Bacteremic typhoid fever in children in an urban slum, Bangladesh.
ABSTRACT We confirmed a bacteremic typhoid fever incidence of 3.9 episodes/1,000 person-years during fever surveillance in a Dhaka urban slum. The relative risk for preschool children compared with older persons was 8.9. Our regression model showed that these children were clinically ill, which suggests a role for preschool immunization.
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ABSTRACT: Typhoid fever remains an important cause of morbidity and mortality in the developing countries. Vi capsular polysaccharide conjugate vaccine demonstrated safety and efficacy in young children in high endemic regions. A novel typhoid conjugate vaccine based on plant polysaccharide pectin was studied in a phase I trial.. Fruit pectin, having the same carbohydrate backbone structure as Vi, was purified from citrus peel and used as the polysaccharide source to prepare a semi-synthetic typhoid conjugate vaccine. Pectin was chemically O-acetylated (OAcPec) to antigenically resemble Vi and conjugated to carrier protein rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa. 25 healthy volunteers, 18-45 years old, were injected once with OAcPec-rEPA. Safety and IgG antibodies reactive with Vi and pectin were analyzed. No vaccine associated serious adverse reaction was reported. Six weeks after the injection of OAcPec-rEPA, 64% of the volunteers elicited >4-fold rise of anti-Vi IgG. At 26 weeks the level declined, but the difference between the levels at 6 and 26 weeks are not statistically significant. There is a direct correlation between the level of anti-Vi IgG before and after the injection (R(2)=0.96). The anti-Vi IgG can be absorbed by Vi, but not by pectin. There was no corresponding increase of anti-pectin after the injection, indicating the antibody response to OAcPec-rEPA was specific to Vi. There is no Vi-rEPA data in US adults for comparison of immune responses. The OAcPec-rEPA elicited significantly less IgG anti-Vi in US adults than those by Vi-rEPA in Vietnamese adults. The O-acetylated pectin conjugate, a plant based typhoid vaccine, is safe and immunogenic in adult volunteers. ClinicalTrial.gov identifier: NCT00277147, NIH Protocol ID number: OH06-CH-0070, FDA BB Investigation New Drug (IND) number 6989.Vaccine 03/2014; · 3.49 Impact Factor
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ABSTRACT: In malaria-endemic regions any febrile case is likely to be classified as malaria based on presumptive diagnosis largely caused by a lack of diagnostic resources. A district-wide prevalence study assessing etiologies of fever in 659 patients recruited in rural and semi-urban areas of Bandarban district in southeastern Bangladesh revealed high proportions of seropositivity for selected infectious diseases (leptospirosis, typhoid fever) potentially being misdiagnosed as malaria because of similarities in the clinical presentation. In an area with point prevalences of more than 40% for malaria among fever cases, even higher seroprevalence rates of leptospirosis and typhoid fever provide evidence of a major persistent reservoir of these pathogens.The American journal of tropical medicine and hygiene 01/2014; · 2.53 Impact Factor
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ABSTRACT: Young children are very susceptible to typhoid fever, emphasizing the need for vaccination in under five age groups. The parenteral Vi polysaccharide vaccine is not immunogenic in children under 2 years and the oral Ty21a vaccine (Vivotif) available in capsular formulation is only recommended for those over 5 years. We studied immune responses to a liquid formulation of Ty21a in children 2-5 years of age. Since children in developing countries are in general hypo responsive to oral vaccines, the study was designed to determine if anti-helminthic treatment prior to vaccination, improves responses. In a pilot study in 20 children aged 4-5 years, the immune responses in plasma and in antibody in lymphocyte secretions (ALS) to the enteric coated capsule formulation of Ty21a was found to be comparable to a liquid formulation (P>0.05). Based on this, children (n=252) aged ≥2-<3 years and ≥3-<5 years were randomized to receive a liquid formulation of Ty21a with and without previous anti-helminthic treatment. The vaccine was well tolerated with only a few mild adverse events recorded in <1% of the children. De-worming did not improve immune responses and both age groups developed 32-71% IgA, IgG, and IgM responses in plasma and 63-86% IgA responses in ALS and stool specimens to a membrane preparation (MP) of Ty21a. An early MP specific proliferative T cell response was also seen. We recommend that safety and efficacy studies with a liquid formulation of the vaccine are carried out in children under five, including those less than two years of age to determine if Ty21a is protective in these age groups and applicable as a public health tool for controlling typhoid fever in high prevalence areas of typhoid fever including Bangladesh.Vaccine 01/2014; · 3.49 Impact Factor
Typhoid Fever in
Children in an
Urban S lum,
W. Abdullah Brooks,* Anowar Hossain,*
Doli Goswami,* Amina Tahia Sharmeen,*
Kamrun Nahar,* Khorshed Alam,* Noor Ahmed,*
Aliya Naheed,* G. Balakrish Nair,* Stephen Luby,*
and Robert F. Breiman*
We confirmed a bacteremic typhoid fever incidence of
3.9 episodes/1,000 person-years during fever surveillance
in a Dhaka urban slum. The relative risk for preschool chil-
dren compared with older persons was 8.9. Our regression
model showed that these children were clinically ill, which
suggests a role for preschool immunization.
with 216,510 deaths (1). The cause of typhoid fever,
Salmonella enterica subspecies enterica serotype Typhi (S.
Typhi), is both waterborne and foodborne, with an annual
incidence approaching 1% in disease-endemic areas (2–4).
Peak incidence is reported to occur in children 5–15 years
of age; however, in regions where the disease is highly
endemic, children <5 years of age may have among the
highest infection rates (1,4–6). Population-based data are
limited (1) and would be helpful for refining estimates of
the impact of disease and for identifying age groups at
highest risk, thereby making it possible to optimize vacci-
nation strategies (7,8).
Data on disease severity and sequelae can contribute to
estimating the impact of disease. Most complications—
including intestinal perforation
encephalopathy, intestinal hemorrhage, hepatospleno-
megaly, vomiting, and diarrhea (4,9)—are late onset.
Whether children <5 years of age (preschool children)
have silent infection or clinical disease is controversial
(4,5,10), which has important implications for both case
management and prevention. We report our findings from
prospective, population-based active surveillance.
yphoid fever is a major cause of illness; the global
incidence in 2000 was an estimated 21,650,974 cases
Since 1998, the ICDDR,B Centre for Health and
Population Research has operated a surveillance and inter-
vention site in Kamalapur, an urban slum in Dhaka,
Bangladesh. We initiated fever surveillance for dengue
fever and dengue hemorrhagic fever in August 2000. To
identify treatable causes of fever, we obtained blood cul-
tures from December 6, 2000, to October 8, 2001.
The community comprises 7 geographic strata, repre-
senting 379 clusters. We selected the surveillance cohort
by using stratified cluster randomization and obtained
informed written consent from all households.
Field research assistants screened household members
for fever in their homes once weekly with a standardized
questionnaire. We defined fever as >3 consecutive febrile
days (reported) for persons >5 years of age, or any duration
of fever for preschool children (<5 years of age). This def-
inition facilitated detection of dengue fever. Field research
assistants referred febrile participants to our field clinic,
where study physicians confirmed fever and collected clin-
ical data by using a standard form. Patients with an axillary
temperature of >38°C were designated as febrile. After col-
lecting blood for serologic tests of dengue and dengue
hemorrhagic fever, we collected an additional 1 mL of
blood from preschool children and >3 mL from older
persons for culture.
Blood cultures were transported within 2 hours to our
clinical microbiology laboratory (12 km from the field
clinic). Specimens were processed by using standard meth-
ods with in-tube lysis centrifugation (Wampole isolator
1.5, Carter-Wallace, Inc., Cranbury, NJ, USA), plated on
blood, chocolate, and MacConkey agar and incubated at
37°C for 16 to 18 hours. Colonies were evaluated with bio-
chemical tests and confirmed by serologic identification
with commercial antisera (Denka, Sieken, Co., Ltd.,
Tokyo, Japan). Antimicrobial susceptibility was deter-
mined by disk diffusion using standard NCCLS methods
We confirmed typhoid fever if we isolated S. Typhi
from blood during a febrile episode. Febrile controls were
culture-negative for S. Typhi, Paratyphi, or Salmonella
group D during fever.
If S. Typhi was isolated, then we treated the infection
with 14 days of standard therapy, adjusting for antimicro-
bial susceptibility. First-line drugs were amoxicillin (40
mg/kg up to 1,500 mg orally divided 3 times daily) or cot-
rimoxazole (10 mg/kg trimethoprim divided into 2 daily
doses). When patients remained febrile after 72 hours or
new danger signs (e.g., lethargy, inability to drink,
cyanosis, convulsions), developed, treatment was consid-
ered to have failed. We treated treatment failure in persons
>12 years of age with ciprofloxacin (500 mg orally twice a
day) and referred younger patients to the hospital. We
defined recovery as >7 consecutive afebrile days after
326Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 11, No. 2, February 2005
*ICDDR,B Centre for Health and Population Research, Dhaka,
Statistical analysis was performed by using Stata/SE
Release 8.2 (Stata Statistical Software: Release 8.0. 2003,
Stata Corporation, College Station, TX, USA). Incidence
was determined by dividing the number of cases by per-
son-years of observation, with calculation of exact 95%
confidence intervals (CIs). Univariate analysis was per-
formed by using 2-by-2 tables for relative odds (RO) and
95% CIs. We obtained p values by using the Fisher 2-tailed
exact test. Multivariate modeling was conducted by step-
wise forward logistic regression, using all covariates sig-
nificantly associated with typhoid fever in univariate
analysis. Covariates that were significant when age, sex,
and geographic location were controlled for, were retained
in the final model. We adjusted models for clustering of
repeat patient visits and tested for goodness-of-fit with
either Pearson or Hosmer-Lemeshow methods (12).
Research Review and Ethical Review Committees of
ICDDR,B approved this study.
During the study period, we took blood for culture from
888 (99.9%) of 889 eligible study participants; 54 (6.1%)
reported prior medication exposure. All specimens had
adequate volume. A microorganism was isolated from 65
(7.3%) cultures. Isolation rates were highest in winter. No
positive culture reported >1 organism (Table 1), nor did
any culture-positive patient have laboratory-confirmed
S. Typhi was isolated from 26 preschool children
(Figure 1) and 23 older study participants (age range 10
months–50 years, median 4.0 years [95% CI 3.0–8.0]).
There were 1,393 person-years of observation for pre-
school children and 11,014 for others. Overall, typhoid
fever incidence was 3.9 episodes/1,000 person-years.
Typhoid fever incidence among preschool children was
18.7 episodes/1,000 person-years and 2.1 episodes/1,000
person-years among older participants. The incidence rate
difference between the 2 age groups was 16.6 cases/1,000
person-years (95% CI 9.4–23.8; p < 0.001). Preschool chil-
dren’s relative risk for typhoid fever was thus 8.9 (95% CI
4.9–16.4). Typhoid fever among preschool children varied
by age, with 4% in the first year of life and 85% occurring
in those 2 to 4 years of age (Figure 2).
We investigated surveillance bias resulting from fever
definition differences between age groups (4). Preschool
children’s mean fever duration (days) prior to visiting the
clinic was 4.0 (95% CI 3.2–4.8) and other patients’ mean
duration was 4.9 (95% CI 2.9–6.8, p = 0.37). We collected
84.6% of preschool specimens and 78.3% of others’after 3
febrile days, and 96.2% and 86.7%, respectively, by day 7.
Amultivariate model showed that typhoid fever patients
were more likely than febrile controls to be preschool age
(RO 2.04; 95% CI 1.09–3.82; p = 0.03), have >3 days of
fever (RO 2.55; 95% CI 1.16–5.63; p = 0.02), have temper-
ature >39°C (RO 1.95; CI 1.01–3.80; p = 0.04), and have
mental status changes (RO 3.94; CI 1.98–7.81; p < 0.02).
Another model indicated preschool typhoid fever patients
were significantly more likely than older patients to have
fever >39°C (RO 1.62; CI 1.21– 2.17), mental status
changes (RO 3.54; CI 2.25–5.55), and crepitations (rales)
on auscultation (RO 4.44; CI 3.11–6.33).
All patients with culture-confirmed typhoid fever
recovered, except for 1 child with tuberculosis. Four adults
required ciprofloxacin. No hospitalizations, complications,
or deaths occurred among confirmed typhoid fever
In vitro antimicrobial susceptibility testing (Table 2)
showed a high prevalence of ampicillin, cotrimoxazole,
and chloramphenicol resistance, with 27 isolates (55.1%)
resistant to all 3; ceftriaxone resistance was found in iso-
lates from 1 preschool child. Routine nalidixic acid testing
was not performed, following NCCLS 2000 guidelines.
Our data indicate a high infection ratio in this urban
population, which is highest among preschool children.
These ratios are comparable to recent regional reports
(4,6,13) and indicate that typhoid fever in preschool chil-
dren may be underappreciated. That preschool children
have 8.9 times the risk for S. Typhi infection as older per-
sons corroborates age-specific rates in highly disease-
endemic areas (1). The antimicrobial susceptibility data
Typhoid Fever in Children in Urban Slum, Bangladesh
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 11, No. 2, February 2005 327
Figure 1. Distribution of typhoid fever by age.
indicate high ratios of in vitro resistance to standard
antimicrobial agents, with a high prevalence of multidrug
The degree of illness of preschool children is controver-
sial; some report benign bacteremia (5,14) and others have
found clinical illness (4,13). Our multivariate model shows
that preschool children are clinically ill. Coexisting condi-
tions, particularly pneumonia, are not only more common
in preschool typhoid fever patients but also may result in
misclassification and underreporting, as well as contribute
to a worsening cycle of repeated infection and deaths.
Future studies should explore these issues in this age
Substantial clinical illness among preschool children
argues the need for them to be enrolled in vaccination pro-
grams. The age-specific infection rates suggest vaccination
in the first year of life, integrating with existing Expanded
Programme on Immunization (EPI) schedules. This prac-
tice would require either a polysaccharide protein-conju-
gate vaccine to stimulate T-cell–dependent responses (15)
or a live attenuated oral vaccine, since T-cell–independent
responses do not mature until the child is 18–24 months of
The limitations of this study could result in an underes-
timate of the incidence of typhoid fever. First, this study
was not designed to measure typhoid fever incidence or
disease impact. The surveillance program was designed to
identify dengue. Thus, febrile episodes for young children
were defined differently than for older persons. Although
we did not find evidence of preferential selection for
young children, future studies may adopt a common fever
definition. Second, the blood volume examined, though
not inadequate, may not have been optimal. Third, blood
culture sensitivity is relatively low, estimated at 25%–50%
(1). Fourth, the 6.1% estimate of earlier medicine exposure
may be an underestimate, as we did not validate these
reports. If these agents were antimicrobial, the number of
serovar Typhi isolates recovered from peripheral blood
would be reduced. Fifth, we had only 10 months of obser-
vation and therefore did not attempt an estimate of disease
impact, adjustments for blood culture sensitivity, or expo-
sure to antimicrobial agents. Ours is thus a conservative
estimate of incidence. Further observation should allow
the impact of disease to be estimated.
We gratefully acknowledge Eric Mintz and Pavani Kalluri for
their suggestions and assistance with the manuscript preparation.
This study was funded by the International Centre for
Tropical Disease Research (ICIDR) of the National Institutes of
Health, by a cooperative agreement from the U.S. Agency for
International Development (HRN-A-00-96-90005-00), and by
core donors to the ICDDR,B Centre for Health and Population
Research. The funding sources had no involvement in the study
design, interpretation, or decision to submit this paper.
Author participation in this article was as follows: W.A.
Brooks was the principal investigator and provided the concep-
tion, design, execution, and principal data analysis of this study,
as well as preparing the manuscript. A. Hossain and K. Alam per-
formed the blood cultures and determined sensitivities. D.
Goswami and A. Naheed provided overall supervision of the
project operation. A.T. Sharmeen and K. Nahar were responsible
for the clinical staff. N. Ahmed supervised field operations. B.
Nair, S. Luby, and R. Breiman were senior team members who
contributed to the design, interim discussions of the project’s
progress, data analysis, and manuscript preparation.
Dr. Brooks is a specialist in pediatrics and preventive medi-
cine. He is on faculty at the Bloomberg School of Public Health
at Johns Hopkins University in Baltimore, Maryland, from where
he was seconded to ICDDR,B. He established an urban field site
in 1998, from which he conducts surveillance and intervention
studies on a variety of infectious diseases, primarily but not
exclusively in children, including acute respiratory disease,
dengue, typhoid fever, and shigellosis.
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Address for correspondence: W. Abdullah Brooks, ICDDR,B: Centre for
Health and Population Research, GPO Box 128, Mohakhali, Dhaka 1000,
Bangladesh; fax:503.210.0453; email: email@example.com
Typhoid Fever in Children in Urban Slum, Bangladesh
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 11, No. 2, February 2005329