Clinical management of Helicobacter pylori: the Latin American perspective.

In most South American countries, Helicobacter pylori infection prevalence is high, affecting over 70% in populations with precarious living conditions. It is worth pointing out that there is initial evidence of a decline in prevalence of H. pylori infection at least in some more privileged fragments of the population. It is estimated that gastric cancer, the main clinical sequela of H. pylori infection, has an average incidence rate of 12.4 cases per 100,000 inhabitants (8.4 cases per 100,000 inhabitants for women and 17.3 cases per 100,000 for men) in the region. Classical triple therapy [proton pump inhibitor (PPI), amoxicillin and clarithromycin] is still the most used regimen with eradication rates around 80%. The rates of resistance to clarithromycin range from 2 to 24%. Recurrence rates of the infection are described as 2.9% in Argentina, 4.2% in Chile, 2-7% in Brazil, and 11.5% in a trial involving 7 Latin American countries. After failure of clarithromycin-containing regimens, second- and third-line therapies using PPI, amoxicillin and levofloxacin and quadruple therapy with PPI, colloidal bismuth subcitrate, tetracycline hydrochloride and metronidazole are recommended. Due to the high rates of primary resistance to metronidazole in the Latin American countries, use of the quadruple therapy, replacing metronidazole for furazolidone, is a frequent option. Rescue triple therapy regimens using furazolidone in association with levofloxacin and PPI have also been used. Most recommended rescue therapies reach eradication rates close to 80%.

Helicobacter pylori and colorectal neoplasms: a concise review.

Helicobacter pylori is the main etiological agent of all malignant tumors caused by an infectious disease. It is a major, at times dominant, factor in the pathogenesis of a large spectrum of diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastric carcinoma, and lymphoma. Epidemiological and experimental studies suggest that H. pylori chronic infection may be related to different extragastric diseases, including colorectal neoplasms. This concise review aims to explore the association of H. pylori infection with colorectal cancer and adenoma, including the recent epidemiological findings, the diagnostic methods employed to detect H. pylori and virulent factors, and the potentially involved mechanisms. Furthermore, is attempted to establish the current data integration for causal inference using the Bradford-Hill causality criteria. The weak, although global, strength of the epidemiological positive association between H. pylori infection and colonic neoplasms associated to new mechanisms postulated to explain this interaction, including intestinal dysbiosis, should stimulate future studies. Prospective confirmatory studies to establish the role of H. pylori eradication in the process of carcinogenic transformation of the colonic epithelium may define its eventual role in the treatment and prevention of colonic neoplasms.

HELICOBACTER PYLORI CHRONIC GASTRITIS ON PATIENTS WITH PREMALIGNANT CONDITIONS: OLGA AND OLGIM EVALUATION AND SERUM BIOMARKERS PERFORMANCE.

BACKGROUND: H. pylori chronic atrophic gastritis is a premalignant lesion, and its staging, according to OLGA and OLGIM systems aims to identify patients at increased risk of developing gastric cancer and optimize their follow-up. GastroPanel®, serum biomarkers panel including pepsinogen I (PGI), pepsinogen II (PGII), Gastrin 17 (G17) and anti- H. pylori antibodies is a noninvasive test for adenocarcinoma risk assessment in chronic H. pylori gastritis patients. OBJECTIVE: Prospective study to evaluate the concordance between OLGA and OLGIM grading systems, as well as to evaluate GastroPanel´s performance in patients with premalignant lesions secondary to H. pylori chronic gastritis in Brazil. METHODS: Patients with H. pylori chronic gastritis with premalignant lesions confirmed by histology were recruited from the gastrointestinal clinic of a University Hospital. All participants underwent endoscopic examination with biopsies which were reported according to updated Sydney system and premalignant lesions grading systems (OLGA and OLGIM). Blood samples were collected for biomarkers serological analysis (GastroPanel®, Biohit, Helsinki, Finland). The cut off values used to define high risk patients were those recommended by the manufacturer: PGI ≤30 µm/L and PGI/PGII ≤3. RESULTS: 41 patients were recruited: 28 women, 13 men, mean age 67.3 (47-89, SD: 9.6) years. By OLGA system, were obtained: OLGA 0 (n=1), OLGA I (n=7), OLGA II (n=17), OLGA III (n=9), and OLGA IV (n=7). By OLGIM system, were obtained: OLGIM 0 (n=14), OLGIM I (n=5), OLGIM II (n=10), OLGIM III (n=10), and OLGIM IV (n=2). Regarding histological staging among patients staged as low risk (OLGA/OLGIM 0, I and II) and high risk (OLGA/OLGIM III and IV) for gastric cancer development, the concordance rate found between both classifications was 85.4%. Considering high risk patients, those patients thus included in at least one of the systems the final distribution of our sample considered 24 low-risk and 17 high-risk patients for the development of gastric cancer. To determine by GastroPanel® whether the patient would be at low or high risk of developing gastric cancer, PGI showed a sensitivity, specificity and accuracy of 0.47 (95%CI: 0.26-0.69), 0.67 (95%CI: 0.47-0.82), and 0.58 (95%CI: 0.43-0.72), respectively, while PGI/PGII showed sensitivity, specificity and accuracy of 0.06 (95%CI: 0.01-0.27), 0.83 (95%CI: 0.64-0.93) and 0.51 (95%CI: 0.36-0.66), respectively. CONCLUSION: The histological classifications OLGA and OLGIM presented a substantial concordance rate among themselves. Simultaneous use of both histological classification systems increased the identification's rate of high-risk patients. Biomarker analysis was not effective to distinguish low to high risk patients in the studied population. Further studies are needed to validate its use in clinical practice in Brazil.

PROSPECTIVE STUDY FOR VALIDATION OF A SINGLE PROTOCOL FOR THE 13C-UREA BREATH TEST USING TWO DIFFERENT DEVICES IN THE DIAGNOSIS OF H. PYLORI INFECTION.

BACKGROUND: 13C-urea breath test (UBT) is the gold-standard, noninvasive method for H. pylori diagnosis. However, there is no uniform standardization of the test. This situation can be unpractical for laboratories running with two or more devices. OBJECTIVE: To perform a prospective comparison validation study of UBT employing one validated protocol for two different devices: BreathID Hp Lab System® (Exalenz Bioscience Ltd, Israel), here called device A and IRIS-Doc2® (Wagner Analysen-Technik, Germany, now Mayoly Spindler Group, France), here called device B, in the diagnosis of H. pylori infection. METHODS: A total of 518 consecutive patients (365 females, 153 males, mean age 53 years) referred for UBT were included. All patients received device A protocol as follow: after at least one hour fasting, patients filled two bags prior to the test, then ingested an aqueous solution containing 75 mg of 13C-urea with a 4.0 g citric acid powder and filled another two bags 15 min after ingesting the test solution. One pair of breath sample bags (before and after ingestion) was analyzed by the two different devices. A delta over baseline (DOB) ≥5‰ indicated H. pylori infection. Statistics: Wilcoxon test, kappa coefficient with 95% CI, Wilson's method. RESULTS: Considering the device A protocol as the gold standard, its comparison with device B showed a sensitivity of 99.3% (95% CI: 96.3-99.9) and a specificity of 98.9% (95% CI: 97.3-99.6). Kappa coefficient was 0.976 (95% IC: 0.956-0.997). CONCLUSION: Correlation between the two devices was excellent and supports a uniform standardization of UBT.

Performance of the 13C-urea breath test for the diagnosis of H. pylori infection using a substrate synthesized in Brazil: A preliminary study.

OBJECTIVE: The 13C-urea breath test is the main non-invasive test for the diagnosis of Helicobacter pylori infection. The availability of this test throughout the country is limited, mainly due to the difficulty in obtaining the labeled isotope from abroad. Recently, researchers from the Nuclear Energy Center in Agriculture at the University of São Paulo (CENA/USP) succeeded in synthesizing 13C-enriched urea for Helicobacter pylori diagnosis. The aim of the study was to compare the performance of the 13C-urea breath test using 13C-urea acquired abroad with that of a test using 13C-urea synthesized in Brazil. METHOD: Sixty-four dyspeptic patients participated in the study (24 men and 40 women). Initially, the patients performed the 13C-urea breath test using the imported substrate (Euriso-Top, France). Seven to fourteen days later, all the patients repeated the test using the Brazilian substrate. The samples from both examinations were processed in an infrared isotope analyzer (IRIS, Wagner Analisen Technik, Germany), and all delta over baseline (DOB) [%] values above four were considered positive results. RESULTS: Twenty-seven patients (42%) exhibited negative results for Helicobacter pylori infection, and thirty-seven patients (58%) exhibited positive results when tested using the foreign substrate (gold standard). There was a 100% concordance regarding the presence or absence of infection when the gold standard results were compared with those obtained using the Brazilian substrate. CONCLUSIONS: Similar performance in the diagnosis of Helicobacter pylori infection was demonstrated when using the 13C-urea breath test with the Brazilian 13C-urea substrate and the test with the substrate produced abroad. This validation represents an important step toward increasing the availability of the 13C-urea breath test throughout the country, which will have a positive influence on the management of Helicobacter pylori infection.

Helicobacter pylori and colorectal neoplasms: a concise review / Helicobacter pylori e neoplasias colorretais: revisão concisa

ABSTRACT Helicobacter pylori is the main etiological agent of all malignant tumors caused by an infectious disease. It is a major, at times dominant, factor in the pathogenesis of a large spectrum of diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastric carcinoma, and lymphoma. Epidemiological and experimental studies suggest that H. pylori chronic infection may be related to different extragastric diseases, including colorectal neoplasms. This concise review aims to explore the association of H. pylori infection with colorectal cancer and adenoma, including the recent epidemiological findings, the diagnostic methods employed to detect H. pylori and virulent factors, and the potentially involved mechanisms. Furthermore, is attempted to establish the current data integration for causal inference using the Bradford-Hill causality criteria. The weak, although global, strength of the epidemiological positive association between H. pylori infection and colonic neoplasms associated to new mechanisms postulated to explain this interaction, including intestinal dysbiosis, should stimulate future studies. Prospective confirmatory studies to establish the role of H. pylori eradication in the process of carcinogenic transformation of the colonic epithelium may define its eventual role in the treatment and prevention of colonic neoplasms.

RESUMO Helicobacter pylori é o principal agente etiológico dos tumores malignos causados por doenças infecciosas. Constitui fator importante, às vezes dominante, na patogênese de um amplo espectro de doenças como gastrite aguda e crônica, úlceras gástricas e duodenais, carcinoma gástrico e linfoma. Estudos epidemiológicos e experimentais sugerem que a infecção crônica por H. pylori pode estar relacionada a diferentes doenças extragástricas, incluindo neoplasias colorretais. Esta concisa revisão tem como objetivo explorar a associação da infecção por H. pylori com câncer colorretal e adenoma, incluindo os recentes achados epidemiológicos, os métodos de diagnóstico empregados para detectar H. pylori e seus fatores de virulência com os mecanismos potencialmente envolvidos nesta relação. Além disso, procura-se estabelecer a integração dos dados atuais na busca de inferência causal com o emprego dos critérios de causalidade de Bradford-Hill. A associação epidemiológica positiva entre infecção por H. pylori e neoplasias do cólon embora classificada como fraca - porém global - do ponto de vista epidemiológico, quando associada a mecanismos recentemente postulados para explicar essa interação, incluindo disbiose intestinal, deverá estimular a realização de investigações futuras. Estudos prospectivos confirmatórios para estabelecer o papel da erradicação do H. pylori no processo de transformação carcinogênica do epitélio do cólon são aguardados para definir seu eventual papel no tratamento e prevenção de neoplasias do cólon.

Estudo prospectivo para validação de protocolo único para o teste respiratório com ureia marcada com carbono-13 empregando dois dispositivos diferentes, no diagnóstico da infecção por H. pylori / Prospective study for validation of a single protocol for the 13c-urea breath test using two different devices in the diagnosis of h. pylori infection

ABSTRACT BACKGROUND: 13C-urea breath test (UBT) is the gold-standard, noninvasive method for H. pylori diagnosis. However, there is no uniform standardization of the test. This situation can be unpractical for laboratories running with two or more devices. OBJECTIVE: To perform a prospective comparison validation study of UBT employing one validated protocol for two different devices: BreathID Hp Lab System® (Exalenz Bioscience Ltd, Israel), here called device A and IRIS-Doc2® (Wagner Analysen-Technik, Germany, now Mayoly Spindler Group, France), here called device B, in the diagnosis of H. pylori infection. METHODS: A total of 518 consecutive patients (365 females, 153 males, mean age 53 years) referred for UBT were included. All patients received device A protocol as follow: after at least one hour fasting, patients filled two bags prior to the test, then ingested an aqueous solution containing 75 mg of 13C-urea with a 4.0 g citric acid powder and filled another two bags 15 min after ingesting the test solution. One pair of breath sample bags (before and after ingestion) was analyzed by the two different devices. A delta over baseline (DOB) ≥5‰ indicated H. pylori infection. Statistics: Wilcoxon test, kappa coefficient with 95% CI, Wilson's method. RESULTS: Considering the device A protocol as the gold standard, its comparison with device B showed a sensitivity of 99.3% (95% CI: 96.3-99.9) and a specificity of 98.9% (95% CI: 97.3-99.6). Kappa coefficient was 0.976 (95% IC: 0.956-0.997). CONCLUSION: Correlation between the two devices was excellent and supports a uniform standardization of UBT.

RESUMO CONTEXTO: O teste respiratório com ureia-marcada com carbono-13 (TR-13C) é o método padrão-ouro para o diagnóstico não invasivo da infecção por H. pylori. Apesar disto, não existe uma uniformização de protocolos para a sua realização, trazendo dificuldades operacionais para laboratórios ou clínicas que operam com equipamentos de fabricantes diferentes. OBJETIVO: Estudo prospectivo e comparativo para validação do TR-13C para o diagnóstico de infecção por H. pylori, com emprego de protocolo único para dois equipamentos diferentes, a saber: BreathID Hp Lab System® (Exalenz Bioscience Ltd, Israel), aqui denominado equipamento A e IRIS-Doc2® (Wagner Analysen-Technik, Alemanha, agora Mayoly Spindler Group, França), aqui denominado equipamento B. MÉTODOS: Um total de 518 pacientes (365 mulheres e 153 homens, idade média de 53 anos) consecutivamente encaminhados para a realização do TR-13C foram incluídos no estudo. Todos os participantes realizaram TR-13C, que foi processado e analisado simultaneamente pelos dois equipamentos. Embora os dois equipamentos possuam protocolos independentes previamente validados, foi optado, por sua maior praticidade, pela utilização de um único protocolo, conforme recomendado pelo fabricante do equipamento A, e assim resumido: após jejum mínimo de 1h, foram amostras de ar expirado coletadas em dois pequenos sacos coletores (120 mL), correspondendo ao tempo-zero (amostra-1, controle). Em seguida, os pacientes ingeriram, em até 2 min, uma solução aquosa (200 mL) contendo 75 mg de 13C-ureia e 4,0 gramas de ácido cítrico em pó, adicionado com edulcorante. Uma segunda coleta de ar expirado era realizada 15 min após a ingestão do substrato em dois novos pequenos sacos coletores, correspondendo à amostra-2. Foram considerados positivos para a presença da infecção por H. pylori quando apresentavam um delta over baseline (DOB) igual ou maior que 5‰. Análise estatística foi realizada com o teste de Wilcoxon, coeficiente kappa com IC 95% e método de Wilson. RESULTADOS: Considerando o protocolo do equipamento A como o padrão-ouro, sua comparação com o equipamento B mostrou sensibilidade de 99,3% (IC 95%: 96,3-99,9) e especificidade de 98,9% (IC 95%: 97,3-99,6). O coeficiente kappa observado foi de 0,976 (IC 95%: 0,956-0,997). CONCLUSÃO: A correlação entre os dois equipamentos foi excelente e contribui para uma uniformização de protocolos para TR-13C.

Performance of the 13C-urea breath test for the diagnosis of H. pylori infection using a substrate synthesized in Brazil: A preliminary study

OBJECTIVE: The 13C-urea breath test is the main non-invasive test for the diagnosis of Helicobacter pylori infection. The availability of this test throughout the country is limited, mainly due to the difficulty in obtaining the labeled isotope from abroad. Recently, researchers from the Nuclear Energy Center in Agriculture at the University of São Paulo (CENA/USP) succeeded in synthesizing 13C-enriched urea for Helicobacter pylori diagnosis. The aim of the study was to compare the performance of the 13C-urea breath test using 13C-urea acquired abroad with that of a test using 13C-urea synthesized in Brazil. METHOD: Sixty-four dyspeptic patients participated in the study (24 men and 40 women). Initially, the patients performed the 13C-urea breath test using the imported substrate (Euriso-Top, France). Seven to fourteen days later, all the patients repeated the test using the Brazilian substrate. The samples from both examinations were processed in an infrared isotope analyzer (IRIS, Wagner Analisen Technik, Germany), and all delta over baseline (DOB) [%] values above four were considered positive results. RESULTS: Twenty-seven patients (42%) exhibited negative results for Helicobacter pylori infection, and thirty-seven patients (58%) exhibited positive results when tested using the foreign substrate (gold standard). There was a 100% concordance regarding the presence or absence of infection when the gold standard results were compared with those obtained using the Brazilian substrate. CONCLUSIONS: Similar performance in the diagnosis of Helicobacter pylori infection was demonstrated when using the 13C-urea breath test with the Brazilian 13C-urea substrate and the test with the substrate produced abroad. This validation represents an important step toward increasing the availability of the 13C-urea breath test throughout the country, which will have a positive influence on the management of Helicobacter pylori infection.

Does low dose (13)C-urea breath test maintain a satisfactory accuracy in diagnosing Helicobacter pylori infection?

CONTEXT: The standard doses of (13)C-urea in (13)C-urea breath test is 75 mg. OBJECTIVE: To assess the diagnostic accuracy of (13)C-urea breath test containing 25 mg of (13)C-urea comparing with the standard doses of 75 mg in the diagnosis of Helicobacter pylori infection. METHODS: Two hundred seventy adult patients (96 males, 174 females, median age 41 years) performed the standard (13)C-urea breath test (75 mg (13)C-urea) and repeated the (13)C-urea breath test using only 25 mg of (13)C-urea within a 2 week interval. The test was performed using an infrared isotope analyzer. Patients were considered positive if delta over baseline was >4.0‰ at the gold standard test. RESULTS: One hundred sixty-one (59.6%) patients were H. pylori negative and 109 (40.4%) were positive by the gold standard test. Using receiver operating characteristic analysis we established a cut-off value of 3.4% as the best value of 25 mg (13)C-urea breath test to discriminate positive and negative patients, considering the H. pylori prevalence (95% CI: 23.9-37.3) at our setting. Therefore, we obtained to 25 mg (13)C-urea breath test a diagnostic accuracy of 92.9% (95% CI: 88.1-97.9), sensitivity 83.5% (95% CI: 75.4-89.3), specificity 99.4% (95% CI: 96.6-99.9), positive predictive value 98.3% (95% CI: 92.4-99.4), and negative predictive value 93.0% (95% CI: 88.6-96.1). CONCLUSIONS: Low-dose (13)C-urea breath test (25 mg (13)C-urea) does not reach accuracy sufficient to be recommended in clinical setting where a 30% prevalence of H. pylori infection is observed. Further studies should be done to determine the diagnostic accuracy of low doses of (13)C-urea in the urea breath test.

Does low dose13C-urea breath test maintain a satisfactory accuracy in diagnosing Helicobacter pylori infection? / Precisão do teste respiratório com pequenas doses de ureia marcada com carbono-13 no diagnóstico da infecção por Helicobacter pylori

CONTEXT: The standard doses of 13C-urea in 13C-urea breath test is 75 mg. OBJECTIVE: To assess the diagnostic accuracy of 13C-urea breath test containing 25 mg of 13C-urea comparing with the standard doses of 75 mg in the diagnosis of Helicobacter pylori infection. METHODS: Two hundred seventy adult patients (96 males, 174 females, median age 41 years) performed the standard 13C-urea breath test (75 mg 13C-urea) and repeated the 13C-urea breath test using only 25 mg of 13C-urea within a 2 week interval. The test was performed using an infrared isotope analyzer. Patients were considered positive if delta over baseline was >4.0‰ at the gold standard test. RESULTS: One hundred sixty-one (59.6 percent) patients were H. pylori negative and 109 (40.4 percent) were positive by the gold standard test. Using receiver operating characteristic analysis we established a cut-off value of 3.4 percent as the best value of 25 mg 13C-urea breath test to discriminate positive and negative patients, considering the H. pylori prevalence (95 percent CI: 23.9-37.3) at our setting. Therefore, we obtained to 25 mg 13C-urea breath test a diagnostic accuracy of 92.9 percent (95 percent CI: 88.1-97.9), sensitivity 83.5 percent (95 percent CI: 75.4-89.3), specificity 99.4 percent (95 percent CI: 96.6-99.9), positive predictive value 98.3 percent (95 percent CI: 92.4-99.4), and negative predictive value 93.0 percent (95 percent CI: 88.6-96.1). CONCLUSIONS: Low-dose 13C-urea breath test (25 mg 13C-urea) does not reach accuracy sufficient to be recommended in clinical setting where a 30 percent prevalence of H. pylori infection is observed. Further studies should be done to determine the diagnostic accuracy of low doses of 13C-urea in the urea breath test.

CONTEXTO: A dose convencional de 13C-ureia para a realização do teste respiratório com 13C-ureia é 75 mg. OBJETIVO: Determinar a precisão diagnóstica do teste respiratório contendo 25 mg de 13C-ureia comparada com a dose convencional de 75 mg para o diagnóstico de infecção por H. pylori. MÉTODOS: Duzentos e setenta pacientes adultos (96 homens, 174 mulheres, idade mediana de 41 anos) realizaram o teste respiratório convencional (75 mg 13C-ureia) e repetiram o teste respiratório usando apenas 25 mg de 13C-ureia dentro de 2 semanas de intervalo. O teste respiratório foi realizado empregando-se analisador de isótopos por infravermelho. Os pacientes foram considerados positivos quando apresentavam valor delta acima da linha de base >4.0 no teste respiratório convencional (padrão-ouro). RESULTADOS: Cento e sessenta e um pacientes (59,6 por cento) eram H. pylori negativos e 109 (40,4 por cento) eram positivos aos testes respiratórios convencionais. Para definição do melhor ponto de corte discriminatório entre positivos e negativos pelo teste respiratório com 25 mg, foi utilizado a curva ROC, obtendo-se o valor de 3,4 por cento, considerando-se a prevalência de 30,2 por cento (IC 95 por cento: 23.9-37.3) da infecção por H. pylori no laboratório, onde se realizou este estudo. Desta forma, para o teste respiratório com 25 mg foi obtida uma precisão diagnóstica de 92,9 por cento (IC 95 por cento: 88,1-97,9), sensibilidade de 83,5 por cento (IC 95 por cento: 75,4-89,3) e especificidade de 99,4 por cento (IC 95 por cento: 96,6-99,9). CONCLUSÕES: Teste respiratório com dose baixa (25 mg) de 13C-ureia não proporciona precisão suficiente para ser recomendado em ambientes clínicos, onde a prevalência de H. pylori está situada em torno de 30 por cento.