Helicobacter pylori in Pediatrics
Abstract
This review concerned the important pediatric studies published between April 2012 and March 2013. Symptomatology in Helicobacter pylori-positive children is nonspecific, except for those suffering from peptic ulcer diseases. Investigation of H. pylori status in children and adolescents with sideropenic anemia is recommended, and it is the aim of several studies worldwide. Associations of H. pylori with plasma ghrelin levels as well as the negative association of H. pylori with atopic disease were interesting objectives for several studies this year. Success rates of sequential therapy tended to be lower in recent studies than in previous trials, which probably reflects the increase in macrolide resistance. A beneficial effect of probiotics was reported although not all trials supported this result in children. Intrafamilial transmission and young age could be major risk factors associated with reinfection in children.
Pathobiology
Several studies were performed to identify Helicobacter pylori virulence factors that could be related to the evolution of disease. High positivity of virulence genes was found in dyspeptic or asymptomatic children 1-3. Acute exposure to VacA initially triggers host autophagy to mitigate the effects of the toxin in epithelial cells. Moreover, chronic exposure leads to the formation of defective autophagosomes. Raju et al. 4 identified a host autophagy gene (ATG16L1), susceptible for H. pylori infection and defined the mechanism by which the autophagy pathway is affected after H. pylori infection.
Altman et al. 5 found 11 isolates that expressed type 1 Leb blood-group antigen (22%) among 50 Greek H. pylori isolates from symptomatic children, a feature relatively uncommon in H. pylori isolates from adults. All Lex- and Ley expressing strains also had a functional cag pathogenicity island and vacAs1 allele. However, no association between bacterial virulence characteristics and the histopathologic observations was observed.
Ikuse et al. 6 analyzed the expression of immune response factors in the H. pylori-infected gastric mucosa of children. Using microarray analysis, the total number of significantly upregulated and downregulated genes was 21 in the antrum and 16 in the corpus, when comparing patients with or without infection. Using real-time PCR, the expression of lipocalin-2, C-C motif chemokine ligand 18, C-X-C motif chemokine ligand (CXCL) 9, and CXCL11 was upregulated, while the expression of pepsinogen I and II was downregulated when comparing patients with or without infection.
A better understanding of the immune response to H. pylori infection in children is important to develop an effective vaccine, as children are the main target of the vaccination. Freire de Melo et al. 7 evaluated IL-17 cell response to H. pylori and compared the gastric levels of Th17 and Treg-associated cytokines in children and adults. They concluded that Treg, instead of Th17, cell response to H. pylori infection predominates in children.
Epidemiology and Transmission
Acquisition of H. pylori infection in childhood reflects the social, environmental, and economic status of the community. Lower prevalence rates are reported in communities with higher socioeconomic status and generally better environmental conditions. A prevalence of 6% in Texas, USA 8, and 13% in Sardinia, Italy, was found 9 as well as 30.9% in Nigerians 10, 38% in school children in Mexico City 11, 30.8% in Cuban symptomatic children 12, and 78.1% in Sherpa residents in Nepal 13. The age of acquisition of H. pylori infection was examined by Muhsen et al. in a prospective study on Israeli Arab children in two villages with different socioeconomic status. Prevalence was 6% in the high socioeconomic status village and 10% in the low socioeconomic village in the first 6 months of life, and at 18 months, it increased to 9.6% and 51.9%, respectively 14. A decrease in prevalence of H. pylori infection in the Czech Republic within a 10-year period was described by Bureš et al. 15, being significantly lower in 2011 than in 2001 (23.5% vs 41.7%). However, between 2000–2001 and 2007–2008, no difference in prevalence was detected in a study carried out in Israel, although differences according to the origin were found 16.
Helicobacter pylori infection can be transient or persistent, as studied by O'Ryan et al. 17 who followed infants during the first 5 years of life in Chile. Persistence was significantly associated with a nonsecretor phenotype (ABO blood group) and daycare attendance, and associated gastrointestinal symptoms were rare.
The prevalence of H. pylori and different parasite infections was studied. A 3-fold higher risk of concomitant Giardia intestinalis and H. pylori infections was described in Uganda 18. Ascaris lumbricoides seropositivity correlated with elevated IgE and anti-inflammatory Th2-IgG1 responses to H. pylori, while Toxoplasma gondii seropositivity was linked to elevated IgE, pro-inflammatory Th1-IgG2, IgG3, and IgG4 responses to H. pylori. These infections may have an impact on inflammatory responses to H. pylori and may partially explain differences in gastric cancer risk in Colombia 19.
Hirsch et al. 20 were able to detect H. pylori DNA by PCR in several plaque and root canal samples, and cultured H. pylori from two root canals, suggesting that root canals of endodontic-infected deciduous teeth may be a reservoir for H. pylori and serve as a potential source of transmission.
Mother-to-child transmission was suspected in 2 of 3 families, and father–child transmission in one family in the study by Osaki et al. 21 using multilocus sequence typing (MLST) of total DNA extracted from fecal specimens.
Clinical Presentation
Gastrointestinal Manifestations
Helicobacter pylori infection is recognized as a cause of gastritis and peptic ulcer disease (PUD) in children. Symptoms, except those related to PUD, are nonspecific. Only a small proportion of children develop symptoms and clinically relevant gastrointestinal disease 22.
Dore et al. 9, in a cross-sectional sero-epidemiologic study, found that nausea or vomiting and diarrhea were significantly associated with H. pylori infection (OR 2.2 and 2.1, respectively), but not with abdominal pain or heartburn. Perforated ulcer is rare, but several cases of peritonitis secondary to duodenal perforation have been described 23, 24.
Extraintestinal Manifestations
Helicobacter pylori infection not only causes damage to the gastric epithelium, it also plays a potential pathogenic role in several extraintestinal diseases. Bradbeer et al. 25 described the resolution of recurrent headaches in a child after eradication of H. pylori infection and postulated this possible association.
Growth retardation
Controversy exists concerning the relationship of H. pylori infection and somatic growth retardation in children. Dehghani et al. 26 evaluated the relationship between H. pylori infection and growth parameters in Indian children and concluded that symptomatic infection does not appear to influence linear growth.
The gastrointestinal hormone ghrelin is a gut–brain peptide that regulates food intake in humans and has strong growth hormone-releasing activity. Decreased appetite in H. pylori-infected children has been related to low plasma ghrelin levels which returned to normal after H. pylori eradication. Deng et al. 27 evaluated plasma and gastric ghrelin production as well as body mass index (BMI), before and after treating H. pylori infection in 50 Chinese children, divided into two groups based on the success of H. pylori treatment. They found that plasma and tissue ghrelin levels increased substantially after treatment in the group with therapeutic success, but only minor changes were observed in the group with treatment failure. However, the BMI in the two groups did not differ significantly 2 months before and after the H. pylori treatment. The results suggest that ghrelin may play an important role in the mechanism of H. pylori-associated dyspepsia in children.
Iron Deficiency Anemia
Several studies have shown an association between low iron status and H. pylori infection, and the investigation of the H. pylori status in children and adolescents is recommended, especially in cases of refractory iron deficiency (ID) anemia. Children have low iron stores because of their increased iron requirement for growth. In the presence of H. pylori infection, they probably develop ID faster than adults. In H. pylori-associated atrophy, hypochlorhydria has a role in ID through changes in the physiology of iron-complex absorption. Harris et al. 28, in a prospective study including 123 children, found that in H. pylori-positive children with hypochlorhydria, serum iron, and transferrin saturation levels were significantly lower than in H. pylori-positive children without hypochlorhydria, indicating that a combination of H. pylori infection and/or inflammation and hypochlorhydria has a role in the etiology of ID.
Hematologic parameters returned to normal 3 months after H. pylori eradication, with disappearance of lymphocytic gastritis, in a 12-year-old premenstrual girl with refractory ID anemia and focal intestinal metaplasia 29.
Pro-oxidant status and ferritin levels were evaluated in H. pylori-infected school children. Serum malondialdehyde and protein carbonyls were significantly increased, and ferritin levels decreased in H. pylori-infected children compared with healthy controls and H. pylori-uninfected children with ID. The authors concluded that an increased level of oxidative stress was found in H. pylori-infected school children 30.
Idiopathic Thrombocytopenic Purpura (ITP)
Xiong et al. carried out a meta-analysis to evaluate this possible association in Chinese children and showed that 49.27% of ITP children had evidence of H. pylori infection compared with 23.39% of the control group. Moreover, H. pylori eradication therapy was able to reduce the recurrence of ITP 31.
Atopic Disorders
The recent increase in asthma and allergy seems to be associated with a decrease in the H. pylori infection prevalence, with some studies reporting a negative relationship.
A significantly lower borderline H. pylori seropositivity was found in children with wheezing compared with nonwheezers; however, no association between H. pylori serological status and allergic rhinitis, atopic dermatitis, or asthma was found by Holster et al. 32. In a meta-analysis performed by Wang et al. 33, little evidence was found for an inverse association between asthma and H. pylori infection both in children and in adults.
Diagnosis
Diagnostic Procedures
In a prospective study, Abdulqawi et al. 34 compared the accuracy of three invasive diagnostic tests (rapid urease test, histology, and culture) and one noninvasive test (IgG serology) in Egyptian children and concluded that the association of urease test and histology with serology leads to greater accuracy in the diagnosis of the H. pylori infection.
In children, especially in the youngest, the usefulness of the diagnostic test based on the detection of H. pylori-specific IgG antibodies (serum, urine, whole blood, saliva) is controversial due to their low sensitivity. Okuda et al. 35 evaluated the accuracy of two urinary IgG antibodies tests (Urine-HpELISA test and Rapid urine-HpAb) obtaining sensitivity and specificity of 91.9% and 96.9% for Urine-HpELISA and 78.4% and 100% for Rapid urine-HpAb and recommended these methods as simple, low cost, rapid, and reliable for screening of H. pylori.
Histopathologic studies are still important to identify mucosal lesions. Carvalho et al. analyzed histopathologic lesions in 96 Brazilian children with H. pylori infection. 70.5% had moderate-to-severe chronic active gastritis. Intestinal metaplasia was not found, and gastric atrophy was not significant. 61.9% had pangastritis, and H. pylori density was higher in the antrum than in the corpus 36.
Molecular Methods
Molecular methods have been used for different purposes: detection of H. pylori in gastric biopsies compared with conventional methods, detection of virulence genes, both in biopsy specimens and in specimens other than biopsies obtained using less invasive methods (string test) or noninvasive methods (stool samples).
Ou et al. 37 found that the fluorescent quantitative PCR test was more sensitive than conventional methods alone or in combination (p<0.01). A nested PCR had a sensitivity of 93.0% and a specificity of 100% compared with the 13C-urea breath test (UBT) on gastric DNA obtained by a string test in asymptomatic children 2. Baskovich et al. 38 also detected a surprisingly high number of new cases with H. pylori by PCR, in both the normal biopsies and test cases, suggesting that PCR could detect colonization in asymptomatic patients.
The sensitivity and specificity of the glmM gene compared with UBT was 42.6% and 100%, respectively, in stools of patients with dyspepsia 1.
Multilocus sequence typing MLST of total DNA extracted from fecal specimens to genotype H. pylori was successfully used by Osaki et al. 21.
Treatment
Drug resistance
Antibiotic resistance is the major cause of failure in the treatment of H. pylori infection. Most of the studies worldwide confirmed an increase in macrolide resistance, while metronidazole resistance either decreased or remained stable. In a prospective multicentre European study, primarily comprised of adults, Megraud et al. 39 found a 31.8% resistance rate to clarithromycin and 25.7% to metronidazole in the 311 H. pylori isolates from children from eight countries included in the study. The increase in clarithromycin resistance in many countries (especially in Western/Central and Southern Europe) has prohibited its empirical use in standard therapeutic regimens. Hojsak et al. 40 found a 17.9% resistance to azithromycin, 11.9% to clarithromycin, 10.1% to metronidazole, and 0.6% to amoxicillin in Croatian children and recommended amoxicillin–metronidazole combinations as first-line therapy. Ogata et al. in Brazilian children and adolescents, reported a high metronidazole (40%), clarithromycin (19.5%), and amoxicillin (10.4%) resistance rate and 18.2% of multiple resistance. All H. pylori strains were susceptible to furazolidone and tetracycline, and they proposed the use of these two antimicrobials, both associated with amoxicillin, in future eradication regimens 41. Seo et al. 42 studied the changing pattern of antibiotic resistance of H. pylori in South Korean children over a 20-year period, and they showed an increase in the resistance rate to clarithromycin from 6.9% to 18.2%, and a decrease in the resistance rate to metronidazole from 32.8% to 27.3%.
Therapeutic Regimens
Children have more difficulty than adults in eradicating H. pylori infection and very often the routine therapeutic combinations do not achieve 80% eradication rates.
In a review of 10 randomized trials performed in different countries, Zullo et al. found that sequential therapy achieved significantly higher eradication rates compared with the 7- and 10-day standard triple therapies, even in clarithromycin and metronidazole resistance H. pylori strains. However, the success rate of the sequential regimen tends to be lower in recent studies compared with previous trials 43.
Horvath et al. 44 reviewed the randomized controlled trial comparing sequential therapy with standard triple therapy for H. pylori eradication involving 857 children. They found that sequential therapy was superior to the 7-day standard triple therapy, but not significantly better than the 10-day or 14-day triple therapies. Huang et al. 45 obtained similar results in a randomized study of Chinese children. An overall eradication rate with the sequential therapy is less than in previous studies.
Nguyen et al. reported a high clarithromycin and metronidazole resistance rate, 50.9% and 65.3%, respectively, in Vietnamese children. They compared the efficacy of two triple therapies: lansoprazole with amoxicillin combined with either clarithromycin or metronidazole, administered over a 2-week period. Overall eradication rates were below 80% with both combinations being lower when the strain was clarithromycin (29.7% vs 78.2%) or metronidazole (60.3% vs 66.7%) resistant 46.
Probiotics
Several meta-analyses suggested that probiotics improve H. pylori eradication and/or reduce the treatment's side effects. Probiotics could help stave off complications by decreasing the bacterial density in gastric mucosa and prevent the reinfection by inhibiting the adherence of the bacteria to gastric epithelial cells. Not all probiotics act in the same manner, and the beneficial effects are strain specific. Moreover, not all of the studies support this beneficial effect in children.
Tolone et al. 47, in a randomized study including 68 H. pylori-infected children, reported significantly fewer treatment side effects after adding a commercial multistrain probiotic and bovine lactoferrin to a 7-day standard triple therapy compared to those observed with the triple therapy alone. In a prospective study, Yang et al. found low Bifidobacterium microflora in the gut of H. pylori-infected children. They concluded that probiotic-containing yogurt offers the benefit of restoring the fecal Bifidobacterium spp./ Escherichia coli ratio, and of suppressing the H. pylori load with an increment of serum IgA and pepsinogen II levels and a reduction in serum IL-6 level, in these children 48.
Reinfection and Spontaneous Clearance
The rate of recurrence of H. pylori infection is higher in developing than in developed communities. Rather than reinfection, recrudescence is the most frequent cause of recurrence. Strain genotyping before and after treatment is necessary to distinguish between them. In pediatrics, there are relatively few studies on this topic. The reinfection rate in children varied between 2% and 10%, being more frequent in developing countries. Intrafamilial transmission could be the major risk factor associated with reinfection in children 49.
Candelli et al. reported a higher prevalence of H. pylori infection in young patients with diabetes than in the control group. Three years after a standard eradication treatment, the reinfection rate in the patients with diabetes was higher than in the control group 50, due to the higher susceptibility of patients with diabetes to develop infections. Age and socioeconomic status are also related to H. pylori reinfection in these patients. There is a higher risk of H. pylori reinfection in young children. In a prospective, 1-year follow-up study on 136 Vietnamese children in whom H. pylori infection was eradicated, Nguyen et al. found a high recurrence rate (25.2%), and they identified young age as the most prominent risk factor for recurrence. This risk gradually decreased from the 3–4 age group to the 9–15 age group 51.
Persistent chronic infection is common in H. pylori infection, and spontaneous clearance is relatively rare. In a 5-year follow-up study in Mexico City 11, Duque et al. found a spontaneous clearance rate of 4.7% per year, being higher in children with iron deficiency and lower in school children with two siblings or more.
Acknowledgements and Disclosures
Competing interests: the authors have no competing interests.
