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Clarithromycin Resistance, Tumor Necrosis Factor Alpha Gene Polymorphism and Mucosal Inflammation Affect H. pylori Eradication Success

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Several bacterial and host-related factors concur in causing Helicobacter pylori eradication failure. We ascertained the role of bacterial virulence genes (cagA, vacA), clarithromycin resistance [ClaR, 23S ribosomal RNA (rRNA) mutations], host polymorphism of CYP2C19 (polyphosphoinositide, PPI, metabolism) and of the cytokines IL-1B-31C>T, IL-1RN VNTR, IFN-γ+874A>T, TNF-α-1031T>C, TNF-α-857C>T, TNF-α-376G>A, TNF-α-308G>A, TNF-α-238G>A, IL-10-1082A>G, IL-10-819C>T, IL-10-592C>A, IL-12A+6686G>A, IL-12B+15485A>C. Two groups of H. pylori-infected and H. pylori-treated patients were retrospectively identified: 45 not eradicated and 57 eradicated. Treatment failure was significantly correlated with ClaR (all resistant strains in non-eradicated patients); with TNF-α-238, IL10-819, IL10-592, IL-12B+15485 single nucleotide polymorphism (SNP); with IL10 ATA/ATA haplotype; and with antral inflammatory grade. On considering ClaS-infected patients only, logistic regression analysis (eradication = dependent; TNF-α-238, IL12B + 15485 genotypes, IL10 ATA/ATA as present or absent, antral gastritis grade = covariates) confirmed as significantly correlated with eradication antral gastritis grade only (Exp(B) = 6.48; 95% CI, 1.2–35.01). In conclusion, the bacterial determinant causing triple therapy failure is clarithromycin resistant, being virulence genes not involved. The host related factors that favor eradication are those linked to inflammation: a higher inflammatory infiltrate in the mucosa, possibly favored by genotypes able to down regulate the anti-inflammatory cytokine response, enhance the chance of eradication success.

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Abbreviations

ClaR :

Clarithromycin resistant

ClaS :

Clarithromycin sensitive

EM:

extensive metabolizer

IM:

intermediate metabolizer

MGB:

DNA minor groove binder

PAI:

pathogenicity island

PCR:

polymerase chain reaction

PM:

poor metabolizer

PPI:

proton pump inhibitor

RFLP:

restriction fragment length polymorphism

rRNA:

ribosomal RNA

SNP:

single nucleotide polymorphism

UBT:

urea breath test

UM:

ultrarapid metabolizer

VNTR:

variable number of tandem repeats

6-FAM:

6-carboxyfluorescin

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Authors and Affiliations

  1. Department of Medical and Surgical Sciences, University of Padova, Padova, Italy

    Carlo-Federico Zambon, Paola Fogar & Sergio Pedrazzoli

  2. Department of Laboratory Medicine, University of Padova, Padova, Italy

    Michela Fasolo, Daniela Basso, Alessia Stranges, Filippo Navaglia, Eliana Greco, Stefania Schiavon, Andrea Padoan, Elisa Fadi & Mario Plebani

  3. Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy

    Anna D’Odorico & Giacomo Carlo Sturniolo

  4. Department of Medical and Surgical Sciences, Clinica Chirurgica IV, Ospedale Giustinianeo, via Giustiniani 2, 35128, Padova, Italy

    Sergio Pedrazzoli

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  1. Carlo-Federico Zambon
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  2. Michela Fasolo
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  3. Daniela Basso
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  4. Anna D’Odorico
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  14. Sergio Pedrazzoli
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Correspondence to Sergio Pedrazzoli.

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DISCUSSION

Kimberly M. Dalal, M.D. (Travis AFB, CA): I would like to commend Dr. Zambon and Dr. Pedrazzoli and their colleagues for their work and thank them for submitting their manuscript to me for comment.

They examined the issue of H. pylori eradication failure, which is clinically important as this may lead to not only peptic ulcers but also gastric adenocarcinoma or MALToma in a subset of patients. They ascertained the association between triple therapy efficacy and various methods of failure, including clarithromycin‑resistance genes, bacterial virulence genes, and host polymorphisms of PPI metabolism as well as various cytokines. Treatment failure was noted to be significantly correlated with clarithromycin resistance and antral gastritis grade. Moreover, inflammation seemed to favor eradication. I have two questions.

You demonstrated that severe antral inflammatory grade is correlated with a higher rate of successful therapy, and you also showed that patients bearing the ATA/ATA genotype who are low IL‑10 producers and develop more severe inflammation were found to be at a higher frequency in the eradicated than the non‑eradicated group. How do you reconcile this role of inflammation with eradication in some patients but also a higher risk of cancer development in others?

Sergio Pedrazzoli, M.D. (Padova, Italy): We found that more inflammation was better and was due to the onset of cytokines locally. Now, there are enough patient studies to tell you what happens with cancers in these patients. On the other hand, the ATA haplotype is significantly associated with lower production of interleukin 10, and this may explain why the result was different in this kind of patient.

Dr. Dalal:My second question is: you mentioned that bacterial resistance to amoxicillin among Italian patients is low while clarithromycin resistance is more prevalent. How will your data that you have shown today change your approach to patient management in Italy?

Dr. Pedrazzoli: The findings from the Maastricht III Consensus Report indicated that you have to change therapy when you have a prevalence higher than 20%. You need to know if the patient is resistant and then change therapy. We in Italy are in the range lower than 20%. But when you have a prevalence that is higher, you need to look for resistance. Otherwise you treat the patient, observe the patient, and if the patient does not recover, you can change therapy.

Jonathan F. Critchlow, M.D. (Boston, MA): You had a high level of resistant patients. You had a 45% resistance rate.

Dr. Pedrazzoli: Sorry, this was a mistake. I am not the specialist on the matter because he was not able to come here. When preparing the discussion, I posed the same question. Allow me to explain why.

It is a selection bias because we selected from among 800 patients a group of patients who responded and a group of patients who did not respond and compared the pattern of patient characteristics and H. pylori characteristics that would influence the response. But our response rate to triple therapy is about 80‑85%, as is usually observed.

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Zambon, CF., Fasolo, M., Basso, D. et al. Clarithromycin Resistance, Tumor Necrosis Factor Alpha Gene Polymorphism and Mucosal Inflammation Affect H. pylori Eradication Success. J Gastrointest Surg 11, 1506–1514 (2007). https://doi.org/10.1007/s11605-007-0246-4

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