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Keywords:

  • Helicobacter pylori;
  • children;
  • prevalence;
  • inflammatory response

Abstract

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

The review summarizes the articles published on Helicobacter pylori in children between April 2007 and March 2008. Evidence is emerging in different populations including developing countries that the prevalence of H. pylori is declining in all age groups. The reasons for this are unclear but it is unlikely that treatment of infection or improvement in socioeconomic conditions fully explains the decline. For the first time, differences in the inflammatory response between adults and children have been well characterized in a group of adults and children from Chile with similar levels of H. pylori infection. This study suggests that the reduced inflammatory response to H. pylori at a cellular level in children could be the consequence of an enhanced Treg cell response, which in turn down-regulates H. pylori-induced inflammation. The publication of the Paediatric European Register for Treatment of Helicobacter pylori study (PERTH) is important as it demonstrates the advantages of different centers working in collaboration for the benefit of children. It also highlights the fact that while bismuth-based treatment is more effective than proton pump inhibitor-based treatment in children, bismuth preparations are not widely available for use in children.


Epidemiology

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

Several recent articles have reported a decline in the prevalence of Helicobacter pylori infection in both children and adults over the last 10 years [1–4]. In Russia, the seroprevalence declined from 30% among children younger than 5 years in 1995 to 2% 10 years later (p = .001) [1]. A similar decline of approximately 10% per decade in all age groups has been reported in Guangzhou province in Southern China which the authors classify as typical of a developing country [2]. While Fujimoto et al. reported a decline in prevalence among adults in three cities in Japan, they did not find a decline in prevalence among children younger than 6 years (9.6% in 1993 vs. 10.3% in 2002) [3]. However, the authors do report that only children of H. pylori-infected mothers were at risk of infection. They found that 21% of children whose mothers were infected with H. pylori acquired the infection compared to 3% of children whose mothers were not infected, confirming that H. pylori-infected mothers are a key source of infection. Transmission of infection from mother to child has again been demonstrated by finding the same strain of H. pylori in a mother and three children [5]. While poor socioeconomic conditions remain a significant risk factor for infection [6–9], it is likely that there are some other key child-rearing practices that determine whether or not a child becomes infected with H. pylori. While exclusive breast-feeding for more than 4 months has been reported as a protective factor for infection, the prevalence of infection among the mothers was not examined in the study [7]. In addition, noninfected children were from higher socioeconomic groups, suggesting the likelihood of lower prevalence of infection in family members. Over the last year, no new study has shed light on how H. pylori is transmitted from one stomach to another. While tonsils have been proposed as a reservoir of H. pylori, Jelavic et al. failed to culture H. pylori from tonsils of infected children diagnosed by rapid urease test or 13C-urea breath test [10].

A number of studies have attempted to determine the incidence of H. pylori infection in young children but these have been hampered by the lack of a suitable noninvasive test for use in children younger than 2 years [11,12]. The most striking feature of these studies is the number of false positive tests in children younger than 1 year. Okuda et al. confirm that stool tests are not suitable for use in studies to determine the incidence of H. pylori infection.

The increasing prevalence of H. pylori-negative peptic ulcer disease is again highlighted by a study of 751 children from Israel, which found that of 169 children with gastric and duodenal erosions and ulcers, 57 (33%) were not infected with H. pylori. Of the 57 H. pylori-negative ulcers, only a third (16) had an associated systemic disease or a history of NSAID use [13].

Pathophysiology

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

In children, antral nodularity has been well described as a feature of H. pylori infection and while the presence of nodularity has a high specificity, it has poor sensitivity. In a study of 725 children, Prasad et al. reported that the sensitivity of antral nodularity was low (42%) with a positive predictive value of 42.4%[14]. Machado et al. found that having a regular arrangement of collecting venules in the gastric mucosa in the absence of antral nodularity is highly suggestive of a noninfected gastric mucosa (post test probability of no H. pylori infection 99.3%) [15]. With the advent of magnifying endoscopy, better characterization of normal and pathologic gastric mucosa will be possible in children and adults and may reduce the need to take multiple gastric biopsies to rule out the presence of H. pylori. Koh et al. found that nodular gastritis was associated with higher gastritis scores in children [16], while a study on young adults in Japan found that atrophy scores were higher in nondiffuse nodular gastritis [17]. The possibility that nodular gastritis is a marker of a more aggressive disease process in patients infected with H. pylori requires further study.

For many years it has been accepted that there are important, yet poorly classified differences in the histologic appearance of H. pylori between adults and children. In a landmark study, Harris et al. prospectively compared the differences in histology using the Sydney classification, and in T-cell response, using immunoassay, immunohistochemistry, and real-time polymerase chain reaction (PCR) between adults and children infected in Chile [18]. They studied 36 children younger than 12 years (50% infected with H. pylori) and 79 adults (65% infected with H. pylori). In children there was minimal polymorphonuclear or mononuclear cell infiltration and no lymphoid follicles and the epithelium was intact compared to adults. The intensity of the gastritis in infected children was much less compared to adults despite the similar levels of Cag-positive H. pylori. It has been shown previously in adults that H. pylori induces T-cell-dependent gastric inflammation. The authors hypothesized that in children T regulatory cells (Treg) down-regulate the inflammatory response to H. pylori. They elegantly demonstrated that the level of Treg is markedly increased in both infected and noninfected children compared to adults. Secondly, they demonstrated that the number of Treg cells and the level of Treg cytokines (TGF-β1 and IL10) were markedly increased in the gastric mucosa of H. pylori-infected children compared to H. pylori-infected adults. In adults, interferon gamma (IFN-γ) mRNA was greatly increased compared to children. These findings suggest that increased Treg activity down-regulates the inflammatory response to H. pylori in children, resulting in much lower gastritis scores when compared to adults with similar bacterial load. Figueiredo Soares et al. have shown that in children who develop duodenal ulcer disease, the number of CD8+/CD3+ T cells and the percentages of activated CD4+ cells and CD8+ cells were higher in children than in adults [19]. Taken together, these studies suggest that the host response to H. pylori evolves over time. The trigger for this change in immune profile is unclear, but future studies on the host immune response to H. pylori should include both adults and children.

Children who are not exposed to enteric and other infections at a young age are much more likely to develop allergic disorders. This phenomenon has been termed the hygiene hypothesis and over the last year a number of very interesting studies have been published which suggest that H. pylori and other microbial infections acquired during early childhood may prevent or diminish atopic sensitization or asthma [20,21]. Chen and Blaser using national health survey data showed that persons infected with Cag-positive H. pylori strains were 40% less likely to have had childhood onset asthma [22]. H. pylori positivity was also protective against other allergens such as ragweed, pollens, and molds. Similarly, H. pylori and other microbial infections were associated with lower risk of allergic sensitization in Russian Karelian children compared to a similar group of children in Finland [23]. Herbarth et al. showed a significant inverse association between H. pylori infection and eczema (adjusted odds ratio (OR) 0.31, p = .006) in children not predisposed to atopy [24].

To understand the mechanism of the possible protective effect of H. pylori against atopic diseases, Oderda et al. took biopsies from 48 children (32 with H. pylori gastritis and 16 H. pylori negative controls) [25]. Using quantitative reverse-transcriptase PCR, the authors found that expression of gastric interleukin (IL)-10 and IFN-γ was significantly higher in H. pylori-infected children compared to noninfected children. This is not in keeping with the findings of Harris et al. who showed that the host response to H. pylori infection was down-modulated by Treg with an increase in both IL-10 and TGF-β1 while there was little or no production of IFN-γ in H. pylori-infected children. The exact mechanism by which H. pylori infection is protective against atopy and allergies remains to be determined but the role of infectious agents such as H. pylori in early life may lead to the development of a mature immune system, which prevents the development of atopy and allergy.

Symptoms

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

Recurrent Abdominal Pain

In the past year, two studies have further added to the body of evidence which shows that H. pylori does not cause symptoms in children. Daugule et al. observed that the prevalence of H. pylori infection was not significantly higher among children with dyspeptic symptoms compared to asymptomatic children of the same age [26], while in a meta-analysis from India there was no relationship between H. pylori infection and symptoms in this high prevalence country [27].

Gastroesophageal Reflux Disease

Recently Daugule et al. showed a significantly higher prevalence of H. pylori among patients with reflux esophagitis compared to patients with hyperemic gastropathy alone. The prevalence of reflux esophagitis was 14.2% among those H. pylori positive and 3.3% among those H. pylori negative with an OR of 5.5 (95% confidence interval (CI): 1.15–26.3, p = .03) for H. pylori infection among children with reflux esophagitis [26]. It could be hypothesized that H. pylori infection increases acid secretion, particularly in older children resulting in increased acid reflux into the esophagus leading to symptomatic gastroesophageal reflux disease. The association between carditis and H. pylori infection was evaluated by Carelli et al. in 45 dyspeptic patients (mean age 10.4 years) [28]. There was a strong association between carditis and the presence of H. pylori infection (OR = 27.08) by multivariate analysis. In contrast, Elitsur et al. investigated 150 children and reported no difference in the prevalence of esophagitis in H. pylori-positive and -negative patients (10% and 18%, respectively; p = .3) [29].

Nongastrointestinal Manifestations

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

Many studies still continue to investigate the relationship between H. pylori and conditions such as iron deficiency anemia (IDA) [7,30–32], short stature [7,9,33], and idiopathic thrombocytopenic purpura (ITP) [34].

Iron Deficiency Anemia

It is often difficult to distinguish between the confounding effects of poverty, poor nutrition, and poor compliance with treatment when examining the relationship between H. pylori and anemia. While a number of studies have shown that eradication of H. pylori in children with refractory anemia results in improved hematologic indices in the short term, to date no study has had sufficient follow up to determine if there is a recurrence of anemia. It is conceivable that occult blood loss from gastric/duodenal erosions could lead to anemia but it is the erosion with blood loss rather than H. pylori infection per se that causes the anemia, and healing of the erosions following therapy for H. pylori infection will result in resolution of the anemia. In children with refractory IDA, endoscopic examination may be indicated which would rule out not only the presence of H. pylori but other causes of anemia such as celiac disease [35]. It has been suggested that strains of H. pylori from patients with IDA show enhanced Fe ion uptake and Fe ion-dependent rapid growth compared with those from patients with non-IDA, implying that H. pylori strains with enhanced Fe ion-uptake ability may be a causative factor in IDA [32]. However, in the presence of adequate iron intake it does not seem biologically plausible that H. pylori could interfere with normal iron absorption.

Short Stature

Discussions about the possible association between H. pylori and growth retardation are ongoing. The following possible mechanism for the association has been proposed: infection leads to a decreased appetite and malabsorption which then results in reduced growth, lowered immunity, and repeated infections [36]. However, it has been argued that the finding could be confounded by low socioeconomic status and many of the studies do not use good measures of family income. In a low-income community in Brazil, 80% (89 of 111) of H. pylori-positive children were below the 25th percentile for height compared with 63% (35 of 56) of H. pylori-negative children (p = .01) [33]. When adjusted for gender, number of residents per household, and number of persons per bed, the OR for H. pylori was 6.62 (p = .006). In Egypt the number of children falling below the 5th percentile of height-for-age was significantly higher in H. pylori-infected children than in noninfected children [9]. However, attending school in a socially deprived area and residing in an overcrowded home were the major risk factors for short stature in the study group. While there is considerable evidence of an association between H. pylori and short stature, no study to date has demonstrated a causal relationship between H. pylori and short stature by showing increase in growth velocity in children following eradication of H. pylori.

Changes in levels of appetite regulating the hormone ghrelin due to H. pylori infection have been proposed as one of the factors associated with increased body weight after eradication of infection. Pacifico et al. have investigated 30 prepubertal children with H. pylori-associated gastritis, 35 children with H. pylori-negative gastric mucosa, and 20 healthy controls in respect to body mass index and serum ghrelin and leptin concentrations [37]. At baseline, while leptin levels were significantly lower in H. pylori-positive patients, ghrelin concentrations did not differ among the three groups. However, a significant inverse correlation between ghrelin concentrations and histologic severity of gastritis was found. Eradication of the organism was associated with a progressive decrease in ghrelin concentrations over baseline. Body mass index, lean and fat mass, as well as leptin concentrations, significantly increased over baseline.

Idiopathic Thrombocytopenic Purpura (ITP)

While eradication of H. pylori has been shown in the past to be effective in the management of ITP, spontaneous improvement in platelet counts makes it difficult to determine the true benefit of H. pylori eradication therapy in ITP. The prevalence of H. pylori infection was similar in 32 children with ITP and a control group of 30 unselected patients with no history of thrombocytopenia (19 vs. 17%). Eradication of H. pylori did not improve the treatment outcome for children with ITP [34].

Diagnostic Tests

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

Falsafi et al. have isolated H. pylori from stools of H. pylori-positive children. They concluded that the density of bacteria in the stomach may influence the recovery of H. pylori from stools. In addition, inactivation of bile with cholestyramine improves the yield in culture and favors isolation of an enhanced metabolic form of bacteria [38].

Monoclonal stool antigen tests are accurate for the diagnosis of H. pylori infection in children. However, their use in children younger than 6 years of age remains controversial. A number of articles have investigated the accuracy of rapid office-based monoclonal tests which have reasonable specificity but poor sensitivity, and have discordant results in over 10% of cases [39,40]. Again rapid office-based tests are less accurate in younger children [41]. In contrast Yang et al. found no significant differences in sensitivity or specificity of the rapid HpSA and HpSA ELISA in children pre- and posteradication therapy [42].

A novel biprobe real-time PCR method: Helicobacter pylori ClariRes assay® (Ingenetix, Wien, Austria), designed for detection of H. pylori infection and the simultaneous clarithromycin susceptibility testing of H. pylori isolates in stool samples was evaluated in 100 symptomatic children [43]. The H. pylori ClariRes assay® was in agreement with the phenotypic results of clarithromycin susceptibility testing by Etest. The specificity of PCR was 100%, while the sensitivity was 63%. It is clear that detection of Helicobacter DNA in stool samples by real-time PCR is not sufficiently sensitive to replace the stool antigen test.

Treatment

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

Treatment studies on children are particularly difficult because of the small number of infected children in each individual center. The recent publication of the results of the PERTH study is a very good example of what can be achieved when centers pool their data [44]. The results show that 27 different treatment regimens were used in 22 different European pediatric hospitals. The overall eradication rate was 65.6%, and it was significantly higher in children with ulcer (79.7%) compared to children without ulcer (63.9%, p = .001). As a first-line treatment, bismuth triple therapies were more efficacious than proton pump inhibitor triple therapies (77 vs. 64%) [OR: 1.88, 95%CI: 1.1–3.3, p = .02,], although PPI triple therapies were most often used.

The most promising new treatment regime for H. pylori in children has been reported from Russia where Nijevitch et al. observed eradication rates of 86% with bismuth subcitrate (8 mg/kg/day, q.d.s.), nifuratel (30 mg/kg/day, q.d.s.), and amoxicillin (50 mg/kg/day, q.d.s.) for 10 days [45].

Zullo et al. published an analysis of pooled data on sequential therapy in adults and children. The cumulative analysis showed that H. pylori infection was cured in 69 of 78 (88.5%) treated children, based on two studies performed on dyspeptic children (mean age: 12.3 years) [46]. Another study shows the success of sequential therapy in only one of six children with prior failure of triple therapy. Therefore at the present time, quadruple therapy possibly offers the best second-line treatment option in children [47].

Antibiotic Resistance

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

The pattern of antibiotic resistance to H. pylori has changed during the last decade. In France over the period 1994–2005, resistance to clarithromycin did not change, while metronidazole resistance decreased significantly from 43.3% (1994–98) to 32% (1999–2005) (p = .001) [48]. In Bulgaria, primary resistance to amoxicillin and nitrofurantoin was low (0.9% and 1.3%, respectively), while primary clarithromycin resistance increased significantly from 10% in 1996 and 1999 to 17.9% in 2005 and 2007. Three strains (0.4%) exhibited triple resistance to amoxicillin, metronidazole, and clarithromycin [49]. In Iranian children, the prevalence of H. pylori resistance was very high to metronidazole and amoxicillin, moderate to clarithromycin, and low to ciprofloxacin and tetracycline [50].

However, there is some concern about the reliability of current methods for testing H. pylori resistance to metronidazole in both children and adults and routine testing of metronidazole was not recommended in the Maastricht III Guidelines [51]. Further research is required to improve the reliability of the test.

Conclusion

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References

The decreasing prevalence of H. pylori worldwide is to be welcomed. Optimal treatment of H. pylori infection in children has not yet been determined and will require further collaborative studies.

References

  1. Top of page
  2. Abstract
  3. Epidemiology
  4. Pathophysiology
  5. Symptoms
  6. Nongastrointestinal Manifestations
  7. Diagnostic Tests
  8. Treatment
  9. Antibiotic Resistance
  10. Conclusion
  11. Conflicts of interest
  12. References
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