Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12158
REVIEW ARTICLE
Helicobacter pylori Infection in Pediatrics czak* and Ruggiero Francavailla† Barbara Iwan *Department of Pediatrics, Gastroenterology and Nutrition, Medical University of Wroclaw, Wrocław, Poland, †Interdisciplinary Department of Medicine-Pediatric Section, University of Bari, Bari, Italy
Keywords Infection, children, epidemiology, diagnosis, treatment. Reprint requests to: Ruggiero Francavilla, Clinica Pediatrica “B. Trambusti”- Giovanni XXIII HospitalVia Amendola 270 Bari, Italy. E-mail: [email protected]
Abstract This review concerns important pediatric studies published from April 2013 to March 2014. New data on pathogenesis have demonstrated that Th1 type cytokine secretion at the gastric level is less intense in children compared with adults. They have also shown that the most significant risk factor for Helicobacter pylori infection is the parents’ origin and frequency of childcare in settings with a high prevalence of infection. A new hypothesis on the positive relationship between childhood H. pylori infection and the risk of gastric cancer in adults has been suggested which calls for an implementation of preventive programs to reduce the burden of childhood H. pylori infection in endemic areas. Several studies have investigated the role of H. pylori infection in iron-deficiency anemia, and results support the role of the bacterium in this condition. Antibiotic resistance is an area of intense research with data confirming an increase in antibiotic resistance, and the effect of CYP2C19 genetic polymorphism on proton-pump inhibitor metabolism should be further investigated as cure rates are lower in extensive metabolizers. Studies confirmed that probiotic supplementation may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea in children.
Pathophysiology In numerous studies, the influence of Helicobacter pylori virulence on the development of various diseases has been studied. Alvarez et al. [1,2] studied methylation of some genes predisposing to gastric cancer. They observed that THBS1 and GATA-4 were methylated already in the early stage of infection and are downregulated. HIC-1 demonstrated the lowest level of methylation and therefore, the main mechanism of downregulation has to be different. On the other hand, methylation of promotor regions of MGMT and MLH 1 depended on the duration of the infection. Nodular gastritis was very frequently associated with H. pylori infection in childhood. Nodular gastritis associated with H. pylori infection can commonly occur in childhood and is regarded as benign with no clinical significance. Yang et al. [3] analyzed gastric mucosa-associated lymphoid tissue (MALT) to clarify the significance of nodular gastritis in 80 H. pylori-infected children; histopathologic grading of MALT and immunohistochemistry were evaluated by CD3, CD20, cytokeratin, and Ki-67. On endoscopy, severe nodular gastritis was observed in 47% of the
46
cases and mild gastritis in 34%; gastritis was absent in 19%. Density of H. pylori and lymphocyte infiltration differed among the 3 groups (p = .022 and .025, respectively) and histologic grading for gastric lymphoid infiltrates was compatible, with grade 1 in 59%, grade 2 in 26%, grade 3 in 9%, and grade 4–5 in 5%. The degree of nodular gastritis, density of H. pylori, neutrophil activity, and gastritis score in the antrum varied with MALT grades (p = .003, p = .042, p = .028, and p = .006, respectively). This study suggests that nodular gastritis may present as a significant gastric manifestation and that thorough histologic investigation may be useful in the evaluation of gastric MALT in children infected with H. pylori as it manifests itself as severe nodular gastritis. Freire de Melo et al. [4] studied the expression of the response in the H. pylori-infected gastritis mucosa of children. The study included 245 children (142 H. pylori negative and 103 H. pylori positive) and 140 adults (40 H. pylori negative and 100 H. pylori positive). The gastric concentrations of cytokines representative of innate and Th1 responses were higher in the H. pylori positive children and adults than in those who were H. pylori negative. The gastric concentrations of IL-1a and TNF-a
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
czak and Francavailla Iwan
were significantly higher, while those of IL-2, IL-12p70 and IFN-c were lower in the H. pylori-infected children as compared to the H. pylori-infected adults. This confirms previously published studies which also showed that Th1 type cytokine secretion at the gastric level is less intense in children compared with adults [5]. However, the sharp drop in secretion of TNF-a and IL-1b when considering the cutoff of 18 years of age suggests a bias perhaps due to inclusion criteria [6].
Epidemiology, Transmission, and Reinfection Overall, we have witnessed a decrease in the prevalence of H. pylori infection over the last decade and H. pylori infection prevalence in children all over the world is diverse and dependent on many factors. Lower prevalence rates are reported in communities with higher socioeconomic status and generally better environmental conditions, while the highest percentage of infected children is observed in developing countries. Among the H. pylori risk factors, the ones most often found are poor socioeconomic and hygiene conditions as well as a high density of people in the household. Porras et al. [7] cited among the risk factors, three or more children in the family as well as the lack of current water and plumbing. Improvement of these conditions leads to a decrease in the H. pylori infection rate [8,9]. Mana et al. [10] estimated the prevalence and risk factors for H. pylori infection in 516 children and young adults in Belgium using the 13C-urea breath test (UBT). They found a prevalence of H. pylori infection of 11%, ranging from 3.2% in children with Belgian parents to 60% in children born of foreign parents in high prevalence countries, concluding that the most significant risk factor found in this study was geographical origin. Bastos et al. [11] confirmed in a meta-analysis a moderate positive association with frequency of childcare as a risk factor for H. pylori infection, especially in settings with a high prevalence of infection. In other studies, the role of transmission of infection from adults to children was emphasized. Urita et al. [12] studied transmission of H. pylori in children in a Japanese rural town. They demonstrated that not only mother-to-child transmission but also grandmother-to-child transmission is an important mechanism for the spread of H. pylori in a three-generation household. In contrast, having an infected father or grandfather was not an independent predictor for children’s infection. In other studies, it was noted that after eradication, a first-year relapse is likely to be a recurrence of the previous infection, while later on it is probably a reinfection
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
H. pylori in Pediatrics
with a new strain [13]. Mendoza et al. [14] directed their attention to a frequent occurrence of cagA-positive strains. A total of 37.9% of school children had an active or past H. pylori infection; of them 73.8% were carrying a cagA-positive strain. School children with iron deficiency and a small height for their age had a higher risk of H. pylori infection. The odds ratio (OR) for active or past infection was 2.30 (95% CI 1.01– 5.23) compared with school children with normal iron status and height or with normal iron status but small height for their age [11]. In the studies of Vanderpas et al. [15], the reinfection rate after eradication during 5 years was 48.6%, while a new infection during 10 years in previously negative people was 38.7%. The risk of infection was fourfold greater in children of non-European origin (p < .001). Infection with H. pylori either in children or in adults is a risk factor for gastric cancer. Ghasemi-Kebria et al. [16] studied 194 children (1–15 years old) enrolled in two different areas in the Golestan province for the incidence of gastric cancer. They found that the prevalence of H. pylori infection was significantly higher in the high-risk area for stomach cancer than in the low-risk area (p = .004) and that the H. pylori (p = .03) and CagA (p = .04) seropositivities were significantly lower in children less than 5 years old than in the others. The authors concluded that there is a positive relationship between childhood H. pylori infection and the risk of gastric cancer and they called for an implementation of preventive programs to reduce the burden of childhood H. pylori infection and gastric cancer in that area. Finally, Hirsch et al. [17] detected H. pylori DNA by PCR in plaque and root canal samples, and cultured H. pylori from two root canals, suggesting that these sites may be a reservoir for H. pylori and serve as a potential source of transmission.
Clinical Presentation Gastrointestinal Manifestations Generally speaking, only a small proportion of H. pyloriinfected children develop symptoms and clinically relevant gastrointestinal disease. Symptoms of H. pylorirelated peptic ulcer disease are nonspecific and may include epigastric pain especially after meals, night-time waking, unexplained nausea and/or vomiting, anorexia, hematemesis, and iron-deficiency anemia. A study on patients aged 5–15 years showed that recurrent abdominal pain was significantly associated with H. pylori infection (p = .023) [18]. However, this finding might be biased by the high prevalence of H. pylori infection in Egyptian children (50%) and therefore may not be
47
H. pylori in Pediatrics
applicable to other settings; as a result, the current recommendation is not to screen children with recurrent abdominal pain for H. pylori infection although upper abdominal pain in a hospital-based setting might be associated with H. pylori infection [19]. In an earlier study, Dore et al. [20] found that nausea or vomiting and diarrhea were significantly associated with H. pylori infection (OR 2.2 and 2.1, respectively), but not with abdominal pain or heartburn. Parzez cka et al. [21] studied the prevalence of dupA (duodenal ulcer-promoting gene) gene in 88 children with dyspeptic symptoms and confirmed H. pylori infection: the presence of dupA gene was found in 20 patients (22.7%), but there was no clinical correlation with the duodenal ulcer disease [22].
Extraintestinal Manifestations Helicobacter pylori infection is not only responsible for gastrointestinal manifestations as it also plays a potential pathogenic role in several extraintestinal diseases. Zakry et al. [23] analyzed the occurrence of diseases of the thyroid gland in 60 children and youngsters with type 1 diabetes. The association between H. pylori infection and type 1 diabetes mellitus was revealed in this study. The patients with diabetes mellitus had significantly higher levels of H. pylori IgG, TSH, and-TPO, and anti-Tg and significantly lower levels of T3 and T4 compared with the control group.
Iron-Deficiency Anemia Harris et al. [24] studied the link between H. pyloriassociated hypochlorhydria and iron deficiency in 123 children. Blood, gastric juice, and gastric biopsies were taken, respectively, for hematologic analyses, pH assessment and H. pylori determination, and duodenal biopsies for exclusion of celiac disease. They found that low serum iron in H. pylori-infected children (but not in noninfected children) is associated with hypochlorhydria, indicating a direct role of H. pylori infection in the etiology of iron deficiency. Soundaravally et al. [25] evaluated the pro-oxidant status and ferritin levels in H. pylori-infected and noninfected school children. Serum levels of protein carbonyls, malondialdehyde, ferritin, total protein, and albumin were evaluated and compared among study groups. The authors found that in H. pylori-infected children, serum MDA,and protein carbonyls were significantly increased, and ferritin levels were significantly decreased compared with the controls; this supports the hypothesis that an increased and prolonged level of oxidative stress may enhance protein degradation in children.
48
czak and Francavailla Iwan
Queiroz et al. [26] studied the mechanism leading to those changes. Higher IL-1b and TNF-a gastric concentrations were observed in H. pylori positive than in negative children. Multiple linear regression models revealed gastric IL-1b, but not TNF-a, as a significant predictor of low ferritin and hemoglobin concentrations. The authors concluded that high gastric levels of IL-1b could be the link between H. pylori infection and iron deficiency or iron-deficiency anemia in children. Hepcidin, a key regulator of iron homeostasis, increases when inflammation and infections occur. It plays a critical role in macrophage iron retention, which underlies anemia caused by inflammation/infection. Ozkasap et al. [27] in their prospective study examined prohepcidin (hepcidin’s precursor) in iron deficiency and iron-deficiency anemia in H. pyloriinfected children. The pretreatment prohepcidin levels were significantly higher in children with iron-deficiency anemia and H. pylori infection compared with the control group. The authors concluded that increased serum prohepcidin might indicate the role of inflammation in the etiology of anemia concurrent with H. pylori infection. Azab et al. [28] compared the serum hepcidin level and the response to oral iron therapy in 60 children with iron-deficiency anemia. Serum hepcidin was significantly lower in H. pylori noninfected children (p < .01) and significantly higher in H. pyloriinfected children with iron-deficiency anemia. Hepcidin increased significantly in noninfected children after 3 months of oral iron therapy. A negative correlation was demonstrated between hepcidin and serum ferritin, Hb, iron, and transferrin in H. pylori-infected children with iron-deficiency anemia. The serum hepcidin level was associated with a diminished response to the oral iron therapy in children with iron-deficiency anemia and H. pylori infection. U gras et al. [29] directed their attention to a frequent intestine parasite infestation in children with H. pylori infection. In this study, among children living in low socioeconomic conditions, 5.7% of them had Blastocytosis hominis and 2 (1.9%) had Lamblia intestinalis. The co-existence of H. pylori infection and intestinal parasites has a negative effect on thriving and iron status in a growing child. Recently, guidelines on H. pylori infection in children recommend that children with refractory IDA should be tested for H. pylori infection [30].
Asthma and Helicobacter pylori Infection Wang et al. [31] analyzed the association between asthma and H. pylori infection. In the presented metaanalysis, pooled OR for all included studies was 0.81
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
czak and Francavailla Iwan
(95% Cl; 0.72–0.91) in children and 0.81 (95% Cl; 0.71–1.08) in adults. The authors found a weak evidence for an inverse association between asthma and H. pylori infection both in children and in adults, To the contrary, Karimi et al. [32] in a cross-sectional study compared the prevalence of H. pylori infection in 98 asthmatic and 98 healthy children. Urea breath test was positive in 18 asthmatic and 23 healthy subjects (p = .38), thus concluding that H. pylori infection plays no role in asthma.
Growth Retardation Controversy exists concerning the relationship of H. pylori infection and growth retardation in children. However, in poor resource settings where malnutrition, parasitic/enteropathogen, and H. pylori infection coexist in young children, H. pylori might play a potential role. The gastrointestinal hormone ghrelin regulates food intake in humans and a decreased appetite in H. pylori-infected children has been related to lowplasma ghrelin levels, which returned to normal after H. pylori eradication. Deng et al. [33] evaluated plasma and gastric ghrelin and body mass index (BMI) before and after H. pylori eradication in 50 children. The authors found that plasma and tissue ghrelin levels significantly increased after successful eradication, although the BMI in the two groups did not differ significantly. There is currently insufficient evidence and no new data in 2013 regarding the causative association between H. pylori infection and otitis media, upper respiratory tract infections, periodontal disease, food allergy, sudden infant death syndrome, idiopathic thrombocytopenic purpura, and short stature [30].
Diagnosis Pourakbari et al. [34] conducted a study to investigate and compare the suitability of rapid urease test, serology, histopathology, and stool antigen tests with polymerase chain reaction (PCR) for detection of H. pylori and to correlate the diagnostic methods with PCR. The authors demonstrated that the rapid urease test and histopathology were as accurate as polymerase chain reaction (PCR) on biopsies and the stool antigen test. Seo et al. [35] showed in their studies that the urease test might be a more accurate diagnostic modality when performed on three or more biopsy samples in children. Pacheco et al. [36] studied the accuracy of reduceddose 13C-urea breath test (UBT) (25 mg of 13C-urea diluted in 100 mL of apple juice) and early sampling (after 10 and 20 min from baseline) of exhaled breath
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
H. pylori in Pediatrics
test for the detection of H. pylori infection in children and adolescents. They demonstrated that low-dose 13Curea with early sampling was accurate for diagnosing H. pylori infection. In another study, they showed that the positivity rate of the urease test using antral biopsy specimens increased with increasing age and had a high concordance with both the density of bacteria and the severity of gastritis [37]. The Enterotest has been validated as a noninvasive procedure to obtain H. pylori from gastric samples, with a variable diagnostic efficacy of culture and/or PCR ranging from 37% to 97%. Arboleda et al. [38] used the noninvasive Enterotest detection of various genotypes of cagA and vacA and compared it to the UBT. According to the authors the Enterotest may be used for detection of virulent strains of H. pylori in asymptomatic children residing in highrisk areas for gastric cancer in adults. The results of this test may be used for decision-making on eradication.
Treatment for Helicobacter pylori Infection In some articles, the results of 10 day sequential therapy and standard triple therapy were assessed [39–41]. Huang et al. [39] compared the results of H. pylori sequential therapy, and 7-day or 10-day standard triple therapy comprising omeprazole, amoxicillin, and clarithromycin. The authors demonstrated that the 10-day sequential therapy was significantly more effective than the standard 7-day or 10-day triple therapy in eradicating H. pylori infection. According to Giorgio et al. [42], the reason for triple therapy eradication failure was the resistance to clarithromycin. Xiong et al. [43] detected the clarithromycin-resistant H. pylori by performing PCR on stool samples from children. According to the authors, this method is reliable, rapid, noninvasive and should be recommended. Seo et al. [44] had studied antibiotic resistance to H. pylori in children for 20 years in Jinju, South Korea. The resistance rate to erythromycin increased significantly from 13.8% in 1990–1994 to 33.3% in 2005– 2009 (p = .032). Clarithromycin resistance increased from 6.9 to 18.2% and metronidazole resistance decreased from 32.8 to 27.3%. A recent systematic review addressed the problem of H. pylori resistance to antibiotics and demonstrated high H. pylori resistance to first-line antibiotics in Latin American countries; in comparison with adults, higher prevalences were observed in the three studies on children concerning resistance to clarithromycin (ranging from 19 to 27%) and dual resistance to clarithromycin and metronidazole (18%), whereas lower prevalences were reported for metronidazole (ranging from 13 to 78%), tetracycline (0%), and furazolidone (0%) [45].
49
czak and Francavailla Iwan
H. pylori in Pediatrics
Settin et al. investigated the effect of CYP2C19 genetic polymorphism on the cure rate of children who received proton-pump inhibitor-based triple therapy; 100 children with H. pylori-positive gastritis were included, and the authors were able to show that the cure rate was higher among both the groups of heterozygote extensive and poor metabolizers compared with the homozygote extensive metabolizers (OR = 2.15, p > .05) concluding that there is a need for a therapy augmentation or modification for the homozygote extensive metabolizers [46].
5
6
7
8
Probiotics Wang and Huang [47] investigated Lactobacillus acidophilus and Bifidobacterium bifidum supplementation to triple therapy for H. pylori eradication and observed changes in intestinal flora. The probiotics supplementation was beneficial to H. pylori eradication compared with sole triple therapy, although without statistical significance. Lactobacillus acidophilus and E. coli showed no statistical difference before or after therapy in the treatment group with standard triple anti-H. pylori therapy and probiotics. Li et al. [48] carried out a meta-analysis of randomized controlled trials on the efficacy of probiotics in H. pylori eradication therapy in children. The authors demonstrated that a probiotics supplementation in triple therapy for H. pylori infection may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea in children. Ahmad et al. [49] showed that probiotics have a positive effect on the eradication of H. pylori infection and change the frequency of antibiotic-induced side effects during treatment.
Acknowledgements and Disclosures
9
10
11
12
13
14
15
16
Competing interests: The authors have no competing interests. 17
References 18 1 Alvarez MC, Ladeira MS, Scaletsky IC, Pedrazzoli J Jr, Ribeiro ML. Methylation pattern of THBS1, GATA-4, and HIC1 in pediatric and adult patients infected with Helicobacter pylori. Dig Dis Sci 2013;58:2850–7. 2 Alvarez MC, Santos JC, Maniezzo N, Ladeira MS, da Silva AL, Scaletsky IC, Pedrazzoli J Jr, Ribeiro ML. MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults. World J Gastroenterol 2013;28:3043–51. 3 Yang HR, Choi HS, Paik JH, Lee HS. Endoscopic and histologic analysis of gastric mucosa-associated lymphoid tissue in children with Helicobacter pylori infection. J Pediatr Gastroenterol Nutr 2013;57:298–304. 4 Freire dMF, Rocha GA, Rocha AM, et al. Th1 immune response to H. pylori infection varies according to the age of the patients
50
19
20
21
and influences the gastric inflammatory patterns. Int J Med Microbiol 2014;304:300–6. Bontems P, Robert F, Van Gossum A, Cadranel S, Mascart F. Helicobacter pylori modulation of gastric and duodenal mucosal T cell cytokine secretions in children compared with adults. Helicobacter 2003;8:216–26. Gil JH, Seo JW, Cho M-S, Ahn J-H, Sung HY. Role of Treg and TH17 cells of the gastric mucosa in children with Helicobacter pylori gastritis. J Pediatr Gastroenterol Nutr 2014;58:252–8. Porras C, Nodora J, Sexton R, et al. Epidemiology of Helicobacter pylori infection in six Latin American countries (SWOG Trial S0701). Cancer Causes Control 2013;24:209–15. Miendje Deyi VY, Vanderpas J, Bontems P, Van den Borre C, De Koster E, Cadranel S, Burette A. Marching cohort of Helicobacter pylori infection over two decades (1988-2007): combined effects of secular trend and population migration. Epidemiol Infect 2011;139:572–80. Bures J, Kapacova M, Koupil I, et al. Significant decrease in prevalence of Helicobacter pylori in the Czech Republic. World J Gastroenterol 2012;18:4412–8. Mana F, Vandebosch S, Miendje Deyi V, Haentjens P, Urbain D. Prevalence of and risk factors for H. pylori infection in healthy children and young adults in Belgium anno 2010/ 2011. Acta Gastroenterol Belg 2013;76:381–5. Bastos J, Carreira H, La Vecchia C, Lunet N. Childcare attendance and Helicobacter pylori infection: systematic review and meta-analysis. Eur J Cancer Prev 2013;22:311–9. Urita Y, Watanabe T, Kawagoe N, Takemoto I, Tanaka H, Kijima S, et al. Role of infected grandmothers in transmission of Helicobacter pylori to children in a Japanese rural town. J Paediatr Child Health 2013;49:394–8. Calvet X, Ramırez L azaro MJ, Lehours P, M egraud F. Diagnosis and epidemiology of Helicobacter pylori infection. Helicobacter 2013;18(Suppl 1):5–11. Mendoza E, Camorlinga-Ponce M, Perez-Perez G, Mera R, Vilchis J, Moran S, Rivera O, Coria R, Torres J, Correa P, Duque X. Present and past Helicobacter pylori infection in Mexican school children. Helicobacter 2014;19:55–64. Vanderpas J, Bontems P, Miendje Deyi VY, Cadranel S. Followup of Helicobacter infection in children over two decades (19882007): persistence, relapse and acquisition rates. Epidemiol Infect 2014;142:767–75. Ghasemi-Kebria F, Ghaemi E, Azadfar S, Roshandel G. Epidemiology of Helicobacter pylori infection among Iranian children. Arab J Gastroenterol 2013;14:169–72. Hirsch C, Tegtmeyer N, Rohde M, Rowland M, Oyarzabal OA, Backert S. Live Helicobacter pylori in the root canal of endodontic-infected deciduous teeth. J Gastroenterol 2012;47:936–40. Abu-Zekry MA, E S Hashem M, Ali AA, Mohamed IS. Frequency of Helicobacter pylori infection among Egyptian children presenting with gastrointestinal manifestations. J Egypt Public Health Assoc 2013;88:74–8. Spee LA, Madderom MB, Pijpers M, van Leeuwen Y, Berger MY. Association between Helicobacter pylori and gastrointestinal symptoms in children. Pediatrics 2010;125:e651–69. Dore MP, Franciulli G, Tomasi PA, Realdi G, Delitala G, Graham DY, Malaty HM, Gastrointestinal symptoms and Helicobacter pylori infection in school-age children residing in Porto Torres Sardinia, Italy. Helicobacter 2012;17:369–73. Parzez cka M, Szaflarska-Popławska A, Gaz siorowska J, Gorzkiewicz M, Grzybowski T. The prevalence of dupA (duodenal ulcer-promoting gene) of Helicobacter pylori in children and adolescents–own observation. Pol Merkur Lekarski 2013;34:277–80.
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
czak and Francavailla Iwan
22 Bontems P, Kalach N, Vanderpas J, et al. Helicobacter pylori infection in European children with gastro-duodenal ulcers and erosions. Pediatr Infect Dis J 2013;32:1324–9. 23 Zekry OA, Abd Elwahid HA. The association between Helicobacter pylori infection, type 1 diabetes mellitus, and autoimmune thyroiditis. J Egypt Public Health Assoc 2013;88:143–7. 24 Harris PR, Serrano CA, Villagran A, Walker MM, Thomson M, Duarte I, Windle HJ, Crabtree JE. Helicobacter pylori-associated hypochlorhydria in children, and development of iron deficiency. J Clin Pathol 2013;66:343–7. 25 Soundaravally R, Pukazhvandthen P, Zachariah B, Hamide A. Plasma ferritin and indices of oxidative stress in Helicobacter pylori infection among schoolchildren. J Pediatr Gastroenterol Nutr 2013;56:519–22. 26 Queiroz DM, Harris PR, Sanderson IR, et al. Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study. PLoS ONE 2013;8:e68833. 27 Ozkasap S, Yarali N, Isik P, Bay A, Kara A, Tunc B. The role of prohepcidin in anemia due to Helicobacter pylori infection. Pediatr Hematol Oncol 2013;30:425–31. 28 Azab SF, Esh AM. Serum hepcidin levels in Helicobacter pyloriinfected children with iron-deficiency anemia: a case-control study. Ann Hematol 2013;92:1477–83. 29 U gras M, Miman O. The prevalence of intestinal parasites in children with Helicobacter pylori gastritis evaluated retrospectively. Turkiye Parazitol Derg 2013;37:245–8. 30 Koletzko S, Jones NL, Goodman KJ, et al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr 2011;53:230–43. 31 Wang Q, Yu C, Sun Y. The association between asthma and Helicobacter pylori: a meta-analysis. Helicobacter 2013;18:41–53. 32 Karimi A, Fakhimi-Derakhshan K, Imanzadeh F, Rezaei M, Cavoshzadeh Z, Maham S. Helicobacter pylori infection and pediatric asthma. Iran J Microbiol 2013;5:132–5. 33 Deng ZH, Chu B, Xu YZ, Zhang B, Jiang LR. Influence of Helicobacter pylori infection on ghrelin levels in children. World J Gastroenterol 2012;18:5096–100. 34 Pourakbari B, Ghazi M, Mahmoudi S, Mamishi S, Azhdarkosh H, Najafi M, Kazemi B, Salavati A, Mirsalehian A. Diagnosis of Helicobacter pylori infection by invasive and noninvasive tests. Braz J Microbiol 2013;15:795–8. 35 Seo JH, Park JS, Yeom JS, et al. Correlation between positive rate and number of biopsy samples on urease test in childhood Helicobacter pylori infection. J Korean Med Sci 2014;29:106–9. 36 Pacheco SL, Ogata SK, Machado RS, Patrıcio FR, Pardo ML, Kawakami E. Diagnosis of Helicobacter pylori infection by means of reduced-dose (13)C-urea breath test and early sampling of exhaled breath. J Pediatr Gastroenterol Nutr 2013;57:607–11.
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
H. pylori in Pediatrics
37 Seo JH, Youn HS, Park JJ, et al. Influencing factors to results of the urease test: age, sampling site, histopathologic findings, and density of Helicobacter pylori. Pediatr Gastroenterol Hepatol Nutr 2013;16:34–40. 38 Arboleda RN, Schneider BG, Bravo LE, Romero-Gallo J, Peek RM Jr, Mera RM, Yepez MC, Campo C, Correa P. Use of the noninvasive entero-test in the detection of Helicobacter pylori in children in an endemic area in Colombia. J Pediatr Gastroenterol Nutr 2013;57:192–6. 39 Huang J, Zhou L, Geng L, Yang M, Xu XW. Randomized controlled trial: sequential vs. standard triple therapy for Helicobacter pylori infection in Chinese children-a multicentre, openlabelled study. Aliment Pharmacol Ther 2013;38:1230–5. 40 Laving A, Kamenwa R, Sayed S, Kimang’a AN, Revathi G. Effectiveness of sequential v. standard triple therapy for treatment of Helicobacter pylori infection in children in Nairobi, Kenya. S Afr Med J 2013;23:921–4. 41 Zullo A, Hassan C, Ridola L, De Francesco V, Vaira D. Standard triple and sequential therapies for Helicobacter pylori eradication: an update. Eur J Intern Med 2013;24:16–9. 42 Giorgio F, Principi M, De Francesco V, Zullo A, Losurdo G, Di Leo A, Ierardi E. Primary clarithromycin resistance to Helicobacter pylori: is this the main reason for triple therapy failure? World J Gastrointest Pathophysiol 2013;15:43–6. 43 Xiong LJ, Tong Y, Wang Z, Mao M. Detection of clarithromycin-resistant Helicobacter pylori by stool PCR in children: a comprehensive review of literature. Helicobacter 2013;18:89–101. 44 Seo JH, Jun JS, Yeom JS, Park JS, Youn HS, Ko GH, Baik SC, Lee WK, Cho MJ, Rhee KH. Changing pattern of antibiotic resistance of Helicobacter pylori in children during 20 years in Jinju, South Korea. Pediatr Int 2013;55:332–6. 45 Camargo MC, Garcıa A, Riquelme A, Otero W, Camargo CA, Hernandez-Garcıa T, Candia R, Bruce MG, Rabkin CS. The problem of Helicobacter pylori resistance to antibiotics: a systematic review in Latin America. Am J Gastroenterol 2014;109:485–95. 46 Settin A, Abdalla AF, Al-Hussaini AS, El-Baz R, Galal A. Cure rate of Helicobacter pylori infection in Egyptian children related to CYP2C19 gene polymorphism. Indian J Gastroenterol 2014 [Epub ahead of print]. 47 Wang YH, Huang Y. Effect of Lactobacillus acidophilus and Bifidobacterium bifidum supplementation to standard triple therapy on Helicobacter pylori eradication and dynamic changes in intestinal flora. World J Microbiol Biotechnol 2014;30:847–53. 48 Li S, Huang XL, Sui JZ, et al. Meta-analysis of randomized controlled trials on the efficacy of probiotics in Helicobacter pylori eradication therapy in children. Eur J Pediatr 2014;173:153–61. 49 Ahmad K, Fatemeh F, Mehri N, Maryam S. Probiotics for the treatment of pediatric Helicobacter pylori infection: a randomized double blind clinical trial. Iran J Pediatr 2013;23:79–84.
51
REVIEW ARTICLE
Helicobacter pylori Infection in Pediatrics czak* and Ruggiero Francavailla† Barbara Iwan *Department of Pediatrics, Gastroenterology and Nutrition, Medical University of Wroclaw, Wrocław, Poland, †Interdisciplinary Department of Medicine-Pediatric Section, University of Bari, Bari, Italy
Keywords Infection, children, epidemiology, diagnosis, treatment. Reprint requests to: Ruggiero Francavilla, Clinica Pediatrica “B. Trambusti”- Giovanni XXIII HospitalVia Amendola 270 Bari, Italy. E-mail: [email protected]
Abstract This review concerns important pediatric studies published from April 2013 to March 2014. New data on pathogenesis have demonstrated that Th1 type cytokine secretion at the gastric level is less intense in children compared with adults. They have also shown that the most significant risk factor for Helicobacter pylori infection is the parents’ origin and frequency of childcare in settings with a high prevalence of infection. A new hypothesis on the positive relationship between childhood H. pylori infection and the risk of gastric cancer in adults has been suggested which calls for an implementation of preventive programs to reduce the burden of childhood H. pylori infection in endemic areas. Several studies have investigated the role of H. pylori infection in iron-deficiency anemia, and results support the role of the bacterium in this condition. Antibiotic resistance is an area of intense research with data confirming an increase in antibiotic resistance, and the effect of CYP2C19 genetic polymorphism on proton-pump inhibitor metabolism should be further investigated as cure rates are lower in extensive metabolizers. Studies confirmed that probiotic supplementation may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea in children.
Pathophysiology In numerous studies, the influence of Helicobacter pylori virulence on the development of various diseases has been studied. Alvarez et al. [1,2] studied methylation of some genes predisposing to gastric cancer. They observed that THBS1 and GATA-4 were methylated already in the early stage of infection and are downregulated. HIC-1 demonstrated the lowest level of methylation and therefore, the main mechanism of downregulation has to be different. On the other hand, methylation of promotor regions of MGMT and MLH 1 depended on the duration of the infection. Nodular gastritis was very frequently associated with H. pylori infection in childhood. Nodular gastritis associated with H. pylori infection can commonly occur in childhood and is regarded as benign with no clinical significance. Yang et al. [3] analyzed gastric mucosa-associated lymphoid tissue (MALT) to clarify the significance of nodular gastritis in 80 H. pylori-infected children; histopathologic grading of MALT and immunohistochemistry were evaluated by CD3, CD20, cytokeratin, and Ki-67. On endoscopy, severe nodular gastritis was observed in 47% of the
46
cases and mild gastritis in 34%; gastritis was absent in 19%. Density of H. pylori and lymphocyte infiltration differed among the 3 groups (p = .022 and .025, respectively) and histologic grading for gastric lymphoid infiltrates was compatible, with grade 1 in 59%, grade 2 in 26%, grade 3 in 9%, and grade 4–5 in 5%. The degree of nodular gastritis, density of H. pylori, neutrophil activity, and gastritis score in the antrum varied with MALT grades (p = .003, p = .042, p = .028, and p = .006, respectively). This study suggests that nodular gastritis may present as a significant gastric manifestation and that thorough histologic investigation may be useful in the evaluation of gastric MALT in children infected with H. pylori as it manifests itself as severe nodular gastritis. Freire de Melo et al. [4] studied the expression of the response in the H. pylori-infected gastritis mucosa of children. The study included 245 children (142 H. pylori negative and 103 H. pylori positive) and 140 adults (40 H. pylori negative and 100 H. pylori positive). The gastric concentrations of cytokines representative of innate and Th1 responses were higher in the H. pylori positive children and adults than in those who were H. pylori negative. The gastric concentrations of IL-1a and TNF-a
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
czak and Francavailla Iwan
were significantly higher, while those of IL-2, IL-12p70 and IFN-c were lower in the H. pylori-infected children as compared to the H. pylori-infected adults. This confirms previously published studies which also showed that Th1 type cytokine secretion at the gastric level is less intense in children compared with adults [5]. However, the sharp drop in secretion of TNF-a and IL-1b when considering the cutoff of 18 years of age suggests a bias perhaps due to inclusion criteria [6].
Epidemiology, Transmission, and Reinfection Overall, we have witnessed a decrease in the prevalence of H. pylori infection over the last decade and H. pylori infection prevalence in children all over the world is diverse and dependent on many factors. Lower prevalence rates are reported in communities with higher socioeconomic status and generally better environmental conditions, while the highest percentage of infected children is observed in developing countries. Among the H. pylori risk factors, the ones most often found are poor socioeconomic and hygiene conditions as well as a high density of people in the household. Porras et al. [7] cited among the risk factors, three or more children in the family as well as the lack of current water and plumbing. Improvement of these conditions leads to a decrease in the H. pylori infection rate [8,9]. Mana et al. [10] estimated the prevalence and risk factors for H. pylori infection in 516 children and young adults in Belgium using the 13C-urea breath test (UBT). They found a prevalence of H. pylori infection of 11%, ranging from 3.2% in children with Belgian parents to 60% in children born of foreign parents in high prevalence countries, concluding that the most significant risk factor found in this study was geographical origin. Bastos et al. [11] confirmed in a meta-analysis a moderate positive association with frequency of childcare as a risk factor for H. pylori infection, especially in settings with a high prevalence of infection. In other studies, the role of transmission of infection from adults to children was emphasized. Urita et al. [12] studied transmission of H. pylori in children in a Japanese rural town. They demonstrated that not only mother-to-child transmission but also grandmother-to-child transmission is an important mechanism for the spread of H. pylori in a three-generation household. In contrast, having an infected father or grandfather was not an independent predictor for children’s infection. In other studies, it was noted that after eradication, a first-year relapse is likely to be a recurrence of the previous infection, while later on it is probably a reinfection
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
H. pylori in Pediatrics
with a new strain [13]. Mendoza et al. [14] directed their attention to a frequent occurrence of cagA-positive strains. A total of 37.9% of school children had an active or past H. pylori infection; of them 73.8% were carrying a cagA-positive strain. School children with iron deficiency and a small height for their age had a higher risk of H. pylori infection. The odds ratio (OR) for active or past infection was 2.30 (95% CI 1.01– 5.23) compared with school children with normal iron status and height or with normal iron status but small height for their age [11]. In the studies of Vanderpas et al. [15], the reinfection rate after eradication during 5 years was 48.6%, while a new infection during 10 years in previously negative people was 38.7%. The risk of infection was fourfold greater in children of non-European origin (p < .001). Infection with H. pylori either in children or in adults is a risk factor for gastric cancer. Ghasemi-Kebria et al. [16] studied 194 children (1–15 years old) enrolled in two different areas in the Golestan province for the incidence of gastric cancer. They found that the prevalence of H. pylori infection was significantly higher in the high-risk area for stomach cancer than in the low-risk area (p = .004) and that the H. pylori (p = .03) and CagA (p = .04) seropositivities were significantly lower in children less than 5 years old than in the others. The authors concluded that there is a positive relationship between childhood H. pylori infection and the risk of gastric cancer and they called for an implementation of preventive programs to reduce the burden of childhood H. pylori infection and gastric cancer in that area. Finally, Hirsch et al. [17] detected H. pylori DNA by PCR in plaque and root canal samples, and cultured H. pylori from two root canals, suggesting that these sites may be a reservoir for H. pylori and serve as a potential source of transmission.
Clinical Presentation Gastrointestinal Manifestations Generally speaking, only a small proportion of H. pyloriinfected children develop symptoms and clinically relevant gastrointestinal disease. Symptoms of H. pylorirelated peptic ulcer disease are nonspecific and may include epigastric pain especially after meals, night-time waking, unexplained nausea and/or vomiting, anorexia, hematemesis, and iron-deficiency anemia. A study on patients aged 5–15 years showed that recurrent abdominal pain was significantly associated with H. pylori infection (p = .023) [18]. However, this finding might be biased by the high prevalence of H. pylori infection in Egyptian children (50%) and therefore may not be
47
H. pylori in Pediatrics
applicable to other settings; as a result, the current recommendation is not to screen children with recurrent abdominal pain for H. pylori infection although upper abdominal pain in a hospital-based setting might be associated with H. pylori infection [19]. In an earlier study, Dore et al. [20] found that nausea or vomiting and diarrhea were significantly associated with H. pylori infection (OR 2.2 and 2.1, respectively), but not with abdominal pain or heartburn. Parzez cka et al. [21] studied the prevalence of dupA (duodenal ulcer-promoting gene) gene in 88 children with dyspeptic symptoms and confirmed H. pylori infection: the presence of dupA gene was found in 20 patients (22.7%), but there was no clinical correlation with the duodenal ulcer disease [22].
Extraintestinal Manifestations Helicobacter pylori infection is not only responsible for gastrointestinal manifestations as it also plays a potential pathogenic role in several extraintestinal diseases. Zakry et al. [23] analyzed the occurrence of diseases of the thyroid gland in 60 children and youngsters with type 1 diabetes. The association between H. pylori infection and type 1 diabetes mellitus was revealed in this study. The patients with diabetes mellitus had significantly higher levels of H. pylori IgG, TSH, and-TPO, and anti-Tg and significantly lower levels of T3 and T4 compared with the control group.
Iron-Deficiency Anemia Harris et al. [24] studied the link between H. pyloriassociated hypochlorhydria and iron deficiency in 123 children. Blood, gastric juice, and gastric biopsies were taken, respectively, for hematologic analyses, pH assessment and H. pylori determination, and duodenal biopsies for exclusion of celiac disease. They found that low serum iron in H. pylori-infected children (but not in noninfected children) is associated with hypochlorhydria, indicating a direct role of H. pylori infection in the etiology of iron deficiency. Soundaravally et al. [25] evaluated the pro-oxidant status and ferritin levels in H. pylori-infected and noninfected school children. Serum levels of protein carbonyls, malondialdehyde, ferritin, total protein, and albumin were evaluated and compared among study groups. The authors found that in H. pylori-infected children, serum MDA,and protein carbonyls were significantly increased, and ferritin levels were significantly decreased compared with the controls; this supports the hypothesis that an increased and prolonged level of oxidative stress may enhance protein degradation in children.
48
czak and Francavailla Iwan
Queiroz et al. [26] studied the mechanism leading to those changes. Higher IL-1b and TNF-a gastric concentrations were observed in H. pylori positive than in negative children. Multiple linear regression models revealed gastric IL-1b, but not TNF-a, as a significant predictor of low ferritin and hemoglobin concentrations. The authors concluded that high gastric levels of IL-1b could be the link between H. pylori infection and iron deficiency or iron-deficiency anemia in children. Hepcidin, a key regulator of iron homeostasis, increases when inflammation and infections occur. It plays a critical role in macrophage iron retention, which underlies anemia caused by inflammation/infection. Ozkasap et al. [27] in their prospective study examined prohepcidin (hepcidin’s precursor) in iron deficiency and iron-deficiency anemia in H. pyloriinfected children. The pretreatment prohepcidin levels were significantly higher in children with iron-deficiency anemia and H. pylori infection compared with the control group. The authors concluded that increased serum prohepcidin might indicate the role of inflammation in the etiology of anemia concurrent with H. pylori infection. Azab et al. [28] compared the serum hepcidin level and the response to oral iron therapy in 60 children with iron-deficiency anemia. Serum hepcidin was significantly lower in H. pylori noninfected children (p < .01) and significantly higher in H. pyloriinfected children with iron-deficiency anemia. Hepcidin increased significantly in noninfected children after 3 months of oral iron therapy. A negative correlation was demonstrated between hepcidin and serum ferritin, Hb, iron, and transferrin in H. pylori-infected children with iron-deficiency anemia. The serum hepcidin level was associated with a diminished response to the oral iron therapy in children with iron-deficiency anemia and H. pylori infection. U gras et al. [29] directed their attention to a frequent intestine parasite infestation in children with H. pylori infection. In this study, among children living in low socioeconomic conditions, 5.7% of them had Blastocytosis hominis and 2 (1.9%) had Lamblia intestinalis. The co-existence of H. pylori infection and intestinal parasites has a negative effect on thriving and iron status in a growing child. Recently, guidelines on H. pylori infection in children recommend that children with refractory IDA should be tested for H. pylori infection [30].
Asthma and Helicobacter pylori Infection Wang et al. [31] analyzed the association between asthma and H. pylori infection. In the presented metaanalysis, pooled OR for all included studies was 0.81
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
czak and Francavailla Iwan
(95% Cl; 0.72–0.91) in children and 0.81 (95% Cl; 0.71–1.08) in adults. The authors found a weak evidence for an inverse association between asthma and H. pylori infection both in children and in adults, To the contrary, Karimi et al. [32] in a cross-sectional study compared the prevalence of H. pylori infection in 98 asthmatic and 98 healthy children. Urea breath test was positive in 18 asthmatic and 23 healthy subjects (p = .38), thus concluding that H. pylori infection plays no role in asthma.
Growth Retardation Controversy exists concerning the relationship of H. pylori infection and growth retardation in children. However, in poor resource settings where malnutrition, parasitic/enteropathogen, and H. pylori infection coexist in young children, H. pylori might play a potential role. The gastrointestinal hormone ghrelin regulates food intake in humans and a decreased appetite in H. pylori-infected children has been related to lowplasma ghrelin levels, which returned to normal after H. pylori eradication. Deng et al. [33] evaluated plasma and gastric ghrelin and body mass index (BMI) before and after H. pylori eradication in 50 children. The authors found that plasma and tissue ghrelin levels significantly increased after successful eradication, although the BMI in the two groups did not differ significantly. There is currently insufficient evidence and no new data in 2013 regarding the causative association between H. pylori infection and otitis media, upper respiratory tract infections, periodontal disease, food allergy, sudden infant death syndrome, idiopathic thrombocytopenic purpura, and short stature [30].
Diagnosis Pourakbari et al. [34] conducted a study to investigate and compare the suitability of rapid urease test, serology, histopathology, and stool antigen tests with polymerase chain reaction (PCR) for detection of H. pylori and to correlate the diagnostic methods with PCR. The authors demonstrated that the rapid urease test and histopathology were as accurate as polymerase chain reaction (PCR) on biopsies and the stool antigen test. Seo et al. [35] showed in their studies that the urease test might be a more accurate diagnostic modality when performed on three or more biopsy samples in children. Pacheco et al. [36] studied the accuracy of reduceddose 13C-urea breath test (UBT) (25 mg of 13C-urea diluted in 100 mL of apple juice) and early sampling (after 10 and 20 min from baseline) of exhaled breath
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
H. pylori in Pediatrics
test for the detection of H. pylori infection in children and adolescents. They demonstrated that low-dose 13Curea with early sampling was accurate for diagnosing H. pylori infection. In another study, they showed that the positivity rate of the urease test using antral biopsy specimens increased with increasing age and had a high concordance with both the density of bacteria and the severity of gastritis [37]. The Enterotest has been validated as a noninvasive procedure to obtain H. pylori from gastric samples, with a variable diagnostic efficacy of culture and/or PCR ranging from 37% to 97%. Arboleda et al. [38] used the noninvasive Enterotest detection of various genotypes of cagA and vacA and compared it to the UBT. According to the authors the Enterotest may be used for detection of virulent strains of H. pylori in asymptomatic children residing in highrisk areas for gastric cancer in adults. The results of this test may be used for decision-making on eradication.
Treatment for Helicobacter pylori Infection In some articles, the results of 10 day sequential therapy and standard triple therapy were assessed [39–41]. Huang et al. [39] compared the results of H. pylori sequential therapy, and 7-day or 10-day standard triple therapy comprising omeprazole, amoxicillin, and clarithromycin. The authors demonstrated that the 10-day sequential therapy was significantly more effective than the standard 7-day or 10-day triple therapy in eradicating H. pylori infection. According to Giorgio et al. [42], the reason for triple therapy eradication failure was the resistance to clarithromycin. Xiong et al. [43] detected the clarithromycin-resistant H. pylori by performing PCR on stool samples from children. According to the authors, this method is reliable, rapid, noninvasive and should be recommended. Seo et al. [44] had studied antibiotic resistance to H. pylori in children for 20 years in Jinju, South Korea. The resistance rate to erythromycin increased significantly from 13.8% in 1990–1994 to 33.3% in 2005– 2009 (p = .032). Clarithromycin resistance increased from 6.9 to 18.2% and metronidazole resistance decreased from 32.8 to 27.3%. A recent systematic review addressed the problem of H. pylori resistance to antibiotics and demonstrated high H. pylori resistance to first-line antibiotics in Latin American countries; in comparison with adults, higher prevalences were observed in the three studies on children concerning resistance to clarithromycin (ranging from 19 to 27%) and dual resistance to clarithromycin and metronidazole (18%), whereas lower prevalences were reported for metronidazole (ranging from 13 to 78%), tetracycline (0%), and furazolidone (0%) [45].
49
czak and Francavailla Iwan
H. pylori in Pediatrics
Settin et al. investigated the effect of CYP2C19 genetic polymorphism on the cure rate of children who received proton-pump inhibitor-based triple therapy; 100 children with H. pylori-positive gastritis were included, and the authors were able to show that the cure rate was higher among both the groups of heterozygote extensive and poor metabolizers compared with the homozygote extensive metabolizers (OR = 2.15, p > .05) concluding that there is a need for a therapy augmentation or modification for the homozygote extensive metabolizers [46].
5
6
7
8
Probiotics Wang and Huang [47] investigated Lactobacillus acidophilus and Bifidobacterium bifidum supplementation to triple therapy for H. pylori eradication and observed changes in intestinal flora. The probiotics supplementation was beneficial to H. pylori eradication compared with sole triple therapy, although without statistical significance. Lactobacillus acidophilus and E. coli showed no statistical difference before or after therapy in the treatment group with standard triple anti-H. pylori therapy and probiotics. Li et al. [48] carried out a meta-analysis of randomized controlled trials on the efficacy of probiotics in H. pylori eradication therapy in children. The authors demonstrated that a probiotics supplementation in triple therapy for H. pylori infection may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea in children. Ahmad et al. [49] showed that probiotics have a positive effect on the eradication of H. pylori infection and change the frequency of antibiotic-induced side effects during treatment.
Acknowledgements and Disclosures
9
10
11
12
13
14
15
16
Competing interests: The authors have no competing interests. 17
References 18 1 Alvarez MC, Ladeira MS, Scaletsky IC, Pedrazzoli J Jr, Ribeiro ML. Methylation pattern of THBS1, GATA-4, and HIC1 in pediatric and adult patients infected with Helicobacter pylori. Dig Dis Sci 2013;58:2850–7. 2 Alvarez MC, Santos JC, Maniezzo N, Ladeira MS, da Silva AL, Scaletsky IC, Pedrazzoli J Jr, Ribeiro ML. MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults. World J Gastroenterol 2013;28:3043–51. 3 Yang HR, Choi HS, Paik JH, Lee HS. Endoscopic and histologic analysis of gastric mucosa-associated lymphoid tissue in children with Helicobacter pylori infection. J Pediatr Gastroenterol Nutr 2013;57:298–304. 4 Freire dMF, Rocha GA, Rocha AM, et al. Th1 immune response to H. pylori infection varies according to the age of the patients
50
19
20
21
and influences the gastric inflammatory patterns. Int J Med Microbiol 2014;304:300–6. Bontems P, Robert F, Van Gossum A, Cadranel S, Mascart F. Helicobacter pylori modulation of gastric and duodenal mucosal T cell cytokine secretions in children compared with adults. Helicobacter 2003;8:216–26. Gil JH, Seo JW, Cho M-S, Ahn J-H, Sung HY. Role of Treg and TH17 cells of the gastric mucosa in children with Helicobacter pylori gastritis. J Pediatr Gastroenterol Nutr 2014;58:252–8. Porras C, Nodora J, Sexton R, et al. Epidemiology of Helicobacter pylori infection in six Latin American countries (SWOG Trial S0701). Cancer Causes Control 2013;24:209–15. Miendje Deyi VY, Vanderpas J, Bontems P, Van den Borre C, De Koster E, Cadranel S, Burette A. Marching cohort of Helicobacter pylori infection over two decades (1988-2007): combined effects of secular trend and population migration. Epidemiol Infect 2011;139:572–80. Bures J, Kapacova M, Koupil I, et al. Significant decrease in prevalence of Helicobacter pylori in the Czech Republic. World J Gastroenterol 2012;18:4412–8. Mana F, Vandebosch S, Miendje Deyi V, Haentjens P, Urbain D. Prevalence of and risk factors for H. pylori infection in healthy children and young adults in Belgium anno 2010/ 2011. Acta Gastroenterol Belg 2013;76:381–5. Bastos J, Carreira H, La Vecchia C, Lunet N. Childcare attendance and Helicobacter pylori infection: systematic review and meta-analysis. Eur J Cancer Prev 2013;22:311–9. Urita Y, Watanabe T, Kawagoe N, Takemoto I, Tanaka H, Kijima S, et al. Role of infected grandmothers in transmission of Helicobacter pylori to children in a Japanese rural town. J Paediatr Child Health 2013;49:394–8. Calvet X, Ramırez L azaro MJ, Lehours P, M egraud F. Diagnosis and epidemiology of Helicobacter pylori infection. Helicobacter 2013;18(Suppl 1):5–11. Mendoza E, Camorlinga-Ponce M, Perez-Perez G, Mera R, Vilchis J, Moran S, Rivera O, Coria R, Torres J, Correa P, Duque X. Present and past Helicobacter pylori infection in Mexican school children. Helicobacter 2014;19:55–64. Vanderpas J, Bontems P, Miendje Deyi VY, Cadranel S. Followup of Helicobacter infection in children over two decades (19882007): persistence, relapse and acquisition rates. Epidemiol Infect 2014;142:767–75. Ghasemi-Kebria F, Ghaemi E, Azadfar S, Roshandel G. Epidemiology of Helicobacter pylori infection among Iranian children. Arab J Gastroenterol 2013;14:169–72. Hirsch C, Tegtmeyer N, Rohde M, Rowland M, Oyarzabal OA, Backert S. Live Helicobacter pylori in the root canal of endodontic-infected deciduous teeth. J Gastroenterol 2012;47:936–40. Abu-Zekry MA, E S Hashem M, Ali AA, Mohamed IS. Frequency of Helicobacter pylori infection among Egyptian children presenting with gastrointestinal manifestations. J Egypt Public Health Assoc 2013;88:74–8. Spee LA, Madderom MB, Pijpers M, van Leeuwen Y, Berger MY. Association between Helicobacter pylori and gastrointestinal symptoms in children. Pediatrics 2010;125:e651–69. Dore MP, Franciulli G, Tomasi PA, Realdi G, Delitala G, Graham DY, Malaty HM, Gastrointestinal symptoms and Helicobacter pylori infection in school-age children residing in Porto Torres Sardinia, Italy. Helicobacter 2012;17:369–73. Parzez cka M, Szaflarska-Popławska A, Gaz siorowska J, Gorzkiewicz M, Grzybowski T. The prevalence of dupA (duodenal ulcer-promoting gene) of Helicobacter pylori in children and adolescents–own observation. Pol Merkur Lekarski 2013;34:277–80.
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
czak and Francavailla Iwan
22 Bontems P, Kalach N, Vanderpas J, et al. Helicobacter pylori infection in European children with gastro-duodenal ulcers and erosions. Pediatr Infect Dis J 2013;32:1324–9. 23 Zekry OA, Abd Elwahid HA. The association between Helicobacter pylori infection, type 1 diabetes mellitus, and autoimmune thyroiditis. J Egypt Public Health Assoc 2013;88:143–7. 24 Harris PR, Serrano CA, Villagran A, Walker MM, Thomson M, Duarte I, Windle HJ, Crabtree JE. Helicobacter pylori-associated hypochlorhydria in children, and development of iron deficiency. J Clin Pathol 2013;66:343–7. 25 Soundaravally R, Pukazhvandthen P, Zachariah B, Hamide A. Plasma ferritin and indices of oxidative stress in Helicobacter pylori infection among schoolchildren. J Pediatr Gastroenterol Nutr 2013;56:519–22. 26 Queiroz DM, Harris PR, Sanderson IR, et al. Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study. PLoS ONE 2013;8:e68833. 27 Ozkasap S, Yarali N, Isik P, Bay A, Kara A, Tunc B. The role of prohepcidin in anemia due to Helicobacter pylori infection. Pediatr Hematol Oncol 2013;30:425–31. 28 Azab SF, Esh AM. Serum hepcidin levels in Helicobacter pyloriinfected children with iron-deficiency anemia: a case-control study. Ann Hematol 2013;92:1477–83. 29 U gras M, Miman O. The prevalence of intestinal parasites in children with Helicobacter pylori gastritis evaluated retrospectively. Turkiye Parazitol Derg 2013;37:245–8. 30 Koletzko S, Jones NL, Goodman KJ, et al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr 2011;53:230–43. 31 Wang Q, Yu C, Sun Y. The association between asthma and Helicobacter pylori: a meta-analysis. Helicobacter 2013;18:41–53. 32 Karimi A, Fakhimi-Derakhshan K, Imanzadeh F, Rezaei M, Cavoshzadeh Z, Maham S. Helicobacter pylori infection and pediatric asthma. Iran J Microbiol 2013;5:132–5. 33 Deng ZH, Chu B, Xu YZ, Zhang B, Jiang LR. Influence of Helicobacter pylori infection on ghrelin levels in children. World J Gastroenterol 2012;18:5096–100. 34 Pourakbari B, Ghazi M, Mahmoudi S, Mamishi S, Azhdarkosh H, Najafi M, Kazemi B, Salavati A, Mirsalehian A. Diagnosis of Helicobacter pylori infection by invasive and noninvasive tests. Braz J Microbiol 2013;15:795–8. 35 Seo JH, Park JS, Yeom JS, et al. Correlation between positive rate and number of biopsy samples on urease test in childhood Helicobacter pylori infection. J Korean Med Sci 2014;29:106–9. 36 Pacheco SL, Ogata SK, Machado RS, Patrıcio FR, Pardo ML, Kawakami E. Diagnosis of Helicobacter pylori infection by means of reduced-dose (13)C-urea breath test and early sampling of exhaled breath. J Pediatr Gastroenterol Nutr 2013;57:607–11.
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 46–51
H. pylori in Pediatrics
37 Seo JH, Youn HS, Park JJ, et al. Influencing factors to results of the urease test: age, sampling site, histopathologic findings, and density of Helicobacter pylori. Pediatr Gastroenterol Hepatol Nutr 2013;16:34–40. 38 Arboleda RN, Schneider BG, Bravo LE, Romero-Gallo J, Peek RM Jr, Mera RM, Yepez MC, Campo C, Correa P. Use of the noninvasive entero-test in the detection of Helicobacter pylori in children in an endemic area in Colombia. J Pediatr Gastroenterol Nutr 2013;57:192–6. 39 Huang J, Zhou L, Geng L, Yang M, Xu XW. Randomized controlled trial: sequential vs. standard triple therapy for Helicobacter pylori infection in Chinese children-a multicentre, openlabelled study. Aliment Pharmacol Ther 2013;38:1230–5. 40 Laving A, Kamenwa R, Sayed S, Kimang’a AN, Revathi G. Effectiveness of sequential v. standard triple therapy for treatment of Helicobacter pylori infection in children in Nairobi, Kenya. S Afr Med J 2013;23:921–4. 41 Zullo A, Hassan C, Ridola L, De Francesco V, Vaira D. Standard triple and sequential therapies for Helicobacter pylori eradication: an update. Eur J Intern Med 2013;24:16–9. 42 Giorgio F, Principi M, De Francesco V, Zullo A, Losurdo G, Di Leo A, Ierardi E. Primary clarithromycin resistance to Helicobacter pylori: is this the main reason for triple therapy failure? World J Gastrointest Pathophysiol 2013;15:43–6. 43 Xiong LJ, Tong Y, Wang Z, Mao M. Detection of clarithromycin-resistant Helicobacter pylori by stool PCR in children: a comprehensive review of literature. Helicobacter 2013;18:89–101. 44 Seo JH, Jun JS, Yeom JS, Park JS, Youn HS, Ko GH, Baik SC, Lee WK, Cho MJ, Rhee KH. Changing pattern of antibiotic resistance of Helicobacter pylori in children during 20 years in Jinju, South Korea. Pediatr Int 2013;55:332–6. 45 Camargo MC, Garcıa A, Riquelme A, Otero W, Camargo CA, Hernandez-Garcıa T, Candia R, Bruce MG, Rabkin CS. The problem of Helicobacter pylori resistance to antibiotics: a systematic review in Latin America. Am J Gastroenterol 2014;109:485–95. 46 Settin A, Abdalla AF, Al-Hussaini AS, El-Baz R, Galal A. Cure rate of Helicobacter pylori infection in Egyptian children related to CYP2C19 gene polymorphism. Indian J Gastroenterol 2014 [Epub ahead of print]. 47 Wang YH, Huang Y. Effect of Lactobacillus acidophilus and Bifidobacterium bifidum supplementation to standard triple therapy on Helicobacter pylori eradication and dynamic changes in intestinal flora. World J Microbiol Biotechnol 2014;30:847–53. 48 Li S, Huang XL, Sui JZ, et al. Meta-analysis of randomized controlled trials on the efficacy of probiotics in Helicobacter pylori eradication therapy in children. Eur J Pediatr 2014;173:153–61. 49 Ahmad K, Fatemeh F, Mehri N, Maryam S. Probiotics for the treatment of pediatric Helicobacter pylori infection: a randomized double blind clinical trial. Iran J Pediatr 2013;23:79–84.
51
