Chronic gastritis in pediatrics

Nina V Gabueva, Violetta S. Kalinchuk, Diana R. Radchenko, Stepan A. Donchenko, Anzhela A. Panesh, Semen A. Popov. Chronic Gastritis in Pediatrics. Cardiometry; Issue No. 29; November 2023; p. 54-61; DOI: 10.18137/cardiometry.2023.29.5461; Available from:

Pediatric gastroenterology emerged as a distinct field in the late 1970s, largely driven by the development and implementation of numerous effective instrumental methods for examining the gastrointestinal tract (GIT). Managing pediatric patients differs significantly from that of adult patients due to the immaturity of many organs and systems, critical developmental stages in childhood, non-equivalent pharmacokinetics, frequent comorbidities, and more [1]. The lifestyle of contemporary children differs from that of their predecessors from past eras, marked by frequent physical inactivity, irregular and irrational high-calorie diets, unwarranted medication use, sometimes harmful habits, and stress. These factors pose additional threats to the development of various diseases within the body, including those affecting the GIT.

Approximately 70-75% of GIT disorders primarily affect its upper segments, with the prevalence of chronic gastritis (CG) reaching 300-400 cases per 1,000 children in the pediatric population [2]. The relevance of the chronic gastritis problem is not only attributed to its high prevalence among children but also the potential development of complications and a decrease in the quality of life, which is particularly perilous during periods of growth and active organ formation.

The aim of this article is to analyze the issue of chronic gastritis in its various clinical aspects.

Materials and Methods

To address the research objectives, a comprehensive literature search was conducted using the PubMed and Google Scholar databases. Articles that were freely accessible and published within the last 5 years were selected.

PubMed: The search query “gastritis in children (last 5 years, open access)” yielded 277 results.

Google Scholar: The search query “gastritis in children (since 2019)” produced 5580 results.

Non-informative and duplicate sources, as well as articles behind paywalls, were excluded during the selection process.

In total, 42 articles were included in the literature review.

Results

Risk Factors for the Development of Chronic Gastritis

Gastritis is defined as histologically confirmed inflammation of the gastric mucosa, affecting up to 50% of the global population. Numerous factors contribute to gastritis, including Helicobacter pylori infection, bile reflux into the stomach, non-steroidal anti-inflammatory drug use, improper dietary habits, chemical injuries, harmful habits, physical and psychological stress. Inflammation of the gastric mucosa can lead to complications such as erosions, hemorrhage, hyperemia, edema with inflammatory infiltration of the gastric layers [3].

The probability of developing gastritis is heightened by genetic predisposition, stress, harmful habits, reflux, physical inactivity, pathological course of pregnancy and childbirth in mothers, and artificial feeding. It has been demonstrated that eliminating adverse living conditions, excessive medication use, consumption of untreated water and fast food, inadequate sleep, and spending summer vacations in urban environments can reduce gastric diseases by 29-53.1%. In the absence of harmful habits among parents and family stress, the frequency of chronic gastritis in children decreases by 26.7-30.9%. Respiratory infections, artificial feeding, and reduced mobility increase the probability of gastric diseases by 32.1%, 53.2%, and 18.628.5%, respectively [4]. In a study by D. Rivera-Nieves et al., gastritis was identified in 26% of children requiring intensive nutrition programs [5]. There exists a correlation between living conditions and the type of gastritis. The severity of gastritis and inflammation may be associated with genetic polymorphism in certain immune receptor genes [6]. Endogenous risk factors for gastritis include diseases of various internal organs (heart, kidneys, blood disorders, diabetes, etc.), which often exert a neuro-reflex influence on the stomach and the gastrointestinal tract as a whole [7].

In a significant number of cases, the cause of gastritis is the infection of H. pylori, which can persist throughout a person’s life, triggering inflammation of the gastric mucosa. In 5-15% of cases, it can lead to peptic ulcer disease, and less frequently, stomach cancer. The prevalence of H. pylori infection encompasses over 50% of the population in Asia, Africa, Latin America, and is dependent on socio-economic status. In Northern and Western Europe, this indicator stands at approximately 10%, in the Middle East it ranges from 24.7% to 68.3%, in India, it’s 45.7-42.8%, and in China, it’s 46%. Among the pediatric population, the prevalence of H. pylori in Ethiopia reaches 48%, in Nigeria - 82%, in Mexico - 43%, in Canada - 7.1%, in Bulgaria - 61.7%, and in the Netherlands -1.2%. In recent years, there has been a decline in the infection rate of Helicobacter in children [8-10].

Among children aged 1-10 years referred to a gastroenterologist, H. pylori is detected in the gastric mucosa in 56% of cases. In younger patients under 5 years old, gastritis tends to be milder, and highly active forms of bacteria are not found. This is attributed to a healthier and more regular diet, the absence of harmful habits, and an immature immune system [11].

In the pathogenesis of H. pylori-induced gastritis, the secretion of urease by bacteria plays a role. Urease hydrolyzes urea into ammonia and carbon dioxide, which helps neutralize the acidic environment of the stomach and aids in the survival of microorganisms. The presence of other enzymes in H. pylori leads to mucin degradation, and bacterial flagella make the bacteria motile, allowing them to penetrate through the mucus layer to the gastric epithelium [7]. Forms of gastritis such as autoimmune, eosinophilic, lymphocytic, and granulomatous are relatively rare.

Types of Gastritis

and Clinical Manifestations

Chronic gastritis is a gradually progressive degenerative-inflammatory condition characterized by disturbances in regeneration, proliferation, secretion, and motility processes. Signs of metaplasia and dysplasia of the gastric mucosa are often observed [7]. Clinicians distinguish three types of CG: Type A - autoimmune, Type B - H. pylori infection-related, Type C - chemical-toxic [2]. Gastritis associated with the use of non-steroidal anti-inflammatory drugs is linked to the suppression of prostaglandin synthesis, which plays a role in the implementation of gastric mucosa protective mechanisms [12]. Other classifications also mention: radiation gastritis; gastritis associated with Crohn’s disease; eosinophilic; sarcoidosis-associated; lymphocytic; ischemic; vasculitis-related gastritis; Menetrier’s disease [13].

Types of chronic gastritis based on clinical manifestations:

• •    Ulcer-like - pain on an empty stomach or 1.5-2 hours after meals (less commonly, nocturnal pain), tenderness in the epigastric region, preserved appetite, heartburn, occasional belching with sour contents or air. This type is associated with H. pylori, and endoscopy reveals edema and hyperemia of the gastric mucosa.

• •    Dyskinetic - aching pain after eating, in the epigastric region, spontaneously subsiding after 1.5 hours, a feeling of fullness, belching, nausea, and occasionally vomiting that provides relief. The dyskinetic type manifests in autoimmune or H. pylori-associated gastritis. Endoscopy shows involvement of the gastric body with no pronounced inflammation, and atrophic processes may be observed.

• •    Atypical - gastritis coexists with the involvement of other parts of the gastrointestinal tract, often presenting with dyspeptic symptoms, pathological reflux, spasms, and a sensation of fullness [7].

For chronic gastritis with H. pylori infection, more severe disease courses are characteristic. In the H. py-lori-positive group of patients, moderate and severe manifestations of gastritis reached 59% compared to 31% in patients with H. pylori-negative gastritis. The level of anemia in gastritis is not dependent on the presence of Helicobacter [14]. However, in a study by S. Kato et al., it was shown that hemoglobin, serum iron, and ferritin values significantly increased 2-3 months after eradication therapy [15, 16].

Eosinophilic gastritis belongs to the group of eosinophilic gastrointestinal disorders caused by eosinophilic inflammation of the gastrointestinal tissues. The mechanism of this inflammation is not fully understood. It is believed that altered T-helper 2-type responses, related to food allergies, play a major role in attracting eosinophils to gastrointestinal tissues, leading to disruptions in their function. Increased eosinophil content in the gastrointestinal tract is promoted by drug and food allergies, parasitic infections, malignant neoplasms, inflammatory bowel diseases, and eosinophilic syndrome [17]. The most common symptoms of eosinophilic gastroenteritis include abdominal pain (100%), diarrhea (59%), nausea/vomit-ing (36%), and abdominal bloating (27%). Pathognomonic endoscopic changes are not detected [18].

Autoimmune gastritis is a chronic atrophic gastritis limited to the body of the stomach, associated with a deficiency of Castle’s intrinsic factor, with or without pernicious anemia. The main pathogenesis is linked to the involvement of CD4+ T cells against parietal cells in the stomach, leading to mucosal atrophy and decreased intrinsic factor production. Typical symptoms are absent or attenuated in this type of gastritis. It is most often incidentally detected during gastric biopsy [19].

An example of an immune-mediated gastritis is collagenous gastritis. This variant of chronic gastritis is rare and affects 2.1 per 100,000 children aged 0-18 years. Forty-seven percent of patients have a family history of autoimmune diseases, 40% of children test positive for autoantibodies, and 53% test positive for DQ2/DQ8 antigen. Amyloid A levels are elevated in 33%, and calprotectin levels are elevated in 67% of children. Pediatric cases of collagenous gastritis may be asymptomatic or present with severe iron-deficiency anemia and/or recurrent abdominal pain, whereas diarrhea and malabsorption are more predominant in adults. Collagenous gastritis is often associated with type 1 diabetes and celiac disease [20, 21].

Diagnostics

In pediatric practice, the diagnosis of H. pylori-as-sociated gastritis relies on a positive bacterial culture result and a positive histological examination. Material for these methods is obtained using invasive procedures. Non-invasive methods are not justified for primary diagnosis, reducing the likelihood of false-positive gastritis diagnoses. In pediatric practice, biopsies are taken from the antral and body regions of the stomach (small and large curvature), along with an additional biopsy for rapid urease testing (RUT) or molecular analysis [10]. Chronic inflammation of the gastric mucosa is associated with neutrophilic inflammation, with the effects depending on the cytotoxicity of the H. pylori strain. The most cytotoxic strains can lead to the development of atrophic gastritis [13]. Sometimes, the gastric wall can be significantly thickened [22].

In a retrospective study involving 248 pediatric patients aged 0-18 years, A.T. Domsa et al. demonstrated a correlation between endoscopic and histopatholog- ical findings in H. pylori infection-related gastritis. A significant association was found between the presence of H. pylori and histopathological parameters, such as acute and chronic inflammatory infiltrate. It was established that bacterial load influenced the intensity of inflammation (p<0.001). Chronic inflammation predominated, while acute inflammation was observed in 23.2% of patients (p<0.001). Predominantly, pangastritis with uniform inflammation in the antral and body regions of the stomach was identified. Mucosal nodularity and lymphoid follicles in histological specimens indicated H. pylori infection [23].

In patients with eosinophilic gastritis, biopsies reveal an increased number of eosinophils and mast cells in addition to signs of inflammation [24].

RUT is characterized by high specificity and rapid result acquisition. False-positive results may occur in cases of recent gastrointestinal bleeding, intake of proton pump inhibitors (PPIs) for 2 or more weeks, antibiotics for 4 weeks, and bismuth-containing compounds [6, 10].

Molecular diagnostic methods can be useful in cases of H. pylori infection. Among the biopsies taken from 104 children, 42.3% showed positive PCR results, while 41.3% and 37.5% exhibited histologically confirmed signs of inflammation and bacterial colonization, respectively. The average scores of histological examination parameters were higher in the PCR-positive group. The use of PCR may be justified for children with negative results in histological or cultural studies but with macroscopic signs of inflammation [25].

Non-invasive tests have been validated, such as stool antigen analysis for H. pylori and the urea breath test (UBT). UBT is rarely used in children due to technical difficulties. Stool antigen analysis is used to confirm the eradication of the pathogen. Serological antigen detection tests are almost never used in pediatric diagnosis since antibodies persist for a long time after the eradication of the pathogen [10].

UBT is the most accurate test among non-invasive methods. It relies on H. pylori’s ability to hydrolyze urea into CO2 and ammonia using urease. Carbon dioxide enters the bloodstream and is exhaled through the lungs. By using urea as a substrate labeled with a carbon isotope, exhaled CO2 with labeled carbon can be measured and quantitatively determined for H. pylori diagnosis [26].

Endoscopic examinations in pediatric patients demonstrate high diagnostic efficiency, especially when a specific disease was suspected beforehand. In the study by T.D. Berger et al., 59% of children were able to receive a new diagnosis based on the results of esophagogastroduodenoscopy, with H. pylori-positive (HP+) gastritis diagnosed in 16.5% of children [27]. The detection of nodularity of the mucous membrane during endoscopic examination in the presence of active gastritis serves as a predictor of H. pylori infection [14]. Comparing the endoscopic findings between HP+ and HP- patients, Shahinyan T. et al. determined that in the HP+ variant, nodular gastric changes (p=0.02), gastric erosions (p=0.056), duodenal erosions (p=0.019) were more frequently identified. HP+ patients also exhibited a higher prevalence of chronic active gastritis (p=0.027) and chronic inactive gastritis (p=0.002), cumulative metaplasia/dysplasia/metaplasia/atrophy events in the stomach (p=0.014), and chronic inactive duodenitis (p=0.016) [28]. Clear indications are necessary when prescribing endoscopic examinations for children. In one publication, it was demonstrated that only 92.2% of all diagnostic esophagogastroduodenoscopies were justified, while 7.8% were prescribed incorrectly [29].

Ultrasound (US) is often used in pediatric emergency care. In US examinations of children with gastritis, a thickened inflamed gastric wall is typically observed. However, this method does not allow for the determination of the gastritis type and requires additional tests [30].

Eosinophilic gastritis is indicated by the elevation of eosinophils ≥30 per high-power field in gastric biopsy at high magnification [17]. Furthermore, a correlation has been established between the endoscopic appearance of eosinophilic gastritis and its clinical and histological features [31]. When there is suspicion of eosinophilic gastritis, the efficacy of biopsy in individuals with eosinophilia in the blood and hypoal-buminemia is nearly 30 times higher than in patients without blood abnormalities [32]. For highly sensitive and highly specific diagnosis of eosinophilic gastritis, a diagnostic panel has been developed, encompassing histological, endoscopic, molecular (18 genes), and serum (cytokines/chemokines) markers. This panel identifies patients with an active form of eosinophilic gastritis and monitors the activity of the pathological process. Serum markers and molecular targets correlate well with the number of eosinophils in the stomach and the histological picture [33].

In autoimmune gastritis, attention is drawn to the presence of two histological types of mucous mem

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branes: a normal mucous membrane of the antral part and an inflamed mucous membrane of the body of the stomach [19].

The diagnosis of collagenous gastritis is based on the detection of increased (more than 10 μm) subepi-thelial collagen deposition in at least one biopsy of the gastric mucosa, in combination with other confirming endoscopic and clinical data. During endoscopy, nodularity of the mucous membrane, hypertrophic folds of the stomach, erythema, and rarely signs of bleeding are more frequently identified. Helicobacter infection is not detected [20].

Treatment

Variants of chronic gastritis associated with H. pylori infection require the prescription of various eradication regimens, hindered by the spread of H. pylori strains resistant to antibiotic therapy. H. pylori does not always serve as the sole cause of gastritis, and its development depends on the child’s immune status [34]. To eliminate H. pylori from the gastric mucosa, triple therapy regimens are widely used, involving a proton pump inhibitor (PPI) and two antimicrobial agents, such as amoxicillin, clarithromycin, metronidazole, levofloxacin, or tetracycline. The most common choices for eradication involve combinations of clarithromycin and amoxicillin or clarithromycin and metronidazole. Despite the fact that the success of eradication therapy depends on various factors (diet, avoidance of harmful habits, etc.), the development of antibiotic resistance is the decisive factor in treatment failure. In one study, the drug resistance of H. pylori was tested, revealing that the rates of primary resistance to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and multiple resistance were 15%, 34.1%, 69.4%, 27.9%, 17.9%, and 48.8%, respectively. Secondary resistance to the same drugs was 9.5%, 74.9%, 61.5%, 45.7%, 23.5%, and 62.3%, respectively [35]. In a publication by L.T. Le et al., a cohort of 237 children showed that H. pylori were most frequently resistant to clarithromycin (80.6%), amoxicillin (71.7%), metronidazole (49.4%), and tetracycline (11.4%). The overall eradication rate was 83.1%. The quadruple regimen with bismuth was the most successful, whereas the efficacy of triple therapy (esomeprazole, amoxicillin, clarithromycin/metronidazole) was low [36]. In another clinical pediatric study, antibiotic resistance rates were 20% for amoxicillin, 45% for clarithromycin, and 59% for metronidazole [37].

In populations with high resistance to drug therapy, it is necessary to assess bacterial sensitivity to antibiotics and include bismuth and tetracycline in treatment regimens. Widespread use of antibiotics by the population leads to a decrease in the effectiveness of H. pylori eradication. Although H. pylori infection is asymptomatic in 90% of individuals, in some cases, it can lead to complications such as atrophic gastritis, mucosal lymphoma, gastric adenocarcinoma, and peptic ulcer disease [10]. Regardless of the geographical region, H. pylori is involved in the pathogenesis of gastric cancer through mechanisms that involve the suppression of the tumor suppressor gene p53 and inhibition of apoptosis [38].

Patients with eosinophilic gastritis are prescribed proton pump inhibitors (PPIs) (61%), topical corticosteroids (23%), systemic corticosteroids (20%), and elimination diets (58%) [17, 39]. For patients with eosinophilic gastritis who do not respond to corticosteroids, integrin blocker vedolizumab is occasionally prescribed, leading to clinical and histological improvement [18]. A clinical study of benralizumab in patients with eosinophilic gastritis demonstrated a significant positive effect of the drug: it led to a depletion of eosinophil pools in the blood and gastrointestinal tissues, disappearance of typical gastrointestinal symptoms after the first month of therapy, and increased levels of anti-inflammatory cytokines IL-4 and IL-5 [40].

Elimination diets show high efficacy in eosinophilic gastritis. The most common allergenic foods include chicken eggs, cow’s milk, rice, soy, wheat, nuts, beef, pork, chicken, fish, and shellfish. Allergic reactions to potatoes, fruits, and vegetables, which are included in the elimination diet along with an amino acid cocktail, are rare. Processed foods and flavorings are not allowed, but select spices are permitted. The nutritional content remains mostly within the normal range, except for fat and selenium. In a clinical study, implementation of the elimination diet led to weight loss due to increased serum protein levels, which eliminated edema. Serum albumin levels increased by an average of 2.9-3.5 g/dL [41].

For autoimmune gastritis, endoscopic surveillance is recommended every 3-5 years to detect epithelial dysplasia, gastric carcinoma, and adenocarcinoma. In cases of anemia, patients are prescribed vitamin B12 and iron supplements [19].

There is no effective treatment for collagenous gastritis. Attempts are made to treat patients with PPIs and dietary modifications (gluten-free, dairy-free, egg-free, wheat-free). Clinical response is observed in 78.5% of patients. However, no histological or endoscopic improvements occur. Due to anemia, patients are prescribed iron supplements to normalize hemoglobin levels [20, 42].

Discussion and Conclusions

Analysis of the literature data demonstrates that “chronic gastritis” represents a group of heterogeneous diseases in terms of etiology and pathogenesis, which results in significant variability in their clinical manifestations and prescribed treatment regimens. Pathological inflammatory changes can be caused by infectious agents as well as other factors, including immune disorders and direct damage to the gastric mucosa, such as by medications. The complexity of diagnosing certain rare forms of gastritis is often associated with asymptomatic courses, and gastritis is occasionally discovered incidentally during esophagogastroduodenoscopy (EGD) and histological examination of gastric biopsy specimens. These two methods, along with bacterial culture, remain the mainstay in the diagnosis of the disease, although attempts are being made to use rapid urease tests and stool antigen analysis for H. pylori.

A significant challenge in gastritis treatment has been the spread of drug-resistant strains of H. pylori in the human population, making susceptibility testing and individualized treatment regimens increasingly necessary. Elimination diets play a significant role in the treatment of various types of gastritis, aiming to reduce allergic sensitization of the gastric mucosa and decrease the activity of immune mechanisms in pathogenesis. In the overwhelming majority of cases, therapy for chronic gastritis in children allows for achieving clinical, endoscopic, and histological improvement.

Conclusions

• 1.    Currently, up to 30-40% of children suffer from chronic gastritis.

• 2.    Traditional triple therapy regimens are used for the eradication of Helicobacter pylori, but in populations with high resistance to antimicrobial drugs, quadruple therapy is often employed.

• 3.    The treatment of eosinophilic gastritis demonstrates high efficacy with medications such as ben-ralizumab and vedolizumab, leading to depletion

• 4.    Effective treatment for collagenous gastritis has not yet been developed. Treatment strategies include elimination diets, proton pump inhibitors, and iron supplements.

of eosinophils in the blood and gastric tissues, as well as clinical improvement.