opportunities for young children to be exposed to enteric pathogens in many locations and from multiple animal sources, regardless of household animal ownership. Animal feces management practices (AFM) used by mothers, such as rinsing feces into ditches and throwing feces into surrounding areas, may increase environmental contamination outside their homes and in their communities. Unsafe AFM practices were similar to unsafe child feces management practices reported in other studies, including practices related to defecation location, feces removal and disposal, environmental contamination cleaning, and handwashing. Findings suggest that animal feces may contaminate the environment along similar pathways as human feces. Identification and incorporation of safe AFM practices, similar to those developed for child feces management, would 1) mitigate child exposure to enteric pathogens by reducing animal feces contamination in domestic and public spaces; and 2) enable an integrated approach to address enteric pathogen exposure pathways related to animal and child feces.
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In this study, the prevalence and impact of rotavirus infections on pediatric patients under six years old were investigated. Rotaviruses emerged as a predominant cause of severe diarrheal illness in newborns and young children globally. A comprehensive observational study in Al Kut city from May to September 2022 included 99 cases, revealing a 46.5 % positive rate for rotavirus. Statistical analysis indicated a significant association between rotavirus infection and increased frequency of diarrhea episodes (P=0.004) and severe dehydration (P=0.001). Moreover, rotavirus-positive cases were more likely to require intravenous fluid therapy (P=0.02). These findings underscore the substantial burden of rotavirus on both the healthcare system and society, emphasizing its role as a major contributor to infant gastroenteritis, often leading to severe complications and hospitalization
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Citation: Zizza, A.; Guido, M.; Sedile, R.; Benelli, M.; Nuzzo, M.; Paladini, P.; Romano, A.; Grima, P. A Multi-Pathogen Retrospective Study in Patients Hospitalized for Acute Gastroenteritis. Diseases 2024, 12, 213. Abstract: Acute gastroenteritis (AGE) is a gastrointestinal tract disease often caused by consuming food or water contaminated by bacteria, viruses, or parasites, that can lead to severe symptoms requiring hospitalization. A retrospective study on patients admitted for AGE between 2021 and 2023 at the Pediatrics and Infectious Diseases Departments of Lecce Hospital was conducted. Demographic characteristics, year and month of admission, length of hospital stay, etiological agents, co-infections, and blood chemistry data of patients were collected. The study included 103 patients ranging in age from 0 to 15 years, with 58.25% being male. A total of 78 bacterial, 35 viral, and 7 parasitic infections were identified. The most commonly detected pathogens were Escherichia coli (38.83%), Norovirus (28.16%), Campylobacter jejuni (22.33%), and Salmonella typhi/paratyphi (10.68%). Only a few cases of Cryptosporidium (5.83%) were identified. Additionally, 17 co-infections (16.50%) were detected. Viral infections are the primary cause of hospitalization for AGE in children <5 years, while bacterial infections are more common among older patients. The significantly higher number of children <5 years old with elevated creatinine compared to children ≥5 years suggested that young children are more susceptible to dehydration than older children. Few cases of AGE were attributed to pathogens for which a vaccine has already been licensed. AGE is a serious health concern that could be effectively prevented by implementing food-based and community-level sanitation systems, as well as by increasing vaccination coverage of available vaccines and developing new effective and safe vaccines.
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Background: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. Methods: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. Findings: In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. Conclusions: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. Funding: Bill & Melinda Gates Foundation.
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Background. Diarrhea is a leading cause of illness and death among children aged <5 years in developing countries. This paper describes the clinical and epidemiological methods used to conduct the Global Enteric Multicenter Study (GEMS), a 3-year, prospective, age-stratified, case/control study to estimate the population-based burden, microbiologic etiology, and adverse clinical consequences of acute moderate-to-severe diarrhea (MSD) among a censused population of children aged 0–59 months seeking care at health centers in sub-Saharan Africa and South Asia. Methods. GEMS was conducted at 7 field sites, each serving a population whose demography and healthcare utilization practices for childhood diarrhea were documented. We aimed to enroll 220 MSD cases per year from selected health centers serving each site in each of 3 age strata (0–11, 12–23, and 24–59 months), along with 1–3 matched community controls. Cases and controls supplied clinical, epidemiologic, and anthropometric data at enrollment and again approximately 60 days later, and provided enrollment stool specimens for identification and characterization of potential diarrheal pathogens. Verbal autopsy was performed if a child died. Analytic strategies will calculate the fraction of MSD attributable to each pathogen and the incidence, financial costs, nutritional consequences, and case fatality overall and by pathogen. Conclusions. When completed, GEMS will provide estimates of the incidence, etiology, and outcomes of MSD among infants and young children in sub-Saharan Africa and South Asia. This information can guide development and implementation of public health interventions to diminish morbidity and mortality from diarrheal diseases.
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To understand the etiology of moderate-to-severe diarrhea among children in high mortality areas of sub-Saharan Africa and South Asia, we performed a comprehensive case/control study of children aged <5 years at 7 sites. Each site employed an identical case/control study design and each utilized a uniform comprehensive set of microbiological assays to identify the likely bacterial, viral and protozoal etiologies. The selected assays effected a balanced consideration of cost, robustness and performance, and all assays were performed at the study sites. Identification of bacterial pathogens employed streamlined conventional bacteriologic biochemical and serological algorithms. Diarrheagenic Escherichia coli were identified by application of a multiplex polymerase chain reaction assay for enterotoxigenic, enteroaggregative, and enteropathogenic E. coli. Rotavirus, adenovirus, Entamoeba histolytica, Giardia enterica, and Cryptosporidium species were detected by commercially available enzyme immunoassays on stool samples. Samples positive for adenovirus were further evaluated for adenovirus serotypes 40 and 41. We developed a novel multiplex assay to detect norovirus (types 1 and 2), astrovirus, and sapovirus. The portfolio of diagnostic assays used in the GEMS study can be broadly applied in developing countries seeking robust cost-effective methods for enteric pathogen detection.
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Background: Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia. Methods: The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measurements, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth. Findings: We enrolled 9439 children with moderate-to-severe diarrhoea and 13,129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8·5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8·5, 95% CI 5·8-12·5, p<0·0001); most deaths (167 [87·9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1·9; 0·99-3·5) and typical enteropathogenic E coli (HR 2·6; 1·6-4·1) in infants aged 0-11 months, and Cryptosporidium (HR 2·3; 1·3-4·3) in toddlers aged 12-23 months. Interpretation: Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes. Funding: The Bill & Melinda Gates Foundation.
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Diarrhoea and pneumonia are the leading infectious causes of childhood morbidity and mortality. We comprehensively reviewed the epidemiology of childhood diarrhoea and pneumonia in 2010-11 to inform the planning of integrated control programmes for both illnesses. We estimated that, in 2010, there were 1·731 billion episodes of diarrhoea (36 million of which progressed to severe episodes) and 120 million episodes of pneumonia (14 million of which progressed to severe episodes) in children younger than 5 years. We estimated that, in 2011, 700 000 episodes of diarrhoea and 1·3 million of pneumonia led to death. A high proportion of deaths occurs in the first 2 years of life in both diseases-72% for diarrhoea and 81% for pneumonia. The epidemiology of childhood diarrhoea and that of pneumonia overlap, which might be partly because of shared risk factors, such as undernutrition, suboptimum breastfeeding, and zinc deficiency. Rotavirus is the most common cause of vaccine-preventable severe diarrhoea (associated with 28% of cases), and Streptococcus pneumoniae (18·3%) of vaccine-preventable severe pneumonia. Morbidity and mortality from childhood pneumonia and diarrhoea are falling, but action is needed globally and at country level to accelerate the reduction.