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This article summarises the epidemiology and pathophysiology of Helicobacter pylori related disease in childhood, to enable the general paediatrician to develop an informed and evidence based approach to management.
H pylori is a unique bacterial pathogen:
it is widespread, so that around 50% of people throughout the world are colonised
it occupies an inhospitable niche (H pylori survives gastric acidity even down to pH of < 2)
colonisation is chronic and may be lifelong.
H pylori was first conclusively identified as a human pathogen, and an aetiological agent of acute gastritis, in 1984.1 The discovery that this bacterium is the cause of most peptic ulcer related disease in adult life has been arguably the most important advance in gastroenterology in recent decades. Approximately 0.5% of the UK population (around 290 thousand people, 20% of all general practice workload) are on long term acid suppression because of peptic ulcer related disease attributable to chronic H pylori infection.
H pylori are Gram negative spiral organisms (fig 1) that live within and beneath the mucus layer of the human stomach. They do not invade the host and can only survive adherent to gastric type mucosa. H pylori utilises a urea splitting enzyme (urease) to neutralise gastric acidity, as it traverses the gastric lumen. Urease negative mutants do not readily colonise animal models of infection.2
Two complete genomes for H pylori have been described.3,4 Among the genes that have excited considerable interest (which include BabA, IceA, neutrophil activating protein, and various flagella and heat shock proteins) are two principle virulence determinants known to play a role in disease causation; the cag pathogenicity island (CagA PAI which codes for several genes including cagA) and vacA (coding for vacuolating cytotoxin A). Most isolates from patients with gastroduodenal disease from industrialised countries carry the cag PAI, while many strains from subjects with more benign colonisation do not. Approximately 26 kb of the 40 kb cag PAI encode components of a type IV secretion complex, which mediates translocation of CagA protein. This targets epithelial cells, where it is tyrosine phosphorylated, interacts with host regulatory factors, and disrupts cell signalling.5 The type IV secretion complex also induces cytokine IL-8 (also known as chemokine CXCL-8) synthesis.6 Despite being separated by a significant distance on the H pylori genome, there is an association between cag PAI and vacA. Most cag+ strains also carry toxigenic ‘s1’-type (signal sequence) alleles of vacA. Most cag− strains contain s2 vacA alleles, which produce a non-toxic protein. The product of vacA s1 exerts a toxic effect on certain epithelial cells, affecting plasma membranes, altering endolysosomal function, inducing apoptosis, and interfering with antigen presentation.7 While it seems likely that these virulence determinants are associated with the development of disease, many subjects with apparently pathogenic strains of H pylori within their stomachs remain symptom-free, and many ulcer patients harbour “non-pathogenic” isolates. The possible explanations for why apparently fully virulent forms of H pylori do not produce overt disease may include variations in the following host factors.
Host immune response—Both peptic ulceration and gastric carcinoma appear to be associated with mucosal Th1 biased responses, resulting in high production of interferon γ (IFN γ), tumour necrosis factor α (TNF α), and interleukin 1β (IL-1β). Humoral responses are readily detectable, with polyclonal immunoglobulins directed against dominant epitopes such as cagA, vacA, and urease subunits8. The type of humoral immune response is affected by the age of the host, and the environment (tropical or industrialised societies).9 Host immune responses do not appear to be associated with clearance of infection, and may contribute to disease expression.
Small bowel immune activation—Murine models of co-infection with virulent strains of H felis, and the small bowel with helminths such as Nipostrongyloides, indicate that polarised small bowel mucosal Th2 activity down regulates Th1 responses within the stomach.10
There are no reported cases of childhood H pylori associated gastric carcinoma, but histological changes in gastric biopsies in children such as gastric glandular atrophy and intestinal metaplasia have been described. These are both recognised risk factors for subsequent development of cancer, and may be present for many years before dysplasia and malignancy occur.
Most reports suggest that H pylori infection typically leads to a cell mediated gastritis with hypergastrinaemia and hyperacidity, although infected stomachs can exhibit normal acid secretory responses. Antral predominant disease tends to be associated with hypergastrinaemia and thus with duodenal ulceration and gastric metaplasia of the duodenum.11 In adults approximately 20% of all cases of H pylori infection are associated with antral predominant disease. In children this proportion is probably higher.12 Gastric malignancy, however, is more common in corporal predominant gastritis which is associated with hypochorhydria and atrophy of parietal cells. Factors which influence whether H pylori causes an antral or corporal predominant disease are unclear, but may include host genotype13,14 and environmental and dietary factors (that is, smoked foods, high salt intake, infrequent fruit and vegetable consumption).
Transmission is thought to occur directly from an infected case via faeco–oral or oral–oral routes. The evidence for this comes from epidemiological studies (with deprivation and crowding being major risk factors)15 and micro-epidemiology16 (showing clustering of identical strains of H pylori on restriction fragment polymorphism analysis within long term care homes). H pylori has been cultured from faeces,17 showing that it passes through the digestive tract in a viable form (particularly when associated with diarrhoea), and has also been isolated from dental caries18 raising the possibility of oro–oral transmission.
Transmission rates vary enormously between populations, although in every situation prevalence increases with age. Prevalence rates vary from 40% in UK 50 year olds9 to 85% by 2 years of age in the developing countries.19 Prevalence can also vary between racial groups even within a geographical area.20
DISEASE IN CHILDREN
H pylori causes acute and chronic gastritis, and can cause duodenal and gastric ulcers. There is strong epidemiological evidence to implicate H pylori gastritis in marginal B cell mucosal lymphomas21,22 and gastric non-cardia type carcinomas.23,24 Although these significant diseases are typically found among adults, there are clear parallels with gastroduodenal disease in children. In particular, the following paediatric disorders have been associated with H pylori.
Peptic ulceration—The strongest evidence for the role of H pylori in childhood disease is that of duodenal ulcer.25,26 The classic history of epigastric pain localised with two fingers, relieved by eating and waking the patient at night, is not reliable in young children. H pylori associated duodenal ulcers are only accurately diagnosed by endoscopy, but when treated with eradication therapy are likely to result in dramatic and long term improvement of the symptoms.26,27
Abdominal pain in the absence of peptic ulceration—In adult medicine this situation is described as non-ulcer dyspepsia. Although H pylori infection causes chronic gastritis (fig 2), the prevailing evidence is that eradication therapy tends not to improve symptoms in the absence of peptic ulcer. There is some uncertainty over the long term issues of treatment and symptomatic response, as much of this evidence is confounded by short term follow up.28,29 Long term histological follow up studies indicate that resolution of lymphonodular hyperplasia may take up to six months to resolve and inflammatory infiltrate may take up to four years.30 It remains difficult to be sure whether H pylori has a major role in abdominal pain in the absence of peptic ulceration, when the temporal associations between infection and symptoms are so distant.
Gastro-oesophageal reflux disease—Initial observational studies suggested there may actually be an increase in the incidence of reflux disease in people treated with H pylori eradication therapy,31 but subsequent studies have consistently failed to show an association.32
The symptoms of the above three conditions can be very similar. Upper gastrointestinal (GI) endoscopy is the only reliable method of diagnosing peptic ulceration, and hence the likely response of symptoms to H pylori eradication.
It is also important to be aware that H pylori is relatively common among UK children (about 5% of 5–16 year olds are colonised). The overwhelming majority of these have no symptoms attributable to gastroduodenal disease. We therefore suggest the following approach to common clinical presentations.
Upper abdominal pain associated with dyspeptic symptoms
When presented with a child with epigastric pain, particularly if associated with mealtimes and occurring during the night, the question of H pylori infection status should be considered only of secondary importance compared to the likely pathology causing the symptoms. In practice, the key issue is whether the child has duodenal ulceration or not. It is still therefore advisable to investigate children with significant dyspeptic symptoms with upper endoscopy before embarking upon H pylori eradication therapy (especially if certain red flag symptoms exist, such as anaemia and family history of peptic ulcer disease).
Recurrent abdominal pain
It is tempting to hypothesise that H pylori associated chronic active gastritis could be a cause of recurrent abdominal pain (RAP) in childhood, and specific serology is often used as part of a screening investigation among children with RAP presenting to paediatricians. There is no consistent evidence that H pylori can cause recurrent abdominal pain among children without peptic ulcer. The most likely explanation for the finding of H pylori colonisation in recurrent abdominal pain is an epiphenomenon—the co-existence of two common, but unrelated conditions. There is convincing evidence that treating these children will not cure their symptoms.
Iron deficiency anaemia
Case reports and intervention studies show that H pylori can be associated with iron deficiency in asymptomatic children at puberty33 and treatment results in increasing iron stores. Whether this is caused by increased iron loss or decreased iron absorption is not clear, but the relatively low iron stores of pubertal children make them vulnerable. It has been recommended, on a personal view basis, that if H pylori is identified in a case of iron deficiency, it should be eradicated.34 This view is not currently supported by position statements from the European Society of Pediatric Gastroenterology, Hepatology and Nutrition/North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN/NASPGHAN), and this finding does not imply that H pylori is a major cause of iron deficiency.
Childhood growth faltering
Some longitudinal studies have suggested that H pylori colonisation in childhood may lead to growth faltering, particularly among vulnerable populations.35 Other cross sectional studies have produced conflicting results.36,37 Potentially confounding variables such as socioeconomic status may contribute to both the development of malnutrition and early H pylori colonisation; early H pylori colonisation is simply a marker for socioeconomic deprivation. If, however, H pylori were found to be a significant cause of infant growth faltering then the implications for the health of children throughout the world are considerable. At present there is insufficient evidence to make such conclusions.
In addition to examination of endoscopic biopsies, non-invasive tests are available for diagnosis of H pylori in childhood. These have been alluded to above, and are: immunoglobulin G (IgG) serology; urea breath tests; faecal antigen tests.
IgG serology is widely available. High concentrations of specific IgG in blood (or salivary IgA) are found in active infection; after successful eradication, these gradually fall to below empirically derived cut offs. The test is therefore not suitable for establishing short or medium term success of eradication therapy.38 It should only be used as a diagnostic tool if there is evidence that H pylori eradication is likely to be beneficial.
Urea breath tests are robust tools in children over the age of 2 years, and may be valuable in younger children.39 They provide information on the presence or absence of H pylori on the gastric mucosa on the day of the test, and are useful in establishing H pylori eradication. 13C urea breath tests are non-radioactive, but require access to a mass spectrometer. These tests are widely available commercially.
Faecal antigen tests are also robust, comparable in price to urea breath tests, and require a single faecal sample tested using a simple enzyme linked immunosorbent assay (ELISA) kit.40 They are a good guide to successful eradication, and because of the ease of use (a single faecal sample can be collected at home and brought or sent to the laboratory), it is likely that this will become the test of choice for assessing eradication in children.41
Endoscopy and histological examination of gastric biopsies remains the gold standard for diagnosis. Pre-pyloric biopsies have the highest yield (unless the patient is on proton pump inhibitors)42 and examination enables the investigator to identify the pathology associated with infection (for example, duodenal ulceration). Rapid urease tests have a high negative predictive value, but a poor positive predictive value in childhood43 and need to be confirmed by histology. While in many situations haematoxylin and eosin stains are adequate to identify H pylori, further stains such as Giemsa will improve the detection rate (fig 3).
WHO SHOULD BE TESTED?
Testing for H pylori should be done in all situations which may influence management. Our simple advice is test only if you intend to treat. While approaches to treatment are discussed below, at the present time advice given by adult and paediatric gastroenterology professional bodies differs.44,45 The “adult position” is that all cases of H pylori should be treated by eradication, regardless of the associated pathology, while NASPGHAN concludes that there is insufficient evidence to recommend this approach to treatment of H pylori in children. The National Institute for Health and Clinical Excellence (NICE) guidelines, entitled Management of dyspepsia in adults in primary care,46 suggests a therapeutic strategy of treating dyspeptic patients without red flag symptoms (that is, rapid weight loss, GI bleeding, or anaemia) with empirical proton pump inhibitors for one month and eradicating those found to be H pylori positive. Endoscopy is only considered in those whose symptoms persist. There is a low threshold in investigating H pylori colonisation in adults, and even though non-ulcer dyspepsia is unlikely to resolve swiftly after eradication, the balance of risk to the individual patient is thought to favour empirical treatment.
The principles for treatment are similar to those for any infectious illness, except that a more complete bactericidal effect is required than for most other infections. Even very small residual innoculae of H pylori will re-colonise the stomach, as they are relatively remote and protected from the body’s own immune defences. The ability of surviving innoculae to re-colonise means that the emergence of antibiotic resistant strains is very likely. It is therefore important to ensure that when treatment is offered, complete courses are given, appropriate protocols that account for common local resistance patterns are followed, and treatment is reserved for those patients who will benefit from eradication. Antibiotic regimens are listed in table 1 and follow guidelines issued by NASPGHAN. It is recommended that eradication is checked with a urea breath test or faecal antigen assay eight weeks after treatment. Failed eradication (with good compliance) should lead the clinician to consider second line treatment. Repeated treatment failures are an indication to undertake further endoscopy so that cultures of H pylori can be obtained for sensitivity testing. It is possible that non-invasive testing of all family members for H pylori, and treatment of all positive cases, may be useful in this situation, but there is little evidence to either support or refute this approach at present.
Specific diseases such as duodenal ulcer require, in addition to eradication of H pylori, further antacid suppression and a three month course of a proton pump inhibitor would normally be used. Gastric mucosal B cell non-Hodgkin lymphomata require specialist oncological evaluation as well as eradication or H pylori, but are very uncommon in children.
INDICATIONS TO TREAT COLONISATION IN CHILDREN
There is complete agreement between adult and paediatric evidence that H pylori must be eradicated if it is detected in cases of duodenal or gastric ulcers and gastric lymphoma.22 Although the symptomatic response to H pylori eradication is poor in non-ulcer dyspepsia, in adult studies it still provides a good protection against development of gastric cancer (if the eradication is effective)24 or duodenal ulcer.47 A prospective observational study in Japanese adults has identified endoscopic warning signs that in an individual patient H pylori colonisation is at enhanced risk of inducing gastric carcinoma. These factors are gastritis associated with atrophy, gastric polyps, or corpus predominant gastritis.24 The literature is also clear that antral lymphonodular hyperplasia (fig 4) regresses after H pylori eradication, but there is no consensus if this needs treatment in its own right in children.48 While there is a rationale, however fragile the evidence base, to advocate eradication in any child with any of these histological abnormalities, most cases of H pylori diagnosed at endoscopy in the absence of peptic ulceration will have chronic active gastritis. In practice, virtually all parents of symptomatic children will opt for H pylori eradication regardless of whether their clinician feels it is likely to improve symptoms or not. Whatever the consensus statements may say, families will expect you to treat H pylori if you find it.
REASONS NOT TO TREAT CHILDREN
Treatment failure is an increasingly frequently encountered problem, and is associated with emerging antibiotic resistance,49 although other factors are involved. It has been observed that treatment of H pylori is associated with an increase in the carriage rate of resistant strains of Enterococcus species.50 It is extremely difficult to establish whether recurrence of infection is caused by reinfection or by persistence of the original strain. In practice, recurrent infections are more difficult to eradicate, and frequently require prolonged courses of different antibiotics.
OTHER DISEASES PROPOSED TO BE ASSOCIATED WITH H PYLORI
Because of the high prevalence rate of H pylori it is susceptible to false association with other diseases. The following diseases have proposed links with H pylori infection, but all are contested: chronic urticaria,51,52 and immune thrombocytopenia. There is also increasing evidence to discount the proposed association between adult cardiovascular disease and long term H pylori infection.53
At present, H pylori eradication can only be shown to be of benefit among the relatively small well defined groups of children with the disease states described above. The overwhelming majority of colonised children do not fall into any of these groups, and are unlikely to obtain symptomatic benefits from specific treatment. Some of them may go on to develop disease in adult life, but, as yet, we have no valid way of predicting who these may be. The bleakest estimate of risk for peptic ulcer is 20% from adult data, and the lifetime risk of developing gastric cancer rises by 4.9 fold in the context of H pylori gastritis. As our understanding of the pathogenesis of H pylori associated disease improves, it is likely that our ability to predict at risk subgroups will also change and targeted treatment in childhood may be possible. The role of endoscopy is primarily for the assessment of gastroduodenal disease and should be performed in those children with a suspected peptic ulcer, rather than a non-ulcer cause of dyspepsia regardless of H pylori status.
Children’s Foundation and Special Trustees, Royal Victoria Infirmary, Newcastle-upon-Tyne for financial assistance.
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