Linee guida sull’infezione da Helicobacter Pylori AIF Tutor Dott.ssa Rossella Turco Prof.ssa Annamaria Staiano Dott. Erasmo Miele

What’s the story H pylori ? Letters to the Editor UNIDENTIFIED CURVED BACILLI ON GASTRIC EPITHELIUM IN ACTIVE CHRONIC GASTRITIS “SPIROCHETES" INHABITING THE GASTRIC GLANDS OF DOGS The first well-known report of gastric helicobacters was by Bizzozero in Turin in 1893 (1). Bizzozero was a well-known anatomist, famous already for his proof that all dividing cells required cell nuclei (4). In his anatomical observations of the gastric mucosa of dogs, Bizzozero reported "spirochetes" inhabiting the gastric glands (9) and even the canaliculi of the parietal cells. In hand-drawn color illustrations, Bizzozero showed gram-negative organisms with approximately 10 wavelengths within the parietal cells and gastric glands. We now know these organisms variously identified as Helicobacter canis, Helicobacter felis (24), and/or Helicobacter heilmannii (18) Giulio Bizzozero, Arch. Mikr. Anat.1893; 42: 82-152 J Robin Warren, Barry Marshall. Lancet. 1983;1:1273-5

Aree con H. Pylori Prevalence of H. pylori infection correlates best socio-economic status rather than race. In the United States, probability of being infected is greater for older persons (>50 years = >50%), minorities (African Americans 40-50%) and immigrants from developing countries (Latino > 60%, Eastern Europeans > 50%). The infection is less common in more affluent Caucasians ( < 40 years = 20%) La prevalenza dell’infezione da H pylori nei bambini del Sud Italia è del 23% Perri F, et al Arch Dis Child. 1997;77:46–49

status socio-economico delle madri dei bambini affetti La percentuale d’Incidenza dell’ infezione da H pylori nei bambini varia tra il 1.7% e il 15%. L’infezione da H pylori è frequente prima dei 3 anni di vita e il rischio d’infezione dopo i 5 anni è basso. Fattori di rischio status socio-economico delle madri dei bambini affetti infezione da H pylori materna infezione dei fratelli più grandi ritardato svezzamento dal biberon (per es. dopo i 24 mesi di vita) GASTROENTEROLOGY 2006;130:65–72

Patogenesi dell’ infezione da H. pylori

Storia naturale dell’infezione da H. pylori Figure 3. Natural History of Helicobacter pylori Infection. H. pylori is usually acquired in childhood. Acute H. pylori infection causes transient hypochlorhydria and is rarely diagnosed. Chronic gastritis will develop in virtually all persistently colonized persons, but 80 to 90 percent will never have symptoms. The further clinical course is highly variable and depends on bacterial and host factors. Patients with higher acid output are likely to have antral-predominant gastritis, which predisposes them to duodenal ulcers. Patients with lower acid output are more likely to have gastritis in the body of the stomach, which predisposes them to gastric ulcer and can initiate a sequence of events that, in rare cases, leads to gastric carcinoma. H. pylori infection induces the formation of mucosa-associated lymphoid tissue (MALT) in the gastric mucosa. Malignant lymphoma arising from such acquired mucosa-associated lymphoid tissue is another rare complication of H. pylori infection.

Complicanze cliniche dell’infezione da H. pylori

Gastriti nodulari ed infezione da Helicobacter pylori nel bambino Gastrite cronica tipo B Gastrite nodulare antrale Bambini: 30-100% Adulti: meno frequente Nodular gastritis (NG) is a form of chronic gastritis with moderate inflammation, eosinophilic infiltration in superficial lamina propria and lymphoid hyperplasia in gastric mucosa. It is associated with the presence of Helicobacter pylori. Lymphoid hyperplasia and NG appear to be more frequent in children than in adults and usually regress following anti-H. pylori therapy. Typically, the inflammatory process in the gastric mucosa of infected individuals is a chronic type B gastritis, which is characterized by crypt atrophy and chronic inflammatory cell infiltrate ANNALS OF GASTROENTEROLOGY 2000, 13(2):138-141-

Complicanze cliniche dell’infezione da H. pylori prevalenza dell’nfezione da H. pylori Mediana Range Ulcere Duodenali 92% 33%-100% Gastrite Ulcerosa 25% 11%-75% Bassa percentuale (<5% to 10%) di malattia ricorrente nei bambini trattati e curati per infezione batterica Among children, the occurrence of H pylori–related gastroduodenal disorders such as gastritis and peptic ulcer disease have been observed as well as, albeit significantly less frequently, gastric atrophy and intestinal metaplasia. However, children infected with H pylori are at substantial risk for primary duodenal ulcer disease, with between 33% and 100% of children with duodenal ulcer disease found to harbor the bacterium. The causative role of H pylori in duodenal ulcer disease among children is supported by the finding of a low rate (<5% to 10%) of disease recurrence in children treated and cured of the bacterial infection Jama 1995; 273: 729-734 Arch Dis Child 1998; 79: 502-505

Helicobacter pylori e sintomatologia nei bambini Manifestazioni gastrointestinali Il ruolo dell’ H.pylori nel dolore addominale ricorrente (RAP) e altri sintomi gastrointeinali (GI) rimane controverso. Non è stata evidenziata nessuna associazione tra RAP e infezione da H pylori nei bambini. L’associazione tra dolore epigastrico e infezione da H pylori rimane contraddittoria. Esiste un’evidenza scientifica per un’associazione con il dolore addominale aspecifico ma questo risultato non è stato confermato nei bambini. Dolore periombelicale, flatulenza, stipsi, nausea, perdita di feci, ripienezza post-prandiale, alitosi, dispepsia, e rigurgito non sono associati con l’infezione da H pylori. Pediatrics 2010;125;e651;

Helicobacter pylori e sintomalogia nei bambini Manifestazioni extraintestinali Diversi dati in letteratura supportano un’associazione tra l’infezione da H pylori e l’anemia ferro-carenziale nei bambini e negli adulti. I meccanismi definitivi dell’anemia ferro-carenziale nei pz affetti da H pylori non sono chiari: perdita di sangue gastrointestinale? scarso apporto di ferro? malassorbimento di ferro? mobilizzazione del ferro nel sistema reticoloendoteliale? meccanismi batterio-specifici? An increasing body of literature supports an association between H pylori infection and iron-deficiency (or sideropenic) anemia in children and adults. For example, among teenagers in South Korea, the relative risk of irondeficiency anemia in those infected with H pylori was 2.9 (95% CI, 1.5 to 5.6), compared with children not infected with the bacterium. Treatment with iron supplementation produced no improvement in hemoglobin levels in those with persistent infection, whereas significant increases in hemoglobin, iron, and ferritin levels were observed in children who underwent H pylori treatment and cure. The definitive mechanism(s) of iron deficiency anemia in those infected with H pylori is unclear. However, a number of biologically plausible causes have been postulated, including gastrointestinal blood loss, poor iron intake, iron malabsorption, or diversion of iron in the reticuloendothelial system. Some studies have suggested a bacteria-specific mechanism(s) of anemia. Theories include receptors on the outer membrane of H pylori organisms in the antrum acting as an iron sequestering focus that captures and utilizes iron for growth, infection-associated changes in either lactoferrin, or changes in intragastric pH that impair iron absorption. Pediatrics 2010;125;e651;

Chi dovrebbe essere testato?

Chi dovrebbe essere testato? Lo scopo primario dell’indagine clinica dei sintomi gastrointestinali è determinare la causa sottostante dei sintomi e non solo la presenza dell’infezione da H pylori. Test diagnostici per l’infezione da H pylori non sono raccomandati nei bambini con dolore addominale funzionale. C’è evidenza insufficiente sull’associazione tra infezione da H pylori e otite media, infezione del tratto respiratorio superiore, malattia peridontale, allergia alimentare, SIDS, porpora trombocitopenica idiopatica e bassa statura. The primary goal of clinical investigation of gastrointestinal symptoms is to determine the underlying cause of the symptoms and not solely the presence of H pylori infection. JPGN 2011;53: 230–243

Chi dovrebbe essere testato? Nei bambini con parenti di primo grado affetti da carcinoma gastrico, l’analisi per H pylori potrebbe essere considerata. Nei bambini con anemia ferro-carienzale refrattaria nella quale le altre cause sono state escluse, l’analisi per H pylori potrebbe essere considerata. A causal relation between H pylori infection and the risk of gastric malignancies, including cancer and gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, has been shown in animal models and is supported by several epidemiological and intervention studies. Both of these cancer types are extremely rare during the first 2 decades of life. Although H pylori–associated gastric cancer has not been reported in children, MALT lymphomas have been described in a few H pylori–infected pediatric patients . In 1994, the World Health Organization declared H pylori a class I carcinogen. A meta-analysis estimated that the risk for gastric cancer is increased by a factor of 2 to 3 in H pylori–infected individuals. Screening for H pylori infection in the general population is not recommended. In populations with a high prevalence of H pylori infection, the benefit of screening can be assessed by considering the risk of H pylori–associated gastric cancer in particular populations, along with the health care priorities of those populations. In populations with a high incidence of gastric cancer and in which gastric cancer–screening programs are in place, children can be included in screening programs for H pylori infection, and close surveillance in those who develop atrophy or intestinal metaplasia is indicated. JPGN 2011;53: 230–243

Quali test diagnostici dovrebbero essere applicati e in quali situazioni ?

Infezione da Helicobacter Pylori: test diagnostici Test Sensibilità Specificità Costi Test Non invasivi Antibiotici Globuli bianchi 70-85 75-90 $ Siero 86-94 75-90 $ ELISA 86-94 80-95 $$ Antigeni fecali 88-98 89-98 $$ 13C-Urea Breath test 90-96 88-98 $$$ Test Invasivi Biopsia con CLOTest 90-95 95-100 $$$$ Istologia 90-95 95-100 $$$$$ Coltura 60-95 100 $$$$$ Numerous tests that detect H pylori are available. They are divided into noninvasive and invasive tests. Invasive tests require gastric tissue for detecting the organism and include culture, rapid urease test, histopathology, polymerase chain reaction, and FISH. Noninvasive tests include different methods for the detection of H pylori antigens in stool, detection of antibodies against H pylori in serum, urine, and oral samples, and the 13C-UBT. subgroup and recently published. All diagnostic tests are generally feasible in children; however, tests requiring patient cooperation, such as the UBT, are more difficult to perform in infants, toddlers, or physically challenged children. A crucial question for all tests performed in a pediatric population is whether the accuracy of the applied method is influenced by the age of the tested child. It is necessary to consider different age groups: infants, toddlers, preschool-age and school age children, and adolescents. Most of the validation studies in children included only a few H pylori–infected infants and toddlers. Therefore, the information with respect to sensitivity is limited in these age groups. It is necessary to compare a test to a reference standard; however, no single test for detection of H pylori infection can be used as a fully reliable reference method. Culture is the only method that is considered to be 100% specific, a positive culture being sufficient to prove H pylori infection, but its sensitivity is lower. For that reason, concordant results of at least 2 tests are needed to define the H pylori infection status. For noninvasive tests, biopsy-based tests should be the reference. If culture was not successful or not performed, concordant positive results for histology and rapid urease test indicate a positive H pylori status. The definition of a negative H pylori status is that all of 2 or 3 invasive tests performed are negative. For the validation of an invasive test, such as histopathology, other biopsy-based tests, with or without the combination of reliable noninvasive tests, should be the reference. All of the tests are suitable for the detection of infection before and after treatment, with the exception of serology, which may remain positive for some time after successful eradication. For the interpretation of test results, factors that can lead to false-positive or false-negative results must be known and considered. Antibiotics, including penicillin and cephalosporines, and acid-suppressive drugs, particularly PPIs, should be discontinued before testing for at least 4 and 2 weeks, respectively. This recommendation is extrapolated from adult studies.

Quali test diagnostici dovrebbero essere applicati e in quali situazioni ? Per la diagnosi dell’infezione da H pylori durante l’ EGDS, sono raccomandate biopsie gastriche (antro e corpo) per l’esame istologico. É raccomandato che la diagnosi iniziale dell’infezione da H pylori sia basata sulla positività dell’istologia e del test rapido all’ureasi o dell’esame colturale. È raccomandato che il medico aspetti almeno 2 settimane dopo la fine della terapia con PPI e 4 settimane dopo la fine della terapia antibiotica per eseguire biopsie e test non-invasivi (UBT, esami sulle feci) per H pylori. For histology, 2 biopsies should be obtained from both the antrum and the corpus, and the findings should be reported according to the updated Sydney classification. Because the density of H pylori may be patchy, the sensitivity increases with the number of biopsies taken. Normally, the highest bacterial count is found in the antrum; however, in cases of low gastric acidity, the bacteria may be present only in the corpus. In children with suspected H pylori infection, it is highly recommended to take not only biopsies for histopathology but also 1 biopsy each for a rapid urease test and, if available, culture. The suspicion of an infection is often based on the macroscopic findings of a nodular mucosa in the antrum or bulbus and/or gastric or duodenal erosions or ulcerations. The rationale for the recommendation to perform more than 1 diagnostic test is based on the sensitivity results of invasive tests, which range from 66% to 100% for histology and from 75% to 100% for rapid urease tests in published series from children . If the results of histology and rapid urease test are discordant, then a noninvasive test (UBT or stool test) should be applied. One exception from the rule of 2 concordant test results is a positive culture, which is 100% specific and therefore in itself sufficient to diagnose H pylori infection. Another exception is the presence of a bleeding peptic ulcer, in which case 1 positive biopsy based test is considered to be sufficient to initiate anti-H pylori therapy. Studies in adults suggest that antibiotic or PPI therapy can cause false-negative test results because of a reduction in bacterial load without eradication of the bacterium. Therefore, it is recommended that testing be performed at least 4 weeks after completion of antibiotic treatment and 2 weeks following cessation of PPI therapy. JPGN 2011;53: 230–243

Quali test diagnostici dovrebbero essere applicati e in quali situazioni ? Il 13C-UBT è un test non invasivo affidabile per determinare se l’H pylori è stato eradicato. L’ELISA per la determinazione dell’antigene dell’ H. pylori nelle feci è un test affidabile non-invasivo per determinare se l’H pylori è stato eradicato Test basati sulla determinazione degli anticorpi (IgG, IgA) contro l’ H pylori nel siero, globuli bianchi, urine e saliva, non sono affidabili per l’uso nella pratica clinica So far, only the EIA based on monoclonal antibodies has achieved the accuracy of the UBT, which is considered the reference standard of the noninvasive tests. A systematic review and meta-analysis of the 8 studies directly comparing the polyclonal with the monoclonal EIA, including pediatric and adult patients, confirmed the significantly better performance with respect to sensitivity of the monoclonal test, both before and after therapy. No difference in accuracy has been observed between studies in adults and children, and within the pediatric studies, young age did not influence the performance of the tests. In general, serologic assays cannot be used on their own to perform the diagnosis of H pylori infection or to monitor the success of therapy because the sensitivity and specificity for detection of antibodies (IgG or IgA) against H pylori in children vary widely. Specific IgG may remain positive for several months or even years after the infection resolves. Thus, the tests cannot be used reliably for treatment outcomes. JPGN 2011;53: 230–243

Chi dovrebbe essere trattato?

THE TEST-AND-TREAT STRATEGY ADULTI THE TEST-AND-TREAT STRATEGY Statement 1: A test-and-treat strategy is appropriate for uninvestigated dyspepsia in populations where the H pylori prevalence is high (>20%). This approach is subject to local cost-benefit considerations and is not applicable to patients with alarm symptoms, or older patients (age to be determined locally according to cancer risk) Evidence level: 1a Grade of recommendation: A Statement 2: The main non-invasive tests that can be used for the test-and-treat strategy are the UBT and monoclonal stool antigen tests. Certain validated serological tests can also be used. Evidence level: 2a Grade of recommendation: B The test-and-treat strategy is appropriate in situations where the risk of the patient having gastric cancer is low; in most countries this means dyspeptic patients below a locally determined age cut-off point (depending on local incidence of gastric cancer in different age groups) and without so-called ‘alarm’ symptoms or signs which are associated with an increased risk of gastric cancer. These include weight loss, dysphagia, overt GI bleeding, abdominal mass and iron deficient anaemia. In young patients with dyspepsia, testing for and treating H pylori is preferable to a strategy of just prescribing a proton pump inhibitor where the H pylori prevalence is >20%.Test and treat must be used cautiously in populations with a low H pylori prevalence as it becomes less accurate in this settingIn patient groups with an increased risk of gastric cancer (over a local age cut-off point or with alarm symptoms or signs), the test-and-treat strategy is not recommended and a strategy of ‘endoscope and treat’ is preferred. In addition, non-invasive tests are less accurate in older adults. Gut 2012;61:646e664.

Chi dovrebbe essere trattato? In caso di duodenite ulcerosa peptica con infezione da H pylori, l’eradicazione dell’oganismo è raccomandata. Quando l’infezione da H pylori è dimostrata istologicamente anche in assenza di duodenite ulcerosa peptica, il trattamento dell’ H pylori potrebbe essere considerato. Nei bambini affetti da H pylori con parenti di primo grado con carcinoma gastrico, il trattamento può essere consigliato Una strategia ‘‘test and treat’’ non è raccomandata nei bambini. Several meta-analyses in adults consistently demonstrate that eradication of H pylori in patients with PUD significantly reduces the relapse rate for ulcer disease and for recurrent bleeding ulcers. Only 1 randomized controlled pediatric trial in H pylori–infected children with PUD (n=106) has been published. This trial compared the eradication rate of H pylori and the cure rate of PUD with 3 different treatment regimens, but did not report the recurrence of ulcer or bleeding ulcer in those who failed bacterial eradication. Although there are differences in the etiologies and clinical presentation and frequency of PUD in children compared with adults, it can be assumed that recurrence of H pylori–related PUD can be prevented in children by eradication of the infection. Therefore, eradication of the infection is recommended in a child with H pylori infection and PUD. The indication applies also for healed ulcers or a history of PUD. The finding of H pylori–associated gastritis in the absence of PUD during diagnostic endoscopy poses a dilemma for the endoscopist (see comment for recommendations 1, 2, and 3). As outlined in the comments for recommendations 1 and 2, there is inadequate evidence supporting a causal relation between H pylori gastritis and abdominal symptoms in the absence of ulcer disease. Therefore, eradication of the organism in the absence of ulcers may not result in improvement of symptoms. As reviewed in the comment for recommendation 3, H pylori is a risk factor for the development of gastric malignancies; however, only a fraction of infected individuals develop cancer. The carcinogenic risk is modified by strain-specific bacterial factors, host responses, and/or specific host–microbe interactions. Current evidence suggests that in high-risk populations such as in China, the eradication of H pylori may have the potential to decrease the risk of gastric cancer in a subset of individuals without precancerous lesions. Therefore, the decision to treat H pylori-associated gastritis without duodenal or gastric ulcer is subject to the judgment of the clinician and deliberations with the patient and family, taking into consideration the potential risks and benefits of the treatment in the individual patient. The primary goal of testing is to diagnose the cause of clinical symptoms. By definition, a ‘‘test and treat’’ strategy (the detection of the presence of H pylori infection by a noninvasive test followed by treatment in the case of a positive test) will not provide this information in children (see comments on recommendations 1 and 2). Therefore, in contrast to current guidelines for adults, current evidence does not support this practice in children. JPGN 2011;53: 230–243

Qulale terapia dovrebbe essere applicata e in quale situazione?

La maggior parte delle evidenze e delle raccomandazioni per il trattamento dell’infezione da H. pylori derivano da dati sull’adulto La maggior parte degli studi pediatrici sono basati su case report e studi osservazionali di singoli centri che includono un numero piccolo di pazienti. Comunque, poichè molte opzioni terapeutiche non sono state ancora formalmente testate nei bambini, soprattutto nei paesi in via di sviluppo, ulteriori studi sono necessari. Aliment Pharmacol Ther 2007; 25, 523–536

First-line treatment recommendations for H pylori eradication in children JPGN 2011;53: 230–243

Raccomandazioni sull’eradicazione dell’H pylori Un test non invasivo affidabile per l’eradicazione è raccomandato almeno dopo 4-8 settimane dalla fine della terapia. Il test di suscettibilità agli antibiotici per la claritromicina è raccomandato prima dell’inizio della terapia a 3 farmaci con claritromicina in aree/popolazioni con una percentuale di resistenza dell’ H pylori alta per la claritromicina. La durata raccomandata della triplice terapia è di 7-14 giorni. Costi, complicanze ed effetti avversi dovrebbero essere presi in considerazione. Even when children become asymptomatic after treatment, it is recommended that the success of treatment regardless of the initial endoscopic findings be evaluated. The absence of symptoms does not necessarily mean the infection has been eradicated. Particularly in children who had PUD, persistence of infection would warrant additional treatment. Reliable tests to monitor successful eradication include the 13C-UBT and a monoclonal ELISA for detection of H pylori antigen in stool. A follow-up endoscopy is not routinely indicated unless other causes of ulceration (eg, eosinophilic gastroenteropathy, Crohn disease) are suspected or if biopsies are needed for culture and antibiotic susceptibility testing. JPGN 2011;53: 230–243

Antibiotic resistance rates in different continental areas Prevalence of H. pylori antibiotic resistance is increasing worldwide, and it is the main factor affecting efficacy of current therapeutic regimens. J Gastrointestin Liver Dis 2010 ;19: 409-414

Se il trattamento fallisce? EGDS con esame colturale e test di suscettibilità, con cambio di terapia antibiotica, se non eseguita prima della terapia di prima linea. FISH su biopsie conservate in paraffina se il test di suscettibilità alla claritromicina non è stata eseguita prima della terapia di prima linea. Cambiare la terapia aggiungendo un antibiotico, usando un differente antibiotico o aggiungendo bismuto e/o aumentando la dose e/o la durata della terapia. JPGN 2011;53: 230–243

Second-line therapy Quadrupla terapia: PPI+ metronidazolo + amoxicillina+ bismuto. Triplice terapia: PPI+ levofloxacina (moxifloxacina)+ amoxicillina. JPGN 2011;53: 230–243

Helicobacter pylori Infection in Children Take Home Messages L’ H pylori è un importante patogeno coinvolto nell’insorgenza di malattia gastroduodenale sia nei bambini che negli adulti. Sintomi specifici suggestivi di infezione da H pylori sono scarsi, inconsistenti e simili ad altri disordini severi più comuni in età pediatrica, che si manifestano con dolore addominale ricorrente, dispepsia o dolore epigastrico. Generalmente non bisogna indagare per H pylori a meno che il bambino non abbia segni d’allarme suggestivi di ulcera. H pylori is an important human pathogen that is a significant source of gastroduodenal disease in adults as well as children. Overall, approximately one half of the world’s population is infected with the bacterium, with acquisition of the infection commonly occurring before age 10 and in some developing populations before age 6 years. Person-to-person transmission occurs through several routes, oral-oral, gastricoral, and fecal-oral, and may occur through contaminated water and/or air. Children living in low socioeconomic, crowded conditions with infected household members are at greatest risk of acquiring the infection and may transmit the infection to their siblings. Specific symptoms suggestive of Hpylori infection are vague, inconsistent, and similar to several other more common childhood disorders, manifesting as recurrent abdominal pain, dyspepsia, or epigastric pain. Generally, one does not investigate for H pylori unless the child has symptoms suggestive of an ulcer.

Helicobacter pylori Infection in Children Take Home Messages Nonostante la disponibilità di molti test non invasivi l’endoscopia con biopsia gastrica resta il gold standard per confermare la diagnosi di H pylori. L’infezione da H pylori può essere eredicata dalla terapia antibiotica, ma nessun regime terapeutico è efficace al 100%. Il numero di farmaci da assumere e la durata del trattamento spesso contribuiscono ad una scarsa compliance del paziente Although several noninvasive tests have been evaluated, endoscopy with gastric biopsy is, at present, considered the gold standard to confirming the diagnosis of H pylori. Despite the lack of clinical evidence, the clinical trend has been to more aggressively test children for the presence of H pylori and to treat those children who are found to have the infection. H pylori infection can be eradicated by antimicrobial therapy, but no treatment regimen is 100% effective, and the multiple drugs, frequent dosing, and length of treatment often contribute to poor patient compliance, and antibiotic eradication therapy is associated with increasing drug resistance.