Helicobacter pylori Infection in Children: An Uphill Climb

to investigate for and treat H. pylori in the pediatric population and there is mauls of antibiotics for H. pylori in general practice. The goal of this review is to concentrate on the prevalence of H. pylori in the pediatric population especially in developing world, indications for treatment and when to investigate for H. pylori according to the guidelines.

Helicobacter pylori (H.pylori) is a worldwide infection and is common in children.Childhood is a crucial stage of life for H. pylori infection because this is when the infection is most commonly picked up.The infection seems to be running in families, also it is transmitted through contaminated water supplies.Once the infection is acquired it almost becomes a chronic infection.The prevalence is different from country to another, and it is more in the developing countries with low socioeconomic levels.The pathogenesis of H. pylori induced diseases differ to some extension in children than in adults.The infection can be asymptomatic, and the symptoms could range from abdominal pain up to peptic ulcer disease.Also, the infection can present with extra gastrointestinal manifestations most commonly iron deficiency anemia and idiopathic thrombocytopenic purpura.Investigations for H. pylori include invasive and non-invasive methods and differ in availability and accuracy.There is argument about indications to investigate for and treat H. pylori in the pediatric population and there is mauls of antibiotics for H. pylori in general practice.The goal of this review is to concentrate on the prevalence of H. pylori in the pediatric population especially in developing world, indications for treatment and when to investigate for H. pylori according to the guidelines.

INTRODUCTION
Helicobacter pylori (H.pylori) is a helical, curved, gramnegative, microaerophilic bacteria.It has 3-7 sheathed flagella on which are responsible for the organism's motion and invasion activities [1].For a chronic infection of the epithelium of gastric mucosa, H. pylori is specially adapted [2].Bizzozero was likely the first person in nineteenth century that mentioned the occurrence of spiral microorganisms in the gut of animals [2].Warren and Marshall cultured H. pylori from gastric tissue for the first time in 1982 [3].Childhood is a crucial stage of life for H. pylori infection because this is when the infection is most commonly picked up.However, the effects of infection are delayed until later in life and are limited in the early years [4].Children who have H. pylori infection differ from adults in that they rarely experience infection-related complications.
Additionally, there are fewer treatment options and indications [5].As there is abuse in general practice in rushing for searching and treating the infection without being indicated, the goal of this review is to concentrate on indications of treatment and when to investigate for H. pylori.

METHODS OF TRANSMISSION
In general, H. pylori spreads most frequently from person to person, especially within families, with mother to child transmission being the most common.Flushed gastric juice or vomitus can cause oralto-oral transmission, which also occasionally happens through the gastro-oral and fecal-oral routes [6].Contaminated water can also serve as a source of infection.Additionally, food may help spread disease [7].It has been demonstrated through molecular fingerprinting that the same strain is passed down through families [8].Once the infection is acquired, it is believed to be a chronic, long-lasting infection [9] and spontaneous clearance is relatively uncommon [9-11].However, there was no increase in prevalence by age in a research of kids where age based prevalence was measured every year [12].This indicates that children can contract transient H. pylori infections [9, 13,14].

PREVELENCE OF H. PYLORI
H. pylori infection is widespread worldwide and can either be symptomatic or asymptomatic.Due to better living conditions, socioeconomic advancement, and sanitation, the frequency of H. pylori infection among adults and children has been declining in the developed world in recent years.However, the developing world continues to have a high prevalence of it [15].In Egypt, a study done in among apparently healthy school children in Al Qulubia governorate using serum IgG against H. pylori, the prevalence found to be 44% [16].Differences in prevalence of H. pylori worldwide are shown in Table 1.Up till now, the exact pathogenesis of H. pylori in gastric and other diseases remains arguable [35].It depends on the strain of bacteria.However, multiple other factors have an effect.The possession of a particular virulence factor is responsible for the interaction between the host and the bacterium [36].Effect on immunity and gastrointestinal microbiota: Innidiation of H. pylori causes an inflammatory reaction in the mucosa of the stomach; that is defined by the increase of production of cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor alpha (TNF-), and is mediated by neutrophils and mononuclear cells [37].These cytokines produce reactive oxygen species (ROS) in the gastric mucosa [38].Gastric

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 PAIpositive 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 (IFNexpression.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

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 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.

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 growthrelated 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

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

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) bismuthbased 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

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][149][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 immunestimulating, 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 followup studies are required before the WHO or FDA can approve its use.
[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 antiinflammatory 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].

33, 34].
In order to survive at a lower pH, it has developed some virulence factors as one of its adaptation mechanisms.The bacterium can use the urease enzyme to neutralize stomach acid [26].

41, 44-46].
Previous research on the gastric microbiome revealed that H. pylori-related diseases may be greatly influenced by the interactions between H. pylori and other microbes [ Chronic H. pylori infection alters gastric acid secretion, which may have an impact on both children and adults' gastric microbiota [41-43].According to several reports, H. pylori has a major effect on the bowel microbiota [43].Table.1: Frequency of H. pylori infection worldwide [16, 17].ELISA: Enzyme-linked Immunosorbent Assay, IgG: Immunoglobulin G, PCR: Polymerase Chain Reaction, SAT: Stool Antigen Test, UBT: Urea Breath Test.
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].
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.