Diagnosis and Treatment in Helicobacter Pylori Infection GIANINA MICU1, FLORICA STĂNICEANU1,2, SABINA ZURAC1,2, CRISTIANA POPP1, ALEXANDRA BASTIAN1, ELIZA GRĂMADĂ1, R. MATEESCU2,3, M. RIMBAŞ2,3, DELIA MARGA IVAN4 1

“Colentina” Clinical Hospital, Department of Pathology, Bucharest, Romania 2 “Carol Davila” University of Medicine, Bucharest, Romania 3 “Colentina” Clinical Hospital, Department of Gastroenterology, Bucharest, Romania 4 “Witing” Hospital, Department of Internal Medicine, Bucharest, Romania

In our days, Helicobacter pylori is considered to be the bacterium responsible for the most frequent and persistent chronic infection worldwide, involving half of the entire world population. Untreated, the infection is lasting for the whole life. In Romania, the number of carrying people is variable between 90–94%, while in western countries, the prevalence of this infection is much lower, under 50–60%, with a high tendency to decrease, due both to the higher socio-economic level and to advanced methods of diagnosis and treatment, with a special focus on prevention. Because a percentage of 10–11% of the infected people develop in time an ulcerous disease, and 5–6% will have premalignant changes on the gastric mucosa and even gastric cancer in 1% of the cases, the goal to detect and treat H. pylori infection is, in our opinion, very much justified by both theoretical and practical reasons. Diagnosis methods for the infection’s detection are numerous and diverse, the choice for one or another depending on several factors, among which: accessibility, advantages and disadvantages specific to each method (particularly the method’s invasive or non invasive character), the cost, the aim (diagnosis, epidemiological, the treatment’s efficiency, etc.). From a clinical point of view the patient’s age, antecedents and digestive symptoms, as well as his psychological state and associated treatments are also important. Once the diagnosis of infection is proved, the treatment of the Helicobacter pylori infection supposes the simultaneous administration of antibiotics and proton pump inhibitors. The idea to create a vaccine for Helicobacter pylori is the evident result of the need to avoid the costs imposed by the diagnosis and treatment of the infection, especially in view of the high percentage of failure in eradicating the infection. If we add to these the socio-economic costs brought by the treatment of gastric ulcers and cancers, the idea of using a vaccine with double role, both in preventing, as well as in treating the infection, is even more attractive. Key words: Helicobacter pylori, diagnosis methods, treatment, prophylaxes, vaccines.

A. DIAGNOSIS STRATEGIES FOR THE H. PYLORI INFECTION

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The methods used to diagnose the Helicobacter pylori infection are the microbiological [1], histopathological [4][6], immunological [3] and methods based on demonstrating the activity of the bacterial enzyme urease [2][3]. The methods can be grouped in two large categories [5]:

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1. Invasive methods: •

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Histopathologic, used for studying the gastric biopsies, allowing the description of the inflammatory lesions of the mucosa [7] The rapid urease test, specific, but not as sensitive as the previous method, useful especially for the patients with duodenal ulcer [9][10]

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PCR with very high diagnostic efficiency [5] 2. Noninvasive methods:

Serological, used for detecting and confirming the infection in case of equivocal results with other methods [9][10] • The urease breath test C13, very performant, which allows standardization [8] • Detecting the antigens in the stool – easy to do, used to determine monoclonal antibodies [12] None of these methods is perfect, each having advantages and disadvantages which makes them more usable in some situations than others. Follow-up four weeks after the end of the antibiotic treatment and minimum two weeks after ending the acid secretion inhibitors treatment to confirm healing is wise [12–14].

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THE ADVANTAGES AND DISADVANTAGES OF THE INVASIVE METHODS

The main inconvenient is having to perform gastric endoscopy. H. pylori is not evenly distributed in the stomach and for this reason several biopsies need to be performed: minimum two from the antrum, two from the corpus, two from the fundus. In addition, although more rarely, there may be possible nosocomial infections. The advantage is that both H. pylori infection and the lesion associated with it can be identified at the same time. The histopathological exam, using simple stains (Giemsa) or complex but precise ones (WarthinStarry) can identify the bacteria. Immunohistochemical techniques are not usually necessary to demonstrate the presence of H. pylori [6][7]. *Disadvantages – the exam cannot be standardized: the accuracy of the exam depends on the number, the size of the biopsy samples and the site where they were taken from. For example, in areas of intestinal metaplasia H. pylori is not present, although, in the rest of the mucosa it may be present [4][6]. *Advantages – the main advantage is being able to mark out the bacteria in the gastric mucus and to quantify the grade of gastritis (see Sydney system). It offers the most dependable diagnosis in case of malignant lesions (lymphoma, adenocarcinoma). Its sensibility and specificity are over 90% [7]. The rapid urease test that detects the enzyme urease by the colour change of an indicator induced by the ammonia production [3][4]. The interpretation is made after 1–2 hours at 37° Celsius. The most practical tests are CLO-test and Pylori-tek. It is 80% sensitive and 95% specific. *Disadvantages – the test has a very low sensibility, especially when the number of the bacteria is lower than 10³–10. Also the sensibility is low if there is blood in the stomach. Sometimes the test can be positive when there is a H. Heilmanni infection [4][6]. *Advantages – the test can become positive in only few minutes if the bacterial density is high, which allows to start the treatment immediately [6]. Cultures – specificity of 100% [5][8]. *Disadvantages are due to the fact that the bacterium grows and survives only on a special medium (microaerophilic incubator, at 37°C). The bacterium grows in approximately 12 days.

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*Advantages – The main advantage is testing the sensibility to antibiotics using the agar diffusion method or determining the minimum inhibitory concentration to the drugs using the Epsilometer test (E-test) [5]. Because it is so sensitive, the test is used to verify if the infection is eradicated. It also highlights H. pylori’s virulence markers, especially the ones associated with a severe evolution of the mucosal lesions. Polymerase chain reaction (PCR) amplification method used for the identification of H. pylorispecific genes, the genes responsible for its pathogenicity. The test’s sensibility is over 90% and its specificity is almost 100%, if the method is correctly performed [9]. *Disadvantages are numerous, the possibility of having a crossed reaction is high. *Advantages – a correctly executed method is sensitive and objective with quick results. No specific preservation and transportation conditions are required, H. pylori can be detected even if the material is damaged. With PCR it can be determined the bacterial sensibility to antibiotics. It can detect the bacteria in other places than the stomach in only a few hours time [13]. ADVANTAGES AND DISADVANTAGES OF THE NONINVASIVE METHODS

The serological methods – the ELISA method and the Western blot method are used to detect the antibodies against H. pylori in the patient’s serum. Purified antigens are used (urease, high molecular weight proteins, external membrane proteins). IgG is positive 2–3 weeks after the onset of infection and their level remains high as long as the infection persists. After eradication, the antibodies level slowly decreases and normalizes at 4–6 months [7]. The sensibility and specificity are between 60 and 90%. Detecting IgG and IgA together is more reliable. *Disadvantages – because the immune response can vary in an individual, the sensibility of the method is deficient in children under 10 years old and it is influenced by the epidemiologic factor [1,7]. *The advantages: are easy to do. The respiratory test for urea uses urea marked with C13. The test is recommended mainly for children and for controlling the eradication of the infection. It is based on the decaying, inside the

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stomach, of the urea in carbon dioxide, followed by its elimination through respiration. The C12–C13 ratio in the respired air is measured 30 minutes before and after the ingestion of a urea solution marked with C13. The respiratory test has a specificity and a sensibility of 90–95% and can be used both before and after the eradication treatment [3][4][14]. *Disadvantages: the test can cause problems with children. There is the risk of fake positive results caused by the ureasic activity of bacteria located in the mouth, while fake negative results can appear when the density of gastric microbes is low after antibiotherapy or anti-secretor treatment [11]. *Advantages of the respiratory test derive mainly from the fact that it is easy to make and is currently considered to be the best method for the diagnosis and eradication of the infection, without having to turn to the endoscopic control. It can be applied both to children and to aged people. The presence of blood in the stomach does not affect its performance [1][5][12]. The detection of antigens in the feces is made by using the Eliza test that uses an anti H. pylori polyclonal antibodies or monoclonal antibodies, as in the HPStAR, from Daco. The sensibility of the test proved to be significant for the eradication control (95%), larger than that of the respiratory test. *The test’s disadvantages devolve from the fact that the anti-entero-hepatic Helicobacter antibodies are also eliminated by defecation, thus interfering and being able to provide fake positive results, a problem improved when using monoclonal antibodies [6]. *The advantages are provided mainly by the completely non invasive character of the test and its simplicity. It can be easily applied to children. It remarkably evaluates eradication after treatment, compared to other techniques [16][17]. Other non invasive methods, such as the detection of antibodies in urine, saliva or in the gum’s transudate, have performances which are currently under study [14][15][18]. DIAGNOSIS STRATEGIES FOR H. PYLORI INFECTION

The infection’s initial diagnosis should be obtained by applying one of the direct techniques

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that affect the bacteria, and often the histological test is combined with the urease test in order to increase the sensibility and specificity of the result [19]. The epidemiological studies suppose the testing of a large group of population, preferably for diagnosis with serological tests. Also, for such a study one can also use the respiratory test, which is more expensive though. Examining the treatment’s efficiency calls for the repetition of the exam by invasive diagnosis methods. Nevertheless, the respiratory test is for following the evolution of infected and treated patients, even if it is significantly more expensive [20][21]. B. THE TREATMENT OF HELICOBACTER PYLORI INFECTION

The treatment of Helicobacter pylori infection supposes the simultaneous administration of antibiotics and proton pump inhibitors [22]. The standard first line treatment scheme contains two variants [19][22][23]: – the triple administration of proton pump inhibitors (omeprazole, esomeprazole – the standard dose) + claritromicine (500mg) + amoxicillin (1000mg) or metronidasol (400–500mg) (the most efficient variant). The treatment lasts for 7–14 days; the 14-days period is statistically proved to be more efficient than the 7-days one but, if the studies for that specific geographical area show that the results obtained through a 7-day cure are satisfactory, the treatment can be limited to one week. – the quadruple scheme which associates bismuth for 10–14 days [24]. The large-scale administration of antibiotics leads Helicobacter pylori to develop resistance for one or several of the antibiotics in the first line treatment scheme [25]. Therefore, Helicobacter pylori’s resistance to claritromicine is on the rise, situation which diminishes the infection’s eradication success rate. The current consensus proposes that claritromicine is maintained in the treatment scheme only for as long as the resistance rate against it in that specific population is maintained at under 20% [26]; for Helicobacter pylori types resistant to claritromicine, the treatment scheme with metronidasol gives better results than the one containing amoxicillin [27][28]. As far as resistance to metronidasol is concerned, the treatment scheme remains useful only if the

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resistance to metronidasol rate in that specific population stays under 40%. Associating the bismuth allows the infection eradication even with patients with double resistance to claritromicine and metronidasol [29–31]. The second line treatment scheme includes the quadruple therapy with bismuth. The triple scheme (proton pump inhibitors associated with two antibiotics) was tried under the reserve of testing specific type of Helicobacter pylori for resistance to claritromicine [32]. The scheme that includes proton pump inhibitors, amoxicillin and metronidasol allows the eradication of the infection in about 2/3 of the cases. Another, more promising, scheme associates proton pump inhibitors, tetracicline and metronidasol and has a success rate of over 90% [31][33]. The third line treatment scheme includes antibiotics from other categories, such as levofloxacine and rifabutine [30][31]. Unfortunately, the rate of resistance to levofloxacine reaches in certain geographical areas 20% and the use of rifabutine is limited by the risk of developing resistance to rifabutine for mycobacteria. The best recommendation for the choice of third line treatment antibiotics is the preliminary testing of the Helicobacter pylori type and identifying the antibiotics to which it is sensible [32]. Taking into account the discussions on reserve treatments for cases in which eradication is not obtained, it is evident that the therapeutic failure rate is fairly high [34–37]. Also, keeping in mind the fact that it is a long-term treatment, fairly expensive and difficult to be followed by the patient, it is more practical to establish the situation in which it is absolutely necessary to eradicate the Helicobacter pylori infection [38]. According to the recommendations of the Maastricht Work Group (the Maastricht III Consensus) the therapeutic attitude varies with the affection involved [23][24]: – in MALT-type malignant nonhodgkinian lymphoma the treatment of the Helicobacter pylori infection is absolutely necessary; in lower grade lymphoma, following the infection’s eradication a complete remission is obtained in 2/3 of the cases, the highest remission rate being obtained in the 1st stage, with a limited invasion of the mucous and sub-mucous membrane of the gastric wall [23]. – in the case of persistant dyspepsia the “test and treat” strategy is recommended; the treatment of the Helicobacter pylori infection is recommended

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to patients with non-ulcerous or uninvestigated dyspepsia; following the infection’s eradication, favorable results are obtained as far as the improvement of the symptomatology is concerned; furthermore, the risk of developing atrophic gastritis, ulcer or gastric cancer is significantly lowered [23][24][31]. in the case of gastro-esophageal reflux the Helicobacter pylori infection’s treatment is not necessary in order to control the affection, because it is not involved in the affection’s pathogenicity. In different geographical areas, the large prevalence of the Helicobacter pylori infection is associated to the low prevalence of gastro-esophageal reflux, and the large prevalence of the gastro-esophageal reflux is associated to the low prevalence of affections correlated to Helicobacter pylori, namely gastric ulcer and cancer; moreover, there is a negative association between the Helicobacter pylori infection, the Barrett esophagus and the cardial adenocarcinoma. On the one hand, the eradication of the Helicobacter pylori infection neither precipitates the appearance of the gastro-esophageal reflux, nor does it aggravate the symptoms of the gastro-esophageal reflux already in place. On the other hand, the prolonged treatment with blockers of H2 receptors or proton pump inhibitors, that are administered to patients with gastro-esophageal reflux when the Helicobacter pylori infection is also present, predisposes the appearance of the corporeal atrophic chronic gastritis (and the subsequent turn to a malignant stage); the infection’s eradication diminishes and even reverses the localization of gastritis, and can even have benefic effects in the prevention of cancer; the current data is insufficient for argumenting this hypothesis [23][33] the eradication of the Helicobacter pylori infection in patients that are chronic users of aspirin (or other non-steroidal anti-inflammatory substances) would be recommended in view of reducing the risk of gastric bleeding due to the development of an ulcerous lesion (the risk of developing hemorrhagic ulcer of patients addicted to non-steroidal anti-inflammatory drugs that also have a Helicobacter pylori infection is greater than set apart). On the one hand, administering proton pump inhibitors has a better efficiency in preventing digestive hemorrhages than the eradication of Helicobacter

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pylori at this category of patients. Even so, taking into account the negative effect of the chronic treatment with proton pump inhibitors of the Helicobacter pylori infection (corporeal atrophic gastritis), the infection eradication is desirable mostly for preventing this complication than for preventing bleeding [23][35][37]. in the iron-deficiency anemia, the eradication of Helicobacter pylori infection is recommended if anemia etiology is uncertain (in this case the loss of blood through micro-hemorrhages due to erosive gastritis is to be blamed, as well as the inefficiency in iron absorption due to hypochlorhydria that follows chronic gastritis; also, with patients with extensive colonization of the gastric mucosa one can also involve the metabolic use of iron by bacteria). The published studies indicate favorable results [21][23][39]. in the case of idiopathic thrombocytic purpura, the eradication of the Helicobacter pylori infection is also highly recommended, as after applying the treatment the thrombocyte level increases [38]. PROPHYLAXY: THE HELICOBACTER PYLORI VACCINE

The idea to create a vaccine for Helicobacter pylori is the evident result of the need to avoid the costs imposed by the diagnosis and treatment of the infection, especially in view of the high percentage of failure in eradicating the infection. If we add to these the socio-economic costs brought by the treatment of gastric ulcers and cancers, the idea of administering a vaccine with double role, both in preventing and treating the infection, is even more attractive [27][40–46]. The difficulties in creating a vaccine against Helicobacter pylori are numerous. Locating the pathogen in the mucosa layer offers some protection against the immune mechanisms, which makes it very hard to create an efficient vaccine. Moreover, until 1990, when the infection was reproduced in mice (infection with Helicobacter felis), there was no simple and accessible animal model; of course, the fact that mice are not natural hosts for the infection, as well as their short lifespan, create problems in interpreting the results and extrapolating them to humans. Rhesus macaques develop a gastric affection similar to the human one, following the infection with Helicobacter

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pylori, but its use in studies is much more difficult [47][48]. Up to the present moment several types of vaccines against Helicobacter pylori have been tested; the main type of vaccine that was tried and gave good results is the proteic one (the first – completely bacterial lysed – or the second generation – purified proteins –), but the promising results were also obtained by vaccines with viral or bacterial vectors, with bacterial ghosts, DNA or with microparticules of degradable polymer [46] [49][50]. Proteic vaccines Administering the vaccine was tried orally / intrajejunal or parenterally. Taking into account the germ’s location at a digestive level, oral administration is followed by better results as far as the antihelicobacter immunization is concerned (because it stimulates the production of both IgG and IgA) [42][54]. Rectal administration has a lower efficiency [51]. Experiments on mice have shown the positive results regarding the protection to Helicobacter felis infection following the immunization with different proteic antigens [51][52]. – recombined urease of Helicobacter pylori; the simultaneous administering of choleric toxin determines better results than administering of urease [52] – urease B138 [52][53] – cag A – vac A [55] – thermal shock proteins of Helicobacter pylori [57] – adhesion factor – NAP – catalysis – lipoprotein 20. Oral administering of recombined Helicobacter pylori urease and the thermal unstable toxin of Escherichia coli to the macaques offers protection against the infection [52][56]. Oral administering of recombined urease associated with adjuvant of the thermal unstable toxin of Escherichia coli to humans (to healthy volunteers) led to titers considered probably protective against anti-urease antibodies, the side effects (diarrhea) depending on the dose of the adjuvant [56]. Administering vaccines from complete lyses of

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Helicobacter pylori led to the development of a B-type immune response in uninfected volunteers, but did not determine the infection’s eradication in infected volunteers [57]. Live vaccines with viral or bacterial vector Several types of vaccines made of different lines of genetically modified Salmonella typhi or thyphimurium (with the elimination of the element responsible for virulence and for the production of type A and B of the Helicobacter pylori urease) were tried. The results in individuals with lines of Salmonella typhi were modest compared with those

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in mice, while better results were obtained with Salmonella thyphimurium [58]. The other vaccines gave promising results but necessitate further studies before being used [59–60]: – DNA vaccines are safe, stable and, as is the case with other types of DNA vaccines, determine a good immune response, both at a humoral and cellular level [59][60]. – Bacterial ghosts are empty bacterial cells that keep their antigenic character but do not have their characteristic virulence [59][61]. – Vaccines with biodegradable polymer microparticles have, until now, a low toxicity and a good immune response [59][62].

Helicobacter pylori se consideră, actualmente, ca fiind bacteria ce produce cea mai răspândită şi mai persistentă infecţie cronică din lume, cu interesarea a jumătate din populaţia globului. Netratată, infecţia persistă toată viaţa. La noi în ţară, numărul persoanelor purtătoare variază intre 90% şi 94%, în timp ce în ţările occidentale prevalenţa acestei infecţii este mult scăzută (sub 50%– 60%), cu tendinţa accentuată de diminuare, atât datorită condiţiilor socioeconomice mai favorabile, cât şi metodelor de diagnostic şi tratament, printre acestea, măsurile profilactice fiind unele de primă atenţie. Cum dintre persoanele infectate un procent de 10–11% dezvoltă, în timp, o boală ulceroasă, iar 5–6% ajung să prezinte leziuni precursoare maligne ale mucoasei gastrice sau, în cca.1% din cazuri, chiar un cancer gastric, preocuparea pentru depistarea şi tratarea infecţiei cu H. pylori îşi justifică, în opinia noastră, interesul teoretic şi, mai ales, practic. Metodele diagnostice pentru detecţia infecţiei sunt numeroase şi diverse, alegerea uneia sau a alteia dintre ele depinzând de numeroşi factori, dintre care: accesibilitatea, avantajele şi inconvenientele proprii fiecărei metode (în mod particular invazivitatea sau nu a metodei), costul, scopul urmărit (diagnostic, epidemiologic, de eficacitate a tratamentului). În plus, din punct de vedere clinic sunt importante şi vârsta pacientului, antecedentele şi simptomele digestive, starea psihică, tratamentele asociate. Odată diagnosticul stabilit, tratarea infecţiei cu H. pylori presupune administrarea simultană de antibiotice şi inhibitori de pompă de protoni. Ideea creării unui vaccin pentru Helicobacter pylori reprezintă rezultatul nevoii diminuării costurilor cerute de diagosticul şi tratarea infecţiei, mai ales în cazurile cu eşec în eradicarea acesteia. Dacă acestora le adăugăm costurile socio-economice pentru tratarea ulcerului gastric şi a cancerului, ideea administrării vaccinului, atât în prevenţia cât şi în tratarea infecţiei, devine chiar mai atractivă! Corresponding author: Gianina Micu “Colentina” Clinical Hospital, Department of Pathology 19–21 Şos. Ştefan cel Mare Bucharest E-mail: [email protected]

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