Helicobacter pylori infection has been reported to increase the risk of cholera. This nested case-control study was conducted to determine whether H. pylori infection is associated with occurrence of typhoid fever. Eighty-three case subjects of culture-proven typhoid fever were identified through a 1-year surveillance of subjects aged 0-40 years in an urban slum. Two age- and sex-matched neighborhood control subjects were concurrently selected for each case subject. Serum anti-H. pylori immunoglobulin G antibodies were measured in case and neighborhood control subjects. For determining other risk factors, 2 additional community control subjects per case were selected. There was a significant association between the presence of serum anti-H. pylori immunoglobulin G antibodies and typhoid fever (adjusted odds ratio, 2.03; 95% confidence interval, 1.02-4.01). Illiteracy, being part of a nuclear family, nonuse of soap, and consumption of ice cream were also associated with a significantly greater risk of typhoid fever. This study provides the first empiric evidence that H. pylori infection is associated with an increased risk of typhoid fever

Bahl, Rajiv

Bhan, Maharaj K.

Clemens, John D.

Kumar, Ramesh

Mahalanabis, Dilip

Sazawal, Sunil

Sinha, Anju

English

Publications of the IAS Fellows

1857
CONCISE COMMUNICATION
Association between Helicobacter pylori Infection and Increased Risk
of Typhoid Fever
Maharaj K. Bhan,1 Rajiv Bahl,1 Sunil Sazawal,3
Anju Sinha,1 Ramesh Kumar,1 Dilip Mahalanabis,2
and John D. Clemens4
1Advanced Center for Diarrheal Disease Research, Department
of Pediatrics, All India Institute of Medical Sciences, New Delhi,
and 2Society for Applied Studies, Kolkata, India; 3Department
of International Health, Johns Hopkins University, Baltimore,
Maryland; 4International Vaccine Institute, Seoul, Korea
Helicobacter pylori infection has been reported to increase the risk of cholera. This nested
case-control study was conducted to determine whether H. pylori infection is associated with
occurrence of typhoid fever. Eighty-three case subjects of culture-proven typhoid fever were
identified through a 1-year surveillance of subjects aged 0–40 years in an urban slum. Two
age- and sex-matched neighborhood control subjects were concurrently selected for each case
subject. Serum anti–H. pylori immunoglobulin G antibodies were measured in case and neigh-
borhood control subjects. For determining other risk factors, 2 additional community control
subjects per case were selected. There was a significant association between the presence of
serum anti–H. pylori immunoglobulin G antibodies and typhoid fever (adjusted odds ratio,
2.03; 95% confidence interval, 1.02–4.01). Illiteracy, being part of a nuclear family, nonuse of
soap, and consumption of ice cream were also associated with a significantly greater risk of
typhoid fever. This study provides the first empiric evidence that H. pylori infection is asso-
ciated with an increased risk of typhoid fever.
Helicobater pylori infection was associated with epidemic Vib-
rio cholerae O1 infection in Peru [1]. A Bangladesh-based article
reported an increased risk of endemic cholera of life-threatening
severity in that country [2]. This effect is probably mediated
through hypochlorhydria, which is a common finding in devel-
oping countries and an important risk factor for cholera. Acute
H. pylori infection is known to cause hypochlorhydria that can
persist for 18 months [3]. Chronic H. pylori infection can cause
hypochlorhydria by causing atrophic gastritis.
The gastric-acid barrier is an important determinant of the
severity of salmonella and shigella infection [4]. We hypothe-
sized that H. pylori infection would increase susceptibility to
Salmonella typhi infection, as a result of the induced hypochlor-
Received 8 July 2002; revised 10 September 2002; electronically published
14 November 2002.
The regulations of the US Department of Health and Human Services
and the All India Institute of Medical Sciences were followed in the conduct
of this clinical research.
Informed consent was obtained from all case subjects and neighborhood
and community control subjects. The study was approved by the institutional
ethics committees of the All India Institute of Medical Sciences and the
National Institute of Child Health and Human Development.
Financial support: Indo-US Vaccine Action Program (National Institutes
of Health and Department of Biotechnology, Government of India) and the
DOMI program of the Bill and Melinda Gates Foundation.
Reprints or correspondence: Dr. Maharaj K. Bhan, Dept. of Pediatrics,
All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029,
India (community.research@cih.uib.no).
The Journal of Infectious Diseases 2002;186:1857–60
 2002 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2002/18612-0024$15.00
hydria. Surveillance for typhoid fever was conducted in an ur-
ban slum community in south Delhi from November 1995 to
October 1996 to determine the incidence of typhoid fever, and
these findings were published elsewhere [5]. We performed a
case-control study nested within the above longitudinal study
to determine whether H. pylori infection is a risk factor for
typhoid fever. In addition, potential associations of socioeco-
nomic status, water source, sanitation, hygiene, and dietary
factors with typhoid fever were examined.
Subjects and Methods
Surveillance for identification of typhoid case subjects. In 1995,
a computerized census of the population of the study area showed
a total of 19,585 residents living in 4361 dwellings. All residents
were assigned a unique identification number, and this gave us the
sample population for the study. The population was divided into
clusters of 70 households, with a mean of 4.49 persons/household,
and 26 such clusters were randomly selected by computer for active
surveillance [5]. The residents in the remaining household clusters
were kept under passive surveillance by health facilities and neigh-
boring practitioners for detection of cases of fever.
Subjects who reported fever were identified though active and
passive surveillance. Blood specimens for culture were obtained
from those 5 years old if they had a body temperature 38C,
irrespective of the duration of fever. Subjects 15 years old had to
have had continuous fever for the previous 3 days to have a blood
culture performed. A passive surveillance system was established
that included all the medical facilities serving the community at
which blood specimens could be drawn.
1858 Bhan et al. JID 2002;186 (15 December)
Table 1. Risk factors for typhoid fever other than Helicobacter pylori among adults and children from an urban slum in
Delhi
Possible risk factor
No. (%) of case
subjects (n p 83)
No. (%) of control
subjects (n p 324)
Matched OR (95% CI)
Crude Adjusteda
Ownership of dwelling 76 (92) 310 (96) 0.5 (0.2–1.29) 0.45 (0.15–1.31)
Nuclear family 67 (81) 206 (64) 2.33 (1.29–4.21)b 2.55 (1.36–4.78)b
No family member literate 6 (7) 6 (2) 3.91 (1.26–12.1)b 3.44 (1.04–11.4)b
Typhoid case in the family in previous 12 months 16 (19) 49 (15) 1.37 (0.72–2.61) 1.5 (0.76–2.96)
Dirty container for storing drinking water 79 (95) 290 (90) 2.43 (0.82–7.15) 1.99 (0.6–6.65)
Nonuse of soap for washing hands 41 (49) 125 (39) 1.69 (1.0–2.86)b 1.82 (1.04–3.21)b
Water or drinks outside home in the previous 3 weeks 47 (56) 157 (48) 1.4 (0.8–2.3) 1.4 (0.77–2.57)
Lunch or dinner outside home in the previous 3 weeks 15 (18) 38 (12) 1.8 (0.9–3.58) 1.27 (0.6–2.68)
Consumption of ice cream in the previous 3 weeks 34 (41) 78 (24) 2.54 (1.44–4.48)b 2.5 (1.35–4.61)b
NOTE. CI, confidence interval; OR, odds ratio.
a Conditional logistic regression, with all the variables shown in the table in the model as covariates.
b .P ! .05
Case-control study to determine the association between H. pylori
and typhoid fever. A total of 97 case subjects with culture-positive
typhoid fever were identified. Of these, 14 were excluded from this
case-control study because they were relapsed case subjects ( ),np 3
out-migrated immediately after diagnosis ( ), or a blood spec-np 5
imen for H. pylori serologic testing could not be obtained ( ).np 6
For each of the remaining 83 case subjects (within 70 house-
holds), 2 neighborhood sex- and age-matched (2 years) control
subjects from the same residence block as the case subject were
selected within a week of onset of fever. For this purpose, a list of
eligible control subjects from the 10 houses preceding and 10 houses
following the residence of the case was generated from the com-
puterized database. Those who had previously been diagnosed as
having had typhoid fever were removed, and the remainder were
arranged in a random order. These households were visited in this
predetermined sequence until 2 control subjects were interviewed
and a blood sample from them was obtained. None of the control
subjects with fever on the day of selection had a blood culture
positive for S. typhi.
A fingerprick blood sample from case subjects and control sub-
jects was collected on 3-mm filter paper for H. pylori IgG detection
(Whatman). The paper was air dried, stored in ziplocked plastic
bags, and frozen at20C until analysis. Presence of H. pylori IgG
antibodies was tested by a commercially available ELISA (Pylori
Stat Test Kit; BioWhittaker) for serum. Five 5-mm filter paper
discs punched out from the blood spot that had ∼10 mL blood each
were soaked in 300 mL buffer, and the supernatant was used as the
test serum. This optimum 1:6 dilution of blood was determined
prior to testing specimens from study subjects, as it achieved results
similar to the manufacturer recommended 1:20 dilution of serum;
the values obtained by 1:10 dilution of blood were lower than those
with 1:20 dilution of serum, even though both contained similar
amounts of serum.
Case and control subjects were queried by the same trained field
workers within a week of their selection for personal and family
characteristics, socioeconomic indicators, and the previous 3 weeks’
food and drink that were consumed by case subjects (before onset
of fever) and matched control subjects. The interviewer also made
direct observations on water handling, garbage disposal, and avail-
ability of soap for hand-washing.
Case-control study to determine other risk factors for typhoid fever.
The case subjects and matched neighborhood control subjects for
this analysis were the same as those selected for testing the hypothesis
related to H. pylori. Furthermore, 2 additional control subjects per
case subject, not living in the case subject’s community, were ran-
domly selected from the computerized database to avoid overmatch-
ing for risk factors like water and sanitation that were expected to
be common to persons living in the immediate vicinity. The com-
munity control subjects were interviewed in the same manner as the
case subjects and neighborhood control subjects, but blood samples
for serologic testing for H. pylori were not obtained.
Data analysis. STATA 6 software (Stata Corp) was used for
statistical analysis. Matched odds ratios (ORs) and 95% confidence
intervals (CIs) were estimated. Conditional logistic regression models
were used to adjust the ORs for different risk factors for potential
confounders, such as age, family size, ownership of dwelling, source
of drinking water, open garbage within the house, and food consumed
outside home in the 3 weeks preceding the date of selection as case
or control. ORs were used to calculate the etiologic fraction of disease
(i.e., the fraction of typhoid fever case subjects that might be attrib-
uted to H. pylori infection using standard methods). The ORs pre-
sented would approximate relative risks because of the rarity of ty-
phoid fever in the community (incidence, 9.8/1000).
Results
Serum anti–H. pylori IgG antibodies were detected in 64%
of case subjects (53 of 83) and 50% of neighborhood control
subjects (83 of 166) (crude matched OR, 1.81; 95% CI,
1.03–3.17). This association remained significant after adjust-
ment for potential confounders in a conditional logistic re-
gression model (adjusted OR, 2.03; 95% CI 1.03–4.01). The
etiologic fraction of typhoid due to H. pylori was ∼34%. The
potential confounders that were adjusted for included age, own-
ership of dwelling, type of family, literacy, condition of storage
of drinking water, use of soap for hand-washing, and con-
sumption of food, water, or ice cream outside of the home in
the previous 3 weeks.
Table 1 shows the association between typhoid fever and
other possible risk factors. Because the associations were similar
when neighborhood or community control subjects were com-
pared with case subjects (data not shown), we have presented
JID 2002;186 (15 December) H. pylori Infection and Typhoid Fever 1859
a combined analysis with 4 control subjects (2 neighborhood
and 2 community control subjects) per case subject. Illiteracy
(adjusted OR, 3.44; 95% CI, 1.04–11.4) and living in a nuclear
family (adjusted OR, 2.29; 95% CI, 1.36–4.78) were significantly
associated with a greater risk of typhoid fever. Not using soap
for washing hands was another important risk factor for ty-
phoid (adjusted OR, 1.82; 95% CI, 1.04–3.21). Among foods
consumed during the 3 weeks prior to onset of fever, only ice
cream consumption was associated with typhoid fever (adjusted
OR, 2.5; 95% CI, 1.35–4.61).
Discussion
This is the first study to indicate that H. pylori infection is
associated with an increased risk of typhoid fever. Illiteracy, non-
use of soap for washing hands, and consumption of ice cream
were other significant risk factors for typhoid fever in this urban
slum population. The results were consistent for case-control
comparisons derived from active and passive surveillance areas
and for different age categories (data not shown).
Whether the observed association between H. pylori infection
and typhoid fever is free of bias and is causal merits careful
consideration. The strength of association was moderate (OR,
∼2). Because the study was nested within a cohort and the control
selection was performed concurrently, the selection bias is likely
to be small. Presence of serum IgG antibodies suggests active or
previous infection with H. pylori, as antibodies may persist be-
yond clearance of infection, thus reducing the validity of the assay
in detecting active infection [6]. However, because the serum sam-
ples from case and control subjects were tested with identical
methods, any misclassification of exposure is likely to be non-
differential and should have acted to diminish, rather than aug-
ment, the observed association. Serum IgG antibodies to H. py-
lori develop 1–3 months after an initial infection. We measured
H. pylori antibodies within a week of selection of case subjects
(i.e., onset of fever) or of control subjects. This indicates that the
H. pylori infection had preceded occurrence of typhoid fever.
Lastly, although the association between H. pylori infection and
typhoid fever remained significant even after adjustment for
many socioeconomic and life-style factors, there could be genetic
and other environmental confounders that were not measured
and therefore were not adjusted.
The gastric-acid barrier has been shown elsewhere to be an
important protective mechanism against salmonella infections [4].
Acute and chronic H. pylori infections are both known to cause
hypochlorhydria and, thus, compromise the gastric-acid barrier
[3], this may be the mechanism by which such infections increase
the risk of typhoid fever. A significant association between H.
pylori infection and depressed gastric-acid output in The Gambia
was found in a setting similar to the one in which the present
study was performed [7]. This is probably the mechanism through
which the increased risk of typhoid fever is mediated. Further-
more, there is a theoretical, but as yet unsubstantiated, possibility
that the chronic H. pylori infection required to produce an IgG
response may alter the mucosal immune response in a way that
increases the risk of developing typhoid fever following S. typhi
ingestion.
In 2 previous studies, the presence of IgG antibodies to H.
pylori was associated with increased risk of cholera [1, 2].
Whereas another 2 studies reported no increase in diarrhea after
colonization with H. pylori, as assessed by breath test [8, 9], a
recent study showed that presence of IgG antibodies to H.
pylori was followed by an increase in diarrheal disease among
Peruvian children [10]. The present study found an increased
risk of typhoid fever in those who had antibodies to H. pylori.
It may be that established infection, reflected by gastritis and
detectable immune response, rather than mere colonization
with H. pylori, is required for the development of hypochlor-
hydria and increased risk of enteric infections.
Previous studies from Pakistan, Indonesia, and Chile have
reported that eating ice cream, flavored ices, or food bought
from outside the home, not washing hands before eating, non-
municipal water supply or drinking water at work site, and
open sewers are risk factors for endemic typhoid [11–13]. The
present study also highlighted eating ice cream and not washing
hands with soap as important risk factors of typhoid. We did
not find water source and sanitation to be important risk fac-
tors, although there was indeed little variability in these factors
in the community.
The findings of this study have particularly important impli-
cations for children and adolescents. H. pylori infections occur
widely among children in developing countries [14, 15]. The sig-
nificance of this childhood infection and the priority to be ac-
corded to its prevention would depend on its association with
risk of gastro-duodenal disease in adult life and its other effects
in childhood. Studies elsewhere have shown that H. pylori in-
fection is associated with increased risk of cholera and diarrhea
[1, 2, 10]. Our results show an association of H. pylori infection
with typhoid fever and therefore provide additional evidence that
will contribute to addressing the issue of whether it is important
to prevent H. pylori infection in developing country children.
References
1. Shahinian ML, Passaro DJ, Swerdlow DL, Mintz ED, Rodriguez M, Par-
sonnet J. Helicobacter pylori and epidemic Vibrio cholerae O1 infection
in Peru. Lancet 2000;355:377–8.
2. Clemens J, Albert MJ, Rao M, et al. Impact of infection by Helicobacter
pylori on the risk and severity of endemic cholera. J Infect Dis 1995;171:
1653–56.
3. Morris A, Nicholson G. Experimental and accidental C. pylori infection of
humans. In: Blaser MJ, ed. Campylobacter pylori in gastritis and peptic
ulcer disease. New York: Ikagu-Shoin, 1989:61–72.
4. Giannella RA, Selwyn A, Broitman, Zamcheck N. Influence of gastric acidi-
ty on bacterial and parasitic enteric infections. Ann Intern Med 1973;78:
271–6.
5. Sinha A, Sazawal S, Kumar R, et al. Typhoid fever in children less than 5
years. Lancet 1999;354:734–7.
6. Bodhidatta L, Hoge CW, Churnratanakul S, et al. Diagnosis of Helicobacter
1860 Bhan et al. JID 2002;186 (15 December)
pylori infection in a developing country: comparison of two ELISA and
a seroprevalence study. J Infect Dis 1993;168:1549–52.
7. Dale A, Thomas JE, Darboe MK, Coward WA, Harding M, Weaver LT.
Helicobacter pylori infection, gastric acid secretion, and infant growth. J
Pediatr Gastroenterol Nutr 1998;26:393–7.
8. Rahman MM, Mahalanabis D, Sarker SA, et al. Helicobacter pylori colo-
nization in infants and young children is not necessarily associated with
diarrhea. J Trop Pediatr 1998;44:283–7.
9. Rothenbacher D, Blaser MJ, Bode G, Brenner H. Inverse relationship be-
tween gastric colonization of Helicobacter pylori and diarrheal illnesses
in children: results of a population-based cross-sectional study. J Infect
Dis 2000;182:1446–9.
10. Passaro DJ, Taylor DN, Meza R, Cabrera L, Gilman RH, Parsonnet J. Acute
Helicobacter pylori infection is followed by an increase in diarrheal disease
among Peruvian children. Pediatrics 2001;108:E87.
11. Black RE, Cisneros L, Levine MM, Banfi A, Lobos H, Rodriguez H. Case-
control study to identify risk factors for paediatric endemic typhoid fever
in Santiago, Chile. Bull World Health Organ 1985;63:899–904.
12. Luby SP, Faizan MK, Fisher-Hoch SP, et al. Risk factors for typhoid fever
in an endemic setting, Karachi, Pakistan. Epidemiol Infect 1998;120:
129–38.
13. Gasem MH, Dolmans WM, Keuter MM, Djokomoeljanto RR. Poor food
hygiene and housing as risk factors for typhoid fever in Semarang, In-
donesia. Trop Med Int Health 2001;6:484–90.
14. Klein PD, Graham DY, Gaillour A, Opekun AR, Smith EO. Water source
as risk factor for Helicobacter pylori infection in Peruvian children. Gas-
trointestinal Physiology Working Group. Lancet 1991;337:1503–6.
15. Perez-Perez GI, Taylor DN, Bodhidatta L, et al. Seroprevalence of Helico-
bacter pylori infections in Thailand. J Infect Dis 1990;161:1237–41.


Association between Helicobacter pylori infection and increased risk of typhoid fever

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Association between Helicobacter pylori infection and increased risk of typhoid fever

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