Introduction

Helicobacter pylori is a gram-negative bacterium which naturally colonises gastric mucosa and causes chronic active and chronic persistent gastritis in both adults and children. Almost half of the world's population is estimated to be infected with H. pylori, and it is a major risk factor for several gastroduodenal diseases, including gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and distal gastric cancer [10, 31, 47]. There are epidemiological data linking chronic H. pylori infection, probably beginning in childhood, with the development of gastric cancer and MALT lymphoma [30]. Infection is usually acquired during early childhood particularly in developing countries, and the prevalence of H. pylori gastritis in children increases with age [42]. Factors determining the subset of infected individuals developing the disease compared with H. pylori carriers remain unclear. Both host and bacterial factors may contribute to differences in H. pylori pathogenicity. Relative infrequency of clinical disease from H. pylori infection among children may suggest that the host response to the bacteria differs between adults and children. Lesser inflammatory response to H. pylori by a developing immune system may alleviate the risk of disruption to the mucosa of gastric epithelium and may modify associated physiological changes which favour survival of H. pylori [9].

Epidemiology and risk factors

At adolescence, approximately 65 % of children in developing countries are infected with H. pylori [48, 49]. The human host remains the principal reservoir. Transmission occurs via person-to-person transmission, and unclean water sources have also been implicated [6, 14]. Several studies have suggested that children acquire H. pylori most frequently from their mothers; hence, infected mothers are the main independent source of H. pylori infection for children [36, 61]. While there is a decline in the prevalence of H. pylori infection in Europe, the high prevalence in Asia and developing countries still persists [48, 56, 59]. A literature search regarding the prevalence of H. pylori among healthy subjects by using different screening methods is presented in Table 1. Since different screening methods such as stool antigen test, serology and 13C-urea breath test (13C-UBT) were used in those studies, the prevalence rates varied according not only to the different geographical areas but also to the sensitivity of the test used to detect H. pylori infection. The rate of infection in developed countries has fallen dramatically over recent decades, with a more precipitous decline in transmission found in children compared to adults [16, 56].

Table 1 Most recent studies reporting prevalence of H. pylori infection in children
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Most of the published studies regarding risk factors focused on socioeconomic indicators, and family income, household crowding, number of children sharing the same room, parents' education and sharing a bed with children were identified as major risk factors associated with H. pylori infection [12, 13, 32, 44, 48, 58]. Cultural factors determine the child-rearing practices in different populations. It has been shown that peculiar eating habits such as sharing plates, glasses, and spoons, and tasting the food before feeding the child might be associated with H. pylori infection particularly in countries with higher prevalence of the infection [16, 44].

Clinical presentation in H. pylori infection

In children, symptoms of H. pylori-related peptic ulcer disease are nonspecific and may include epigastric pain especially after meals, night-time waking, unexplained nausea and/or vomiting, anorexia, hematemesis and iron deficiency anaemia.

The association between H. pylori infection and iron deficiency anaemia (IDA) has been the focus of attention for more than one decade [4, 5, 43, 50, 53]. However, it is often difficult to distinguish between IDA due to H. pylori infection and to the other confounding factors such as poor nutritional status or another underlying disease. Hence, endoscopic examination may be indicated in children with refractory IDA in order to rule out not only the presence of H. pylori but also other causes of IDA such as malabsorption syndromes. Recently published guidelines regarding H. pylori infection in children have recommended that children with unexplained IDA should be tested for H. pylori infection [35].

H. pylori infection is the most important cause of primary duodenal ulcers in children. Since duodenal ulcer and use of nonsteroidal antiinflammatory drugs are the most common aetiologies of upper gastrointestinal bleeding during childhood, H. pylori infection should be sought in children with acute upper gastrointestinal bleeding [28].

There are several studies investigating the association between recurrent abdominal pain (RAP) and H. pylori infection, but no association has been identified [7, 42]. Hence, children with RAP should not undergo non-invasive or endoscopy-based tests in order to seek evidence of H. pylori infection in primary care [35]. Several consensus statements and guidelines have suggested that children with recurrent abdominal pain should be investigated for H. pylori only when upper gastrointestinal endoscopy is required to look for an organic disease such as peptic ulcer or esophagitis [9, 35, 39]. In the revised guidelines regarding the management of H. pylori infection, recurrent abdominal pain is not an indication for a “test and treat” strategy for H. pylori infection in children [35, 39]. Whether H. pylori gastritis per se causes abdominal pain in the absence of peptic ulcer disease is still debatable.

There is insufficient evidence regarding the causative association between H. pylori infection and otitis media, upper respiratory tract infections, periodontal disease, food allergy, sudden infant death syndrome, idiopathic thrombocytopenic purpura and short stature [35].

Epidemiological evidence has indicated that there is a link between gastric cancer and H. pylori infection; however, no study has yet shown that H. pylori eradication during childhood prevents the development of gastric malignancies. The significance of H. pylori infection in children in terms of the risk of gastric cancer occurring in adult life requires further studies, because it is likely to be a critical issue in determining whether widespread screening and treatment strategies are implemented among children [26, 30, 54]. The World Health Organisation's statement classifying H. pylori as a group 1 carcinogen could result in significant parental pressure for screening of children and treatment if H. pylori is found to be present [31]. Screening of children with a family history of gastric cancer is recommended if they are symptomatic [35].

Diagnosis: non-invasive and invasive tests

H. pylori infection can be diagnosed by several methods. Non-invasive techniques include the 13C-UBT, detection of H. pylori antigen in stool and detection of antibodies against H. pylori in serum, urine and saliva.

Invasive techniques require endoscopy and biopsy (histological examination, rapid urease test, culture, polymerase chain reaction and fluorescence in situ hybridization, FISH) (Table 2). At least two tests are needed to diagnose the H. pylori infection, and a biopsy-based test (such as culture or histology or rapid urease test) should be the reference for non-invasive tests.

Table 2 Tests for investigating H. pylori infection
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In a large number of paediatric studies of high quality, the 13C-UBT has been evaluated against biopsy-based tests, showing high accuracy, sensitivity and specificity [15, 41]. However a positive 13C-UBT does not confirm or exclude the presence of an ulcer, gastritis or esophageal pathologies. Detection of H. pylori antigen in stool is a reliable and cost-effective non-invasive method that seems suitable for both clinical use and epidemiological studies. Several methods are available for the detection of H. pylori antigen in stool, such as enzyme immunoassay (EIA) based on polyclonal or monoclonal antibodies and immunochromatographic tests (so-called rapid or quick tests) [51, 56, 62]. So far, only the EIA based on monoclonal antibodies has achieved the accuracy of the 13C-UBT.

There are several commercially available, easy to perform and inexpensive tests based on detection of antibodies (IgG and IgA) against H. pylori in blood and body secretions. Despite the advantages, the lower sensitivity and a wide test-to-test variability of these IgG-based tests prevent the use of serological tests in the clinical setting [35, 37]. Therefore, tests detecting antibodies against H. pylori in serum, whole blood, urine and saliva are not reliable for use in children of any age group [35].

Recently, Guarner et al. published a study regarding the diagnostic tests for H. pylori infection in children by reviewing literature from 1999 to 2009 and concluded that most of the commercially available non-invasive tests such as the 13C-UBT, monoclonal stool antigen test have adequate sensitivity and specificity for detecting the presence of H. pylori. They emphasized that endoscopy with histopathology is the only method which can diagnose and confirm H. pylori infection, its associated lesions (atrophy, intestinal metaplasia) and other causes of gastrointestinal symptoms as well [22]. In symptomatic children with suspected H. pylori infection, gastric biopsies should be obtained not only for histopathology but also for rapid urease test and, if available, for culture. Rapid urease test can be performed in endoscopic biopsy specimens by using commercially available reagents [38].

FISH or PCR techniques can be applied to the frozen or paraffin-embedded gastric tissues for the diagnosis of H. pylori infection [35]. The major advantage of these methods is the ability to study antibiotic resistance in biopsy specimens. Culture is the only method that consistently has 100 % specificity, but sensitivity varies depending on the experience of the laboratory [22]. At present, culture procedures have not been standardized, and relatively few clinical laboratories offer this service routinely in several countries.

In summary, upper gastrointestinal endoscopy with biopsies is the preferred method of investigation in children with upper digestive symptoms suggestive of organic disease and is the gold standard for diagnosing pathologies related to H. pylori. Therefore, it has been recommended that the initial diagnosis of H. pylori infection should be based on either positive histopathology plus a positive rapid urease test or a positive culture [35]. That is, the diagnosis of H. pylori infection in children requires an esophagogastroduodenoscopy and obtaining gastric biopsies.

Who should be tested and treated?

Children with a suspicion of organic upper gastrointestinal disease should be tested for H. pylori infection and should be treated if they are infected [35, 39]. In adults, eradication of H. pylori in patients with peptic ulcer disease (PUD) significantly reduces the relapse rate of ulcer disease and the recurrence of bleeding. Although the data regarding children with PUD were not as convincing as in adult studies, eradication of H. pylori is recommended in children with H. pylori-associated PUD [35]. Unexplained and refractory iron deficiency anaemia is another indication for testing for H. pylori infection in children and for eradication if the patient is found to be positive. H. pylori infection is the most consistent risk factor for gastric cancer; hence, its elimination has been regarded as the most promising strategy to reduce the incidence of gastric cancer in adulthood [40]. Therefore, endoscopy and treatment should be considered in children who are found to be infected with H. pylori and having a first-degree relative with gastric cancer (Table 3).

Table 3 Indications for H. pylori investigation in children
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Treatment options for H. pylori infection in children

The goal of treatment is at least a 90 % eradication rate of H. pylori at the first attempt so that a high initial eradication rate will prevent the development of antibiotic resistance and spread of resistant H. pylori strains in the population. Since the initial guidelines, first-line treatment options include triple therapy, i.e. a proton pump inhibitor (PPI) plus two antibiotics. In the last guidelines, several alternative first-line therapies have been recommended (Table 4) [21, 35, 55]. Although there are no well-designed randomised studies comparing bismuth-based triple therapy with the alternate recommended first-line therapies, bismuth salts are included in the latest guidelines as an alternative first-line therapy in countries where bismuth salts are available commercially [35, 46]. The period of triple therapy should be 10–14 days, taking the cost, compliance and side effects into consideration. Tetracycline should not be used to treat H. pylori infection in children younger than 12 years of age with incomplete teeth development.

Table 4 First-line treatment recommendations for H. pylori eradication in children
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Eradication rates of H. pylori infection following standard triple therapies are largely decreasing all over the world, and this phenomenon has been related to an increasing prevalence of bacterial resistance which varies in different regions [45, 46]. Today, the overall eradication rate of H. pylori is around 65 % which is lower than the ratios reported previously [38], and the major reason for this eradication failure is antibiotic resistance, particularly clarithromycin resistance [1–3, 11, 18, 27]. A multicenter antibiotic resistance study which included children from 14 European countries revealed a resistance rate of 25 % to metronidazole, 24 % to clarithromycin and double resistance rate of 6.9 % [34]. In this study, resistance to amoxicillin was exceptional as expected.

There are limited data regarding the susceptibility testing to target initial therapy in children; nevertheless, susceptibility test-guided treatments demonstrated higher eradication rates in children [1]. Antibiotic susceptibility testing for clarithromycin is recommended before initial clarithromycin-based triple therapy in areas with a known high resistance rate (>15–20 %) of H. pylori to clarithromycin. The combination of PPI–amoxicillin–metronidazole is preferable in areas where the metronidazole resistance is lower than 40 % [27, 35, 40].

Declining eradication rates with the triple regimens have led to the development of alternate first-line treatment options [17, 20]. Sequential therapy involves 5 days of therapy with a PPI and amoxicillin followed sequentially by 5 days of PPI–clarithromycin–imidazole. The sequential treatment, which is now widely used in adults, yielded a superior eradication rate compared to the conventional 7- or 10-day triple regimens [17]. However, eradication failure secondary to clarithromycin resistance is still a problem for the sequential therapy as well. In the most recently published paediatric guidelines, the sequential therapy is recommended as an initial therapy in eradication of childhood H. pylori infection [35].

Primary antibiotic resistance adversely affects the success of H. pylori eradication; however, development of secondary antibiotic resistance seems to be more common in children [8, 33]. When the initial treatment with one of the first-line alternatives fails in a child infected with H. pylori, primary culture with antibiotic sensitivity testing should be performed along with endoscopy to guide second-line therapy. Another option may be FISH on previously obtained paraffin-embedded biopsies to test clarithromycin resistance. If culture or susceptibility tests are not available, trying second-line treatment options or increasing the dose of PPIs (2 mg/kg/day) and/or duration of treatment (14 instead of 10 days) may be recommended.

The choice of second-line therapy should take the initial therapy into account, and the physician should avoid using an antibiotic that was previously prescribed. Second-line treatment options and doses are listed in Table 5. Fluoroquinolone resistance is an emerging problem in the adult population; thus, fluoroquinolones should be cautiously used in children who were previously exposed to this drug [29]. Supplementation of Saccharomyces boulardii to H. pylori eradication regimens emerged as an alternative at the beginning of the 2000s [60]. However, rather than being an additional therapeutic effect, probiotics significantly reduced the incidence of side effects [57, 60]. To date, the most reasonable policy to adopt is to treat a child according to the result of the antibiotic susceptibility test whenever possible, or at least according to what is known about the antibiotic susceptibility of H. pylori strains cultured in this geographical area [35].

Table 5 Second-line treatment for H. pylori in children who failed the initial therapy
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Regardless of being asymptomatic after the treatment, it is recommended that the success of eradication therapy should be evaluated in children with H. pylori infection [35]. Persistence of infection, particularly in children who had PUD, would warrant additional treatment. The 13C-UBT is recommended as a reliable non-invasive test for evaluation of the eradication success. Today, it is considered the reference standard of the non-invasive tests for assessment of the eradication success [15, 41, 63]. Since collecting breath samples is not easy in small children, stool samples can be used for follow-up of eradication success in small children. A laboratory-based validated monoclonal stool test can be used in children who cannot supply a breath sample as well. Factors that can lead to false-positive or false-negative results should be considered before interpreting the test results. Data extrapolated from the adult studies show that antibiotics and acid-suppressive drugs, particularly PPIs, should be discontinued before testing for at least 4 and 2 weeks, respectively [35, 40]. Tests based on the detection of antibodies (IgG, IgA) against H. pylori in serum, whole blood, urine and saliva are not reliable for evaluation of the eradication success [35, 40].

Vaccination

H. pylori infection is usually acquired during childhood and tends to persist unless treated. It is highly prevalent all over the world and an important cause of gastritis, peptic ulcer disease, MALT lymphoma and gastric adenocarcinoma [40]. Treatment of H. pylori requires multidrug regimens because of the barrier function of the gastric mucus layer, and resistance is also an important issue with the antibiotics commonly used for eradication of the bacteria. Hence, a vaccine, administered during infancy would obviate many treatment concerns and could be an attractive strategy to control H. pylori infection [25, 52].

Since the initial studies have demonstrated that it was possible to reduce gastric H. pylori colonisation by vaccination with H. pylori antigen and adjuvant, various approaches including whole cell vaccines, recombinant antigens (e.g. urease A/B subunits, CagA, VacA, NapA, catalase or heat shock proteins) in combination with bacterial toxins or other adjuvants have been successfully tested in animals [23, 24]. However, similar vaccine trials in humans have shown adjuvant-related adverse effects and only moderate effectiveness [25, 52]. It is obvious that infections caused by microorganisms which gain access to the body via the mucosal membranes are best prevented by mucosal vaccination. Further, vaccination at mucosal surfaces may stimulate both systemic and mucosal immunity not only at the site of vaccination, but also at distant mucosal epithelia [19, 25]. Transcutaneous immunization may be effective as a route for inducing protection against H. pylori colonisation and warrants further studies.