Clinical significance of Helicobacter infection in children

Clinical significance of Helicobacter infection in children Marion Rowland and Brendan Drumm Department of Paediatrics, University College Dublin, Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland Helicobacter pylori infection of the gastric mucosa causes chronic gastritis and is associated with peptic ulcer disease and gastric carcinoma. These are conditions which usually occur in adult life. However, H. pylori is an infection which is mainly acquired in childhood. The overall prevalence of H. pylori in children is 10% in developed countries but can be as high as 30-40% in children from lower socio-economic groups. In developing countries, the prevalence of H. pylori in children ranges from 80-100%. H. pylori gastritis does not appear to be associated with symptoms in children in the absence of duodenal ulcer disease. H. pylori infection is present in the vast majority of children with duodenal ulcer disease and, as in adults, eradication of the organism results in long-term healing of duodenal ulceration. H. pylori infection acquired in childhood is now considered to be a significant risk factor for the development of gastric carcinoma. The World Health Organization has classified H. pylori as a Group 1 carcinogen. Specific epidemiological questions which need to be answered in children include the age at which infection is acquired, specific risk factors for infection, the mode of transmission and the risk of reinfection following treatment. Recently, a one week treatment regimen using colloidal bismuth subcitrate, metronidazole and clarithromycin has been shown to be effective in treating children, but compliance is important. Currently there are no guidelines on the need to treat children and a consensus is urgently required on this issue. Correspondence to: Dr Marion Rowland, Department of Paediatrics, University College Dublin, Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland H. pylori is a Gram-negative spiral-shaped organism which is found within and beneath the mucous layer of the gastric epithelium 1 " 5. Colonisation of the gastric mucosa by H. pylori is associated with histological evidence of gastritis in adults and children 1 " 5. H. pylori is not an opportunistic coloniser of inflamed gastric tissue. Children with secondary gastritis due to Crohn's disease or eosinophilic gastritis are not colonised by H. pylori 3. In contrast, the majority of children with primary gastritis are colonised by the organism 3. The mucosal inflammatory infiltrate in children with H. pylori is different from that in adults, but is identical to that which occurs in animal models of Helicobacter infection. British Medical Bulletin 1998,54 (No. 1): 95-103 C The British Council 1998

Helicobacter infection In children, there is predominantly a lymphocytic and plasma cell infiltrate with few neutrophils present 5. Epidemiology It has recently been recognised that H. pylori, like most enteric infections, is mainly acquired in childhood 3 ' 4-6 " 8. Adults rarely become infected with seroconversion rates varying between 0.33-0.5% per person year 7-8. The prevalence of infection increases with age from 10% at age 10 to 60% at age 60 in developed countries 3 * 4. The high prevalence seen in older age groups is consistent with a cohort phenomena, whereby infected adults acquired the infection as children 6-8 and infection is usually lifelong unless treated. As socio-economic conditions have improved in successive generations in the developed world, the prevalence of H. pylori has decreased. In developing countries, up to 100% of children are infected by 10 years of age 3-4. Cross sectional studies in developing countries indicate that young children are the group who become infected. Ethiopian children appear to become infected between 2 and 4 years of age with 60% of 4 year olds being infected 9. A study from Peru suggests that children are most likely to become infected between 18 and 30 months in developing countries 10. In contrast, the rate of acquisition of H. pylori infection in children over 5 years of age in a large Chinese study was 1% per year which was similar to the rate of acquisition of infection in adults 11. While, overall, only 10% of all children under the age of 10 years in developed countries are infected, the prevalence of infection is much greater among children in socially deprived families 3 ' 4. The presence of poor socio-economic conditions in childhood is a major risk factor for infection 3-4. Close personal contact, such as sharing a bed in childhood, may be important. However, it is difficult to separate overcrowding from poor sanitation, large sibships and bed sharing. In a US study, 30% of 3-5 year-olds and almost 50% of 6-10 year-olds in the lowest income group were infected 12. A recent study from Belfast found that 30% of children between 4 and 13 years of age, attending hospital for routine day case surgery, were seropositive for H. pylori with 32% of 6-7 yearolds being infected 13. In London, 23% of a group of 5 year-old school children were infected with H. pylori and there was only a very small increase in prevalence in the 8 year-old age group, suggesting that children had acquired the infection prior to school entry 14. Children under the age of 1 year rarely become infected in developed countries, even when exposed to infected mothers 15. Many groups have reported a high prevalence of H. pylori-speciiic IgG antibodies in the 96 British Medial Bulletin 1998;54 (No. 1)

Clinical significance of Helicobacter infection in children first 6 months of life which subsequently decline by 12 months 15. This represents maternal transfer of H. pylori specific antibodies to the fetus. There is no known natural reservoir of H. pylori. The mode of transmission is not known but this may be because most of the epidemiological studies have focused on adults who rarely become infected. There is marked clustering of infection among children within families 2 "*, and this has also been reported within institutions for mentally handicapped children 2-3. Person-to-person transmission, therefore, appears to be important, but it is not known if this is predominantly adult-to-child or child-to-child transmission. Faecal-oral transmission has been suggested, but difficulty in culturing H. pylori from faeces has greatly hampered investigation of faecal oral transmission 15. Oral-oral transmission may be possible, as H. pylori has on one occasion been cultured from saliva 15. Gastric-oral transmission has been postulated and, in children where reflux and vomiting are common, this mode of transmission requires further study. Reinfection following successful treatment of H. pylori is uncommon in adults in developed countries, ranging from 0.62% to 1.2% 15 annually. As infection occurs predominantly in children, the low reinfection rate in adults in developed countries is not surprising. Reinfection of children who have been successfully treated is much more likely as this is the group who acquire primary infection. Studies of children are necessary in order to assess accurately the risk of reinfection following treatment. This will help to determine if a vaccine is necessary or if antibiotic treatment is likely to be sufficient to eradicate H. pylori in the community. Duodenal ulcer disease Duodenal ulcer disease is associated with chronic gastritis and H. pylori is present on the gastric mucosa of almost all adults and children with duodenal ulcer disease 1 " 5. However, most people who are infected with H. pylori will not develop a duodenal ulcer. H. pylori will only colonise gastric mucosa and, therefore, its association with duodenal ulcer disease appears paradoxical. It has been hypothesised that H. pylori colonises areas of gastric metaplasia in the duodenum. In children, it has been shown that H. pylori infection of the antral mucosa and gastric metaplasia in the duodenum are independent risk factors for duodenal ulceration 16-17. However, the co-existence in an individual of both H. pylori and gastric metaplasia results in a greatly increased risk of duodenal disease 17. Eradication of the organism from the gastric mucosa leads to long term healing of duodenal ulcer disease in children 3-4 as in adults 1. British Medical Bulletin 1998;54 (No. 1) 97

Helicobacter infection Gastric cancer Symptoms in children H. pylori has been classified as a Group 1 carcinogen by the World Health Organization 18. The relative risk of gastric carcinoma is 2.3-8.7 times greater in infected adults compared to uninfected controls 19. The incidence of gastric cancer has decreased markedly over the past 30 years in developed countries, as has the prevalence of H. pylori gastritis 8 ' 19. Gastric cancer appears to be the end result of a progression from gastritis to gastric atrophy, intestinal metaplasia and dysplasia 19. Development of gastric atrophy is probably not the direct result of ageing, but the result of infection with H. pylori 20. Infection of the gastric mucosa in childhood may be a particular risk factor for the development of gastric carcinoma in adult life 21 ' 22. Strategies for the prevention of gastric cancer based on H. pylori eradication in adults are unlikely to be effective because of the long duration of infection in most adults. The prevention of infection in children would be a much more effective approach if this were possible. There is no significant evidence that H. pylori gastritis in the absence of duodenal ulcer disease is a cause of symptoms in children. H. pylori infection occurs frequently in asymptomatic children 2 "*' 12 " 14 ' 25 * 25. The clustering of H. pylori infection within families and the very high prevalence in underdeveloped countries also suggest that the infection is not associated with specific symptoms 2 " 4. In a recent meta-analysis, McArthur et al found that recurrent abdominal pain is not associated with an increased prevalence of H. pylori associated gastritis 23. H. pylori infected children cannot be differentiated from those who are not infected on the basis of their presenting symptoms 24. Furthermore H. pylori eradication was associated with an improvement in symptoms only in children who had duodenal ulcer disease but not in those with gastritis alone 25. This implies that the effect of H. pylori eradication on symptoms in these children relates to healing of duodenal ulcer disease rather than clearing of gastritis. Diagnosis of H. Pylori in children Endoscopy Upper gastrointestinal endoscopy and biopsy of the gastric mucosa has, until recently, been the investigation of choice for the diagnosis of H. 98 British Medical Bulletin 1998;54 (No. 1)

Clinical significance of Helicobacter infection in children pylori infection in children. The stomach is often reported as macroscopically normal in cases of H. pylori associated gastritis. More recently, a nodularity of the antral mucosa has been described in the majority of children with H. pylori gastritis 5. These nodules give the antrum a cobblestone appearance. This appearance is not usually seen in adults with H. pylori gastritis. The reason for this appearance of the gastric mucosa in association with H. pylori in children is unknown. Biopsies obtained from the gastric mucosa at endoscopy can be assessed for H. pylori infection by culture, histological examination and urease testing. Culture Culture of an antral biopsy is considered as the gold standard to confirm the presence of H. pylori on the gastric mucosa. However, it must be stressed that a very small number of colonies may be present on plates when gastric biopsies from children are cultured as compared to adults. Biopsy specimens may be cultured on Columbia blood agar (GEBCO) plates containing 7% (v/v) dehbrinated horse blood in an atmosphere of 5% O 2 and 10% CO r Organisms can then be identified as H. pylori on the basis of colony morphology, Gram stain, and the production of urease, oxidase and catalase. Histology Because of the characteristic appearance and unique location of H. pylori on the gastric mucosa, a presumptive diagnosis of H. pylori can be made by identifying spiral shaped organisms on gastric sections. The Warthin Starry silver stain is 100% sensitive and specific 3. A modified Giemsa stain is less expensive and easier to perform than the Warthin Starry silver stain and is also very sensitive in identifying H. pylori 3. Urease test As H. pylori produces high levels of the enzyme urease, this property can be used to screen for the presence of bacteria in antral biopsy specimens. In some children, because of the reduced number of bacteria, the colour reaction may take up to 24 h, and, on occasion, rapid urease tests have not been as sensitive as in adults 3-4. When a full biopsy specimen is placed in the urea medium, as against a fragment of the biopsy, the sensitivity of this test increases and is close to 100% 3. Serology The H. pylori specific serum IgG response has been reported as highly specific (99%) and sensitive (96%) in detecting children with H. pylori British Medial Bulletin 1998;54 (No. 1) 99

Helicobacter infection colonisation of the gastric antrum 3-4. This sensitivity and specificity varies considerably, however, depending on the assay employed 2 ' 15 * 26. It is important that ELISA assays used to diagnose H. pylori colonisation in children are standardised using children's sera. A positive serological response using an ELISA assay is generally defined as an optical density greater than 2 standard deviations above the mean value obtained for non colonised individuals. This cut off point is higher in adults than in children. If the assay is based on adult antibody levels, a significant number of children colonised with H. pylori will not be detected. Crabtree et ap 6 found that a H. pylori specific serum IgG assay based on adult cut off values was less than 50% sensitive in identifying colonised children. More recently, second generation serological tests have failed to diagnose up to 20% of children under 10 years of age 27. The mean antibody level in infected Chilean children under 10 years of age is significantly lower than infected children over 10 years of age 28. Furthermore, the pattern of serological response differs according to the antigen used and may take up to 60 days to develop in children 29. Following treatment for H. pylori infection, antibody levels may take 6 months or longer to return to normal in adults, and there is no data on serology testing in children following treatment. Measurement of H. pylori specific serum IgM and IgA antibodies in children are not a sensitive indicator of gastric colonisation 3. P 3 CJ-urea breath test The [ 13 C]-urea breath test (UBT) is an non-invasive test for the diagnosis of H. pylori infection. It is based on the fact that H. pylori produces large amounts of urease. When labelled urea is given to a patient who is infected with H. pylori, the urease enzyme splits the urea into ammonia and labelled carbon dioxide which can be measured in the expired breath. This test has been shown to be safe and highly sensitive and specific for the diagnosis of H. pylori infection in adults 30. It is also accurate in determining the success of treatment in eradicating H. pylori 30. The UBT has recently been shown to be 100% sensitive and 97.6% specific in the diagnosis of H. pylori infection in children 31. More importantly in terms of its use in children, a two hour fast is sufficient in this age group, and a test meal is not required. In fact a test meal may interfere with the sensitivity of the test in children. The UBT is also 100% sensitive and specific in children following treatment for H. pylori infection, and can easily replace the need for follow-up endoscopy in these children. 100 British Medical Bulletin 1998,54 (No. 1)

Clinical significance of Helicobacter infection in children Treatment in children In children, standard therapy has consisted of a bismuth containing preparation combined with one antibiotic for periods of 2-6 weeks 3. Compliance is a very important factor in achieving high eradication rates in children 32 * 33. The long duration of treatment, and the strong taste of ammonia which is associated with liquid bismuth, may reduce compliance. A combination of bismuth and amoxycillin eradicated H. pylori in approximately 70% of cases 15, while Gormally et ol eradicated the organism in 84% using metronidazole and bismuth for 2 weeks 17. More recently, a 1 week treatment regimen of colloidal bismuth subcitrate 480 mg/1.73 m 2 /day (maximum 120 mg qid), clarithromycin 7.5 mg/kg/day (maximum 250 bd), and metronidazole 20 mg/kg/day (maximum 200 mg tds) eradicated H. pylori in 21 out of 22 children - 95.5% {95% CI: 77-100%) 33. Only 2 children had significant side effects of diarrhoea and vomiting. The shorter duration of treatment probably improved compliance as did the use of a Redidose Box (Redidose Company, Evolution Health Centre, 2 Sillwood Terrace, Brighton BN1 2LR, UK) with individual compartments for each dose of medication. It is questionable if this level of compliance could be achieved in routine practice and the effectiveness of a 1 week regimen needs to be assessed under such circumstances. Metronidazole resistance in an increasing problem in adults but is less common in children. However, it can occur and further studies are required in children of treatment regimens which do not include metronidazole. While concern has been expressed about the use of bismuth salts in children, none of the potential toxic side effects have been reported in children treated for H. pylori infection 3. Proton pump inhibitors are widely used in treatment regimens in adults but, as yet, there is no information on their usefulness in children. The National Institutes of Health consensus statement recommends that adults with gastric or duodenal ulcer disease who are infected with H. pylori should receive antimicrobial treatment for this infection 34. In children, long term remission of duodenal ulcer disease can also be achieved with antimicrobial regimens which eradicate H. pylori 3>Ai2. The necessity to treat H. pylori infection in the absence of duodenal ulcer disease in children is controversial. In the past, there has been no evidence to suggest that it is necessary to treat children with H. pylori infection in the absence of duodenal disease as H. pylori associated gastritis does not appear to be a cause of symptoms. This situation will have to be reviewed as evidence supporting an association between H. pylori infection and gastric carcinoma increases. Treatment of children may be the most cost effective method of reducing the prevalence of infection and the morbidity and mortality associated with H. pylori infection. British Medical Bulletin 1998;54 (No. 1) 101

Helicobacter infection Conclusion H. pylori is an infection which is acquired in childhood with the major risk factor for infection being poor socio-economic conditions. H. pylori gastritis alone is not a cause of symptoms in children. Duodenal ulcer disease in children is nearly always associated with H. pylori infection and long term healing of duodenal ulcers can be achieved by eradication of the organism. Recent studies indicate a strong association between H. pylori infection acquired during childhood and the development of gastric carcinoma in adult life. However, there are no guidelines at present in relation to the need to treat H. pylori in children, and it is vital that a consensus is achieved on this issue. References 1 Peterson WL. HelicobacUr pylori and peptic ulcer disease. N Engl J Med 1991; 324: 1043-8 2 Drumm B, Perez-Perez GI, Blaser MJ, Sherman PM. Imrafamihal clustering of Helicobacter pylori infection. N Engl J Med 1990; 322: 359-63 3 Drumm B. Helicobacter pylori in the pediatric patient. Gastroenterol Clin North Am 1993; 22: 169-82 4 Bourke B, Jones N, Sherman PM. Helicobacter pylori infection and peptic ulcer disease in children. Pediatr Infect Dis J 1996: 15: 1-13 5 Hassall E, Dimmick JE. Unique features of Helicobacter pylori disease in children. Dig Dis Sci 1991; 36: 417-23 6 Banatvala N, Mayo K, Megraud F, Jennings R, Decks JJ, Feldman RA. The cohort effect and Helicobacter pylori. J Infect Dis 1993; 168: 219-21 7 Parsonnet J, Blaser MJ, Perez-Perez GI, Hargrett-Bean N, Tauxe RV. Symptoms and risk factors of Helicobacter pylori infection in a cohort of epidemiologists. Gastroenterology 1992; 102: 41-6 8 Cullen DJE, Collins BJ, Christiansen KJ et al. When is Helicobacter pylori infection acquired? Gut 1993; 34: 1681-2 9 Lindkvist P, Asrat D, Nilsson I et al. Age at acquisition of Helicobacter pylori infection: comparison of a high and a low prevalence country. Scand] Infect Dis 1996; 28: 181 4 10 Klein PD, Gilman RH, Leon-Barua R et al. The epidemiology of Helicobacter pylori in Peruvian children between 6 and 30 months of age. Am J Gastroenterol 1994; 89: 2196-200 11 Mitchell HM, Li YY, Hu PJ et al. Epidemiology of Helicobacter pylori in Southern China: identification of early childhood as a critical period for acquisition. / Infect Dis 1992; 166: 149-53 12 Fiedorek SC, Malaty HM, Evans DL et al. Factors influencing the epidemiology of Helicobacter pylori infection in children. Pediatrics 1991; 88: 578-82 13 McCallion WA, Ardill JE, Bamford KB, Potts SR, Boston VE. Age dependant hypergastrinaemia in children with Helicobacter pylori gastritis - evidence of early acquisition of infection. Gut 1995; 37: 35-8 14 O'Donohoe JM, Sullivan PB, Scott R, Rogers T, Brueton MJ, Barltrop D. Recurrent abdominal pain and Helicobacter pylori in-a community-based sample of London children. Acta Paedtatr 1996; 85: 961-4 15 Rowland M, Drumm B. Helicobacter pylori infection and peptic ulcer disease in children. Curr Opin Pediatr 1995; 7: 553-9 16 Shabib S, Cutz E, Drumm B, Sherman P. Helicobacter pylori infection is associated with gastric metaplasia in the duodenum. Am] Clin Pathol 1994; 102: 188-91 17 Gormally SM, Kierse B, Daly L, Bourke W, Durnin M, Drumm B. Gastric metaplasia and duodenal ulcer disease in children. Gut 1996; 38: 513-7 102 British Medical Bulletin 1998;54 (No. 1)

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