OVERVIEW: What every practitioner needs to know

Are you sure your patient has infection? What are the typical findings for this disease?

The most common symptoms of infection with Helicobacter pylori are recent onset of epigastric pain (0.5-3 months’ duration) and unspecified abdominal pain with no clear evidence for an association between H. pylori infection and recurrent abdominal pain in children.

There have been several case reports of children with refractory anemia responding to treatment after eradication of H. pylori.

What other disease/condition shares some of these symptoms?

Abdominal pain due to H. pylori infection must be distinguished from other causes of gastritis, such as the following:

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  • Chemical gastritis from nonsteroidal antiinflammatory medications

  • Gastritis due to infectious causes

  • Other inflammatory causes such as eosinophilic gastroenteropathy

  • Gastroesophageal reflux with esophagitis

  • Inflammatory bowel disease with upper gastrointestinal (GI) tract involvement

  • Pancreatitis

What caused this disease to develop at this time?

H. pylori infection is usually acquired during childhood, frequently in children younger than 5 years of age.

A major risk factor for infection is poor socioeconomic status. Eighty percent of children in developing countries have evidence of previous infection, with increasing prevalence of infection with age.

Humans are the only known reservoir. Transmission is likely person to person through the fecal-oral, oral-oral, or gastric-oral route.

Postulated bacterial virulence factors include motility, adherence to the gastric mucosa, urease activity, toxin production, and impairment of host cell signal transduction.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Upper GI endoscopy is the investigation of choice for the diagnosis, with nodularity of the antral mucosa frequently reported.

The 13C urea breath test is a safe and noninvasive method for detection of H. pylori infection but is problematic in children less than 2 years of age because of technical issues associated with sample collection.

Serologic tests do not have the sensitivity and specificity to accurately diagnose active H. pylori infection in children less than 12 years of age.

Fecal H. pylori antigen testing using a monoclonal antibody assay has very good sensitivity (98%), specificity (99%), positive predictive value (98%), and negative predictive value (99%). Of note, no data are available for children younger than 2 years of age.

Would imaging studies be helpful? If so, which ones?

Imaging studies might be helpful if clinically warranted to evaluate for other causes of abdominal pain such as pancreatitis, hiatal hernia/malrotation, or constipation.

If you are able to confirm that the patient has infection, what treatment should be initiated?

Several treatment regimens are used to treat H. pylori infection in children. The following is from The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Position Statement: Recommended Regimens for Helicobacter pylori treatment (2000). Additional probiotics are thought to be beneficial.

First line regimens: each administered twice daily for 10 to 14 days:

  • Regimen 1: proton pump inhibitor (1-2 mg/kg/d) plus amoxicillin (50 mg/kg/d) plus clarithromycin (15 mg/kg d)

  • Regimen 2: proton pump inhibitor (1-2 mg/kg/d) plus amoxicillin (50 mg/kg/d) plus metronidazole (20 mg/kg/d)

  • Regimen 3: proton pump inhibitor (1-2 mg/kg/d) plus metronidazole (20 mg/kg/d) plus clarithromycin (15 mg/kg/d)

What are the adverse effects associated with each treatment option?

Proton pump inhibitors: Adverse effects are generally rare. Atrophic gastritis or osteoporosis-related bone fracture (of the hip, wrist, or spine) may occur with proton pump inhibitor use; the risk is increased with higher dose (multiple daily doses) and/or longer duration of use (1 year or longer). Hypomagnesemia has been reported with prolonged administration. Concomitant use of drugs that cause hypomagnesemia may increase this risk, and monitoring of magnesemia is recommended; discontinuation may be necessary.

Amoxicillin: Adverse effects other than self-limited diarrhea are relatively uncommon. Patients with hypersensitivity to cephalosporins have some risk of cross-sensitivity reactions. Ampicillin-class antibiotics should be avoided in patients with mononucleosis. Of note for patients with phenylketonuria, Amoxil(R) 200 mg and 400 mg chewable tablets contain phenylalanine.

Clarithromycin: This drug is contraindicated with certain medications such as cisapride, terfenadine, ergotamine, dihydroergotamine, among others. Potential for drug interactions with several agents. There is some risk for the development of pseudomembranous colitis during treatment. Potential problems with acute porphyria can occur when used with ranitidine and bismuth preparations. Dosage adjustment is required in the setting of severe renal impairment.

Metronidazole: Ethanol use during or for at least 3 days after metronidazole is discontinued is contraindicated. Use of metronidazole within 2 weeks of use of disulfiram is contraindicated. If there is a history of hypersensitivity to metronidazole, it should not be used. It is also contraindicated during the first trimester of pregnancy. Dose adjustment may be required in the setting of severe hepatic disease. Aseptic meningitis has been reported with oral use, and metronidazole should be discontinued if neurologic signs occur. Blood dyscrasia, including mild leukopenia, has been reported. Peripheral neuropathy, including optic neuropathy and convulsive seizures, has been reported with oral use.

What are the possible outcomes of infection?

Numerous factors contribute to treatment failure, including poor patient compliance, suboptimal drug delivery, and antimicrobial resistance. Previous studies have noted decreased rates of bacterial clearance with consumption of less than 75% of the prescribed medication. Resistance to metronidazole ranges from 20%-50% in the United States and Australia.

There is a higher prevalence of resistant strains in women, potentially due to previous treatment exposure for gynecologic issues. Clarithromycin resistance has arisen because of emergence of point mutations in two ribosomal RNA genes of H. pylori. The rates of clarithromycin resistance among children may be increasing; data show increasing population trends for resistance from 4%-18% over a few years.

Current treatment regimens fail to eradicate H. pylori infection in 5%-30% of children. For those with refractory disease, there are a few other regimens available that the family can discuss with the child’s pediatric gastroenterologist.

H. pylori has been implicated in the pathogenesis of mucosa-associated lymphoid tissue lymphomas of the stomach (MALT lymphomas). Eradication of H. pylori results in complete resolution of 75% of MALT lymphomas. A few cases of MALT lymphoma have been reported during childhood.

What causes this disease and how frequent is it?

H. pylori is an enteric infection usually acquired in children younger than the age of 5 years. Without treatment, the infection is usually lifelong. Infection is more prevalent in men than in women.

The bacterium is acquired through person-to person transmission. Humans are the only known reservoir. H. pylori has been cultured from stool, saliva, dental plaque, and gastric-oral secretions in children with reflux and regurgitation. H. pylori has also been cultured from waste water in Mexico and has been found on the bodies of houseflies.

The major risk factor for infection is low socioeconomic status with associated risk factors that include bed sharing and large sibships.

Cytotoxin associated gene (CagA) has been identified as a marker for more virulent strains. In children, duodenal ulcer disease has been associated with cagE-positive strains.

Oral vaccines against H. pylori are currently under development.

How do these pathogens cause the disease?

Acute infection causes hypochlorhydria, which can continue for several months. Acute hypochlorhydria may augment transmission of the disease. During infection, a strong host response arises, but long-term infection frequently occurs despite the vigorous response. Postulated mechanisms of host defense evasion during H. pylori infection include subversion of phagocytosis and induction of ineffective T-cell response.

What complications might you expect from the disease or treatment of the disease?

H. pylori has been implicated in the pathogenesis of the development of MALT lymphomas of the stomach. Eradication of H. pylori results in complete resolution of 75% of MALT lymphomas. A few cases of MALT lymphoma have been reported during childhood.

How can this disease be prevented?

The major risk factor for infection is low socioeconomic status, with associated risk factors that include bed sharing and large sibships.

What is the evidence?

Li, S,, Huang, XL,, Sui, JZ,, Chen, SY. “Meta-analysis of randomized controlled trials on the efficacy of probiotics in Helicobacter pylori eradication therapy in children.”. Eur J Pediatr. vol. 173. 2014. pp. 153-61.

Zeng, M,, Mao, XH,, Li, JX,, Tong, WD. “Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial.”. Lancet. vol. 386. 10. pp. 1457-64.

Spee, LAA,, Madderom, MB,, Pijpers, J. “Association between Helicobacter pylori and gastrointestinal symptoms in children.”. Pediatrics. vol. 125. 2010. pp. e651-69.

Ashorn, M,, Ruuska, T,, Mäkipernaa, A.. “Helicobacter pylori and iron deficiency anaemia in children”. Scand J Gastroenterol. vol. 36. 2001. pp. 701-5.

Malaty, HM,, El-Kasabany, A,, Graham, DY. “Age at acquisition of Helicobacter pylori infection: a follow-up study from infancy to childhood.”. Lancet. vol. 359. 2002. pp. 931-5.

Bourke, B,, Jones, N,, Sherman,, P. “Helicobacter pylori and peptic ulcer disease in children.”. Pediatr Infect Dis J. vol. 15. 1996. pp. 1-13.

Czinn, SJ. “Serodiagnosis of Helicobacter pylori in pediatric patients”. J Pediatr Gastroenterol Nutr. vol. 28. 1999. pp. 132-4.

Hassall, E,, Macarthur, C,, Snyder, J. “Helicobacter pylori infection in children: recommendations for diagnosis and treatment”. J Pediatr Gastroenterol Nutr. vol. 31. 2000. pp. 490-7.

Graham, DY. “Antibiotic resistance in : implications for therapy.”. Gastroenterology. vol. 115. 1998. pp. 1272-7.

Du, MQ,, Isaaccson, PG. “Gastric MALT lymphoma: from aetiology to treatment.”. Lancet Oncol. vol. 3. 2002. pp. 97-104.

Bourke, B,, Jones, NL. “Pathogenesis of infection.”. Curr Opin Gastroenterol. vol. 17. 2001. pp. 24-9.

Shan, Li,, Xiu-li, Huang,, Jing-zhe, Sui. “Meta-analysis of randomized controlled trials on the efficacy of probiotics in Helicobacter pylori eradication therapy in children.”. Eur J Pediatr. vol. 173. 2014. pp. 153-161.