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Journal of Clinical Microbiology, May 2000, p. 1971-1973, Vol. 38, No. 5
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Evidence from a Nine-Year Birth Cohort Study in
Japan of Transmission Pathways of Helicobacter pylori
Infection
Hoda M.
Malaty,1,*
Toshiko
Kumagai,2
Eiji
Tanaka,3
Hiroyoshi
Ota,2
Kendo
Kiyosawa,3
David Y.
Graham,1,4 and
Tsutomu
Katsuyama2
Department of
Medicine1 and Division of Molecular
Virology,4 Veterans Affairs Medical
Center and Baylor College of Medicine, Houston, Texas, and
Department of Laboratory Medicine2 and
Second Department of Internal
Medicine,3 Shinshu University School of
Medicine, Matsumoto, Japan
Received 7 December 1999/Returned for modification 22 January
2000/Accepted 15 February 2000
 |
ABSTRACT |
We examined the longitudinal changes of Helicobacter
pylori infection within 46 families with children and 48 couples
without children living in Japan. The study cohort was monitored from 1986 to 1994. H. pylori status was assessed by the presence
of anti-H. pylori immunoglobulin G antibodies. At study
entry, H. pylori prevalence in children with positive
mothers was 23% versus 5% in children with negative mothers (odds
ratio = 5.3; 95% confidence interval = 0.6 to 42.8).
Seroconversion (rate of 1.5%/year) was evident only among children
living with positive mothers and did not differ among adults living
with or without children. These data strongly support the cluster
phenomenon of H. pylori infection among families, the key
role of the infected mothers in the transmission within families, and
the importance of adult-child transmission and not vice versa.
| |
TEXT |
Helicobacter pylori
infection is causally related to chronic gastritis, peptic ulcer
disease (4, 12), and primary gastric B-cell lymphoma
(5, 9). Clustering of the organism in families (3, 7,
18) suggests person-to-person transmission, a common environmental source, and a genetic basis for differences in
susceptibility to the infection (19). Childhood is thought
to be the primary period of risk for H. pylori acquisition
(20, 21, 23). However, whether the organism is transmitted
between adults, between adults and children, and/or between children is
still not clear. We studied the pattern of H. pylori
seroepidemiology over a 9-year period in a cohort of Japanese families
living in a typical mountain village in the district of the Nagano
Prefecture, Japan. We examined the longitudinal changes of the
infection within families with and without children residing in the
same area.
The study was carried out in the Arahiro area, a small district of
South Kiso in central Japan, which is surrounded by mountains. The
current water supply system was introduced in 1959 and there is a
central sewage system. Adults and children were monitored between 1986 and 1994 with repeated blood sample testing and questionnaires within
the framework of a study of hepatitis C transmission (14). Blood samples were collected each year; one-third of each sample volume
was stored at 
80°C until the current study was begun. Subjects were
eligible for this study if they had at least two serum samples in two
or more successive years available. Anti-H. pylori
"eradication therapy" was not used during the period of study.
H. pylori status was determined by the presence of
anti- H. pylori immunoglobulin G (IgG) antibodies in
the enzyme-linked immunosorbent assay (ELISA) using the GAP-IgG kit,
with whole-cell (H. pylori) extracts (Biomerica, Newport
Beach, Calif.). A standard curve was drawn by measuring the absorbance
of the reference serum included in the kit, which was diluted serially
from 1:2 to 1:16 with phosphate-buffered saline (pH 7.2), and the
amount of anti-H. pylori IgG corresponding to 1:8 was
expressed as an arbitrary index of 1.0. The cross-reactivity of the
antibody in a patient's sera against closely related bacteria
four
strains of Campylobacter jejuni (7.4%), one strain of
Campylobacter ralidis (0.2%), and one strain of
Escherichia coli (2.4%)was examined as described previously (1, 24). In brief, sera from 10 adults and 10 children, who had been revealed to carry anti-H. pylori IgG,
were incubated 30 min at 37°C with the sonicated cell extracts of the bacterial strains, and the unabsorbed anti-H. pylori IgG was
measured. A control test employing an authentic H. pylori
strain (ATCC 43504) was run in parallel. The ELISA was validated in
this population by using a receiver operating characteristic curve to
determine the cutoff value (arbitrary index of 0.51). When the results
were compared with those obtained by bacteriological and/or
histological examinations from patients with gastritis and peptic ulcer
disease, the specificity and sensitivity were 93 and 96.7%,
respectively (24, 27, 29).
H. pylori infection was defined as a positive ELISA result.
A family with children was defined as at least one parent (mother) with
one or more children living in the same household. The mother/wife was
chosen as the index person for each family before H. pylori status was identified, and she was excluded from the analysis. The
objective of the analyses was to compare the seroprevalence at the
entry of the study among children living with positive and negative
index mothers and among adults living with positive and negative index
spouses. We also examined the seroconversion and seroreversion rates
over the 9-year period within families with and without children. The
cohort was grouped according to age when the first blood sample was
taken. The data were analyzed with the SAS program (version 5; SAS
Institute, Inc., Cary, N.C.).
The cohort consisted of 46 families with children, totaling 161 participants who were monitored. There were 36 positive index mothers,
with 27 spouses and 62 children, and 10 negative index mothers with 7 spouses and 19 children. Forty-eight couples with no children,
including 38 positive and 10 negative index wives, were monitored for
the same 9-year period. Parents living with children were between the
ages of 27 and 54 years, and couples without children were between the
ages of 23 and 58 years.
Initial data.
The prevalence of seropositivity in children
living with positive mothers was five times higher than in children
living with negative mothers (23 and 5%, respectively; odds ratio = 5.3; 95% confidence interval = 0.6 to 42.8). No significant
difference was observed between spouses who lived with positive or
negative index mothers (85 and 100%, respectively; P = 0.2) (Table 1). There were also no
significant differences in seropositivity between spouses who lived
with positive or negative wives (82 and 90%, respectively;
P = 0.9).
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TABLE 1.
Prevalence of H. pylori infection in children
and spouses according to infection status of the mothers at entry
into the study (1986) in South Kiso town, Japan
|
|
Longitudinal changes.
Of the 48 seronegative children living
with positive mothers, 4 (8%) became infected by the end of the study
period, while none of the 18 seronegative children living with their
negative index mothers became infected. The 4 seroconverted children
were between the ages of 6 and 12 years and included 2 boys and 2 girls. Of the 14 seropositive children living with positive mothers, 12 (86%) had persistence of the antibodies and 2 seroreverted by the end
of the study, giving a cumulative seroreversion rate of 14%. The
annual seroconversion and seroreversion rates among children (i.e.,
incidence and loss rate of infection) were 1.5 and 2.5%/year,
respectively, based on the assumption that these rates were equally
distributed throughout the mean observation period of 5.5 (standard
deviation, 2.7) years. None of the 18 seronegative children or the
seropositive child who lived with negative mothers had seroconverted or
seroreverted (Table 2).
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TABLE 2.
Rates of seroconversion and seroreversion in H. pylori infection in children according to infection status of
the mother, South Kiso town, Japan
|
|
Of the 14 parents who were seronegative at their initial visit, one
husband (7%) became infected by the end of the follow-up
study.
Interestingly, the wife of the seroconverted husband was
seropositive while their two children were seronegative throughout
the
follow-up period. One (6%) of the 18 seronegative adults living
with
no children became infected at the end of the study. The
annual
seroconversion rates among adults living with and without
children were
0.9 and 0.7%/year, respectively, based on the assumption
that these
rates were equally distributed throughout the mean
observation period
for adults of 7.5 (standard deviation, 2) years
(Table
3). The risk of infected adults with
H. pylori remaining
infected did not differ between those
living with and without
children, 83 and 87% (
P = 0.45), respectively. The annual seroreversion
rates were 2.4 and
1.7%/year among adults living with and without
children, respectively
(Table
3).
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|
TABLE 3.
Rates of seroconversion and seroreversion in H. pylori infection among adults living with or without children,
South Kiso town, Japan
|
|
In the present study, important points regarding transmission pathways
of
H. pylori infection among families were clarified.
The
fact that the prevalence of
H. pylori infection was four
times
higher among children living with positive index mothers than
among children living with negative index mothers confirms the
clustering among families. The study provided evidence of transmission
of infection from mother to child which is supported by several
observations, such as seroconversion being observed only among
those
children living with infected mothers. Since the prevalence
of
H. pylori infection among mothers is much higher than in children,
it
is likely that the infection is transmitted from mother to
child and
not vice versa. Although the pattern for risk of
H. pylori
infection in children did not change if the index person
was the
father, the association with the mother is more likely
to occur among
Japanese families since the mother is the primary
caretaker of the
children. Interestingly, the four seroconverted
children either had
older seronegative siblings or were the only
child in the family.
Although sibling transmission was reported
in a study from Colombia
(
11), we did not demonstrate such an
association in the
present study. This could be explained by the
difference in the family
structure in different cultures. For
example, it is unlikely for a
Japanese family to have more than
three children, while it is common to
have several children in
a family in developing
countries.
The results revealed a 0.8%/year incidence rate among adults, a
slightly higher rate than that reported for adults in developed
countries (0.3 to 0.6%/year) (
8,
17). It is interesting
that
of two seroconverted adults who had seropositive spouses, one
had
no children and the second had two seronegative children during
the
observation period. This reflects the importance of the adult-to-adult
or adult-to-child but not child-to-adult pathway of transmission.
The
identification of the organism from parents and children as
the same
strain of
H. pylori, using DNA fingerprinting
techniques,
has been reported, suggesting person-to-person transmission
among
family members (
3).
A common environmental source cannot be excluded, since parents and
children share the same environment. Laboratory studies
have reported
that the coccoid form of
H. pylori can survive in
an aquatic
environment (
28). Studies reported that unclean water
in
Peru (
15) and consumption of fresh vegetables in Chile
(
13)
have both been associated with acquisition of the
infection. However,
in Japan there was a rapid change in sanitary
conditions after
World War II and clean public water systems were
introduced in
the 1950s. A previous study from Japan reported a
significant
difference in the seroprevalence of
H. pylori
infection between
those older than 40 years and those younger
(
2). It is unlikely
that common environmental factors fully
explain the described
association, especially since the human is the
only known host
reservoir for
H. pylori infection
(
30). In addition, if a common
environmental source is the
pathway of transmission, we would
expect to observe some clustering of
seroconversions among families
within the study period. However, all
seroconverters, including
children and adults, were from different
families.
There are some limitations in our study that must be considered. The
small number of transmitting adults and children limited
the power to
identify multiple risk factors for transmission.
We are unable to fully
explain the route of transmission, whether
it is fecal-oral or
oral-oral, due to the unavailability of information
on all
environmental factors and household structure.
H. pylori can
be found in saliva, dental plaque (
10,
16), and feces
(
6; M. A. Leverstein van Hall, A. van der Enfe,
M. van Milligan
de Wit, G. N. Tytgat, and J. Dankert, Letter,
Lancet
342:1419-1420,
1993), which could be the vehicle of
transmission through anything
contaminated by them. While PCR
identifies the organism in human
feces, saliva, and dental plaque
(
22,
26; N. P. Mapstone,
D. A. Lynch, and
F. A. Lewis, Letter, Lancet
431:447, 1993),
it is still
difficult to culture the organism from materials other
than gastric
tissue.
In conclusion, this study demonstrated a clear pathway of transmission
from adult to child and not vice versa. The knowledge
that an infected
mother could be the key agent for transmitting
H. pylori to
her children could allow the development of strategies
to prevent
transmission of the
infection.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Veterans Affair
Medical Center (111D), 2002 Holcombe Blvd., Houston, TX 77030. Phone: (713) 795-0232. Fax: (713) 790-1040. E-mail:
Hmalaty{at}bcm.tmc.edu.
| |
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Journal of Clinical Microbiology, May 2000, p. 1971-1973, Vol. 38, No. 5
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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