 |
|
 |
|
 |
 |
|
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PEDIATRICS Vol. 104 No. 2 August 1999, pp. 216-221
,,
From the * Unité de Gastro-entérologie,
Hépatologie et Nutrition, Clinique de Pédiatrie,
Hôpital Jeanne de Flandre, Lille, France; the Laboratoire de
Bactériologie, Faculté de Médecine, Lille, France;
and the § Service d'Anatomie et de Cytologie Pathologique,
Faculté de Médecine, Lille, France.
 |
ABSTRACT |
|---|
Top
Abstract
MaterialsMethods
Results
Discussion
Conclusion
References
|
|---|
Background and Objectives. It is known that Helicobacter pylori can be acquired in early childhood. There is not enough data to know whether or not infected children should be treated. A better knowledge of the natural outcome and implications of H pylori infection may provide evidence that eradication therapy is beneficial in childhood. This prospective study looks at clinical symptoms, endoscopic, microbial, and histologic changes during a 2-year period in infected asymptomatic children. It is hoped that some prognostic indicators will be found that select out the children that later need therapy.
Patients and Methods. During epidemiologic study of the prevalence of H pylori infection, 18 children aged 7 ± 4 years (mean ± 1 SD) were discovered to have H pylori infection and enrolled in the 2-year follow-up study. These patients had received no eradication therapy because they were asymptomatic. The follow-up for each patient consisted of an initial assessment, a clinical examination every 6 months, and an endoscopic reevaluation at the end of the first and second years. Gastric mucosal samples were analyzed for bacteriologic and histologic changes. Various factors were initially recorded: individual factors included sex, age, and housing conditions; microbial factors included bacterial load and the presence of the CagA gene. Inflammatory changes were also noted, such as the presence of active gastritis and nodular formation, and these were correlated with the histology which was described using the Sydney classification. Typing polymerase chain reaction-restriction fragment length polymorphism was performed to check the persistence of the same strain of H pylori in each patient.
Results. All of the children were still infected after 2 years with the same strain as in the initial assessment with the
exception of 1 child whose infection cleared spontaneously. The density of antral and fundal mucosal colonization with H pylori
also remained stable. There were progressive inflammatory changes in
this cohort, particularly between the first and second year (histologic
score, 3.5 ± 1.3 vs 5 ± 1). Active antral gastritis
occurred in 3 out of 14 and 1 out of 8 children during the first and
second year, respectively. Gastritis became active in the fundus in 2 out of 14 and 2 out of 8 children during the same period. Increases in the histologic score were found particularly in male children, and
children colonized by cagA
strains of H
pylori during the follow-up. The frequency of nodular gastritis
significantly rose from 11% (2 out of 18 children) to 64% (9 out of 14 children) after 1 year, and to 80% (8 out of 10 children)
after 2 years.
Conclusion. These findings demonstrate a deterioration in the histologic features of the gastric mucosa of infected children despite stable H pylori colonization and the absence of symptoms. Key words: Helicobacter pylori, child, gastritis.
Helicobacter pylori infection is known to be
acquired early in childhood1 and has been described in
infants aged 6 days, 5 to 7 weeks, and 2.5 to 5.5 months.2-5 It is thought to be frequently acquired before
5 years of age, both in the industrialized world6 and in
developing countries.7,8 Spontaneous eradication is an
unusual phenomenon.4 Once colonized by H
pylori, the gastric mucosa is the focus of a chronic infection
that is thought to persist indefinitely. This long-term infection can
cause severe pathology. Various gastroduodenal diseases seen in adults
are known to be linked to H pylori infection. These include:
gastric and duodenal ulcers, gastric lymphoma, atrophic or metaplastic
gastritis, and gastric adenocarcinoma.9 In children,
histologic changes are mild to moderate and the outcome of an infection
diagnosed at an early stage in children remains unknown.7,10 Because the implication of H
pylori in abdominal and digestive symptomatology has not been
clearly identified, there is too little data to know whether or not
infected children need to be treated. Better knowledge of the natural
outcome of H pylori infection could provide rationale for
eradication, screening, and even a vaccination policy.
To assess the natural evolution of the infection and the outcome in
infected children, we conducted a 2-year follow-up study on microbial,
histologic, endoscopic, and clinical evolution in asymptomatic
children. Furthermore, follow-up of these patients may identify
prognostic indicators that could be used to select those requiring
early eradication.
Patients
Between August 1993 and February 1995, 518 children were
included in an epidemiologic study on the prevalence of H
pylori infection in the population of children undergoing
esophagogastroduodenoscopy. Forty-four children out of the 518 were
found to have an infection (Fig 1). In
these patients, the diagnosis of H pylori infection was
based on histology and/or bacteriology. Eighteen of these, discovered
by chance to be infected by H pylori, underwent upper
gastrointestinal tract endoscopy for other reasons including: suspicion
of esophagitis (n = 8), gastritis (n = 2), small bowel biopsy for celiac disease (n = 5),
portal hypertension (n = 2), and perendoscopic
gastrostomy (n = 1). These 18 children (Fig 1) included
8 patients completely free from digestive symptoms
(esophagogastroduodenoscopy was performed in these children for
possible celiac disease, portal hypertension follow-up, and requirement
of perendoscopic gastrostomy) and 10 presenting with abdominal pain,
vomiting, and hematemesis. In the latter, digestive symptoms
disappeared after treatment against esophagitis (prokinetics and
antacids), as a result no anti-H pylori therapy was started
because the symptoms were considered to be related to esophagitis and
not to the H pylori infection. These 18 patients were
included in a follow-up study for at least 2 years. If digestive
symptoms related to H pylori infection occurred during the
follow-up (abdominal pain, vomiting), treatment for eradication of
H pylori infection was given and the child was excluded from
the follow-up. This study was approved by the Lille University Hospital
Ethical Committee. Informed consent of each patient and parents was
obtained before their inclusion in the study.
MATERIALS AND METHODS
Top
Abstract
MaterialsMethods
Results
Discussion
Conclusion
References
View larger version (19K):
[in a new window]
Fig. 1.
Selection of the patients from an epidemiologic study.
In all of the patients, the diagnosis of H pylori infection was based on the isolation of H pylori from gastric biopsy specimens. Factors potentially linked to evolution of infection were recorded including: individual factors (sex, age, and housing conditions); microbiologic factors (density of colonization, CagA gene); and gastritis characteristics (visualization of nodule by endoscopy, presence of active gastritis).
The follow-up protocol included an assessment of clinical symptoms (every 6 months) and 2 gastroscopies (1 and 2 years after the H pylori infection diagnosis) for endoscopic evaluation, and bacteriologic and histologic studies. To exclude cases of possible multiple and recurrent infections by various H pylori strains, genomic fingerprinting was performed on each sample to check the persistence of the same strain of H pylori in each patient.
Eleven girls and 7 boys, ages 1 to 17 years (mean ± SD = 7.4 ± 4.4 years) were included in the follow-up study. After 1 year, 14 of the 18 children underwent endoscopy. After 2 years, the number of children followed-up was 10. Among the 4 children who did not
return for follow-up at 1 year, 2 underwent endoscopy at the
second year and the remaining 2 refused endoscopy. Among the 14 children seen after 1 year, 8 were examined endoscopically again after
2 years (the other 6 were excluded from follow-up
4 cases with
abdominal pain requiring a prescription of anti-H pylori treatment (omeprazole, amoxicillin, and clarithromycin); these patients
did not differ with those who remained asymptomatic during the
follow-up, on endoscopic, histologic, or bacteriologic features, both
initially and at 1 year of follow-up (1 patient with documented spontaneous clearance of infection and 1 case of refusal).
Endoscopy
Before esophagogastroduodenoscopy each child received premedication consisting of midazolam and atropine. An Olympus GIF XP20 fiberendoscope was used for all the children. Nodular gastritis was defined by the presence of one or more nodular features on at least the antral mucosa, and erythematous gastritis was described when the gastritic mucosa appeared friable and erythematous. Three antral and two fundal biopsies were performed at each endoscopy for bacteriologic and histologic studies.
Histologic Study
Two biopsy samples (one antral and one from the fundus) were fixed in Bouin's liquid, embedded in paraffin, cut serially into 5-µm sections, stained with hematoxylin-eosin, and assessed under light microscopy. All histologic examinations were performed by a single experienced pathologist (E.M.S.). The histologic changes were quantified according to a score derived from the Sydney classification.11 A final score (range, 0-13) was calculated as the sum of the histologic features. This accounted for the presence of mononuclear cells in the lamina propria, inflammatory cells in the epithelia, glandular atrophy, and intestinal metaplasia, which were evaluated as follows: absent = 0, mild = 1, moderate = 2, and severe = 3, and the presence of polynuclear cells in the lamina propria (absent = 0, present = 1).
Bacteriologic Study
Samples for microbiology (2 antral and 1 fundal) were stored in a saline buffer at 4°C and taken to the laboratory within 2 hours. Bacteriologic analysis included direct examination with Gram staining, test of the urease activity (colored reaction in liquid media after 3 hours of incubation at 37°C), and culture. The latter was performed on Columbia agar medium with 10% horse blood, for 3 to 7 days under microaerobic conditions. To obtain quantitative results, samples were weighed before homogenization and then plated using the Spiral system (Intertechniques, Saint-Nom, France).12 Results were analyzed using the decimal logarithm of the bacterial population.
The genomic fingerprinting of isolates was performed using the restriction fragment length polymorphism of H pylori within the ureB (urease) and htrA (heat shock protein) genes. The polymerase chain reaction amplified products were digested by AluI and HaeIII restriction enzymes, as described previously.13
For CagA gene analysis, the homogenized isolates were grown on Müeller-Hinton agar supplemented with 7% fetal calf serum for 3 days at 35°C under microaerophilic conditions for polymerase chain reaction tests. Amplification of the CagA gene was performed with previously described primers.14 This study used the CagA gene-positive strain (H pylori ATCC 49 503) and the CagA gene-negative strain (strain Tx30a) as controls.
Statistical Analysis
Comparative analysis of quantitative data were done by means of the Student's t test, using decimal logs for analysis of bacterial population. Discontinuous variables (histologic grading) were compared by the Wilcoxon rank test. Paired tests were performed to analyze evolution in the same patient. Spearman's coefficient was used to link quantitative variables. A P value <.05 was considered significant.
| |
RESULTS |
|---|
|
Top
Abstract
MaterialsMethods
Results
Discussion
Conclusion
References
|
|---|
With the exception of 1 case in which the infection was eradicated, molecular typing of isolates showed that in every child the same strain of H pylori persisted during the follow-up. The mean bacterial load remained the same throughout the 2-year period (6.5 to 7 log10 bacteria/g of antral tissue, 6.2 to 6.5 log10 bacteria/g of fundal tissue). Significant correlations were found between the H pylori colonizations in the antrum and fundus not only at the time of diagnosis but also 1 and 2 years later (r = 0.49, r = 0.76, r = 0.75, respectively; P < .05). The density of mucosal colonization by H pylori did not vary and for each child the difference was not significantly deviated from the values obtained initially (Table 1).
|
All of the children had abnormalities in antral mucosal histology at different times during follow-up. An increase in the histologic score of antral tissue was seen in 6 out of 14 children at the first year examination and in 7 out of 8 children at the second year examination, and in fundal tissue of 8 out of 14 and 5 out of 8 children, respectively. Although some children showed a mild decrease in lesional score (5 out of 14 and 1 out of 8 in antrum, 2 out of 14 and 2 out of 8 in fundus, respectively, at examinations of 1 and 2 years), lesions in the cohort significantly increased between the first year and the second year in the antrum (histologic score, 3.5 ± 1.3 vs 5 ± 1; P < .05) (Table 1). During the follow-up, glandular atrophy and intestinal metaplasia were never found.
In the antrum, gastritis was still active in 8 out of 14 and 6 out of 8 patients, respectively, at 1 and 2 years (fundus, 6 out of 14 and 4 out of 8 children, respectively). In the remainder, an active antral gastritis occurred in 3 out of 6 and 1 out of 2 children, respectively, during the first year and the second year (fundus, 2 out of 8 and 2 out of 4, respectively). Active gastritis disappeared at the first examination in both the antrum and fundus in only 3 children.
At the time of diagnosis of infection, lymphoid follicles were present in 4 out of 18 children in the antrum (fundus, 2 out of 18 patients). During the first year of follow-up, lymphoid follicles appeared in the antrum in 3 children (fundus, 8 children) and disappeared in 4 patients. Three children had no lymphoid follicles in the antral mucosa (fundus, 4 children). During the second year, lymphoid follicles persisted in 4 children and appeared in 2 patients in the antrum (fundus, 4 children and 1 child, respectively). During the follow-up, only 2 children had no lymphoid follicles in the antrum (1 child in the fundus).
In the 3 children who had a disappearance of active gastritis, the presence of lymphoid follicles was observed. One of them was the child who presented with spontaneous eradication of H pylori.
Twelve children of this series were infected by the CagA
strain of H pylori and 6 by the CagA+ strain. At
the first year examination, 5 out of 6 children infected by the
CagA+ strain had an active antral gastritis versus 5 out of
8 children infected by the CagA strain (active fundal
gastritis, 5 out of 6 vs 5 out of 8, respectively); at the second year,
2 out of 3 children infected by the CagA+ strain versus 5 out of 5 infected by the CagA strain had active antral
gastritis (active fundal gastritis, 2 out of 3 vs 4 out of 5, respectively).
Lymphoid follicles were found in the antrum at 1 year in 2 out of 6 children infected by the CagA+ strain versus 5 out of 8 infected by the CagA strain (in the fundus in 3 out of 6 vs 7 out of 8 children); and at 2 years in 3 out of 3 vs 3 out of 5, respectively, in the antrum (in the fundus in 1 out of 3 vs 4 out of 5, respectively).
No association was found between the histologic evolution and the
initial density of colonization of the mucosa (Table
2). Evolution of the lesions was neither
associated with individual factors (age, living in institution), nor to
initial histologic status of the mucosa. In this cohort, children
colonized by cagA strains of H pylori had a
significant increase in their histologic score in the 2 years after
diagnosis (Table 2). Surprisingly, an increase in histologic score was
found to be significantly linked to male gender (Table 2).
|
At endoscopy, the mucosa showed no more erythematous features during follow-up than at initial examination. By contrast, micronodular lymph nodes appeared in 11 children during the follow-up. The frequency of nodular gastritis significantly rose from 11% (2 out of 18) to 64% (9 out of 14) at 1 year and to 80% (8 out of 10) at 2 years. Occurrence of nodular gastritis during the follow-up period was not associated with individual, histologic, or bacterial factors.
Clinically, abdominal pain and vomiting initially attributed to esophagitis recurred in 4 cases after 1 year of follow-up despite treatment against gastroesophageal reflux. These 4 patients received an anti-H pylori treatment with no further follow-up. In these patients, the antral and fundal gastritis was still active after 1 year and nodular gastritis had appeared during the first year in all cases. No factors recorded at the outset could differentiate these 4 cases with clinical manifestations of gastroesophageal reflux. No clinical symptoms were found in the other 14 children during the follow-up.
| |
DISCUSSION |
|---|
|
Top
Abstract
MaterialsMethods
Results
Discussion
Conclusion
References
|
|---|
During this follow-up, the levels of both antral and in fundal H pylori colonization remained unchanged and abdominal pain was rare in these initially asymptomatic patients despite histologic evidence of increased damages to the gastric mucosa. The present 2-year follow-up study of H pylori infection with histologic reference is the first performed in childhood. To the best of our knowledge, there is only one study in adults that addresses the evolution of histologic changes which was done during a 10-year period.15 In childhood, the follow-up studies that were previously published include only serologic or breath-test data.16,17
This study has some methodologic limitations. At inclusion we may have introduced some bias due because of a selection of an asymptomatic population and, furthermore, 6 children were lost on follow-up. From our point of view, it was unethical not to treat H pylori infection when children presented with digestive symptoms. So the 4 children presenting with abdominal symptoms 1 year after diagnosis of infection received treatment against H pylori and were not followed-up, because the goal of the study was to assess the natural history of H pylori infection in asymptomatic children. Thus, we have no information on the natural history of H pylori infection in symptomatic children. The loss of 6 children was not simply linked to the absence of symptomatology because asymptomatic children were seen again 1 and 2 years after inclusion. An additional point is that this study was limited to 2 years and that features of infection occurring after this period remain unknown and ideally a longer follow-up should be done. Nevertheless, these results give information on the natural evolution of H pylori infection in asymptomatic children.
There is no specific symptomatology related to H pylori infection in children18 apart from the association between H pylori infection and duodenal ulcer.19-21 The role of H pylori in recurrent abdominal pain is still controversial.22,23 Both in adults and in children, asymptomatic H pylori infection has been reported previously.24-29 All these studies are from cross-sectional surveys without information concerning the duration of H pylori infection. Our results show that most initially asymptomatic-infected children remained asymptomatic during a 2-year time period despite a deterioration at histologic level.
This follow-up study also demonstrated an increase in the severity of histologic damages on antral mucosa after 2 years. In one adult study of patients with persistent H pylori infection without eradication therapy, it was found that during a 10-year period there was a regression of antral gastritis and both progression and regression of superficial inflammatory changes in the fundus.15 Active chronic gastritis and nonactive chronic gastritis are the histologic changes commonly described at light microscopy,30-32 but the gastric mucosa may still be normal.31,33,34 In the present study all the children presented with histologic abnormalities of the antral mucosa but not of the fundal mucosa, and most of the patients had a persistence of active gastritis or the appearance of active gastritis. However, glandular atrophy and intestinal metaplasia were not found in any of our patients during the follow-up. In the adult series, these histologic lesions remained unchanged after 10 years in patients with persistent infection.15 Two-year follow-up of H pylori infection is probably too short to observe atrophy and metaplasia.
One patient from our series had an apparent spontaneous eradication of H pylori infection. He became negative for H pylori both histologically and microbiologically, without mention of treatment against H pylori. It was checked at follow-up and by practitioner recall that this healthy child received also no antisecretory drug during the follow-up and only amoxicillin had been given for a few days for pharyngitis. Such a treatment is ineffective most of the time to eradicate H pylori infection. Spontaneous clearance of H pylori infection has been rarely reported in children monitored by serologic tests16 or breath tests17 and also in adults by serologic or histologic examinations.15 In the present study, the spontaneous eradication rate was 3.8% children per year, contrasting with the very high reported rate of spontaneous H pylori infection clearance that ranged between 22% and 45% in Peruvian children by breath test.17 In an adult series evaluated throughout a period of 10 years, 13% of the patients had a spontaneous disappearance of H pylori infection.15
In adults, a relationship between the gene status CagA+ of
H pylori and gastric ulcer disease or gastric adenocarcinoma
has been demonstrated35 and we have previously reported that the gene status CagA+ was associated with more severe
gastritis and clinical symptoms in children.14 The present
study suggests that when asymptomatic children are infected by
CagA+ strains, they do not become symptomatic more often,
and that the histologic deterioration is not more rapid than in
children infected by CagA strains. Among individual
factors studied in our study, surprisingly only the male sex and the
gene status CagA were related to significant deterioration
of histologic damages on gastric mucosa.
During the follow-up study, an increase in the frequency of nodular gastritis was observed at endoscopy. The rate of nodular and erythematous gastritis in the initial endoscopies may be underestimated and explained by a less thorough examination at this time period. Nevertheless, biopsies on antral and fundal mucosa were performed during all endoscopies achieved during the prospective endoscopical study on the prevalence of H pylori infection, so gastric mucosa was carefully looked at during different endoscopies (because a questionnaire on endoscopical findings was filled-up systematically during the prospective study) and nodular formations on gastric mucosa are usually evident. Nodular antral gastritis is a common macroscopical finding in children and young adults infected by H pylori,4,36 although not pathognomonic.37 According to various authors, it occurs in a large range from 30% to 100% of infected children.30,36 The macroscopic findings found in the present study suggest that the frequency of nodular gastritis rises in accordance with H pylori infection duration in children. These endoscopic results suggest that nodular gastritis findings at endoscopy indicated a chronic H pylori infection; a dependence on the duration of the infection could explain the great difference in the frequency of nodular gastritis reported in different studies of children infected by H pylori.30,36
| |
CONCLUSION |
|---|
|
Top
Abstract
MaterialsMethods
Results
Discussion
Conclusion
References
|
|---|
In summary, this 2-year follow-up study has shown that the spontaneous clearance of H pylori infection in childhood is a possible but probably rare phenomenon; in most of the cases, significant and moderate aggravation of histologic features occurs with a persistence or appearance of active gastritis and also an increase in the frequency of nodular gastritis, despite a stability of H pylori density on gastric mucosa.
Longer longitudinal studies are needed to confirm the evolution of gastritis of childhood into atrophic gastritis in adults and to predict the best time to start specific anti-H pylori therapy.
| |
ACKNOWLEDGMENTS |
|---|
We thank Sarah de Freitas and James Dinsmore, medical students at United Medical and Dental Schools (UMDS) London, for proofreading.
| |
FOOTNOTES |
|---|
Received for publication Nov 13, 1998; accepted Feb 17, 1999.
Address correspondence to Frédéric Gottrand, MD, Unité de Gastro-entérologie, Hépatologie et Nutrition, Clinique de Pédiatrie, Hôpital Jeanne de Flandre, 59037 Lille, France. E-mail: fgottrand{at}chru-lille.fr
| |
REFERENCES |
|---|
|
Top
Abstract
MaterialsMethods
Results
Discussion
Conclusion
References
|
|---|
This article has been cited by other articles:
 |
|
 |
|
  L. Martigne, L. Michaud, F. Gottrand, F. Boman, and M.-O. Husson Thirteen-Year Spontaneous Evolution of Helicobacter pylori Gastritis Acquired During Early Childhood Pediatrics, March 1, 2007; 119(3): 658 - 658. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
||
|
||
Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 1999 American Academy of Pediatrics. All rights reserved. |
||
|
||
