Filipe Ant?nio Fran?a da Silva, Breno Bittencourt de Brito, Maria Luísa Cordeiro Santos, Hanna Santos Marques, Mariana Miranda Sampaio, Ronaldo Teixeira da Silva Júnior, Jonathan Santos Apolonio, Lorena Sousa de Carvalho, Camilo Santana Silva, Luana Kauany de Sá Santos, Márcio Vasconcelos Oliveira, Gifone Aguiar Rocha, Dulciene Maria de Magalh?es Queiroz,Fabrício Freire de Melo

Filipe Ant?nio Fran?a da Silva, Breno Bittencourt de Brito, Maria Luísa Cordeiro Santos, Mariana Miranda Sampaio, Ronaldo Teixeira da Silva Júnior, Jonathan Santos Apolonio, Lorena Sousa de Carvalho, Camilo Santana Silva, Luana Kauany de Sá Santos, Márcio Vasconcelos Oliveira, Fabrício Freire de Melo, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil

Hanna Santos Marques, Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil

Gifone Aguiar Rocha, Dulciene Maria de Magalh?es Queiroz, Laboratory of Research in

Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte 30130-100, Minas Gerais, Brazil

Abstract

Key Words: Helicobacter pylori; Children; Pediatric treatment; Standard triple therapy; Probiotics; Sequential therapy; Eradication therapies

INTRODUCTION

Helicobacter pylori(H. pylori) is a gram-negative spiral bacterium that colonizes the gastric mucosa of more than 50% of the population worldwide. The infection is acquired predominantly in childhood, and is more prevalent in developing countries where about 70% of children are infected until 15-years-old[1,2], whereas it is disappearing in developed countries. Once acquired, the bacterium is rarely eliminated without adequate antibiotic therapy and individuals remain infected throughout life[3]. Most infected individuals do not develop complications, but gastric colonization can progress to chronic gastritis, duodenal ulcer, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma, and bacterial eradication is associated with the prevention of such diseases[4].H. pyloriinfection has also been implicated in the pathogenesis of extra-gastric diseases, including iron deficiency anemia and chronic immune thrombocytopenic purpura.

The mechanisms by which the infection progresses to the above-mentioned diseases are not completely understood and depend on the relationship between host genetics and factors regarding the environment and bacterial virulence.

SevereH. pylori-associated diseases are more common in adults than in children. This phenomenon can be explained, in part, by the differences in immune response between the two age groups, which seems to be a relevant factor influencing mucosal damage and clinical outcomes[5]. In general,H. pyloriinfection induces a T helper type 1 (Th1)-polarized response with high levels of interferon-γ that stimulate gastric inflammation and mucosal damage in adults. Moreover, Th17 cells and interleukin (IL)-17 levels are important in that process because they stimulate the recruitment and activation of neutrophils in the gastric mucosa, increasing the inflammatory environment against the bacterium. In contrast to the pro-inflammatory response found in adults, children tend to exhibit an immune response pattern with a predominance of regulatory T cells that contribute to the persistence of the infection and milder clinical manifestations[6,7]. Children tend to have lower levels of Th1- and Th17-related cytokines as well as overexpression of IL-10 and transforming growth factor-β, resulting in a lower degree of polymorphonuclear cell activation in the acute phase of infection[8,9]and prominent mononuclear cell infiltration in chronic infection compared with adults[10].

H. pylorivirulence factors also play an important role in the pathogenesis of infection in childhood. It is well documented that genes such as cytotoxin gene A (cagA) and vacuolating cytotoxin gene A (vacA) increase the risk of severe gastric diseases such as duodenal ulcer and gastric cancer[11].

H. pylorieradication prevents duodenal ulcer recurrence and prevention of gastric cancer. In addition,H. pylorieradication in children induces platelet and iron recovery in immune thrombocytopenic purpura and iron deficiency anemia, respectively.

Since eradication therapies show variable failure rates, retesting forH. pyloriinfection after an antimicrobial regimen is recommended to ensure that patients have been successfully treated[12]. There are various available therapeutic options aimed towardH. pylorieradication, and clarithromycin-based triple therapy, sequential therapy, bismuth-containing quadruple therapy or triple therapy, and hybrid therapy are the regimens most often used[13]. Moreover, various alternative approaches have been attempted in order to improve bacterial eradication such as susceptibility-guided therapies, probiotics, and vaccines[14-16]. In that context, a number of factors influence the choice of appropriate treatment, including antimicrobial susceptibility profile, economic factors, and importantly, individual characteristics such as previous exposure to antibiotics and age[17].

PerformingH. pylorieradication in children demands specific precautions, of which avoiding regimens with unacceptable rates of adverse events (AEs) for this population is very important[18]. In this context, the number of treatment options usually available for children tends to be significantly lower compared to the range of treatments at hand for adults. Clarithromycin-based triple therapy is the most used therapeutic scheme for children, although other standard therapies have also been tried[19]. Moreover, to reduce the frequency and severity of side effects as well as to improve eradication rates, probiotics in association with standard therapy have been tested in children[20].

Therefore, we reviewed the randomized controlled trials (RCTs) of treatments forH. pylorieradication children.

MATERIALS AND METHODS

In this systematic review, the criteria recommended by the PRISMA checklist were used[21].

Types of studies

Prospective RCTs, published in peer-reviewed journals from 2010 to April 2020 and reporting the results of antibiotic therapy and/or supplementation with other drugs for theH. pylori eradication in infected children under 18-years-old, were included. There was no restriction regarding the therapeutic schemes used. Excluded studies were those including adults or lacking their complete or free full text. Only English language studies were included. The inclusion criteria are outlined in Table 1.

Types of participants

H. pylori-positive patients under 18-years-old diagnosed by any validated test accepted by the scientific community forH. pyloridetection. Patients who had previous failed antibiotic therapies were included.

Types of intervention

Prospective RCTs evaluatingH. pylorieradication rates in children.

Types of outcome measures

We collected outcomes of intention-to-treat (ITT), per protocol (PP), and simple percentages ofH. pyloriinfection eradication.

Table 1 Inclusion criteria

Information sources

We surveyed the relevant articles published in English language from 2010 to April 2020 in the PubMed and MEDLINE databases. The term strategies used for the search at both databases were: ((Helicobacter pylori[and] children [and] treatment) [OR] eradication) and (Helicobacter pylori[and] childhood [and] (treatment [OR] eradication)).

一是內(nèi)容過難，主要體現(xiàn)在對知識的內(nèi)涵介紹過深，增加了學(xué)生的學(xué)習(xí)難度，這不符合高職院校強調(diào)的“理論知識適度”的人才培養(yǎng)理念。二是內(nèi)容過于膚淺，核心內(nèi)容介紹不到位。以林從綱主編的《新編旅游韓國語》教材為例，該教材在介紹我國宗教文化時，對內(nèi)容的把握比較寬松，對宗教文化中的核心內(nèi)容介紹不到位，不利于學(xué)生職業(yè)能力的提高，也不利于旅游文化的傳播。

Study selection

The eligibility of the articles was evaluated by two independent reviewers (Da Silva FAF and de Brito BB). Duplicate articles were excluded. The abstracts of the articles were evaluated and studies that were not prospective RCTs and/or did not evaluateH. pylorieradication rate in children were excluded. A third reviewer (de Melo FF) resolved disagreements between the two reviewers. To verify if the articles met all previously established criteria, each article was individually analyzed. To statistically evaluate the agreement between the reviewers, the Kappa coefficient (K) was calculated, which indicated aK= 0.752, considered as a substantially strong degree of agreement between the reviewers.

Data collection process

We developed a structured data extraction spreadsheet specifically for this review based on the criteria recommended by the Cochrane Handbook of Systematic Reviews for Interventions[42]. We independently reviewed the relevant study data and results of interest such as rates of eradication ofH. pyloriinfection in childhood.

Data items

Information was extracted from each study including: General characteristics of the participants and studies, type of intervention, therapeutic regimen used, type of outcome measure, and positive and negative outcomes.

Risk of bias

To assess the validity of RCTs, two authors independently analyzed the risk of bias criteria recommended by the Cochrane Handbook of Systematic Reviews for Interventions[42]: Generation of the random sequence, concealment of allocation, blinding of participants and professionals, blinding of outcome evaluators, incomplete outcomes, and reporting of the selective outcome. Then the risk of bias was categorized as high, low, or uncertain.

RESULTS

Study selection

Of the 1144 articles reviewed (861 in NCBI and 283 in MEDLINE), 1118 were excluded using previously established inclusion criteria. Twenty-six articles were selected for complete analysis; however, eight were duplicate and thus were excluded. Finally, 2 studies were an additional reference list and 20 articles were included. Figure 1 shows the selection and distribution of articles according to the databases searched, from the first search to the application of all of the selection criteria.

Study characteristics

The characteristics of the 20 selected studies are summarized in Table 2. A total of 2261 children aged 22 mo to 18 years were included. Regarding the geographic distributionof the studies, 25% of the articles were from Iran; 25% from Turkey; 10% from China; and 40% from Algeria, Italy, Poland, India, Kenya, United States, Belgium, and France. The studies had a follow-up average of 6 wk. In addition, the articles evaluated conventional eradication therapies, probiotics, or sequential therapies as well as the eradication rates ofH. pyloriinfection in childhood.

Table 2 Summary of included studies

Figure 1 Summary of the study selection process.

Results of individual studies

All patients wereH. pylori-positive children diagnosed by validated methods. Randomization methods and loss of follow-up were highlighted for analysis of the risk of bias. All articles were classified according to the criteria of the Oxford Center for Evidence-based Medicine - Levels of Evidence[43](Table 3). Standard triple therapy was the main therapeutic scheme evaluated. The studies compared conventional triple therapy alone to triple therapy containing probiotics and to sequential therapies (Table 4).

Synthesis of results

Table 5 summarizes the positive and negative outcomes of the studies.

很多媽媽認(rèn)為發(fā)燒會燒壞腦子，其實這是誤解，只有腦炎才會對大腦有影響，并且也不是發(fā)燒引起的。還有人說幼兒急疹要燒到一定的溫度疹子才會出來，也是誤解，幼兒急疹是自限性疾病，沒有特效藥，用不用藥都是發(fā)燒3天左右，對癥治療即可。

Risk of bias assessment

Using the Cochrane risk of bias tool[44], seven RCTs[23,26,27,34,37-39]had a low risk of bias for the following criteria: Generation of the random sequence, allocation concealment, blinding of participants and professionals, and blinding of outcome evaluators. Only the work by Akcamet al[24]was classified as high risk of bias for generating the random sequence. All other RCTs had an uncertain or low rating for all of the criteria mentioned above. In general, we observed some risks of biases through deviations from the intended interventions, represented by the concealment of how the drugs were distributed and how the researchers made recommendations to the participants. In addition, interaction with a healthcare professional can improve symptoms and treatment adherence, becoming a possible bias for all the analyzed results.

Table 3 Criteria analyzed individually in the studies

Table 4 Summary of therapeutic schemes used in included studies

H. pylori: Helicobacter pylori.

DISCUSSION

In pediatric clinical practice,H. pyloriinfection is common, especially in developing countries and certain populations such as ethnic minorities and migrant communities living in developed countries. In this systematic review, standard triple therapies, given for 7, 10, or 14 d were compared with sequential, third-line, and quadruple therapies forH. pylorieradication. In addition, some studies evaluated the efficacy of probiotics as adjuvant therapy for triple therapy.

Currently, triple therapies recommended by the main guidelines forH. pylorieradication include a proton pump inhibitor (PPI) or ranitidine, amoxicillin, and either clarithromycin or metronidazole, considered the first-line regimen, and bismuth, administered for 7, 10, or 14 d[45]. The desirable target of anti-H. pyloritreatment regimens is to reach an eradication rate of at least 90% in the per-protocol analysis whereas antibiotic use eradication rate below 80% is considered unacceptable[46]. However, few studies have achieved this goal. The low efficacy of triple therapy observed in diverse geographic areas has been attributed to the rising resistance ofH. pyloristrains to clarithromycin and metronidazole, poor compliance, duration of treatment, and inadequate dosage and number of daily doses. The growingH. pyloriresistance is due to the previous exposition of children to these antimicrobials that areoverused to treat upper and lower respiratory diseases that are very common in childhood. Eradication rates of standard triple therapies are often below 80% in various regions of the world[47]. In this study, extremely low eradication rates were observed in China, India, Kenya, and Turkey. The frequency ofH. pylori-resistant strains was 16.4%, 75.2%, and 0.06% to clarithromycin, metronidazole, and amoxicillin,respectively, in children from the southeast regions of China[48]. The resistance to clarithromycin in Turkish children ranges from 9.5% to 27%[49]. No data are available on clarithromycin resistance in Indian and Kenyan children. Concerning resistance to metronidazole, no data are available on those countries.

Table 5 Synthesis of results from included studies

ITT: Intention-to-treat; PP: Per protocol; H. pylori: Helicobacter pylori.

Standard triple therapy

A trial comparing amoxicillin-based with metronidazole-based triple therapy, by ITT analysis, found that the latter showed a significantly higher eradication rate (68%vs80%, respectively)[22]. The 7 and 10 d triple therapy failed to eradicateH. pyloriinfection in most of the studies[22,26,27,30,34,37-39]. In some of them, the eradication rates were less than 60%.

Esmaeili-Dookiet al[37]compared a triple therapy consisting of azithromycin once daily plus amoxicillin and omeprazole given twice daily for 6 d with clarithromycin in association with amoxicillin and omeprazole twice daily for 10 d. Based on the ITT analysis, the eradication rates in the azithromycin and clarithromycin groups were 56.2% and 62.5%, respectively (P= 0.40)[37]. AEs were 15.6% in the omeprazole, clarithromycin, and amoxicillin group and 3.1% in the omeprazole, azithromycin, and amoxicillin group (P= 0.19). Per protocol, the eradication rate was 61.9% in the azithromycin group and 69% in the clarithromycin group (P= 0.431).

High resistance ofH. pylorito clarithromycin and metronidazole, poor compliance, and a short duration of treatment may explain these findings, in part. European Society for Paediatric Gastroenterology, Hepatology and Nutrition and North American Society for Paediatric Gastroenterology, and Hepatology and Nutrition guidelines recommend when antimicrobials susceptibility profiles are either unknown orH. pyloriis susceptible to clarithromycin or metronidazole, a high-dose triple therapy with PPI, amoxicillin and triple for 14 d or bismuth-base quadruple therapy. In this review, the effectiveness of a triple therapy for 14 d was evaluated in eight studies. Eradication rate superior to 80% was observed in two of them[29,40]. Kasiriet al[29]did not observe a significant difference in the eradication rate between 14 d amoxicillin-based (87.2%) and for metronidazole-based triple therapy (92.5%) in Iranian children.

A study from Vietnam, triple therapy consisting of lansoprazole amoxicillin and either clarithromycin or metronidazole (LAM) therapy given once or twice daily for 14 d were compared[40]. Eradication success was associated with the strain susceptibility to clarithromycin (78.2%vs29.3%,P= 0.0001). PPI and clarithromycin given twice daily was superior to once-daily dosage for resistant strains (50.0%vs14.7%,P= 0.004) and tended to be effective so also for sensitive strains (87.5%vs65.2%,P= 0.051). The differences were less pronounced with LAM when PPI was given twice daily in comparison with PPI once a day (69.2%vs50.0%,P= 0.096). The reported resistance to clarithromycin, metronidazole, and amoxicillin was 50.9%, 65.3%, and 0.5%, respectively. The authors found that resistance to clarithromycin was an important cause for treatment failure[40]. Higher doses of PPI improve the success of eradication rate of clarithromycin and amoxicillin based-therapy[46]. Moreover, younger children need a higher PPI dose per kg of bodyweight compared to adolescents and adults to obtain sufficient acid suppression[46].

Eradication rate with triple therapy for 14 d ranged from 46% to 76.4% in five studies[24,25,31,33,36].

One study evaluated the efficacy of a third-line therapy. Farahmandet al[26]compared a regimen consisting of ciprofloxacin, amoxicillin, and omeprazole, thirdline therapy, with the standard triple therapy, amoxicillin, and omeprazole twice a day plus furazolidone once a day. Both regimens given for 1 wk reported that the eradication rate was significantly higher (P= 0.011) in the group treated with ciprofloxacin (87.9%) than in that receiving furazolidone (60.6%)[32].

Standard triple therapy and probiotics

Probiotics have been proposed as an adjuvant to triple therapy to improve the efficacy and diminish AEs in both children and adults. Diarrhea, nausea, and vomiting are the most frequent side effects of eradication therapy and are an important cause of poor compliance and treatment failure.

Several studies did not show an increase in the eradication rate when triple therapy was supplemented with probiotics[23,24,25,33], by contrast, an increase in theH. pylorieradication rate was observed by others[27,28,35]. Although the beneficial effects of probiotics depend on the strains of the microorganisms selected, more robust studies and meta-analyses on this issue should be performed to clarify these discrepant results[50]. Of note, some studies demonstrated a statistically significant decrease in adverse gastrointestinal effects during the treatment[25,27,28,35]. This result was also observed in a meta-analysis using multiple strains to eradicateH. pyloriand prevent AEs, in children and adults[51]. Another meta-analysis observed that the addition of

Lactobacillus, Bifidobacterium, andSaccharomycesto standard triple therapy improved medication tolerance and patient compliance due to the decrease in side effects, both in children and adults[52]. In the studies included in this review, commercial probiotics were used; however, the use in clinical practice is not economically accessible for many countries with high prevalence rates ofH. pylori.

Standard triple therapy and antioxidant vitamins

Tümg?ret al[31]evaluated the use of vitamin E with clarithromycin-based triple therapy in children and found no statistically significant difference between its eradication rate and triple therapy alone. Although the addition of antioxidant vitamins in the eradication treatments has been evaluated[53,54], no statistically significant differences were observed. It is important to highlight that the available studies on this therapeutic alternative have a small sample size and to moderate methodological design[53].

Sequential therapy

Sequential therapy has been related to highH. pylorieradication rates[47], and some articles included here corroborated this, showing success rates of 91.3%, 81.4%, and 84.6%, whereas the effectiveness of standard triple therapy ranged from 48.8% to 78.2%[30,34,38]. However, two studies did not observe a statistically significant increase in eradication rates when this regimen was used[32,36]. A meta-analysis that evaluated sequential therapy compared to triple therapy in 13 RCTs also found a higher rate ofH. pylorieradication in children when using sequential therapy, in accordance with the results of the articles analyzed in this review[55]. Although it is a therapeutic regimen with encouraging rates ofH. pylorieradication, more robust studies are necessary to prove its effectiveness and safety to substitute triple therapy in high clarithromycin and/or nitroimidazole resistance settings[56].

Study limitations

This study had some limitations due to the small number of available studies evaluating each therapeutic regimen in children. The quality of included studies, the great diversity of treatment regimens, and the duration of treatment, doses, and administration frequency of the drugs as well as lack of antimicrobial susceptibility tests limit the comparison of the results. Most studies had an uncertain degree of bias for concealing the processes of allocation of patients as well as the blinding of participants, professionals, and outcome evaluators.

In summary, the eradication rate associated with current treatments is not satisfactory in many geographical areas. Unfortunately, many of the published works onH. pylorieradication in children have weaknesses in their methods and do not meet the ideal scientific criteria to be indicated in practice. It has to be emphasized that, becauseH. pyloriis disappearing in developed, studies investigatingH. pyloritreatment are scarce in adults and children. Otherwise, a number of countries that have a high prevalence ofH. pyloriinfection face difficulties in conducting research with a good level of evidence due to the lack of structural and financial supports. Finally, the studies were limited to a few countries (n= 10), and good results observed in some studies may not work well in other geographical areas.

CONCLUSION

In conclusion, although some studies support the use of new therapeutic regimens in the treatment ofH. pyloriinfection in children, more methodologically reliable prospective studies evaluating the most promising new therapeutic regimens are needed to assess the applicability of these treatments in pediatric clinical practice.

ARTICLE HIGHLIGHTS

Research background

Helicobacter pylori (H. pylori) is a gram-negative microaerophilic bacterium that infects the gastric epithelium and whose acquisition occurs mainly during childhood. In the last several years, no significant changes in the treatment of infected children have been observed, mainly due to the lack of studies with satisfactory scientific evidence to support the indication of new therapies in clinical practice. This systematic review evaluated the eradication rates ofH. pyloriinfection using various therapeutic regimens and their positive and negative outcomes in pediatric patients.

Research motivation

Standard triple therapy for the eradication ofH. pyloriinfection has been used as firstline treatment in children worldwide. However, the effectiveness of standard triple therapy in eradicatingH. pyloriis decreasing in various geographical areas as a consequence of increasing bacterial resistance to clarithromycin and nitroimidazoles.

Research objectives

To compare the eradication rates ofH. pyloriinfection in childhood in controlled, randomized, and prospective studies evaluating different therapeutic schemes during the last 10 years.

Research methods

We systematically reviewed in PubMed and MEDLINE relevant publications from 2010 to April 2020. Twenty studies were shortlisted. This systematic review uses guidance from the PRISMA checklist.

Research results

The results were quite heterogeneous. Standard triple therapy is still the most used regimen and its eradication rates vary according to theH. pylorisusceptibility profiles in different world regions. The addition of probiotics to therapeutic schemes shows discrepant results in eradication rate, but decrease the incidence of side effects and increases the treatment adherence. Sequential therapy has been associated with higher eradication rates than triple therapies and is a promising therapeutic regimen for this population.

Research conclusions

Currently, standard triple therapy is the most recommendedH. pylorieradication regimen for children worldwide. However, other therapeutic schemes have shown promising results in controlled trials and in a near future may be included in the guidelines recommendations.

Research perspectives

There are still few studies with satisfactory evidence levels evaluating the eradication ofH. pyloriinfection in children, mainly due to the difficulties to conduct controlled clinical trials as well as to the low availability of sources for research in many developing countries where the prevalence ofH. pyloriinfection remain elevated. Well-designed studies evaluating treatments forH. pylorieradication in children are needed to further evaluate new therapeutic options in pediatric clinical practice in high bacterial resistance settings.