Helicobacter Pylori Infection: From Diagnosis to Treatment and Future Challenges

Q&A with Colm O'Morain
Professor of Medicine at Trinity College, Dublin, and European Representative of OMGE, the World Organisation of Gastroenterology.
By Andrea Massa 

Helicobacter pylori is found predominantly in human gastric mucosa. Why is it that transfer still remains an open topic today?
The reason transmission is still such an interesting topic is that man appears to be the only host in which H.pylori has successfully thrived. Many interesting questions remain about the exact mechanisms of transfer, be it faeco-oral or familial. Until all these questions are answered, it will remain an open topic.

Data suggests that over 80% of people infected with the bacteria are clinically silent and/or become infected in childhood. Has science found any explanations for this yet? What kind of interaction exists between the environmental and bacterial factors in the pathogenesis of H.pylori?  
Lots of explanations have been proposed for this. The major concern regarding H.pylori infection is its ability to cause peptic ulcers and stomach cancer. When one considers that 50% of the world's population is infected, it is clear that there must be a strong interplay between bacterial and host factors in determining  the disease phenotype. Certain bacterial genes, such as cagA, vacAs1m1 and iceA2, predispose to more virulent disease whereas the absence of these genes tends to occur in more "silent" infection. As regards the host, the genotype here too has a role to play and certain cytokines such as Interleukin-8 are expressed in varying ways, which can predispose the patient to more sinister pathology. Infection in childhood is explained by the fact that we believe H.pylori is transmitted by faeco-oral and hand to hand contact. Children tend to have poorer hand hygiene and spend a lot of time in close proximity in school. There they make a lot of hand to hand contact, playing games and such like, which leads to spread at an early age. The risk of acquiring H. pylori infection is related to socioeconomic status and living conditions early in life. Factors such as density of housing, overcrowding, number of siblings, sharing a bed, and lack of running water have all been linked to a higher acquisition of H. pylori infection. A recent study from Iran has linked childhood hygiene practices and family education with a higher prevalence of H. pylori infection.

Which instrument does the scientific community rely on to diagnose the  presence of H.pylori infection? 
There are several tests used for diagnosing H.pylori infection. The accuracy of these tests, however, can all be interfered with by using proton pump inhibitors. These have different utilities depending on the clinical or research scenario at hand. 13C urea Breath testing is an efficacious, non-invasive and cost-effective means of testing for H.pylori which is particularly useful in evaluating dyspeptic symptoms in young adults. Other non-invasive tests include testing for H.pylori antigen in stool and serum and these are used in various centres. More invasive tests require an endoscopy and biopsy. These include rapid urease testing which allows for point-of-care diagnosis and treatment prior to discharge. Direct observation of H.pylori on a histology specimen can also be used to diagnose H.pylori. Culturing of H.pylori from biopsy specimens is probably not done frequently enough. This is particularly useful in cases of bacterial resistance and enables us to select the antibiotics which are most likely to lead to a cure. These tools are all very useful to clinical gastroenterologists. For research purposes, it is necessary to have at least two and sometimes three positive diagnostic tests to standardise results with other published data.

Since the discovery of H.pylori in the early 80s, how radically has the scientific approach changed to treat this infection?
Following the discovery of H.pylori in the 1980s, various combinations of antibiotics, H2 receptor antagonists and Bismuth were initially used with modest success. However, the landscape changed with the discovery of proton pump inhibitors and in 1996 a randomised controlled trial (the MACH-1 study), which I was a part of, established the current paradigm of two antibiotics and a proton pump inhibitor. Manipulation of gastric acid is crucial. The antibiotics used must also be tailored to local resistance levels. The advent of susceptibility testing has also enabled us to more accurately choose the most appropriate antibiotics. This has been a big help but is not widely used unfortunately. In many ways the most important issue going forward will be in ensuring patient compliance with therapy. Most eradication regimes are complex and involve many drugs. Newer regimes such as sequential therapy are becoming increasingly complicated. We must work to make eradication regimes more user-friendly to the patient.

What is  the most popular treatment for the eradication of H.pylori at the moment?
The current guidelines from both the European Helicobacter Study Group and the American College of Gastroenterology recommend using twice daily PPI combined with amoxicillin and clarithromycin or metronidazole. This remains the most popular firstline treatment worldwide.

How significant is the impact of individual therapy and its duration in the eradication of the bacteria?
Individualised therapy based on antibiotic sensitivities is promising but unfortunately not widespread. The question regarding duration is interesting. Two meta-analyses addressing the effect of duration of therapy on eradication rates showed contrasting results. However, the experts responsible for these meta-analyses are currently collaborating to carry out a Cochrane review of the topic which should clarify the situation.

What role does H.pylori play in functional dyspepsia (indigestion)?
In H.pylori positive patients with chronic dyspepsia who do not have ulcer disease, the role of H.pylori eradication therapy has not been proven. Therefore, other diagnoses must be outruled. The most recent expert consensus (Maastricht-3 consensus) recommends that considering a trial of anti-H.pylori therapy is potentially useful, safe and cost-effective in such patients. In some patients an immediate response is seen but in others gradual improvement occurs over several months.

How strong are the links between H.pylori infection and the development of gastric cancer?
In 1994 the WHO's International Agency for Research in Cancer (IARC) declared H.pylori to be a Class I human carcinogen. The Eurogast Study Group determined that presence of H.pylori confers an approximately six fold risk of gastric cancer, accounting for about half of all gastric cancers. It is proposed that a predefined sequence of preneoplastic histological change occurs which leads from a healthy stomach to cancer, via chrinic and atrophic gastritis and intestinal metaplasia. It has been proven that eradication of H.pylori in patients with intestinal metaplasia is worthwhile and can lead to regression of some precancerous lesions, thus reducing the risk of cancer. However, it may equally be the case in many lesions that once chronic gastritis has become established, the mucosa is irreparably and irreversibly damaged and eradication will not induce regression in all patients.

Increasing anti-microbial resistance and falling eradication rates highlight the need for new guidelines. Are there any prevention strategies in place?
I think the current guidelines have worked very well. Two studies published in the last 12 months, one by Rokkas and the other by Seppala, have proven that universal cure is achievable if current Maastricht-3 guidelines are followed. That said, the guidelines are due to be reviewed in the next 2 years. As H.pylori infection is related to socioeconomic status, improving people's social milieu may be the best way to prevent infection.

Do you see any progress, or answer, from research for a vaccine? 
Progress on a vaccine has been very slow, however an effective vaccine does have the potential to revolutionise the management of gastroduodenal disease and digestive cancer prevention.

Thank you very much for answering our questions Professor O'Morain.