Helicobacter pylori Infection in Children: a Comprehensive Review

Abstract

Helicobacter pylori infection is a worldwide health problem, presenting with gastrointestinal (GI) or extra GI symptoms. The infection is more common in developing than developed countries. Crowded families, paternal education level, and socioeconomic status are among the risk factors of H. pylori infection. The infection is associated with some diseases such as iron-deficiency anemia, B12 deficiency, acute idiopathic thrombocytopenic purpura (ITP). Invasive and non-invasive tests could be used for diagnosis, while the gold standard is a biopsy specimen of GI tract. Nodular gastritis is the most common finding of childhood H. pylori infection. Based on the susceptibility profile and compliance, different treatment options could be applied.

Keywords:H. pylori, infection, children.

INTRODUCTION

The most common bacterial infection in the world is H. pylori, which has first manifested in humans in East Africa, 58000 years ago (1). H. pylori was introduced in 1982, by Warren and Marshall, in cases with chronic gastritis and peptic ulcers (2-5). In 1994, the World Health Organization (WHO) considered H. pylori as a causative agent for gastric cancer (6). H. pylori is a spiral-shaped, Gram-negative bacillus, which is more prevalent in developing countries than developed ones (7). It has two to six flagella, enabling it to survive during gastric contractions (8). The human stomach, especially the antrum, is the most common reservoir of this agent (7). As this bacterium could produce urease, it could survive in the acidic stomach environment (7). Basic characteristics such as ABO blood group and Lewis blood-group antigen might expose cases to H. pylori infection (9).

Epidemiology of H. pylori

H. pylori is common in the developing countries of Africa, South America and Asia. Reviewing the literature from Asia-Pacific region, Africa, Europe, and North and South America, Goh et al. reported higher rates of H. pylori infection in Korean, Chinese and African populations (10). H. pylori is usually acquired during the first five years of life (11). More than half of the world’s population have H. pylori infection (11, 12), without any signs or symptoms. In developed countries, the frequency of H. pylori infection among children is 1.2-12.2%, while in developing countries H. pylori is the most commonly isolated infectious agent in children (13-15). Previous studies showed that geographic area, age, race, educational level, sanitation, and socioeconomic status are among the factors that influence the prevalence of H. pylori infection (8). No gender differences were found in the prevalence of H. pylori infection, while it was much higher among white people (8).

In a previous study conducted by Hunt et al., the prevalence of H. pylori was reported to be 48% among 2-4-year-old children in Ethiopia, while in Nigeria and Mexico it was 82% and 43%, respectively, among 5-9-year-old children (16). Rowland et al. reported the presence of H. pylori in 28 out of the 327 children studied by them (17). In Sudan, a prevalence of about 56% of H. pylori infection was reported in children (13% in subjects under 36 months and 40.6% in those over 109 months) (7), while in other African countries such as Uganda, Kenya, and Cameroon, it was 44%, 45%, and 37%, respectively (18-20). In Sweden, the reported prevalence of H. pylori infection was 13.6% in children between 18 and 24 months, while in Irish and German studies the rates were 8.6% and 2.4%, respectively (21-23). A study conducted in Europe showed that most infected children were from Bulgaria, with an age range of 1-17 years, while the least infected children came from the Netherlands (6).

A previous study conducted in Iran reported a prevalence of H. pylori infection of 57-82% in children between nine months and 15 years of age (24). Two previous studies showed that the prevalence of H. pylori infection had decreased during recent decades, which was in contrast to a study from Denmark (25-27).

Poor socio-economic status and high population density are the most important risk factors of H. pylori infection in children (10, 28, 29) – for example, more than two children at home with lack of access to running water and sanitation have a high risk of infection (30). In a study conducted by Urita et al., it was found that H. pylori infection could be transmitted from mother to child or grandmother to grandchildren, but not from grandfather to grandchildren in rural regions of Japan (31). It was also reported that re-infection could occur five years after eradication in 48%, and 10 years after in 38% of patients (32). Patients with peptic ulcers and gastric MALT lymphoma are a high-risk population for H. pylori infection who can benefit from a test and treat approach (33). Recent studies showed that the prevalence of H. pylori infection has been reduced in some Asian countries such as Japan, Iran and China in the last few years (34-37).

Risk factors

In different studies, various risk factors were considered for H. pylori infection in children, as summarized in Table 1.

Presentation

The exact time of the acquisition of H. pylori infection is not clear, as acute infection is asymptomatic (8). Up to 20% of all infected cases may develop stomach/duodenal ulcers, metaplasia, dysplasia, lymphoma, or adenocarcinoma (5, 42). Clinical presentation depends on virulence features, characteristics of the host, and the environment (6). According to a previous study, cagA(+) s1m1 genotype mostly occurred in children, while cagA(–) s2m2 strain was mostly detected in adults (6). Furthermore, in children, no correlation was found between infection and clinical presentations such as nausea, vomiting, heartburn, and abdominal pain, while among adults, there was a direct relationship (43). The literature also shows a relationship between H. pylori infection and other diseases such as iron-deficiency anemia, B12 deficiency, and acute idiopathic thrombocytopenic purpura (ITP) (44-46). In a previous meta-analysis, Xiong et al. reported a possible link between H. pylori infection in children and Henoch-Schonlein purpura (HSP) (27).

There are controversies over the relationship between H. pylori infection and asthma (47, 48). Controversies also exist regarding the relationship with diabetes. In a previous cross-sectional study, the prevalence of H. pylori infection was significantly higher in diabetic children than non-diabetic children, while another study did not confirm this finding (49, 50). It has been considered that eradication of H. pylori may improve children’s nutritional status (51).

Diagnosis

The diagnosis of H. pylori has been previously based on isolation of the agent from biopsy specimens (8). Non-invasive or minimal invasive tests, and available and inexpensive accurate tests are preferred for pediatric patients (52). However, the positive results of non-invasive tests should not constitute the base of treatment in H. pylori infection in children (58).

Hematoxylin and eosin (H&E) stain can be used for H. pylori and inflammation detection (11). If H&E was negative, other tests such as Giemsa, Warthin–Starry, Genta, and Acridine orange could be used (53). Genta stain, which is a combination of silver, H&E, and Alcian blue stains, is expensive but could show H. pylori along with inflammation (53). Giemsa method is cheaper, though it is highly sensitive and would be easily performed in clinical practices (53). The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommended the diagnosis of H. pylori by gastroduodenoscopy and biopsy when alarming symptoms (vomiting, persistent abdominal pain on right upper or lower quadrant, and gastrointestinal bleeding) appeared in children.

Rapid urease test and polymerase chain reaction (PCR) are two invasive tests that could be used for diagnosis, while non-invasive tests such as urea breath test (UBT) and H. pylori antigens in stool (55-57) could be performed to evaluate the successfulness of eradication 4–8 weeks after therapy (6). The antibody-based tests (IgG and IgA in serum, whole blood, saliva and urine) are not recommended for either detection of active H. pylori infection oruse in post-treatment evaluation (58). Individual assessment should be considered for each child. Urea breath test is one of the non-invasive tests that is mostly used in adults and teenagers, but it is rarely used in infants and young children (59, 60). If endoscopy is not applicable, UBT is the best choice for the detection of H. pylori in children aged five and over (59). H. pylori stool antigen test is the other non-invasive technique, with sensitivity and specificity depending on the treatment status, cut-off value, and commercial status (54, 61). The PCR tests are rapid and reliable tests that could be used on tissue and stool specimens, and could also detect genes leading to antibiotic resistance (56).

Real-time PCR (qPCR) was introduced by Kalach et al. to detect H. pylori in gastric biopsy samples of children, which is more sensitive and provides the detection of low bacterial loads (62). In children, nodular gastritis and chronic inflammation found in endoscopic evaluation are indicatives of H. pylori infection (63). A positive culture is considered as the gold standard of diagnosis (8), which needs the endoscopic biopsy specimens; therefore, it is time-consuming, is not cost-effective, and requires special media (11, 64). It should be noted that children have higher rates of false-positive results (63).

Treatment

In children with active H. pylori infection (identified by histopathologic examination) it is crucial to initiate treatment. However, the best treatment for children is not clear. Patient compliance, treatment period, and sensitivity of H. pylori strains to treatment regiments play important roles in the therapeutic success (56, 57). Children who most benefit from treatment of H. pylori infection are the ones with gastric or duodenal ulcer (58).

In vitro sensitivity to a specific antibiotic or drug does not guarantee the complete eradication of H. pylori. The number of medications, duration of treatment, and frequency of administration are among the most important issues for treatment success (52). Clarithromycin and metronidazole are the most effective drugs for the eradication of H. pylori (6). According to a previous study, low level of resistance to amoxicillin was observed in China, Thailand and Korea (6). If the regimen includes three or four medications, the first antimicrobial resistance can result in treatment failure (52).

The first-line treatment could be as follows:

1. PPI (proton pump inhibitor) 1–2 mg/kg/day + amoxicillin (50 mg/kg/day) + metronidazole (20 mg/kg/day),

2. PPI + amoxicillin + clarithromycin (20 mg/kg/day), if the resistance to H. pylori does not exceed 15% in the region, or

3. Bismuth salts (subcitrate or subsalicylate) 8 mg/kg/day + amoxicillin + metronidazole (6).

The second-line treatment could be as follows:

1. bismuth subsalicylate 1 tablet (262 mg) qid or 15 ml (17.6 mg/mL qid) + metronidazole 20 mg/kg/day–500 mg bid+PPI 1 mg/kg/day up to 20 mg bid + amoxicillin (1 g bid), or tetracycline (50 mg/kg/day up to1 g bid), or clarithromycin (15 mg/kg/day–500 mg bid)

2. Ranitidine, bismuth-citrate (1 tablet qid) + clarithromycin (15 mg/kg/day–500 mg bid) + metronidazole (20 mg/kg/day–500 mg bid) (52).

In Poland, resistance to clarithromycin was reported in 9-26% of patients, and resistance to metronidazole in 16-43% of patients (43). In case of non-response, sequential treatment, including two five-day treatment sequences are recommended: [Amoxicillin (50 mg/kg/day—maximum 2 g) and PPI (1 mg/kg/day—maximum 40 mg) twice daily, then metronidazole combination (20 mg/kg/day—maximum 1 g) and clarithromycin (15 mg/kg/day—maximum 1 g) with a PPI] (65, 66). Amoxicillin will reduce bacterial burden, and maximize bacterial cell wall destruction in the first five days. So, the level of intracellular clarithromycin will increase without significant side-effects (67).

It should be noted that sequential treatment is useful if the agent is sensitive to antibiotics (clarithromycin, metronidazole, and amoxicillin), and it will increase the risk of double resistance to clarithromycin and metronidazole (63). In children from Northern Iran, reports show resistance rates of H. pylori strains of 57% to metronidazole, 24% to tetracycline, and 16% to clarithromycin (68). Eradication medications will cause diarrhea, nausea, and vomiting. Therefore, supplements such as probiotics could increase drug compliance of children (63). Some meta-analyses showed that including probiotics in the H. pylori eradication regimen reduced adverse effects and improved efficacy (69-71).

CONCLUSIONS

Helicobacter pylori infection in children should be considered especially in the developing countries, and proper diagnostic tests and treatments should be applied. Antibiotics resistance is a core issue in the eradication protocol.

Conflict of interests: none declared

Financial support: none declared.