The Journal of Pediatrics
Volume 146, Issue 3, Supplement , Pages S21-S26, March 2005

Helicobacter pylori infection: Detection, investigation, and management

  • Steven J. Czinn, MD, FAAP, FACG

      Affiliations

    • Corresponding Author InformationReprint requests: Dr Steven J. Czinn, Pediatrics and Pathology, Rainbow Babies' and Children' Hospital, Case Western Reserve University, Cleveland, OH 44106.

From Pediatrics and Pathology, Rainbow Babies' and Children' Hospital, Case Western Reserve University, Cleveland, Ohio

Received 4 October 2004; received in revised form 19 November 2004

Article Outline

Helicobacter pylori infection causes gastritis and peptic ulcers and is associated with the development of gastric cancer. Approximately 50% of the world population is infected with H pylori, with the highest prevalence rates in developing countries. In the vast majority of individuals, infection is acquired during childhood with those of low socioeconomic means and having infected family members being at highest risk for early childhood acquisition. Definitive routes of transmission of the infection are unclear, with evidence suggesting oral-oral, gastric-oral, and fecal-oral routes. If untreated, H pylori infection is lifelong. Although clinical disease typically occurs decades after initial infection acquisition, children infected with H pylori may have gastritis, ulcers, mucosal-associated lymphoid type lymphoma, and, rarely, gastric atrophy with/without intestinal metaplasia (ie, both precursor lesions for gastric cancer). Controversy persists regarding testing for and treating H pylori, if found, in the large number of children who present with recurrent abdominal pain. Because young children (ie, younger than 5 years of age) who are treated and cured of their H pylori infection may be at risk for reinfection, the current recommendations do not recommend treatment unless an ulcer or gastric atrophy is present. However, despite the lack of clinical evidence, the trend is to more aggressively screen children for the presence of H pylori and to treat those children who are found to have the infection. H pylori infection can be eradicated by antimicrobial therapy plus a proton pump inhibitor, but no treatment regimen is 100% effective. Multiple drugs, frequent dosing, and length of treatment often contribute to poor patient compliance, and antibiotic eradication therapy is associated with increasing drug resistance.

UBT, Urea breath test

 

The Gram-negative, spiral-shaped bacterium Helicobacter pylori is a common human pathogen and public health problem that causes gastritis and peptic ulcers.1 Infection with H pylori has also been linked pathologically to the development of gastric cancer. Worldwide, infection with H pylori is highly prevalent-approximately 50% of the world population is infected, with prevalence rates in countries ranging from 20% to more than 80%.2 The highest rates of H pylori prevalence are in Eastern Europe, Asia, and many developing countries and developing populations in developed countries (eg, Native Americans).2 Among selected populations in the United States (ie, non-Hispanic blacks and Hispanics) prevalence rates (ie, >50%) approach those observed in these countries.3, 4, 5

Infection with H pylori may manifest as a number of clinical disorders, primarily of the gastroduodenal mucosa. Unfortunately, without available validated symptom assessment instruments, there are few clues in a child's history or physical examination that lead one to suspect H pylori infection. A substantial percentage of children who present to their primary care physician or pediatrician report abdominal or periumbilical pain (represents up to 5% of all primary care physician pediatric office visits). However, this abdominal pain may be due to a wide variety of causes, such as functional bowel disease, gastroesophageal reflux disease, constipation, and other causes, with H pylori infection being lower in the differential diagnosis. Studies attempting to establish a causal relation between infection with H pylori and recurrent abdominal pain have reported inconsistent results, with odds ratios ranging from 0.32 to 1.80.6, 7 A recent study8 found that children referred for endoscopy due to abdominal pain (n=373) had a higher rate of H pylori seropositivity (22.5%) compared with control children without gastrointestinal complaints from the same geographic region (14.1%, n=619). The presence of gastrointestinal symptoms was associated with an increased risk of H pylori seropositivity (odds ratio, 1.77; 95% CI, 1.27 to 2.47). In particular, these authors reported a statistically significant association between H pylori seropositivity and subjects who had epigastric pain (relative risk, 2.21; 95% CI, 1.33 to 3.66), or those having 3 or more episodes of abdominal pain in the last 3 months (relative risk, 0.59; 95% CI, 0.35 to 0.99).

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Case continued 

The patient lived with his parents, one grandparent (the paternal grandfather died of gastric cancer), and 4 siblings. His father had been hospitalized repeatedly for peptic ulcer disease, was treated for a “bug,” and had been ulcer-free for 4 years. The patient's younger brother, 5 years old, often slept with him and had recently missed several days of school because of a recurrent stomach ache.

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Infection with H pylori: Risk factors and acquisition 

The medical and family history reveals several clues that implicate H pylori infection as more likely on the differential diagnosis list. In particular, this patient's father's history of peptic ulcer disease caused by a “bug” and his grandfather dying of gastric cancer are typical features of the familial disposition for H pylori infection. Whereas the routine testing for H pylori infection in children who present with recurrent abdominal pain is not recommended, given this patient's history, there were data to support more aggressive investigation of this child.

H pylori is almost always acquired in childhood (usually before age 10 years),9 and, if untreated, infection is lifelong. In the developing world, up to 70% of children are infected with H pylori by age 15 years (Figure 1).4 Although H pylori seroprevalence among children residing in the United States is much lower—on the order of 10% among those 10 years of age1 (Figure 2)—selected populations are at higher risk. A recent epidemiologic study by O'Rourke et al10 found that H pylori infection was much higher in children under age 6 living on the Mexico side of the Rio Grande compared with those on the US side (odds ratio for H pylori infection, 1.70; 95% CI, 0.64 to 4.52).

  • View full-size image.
  • Figure 1. 

    Prevalence of H pylori infection by age in developing and developed countries. Overall prevalence and age at which H pylori infection is acquired varies substantially between developing and developed countries. Overall estimates are that approximately 70% of children in developing countries are infected with H pylori by age 15 as compared with approximate 10% infection rate prevalence in developed countries. Reproduced from Logan RP, Walker MM. ABC of the upper gastrointestinal tract: epidemiology and diagnosis of Helicobacter pylori infection. Br Med J 2001;323:920-2, with permission from the BMJ Publishing Group.

  • View full-size image.
  • Figure 2. 

    Age-specific H pylori seroprevalence rates in Bolivian, Native Alaskan, and US children (0 to 9 years of age). Bolivian and Native American children have similar rates of H pylori acquisition, with the majority becoming infected by approximately 6 years of age. Gold BD. New approaches to Helicobacter pylori infection in children. Curr Gastroenterol Rep 2001;3:235-47.

Children with an infected family member, those residing under crowded living conditions (ie, sharing a bed), with two or more siblings, who attend day care, or have poor hygiene are at increased risk for H pylori infection.10, 11, 12, 13 Other children who have higher rates of H pylori infection include those of lower socioeconomic means, immigrant children, American-born children of immigrant parents, and internationally adopted children.14

To date, human beings are the only known reservoir for H pylori. Increasing evidence suggests that transmission of the infection may potentially be facilitated through contaminated water.2, 4 Routes of H pylori transmission described include fecal-oral, oral-oral, and gastric-oral. The latter route of transmission was reported after identification of viable H pylori organisms in the vomitus of infected adults and air samples collected near the vomiting subjects.15, 16

Person-to-person routes of transmission place a child such as our patient, as well as the younger sibling, at increased risk of acquiring the infection.17 H pylori appears to be transmitted most readily within families, possibly from parent to child (such as from the father and/or grandfather) and among siblings.18 Evidence also supports child-to-child transmission among those in crowded school or living conditions as well as in chronic care facilities for multiple handicapped children.1 In contrast, transmission among adults is rare—adults have a H pylori seroconversion rate of approximately 0.3% per person-year. Studies of families have found that one spouse may be positive, whereas the other remains negative, and that an uninfected parent remains negative even if children in the household are infected. In cases such as this, in which the brothers share a bed, it may be prudent to investigate the younger sibling, especially if he begins manifesting gastrointestinal symptoms (eg, epigastric pain, dyspepsia).

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Case continued 

The patient's mother stated that about 4 years ago, the patient had a severe stomachache that was associated with vomiting “some dark stuff” and was treated by his primary care physician with a course of antacids. She recalled having to collect his stool and mailing it back to the doctor for a test to be performed. The patient's current medications included an iron-fortified multivitamin, as he was found to be anemic at a previous clinic visit. Despite taking the iron therapy and increasing his intake of iron-rich foods, the patient's mother reported that the anemia does not appear to be improving. The mother wondered if the child had inherited the stomach bug from his father.

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Diagnosing H pylori in children 

There are two types of diagnostic tests used to detect H pylori infection: noninvasive and invasive. Noninvasive tests include the urea breath test, stool tests, and blood tests, which include whole blood and serologic assays. Noninvasive tests detect the presence or absence of infection. Invasive tests include the performance of upper gastrointestinal endoscopy with gastric biopsy. Invasive tests can determine both presence/absence of infection and the extent and severity of mucosal injury (ie, disease).

The urea breath test (UBT) is widely used in adults as a diagnostic agent and to confirm treatment results (ie, persistent infection versus cure). Performance of the study involves having the patient drink a solution of 13C- or 14C-labeled urea an important substrate for H pylori metabolism. If H pylori is present in the stomach, the bacteria's enzyme urease will hydrolyze the ammonia, a primary constituent of urea into water and CO2. The labeled (either 13C or 14C) carbon atom is then exhaled in the breath and measured. Because of radioactivity risks, particularly in children, there are very few data on the use of 14C-labeled urea breath tests in the pediatric population. Although the UBT has been studied in children,9, 19, 20, 21, 22 its diagnostic ability, especially in those younger than 3 years of age, may be limited by several factors. For example, performance of the test requires some level of oral-pharyngeal coordination, with children being more likely to retain the compound in the oropharynx that also harbors urease-producing organisms, thereby producing false-positive test results. Being able to breathe into a straw may also affect the test reliability and accuracy. False-negative results may result in those who have recently taken gastric acid antisecretory agents, bismuth compounds, or antibiotic agents. Although the 13C-labeled UBT has been used in children and appears promising, reliability and determination of threshold values have not been adequately validated in multiple, large multicenter, randomized, controlled trials.23

Serology with immunoglobulin G (IgG) is widely used and is considered the first line of noninvasive diagnostic tests in adults, particularly in Europe, with suspected H pylori infection. Unfortunately, serology does not provide any data as to whether there is active or past infection. In addition, as with the UBT, serology cannot determine the current gastroduodenal pathology. Even in those treated and cured of their H pylori infection, evidence of IgG antibodies (ie, a positive serology) may exist for months and possibly years. Therefore, serologic assay is not appropriate for monitoring the effects of an anti–H pylori treatment regimen. The serologic assays also have varying levels of sensitivity and specificity when used in different populations, particularly in children, because of lack of validation of these assays in the population in which they are then used. Studies have observed sensitivities ranging from 54% to 94% and specificities between 59% and 97%.24 In children, serologic assay cutoff values (ie, differentiating between positive and negative serology) may be very different, compared with adults. Serologic titers in children do not appear to be related to the duration of infection and may not attain levels typically observed in an infected adult until the infected child reaches early adolescence.25, 26 To date, there are no validated commercial IgM or IgA serologic assays that are commercially available, and none of the commercially available IgG assays are approved for use in children. Salivary IgG tests are under investigation.27

The stool antigen test (polyclonal and monoclonal) for H pylori holds promise for the detection of infection in children as well as assessing cure. However, studies have found that the positive predictive values were 54%28 and 87%,29 which may limit the tests reliability. The negative predictive values of these stool antigen tests were high, 100% and 94.9%, respectively, as were the sensitivity (89% to 100%) and specificity (70% to 94%).20, 28, 29, 30, 31 Koletzko et al32 evaluated a monoclonal enzyme stool antigen assay in 302 children whose H pylori status was defined by results of culture, histology, the rapid urease test, and the 13C-urea breath test. The investigations found the stool antigen test to have high sensitivity (98%), specificity (99%), and positive (98%) and negative (99%) predictive values.

Until more reliable, validated, noninvasive tests are developed for use in children, the use of upper gastrointestinal endoscopy with gastric biopsy remains the diagnostic strategy of choice in those with suspected H pylori infection.33 Ou patient was scheduled for upper gastrointestinal endoscopy with gastric biopsy. On endoscopy and biopsy, he was found to have a duodenal ulcer, and antral biopsy specimens were positive for H pylori.

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Clinical complications of H pylori infection 

H pylori infection, which has a very narrow host range, colonizing and persisting in only the gastric mucosa, generally manifests as gastroduodenal disorders. These conditions include gastritis and peptic ulcer disease (primarily duodenal ulcers, and to a lesser extent gastric ulcers)—in which the ulcers are present as an infection sequelae in approximately 15% of those infected.34, 35, 36, 37 In addition, H pylori infection can result in atrophic corpus-predominant gastritis with and without intestinal metaplasia, which has been described in childhood.38 These lesions are precursors for neoplasia/dysplasia and have long been described in the natural history of gastric cancer development. Thus, the presence of these lesions increases the risk for gastric adenocarcinoma and gastric mucosa–associated lymphoid tissue lymphoma—affecting less than 1% and 0.1% of infected individuals, respectively.2, 34, 39, 40 Generally, these H pylori–related clinical diseases occur decades after the acquisition of infection.

Among children, the occurrence of H pylori–related gastroduodenal disorders such as gastritis and peptic ulcer disease have been observed as well as, albeit significantly less frequently, gastric atrophy and intestinal metaplasia.38 However, children infected with H pylori are at substantial risk for primary duodenal ulcer disease, with between 33% and 100% of children with duodenal ulcer disease found to harbor the bacterium.41 The causative role of H pylori in duodenal ulcer disease among children is supported by the finding of a low rate (<5% to 10%) of disease recurrence in children treated and cured of the bacterial infection.33, 41, 42

In addition to predisposing children to gastrointestinal diseases, H pylori has been observed in association with other clinically significant disorders, including growth retardation and anemia.43 An increasing body of literature44, 45, 46, 47, 48, 49, 50, 51 supports an association between H pylori infection and iron-deficiency (or sideropenic) anemia in children and adults. For example, among teenagers in South Korea, the relative risk of iron-deficiency anemia in those infected with H pylori was 2.9 (95% CI, 1.5 to 5.6), compared with children not infected with the bacterium.46 Treatment with iron supplementation produced no improvement in hemoglobin levels in those with persistent infection, whereas significant increases in hemoglobin, iron, and ferritin levels were observed in children who underwent H pylori treatment and cure.

The definitive mechanism(s) of iron deficiency anemia in those infected with H pylori is unclear. However, a number of biologically plausible causes have been postulated, including gastrointestinal blood loss, poor iron intake, iron malabsorption, or diversion of iron in the reticuloendothelial system.52 Some studies have suggested a bacteria-specific mechanism(s) of anemia. Theories include receptors on the outer membrane of H pylori organisms in the antrum acting as an iron sequestering focus that captures and utilizes iron for growth,52 infection-associated changes in either lactoferrin,50 or changes in intragastric pH that impair iron absorption.53

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Treatment of H pylori infection in children 

It is well established in the literature as well as in clinical practice that treatment of H pylori infection requires a combination of gastric acid antisecretory plus antimicrobial agents administered for 7 to 14 days. In adults infected with H pylori, the greatest rates of bacterial eradication, on the order of >80%, have been observed with triple and quadruple regimens. In children, several first-line regimen options, each administered for 14 days, have been recommended by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Table).33 Once treated and cured of H pylori, studies indicate that children are at low risk for reinfection.54

Table. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Statement: Recommended Regimens for Helicobacter pylori Treatment
First-line regimens, each agent administered twice-daily for 10 to 14 days
•Proton pump inhibitor (1-2 mg/kg/day) plus amoxicillin (50 mg/kg/day) plus clarithromycin (15 mg/kg/day)
•Proton pump inhibitor (1-2 mg/kg/day) plus amoxicillin (50 mg/kg/day) plus metronidazole (20 mg/kg/day)
•Proton pump inhibitor (1-2 mg/kg/day) plus metronidazole (20 mg/kg/day) plus clarithromycin (15 mg/kg/day)

Adapted from: Gold BD, Colletti RB, Abbott M, Czinn SJ, Elitwar Y, Hassall E, Macarthur C, Snyder J, Sherman PM. Helicobacter pylori infection in children: Recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr 2000;31:490-497.

Few clinical studies of cure rates with triple therapy regimens in children have been published in particular multicenter, randomized, placebo-controlled trials. In one of these, Gottrand et al55 randomly assigned 73 children with confirmed H pylori to 7 days of treatment with triple therapy (omeprazole, amoxicillin, and clarithromycin, n=31) or dual therapy (amoxicillin and clarithromycin, n=32). In analyses of the intent-to-treat and the per-protocol cohorts, significantly higher rates of H pylori cure (confirmed by UBT) were observed with triple therapy (74.2% and 80%) as compared with dual therapy (9.4% and 10.7%). The cure rates observed with triple therapy in this study are lower than clinically desirable and may have been influenced by the low duration of therapy (7 days instead of 14), the reliability of the UBT to assess eradication, compliance issues, or a combination of these factors.

Children with persistent H pylori despite treatment with a triple therapy regimen should be assessed for several predictors of treatment failure, in particular, treatment compliance. H pylori antimicrobial resistance is one the other top reasons for treatment failures and thus should also be considered in a child with persistent infection. Several studies observed treatment failure associated with H pylori resistance to either metronidazole or clarithromycin.55, 56, 57 Worldwide, the rates of clarithromycin resistance range from 0% to 20%, with much higher rates of resistance to metronidazole (on the order of 7% to 95%) being reported.58 Some studies report that H pylori resistance to metronidazole can be overcome despite conferring treatment failures of up to 37%, but that clarithromycin resistance is not only associated with treatment failures of >50%, but that resistance is then conferred to all of the macrolide antibiotics, thereby making these strains of H pylori very difficult to eradicate. Song et al57 reported that 19% of H pylori strains obtained in children were resistant to clarithromycin, 22% were resistant to metronidazole, and 11.6% (8/69) were resistant to both antimicrobial agents. This study demonstrated that H pylori strains isolated from children tend to have higher rates of resistance to clarithromycin overall and may in fact be more difficult to cure.

In a case such as our patient, particularly in a patient with H pylori infection complicated by duodenal ulcer, confirmation of cure may be desirable to allay parents' fear that the disorder will recur. Unfortunately, at present, the only reliable method to test for cure is repeat endoscopy. However, urea breath testing or stool antigen testing may have some value for posteradication “cure” confirmation. Because endoscopy is an invasive procedure, confirmation of H pylori eradication is generally not performed unless the child has a history of complications such as an ulcer. If endoscopy, UBT, or stool antigen testing is to be performed, it is best to wait at least 6 weeks and preferably 3 months after the completion of the triple-therapy regimen to improve the diagnostic value.

Children who retest positive for H pylori should be assessed for bacterial resistance, if a laboratory that has the expertise is available for the clinician. Retreatment should be initiated, using a regimen that does not include the antimicrobial agent with documented resistance. The need for good compliance and the use of the entire 14 days of the triple-therapy regimen should be reinforced. Alternatively, the use of proton pump inhibitor–based quadruple therapy or ranitidine-bismuth citrate–based triple-therapy regimen may be considered.56, 57, 58, 59

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Summary 

H pylori is an important human pathogen that is a significant source of gastroduodenal disease in adults as well as children. Overall, approximately one half of the world's population is infected with the bacterium, with acquisition of the infection commonly occurring before age 10 and in some developing populations before age 6 years. Person-to-person transmission occurs through several routes, oral-oral, gastric-oral, and fecal-oral, and may occur through contaminated water and/or air. Children living in low socioeconomic, crowded conditions with infected household members are at greatest risk of acquiring the infection and may transmit the infection to their siblings. Specific symptoms suggestive of H pylori infection are vague, inconsistent, and similar to several other more common childhood disorders, manifesting as recurrent abdominal pain, dyspepsia, or epigastric pain. Generally, one does not investigate for H pylori unless the child has symptoms suggestive of an ulcer. Although several noninvasive tests have been evaluated, endoscopy with gastric biopsy is, at present, considered the gold standard to confirming the diagnosis of H pylori. Despite the lack of clinical evidence, the clinical trend has been to more aggressively test children for the presence of H pylori and to treat those children who are found to have the infection. H pylori infection can be eradicated by antimicrobial therapy, but no treatment regimen is 100% effective, and the multiple drugs, frequent dosing, and length of treatment often contribute to poor patient compliance, and antibiotic eradication therapy is associated with increasing drug resistance.

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PII: S0022-3476(04)01192-8

doi:10.1016/j.jpeds.2004.11.037

The Journal of Pediatrics
Volume 146, Issue 3, Supplement , Pages S21-S26, March 2005

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