Helicobacter pylori: getting to grips with the guidance

Abstract

Helicobacter pylori is a Gram-negative bacterium that inhabits the mucus layer above the gastric mucosa. While infection rates vary by region, the global prevalence is estimated at 50%. While asymptomatic carriage is common, infection can result in significant morbidity and mortality from complications including peptic ulcer disease, atrophic gastritis and gastric cancer. Paediatric and adult practices diverge due to differences in complication rate, symptomatology, practicalities with investigations and treatment options. Widespread use of standard antibiotic regimens has however resulted in a rapid global increase in antibiotic resistance and treatment failure in all ages. There is urgent need to optimise treatment regimens and maximise first-time eradication rates. This need is reflected in the latest guidelines from the European Society for Paediatric Gastroenterology Hepatology and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for paediatric practice and the Maastricht Guidelines for adult practice. This article aims to provide a practical overview of the investigations and management of H. pylori by comparing and contrasting these guidelines.

Introduction

Helicobacter pylori is a microaerophilic Gram-negative bacterium that inhabits the mucus layer above the gastric mucosa. It is a major source of morbidity and mortality worldwide due to its role in the development of peptic ulcer disease (PUD) and gastric cancer. The exact mechanism of transmission is yet to be fully defined but is most likely oral–oral or faecal–oral. The bacterium typically infects the host in early childhood and remains part of the gastric microbiome throughout adult life.¹ The prevalence of global infection sits around 50%, with increased incidence in developing countries and areas of high population density.² There is wide variation in the prevalence between global regions. Those in Northern and Western Europe have a rate of around 10%,³ while this rises to 24.7%–68.3% in the Middle East, 45.7%–42.8% in India, 46% in China and 51.4%–72.4% in North Africa.^{4 5} A trend of decreasing incidence of new infection has been demonstrated in several studies worldwide.^{5 6}

Modern humans carried H. pylori worldwide as they migrated out of Africa.⁷ Unsurprisingly, this has resulted in great diversity in strains of the bacterium with widely variable pathogenicity. While infection results in microscopic gastric inflammation in the majority of infected individuals, the immediate and long-term consequences differ. Up to 90% of people remain asymptomatic, while others develop diseases that include atrophic gastritis, mucosal-associated lymphoid tissue (MALT) lymphoma, gastric adenocarcinoma and PUD.⁸ There are currently no effective biomarkers that predict progression to these disease states. The heterogeneity between strains, populations and patterns of antibiotic resistance hinders generalisable guidance. However, worldwide there is a trend to increasing antibiotic resistance and decreasing efficacy of standard treatment regimens.

The updated 2016 version of the Maastricht Consensus Report⁹ provides guidance on the management of H. pylori in adult populations, focusing on a test-and-treat strategy in low-risk individuals while further investigating those at high risk of complications.

There are several reasons why adult guidance may not be applicable to paediatrics, including the low level of complications, low risk of malignancy, age-related issues with investigations and fewer licensed treatments. Additionally, there is evidence emerging of health benefits associated with acquiring and retaining H. pylori from early life, including reductions in allergic and autoimmune diseases.^{10 11} There is therefore a need to continue the development of paediatric-specific guidance.

A number of countries have produced their own position papers, while the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) jointly renewed their guidance in 2011, with a subsequent update in 2016.^{3 12} This provides guidance on investigation and treatment strategies in this distinct population in light of changing patterns of antibiotic resistance and higher rates of treatment failure.¹³

The aim of this paper is to discuss the clear differences between paediatric and adult populations and the potential consequences for future guidelines, with a focus on the indications for assessment and treatment.

Indications for assessment

In adults, there is well-documented correlation between H. pylori colonisation and the risk of complications. The factors that determine the development of complications are not fully understood but likely reflect strain-specific bacterial factors and complex host–microbe interactions. Successful eradication cures active gastritis and alters the progression to disease states including malignancy. This led H. pylori to be classified in the recent Kyoto consensus as an infectious disease,¹⁴ in addition to its classification by WHO as a class I carcinogen.

The focus of care in adults with uninvestigated dyspepsia is identification and eradication of the organism while exploring possible complications. This is broadly separated into two tiers based on the level of risk. The first tier are young adult patients with no red flag features (see table 1) who have a low risk of significant pathology. In this case a test-and-treat strategy can be adopted with non-invasive testing and empirical antibiotics. This approach is safe and effective while reducing cost, inconvenience and discomfort. In this cohort endoscopy-and-treat is the alternative. The evidence comparing these suggests modest improvements in patient satisfaction and symptom recurrence with an early endoscopy; however, no trials have demonstrated this to be a cost-effective strategy.^15–18 The second tier are older adult patients and those with ‘red flag’ symptoms. In this cohort the risk of malignancy is significant and a test-and-treat strategy would expose the patient to undue risk; they should therefore proceed to early endoscopy.⁹

Table 1.

Red flag symptoms

Adult practice	Paediatric practice
Weight loss. Dysphagia. Overt gastrointestinal bleeding. Abdominal mass. Iron deficiency anaemia.	Right upper or right lower quadrant pain. Dysphagia. Odynophagia. Persistent vomiting. Overt gastrointestinal blood loss. Weight loss. Decelerating linear growth. Delayed puberty. Unexplained fever. Family history of inflammatory bowel disease, coeliac disease or peptic ulcer disease.

In paediatrics there is debate about the benefits of investigating and treating H. pylori infection. If red flag features are present then an upper gastrointestinal (GI) endoscopy is indicated to investigate the cause of symptoms. If gastric or duodenal PUD is found then H. pylori testing should be performed, the patient treated and eradication confirmed. However, in the absence of PUD there is no correlation between infection and abdominal symptoms.^{19 20} Wider complications including adenocarcinoma and MALT lymphoma are very rare, with only a few case reports in the literature. Therefore, in children fulfilling the Rome criteria²¹ for functional abdominal pain, diagnostic testing for H. pylori is not recommended. Additionally, in children without red flag features there is little evidence to suggest endoscopy should be included in the diagnostic work-up.³

Typical macroscopic features of H. pylori infection are often seen incidentally during endoscopy. Current guidelines suggest not testing in this case if treatment will not be offered. While this strategy reduces treatment complications and healthcare utilisation, there is a risk it will increase the complication rate later in life and prolong an individual’s exposure to a recognised carcinogen. This possible increased risk has not been fully studied. Treatment of asymptomatic colonisation in children should probably only proceed following discussion with parents around the positives and negatives of eradication, including the risk of complications later in life versus treatment failure, exposure to antibiotics, and poor symptom response to treatment.

Other possible associations including iron deficiency anaemia, idiopathic thrombocytopaenic purpura, cardiovascular disease, neurodegenerative disease and metabolic disorders are beyond the scope of this review.

Diagnostic testing

The criteria for diagnosis of H. pylori infection vary between adult and paediatric guidance. The paediatric guidance recommends the diagnosis should be based on either a positive culture, or on positive histology plus one other positive biopsy-based test. Non-invasive methods should not be used for the initial diagnosis. This approach reduces false positives, therefore reducing unnecessary treatments and parental anxiety. Conversely, in adult practice a lower level of evidence is required, with a positive non-invasive test or a single rapid urease test (RUT) sufficient to commence treatment. Investigations are categorised into invasive and non-invasive.

Biopsy and histology remain the most widely used invasive methods of diagnosis. The density of bacterial colonisation varies between disease states, with areas of atrophy containing comparatively fewer organisms. Accuracy therefore varies according to the site and number of biopsies. Current adult recommendations are two biopsies from both the antrum and the body, including both the greater and lesser curves. In paediatric practice additional biopsies from both areas for culture plus one for another test (RUT or molecular-based assays) are recommended. The histology is then assessed by the updated Sydney classification.²²

RUT has excellent specificity while providing almost immediate results.²³ False negatives can occur if there is fresh GI bleeding, proton pump inhibitor (PPI) use within 2 weeks, antibiotic use within 4 weeks or prior use of bismuth regimens. Biopsies taken from the body and incisura will provide the most accurate results.²⁴

Validated non-invasive tests include stool antigen and urea breath test (C-UBT). In adult practice the C-UBT is the first-line non-invasive test used for the test-and-treat strategy. It has high sensitivity and specificity and its performance is well documented across the literature. In children technical difficulties and availability often limit its use. In children stool antigen testing is considered the first-line non-invasive test; however, its application is in confirming eradication rather than initial diagnosis. The role of stool antigen testing as a non-invasive diagnostic tool in children warrants further consideration, with benefits including a reduction in invasive endoscopy under general anaesthetic, but disadvantages including a reduced capacity to link the presence of the organism to endoscopic pathology prior to treatment.

Serum serology is not currently recommended in paediatric practice; however, it remains important in adult practice for initial diagnosis. Patients with GI bleeding, MALT lymphoma, atrophic gastritis or gastric carcinoma may have a low bacterial load in the stomach, which reduces the accuracy of tests other than serology. Similarly, serology can give useful guidance as to the possible cause in patients ‘stuck’ on PPI therapy. Serology cannot be used for confirming eradication as it will remain positive for some time. Serology from saliva and urine has poor sensitivity and specificity and is not recommended in either the adult or paediatric guidance.

In populations where the prevalence of H. pylori infection is under 10% (as in many parts of Northern Europe and North America), the sensitivity and specificity of non-invasive testing reduce and alternative diagnoses become more likely. In these regions it may be appropriate to proceed to early endoscopy. While increased cost and healthcare utilisation may otherwise militate against early endoscopy, it demonstrates why an understanding of epidemiological patterns is fundamental to decision making.

H. pylori replication may be suppressed by PPI,²⁵ or recent antibiotic use, thereby producing false negative results. It is therefore recommended across all guidance to stop acid-suppressing medication 2 weeks prior to testing and allowing 4 weeks after the completion of antibiotics. If the patient is unable to tolerate symptoms without acid suppression, PPI can be substituted by an H2 receptor blocker, which can be stopped 2 days prior to testing.

Treatment

Rates of antibiotic-resistant H. pylori have increased rapidly over the past 20 years. Clarithromycin resistance is 30% in Italy and Japan and up to 50% in regions of China. While not as pronounced, the increase in metronidazole and levofloxacin resistance rates shows a similar pattern. This corresponds to a decline in efficacy of standard treatment regimens and increasing treatment failure.²⁶ In order to slow this spread and ensure future treatment options, it is imperative to maximise first-time eradication rates. Careful antibiotic choice based on knowledge of local resistance patterns is fundamental. Promoting strict adherence, providing adequate acid suppression and optimising course length are important considerations.

Wide regional variability in resistance rates means generalisable antibiotic recommendations are difficult. The aim of the paediatric guidelines is to achieve >90% first-time eradication rate. In order to achieve this, the suggested first-line strategy is endoscopy with biopsy culture and sensitivities to guide individually tailored antibiotics. In adults this is desirable but often reserved for treatment failure. However, there is debate around whether this is a realistic approach. It is not routinely available in many centres and adds additional cost, invasiveness and burden to the diagnostic process. This has to be balanced with the relative paucity of data on the efficacy of culture-based treatment versus a pragmatic antibiotic choice based on local resistance patterns.^{27 28} Alternative strategies to assess for clarithromycin resistance include molecular biopsy-based techniques and stool-based PCR tests. While not widely available these may be a more practical alternative in future practice.

Data on individual organism sensitivity and local antibiotic resistance rates guide empirical paediatric recommendations (figure 1). In comparison with adult practice, there are relatively few licensed medications, which in turn limits treatment options. The combinations and doses of first-line therapy in paediatrics can be found in table 2; these are adapted from the ESPGHAN/NASPGHAN guidelines. A 14-day course is recommended in all cases due to increased efficacy over both 7-day and 10-day courses. Sequential therapy is no longer recommended in paediatric practice outside of proven clarithromycin and metronidazole sensitivity.

Figure 1.

ESPGHAN/NASPGHAN paediatric antibiotic algorithm. AMO, amoxicillin; CLA, clarithromycin; ESPGHAN, European Society for Paediatric Gastroenterology Hepatology and Nutrition; MET, metronidazole; NASPGHAN, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition; PPI, proton pump inhibitor.

Table 2.

Suggested approach for diagnosis, treatment and confirmation

	Diagnosis	First-line treatment regimens	Confirmation*
Children	Endoscopy:	Susceptible to CLA+MET.	Stool antigen test.
	Positive culture.	PPI-AMO-CLA 14 days with standard dose.	Urea breath test (if child able to cooperate).
	Or	Resistant CLA susceptible MET.
	Positive histology.	PPI-AMO-MET 14 days or bismuth-based.
	And	Resistant MET susceptible CLA.
	One other biopsy-based test (RUT or PCR).	PPI-AMO-CLA 14 days or bismuth-based.
		Resistant CLA+MET.
		PPI-AMO-MET 14 days with high-dose amoxicillin or bismuth-based.
		Unknown.
		High-dose PPI-AMO-MET 14 days or bismuth-based.
Low-risk adults	Urea breath test.	Low CLA resistance (<15%)†.	Urea breath test.
	Stool antigen test.	PPI-AMO-CLA.	Stool antigen test.
	Serum serology (in validated areas).	High CLA resistance (>15%) +Low MET resistance.	Avoid serology.
		PPI-AMO-MET.
		+Low dual CLA and MET resistance (<15%).
		Bismuth quadruple or concomitant non-bismuth-containing quadruple.
		+High dual CLA and MET resistance (>15%).
		Bismuth-containing quadruple therapies‡.
High-risk adults	Endoscopy:		Urea breath test.
	Positive RUT.		Stool antigen test.
	Or		Avoid serology.
	Positive histology.
	Or
	Positive culture.

*To be performed 4–8 weeks after the completion of therapy with no PPI for 2 weeks and no antibiotics for 4 weeks.

†Patients who have previously taken clarithromycin and/or metronidazole should be considered high risk for dual resistance.

‡If bismuth not available, levofloxacin, rifabutin and high-dose dual (PPI+AMO) may be considered.

AMO, amoxicillin; CLA, clarithromycin; MET, metronidazole; PPI, proton pump inhibitor; RUT, rapid urease test.

There is a wider range of treatment options in adult practice. The Maastricht Guidelines outline treatment combinations in different scenarios and according to patterns of resistance. A suggested algorithm for first-line treatments adapted from the Maastricht Guidelines can be found in table 2.

There are several other areas that need to be optimised to complement the correct antibiotic choice. H. pylori is less likely to be in a replicative state with low gastric pH (pH 3–6). Increasing the pH with effective acid suppression increases replication and therefore the effectiveness of clarithromycin and amoxicillin. The metabolism of PPI is determined by CYP2C19 polymorphisms, with Caucasian populations having a higher rate of rapid metabolisers. In these cases higher PPI doses or alternative PPIs may be needed to adequately raise gastric pH.

Poor adherence is a major factor in treatment failure. Schwarzer et al ²⁹ demonstrated high success rates were only achieved in those taking >90% of the prescribed medication. It is essential to fully explain to patients and their families the importance of strict adherence in order to prevent further antibiotics, investigations and prevent the spread of resistance. A twice-daily dosing regimen has been adopted in the paediatric guidance to facilitate this.

Confirming eradication following a course of treatment is fundamental. This should be performed 4 weeks after the completion of therapy with either a C-UBT or stool antigen testing and in the absence of PPI and antibiotics for 2–4 weeks, respectively.

Discussion

H. pylori infection is common worldwide and remains an important factor in the development of PUD, gastric cancer and wider complications. There are clear differences in its impact depending on patient age; this is reflected in the differing recommended strategies for investigation and treatment between adult and paediatric guidelines.

The aim however is to minimise the risk of harm to patients by correctly identifying those at high risk and investigating appropriately while maximising the efficacy of treatment regimens. In paediatric practice this level of risk is often lower with complications of infection, including the risk of malignancy, being less common. Therefore if red flag features are present, consideration should be given to the wider differential diagnosis and investigation should proceed to upper GI endoscopy rather than non-invasive H. pylori investigations. It should be emphasised that there is no proven correlation between H. pylori carriage and abdominal pain in children in the absence of established complications. When considering the options for eradication therapy, this should take into account age-related issues with investigation and treatment including the availability of fewer licensed treatment options.

This is in contrast to adult practice, where there is a huge global burden of infection that leads to significant morbidity and mortality. High-risk individuals should be investigated with upper GI endoscopy and managed appropriately. In those with low risk of complications a test-and-treat strategy has been shown to be a practical, safe and effective approach. There are a greater range of treatment options with more robust efficacy data. First-line treatment should ideally be based on local resistance patterns with biopsy and culture limited to those with treatment-refractory disease.

Several studies have demonstrated increasing rates of antibiotic resistance worldwide. If treatment is offered it should ideally be individualised, taking into account patient preference and local resistance patterns. Vaccination may be an option in the future in endemic areas; however, increasing first-time eradication rates is essential to limit the spread of resistance. While it may not be practical in all centres to base antibiotic choice on culture and sensitivities, this individualised approach can help to achieve the target first-time eradication rate of 90%. In centres where culture is not freely available, eradication rates can be optimised by careful antibiotic choice, longer regimens and engaging the family to maximise adherence. Confirming eradication after any therapeutic course is an absolutely essential step and should be performed at least 4 weeks after stopping antibiotics and 2 weeks after stopping PPI. Failure to confirm eradication may falsely reassure individuals while providing ongoing exposure to a recognised carcinogen. In children, where the decision is made not to treat or licensed medications have been unsuccessful, their H. pylori status should be clearly documented and follow-up provided. Local resistance patterns and changing antibiotic efficacy mean that the guidelines will be updated regularly to capture progress in the field.

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