helicobacter in the developing world

Forum in immunology

Helicobacter in the developing world

Robert W. Frenck Jr a,*, John Clemens b

a Enteric Disease Research Program, US Naval Medical Research Unit #3, Cairo, Egyptb International Vaccine Institute, Seoul, South Korea

Abstract

Helicobacter pylori in the developing world is associated with many unique challenges not encountered in an industrialized setting. The20% prevalence of infection with H. pylori among adolescents in the United States pales in comparison to infection rates exceeding 90% by5 years of age in parts of the developing world. While H. pylori within the developed world is associated with gastritis, which may lead topeptic ulcer and gastric carcinoma, the infection in the developing world appears to also be linked with chronic diarrhea, malnutrition andgrowth faltering as well as predisposition to other enteric infections, including typhoid fever and cholera. Once identified, treatment of H.pylori within the developing world presents increased difficulties due to the frequency of antibiotic resistance as well as the frequency ofrecurrence after successful treatment. Control, and possibly eradication, of H. pylori could likely be achieved through increased standards ofliving and improved public health, as it has in the industrialized world. However, these measures are distant objectives for most developingcountries, making long-term control of the organism dependent on the development and administration of an effective vaccine.

© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

Keywords: Helicobacter pylori; Risk factors; Human; Epidemiology

1. Introduction

Awareness of the Gram-negative, spiral gastric bacteria,Helicobacter pylori is less than two decades old [1]. Follow-ing the initial skepticism regarding the etiologic importanceof the organism, it is now recognized that infections with H.pylori are associated with some of the most common clinicalproblems in medicine. Irrefutably the cause of chronic-activegastritis and a majority of cases of peptic ulcer disease, theorganism is also thought to be associated with the develop-ment of gastric adenocarcinoma, the fourth most commonmalignancy in the world, and mucosa-associated lymphoidtissue lymphoma [2]. Numerous studies have demonstratedthat H. pylori is ubiquitous; approximately 50% of theworld’s population is infected with the organism [3]. How-ever, the age at infection, the prevalence of infection, andpossibly symptoms and sequelae of infection differ dramati-cally in developed versus developing countries. This paperwill describe the experience of the authors, as well as reviewthe literature on the key points of H. pylori within thedeveloping world.

2. Epidemiology

2.1. Prevalence and incidence

In contrast with industrialized nations, H. pylori infec-tions occur earlier in life and with a higher frequency in thedeveloping world. Also, while the prevalence of the infectionhas dropped significantly in many parts of North America,Western Europe and Asia (especially Korea), no such declinehas been noted in the developing world [3]. However, as inindustrialized nations, gender does not appear to be related toinfection with H. pylori.

In many developing countries, the prevalence of infectionwith H. pylori exceeds 50% by 5 years of age, and byadulthood, infection rates exceeding 90% are not unusual[4–6] (see Table 1). In a study of 569 Bangladeshi childrenbetween 2 and 10 years of age, the prevalence of H. pyloriwas already 42% by 2 years of age and quickly rose to 67%by 10 years of age [7,8]. Similar findings were reported fromstudies performed on children from many parts of the devel-oping world including Peru, the Gambia and China [9–11].For the past 6 years, we have conducted epidemiologicalstudies of H. pylori in Egypt. Of 200 mothers tested from aproject in Alexandria, Egypt, 90% were infected with H.pylori, and 15% of their infants had become infected by 9months of age, with the prevalence increasing to 25% by the

* Corresponding author. Present address: NAMRU-3, PSC 452, Box121, FPO AE, 09835, USA. Tel.: +1-202-684-1375x252; fax:+1-202-684-9625/683-1382.

E-mail address: [email protected] (R.W. Frenck).

Microbes and Infection 5 (2003) 705–713

www.elsevier.com/locate/micinf

© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.DOI: 10.1016/S1286-4579(03)00112-6

time the children reached 18 months of age [12]. A subse-quent serosurvey using children participating in a 3-yearstudy found that H. pylori infection increased with age andreached 30% by 3 years of age [13].

Incidence data for infection with H. pylori are not asabundant as information on prevalence. However, few stud-ies on the incidence of infection have been performed, but theones available suggest that rates of infection within the devel-oping world are much higher than the 1–2% yearly incidencereported in industrialized settings. Additionally, as expectedfrom the prevalence data, the incidence of infection with H.pylori is highest within the first few years of life. Among186 Bolivian children serially tested over a 2-year period oftime, seroincidence averaged 18% per year with a peak of22% per year occurring in children between 2 and 3 years ofage [14]. Supporting this finding is a 1-year seroincidence of24% among 112 Ethiopian children between 2 and 4 years ofage [15]. In a study conducted in 187 Egyptian childrenbetween 6 and 36 months of age participating in a longitudi-nal study of diarrhea, we demonstrated the 6-month inci-dence of infection with H. pylori to be 15% [13]. There areno studies providing data on the incidence rate of H. pyloriinfection among adults native to a developing country be-

cause they are almost universally infected with the bacteria.However, a unique group, adults from an area with a lowprevalence of H. pylori who resided for an extended period oftime in a high-prevalence country, provides an opportunity tostudy the risk in adults. While US troops sent to the ArabianGulf during the Gulf War had a 1-year seroconversion of14%, another study of 312 North American missionaries whowere long-term residents (mean 7.4 years) of sub-SaharanAfrica had an annual incidence rate of infection of only 1.9%[16,17]. The reason for the dramatic difference between therates of infection between the two groups is not clear but mayreflect different living standards including overcrowding,diet and water supply.

Another ongoing question regarding infection with H.pylori is whether some infections are transient. In a serostudyof Egyptian children between 6 and 36 months of age duringthe period of observation, 42% of the children had serorever-sion between the first and second blood test, suggesting aspontaneous clearance of the infection [13]. Similar findingswere reported from a cohort of Peruvian children diagnosedwith H. pylori using the urea breath test [9]. The prevalenceof infection was 71% in children 6 months of age but droppedto 48% by 18 months of age. Supporting these observationsare several studies from developed countries, which haveindicated that H. pylori infection may indeed be a reversibleprocess. Thus while H. pylori infections in adults may bechronic, it appears that children may have repeated cycles ofacquiring and losing the infection until the infection eventu-ally becomes chronic, at least in developing country settings.

2.2. Source of infection

Despite many attempts at discovery, the exact source ofinfection has yet to be determined. Contaminated food orwater sources have been cited as important risks for becom-ing infected with H. pylori. Laboratory experiments havefound that H. pylori may survive up to a week in water [18].However, only one team has been able to culture the organ-ism from an environmental water source [19]. Using a multi-step method, investigators cultured H. pylori from wastewa-ter at a plant on the Mexican-US border. While this report isto date unique, it certainly supports the theory that water maybe a source of infection, especially in the developing world,where water treatment is often sub-optimal. Further supportcomes from epidemiological findings from the developingworld. In a study of 407 children from Peru, an external watersource was associated with a significantly increased risk of achildhood infection with H. pylori [20]. Compared to chil-dren using well water, children living in households with amunicipal water supply had a 12-fold higher risk of beinginfected. The unexpected finding was thought to be due tobreaks in the municipal pipes allowing for surface contami-nation of the water. A report from Bolivia also indicated thatcontaminated water is a common source of infection with H.pylori [14]. Children living in families using special watercontainers that prevented hands or objects from coming indirect contact with the family drinking water were signifi-

Table 1Prevalence of H. pylori in areas of the world

Country/region Adults (>21)(%)

Children

AfricaEthiopia [15] >95 48% (2–4 years) to 80% (6 years)Gambia [10] >95 95% (5 years)Nigeria [67,68] 91 82% (5–9 years)

AsiaBangladesh[69,70]

>90 58% (0–4 years) to 82% (8–9)

China [71] 86 68% (3–12 years)India [72] 88 22% (0–4 years) to 87% (10–19)Siberia [73] 85 30% (5 years) to 63% (15–20 years)Sri Lanka [74] 72 67% (6–19 years)

Middle EastEgypt 90 50% (3 years)Jordan [75] 82Libya [76] 94 50% (1–9 years) to 84%

(10–19 years)Saudi [77] 80 40% (5–9 years)Turkey [78,79] 80 64% (6–17 years)

North AmericaGuatemala [25] 65 51% (5–10 years)Mexico [80] 43% (5–9 years)

South AmericaBolivia [14] 54% (5 years)Brazil [81,82] 82 30% (6–8 years) to 78%

(10–19 years)Chile [83,84] 72 36% (3–9 years)Peru [9] 52% (3 years)

706 R.W. Frenck Jr, J. Clemens / Microbes and Infection 5 (2003) 705–713

cantly less likely to be infected with H. pylori than childrenwhose family did not use the special water container. Suchfindings would support the thought that hands contaminatedwith H. pylori, rather than a contaminated water deliverysystem, transfer the bacteria to the drinking water. Unfortu-nately the study was not designed specifically to evaluateroutes of transmission of H. pylori, thus no attempts weremade to isolate the bacterium from the water sources. In astudy of Chilean children, consumption of uncooked veg-etables was associated with H. pylori infection, and it waspostulated that this association resulted from ingestion ofvegetables contaminated with irrigation water [21]. A studyfrom Bangladesh, however, was unable to show any relationbetween water source and risk of infection with H. pylori,suggesting that while water may be a source of infection,other sources likely exist [8].

2.3. Mode of transmission

Although not definitively known, epidemiologic studiesstrongly suggest person-to-person transmission, by either afecal-oral or oral-oral route, to be the major means by whichH. pylori is spread [22]. Reports from the developing worldhave helped support this hypothesis. In both China and Bang-ladesh, an increased number of individuals sleeping in aroom was the factor most highly related to infection with theorganism, suggesting direct transmission through over-crowding [8,23].

Specific behaviors within the developing world may con-tribute to the transmission of H. pylori. An example is that inBangladesh, Hindu mothers, in contrast to Muslim mothers,regularly coat their nipples with saliva before breast-feeding[8]. While possibly a chance finding, a study found theprevalence of H. pylori to be higher among the Hindu babiesthan among Muslim babies in rural Bangladesh, and couldsupport a finding of oral-oral transmission. Pre-masticationof food has been found in both Bangladesh and Ethiopia to beassociated with an increased prevalence of H. pylori inbabies, again supporting the possibility of oral-oral transmis-sion [8,24].

Evidence supporting a fecal-oral spread of the organismhas recently been reported in an interesting study from Cen-tral America. Using PCR-based technology, investigatorswere commonly able to amplify H. pylori DNA from oralsecretions of study subjects [25]. Scrapings from underneaththe fingernail were also taken from the study subjects, and H.pylori DNA was detected in 58% of the samples. Further-more, H. pylori was more likely to be found in the mouth ofa study subject if the bacteria was found under his/her nails.

The housefly, a common resident of homes in the devel-oping world, has been touted as a potential mode of transmis-sion of H. pylori. Previous studies have demonstrated thathouseflies are associated with transmission of enteric infec-tions including Shigella, raising the possibility that flies mayalso transmit H. pylori. Initial controlled laboratory experi-ments demonstrated H. pylori could be cultured from thebody of flies up to 12 h after being in contact with pure

colonies of the organism [26]. Additionally, H. pylori couldbe cultured from the gut and excrement of the fly for up to 30h after the fly was exposed to the bacteria. In a subsequentstudy, using flies caught at our Egyptian field sites, H. pyloriwas detected from the gut of 33% of the pools of housefliestested [27]. While neither study proves the ability of the fly totransmit H. pylori nor how common this transmissionmethod would be, these intriguing preliminary findings maywarrant further study.

3. Risk factors

Poverty-related factors have repeatedly been found to beassociated with an increased risk of acquiring H. pylori.These factors include overcrowding, poor hygiene, uncleanwater, sharing beds during childhood and lack of maternaleducation [24,28–31]. Other factors are potentially associ-ated with an increased risk of acquiring H. pylori, includingfamily members with H. pylori, pre-mastication of food bythe mother, not breast-feeding, low education level in par-ents, and possibly, contaminated food, and race/ethnicity.The overwhelming poverty of many parts of the developingworld has prevented the elimination of the risk factors for H.pylori and helps explain why there has not been the dramaticdecrease in infection with the organism seen in the developedworld.

While socioeconomic factors are strongly associated withthe risk of acquiring H. pylori, genetic and behavioral vari-ables also influence the risk of becoming infected with H.pylori. One study from Malaysia found that throughout thecountry, under similar economic and living conditions,people of Malay ancestry were significantly less likely to beinfected than Chinese and Indian populations in the sameregion of Malaysia [32]. A second study of asymptomaticchildren of different ethnic backgrounds but all born andraised in Belgium found that the Caucasian children weresignificantly less likely to be infected than the non-Caucasianchildren [33]. However, other studies within industrializedsettings have not been able to reproduce these findings,suggesting that while there may be true racial or ethnicpredispositions to infection with H. pylori, the findings couldalso be explained by unrecognized environmental or behav-ioral differences [34,35]. Further work in this area is neces-sary.

There are indications that behavioral practices can influ-ence the risk of transmission of H. pylori. Pre-mastication,still common in parts of the developing world, has beenlinked with an increased risk of transmission of H. pylori.After an initial report from Bangladesh, a subsequent studyin Ethiopia also made the observation that maternal pre-mastication of food increased the risk of transmission of H.pylori [8]. Of the eight Ethiopian mothers who chewed thefood before feeding it to their children, seven of these off-spring were infected with H. pylori compared to 37 of 69children being infected if their mothers did not pre-chewtheir food [36]. While pre-mastication could be a surrogate

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marker for other factors, it lends support to the idea thatdirect oral-oral spread of H. pylori is possible.

While breast-feeding has been shown to decrease the riskof infections in infants, especially from diarrheal disease, it isunclear whether the practice affects the risk of acquiring H.pylori. One difficulty in discerning the relationship betweenbreast-feeding and infection is the fact that breast-feeding isalmost ubiquitous in the developing world until at least a yearof age. In a study from the United States, breast-feeding wasfound to play a protective role against acquisition of H.pylori [37]. However, other studies have been unable todemonstrate a protective effect of breast-feeding, and onestudy even found the practice increased the risk of childhoodinfection [38–40]. Further evaluation demonstrated that theincreased risk was associated with the mother not washingher nipples and hands prior to breast-feeding. Direct trans-mission of H. pylori to the infant, rather than lack of protec-tion from breast milk, likely explains this finding and isconsistent with the hypothesis that direct transmission of H.pylori occurs by mothers coating their nipples with salivaprior to breast-feeding.

4. Sequelae of H. pylori infections

As in industrialized nations, H. pylori within the develop-ing world has been associated with chronic gastritis, pepticulcer disease and gastric cancers. However, the strength ofassociation varies, depending on the setting. Associationswith chronic gastritis and peptic ulcers are more commonlyreported in the developed world, and gastric carcinoma ismore commonly found in the developing world [41]. Rea-sons for this difference are not clear and may be related toreporting. An alternative theory is that disease presentation isrelated to the age at which an individual is infected with H.pylori [42]. Infections early in childhood are postulated toinduce a low-grade chronic inflammatory condition which,over time, develops into pre-malignant changes and eventu-ally gastric carcinoma in a subset of individuals. In contrast,when infection is acquired later in life, it is more likely toinduce a brisk inflammatory response and ulcer disease. The“African enigma” indicates that H. pylori-associated pathol-ogy is more complicated than described above [43]. Theso-called “enigma” is that in many parts of Africa the preva-lence of infection with H. pylori is high and most infection isacquired early in life. However, in the same setting, gastriccarcinoma is unexpectedly low. This is just one example ofthe complexities of infection with H. pylori that requirefurther research.

Since only 10–15% of patients infected with H. pylori arethought to become symptomatic and because of concernabout high rates of re-infection, especially within the devel-oping world, it is not currently recommended to treat asymp-tomatic H. pylori.

However, accumulating data from epidemiological stud-ies suggest that H. pylori may produce significant sequelae in

children even before symptoms of gastritis or peptic ulcerdevelop. Pathologic evidence suggests that H. pylori infec-tions of children in less-developed settings can produce rap-idly destructive gastric mucosal lesions, which could con-ceivably destroy the gastric acid barrier even duringchildhood [3,44]. Achlorhydria may persist for months afteracute H. pylori infections in adults, and evidence suggeststhat the condition may last up to a year in children [45–47].As the acid barrier of the stomach constitutes an importanthost defense against enteric pathogens, destruction of thebarrier could render children more vulnerable to diarrhealdiseases and adverse nutritional sequelae.

The relationship between infection with H. pylori andenteric infections was demonstrated in a study from Bang-ladesh, in which persons infected with H. pylori were foundto be more likely to develop severe cholera [48]. Studies fromIndia have recently reported an association between infectionwith H. pylori and the development of typhoid fever [49].Children from the Gambia with chronic diarrhea were foundto be twice as likely to be infected with H. pylori, andresearchers from Peru found that children acutely infectedwith H. pylori were at an increased risk of developing diar-rhea [50,51]. However, other investigators have been unableto show an association between infection with H. pylori andincreased diarrhea rates in children [52,53]. The reason forthe discrepancy between the results is not certain but is likelymulti-factorial, including different study methodology, aswell as host and environmental factors.

The long-term sequelae of repeated or chronic diarrhea inchildren in the developing world include malnutrition,growth failure and death. In the study from the Gambiadescribed above, children infected with H. pylori, in additionto being more likely to develop chronic diarrhea, were also ata significantly higher risk of malnutrition than a group ofchildren not infected with H. pylori [50]. Infection with H.pylori may even affect growth in well-nourished childrenfrom industrialized areas. A study of Scottish school childrenfound that H. pylori-infected girls had mild growth failurewhen compared to uninfected controls [54]. The associationbetween infection with H. pylori and diminished growth inchildren, however, remains unsettled. No association be-tween infection with H. pylori and poor nutritional status wasfound in a group of Bangladeshi children, but this may berelated to the high baseline rate of malnutrition in that popu-lation [8]. Future research supporting the finding that H.pylori is associated with the development of diarrhea couldhave important public health ramifications for the developingworld, including decisions about the use of vaccines to con-trol H. pylori in these settings.

5. Re-infection with H. pylori

Since H. pylori infection rates are much higher in thedeveloping world than in industrialized countries, it has beenpresumed that re-infection rates with the organism following


successful eradication therapy would also be higher than the1% rate documented in the developed world. Data fromBangladesh, Chile and Peru support this theory. In the Bang-ladeshi study, 105 patients with duodenal ulcer disease werefollowed up to 2 years after successful eradication therapy[55]. Using urea breath tests as the diagnostic test, re-infection rates of 13% per year were documented, with themajority of re-infections occurring within the first year aftereradication therapy. Similarly, of 96 Chilean patients whosuccessfully had their infections eradicated, 12 (13%) hadendoscopic confirmation of the infection returning, and innine of 12 cases, infection recurred within a year of complet-ing therapy [56]. However, neither the Bangladeshi nor theChilean studies were able to differentiate re-infection fromrecrudescence. One study that attempted to discriminate be-tween these two possibilities was performed in China [57].An important finding of this study was that only four of the184 patients (1.1%) were re-infected over the 2 years ofobservation, with three of four becoming re-infected within 6months of completing therapy. Additionally, molecularanalysis of H. pylori isolates from the three patients withapparent re-infection documented that one of the three caseswas actually a recrudescence rather than a true re-infection.The reason for the differing results between the Chinesestudy and the other two reports is not clear but indicatesfurther data needs to be collected to settle the question.Although the re-infection rate may indeed be higher in the

developing world than in industrialized settings, data stillsupport the recommendation that incorporating H. pyloritreatment into standard therapy for peptic ulcers is war-ranted. However, if further studies in the developing worldconsistently document the high rate of recurrence after eradi-cation therapy, treatment of asymptomatic H. pylori infec-tions within the developing world would probably not bewarranted.

6. Antibiotic sensitivity

The ready availability of over-the-counter antibiotics inmost of the developing world has led to an increased level ofresistance of bacteria to many of the commonly used antibi-otics, and H. pylori has been no exception. Antibiotic resis-tance data for H. pylori is not available from much of thedeveloping world, but that which is available shows disturb-ing trends [58–62] (see Table 2). The greater than 50% rate ofresistance of H. pylori isolates to metronidazole has renderedthis antibiotic nearly useless for the treatment of the organ-ism. Although not certain, the high resistance to metronida-zole is thought to be related to the frequent use of metronida-zole to treat parasitic infections such as giardiasis andamebiasis. A most dramatic example of metronidazole resis-tance has been found in one of our ongoing studies of H.pylori among children evaluated in the gastroenterology-

Table 2Antibiotic resistance in H. pylori isolates from selected countries

Country Number tested Antibiotic (% resistant)Amp Metronidazole Clarithromycin

AfricaNigeria [59] 55 0 40 13

AsiaChina [85] 50 50 8Hong Kong [86] 1000 0.3 50 4.5India [87] 78 90SE Asia [88] 246 34Europe 485 0 27 3

Middle EastBahrain [89] 83 57 33Egypt 42 0 100 3Iran [90] 112 42Israel [91] 138 0.8 40–60 10Lebanon [92] 54 0 30 2Saudi [89] 223 1.3 80 4UAE [77] 16 63

North AmericaMexico [93] 195 18 77 24United States [94] 179 0 37 6

South AmericaBrazil [95] 202 54 12Ecuador [96] 86 0 81 10


clinic. Of the 46 children from whom an isolate of H. pyloriwas obtained, none of the isolates were sensitive to metron-idazole, with a mean inhibitory concentration of greater than256 µg/ml. An interesting report from Japan found that overonly a 3-year period, H. pylori resistance to clarithromycinand metronidazole doubled, and the increase in resistanceparalleled the increased use of these antibiotics within thecountry [63]. Thus, judicious use of antibiotics along withobtaining data on the antibiotic resistance patterns for H.pylori within a country, and potentially within regions of acountry, is critical for selecting an appropriate treatmentregimen.

A study on the efficacy of therapy among 138 Israelipatients infected with H. pylori clearly demonstrates theneed for selection of antibiotic therapy based on resistancepatterns [64]. Resistance to metronidazole and clarithromy-cin was significantly higher in patients who failed antibiotictreatment than in those who achieved a cure. Eradication ofH. pylori is much less likely if the patient fails the initialtherapy, often due to antibiotic resistance with lack of alter-native therapies, making it all the more critical to have aneffective first-time therapy.

Industrialized settings routinely report successful treat-ment in up to 90% of cases with as short as a 7-day course oftherapy [65]. However, it appears that treatment success isnot as likely within the developing world, and a longer lengthof therapy is required. In a Brazilian study using a standardtreatment regimen of amoxicillin, clarithromycin and ome-prazole, overall cure rates of only 64% were achieved, andthe rates dropped to 50% if less than 10 d of therapy wereused [66]. Multiple factors are likely involved with the poorertreatment outcomes within the developing world but, at aminimum, the data suggests that treatment regimens fromindustrialized countries as well as the reported successes inthat setting may not necessarily be translatable to the devel-oping world.

7. Future directions

In summary, H. pylori is a significant problem within thedeveloping world, and its importance is unlikely to diminishin the foreseeable future. Future research opportunitiesabound. It is most urgent that we acquire a better understand-ing of the risk factors for acquiring the infection and offeasible means for decreasing the risk of transmission. De-velopment of appropriate and affordable treatment regimensis also a priority. In this regard, the high rate of antibioticresistance of H. pylori, which likely explains the lower ratesof cure found within the developing world, also demonstratesthe importance of providing preventive measures such as avaccine if we are to decrease the burden of disease within theless fortunate areas of the world.

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