Helicobacter pylori infection

Abstract

Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but prevalence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship.

Fig. 1 |. Key developments in H. pylori clinical research and management.

Helicobacter pylori was discovered and reported at a conference in 1982 but the finding was not further disseminated before the first publication in 1983 (ref. 7). The timeline highlights key developments in clinical research of H. pylori infection and its therapeutic management since 1982 (refs. ,–,,,,,,,,,,,–383). OLGA, Operative Link on Gastritis Assessment; OLGIM, Operative Link on Gastritis/Intestinal Metaplasia Assessment; PPI, proton pump inhibitor.

Fig. 2 |. Prevalence of H. pylori infection in adults and children.

a,b, Global map of Helicobacter pylori infection prevalence in adults during 1970–2016 (part a) and in children and adolescents (<20 years) during 2000–2021 (part b). In adults, the prevalence was highest in Africa, Eastern Mediterranean regions, Russia, Middle America and South America. In children, the prevalence was lower than that in adults in Russia, Western Pacific regions and European regions. However, the prevalence of H. pylori infection was similarly high in children and adults in Africa, Eastern Mediterranean regions, and Middle America and South America^,.

Fig. 3 |. H. pylori infection and pathogenesis.

Key aspects of bacterial colonization involve flagellar motility, urease activity, mechanisms of adhesion and damage to the gastric epithelium via vacuolization. The Helicobacter pylori pathogenicity island exerts a key role in inflammation, composes a type IV secretory system (T4SS) and promotes the intracellular injection of cytotoxin-associated gene A (CagA) antigen. The host immune response is characterized by initial mucosal invasion with polymorphonuclear cells followed by activation of the innate and adaptive immune system with complex T helper 1 (T_H1), T_H17 and regulatory T (T_reg) cell interactions. Le^b, Lewis b blood group antigen; sLe^x, sialyl-Lewis x antigen.

Fig. 4 |. Pathogenesis of gastric adenocarcinoma triggered by H. pylori.

The Correa cascade describes the dynamic progress of gastric carcinogenesis along the stepwise evolution of chronic gastritis initiated by Helicobacter pylori infection. H. pylori causes chronic gastritis that is associated with the generation of reactive oxygen species and nitric oxide metabolites and a reduction in antioxidant vitamin C levels. The risk of gastric cancer is highest in individuals who have infection by more virulent H. pylori strains, have pro-inflammatory host genetic factors, poor diet (high salt, smoked foods), low iron levels, unhealthy lifestyle and/or smoking habit. In these individuals, sustained chronic inflammation leads to damage and loss of acid-producing parietal cells, which leads to hypochlorhydria and finally achlorhydria. The loss of acidity facilitates colonization by harmful pro-inflammatory gastric microbiota, which in turn may produce more genotoxic pro-inflammatory metabolites and carcinogens that act directly on malignant epithelial cell transformation in the stomach^–.

Fig. 5 |. H. pylori diagnostic procedures.

Diagnostic procedures are selected according to clinical scenarios. Non-invasive testing with the ¹³C-urea breath test and stool antigen test enables diagnosis of a current infection. Serological Helicobacter pylori antibody detection does not enable differentiation between current and previous H. pylori infection, necessitating confirmation by ¹³C-urea breath test or stool antigen test. All invasive tests are based on biopsy samples from gastroscopy. These enable histological assessment for gastritis grading and staging, direct H. pylori detection via PCR, microbial culture, rapid urease test, and molecular examinations. Antibiotic susceptibility testing (AST) can be performed from stool or biopsy samples using microbial culture, next-generation sequencing (NGS) or real-time PCR (RT-PCR) techniques. FISH, fluorescence in situ hybridization; qPCR, quantitative PCR.

Fig. 6 |. Suggested H. pylori therapy algorithm.

Helicobacter pylori therapy algorithm with the indication of regimens that consist of triple or quadruple combinations to be used in first-line and subsequently in case of failure. Proton pump inhibitors (PPIs) or, where available, potassium-competitive acid blockers are essential components for acid suppression to render antibiotics more effective. PPI can be substituted by potassium-competitive acid blockers where available. Antibiotics are selected according to individual antibiotic susceptibility testing (AST) or according to regional antibiotic susceptibility based on surveillance as well as according to local availability. Clarithromycin-based PPI triple therapy (PPI-TT) is a first-line therapy if local clarithromycin resistance prevalence is <15%. If clarithromycin resistance exceeds 15% or is unknown, the recommended first-line regimen is BiQT (PPI, bismuth, tetracycline and a nitroimidazole antibiotic). Levofloxacin-based regimens are recommended as second-line treatments if a first-line regimen with BiQT fails. Levoflaxin-based regimens include amoxicillin and PPI. If levofloxacin resistance in regional surveillance exceeds 15%, it is advisable to directly select third-line or fourth-line regimens as rescue therapy. The fourth-line regimen (rescue therapy) consists of PPI, rifabutin and amoxicillin (or clarithromycin in case of penicillin allergy).