Helicobacter pylori Infection in Children: An Uphill Climb

H. pylori cytotoxins:

Bacterial persistence in the stomach depends on two major toxins that are encrypted by the pathogenicity island (PAI) genetic locus: cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA). Numerous host cellular processes are known to be impacted by CagA and VacA in order for the pathogen to successfully establish itself [48]. Cag PAI encodes a number of proteins that make up the constitutional elements of the bacterial type IV secretion system (T4SS) in addition to CagA and VacA expression. While the cag PAI is absent in some H. Pylori strains, those that are cag PAI-positive cause epithelial cells to overproduce IL-8. People infected with cag PAI-positive strains experience peptic ulcer disease (PUD) and gastric malignancy more common than those had infection with cag PAI-negative strains [49].

Difference between pathogenesis in adults and children: The strains that infect either children or adults differ only slightly from one another. The main recognized colonizing and pathogenic factors, such as Blood group antigen-binding adhesion (BabA), Sialic acid-binding adherence (SabA), cagPAI, VacA, and others, are the same. However, as people develop, the host response can vary between children and adults. Additionally, the expression of H. pylori virulence factors may alter in response to variations in the gastric conditions brought on by infection. The majority of environmental factors that can influence how an infection develops, like smoking, alcohol consumption, and using drugs, are largely absent in pediatrics, resulting in almost "pure" pathology in comparison to adults [4].

In Chile, Harris and colleagues showed differences between the histopathology and T cell responses among 79 adults (65% infected) and 36 children under the age of 12 (50% of whom had H. pylori infection) [50]. They found fewer Polymorphonuclear leukocytes (PMNs) and mononuclear cell infiltrate and a healthy epithelium in pediatrics compared to adults. They were able to show that, compared to adults, both infected and uninfected children have significantly higher levels of T regulatory cells (Treg) and Treg cytokines, while adults have higher levels of interferon alpha (IFN-) expression. Then, in comparison to adults, it seems that Treg activity in children reduces the inflammatory process, so the gastritis scores are less [50].

 Identical outcomes were collected by Freire de Melo and colleagues, they came to the conclusion that the children's higher vulnerability to infection and bacterial persistence can be due to decreased inflammatory response in the  mucosa of the stomach [51, 52].

Because of this, H. pylori infection cannot be completely cleared by pediatric patients' immune systems, and if left untreated, the bacterium remains in the gastric environment.

CLINICAL PRESENTATION

1. Gastrointestinal Manifestations

Children of school age frequently experience GIT complaints, and 25% of them experience severe abdominal pain that interferes with daily activities. Infection with H. pylori is believed to be almost asymptomatic in children, but also it is attributed to some of GIT symptoms. The most frequent correlation between infection with H. pylori and abdominal pain or vomiting is with the presence of PUD. H. pylori infection symptoms have also been linked to localized epigastric pain and nocturnal awakening [53].

Gastritis

As previously mentioned in the pathogenesis, H. pylori innidiation causes an inflammation in the stomach mucosa. After the acute phase, it progresses to chronic gastritis, that is marked by the accumulation of lymphocytes or plasma cells, the development of lymphoid follicles, and the hyperplasia of cells that make up the gastric glands. It results in a lifelong inflammatory response that is persistently chronic and low intensity in the gastric and duodenal mucosa [54].

Peptic ulcer (PU)

Epigastric pain, usually relieved by food or alkali, is the main symptom of PUD. H. pylori causes ulceration in the stomach and duodenal mucosa when it attacks metaplastic stomach epithelium because it is trophic for this type of epithelium [55].

The degree and distribution of gastritis determine the location of a PU. Bile inhibits H. pylori, so it typically cannot infect the duodenum [55]. However, DU could occur if pH is chronically low enough in the duodenal bulb, facilitating the infection and swelling of the metaplastic stomach mucosa in the duodenal bulb as low pH precipitates bile salts [55].

Gastritis tends to start out being the worst in the antrum and then advance proximally into the fundus because H. pylori density and affection of the gastric mucosa are the largest in the non-acid producing part of the stomach (i.e., the antrum) [56].

Marshall and Warren [3]linked H. pylori infection with PUD in 1983. Since then, it has been established that non-steroidal anti-inflammatory drugs (NSAID) and H. pylori are the two main causes of PUD [57].

In children with symptoms who undergo endoscopy, H. pylori-related ulcers are uncommon. Only 3.5% of children under the age of 6, 4.6% of children  aged 6 to 11 years, and 10.4% of children over the age of 11 years had gastric or duodenal ulcers, according to a European research involving 1322 kids that had H. pylori infection [58].

Functional dyspepsia (FD)

In the developing and developed worlds, FD has a community prevalence of 1.8–3.5 percent and 5–10 percent, respectively. It is a common functional gastrointestinal disorder in children [59, 60].

As regard Rome IV criteria, published in 2016, FD is the existence of one or more of these symptoms: early satiety, epigastric pain, fullness postprandial or epigastric burning. These symptoms must have been present for at least three months prior to diagnosis and their onset must have been at least six months prior to diagnosis [61].

A subset of FD patients who receive H. pylori eradication treatment report improved dyspeptic symptoms, despite the fact that the method of affection of  GIT pathophysiology by H. pylori is still unknown [62-64]. The Kyoto Global Consensus Meeting for H. pylori Infection, that took place in 2014, established that resolution of symptoms from 6 months to 1 year after effective elimination indicates that H. pylori is the reason for the symptoms and justifies classifying H. pylori-associated dyspepsia as a distinct clinical entity [65]. Rome IV also agrees with this idea [61].

H. pylori and gastroesophageal reflux disease (GERD)

The relation between GERD and H. pylori remains debatable. A study done in Romania, included 72 children proven GERD by 24 pH monitoring, and 62 controls, there was non-significant difference between patients and controls in the Prescence of H. pylori as proved by biopsy (26% and 16 % respectively) [66].

While another study in New York, involved 420 patients underwent upper endoscopy and biopsy, found that the prevalence of reflux esophagitis in the H. pylori positive population was 81.3% compared to 38.1% in the H. pylori negative population [67].

In a Mongolian research, people with GERD were less infected with H. pylori (63.6%), in comparison to those with DU (100%), GU (90%) and atrophic gastritis (77%) [68]. According to an Iranian research, no discrepancy was found in the prevalence of H. pylori in patients with GERD in comparison to controls[69].

Regarding laryngopharyngeal reflux disease, screening for H. pylori in specimens from tonsils taken from patients undergoing tonsillectomy in Lithuania was done. Compared to the control group, the chronic tonsillitis group had a noticeable greater incidence of infection (56.5%) while it was 31.4 % in the control. Adults and kids both came to the same conclusions. Oedema of the vocal cord, disseminated laryngeal edema, and posterior commissure hypertrophy were laryngopharyngeal reflux-related symptoms that were found to be significantly correlated with a positive H. pylori test [70]. However, pathogenesis of GERD with H. pylori infection still unknown, and GERD is not an indication to investigate for H. pylori.

2. Non-GIT manifestations:

A-Hematological disorders

Iron Deficiency Anemia (IDA)

Searching for H. pylori infection in pediatric population is advised in cases of refractory IDA because several studies have linked low iron status and H. pylori infection. Children's low iron stores are a result of their elevated growth-related iron needs. They most likely develop iron deficiency (ID) more quickly in the presence of infection than adults. Hypochlorhydria is a cause of ID in H. pylori-associated atrophy by altering the physiology of iron-complex absorption. In a prospective study involving 123 kids, Harris et al. [71] discovered that hypochlorhydria, infection with H. pylori as well as inflammation all play a part in the cause of ID.

Hepcidin, a small protein made in the liver that controls the body's iron balance and recycling, as well as enterocyte iron absorption and macrophage iron release, was the material of a study by Azab et al. [72,73]. Serum value of hepcidin is elevated by H. pylori infection, that blunts the efficacy of iron therapy [74]. Other potential reasons for IDA in people with H. pylori include GIT bleeding either chronic or acute brought on by erosive gastritis [75-77]. According to Hershko et al. [78], after H. pylori was eradicated, IDA completely vanished in 64 percent to 75 percent of patients who had both IDA and H. pylori infections.

In cases of IDA, according to recommendations for treating H. pylori infection, the infection should be cleared up [79].

Immune thrombocytopenic purpura (ITP)

An autoimmune condition known as ITP is characterized by the immune system destroying otherwise healthy platelets [80]. ITP secondary causes include the well-known H. pylori infection. ITP patients are more frequently infected with of H. pylori than healthy people of the same age and gender [81].

In 1998, Gasbarrini et al [82] first noted an association when they discovered that ITP patients' platelet counts significantly increased after H. pylori removal.

Further supporting the causal relationship was a review of 11 controlled studies that revealed an improvement in the platelet count in 51% of patients with H. pylori infection as opposed to an increase in platelet count in 8.8% of H. pylori-negative controls [83].

ITP caused by H. pylori has a good long-term prognosis, according to research. After successful eradication, no recurrence was observed in an 8-year follow-up study[84].

Regarding the part played by H. pylori in the pathogenesis of ITP, no mechanism is established. Antibodies to the H. pylori CagA  and platelet antigens are linked to molecular mimicry [85].

In summary, the identification and eradication of H. pylori in ITP is supported by studies to date. Patients with H. pylori infection may benefit from eradication therapy, according to the most recent American Society of Hematology guidelines [80]. Additionally, as regarding the most recent European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) guidelines, chronic ITP is a sign that an infection with H pylori may exist and should be treated if it does.

Vitamin B12 deficiency

O'Connor first identified the connection of insufficiency of vitamin B12 with H. pylori infection in 1984. He found organisms look like  campylobacter in patients that had pernicious anemia and type A gastritis [86]. Researches have shown a connection between persistent H. pylori infection and vitamin B12 malabsorption [87]. Another study revealed that 29 out of 43 patients with H. pylori infection had vitamin B12 deficiency (67.4% of them) [88]. However, there are insufficient interventional studies showing how anti-H. pylori therapy affects vitamin B12 deficiency [89].

B- Effect on growth:

H. pylori has been linked to effects on growth metrics in young children. The conclusions of studies examining how H. pylori infection affects a child's growth have a wide range of variance. Numerous studies have connected H. pylori infection to a reduction in children's growth [90-92]. However, cross-sectional research from various nations indicates that there is no association [93-96].

According to one mechanism, H. pylori reduces gastric acid secretion, which may lead to enteropathogenic infection, which may cause diarrhea, malabsorption of nutrients, decreased food intake due to dyspepsia, and iron-deficiency anemia [97, 98]. However, it is challenging to demonstrate that H. pylori alone causes childhood growth impairment in the presence of so many confounding factors, including socioeconomic status and diet [99].

C- Effect of H. pylori on asthma and allergy:

Early H. pylori acquisition may protect against allergy and atopic diseases, according to previous epidemiological studies [100]. This relationship was examined in three studies, with varying conclusions. In a case-control study from Greece, stool antigen test (SAT) for H. Pylori results showed that 29.6% of kids without asthma had the infection, compared to 11% of asthmatic children (P =.026) [101]. Additionally, 274 patients aged 3-76 participated in an Istanbul cross-sectional study to estimate the prevalence of H. pylori among people that had allergic and nonallergic nasal disorders in comparison to controls. In the pediatric group, no connection was found between the infection with H. pylori and the prevalence of allergic disease [102].

D- Long-term complications of H. pylori infection:

Long-lasting  H. pylori infection is a Group 1 carcinogen with sufficient evidence to suggest that it can result in low-grade B-cell gastric MALT lymphoma and non-cardia gastric carcinoma [103].

DIAGNOSIS

ESPGHAN and NASPGHAN guidelines state that, unless certain conditions apply, pediatric patients should not be treated using a "test and treat" strategy, which involves using a noninvasive test instead of an upper GIT endoscopy to establish H. pylori infection [104]. Contrary to recommendations for adult populations, H. pylori testing is not advised for kids who present with functional abdominal pain [104].

Indications to test for H. pylori in children:

Children that have first-degree relatives with gastric cancer are advised to be tested and treated [104]. The guidelines also suggest that after ruling out other potential causes, searching for H. pylori should be taken into consideration in kids with refractory IDA [105].

According to the evidence currently available, therapy for H pylori eradication is not anticipated to alleviate symptoms in pediatric population, with the exception of PUD cases [106]. Consequently, invasive tests done for the only aim of detecting H pylori infection ought not to be carried out if peptic lesions are not probable clinically or not diagnosed with endoscopy.

Noninvasive testing should be used in the patient with chronic ITP to determine the possibility infection. If it is positive, it must be determined individually whether an upper endoscopy is required prior to eradication therapy depending on the platelet count [100].

Methods of diagnosis

Invasive and noninvasive tests for diagnosing H. pylori infection are the two categories of diagnostic techniques [107].

Noninvasive methods include:

Urea Breath Tests (UBT): Two tests are available and have received FDA approval: ¹³C & ¹⁴C tests. Both offer reasonably priced, immediate results. A positive UBT indicates ongoing infection, that need treatment or another test with invasive procedures [108]. It  is accurate in patients who underwent gastrectomy or recently have administered  antibiotics or proton pump inhibitors (PPI), and it is excellent for assessing treatment response in children over the age of six[ 109]. False-negative results in recent treatments with bismuth, PPI and antibiotics, should not be used in children as a primary diagnosis due to high false-positive results in children under the age of six [110],  due to different CO2 production rate and  also due to technical difficulties in performing 13C-UBT in young children as they are often unwilling to swallow the substrate, so oral urease–producing organisms can then split the substrate [100].

Stool Antigen Test (SAT): This test uses antibodies to identify the presence of antigens for H. pylori in faeces based on enzyme immunoassay (EIA) or immunochromatography (ICA), allowing the confirmation of active infection either before treatment or after to assess the effectiveness of treatment [111-113]. It is inexpensive, not dependent on age, quick and simple, and helpful after therapy. False-negative outcomes in recent bismuth, PPI, and antibiotic treatments.

Serology: It depends on how an enzyme-linked immunosorbent assay (ELISA) measures the presence of immunoglobulin G (IgG) antibodies for H. pylori. IgG antibodies start to appear about three weeks after the infection starts, remain high for the duration of the infection, and then return to normal in about a year [112]. It is widely accessible and reasonably priced, and the results are unaffected by using PPI or other medications. Since the antibodies can still be detectable years after infection [114], it is unable to differentiate between recent and past infections, sensitivity in children is also low, so it is not used to verify eradication.

Invasive methods:

The invasive techniques rely on biopsies obtained during gastroduodenal endoscopy; at least six biopsies from the antrum, greater and lesser curvatures, and the middle of the gastric body should be obtained to evaluate H. pylori gastritis. Additional biopsies may be needed if suspicious lesions such as ulcers or masses are found [115].

Biopsies are used for rapid urea test, histological examination, the gold standard for diagnosis and H. pylori cultures [79].

Histology is the first method used to detect H. pylori and is regarded as the benchmark in the confirmation of H. pylori infection. Although HE stain is almost enough for diagnosing H. pylori infection practically, immunohistochemical stain is the most sensitive and specific stain [116, 117]. It is useful to find the level of ongoing inflammation and activity, diagnose precancerous lesions like gastric intestinal metaplasia and grade of atrophy, and find malignancy and coccoid forms. PPI, antibiotics, and the experience of pathologists are just a few of the variables that affect the accuracy of histology[118].

Rapid urease test (RUT): it is cheap, quick, and precise [119, 120]. Furthermore, the gastric biopsy used for the RUT can be utilized for different tests, such as the H pylori PCR. Also, RUT is more sensitive than histology if there had been prior exposure to PPI and/or antibiotics [121]. False-negative results if there is GI hemorrhage and achlorhydria, or if the bacterial load in the biopsy is less than 10⁴. Additionally, other urease-positive bacteria may produce false-positive results [122].

Culture: It indicates an active infection and is advised whenever a treatment fails to find H. pylori that is fluoroquinolone- and clarithromycin-resistant [123, 124]. It has 100% specificity, and it provides antimicrobial resistance pattern. The quality of biopsy samples, the timing of the transport, and exposure to an aerobic environment are all factors in H. pylori cultivation [124-127]. Antibiotics should be avoided for at least four weeks prior to the culture because factors like low bacterial load, use of PPIs, antibiotics, alcohol, and bleeding can affect the outcome of the culture [128, 129].

PCR: There are several commercial PCRs available to detect resistance to different antibiotics [122]. Compared to other methods, it is almost the most accurate method for H. pylori detection and antibiotic susceptibility testing in gastric biopsies [130]. False-positive results brought on by the finding of bacteria's dead DNA.

To sum up, availability and cost play a significant role in the test selection process. According to the most recent ESPGHAN/NASPGHAN guidelines, a diagnosis should include at least six gastric biopsies, histopathology, or culture and one other positive biopsy-based test. The guidelines also suggested that follow-up testing be done after 4 weeks of treatment with either the UBT or the SAT.

Monoclonal SAT is more appropriate in children under the age of 6 years (sensitivity: 88.0%-88.1%, specificity: 93%-94.2% %) because UBT was found to have a high rate of false positive results in this age group [104].

MANEGEMENT IN CHILDERN

It is advised that the initial diagnosis of H. pylori infection be based on either a positive histopathology, a positive rapid urease test, or a positive culture, per Evidence-based Guidelines from ESPGHAN and NASPGHAN for H. pylori infection in Children [104].

Indications for treatment

Eradication of the organism is advised in cases of H pylori-positive PUD. H. pylori treatment may be considered when infection is found using invasive methods in the absence of PUD.

Treatment can be considered to children who have H pylori infection and a first-degree relative with gastric cancer. The goal of therapy is to lower the opportunity of gastric cancer that may override the hazards of therapy in regions with a high prevalence of gastric cancer, like China or Japan [131].

The ESPGHAN/NASPGHAN guidelines included a weak advisement for diagnosing and treating H pylori infection in patients with chronic ITP. However, more carefully planned interventional studies are needed to back up this suggestion [132]. Additionally, H pylori eradication therapy should be used in conjunction with iron supplementation if it is found that the infection is present in the context of refractory IDA.

Treatment regimens

Standard triple therapy, since 1996, first-line therapy, which includes two antimicrobials and PPI has been advised [133]. Recent data, however, indicate that this combination has become less effective and the rates of recovery have decreased to 80% in the majority of Asia-Pacific region as a result of clarithromycin (CLA) resistance [134]. As a result, alternatives have been created, including quadruple therapies that do not contain bismuth and those that do.

Sequential therapy (ST) involves PPI and amoxicillin (AMO) for five days, then PPI, metronidazole (MET) and CLA for another five days. In many nations, sequential therapy has shown more efficacy than seven or ten day standard triple therapy, with an eradication rate of between 73% and 81.4 percent [135, 136].

Bismuth quadruple therapy (BQT) bismuth-based ten days quadruple treatment with bismuth sub-citrate, PPI, MET and AMO to eradicate H. pylori in pediatric patients is effective and secure. Use of this regimen is of special concern in patients those received treatment before and in case of dual antibiotics resistance [137].

Concomitant therapy (CT) consisting of PPI, AMO, CLA, and MET was among the most efficient therapies with a high elimination rate, and it was demonstrated to be more efficient than triple therapy. Many reports suggest that in areas that have strong antibiotic resistance or where testing for sensitivity is unavailable, BQT and CT can both be used as first-line treatments [79].

The treatment recommendations for children and adolescents have been updated by the ESPGHAN and NASPGHAN to increase the elimination rate after H. pylori infection. If the strain is sensitive to MET and CLA, then the triple therapy consisting of PPI (1-2 mg/kg/day), AMO (50 mg/kg/day), and CLA (20 mg/kg/day) for 2 weeks is the preferred course of action [129].

Salvage therapy

If the triple therapy is unsuccessful, MET (20 mg/kg/day) can take the place of CLA without the need for additional antibiotic susceptibility testing. For pediatric patients infected with fully susceptible strains, ST lasting ten days (PPI and AMO for five days, then PPI, MET and CLA for five days) is an additional treatment option. In case of the strain is not sensitive to MET or CLA, ST should not be used.; however, this plan of treatment put the child in exposure to three antibiotics. BQT, which consists of bismuth salts (8 mg/kg/day), PPI, AMO (before the age of eight) or tetracycline (after the age of eight), and MET, is efficient in cases of resistance to both CLA and MET as well as when antibiotic sensitivity is unknown. The other regimen suggested in this situation combines high dose AMO triple therapy with MET, despite the limited available evidence [104, 132]. Antibiotic resistance is a significant issue that varies from region to region. The emergence of H. pylori CLA resistance is a result of the use of the macrolide class of antibiotics to treat respiratory tract infections [138].

Causes of treatment failure

Antimicrobial resistance is rising globally and is the primary cause of H. pylori eradication failure [139]. A meta-analysis study was done to evaluate the resistance distribution of H. pylori to the most widely prescribed antibiotics, it was found that in Eastern Mediterranean region the highest antibiotic resistance was for metronidazole [140]. A study was done in one Egyptian university hospital to detect H. pylori antibiotic susceptibility to CLA, MET, fluroquinolones and AMO. The highest resistance found to be against clarithromycin , then amoxicillin [141].

Antibiotic resistance is known to positively correlate with prior antibiotic use. The primary risk factor for the emergence of  resistance to CLA in Europe appeared to be its use for other indications, primarily for respiratory tract infections [139]. There is higher rates of primary resistance of MET recorded in pediatric patients from Africa and Asia that may be caused by the repeated use of metronidazole for parasitic or diarrheal diseases [58]. The most accurate method for predicting a patient's response to treatment is culture-based antibiotic susceptibility testing. However, the expense, time commitment, and reliance on biopsy from stomach mucosa make this an unsuitable option for determining first or second choice of treatment [107].

Recurrence of infection after treatment makes H. pylori infection a chronic infection. Persister cells, which develop extremely strong persistence to a specific antibiotic without any genetic justification, are one of the main causes of chronic infections. Persister cells are still present after antibiotic therapy and the removal of nonpersister cells, which leads to an infection relapse. This procedure is repeatable numerous times and results in an untreatable infection [142, 143].

Additionally, a reservoir for gastric infection and transmission may exist in the oral cavity [144].

According to a study, when gastric infection with H. pylori was eradicated, the risk of  H. pylori recurrence was less in the group receiving  therapy for gastric and periodontal H. pylori than in the group that received only gastric treatment [145].

Role of probiotics in management of H. pylori

Probiotic supplementation therapy is a newly developed method of treating H. pylori [146]. Probiotics are defined as live microorganisms that, when given to a host in sufficient quantities, have positive effects on their health [147]. The majority of probiotics are thought to inhabit the human GIT, and some species, like Lactobacillus spp., have been shown to colonize the stomach and either directly or indirectly compete with H. pylori [148-150]. Probiotics have been shown to reduce bacterial load when taken alone, but when combined with antibiotics, they have been shown to increase eradication rates and reduce side effects [151, 152]. However, the best dosage, timing, length of therapy, and mechanisms governing interactions between the chosen probiotics and antibiotics are still unknown [146].

Vaccination against H. pylori

Epitope-based vaccines have become more popular recently as a result of changing trends in vaccine design[153]. Bacterial colonization and virulence factors have an effect on the pathogenesis of an H. pylori infection. The main prerequisite for its pathogenesis is colonization of the gastric mucosa, and adhesion comes before colonization. The flagellin A (FlaA) and FlaB dimer, of which FlaA is the principle flagellin and has a high immunogenicity, combine to form flagella, which have an important role in the adherence to GIT mucosa [154]. It could be used clinically to develop new vaccines [155]. Additionally, urease, a crucial component of H. pylori's virulence, is found on the bacteria's surface [156]. The two subunits that make up urease are urease A subunit (UreA) and urease B subunit (UreB), with the latter being the most promising candidate vaccine antigen due to its high immunogenicity and low toxicity [157, 158].

Exotoxin VacA, which is secreted by H. pylori and causes host cells to develop vacuoles, has been suggested as a potential vaccine target[159]. The oncogenic factor [160] CagA, which is present in 50 to 70% of H. pylori species and is transported into gastric epithelium by bacterial production, is a target for vaccine development [161].

To date, a lot of work has been incorporated into developing a vaccine for H. pylori, primarily in animal models. In these researches, cholera toxin, Escherichia coli (E. Coli) heat-labile enterotoxin (LT), synthetic oligodeoxynucleotides and aluminum hydroxides are the most frequently used adjuvants to increase vaccine efficacy [162].

A randomized, double-blind, placebo-controlled phase 3 clinical trial on intact kids aged 6 to 15 discovered a significant decrease in infection in the kids who administered the vaccination after one year, with the beneficial results lasting for about three years. This discovery represents the biggest progress in developing an efficient H. pylori vaccine in humans till now [163]. The recombinant oral vaccine is made up of the H. pylori UreB subunit joined with the E. coli LT B subunit and is intended to stop a future natural infection rather than be used as a curative vaccine. Overall, the vaccine was immune-stimulating, secure, and safe, but extended follow-up studies are required before the WHO or FDA can approve its use [163].

CONCLUSIONS

H. pylori is a chronic infection that is mostly acquired during childhood. The prevalence is widespread worldwide, it is more prevalent in developing nations owing to low socioeconomic conditions.

The two major toxins for pathogenesis are encrypted by the pathogenicity island (PAI); cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA).

The strains that infect either children or adults differ only slightly from one another, but the host response can differ from adults to children.

H. pylori is commonly believed to be asymptomatic in children, it also has been linked to the pathogenesis of gastrointestinal manifestations, abdominal pain is a frequent complaint mostly due to peptic ulcer disease.

Even though most of H. pylori infected patients may stay asymptomatic through their whole lives, nearly everyone develops chronic inflammation.

GI involvement range from mild antral gastritis, atrophic gastritis, peptic ulceration, and stomach cancer. H. pylori also is found to be linked to iron deficiency anemia and thrombocytopenia.

ESPGHAN and NASPGHAN guidelines declare that pediatric patients should not be treated using a "test and treat" strategy, which involves using a noninvasive test instead of an upper GIT endoscopy to establish H. pylori infection.

Diagnosis should include gastric biopsies, histopathology, or culture and one other positive biopsy-based test. The guidelines also suggested that follow-up testing be done after 1 month of therapy using the urea breath test or the stool antigen test.

Eradication of the organism is advised in cases of H pylori-related peptic ulcer disease. Treatment for H. pylori could be taken into consideration if H pylori infection is found using invasive tests in the absence of PUD. Also, treatment could be made available to children who have H pylori infection with a first-degree relative that has stomach cancer. Treatment regimens include standard triple therapy, sequential therapy, bisthmus quadrable therapy and concomitant therapy. Failure of treatment can be caused by drug resistance or incompliance. There are trials for vaccination for H. pylori, but longer follow-up studies are required before the WHO or FDA can approve its use.