A Comprehensive Review of the Natural History of Helicobacter pylori Infection in Children

Archives of Medical Research 31 (2000) 431–469

0188-4409/00 $–see front matter. Copyright © 2001 IMSS. Published by Elsevier Science Inc.

PII S0188-4409(00)00099-0

REVIEW ARTICLE

A Comprehensive Review of the Natural History of

Helicobacter pylori

Infection in Children

Javier Torres,* Guillermo Pérez-Pérez,** Karen J. Goodman,*** John C. Atherton,****

Benjamin D. Gold,*****

,

****** Paul R. Harris,******* Armando Madrazo-de la Garza,******** Jeannette Guarner********* and Onofre Muñoz*

*Unidad de Investigación Médica en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico

**Division of Infectious Diseases, School of Medicine, Vanderbilt University, Nashville, TN, USA***University of Texas-Houston School of Public Health, Houston, TX, USA

****Division of Gastroenterology and Institute of Infections and Immunity, University of Nottingham, Nottingham, UK*****Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Emory University School of Medicine,

Children’s Healthcare of Atlanta at Egleston Children’s Hospital, Atlanta, GA, USA******Foodborne and Diarrheal Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases,

Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA*******Department of Pediatrics, Section of Gastroenterology, Escuela de Medicina, Universidad Católica Pontífica, Santiago, Chile

********Departamento de Gastroenterología, Hospital de Pediatría, IMSS, Mexico City, Mexico *********Infectious Disease Pathology Activity, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Atlanta, GA, USA

Received for publication May 3, 2000; accepted May 31, 2000 (00/068).

Across populations of children,

Helicobacter pylori

prevalence ranges from under 10% toover 80%. Low prevalence occurs in the U.S., Canada, and northern and western Europe;high prevalence occurs in India, Africa, Latin America, and eastern Europe. Risk factorsinclude socioeconomic status, household crowding, ethnicity, migration from high preva-lence regions, and infection status of family members.

H. pylori

infection is not associatedwith specific symptoms in children; however, it is consistently associated with antral gas-tritis, although its clinical significance is unclear. Duodenal ulcers associated with

H. py-lori

are seldom seen in children under 10 years of age.

H. pylori

-infected children demon-strate a chronic, macrophagic, and monocytic inflammatory cell infiltrate and a lack ofneutrophils, as compared with the response observed in adults. The effect of

H. pylori

in-fection on acid secretion in children remains poorly defined. The events that occur during

H. pylori

colonization in children should be studied more thoroughly and should includeurease activity, motility, chemotaxis, adherence, and downregulation of the host response.The importance of virulence determinants described as relevant for disease during

H. py-lori

infection has not been extensively studied in children. Highly sensitive and specificmethods for the detection of

H. pylori

in children are needed, especially in younger pediat-ric populations in which colonization is in its early phases. Criteria for the use of eradica-tion treatment in

H. pylori

-infected children need to be established. Multicenter pediatricstudies should focus on the identification of risk factors, which can be used as prognosticindicators for the development of gastroduodenal disease later in life. © 2001 IMSS.Published by Elsevier Science Inc.

Key Words:

Children,

Helicobacter pylori

, Epidemiology, Clinical manifestations, Histopathology,Virulence factors, Diagnosis, Treatment, Immune response.

Address reprint requests to: Dr. Javier Torres, Unidad de Investigación Médica en Enfermedades Infecciosas, Hospital de Pediatría, CMN-SXXI, IMSS,

Av. Cuauhtémoc 330, Col. Doctores, 06725 México, D.F., México. Tel: (

1

525) 627-6940; FAX: (

1

525) 627-6949; E-mail: [email protected]

432

Torres et al./ Archives of Medical Research 31 (2000) 431–469

Introduction

Helicobacter pylori

colonizes over 50% of the world popula-tion, yet less than 20% of those infected individuals will de-velop a gastroduodenal disease.

H. pylori

colonization is themost common cause of chronic gastritis and is etiologicallyassociated with duodenal ulcer, gastric ulcer, gastric adeno-carcinoma, and mucosa-associated lymphoid tissue (MALT)lymphoma. Gastroduodenal diseases associated with

H. py-lori

infection are manifested principally in adults. However,it is usually during childhood that the infection is acquired,and it is possible that mucosal and humoral responses at thistime may determine, at least in part, the course of the naturalinfection. Thus, it is important to study

H. pylori

infection inchildhood. Studies on the following areas are of special inter-est in children: 1) risk and protective factors for acquisition ofthe infection; 2) mechanism(s) of transmission; 3) importanceof spontaneous eradication; 4) clinical and histopathologicmanifestations during the acute phase of the infection; 5)initial inflammatory and physiologic responses to infection;6) genotypic characteristics and pathogenesis of

H. pylori

strains infecting infants and children; 7) efficacy of differenttreatment regimens, and 8) utility of invasive and non-invasivediagnostic methods.

The aim of this review is to synthesize the current litera-ture and discuss what has been reported on the infection by

H.pylori

in children, to emphasize aspects on which more stud-ies are needed, and to suggest directions for future research.

Epidemiology

Epidemiologic studies of

H. pylori

infection began appear-ing in the literature in 1986. Early epidemiologic studies fo-cused on adults, but as accumulating evidence suggestedthat most adult infections were acquired in childhood (1),studies in children were initiated. Few epidemiologic stud-ies of children were published before 1996. Thus, evidencehas just begun to emerge.

Methods

Review of the literature on

H. pylori

epidemiology in chil-dren includes published studies identified in the Medlinesearch including the subject headings

Helicobacter pylori

and

Helicobacter

infections and child and were cross-refer-enced with the following key words: epidemiology; seroepi-demiologic prevalence; incidence; seroprevalence; acquisi-tion; risk factors, and transmission. Studies corresponding tothese topics found in previous literature searches were usedas well. Identified publications were included if they reportedepidemiologic data related to

H. pylori

infection in asymp-tomatic children, who were defined as children not identifiedas patients seeking medical attention for symptoms of gas-trointestinal diseases. When sufficient details were includedin study reports, epidemiologic data summaries were entered

into tables with studies grouped as follows: community-basedstudies of prevalence as detected by the urea breath test; com-munity-based seroprevalence studies; seroprevalence studiesin populations sampled from preventive health centers, hospi-tal births, or vaccination trials; prevalence studies of asymp-tomatic children sampled from clinics providing medicalcare, and longitudinal studies of incidence and elimination.Tabular data for prevalence studies included location, de-scription of study population, age range, subgroups for whichprevalence was reported, sample size, and prevalence esti-mates. Tabular data for incidence studies included location,timing of follow-up, age range, subgroups for which inci-dence was reported, sample size, estimates of incidence rates,and estimates of elimination rates, if reported.

General Features of

H. pylori

Infection Across All Age Groups

H. pylori

infection occurs worldwide. Infection occurs mostoften in poor socioeconomic conditions and has been con-sistently linked to residential crowding and migration fromhigh-prevalence regions (1). Prevalence increases generallywith age, but decreases have been noted in narrow ageranges in childhood (2). Various lines of evidence suggestthat onset of infection occurs most frequently in childhood(1). In populations of low socioeconomic status, high preva-lence often occurs by adolescence and remains relativelyconstant throughout adulthood (3). Age-specific seropreva-lence has shown declines over recent decades in cohortsfrom developed countries (4–7). The mode of transmissionof

H. pylori

has not yet been clearly identified. Abundantevidence suggests that direct person-to-person transmissionoccurs, but the relative importance of the fecal-oral andoral-oral routes is not apparent, nor has the relevance ofwaterborne or zoonotic pathways been fully determined (1).Little is known concerning the host factors that influencesusceptibility to acquisition or persistence of infection.

Methodological Challenges in Epidemiologic Research of

H. pylori

Infection

Natural history.

Signs and symptoms of

H. pylori

infectiondo not generally permit identification of cases at onset. Acuteinfection produces superficial gastritis accompanied by dys-peptic symptoms (8) with an unknown spectrum of severity.Persistent infection leads to chronic gastritis, which may beasymptomatic or may manifest general dyspeptic symptoms(8). Because infection is not normally detected at onset, theproportion of acute infections that persist is unknown. IgGantibodies have been observed to appear within a few weeksof the onset of a persistent infection (9). Following elimina-tion of infection, antibody titers decline, often reverting to un-detectable levels within 1 year or 2 (10–14). In prospectivestudies of infants born to

H. pylori

-seropositive mothers in

Torres et al. / Archives of Medical Research 31 (2000) 431–469

433

Belgium and Taiwan, nearly all infants had detectable IgGantibodies at birth (15,16); in almost all cases, the passivelyacquired maternal antibodies disappeared by 3 months of age.The natural immune response to active infection does not ap-pear to confer lasting immunity, given that reinfection occurs.Co-infection with multiple strains is not uncommon (17),suggesting the possibility of continual reinfection.

Detection.

Population-based epidemiologic studies rely onnon-invasive procedures to detect infection. Most epidemio-logic studies conducted to date have used serological assays todetect the presence of IgG antibodies to

H. pylori

infection. El-evated antibodies may reflect either an active or a cleared in-fection, whereas undetectable antibody levels can occur in aperson not currently and never infected, not currently infectedbut infected in the past, or infected recently. Thus, interpreta-tion of antibody status is problematic, not even considering test

error. However, test error is an important consideration, be-cause the validity of assays developed in one population maybe greatly reduced in other populations (18). The usefulness ofserologic methods may be further reduced in studies of veryyoung children (19) because young children may be slow todevelop detectable antibodies in response to

H. pylori

infection(20). Several recent studies of

H. pylori

infection in childrenhave used the urea breath test (Table 1), which exclusively andaccurately detects active infection (21), although validation ofthis method in very young children has been limited (22–26). Astool antigen test has been introduced recently and is currentlyundergoing evaluation in field studies (27–30).

Measurement of incidence.

Most knowledge concerning theepidemiology of

H. pylori

infection is based on studies ofprevalent infection, i.e., existing cases with an unknowntime of onset detected in a screened population. Disease

Table 1.

H. pylori

prevalence detected by the urea breath test in community-based studies of children

Location Population Age (years) No. Prevalence (%)

Bangladesh (43)Periurban Dhaka Urban slum 0–8 406 68

0–4 263 585–9 143 82

China (42)Linqu County Rural village 3–12 98 69

3–4 19 535–10 58 75

11–12 21 67Colombia

Aldana (37) Andean village Rural 2–9 684 692–5 373 616–9 311 79

Ipiales (1) Health professionals’ children Urban 2–9 57 54Gambia (19)

Keneba Three rural villages 12 (mo) 85 79Germany

Ulm School fitness exam attendees, 1996 (40)

5–8 945 13German 685 6Turkish 105 45

School fitness exam attendees, 1997 (46)

5–8 1,143 11German 874 5Turkish 118 44

India (47)Bangalore Urban school children 6–18 50 82

Italy (48)S. Giovanni Rotondo School children 4–18 304 28

PeruLima (49) Community group members High SES 2–12 141 32

Low SES 266 56Periurban Lima (35) Urban slum 6 (mo) 105 71

30 (mo) 56 52Switzerland (50)

St. Gallen Preschool children 5–7 432 7Swiss 359 4Immigrant 73 19

U.S. (51)Houston Volunteers recruited through

newspapers and flyers1–18 69 22

Black 30 37White 39 8

434


prevalence depends on factors that influence the rate of newcases as well as on those that influence disease duration.Identification of risk factors for acquisition requires studiesthat measure the incidence of infection, i.e., the rate of newcases in comparison groups. Given that new cases of

H. py-lori

infection are not generally detected at onset, knowledgeof

H. pylori

incidence must be inferred from age-specificprevalence patterns or from studies that follow individualsover time and repeatedly measure prevalent infection (31).Investigators must consider the possibility that acute

H. py-lori

infection may appear and depart, leaving no trace, asoccurred in the first documented instance of voluntary inoc-ulation (32). Thus, optimal studies of

H. pylori

incidence re-quire frequent follow-up intervals; even with an optimal de-sign, investigators must acknowledge the possibility thatcases may be missed between follow-up exams.

Epidemiology of

H. pylori

Infection in Children

The search of the literature conducted identified 83 publica-tions—67% published after 1995—that presented epidemio-logic data on asymptomatic children. These publications pro-vided adequate data on the frequency of infection for 69distinct populations of children: 65 presented data on preva-lence (Tables 1–4), and 12 reported follow-up studies withdata on incidence (Table 5). Fifteen (22%) of the eligible stud-ies used the urea breath test to detect infection; the remainderused serology. Of the 69 distinct populations, 34 (49%) wererecruited from community settings. The remaining 35 studiesrecruited subjects from health centers, vaccination trials, hos-pitals, or clinics, sources likely to select for children of highersocioeconomic status and who receive more frequent medicalattention, which would increase the probability of exposure toantibiotics. Thus, non-community-based studies are likely tounderestimate prevalence of infection among children in thecorresponding geographic locations. Thirty-one studies exam-ined associations between

H. pylori

infection and potentialrisk factors other than age and sex (Table 6).

H. pylori

Prevalence

Across populations of children,

H. pylori

prevalence rangesfrom under 10% to over 80% (Tables 1–4). Low prevalencehas been observed in populations of northern and western Eu-ropean ancestry and in Japanese and other Asian populations.High prevalence has been observed in India and Bangladeshand in countries of Africa and Latin America (Figure 1). Onlyone study included in this review presented prevalence datafrom eastern Europe: a moderately high prevalence was ob-served in a Polish pediatric population (33). In all studies thatexamined prevalence by ethnicity, increased prevalence wasobserved in immigrant groups from higher prevalence re-gions and in ethnic groups that are on average of lower socio-economic status. In general, prevalence increases with age;

however, exceptions must be noted. Many studies that re-ported prevalence estimates for narrow age ranges show de-creasing prevalence at various ages in childhood (Figure 2).Few studies reported sex-specific prevalence estimates.Those that did revealed inconsistent patterns (34–42).

Drawing conclusions regarding worldwide age-specificprevalence patterns in children is hampered by inconsisten-cies in study design and reporting. Studies are designed totarget distinct age groups, often with sample sizes that areinadequate for estimating prevalence within meaningful ageranges, such as 0–4 , 5–9 , 10–14 , and 15–19 years of age,or narrower increments, which are of particular interest atyounger ages. Across study reports, results are presented forinconsistent age categories. Few reports provide data for 1-yearage increments, which would allow a reviewer to constructuniform age categories across studies. Many reports do notpresent actual prevalence estimates; instead, estimates areplotted on graphs with 20% increments on the y-axis, ren-dering it difficult to discern the precise value. Some reportspresent no data from which prevalence estimates can be ob-tained for defined age groups.

H. pylori

Incidence and Elimination

Few studies have examined

H. pylori

incidence in children. Aswith prevalence reports, patterns are difficult to discern due todiverse age ranges and follow-up intervals (Table 5). Incidenceestimates range from 0.3% per year among 3–12-year olds inFinland to 12–13% per month in infants and toddlers in Gam-bia and Peru. Although data on age-specific incidence arescant, available evidence suggests that higher rates occur atearlier ages. A wide range of spontaneous elimination rates hasalso been reported: 0.3% per year among black children fromLouisiana, USA between 7 and 21 years of age; 5.5% per yearamong white children in the same Louisiana state cohort, and7% per month among Peruvian children aged 6–30 months.

Prospective data from infants in Peru, Gambia, and Bang-ladesh followed with breath tests at frequent intervals revealthat most infants in these populations showed evidence of in-fection at some point during the first year of life, and morethan one half were infected at 2 years of age (20,35,43) (Fig-ure 3). In contrast, among 67 Belgian infants born to

H. py-lori

-positive mothers, only 1 (1.5%) had a positive breathtest at 12–15 months of age (22). It should be noted that theurea breath test has not been adequately validated in infantsand very young children, although the test accurately classi-fied 13 of 14 Gambian infants (93%) for whom a biopsy-based diagnosis existed, including 7 of 7 biopsy-negative in-fants and 6 of 7 biopsy-positive infants (44).

Prospective data from infants in Gambia, Taiwan, Fin-land, and Sweden in whom

H. pylori

serostatus was deter-mined at frequent intervals during infancy show that anti-bodies detected at birth or early in infancy declined tonondetectable levels later in infancy (16,20,45,46) (Figure


435

Table 2.

H. pylori

seroprevalence from community-based studies of children


Bangladesh (52)Matlab Rural families 2–9 569 56

2–5 257 486–9 312 63

Brazil (53)Mato Grosso Rural municipality 10–19 40 78

Chile (54)Santiago/Punta Arenas Household cluster sample High SES 3–9 435 25

a

Low SES 235 36

a

China (55)Guangdong Six rural villages 0–9 329 19

a

0–4 112 15

a

5–9 217 21

a

Costa Rica (56) 7–10 97 60Two regions Rural school children 11–20 182 74

Estonia (34) 9 94 49Southern counties School children 12 147 55

15 180 60England (57)

London School children 5–13 640 17Finland (58)

Diverse regions Cohort study of atherosclerosis precursors 3–18 461 10Gambia (59)

Ferafenni Rural villages 0–5 353 31Guatemala (60)

Guatemala City All-girls school 5–10 211 51Italy (61)

Campogalliano Small town 12–16 186 30Japan

Central region (62) National serum bank 0–9 45 5

a

10–19 41 9

a

Nagano (63) Rural mountain village 6–19 112 20Mexico (64) National serum survey 1–20 5,608 50

1–4 527 255–9 1,809 43

10–14 1,854 5515–19 1,418 65

Nepal (65) Two villages Suburban 4–9 18 17Kathmandu vicinity 10–19 86 64

Isolated rural 4–9 18 1710–19 89 25

New ZealandSouth Auckland (38) School children European 11–12 44 7

Maori 102 21Pacific Islander 153 48

Dunedin (41) Birth cohort 11 561 7Nigeria (66)

Near Maiduguri Rural villages 5–9 17 82Northern Ireland (67) National surveys 12–19 661 24Russia (33)

Daycare centers, well-child clinics,community apartments, orphanages

1–4 44 30St. Petersburg 5–9 102 39

10–14 94 5215–19 67 48

Scotland (68)Edinburgh School children 11 554 11

b

South Africa (39)KwaZulu/Natal Schools/households 0–13 681 66

TaiwanDiverse regions (69) Random sample 0–9

c

2710–19

c

41

(

continued

)

436


3). Detectable seroconversion from negative to positive inthese populations appeared to begin after 12 months of age.In Gambia, nearly one half of the children were seropositiveby 18 months of age, and over 70% by 24 months (20). Atotal of 7.5% of Taiwanese infants became seropositive by14 months of age (16), 5% of Finnish children by 24 monthsof age (45), and among Swedish children, 5% were seropos-itive at 18 months and 10% at 24 months (46).

Risk Factors

Aside from age and sex, various exposures have been exam-ined as predictors of prevalent infection; however, few havebeen evaluated in more than one study (Table 6). Conclusionsmust be cautiously drawn from this evidence because limita-tions in sample size and study design, as well as inadequatecontrol of confounding, may have biased the results of some

Table 2.

Continued


Taipei (70) Primary and preschools, 1–2 106 1well-baby clinics 3–5 109 4

6–8 106 139–11 67 19

U.S. (36) National Health and Nutrition Examination Survey III

6–19 2,581 25

d

6–9 869 17

d

10–14 902 26

d

15–19 810 29

d

Non-Hispanic White 6–19 782 17Non-Hispanic Black 639 40Mexican-North American 1,052 42

El Paso, TX (2) Preschool children Hispanic 4–7 365 21Bogalusa, LA (71) Community-based cohort Black 7–9 62 40

White 150 11

SES, socioeconomic status;

a

approximated from graph;

b

salivary IgG measured by enzyme-linked immunosorbent assay;

c

group sizes not reported; from astudy of 823 persons, 268 of whom were aged 16 years or less;

d

weighted to U.S. ethnic distribution.

Table 3.

H. pylori

seroprevalence in asymptomatic children from preventive health centers, hospital births, and vaccination trials


Chile (72)Iquique Vaccine trial participants 1–5 229 24

a

6–10 72 55

a

15–16 87 73

a

China (55)Guangzhou Preventive health station attendees 0–4 63 31

a

5–9 88 34

a

Ethiopia (73)Addis Ababa Vaccine trial participants 2–14 Plotted in

Figure 2

b

Finland (44)Tampere Infants delivered at university hospital 2 195 6

Greece (74)Diverse regions Vaccination clinic attendees 1–10 188 39

Korea (75)Seoul Health screening patients Upper SES 1–19 67 12

Middle SES 168 25Lower SES 17 41

Sweden (45)Stockholm Vaccine trial participants-

same children at distinct ages1.5 239 52 237 104 185 8

11 201 3Turkey (76)

Ankara Patients attending check-ups 1–4 58 165–9 62 31

10–14 57 4715–19 53 58

SES, socioeconomic status;

a


b

data not provided for age groups.


437

Table 4.

H. pylori

prevalence

a

in asymptomatic children from clinic-based samples


Algeria (32) Clinic patients 0–9 42 45

b

Australia (77) Elective minor surgery patients 0–14 147 14Barbados (78) Clinic outpatients 1–18 50 22Belgium (79) Elective minor surgery patients 1–17 883 8

Belgian 740 6African 69 20Mediterranean 74 19

Brazil (80) Laboratory patients 0–8 171 27Belo Horizonte 9–18 78 50

France (32) Emergency/surgery outpatients 0–9 113 4Germany (81) Minor surgery patients 0–11 144 9

Ulm 12–17 72 32Iceland (82) Elective surgical and other patients 0–19 49 10India (83) Public hospital pediatric outpatients 3–10 30 60

b

Hyderabad 11–15 18 50

b

16–20 21 85

b

Italy (84) Medical outpatients, rural townCiro 1–10 32 22

11–20 30 40Ivory Coast (32) Clinic patients 0–9 116 55Japan (85) Non-GI viral study patients 0–6 75 5

b

Tokyo (86) Outpatients 1–9 89 1310–19 62 21

Tokyo (87) University hospital patients 0–9 246 910–19 100 21

Malaysia (88) Elective minor surgery patients 0–5 261 7Kuala Lumpur 6–17 253 13

Malay 0–5 119 6Chinese 92 8Indian 50 10Malay 6–17 110 7Chinese 81 14Indian 62 24

Netherlands (7) Municipal health center serosurvey 6–8 80 9Rotterdam 12–15 80 11

Nicaragua (89) Pediatric health center patients 0–5 64 80Nigeria (66) Teaching hospital patients 0–9 100 69Poland (90)

Lodz Pediatric and surgical patients 0–5 120 166–10 60 28

11–17 60 42Portugal (91) Patients without digestive diseases 3–14 197 46

11 cities 3–6 437–9 49

10–14 48Spain

Asturias (92) Emergency/other patients 0–9 51 1410–19 67 25

Basque Country (93) Trauma/elective surgery patients 2–9 203 1110–19 210 33

South Africa (94) Pediatric outpatientsBloemfontein 0–2 104 14

2–5 103 495–10 104 67

10–15 101 84Sweden

Lund (82) Primary care patients/medical students 10–19 49 6Stockholm (73) Pediatric patients 1–15 295 Plotted in

Figure 2

c

U.S.Arkansas (95) Minor surgery outpatients White 3–10 141 24

Black 3–10 36 42

(

continued

)

438


studies. It must be further noted that cross-sectional studiescannot differentiate factors that influence acquisition fromfactors that influence persistence of infection. Two studiesalone identified factors related to incidence of infection. In acohort of Peruvian infants, males were more likely than fe-males to become infected and less likely to be rid of infection(35). In a Taiwanese cohort, breastfed infants were morelikely than non-breastfed infants to become infected (16).

Factors linked to increased

H. pylori

prevalence in morethan one study include low socioeconomic status indicators,household crowding indicators, migration from high preva-lence regions, urban residence, having

H. pylori

-infected par-ents, number of children in the home, high-ranking birth or-der, institutional residence, indicators of poor nutritionalstatus, drinking water source, consumption of raw vegetables,

and swimming in rivers or streams. Two factors have beenlinked to decreased prevalence in more than one study: antibi-otic use and possession of pets. The following were reportedto be unassociated with infection in more than one study:household crowding; parents’ educational level; family in-come; urban/rural residence; nutritional status indicators; day-care attendance; drinking water source, and possession of pets.

Conflicting results for factors related to waterbornetransmission of infection correspond to diverse geographicregions. The studies that showed positive associations withdrinking water source, consumption of raw vegetables, andswimming in rivers and streams were conducted in Andeancountries, whereas studies not showing associations withdrinking water source were conducted in the U.S., China,and Taiwan. In some studies, possession of pets appeared to

Table 4.

Continued


West Virginia (96) Hospital and health fair attendees 1–10 318 3511–15 375 3816–20 469 45

Rural 1–20 769 40Urban 367 46

Vietnam (32) Clinic patients 0–9 61 13

a

As detected by serology, except for the Nicaraguan study, which used the urea breath test;

b


c

data not provided for age groups.

Table 5.

H. pylori

incidence and elimination in children

a

Location Timing of follow-up Age range

n

Person-years

Incidence rate

Elimination rate

Urea breath test studiesBelgium (14) 1-month intervals from birth to 12 mo

for serostatus; one breath test at 12–15 mo0–15 mo 67 75 1.5%/year

b

Gambia (19)

c

3-month intervals, ages 3–12 mo 3–12 mo 85 85 12%/mo

c

Italy (97) 6-month intervals for 2 years; positive children only 4–18 years 48 87 — 10%/yearPeru (35) 6-month intervals, ages 6–30 mo 6–30 mo 56 112 12.6%/mo 7.1%/mo

Serological studiesFinland (58) 3-year intervals, ages 3–12 years 3–12 years 74 666 0.3%/year 6.3%/yearFinland (44) Serum collected at birth and ages 1, 7, 12, and 24 mo 0–2 years 195 390 2.6%/year

b

0–12 mo 195 1.5%/year12–24 mo 195 3.7%/year

Japan (63) 1-year intervals, 1986–1994 6–19 years 112 594 1.1%/year 1.8%/yearNew Zealand (41) 10-year interval, age 11–21 years 11–21 years 434 4,340 0.1%/year 7.6%/yearSweden (45) Ages 0, 2, 4, 6, 8, 10, 12, and 18 mo, and 2, 4, and 11 years 0–11 years 294 2,334 1.7%/year

d

10–18 mo 188 6.4%/year18–24 mo 113 13%/year2–4 years 417 2.4%/year4–11 years 1,407 0

Taiwan (15) 2-month intervals, birth to 14 mo 0–14 mo 80 93 6%/year

b

Thailand (98) 6-month intervals for 1 year 0–5 years 95 95 13%/year

b

U.S. (71) 12-year intervals initiating at age 7–9 years 7–21 years 212 2,544 1.9%/year 1.8%/yearWhite 150 1,800 1.5%/year 5.5%/yearBlack 62 744 4.6%/year 0.3%/year

a

Person-years and rates estimated from data presented in papers; antibodies detected at birth presumed to be maternal; incidence rate defined as person-timerate of change from negative to positive; elimination rate defined as person-time rate of change from positive to negative;

b

follow-up data on positive childrennot presented;

c

data for rates presented for 85 children with complete breath tests from 3–12 months of age; 48 of 248 children had a negative breath test in as-sociation with falling antibody levels subsequent to a positive breath test;

d

most children infected at younger ages had lost their infection by 11 years of age.


439

be an indicator of high socioeconomic status and thereforewas related to decreased prevalence of infection. Negativefindings for some socioeconomic status indicators in a fewstudies may have resulted from study populations overlyhomogeneous in these factors. Alternately, it may be thatsusceptibility to infection is widespread among children,particularly at certain ages; thus, some factors that consis-

tently predict prevalent infection in adults do not predictprevalent infection in children.

Future Directions for Research

Further studies are needed to describe the occurrence of

H.pylori

infection in populations of children. Prevalence stud-

Table 6. Predictors of H. pylori prevalence in children

Factors Location of study

Associated with increased prevalenceLow SES indicators Australia (77), Bangladesh (43), Chilea (54), Colombia (37), Guatemala (60), Italy

(48,61), Korea (75), Mexico (64), Peru (35), Russia (33), Scotland (68), Spain (93), U.S. (2,36,95)

Household crowding indicators Bangladesh (52), Chinaa (55), Colombia (37), Germany (40), Guatemala (60), Italy (48), Mexico (64), Poland (90), Russia (33), Scotland (68), U.S. (36)

Ethnicity Australia (77), Bangladesh (52), Belgium (99), Germany (40,46), Malaysia (88), New Zealand (38), U.S. (36,51,71,95)

Migration from high prevalence region Australia (77), Belgium (99), Germany (40,46), Switzerland (50), U.S. (36)Urban vs. rural residence Chinaa (55), Nepal (65), U.S. (96)Rural vs. urban residence Estonia (34)Maternal history of ulcer Germany (100)H. pylori-infected parents Australia (101), China (42), Germany (46), Italy (61), U.S. (51)H. pylori-infected family members Poland (90)H. pylori-infected siblings Australia (101), Colombia (102), Russia (33)No. of children at home Colombia (37), Taiwan (69), U.S. (96)High birth order Colombia (37), Taiwan (69)Residence in an institution France (103), Hong Kong (104), Japan (105), Russia (33)Poor nutritional status/diminished growth Colombia (106), Italy (48), Peru (49), Scotland (68)No toilet or latrine in or near home Colombia (37), U.S. (2)Infrequent handwashing with soap Colombia (37)Drinking water from streams/lack of internal tap water in home Colombia (37), Peru (49)Swimming in rivers/streams/swimming pools Chilea (54), Colombia (37)Consumption of raw vegetables Chilea (54), Colombia (37)Frequent drinking from common receptacles Colombia (37)Contact with sheep Colombia (37)Paternal smoking Germany (107)

Associated with decreased prevalenceDaycare attendance U.S. (36)No. of (elderly) adults in the home Colombia (37), Taiwan (69)Increased intake of fruits/vegetables Colombia (106)Recent history of amebiasis Colombia (37)History of antibiotic use Chinaa (55), Germany (108)Drinking water from community wells Peru (49)Pets (dogs, cats) U.S. (36,95)Maternal smoking Germany (107)

Minimal association with prevalenceHousehold crowding U.S. (2), South Africa (39)Parental educational level Bangladesh (52), Germany (40), Guatemala (60), South Africa (39), Taiwan (69)Family income Bangladesh (52), Taiwana (69)Paternal history of ulcer Germany (100)No. of siblings Germany (40)Birth order Germany (40)Urban vs. rural residence Mexico (64), U.S. (36,95)Nutritional status Bangladesh (43), Brazil (80), Guatemala (60), Hong Kong (104)History of breastfeeding Peru (49)Daycare attendance Colombia (37), South Africa (39)Drinking water source Chinaa (55), U.S. (2,95), Taiwan (69)Toilet or latrine in or near home Bangladesh (52), Taiwan (69)Lack of sewer connection Brazil (80)Pets Germany (109), South Africa (39)Exposure to dogs U.S. (36)

aStudy population includes children and adults.

440 Torres et al./ Archives of Medical Research 31 (2000) 431–469

ies should be designed so that the sample size is adequateenough to permit estimates for narrow age ranges, prefera-bly 1-year increments. Such studies should draw partici-pants from community settings so that prevalence can bedescribed for representative populations of interest. Reportsshould clearly present actual observed prevalence values, ornumber positive of the total, by 1-year age groups, sex, anddistinct subgroups. Prevalence studies can also serve toidentify factors that influence prevalent infection, providingthat the sample size is adequate for detecting associations.However, it must be kept in mind that cross-sectional datacannot be used to differentiate factors that influence acqui-sition of infection from factors that determine persistence.

Studies of incidence are urgently needed to fill knowl-edge gaps regarding the natural history of infection. Inci-dence studies should follow community-based cohorts,screening for infection at regular intervals over variouschildhood age ranges. Investigators should make special ef-forts to ensure that loss-to-follow-up does not occur differ-entially by characteristics, such as aspects of socioeconomicstatus, that may influence the course of infection. Childrenwho acquire the infection should continue to be followed inaddition to those who do not, so rates of both incidence andelimination can be estimated. These rates should be basedon the number of events divided by the person-time of fol-

low-up among those at risk for the event over defined timeintervals. Such rates can be calculated without excludingchildren with incomplete follow-up, whereas including allchildren for whom any follow-up data exists is preferred, tominimize selection bias and increase statistical power. Inci-dence and elimination rates should be reported by agerange, sex, and other attributes of interest.

Longitudinal studies designed to estimate incidence andelimination rates can also serve to identify risk factors for in-fection if investigators plan for sufficient person-time of fol-low-up and carefully collect accurate information on poten-tial determinants of infection. Given evidence that H. pyloriinfection is most dynamic in early childhood, prospectivestudies of young children are needed to differentiate determi-nants of acquisition, persistence, and recurrence of infection.

Clinical Manifestations

Although many people are infected with H. pylori, only asmall proportion will have clinical manifestations of the dis-ease (Figure 4). H. pylori fulfills Koch’s postulates becauseit is an infection causing chronic-active gastritis: all infectedpersons have this histologically defined gastric inflamma-tion, which in itself is asymptomatic but which may be asso-ciated with disease (110). Approximately 20% of infectedpersons will develop peptic ulcer disease during their lifetime.The epidemiologic association between H. pylori infectionand peptic ulceration is strong (excluding ulcers associatedwith aspirin or with the use of non-steroidal anti-inflamma-

Figure 1. H. pylori prevalence in selected populations of children.

Figure 2. H. pylori prevalence by age in selected populations of children.

Torres et al. / Archives of Medical Research 31 (2000) 431–469 441

tory drugs (NSAID) (111). Furthermore, eradicating H. py-lori heals ulcers and prevents recurrence. Whether H. pyloriare the cause of peptic ulcer disease in children is less wellestablished, although evidence for this is accumulating(112). Infected adults also have a 2- to 6-fold increased riskof developing gastric cancer and MALT lymphoma com-pared with their uninfected counterparts.

Gastritis

H. pylori infection causes gastritis in almost all infected per-sons, but the majority of infected adults and children remainasymptomatic. Hill’s criteria, initially proposed for an asso-ciation between lung cancer and smoking, have been used tostudy the possible association between H. pylori infectionand gastroduodenal diseases (Table 7). The natural historyof H. pylori infection can be thought of in two phases. In theacute phase, intense bacterial proliferation and gastric in-flammation occur with a transient period of upper gas-trointestinal symptoms. Hypochlorhydria develops duringthis time. After a period of weeks, a chronic phase is estab-lished and the inflammatory response is reduced to a low-level state denominated chronic diffuse superficial gastritis.Normal gastric pH is restored. The infected person becomesasymptomatic, and this symptom-free chronic infection isthe most common outcome. The subset of subjects with H.pylori infection who proceed to develop specific complica-tions such as peptic ulceration and gastric cancers should be

viewed as special targets for intervention (111). However,accurate delineation of asymptomatic H. pylori-infected hu-mans at risk of developing complications is not possible atpresent (Figure 4).

Several studies have demonstrated that H. pylori infection isnot associated with specific symptomatology in children (113–116). In a study of 245 healthy children, H. pylori colonizationwas demonstrated in 30%, but the parents of these childrenconsidered them to be asymptomatic (95). In another study, thepresence of abdominal pain and vomiting did not differ be-tween children with and without H. pylori colonization(117,118). After H. pylori eradication, symptoms improvedonly in children with duodenal ulcer (115). Therefore, it is dif-ficult to distinguish between children with H. pylori gastritisand non-infected children based on initial symptoms (114).

Peptic Ulcer Disease

Peptic ulcer disease is uncommon in children and its inci-dence is unknown. Scant studies have reported prevalence ofthe disease (119–122). The most common ulcer symptom inchildren is burning pain in the epigastrium, which typicallyoccurs when the stomach is empty, between meals, and in themorning hours, although it can also occur at other times. Itmay last from minutes to hours and may be relieved by eatingor by taking antacids. Less common ulcer symptoms includenausea, vomiting, and loss of appetite. Bleeding can also oc-cur, present as hematemesis or melena. Minor and prolongedbleeding may lead to weakness and fatigue with anemia.

Duodenal Ulcer

H. pylori-associated duodenal ulcers are seldom seen in chil-dren under 10 years of age (120,123). Children with duodenal

Figure 3. H. pylori prevalence by age in cohorts of infants followed pro-spectively.

Figure 4. H. pylori infection in children is associated with a number ofpotential outcomes. However, most of the children will develop chronicsuperficial gastritis without any symptomatology. A minor group of chil-dren will develop duodenal ulcer as older children or adolescents. MALTlymphoma and gastric ulcers are very rarely seen in pediatrics.


ulcer have relapsing symptoms and the disease is generallyquiescent while treatment with agents such as H2-antagonistis maintained (119,123,124). Recurrence of ulceration is verycommon after withdrawal of such therapy (124).

Symptoms of peptic ulcers in children vary with age andare less specific in infants and young children, in whom ini-tial symptoms often include feeding problems or vomiting. Insome, the first sign of duodenal ulcer is upper gastrointestinalbleeding or acute abdominal pain resulting from perforation.Young children with duodenal ulcer often complain of poorlylocalized abdominal pain, periumbilical pain, and rarely ofpain in the right lower quadrant (120). The pain may bepresent nocturnally or early in the morning and be neitherprecipitated nor relieved by meals or antacid use (121).

Gastric Ulcer

Gastric ulcers are very rare in children, and in most cases aresecondary to aspirin or NSAID use. The overall incidencerate of H. pylori in gastric ulcer in children is approximately25% (Table 8). However, gastric ulcer in the clinical settingof H. pylori gastritis without concurrent diseases or medica-tion usage is rare in children (120,125). In fact, most ulcersof the gastric mucosa are observed in the setting of NSAIDsor corticosteroid usage, regardless of H. pylori status(111,126). Most ulcers in children under 6 years of age aregastric, and like duodenal ulcer in this age group maypresent atypically. Older children and adolescents describesymptoms more typical of adults, with pain developing anhour or more after meals in the epigastrium or toward theright upper quadrant. The pain is relieved by eating or bytaking antacids, and aggravated by the ingestion of soda (pH2.8–3.2), juices, pickles, vinegar, tomatoes, and spices (127).

In summary, there is strong and consistent evidence that H.pylori infection is associated with duodenal ulcer disease inchildren. However, H. pylori infection is neither necessary norsufficient for ulcer development. There is weak evidence of anassociation between H. pylori and gastric ulcer in children.

Gastric Adenocarcinoma and MALT Lymphoma

In 1994, the World Health Organization’s (WHO’s) Interna-tional Agency for Research on Cancer classified H. pylori

as a definite carcinogen, based largely on epidemiologic ev-idence (128). Prospective studies have demonstrated a linkbetween H. pylori and gastric cancer; the time between di-agnosis of the infection and discovery of the cancer is from6–14 years. In the EUROGAST Study Group, H. pylori in-fection increased the risk of gastric cancer by a factor of 6(129). Gastric cancer rarely occurs before the age of 40years. Children do not develop gastric cancer, but acquisi-tion of H. pylori in early childhood may lead to increasedprevalence of gastric atrophy in young adults, with a lowaverage acid secretion that may, in turn, increase the risk oflater developing gastric cancer (130,131).

In children, lymphomas account for only 10% of all ma-lignancies, and only 13% of these tumors are non-Hodgkin’slymphomas originating in the abdomen (132). The normalstomach does not contain lymphoid follicles, but variablenumbers of mucosal lymphoid follicles are present in almostall patients with H. pylori-associated chronic active gastritis.The fact that H. pylori infection preceded the diagnosis oflymphoma by a median of 14 years supports the argumentthat H. pylori-induced gastritis may be a precursor of thelymphoma (133). To our knowledge there have been threepediatric patients described with H. pylori-associated lym-phoproliferative disease: an 11-year-old boy with prolongedabdominal symptoms who was disease-free after antibioticsand a course of 6 months of chemotherapy (134); a 16-year-old girl with chronic abdominal pain who required chemo-therapy and radiation therapy after failure to cure the lym-

Table 8. Clinical associations with H. pylori infection in children and adolescents compared to adults

Children and adolescentsAdults

(%)Condition %a Rangea

Chronic active gastritis 95 90–100 90–100Duodenal ulcer 92 33–100 88–100Gastric ulcer 25 11–75 58–100Recurrent abdominal pain 22 0–81 NAb

Recurrent abdominal pain(applying Apley’s criteria) 6 0–9 NAb

Non-ulcer dyspepsia NAb NAb 40–80Gastric cancer NAb NAb 46–94

aBased on Reference 113; bNA: not applicable.

Table 7. Hill’s Criteria for causal inference in children infected with H. pyloria

ConditionExperimental

evidenceTemporalsequence

Strength of theassociation

Consistency of the association

Specificity ofthe association

Biologicalplausibility

Chronic gastritis Yes Yes Yes Yes Yes YesDuodenal ulcer No No Yes Yes ? YesGastric ulcer No No ? ? No YesRecurrent abdominal pain No No ? ? No No

aModified from Reference 113.


phoma with H. pylori eradication therapy (135), and a 14-year-old girl treated for lymphoma solely with eradicationof the bacteria (136). All had remission of lymphoma aftereradication of H. pylori.

Recurrent Abdominal Pain

Recurrent abdominal pain (RAP) is defined by the presenceof at least three discrete episodes of pain, debilitatingenough to interfere with routine activity and occurring 3months or more during the year preceding clinical examina-tion (137). Under this classic definition by Apley, RAP maybe seen in a much broader concept that includes differentpatterns of abdominal pain in children, such as paroxysmalperiumbilical pain, epigastric pain, dyspepsia, and lower ab-dominal pain with alteration in bowel patterns (138). Only10% of children have RAP with an organic etiology, whichmay include cardiovascular, pulmonary, genitourinary, orgastrointestinal disease. RAP is usually considered func-tional in nature with a well-characterized epidemiology. Itaffects about 10% of children (usually the 5–14-years-of-age group) and affects one in four 9-year-old girls. After theage of 7 years, girls are more affected than boys. Pain ispoorly localized and usually periumbilical: it is often severebut short-lived, rarely interferes with appetite or voluntaryactivity, rarely awakens the child, and may occur at specifictimes (for example, on school mornings). There are someclues suggesting an organic etiology for RAP, such as night-time pain, oral regurgitation, recurrent vomiting, heartburn,epigastric pain, growth failure, and failure to respond tostandard approaches. Some authors consider RAP and dys-pepsia as different entities, based on localization and associ-ated symptoms. In future studies, it is important to establishhomogeneous groups of patients to better define the role ofH. pylori infection in causing specific symptoms.

Several studies have failed to demonstrate an associationbetween H. pylori infection and RAP in children (113,139).In a retrospective study of 296 children who underwent up-per endoscopy, clinical history did not reliably distinguishchildren with or without H. pylori infection (140). H. pyloriinfection was not associated with specific clinical sympto-matology, including duration of abdominal pain, location ofpain, and history of melena or vomiting (114). In a prospec-tive case-control study of 111 children, Hardikar et al. (139)found a negative association between H. pylori and RAP,suggesting that H. pylori is unlikely to have an importantetiologic role in this disorder. Other studies have found sim-ilar results (140–142).

It is unclear whether children with RAP and H. pylori in-fection represent an entity different from children with RAPand without H. pylori. Eight studies have estimated theprevalence of H. pylori infection in children with RAP(113). Findings from these studies have been inconsistent,with reported prevalence rates of H. pylori infection ranging

from 0–81% (median, 22%). All children in these studieswere referred to tertiary-care hospitals because of gas-trointestinal complaints. Three of these studies defined theirpopulation based on Apley’s criteria for RAP (137). In thesechildren the prevalence of H. pylori infection was muchlower, ranging from 0–9% (median, 6%) (143–145). In an-other case-control report (146), 82 children with RAP (byApley’s criteria) and 246 age- and sex-matched healthychildren were studied for H. pylori infection. In contrast tothese studies, H. pylori infection was significantly higher inchildren with RAP (65%) than in healthy children (48%). Insummary, there is weak and inconsistent evidence of an as-sociation between H. pylori infection and classic RAP inchildren. Well-designed studies with appropriate age-matchedand sex-matched controls are needed.

Non-ulcer Dyspepsia

Dyspepsia is a term used by physicians when referring toadults. This term has, in recent years, been extrapolated tochildren. Dyspepsia may be defined as the presence of non-specific symptoms related to the upper gastrointestinal tractthat are intermittent or continuous for at least 2 months Al-ternatively, it may be defined in a broader sense as pain ordiscomfort centered in the middle part of the upper abdo-men. The most common symptoms associated with dyspep-sia in children are epigastric pain, recurrent vomiting, night-time pain, pain with meals, anorexia, and weight loss.Organic causes of dyspepsia include gastroesophageal re-flux disease, parasitic infections, pancreatitis, celiac dis-ease, bacterial overgrowth, peptic ulcer disease, and drug-induced gastritis (e.g., NSAIDs).

Non-ulcer dyspepsia is defined as the presence of dys-peptic symptoms in the absence of endoscopic findings. Al-though some cases of non-ulcer dyspepsia in adults are un-doubtedly linked to H. pylori infection, it is not possible toidentify these cases, and the strength of the association isweak overall. For example, the frequency of H. pylori in pa-tients with non-ulcer dyspepsia is roughly equal to that ofasymptomatic patients. In addition, prospective trials of an-timicrobial therapy directed against H. pylori have been dis-appointing (147–149). Nonetheless, many physicians aretesting for H. pylori infection in dyspeptic adults, and evi-dence of infection is usually followed by treatment (150).The issue of whether H. pylori infection and chronic activegastritis causes clinical symptoms in the absence of mucosalulceration remains contentious (115,151).

Identification of H. pylori in symptomatic children does notprobe whether the infection is the cause of symptoms, particu-larly because there is a comparable rate of infection in asymp-tomatic, age-matched, and community-matched controls. Simi-larly, resolution of symptoms with anti-Helicobacter therapy isdifficult to interpret because frequency of improvement is oftensimilar with placebo (112,148, 152,153).


Gastroesophageal Reflux Disease

Whether H. pylori infection is important in gastroesoph-ageal reflux disease (GERD) is unclear (154). H. pylori haspredictable effects on acid secretion, which links the infec-tion with GERD and its associated diseases (155,156). Theseverity of GERD and the presence of associated complica-tions are related to acid exposure which is in turn related tothe extent of abnormality in the barrier function. In any pa-tient, the extent and severity of corpus inflammation dic-tates the range of acid secretion. Therefore, average acid se-cretion would be higher in patients without H. pyloriinfection than in patients with the infection who addition-ally have corpus gastritis. Acid secretion appears to belower in patients with more severe corpus gastritis (157).This suggests that the prevalence of GERD should be higherin patients without H. pylori infection. Accordingly, it hasbeen suggested that the cure of H. pylori infection in a pa-tient with duodenal ulcer may increase the probability of de-veloping GERD, and that severity might be intensified be-cause regular use of anti-secretory drugs is no longernecessary to treat symptoms of duodenal ulcer. Conversely,if acid secretion falls after the cure of infection in a patientwith duodenal ulcer, esophageal reflux may become less se-vere. Thus, even though H. pylori infection does not causeGERD, cure of infection might increase the severity of re-flux in patients with corpus gastritis, thus uncovering pre-existing abnormalities in barrier function (158). BecauseGERD in children is related to transient abnormalities inlower esophageal sphincter (LES) function, extrapolation ofdata from adults to children is not appropriate. Further stud-ies are needed to clarify any potential relationship betweenGERD and H. pylori infection in children.

Other Clinical Associations

H. pylori infection has been associated with a wide varietyof other medical conditions in adults including coronaryheart disease, protein-losing gastropathies, recurrent entericinfections, periodontal diseases, headache, diabetes, rosa-cea, food allergy, gallstones, short stature, thyroid disease,and Raynaud’s syndrome. However, many of these observa-tions were obtained from poorly designed studies; futurestudies should include appropriate age- and sex-matchedcontrols. In children, prospective-cohort studies will be nec-essary to answer some of the questions.

Short Stature

Little is known about the effect that H. pylori infection dur-ing childhood may have on health and development. Fourstudies have suggested that persons infected with H. pyloriare shorter than uninfected individuals. Three of these stud-ies are focused on children. Only one was carried out in a

developing country. It showed that height in infected chil-dren was significantly lower than in uninfected children(106). A second study showed that over one half of childrenbeing investigated for short stature over a period of 2 yearswere infected with H. pylori (159); this study, however,lacked appropriate controls. The third study showed greatergrowth reduction among infected girls, raising the possibil-ity that H. pylori infection may delay or diminish the puber-tal growth spurt (68). One theory is that the chronic effectsof systemic inflammatory mediators may directly affect theepiphyseal plate or indirectly affect via gonadal sex ste-roids. Social class, family structure, and childhood crowd-ing are factors that may be related to the timing of growthand might be the reason for the observed association be-tween growth and H. pylori infection.

Enteric Infections

There is evidence that acute H. pylori infection results inhypochlorhydria, which may persist for a lengthy period oftime. Such suppression of gastric acid secretion may predis-pose to enteric infections. This is particularly important indeveloping countries, where both H. pylori and enteric in-fections are common in children (160). Whether these dif-ferences reflect poverty or may in some way be associatedwith H. pylori infection is unclear.

Future Directions

Carefully designed studies will aid in distinguishing subsetsof children whose symptoms are consistent with H. pylori in-fection and in determining whether symptoms are relievedwith eradication of the infection. Multicenter pediatric H. py-lori study groups should be established to address unan-swered questions concerning disease spectrum (161). The0–7-year age group has been considered a critical populationfor studying prospectively to better understand disease mani-festations, as well as epidemiology and pathogenesis. Furtherstudies are required to determine the role of H. pylori infec-tion in other diseases in children, including GERD, RAP, andpredisposition to enteric infections in the developing world.Finally, we need to know whether H. pylori infection may bebeneficial under certain circumstances and whether eradicat-ing the infection may be disadvantageous to some children.

H. pylori-Associated Pathology in Children

IntroductionIt is easy to surmise that if initial H. pylori infection in chil-dren progresses to adult disease, the possibility exists for tar-geted treatment strategies to prevent lifelong disease. How-


ever, a screen-and-treat policy has not been warranted oradvocated in North America (i.e., Canada and the U.S.). Thisis because fewer than 20% of infected persons actually de-velop peptic ulcers or gastric cancer and because the treat-ment itself entails some risks for the patient, as well as pre-disposing strains to develop antibiotic resistance (162,163).Additional obstacles to the development of interventionstrategies in children have included a paucity of informationregarding changes in the gastric and duodenal mucosa of in-fected children. This section will summarize some currentviews regarding the pathobiology of gastroduodenal diseaseassociated with childhood H. pylori infection.

To understand the pathology associated with H. pylori in-fection in children, a general overview of mechanisms under-lying gastritis and mucosal ulceration is needed. Gastritis andulcers of the duodenum or stomach have historically beenclassified either as primary or secondary (164). Previous to themid-1980s, it was believed that gastritis and ulcers in thestomach or duodenum in children was a secondary phenome-non. Secondary ulcers of the gastric or duodenal mucosa gen-erally occur due to systemic conditions such as trauma or sep-tic shock, or as a result of drug ingestion (i.e., NSAIDs)(165,166). In addition, secondary gastric or duodenal ulcer-ation is described in specific diseases such as Zollinger-Elli-son syndrome or Crohn’s disease (164,167). Our group andothers have previously reported that the distinguishing factorof secondary compared with primary ulcers can be elicited bytaking a good patient history on initial evaluation, i.e., childrenwith secondary ulcers rarely reveal a family history of pepticulcer disease or other upper gastrointestinal disorders (168).

Investigations in the late 1980s indicated that duodenaland gastric ulcers in children younger than 18 years of agewho had no other systemic conditions invariably have pri-mary gastroduodenal ulceration (112,169). An easily elic-ited family history of peptic ulcer disease is a frequent posi-tive finding in these patients (170). In virtually all thesechildren, inflammation of the mucosa, and if present, ulcer-ation is caused by H. pylori (171,172). Further evidence forthe familial nature of primary gastritis and peptic ulcerationoccurring in children is the findings of H. pylori clusteringin family members of affected individuals. Moreover, thehighest rates of reinfection occur in families with childrenyounger than 6 years of age (173).

Mounting evidence demonstrates that there is a multifac-torial process in the evolution of mucosal disease associatedwith H. pylori infection. Both host and bacterial factors havebeen identified as potentially playing a role in gastroduode-nal pathology associated with H. pylori infection (154,174–176). The complex interaction between bacterial-specificand host-specific factors still deserves critical attention.Moreover, there are still many features of H. pylori-associ-ated disease in humans that remain undefined. An under-standing of H. pylori as the etiologic agent in gastroduodenalinflammation and neoplasia is critical for defining the patho-biology of gastritis and peptic ulcer disease.

Pathobiology of H. pylori Infection

Bacterial factors. A more detailed discussion of the biol-ogy of H. pylori and its virulence determinants is providedelsewhere in this publication. Preliminary studies at our lab-oratory concerning H. pylori virulence gene alleles and thecorresponding gastroduodenal pathology in children dem-onstrate that specific correlations among cagA, vacA, andiceA genes and the severity of gastroduodenal mucosal in-flammation in early infection cannot be made (177). Weevaluated the genotype of H. pylori strains isolated from 45children at four participating centers in North America (Mi-ami, FL, Cleveland, OH, and Atlanta, GA, USA and Tor-onto, Ontario, Canada) and compared the cagA, vacA, andiceA genotype to the clinical, demographic, endoscopic, andhistopathologic characteristics of these infected children.cagA-positive H. pylori strains were not more frequent inchildren with documented ulcer disease as compared withchildren infected by cagA-negative strains. In addition,cagA status did not appear to be correlated with inflamma-tion severity, as determined by the updated Sydney classifi-cation for gastritis (Figure 5). In addition, neither of thevacA s- and m-alleles were associated with ulcer disease orincreased severity of gastric mucosal inflammation. A lackof correlation with inflammation severity was also foundwith iceA and cagA genotype in this pediatric cohort. Therewere a number of children (5/45, 11%) who were colonizedby H. pylori strains with more than one genotype, providingevidence of initial mixed infection. In addition, the straingenotype did appear to cluster in association with geo-graphic origin and ethnicity; this, however, was not associ-ated with disease correlation (177).

Host factors. Gastric acid secretion has been described asthe critical factor for the development of mucosal ulcerationin the stomach or duodenum for many years. The effect of H.pylori colonization on gastric acid secretion is a rather contro-versial subject. In particular, the effect of H. pylori infectionon acid secretion in children remains poorly defined. One re-cent study demonstrated that there might be a difference be-tween acid secretion in children with gastric ulcers as com-

Figure 5. Lack of correlation between pediatric H. pylori cagA status andseverity of antral inflammation.


pared with children with duodenal ulcers (178). The authorsevaluated 24-h pH measurements as a determination of acidsecretion in 82 subjects: 10 children with gastric ulcers, 9with duodenal ulcers, and 58 non-ulcer patients, as well as 5healthy adults. Gastric acidity was significantly reduced inpatients with primary gastric ulcers (i.e., H. pylori-associatedgastric ulcers). However, gastric acidity was increased or wasabove adult levels in children with duodenal ulcers (178).

Other pediatric studies demonstrated 24-h acid outputsthat were distinctly different in ulcer and in normal controls(179). Intragastric pH monitoring was performed over a 48-hperiod: the first 24 h were untreated, and the second 24 hwere treated with three doses of an H2 receptor antagonist(cimetidine). Children with duodenal ulcers lacked the in-tragastric pH inversion that occurs in control subjectsaround midnight, and had persistent hypergastric acidity forthe majority of the 24 h. However, H. pylori infection statuswas not clearly defined in the study cohort. Moreover, themajority of adult studies are equivocal; maximal acid out-put, acid output values over a 24-h period, or even basalacid output do not appear to be predictive of the likelihoodof ulcer development.

The pathobiology of gastritis and gastroduodenal ulcer-ation due to H. pylori infection may also be mediated by dis-turbances in gastric and duodenal bicarbonate secretion. Themucus layer serves as a barrier to luminal pepsin and hydro-chloric acid, preventing access of pepsin to the apical surfaceof gastric epithelial cells. Bicarbonate secreted into the mucuslayer will then serve as a subsequent barrier by neutralizingthe acid. The mucus layer also provides protection for epithe-lial cell turnover in both normal and perturbed states, as wellas from mechanical damage during the hyper-motile state ofthe digestive and intestinal phases of digestion. Recent stud-ies demonstrate that there are impaired rates of proximalduodenal bicarbonate production in patients with duodenalulceration (180). Studies of gastric acid and duodenal bicar-bonate secretion in H. pylori-infected compared with unin-fected children are lacking and, therefore, critically needed.

Helicobacter infection in both humans and ferrets pro-duces a decrease in gastroduodenal mucosal surface hydro-phobicity. This is believed to be due to a disturbance in thegastric surface mucus layer content and character (181,182).It is postulated that mucus confers hydrophobicity to thestomach and that its decreased production leads to exposureof gastric epithelial cells to pepsin, acid, and other aggres-sive factors, with eventual erosion of the epithelial celllayer. Adult studies have demonstrated that a decreased po-lymerization of the component glycoproteins of mucus con-tributes to the deficient structure of mucus in patients withduodenal ulcers (183,184). However, these studies have notbeen performed in H. pylori-infected children.

Gastric hormones, specifically gastrin (185) and pepsino-gens I and II (186), may also play an important role in H. py-lori infection. Early studies suggested an inheritable patternof increased serum pepsinogen levels. These investigations

showed that children with duodenal ulcers and their parentshad increased levels of serum pepsinogen I (187,188). Sub-sequent studies of H. pylori-infected children and familymembers demonstrate that chronic infection is associatedwith elevated levels of serum pepsinogen (189). In addition,children infected by H. pylori have been shown to have de-creased numbers of D-cells (somatostatin-secreting cells),decreased circulating somatostatin levels, and thus increasedcirculating gastrin levels compared with uninfected controls.This observation is more common in younger than olderchildren and even more so than in adults, possibly a reflec-tion of the evolving pathobiology associated with this infec-tion. Following eradication of H. pylori in the infected child,D-cell numbers, D-cell to G-cell ratios, and circulating so-matostatin and gastrin levels return to normal (189).

A vigorous local and systemic host immune response isobserved after gastric colonization by H. pylori organisms,yet spontaneous clearance is rare (190,191). A monocyteand macrophage response can be seen in infected gastricmucosa, particularly in children (Tables 9 and 10). In adults,both polymorphonuclear cells and plasma cells are also presentin the inflammatory infiltrate (192–194). Our laboratory hasperformed comparative studies of H. pylori-infected chil-dren vs. H. pylori-infected adults that demonstrate achronic, macrophagic, monocytic inflammatory cell infil-trate in the early infection, and a lack of neutrophils com-pared with the polymorphonuclear inflammatory cell re-sponse observed in many infected adults (Tables 9 and 10)(Figure 6) (195). A lymphofollicular gastritis has also beendescribed in childhood, yet the clonality of the T cells, mac-rophages, and plasma cells in these lymphoid follicles re-mains undefined. It is still not clear whether T cells play amajor role in the inflammation associated with H. pylori in-fection, yet elevated levels of interleukin-1 (IL-1), IL-2,

IL-6, and IL-8, as well as tumor necrosis factor-alpha,are detectable in the gastric epithelium of infected individu-als (196).

Pathologic Sequelae

Gastritis. Warren and Marshall first reported the associa-tion of H. pylori colonizating the gastric mucosa with antralgastritis in adults in 1983 (197). Shortly thereafter in 1986,Hill et al. (198) described four children with chronic mono-nuclear cell gastritis who were infected with H. pylori. Laterthat year, Cadranel and colleagues (199) described organ-isms present in a group of eight children with chronic, lym-phocytic-type gastritis. Subsequently, Drumm et al. (171)observed Helicobacter-like organisms in 70% of 67 pediat-ric patients with a chronic active gastritis. Similar observa-tions of gastric mucosal inflammatory infiltrates associatedwith spiral-shaped organisms colonizing the mucosa and inthe mucus layer overlying gastric epithelium were alsonoted by Czinn et al. (172) in 25 children. Additional stud-


ies confirmed that H. pylori colonization of the gastric mu-cosa is virtually always associated with gastritis of predom-inantly chronic inflammatory cell infiltrates in children(200–202). Single-center case series reports of eradicationof H. pylori from the gastric mucosa demonstrate that thereis an associated healing of the antral gastritis, another find-ing in favor of H. pylori as the cause of primary gastritis inchildren (202). However, multicenter, randomized, con-trolled eradication trials of H. pylori-infected children arecritically needed.

Studies in adults established the presence of the organismin nearly all cases of chronic gastritis (203). It was initiallysuggested that H. pylori colonized inflamed tissue ratherthan caused the inflammation, because gastritis is a commonfinding in adults (203). However, the prevalence of gastritisis less frequent in children, thereby enabling investigation ofH. pylori as a cause for gastritis rather than as an opportunis-tic colonizer of inflamed tissue (204). Subsequent studiesshowed that H. pylori colonization was not a common find-ing in the gastric mucosa of children with secondary causesof gastritis, e.g., eosinophilic gastroenteritis and Crohn’s dis-ease (205). Taken together, these observations providestrong evidence for the pathogenic role of H. pylori in thedevelopment of chronic antral gastritis in children.

H. pylori-infected gastric mucosa almost always demon-strates a combination of inflammation and epithelialchanges. In adults, the inflammatory infiltrate generallyconsists of monocytes and neutrophils. However, in chil-

dren the inflammatory infiltrate is more a chronic, mononu-clear cell phenotype. Studies from our laboratory show, infact, that the macrophage may play an important role in thepathobiology of H. pylori-associated gastroduodenal in-flammation (Figures 7 and 8) (206).

H. pylori-associated gastritis is also characterized by thepresence of acute or chronic inflammation with immaturesurface epithelial cells. Depletion of mucus is often presentin epithelial cells, due to overactive cell renewal. The de-gree of inflammation varies in severity from a minimal in-flammatory infiltrate in the lamina propria, with preservedarchitecture, to severe gastritis with dense inflammation. Invery severe cases, intraepithelial neutrophils can be detectedin both the surface epithelium and in the gastric pits as mi-croabscesses. However, we have found that H. pylori-infectedchildren have lesser degrees of neutrophilic infiltrates ascompared with adults (191,207).

It was previously believed that in H. pylori gastritis, thefundic inflammation is usually less important than that ofthe antral mucosa (208,209). However, the controversial re-lationship between H. pylori and the development of—orconcurrent presence of—gastroesophageal reflux diseasemay in fact be due to the anatomic location of the inflamma-tory infiltrate (210,211). Moreover, patients who have beenadministered some form of acid suppression, in particular inthe form of proton pump inhibitors, are often found to havefrequent colonization of fundic and cardia mucosa by in-fecting organisms. Carditis of both a chronic and active phe-notype is frequent in H. pylori-infected adults (211,212).Studies are needed in children to determine the relationshipof H. pylori infection, the site of gastric inflammation, andlong-term disease sequelae.

H. pylori-associated gastritis in children is commonlynot apparent at endoscopy, thereby making biopsy essentialfor definitive diagnosis (172,204). Nodularity of the antralmucosa has also been described in association with H. py-lori gastritis in children (213). However, its significance isstill not yet defined, although antral nodularity has also beenobserved in adults (214–216), albeit less commonly.

Table 9. Percent of pediatric and adult H. pylori-infected patients with different degrees of various inflammatory components and amounts of bacteria in biopsies studied

Children Adults

Pathology Mild Moderate Marked Mild Moderate Marked p

H. pylori 19 29 52 36 29 35 0.05Neutrophils 48 25 25 22 18 53 0.02Plasma cells 24 36 40 5 31 64 0.005Lymphocytes 13 31 56 9 33 58 NSEosinophils 42 38 12 16 20 62 0.0001

NS 5 Not significant.

Table 10. Lymphoid follicles in biopsy specimens of children and adults with H. pylori infection

Characteristic Children Adults

Total biopsies 52 45No. (%) specimens without

limphoid follicles 20 (38) 19 (42)No. (%) specimens with

lymphoid follices 32 (61) 26 (58)a

Mean 6 SD (no. of lymphoid follicles per specimen) (range) 2.00 6 1.08 (1–5) 2.08 6 1.48 (1–7)

ap ,0.05.

Figure 6. Quantitation of macrophages in H. pylori-infected vs. -unin-fected children depicting increased numbers in the infected child.


Ulcers. Despite the notable lack of good large population-based pediatric studies, rates of peptic ulcer disease in child-hood appear to be low. Large pediatric endoscopy centers inthe 1980s reported an incidence of five to seven childrenwith gastric or duodenal ulcers per year (120). More recentstudies in children’s hospitals in the U.S. showed that ulcersoccurred in 1–2% of all hospitalizations (217). There was aslight male predominance, and more advanced ages tendedto have higher prevalence rates than younger ages. A trendwas observed in increased prevalence in black and Hispanicindividuals compared with white children, but these differ-ences were not statistically significant. Although the ICD-9diagnosis code for H. pylori was not published until late1995, there was a strong association with children withduodenal ulcers, and to a lesser extent with gastric ulcersand H. pylori infection.

Some investigators contend that nearly all peptic ulcersin children are located in the duodenum and that gastric ul-cers are extremely rare in children (218). A strong correla-tion has also been demonstrated between duodenal ulcer-ation, H. pylori gastritis, and duodenal gastric metaplasia inchildren (219). Other studies have shown that H. pylori gas-tritis has been found in 90–100% of pediatric duodenal ul-cer disease patients (200). In both adults and children, thepresence of severe antral inflammation will often correlatewith an increased association with duodenal ulceration(212,220). In addition, in a more recent single-center pediat-ric study, pre-pylori channel ulcers and duodenal ulcerswere found associated with severe antral gastritis andcagA1 H. pylori strains (221,222). As in adults, duodenalulcerations in the absence of H. pylori are less common inchildhood. However, there is a growing number of smallsingle-center series that report an increase in H. pylori-neg-ative ulcers in the U.S. and Canada (unpublished data). Thismay be due to a number of factors: missing the organism onbiopsy due to small numbers; a proximal shift in coloniza-

tion distribution due to bacterial preference, or the use ofproton pump inhibitors or incidental use of antimicrobials(212). Conversely, these H. pylori-negative ulcers may infact be due to other factors, i.e., NSAIDs.

It has also been demonstrated that duodenal ulcer diseasein children does not relapse if H. pylori are eradicated fromthe gastric mucosa (162). In one study, 23 children with H.pylori gastritis associated with duodenal ulcer disease weretreated using either cimetidine alone or a combination of ci-metidine and amoxicillin (202). Although only a small por-tion of children remained uninfected, no recurrence ofduodenal ulcer disease was detected 6 months after the endof treatment when H. pylori was eradicated from the gastricmucosa using combination therapy. In contrast, 50% of pa-tients whose ulcers were originally healed but remained col-onized by H. pylori (cimetidine-only therapy) had a recur-rence of the ulcer by 6 months. Additionally, it has beenshown that healing of duodenal ulcers following eradicationof H. pylori is often followed by re-epithelialization of theduodenal ulcer by gastric rather than by intestinal mucosa.

Gastric cancer. The role of H. pylori in intestinal-type gas-tric adenocarcinoma has been defined by a variety ofsources: studies paralleling the epidemiologic features ofcancer with those of H. pylori infection (223); cross-sec-tional studies of H. pylori infection in patients with cancer(224), and prospective studies of H. pylori infections (225–228). This poses a difficult problem for the pediatricianmanaging the child infected with H. pylori. Evidence of thepresence of gastric adenocarcinoma and adenomas in chil-dren is limited to fewer than two case reports and anecdotes.Thus, establishing causality and thereby treatment guide-lines for infected children based on the role of H. pylori ingastric carcinoma cannot be done at present (162,163).

Gastric cancer prevalence is higher in areas of poverty,afflicting people in developing nations and lower socioeco-nomic classes of the industrialized world (227). In manycountries of Latin America and Asia, gastric cancer remainsthe most common malignancy among men and the secondmost common among women. Incidence rates as high as 80per 100,000 population have been reported in Colombia andJapan. In contrast, gastric cancer affects fewer than 10 per100,000 people per year in the U.S. and western Europe(228,229). However, within low-risk countries there are eth-nic groups with increased risk. In the U.S, for example, theprevalence of gastric cancer among blacks, Asians, and His-panics is almost double that of whites (230). Interestingly,in all these populations, the prevalence rates of H. pylori are2- to 10-fold higher than in base populations.

H. pylori infection is a marker of increased gastric ade-nocarcinoma risk. However, definite proof of cause wouldbe accomplished only when controlled trials demonstratethat elimination or prevention of infection prevents malig-nancy. As previously mentioned, studies of H. hepaticus asa cause of liver cancer in mice and H. mustelae as an etio-

Figure 7. Macrophage-specific stain of gastric biopsies from children: A)Biopsy from a child without H. pylori infection. There is minimal stainingwithin the lamina propria denoted decreased to minimal numbers in theuninfected child; B) biopsy from an H. pylori-infected child. Note theincreased numbers of labeled inflammatory cells, macrophages.


Figure 8. Macrophage-specific immunostain of gastric biopsies from children: A) Shows a lack of presence of macrophages in uninfected child; B) shows theincreased numbers of macrophages in an H. pylori-infected child.


logic agent in gastric adenocarcinoma in ferrets add biologi-cal plausibility to the role of H. pylori in gastric cancer inhumans (231–233). In addition, long-term studies docu-menting reversal of pre-neoplastic conditions with anti-H.pylori therapy are needed to support the association of H.pylori and cancer. These studies should focus on the revers-ibility of intestinal metaplasia and, in particular, of gastricepithelial cell dysplasia, as H. pylori infection is eradicated(234,235).

Gastric lymphomas. In infancy and early childhood, thestomach lacks a significant number of immunocompetentlymphocytes and plasma cells. Chronic inflammation candevelop. As the child gets older, lymphocytes accumulate inthe submucosa and gradually increase in number. With theeradication of H. pylori, chronic inflammation decreasesand the density of submucosal lymphocytes dramaticallydeclines. Because most gastric lymphomas arise in areas ofchronic inflammation, it seems plausible that prior H. pyloriinfection and gastric lymphomas are linked. Primary non-Hodgkin’s lymphoma of the stomach is an uncommon can-cer, accounting for only 10% of lymphomas and 3% of gas-tric neoplasms. However, gastric non-Hodgkin’s lymphomaremains the most common extranodal form of this lym-phoma, accounting for 20% of primary extranodal disease.In addition, immunologic studies have shown these tumorsto be of B-cell lineage (236).

Low-grade B-cell lymphomas that arise in the stomach,lung, salivary gland, and thyroid recapitulate the structuralfeatures of MALT as typified in Peyer’s patches (237).These lymphomas, together with the high-grade lesions thatmay evolve from them, are collectively known as MALTlymphomas (237). MALT lymphomas were first describedin the early 1980s when Isaacson and Wright (238) notedthat the histology of certain low-grade B-cell gastrointesti-nal lymphomas was unlike that of comparable low-gradenodal lymphomas, but similar to that of mucosa-associatedlymphoid tissue. However, paradoxically MALT is notpresent in either the normal stomach or other sites in whichMALT lymphomas arise.

In the stomach, lymphoid tissue is acquired as a result ofthe colonization of gastric mucosa by H. pylori (239).Wotherspoon and colleagues (240) demonstrated that thisH. pylori-associated lymphoid tissue is of MALT type.They subsequently suggested that MALT acquired in re-sponse to H. pylori infection provides the background onwhich other yet unidentified factors act, and led to the de-velopment of lymphomas in a small proportion of cases.Very recently, Hussell et al. (241) demonstrated that cellu-lar proliferation of low-grade B-cell gastric MALT lympho-mas to H. pylori is dependent on H. pylori-specific T cellsand their products rather than on the bacteria themselves.Multiple serologic studies provide evidence suggesting thatinfection with H. pylori may increase the risk of gastric non-Hodgkin’s lymphoma (232,242).

Specific colonization of lymphoid follicle centers byneoplastic cells (243) and the binding of specific antibodiessuggest that MALT tumors are immunologically responsive(244). Given the close association between gastric MALTlymphoma and H. pylori, this organism might evoke the im-munologic response, and eradication of H. pylori mightthereby inhibit the tumor. Studies have suggested that anti-H. pylori therapy may eradicate MALT lymphoma in somecases (245).

Pathogenesis

The clinical outcome of H. pylori infection is influenced byfactors of the environment, the host, and the bacteria. In thissection, we will discuss the characteristics of bacteria thatprobably favor colonization and persistence of infection orthat cause damage to the gastroduodenal mucosa.

Colonization. The events necessary for colonization of thehuman stomach by H. pylori should be studied more thor-oughly in children, as they usually occur in this age group.Factors probably involved in the process have been studiedin vitro and in animal models; the emphasis should now beon studies in humans. Colonization factors and their possi-ble role in pathogenesis are described later in this paper.

Urease. The stomach presents a hostile acid milieu thatmust be counteracted by colonizing bacteria. H. pylori ex-presses high levels of a potent urease that catalyzes hydroly-sis of urea with the production of ammonia. The ammoniaforms a neutralizing cloud that protects H. pylori from acid.Urease has been demonstrated as essential for the coloniza-tion of animal models, as evidenced by the fact that urease-negative mutants were unable to colonize piglets or mice(246,247). Although urease is needed for colonization, it ad-ditionally evokes a host immune response that may causedamage to the host. This response includes activation of theoxidative burst in phagocytes and release of cytokines suchas IL-1, IL-6, IL-8, and TNF-a (248,249). Furthermore, ex-cess ammonia could be toxic for the gastric mucosa. Giventhe potential damaging action of urease and of the humoralresponse to it, it is interesting that most children colonizedwith H. pylori have gastritis with relatively low numbers ofneutrophils and limited damage to epithelial cells. One ex-planation is that H. pylori may possibly have evolved todownregulate urease expression during the initial phase ofthe infection in order to minimize inflammation and tissuedamage and improve chances for successful colonization.However, the levels of urease expressed in vivo in childrenare unknown. We found that in antral biopsies of childrenpositive for H. pylori by 13C-urea breath test and histology,the rapid urease test had a sensitivity of 100%, suggestingthat urease is efficiently expressed in vivo (250). Nijevitch(251) reported that ammonia concentration in gastric juice


(reflecting urease activity) correlated with gastritis score,dissemination of the organism, and anti-H. pylori IgG re-sponse. These results suggest that urease activity is an indi-cator of successful colonization and of the pathogenic roleof H. pylori in children. In contrast, we reported that fewerthan 20% of H. pylori-infected children produce antibodiesagainst urease (252), which suggests that either urease is apoor immunogen in children or that it downregulates theimmune response to favor colonization.

Motility. Motility is essential for H. pylori to cross the mu-cus layer and reach its juxtamucosal niche. H. pylori havefour to eight unipolar flagella and more than 60 genes in-volved in flagella biogenesis, assembly, and chemotaxis.Mutations in either of the two genes encoding major flagellaproteins—flaA and flaB—severely impair the ability of H.pylori and H. mustelae to colonize piglets or ferrets, respec-tively (253,254). Like the genes encoding urease, theseflagella genes are conserved among all H. pylori strains. Itis conceivable that motility genes would be upregulated instrains colonizing children, in that their activity is essentialto establish the infection. However, motility may also evokean immune response by inducing cytokine expression, thusenhancing inflammation in the gastric mucosa (255).

Degradative enzymes. H. pylori appears to degrade the mu-cus layer. This may facilitate access to nutrients, although itmay also lead to epithelial damage through removal of pro-tective mucus. Production of specific proteases has been de-scribed, but this is controversial (256). H. pylori also pro-duces phospholipases, which alter the hydrophobicity of themucus layer. This may render the mucosa more susceptibleto damage and lead to direct formation of ulcerogenicbyproducts (257).

Adherence. Once H. pylori has swum across the mucuslayer, adherence is needed to achieve a lasting colonization.A variety of potential epithelial cell receptors have beenproposed, including phosphatidylethanolamine (258), extra-cellular matrix components (259), heat shock protein B(260), and Leb blood group antigen (261). The selective tro-pism of H. pylori toward gastric epithelia suggests that itbinds to specific gastric receptors. Thus, ubiquitous com-pounds such as phosphatidylethanolamine are unlikely to bethe sole gastric receptor. Furthermore, it has been reportedthat H. pylori may adhere to human gastric cells indepen-dently of the expression of either Lea or Leb on human gas-tric cells (262). Thus, the role of these eukaryotic cell recep-tors in vivo remains to be determined. On the bacterial side,some outer membrane proteins have been identified as ad-hesins, including BabA2, AlpA, and AlpB, which have beensuggested as cooperating to form a multicomponent adhe-sive complex. BabA2 has been suggested as the putativeLeb-binding adhesin (263). However, these proteins are notexpressed by all H. pylori strains, which suggests that they

are not essential for colonization. A 25-kD protein of H. py-lori was identified as necessary for binding to laminin.Binding to this substrate might not participate in initial col-onization events, but was suggested as participating in theassociation of the bacteria with intercellular junctions (264).It was recently demonstrated that cagA1 H. pylori strainsexhibit a Leb-independent adherence to gastric cells that re-quires de novo protein synthesis in both the bacteria and thehost (265). This suggests that H. pylori adherence is a com-plex process requiring active signaling between host andbacteria. This interactive adherence was not observed withcagA2 strains.

Heat shock proteins. H. pylori expresses heat shock pro-teins with homology to human GroEL and GroES proteins.These may act as chaperonins for H. pylori urease. In onestudy, when hspA-hspB genes were cloned in conjunctionwith the urease gene cluster into E. coli the activity of ure-ase was increased (266). If this phenomenon occurs in vivo,heat shock proteins may facilitate early colonization eventsby enhancing the activity of urease. In adults, heat shockproteins provoke an antibody response, and it has been sug-gested that these antibodies may cause gastric damage by anautoimmune mechanism (267). However, these data arecontroversial, and even if such an event occurred, the matu-ration of the response would likely occur over many yearsand would thus be unlikely to be clinically relevant in H. py-lori-infected children.

Lewis antigens. Once established in the gastric mucosa, H.pylori must have a mechanism for persisting without pro-voking the host immune response to the extent that it iseliminated. One such mechanism is to evade immune re-sponse by antigenic mimicry. H. pylori expresses fucosyl-transferases that enable the bacteria to synthesize Lewisantigens (268), also commonly expressed on host cells. Byexpressing cross-reactive antigens, the bacterium poten-tially avoids stimulating an immune response and decreasesinflammatory reactions. However, cross reaction with anti-gens of the host may potentially give rise to autoimmune re-sponses deleterious to the gastric epithelium. About 80% ofH. pylori strains express Lex and/or Ley (269). H. pyloriLPS displays phase variation, giving rise to marked hetero-geneity in the expression of Le antigens (270). In a recentstudy, we assessed the heterogeneity in the expression of Leantigens by multiple single H. pylori colonies isolated fromchildren and adults (271). A total of 210 clones from 16children with recurrent abdominal pain and 229 clones from16 adults, five with gastritis and 11 with duodenal ulcer,were studied. Clones expressing Lex were significantlymore common in children than in adults (p ,0.001),whereas the expression of Ley was significantly more com-mon in adults than in children (p ,0.001). A linear trendanalysis showed a significant decline in the frequency ofclones expressing Lex with age (p 50.029). High diversity


in the expression of both Le antigens was found amongclones from the same patient in both children and adults.Thus, in our Mexican community, expression of Le antigensdiffers in H. pylori isolates from children and from adults. Itremains to be seen whether these results are reproducible inother populations.

H. pylori lipopolysaccharide (LPS) is less proinflamma-tory than the LPS of other Gram-negative bacteria, partly be-cause lipid A moiety is less phosphorylated and less acety-lated. This property may favor persistence of the infection. H.pylori LPS may also cause acid hypersecretion by stimulatinghistamine release and proliferation of enterochromaffin-likecells (272), or may alter gastric emptying (273).

Documented Virulence Factors

In most individuals, the presence of H. pylori causes histo-logic gastritis that is, in most cases, asymptomatic. However,peptic ulcer disease will develop in about 15% of cases, gas-tric adenocarcinoma in less than 1% of infected patients and,rarely, there will be development of primary gastric lym-phoma. These diseases are expressed after years of infectionand thus occur principally in adults. One reason that only asmall portion of adults develops the disease is that somestrains of H. pylori have enhanced virulence, and severaldisease-associated virulence factors have been identified.However, the importance of these virulence determinants inchildhood infection—and in particular whether they are im-portant for disease in childhood—has not been extensivelystudied.

cag Pathogenicity Island

Some strains of H. pylori have a 38–40 kb DNA locus con-taining over 31 potential genes that is called the cag patho-genicity island (cag PAI). The original source of the cagPAI is unknown, but it is thought to have been acquired hor-izontally and inserted into the glutamate racemase gene atsome distant stage in H. pylori evolution (274,275). Somecag PAI genes are homologous to genes present in otherbacterial pathogens in operons encoding for type IV secre-tory systems. Type IV secretory systems are export machin-eries specialized for the transfer of molecules to other cellsand are often involved in virulence. cagA is a gene at oneend of the cag PAI. CagA is delivered by cag PAI-encodedsyringe into gastric epithelial cells, where it is phosphory-lated on tyrosine residues and triggers profound changes inthe host cytoskeleton (276–279). This should help explainthe enhanced virulence of CagA-positive H. pylori strains.The association between the presence of cagA and diseasewas observed before the cag PAI was discovered, and atpresent the importance of cagA is as a marker (albeit imper-fect) for the cag PAI. cagA codes for a highly immunogenicprotein (CagA); thus, IgG response to this antigen is an ex-

cellent and easy serologic marker for the presence of the cagPAI in H. pylori strains carried by colonized individuals.Using this serologic marker, many studies have demon-strated an association between CagA-positive (and thusprobably cag PAI-positive) strains and peptic ulcers, mu-cosa-associated, lymphoid type B-cell lymphomas, and gas-tric cancer (280–284). cagA-positive strains induce the re-lease of IL-8 from gastric epithelial cells, this effectdependent on the presence of several genes in the cag PAI(284). Other activities associated with cag PAI genes in-clude pedestal formation for intimate bacterial adherence,activation of the transcription factor AP-1, and expressionof the proto-oncogenes c-fos and c-jun (285).

Vacuolating cytotoxin. The H. pylori vacuolating cytotoxin(VacA) is a protein that causes vacuolization of cultured eu-karyotic cells. Vacuolating cytotoxin activity is expressedby about 40% of strains (286). Early studies showed a mod-erate link between strains that exhibited cytotoxin activityin vitro and disease (287). At present, the genetic basis fortoxin expression is becoming better understood. The genethat encodes the cytotoxin vacA is present in essentially allstrains, but is a mosaic that varies markedly between strains,particularly in the region encoding its signal sequence (s)and its mid-region (m). The s region may be type s1 (thatcan be subdivided into s1a, b, and c) or type s2, and the mregion type m1, or type m2. All possible combinations of sand m types are found, although some (notably s2/m1) arerare. Strains with vacA s1 alleles often exhibit vacuolatingcytotoxin activity and are associated with disease, whereass2 alleles do not exhibit vacuolating activity and are rarelyassociated with disease. Strains with m2 alleles are mini-mally or noncytotoxic to most epithelial cell lines used, butin most studies appear to be commonly associated with dis-ease, such as vacA m1 strains (288,289).

Studies in children. Several studies in children have assessedthe importance of virulence determinants linked with adultdisease. Some have failed to show an association with child-hood disease, although these were often small studies withsubject numbers insufficient to detect even a moderate link.Celik et al. (290) studied the virulence properties of 29 H. py-lori isolates from children with recurrent abdominal pain. Nosignificant correlation was found between degree of inflam-mation and presence of the cag pathogenicity island, vacA al-leles, or cytotoxin production. Only four of these isolates wereable to bind Leb, in contrast to isolates from adults, most ofwhich bind Leb. In another study, 23 symptomatic childrenand 132 asymptomatic children were studied for serum anti-bodies to CagA and VacA. The combined response to eitherCagA or VacA was weakly associated with severity of gastri-tis. No correlation was found with either histologic features ordensity of H. pylori colonization (221). Similarly, in a smallstudy in Australia no significant difference in serologic re-sponse to CagA was found between children with peptic ulcer


and children with non-ulcer dyspepsia (291). In 40 H. pylori-positive Japanese children, the prevalence of CagA antibodieswas similar in patients with nodular gastritis and in patientswith gastric or duodenal ulcers (292). In contrast to these stud-ies, some researchers have shown a link between known H.pylori virulence determinants and disease. In a study of 45 H.pylori strains isolated from children, the presence of the cagAgene was significantly associated with hemorrhagic gastritis,severe gastritis, and vomiting (293). In Finland, a study in 39infected children compared gastric inflammation in relation toantibodies to CagA. Mononuclear cell infiltration in the an-trum was more intense in CagA-positive than in CagA-nega-tive children; this difference was not observed in the gastricbody (294). In a study of 64 H. pylori-infected children in It-aly, a strong correlation was found between CagA antibodiesand scores of inflammation and activity in both the antrum andcorpus. However, no differences were found in clinical diag-nosis or symptoms (295).

There have been a number of studies presented at meet-ings. In these studies, the presence of CagA was reported tobe associated with increased gastric inflammation and lym-phocytic mucosal infiltration in children and with duodenalulcer (296,297). Similarly, VacA production and specificvacA types were reported as associated with duodenal ulcer(298) and with higher inflammatory reaction in antral andoxyntic mucosa (299,300).

Summary

In conclusion, studies of virulence factors and childhooddisease yield conflicting results: an association appears toexist, but the studies show that it is not as simple as virulentstrains always causing disease and non-virulent strainsnever causing it. The conflicting results might be due to dif-ferences in the timing of infection, possibly with associa-tions becoming stronger as the duration of infection in-creases. To address this issue, we need to find markers thatmay indicate length of time elapsed with the infection.

By observing the number of studies reported at meetings, itis obvious that interest in the study of the pathogenesis in chil-dren is increasing and that we should see more articles in thisarea in the near future. In upcoming studies, we should con-sider the differences observed between children and adults inthe natural history of disease. Thus, H. pylori seldom causepeptic ulcers in children, although several cases have been re-ported (see the Clinical Manifestations section). In contrast topeptic ulcers in adults, ulcer formation in children seems to oc-cur shortly after colonization. This might suggest that differ-ences are present between the ulcerogenic strains that infectchildren and adults, and that strains associated with peptic ulcerin children may be more toxic to the gastroduodenal epithe-lium. This possibility deserves further study. It is also impor-tant to investigate whether expression of H. pylori virulencefactors in the gastric mucosa of children might increase the riskfor peptic ulceration or gastric cancer later in life.

Host Response

Inflammatory reaction. The initial host response to H. pyloriinfection in adults is characterized by intense neutrophil infil-tration associated with a transient period of achlorhydria, asdocumented in human volunteers. Chronic infection is charac-terized by a lymphocytic infiltrate with varying levels of con-tinuing neutrophil infiltration. This phase may be accompaniedby reduced or increased acid production. It is possible that theresponse to initial infection, particularly achlorhydria, may bebeneficial to the bacteria in that it may allow successful gastriccolonization; H. pylori may have evolved to induce this re-sponse. Furthermore, it has been suggested that the sustainedlow-grade response may also prove advantageous for the bac-teria by providing accessibility to nutrients (301).

The influx and activation of inflammatory cells may be in-duced directly by bacterial factors or indirectly by stimulationof release of inflammatory mediator from epithelial cells andsubsequently other cells. H. pylori produce several factorsthat attract and activate inflammatory cells directly (302). Epi-thelial cells release various cytokines, including IL-8, follow-ing stimulation by H. pylori (303). IL-8 production occurs viaactivation of the transcription factor NF-kB (304). Increasedlevels of TNF-a, IL-1b, IL-6, IL-7, and IL-10 have been re-ported in gastric biopsies of H. pylori-infected patients(305,306). It has been shown that cagA-positive strains in-duce a significantly higher cytokine response and a more se-vere infiltration of inflammatory cells in the gastric mucosaof patients than cagA-negative strains (305,307). The cyto-kines induced by cagA-positive strains—TNF-a, IL-1b, IL-6,and IL-8—are well-known proinflammatory cytokines andmay participate in damage to the gastric mucosa.

Some cytokines may affect gastric physiology; thus, IL-8stimulates release of gastrin from G cells (308) and prelimi-nary data suggest that TNF-a and IFN-g stimulate the re-lease of pepsinogen from human gastric chief cells (309).

Cellular response. Recent studies show the importance thatthe type of cytokine response has on the clinical outcome ofinfection. Thus, T helper cells isolated from gastric antralmucosa of patients with ulcers produce IFN-g, but not IL-4.This is a pattern of cytokines polarized to a Th1 response(310). Patients with peptic ulcers have detectable in vivo ex-pression of IFN-g, TNF-a, and IL-12, but not IL-4. CD301T cells producing Th2-type cytokines are not detected (311).On the other hand, most T helper clones from patients withgastritis and no peptic ulcer disease produced IL-4 or -5,which are Th2-type cytokines (310). In summary, it appearsthat a cellular response predominantly of the Th1 type is as-sociated with more severe peptic ulcer diseases, whereaswhen a Th2 response predominates, inflammation may belimited to gastritis without significant tissue damage.

Studies in children. In gastric mucosal biopsies of childrenwith H. pylori-associated gastritis, TNF-a and IL-6 have


been found elevated when compared with levels in biopsiesof non-infected children; however, IL-1-b was not in-creased (312). This cytokine pattern would suggest that inchildren, as in adults, H. pylori infection preferentially in-duces a Th1 type of response. We recently studied childrenwith non-ulcer dyspepsia and compared cytokines in gastrictissue from infected and non-infected patients. IL-8 and IL-10were significantly elevated in H. pylori-infected children. Itis noteworthy that the levels of IL-4 correlated strongly withthose of IFNg, suggesting equilibrium between Th1 andTh2 responses in H. pylori-infected children. Our resultswould suggest that, in infected children, a regulated Th1-Th2 response is elicited, thus decreasing the deleterious ef-fect of a predominant Th1 response. There is an obviousneed for more studies on the production of ILs and its rolein disease in children.

The levels of superoxide dismutase in the gastric antrumare significantly higher in children with H. pylori-positiveantral gastritis than in the antrum of H. pylori-negative chil-dren. This suggests that in children, as in adults, oxygen rad-icals are implicated in injury to gastric mucosa associatedwith H. pylori infection (313). A preliminary report suggeststhat NO may play a role in antral gastritis in children (314).

The inflammatory response might be responsible for in-creased serum levels of gastrin and pepsinogen in both chil-dren and adults (189,314–316). Kim et al. (317) reported thatthe serum levels of pepsinogen I and II were higher in chil-dren infected with H. pylori cagA1 strains than in those in-fected with cagA2 strains. H. pylori infection is associatedwith hypergastrinemia in children, but increased gastrin lev-els were not related to recurrent abdominal pain (318). Hy-pergastrinemia in H. pylori-infected children appears to bedue to a decrease in the density of D-cells and lower levels ofantral somatostatin, which inhibits the synthesis of gastrin(319). These studies indicate that in children, as in adults, theinflammatory response may alter gastric physiology.

Humoral response. The immune response to an acute H.pylori infection appears to differ between children andadults. In children, the initial antibody response is directedto small-molecular-weight H. pylori proteins such as 19,26.5, and 29 kD, whereas in adults, the response to largeand immunodominant antigens such as CagA often is ef-fected over months. In acute infection in adults, the re-sponse to small-molecular-weight proteins might occurslightly later (320). In support of this, López-Brea et al.(321) reported that sera from infected children reacted pref-erentially to low-molecular-weight antigens of 30, 26.5, and19.5 kD.

We recently reported that in a community-based popula-tion, only 20% of H. pylori-infected children were positivefor IgG anti-urease, which contrasted with the 50% ob-served in infected adults (252). In Table 11, we compare theimmune response in symptomatic children and adults seenat the gastroenterology services at the CMN-SXXI, IMSS

Medical Center in Mexico City (unpublished results). Asfound in community-based population, in symptomatic H.pylori-infected children the frequency of response to ureaseis significantly lower than that observed in symptomaticadults (15 vs. 54 to 63%, p ,0.01). Frequency of responseto CagA was also lower in children. Figure 9 presents themagnitude of response to whole cell extract, CagA, and ure-ase according to age in 80 children and 225 adults, patientspositive for anti-H. pylori antigens. Response to whole cellextract is significant from childhood; response to CagA isalso observed from childhood and increases steadily withage. In contrast, response to urease is minimal in children,only becoming significant during adulthood. These studiessuggest that in a natural infection, antibody response to ure-ase may take years. Differences in antibody response to dif-ferent antigens between children and adults have importantimplications for serodiagnosis and will be discussed subse-quently in the Diagnosis section.

Diagnosis

Several reports from developing countries and from minor-ity communities in developed countries have suggested thatcolonization with H. pylori may occur very early in child-hood (20,322). However, there are to date no clinical indica-tors that allow us to determine when H. pylori is acquired.Therefore, there is a real need for highly sensitive and spe-cific methods for the detection of H. pylori in children. Thisis particularly important in infants and younger pediatricpopulations in which colonization is likely to take placeduring the early phases of its establishment. Therefore, bac-terial density may be extremely low and the amount of or-ganisms present may be below the sensitivity of most of thecurrent diagnostic assays. Furthermore, some investigatorshave suggested that RAP might represent the acute phase ofH. pylori infection in children (146), making it more diffi-cult to establish a precise diagnosis. Because this may repre-sent the initiation of the bacteria and host interaction, mostof the assays may show poor sensitivity and specificity.

Similar to methods of diagnosing H. pylori in the adultpopulation, there are two main alternatives for diagnosingH. pylori in children: invasive and non-invasive methods.These two modalities have been evaluated in different areasof the world. As expected, invasive methods are considered

Table 11. Comparison of the immune response to H. pylori antigens in children and in adults

Totalinfected

Number positive (%)

Group Anti-urease Anti-CagA

Children with abdominal pain 80 12 (15) 53 (66.3)Adults with gastritis 108 68 (63) 82 (75.9)Adults with duodenal ulcer 117 64 (54.7) 100 (85.5)


the gold standard in H. pylori identification because the or-ganism can be demonstrated either by culture or by bacterialvisualization in gastric tissue. However, because most chil-dren colonized with H. pylori are asymptomatic, most stud-ies that have evaluated the reliability of diagnostic tests inlarge populations are based on non-invasive tests. Thus, theaccuracy of invasive methods in children has not been wellevaluated.

Invasive Diagnostic Tests

Invasive tests included methods in which the detection of H.pylori is performed on a biopsy sample obtained during thecourse of a gastroduodenoscopy procedure. Among the in-vasive assays evaluated in pediatric populations, most stud-ies have concentrated on culture, histology, rapid ureasetest, and transcription-polymerase chain reaction (PCR) us-ing gastric biopsy specimens. However, a small number ofstudies have reported on the culture of H. pylori from stoolor the use of PCR assays on gastric juice or saliva.

Urease tests. The rapid urease test is a method that permitsrapid detection of H. pylori based on the presence of ureaseactivity in a small sample of gastric mucosa. This is a quali-tative analysis in which sensitivity depends on bacterial den-sity (323,324). There have been several modifications to thisassay with the purpose of obtaining quick results and im-proving sensitivity and specificity (325). Overall, most teststhat are available performed equally well. In addition, the as-say is apparently not affected by the size of the biopsy speci-men (326), a relevant concern for the pediatric population.

Culture. The gold standard method for establishing the di-agnosis of H. pylori is culturing the bacteria. Isolation of H.pylori has usually been carried out from gastric biopsy spec-imens but it occasionally has been cultured from stool anddental plaque as well (327). Isolation of bacteria permits de-termination of susceptibility to antimicrobial agents, de-tailed investigation of virulence factors by strain, and appli-cation of molecular methods to differentiate between strainseither in a familial setting or strains isolated before and after

treatment failure. Despite the major controversy concerningwhich transport conditions are the best for isolation of H.pylori, it is now accepted that the composition of the trans-port media is not the most important factor for recovery ofH. pylori in culture. It is, rather, the length of time betweenthe collection of the biopsy and its inoculation into the agarplates (328). Of the two types of media used for isolation ofH. pylori—selective and non-selective media—the selectivemedia includes an enrichment media (blood base) contain-ing a mix of antimicrobial agents and the non-selective me-dia has the same base media without antimicrobials. In chil-dren in whom achlorhydria might be present, the use ofselective media to prevent the overgrowth of potential con-taminants (E. El-Omar, personal communication) is recom-mended. This approach is also useful when endoscoped pa-tients are from less developed countries.

Histology. Histologic examination of gastric biopsy speci-mens can be carried out using Giemsa or Warthin-Starrystains to enhance visualization. Because histology is impor-tant not only for diagnosis of H. pylori but also for detectionof other histopathologic changes, it is important to handlebiopsy samples appropriately.

Although successful eradication of H. pylori results inreduction of inflammatory cells, endoscopy is not recom-mended as a follow-up method to assess treatment efficacyin the pediatric population (329). This is important becauseinflammatory changes in children are not very dramatic. Inaddition, special techniques might be necessary, partly be-cause of the lesser severity of the lesions, which are difficultto recognize in younger patients (330). Furthermore, histol-ogy yields significantly higher sensitivity and specificitywhen experienced pathologists examine slides than whenthey are interpreted by trainees or by rotating staff (331).

Stool culture. As previously mentioned, H. pylori has beencultured from stool specimens (332). However, the use ofthis technique for the diagnosis of H. pylori in children hasnot been widely accepted. Although the highest incidence ofH. pylori infection occurs during childhood, there are rela-tively few publications that confirm the successful isolationof this bacterium from stool (327). It is unclear whether theexcretion of H. pylori in stools is a persistent phenomenonor only a sporadic event, but stool culture is clearly not a re-liable method for the diagnosis of H. pylori.

Molecular methods. Molecular methods are the logical al-ternative for the diagnosis of H. pylori in pediatric popula-tions because a low grade of colonization may be frequentin pediatric patients. Of all molecular methods evaluated fordiagnosis of H. pylori (333), PCR is probably the bestmethod for detecting H. pylori in children. This method al-lows differentiation of children who are colonized with H.pylori, based on the fact that PCR shows excellent correla-tion with culture and histology (334).

Figure 9. Serologic IgG response to H. pylori antigens in children andadults infected with H. pylori according to age.


PCR detection. Many PCR methods have been developedto detect H. pylori directly in clinical specimens (335–338).Most methods have been developed for detection of H. py-lori in gastric biopsy specimens. However, different meth-ods have also been used for H. pylori detection in specimensother than gastric tissue, e.g., saliva, dental plaque, stools.Apparently the sensitivity and specificity of the PCR meth-ods vary considerably across studies. A recent study thatcompared different PCR methods concluded that the glmMgene PCR was the most appropriate of the methods com-pared for the detection of H. pylori (339). However, PCRtechniques are not yet standardized, in either adult popula-tions or in pediatric populations. Therefore, each assay re-quires validation and comparison by more traditional meansof diagnosis.

Non-invasive Diagnostic Tests

The use of non-invasive methods allows clinicians to knowthe H. pylori status of their pediatric patients without sub-jecting them to an endoscopy. The economic, ethical, andpublic health implications of the presence of H. pylori inchildren have motivated the search for accurate non-inva-sive tests. It is therefore not surprising that most of the suc-cess in the diagnosis of H. pylori in children has derivedfrom studies evaluating non-invasive diagnosis tests (340).Of all non-invasive tests reported, there are two in particularthat have confirmed their value for diagnosis of H. pylori inchildren—the urea breath test and the determination of spe-cific antibodies to H. pylori.

Urea breath test. The 13C-urea breath test in children hasconfirmed its diagnostic value (24,341). The reported sensi-tivity and specificity of this assay compared with histologyand culture methods are often .95%. Despite some contro-versy, similar sensitivity and specificity estimates have beenreported for this assay independent of the concentration ofthe 13C-urea used (22,24). Similar to studies reported inadults, the 13C-urea breath test has confirmed its value forthe evaluation of H. pylori eradication in patients after treat-ment (342). It is clear that the results of the 13C-urea breathtest, as with other assays, correlate with the degree of gas-tric colonization. Therefore, it is recommended to performthe test 3–6 months after treatment to confirm H. pylorieradication. Epidemiologic studies have found significantvariation in 13C-urea breath test values by nationality, sug-gesting that genetic or ethnic factors could influence H. py-lori colonization. These findings suggest that the 13C-ureabreath test should be validated in the local population. Mostpapers published over the last 2 years demonstrate that the13C-urea breath test is an accurate method for diagnosis ofH. pylori infection in children. A wide range of test condi-tions, including collection time, urea dose, and test mealamong others, can be used without affecting the results. One

area that requires further investigation is the assessment ofthe sensitivity and specificity of the 13C-urea breath test inchildren of preschool age, given reports of more frequentfalse results in young children (342).

Antibody detection methods. The other major method toscreen for H. pylori infection in children is demonstrating an-tibodies specific to H. pylori in serum, gastric juice, urine, sa-liva, or other fluids. Most assays used for diagnosis of H.pylori in children are based on an enzyme-linked immunosor-bent assay (ELISA) for detection of specific antibodies in se-rum (146,343). Use of cut-off values predetermined in adultsyields low sensitivity in infants and young adults in both de-veloped and developing countries (344). The poor sensitivityof most of the commercial serologic assays available on themarket can be explained by the presence of relatively lowerH. pylori antibody levels in children as compared with adults(345). Recently, Oliveira et al. (346) confirmed that the accu-racy of the test in children with duodenal ulcer and in chil-dren older than 12 years of age was good. However, for chil-dren younger than 12 years of age without duodenal ulcer, thesensitivity of the test was low. It is important that, as in thecase of the serologic assays for adults, the ELISA methodsdescribed for children include well-defined specific cut-offvalues, and that each assay be appropriately validated in thelocal population. This practice can dramatically improve thesensitivity and specificity of the assay in children, especiallyin those from 2–17 years of age (146).

Antigen detection methods. Stool antigen validation studieswill provide the most important evidence to confirm theusefulness of the stool antigen assay for determination of H.pylori status in both adult and child populations. Prelimi-nary studies suggest that the sensitivity and specificity ofthis assay might be better than in any other test (28,29,347).Further studies are needed, particularly in patient groupssuch as infants. It is in this group that the stool antigen testcould provide major advantages over other tests.

Future Developments

Nearly 20 years after the first description of H. pylori in hu-mans, there remain several problems that continue to com-plicate the diagnosis of this organism in children. There islittle information regarding whom to test, what test to use,and what to do with the results (348). Recently, severalguidelines have been published that summarize some of themajor points expressed in this review (162,163). An area ofoverwhelming agreement among the experts is that diagnos-tic tests should be carefully evaluated and reserved, in thecase of pediatric populations, for children who are mostlikely to derive a measurable benefit.

When invasive and non-invasive tests are compared,most invasive tests clearly showed poor sensitivity and


specificity for diagnosis of H. pylori in children, probablyreflecting the low grade of colonization in this group of pa-tients, or perhaps due to the fact that colonization is not yetfully expressed. An alternative possibility is that most pa-tients for whom diagnostic tests have been evaluated are pe-diatric patients with RAP who require endoscopy, and RAPmight represent a syndrome with different etiologic origins.If this is the case, diagnostic assays tested in this populationmay have poor reliability in other populations. Clearly, the13C-urea breath test is currently the test of choice in childrenolder than preschool age for diagnosis of H. pylori, eitherbefore or after treatment, as recently reported by Yáñez etal. (250).

A major goal in H. pylori research is the development ofbetter diagnostic assays in children. New and better non-invasive methodologies will help us to offer more reliabletests for the diagnosis of H. pylori in children of any age.

Treatment

The natural history of peptic ulcer disease changed dramat-ically after the discovery of H. pylori in 1983 (349). Use ofantibiotics and eradication of H. pylori significantly de-creased the recurrence rate of gastric and duodenal ulcersin adults and children (350). The European HelicobacterStudy Group’s Maastricht Consensus Report in 1997 pro-vided clinical guidelines for H. pylori eradication therapyin adults. Peptic ulcer disease, bleeding peptic ulcer, andlow-grade gastric MALT lymphoma were associated dis-eases for which eradication therapy was strongly recom-mended. Non-ulcer dyspepsia and non-ulcerative gastritisassociated with H. pylori in adults were determined todemonstrate insufficient evidence for the initiation of H.pylori treatment (351).

Recently, two consensus conference proceedings on H.pylori infection in children were published by the Cana-dian and the European groups (162,163). Both groupsagreed that treatment and eradication of H. pylori in chil-dren leads to the cure of gastritis and of duodenal and gas-tric ulcers. However, when H. pylori is not associated withulcers, there is no evidence that eradication will alleviatethe symptoms. It was concluded that extensive studiesshould be performed to detect which patients may benefitfrom therapy. It was agreed that children should be inves-tigated for H. pylori only when their symptoms are severeenough to justify the risks of therapy, or when there is ahigh possibility of organic disease, such as esophagitis orulcer. If endoscopy is indicated to investigate organic dis-ease and H. pylori is found, the child should receive treat-ment. However, in the absence of ulcer disease, relativesof the patient should be informed that eradication of H. py-lori does not necessarily lead to relief of symptoms, andthese individuals should be given the option to refuse treat-ment (162,163).

Eradication of H. pylori Infection in Children

The definition of eradication of H. pylori infection is nowgenerally accepted as the clearance of the bacteria, con-firmed by at least two reliable methods (i.e., urea breathtest, histology, rapid-urease test, or culture) 4–6 weeks afterthe completion of the treatment. If the tests are performedbefore 4 weeks, there is a risk of false negative results dueto a decrease in the bacterial load without clearance (352).

In view of the existence of few properly designed popu-lation-based studies in children as outlined by the two pedi-atric consensus conferences summarized previously (162,163), there are few conditions associated with H. pylori forwhich there are clear indications for treatment in children.Natural history studies identifying risk factors in childrenfor the development of peptic ulcer disease, MALT lym-phoma, or adenocarcinoma of the stomach will better defineindications for initiation of eradication therapy.

When reviewing the literature regarding treatment trialsconducted in H. pylori-infected children, the end points thatdefine success of therapy are often vague and ill-defined.Outcome of therapy is sometimes defined as clearance of theorganism, reduction in symptoms, or both, and is often dif-ferent from the enrollment criteria. Thus, interpreting the ra-tionale for initiation of eradication therapy and the optimaltherapeutic regimen based on the best-available literature isdifficult. In other words, eradication therapy for H. pylori-in-fected children should be inexpensive, well tolerated, andeasily administered, should successfully cure the infection in.90% of infected cases, and more importantly, should re-solve the gastroduodenal disease that led to the symptoms ofthe child seeking medical attention. A primary reason forconfusion in pediatric H. pylori literature is that the associa-tion of symptoms with H. pylori infection in children re-mains controversial, primarily due to poorly defined criteriafor the gastrointestinal symptoms observed in children in-fected by H. pylori. To date, there is no validated, reproduc-ible, and standardized symptom-scoring instrument for dys-pepsia in children or for children with gastroduodenaldisease with or without concurrent H. pylori infection. In ad-dition, some studies report that up to 70% of cases with re-current abdominal pain (RAP) have no evidence of H. pyloriinfection (146). Curing symptoms when initiating H. pylorieradication therapy might be an argument in favor of admin-istration of the treatment. However, there are no randomized,multicenter, controlled studies that demonstrate a beneficialeffect of bacterial eradication on symptom improvement. Inour experience, children with abdominal pain and gastritisassociated with H. pylori showed a significant reduction inabdominal pain after eradication compared with children inwhom the infection persisted (353). However, we did not in-clude a placebo control group for comparison. Based on ourexperience and on a review of available evidence, we cannotrecommend eradication treatment for all children with ab-dominal pain and H. pylori-positive gastritis.


Therapeutic trials in H. pylori-infected adults reveal awide spectrum of results (352). In addition, randomizedcontrolled trials in H. pylori-infected adults showed thateradication success is different in developing as comparedwith developed countries. In developing countries, it is pos-tulated that early exposure to antibiotics (e.g., metronida-zole and clarithromycin) may predispose to the develop-ment of antibiotic resistance. For example, the reportedresistance to metronidazole is over 80% in some developingcountries (354). In contrast, H. pylori antibiotic resistance islower in developed countries (i.e., 5–25% for metronida-zole) and concordant higher eradication rates are observedin multicenter therapeutic trials (355).

To date, there are no placebo-controlled, randomized,multicenter trials in H. pylori-infected children in the U.S.or in Europe. Single-center, unblinded, case series studiesevaluating eradication therapy in H. pylori-infected childrenhave used different combinations of antibiotics and anti-secretory agents (Table 12). A wide variety of eradicationrates has been observed in these pediatric studies, rangingfrom 48–96% (356–362). Recent observations suggest thatin H. pylori-infected children, eradication might be moredifficult to achieve than in adults (363). In addition, somestudies demonstrate that children are less compliant andmight be more prone to intrafamilial reinfection (364).

Metronidazole and bismuth subsalicylate were the firstantimicrobials employed to cure H. pylori infection. Whenthese drugs were given as single agents, eradication ratesdid not reach more than 10% (365–367). Other drugs testedto improve those results included amoxicillin, furazolidone,and clarithromycin. Use of these agents increased the eradi-cation rate from 15–60% when given as a single therapeuticagent (368,369). To achieve .90% eradication rates, regi-mens with more than one antibiotic are necessary (163).

Amoxicillin together with clarithromycin and a protonpump inhibitor is one of the preferred regimens to eradicateH. pylori in both adults and children (163). Therapeutic tri-als in children with this regimen yield success rates between58–92% (Table 12). The combination of omeprazole, met-ronidazole, and clarithromycin has demonstrated successrates approximating 90% (357,360). However, the use ofclarithromycin induces the appearance of resistant strains(370), and cost precludes its use in developing countries.Other bismuth-based regimens in combination with metro-nidazole and amoxicillin result in eradication rates between63 and 95% (371). The cost of bismuth-based regimens ismoderate, but side effects are more frequent, especiallywhen given in combination with metronidazole (371).

In our experience, antibiotics in combination with ome-prazole or other antisecretory agents appear to improvecompliance, perhaps due to more rapid resolution of symp-toms. In adults, other proton pump inhibitors, such as panto-prazole, lansoprazole, and rabeprazole in combination withantibiotics have shown similar efficacy to omeprazole-based eradication regimens (372–374). Experience with

these new proton pump inhibitors in children is limited.However, in small case series the proton pump inhibitor–based regimens have not shown significant adverse effects(358–361). In adult trials, ranitidine bismuth citrate in asso-ciation with two antibiotics has been an effective optionwith efficacy rates of 90% (375).

We have tested different therapeutic regimens in H. py-lori-infected Mexican children with abdominal pain and insome with peptic ulcers (Table 13). In a study with 25 H.pylori-infected children, a 14-day course of metronidazole,amoxicillin, and bismuth subcitrate resulted in 72% eradica-tion (376). Of the children treated, 32% of the cohort devel-oped side effects such as diarrhea, nausea, and glossitis. To

Table 12. Therapeutic trials in children

Antibiotic Antiacid Time Efficacy Reference

Metronidazole Omeprazole 2 weeks 93.0% 356250 mg bid ,10 y 20 mg qd ,10y500 mg bid .10 y 20 mg bid .10y

Clarithromycin250 mg bid ,10 y500 mg bid .10 y

Metronidazole Omeprazole 1 week 87.5% 3577.5 mg/kg 10 mg ,20 kg

max 1.2 g/d 20 mg .20 kgClarithromycin

7.5 mg/kg max 250mg bid

Metronidazole Lanzoprazole 2 weeks 83.3% 35830 mg/kg/d 30 mg/d

Amoxicillin100 mg/kg/d

Metronidazole Lanzoprazole 2 weeks 63.6% 35830 mg/kg/d 30 mg/d

Spiramycin300,000 IU/kg/d

Amoxicillin Omeprazole 2 weeks 70.0% 35930 mg/kg/bid 0.6 mg/kg

Clarithromycin Omeprazole 2 weeks 92.0% 35915 mg/kg/bid 0.6 mg/kg

Bismuth subcitrate — 4 weeks 96.0% 360120 mg qid

Amoxicillin250/mg/qid

Metronidazole250 mg/qid

Bismuth subcitrate — 1 week 95.45% 361480 mg/1.73 m2/d

Metronidazole20 mg/kg/d

Clarithromycin7.5 mg/kg/d

Clarithromycin Omeprazole 2 weeks 77.7% 36215 mg/kg/bid 1 mg/kg bid

Amoxicillin50 mg/kg/bid

Clarithromycin Omeprazole 2 weeks 67.6% 36215 mg/kg/bid 0.5 mg/kg

Metronidazole20 mg/kg/bid


simplify the therapeutic regimen, we simultaneously testedthe combination of a 14-day course of omeprazole andamoxicillin. The dual therapeutic regimen of omeprazoleand amoxicillin achieved eradication in only 48% of chil-dren. A total of 4% of the study subjects developed side ef-fects (i.e., diarrhea, nausea, or glossitis) and compliancewith the drugs reached 94%. In both treatment groups, wefound a significant decrease of symptoms when eradicationwas achieved (353). To improve efficacy, a 7- and 14-daycourse of amoxicillin, clarithromycin, and omeprazole(OAC) was evaluated (250). Eradication rates were 57 and62% for the two treatment durations, respectively (Table13). A significant improvement of symptoms was observedin children who cleared the infection. We are currently test-ing higher doses of each drug, as indicated in Table 13, inan attempt to achieve greater eradication rates. Eradicationhas been achieved in 8 of the first 10 patients treated withhigher dosing regimens of the OAC triple therapy with nosignificant side effects. In conclusion, regimens used in H.pylori-infected children should include a proton pump in-hibitor in combination with at least two antibiotics, e.g.,clarithromycin and amoxicillin. We suggest initiation oferadication therapy with high-dose, proton pump inhibitor-based regimens for 14 days in children with documentednon-ulcerative H. pylori infection and abdominal pain inwhich symptom resolution has not been achieved with stan-dard antisecretory therapy.

Resistance to Antibiotics

The development of antibiotic resistance decreases the effi-cacy of eradication therapy. Among the antibiotics com-monly used to treat H. pylori, metronidazole appears to have

the highest rates of resistance (range 15–90%, depending onthe country evaluated). These rates are higher in developingcountries, where children often receive metronidazole totreat intestinal infections. In these countries, H. pylori resis-tance to metronidazole has been reported to be as high as80% (358–365). A number of published trials have foundthat resistance to metronidazole correlates with poor eradica-tion rates for H. pylori in adults (377). Raymond et al. (358)studied 23 H. pylori-infected children and reported that inmost cases with failure to eradicate the infection, H. pyloristrains were found to be resistant to metronidazole.

The use of clarithromycin induces the appearance of re-sistant strains and its clinical use is decreasing (377,378).After one course of clarithromycin, mutations leading to re-sistance may appear in about 20% of patients (377,378).Amoxicillin is effective, cheap, and well tolerated. Re-cently, cases of transitory resistance have been reported(379), but the meaning of these findings is still unclear.Amoxicillin continues to be one of the most commonly usedantibiotics in eradication regimens for H. pylori (379).

We studied susceptibility to antibiotics in 195 H. pyloristrains isolated of Mexican children and adults using theE-test. H. pylori resistance was 81% to metronidazole, 18%to clarithromycin, and 14% to amoxicillin (transitory, be-cause resistance disappears after subculturing or freezing).Of note is that 11% of the isolates were resistant to bothmetronidazole and clarithromycin (unpublished results).

Reinfection

Reinfection has been assessed in very few pediatric studies.Rowland et al. (380) studied a group of 45 children with amean of 21.3 months of follow-up, and observed a reinfec-

Table 13. Therapeutic trials in children seen at the Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Mexico City

Antibiotic Antiacid Time Patients Efficacy Reference

Amoxicillin Omeprazole 2 weeks 25 48% 37640 mg/kg/d 40 mg/1.7 m2

Amoxicillin — 2 weeks 25 72% 37640 mg/kg/d

Metronidazole30 mg/kg/d

Bismuth subcitrate260 mg 10 y or520 mg .10 y

Amoxicillin Omeprazole 1 week 22 57% 25040 mg/kg/d 40 mg/1.7 m2

Clarithromycin 2 weeks 22 62% 25015 mg/kg/d

Amoxicillin60 mg/kg/d

Omeprazole1.5 mg/kg/d

10 days 10 80% notpublished

max 2 g/d max 40 mg/dClarithromiycin

40 mg/kg/dmax 1.5 g/d


tion rate of 11.1%. In this study, children under 5 years ofage were at highest risk of reinfection. Kato et al. (359) inJapan found a reinfection rate of 2.4% per patient year. Wefollowed 30 children during 6 months after eradicationtreatment; only one had a reinfection (4.8%) (381).

Future Considerations

There is clearly a need to establish criteria for the use oferadication treatment in H. pylori-infected children. Multi-center, multinational pediatric studies should focus on theidentification of risk factors, which can then be used asprognostic indicators for the development of gastroduode-nal disease later in life. Only randomized, controlled, multi-center studies of this nature will be able to determinewhether H. pylori eradication should be directed at the in-fection or at the resolution of disease and/or at the symp-toms thereof. It is also important to understand whether H.pylori eradication would prevent the development of theatypical symptoms postulated to be associated with the in-fection, i.e., weight loss, malabsorption, diarrhea, and shortstature. Therapeutic regimens need to be simpler, afford-able, and to have minimal side effects for improving com-pliance in children. Additionally, due to the differences inprevalence of resistance among countries, resistance ratesshould be addressed locally for further definition of appro-priate treatment regimens according to the epidemiology ofthe infection in a specific population.

AcknowledgmentsJT is supported by grants received from the Coordinación de In-vestigación Médica-IMSS and from CONACYT (Mexico), grant #28040M. JA is funded by a Senior Clinical Fellowship from theMedical Research Council (UK), while BG is supported by a grantreceived from the National Institutes of Health (NIH), Bethesda,MD, USA (NIDDK, R01–DK53708). PH is supported in part bygrants received from NIH (NIDDK, RO1, DK54495-01) and agrant (FONDECYT #1000734) from the Chilean Government.

References1. Goodman KJ, Correa P. The transmission of Helicobacter pylori. A

critical review of the evidence. Int J Epidemiol 1995;24:875.2. Redlinger T, O’Rourke K, Goodman KJ. Age distribution of Helico-

bacter pylori seroprevalence among young children in a UnitedStates/Mexico border community: evidence for transitory infection.Am J Epidemiol 1999;150:225.

3. Pounder RE, Ng D. The prevalence of Helicobacter pylori infectionin different countries. Aliment Pharmacol Ther 1995;9(Suppl 2):33.

4. Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, Feldman RA.The cohort effect and Helicobacter pylori. J Infect Dis 1993;168:219.

5. Cullen DJE, Collins BJ, Christiansen KJ, Epis J, Warren JR, Sur-veyor I, Cullen KJ. When is Helicobacter pylori infection acquired?Gut 1993;34:1681.

6. Kosunen TU, Aromaa A, Knekt P, Salomaa A, Rautelin H, Lohi P,Heinonen OP. Helicobacter pylori antibodies in 1973 and 1994 in theadult population of Vammala, Finland. Epidemiol Infect 1997;119:29.

7. Roosendaal R, Kuipers EJ, Buitenwerf J, van Uffelen C, MeuwissenSG, van Kamp GJV-GCM. Helicobacter pylori and the birth cohorteffect: evidence of a continuous decrease of infection rates in child-hood. Am J Gastroenterol 1997;92:1480.

8. Rauws EAJ, Tytgat GNJ. Natural history of C. pylori infection. In:Blaser MJ, ed. Campylobacter pylori in gastritis and peptic ulcer dis-ease. New York: Igaku-Shoin;1989. p. 187.

9. Morris AJ, Ali MR, Nicholson GI, Pérez-Pérez GI, Blaser MJ. Long-term follow-up of voluntary ingestion of Helicobacter pylori. Ann In-tern Med 1991;114:662.

10. Kosunen TU. Antibody titres in Helicobacter pylori infection: implica-tions in the follow-up of antimicrobial therapy. Ann Med 1995;27:605.

11. Fradkin A, Yahav Y, Diver-Haber A, Weisselberg B, Jonas A. Thevalue of anti-Helicobacter pylori IgG antibodies in establishing erad-ication of infection in children. Isr J Med Sci 1997;33:87.

12. Cutler AF, Prasad VM. Long-term follow-up of Helicobacter pyloriserology after successful eradication. Am J Gastroenterol 1996;91:85.

13. De Giacomo C, Lisato L, Negrini R, Licardi G, Maggiore G. Serumimmune response to Helicobacter pylori in children: epidemiologicand clinical applications. J Pediatr 1991;119:205.

14. Blecker U, Lanciers S, Keppens E, Vandenplas Y. Evolution of Heli-cobacter pylori positivity in infants born from positive mothers. J Pe-diatr Gastroenterol Nutr 1994;19:87.

15. Gold B, Khanna B, Huang LM, Lee CY, Banatvala N. Helicobacterpylori acquisition in infancy after decline of maternal passive immu-nity. Pediatr Res 1997;41:641.

16. Hazell SL. Mixed gastric infections and infection with other Helico-bacter species. In: Hunt RH, Tytgat GNJ, eds. Helicobacter pylori.Basic mechanisms to clinical cure. Dordrecht, The Netherlands: Klu-wer Academic Publishers;1996; p. 1.

17. Bodhidatta L, Hoge CW, Churnratanakul S, Nirdoy W, SampathanukulP, Tungtaem C, Raktham S, Smith CD, Echeverría P. Diagnosis ofHelicobacter pylori infection in a developing country: comparison oftwo ELISAs and a seroprevalence study. J Infect Dis 1993;168:1549.

18. Khanna B, Cutler A, Israel NR, Perry M, Lastovica A, Fields PI,Gold BD. Use caution with serologic testing for Helicobacter pyloriinfection in children. J Infect Dis 1998;178:460.

19. Thomas JE, Dale A, Harding M, Coward WA, Cole TJ, Weaver LT.Helicobacter pylori colonization in early life. Pediatr Res 1999;45:218.

20. Graham DY, Klein PD. What you should know about the methods,problems, interpretations, and uses of urea breath tests. Am J Gastro-enterol 1991;86:1118.

21. Vandenplas Y, Blecker U, Devreker T, Keppens E, Nijs J, CadranelS, Pipeleers-Marichal M, Goossens A, Lauwers S. Contribution ofthe 13C-urea breath test to the detection of Helicobacter pylori gastri-tis in children. Pediatrics 1992;90:608.

22. Rowland M, Lambert I, Gormally S, Daly LE, Thomas JE, Hether-ington C, Durnin M, Drumm B. Carbon 13-labeled urea breath testfor the diagnosis of Helicobacter pylori infection in children. J Pedi-atr 1997;131:815.

23. Cadranel S, Corvaglia L, Bontems P, Deprez C, Glupczynski Y, VanRiet H, Keppens E. Detection of Helicobacter pylori infection in chil-dren with a standardized and simplified 13 C-urea breath test. J Pedi-atr Gastroenterol Nutr 1998;27:276.

24. Kalach N, Briet F, Raymond J, Benhamou P, Barbet P, Bergeret M,Senouci L, Maurel M, Flourié B, Dupont C. The 13carbon ureabreath test for the non-invasive detection of Helicobacter pylori inchildren: comparison with culture and determination of minimumanalysis requirements. J Pediatr Gastroenterol Nutr 1998;26:291.

25. Delvin EE, Brazier JL, Deslandres C, Alvarez F, Russo P, Seidmen E.Accuracy of the [13C]-urea breath test in diagnosing Helicobacter pylorigastritis in pediatric patients. J Pediatr Gastroenterol Nutr 1999;28:59.

26. Thomas JE, Dale A, Harding M, Coward WA, Cole TJ, Sullivan PB,Campbell DI, Warren BF, Weaver LT. Interpreting the 13C-ureabreath test among a large population of young children from a devel-oping country. Pediatr Res 1999;46:147.


27. Kindermann A, Demmelmair H, Koletzko B, Krauss-Etschmann S,Wiebecke B, Koletzko S. Influence of age on 13 C-urea breath testresults in children. J Pediatr Gastroenterol Nutr 2000;30:85.

28. Vaira D, Malfertheiner P, Megraud F, Axon A, Delterne M, HirschlAM, Gasbarrini G, O’Morain C, Pajares-García JM, Quina M, TytgatGNJ. Diagnosis of Helicobacter pylori infection with a new non-in-vasive antigen-based assay. Lancet 1999;354:30.

29. Oderda G, Rapa A, Ronchi B, Lerro P, Pastore M, Staiano A, de An-gelis GL, Strisciuglio P. Detection of Helicobacter pylori in stoolspecimens by non-invasive antigen enzyme immunoassay in chil-dren: multicenter Italian study. BMJ 2000;320(7231):347.

30. Parsonnet J. The incidence of Helicobacter pylori infection. AlimentPharmacol Ther 1995;9(Suppl 2):45.

31. Morris A, Nicholson G. Experimental and accidental C. pylori infec-tion of humans. In: Blaser MJ, ed. Campylobacter pylori in gastritisand peptic ulcer disease. New York: Igaku-Shoin;1989. p. 61.

32. Mégraud F, Brassens-Rabbé MP, Denis F, Belbouri A, Hoa DQ. Se-roepidemiology of Campylobacter pylori infection in various popula-tions. J Clin Microbiol 1989;27:1870.

33. Malaty HM, Paykov V, Bykova O, Ross A, Graham DP, AnnegersJF, Graham DY. Helicobacter pylori and socioeconomic factors inRussia. Helicobacter 1996;1:82.

34. Vorobjova T, Grünberg H, Oona M, Maaroos HI, Nilsson I, WadströmT, Covacci A, Uibo R. Seropositivity to Helicobacter pylori and CagAprotein in schoolchildren of different ages living in urban and rural areasin southern Estonia. Eur J Gastroenterol Hepatol 2000;12:97.

35. Klein PD, Gilman RH, León-Barua R, Díaz F, Smith EO, GrahamDY. The epidemiology of Helicobacter pylori in Peruvian childrenbetween 6 and 30 months of age. Am J Gastroenterol 1994;89:2196.

36. Staat MA, Kruszon-Morán D, McQuillan M, Kaslow RA. A popula-tion-based serologic survey of Helicobacter pylori infection in childrenand adolescents in the United States. J Infect Dis 1996;174:1120.

37. Goodman KJ, Correa P, Tengana Aux HJ, Ramírez H, DeLany JP,Guerrero Pepinosa O, López Quiñones M, Collazos Parra T. Helico-bacter pylori infection in the Colombian Andes: a population-basedstudy of transmission pathways. Am J Epidemiol 1996;144:290.

38. Fraser AG, Scragg R, Metcalf P, McCullough S, Yeates NJ. Preva-lence of Helicobacter pylori infection in different ethnic groups inNew Zealand children and adults. Aust N Z J Med 1996;26:646.

39. Sathar MA, Gouws E, Simjee AE, Mayat AM. Seroepidemiologicalstudy of Helicobacter pylori infection in South African children.Trans R Soc Trop Med Hyg 1997;91:393.

40. Rothenbacher D, Bode G, Berg G, Gommel R, Gonser T, Adler G,Brenner H. Prevalence and determinants of Helicobacter pylori infec-tion in preschool children: a population-based study from Germany.Int J Epidemiol 1998;27:135.

41. Fawcett JP, Shaw JP, Brooke M, Walker A, Barbezat GO. Seropreva-lence of Helicobacter pylori in a longitudinal study of NewZealanders at ages 11 and 21. Aust N Z J Med 1998;28:585.

42. Ma J, You W, Gail MH, Zhang L, Blot WJ, Chang Y, Jiang J, Liu W,Hu Y, Brown LM, Xu G, Fraumeni JF. Helicobacter pylori infectionand mode of transmission in a population at high risk of stomach can-cer. Int J Epidemiol 1998;27:570.

43. Sarker SA, Mahalanabis D, Hildebrand P, Rahaman MM, Bardhan PK,Fuchs G, Beglinger C, Gyr K. Helicobacter pylori: prevalence, trans-mission, and serum pepsinogen II concentrations in children of a poorperiurban community in Bangladesh. Clin Infect Dis 1997;25:990.

44. Ashorn M, Miettinen A, Ruuska T, Laippala P, Maki M. Seroepide-miological study of Helicobacter pylori infection in infancy. ArchDis Child Fetal Neonatal Ed 1996;74(2):F141.

45. Granstrom M, Tindberg Y, Blennow M. Seroepidemiology of Helico-bacter pylori infection in a cohort of children monitored from 6months to 11 years of age. J Clin Microbiol 1997;35:468.

46. Rothenbacher D, Bode G, Berg G, Knayer U, Gosner T, Adler G, Bren-ner H. Helicobacter pylori among preschool children and their parents:evidence of parent-child transmission. J Infect Dis 1999;179:398.

47. Dore SP, Krupadas S, Borgonha S, Kurpad AV. The 13C urea breathtest to assess Helicobacter pylori infection in school children. NatlMed J India 1997;10:57.

48. Perri F, Pastore M, Leandro G, Clemente R, Ghoos Y, Peeters M,Annese V, Quitadamo M, Latiano A, Rutgeerts P, Andriulli A. Heli-cobacter pylori infection and growth delay in older children. ArchDis Child 1997;77:46.

49. Klein PD, Graham DY, Gaillour A, Opekun AR, Smith EO. Watersource as a risk factor for Helicobacter pylori infection in Peruvianchildren. Lancet 1991;337:1503.

50. Boltshauser S, Herzog D. Prävalenz der asymptomatishcen Helico-bacter-Infektion bei den 5-7jährigen Kindern des Kantons St. GallenSchweiz Med Wochenschr 1999;129:579.

51. Malaty HM, Graham DY, Klein PD, Evans DG, Adam E, Evans DJ.Transmission of Helicobacter pylori infection. Studies in families ofhealthy individuals. Scand J Gastroenterol 1991;26:927.

52. Clemens J, Albert MJ, Rao M, Huda S, Qadri F, Van Loon RPL, Bo-drul P, Naficy A, Banik A. Sociodemographic, hygienic and nutri-tional correlates of Helicobacter pylori infection of young Bang-ladeshi children. Pediatr Infect Dis J 1996;15:1113.

53. Souto FJ, Fontes CJ, Rocha GA, de Oliveira AM, Mendes EN,Queiroz DM. Prevalence of Helicobacter pylori infection in a ruralarea of the State of Mato Grosso, Brazil. Mem Inst Oswaldo Cruz1998;93:171.

54. Hopkins RJ, Vial PA, Ferreccio C, Ovalle J, Prado P, Sotomayor V,Russell RG, Wasserman SS, Morris JG. Seroprevalence of Helico-bacter pylori in Chile: vegetables may serve as one route of transmis-sion. J Infect Dis 1993;168:222.

55. Mitchell HM, Li YY, Hu PJ, Liu Q, Chen M, Du GG, Wang ZJ, LeeA, Hazell SL. Epidemiology of Helicobacter pylori in southernChina: identification of early childhood as the critical period for ac-quisition. J Infect Dis 1992;166:149.

56. Sierra R, Muñoz N, Peña AS, Biemond I, Van Duijn W, LamersCBHW, Teuchmann S, Hernández S, Correa P. Antibodies to Helico-bacter pylori and pepsinogen levels in children from Costa Rica:comparison of two areas with different risks for stomach cancer. Can-cer Epidemiol Biomarkers Prev 1992;1:449.

57. O’Donohoe JM, Sullivan PB, Scott R, Rogers T, Brueton MJ, BarltropD. Recurrent abdominal pain and Helicobacter pylori in a community-based sample of London children. Acta Paediatr 1996;85:961.

58. Ashorn M, Maki M, Uhari M, Akerblom HK, Viikari J, Miettinen A.Helicobacter pylori infection in Finnish children and adolescents.Scand J Gastroenterol 1995;30:876.

59. Sullivan PB, Thomas JE, Wight DGD, Neale G, Eastham EJ, Corrah T,Lloyd-Evans N, Greenwood BM. Helicobacter pylori in Gambian childrenwith chronic diarrhoea and malnutrition. Arch Dis Child 1990;65:189.

60. Quiñonez JM, Chew F, Torres O, Bégué RE. Nutritional status ofHelicobacter pylori-infected children in Guatemala as compared withuninfected peers. Am J Trop Med Hyg 1999;61:395.

61. Dominici P, Belentani S, Di Biase AR, Saccoccio G, Le Rose A, Ma-sutti F, Viola L, Balli F, Tiribelli C, Grilli R, Fusillo M, Grossi E. Fa-milial clustering of Helicobacter pylori infection: population basedstudy. BMJ 1999;319:537.

62. Fujisawa T, Kumagai T, Akamatsu T, Kiyosawa K, Matsunaga Y.Changes in seroepidemiological pattern of Helicobacter pylori andhepatitis A virus over the last 20 years in Japan. Am J Gastroenterol1999;94:2094.

63. Kumagai T, Malaty HM, Graham DY, Hosogaya S, Misawa K, Furi-hata K, Ota H, Sei C, Tanaka E, Akamatsu T, Shimuzu T, KiyosawaK, Katsuyama T. Acquisition versus loss of Helicobacter pylori in-fection in Japan: results from an 8-year birth cohort study. J InfectDis 1998;178:717.

64. Torres J, Leal-Herrera Y, Pérez-Pérez G, Gómez A, Camorlinga-Ponce M, Cedillo-Rivera R, Tapia-Conyer R, Muñoz O. A commu-nity-based seroepidemiologic study of Helicobacter pylori infectionin Mexico. J Infect Dis 1998;178:1089.


65. Kawasaki M, Kawasaki T, Ogaki T, Itoh K, Kobayashi S, YoshimizuY, Aoyaki K, Iwakawa A, Takahashi S, Sharma S, Acharya GP. Se-roprevalence of Helicobacter pylori infection in Nepal: low preva-lence in an isolated rural village. Eur J Gastroenterol Hepatol1998;10:47.

66. Holcombe C, Omotara BA, Eldridge J, Jones DM. H. pylori, the mostcommon bacterial infection in Africa: a random serological study.Am J Gastroenterol 1992;87:28.

67. Murray LJ, McCrum EE, Evans AE, Bamford KB. Epidemiology ofHelicobacter pylori infection among 4742 randomly selected subjectsfrom Northern Ireland. Int J Epidemiol 1997;26:880.

68. Patel P, Mendall MA, Khulusi S, Northfield TC, Strachan DP. Heli-cobacter pylori infection in childhood: risk factors and effect ongrowth. BMJ 1994;309:1119.

69. Teh BH, Lin JT, Pan WH, Lin SH, Wang LY, Lee TK, Chen CJ. Se-roprevalence and associated risk factors of Helicobacter pylori infec-tion in Taiwan. Anticancer Res 1994;14(3B):1389.

70. Tsai CJ, Chang MH. Seroepidemiogic study of Helicobacter pyloriinfection in children in Taipei City. Acta Paed Sin 1995;36:254.

71. Malaty HM, Graham DY, Wattigney WA, Srinivasan SR, Osato M,Berenson GS. Natural history of Helicobacter pylori infection inchildhood: 12-year follow-up cohort study in a biracial community.Clin Infect Dis 1999;28:279.

72. Russell RG, Wasserman SS, O’Donnoghue JM, Taylor DN, BoslegoJ, García-Moreno J, Hopkins RJ, Detolla LJ, Morris JG. Serologic re-sponse to Helicobacter pylori among children and teenagers in north-ern Chile. Am J Trop Med Hyg 1993;49:189.

73. Lindkvist P, Asrat D, Nilsson I, Tsega E, Olsson G, Wretlind B,Giesecke J. Age at acquisition of Helicobacter pylori infection: com-parison of a high and a low prevalence country. Scand J Infect Dis1996;28:181.

74. Pateraki E, Mentis A, Spiliadis C, Sophianos D, Stergiatou I, Skanda-lis N, Weir DM. Seroepidemiology of Helicobacter pylori infectionin Greece. Fed Eur Microbiol Soc Microbiol Immunol 1990;64:129.

75. Malaty HM, Kim JG, Kim SD, Graham DY. Prevalence of Helico-bacter pylori infection in Korean children: inverse relation to socio-economic status despite a uniformly high prevalence in adults. Am JEpidemiol 1996;143:257.

76. Us D, Hasçelik G. Seroprevalence of Helicobacter pylori infection inan asymptomatic Turkish population. J Infect 1998;37:148.

77. Hardikar W, Grimwood K. Prevalence of Helicobacter pylori infec-tion in asymptomatic children. J Pediatr Child Health 1995;31:537.

78. Edwards CN, Douglin CP, Prussia PR, Garriques SA, Levett PN. Ep-idemiology of Helicobacter pylori infection in Barbados. West IndianMed J 1997;46:3

79. Lanciers S, Hauser B, Vandenplas Y, Blecker U. The prevalence ofHelicobacter pylori positivity in asymptomatic children of differentethnic backgrounds living in the same country. Ethn Health1996;1:169.

80. Oliveira AMR, Queiroz DMM, Rocha GA, Mendes EN. Seropreva-lence of Helicobacter pylori infection in children of low socioeconomiclevel in Belo Horizonte, Brazil. Am J Gastroenterol 1994;89:2201.

81. Hornemann F, Nilius M, Malfertheiner P, Bartmann P. Seropreva-lence of Helicobacter pylori in German infants and children. Helico-bacter 1997;2:176.

82. Bergenzaun P, Kristinsson KG, Thjodleifsson B, Sigvaldadottir E, Möl-stad S, Held M, Wadström T. Seroprevalence of Helicobacter pylori inSouth Sweden and Iceland. Scand J Gastroenterol 1996;31:1157.

83. Graham DY, Adam E, Reddy GT, Agarwal JP, Agarwal R, Evans DJ,Malaty HM, Evans DG. Seroepidemiology of Helicobacter pylori in-fection in India. Dig Dis Sci 1991;36:1084.

84. Luzza F, Imeneo M, Maletta M, Paluccio G, Giancotti A, Focà A,Pallone F. Seroepidemiology of Helicobacter pylori infection andhepatitis A in a rural area: evidence against a common mode of trans-mission. Gut 1997;41:164.

85. Asaka M, Kimura T, Kudo M, Takeda H, Mitani S, Miyazaki T, Kiki K,

Graham DY. Relationship of Helicobacter pylori to serum pepsinogens inan asymptomatic Japanese population. Gastroenterology 1992;102:760.

86. Matsukura N, Onda M, Tokunaga A, Teramoto T, Fujita I, Okuda T,Yamashita K. Detection of serum IgG antibody against Helicobacterpylori from childhood in a Japanese population. J Gastroenterol1994;29:403.

87. Replogle ML, Kasumi W, Ishikawa KB, Yang SF, Juji T, Miki K, Ka-bat C, Pasonnet J. Increased risk of Helicobacter pylori associated withbirth in wartime and post-war Japan. Int J Epidemiol 1996;25:210.

88. Boey CC, Goh KL, Lee WS, Parasakthi N. Seroprevalence of Helico-bacter pylori infection in Malaysian children: evidence for ethnic dif-ferences in childhood. J Paediatr Child Health 1999;35:151.

89. Kehrt R, Becker M, Brösicke H, Krüger N, Helge H. Prevalence ofHelicobacter pylori infection in Nicaraguan children with persistentdiarrhea, diagnosed by the 13C-urea breath test. J Pediatr Gastroen-terol Nutr 1997;25:84.

90. Czkwianianc E, B•k-Romaniszyn L, Ma ecka-Panas E, Suski S,Woch G. Prevalence of Helicobacter pylori in children dependentlyon age and living conditions. J Physiol Pharmacol 1996;47:203.

91. Quina MG. Helicobacter pylori: the Portuguese scene. Eur J CancerPrev 1994;3(Suppl 2):65.

92. Rodrigo Sáez L, Riestra Menéndez S, Fernández Velázquez MR,García Alonso S, Lauret Braña ME. Estudio epidemiológico de laprevalencia de la infección por Helicobacter pylori en población gen-eral en Asturias. Rev Esp Enferm Dig 1997;89:511.

93. Cilla G, Pérez-Trallero E, García-Bengoechea M, Marimún J, ArenasJI. Helicobacter pylori infection: a seroepidemiological study inGipuzkoa, Basque Country, Spain. Eur J Epidemiol 1997;13:945.

94. Pelser HH, Househam KC, Joubert G, van der Linde G, Kraaij P,Meinardi M, McLeod A, Anthony M. Prevalence of Helicobacter py-lori antibodies in children in Bloemfontein, South Africa. J PediatrGastroenterol Nutr 1997;24:135.

95. Fiedorek SC, Malaty HM, Evans DL, Pumphrey CL, Casteel HB,Evans DJ, Graham DY. Factors influencing the epidemiology ofHelicobacter pylori infection in children. Pediatrics 1991;88:578.

96. Elitsur Y, Short JP, Neace C. Prevalence of Helicobacter pylori in-fection in children from urban and rural West Virginia. Dig Dis Sci1998;43:773.

97. Perri F, Pastore M, Clemente R, Festa V, Quitadamo M, Niro G,Conoscitore P, Rutgeerts P, Andriulli A. Helicobacter pylori infec-tion may undergo spontaneous eradication in children: a 2-year fol-low-up study. J Pediatr Gastroenterol Nutr 1998;27:181.

98. Isenbarger DW, Bodhidatta L, Hoge CW, Nirdnoy W, Pitarangsi C,Umpawasiri U, Echeverría P. Prospective study of the incidence ofdiarrheal disease and Helicobacter pylori in an orphanage in Thai-land. Am J Trop Med Hyg 1998;59:796.

99. Blecker U, Hauser B, Lanciers S, Peeters S, Suys B, Vandenplas Y.The prevalence of Helicobacter pylori-positive serology in asymp-tomatic children. J Pediatr Gastroenterol Nutr 1993;6:252.

100. Brenner H, Rothenbacher D, Bode G, Adler G. Parental history of gas-tric or duodenal ulcer and prevalence of Helicobacter pylori infectionin preschool children: population based study. BMJ 1998;316:665.

101. Mitchell HM, Bohane T, Hawkes RA, Lee A. Helicobacter pylori in-fection within families. Zentralbl Bakteriol 1993;280:128.

102. Goodman KJ, Correa P. Helicobacter pylori transmission among sib-lings. Lancet 2000;355:358.

103. Vincent P, Gottrand F, Pernes P, Husson MO, Lecomte-Houcke M,Turck D, Leclerc H. High prevalence of Helicobacter pylori infectionin cohabitating children. Epidemiology of a cluster, with special em-phasis on molecular typing. Gut 1994;35:313.

104. Lewindon PJ, Lau D, Chan A, Tse P, Sullivan PB. Helicobacter py-lori in an institution for disabled children in Hong Kong. Dev MedChild Neurol 1997;39:682.

105. Kimura A, Matsubasa T, Kinoshita H, Kuriya N, Yamashita Y, FujisawaT, Terakura H, Shinohara M. Helicobacter pylori seropositivity in pa-tients with severe neurologic impairment. Brain Dev 1999;21:113.

c


106. Goodman KJ, Correa P, Tengana Aux HJ, DeLany JP, Collazos T.Nutritional factors and Helicobacter pylori infection in Colombianchildren. J Pediatr Gastroenterol Nutr 1997;25:507.

107. Brenner H, Rothenbacher D, Bode G, Gommel R, Berg G, Adler G.Parental smoking and infection with Helicobacter pylori among pre-school children in Southern Germany. Epidemiology 1998;9:545.

108. Rothenbacher D, Bode G, Adler G, Brenner H. History of antibiotictreatment and prevalence of H. pylori infection among children: re-sults of a population-based study. J Clin Epidemiol 1998;51:267.

109. Bode G, Rothenbacher D, Brenner H, Adler G. Pets are not a risk factorfor Helicobacter pylori infection in young children: results of a popula-tion-based study in southern Germany. Pediatr Infect Dis J 1998;17:909.

110. Veldhuyzen van Zanten S, Sherman P. A systematic overview ofHelicobacter pylori infection as the cause of gastritis, duodenal ulcer,gastric cancer, and non-ulcer dyspepsia: applying eight diagnosticcriteria in establishing causation. Can Med Assoc J 1994;150:177.

111. NIH Consensus Conference. Helicobacter pylori in peptic ulcer dis-ease. JAMA 1994;272:65.

112. Sherman P. Peptic ulcer disease in children. Diagnosis, treatment,and the implication of Helicobacter pylori. Gastroenterol Clin NorthAm 1994;23:707.

113. McArthur C, Saunders N, Feldman W. Helicobacter pylori, gas-troduodenal disease, and recurrent abdominal pain in children. JAMA1995;273:729.

114. Reifen R, Rasooly I, Drumm B, Murphy K, Sherman P. Helicobacterpylori infection in children. Is there any specific symptomatology?Dig Dis Sci 1994;39:1488.

115. Gormally SM, Prakash N, Durnin MT, Daly LE, Clyne M, KierceBM, Drumm B. Association of symptoms with Helicobacter pyloriinfection in children. J Pediatr 1995;126:753.

116. Blecker U, Hauser B, Lanciers S, Keynolen K, Vandenpals Y. Symp-tomatology of Helicobacter pylori infection in children. Acta Paedi-atr 1996;85:1156.

117. Glassman MS, Dallal S, Berezin SH, Bostwick HE, Newman LJ,Pérez-Pérez GI, Blaser M. Helicobacter pylori-related gastroduode-nal disease in children: diagnostic utility of enzyme-linked immu-nosorbent assay. Dig Dis Sci 1990;35:993.

118. Glassman MS, Schwartz SM, Medow MS, Beneck D, Halata M, Be-rezin S, Newman L. Campylobacter pylori-related gastrointestinaldisease in children. Dig Dis Sci 1989;34:1501.

119. Deckelbaum RJ, Roy CC, Lussier-Lazaroff J, Morin CL. Peptic ulcerdisease: a clinical study in 73 children. Can Med Assoc J 1974;111:225.

120. Drumm B, Rhoads JM, Stringer DA, Sherman P, Ellis L, Durie P.Peptic ulcer disease in children: etiology, clinical findings, and clini-cal course. Pediatrics 1988;82:410.

121. Murphy MS, Eastham EJ, Jiménez M, Nelson R, Jackson RH. Duode-nal ulceration: review of 110 cases. Arch Dis Child 1987;62:554.

122. Puri P, Boyd E, Blake N, Guiney EJ. Duodenal ulcer in childhood: acontinuing disease in adult life. J Pediatr Surg 1978;13:525.

123. Chiang BL, Chang MH, Lin MI, Hsu JY, Wang CY, Wang TH.Chronic duodenal ulcer in children: clinical observation and responseto treatment. J Pediatr Gastroenterol Nutr 1989;8:161.

124. Tam PK, Saing H. The use of H2-receptor antagonist in the treatment ofpeptic ulcer disease in children. J Pediatr Gastroenterol Nutr 1989;8:41.

125. Oderda G, Farina L, Ansaldi N. Peptic ulcer in children: 5 years fol-low-up after ranitidine therapy. Pediatr Res 1988;24:417.

126. Bourke BG, Sherman PM, Drumm B. Peptic ulcer disease: what isthe role for Helicobacter pylori? Semin Gastrointest Dis 1994;5:24.

127. Gryboski J. Peptic ulcer disease in children. Pediatr Rev 1990;1:15.128. International Agency for Research on Cancer. Schistosomes, liver

flukes and Helicobacter pylori. Evaluation of carcinogenic risks tohumans. IARC Monogr Eval Carcinog Risks Hum 1994;177.

129. The EUROGAST Study Group: an international association betweenHelicobacter pylori infection and gastric cancer. Lancet 1993;341:1359.

130. Harris P, Guiraldes E. Epidemiology of gastric cancer and Helico-bacter pylori in Chile. Rev Chil Pediatr 1996;67:87.

131. Correa P. Helicobacter pylori and gastric cancer: state of the art. Can-cer Epidemiol Biomarkers Prev 1996;5:477.

132. Blecker U, McKeithan T, Hart J, Kirschner B. Resolution of Helico-bacter pylori-associated gastric lymphoproliferative disease in achild. Gastroenterology 1995;109:973.

133. Parsonnet J, Hansen S, Rodríguez L, Gelb A, Warnke R, Jellum E,Oretreich N, Vogelman J, Friedman G. Helicobacter pylori infectionand gastric lymphoma. N Engl J Med 1994;330:1267.

134. Ashorn P, Lahde PL, Ruuska T, Makipernaa A. Gastric lymphoma inan 11-year-old boy: a case report. Med Pediatr Oncol 1994;22:66.

135. Horstmann M, Erttmann R, Winkler K. Relapse of MALT lymphomaassociated with Helicobacter pylori after antibiotic treatment. Lancet1994;343:1098.

136. Sorrentino D, Ferraccioli GF, DeVita S, Avellini C, Beltrami CA, La-bombarda A, Bernardis V, De Biase F, Trevisi A, Pivetta B, BoiocchiM, Bartoli E. B-cell clonality and infection with Helicobacter pylori:implications for development of gastric lymphoma. Gut 1996;38:837.

137. Apley J, Naish N. Recurrent abdominal pain: a field survey of 1000school children. Arch Dis Child 1958;33:165.

138. Farrell K. Dr. Apley meets Helicobacter pylori. J Pediatr Gastroen-terol Nutr 1993;16:118.

139. Hardikar W, Feekery C, Smith A, Oberklaid F, Grimwood K. Helico-bacter pylori and recurrent abdominal pain in children. J Pediatr Gas-troenterol Nutr 1996;22:148.

140. Gremse D, Sacks A. Symptoms of gastritis due to H. pylori in chil-dren. South Med J 1996;89:278.

141. Dill S, Payne-James J, Misiewicz J, Grimble GK, McSwiggan D,Pathak K, Wood AJ, Scrimgeour CM, Rennie MJ. Evaluation of 13C-urea breath test in the detection of Helicobacter pylori and in moni-toring the effect of tripotassium dicitratobismuthate in non-ulcer dys-pepsia. Gut 1990;31:1237.

142. Dooley CP, Cohen H. The clinical significance of Campylobacter py-lori. Ann Intern Med 1988;108:70.

143. Fiedorek SC, Casteel HB, Pumphrey CL, Evans DJ, Evans DG, KleinPD, Graham DY. The role of Helicobacter pylori in recurrent, func-tional abdominal pain in children. Am J Gastroenterol 1992;87:347.

144. Van der Meer S, Forget PP, Loffeld RJ, Stobberingh E, Kuijten RH,Arends JW. The prevalence of Helicobacter pylori serum antibodies inchildren with recurrent abdominal pain. Eur J Pediatr 1992;151:799.

145. Mavromichalis I, Zaramboukas T, Richman P, Slavin G. Recurrentabdominal pain of gastrointestinal origin. Eur J Pediatr 1992;151:560.

146. Camorlinga-Ponce M, Torres J, Pérez-Pérez G, Leal-Herrera Y,González-Ortiz B, Madrazo de la Garza A, Gómez A, Muñoz O. Val-idation of a serologic test for the diagnosis of Helicobacter pylori in-fection and the immune response to urease and CagA in children. AmJ Gastroenterol 1998;93:1264.

147. Talley NJ. Helicobacter pylori and non-ulcer dyspepsia. Scand J Gas-troenterol Suppl 1996;220:19.

148. Talley NJ. A critique of therapeutic trials in Helicobacter pylori-pos-itive functional dyspepsia. Gastroenterology 1994;106:1174.

149. Talley NJ, Vakil N, Ballard D, Fennerty MB. Absence of benefit oferadicating Helicobacter pylori in patients with non-ulcer dyspepsia.N Engl J Med 1999;341:1106.

150. Rabeneck L, Graham DY. Helicobacter pylori: when to test, when totreat. Ann Intern Med 1997;126:315.

151. Gormally S, Drumm B. Helicobacter pylori and gastrointestinalsymptoms. Arch Dis Child 1994;70:165.

152. McCarthy C, Patchett S, Collins RM, Beattie S, Keone C, O’MorainC. Long term prospective study of Helicobacter pylori in non-ulcerdyspepsia. Dig Dis Sci 1995;40:114.

153. Van Zanten S, Sherman P. Indications for treatment of Helicobacter py-lori infection: a systematic overview. Can Med Assoc J 1994;150:189.

154. Graham DY, Yamaoka Y. H. pylori and cagA relationships with gas-tric cancer, duodenal ulcer, and reflux esophagitis and its complica-tions. Helicobacter 1998;3:145.

155. Richter J, Falk G, Vaezi M. Helicobacter pylori and gastroesophageal


reflux disease: the bug may not be all bad. Am J Gastroenterol1998;93:1800.

156. Henihan RD, Stuart RD, Nolan N, Path FR, Gorey TF, Hennessy TP,O’Morain CA. Barrett’s esophagus and the presence of Helicobacterpylori. Am J Gastroenterol 1998;93:542.

157. Vicari J, Falk G, Richter J. Helicobacter pylori and acid peptic disordersof the esophagus: is it conceivable? Am J Gastroenterol 1997;92:1097.

158. Labenz J, Blum L, Bayerdorffer E, Meining A, Stolte M, Borsch G.Curing Helicobacter pylori in patients with duodenal ulcer may pro-voke reflux esophagitis. Gastroenterology 1997;112:1442.

159. Raymond J, Bergert M, Benhamou H, Mensah K, Dupont C. A 2-yearstudy of Helicobacter pylori in children. J Clin Microbiol 1994;32:461.

160. McColl K. What remaining questions regarding Helicobacter pyloriand associated diseases should be addressed by future research? Gas-troenterology 1997;113:S158.

161. Gold B, Robie-Suh K, Sherman P. Pediatric issues workshop sum-mary (meeting report). Helicobacter 1998;3:305.

162. Drumm B, Koletzko S, Oderda G. Helicobacter pylori infection inchildren: a consensus statement. Medical Position Paper: report of theEuropean Paediatric Task Force on Helicobacter pylori in a Consen-sus Conference, Budapest, Hungary, September 1998. J Pediatr Gas-troenterol Nutr 2000;30:207.

163. Sherman P, Hassall E, Hunt RH, Fallone CA, Veldhuyzen van ZantenS, Thomson ABR. Canadian Helicobacter Study Group ConsensusConference on the approach to Helicobacter pylori infection in chil-dren and adolescents. Can J Gastroenterol 1999;13:553.

164. Gold BD. Pediatric Helicobacter pylori infection: clinical manifestations,diagnosis, and therapy. Curr Top Microbiol Immunol 1999; 241:71.

165. Sonnenberg A, Schwartz JS, Cutler AF, Vakil N, Bloom BS. Costsavings in duodenal ulcer therapy through Helicobacter pylori eradi-cation compared with conventional therapies: results of a random-ized, double-blind, multicenter trial. Gastrointestinal Utilization TrialStudy Group. Arch Intern Med 1998;158:852.

166. Sonnenberg A, Everhart JE. The prevalence of self-reported pepticulcer in the United States. Am J Public Health 1996;86:200.

167. Hirschowitz BI. Nonsteroidal anti-inflammatory drugs and the gut.South Med J 1996;89:259.

168. Bourke B, Jones N, Sherman P. Helicobacter pylori infection andpeptic ulcer disease in children. Pediatr Infect Dis J 1996;15:1.

169. Mitchell HM, Hazell SL. Helicobacter pylori, gastric ulcer, andduodenal ulcer. N Engl J Med 1996;335:1841.

170. Malaty HM, Graham DY, Isaksson I, Engstrand L, Pedersen NL. Are ge-netic influences on peptic ulcer dependent or independent of genetic influ-ences for Helicobacter pylori infection? Arch Intern Med 2000;160:105.

171. Drumm B, O’Brien A, Cutz E, Sherman P. Campylobacter pyloridis-associated primary gastritis in children. Pediatrics 1987;80:192.

172. Czinn SJ, Dahms BB, Jacobs GH, Kaplan B, Rothstein FC. Campylo-bacter-like organisms in association with symptomatic gastritis inchildren. J Pediatr 1986;109:80.

173. Rowland M, Kumar D, Daly L, O’Connor P, Vaughan D, Drumm B.Low rates of Helicobacter pylori reinfection in children. Gastroenter-ology 1999;117:336.

174. Blaser MJ. The versatility of Helicobacter pylori in the adaptation tothe human stomach. J Physiol Pharmacol 1997;48:307.

175. Blaser MJ. Ecology of Helicobacter pylori in the human stomach. JClin Invest 1997;100:759.

176. Blaser MJ. Not all Helicobacter pylori strains are created equal:should all be eliminated? Lancet 1997;349:1020.

177. Gold BD, Owens ML, van Doorn LJ, Pierce-Smith DP, Guarner J,Sherman PM, Loret de Mola O, Czinn SJ. Correlation of Helico-bacter pylori genotype with clinical and demographic characteristicsof infected children. Gastroenterology 1999;116:174.

178. Nagita A, Amemoto K, Yoden A, Aoki S, Sakaguchi M, Ashida K,Mino M. Diurnal variation in intragastric pH in children with andwithout peptic ulcers. Pediatr Res 1996;40:528.

179. Yamashiro Y, Shioya T, Ohtsuka Y, Nagata S, Oguchi S, Shimizu T,Sato M. Patterns of 24 h intragastric acidity in duodenal ulcers in

children: the importance of monitoring and inhibiting nocturnal acid-ity. Acta Paediatr Jpn 1995;37:557.

180. Isenberg JI, Selling JA, Hogan DL, Koss MA. Impaired proximalduodenal mucosal bicarbonate secretion in patients with duodenal ul-cer. N Engl J Med 1987;316:374.

181. Lichtenberger LM, Romero JJ. Effect of ammonium ion on the hy-drophobic and barrier properties of the gastric mucus gel layer: impli-cations on the role of ammonium in H. pylori-induced gastritis. JGastroenterol Hepatol 1994;9:S13.

182. Gold BD, Islur P, Policova Z, Czinn S, Neumann AW, Sherman PM.Surface properties of Helicobacter mustelae and ferret gastrointesti-nal mucosa. Clin Invest Med 1996;19:92.

183. Asante M, Ahmed H, Patel P, Davis T, Finlayson C, Mendall M,Northfield T. Gastric mucosal hydrophobicity in duodenal ulceration:role of Helicobacter pylori infection density and mucus lipids. Gas-troenterology 1997;113:449.

184. Goggin PM, Marrero JM, Spychal RT, Jackson PA, Corbishley CM,Northfield TC. Surface hydrophobicity of gastric mucosa in Helico-bacter pylori infection: effect of clearance and eradication. Gastroen-terology 1992;103:1486.

185. Taylor IL. Gastrointestinal hormones in the pathogenesis of peptic ul-cer disease. Clin Gastroenterol 1984;13:355.

186. Westerveld BD, Pals G, Lamers CB, Defize J, Pronk JC, Frants RR,Ooms EC, Kreuning J, Kostense PJ, Eriksson AW. Clinical signifi-cance of pepsinogen A isozymogens, serum pepsinogen A and C lev-els, and serum gastrin levels. Cancer 1987;59:952.

187. Rotter JI, Sones JQ, Samloff IM, Richardson CT, Gurksy JM, WalshJH, Rimoin DL. Duodenal-ulcer disease associated with elevated se-rum pepsinogen I: an inherited autosomal dominant disorder. N EnglJ Med 1979;300:63.

188. Rotter JI, Petersen G, Samloff IM, McConnell RB, Ellis A, SpenceMA, Rimoin DL. Genetic heterogeneity of hyperpepsinogenemic Iand normopepsinogenemic I duodenal ulcer disease. Ann Intern Med1979;91:372.

189. Oderda G, Vaira D, Dell’Olio D, Holton J, Forni M, Altare F, AnsaldiN. Serum pepsinogen I and gastrin concentrations in children positivefor Helicobacter pylori. J Clin Pathol 1990;43:762.

190. Wyatt JI. Histopathology of gastroduodenal inflammation: the impactof Helicobacter pylori. Histopathology 1995;26:1.

191. Ashorn M. What are the specific features of Helicobacter pylori gas-tritis in children? Ann Med 1995;27:617.

192. Genta RM, Graham DY. Comparison of biopsy sites for the histo-pathologic diagnosis of Helicobacter pylori: a topographic study ofH. pylori density and distribution. Gastrointest Endosc 1994;40:342.

193. Genta RM, Hamner HW. The significance of lymphoid follicles inthe interpretation of gastric biopsy specimens. Arch Pathol Lab Med1994;118:740.

194. Genta RM, Graham DY. Helicobacter pylori: the new bug on the(paraffin) block. Virchows Arch 1994;425(4):339.

195. Whitney AE, Guarner J, Hutwagner L, Gold BD. Histopathologicaldifferences between Helicobacter pylori gastritis of children andadults. Gastroenterology 1998;114:331.

196. Ernst PB, Gold BD. Helicobacter pylori in childhood: new insights intothe immunopathogenesis of gastric disease and implications for manag-ing infection in children. J Pediatr Gastroenterol Nutr 1999;28:462.

197. Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epi-thelium in active chronic gastritis. Lancet 1983;1:1273.

198. Hill R, Pearman J, Worthy P, Caruso V, Goodwin S, Blincow E.Campylobacter pyloridis and gastritis in children. Lancet 1986;1:387.

199. Cadranel S, Goossens H, De Boeck M, Malengreau A, Rodesch P,Butzler JP. Campylobacter pyloridis in children. Lancet 1986;1:735.

200. Kilbridge PM, Dahms BB, Czinn SJ. Campylobacter pylori-associ-ated gastritis and peptic ulcer disease in children. Am J Dis Child1988;142:1149.

201. Drumm B, Pérez-Pérez GI, Blaser MJ, Sherman PM. Intrafamilial clus-tering of Helicobacter pylori infection. N Engl J Med 1990;322:359.

202. Yeung CK, Fu KH, Yuen KY, Ng WF, Tsang TM, Branicki FJ, Saing


H. Helicobacter pylori and associated duodenal ulcer. Arch Dis Child1990;65:1212.

203. Peterson WL. Helicobacter pylori and peptic ulcer disease. N Engl JMed 1991;324:1043.

204. Drumm B, Sherman P, Cutz E, Karmali M. Association of Campylo-bacter pylori on the gastric mucosa with antral gastritis in children. NEngl J Med 1987;316:1557.

205. Drumm B. Helicobacter pylori. Arch Dis Child 1990;65:1278.206. Whitney AE, Emory TS, Marty AM, O’Shea PA, Newman GW, Ot-

terback V, Gold BD. Macrophage infiltration of the gastric mucosa inchildren with and without Helicobacter pylori infection. J PediatrGastroenterol Nutr 1996;23:348.

207. Quieroz DMM, Rocha GA, Mendes EN, Carvalho AST, BarbosaAJA, Oliveira CA, Lima GF. Differences in the distribution and se-verity of Helicobacter pylori gastritis in children and adults withduodenal ulcer disease. J Pediatr Gastroenterol Nutr 1991;12:178.

208. Loffeld RJ, Potters HV, Arends JW, Stobberingh E, Flendrig JA, vanSpreeuwel JP. Campylobacter-associated gastritis in patients withnon-ulcer dyspepsia. J Clin Pathol 1988;41:85.

209. Louw JA, Falck V, van Rensburg C, Zak J, Adams G, Marks IN. Dis-tribution of Helicobacter pylori colonisation and associated gastricinflammatory changes: difference between patients with duodenaland gastric ulcers. J Clin Pathol 1993;46:754.

210. Peters FT, Kuipers EJ, Ganesh S, Sluiter WJ, Klinkenberg-Knol EC,Lamers CB, Kleibeuker JH. The influence of Helicobacter pylori onoesophageal acid exposure in GERD during acid suppressive therapy.Aliment Pharmacol Ther 1999;13:921.

211. Genta RM, Huberman RM, Graham DY. The gastric cardia in Heli-cobacter pylori infection. Hum Pathol 1994;25:915.

212. Genta RM. Atrophy, acid suppression and Helicobacter pylori infec-tion: a tale of two studies. Eur J Gastroenterol Hepatol 1999;11:S29.

213. Hassall E, Dimmick JE. Unique features of Helicobacter pylori dis-ease in children. Dig Dis Sci 1991;36:417.

214. Goodwin CS, Armstrong JA, Marshall BJ. Campylobacter pyloridis,gastritis, and peptic ulceration. J Clin Pathol 1986;39:353.

215. Marshall BJ. Campylobacter pyloridis and gastritis. J Infect Dis1986;153:650.

216. Sbeih F, Abdullah A, Sullivan S, Merenkov Z. Antral nodularity, gas-tric lymphoid hyperplasia, and Helicobacter pylori in adults. J ClinGastroenterol 1996;22:227.

217. Gold BD, Kennedy M, Stockwell J, Friedman CR. Epidemiology ofpeptic ulcer disease and Helicobacter pylori (Hp) in hospitalized chil-dren using the Pediatric Hospital Information System. J Pediatr Gas-troenterol Nutr 1999;29:491.

218. Chong SK, Lou Q, Asnicar MA, Zimmerman SE, Croffie JM, LeeCH, Fitzgerald JF. Helicobacter pylori infection in recurrent abdomi-nal pain in childhood: comparison of diagnostic tests and therapy. Pe-diatrics 1995;96:211.

219. Shabib SM, Cutz E, Drumm B, Sherman PM. Association of gastricmetaplasia and duodenitis with Helicobacter pylori infection in chil-dren. Am J Clin Pathol 1994;102:188.

220. Genta RM, Franceschi F. Treating biopsies to cure patients: the man-agement of histological findings in mucosa-associated lymphoid tis-sue (MALT). J Clin Gastroenterol 1999;29:116.

221. Elitsur Y, Neace C, Werthammer MC, Triest WE. Prevalence ofCagA, VacA antibodies in symptomatic and asymptomatic childrenwith Helicobacter pylori infection. Helicobacter 1999;4:100.

222. Elitsur Y. H. pylori-CagA serum antibody and RAP in children. Am JGastroenterol 1999;94:539.

223. Correa P. Helicobacter pylori and gastric carcinogenesis. Am J SurgPathol 1995;19:S37.

224. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH,Orentreich N, Sibley RK. Helicobacter pylori infection and the riskof gastric carcinoma. N Engl J Med 1991;325:1127.

225. Parsonnet J, Vandersteen D, Goates J, Sibley RK, Pritikin J, ChangY. Helicobacter pylori infection in intestinal- and diffuse-type gastricadenocarcinomas. J Natl Cancer Inst 1991;83:640.

226. Forman D, Newell DG, Fullerton F, Yarnell JW, Stacey AR, Wald N,Sitas F. Association between infection with Helicobacter pylori andrisk of gastric cancer: evidence from a prospective investigation.BMJ 1991;302:1302.

227. Forman D. The etiology of gastric cancer. IARC Sci Publ 1991;105:22.228. Chiba N, Thomson AB, Sinclair P. From bench to bedside to bug: an

update of clinically relevant advances in the care of persons withHelicobacter pylori-associated diseases. Can J Gastroenterol2000;14:188.

229. Hansson LE. Risk of stomach cancer in patients with peptic ulcer dis-ease. World J Surg 2000;24:315.

230. El-Omar EM, Oien K, Murray LS, El-Nujumi A, Wirz A, Gillen D,Williams C, Fullarton G, McColl KE. Increased prevalence of pre-cancerous changes in relatives of gastric cancer patients: critical roleof H. pylori. Gastroenterology 2000;118:22.

231. Ward JM, Anver MR, Haines DC, Benveniste RE. Chronic activehepatitis in mice caused by Helicobacter hepaticus. Am J Pathol1994;145:959.

232. Ward JM, Fox JG, Anver MR, Haines DC, George CV, Collins MJJr, Gorelick PL, Nagashima K, Gonda MA, Gilden RV. Chronic ac-tive hepatitis and associated liver tumors in mice caused by a persis-tent bacterial infection with a novel Helicobacter species. J Natl Can-cer Inst 1994;86:1222.

233. Fox JG, Dewhirst FE, Tully JG, Paster BJ, Yan L, Taylor NS, CollinsMJ, Gorelick PL, Ward JM. Helicobacter hepaticus sp. nov., a mi-croaerophilic bacterium isolated from livers and intestinal mucosalscrapings from mice. J Clin Microbiol 1994;32:1238.

234. Correa P, Haenszel W, Cuello C, Zavala D, Fontham E, Zarama G,Tannenbaum S, Collazos T, Ruíz B. Gastric precancerous process ina high risk population: cohort follow-up. Cancer Res 1990;50:4737.

235. Chen VW, Abu-Elyazeed RR, Zavala DE, Haenszel W, Ktsanes K,Rice J, Cuello C, Montes G, Correa P. Risk factors of gastric precan-cerous lesions in a high-risk Colombian population. II. Nitrate and ni-trite. Nutr Cancer 1990;13:67.

236. Villar HV, Wong R, Paz B, Bull D, Neumayer L, Grogan T, Spier C.Immunophenotyping in the management of gastric lymphoma. Am JSurg 1991;161:171.

237. Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associatedlymphoid tissue. Histopathology 1987;11:445.

238. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associatedlymphoid tissue. A distinctive type of B-cell lymphoma. Cancer1983;52:1410.

239. Stolte M, Eidt S. Lymphoid follicles in antral mucosa: immune re-sponse to Campylobacter pylori? J Clin Pathol 1989;42:1269.

240. Wotherspoon AC, Ortíz-Hidalgo C, Falzon MR, Isaacson PG. Heli-cobacter pylori-associated gastritis and primary B-cell gastric lym-phoma. Lancet 1991;338:1175.

241. Hussell T, Isaacson PG, Spencer J. Proliferation and differentiation oftumour cells from B-cell lymphoma of mucosa-associated lymphoidtissue in vitro. J Pathol 1993;169:221.

242. Forman D, Webb P, Parsonnet J. H. pylori and gastric cancer. Lancet1994;343:243.

243. Isaacson PG. Mucosa-associated lymphoid tissue lymphoma. SeminHematol 1999;36:139.

244. Isaacson PG. Gastrointestinal lymphomas of T- and B-cell types.Mod Pathol 1999;12:151.

245. Wotherspoon AC. Helicobacter pylori infection and gastric lym-phoma. Br Med Bull 1998;54:79.

246. Eaton KA, Brooks CL, Morgan DR, Krakowka S. Essential role ofurease in pathogenesis of gastritis induced by Helicobacter pylori ingnotobiotic piglets. Infect Immun 1991;59:2470.

247. Tsuda M, Karita M, Morshed MG, Okita K, Nakazawa T. A urease-negative mutant of Helicobacter pylori constructed by allelic ex-change mutagenesis lacks the ability to colonise the nude mousestomach. Infect Immun 1994;62:3586.

248. Makristathis A, Rokita E, Labigne A, Willinger B, Rotter ML, HirschlAM. Highly significant role of Helicobacter pylori urease in phago-


cytosis and production of oxygen metabolites by human granulo-cytes. J Infect Dis 1998;177:803.

249. Harris PR, Mobley HTL, Pérez-Pérez GI, Blaser MJ, Smith PD. Heli-cobacter pylori urease is a potent stimulus of mononuclear phagocyteactivation and inflammatory cytokine production. Gastroenterology1996;11:419.

250. Yáñez P, Madrazo-de la Garza A, Pérez-Pérez GI, Cabrera L, MuñozO, Torres J. Comparison of invasive and non-invasive methods forthe diagnosis and evaluation of eradication of Helicobacter pylori in-fection in children. Arch Med Res 2000;31:415.

251. Nijevitch AA. Helicobacter pylori-dependent intragastric urea bio-degradation in children: diagnostic and pathogenic importance. ActaPaediatr Jpn 1998;40:122.

252. Leal-Herrera Y, Torres J, Pérez-Pérez G, Gómez A, Monath T,Tapia-Conyer R, Muñoz O. Serologic IgG response to urease in Heli-cobacter pylori-infected persons from Mexico. Am J Trop Med Hyg1999;60:587.

253. Eaton K, Suerbaum S, Josenhans C, Krakowka S. Gastric coloniza-tion of gnotobiotic piglets by Helicobacter pylori deficient in twoflagellin genes. Infect Immun 1996;64:2445.

254. Andrutis KA, Fox JG, Schauer DB, Marini RP, Li X, Yan L, JosenhansC, Sierbaum S. Infection of the ferret stomach by isogenic flagellar mu-tant strains of Helicobacter pylori. Infect Immun 1997;65:1962.

255. Jung HC, Kim JM, Song IS, Kim CY. Increased motility of Helico-bacter pylori by methylcellulose could upregulate the expression ofproinflammatory cytokines in human gastric epithelial cells. Scand JClin Lab Invest 1997;57:263.

256. Sarosiek J, Slomiany A, Slomiany BL. Evidence for weakening ofgastric mucus integrity by Campylobacter pylori. Scand J Gastroen-terol 1988;23:585.

257. Langton SR, Cesareo SD. Helicobacter pylori associated phospholi-pase A2 activity: a factor in peptic ulceration? J Clin Pathol1992;45:221.

258. Lingwood CA, Wasfy G, Han H, Huesca M. Receptor affinity purifi-cation of a lipid-binding adhesin from Helicobacter pylori. Infect Im-mun 1993;61:2474.

259. Valkonen KH, Wadstrom T, Morán AP. Interaction of lipopolysac-charides of Helicobacter pylori with basement membrane proteinlaminin. Infect Immun 1994;62:3640.

260. Yamaguchi H, Osaki T, Kurihara N, Taguchi H, Hanawa T, Yama-moto T, Kamiya S. Heat-shock protein 60 homologue of Helico-bacter pylori is associated with adhesion of H. pylori to human gas-tric epithelial cells. J Med Microbiol 1997;46:825.

261. Boren T, Falk P, Roth KA, Larson G, Normark S. Attachment ofHelicobacter pylori to human gastric epithelium by blood group anti-gens. Science 1993;262:1892.

262. Clyne M, Drumm B. Absence of effect of Lewis A and Lewis B ex-pression on adherence of Helicobacter pylori to human gastric cells.Gastroenterology 1997;113:72.

263. Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET,Berg DE, Covacci A, Engstrand L, Boren T. Helicobacter pylori ad-hesin binding fucosylated histo-blood group antigens revealed byretagging. Science 1998;279:373.

264. Valkonen KH, Wadström T, Morán AP. Identification of the N-acetyl-neuraminyllactose-specific laminin-binding protein of Helicobacterpylori. Infect Immun 1997;65:916.

265. Su B, Hellström PM, Rubio C, Çelik J, Granström M, Normark S.Type I Helicobacter pylori shows Lewis b-independent adherence togastric cells requiring de novo protein synthesis in both host and bac-teria. J Infect Dis 1998;178:1379.

266. Suerbaum S, Thiberge JM, Kansau I, Ferrero RL, Labigne A. Helico-bacter pylori hspA-hspB heat shock gene cluster: nucleotide se-quence, expression, putative function and immunogenicity. Mol Mi-crobiol 1994;14:959.

267. Macchia G, Massone A, Burroni D, Covacci A, Censini S, RappuoliR. The Hsp60 protein of Helicobacter pylori: structure and immune

responses in patients with gastroduodenal diseases. Mol Microbiol1993;9:645.

268. Martin SL, Edbrooke MR, Hodgman TC, van den Eijnden DH, BirdMI. Lewis X biosynthesis in Helicobacter pylori. J Biol Chem1997;272:21349.

269. Simoons Smit IM, Appelmelk BJ, Verboom T, Negrini R, Penner JL,Aspinall GO, Morán AP, Fei SF, Bi-Shan S, Rudnica W, Savio A, deGraaff J. Typing of Helicobacter pylori with monoclonal antibodiesagainst Lewis antigens in lipopolysaccharide. J Clin Microbiol1996;34:2196.

270. Appelmelk BJ, Shiberu B, Trinks C, Tapsi N, Zheng PY, Verboom T,Maaskant J, Hokke CH, Schiphorst WECM, Blanchard D, Simoons-Smit IM, van den Eijnden DH, Vandenbroucke-Grauls CMJE. Phasevariation in Helicobacter pylori lipopolysaccharide. Infect Immun1998;66:70.

271. Muñoz L, González G, Pérez-Pérez G, Giono S, Muñoz O, Torres J.Expression of Le antigens in H. pylori is different in strains isolatedfrom children and from adults. Gut 1999;45(Suppl III):A33.

272. Kidd M, Miu K, Tang LH, Pérez-Pérez GI, Blaser MJ, Sandor A,Modlin IM. Helicobacter pylori lipopolysaccharide stimulates hista-mine release and DNA synthesis in rat enterochromaffin-like cells.Gastroenterology 1997;113:1110.

273. Okumura T, Shoji E, Takahashi N, Wakebe H, Imagawa K, KikuchiM, Kohgo Y. Delayed gastric emptying by Helicobacter pylori li-popolysaccharide in conscious rats. Dig Dis Sci 1998;43:90.

274. Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M,Rappuoli R, Covacci A. cag, a pathogenicity island of Helicobacterpylori, encodes a type I-specific and disease-associated virulence fac-tors. Proc Natl Acad Sci USA 1996;93:14648.

275. Tomb J-F, White O, Kerlavage AR, et al. The complete genome se-quence of the gastric pathogen Helicobacter pylori. Nature 1997;388:539.

276. Segal ED, Cha J, Falkow S, Tompkins LS. Altered states: involve-ment of phosphorylated CagA in the induction of host cellular growthchanges by Helicobacter pylori. Proc Natl Acad Sci USA 1999;96:14559.

277. Stein M, Rappuoli R, Covacci A. Tyrosine phosphorylation of theHelicobacter pylori CagA antigen after cag-driven host cell translo-cation. Proc Natl Acad Sci USA 2000;97:1263.

278. Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, Tsubokawa M, To-hyama Y, Maeda S, Omata M, Suzuki T, Sasakawa C. Helicobacterpylori cagA protein can be tyrosine phosphorylated in gastric epithe-lial cells. J Exp Med 2000;191:593.

279. Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R.Translocation of Helicobacter pylori CagA into gastric epithelialcells by type IV secretion. Science 2000;287:1497.

280. Ching CK, Wong BCY, Kwok E, Ong L, Covacci A, Lam SK. Preva-lence of CagA-bearing Helicobacter pylori strains detected by theanti-CagA assay in patients with peptic ulcer disease and in controls.Am J Gastroenterol 1996;91:949.

281. Weel JFL, Van der Hulst RWM, Gerritis Y, Roorda P, Feller M,Dankert J, Tytgat GNJ, van der Ende A. The interrelation betweencytotoxin-associated gene A, vacuolating cytotoxin, and Helico-bacter pylori-related diseases. J Infect Dis 1996;173:1171.

282. Parsonnet J, Friedman GD, Orentreich N, Vogelman H. Risk factorfor gastric cancer in people with CagA positive or CagA negativeHelicobacter pylori infection. Gut 1997;40:297.

283. Torres J, Pérez-Pérez G, Leal-Herrera Y, Muñoz O. Infection withCagA1 Helicobacter pylori strains as a possible predictor of risk inthe development of gastric adenocarcinoma in Mexico. Int J Cancer1998;78:298.

284. Tummuru MKR, Sharma SA, Blaser MJ. Helicobacter pylori picB, ahomolog of the Bordetella pertussis toxin secretion protein, is re-quired for induction of IL-8 in gastric epithelial cells. Mol Microbiol1995;18:867.

285. Covacci A, Telford JL, Del Giudice G, Parsonnet J, Rappuoli R. Heli-


cobacter pylori, virulence, and genetic geography. Science 1999;284:1328.

286. Leunk RD. Production of a cytotoxin by Helicobacter pylori. Rev In-fect Dis 1991;13:S686.

287. Figura N, Guglielmetti P, Rossolini A, Barberi A, Cusi G, MusmannoR, Russi M, Quaranta S. Cytotoxin production by Campylobacter py-lori strains isolated from patients with peptic ulcers and from patientswith chronic gastritis only. J Clin Microbiol 1989;27:225.

288. Atherton JC, Cao P, Peek RM, Tummuru MKR, Blaser MJ, CoverTL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter py-lori: association of specific vacA types with cytotoxin production andpeptic ulceration. J Biol Chem 1995;270:17771.

289. Atherton JC, Peek RM, Tham KT, Cover TL, Blaser MJ. Clinical andpathologic importance of heterogenicity in vacA, the vacuolating cy-totoxin gene of Helicobacter pylori. Gastroenterology 1997;112:92.

290. Celik J, Su B, Tirén U, Finkel Y, Thoresson AC, Engstrand L, Sand-stedt B, Bernander S, Normark S. Virulence and colonization-associ-ated properties of Helicobacter pylori isolated from children and ado-lescents. J Infect Dis 1998;177:247.

291. Mitchell HM, Hazell SL, Bohane TD, Hu P, Chen M, Li YY. Theprevalence of antibody to CagA in children is not a marker for spe-cific disease. J Pediatr Gastroenterol Nutr 1999;28:71.

292. Kato S, Sugiyama T, Kudo M, Ohnuma K, Ozawa K, Iinuma K,Asaka M, Blaser MJ. CagA antibodies in Japanese children with nod-ular gastritis or peptic ulcer disease. J Clin Microbiol 2000;38:68.

293. Husson MO, Gottrand F, Vachee A, Dhaenens L, de la Salle EM,Turck D, Houcke M, Leclerc H. Importance in diagnosis of gastritisof detection by PCR of the cagA gene in Helicobacter pylori strainsisolated from children. J Clin Microbiol 1995;33:3300.

294. Kolho KL, Karttunen R, Heikkila P, Lindahl H, Rautelin H. Gastricinflammation is enhanced in children with CagA-positive Helico-bacter pylori infection. Pediatr Infect Dis J 1999;18:337.

295. Luzza F, Contaldo A, Imeneo M, Mancuso M, Pensabene L, Gian-cotti L, La Vecchia AM, Costa MC, Strisciuglio P, Docimo C, Pal-lone F, Guandalini S. Testing for serum IgG antibodies to Helico-bacter pylori cytotoxin-associated protein detects children withhigher grades of gastric inflammation. J Pediatr Gastroenterol Nutr1999;29:302.

296. Luzza F, Mancuso M, Imeneo M, Mesuraca L, Contaldo A, GiancottiL, Costa MC, Maletta M, La Vecchia A, Docimo C, Strisciuglio P,Guandalini S, Pallone F. Serum cagA antibodies are associated withhigher grades of gastric inflammation in children. Gut 1998;43(Suppl2):A72.

297. Queiroz DMM, Mendes EN, Nogueira AMMF, Carvalho AST,Rocha GA, Magalhães PP. CagA status in H. pylori positive childrenwith and without duodenal ulcer: a histopathological study. Gut1997;41(Suppl 1):A16.

298. Alarcón T, Martínez MJ, Urruzuno P, Cilleruelo ML, Madruga D, Se-bastián M, Domingo D, Sánz JC, López-Brea M. Detection of anti-bodies against CagA and VacA proteins in a paediatric population in-fected with Helicobacter pylori. Gut 1999;45(Suppl III):A100.

299. Mitchell HM, Hu PJ, Li YY, Chen MH, Hazel SL. VacA not CagAassociated with duodenal ulcer disease in children from a developingcountry. Gut 1998;43(Suppl):A73.

300. Rocha GA, Mendes EN, Gusmão VR, Queiroz DMM, NogueiraAMMF, Magalhães PP, Esteves AMB, Carvalho AST. VacA geno-types in Helicobacter pylori strains isolated from children. Gut1998;43(Suppl 2):A72.

301. Blaser MJ. Hypothesis on the pathogenesis and natural history of Heli-cobacter pylori-induced inflammation. Gastroenterology 1992;102:720.

302. Kirchner T, Steininger H, Faller G. Immunopathology of Helico-bacter pylori gastritis. Digestion 1997;58(Suppl 1):14.

303. Crabtree JE, Farmery SM, Lindley IJD, Figura N, Peichl P, TompkinsDS. CagA/cytotoxic strains of Helicobacter pylori and interleukin-8in gastric epithelial cell lines. J Clin Pathol 1994;47:945.

304. Keates S, Hitti YS, Upton M, Kelly CP. Helicobacter pylori infection

activates NF-kB in gastric epithelial cells. Gastroenterology 1997;113:1099.

305. Yamaoka Y, Kita M, Kodama T, Sawai N, Imanishi J. Helicobacterpylori cagA gene and expression of cytokine messenger RNA in gas-tric mucosa. Gastroenterology 1996;110:1744.

306. Noach LA, Bosma NB, Jansen J, Hoek FJ, van Deventer SJ, TytgatGN. Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and in-terleukin-8 production in patients with Helicobacter pylori infection.Scand J Gastroenterol 1994;29:425.

307. Yamaoka Y, Kita M, Kodama T, Sawi N, Kashima K, Imanishi J. In-duction of various cytokines and development of severe mucosal in-flammation by cagA gene positive Helicobacter pylori strains. Gut1997;41:442.

308. Beales I, Blaser MJ, Srinivasan S, Calam J, Pérez-Pérez GI, YamadaT, Scheiman J, Post L, Del Valle J. Effect of Helicobacter pyloriproducts and recombinant cytokines on gastric release from culturedcanine G cells. Gastroenterology 1997;113:465.

309. D’Elios MM, Andersen LP, Del Prete G. Inflammation and host re-sponse. Curr Opin Gastroenterol 1998;14(Suppl 1):S15.

310. D’Elios MM, Manghetti M, Almerigogna F, Amedei A, Costa F,Burroni D, Baldari CT, Romagagni S, Telford JL, Del Prete G. Dif-ferent cytokine profile and antigenic-specificity repertoire in Helico-bacter pylori-specific T cell clones from the antrum of chronic gas-tritis patients with or without peptic ulcer. Eur J Immunol 1997;27:1751.

311. D’Elios MM, Romagnani P, Scaletti C, Annunziato F, Manghetti M,Mavilia C, Parronchi P, Pupilli C, Pizzolo G, Maggi E, Del Prete GF,Romagnani S. In vivo CD30 expression in human diseases with pre-dominant activation of Th2-like T cells. J Leukoc Biol 1997;61:539.

312. Kütükçüler N, Aydogdu S, Göksen D, Çaglayan S, Yagcyi RV. In-creased mucosal inflammatory cytokines in children with Helico-bacter pylori-associated gastritis. Acta Paediatr 1997;86:928.

313. Broide E, Klinowski E, Varsano R, Eshchar J, Herbert M, Scapa E.Superoxide dismutase activity in Helicobacter pylori-positive antralgastritis in children. J Pediatr Gastroenterol Nutr 1996;23:609.

314. Sbarbati A, Bertini M, Peng ZC, Tonolli E, Osculati F. NADPH-dia-phorase in antral gastritis of childhood. J Pediatr Gastroenterol Nutr1997;25:89.

315. Graham DY, Opekun A, Lew GM, Klein PD, Walsh JH. Helico-bacter pylori-associated exaggerated gastrin release in duodenal ulcerpatients. Gastroenterology 1991;100:1571.

316. Oderda G, Holton J, Ainley C, Altate F, Ansaldi N. Amoxycillin plustinidazole for Campylobacter pylori gastritis in children: assessmentby serum IgG antibody, pepsinogen I and gastrin levels. Lancet1989;1:690.

317. Kim JW, Chung KS. Serum gastrin and pepsinogen I, II concentra-tions in children with Helicobacter pylori infection: the role of CagAand VacA. Yonsei Med J 1998;39:159.

318. McCallion WA, Bailie AG, Ardill JE, Bamford KB, Pott SR, BostonVE. Helicobacter pylori, hypergastrinaemia, and recurrent abdominalpain in children. J Pediatr Surg 1995;30:427.

319. Queiroz DMM, Moura SB, Mendes EN, Rocha GA, Barbosa AJA, deCarvalho AST. Effect of Helicobacter pylori eradication on G-celland D-cell density in children. Lancet 1994;343:1191.

320. Mitchell HM, Hazell SL, Kolesnikow T, Michtell J, Frommer D. An-tigen recognition during progression from acute to chronic infectionwith cagA-positive strain of Helicobacter pylori. Infect Immun1996;64:1166.

321. López-Brea M, Alarcón T, Domingo D, Sánchez I, Martínez MJ, SánzJC. Evaluación de una técnica de Western-blot (Helicoblot 2.0) para ladetección de anticuerpos frente a antígenos específicos de Helicobacterpylori en niños. Enferm Infecc Microbiol Clin 1998;16:275.

322. Pérez-Pérez GI, Sack RB, Reid R, Santoham M, Blaser MJ. Transientand persistent colonization by Helicobacter pylori in Native Ameri-can children. Gut 1998;43:A40.

323. Elitsur Y, Hill I, Lichtman SN, Rosenberg AJ. Prospective compari-


son of rapid urease tests (PyloriTek, CLO Test) for the diagnosis ofHelicobacter pylori infection in symptomatic children: a pediatricmulticenter study. Am J Gastroenterol 1998;93:217.

324. Murata H, Kawano S, Tsuji S, Tsuji M, Sawaoka G, Lijima H, KawaiN, Hori M. Evaluation of the Pylori Text Test for detection of Helico-bacter pylori infection in cases with and without eradication therapy.Am J Gastroenterol 1998;93:2102.

325. López-Brea M, Alarcón T, Mégraud F. Diagnosis of Helicobacter py-lori infection. Curr Opin Gastroenterol 1997;13:13.

326. Yousti MM, EL-Zimaty HMT, Cole RA, Genta RM, Graham DY.Detection of Helicobacter pylori by rapid urease tests: is biopsy sizea critical variable? Gastrointest Endosc 1996;43:222.

327. Parsonnet J, Shmuely H, Haggerty T. Fecal and oral shedding of Heli-cobacter pylori from healthy infected adults. JAMA 1999;282:2240.

328. Han SW, Flamm R, Hachem CY, Kim HY, Clarridge JE, Evans DG,Breyer J, Drnec J, Graham DY. Transport and storage of Helico-bacter pylori from gastric mucosal biopsies and clinical isolates. EurJ Clin Microbiol Infect Dis 1995;14:349.

329. Oderda G, Frocca R, Villani L, Forni M, Ansaldi N. Gastric and so-matostatin cells in antral mucosa of Helicobacter pylori positive andnegative children. Am J Gastroenterol 1994;89:1329.

330. Oderda G, Candranel S. Paediatrics Helicobacter pylori. Curr OpinGastroenterol 1995;11(Suppl 1):42.

331. Maconi G, Vago L, Galletta G, Imbesi V, Sangaletti O, Parente F,Cucino C, Bonetto S, Porro GB. Is routine histological evaluation anaccurate test for Helicobacter pylori infection? Aliment PharmacolTher 1999;13:327.

332. Kelly SM, Pitcher MCL, Farmery SM, Gibson GR. Isolation of Heli-cobacter pylori from feces of patients with dyspepsia in the UnitedKingdom. Gastroenterology 1994;107:1671.

333. Westblum TU. Molecular diagnosis of Helicobacter pylori. ImmunInvest 1997;26:163.

334. Li C, Ha T, Ferguson DA, Chi DS, Zhao R, Patel NR, KrishnaswamyG, Thomas E. A newly developed PCR assay of H. pylori is gastricbiopsy, salvia and feces. Evidence of high prevalence of H. pylori insaliva supports oral transmission. Dig Dis Sci 1996;41:2142.

335. Valentine JL, Arthur RR, Mobley HTL, Dick JD. Detection of Heli-cobacter pylori by using the polymerase chain reaction. J Clin Micro-biol 1991;29:689.

336. Hammer M, Tyszkiewicz T, Wadstrom T, O’Toole PW. Rapid detec-tion of Helicobacter pylori in gastric biopsy material by polymerasechain reaction. J Clin Microbiol 1992;30:54.

337. Clayton CL, Kleanthous H, Coates PJ, Morgan DD, Tabaqchalli S.Sensitive detection of Helicobacter pylori by using polymerase chainreaction. J Clin Microbiol 1992;30:192.

338. Bickley J, Owen RJ, Fraser AG, Pounder RE. Evaluation of the chainreaction for detecting the urease C gene of Helicobacter pylori in gas-tric biopsy samples and dental plaque. J Med Microbiol 1993;39:338.

339. Lu J-J, Perng C-L, Shyu R-Y, Chen C-H, Lou Q, Chong SKF, Lee C-H.Comparison of five PCR methods for the detection of Helicobacterpylori DNA in gastric tissues. J Clin Microbiol 1999;37:772.

340. Thomas JE. 13C urea breath test. Gut 1998;43(Suppl 3):S7.341. Rutigliano V, Lerardi E, Francavilla R, Castellaneta S, Margiotta M,

Amoruso S, Marrazza E, Traversa A, Panella C, Rigillo N, Francav-illa A. Helicobacter pylori and non-ulcer dyspepsia in childhood:clinical pattern, diagnostic techniques and bacterial strains. J PediatrGastroenterol Nutr 1999;28:296.

342. Guimber D, Chelimsky G, Gottrand F, Czinn S. Paediatrics. CurrOpin Gastroenterol 1999;15:S49.

343. Koletzko S, Ashorn M. Paediatrics. Curr Opin Gastroenterol 1998;14(Suppl 1):557.

344. Casswall TH, Nilsson HO, Bergström M, Aleljung P, Wadström T,Dahlström AK, Albert MJ, Sarker SA. Evaluation of serology, 13C-urea breath test and polymerase chain reaction of stool samples to de-tect Helicobacter pylori in Bangladeshi children. J Pediatr Gastroen-terol Nutr 1999;28:31.

345. Czinn SJ. Serodiagnosis of Helicobacter pylori in pediatric patients. JPediatr Gastroenterol Nutr 1999;28:132.

346. Oliveira AM, Rocha GA, Queiroz DM, Mendes EM, de Carvalho AS,Ferrari TC, Nogueira AM. Evaluation of enzyme-linked immunosor-bent assay for the diagnosis of Helicobacter pylori infection in chil-dren from different age groups with and without duodenal ulcer. J Pe-diatr Gastroenterol Nutr 1999;28:157.

347. Makristathis A, Pashing E, Schütze K, Wimmer M, Rottei M, HirschlAM. Detection of Helicobacter pylori in stool specimens by PCR andantigen enzyme immunoassay. J Clin Microbiol 1998;36:2772.

348. Vandenplas Y, Blecker U. Helicobacter pylori infection in children.Acta Pediatr 1998;87:1105.

349. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomachof patients with gastritis and peptic ulceration. Lancet 1984;1:1311.

350. Buckley N, O’Morain C. Helicobacter pylori eradication—a surro-gate marker for duodenal ulcer healing. Eur J Gastroenterol Hepatol1996;8:415.

351. European Helicobacter pylori Study Group. Current European con-cepts in the management of Helicobacter pylori infection. The Maas-tricht Consensus Report. Gut 1977;41:8.

352. Blecker U, Gold B. Treatment of Helicobacter pylori infection: a re-view. Pediatr Infect Dis J 1997;16:391.

353. Delgado J, Yáñez P, Cura I, Ramón G, Torres J, Morán S, MadrazoA. Evolución clínica de niños con dolor abdominal crónico recurrentedespués del tratamiento de erradicación para Helicobacter pylori.Rev Gastroenterol Mex 1999;64:47.

354. Lian JX, Carrick J, Doskalopoulos G. Metronidazole resistance sig-nificantly affects eradication of H. pylori infection. Gastroenterology1993;104:133.

355. Lind T, Mégraud F, Bardhan KD, Bayerdörffer E, Hellblom M,O’Morain C, Spiller RC, Unge P, Veldhuyzen van Zanten SJO. TheMACH2 study: antimicrobial resistance in Helicobacter pylori ther-apy: the impact of omeprazole. Gut 1997;41(Suppl 1):A89.

356. Dohil R, Israel DM, Hassall E. Effective 2 week therapy for Helicobacterpylori eradication therapy in children. Am J Gastroenterol 1996;92:244.

357. Casswall TH, Alfvén G, Drapinski M, Bergström M, Dahlström KA.One-week treatment with omeprazole, clarithromycin, and metro-nidazole in children with Helicobacter pylori infection. J Pediatr Gas-troenterol Nutr 1998;27:415.

358. Raymond J, Kalach N, Bergeret M, Benhamou H, Barbet JP, GendrelD, Dupont C. Effect of metronidazole resistance on bacterial eradica-tion of Helicobacter pylori in infected children. Antimicrob AgentsChemother 1998;42:1334.

359. Kato S, Abukawa D, Furuyama N, Iinuma K. Helicobacter pylori re-infection rates in children after eradication therapy. J Pediatr Gastro-enterol Nutr 1998;27:543.

360. Huang FC, Chang MH, Hsu HY, Lee PI, Shun CT. Long-term fol-low-up of duodenal ulcer in children before and after eradication ofHelicobacter pylori. J Pediatr Gastroenterol Nutr 1999;28:76.

361. Walsh D, Goggin N, Durnin M, Moriarty S, Drumm B. One weektherapy for Helicobacter pylori infection in children. Gut 1996;39(Suppl 2):A50.

362. Oderda G, Lerro P, Caristo P, Kuvidi M, Forni M, Ansaldi N, Mar-telli P, Chiorboli E, Monga G, Bona G. Triple therapy in childhoodH. pylori gastritis. Gut 1996;39(Suppl 2):A51.

363. Oderda G. Management of Helicobacter pylori infection in children.Gut 1998;43(Suppl 1):A10.

364. Tolia V. Helicobacter pylori infection in pediatric patients. Curr Gas-troenterol Rep 1999;1:308.

365. Marshall BJ. Treatment strategies for Helicobacter pylori infection.Gastroenterol Clin North Am 1993;22:183.

366. Marshall BJ, Valenzuela JE, McCallum RW, Dooley CP, GuerrantRL, Cohen H, Frierson HF, Field LG, Jerdack GR, Mitra S. Bismuthsubsalicylate suppression of Helicobacter pylori in non-ulcer dyspep-sia: a double-blind placebo-controlled trial. Dig Dis Sci 1993;38:1674.


367. Rauws EAJ, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GN.Campylobacter pyloridis-associated chronic active antral gastritis: aprospective study of its prevalence and the effects of antibacterial andantiulcer treatment. Gastroenterology 1988;94:33.

368. Morgan D, Kraft W, Bender M, Pearson A. Nitrofurans in the treat-ment of gastritis associated with Campylobacter pylori: The Gas-trointestinal Physiology Working Group of Cayetano Heredia andThe Johns Hopkins Universities. Gastroenterology 1988;95:1178.

369. Peterson WL, Graham DY, Marshall B, Blaser MJ, Genta RM, KleinPD, Stratton CW, Drnec J, Prokocimer P, Siepman N. Clarithromycinas monotherapy for eradication of Helicobacter pylori. Am J Gastro-enterol 1993;88:1860.

370. Megraud F. Antibiotic resistance in Helicobacter pylori infection. BrMed Bull 1998;54:207.

371. Burette A, Glupczynski Y, Deprez C. Two weeks of triple therapyovercomes metronidazole resistance: results of a randomized doubleblind study. Gastroenterology 1992;102:A46.

372. Kihira K, Sugano K, Kimusa K, Satoh K. Effect of triple therapy withnew proton pump inhibitor rabeprazole, amoxicillin and low or highdose of clarithromycin for Helicobacter pylori infection. Gut 1999;45(Suppl III):A117.

373. Bock H, Heep M, Lehn N. Rifabutin, amoxicillin and lanzoprazole-eradication of H. pylori after multiple therapy failures. Gut 1999;45(Suppl III):A109.

374. Gisbert JP, Carpio D, Marcos S, Gisbert JL, Cabrera MM, CruzadoAI, García Gravalos R, Pajares JM. Pantoprazole vs. ranitidine bis-

muth citrate plus two antibiotics for H. pylori eradication. Gut1999;45(Suppl III):A108.

375. Cammarota G, Cannizzaro O, Cianci R, Armuzzi A, Gasbarrini A,Pastorelli A, Papa A, Gasbarrini G. Six-day or seven-day regimenswith ranitidine bismuth citrate plus high-dose clarithromycin and ti-nidazole are both effective against Helicobacter pylori infection. DigDis Sci 1999;44:2386.

376. González-Ortíz B, Torres J, Carmolinga M, Rojas-Pineda N, Flores-Calderón J, Madrazo-de la Garza JA. Two week double vs. tripletherapy for Helicobacter pylori (Hp) eradication in Mexican children.J Pediatr Gastroenterol Nutr 1997;25:468.

377. Graham DY. Antibiotic resistance in Helicobacter pylori: implica-tions for therapy. Gastroenterology 1998;115:1272.

378. Tompkins DS, Perkin J, Smith C. Failed treatment of Helicobacterpylori infection associated with resistance to clarithromycin. Helico-bacter 1997;2:185.

379. Han SR, Bhakdi S, Maeurer MJ, Schneider T, Gehring S. Stable andunstable amoxicillin resistance in Helicobacter pylori: should antibi-otic resistance testing be performed prior to eradication therapy? JClin Microbiol 1999;37:2740.

380. Rowland M, Kumar D, O’Connor P, Daly LE, Drumm B. Reinfectionwith Helicobacter pylori in children. Gastroenterology 1997;112: A273.

381. Torres J, Leal-Herrera Y, Ramos I, Madrazo-de la Garza A, MonathT, Muñoz O. Comparison of H. pylori reinfection and primary acqui-sition in children from a community with high prevalence of infec-tion. Gut 1999;45(Suppl III):A95.

Documents

A Comprehensive Review of the Natural History of Helicobacter pylori Infection in Children