Helicobacter pylori is a Gram-negative spiral bacterium found in association with the gastric epithelium. It stays on the surface of the cells and does not invade them. In 1983, Warren and Marshall(1) discovered this organism and it has fulfilled Koch's postulation as a cause of chronic active gastritis in human(2). Since its discovery it has generated much interest among medical scientists. There were 8996 publications till April 1999 (on MEDLINE search) and even whole sections of gastroenterology journals like Gut, Gastroenterology etc. are being devoted exclusively to H. pylori for quite some years now. It has made a place for itself in the mainstream of modern medical practice. Though the infection begins in childhood, the literature and research on H. pylori in children is lagging behind as compared to that in adults. There are very few publications(3-7) on this from India. We have to rely mainly on Western literature to enrich our knowledge about H. pylori infection in children.

Epidemiology

It has been recognized that H. pylori, like most enteric infections, is mainly acquired in childhood. In India, like other developing countries, due to poor socio-economic status, poor hygiene and overcrowding the prevalence of H. pylori infection is very high. A study from Delhi in children(7) has shown that there is no correlation of these above mentioned factors and H. pylori infection, though the number of children (n = 31) was very small. In 1991, a study from Hyderabad(8) has shown that H. pylori infection increases with age and the prevalence reaches 84% by 20 years of age. IgG anti H. pylori antibody was assayed (by ELISA) in the serum of 238 individual ages 3 to 70 years. In the 3 to 10 years age group H. pylori positivity was 60%, in 11 to 15 years group 50% and in 16 to 20 years group 84%. In a similar study from Bombay in 1994(9), it has been shown that the prevalence of IgG antibody was 22%, 56% and 87% in 0-4, 5-9 and 10-19 years age group, respectively in 340 subjects. Another study from Bangalore(10) has detected H. pylori infection in 82% of 50 children (6-18 years) by ¹³C urea breath test. There are two studies in adults, one from Karnataka(11) and Allahabad(12) which have shown a 77.2% and 78% prevalence of H. pylori in adults. All these studies have shown that H. pylori infection is very common in India and most of our pediatric population is infected.

Infants (£1 year) are rarely infected in the developed world because of passively transferred immunity from the mother. In developing countries, however, H. pylori, like other enteric infections is common in infants also. In a study from Bangladesh, H. pylori infection has been shown in 41 of 90 (46%) infants aged 1-12 months(13).

Children acquire infection mainly through fecal-oral route as H. pylori has been cultured from the stool of infected children(14). Gastro-oral route of transmission is also recognized as regurgitation and vomiting are common in children. Other modes of transmission in children are contaminated water(15) and person to person transmission due to overcrowding. Recently a H. pylori, like organism has been isolated from drinking water(16). Another route is oro-oral (by kissing, premastication of food) as H. pylori has been cultured from dental plaques in 100% of healthy volunteers from India(17) and it is detected in 84% cases by PCR from saliva(18).

H. pylori is associated with gastritis, duodenal ulcer, gastric carcinoma and low grade MALT lymphoma. However, only 15% of infected persons develop peptic ulcer(19). Of those infected, who will develop disease (ulcer, cancer, lymphoma) is influenced by the viru-lence of the infecting H. pylori strain, and various host factors. Bacterial virulence factors are characteristically present in some bacteria which enable them to cause disease. It has been shown that virulence factors like vac A, cag A are present more frequently in those strains which are associated with peptic ulcer than those which are not. But except gastritis rest are rarely seen in children. H. pylori has been shown to be associated with duodenal ulcer disease in 90-100% cases in children(20) and duodenal ulcer is not so uncommon in the West. Seven of 19 H. pylori positive children had duodenal ulcer in a study(21). Similarly other workes(22) have shown that 23 of their 37 H. pylori positive children had duodenal ulcer. In our series(3) of 27 children only 1 had duodenal ulcer while others from India(4-7) did not encounter any case of duodenal ulcer. Though H. pylori infection is almost universal in our children and it is strongly associated with duodenal ulcer, the latter is rarely seen in our children. This may be due to several reasons. Firstly, though H. pylori produces gastritis in almost all patients, it takes several years (10 to 18 years)(23) to cause ulcer. Our children though infected early, probably develop ulcer in the late 2nd or 3rd decade when they are adults. The most plausible explanation has been given by Graham(24). He postulated that the main variable determining the outcome of H. pylori infection is the health of the stomach (ability to secrete acid) at the time of infection. If the acid secretion is low H. pylori produces more inflammation, which progress to corpus and subsequently atrophic gastritis. However, if the acid secretion is high it produces duodenal ulcer. Malnutrition and enteric infections which are widely prevalent in our children, give rise to low acid secretion and that may be the reason for the low incidence of ulcer disease in our children.

There is a lot of controversy about the association of H. pylori and recurrent abdominal pain (RAP). Before drawing any conclusion we should try to find out the answers of two important questions. Firstly, if H. pylori produces pain abdomen then it should be more prevalent in symptomatic than asymptomatic children. Secondly if it produces symptoms then after eradication symptoms should disappear and with relapse symptoms should reappear.

Table I summarizes the prevalence of H. pylori in RAP and control in various series. All these studies(5-7,25) have shown that there is no difference in the prevalence of H. pylori in RAP vs control. Reports of 110 children from Canada(27), 143 children from Belgium (28) and 945 children from Germany (29) have shown that there was no difference between the symptoms experienced by H. pylori infected and non-infected children. Drumm et al.(30) have shown that children with H. pylori gastritis alone continue to have symtoms, despite its eradication. Oderda et al.(31) treated H. pylori gastritis in ch ildren with RAP and showed that symptoms resolved in majority after eradication but symptoms recurred only in 13% children while H. pylori gastritis recurred in 73% children. All these studies suggest that H. pylori is not associated with any symptoms or RAP in children. But there are many proponents also(26,33). A study of 456 children has shown a high prevalence of H. pylori in RAP than in those without pain (17% vs 10%). Table I summarizes the results of treatment in H. pylori positive RAP. All these series (3,4,26) have shown a significant response to anti H. pylori treatment. At present it is difficult to say whether H. pylori is associated with RAP or not. But a recent meta-analysis(33) of 45 series of H. pylori in children has shown that H. pylori is not associated with RAP.

A recent study from Italy(34) has shown that H. pylori infection is associated with growth delay in older children. But we need more evidence atleast from our country where children acquire infection early to say whether H. pylori causes growth delay or not.

The various available diagnostic tests(35) are summarized in Table II. Endoscopic antral biopsy for rapid urease test, histology and culture are the gold standard in the diagnosis of H. pylori infection. But in children, we should have simple, noninvasive tests. These include serology, urea breath test, and PCR.

Serology is the simplest and most widely used diagnostic test. Since H. pylori is a chronic infection that usually does not resolve spontaneously, elevated IgG is taken as an indicator of active infection, unless the patient has been treated for H. pylori recently (2 years). The H. pylori specific serum IgG is highly specific (99%) and sensitive (96%) in detecting H. pylori infection in children(36). This test is not useful in assessing treatment efficacy as it takes 6 months or more for antibody levels to return to normal. Another disadvantage of serology is that it may be falsely negative in recently acquired infection (upto 60 days). It is important to note that ELISA assay used to diagnose H. pylori in children should be standardized using children’s sera of that country because children usually have low antibody titer as compared to adults. If we use an ELISA assay based on adult antibody levels, a significant (upto 20%)(37) number of children with H. pylori infection will not be detected.

Recently(38) it has been shown in 112 H. pylori positive children that saliva can be used to detect IgG antibody against H. pylori. It has got a sensitivity of 93% and specificity of 82%. If available commercially, it will prove very useful in children.

PCR has been used to detect H. pylori DNA in saliva of 88 H. pylori positive patients in a recent study(20) and was successful in detecting H. pylori DNA in 84% cases. This test can again be very useful in children.

13C and 14C urea breath tests (UBT) are non-invasive and simple techniques. Sensitivity and specificity of these tests are 100% and 98% respectively in diagnosing H. pylori in children(39). Another advantage of these tests is that they can be used for follow-up after H. pylori eradication. 13C has an added advantage of being a non-radioactive isotope. But the main disadvantage is non-availability of this facility in most of the developing countries. Recently, 13C UBT has been used in Bangalore to detect H. pylori prevalence in children. By modifying the collecting bag or using a syringe attached to an intranasal tube/prong this test can even be used in infants(13).

Table II - Available Diagnostic Tests

The aim of treatment of H. pylori infection in any clinical situation is eradication of bacterium from the foregut. Eradication is currently defined as negative tests for H. pylori at least 2 days after the end of antimicrobial therapy. The most reliable technique to document eradication is gastric biopsy for histology. The urea breath test is also a valid noninvasive method.

Treatment of H. pylori infection is difficult for two reasons. First, the bacterium lives below the gastric mucus adherent to gastric epithelium and access of antimicrobial drugs to this site is restricted, both from the lumen and from the gastric blood supply. Second, H. pylori may have acquired resistance to the commonly used antimicrobial agents, such as 5-nitroimidazoles (metronidazole, tinidazole) and macrolides (Clarithromycin). Pre-treatment metronidazole-resistant strains (MRS) of H. pylori are more common in countries like ours’ where these drugs are used quite frequently to treat diarrhea. Fortunately, MRS of H. pylori are less common in children. Because of these reasons various combination (dual, triple or quadruple) of drugs are used to eradicate H. pylori.

Whom to treat? Mere isolation or detection of H. pylori does not merit treatment. Duodenal ulcer disease is a definite indication for treatment. The majority of our children present

with pain abdomen. Should we treat these children? Though Kumar et al.(5) have shown that 10 of 12 children (85%) improved on triple therapy, other studies have shown that following H. pylori eradication, Symptoms resolve in those children who had H. pylori gastritis with duodenal ulcer only and there was no change of symptoms in children with H. pylori gastritis alone(22,31). Moreover recurrence of H. pylori in children after eradication is 18% per year(40) and it may be higher in our children. At present the data is inconclusive regarding this issue and probably children with refractory symptoms (failed acid blockade therapy) and documented H. pylori infection with histopathological findings (chronic-active gastritis) may be treated.

Epidemiological studies have suggested a strong association between H. pylori infection and the subsequent development of gastric cancer. This has resulted in H. pylori being considered a group 1 carcinogen by WHO(41). It may soon be necessary to consider treating all children with H. pylori infection to prevent gastric carcinoma. Fortunately though H. pylori infection is almost universal in India the incidence of gastric carcinoma is low.

Drugs used in the treatment of H. pylori are summarized in Table III and various regimes used in children in Table IV(32,42–51). Previous regimes were with one or two drugs (for 4-6 wks period) and H. pylori eradication ranged from 27 to 94% using amoxycillin, amoxycillin and tinidazole or bismuth sub-salicylate and amoxycillin(47). With this prolonged therapy compliance goes down (upto 26% noncompliance)(51) and this may lead to failure of treatment and development of resistance. Shorter therapeutic regimens such as amoxycillin and omeprazole for 14 days have resulted in only 25% eradication in children despite full compliance(52). Two weeks therapy with metronidazole, omeprazole and clarithro-mycin resulted in 93% eradication(47). More recently, a 1 week treatment regimen of colloid bismuth subcitrate, clarithromycin and metro-nidazole eradicated H. pylori in 21 out of 22 (95.5%) children(48). Kumar et al.(5) used colloid bismuth subcitrate, amoxycillin and metronidazole for 2 weeks and achieved eradication in 71% children. Proton pump inhibitors and recently introduced ranitidine bismuth citrate are widely used in treatment regimes in adults but as yet, there is not much information on their utility in children.

At present the best available regime is a PPI (Proton pump inhibitor e.g., Omeprazole; lansoprazole; Pantoprazole) in combination with clarithromycin and either amoxycillin or metronidazole for 1 week. A second line regime of a week’s treatment with PPI, amoxycillin and metronidazole has been shown to eradicate H. pylori in over 75% of the first line failures(53). Quadruple therapy is best reserved as a third line. Inexpensive therapy comprises of fura-zolidone and bismuth subsalicylate for 4 weeks with an eradication rate of 72%(54).

Table III - Drugs Used in the Treatment of H. pylori Infection in Children

Table IV - Different Anti H. pylori Regimes

H. pylori infection can be prevented by in terrupting the transmission of the infection by improving environment, socioeconomic status and personal hygiene. It has been shown convincingly that with the improvement of socioeconomic status in developed countries H. pylori infection has gone down by 50% over the last 3 decades(55). In a country like ours where it is difficult to change the socio-economic status, the best way to prevent this infection is to vaccinate all children. Extensive efforts in many laboratories are currently under way worldwide to develop a vaccine. Recently in a mouse model it has been demonstrated that oral immunization with a crude lysate of H. felis induced protection against gastric infection by H. pylori(56). Further studies have shown that superficial gastric ulcers in a mouse model infected with H. pylori can be prevented by the administration of a recombinant oral vaccine with E. coli heat labile toxin (LT) given as adjuvant(57). A human trial(58) has aleady been conducted with recombinant oral H. pylori vaccine using urease as antigen with some success. We hope that in the near future we shall be able to eradicate and prevent H. pylori more effectively with the vaccine.

Contributors: UP conceived and drafted the article. BRT co-drafted the article.
Funding : None.
Competing interests: None state.

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