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Spatial Heterogeneity of Enteric Fever in 2 Diverse Communities in Nepal

Authors:
  • Kathmandu University School Of Medical Sciences, Nepal

Abstract and Figures

Background Typhoid fever is endemic in the urban Kathmandu Valley of Nepal; however, there have been no population-based studies of typhoid outside of this community in the past 3 decades. Whether typhoid immunization should be prioritized in periurban and rural communities has been unclear. Methods We performed population-based surveillance for enteric fever in 1 urban catchment (Kathmandu) and 1 periurban and rural catchment (Kavrepalanchok) as part of the Surveillance for Enteric Fever in Asia Project (SEAP). We recruited individuals presenting to outpatient and emergency departments at 2 study hospitals with suspected enteric fever and performed blood cultures. Additionally, we conducted a household survey in each catchment area to characterize care seeking for febrile illness. We evaluated spatial heterogeneity in febrile illness, care seeking, and enteric fever incidence. Results Between September 2016 and September 2019, we enrolled 5736 participants with suspected enteric fever at 2 study hospitals. Among these, 304 (5.3%) were culture positive for Salmonella Typhi (249 [81.9%]) or Paratyphi A (55 [18.1%]). Adjusted typhoid incidence in Kathmandu was 484 per 100 000 person-years and in Kavrepalanchok was 615 per 100 000 person-years. While all geographic areas for which estimates could be made had incidence >200 per 100 000 person-years, we observed spatial heterogeneity with up to 10-fold variation in incidence between communities. Conclusions In urban, periurban, and rural communities in and around Kathmandu, we measured a high but heterogenous incidence of typhoid. These findings provide some support for the introduction of conjugate vaccines in Nepal, including outside urban areas, alongside other measures to prevent enteric fever.
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SUPPLEMENT ARTICLE
Typhoid Heterogeneity inNepal • CID 2020:71 (Suppl 3) • S205
Clinical Infectious Diseases
Correspondence: J.R. Andrews, Division of Infectious Diseases and Geographic Medicine,
Stanford University School of Medicine, 300 Pasteur Drive, Lane Bldg, Suite 143, Room 141,
Stanford, CA 94305 (jandr@stanford.edu).
Clinical Infectious Diseases® 2020;71(S3):S205–13
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society
of America.This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: 10.1093/cid/ciaa1319
Spatial Heterogeneity of Enteric Fever in 2 Diverse
Communities inNepal
Dipesh Tamrakar,1 Krista Vaidya,1 AlexanderT. Yu,2 Kristen Aiemjoy,2 ShivaRam Naga,1 Yanjia Cao,2 Caryn Bern,3 Rajeev Shrestha,1 Biraj M. Karmacharya,1
Sailesh Pradhan,4 Farah Naz Qamar,5 Samir Saha,6 Kashmira Date,7 Ashley T. Longley,7,8 Caitlin Hemlock,9 Stephen Luby,2 Denise O. Garrett,9 IsaacI. Bogoch,10
and JasonR. Andrews2,
1Dhulikhel Hospital, Kathmandu University Hospital, Kavrepalanchok, Nepal, 2Division of Infectious Diseases and Geographic Medicine, School of Medicine, Stanford University, Stanford, California, USA,
3Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA, 4Kathmandu Medical College and Teaching Hospital, Kathmandu, Nepal, 5Department
of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan, 6Child Health Research Foundation, Department of Microbiology, Dhaka Shishu (Children’s) Hospital, Dhaka, Bangladesh, 7Global
Immunization Division, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, 8National Foundation for the Centers for Disease Control and Prevention, Atlanta, Georgia, USA, 9Applied
Epidemiology, Sabin Vaccine Institute, Washington, DC, USA, and 10Department of Medicine, University of Toronto, Toronto, Canada
Background. Typhoid fever is endemic in the urban Kathmandu Valley of Nepal; however, there have been no population-
based studies of typhoid outside of this community in the past 3 decades. Whether typhoid immunization should be prioritized in
periurban and rural communities has been unclear.
Methods. We performed population-based surveillance for enteric fever in 1 urban catchment (Kathmandu) and 1 periurban
and rural catchment (Kavrepalanchok) as part of the Surveillance for Enteric Fever in Asia Project (SEAP). We recruited individuals
presenting to outpatient and emergency departments at 2 study hospitals with suspected enteric fever and performed blood cultures.
Additionally, we conducted a household survey in each catchment area to characterize care seeking for febrile illness. We evaluated
spatial heterogeneity in febrile illness, care seeking, and enteric fever incidence.
Results. Between September 2016 and September 2019, we enrolled 5736 participants with suspected enteric fever at 2 study
hospitals. Among these, 304 (5.3%) were culture positive for Salmonella Typhi (249 [81.9%]) or Paratyphi A(55 [18.1%]). Adjusted
typhoid incidence in Kathmandu was 484 per 100000 person-years and in Kavrepalanchok was 615 per 100000 person-years. While
all geographic areas for which estimates could be made had incidence >200 per 100000 person-years, we observed spatial heteroge-
neity with up to 10-fold variation in incidence between communities.
Conclusions. In urban, periurban, and rural communities in and around Kathmandu, we measured a high but heterogenous
incidence of typhoid. ese ndings provide some support for the introduction of conjugate vaccines in Nepal, including outside
urban areas, alongside other measures to prevent enteric fever.
Keywords. typhoid; enteric fever; Salmonella; Nepal; geospatial.
Enteric fever, caused by Salmonella enterica subspecies enterica sero-
types Typhi and Paratyphi A, B, and C, is among the leading causes
of invasive bacterial infection in South Asia [1, 2]. The World Health
Organization has recommended the introduction of typhoid conju-
gate vaccine (TCV) in settings with high typhoid incidence or high
rates of antimicrobial-resistant typhoid [3]. Health policy makers
in Nepal, as in many other countries, have been faced with deciding
whether and where to deploy TCV vaccinations with limited typhoid
incidence data outside of focused areas. As part of the Surveillance of
Enteric Fever in Asia Project (SEAP), we sought to understand the
population incidence of enteric fever in diverse communities inNepal.
Studies over the past 2 decades have revealed a high degree
of endemicity in the Kathmandu Valley, the largest urban center
in the country [4, 5]. However, the majority of typhoid studies
conducted over the past 20years have been in a single urban
center in the Kathmandu Valley, Lalitpur [4–7], which has con-
sistently shown a high burden of typhoid in children (428 cases
per 100000 person-years [PY] in the control arm of the recent
vaccine trial). ere have been no population-based typhoid
studies in Nepal outside of this community since the 1980s,
when the Vi polysaccharide vaccine was rst evaluated [8].
Even elsewhere within the Kathmandu Valley, the only avail-
able data have been through retrospective analysis of passively
collected culture data, which do not provide population-level
incidence estimates [9].
As 80% of the population of Nepal lives outside of urban
areas [10], there is need for typhoid incidence estimates from
periurban and rural communities to determine whether the
pattern of enteric fever occurrence warrants introduction of
TCVs nationwide. While data on clinically diagnosed enteric
fever cases are collected through a national reporting system,
S206 • CID 2020:71 (Suppl 3) • Tamrakar etal
such diagnoses are not based on culture conrmation, and a
recent study in the country found poor correlation between
clinically reported typhoid and culture-conrmed disease
[11]. To address this knowledge gap, we undertook prospec-
tive, population-based surveillance using blood cultures in
urban, periurban, and rural communities in Kathmandu
and Kavrepalanchok, Nepal. Here, we report on spatial het-
erogeneity in enteric fever symptoms, care-seeking, and
culture-conrmed typhoid and paratyphoid disease in these
communities.
METHODS
StudyDesign
SEAP was a prospective, population-based study conducted
in communities in Nepal, Bangladesh, and Pakistan between
September 2016 and September 2019. The study utilized a “hy-
brid surveillance” approach to estimate incidence [12], com-
bining hospital-based surveillance to identify enteric fever cases
and a community-based healthcare utilization survey to esti-
mate the proportion of enteric fever cases captured by surveil-
lance hospitals. The clinical characteristics and outcomes were
reported separately [13, 14]. Here, we report on heterogeneity
in healthcare seeking and enteric fever incidence in Nepal.
Study Site and Population
This study was conducted in 2 settings in Nepal, defined by
the catchment area for the 2 main SEAP surveillance hos-
pitals: Kathmandu Medical College and Teaching Hospital
in Kathmandu Metropolitan City and Dhulikhel Hospital in
Kavrepalanchok District, which is approximately 30 km east of
Kathmandu. Kathmandu is the capital of Nepal and has a dense,
urban population of >20000 people per square kilometer. The
Kathmandu catchment area for this study was identified based
on review of the home addresses of 100 consecutive patients
meeting SEAP clinical enrollment criteria (fever on at least
3days within the past 7days). We selected 9 wards (6, 7, 8, 9, 10,
32, 33, 34, and 35)within Kathmandu, which accounted for the
home addresses of >60% of patients meeting the study defini-
tion. In Kavrepalanchok, which has periurban and rural popu-
lations, we identified the home address of the past 100 patients
with culture-confirmed enteric fever diagnosed at Dhulikhel
Hospital and selected 4 municipalities, which accounted for
>60% of cases. These municipalities consisted of Dhulikhel
(12.1 km2; density: 1066 persons/km2), Banepa (5.6 km2; 4050
persons/km2), Paanchkhal (19.1 km2; 387 persons/km2), and
Panauti (31.7 km2; 723 persons/km2). We utilized administra-
tive geographical units (eg, wards, municipalities) rather than
physical boundaries to facilitate the determination of whether
participants arriving at the hospital lived within the catchment
area. Because the most recent available population census was
8 years old, and there had been substantial population shifts
over the interim (particularly following the 2015 earthquake),
we estimated the population from the healthcare utilization
survey as described below.
Study Procedures and Definitions
Clinical Surveillance
We prospectively enrolled participants from the 2 main SEAP
surveillance hospitals. At each hospital, we screened all pa-
tients presenting to the outpatient departments (adult and pe-
diatric) and emergency department for history of fever. Those
reporting fever on at least 3 consecutive days within the past
7days who resided within the predefined catchment area were
invited to participate in the study. In the inpatient department,
we recruited all participants who were suspected of enteric fever
by clinicians. There were no age restrictions for enrollment.
Participants were recruited 6days per week (Sunday through
Friday); those who sought care in the emergency room or in-
patient department overnight or on Saturdays were recruited
the following day if still present. After obtaining informed con-
sent, we administered a standardized questionnaire to ascertain
demographic and clinical information. We collected 2–10mL
of peripheral blood, which were inoculated into BACTEC
Aerobic or Peds Plus bottles and incubated using a BACTEC
automated system for up to 5days. Bottles showing growth were
subcultured on sheep blood agar and MacConkey agar, and bi-
ochemical and antisera testing was performed to identify iso-
lates. We defined typhoid and paratyphoid cases as individuals
with positive blood cultures for Salmonella Typhi or Salmonella
Paratyphi A, B, or C. Additionally, we established a network
of 7 microbiology laboratories in Kathmandu (Bir Hospital,
Helping Hands Community Hospital, Nepal Medical College,
Kathmandu Model Hospital, Alka Hospital, Kanti Childrens
Hospital, and Nepal Police Hospital). We contacted all patients
identified at these laboratories with culture-confirmed enteric
fever cases for enrollment in the study.
Healthcare UtilizationSurvey
We conducted a household-based healthcare utilization survey
in both catchment areas [15, 16]. In brief, we used grid-based
random sampling to select geographic clusters, from which all
households were approached. Astandardized questionnaire was
administered to the head of all consenting households, with the
primary objective of determining the proportion of individuals
with a typhoid-like illness (fever 3days) who sought care at
the 2 surveillance hospitals. We inquired about any healthcare
seeking for fever 3days that occurred within the past 8 weeks,
as well as any hospitalization for fever within the past year, rea-
soning that recall accuracy would be longer for hospitalization.
Analytic Approach
We characterized enteric fever cases by demographic variables,
reporting median and interquartile range (IQR) for continuous
Typhoid Heterogeneity inNepal • CID 2020:71 (Suppl 3) • S207
variables and proportions for dichotomous variables. For the
healthcare utilization survey, we used mixed effects logistic re-
gression models with random effects for cluster to estimate the
proportion seeking care at the study site. We performed spatial
interpolation to estimate local density of fever and care seeking
using an inverse distance weighted model. We assessed spatial
risk factors for fever and care seeking using logistic regres-
sion, and investigated the effects of community water sources
and wealth. We defined improved water sources as municipally
supplied water or that purchased from a vendor, and unim-
proved water sources as surface waters, rainwater, public taps,
or groundwater. We created a household wealth index using
principal components analysis using the following assets: elec-
tricity, ownership of radio, television, landline telephone, mo-
bile phone, computer, watch, bicycle, motorcycle, car, and bank
account. We classified administrative areas (wards and munici-
palities) by population density as urban (5000 persons/km2),
periurban (1000–4999 persons/km2), or rural (<1000 persons/
km2).
We used OpenStreetMap (accessed in October 2019
using QGIS 3.8) to build a street network and estimated
road distance from household to surveillance hospital using
Origin-Destination Matrix in ArcGIS 10.7.1 (Esri, Redlands,
California). To assess the relationship between distance and
care seeking, we t both generalized linear models and gener-
alized additive models, both with logistic link functions, and
compared models by Akaike Information Criteria and χ
2 good-
ness oft.
e primary objective of this study was to estimate incidence
of typhoid and paratyphoid fever in various geographic areas.
We have previously described the overall analytic approach
used for this study [12]. We rst estimated the crude, culture-
conrmed typhoid and paratyphoid incidence by dividing all
culture-conrmed cases by the catchment population and du-
ration of the study. e catchment population and population
of each administrative area was estimated by dividing the meas-
ured population from the healthcare utilization survey by the
cluster sampling fraction and the response rate. In the crude
Figure 1. Population density in the Kathmandu wards and Kavrepalanchok municipalities comprising the study catchment area. Yellow crosses denote the location of study
surveillance hospitals. Abbreviation: SEAP, Surveillance for Enteric Fever in Asia Project.
S208 • CID 2020:71 (Suppl 3) • Tamrakar etal
estimates, we included all cases who resided in the catchment
area that were identied through surveillance at the hospital
and laboratory networksites.
We then undertook several adjustments to estimate the true
incidence of typhoid and paratyphoid. For the adjusted esti-
mates, we excluded cases enrolled from the laboratory net-
work, as systematic active surveillance was not undertaken at
those facilities. First, we adjusted for blood culture sensitivity,
estimating it to be 59% (95% condence interval [CI], 54%–
64%) [17], and dividing our crude estimate by this number.
Second, we adjusted to account for eligible patients who were
missed by surveillance, either because they presented during
evenings, weekends, or when the study sta were unavail-
able, consented to enrollment but did not have a blood cul-
ture obtained, or because they were approached but declined
to participate. We divided our estimate by the proportion of
cases that were captured by the surveillance study. Finally, we
adjusted for individuals who sought care at sites other than the
surveillance sites by dividing by the proportion seeking care
at the study site, stratied by each age group and geographical
unit. We propagated uncertainty in culture sensitivity and care
seeking through Monte Carlo sampling from distributions es-
timated for each of these parameters and generated 95% cred-
ible intervals for incidence estimates.
All analyses and geo-visualization were performed using
ArcGIS 10.7.1 (Esri) and R soware.
Ethics Statement
All participants provided informed consent. For participants
under age 18, a parent or guardian provided informed con-
sent, and those 7–17years of age provided assent. The study
was approved by the institutional review boards at Kathmandu
University School of Medical Sciences, Stanford University,
the Nepal Health Research Council, and through local ethics
boards at participating hospitals.
Figure 2. Proportion of individuals with fever in the past 8 weeks (top) and hospitalized for fever in the past year (bottom) for Kathmandu and Kavrepalanchok. Yellow
crosses denote the location of study surveillance hospitals.
Typhoid Heterogeneity inNepal • CID 2020:71 (Suppl 3) • S209
RESULTS
Between September 2016 and September 2019, we enrolled 5667
participants with suspected enteric fever at the 2 study hos-
pitals (Dhulikhel Hospital: 2434; Kathmandu Medical College
Hospital: 3233). Among these, 4827 (85.2%) were enrolled from
outpatient or emergency departments, and the remaining 841
were enrolled from inpatient wards. Overall, 304 (5.4%) of these
patients were culture positive for enteric fever. Additionally, we
identified 1296 cases from the laboratory network sites. Among
all culture-confirmed cases, 1366 (85.4%) were Salmonella Typhi
and 234 (14.6%) were Salmonella Paratyphi A. The majority
(58.9%) of cases occurred among males. The median age of S.
Paratyphi Apatients (21 [IQR, 17–26] years) was slightly higher
than that of Typhi patients (19.5 [IQR, 15–24] years; P = .0003).
Approximately one-quarter of typhoid cases (369/1369 [27.0%])
occurred among children <16 years of age, and more than
half (720/1369 [52.6%]) occurred among individuals aged
16–25years. Age distribution of typhoid cases did not differ be-
tween Kathmandu and Kavrepalanchok (P = .414).
We conducted healthcare utilization surveys continuously
for 24months, from January 2017 through December 2018. We
enrolled 16 744 households in Kathmandu (covering 50039
participants) and 8729 households in Kavrepalanchok (34041
participants) (Figure 1). Among those in Kavrepalanchok,
59% were in periurban areas and 41% were in rural areas. e
most common drinking water source in urban areas was de-
livery by truck (38.0%) followed by piped into house (23.9%).
In periurban areas, the most common drinking water source
was water piped into the household (61%), and in rural areas,
surface waters were the most common source of drinking
water (38.6%). Household toilet ownership was high (>95%)
in allareas.
Among enrolled households, 919 (5.4%) in Kathmandu and
1353 (15.5%) in Kavrepalanchok, respectively, reported at least
1 member with febrile illness within the past 8 weeks, and 188
Figure 3. Proportion of individuals with fever in past 8 weeks (top) or hospitalized in past month (bottom) who sought care at the study hospitals in Kathmandu and
Kavrepalanchok. Yellow crosses denote the location of study surveillance hospitals.
S210 • CID 2020:71 (Suppl 3) • Tamrakar etal
(1.1%) and 324 (3.7%) reported 1 member with hospitalization
for fever within the past year. We found spatial heterogeneity
in the proportion of households reporting febrile illness in the
past 8 weeks (Figure 2). Households in communities lacking
improved water (odds ratio [OR], 2.26; P < .0001) and lower
wealth quintiles (OR, 1.06 per quintile; P = .008) were more
likely to report a member having fever in the past 8weeks.
In Kathmandu, 6.6% of individuals with fever in the past
week and 4.2% of individuals hospitalized for fever in the past
year sought care at the study site. In Kavrepalanchok, 13.3% of
individuals with fever and 12.6% of individuals hospitalized for
fever sought care at the study site. We noted substantial heter-
ogeneity across each catchment area in the proportion seeking
care at the study site (Figure3). We tested how geodesic distance
and road length between households and surveillance hospitals
aected probability of seeking care at that study site. We found
that road length was a better predictor of care seeking than ge-
odesic distance for both catchment areas (P < .0001 for model
comparisons), and that the relationship was nonlinear (Figure4).
In both communities, participants in the rst quintile of road dis-
tance were far more likely to seek care at the study site compared
with those in the top 3 quintiles for distance (Kathmandu: 17.7%
vs 3.1%; P < .0001; Kavrepalanchok: 34.2% vs 7.0%; P < .0001).
e crude incidence of blood culture–conrmed typhoid
and paratyphoid fever was 31 (95% CI, 26–37) and 6 (95% CI,
4–9) cases per 100000 PY, respectively, in Kathmandu and 36
(95% CI, 24–51) and 7 (95% CI, 3–16) cases per 100000 PY,
respectively, in Kavrepalanchok. Aer adjusting for culture sen-
sitivity, enrollment capture, and care-seeking, we found a high
incidence of typhoid in both communities (484 [95% CI, 384–
612] per 100000 PY in Kathmandu; 615 [95% CI, 527–721] per
100000 PY in Kavrepalanchok). In 1 ward of Kathmandu (ward
6), which was furthest from the surveillance hospital, only 25
participants were enrolled in clinical surveillance and none had
typhoid. For the remaining 8 wards in Kathmandu and 4 muni-
cipalities in Kavrepalanchok, estimated typhoid incidence was
>200 per 100000 PY (Figure 5). e highest incidence was in
wards 7 and 33 (2510 per 100000 PY and 2661 per 100 000
PY), and the lowest incidence occurred in ward 34 (223 per
100000 PY) and Panauti municipality (309 per 100000 PY).
Paratyphoid incidence was 117 (95% CI, 93–148) per 100000
PY in Kathmandu and 105 (95% CI, 90–123) cases per 100000
PY in Kavrepalanchok, with substantial geographic heteroge-
neity ranging between 642 per 100000 ward 10 to 0 per 100000
in ward 33 of Kathmandu.
DISCUSSION
In this population-based study in 2 areas in Nepal, we found an
overall high incidence of enteric fever, >200 cases per 100000
Figure 4. Probability of seeking care at study site as a function of road distance between household and the study site for Kathmandu (top) and Kavrepalanchok (bottom).
Typhoid Heterogeneity inNepal • CID 2020:71 (Suppl 3) • S211
PY in all geographic areas for which we were able to make es-
timates. We also noted substantial heterogeneity in incidence,
ranging from just over 200 cases per 100 000 PY to >2000
cases per 100000 PY. Incidence of typhoid fever was 4–6 times
greater than that of paratyphoid fever, which was an average of
80–100 cases per 100000 PY. While individuals living far from
study sites were less likely to seek care for febrile illness, after
adjusting for this we did not detect a consistent relationship be-
tween population density and typhoid incidence. These find-
ings suggest that there is substantial burden of typhoid even in
periurban and rural areas outside of Kathmandu.
Over the past 20years, virtually all of the prospective en-
teric fever studies in Nepal have been conducted in Lalitpur, a
metropolitan city in the Kathmandu Valley [4–7]. e placebo
arm of the recent TCV trial conducted in this community
demonstrated a high incidence (428 per 100000 PY) among
children 6months to 15years of age [18]. Population-based
data outside of this community are lacking. One recent study
found that cases of clinically diagnosed enteric fever reported
through the national Health Management Information System
had grown over the past 15years, reaching reported rates of
1800 per 100000 PY, highest in the rural areas [11]. However,
in prospective surveillance at sites with blood culture ca-
pacity, only 4.1% of those clinically diagnosed with typhoid
had positive blood cultures for typhoidal Salmonella, and this
rate ranged between 0 and 2.8% in rural areas of Nepal [11].
Culture positivity in that study was strongly, positively asso-
ciated with population density. However, the earlier study in-
cluded fever patients from all rural areas in the catchment of
Dhulikhel Hospital. Within the more limited catchment pop-
ulation of the present study, we found no consistent dier-
ences in typhoid incidence between the urban (Kathmandu),
periurban (Banepa, Dhulikhel) and rural (Paanchkhal,
Panauti) communities. In other settings, some studies have
shown higher incidence in urban than rural areas [19, 20],
whereas others have found the converse [21].
The study catchment area for the periurban and rural area
communities was selected based on where enteric fever cases
Figure 5. Incidence (cases per 100000 person-years) of typhoid (A) and paratyphoid (B) by ward in Kathmandu and by municipality in Kavrepalanchok. Yellow crosses de-
note the location of study surveillance hospitals. Abbreviation: SEAP, Surveillance for Enteric Fever in Asia Project.
S212 • CID 2020:71 (Suppl 3) • Tamrakar etal
had been detected in the previous 2years, which biased to-
ward selection of higher-risk communities. Furthermore,
Nepal has highly diverse ecosystems, from subtropical com-
munities in the South to alpine villages in the Himalaya. The
communities selected for this study were all in 1 province
and are not likely to be representative of the typhoid risk in
areas throughout the country. Nevertheless, this study adds
to what was a sparse collection of population-based data on
enteric fever in the country. Amajor obstacle to generating
such data is the resource-intensive nature of population-
based surveillance systems; emerging approaches including
seroepidemiology and environmental surveillance may
enable more efficient typhoid risk mapping in resource-
constrained settings [22].
We observed moderate spatial heterogeneity in febrile ill-
ness in both catchment areas, with overall higher rates of fever
in the rural communities. As anticipated, care seeking for fe-
brile illness at study sites in both communities was strongly
predicted by road distance from the site. We found that most
of this eect occurred at smaller distances, and that aer a
point, distance did not further aect the probability of seeking
care at the site. Understanding these heterogeneities can be
important to the design and interpretation of surveillance
approaches.
The median age of enteric fever cases in our study was
20years, and nearly half of all cases occurred among indi-
viduals between the ages of 16 and 25years. This age distri-
bution is higher than reported in some neighboring South
Asian countries, but similar to what has been reported in
Lalitpur (median ages of 16 and 20years for typhoid and
paratyphoid, respectively) [4]. In retrospective data reported
from Nepal and India for phase 1 of the SEAP study, the
median age of typhoid was 19years in Nepal and 24years
in India [23]. In these settings, catch-up vaccination cam-
paigns among older children, adolescents, and young adults
may be important for addressing the burden of typhoid and
preventing transmission.
ese results should be interpreted within the context of the lim-
itations of the study design and available data. We used healthcare
utilization data to adjust for the proportion of patients with en-
teric fever who did not seek care at the study site; it is possible that
individuals who sought care at the study site diered from those
who did in ways that were related to their risk of typhoid. One ap-
proach to handle this confounding is inverse probability weighting
based on household characteristics; while we performed this ap-
proach for the overall area estimates, we were unable to do this at
ner geographical resolution due to lack of power. We made esti-
mates based on administrative boundaries (wards, municipalities),
because this address information was available for all participants
enrolled in clinical surveillance. ere are no conventional street
addresses in Nepal, which precluded more precise geocoding of
participants based on the available data. Our estimates are based on
the participant’s household address, but typhoid may be acquired
outside the household, so the geospatial estimates may not reect
where transmission occurs. We assumed a xed blood culture sen-
sitivity for all participants based on a previous meta-analysis [17]; in
reality, this may vary by age, blood volume, and prior antibiotic use.
We opted for more parsimonious and data-driven adjustments to
our incidencemodel.
In conclusion, we found a high incidence of typhoid fever
in urban, periurban, and rural communities in and nearby
to Kathmandu, with no clear relationship between typhoid
incidence and population density. e incidence in all com-
munities was above previously proposed thresholds at which
typhoid vaccination would be deemed cost-eective [24].
ese ndings support the introduction of TCV in Nepal,
alongside improved water and sanitation interventions, to
prevent both typhoid and paratyphoid fever in communities
throughout the country.
Notes
Acknowledgments. The authors are grateful for the efforts of the
Surveillance for Enteric Fever in Asia Project (SEAP) Nepal research
assistants, field team, laboratory staff, and laboratory networkteams.
Disclaimer. e ndings and conclusions in this study are those of the
authors and do not necessarily reect the position of the Centers for Disease
Control and Prevention.
Financial support. is work was supported by the Bill & Melinda Gates
Foundation (BMGF) (award number OPP1113007).
Supplement sponsorship. is supplement is sponsored by the Sabin
Vaccine Institute and made possible by a grant from the Bill & Melinda
Gates Foundation.
Potential conicts of interest. e authors all acknowledge grant support
from BMGF. K.D.reports a conditional gi agreement between the Sabin
Vaccine Institute (primary grantee for the SEAP grant from BMGF) and the
CDC Foundation. S.S.reports grants from the World Health Organization
(WHO) during the conduct of the study, and grants from the WHO, BMGF,
GlaxoSmithKline, Pzer, Sano Pasteur, and Edinburgh University, out-
side the submitted work. All other authors report no potential conicts
of interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conicts of Interest. Conicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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... While they clearly show variation at the country level, existing studies fail to emphasize that the burden of typhoid fever also shows significant sub-national variation for each country. Outbreaks often show district-level variation of typhoid incidence [7][8][9] and country-level surveys show sub-national heterogeneity of incidence [10][11][12][13] . Understanding idiosyncratic behaviour of typhoid transmission between communities will be critical for a country to implement intervention programs such as campaign vaccination against endemic or epidemic typhoid fever more efficiently and effectively. ...
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Typhoid fever, caused by Salmonella enterica serovar Typhi, results in over 1.2 million cases and 29 thousand deaths annually from sub-Saharan Africa. Combating this disease requires various intervention approaches, such as typhoid conjugate vaccines and improving water, sanitation, and hygiene. Enhancing the effectiveness of these strategies necessitates a deeper understanding of the variation of the typhoid fever across the target region. Although the magnitude and variation of typhoid fever at the country level have been studied globally, sub-national variation remains underexplored. To address this gap, we collected data from 229 published reports on typhoid fever occurrences in sub-Saharan Africa between January 2000 and December 2020. The dataset includes information on the year and geographical location of observation, diagnostic tests used, and the type of studies in which typhoid fever was reported. By analyzing this dataset, we can gain insights into the sub-national heterogeneity of typhoid fever’s burden in the region. This knowledge will be instrumental in designing more effective intervention strategies to combat the disease.
... Tamrakar et al. studied 5,736 patients with suspected enteric fever from 2 diverse communities in Nepal (Kathmandu and Kavrepalanchok) and detected S. Typhi in 5.3% by microbiological culture. Adjusted enteric fever incidence in Kathmandu was 484 per 100 000 personyears and 615 per 100 000 person-years in Kavrepalanchok [36]. ...
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Background Febrile illnesses that persist despite initial treatment are common clinical challenges in (sub)tropical low-resource settings. Our aim is to review infectious etiologies of “prolonged fevers” (persistent febrile illnesses, PFI) and to quantify relative contributions of selected neglected target diseases with limited diagnostic options, often overlooked, causing inadequate antibiotic prescriptions, or requiring prolonged and potentially toxic treatments. Methods We performed a systematic review of articles addressing the infectious etiologies of PFI in adults and children in sub-/tropical low- and middle-income countries (LMICs) using the PRISMA guidelines. A list of target diseases, including neglected parasites and zoonotic bacteria (e.g., Leishmania and Brucella), were identified by infectious diseases and tropical medicine specialists and prioritized in the search. Malaria and tuberculosis (TB) were not included as target diseases due to well-established epidemiology and diagnostic options. Four co-investigators independently extracted data from the identified articles while assessing for risk of bias. Results 196 articles from 52 countries were included, 117 from Africa (33 countries), 71 from Asia (16 countries), and 8 from Central and -South America (3 countries). Target diseases were reported as the cause of PFI in almost half of the articles, most frequently rickettsioses (including scrub typhus), relapsing fever borreliosis (RF-borreliosis), brucellosis, enteric fever, leptospirosis, Q fever and leishmaniasis. Among those, RF-borreliosis was by far the most frequently reported disease in Africa, particularly in Eastern Africa. Rickettsioses (including scrub typhus) were often described in both Africa and Asia. Leishmaniasis, toxoplasmosis and amoebiasis were the most frequent parasitic etiologies. Non-target diseases and non-tropical organisms (Streptococcus pneumoniae, Escherichia coli, and non-typhoidal Salmonella spp) were documented in a fifth of articles. Conclusions Clinicians faced with PFI in sub-/tropical LMICs should consider a wide differential diagnosis including enteric fever and zoonotic bacterial diseases (e.g., rickettsiosis, RF-borreliosis and brucellosis), or parasite infections (e.g., leishmaniasis) depending on geography and syndromes. In the absence of adequate diagnostic capacity, a trial of antibiotics targeting relevant intra-cellular bacteria, such as doxycycline or azithromycin, may be considered.
... Salmonella Typhi and Paratyphi A are known to have spatial and temporal variation in their dominant route of transmission [12]. Within Kathmandu and Kavre Districts of Nepal, enteric fever incidence rates vary widely by ward, a sub-administrative unit, with S. Typhi and S. Paratyphi A infections clustering nearby one another in low lying areas [13,14]. Drinking water has long been recognized as an important route of Salmonella Typhi and Paratyphi A [13]. ...
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Introduction Salmonella Typhi and Salmonella Paratyphi, fecal-oral transmitted bacterium, have temporally and geographically heterogeneous pathways of transmission. Previous work in Kathmandu, Nepal implicated stone waterspouts as a dominant transmission pathway after 77% of samples tested positive for Salmonella Typhi and 70% for Salmonella Paratyphi. Due to a falling water table, these spouts no longer provide drinking water, but typhoid fever persists, and the question of the disease’s dominant pathway of transmission remains unanswered. Methods We used environmental surveillance to detect Salmonella Typhi and Salmonella Paratyphi A DNA from potential sources of transmission. We collected 370, 1L drinking water samples from a population-based random sample of households in the Kathmandu and Kavre Districts of Nepal between February and October 2019. Between November 2019 and July 2021, we collected 380, 50mL river water samples from 19 sentinel sites on a monthly interval along the rivers leading through the Kathmandu and Kavre Districts. We processed drinking water samples using a single qPCR and processed river water samples using differential centrifugation and qPCR at 0 and after 16 hours of liquid culture enrichment. A 3-cycle threshold (Ct) decrease of Salmonella Typhi or Salmonella Paratyphi, pre- and post-enrichment, was used as evidence of growth. We also performed structured observations of human-environment interactions to understand pathways of potential exposure. Results Among 370 drinking water samples, Salmonella Typhi was detected in 7 samples (1.8%) and Salmonella Paratyphi A was detected in 4 (1.0%) samples. Among 380 river water samples, Salmonella Typhi was detected in 171 (45%) and Salmonella Paratyphi A was detected in 152 (42%) samples. Samples located upstream of the Kathmandu city center were positive for Salmonella Typhi 12% of the time while samples from locations in and downstream were positive 58% and 67% of the time respectively. Individuals were observed bathing, washing clothes, and washing vegetables in the rivers. Implications These results suggest that drinking water was not the dominant pathway of transmission of Salmonella Typhi and Salmonella Paratyphi A in the Kathmandu Valley in 2019. The high degree of river water contamination and its use for washing vegetables raises the possibility that river systems represent an important source of typhoid exposure in Kathmandu.
... Enteric fever, caused by the Salmonella enterica serovars Typhi and Paratyphi A, is a significant health burden in many low-and middle-income countries [1,2]. The disease caused by S. Typhi and S. Paratyphi A is clinically indistinguishable [3] and has an estimated global annual incidence of >14 million cases with >135 000 deaths [1]. ...
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Background: Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, is a major public health problem in low and middle-income countries. Moderate sensitivity and scalability of current methods likely underestimate enteric fever burden. Determining the serological responses to organism-specific antigens may improve incidence measures. Methods: Plasma samples were collected from blood culture-confirmed enteric fever patients, blood culture-negative febrile patients over the course of three months and afebrile community controls. A panel of 17 Salmonella Typhi and Paratyphi A antigens was purified and used to determine antigen-specific antibody responses by indirect ELISAs. Results: The antigen-specific longitudinal antibody responses were comparable between enteric fever patients, patients with blood culture-negative febrile controls, and afebrile community controls for most antigens. However, we found that IgG responses against STY1479 (YncE), STY1886 (CdtB), STY1498 (HlyE) and the serovar-specific O2 and O9 antigens were greatly elevated over a three-month follow up period in S. Typhi/S. Paratyphi A patients compared to controls, suggesting seroconversion. Conclusions: We identified a set of antigens as good candidates to demonstrate enteric fever exposure. These targets can be used in combination to develop more sensitive and scalable approaches to enteric fever surveillance and generate invaluable epidemiological data for informing vaccine policies.
... Although the SEFI study sites provide high-quality typhoid fever incidence data for these sites, there is a need for broader estimates of typhoid burden Downloaded from https://academic.oup.com/jid/article/224/Supplement_5/S475/6433809 by guest on 02 December 2021 across India. The use of spatial modeling approaches has become increasingly common to predict epidemiologic measures (eg, incidence and prevalence) in infectious diseases (eg, malaria and schistosomiasis) in the absence of primary data [23][24][25][26]. This modeling approach aims to leverage variables from secondary datasets to predict incidence in areas without primary data on incidence, by calibrating the relationship of these variables with incidence in areas with primary data on incidence. ...
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Background: Typhoid fever remains a major public health problem in India. Recently, the Surveillance for Enteric Fever in India program completed a multisite surveillance study. However, data on subnational variation in typhoid fever are needed to guide the introduction of the new typhoid conjugate vaccine in India. Methods: We applied a geospatial statistical model to estimate typhoid fever incidence across India, using data from 4 cohort studies and 6 hybrid surveillance sites from October 2017 to March 2020. We collected geocoded data from the Demographic and Health Survey in India as predictors of typhoid fever incidence. We used a log linear regression model to predict a primary outcome of typhoid incidence. Results: We estimated a national incidence of typhoid fever in India of 360 cases (95% confidence interval [CI], 297-494) per 100 000 person-years, with an annual estimate of 4.5 million cases (95% CI, 3.7-6.1 million) and 8930 deaths (95% CI, 7360-12 260), assuming a 0.2% case-fatality rate. We found substantial geographic variation of typhoid incidence across the country, with higher incidence in southwestern states and urban centers in the north. Conclusions: There is a large burden of typhoid fever in India with substantial heterogeneity across the country, with higher burden in urban centers.
... The distance to the study hospital was not correlated with participation. Additional analyses of spatial risk factors associated with household wealth, fever, care seeking, water source and distance to facility are described elsewhere in this supplement [12]. ...
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Background Implementation of population-based surveys is resource intensive and logistically demanding, especially in areas with rapidly changing demographics and incomplete or no enumeration of the underlying population and their residences. To remove the need for pre-enumeration and to simplify field logistics for the population healthcare utilization survey used for the Surveillance for Enteric Fever in Asia Project in Nepal, we incorporated a geographic information system–based geosurvey and field mapping system into a single-stage cluster sampling approach. Methods A survey was administered to ascertain healthcare-seeking behavior in individuals with recent suspected enteric fever. Catchment areas were based on residential addresses of enteric fever patients using study facilities; clusters were randomly selected from digitally created grids using available satellite images and all households within clusters were offered enrollment. A tablet-compatible geosurvey and mapping system that allowed for data-syncing and use in areas without cellular data was created using the ArcGIS suite of software. Results Between January 2017 and November 2018, we surveyed 25 521 households in Nepal (16 769 in urban Kathmandu and 8752 in periurban Kavrepalanchok), representing 84 202 individuals. Overall, the survey participation rate was 90.9%, with geographic heterogeneity in participation rates within each catchment area. Areas with higher average household wealth had lower participation rates. Conclusion A geographic information system–based geosurvey and field mapping system allowed creation of a virtual household map at the same time as survey administration, enabling a single-stage cluster sampling method to assess healthcare utilization in Nepal for the Surveillance for Enteric Fever in Asia Project . This system removed the need for pre-enumeration of households in sampling areas, simplified logistics and could be replicated in future community surveys.
... Patients were recruited from inpatient, outpatient (including emergency departments), and hospital laboratories in 6 hospitals: Aga Khan University Hospital and Kharadar General Hospital (Pakistan); Dhaka Shishu Hospital and Shishu Sasthya Foundation Hospital (Bangladesh); Dhulikhel Hospital and Kathmandu Medical College Hospital (Nepal) ( Table 1). More information on the sites is available in this supplement [19][20][21]. ...
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Background Blood culture is the current standard for diagnosing bacteremic illnesses, yet it is not clear how physicians in many low- and middle-income countries utilize blood culture for diagnostic purposes and to inform treatment decisions. Methods We screened suspected enteric fever cases from 6 hospitals in Bangladesh, Nepal, and Pakistan, and enrolled patients if blood culture was prescribed by the treating physician. We used generalized additive regression models to analyze the probability of receiving blood culture by age, and linear regression models to analyze changes by month to the proportion of febrile cases prescribed a blood culture compared with the burden of febrile illness, stratified by hospital. We used logistic regression to analyze predictors for receiving antibiotics empirically. We descriptively reviewed changes in antibiotic therapy by susceptibility patterns and coverage, stratified by country. Results We screened 30 809 outpatients resulting in 1819 enteric fever cases; 1935 additional cases were enrolled from other hospital locations. Younger outpatients were less likely to receive a blood culture. The association between the number of febrile outpatients and the proportion prescribed blood culture varied by hospital. Antibiotics prescribed empirically were associated with severity and provisional diagnoses, but 31% (1147/3754) of enteric fever cases were not covered by initial therapy; this was highest in Pakistan (50%) as many isolates were resistant to cephalosporins, which were commonly prescribed empirically. Conclusions Understanding hospital-level communication between laboratories and physicians may improve patient care and timeliness of appropriate antibiotics, which is important considering the rise of antimicrobial resistance.
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Background Environmental surveillance, using detection of Salmonella Typhi DNA, has emerged as a potentially useful tool to identify typhoid-endemic settings; however, it is relatively costly and requires molecular diagnostic capacity. We sought to determine whether S. Typhi bacteriophages are abundant in water sources in a typhoid-endemic setting, using low-cost assays. Methodology We collected drinking and surface water samples from urban, peri-urban and rural areas in 4 regions of Nepal. We performed a double agar overlay with S. Typhi to assess the presence of bacteriophages. We isolated and tested phages against multiple strains to assess their host range. We performed whole genome sequencing of isolated phages, and generated phylogenies using conserved genes. Findings S. Typhi-specific bacteriophages were detected in 54.9% (198/361) of river and 6.3% (1/16) drinking water samples from the Kathmandu Valley and Kavrepalanchok. Water samples collected within or downstream of population-dense areas were more likely to be positive (72.6%, 193/266) than those collected upstream from population centers (5.3%, 5/95) (p=0.005). In urban Biratnagar and rural Dolakha, where typhoid incidence is low, only 6.7% (1/15, Biratnagar) and 0% (0/16, Dolakha) river water samples contained phages. All S. Typhi phages were unable to infect other Salmonella and non-Salmonella strains, nor a Vi-knockout S. Typhi strain. Representative strains from S. Typhi lineages were variably susceptible to the isolated phages. Phylogenetic analysis showed that S. Typhi phages belonged to the class Caudoviricetes and clustered in three distinct groups. Conclusions S. Typhi bacteriophages were highly abundant in surface waters of typhoid-endemic communities but rarely detected in low typhoid burden communities. Bacteriophages recovered were specific for S. Typhi and required Vi polysaccharide for infection. Screening small volumes of water with simple, low-cost (~$2) plaque assays enables detection of S. Typhi phages and should be further evaluated as a scalable tool for typhoid environmental surveillance.
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Objective To determine whether a history of cerebrovascular disease (CVD) increases risk of severe coronavirus disease 2019 (COVID-19).Methods In a retrospective multicenter study, we retrieved individual data from in-patients treated March 1 to April 15, 2020 from COVID-19 registries of three hospitals in Saxony, Germany. We also performed a systematic review and meta-analysis following PRISMA recommendations using PubMed, EMBASE, Cochrane Library databases and bibliographies of identified papers (last search on April 11, 2020) and pooled data with those deriving from our multicenter study. Of 3762 records identified, 11 eligible observational studies of laboratory-confirmed COVID-19 patients were included in quantitative data synthesis.Risk ratios (RR) of severe COVID-19 according to history of CVD were pooled using DerSimonian and Laird random effects model. Between-study heterogeneity was assessed using Cochran’s Q and I2-statistics. Severity of COVID-19 according to definitions applied in included studies was the main outcome. Sensitivity analyses were conducted for clusters of studies with equal definitions of severity.ResultsPooled analysis included data from 1906 laboratory-confirmed COVID-19 patients (43.9% females, median age ranging from 39 to 76 years). Patients with previous CVD had higher risk of severe COVID-19 than those without [RR 2.07, 95% confidence interval (CI) 1.52–2.81; p < 0.0001]. This association was also observed in clusters of studies that defined severe manifestation of the disease by clinical parameters (RR 1.44, 95% CI 1.22–1.71; p < 0.0001), necessity of intensive care (RR 2.79, 95% CI 1.83–4.24; p < 0.0001) and in-hospital death (RR 2.18, 95% CI 1.75–2.7; p < 0.0001).ConclusionA history of CVD might constitute an important risk factor of unfavorable clinical course of COVID-19 suggesting a need of tailored infection prevention and clinical management strategies for this population at risk.
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Background Enteric fever, a bacterial infection caused by Salmonella enterica serotypes Typhi and Paratyphi A, frequently presents as a nonlocalizing febrile illness that is difficult to distinguish from other infectious causes of fever. Blood culture is not widely available in endemic settings and, even when available, results can take up to 5 days. We evaluated the diagnostic performance of clinical features, including both reported symptoms and clinical signs, of enteric fever among patients participating in the Surveillance for Enteric Fever in Asia Project (SEAP), a 3-year surveillance study in Bangladesh, Nepal, and Pakistan. Methods Outpatients presenting with ≥3 consecutive days of reported fever and inpatients with clinically suspected enteric fever from all 6 SEAP study hospitals were eligible to participate. We evaluated the diagnostic performance of select clinical features against blood culture results among outpatients using mixed-effect regression models with a random effect for study site hospital. We also compared the clinical features of S. Typhi to S. Paratyphi A among both outpatients and inpatients. Results We enrolled 20 899 outpatients, of whom 2116 (10.1%) had positive blood cultures for S. Typhi and 297 (1.4%) had positive cultures for S. Paratyphi A. The sensitivity of absence of cough was the highest among all evaluated features, at 65.5% (95% confidence interval [CI], 55.0–74.7), followed by measured fever at presentation at 59.0% (95% CI, 51.6–65.9) and being unable to complete normal activities for 3 or more days at 51.0% (95% CI, 23.8–77.6). A combined case definition of 3 or more consecutive days of reported fever and 1 or more of the following (a) either the absence of cough, (b) fever at presentation, or (c) 3 or more consecutive days of being unable to conduct usual activity--yielded a sensitivity of 94.6% (95% CI, 93.4–95.5) and specificity of 13.6% (95% CI, 9.8–17.5). Conclusions Clinical features do not accurately distinguish blood culture–confirmed enteric fever from other febrile syndromes. Rapid, affordable, and accurate diagnostics are urgently needed, particularly in settings with limited or no blood culture capacity.
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Background Characterizing healthcare-seeking patterns for acute febrile illness is critical for generating population-based enteric fever incidence estimates from facility-based surveillance data. Methods We used a hybrid model in the Surveillance for Enteric Fever in Asia Project (SEAP) to assess incidence of enteric fever at 6 study hospitals in 3 countries. We recruited individuals presenting to the hospitals and obtained blood cultures to evaluate for enteric fever. For this analysis, we undertook cluster random household surveys in Dhaka, Bangladesh (2 sites); Karachi, Pakistan; Kathmandu, Nepal; and Kavrepalanchok, Nepal between January 2017 and February 2019, to ascertain care-seeking behavior for individuals with 1) fever for ≥3 consecutive days within the past 8 weeks; or 2) fever resulting in hospitalization within the past year. We also collected data about disease severity and household demographics and assets. We used mixed-effect multivariable logistic regression models to identify determinants of healthcare seeking at study hospitals and determinants of culture-confirmed enteric fever. Results We enrolled 31 841 households (53 926 children) in Bangladesh, 25 510 households (84 196 children and adults) in Nepal, and 21 310 households (108 031 children and adults) in Pakistan. Children <5 years were most likely to be taken to the study hospitals for febrile illness at all sites. Household wealth was positively correlated with healthcare seeking in 4 of 5 study sites, and at least one marker of disease severity was positively associated with healthcare seeking in 3 of 5 catchment areas. Wealth and disease severity were variably predictive of blood culture-confirmed enteric fever. Conclusions Age, household wealth, and disease severity are important determinants of healthcare seeking for acute febrile illness and enteric fever risk in these communities, and should be incorporated into estimation models for enteric fever incidence.
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Background Enteric fever can lead to prolonged hospital stays, clinical complications, and death. The Surveillance for Enteric Fever in Asia Project (SEAP), a prospective surveillance study, characterized the burden of enteric fever, including illness severity, in selected settings in Bangladesh, Nepal, and Pakistan. We assessed disease severity, including hospitalization, clinical complications, and death among SEAP participants. Methods We analyzed clinical and laboratory data from blood culture–confirmed enteric fever cases enrolled in SEAP hospitals and associated network laboratories from September 2016 to September 2019. We used hospitalization and duration of hospital stay as proxies for severity. We conducted a follow-up interview 6 weeks after enrollment to ascertain final outcomes. Results Of the 8705 blood culture-confirmed enteric fever cases enrolled, we identified 6 deaths (case-fatality ratio, .07%; 95% CI, .01–.13%), 2 from Nepal, 4 from Pakistan, and none from Bangladesh. Overall, 1.7% (90/5205) of patients recruited from SEAP hospitals experienced a clinical complication (Bangladesh, 0.6% [18/3032]; Nepal, 2.3% [12/531]; Pakistan, 3.7% [60/1642]). The most identified complications were hepatitis (n = 36), septic shock (n = 22), and pulmonary complications/pneumonia (n = 13). Across countries, 32% (2804/8669) of patients with hospitalization data available were hospitalized (Bangladesh, 27% [1295/4868]; Nepal, 29% [455/1595]; Pakistan, 48% [1054/2206]), with a median hospital stay of 5 days (IQR, 3–7). Conclusions While defined clinical complications and deaths were uncommon at the SEAP sites, the high proportion of hospitalizations and prolonged hospital stays highlight illness severity and the need for enteric fever control measures, including the use of typhoid conjugate vaccines.
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Background Implementation of population-based surveys is resource intensive and logistically demanding, especially in areas with rapidly changing demographics and incomplete or no enumeration of the underlying population and their residences. To remove the need for pre-enumeration and to simplify field logistics for the population healthcare utilization survey used for the Surveillance for Enteric Fever in Asia Project in Nepal, we incorporated a geographic information system–based geosurvey and field mapping system into a single-stage cluster sampling approach. Methods A survey was administered to ascertain healthcare-seeking behavior in individuals with recent suspected enteric fever. Catchment areas were based on residential addresses of enteric fever patients using study facilities; clusters were randomly selected from digitally created grids using available satellite images and all households within clusters were offered enrollment. A tablet-compatible geosurvey and mapping system that allowed for data-syncing and use in areas without cellular data was created using the ArcGIS suite of software. Results Between January 2017 and November 2018, we surveyed 25 521 households in Nepal (16 769 in urban Kathmandu and 8752 in periurban Kavrepalanchok), representing 84 202 individuals. Overall, the survey participation rate was 90.9%, with geographic heterogeneity in participation rates within each catchment area. Areas with higher average household wealth had lower participation rates. Conclusion A geographic information system–based geosurvey and field mapping system allowed creation of a virtual household map at the same time as survey administration, enabling a single-stage cluster sampling method to assess healthcare utilization in Nepal for the Surveillance for Enteric Fever in Asia Project . This system removed the need for pre-enumeration of households in sampling areas, simplified logistics and could be replicated in future community surveys.
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Enteric fever remains a major cause of morbidity in developing countries with poor sanitation conditions that enable fecal contamination of water distribution systems. Historical evidence has shown that contamination of water systems used for household consumption or agriculture are key transmission routes for Salmonella Typhi and Salmonella Paratyphi A. The World Health Organization now recommends that typhoid conjugate vaccines (TCV) be used in settings with high typhoid incidence; consequently, governments face a challenge regarding how to prioritize typhoid against other emerging diseases. A key issue is the lack of typhoid burden data in many low- and middle-income countries where TCV could be deployed. Here we present an argument for utilizing environmental sampling for the surveillance of enteric fever organisms to provide data on community-level typhoid risk. Such an approach could complement traditional blood culture-based surveillance or even replace it in settings where population-based clinical surveillance is not feasible. We review historical studies characterizing the transmission of enteric fever organisms through sewage and water, discuss recent advances in the molecular detection of typhoidal Salmonella in the environment, and outline challenges and knowledge gaps that need to be addressed to establish environmental sampling as a tool for generating actionable data that can inform public health responses to enteric fever.
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Background Salmonella Typhi is a major cause of fever in children in low- and middle-income countries. The recently WHO prequalified typhoid conjugate vaccine (TCV) was shown to be efficacious in a human challenge model but no efficacy trials in endemic populations have been completed. Methods In this phase III participant- and observer-blinded randomized controlled trial in Lalitpur, Nepal, children aged 9 months to <16 years of age, were randomized 1:1 to receive either TCV or a capsular group A meningococcal conjugate vaccine (Men A) as control. The primary endpoint was blood culture-confirmed typhoid fever. Study follow-up continues for 2 years; here we present the interim analysis after 12 months of follow-up, for safety, immunogenicity and efficacy. Results 10,005 participants received TCV and 10,014 received Men A. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV and 38 receiving Men A; vaccine efficacy: 81.6% (95% CI, 58.8%, 91.8%, P<0.001). 132 SAEs occurred in the first 6 months with one (pyrexia) identified as vaccine-related. The participant remains blinded. Seroconversion (≥ four-fold rise in Vi-IgG 28 days after vaccination) was 99% in the TCV group (N=677/683) and 2% in the control group (N=8/380). Conclusion A single dose of TCV is safe, immunogenic, and effective, and the deployment of the vaccine will reduce the burden of typhoid in high-risk populations. This new evidence of efficacy is especially timely with the recent spread of extensively drug resistant typhoid fever which threatens child health in affected regions. Trial registration number ISRCTN43385161
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Background: Efforts to quantify the global burden of enteric fever are valuable for understanding the health lost and the large-scale spatial distribution of the disease. We present the estimates of typhoid and paratyphoid fever burden from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, and the approach taken to produce them. Methods: For this systematic analysis we broke down the relative contributions of typhoid and paratyphoid fevers by country, year, and age, and analysed trends in incidence and mortality. We modelled the combined incidence of typhoid and paratyphoid fevers and split these total cases proportionally between typhoid and paratyphoid fevers using aetiological proportion models. We estimated deaths using vital registration data for countries with sufficiently high data completeness and using a natural history approach for other locations. We also estimated disability-adjusted life-years (DALYs) for typhoid and paratyphoid fevers. Findings: Globally, 14·3 million (95% uncertainty interval [UI] 12·5-16·3) cases of typhoid and paratyphoid fevers occurred in 2017, a 44·6% (42·2-47·0) decline from 25·9 million (22·0-29·9) in 1990. Age-standardised incidence rates declined by 54·9% (53·4-56·5), from 439·2 (376·7-507·7) per 100 000 person-years in 1990, to 197·8 (172·0-226·2) per 100 000 person-years in 2017. In 2017, Salmonella enterica serotype Typhi caused 76·3% (71·8-80·5) of cases of enteric fever. We estimated a global case fatality of 0·95% (0·54-1·53) in 2017, with higher case fatality estimates among children and older adults, and among those living in lower-income countries. We therefore estimated 135·9 thousand (76·9-218·9) deaths from typhoid and paratyphoid fever globally in 2017, a 41·0% (33·6-48·3) decline from 230·5 thousand (131·2-372·6) in 1990. Overall, typhoid and paratyphoid fevers were responsible for 9·8 million (5·6-15·8) DALYs in 2017, down 43·0% (35·5-50·6) from 17·2 million (9·9-27·8) DALYs in 1990. Interpretation: Despite notable progress, typhoid and paratyphoid fevers remain major causes of disability and death, with billions of people likely to be exposed to the pathogens. Although improvements in water and sanitation remain essential, increased vaccine use (including with typhoid conjugate vaccines that are effective in infants and young children and protective for longer periods) and improved data and surveillance to inform vaccine rollout are likely to drive the greatest improvements in the global burden of the disease. Funding: Bill & Melinda Gates Foundation.
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Background: Blood culture is the standard diagnostic method for typhoid and paratyphoid (enteric) fever in surveillance studies and clinical trials, but sensitivity is widely acknowledged to be suboptimal. We conducted a systematic review and meta-analysis to examine sources of heterogeneity across studies and quantified the effect of blood volume. Methods: We searched the literature to identify all studies that performed blood culture alongside bone marrow culture (a gold standard) to detect cases of enteric fever. We performed a meta-regression analysis to quantify the relationship between blood sample volume and diagnostic sensitivity. Furthermore, we evaluated the impact of patient age, antimicrobial use, and symptom duration on sensitivity. Results: We estimated blood culture diagnostic sensitivity was 0.59 (95% confidence interval [CI], 0.54-0.64) with significant between-study heterogeneity (I2, 76% [95% CI, 68%-82%]; P < .01). Sensitivity ranged from 0.51 (95% CI, 0.44-0.57) for a 2-mL blood specimen to 0.65 (95% CI, 0.58-0.70) for a 10-mL blood specimen, indicative of a relationship between specimen volume and sensitivity. Subgroup analysis showed significant heterogeneity by patient age and a weak trend towards higher sensitivity among more recent studies. Sensitivity was 34% lower (95% CI, 4%-54%) among patients with prior antimicrobial use and 31% lower after the first week of symptoms (95% CI, 19%-41%). There was no evidence of confounding by patient age, antimicrobial use, symptom duration, or study date on the relationship between specimen volume and sensitivity. Conclusions: The relationship between the blood sample volume and culture sensitivity should be accounted for in incidence and next-generation diagnostic studies.
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Cohort studies and facility-based sentinel surveillance are common approaches to characterizing infectious disease burden, but present trade-offs; cohort studies are resource-intensive and may alter disease natural history, while sentinel surveillance underestimates incidence in the population. Hybrid surveillance, whereby facility-based surveillance is paired with a community-based healthcare utilization assessment, represents an alternative approach to generating population-based disease incidence estimates with moderate resource investments. Here, we discuss this method in the context of the Surveillance for Enteric Fever in Asia Project (SEAP) study. We describe how data are collected and utilized to adjust enteric fever incidence for blood culture sensitivity, facility-based enrollment, and healthcare seeking, incorporating uncertainty in these parameters in the uncertainty around incidence estimates. We illustrate how selection of surveillance sites and their coverage may influence precision and bias, and we identify approaches in the study design and analysis to minimize and control for these biases. Rigorously designed hybrid surveillance systems can be an efficient approach to generating population-based incidence estimates for infectious diseases.